WHO Drug Informationapps.who.int/medicinedocs/documents/s19565en/s19565en.pdf · Levofloxacin...

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WHO Drug Information Vol. 26, No. 2, 2012

WHO Drug Information

WHO Prequalification of Medicines ProgrammeThe Expert Review Panel 97

Safety and Efficacy IssuesTolvaptan: risk of serious neurological events 109Strontium ranelate: new contra- indications and revised warnings 109Fingolimod: new safety advice 109Pioglitazone: bladder cancer 110Benzocaine: new risk statements 110Minocycline: lupus erythematosus and autoimmune hepatitis 110Domperidone maleate: ventricular arrhythmias and cardiac death 111Vandetanib: risk of fatal outcome 112Finasteride and dutasteride: prostate cancer 112Lenalidomide: increased malignancies 112Antithrombotic medicines and bleeding 113Belimumab: hypersensitivity and infusion reactions 113Escitalopram: abnormal heart rhythm 113Empowering patient ADR reporting 114

Regulatory Action and NewsCommercially confidential information and personal data 115Pyronaridine and artesunate: new anti-malarial approved 115Aprotinin: suspension lifted 116Pixantrone: conditional approval for non-Hodgkin B-cell lymphoma 116Levofloxacin approved for plague 116Pazopanib: approved for soft tissue sarcoma 117Capsaicin: withdrawal of marketing authorization application 117

Rivastigmine: withdrawal of marketing authorization application 118Megestrol: withdrawal of marketing authorization application 118Lapatinib: withdrawal of marketing authorization application 118

ATC/DDD ClassificationATC/DDD Classification (temporary) 119ATC/DDD Classification (final) 122

Recent Publications, Information and EventsEvolving threat of antimicrobial resistance 125Safety of medicines in sub-Saharan Africa 125International meeting of world pharmacopoeias 126Interagency emergency health kit 2011 126Guide on estimating pain medication requirements 127Persisting pain in children: treatment guidelines 127

Consultation DocumentsThe International PharmacopoeiaLevonorgestrel and ethinylestradiol tablets 128Mefloquine hydrochloride 132Fluconazole 136Fluconazole capsules 141Fluconazole injection 144Sulfamethoxazole and trimethoprim intravenous infusion 147Sulfamethoxazole and trimethoprim oral suspension 152

International Nonproprietary NamesProposed List No. 107 157

Contents

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Announcement

The 15th International Conference

of Drug Regulatory Authorities (ICDRA)

will be hosted by the State Agency for

Medicines, Estonia, in collaboration with

the World Health Organization

The ICDRA will take place in

Tallinn, Estonia, 23 – 26 October 2012

Information and registration at:

http://www.icdra.ee

http://www.who.int/medicines/icdra

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WHO Prequalification of Medicines ProgrammeThe Expert Review Panel

WHO prequalification of medicines for procurement by United Nations (UN) and other agencies has levelled the playing field by creating a competitive supply of quality products in response to donor demand. However, there are still too few WHO-prequalified or stringently authorized finished products available on the mar-ket to ensure a sustainable supply of medicines needed in treatment programmes. Since 2009, the WHO Prequalification of Medicines Programme (PQP) has been hosting and coordinating a novel quality risk assessment mechanism on behalf of the Global Fund to Fight AIDS, Tuberculosis and Malaria. The Expert Review Panel (ERP) assesses quality risks of pharmaceutical products which do not yet meet stringent quality requirements. Based on standardized, transparent criteria, it gives advice on whether each product is acceptable for procurement for the next 12 months.

In six review rounds, the ERP has assessed a total of 310 dossiers of antiretroviral medicines (ARVs), antituberculosis products and antimalarials, with a time frame of 4–6 weeks for completion of each round. The cost of ERP review is moderate as it is a once-off, abbreviated assessment. The outcomes have been crucial in securing a sustained supply of needed medicines, especially anti-TB products and some antimalarials.

The process has been well accepted by manufacturers and procurement agencies and has promoted progression of medicines to prequalification. Of 115 eligible pro-ducts assessed by the ERP in 2009 and 2010, 44 became prequalified or appro-ved by a stringent regulatory authority thereafter. Agencies have harmonized their quality assurance policies and are using the mechanism jointly with the Global Fund. This has resulted in unified quality standards and efficiency gains for all stakeholders.

The ERP approach could be adapted for assessment of additional product catego-ries such as life-saving antibiotics or zinc for the treatment of diarrhoea in children. But it should be borne in mind that ERP is not intended to replace WHO prequalifi-cation or stringent regulatory assessment.

Incentives for manufacturers to submit products to ERP for evaluation may remain limited for medicines that have a market outside donor-funded programmes but this does not signify that such products need not adhere to stringent quality stand-ards or that such standards should apply to donor-funded products only. On the contrary, WHO is working with manufacturers and regulators around the world to strengthen regulatory capacity in line with internationally accepted standards, so that all medicines are safe, effective and of good quality.

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plied to product selection that balance the benefit of treatment against quality risks of products which do not yet meet strin-gent standards. This can be a complex process, with decisions often made on a case-by-case basis.

Specialized agencies such as UNICEF and Médecins Sans Frontières (MSF) have developed their own systems to perform these risk reviews and the WHO Quality and Safety of Medicines (QSM)team in the Department of Essential Medicines and Health Products (EMP)supports the Global Drug Facility (GDF) (5) and UNITAID (6) in this respect. The outcomes of such reviews are shared among The Interagency Pharmacist Group comprising PQP, WHO procure-ment services, UNICEF, MSF, the Inter-national Committee of the Red Cross (ICRC), and the Global Fund. The Group works together by discussing the out-comes and challenges of risk reviews on a confidential basis.

The Global Fund has formally defined al-ternative quality criteria and has succes-sively strengthened these over the years to encourage competition and promote prequalification. In 2008, it conducted a major policy review in wide consultation with stakeholders. The revised policy, ef-fective since July 2009, applies stringent quality requirements to all ARVs, anti-TB products and antimalarials, and relies on a novel mechanism to ensure a continued supply of needed products not yet meet-ing these requirements: the Expert Re-view Panel. Based on some of the earlier risk assessment approaches developed by WHO and other agencies, this mecha-nism serves to assess product quality risks according to transparent criteria.

The Expert Review Panel The ERP is an independent technical body hosted by WHO (7). It is composed of external regulatory experts and coor-dinated by QSM. To date, the ERP has met twice a year to review submissions

Quality policies in medicines procurement

Stringent standards for key medicines Significant progress has been achieved in the last decade to increase access to medicines in low- and middle-income countries. The treatment of HIV, tuber-culosis and malaria has attracted inter-national funding. Competitively-priced medicines are now being sourced from emerging countries, especially India, and from local manufacture in some develop-ing countries.

Presently, donors and healthcare work-ers are relying on the high standards of the PQP and stringent regulatory authori-ties (SRAs) (1, 2) to ensure the quality of products which they source from diverse regulatory environments (3). Likewise, the Medicines Patent Pool (4), which aims to bring down medicines prices through voluntary licensing of critical intellectual property from patent-holders, will require its licensees to submit their products to either the PQP or to an SRA for evalua-tion.

The Global Fund has played a leading role in promoting this development. From its inception in 2002, it has defined a formal quality policy for pharmaceutical products for implementation by its grant recipients, requiring WHO prequalifica-tion or SRA authorization for key prod-ucts that are procured with its funds (2). As these funds account for a significant market share of key products, especially ARVs and artemisinin-based combination therapies (ACTs), the policy has had a significant market impact.

Alternative criteria to ensure continued supplyDespite an increasing demand by donors, WHO-prequalified or SRA-approved prod-ucts are not available on the market for all needed medicines. To ensure a continued supply, alternative criteria must be ap-

WHO Prequalification of Medicines Programme

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received in response to Global Fund in-vitations to manufacturers to submit an Expression of Interest (EOI), and to advise on whether or not each of the products concerned can be considered acceptable for procurement during the following 12 months. Ad-hoc reviews can be arranged for urgently needed pro-ducts, for both the Global Fund and other interested parties.

Product data are submitted in question-naire-type abridged dossiers based on a format published in WHO technical guidance (8) and further developed by the Interagency Pharmacist Group. The manufacturer can provide cross-references to more detailed information already submitted in a full prequalification dossier.

The ERP coordinator manages the selection of ERP members, ensures that they remain current with latest PQP and SRA guidelines, arranges timely review of submissions and advises the Global Fund on the acceptability for procurement of each specific finished product, based on the results of the ERP review.

Eligibility criteria for ERP review To be eligible for ERP review, a product must be manufactured at a site and on a production line complying with good manufacturing practices (GMP) as de-termined by PQP, an SRA or a member of the Pharmaceutical Inspection Con-vention and Pharmaceutical Inspection Cooperation Scheme (PIC/S) (9). Before ERP finalizes its advice, it will verify the GMP status of each product with the PQP inspectorate.

Secondly, a product dossier must already have been accepted for review, after screening for completeness, by PQP or a stringent regulatory authority. Most submissions received since 2009 had been in the pipeline for prequalification, although approximately 40% of HIV-related products submitted to ERP had been submitted to the US Food and Drug Administration (FDA) for evaluation and

tentative approval under the President’s Emergency Plan for AIDS Relief (PEP-FAR) (10) but not to PQP.

Some needed products are not on the EOI list for WHO prequalification. These products have no pathway for prequali-fication, and are also unlikely to be submitted for marketing approval in a country with an SRA. Medicines in this group include special strengths of anti-TB medicines used in India, and older, non-artemisinin-based antimalarials still used in certain regions and situations. The ERP will review such products even if they are not under assessment by a stringent body, as long as they are manu-factured in compliance with international GMP standards.

Transparent assessment criteriaThe ERP assesses four main quality ele-ments, and categorizes each product into one of four risk categories (see Table 1).

As most innovator products have been assessed and registered in countries with stringent regulatory environments, the ERP’s review mechanisms are geared towards rapid review of generic prod-ucts rather than the safety and efficacy aspects of new molecules. The excep-tion has been DHA-piperaquine, an artemisinin-based combination antima-larial developed and registered in China: not considered an SRA as defined by the Global Fund (1). Submissions from two manufacturers were reviewed by the ERP and assigned to risk category 4 because the data provided was not sufficient to as-sign them to category 1, 2 or 3.

Time-limited advice The ERP’s advice is valid for 12 months. During this time, the product is expected to progress to WHO prequalification or SRA-approval. For products in risk cat-egories 1 and 2, manufacturers can apply for an extension by submitting an updated dossier and a progress report on the product’s progression towards stringent approval.


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Products in risk categories 1 and 2 are included on the Global Fund on-line prod-uct list (11), together with the date until which the ERP’s advice will remain valid. Grant recipients can conclude procure-ment contracts until the last day of the validity period, for a maximum duration of one year.

Use of the ERP mechanism by agenciesHarmonizationThe Global Fund invites EOIs for ERP re-view twice a year for medicines which are on the WHO EOI list for prequalification, and for which there are fewer than three WHO-prequalified or SRA-authorized finished products on the market. The ERP mechanism builds on experience with WHO’s ad hoc quality risk reviews performed before 2009 for GDF and

UNITAID, providing an opportunity for these organizations to harmonize their quality standards.

During 2009, the Global Fund and GDF organized separate quality risk reviews and, after a thorough review of the pro-cesses used, mutually recognized the outcome of the ad hoc reviews that each agency had organized. From 2010 on-wards, GDF and UNITAID have provided input to the EOIs issued by the Global Fund for ERP review of medicines for TB and HIV/AIDS, respectively. UNICEF has been reviewing dossiers as part of its ACT tender process with WHO, and will adapt this process to link it with the ERP procedure as of 2012.

Process and timelinesOn receipt of submissions, the Global Fund liaises with manufacturers, screens dossiers for completeness and forwards


Risk 1 & 2: No objection to procure- 3: Objection, but can 4: Objectioncategory ment. (Only for products under be procured if the bene- to procurement assessment by PQP or SRA) fit outweighs the risk

Quality element

Finished product Acceptable specifications, and Acceptable specification Unacceptable speci -manufacturing verified and validated compendial but analytical methods fication or analyticalprocess and and/or in-house tests/methods. not sufficiently validated. validation for a criti-specifications cal test parameter.

Stability and The submitted data support the The available stabilityshelf-life claimed or acceptable shelf life data does not allow during which the product will any assignment of comply with in-house or com- shelf-life. pendial specifications. Efficacy and safe- Acceptable proof of safety and Bioequivalence not sub- Efficacy and safetyty for generics: efficacy OR (for generics) bio- mitted, but multi-media data not submitted,Evidence of thera- equivalence with a prequalified dissolution data show or unsatisfactorypeutic equi valence or SRA-authorized comparator similarity, AND/OR (e.g., several majorwith a safe and product shown, OR (for generics comparator product not deficiencies).effective com- exempt from bioequivalence prequali fied or SRA-parator studies): acceptable multi-media authorized. dissolution data.

Source and API has acceptable specifi - API has acceptable API specificationquality of active cations with no major quality specifi cations but there not acceptable forpharmaceutical concern and is manufactured are GMP issues. a critical testingredients (API) at a licensed site with no known parameter. GMP issues.

Table 1: Summarized overview of ERP assessment criteria

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the submissions to the ERP Coordina-tor ahead of each session. In the first six ERP sessions, 79% of submissions received were eligible and complete and were forwarded for review.

In its first six sessions, the ERP assessed between 15 and 96 submissions per ses-sion. The median turn-around time from the start of the review until communica-tion of final advice by the ERP Coordina-tor to the Global Fund was 35 calendar days (17–49 days). The session-based system has proved efficient, with predict-able timelines for manufacturers and agencies.

Outcomes of reviewsIn the first six sessions, the ERP as-sessed 310 submissions (involving 220 products), and had no objections to pro-curement of 74 products.

Only products under assessment by PQP or an SRA can be classified in risk categories 1 or 2 (“no objection”), and this was the case with two-thirds of ARVs, about a third of anti-TB products and less than one in eight of the antimalarials as-sessed. Among the products not under stringent assessment, more than half of the anti-TB products and a third of the antimalarials were considered acceptable for procure-ment in exceptional situations.

Major deficiencies identified The ERP identified major deficiencies in 253 of the 310 submissions. Figure 1 shows the percentage of dossiers in each product category which had major defi-ciencies. For some products, additional information was subsequently submitted

Figure 1. Frequency of major deficiencies in ERP submissions (Rounds I to VI)

ARVs under stringent assessment (28 dossiers)

Anti-TB products under stringent assessment (55 dossiers)Anti-TB products not under stringent assessment (117 dossiers)

Anti-malaria products under stringent assessment (35 dossiers)Anti-malaria products not under stringent assessment (18 dossiers)

Active Specification Stability data Efficacy data Pharmaceutical (bioequivalence) Ingredients (API)

Unsatisfactory Insufficient Unsatisfactory Not Unsatisfactory Comparator Manu-(e.g., un- (e.g., from (e.g., out of submitted (e.g., several unsatis- factereracceptable one batch limits results) major factory not GMPlimits for only) deficiencies) compliantimpurities)

100%

80%

60%

40%

20%

0%


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by the manufacturer, so that ultimately they formed part of the group of 74 prod-ucts, each of which was categorized in category 1 or 2.

As Figure 1 shows, problems for ARVs related mostly to specifications and incomplete stability data. Anti-TB prod-ucts were the only products to have GMP issues with respect to active pharmaceuti-cal ingredients (APIs). Antimalarials had unsatisfactory specifications, and prob-lems with stability and efficacy data were observed more frequently than in other medicines. As can be expected, insuf-ficient or missing data were most com-mon among products that were not under stringent assessment.

Progression towards stringent ap-provalOf the 115 products reviewed by the ERP between June 2009 and November 2010, 44 (38%) had become WHO prequalified or SRA-authorized as at March 2012 (see Figure 2). For products reviewed in 2011, it is too early to estimate the rate of pro-gression; but already by March 2012, two ARVs, one anti-TB product and two varia-tions of anti-TB products have become prequalified, and others may follow.

Thirty-four of 56 favourably reviewed products — compared with 10 of 59 unfa-vourably reviewed ones — progressed to stringent approval, meaning that catego-rization of a product in category 1 or 2 (which may be considered as a positive categorization) has a good predictive value. Most of the successful products progressed to WHO prequalification; some ARVs progressed to FDA tentative approval under PEPFAR, and many of these also became WHO prequalified.

The ten unfavourably reviewed products that progressed to stringent approval were all reviewed in the first two ERP sessions. Manufacturers thereafter submitted improved dossiers directly to a stringent assessment body without re-submitting them to ERP.

Extension of ERP adviceFour months before the expiry of ERP advice, the Global Fund contacts manu-facturers of products classified into categories 1 or 2 to provide a progress report and additional product data. Based on this information, the ERP will consider extending its advice for another year. Of the 28 products relating to ERP sessions I to VI, the ERP granted an extension in

Figure 2. Progression of eligible ERP-reviewed products (2009–2010) to prequalification or SRA approval

Subsequently approved by PQP or an SRA (as at March 2012): yes no

ERP objection No ERP objection

ARVs 6 6 24 7

Antimalarials 25 2 2 3

Anti-TB products 18 2 8 12


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first-line anti-TB products (including strep-tomycin), 5% of all antimalarials and 0.6% of all ARVs reported as procured. Sec-ond-line anti-TB products were approved by the Green Light Committee until the second half of 2011 and were therefore not yet reported as ERP-reviewed prod-ucts.

The use of ERP-reviewed products has increased. During 2011, the Global Fund received 88 funding requests for ERP-reviewed anti-TB products and 32 for antimalarials (compared with 48 and 7 respectively in 2010). Two requests for ARVs were received in 2012 — the first since June 2009.

These figures reflect the availability of prequalified, SRA-authorized and ERP-reviewed products in each of the three disease categories.

• For ARVs, a wide choice of prequali-fied or SRA-authorized products is available. Few ERP-reviewed products are needed, mainly for new paediatric formulations, and where stringently as-sessed products are not accessible due to patent issues.

• For anti-TB medicines, WHO prequali-fied finished products are available but ERP-reviewed products have been crucial in securing a continued, com-petitive supply. Requests are increasing for ERP-reviewed products for second-line treatment.

• For antimalarials, the numbers of WHO prequalified and of ERP-reviewed prod-uct choices are the lowest. The Global Fund list of January 2012 proposes 19 prequalified or SRA-authorized formula-tions, for 17 of which there was only one supplier. No ERP-reviewed product was listed for general use, although some non-artemisinin-based products can be procured under exceptional circumstances.

Quality control testing outcomesIn 2010 and 2011, the Global Fund and

five cases and a further five products be-came WHO-prequalified while extension was being considered. The remaining 18 were not granted an extension. Extension of ERP advice has thus been the excep-tion rather than the norm.

Procurement decisionsAlthough the ERP advises on procure-ment of a product, donors and procure-ment entities are responsible for deciding on the use of the product in the treatment programmes that they support. Although the Global Fund lists products classified in categories 1 and 2 on its web site for information of grant recipients and other organizations, grant recipients must obtain the Global Fund’s approval before procurement of an ERP-reviewed prod-uct.

Products in risk category 3 are not listed, and will be funded only if experts of the respective WHO disease programme have confirmed that the treatment benefit in each specific context outweighs the quality risk identified by the ERP. If not, grant recipients can either work with the Global Fund to identify an acceptable clinical alternative, or they can purchase the product at their own risk and expense.

As an additional safeguard, batches of all ERP-reviewed products must pass random quality control testing before shipment.

Past procurement of ERP-reviewed productsUse by Global Fund grant recipientsMost ARVs and antimalarials, and a significant proportion of anti-TB medi-cines reviewed by the ERP are procured with Global Fund grants. According to the Global Fund’s online Price and Qual-ity Reporting (PQR) database as at 31 October 2011, recipients had reported purchasing ERP-reviewed products worth US$ 13.2 million since July 2009. In value terms, this corresponded to 13% of all


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GDF jointly arranged for pre-shipment quality control testing of almost 800 batches of ERP-reviewed products by competitively selected WHO-prequalified laboratories. All batches passed the test-ing, although in a few cases non-compli-ant results were initially reported due to methodological and interpretation issues. Certificates of analysis for all batches tested are available on the Global Fund web site (12). This experience suggests firstly that quality problems at the pre-shipment stage in the supply chain are rare. It also underscores the importance of in-country quality monitoring. Many quality problems will only emerge once the product has been received, stored and distributed in the destination country. It also demonstrates that coordination and communication between manufactur-ers, procurement agencies, laboratories and recipients — for organizing efficient testing and correct interpretation of test results — are crucial.

Proven publc health impact of the ERPSecuring the supply of needed productsThe ERP mechanism has proved effec-tive to support procurement of needed medicines of which there are not enough WHO-prequalified or SRA-authorized finished products available, avoiding treatment disruption and mitigating the risk of stock outs.

The impact has been greatest for anti-TB medicines. A core group of manufacturers have been submitting dossiers to ERP and working towards prequalification of their products, and two sources of fin-ished products are now available for most medicines. This has helped to achieve shorter lead times and competitive prices.

Moreover, a successful transition was made whereby GDF procurement policy was harmonized with that of the Global

Fund (13). Some initial price increases did occur before a competitive supply of quality-assured products was estab-lished. But this was only in a few cases. ERP review has also helped to secure a sustainable supply of some second-line products for which the production capac-ity of individual suppliers is limited.

A single process with unified requirementsMajor procurement actors are harmo-nizing their quality assurance policies (14–15) to incorporate the ERP process, which is both defined and flexible enough to result in useful procurement outcomes. This has resulted in efficiency gains not only for procurement agencies but also for manufacturers, since they can now follow a single quality assurance process with transparent, unified requirements.

Interim risk assessment leads to stringent approvalThe ERP review mechanism has chal-lenged initial concerns that it might duplicate prequalification and merely add another layer of procedures. To the contrary, ERP review complements WHO prequalification, as shown by the rates of progression in Figure 2.

The mechanism works best where it is linked to WHO prequalification, which — unlike marketing authorization in a country with an SRA — will ensure regular follow up and requalification in the destination countries.

Manufacturers have welcomed this process, which has helped them to bring needed products to market quickly while progressing towards WHO prequalifica-tion. The intensive communication during each ERP session has in some cases laid the groundwork for speedy develop-ment of full dossiers for submission to the PQP. Twelve of 19 anti-TB products and all three antimalarials which have been prequalified since 2009 had been submit-ted to the ERP.


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ChallengesIncentives for ERP review Incentives for manufacturers to meet the stringent quality requirements of donors are currently limited when other than do-nor-funded markets are available. More-over, donor-funded markets are often fragmented, with inaccurate forecasting and frequent payment issues. To invest in quality systems. manufacturers require a prospect of predictable sales over a period of several years, possibly across product categories. Advance information on the magnitude of the quality invest-ment they are required to make in order to meet international quality standards and potential sales would be helpful. However, these are influenced by many factors and are difficult to project.

Ongoing availability of quality-assured productsUnexpected quality issues can arise in connection with any of the quality ele-ments of a product that has been as-sessed by the ERP. These can result in de-listing or downgrading of an ERP-reviewed product. For example, a notice of concern issued by PQP for an API recently affected the quality status of sev-eral anti-TB products from different sup-pliers. In 2011, PQP started to prequalify APIs, hopefully reducing the likelihood of this particular issue arising in the future. More generally, the example emphasizes the importance of diversified supply sources and of vigilance in procurement by verifying that the product purchased has the same specifications as the WHO prequalified or ERP-reviewed product.

Future perspectivesERP reviews of additional essential medicinesThe ERP mechanism has been well accepted by manufacturers and procure-ment agencies, and clearly continues to be needed to support procurement of anti-malarials, anti-TB products and re-

productive health products in compliance with quality assurance policies.

Donors, procurement agencies and im-plementers are also considering whether to introduce more stringent require-ments — including stringent follow-up in recipient countries — for other essential medicines. Obvious candidates include products on the PQP EOI lists, such as life-saving antibiotics and zinc for treat-ment of diarrhoea in children.

Not all essential medicines needed by agencies are currently on PQP’s EOI lists. If the ERP mechanism were to be used to ensure the quality of these medicines, methods would need to be designed to ensure regular follow-up. Currently, the ERP provides interim advice only. It is not designed to verify continued compliance of manufacturers with stringent quality standards on an ongoing basis.

For certain product groups, such as life-saving antibiotics that are vulnerable to emerging resistance, modification of ERP eligibility and assessment criteria might be justified, provided sufficient technical rationale can be demonstrated. However, more work would be needed to group such products in risk-based categories and to determine the technical criteria that the ERP should apply to each prod-uct group to mitigate any risks.

Cost recoveryAlthough ERP review has proved to be rapid and cost-effective, the cost will in-crease if dossiers for additional products are reviewed. The cost of administrative and communication support which has so far been assured by the Global Fund must also be considered. In the future, a full cost recovery system may be envis-aged to make ERP review a sustainable mechanism for wider use.

Replication of the ERP mechanism may seem an attractive prospect from the point of view of ensuring a continued supply of needed products across differ-


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ent therapeutic categories. However, this could lead to divergent standards and procedures — potentially weakening the unified approach that has been the ERP’s major strength.

Beyond donor-funded programmesMedicines quality has very real implica-tions for patients and for public health. The ERP mechanism is a unique tool for supporting evidence-based decision-making in procurement of needed treat-ment options. It has also raised aware-ness of medicines quality issues among suppliers and recipients.

However, stringent quality assurance cannot and should not remain limited to donor-funded medicines. WHO is work-ing with regulatory authorities around the world to implement internationally accept-ed quality standards across the board.

The full report: Expert Review Panel, Briefing Paper, 27 April 2012 is available at http://apps.who.int/prequal/info_press/documents/ERP_article.pdf

References and notes

1. Up to 30 June, the Global Fund’s Quality Assurance Policy for Pharmaceutical Prod-ucts defined an SRA as a member of ICH or (PIC/S) and, as of 1 July 2009, as a member, observer or associate of ICH through a legally binding mutual recognition agreement. ICH is the International Conference on Harmonisa-tion of Technical Requirements for Registra-tion of Pharmaceuticals for Human Use (ICH) and PIC/S is the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Cooperation Scheme (jointly referred to as PIC/S).

2. The Global Fund. Global Fund Quality As-surance Policy for Pharmaceutical Products, at http://www.theglobalfund.org/documents/psm/PSM_QAPharm_Policy_en/

3. World Health Organization. Dickens, T. Pro-curement of medicines. In: The World Medi-cines Situation. WHO/EMP/MIE/2011.2.9. 3rd ed. 2011 at http://apps.who.int/medicinedocs/documents/s18769en/s18769en.pdf


4. Medicines Patent Pool, at http://www.medi-cinespatentpool.org/

5. Global Drug Facility. Quality Assurance Policy and Procedures, at http://www.stoptb.org/assets/documents/gdf/drugsupply

6. UNITAID, at http://www.unitaid.eu

7. The Global Fund. Expert Review Panel, Terms of Reference at http://www.theglobal-fund.org/documents/psm/PSM_ERP_TOR_en/

8. World Health Organization. Global Fund Quality Assurance Policy for Pharmaceuti-cal Products. Attachment A to Annex 8. WHO Expert Committee on Specifications for Phar-maceutical Preparations. Thirty-eighth Report, 2004. Technical Report Series, 917 at http://www.who.int/medicines/publications/pharm-prep/en/index. html

9. Pharmaceutical Inspection Convention and Pharmaceutical Inspection Cooperation Scheme (PIC/S) at http:www.picscheme.org

10. President’s Emergency Plan for AIDS Relief (PEPFAR) at http://www.pepfar.gov

11. The Global Fund. Global Fund lists of products, at http://wwww.theglobalfund.org/en/procurement/quality/pharmaceutical.

12. The Global Fund. Pre-shipment QC testing and results at http://www.theglobalfund.org/en/procurement/quality/pharmaceutical.

13. The Global Fund. Report of the Market Dynamics Commodities Ad-Hoc Committee to the Global Fund Board. 22nd Meeting, at http://www.theglobalfund.org/documents/board/22/BM22_11MDCCommittee_Report_en

14. UNITAID. Schedule 6. Summary of Appli-cable UNITAID Quality Assurance Standards for Drugs Procured in Paediatric and Second Line ARV Projects, at http://www.unitaid.eu/images/news/CHAI-UNITAID_Supplier_Let-ter_2010-11_-__20_Oct_2009_template.pdf

15. UNFPA. Quality Assurance Policy for Reproductive Health Medicines, at http://www.unfpa.org/webdav/site/global/shared/procure-ment/03_proc_procedures_policies/01_qua-lity_assurance/UNFPA%20QA%20Policy%20for%20RH%20medicines_31March11.pdf

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Safety and Efficacy IssuesTolvaptan: risk of serious neurological eventsUnited Kingdom — Treatment with tolvaptan (Samsca®) can result in over-rapid correction of hyponatraemia leading to serious neurological events. Careful monitoring of serum sodium is therefore important and co-administration of other drugs that may increase serum sodium is not recommended. Tolvaptan may also reduce the effect of vasopressin analo-gues used to control or prevent bleeding.

Tolvaptan is a selective vasopressin V2-receptor antagonist licensed in the UK since 2009 for the treatment of adults with hyponatraemia secondary to inap-propriate antidiuretic hormone secretion (SIADH) at a dose of 15–60 mg once a day.

Serum sodium should be closely moni-tored in patients receiving tolvaptan, especially those with very low serum sodium at baseline or where there is in-creased risk of demyelination syndromes. Increases in serum sodium which are too rapid can be harmful and cause osmotic demyelination, resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, or death.

Reference: Medicines and Healthcare Products Regulatory Agency (MHRA). Drug Safety Update, April 2012, vol 5 issue 9 at http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON149776

Strontium ranelate: new contra-indications and revised warningsEuropean Union — The European Medi-cines Agency’s Committee for Medicinal Products for Human Use (CHMP) has

finalized a review of strontium ranelate (Protelos® and Osseor®), indicated for treatment of osteoporosis in post-menopausal women. The Committee concluded that these medicines remain an important treatment but that changes to the prescribing advice are necessary to better manage associated risks.

The review was initiated following publi-cation of a study in France identifying 199 severe adverse reactions reported with these medicines from January 2006 to March 2009. Around half of these were VTE events, and about a quarter related to skin reactions. The CHMP has re-viewed all available data which show that the risk is higher in patients with a history of VTE, as well as in patients who are temporarily or permanently immobilized.

Data also show that the incidence rate of serious skin reactions is low and no possible mechanism of action has been identified so far.

Reference: European Medicines Agency. Press Release, EMA/CHMP/185175/2012 16 March 2012 at http://www.ema.europa.eu

Fingolimod: new safety adviceEuropean Union — The European Medicines Agency (EMA) recommends new advice to healthcare professionals to reduce the risk of adverse effects on the heart associated with the use of the mul-tiple sclerosis (MS) treatment fingolimod (Gilenya®).

Following a review, the Agency’s Com-mittee for Medicinal Products for Human Use (CHMP) recommends that doc-tors should not prescribe fingolimod to patients with a history of cardiovascular and cerebrovascular disease or who take

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heart-rate lowering medication. However, when treatment with fingolimod is consi-dered necessary, heart activity should be monitored at least overnight following the first dose of fingolimod and doctors should seek advice from a cardiologist on appropriate monitoring.

Fingolimod has been authorized in the EU since March 2011 for the treatment of relapsing-remitting MS in patients who have not responded to treatment with beta-interferon or whose disease is severe and getting worse rapidly. It is the first disease-modifying MS treatment available as an oral formulation.

Reference: European Medicines Agency. Press Release, EMA/CHMP/263105/2012, 20 April 2012 at http://www.ema.europa.eu and http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/2012/04/WC500125689.pdf .

Pioglitazone: bladder cancerCanada — Important safety information has been released concerning a potential risk of bladder cancer in patients treated with pioglitazone hydrochloride (Actos®).

Pioglitazone, an oral anti-diabetic drug, is authorized in Canada in patients with type 2 diabetes mellitus as an adjunct to de-crease blood glucose levels not controlled by diet and exercise alone. It is also indi-cated in combination with a sulfonylurea or metformin when diet and exercise plus the single agent do not result in adequate glycaemic control.

• Findings from new studies reveal that there is a potential increased risk of bladder cancer in patients treated with pioglitazone-containing products.

• Pioglitazone is now contraindicated in patients with active bladder cancer, a history of bladder cancer or uninves-tigated macroscopic haematuria. Any macroscopic haematuria should be investigated before starting pioglitazone therapy.

• Risk factors for bladder cancer should be assessed before initiating treatment with pioglitazone.

• Patients prescribed pioglitazone should be advised to seek medical attention if macroscopic haematuria or other symp-toms such as dysuria or urinary urgen-cy develop during treatment, as these may be symptoms of bladder cancer.

Reference: Communication from Takeda Canada, Inc. 16 April 2012 at http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2012/actos_3_hpc-cps-eng.php

Benzocaine: new risk statements Canada — Health Canada has requested companies to add new risk statements to the packaging and labelling of licensed benzocaine products. Health Canada has advised of certain health risks associated with benzocaine products, including methemoglobinaemia. The label changes apply to all benzocaine products except lozenges.

The new risk statements provide added instructions with respect to the risk of methemoglobinaemia and for safe product use, including the importance of using the smallest amount possible.

Reference: Health Canada Information Update, 2012-52. 5 April 2012 at http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2012/2012_52-eng.php

Minocycline: lupus erythematosus and autoimmune hepatitis Canada — Minocycline is a second-generation tetracycline that exhibits both antibacterial and anti-inflammatory properties.

Because the pathogenesis of acne can include bacterial proliferation (Propio-nibacterium acnes) and inflammation, oral antibiotics such as tetracyclines are frequently prescribed for the treatment of moderate to severe acne. Response


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4. Björnsson E, Talwalkar J, Treeprasertsuk S, et al. Drug-induced autoimmune hepatitis: clinical characteristics and prognosis. Hepato-logy 2010;51(6):2040–8.

5. Chang C, Gershwin ME. Drug-induced lupus erythematosus: incidence, management and prevention. Drug Saf 2011;34(5):357–74.

6. Chang C, Gershwin ME. Drugs and autoimmunity: a contemporary review and mechanistic approach. J Autoimmun 2010;34(3):J266–75.

7. El-Hallak M, Giani T, Yeniay BS, et al. Chronic minocycline-induced autoimmunity in children. J Pediatr 2008;153(3):314–9.

8. Czaja AJ. Drug-induced autoimmune-like hepatitis. Dig Dis Sci 2011;56(4):958–76.

Domperidone maleate: ventricular arrhythmias and cardiac deathCanada — Healthcare professionals have been informed that the gastrointesti-nal motility modifier, domperidone, should be initiated at the lowest possible dose in adults. Recent epidemiological studies have shown that the use of domperidone may be associated with an increased risk of serious ventricular arrhythmias or sud-den cardiac death, particularly in patients taking daily doses greater than 30 mg, and in patients older than 60 years of age.

Domperidone is indicated in adults for the symptomatic management of upper gastrointestinal motility disorders asso-ciated with chronic and subacute gastritis and diabetic gastroparesis. Domperidone is also indicated to prevent gastrointesti-nal symptoms associated with the use of dopamine agonist antiparkinson agents.

Caution should be exercised when using domperidone concomitantly with drugs that prolong the QT interval, in patients who have existing prolongation of cardiac conduction intervals, particularly QTc, and in patients with significant electrolyte dis-turbances or underlying cardiac disease such as congestive heart failure.

to oral antibiotics is usually seen after at least six weeks of therapy, and treatment can last for several months.

The occurrence of autoimmune disorders, such as lupus erythematosus and autoim-mune hepatitis, has been associated with the use of a number of products, inclu-ding minocycline. Drug-induced lupus erythematosus can produce symptoms that include myalgia, arthralgia and serositis, as well as abnormal labora-tory results such as elevated markers of inflammation and the presence of anti-nuclear antibodies.

Minocycline-induced autoimmune hepatitis shares many characteristics with autoimmune hepatitis, such as the presence of antinuclear and antismooth-muscle antibodies, elevated immunoglo-bulin levels and histologic features.

As of 30 September 2011, Health Canada has received four reports of drug-induced lupus erythematosus and three reports of autoimmune hepatitis suspected of being associated with minocycline use in adolescents. All the adverse reactions (ARs) were serious, involved the use of minocycline for the treatment of acne and occurred between 2004 and 2009.

If minocycline-induced autoimmune hepa-titis is unrecognized and drug exposure continues, hepatic fibrosis and chronic liver disease may develop.

Extracted from Canadian Adverse Reaction Newsletter, Volume 22, Issue 2, April 2012 at http://www.hc-sc.gc.ca/dhp-mps/medeff/bulle-tin/carn-bcei_v22n2-eng.php#article1

References

1. Ochsendorf F. Minocyline in acne vulgaris. Am J Clin Dermatol 2010;11(5):327–41.

2. Minocin® (minocycline) [product mono-graph]. Mississauga (ON) : GlaxoSmithKline Inc; 2010.

3. Kraft J, Freiman A. Management of acne. CMAJ 2011;183(7):E430–5.


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Reference: Health Canada. Safety Advisory. 2 March 2012 at http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2012/dom-peridone_hpc-cps-eng.php

Vandetanib: risk of fatal outcome Canada — Health Canada has issued safety information regarding vandetanib (Caprelsa®) approved as monotherapy for the treatment of symptomatic or progressive medullary thyroid cancer in adult patients with unresectable locally advanced or metastatic disease.

• Vandetanib can prolong the QTc inter-val and cases of Torsade de Pointes and sudden death have been reported in clinical trials.

• Vandetanib is only available through a Restricted Distribution Programme where physicians are required to com-plete mandatory online training.

In addition to QTc interval prolongation, Torsade de Pointes, sudden death, rash and other skin reactions, diarrhoea, hypertension and vision abnormalities have also been reported.

Reference: Communication from AstraZeneca dated 13 February, at http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2012/caprelsa_hpc-cps-eng.php

Finasteride and dutasteride: prostate cancerCanada — Health Canada has informed healthcare professionals that finasteride and dutasteride may be associated with an increased risk of developing rare, high-grade prostate cancer.

Finasteride is available under the brand names Proscar® and Propecia® and their generic equivalents. Dutasteride is avai-lable under the brand names Avodart® and Jalyn®. Finasteride and dutaste-ride are for use in men only. Proscar®, Avodart®, and Jalyn® are used for the treatment of benign prostatic hyperpla-

sia (BPH), which is an enlargement of the prostate that is not cancerous. BPH is a common condition in men over 40. Propecia® is used to treat male pattern hair loss.

The new safety information is based on a review of two large international clini-cal trials: the Prostate Cancer Preven-tion Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial. The trials showed that long-term daily use of finasteride and dutasteride in men aged 50 years and older was associated with a small but statistically significant increased risk of high-grade prostate cancer. Propecia® was not included in these trials but a potential risk has not been ruled out.

Reference: Health Canada. Safety Advi-sory, 2012-38. 19 March 2012 at http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2012/2012_38-eng.php

Lenalidomide: increased malignanciesCanada — Health Canada has issued information regarding lenalidomide (Revlimid®) capsules. Lenalidomide is an antineoplastic and immunomodulatory agent indicated for the treatment of trans-fusion-dependent anaemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS). Lenalidomide is also indicated in combination with dexametha-sone for the treatment of multiple mye-loma (MM) in patients who have received at least one prior therapy.

• An increase of second primary ma-lignancies (SPM) has been observed in clinical trials in previously treated multiple myeloma patients receiving lenalidomide and dexamethasone com-pared to controls.

• In clinical trials of newly diagnosed multiple myeloma (not an authorized in-dication in Canada), a 4-fold increased incidence of SPM has been observed in patients receiving lenalidomide.


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active, auto-antibody-positive, systemic lupus erythematosus.

Recently, a number of post-marketing reports concerning serious acute hyper-sensitivity reactions have been received globally. Health professionals have been informed that:

• Administration of belimumab may result in infusion and hypersensitivity reac-tions.

• Patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk.

• In clinical trials, severe and/or serious infusion or hypersensitivity reactions were reported in 1.2% and 0.6% of subjects receiving belimumab 10 mg/kg and placebo, respectively.

Reference: Communication from GlaxoS-mithKline Inc. dated 3 May 2012 at http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2012/benlysta_hpc-cps-eng.php

Escitalopram: abnormal heart rhythmCanada — Clinical trial data has shown that escitalopram (Cipralex®), a selective serotonin reuptake inhibitor (SSRI), can cause life threatening QT interval pro-longation. A warning and dosing recom-mendations have been added to the drug label.

• Escitalopram should not be used in patients with congenital long QT syn-drome, or in patients with QT interval prolongation.

• Use of escitalopram is discouraged in patients who are also taking drugs that prolong QT interval or that decrease electrolyte levels in the body.

• 10 mg per day is the maximum recom-mended dose for patients who are 65 years of age or older, have liver pro-blems or are taking the heartburn drugs omeprazole or cimetidine.

• The risk of occurrence of SPM must be taken into account before initiating treatment with lenalidomide. Physi-cians should carefully evaluate patients before and during treatment to screen for the occurrence of new malignancies.

Reference: Communication from Celgene dated 1 May 2012 at http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2012/revlimid_hpc-cps-eng.php

Antithrombotic medicines and bleedingNew Zealand — Antithrombotics are widely used to treat a number of condi-tions and guidance on their use has recently been issued by the Best Practice Advocacy Centre (BPAC). Bleeding is the major risk associated with all antithrom-botics. The Centre for Adverse Reaction Monitoring (CARM) continues to receive reports of serious bleeding experienced by patients taking these medicines.

An overview of 12 months of reports to CARM showed that the main sites of serious bleeding were most often gastrointestinal or intracranial in origin. Although combination therapy is recom-mended for some conditions, adverse reaction data continues to indicate a major risk factor for bleeding to be the concomitant use of more than one antithrombotic medicine. Extracted from The Prescriber Update, 2012; 33(1):1 at http.www.medsafe.govt.nz

Reference: A New Zealand Consensus Forum. 2011. The use of antithrombotic medicines in general practice: a consensus statement. Best Practice Journal, 39: 10-21

Belimumab: hypersensitivity and infusion reactionsCanada — Health Canada has issued information regarding hypersensitivity and infusion reactions associated with belimu-mab (Benlysta®) indicated, in addition to standard therapy, for adult patients with


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acknowledge the role of the consumer in spontaneous reporting.

In 2008, representatives of national phar-macovigilance centres requested WHO to develop a handbook on how to esta-blish a reporting system for medicine-related problems for the general public. Implementation of this task became feasible within the objectives of the MM Project. A WHO guidance document Safety Monitoring of Medicinal Products – Reporting system for the general public is now available as a direct project delive-rable.

In tandem with this development, the UMC has been working on a tool to sup-port consumer reporting of ADRs. Seve-ral patient organizations have provided their inputs in developing this tool. The WHO guidance document and tool were introduced to pharmacovigilance centres and consumer/patient organizations at a recent workshop in the Netherlands, 7–9 March 2012.

Piloting the UMC patient reporting tool in selected countries and any subsequent adaptation of the tool will form the next steps in this journey towards patient empowerment in pharmacovigilance.

Reference: World Health Organization. Pharmaceuticals Newsletter, Number 2, 2012 at http://www.who.int/medicines

• 20 mg per day is still the maximum recommended dose for most other patients.

Reference: Health Canada Information Update, 2012-63, 7 May 2012 at http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2012/2012_63-eng.php

Empowering patient ADR reportingThe Monitoring Medicines (MM) Project was developed within a wider WHO stra-tegy Optimizing drug safety monitoring to enhance patient safety and achieve better health outcomes. It began in September 2009 and is coordinated by the Uppsala Monitoring Centre (UMC), Sweden, with funds from the European Commission.

The MM Project aims to improve patient safety both within the European Union and in other regions. One objective is to support and strengthen consumer repor-ting of suspected adverse drug reactions(ADRs). The project consortium com-prises eleven partners representing a wide range of organizations dedicated to improving public health through the safe use of medicines.

An increasing number of consumers are being encouraged to report adverse reac-tions to medicines. Organizations such as WHO and the European Commission


Spontaneous monitoring systems are useful in detecting signals of relatively rare, serious or unexpected adverse drug reactions. A signal is defined as “reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented pre-viously. Usually, more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information”. All signals must be vaidated before any regulatory decision can be made.

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Regulatory Action and NewsCommercially confidential information and personal dataEuropean Union — The Heads of Medi-cines Agencies (HMA) and the European Medicines Agency (EMA) have adopted a joint guidance document providing a consistent Europe-wide approach to the identification of commercially confi-dential information (CCI) and personal data (PPD) in a marketing authorization application.

In future, regulatory authorities in the Eu-ropean Economic Area (EEA) will apply the same principles to identify which parts of an application dossier can or cannot be released in response to requests to access documents. This is regardless of whether the medicine concerned has been authorized using the centralized, mutual recognition or decentralized pro-cedures.

The guidance document limits the scope of what information regulators will consi-der to be commercially confidential in a marketing authorization application. The exceptions mainly relate to information about quality and manufacturing of a medicine, as well as information about facilities or equipment and some contrac-tual arrangements between companies.

In addition, the guidance document sets out how personal data as defined by the EU Directive 95/46/EC will be protec-ted if it can lead to the identification of a person. The document gives further guidance on how to identify personal data relating to experts, staff or patients that should be redacted.

Dossiers such as orphan designations, paediatric investigation plans and vete-rinary medicines are not covered by the

guidance. Together with those applica-tions that have been withdrawn or rejec-ted, these will be handled by regulators according to their existing practices and legal provisions.

The two guidance documents should be interpreted jointly.

• HMA/EMA Guidance document on the identification of commercially confiden-tial information and personal data within the structure of the Marketing Autho-rization (MA) Application – release of information after the granting of a Marketing Authorization

• Principles to be applied for the imple-mentation of the HMA/EMA Guidance on the identification of CCI and PPD in MA Applications

Reference: European Medicines Agency. Press Release, EMA/211884/2012, 27 March 2012 at http://www.ema.europa.eu

Pyronaridine and artesunate: new anti-malarial approvedEuropean Union — The European Medicines Agency (EMA) has recom-mended Pyramax®, a fixed combination consisting of pyronaridine and artesunate for the treatment of acute, uncomplicated malaria infection caused by Plasmodium falciparum or by Plasmodium vivax in adults and children weighing 20 kg or more in areas of low transmission with evidence of artemisinin resistance.

The scientific opinion for Pyramax® was given under Article 58 of Regulation (EC) No 726/2004, which allows the Agency’s Committee for Medicinal Products for Human Use (CHMP) to give a scientific opinion, in cooperation with the World

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The Committee found that the BART study’s results were not replicated in other studies and that the overall data available showed that aprotinin’s benefits are greater than its risks in the restricted indication.

Reference: European Medicines Agency. Press Release, EMA/CHMP/119704/2012. 17 February 2012 at http://www.ema.europa.eu

Pixantrone: conditional approval for non-Hodgkin B-cell lymphomaEuropean Union —The European Medi-cines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended that pixanthrone (Pixuvri®) be granted conditional approval for non-Hodgkin B-cell lymphoma. The new medi-cine is to be used alone in patients whose cancer is aggressive and has come back after multiple rounds of previous che-motherapy or is not responding to other treatments.

The Committee recommended conditional approval because the data supplied show that the medicine’s benefits outweigh its risks but are not yet comprehensive. The most frequent side-effect seen in clinical studies was suppression of bone marrow, resulting in low levels of white blood cells, platelets and red blood cells. Infections were common but were only serious in a few patients.


Levofloxacin approved for plagueUnited States of America — The Food and Drug Administration (FDA) has ap-proved levofloxacin (Levaquin®) to treat patients with plague. The agency also approved the drug to reduce the risk of plague after exposure to Yersinia pestis. The three most common forms of plague are bubonic, pneumonic and septicemic plague.

Health Organization (WHO), on medi-cines for human use intended exclusively for markets outside the European Union (EU). Applicants can use the CHMP’s scientific opinion as a basis when ap-plying for a marketing authorization in countries outside of the EU. The scientific opinion also facilitates the WHO prequali-fication process.

Due to concerns about severe liver problems associated with repeated use, Pyramax® should only be used as a single 3-day treatment course in areas of low transmission with evidence of de-creased efficacy of other oral artemisinin-based combination therapies, consistent with WHO recommendations. Pyramax® should only be used at controlled sites where a patient’s liver function can be systematically monitored and where exhaustive collection of adverse events as well as reliable information on resis-tance can be ensured.


Aprotinin: suspension liftedEuropean Union — The European Medicines Agency (EMA) has recom-mended that suspension of the marketing authorizations for aprotinin-containing medicines in the European Union (EU) be lifted. This follows a full review of the benefits and risks of all antifibrinolytic medicines, which found that the results of the BART study on which the suspen-sion was based are unreliable. Prior to its suspension in 2008, aprotinin was authorized for patients undergoing heart bypass surgery.

The Agency’s Committee for Medicinal Products for Human Use (CHMP) has now concluded that aprotinin’s benefits in preventing blood loss outweigh its risks in patients undergoing isolated heart bypass surgery who are at high risk of major blood loss.

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Common side effects reported in more than 3% of patients were nausea, hea-dache, diarrhea, insomnia, constipation, and dizziness. Serious but rare side effects include tendinitis and tendon rupture, worsening of muscle weakness in people with the neuromuscular disor-der myasthenia gravis, allergic reactions, liver damage, abnormalities of the blood, effects on the nervous system, and abnormal heart rhythm.

Reference: FDA News Release, 27 April 2012 at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm302220.htm

Pazopanib: approved for soft tissue sarcomaUnited States of America — The Food and Drug Administration (FDA) has approved pazopanib (Votrient®) to treat patients with advanced soft tissue sarcoma who have previously received chemotherapy. The drug is not approved for patients with adipocytic soft tissue sarcoma and gastrointestinal stromal tumours.

The most common side effects reported were fatigue, diarrhoea, nausea, weight loss, high blood pressure, decreased appetite, vomiting, tumour and muscle pain, hair color changes, headache, a dis-torted sense of taste, shortness of breath, and skin discoloration.

Pazopanib carries a boxed warning aler-ting patients and health care professio-nals to the potential risk of hepatotoxicity, which can be fatal. Patients should be monitored for liver function and treatment should be discontinued if liver function declines.

Votrient® was first approved in October 2009 for the treatment of advanced kid-ney cancer. Reference: FDA News Release, 26 April 2012 at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm302065.htm

Florbetapir: approved to estimate brain amyloid plaque contentUnited States of America — The Food and Drug Administration (FDA) has approved Florbetapir F 18 Injection (Amyvid®) a drug for positron emission tomography (PET) imaging of the brain in adults who are being evaluated for Alzheimer disease and other causes of cognitive decline. Amyvid® is used to produce PET scans that estimate the brain β-amyloid neuritic plaque density in patients with cognitive impairment. Until now, this could only be determined with a brain biopsy or examination of the brain at autopsy. Following intravenous injec-tion, Amyvid® binds to brain β-amyloid. A radioactive signal is detected and pro-duces images of the plaque in the brain.

Common adverse reactions include hea-dache, musculoskeletal pain, fatigue, and nausea.

Reference: FDA Press Release, 10 April 2012 at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm299678.htm

Capsaicin: withdrawal of marketing authorization applicationEuropean Union — The European Medicines Agency (EMA) has been notified of the manufacturer’s decision to withdraw the application for an exten-sion of the therapeutic indication for the centrally authorized medicine capsaicin (Qutenza®), 179 mg cutaneous patch.

Capsaicin was first authorized in the European Union on 5 May 2009 and it is currently indicated for the treatment of peripheral neuropathic pain in non-diabe-tic adults either alone or in combination with other medicinal products for pain.

The application was withdrawn based on the CHMP’s view that the data provided do not allow the Committee to conclude on a positive benefit-risk balance for the extension.

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Reference: European Medicines Agency. Press Release, EMA/174944/2012 , 13 March 2012 at http://www.ema.europa.eu

Lapatinib: withdrawal of marketing authorization applicationEuropean Union — The European Medi-cines Agency (EMA) has been notified of the manufacturer’s decision to withdraw the application for a centralized marke-ting authorization for an extension of the therapeutic indication for the centrally authorized medicine lapatinib (Tyverb®), 250 mg film-coated tablets.

Tyverb® was intended to be used in com-bination with paclitaxel for the treatment of patients with metastatic breast can-cer whose tumours overexpress HER2 (ErbB2). The patients in the registration study were not previously treated with trastuzumab in either the adjuvant or metastatic setting. At the time of with-drawal, the application was under review by the Agency’s Committee for Medicinal Products for Human Use (CHMP).

Lapatinib is currently authorized:

• For treatment of patients with breast cancer whose tumours overexpress HER2 (ErbB2).

• In combination with capecitabine for advanced or metastatic disease with progression following prior therapy, which must have included anthracy-clines and taxanes and therapy with trastuzumab in the metastatic setting.

• In combination with an aromatase inhibitor for postmenopausal women with hormone receptor positive metas-tatic disease, not currently intended for chemotherapy.

Reference: European Medicines Agency. Press Release, EMA/121832/2012. 16 February 2012 at http://www.ema.europa.eu


Rivastigmine: withdrawal of marketing authorization applicationEuropean Union — The European Medi-cines Agency (EMA) has been notified of the manufacturer’s decision to withdraw the application for an extension of the therapeutic indication for the centrally au-thorized medicine rivastigmine (Exelon® and Prometax®) 4.6 mg/24 h and 9.5 mg/24h transdermal patches. The trans-dermal patches are currently indicated for the symptomatic treatment of mild to moderately severe Alzheimer dementia.

The application requested an extension of indication to include the symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson disease. The application was withdrawn because the additional data required could not be generated within the timeframe allowed in the centralized procedure.


Megestrol: withdrawal of marketing authorization applicationEuropean Union — The European Medi-cines Agency (EMA) has been notified of the manufacturer’s decision to withdraw the application for a centralized marketing authorization for megestrol (Megestrol Alkermes®), 125 mg/ml oral suspension. Megestrol was intended to be used for the treatment of anorexia, cachexia or an unexplained significant weight loss in adult AIDS and oncology patients. The application was withdrawn following com-pany portfolio prioritization.

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ATC/DDD Classification

New ATC 5th level codes:

metformin and alogliptin A10BD13 glycerol phenylbutyrate A16AX09 trenonacog alfa B02BD12 peginesatide B03XA04 eberconazole D01AC17 tamsulosin and solifenacin G04CA53 poliomyelitis oral, bivalent, live attenuated J07BF04 pertuzumab L01XC13 regorafenib L01XE21 masitinib L01XE22 vismodegib L01XX43 lipegfilgrastim L03AA14 tofacitinib L04AA29 lurasidone N05AE05 fluticasone, combinations R01AD58 quifenadine R06AX31 limbal stems cells, autologous S01XA19 linaclotide A06AX04

New ATC level codes (other than 5th level):Direct factor Xa inhibitors B01AFFluoroquinolones S01AE

ATC code changes:

prucalopride A03AE04 A06AX05

ATC/DDD Classification (Temporary)

The following anatomical therapeutic chemical (ATC) classifications and defined daily doses (DDDs) were agreed by the WHO International Working Group for Drug Statistics Methodology in March 2012. Comments or objections to the decisions should be forwarded to the WHO Collaborating Centre for Drug Statistics Methodo-logy at [email protected]. The new ATC codes and DDDs will be considered final and be included in the January 2013 issue of the ATC Index. The inclusion of a substance in the lists does not imply any recommendation for use in medicine or pharmacy.

ATC level INN Common name ATC code

INN Common name Previous ATC New ATC

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Previous New ATC code


ATC name changes:

Drugs for functional bowel disorders Drugs for functional gastrointestinal disorders A03AOther drugs for functional bowel Other drugs for functional gastro- disorders intestinal disorders A03AXLaxatives Drugs for constipation A06Laxatives Drugs for constipation A06ABulk producers Bulk-forming laxatives A06ACOther laxatives Other drugs for constipation A06AXetynodiol and estrogen etynodiol and ethinylestradiol G03AA01quingestanol and estrogen quingestanol and ethinylestradiol G03AA02lynestrenol and estrogen lynestrenol and ethinylestradiol G03AA03megestrol and estrogen megestrol and ethinylestradiol G03AA04norethisterone and estrogen norethisterone and ethinylestradiol G03AA05norgestrel and estrogen norgestrel and ethinylestradiol G03AA06levonorgestrel and estrogen levonorgestrel and ethinylestradiol G03AA07medroxyprogesterone and estrogen medroxyprogesterone and ethinylestradiol G03AA08desogestrel and estrogen desogestrel and ethinylestradiol G03AA09gestodene and estrogen gestodene and ethinylestradiol G03AA10norgestimate and estrogen norgestimate and ethinylestradiol G03AA11drospirenone and estrogen drospirenone and ethinylestradiol G03AA12norelgestromin and estrogen norelgestromin and ethinylestradiol G03AA13nomegestrol and estrogen nomegestrol and estradiol G03AA14chlormadinone and estrogen chlormadinone and ethinyl estradiol G03AA15megestrol and estrogen megestrol and ethinylestradiol G03AB01lynestrenol and estrogen lynestrenol and ethinylestradiol G03AB02levonorgestrel and estrogen levonorgestrel and ethinylestradiol G03AB03norethisterone and estrogen norethisterone and ethinylestradiol G03AB04desogestrel and estrogen desogestrel and ethinylestradiol G03AB05gestodene and estrogen gestodene and ethinylestradiol G03AB06chlormadinone and estrogen chlormadinone and ethinylestradiol G03AB07dienogest and estrogen dienogest and estradiol G03AB08Other urologicals, incl. antispasmodics Urologicals G04B Urinary antispasmodics Drugs for urinary frequency and incontinence G04BD

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New DDDs:

linagliptin 5 mg O A10BH05rilpivirine 25 mg O J05AG05pirfenidone 2.4 g O L04AX05leuprorelin 60 mcg Depot implant L02AE02droperidol 2.5 mg P N05AD08dexmedetomidine 1 mg P N05CM18

Herbal medicinal products*


Hederae helicis folium R05CA12

* Assessed and approved by regulatory authorities based on dossiers including efficacy, safety, and quality data (e.g. the well-established use procedure in EU).

DDD Unit Adm.R ATC code


Name ATC code

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ATC/DDD ClassificationATC/DDD Classification (Final)

The following anatomical therapeutic chemical (ATC) classifications and defined daily doses (DDDs) were agreed by the WHO International Working Group for Drug Statistics Methodology in October 2011. They will be included in the January 2013 version of the ATC Index. The inclusion of a substance in the lists does not imply any recommendation for use in medicine or pharmacy. The WHO Collaborating Centre for Drug Statistics Methodology can be contacted at [email protected].


aclidinium bromide R03BB05 alcaftadine S01GX11 alendronic acid and alfacalcidol, sequential M05BB06 apixaban B01AF02 atorvastatin and ezetimibe C10BA05 boceprevir J05AE12 cefuroxime S01AA27 ciclesonide R01AD13 cobicistat V03AX03 dextromethorphan, combinations N07XX59 electrolytes in combination with other drugs B05BB04 elvitegravir J05AX11 emtricitabine, tenofovir disoproxil, elvitegravir and cobicistat J05AR09 faropenem J01DI03 fidaxomicin A07AA12 florbetapir (18F) V09AX05 fluoxetine and psycholeptics N06CA03 flutemetamol (18F) V09AX04 glycopyrronium bromide R03BB06 ingenol mebutate D06BX02 ivacaftor R07AX02 lomitapide C10AX12 meningococcus A, purified polysaccharides antigen conjugated J07AH10 mirabegron G04BD12 nafcillin J01CF06 ormeloxifen G03XC04

INN Common name ATC code

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New ATC 5th level codes (cont.):

pioglitazone and sitagliptin A10BD12 ridaforolimus L01XE19 rubidium (82Rb) chloride V09GX04 simvastatin and fenofibrate C10BA04 sitagliptin and simvastatin A10BH51 technetium (99mTc) ethylene- dicysteine V09CA06

ATC code changes:

besifloxacin S01AX23 S01AE08ciprofloxacin S01AX13 S01AE03diamorphine N02AA09 N07BC06droperidol N01AX01 N05AD08 (existing code)gatifloxacin S01AX21 S01AE06histrelin H01CA03 L02AE05levofloxacin S01AX19 S01AE05lomefloxacin S01AX17 S01AE04lopinavir and ritonavir * J05AE06 J05AR10moxifloxacin S01AX22 S01AE07norfloxacin S01AX12 S01AE02ofloxacin S01AX11 S01AE01rivaroxaban B01AX06 B01AF01

* New ATC level name (previous name: lopinavir)

ATC name changes:

Other cephalosporins Other cephalosporins and penems J01DI

New DDDs:

abiraterone 1 g O L02BX03amifampridine 40 mg O N07XX05apixaban 5 mg O B01AF02belatacept 12.5 mg P L04AA28belimumab 25 mg P L04AA26boceprevir 2.4 g O J05AE12ciclesonide 0.2 mg N R01AD13collagenase clostridium histolyticum 0.9 mg P M09AB02delavirdine 1.2 g O J05AG02dextromethorpen, combinations 40 mg1 O N07XX59


INN Common name ATC code

INN/Common name Previous ATC New ATC

Previous New ATC code


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exenatide 0.286 mg P depot inj A10BX04fidaxomicin 0.4 g O A07AA12histamine dihydrochloride 0.5 mg P L03AX14inosine pranobex 3 g O J05AX05lorazepam 2.5 mg P N05BA06nabiximols 42 mg SL N02BG10naproxen and esomeprazole 0.5 g2 O M01AE52pyrvinium 0.35 g O P02CX01retigabine 0.9 g O N03AX21rifaximin 0.6 g O A07AA11telaprevir 2.25 g O J05AE11tobramycin 0.112 g Inhal. powder J01GB01triptorelin 0.1 mg P L02AE04vinpocetine 15 mg O N06BX18von Willebrand factor 6 TU P B02BD10

1 expressed as dextromethorphan2 refers to naproxen

Herbal medicinal products*


Agni casti fructus G02CX03 Cimicifugae rhizoma G02CX04

* Assessed and approved by regulatory authorities based on dossiers including efficacy, safety, and quality data (e.g. the well-established use procedure in EU).


Name ATC code

New DDDs (cont.):


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Recent Publications, Information and Events

trout together with improved fish health management reduced the annual use of antimicrobials in farmed fish by 98% between 1987 and 2004.

• In 2010, the University of Zambia School of Medicine revised its under-graduate medical curriculum. The top-ics of AMR and rational use of medi-cines were given prominence.

Reference: World Health Organization. The evolving threat of antimicrobial resistance: options for action, at http://whqlibdoc.who.int/publications/2012/9789241503181_eng.pdf. More WHO resources on antimicrobial resis-tance at http://www.who.int/topics/drug_resis-tance/en/index.html

Safety of medicines in sub-Saharan AfricaWith an increase in access to new essen-tial medicines in Africa, there is a greater need to monitor and promote safety, quality, and effectiveness of medicines. The burden of adverse events from poor product quality, adverse drug reactions, and medication errors pose great chal-lenges to health care systems, besides the impact on morbidity and mortality. Yet few developing countries have the struc-tures, systems, or resources in place to conduct pharmacovigilance activities, and countries often lack unbiased, evidence-based information to help guide regula-tory and patient safety decisions.

Safety of medicines in sub-Saharan Africa: assessment of pharmacovigilance systems and their performance has been developed by the Strengthening Phar-maceutical Systems (SPS) Programme funded by USAID and implemented by Management Sciences for Health (MSH). It provides a comprehensive description

Evolving threat of antimicrobial resistanceAntimicrobial resistance (AMR) has evolved to become a worldwide health threat and every antibiotic ever developed is now at risk. The evolving threat of anti-microbial resistance: options for action, launched by the World Health Organi-zation (WHO), showcases examples of action taken to slow down drug resistance and preserve the ability of medicine to effectively treat many infectious diseases. The steps taken by governments, health facilities and providers and others are examples of what is recommended in the 2001 WHO Global Strategy for Contain-ment of Antimicrobial Resistance.

Drug resistance causes increased and prolonged illness, a greater risk ofcomplications and higher death rates. Infections which are increasingly resis-tant to antibiotics are causing a heavy disease burden, particularly in developing countries.

Some examples of a number of suc-cessful strategies and measures are highlighted in the book and include:

• In Thailand, the «Antibiotic Smart Use» programme has shown an 18%–46% reduction in antibiotic use.

• A programme targeting pharmacies in Viet Nam and consisting of inspection of prescription-only drugs, education on pharmacy treatment guidelines and group meetings of pharmacy staff resulted in a significant reduction in antibiotic dispensing for acute respira-tory infections.

• In Norway, the introduction of effec-tive vaccines in farmed salmon and

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Interagency emergency health kit 2011UN agencies and international and nongovernmental organizations are increasingly called upon to respond to large-scale emergencies to prevent and manage serious threats to the survival and health of affected populations. Medi-cines and medical devices have been supplied by relief agencies for decades.

In the 1980s, the World Health Organiza-tion (WHO) facilitated a process to encou-rage the standardization of medicines and medical devices needed in emergenciesto allow efficient and effective response to the need for medicines and medical devices. This initial work led to the supply of standard, pre-packed kits that could be kept in readiness to meet priority healthneeds in emergencies. The concept of the emergency health kit has been adop-ted by many organizations and national authorities as a reliable, standardized, affordable and quickly available source of the essential medicines and medical devices urgently needed in a disaster situation. Its content is based on the health needs of 10000 people for a period of three months.

The interagency emergency health kit, now in its fourth edition, explains how to use standardized packages of essential medicines, supplies and equipment in such circumstances. The 2011 edition improves the kit content and takes into account the need for mental health care in emergency settings and the special needs of children. It also provides back-ground information on the composition and use of the emergency health kit. Chapter one describes supply needs in emergency situations and is intended as a general introduction for health admi-nistrators and field officers. Chapter two explains the selection of medicines and medical devices — renewable and equipment — that are included in the kit, and also provides more technical details intended for prescribers. Chapter three


and analysis of pharmacovigilance sys-tems and their performance in sub-Saha-ran Africa. The data was compiled in 2011 using more than 400 literature reviews and assessments in 46 sub-Saharan African countries.

Reference: Strengthening Pharmaceutical Systems Programme. Safety of medicines in sub-Saharan Africa: assessment of pharma-covigilance systems and their performance at http://www.msh.org/projects/sps/SPS-Documents/loader.cfm?csModule=security/getfile&pageid=60382

International meeting of world pharmacopoeiasIn a world of increased globalization, international pharmaceutical standards are becoming increasingly important to safeguard quality and improve access to medicines.

At a meeting hosted by the World Health Organization (WHO) in Geneva in early 2012, representatives from 23 pharmaco-poeias and pharmacopeia commissions came together and committed to working towards harmonization and strengthening WHO’s role in developing global stan-dards for the production and testing of medicines.

The meeting has launched greater colla-borative work and sharing of information between world pharmacopoeias. Future projects discussed include a newinternet-based system for information exchange hosted by WHO, as well as a guide to «good pharmacopoeial prac-tices», currently under development by Argentina, Brazil, the European Phar-macopoeia, India, Japan, Mexico, the Russian Federation, Ukraine, the United Kingdom and the United States Pharma-copeia.

Reference: The International Pharmacopoeia at http://www.who.int/medicines/publications/pharmacopoeia/overview/en/index.html and http://www.who.int/medicines/areas/qua-lity_safety/quality_assurance/en/index.html.

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describes the composition of the kit, which consists of basic and supplemen-tary units.

The annexes provide references to treatment guidelines, sample forms, a health card, guidelines for suppliers, other kits for emergency situations, a standard procedure for importation of controlled medicines, and useful addresses. A feedback form is also included to report on experiences when using the kit and to encourage comments and recommen-dations on the contents of the kit from distributors and users for consideration when updating the contents.

Reference: The interagency emergency health kit, (IEHK 2011) is available at: http://www.who.int/medicines/publications/emergen-cyhealthkit2011

Guide on estimating pain medication requirements

The World Health Organization (WHO), the International Narcotics Control Board (INCB), and global experts have joined forces to develop a new tool to assist countries to estimate their annual requirements for narcotic drugs for medical purposes. An important treaty requirement of the Single Convention on Narcotic Drugs is that national com-petent authorities (NCA) should submit estimates annually to the INCB in order to ensure that the amounts of available narcotic drugs and other psychoactive substances are limited to quantities requi-red for medical and scientific purposes.

In order to allow availability of these medications, the WHO and INCB conve-ned a working group to draft a new docu-ment called Guide on estimating require-ments for substances under international control. It is intended to assist NCAs in calculating requirements for controlled substances. The Guide identifies dif-ferent methods, explains their potential

strengths and weaknesses, and provides an overview of the major issues that need to be considered in order to apply these methods accurately.

Reference: World Health Organization. Guide on estimating requirements for substances under international control, at http:www.who.int/medicines and http://www.painpolicy.wisc.edu

Persisting pain in children: treatment guidelinesWHO guidelines on the pharmacological treatment of persisting pain in children with medical illnesses have recently been published. The guidelines address persis-ting pain in children caused by conditions such as cancer, HIV/AIDS, sickle-cell disease, burns, trauma, and phantom limb pain.

A new recommendation in the guidelines is a two step approach to treat the child’s pain according to severity: use of a three step ladder is no longer recommended for pain in children. WHO has identified mor-phine as one of the key medicines neces-sary to treat chronic pain in children.

Recommendations were developed fol-lowing a careful and transparent appraisal of available evidence and are presented for the pharmacological treatment of mild, moderate and severe pain.

The Persisting pain in children package contains the WHO guidelines, three bro-chures targetting physicians and nurses, pharmacists, or policy-makers; a dosing card; two pain scales for children, and a wall chart for waiting rooms.

Reference: World Health Organization. WHO guidelines on the pharmacological treatment of persisting pain in children with medical illnesses, at http:www.who.int/medicines. The Persisting pain in children package is avail-able from WHO Press at [email protected]


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Levonorgestrel and ethinylestradiol tablets

Draft proposal for The International Pharmacopoeia (January 2012). Please addess any comments to Quality Assurance and Safety: Medi-cines, World Health Organization, 1211 Geneva 27, Switzerland; fax: (+41 22 791 4730 or e-mail to [email protected]. Working documents are available for comment at http://www.who.int/medicines.

Category. Contraceptive.

Storage. Levonorgestrel and Ethinylestradiol tablets should be kept in well-closed containers, protected from light.

Labelling. For Levonorgestrel and Ethinylestradiol tablets presented in 21-day or 28-day calendar packs, apply the requirements separately to tablets of each combi-nation of different proportions, by weight, of the active ingredients. Where applicable, disregard any tablets that contain no active ingredient (placebo tablets).

Additional information. Strengths in the current WHO Model List of Essential Medi-cines: 150 µg Levonorgestrel and 30 µg Ethinylestradiol.

The tablets may be coated.

Requirements

Comply with the monograph for "Tablets".

Definition. Levonorgestrel and ethinylestradiol tablets contain Levonorgestrel and Ethinylestradiol. They contain not less than 90.0% and not more than 110.0% of the amounts of levonorgestrel (C21H28O2) and ethinylestradiol (C20H24O2) stated on the label.

Identity tests

Either tests A, C and D or tests B, C and D may be applied

A. Carry out test A.1 or, where UV detection is not available, test A.2.

A.1 Carry out the test as described under 1.14.1. Thin-layer chromatography, using silica gel R1 as the coating substance and a mixture of 70 volumes of cyclohexane R and 30 volumes of acetone R as the mobile phase. Apply separa-tely to the plate 10 µl of each of the following three solutions. For solution (A), to a quantity of the powdered tablets containing about 300 µg of Levonorgestrel and about 60 µg of Ethinylestradiol, add 1 ml of dichloromethane R, shake to dissolve,

Consultation DocumentsThe International Pharmacopoeia

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centrifuge and use the clear supernatant. For solution (B) use about 300 µg of levonorgestrel RS per ml in dichloromethane R. For solution (C) use about 60 µg of ethinylestradiol RS per ml in dichloromethane R. After removing the plate from the chromatographic chamber, allow it to dry in air. Spray the plate with 4-toluene-sulfonic acid/ethanol TS, and heat at 110 °C for 10 minutes .Examine the chroma-togram in ultraviolet light (365 nm).

One of the principal spots in the chromatogram obtained with solution A corres-ponds in position, appearance and intensity with that obtained with solution B and the other principal spot corresponds to that in the chromatogram obtained with solution C.

A.2 Carry out the test as described under 1.14.1 Thin-layer chromatography, using the conditions described under test A.1. Examine the chromatogram in daylight.

One of the principal spots in the chromatogram obtained with solution A corres-ponds in position, appearance and intensity with that obtained with solution B and the other principal spot corresponds to that in the chromatogram obtained with solution C.

B. See the test described below under Assay, method A. The retention times of the principal peaks in the chromatogram obtained with solution (1) are similar to those in the chromatogram obtained from solution (2).

C. See the method described below under the test for Dextronorgestrel. The retention time of the principal peak in the chromatogram obtained with solution (4) is similar to that in the chromatogram obtained with solution (5).

D. To a quantity of the powdered tablets containing about 750 µg of Levonorgestrel and about 150 µg of Ethinylestradiol, add 10 ml of dichloromethane R, stir thoroughly and filter. To 2 ml of successive filtrate add 2 ml of trinitrophenol alkaline TS1 and allow to stand for 30 minutes; a brownish-yellow color is produced.

DissolutionCarry out the test as described under 5.5 Dissolution test for solid oral dosage forms, using as the dissolution medium, 500 ml of polysorbate 80 (~5 µg/ml) VS, and rotating the paddle at 75 revolutions per minute. At 30 minutes withdraw a sample of about 15 ml of the dissolution medium through an in-line filter, discarding the first 10 ml of the filtrate [solution (1)].

Determine the concentration in solution (1) by carrying out the test as described under 1.14.4 High-performance liquid chromatography, using the chromatographic conditions given under Assay, method A.

For solution (2) transfer 1 ml of the solution (2) obtained from the Assay, method A to a 100 ml volumetric flask and make up to volume with the dissolution medium.

Operate with a flow rate of 1 ml per minute. As a detector, use an ultraviolet spectro-photometer set at a wavelength of 247 nm for levonorgestrel analysis, and a spectro-fluorometric detector for ethinylestradiol analysis with an excitation wavelength of 285 nm and an emission wavelength of 310 nm.

Inject separately 100 µl each of solutions (1) and (2).

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Measure the areas of the two principal peaks obtained in the chromatograms from solutions (1) and (2), and calculate the content of levonorgestrel (C21H28O2) and ethinylestradiol (C20H24O2).

For uncoated tablets. For each of the six tablets tested, the amounts in solution are not less than 85% of the amount of levonorgestrel and not less than 80% of the amount of ethinylestradiol stated in the label. If for one of the six tablets the amount of levonorgestrel is less than 85% and/or the amount of ethinylestradiol is less than 80%, repeat the test using a further six tablets ; the average amounts for all 12 tablets tested are not less than 80% of levonorgestrel and not less than 75% of ethinylestra-diol; and no tablet releases less than 65% of levonorgestrel and/or less than 60% of ethinylestradiol.

For coated tablets. For each of the six tablets tested, the amounts in solution are not less than 65% of the amounts of levonorgestrel and ethinylestradiol stated in the label. If for one of the six tablets the amounts of levonorgestrel and/or ethinylestradiol are less than 65%, repeat the test using a further six tablets ; the average amounts for all 12 tablets tested are not less than 60% of levonorgestrel and ethinylestradiol; and no tablet releases less than 45% of levonorgestrel and ethinylestradiol.

[Note from the Secretariat: A dissolution test using 0.1% sodium dodecyl sulfate R in hydrochloric acid (0.1 mol/l) VS as a medium is under investigation.]

DextronorgestrelCarry out the chromatographic procedure as described under 1.14.4 High-perfor-mance liquid chromatography, using a stainless steel column (15 cm × 4.6 mm) pac-ked with particles of silica gel, the surface of which has been modified with chemically bonded octadecylsilyl group (5 µm). (Hypersil ODS is suitable.) As the mobile phase, use a filtered and degassed solution containing equal volumes of methanol R and gamma-cyclodextrin (~10 g/l) TS.

Prepare the following solutions in a dissolution solvent prepared by mixing 80 volumes of methanol R and 20 volumes of water R. For solution (1), transfer a quantity of pow-dered tablets containing about 1.2 mg of Levonorgestrel to a 10-ml volumetric flask. Add about 8 ml of the dissolution solvent, heat in a water-bath at 60 °C for 10 minutes, shaking occasionally. Allow to equilibrate to room temperature, dilute to volume with the dissolution solvent and mix. Filter through a 0.45-µm. filter. For solution (2), use 12 µg of norgestrel RS per ml. For solution (3), use 0.12 µg of Levonorgestrel RS per ml. For solution (4), dilute a suitable volume of solution (1) to obtain a concentration of 6.0 µg of Levonorgestrel per ml. For solution (5) use 6.0 µg of levonorgestrel RS per ml.

Operate with a flow rate of 1.5 ml per minute. As a detector, use an ultraviolet spectro-photometer set at a wavelength of 242 nm.

Inject 20 µl of solution (2). The test is not valid unless, in the chromatogram obtained with solution (2), the resolution factor between the two principal peaks (due to levo-norgestrel, eluting first and dextronorgestrel) is at least 1.5.

Inject separately 20 μl, each of solutions (1) and (3); and if needed for Identity test C, solutions (4) and (5).


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In the chromatogram obtained with solution (1) the area of any peak corresponding to dextronorgestrel, is not greater than the area of the principal peak in the chromato-gram obtained with solution (3) (0.1%).

Assay

Either method A or B may be applied

A. Weigh and powder 20 tablets. Carry out the test as described under 1.14.4 High-performance liquid chromatography, using a stainless steel column (25 cm × 4.6 mm) packed with particles of silica gel, the surface of which has been modified with che-mically bonded octadecylsilyl group (5 µm). (Hypersil ODS is suitable.) As the mobile phase, use a solution prepared by mixing 57 volumes of acetonitrile R and 43 volumes of water R.

Prepare the following solutions using the mobile phase as diluent. For solution (1), transfer an accurately weighed quantity of the powdered tablets containing about 150 µg of Levonorgestrel and about 30 µg of Ethinylestradiol to a 5-ml volumetric flask. Add about 4 ml of the mobile phase and shake for 20 minutes, dilute to volume and mix. Centrifuge and use the clear supernatant. For solution (2), prepare a solution containing about 30.0 µg of levonorgestrel RS per ml and 6.0 µg of ethinylestradiol RS per ml.

Operate with a flow rate of 1 ml per minute. As a detector, use an ultraviolet spectro-photometer set at a wavelength of 215 nm.

Inject separately 50 µl each of solutions (1) and (2). In the chromatogram obtained with solution (2), the test is not valid unless the resolution factor between the peaks due to levonorgestrel and ethinylestradiol is at least 2.0.

Measure the areas of the peak responses obtained in the chromatogram from solu-tions (1) and (2), and calculate the content of levonorgestrel (C21H28O2) and ethiny-lestradiol (C20H24O2) in the tablets.

B. Use the average of the 10 individual results obtained in the test for Uniformity of content.

Uniformity of contentThe tablets comply with the test for 5.1 Uniformity of content for single-dose prepara-tions, using the following method of analysis.

Carry out the test described under 1.14.4 High-performance liquid chromatography, using the chromatographic conditions as described under Assay, method A.

Prepare the following solutions using the mobile phase as diluent. For solution (1), transfer one tablet to a 5-ml volumetric flask. Add about 4 ml of the mobile phase, sonicate to disintegrate the tablet and shake for 20 minutes. Centrifuge and use the clear supernatant. For solution (2) prepare a solution containing about 30.0 µg of levo-norgestrel RS per ml and 6.0 µg of ethinylestradiol RS per ml.

Inject separately 50 µl each of solutions (1) and (2). In the chromatogram obtained with solution (2), the test is not valid unless the resolution factor between the peaks due to levornorgestrel and ethinylestradiol is at least 2.0.


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N

N

CF3

CF3

HO

HH

HN

HCl and enantiomer,

Measure the areas of the peak responses obtained in the chromatograms from solu-tions (1) and (2), and calculate the content of levonorgestrel (C21H28O2) and ethiny-lestradiol (C20H24O2) in each tablet.

*****New reagents to be added to Ph.Int:

Gamma-cyclodextrin (~10g/l) TS. Dissolve 5.0 g of gamma-cyclodextrin R in 500 ml of water R.

Trinitrophenol, alkaline, TS1. Immediately before use, mix equal volumes of a (~6g/l) solution of trinitrophenol R in ethanol (~750g/l) TS, sodium hydroxide (~70g/l)TS, and a mixture of 52 volumes of ethanol (~750g/l) TS and 48 volumes of water R.

Mefloquini hydrochloridumMefloquine hydrochloride

Draft proposal for The International Pharmacopoeia (January 2012). Please addess any comments to Quality Assurance and Safety: Medicines, World Health Organization, 1211 Geneva 27, Switzerland; fax: (+41 22 791 4730 or e-mail to [email protected]. Working documents are available for comment at http://www.who.int/medicines.

[Note from the Secretariat: following the adoption of the text for Mefloquine tablets in October 2010, it is proposed to revised the monograph for the API accordingly]

C17H16F6N2O,HCl

Relative molecular mass. 414.8

Chemical name. DL-erythro-α-2-piperidyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol monohydrochloride; (R*,S*)-(±)-α-2-piperidinyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol monohydrochloride; CAS Reg. No. 51773-92-3.

Description. A white to slightly yellow, crystalline powder.

Solubility. Very slightly soluble in water; freely soluble in methanol R; soluble in etha-nol (~750 g/l) TS; sparingly soluble in dichloromethane R.


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Category. Antimalarial.

Storage. Mefloquine hydrochloride should be kept in a tightly closed container, protec-ted from light.

Additional information. Mefloquine hydrochloride may exhibit polymorphism. It melts at about 260 °C, with decomposition.

Requirements

Mefloquine hydrochloride contains not less than 99.0% and not more than 101.0% of C17H16F6N2O,HCl, calculated with reference to the anhydrous substance.

Identity tests

Either test A or tests B and C may be applied, together with test D.

A. Carry out the examination as described under 1.7 Spectrophotometry in the infra-red region. The infrared absorption spectrum is concordant with the spectrum obtai-ned from mefloquine hydrochloride RS or with the reference spectrum of mefloquine hydrochloride. If the spectra thus obtained are not concordant, repeat the test using the residues obtained by separately dissolving the test substance and mefloquine hydrochloride RS in methanol R and evaporating to dryness. The infrared absorption spectrum is concordant with the spectrum obtained from mefloquine hydrochloride RS.

B. Carry out test B.1 or, where UV detection is not available, test B.2.

B.1 Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R6 as the coating substance and a mixture of 70 volumes of toluene R, 30 volumes of ethanol R and 2 volumes of 25% ammonia solution R as the mobile phase. Apply separately to the plate 10 μl of each of the following two solutions in methanol R. For solution (A) use 10 mg of the test substance per ml. For solution (B) use 10 mg of mefloquine hydrochloride RS per ml. After removing the plate from the chromatographic chamber, allow it to dry in a current of air and examine the chromatogram in ultraviolet light (254 nm).

The principal spot obtained with solution A corresponds in position, appearance and intensity to that obtained with solution B.

B.2 Carry out the test as described under 1.14.1 Thin-layer chromatography, using the conditions described above under test B.1 but using silica gel R5 as the coating substance. Stain the plate with iodine vapours. Examine the chromatogram in daylight.

The principal spot obtained with solution A corresponds in position, appearance, and intensity to that obtained with solution B.

C. The absorption spectrum (1.6) of a 54 μg/ml solution in methanol R, when observed between 250 nm and 290 nm, exhibits one maximum at about 283 nm.

D. A 50 mg/ml solution yields reaction B described under 2.1 General identification tests as characteristic of chlorides.


134


O

N

N

CF3

CF3

[Note from the Secretariat: similarly as for Mefloquine tablets

- former Test B has been replaced by a TLC method;

- former Test C and D have been replaced by a UV method.]

Heavy metals. Use 1.0 g for the preparation of the test solution as described under 2.2.3 Limit test for heavy metals, Procedure 3; determine the heavy metals content according to Method A; not more than 20 μg/g.

[Note from the Secretariat: the former test for Solution in methanol has been deleted in this proposal to take into account current practice.]

Sulfated ash. Not more than 1.0 mg/g.

Water. Determine as described under 2.8 Determination of water by the Karl Fischer method, Method A, using 1.0 g of the substance; the water content is not more than 30 mg/g.

Related substancesCarry out the test as described under 1.14.4 High-performance liquid chromatography, using a stainless steel column (25 cm x 4.6 mm) packed with particles of silica gel, the surface of which has been modified with chemically bonded octadecylsilyl groups (5 μm). (Luna® was found suitable.)

As the mobile phase, use a mixture of 22 volumes of methanol R, 38 volumes of acetonitrile R and 40 volumes of buffer pH 3.5 prepared as follows: dissolve 13.6 g potassium dihydrogen phosphate in about 900 ml of water R, adjust the pH to 3.5 by addition of 10% phosphoric acid and dilute to 1000 ml.

Prepare the following solutions in the mobile phase. For solution (1) use about 2.2 mg of the test substance per ml. For solution (2) dilute a suitable volume of solution (1) to obtain a concentration equivalent to 4.4 μg of Mefloquine hydrochloride per ml. For solution (3) use about 0.22 mg of mefloquine hydrochloride RS and about 0.04 mg of sulfadoxine R per ml.

Operate with a flow rate of 1.5 ml per minute. As a detector, use an ultraviolet spectro-photometer set at a wavelength of about 283 nm.

Inject 20 μl of solution (3). The test is not valid unless the resolution between the two principal peaks is at least 5.

Inject separately 20 µl each of solutions (1) and (2). Record the chromatograms for about 10 times the retention time of mefloquine.

In the chromatogram obtained with solution (1) the following impurities, if present, are eluted at the following relative retention with reference to mefloquine (retention time about 3.9 minutes): impurity A about 0.9, impurity C about 3.6 and impurity B about 7.4.

In the chromatogram obtained with solution (1) the area of any peak corresponding to impurity A, is not greater than the area of the principal peak in the chromatogram


135


O

N

N

CF3

CF3

obtained with solution (2) (0.2%) and the area of any other peak, apart from the principal peak, is not greater than 0.5 times the area of the peak in the chromatogram obtained with solution (2) (0.1%). The sum of the areas of all peaks, other than the peak due to mefloquine, is not greater than 2.5 times the area of the principal peak in the chromatogram obtained with solution (2) (0.5%). Disregard any peak with an area less than 0.25 times the area of the principal peak in the chromatogram obtained with solution (2) (0.05%).

[Note from the Secretariat: The former specific test for Ethanol, methanol and acetone has been deleted in this proposal. The possibility to include under the Sup-plementary section of the Ph.Int., a general text on residual solvents for APIs is under review.]

AssayDissolve about 0.31 g, accurately weighed, in 70 ml of glacial acetic acid R1, add 5 ml of mercuric acetate/acetic acid TS, and titrate with perchloric acid (0.1 mol/l) VS as described under 2.6 Non-aqueous titration, Method A.

Each ml of perchloric acid (0.1 mol/l) VS is equivalent to 41.48mg of C17H16F6N2O, HCl.

[Note from the Secretariat: due to the toxicity of mercuric acetate/acetic acid TS, replacement of this reagent is under review.]

Impurities

[Note from the Secretariat: this section has been transferred from the Mefloquine tablets monograph. The latter should have instead a cross-reference to this API mono-graph.]

A. (RS)-[2,8-bis(trifluoromethyl)quinolin-4-yl][(2RS)-piperidin-2-yl]methanol (threo-me-floquine)

B. (RS)-[2,8-bis(trifluoromethyl)quinolin-4-yl](pyridin-2-yl]methanone


N

CF3

CF3

H

HOH

HN

and enantiomer

136


N

N

CF3

CF3

HO

H

and enantiomer

OH

N N

N

N N

N

F

F

H2C CH2C

C. (RS)-[2,8-bis(trifluoromethyl)quinolin-4-yl](pyridin-2-yl]methanol

*****New reagents to be added to Ph.Int.

Hydrochloric acid (~4 g/l) TS. Dilute 10 ml of hydrochloric acid (~420 g/l) TS with sufficient water to produce 1000 ml (approximately 0.1 mol/l).

Sulfadoxine R. N 1-(5,6-Dimethoxy-4-pyrimidinyl)sulfanilamide; 4-amino-N-(5,6-dime-thoxy-4-pyrimidinyl)benzenesulfonamide; C12H14N4O4S

A commercialy available reagent of suitable grade.

Description. A white or creamy white, crystalline powder.

Solubility. Very slightly soluble in water; slightly soluble in ethanol (~750 g/l) TS and in methanol R; practically insoluble in ether R.

FluconazoliFluconazole

Draft proposal for The International Pharmacopoeia (April 2012). Please addess any comments to Quality Assurance and Safety: Medicines, World Health Organization, 1211 Geneva 27, Switzerland; fax: (+41 22 791 4730 or e-mail to [email protected]. Working documents are available for com-ment at http://www.who.int/medicines.

C13H12F2N6O


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Relative molecular mass. 306.3

Chemical name. 2-(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol; CAS Reg. No.86386-73-4.

Description. A white or almost white, hygroscopic, crystalline powder.

Solubility. Slightly soluble in water, freely soluble in methanol, soluble in acetone.It shows polymorphism.

Category. Antifungal.

Storage. Fluconazole should be kept in a tightly closed container, stored below 30℃.

Requirements

Definition. Fluconazole contains not less than 99.0% and not more than 101.0% of C13H12F2N6O, calculated with reference to the dried substance.

Identity tests

Either test A alone or tests B and C may be applied.

A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from Fluconazole RS or with the reference spectrum of fluconazole. If the spectra obtained in the solid state show differences, dissolve the substance to be examined and the reference substance separately in the minimum volume of methylene chloride R, evaporate to dryness on a water-bath and record new spectra using the residues.

B. Carry out the test as described under 1.14.1 Thin-layer chromatography, using sili-ca gel R6 as the coating substance and a mixture of 80 volumes of dichloromethane R, 20 volumes of methanol R, and 1 volume of concentrated-ammonia R solution as the mobile phase. Apply separately to the plate 20 μl of each of the following three solutions in methanol R. For solution (A) use 10 mg of Fluconazole per ml. For solu-tion (B) use 10 mg of fluconazole RS per ml. For solution (C) use a solution containing 10 mg of fluconazole RS per ml and 10 mg of fluconazole impurity A RS per ml. After removing the plate from the chromatographic chamber, allow it to dry in a current of air, and examine the chromatogram in ultraviolet light (254 nm).

The principal spot obtained with solution (A) corresponds in position, appearance and intensity with that obtained with solution (B). The test is not valid, unless the chromato-gram obtained with solution (C) shows two clearly separated spots.

C. The absorption spectrum (1.6) of a 200 μg/ml solution in ethanol R, exhibits maxi-ma at about 261 nm and 267 nm, and a minimum at 264 nm.

Clarity and colour of solution. A solution of 1.0 g in 20 ml of methanol R is clear and colourless.


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HO

N N

N

NN

N

N

F

N

N

H2C

CH2

C

Heavy metals. Use 1.0 g for the preparation of the test solution as described under 2.2.3 Limit test for heavy metals, Procedure 3; determine the heavy metals content according to Method A; not more than 10 μg/g.

Sulfated ash (2.3). Not more than 1.0 mg/g, using Method B and a platinum crucible.

Loss on drying. Dry to constant weight at 105 ℃; it loses not more than 5 mg/g.

Related substancesCarry out the test as described under 1.14.4 High-performance liquid chromatography, using a stainless steel column (25 cm × 4.6 mm) packed with particles of silica gel, the surface of which has been modified with chemically bonded octadecylsilyl groups (5 µm). As the mobile phase, use a mixture of 86 volumes of a (0.63 g/l) solution of ammonium formate R and 14 volumes of acetonitrile R

Prepare the following solutions in the mobile phase. For solution (1) use 10 mg of Fluconazole per ml. For solution (2) dilute 5 volumes of solution (1) to 100 volumes , then dilute l volume of this solution to 10 volumes. For solution (3) use 0.5 mg of flu-conazole for peak identification RS (containing impurity A) per ml. For solution (4) use 0.03 mg of fluconazole impurity B RS per ml. For solution (5) use0.1 mg of fluconazole impurity C RS per ml. To 1.0 ml of this solution add 1.0 ml of solution (1) and dilute to 10.0 ml.

Operate with a flow rate of 1.0 ml per minute. As a detector use an ultraviolet spectro-photometer set at a wavelength of about 260 nm.

Inject separately 20 μl each of solutions (1), (2), (3), (4) and (5). Record the chroma-tograms to 3.5 times the retention time of fluconazole and identify the impurity peaks. The peaks are eluted at the following relative retentions with reference to fluconazole (retention time about 11 minutes): impurity B about 0.4; impurity A about 0.5; impurity C about 0.8. The test is not valid, unless in the chromatogram obtained with solution (5), the resolution between the peaks due to impurity C and to fluconazole is at least 1.5.

In the chromatogram obtained with solution (1), the area of any peak corresponding to impurity A is not greater than 0.8 times the area of the principal peak in the chromato-gram obtained with solution (2) (0.4%); the area of any peak corresponding to impurity B is not greater than the area of the principal peak in the chromatogram obtained with solution (4) (0.3%); the area of any peak corresponding to impurity C is not greater than the area of the principal peak in the chromatogram obtained with solution (5) (0.1%); the area of any other impurity peak is not greater than 0.2 times the area of the principal peak in the chromatogram obtained with solution (2) (0.1%). The sum of the areas of all peaks, other than the peak due to fluconazole is not greater than 1.2 times the area of the principal peak in the chromatogram obtained with solution (2) (0.6%). Disregard any peak with an area less than 0.1 times the area of the principal peak in the chromatogram obtained with solution (2) (0.05%).

AssayDissolve about 0.1 g, accurately weighed, in 50 ml of anhydrous acetic acid R and titrate with perchloric acid (0.1 mol/l) VS as described under 2.6 Non-aqueous titration, Method A, determining the end-point potentiometrically.


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OH

N N

N

N

N

N

F

F

H2C CH2C

and enantiomer

HO

N N

N

NN

N

N

F

N

N

H2C

CH2

C

N N

N N

N

N

Each ml of perchloric acid (0.1 mol/l) VS is equivalent to 15.32 mg of C13H12F2N6O.

Impurities

A. (2RS)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-(4H-1,2,4-triazol-4-yl)pro-pan-2-ol,

B.2-[2-fluoro-4-(1H-1,2,4-triazol-1-yl)phenyl]-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol,

C. 1,1’-(1,3-phenylene)di-1H--1,2,4-triazole,


140


N

NN

F

F

H3C C

O

and enantiomer

R

F

F

H2C

OH

N N

N

H2C C

and enantiomer

FSO3H

N

NN

H2C

H2CC

O

Fand enantiomer

OH

N N

N

N N

N

F

H2C CH2C

and enantiomer

OH

N +N

N

N N

N

F

F

H2CH2N

CH2C

D. 2-(4-fluorophenyl)-1,3-bis(1H--1,2,4-triazol-1-yl)propan-2-ol,

E.1-[(6RS)-4,6-difluoro-6-(1H--1,2,4-triazol-1-yl)cyclohexa-1,4-dienyl]ethanone,

F. R=OH:(2RS)-2-(2,4-difluorophenyl)-3-(1H--1,2,4-triazol-1-yl) propan-2-diol,H. R=Br:(2RS)-1-bromo-2-(2,4-difluorophenyl)-3-(1H--1,2,4-triazol-1-yl) propan-2-ol,

G.[3-[[(2RS)-2-(2,4-difluorophenyl)oxiran-2-yl]methyl]1H--1,2,4-triazol-1-yl)]methane-sulfonic acid,


141


and enantiomer

OH

N +N

N

N N

N

F

F

H2CH2N

CH2C

I. 4-amino-1-[(2RS)-2-(2,4-difluorophenyl)-2-hydroxy-3(1H--1,2,4-triazol-1-yl)propyl]- 4H-1,2,4-triazolium.

[Note from Secretariat: chemical names and structures to be confirmed.]

Fluconazoli compressiFluconazole capsules



Storage. Fluconazole capsules should be kept in a tightly closed container and stored at a temperature not exceeding 30 °C.

Additional information. Strengths in the current WHO Model List of Essential Medi-cines: 50 mg, 200 mg. Strength in the current WHO Model List of Essential Medicines for Children: 50 mg.

Requirements

Comply with the monograph for «Capsules».

Definition. Fluconazole capsules contain Fluconazole. They contain not less than 90.0% and not more than 110.0% of the amount of fluconazole (C13H12F2N6O) sta-ted on the label.

Identity tests

Either tests A and C or tests B and C may be applied.

A. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R6 as the coating substance and a mixture of 80 volumes of dichlorome-thane R, 20 volumes of methanol R, and 1 volume of concentrated-ammonia R solu-tion as the mobile phase. Apply separately to the plate 10 μl of each of the following three solutions in methanol R. For solution (A) shake a quantity of the contents of the


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capsules containing about 100 mg of Fluconazole with 10 ml of methanol R, filter, and use the clear filtrate. For solution (B) use 10 mg of fluconazole RS per ml. For solution (C) use a mixture of 10 mg of fluconazole RS and 10 mg of fluconazole impurity A RS per ml. After removing the plate from the chromatographic chamber, allow it to dry in a current of air, and examine the chromatogram in ultraviolet light (254 nm).


B. See the test described below under Assay B. The retention time of the principal peak in the chromatogram obtained with solution (1) corresponds to that of the princi-pal peak in the chromatogram obtained with solution (2).

C. To a quantity of the contents of the capsules containing 2 mg of Fluconazole, add 10 ml of ethanol R, shake and filter. The absorption spectrum (1.6) of the solution exhi-bits maxima at 261 nm and 267 nm, and a minimum at 264 nm.

Related substancesCarry out the test as described under 1.14.4 High-performance liquid chromatography, using the conditions given below under Assay. Prepare the following solutions in the mobile phase. For solution (1) use an amount of the mixed contents of 20 capsules to produce a solution containing 10 mg of Fluconazole per ml. For solution (2) dilute 5 volumes of solution (1) to 100 volumes, then dilute l volume of this solution to 10 volumes. For solution (3) use 0.5 mg of fluconazole for peak identification RS (contai-ning impurity A) per ml. For solution (4) use 0.03 mg of fluconazole impurity B RS per ml. For solution (5) use 0.1 mg of fluconazole impurity C RS per ml. To 1.0 ml of this solution, add 1.0 ml of solution (1) and dilute to 10.0 ml.


Inject separately 20 μl each of solutions (1), (2), (3), (4) and (5). Record the chromato-grams to 3.5 times the retention time of Fluconazole and identify the impurity peaks. The peaks are eluted at the following relative retentions with reference to fluconazole (retention time about 11minutes): impurity B about 0.4; impurity A about 0.5; impurity C about 0.8. The test is not valid, unless in the chromatogram obtained with solution (5), the resolution between the peaks due to impurity C and to fluconazole is at least 1.5.

In the chromatogram obtained with solution (1), the area of any peak corresponding to impurity A is not greater than 0.8 times the area of the principal peak in the chromato-gram obtained with solution (2) (0.4%); the area of any peak corresponding to impurity B is not greater than the area of the principal peak in the chromatogram obtained with solution (4) (0.3%); the area of any peak corresponding to impurity C is not greater than the area of the principal peak in the chromatogram obtained with solution (5) (0.1%); the area of any other impurity peak is not greater than 0.2 times the area of the principal peak in the chromatogram obtained with solution (2) (0.1%). The sum of the areas of all peaks other than the Fluconazole peak is not greater than 1.2 times the area of the principal peak in the chromatogram obtained with solution (2) (0.6%). Disregard any peak with an area less than 0.1 times the area of the principal peak in the chromatogram obtained with solution (2) (0.05%).


143


Dissolution testCarry out the test as described under 5.5 Dissolution test for solid oral dosage forms, using as the dissolution medium, 500 ml (for strength 50 mg capsules) of hydrochloric acid (0.1 mol/l) TS or using 1000 ml (for strength 200 mg capsules) hydrochloric acid (0.1 mol/l) TS and rotating the paddle at 100 revolutions per minute. At 45 minutes withdraw a sample of about 10 ml of the medium through a suitable 0.45 μm filter. Measure the absorbance (1.6) of a 1 cm layer of the successive filtrate, suitably diluted if necessary, at the maximum at 261 nm. Measure the absorbance (1.6) at the maximum at about 261 nm of a reference solution containing 0.1 mg of fluconazole RS per ml in the dissolution medium, using the same solution as the blank.

For each of the six capsules tested, calculate the total amount of fluconazole (C13H12F2N6O) in the medium. The amount in solution for each capsule is not less than 80% of the amount declared on the label. If the amount obtained for one of the six capsules is less than 80%, repeat the test using a further six tablets the average amount for all 12 capsules tested is not less than 75% and no capsule releases less than 60%.

Assay

Either test A or B may be applied.

A. Mix the contents of 20 capsules and transfer a quantity containing about 50 mg of Fluconazole, accurately weighed, to a 10 ml volumetric flask, and dilute to volume with hydrochloric acid (0.1 mol/l) TS. Shake to dissolve, filter a portion of this solution through a 0.45 μm filter anddilute 10 ml of the successive filtrate to 25 ml with the same solution. Measure the absorbance of a 1 cm layer at the maximum at about 261 nm.

Calculate the percentage content of fluconazole (C13H12F2N6O) using as reference a solution containing 0.2 mg of fluconazole RS per ml of hydrochloric acid (0.1 mol/l) TS prepared and examined in the same manner.

B. Carry out the test as described under 1.14.4 High-performance liquid chromatogra-phy, using a stainless steel column (25 cm × 4.6 mm) packed with particles of silica gel, the surface of which has been modified with chemically bonded octadecylsilyl groups (5μm). Capcell Pak® C18 MGII (4.6×250 mm, 5 μm) has been found suitable. As the mobile phase, use a mixture of 86 volumes of a (0.63 g/l) solution of ammo-nium formate R and 14 volumes of acetonitrile R Prepare the following solutions in the mobile phase. For solution (1) use an amount of the mixed contents of 20 capsules to produce a solution containing 0.5 mg of Flu-conazole per ml and filter. For solution (2) use 0.5 mg of fluconazole RS per ml. For solution (3) use a solution containing 0.01 mg of fluconazole impurity C RS per ml and 1 mg of fluconazole RS per ml.


Inject separately 20 μl of each of solutions (1), (2) and (3). The test is not valid, unless in the chromatogram obtained with solution (3), the resolution between the peaks due to impurity C and to fluconazole is at least 1.5.


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Measure the areas of the peak responses obtained in the chromatograms from solu-tions (1) and (2), and calculate the percentage content of fluconazole (C13H12F2N6O) in the capsules.

Fluconazoli injectioFluconazole injection


Description. A clear, colourless solution.


Storage. Fluconazole injection should be kept in a tightly closed container, stored at controlled room temperature and protected from light.

Additional information. Strength in the current WHO Model list of Essential Medicines: 2 mg/ml in vial.

Requirements

Complies with the monograph for «Parenteral preparations».

[Note from Secretariat: Some of the Ph.Int. monographs for parenterals have the fol-lowing general requirements statement: “Comply with the monograph for «Parenteral preparations» and with 5.6 Test for extractable volume for parenteral preparations, 3.4 Test for bacterial endotoxins, and 5.7 Visual inspection of particulate matter in injec-table preparations.”

In October 2011, the Expert Committee adopted the following PDG harmonized texts:

• 3.2 Test for sterility, • 3.4 Test for bacterial endotoxins, • 5.6 Extractable volume for parenteral preparations, and• 5.7 Test for particulate contamination.

As a consequence, it was recommended that the general monograph on Parenteral preparations be revised in order to make these new/revised tests mandatory for these dosage forms. A revision proposal for the general monograph on Parenteral prepara-tions is currently under elaboration where the compliance to these tests is now invo-ked. It is, therefore, no longer needed to mention these tests in individual monogra-phs, unless specific limits apply.]

Definition. Fluconazole injection is a sterile solution of Fluconazole in water for injec-tions.


145


The solution is sterilized by a suitable method (see 5.8 Methods of sterilization).

Fluconazole injection contains not less than 90.0% and not more than 110.0% of the amount of fluconazole (C13H12F2N6O) stated on the label.

Identity tests

Either test A and C or test B and C may be applied.

A. Carry out the test as described under 1.14.1 Thin-layer chromatography, using sili-ca gel R6 as the coating substance and a mixture of 80 volumes of dichloromethane R, 20 volumes of methanol R, and 1 volume of concentrated-ammonia R solution as the mobile phase. Apply separately to the plate 20 μl of each of the following three solutions. For solution (A) use the injection as the resulting solution. For solution (B) use 2 mg of fluconazole RS per ml in methanol R. For solution (C) use a mixture of 2 mg of fluconazole RS per ml and 2 mg of fluconazole impurity A RS per ml in metha-nol R. After removing the plate from the chromatographic chamber, allow it to dry in a current of air, and examine the chromatogram in ultraviolet light (254 nm).


B. See the test described below under Assay. The retention time of the principal peak in the chromatogram obtained with solution (1) corresponds to that of the principal peak in the chromatogram obtained with solution (2).

C. Dilute a volume of the injection containing 2 mg of Fluconazole to 10 ml with water R, the absorption spectrum (1.6) of the resulting solution exhibits maxima at 261 nm and 267 nm, and a minimum at 264 nm.

pH value (1.3). pH of the injection, 4.0-6.0.

Related substancesCarry out the test as described under 1.14.4 High-performance liquid chromatography, using the conditions given below under Assay. Prepare the following solutions in the mobile phase. For solution (1) use the injection. For solution (2) dilute 5 volumes of solution (1) to 100 volumes , then dilute l volume of this solution to 10 volumes. For solution (3) use 0.5 mg of fluconazole for peak identification RS (containing impurity A) per ml. For solution (4) use 0.006 mg of fluconazole impurity B RS per ml. For solution (5) use 0.02 mg of fluconazole impurity C RS per ml. To 1.0 ml of this solution, add 1.0 ml of solution (1) and dilute to 10.0 ml. For solution (6) use 1 μg of fluconazole RS per ml.


Inject separately 20 μl each of solutions (1), (2), (3), (4), (5) and (6). Record the chromatograms to 3.5 times the retention time of fluconazole and identify the impurity peaks. The peaks are eluted at the following relative retentions with reference to flu-conazole (retention time about 11minutes): impurity B about 0.4; impurity A about 0.5; impurity C about 0.8. The test is not valid, unless in the chromatogram obtained with


146


solution (5), the resolution between the peaks due to impurity C and to fluconazole is at least 1.5; the test is also not valid if the signal-to-noise ratio for solution (6) is at least 10.

In the chromatogram obtained with solution (1), the area of any peak corresponding to impurity A is not greater than 0.8 times the area of the principal peak in the chromato-gram obtained with solution (2) (0.4%); the area of any peak corresponding to impurity B is not greater than the area of the principal peak in the chromatogram obtained with solution (4) (0.3%); the area of any peak corresponding to impurity C is not greater than the area of the principal peak in the chromatogram obtained with solution (5) (0.1%); the area of any other impurity peak is not greater than 0.2 times the area of the principal peak in the chromatogram obtained with solution (2) (0.1%). The sum of the areas of all peaks other than the fluconazole peak is not greater than 1.2 times the area of the principal peak in the chromatogram obtained with solution (2) (0.6%). Disregard any peak with an area less than 0.1 times the area of the principal peak in the chromatogram obtained with solution (2) (0.05%).

AssayCarry out the test as described under 1.14.4 High-performance liquid chromatography, using a stainless steel column (25 cm × 4.6 mm) packed with particles of silica gel, the surface of which has been modified with chemically bonded octadecylsilyl groups (5μm). Capcell Pak® C18 MGII (4.6×250 mm, 5 μm) has been found suitable.

As the mobile phase, use a mixture of 86 volumes of a (0.63 g/l) solution of ammo-nium formate R and 14 volumes of acetonitrile R.

Prepare the following solutions in the mobile phase. For solution (1) dilute an accura-tely measured volume of the injection containing about 5 mg of Fluconazole to 10 ml. For solution (2) use 0.5 mg of fluconazole RS per ml. For solution (3) use a solution containing 0.01 mg of fluconazole impurity C RS per ml and 1 mg of fluconazole RS per ml.


Inject separately 20 μl of each of solutions (1), (2) and (3). The test is not valid, unless in the chromatogram obtained with solution (3), the resolution between the peaks due to impurity C and to fluconazole is at least 1.5.

Measure the areas of the peak responses obtained in the chromatograms from solu-tions (1) and (2), and calculate the percentage content of fluconazole (C13H12F2N6O) in the injection.

Bacterial endotoxins. Carry out the test as described under 3.4 Test for bacterial endotoxins, using Method A; contains not more than 0.416 IU of endotoxin RS per mg of Fluconazole.

[Note from the Secretariat: in accordance with the revised test 3.4 Bacterial Endo-toxins adopted in October 2011 (harmonized text from PDG), the specific method to be used when carrying out the test is now mentioned (gel-clot, turbidimetric technique or chromogenic techniques).]


147


Sulfamethoxazoli et trimethoprimi infusio intravenoSulfamethoxazole and trimethoprim intravenous infusion


[Note from the Secretariat: This draft text is proposed for inclusion in Ph.Int. in the context of a collaboration between WHO and the Medicines and Healthcare Pro-ducts Regulatory Agency of the United Kingdom of Great Britain and Northern Ireland (MHRA) hosting The British Pharmacopoeia (BP), on which this text is based. Use of «injection» or «infusion» to define this type of dosage form would need to be harmo-nized with either the WHO Model List of Essential Medicines where the term “injection” is used for this product, or with the existing monograph of a similar dosage form in the Ph.Int. (see Zidovudine intravenous infusion).]

Category. Antibacterials.

Requirements

Complies with the monograph for “Parenteral preparation”.

Definition. Sulfamethoxazole and Trimethoprim intravenous infusion is a sterile solu-tion of Sulfamethoxazole and Trimethoprim in glucose or sodium chloride intravenous infusions. It is prepared immediately before use by diluting Sulfamethoxazole and Trimethoprim sterile concentrate with a 5% glucose infusion or a 0.9% sodium chloride intravenous infusion.

Sulfamethoxazole and trimethoprim sterile concentrate

Description. A colourless or slightly yellow solution.

Storage: Sulfamethoxazole and Trimethoprim sterile concentrate should be kept in tightly closed, single-dose, light-resistant containers, preferably of Type I glass.

[Note from the Secretariat: The BP monograph recommends the storage of the infu-sion in a “Type I glass container”; however, glass container categories are not descri-bed in Ph.Int. Moreover, as described in BP (Appendix XIX B refers – Glass containers for Pharmaceutical use): “Type I glass containers are suitable for most preparations whether or not for parenteral use”.

As this type of glass container is in common use and does not have particular charac-teristics that would need to be specified in this monograph, it is proposed to omit this information and to mention the general term “glass container” instead.]

Additional information. Strengths in the current WHO Model List of Essential Medi-cines:

80 mg per ml Sulfamethoxazole, 16 mg per ml Trimethoprim in 5 ml ampoule 80 mg per ml Sulfamethoxazole, 16 mg per ml Trimethoprim in 10 ml ampoule


148


Strengths in the current WHO Model List of Essential Medicines for Children:

80 mg per ml Sulfamethoxazole, 16 mg per ml Trimethoprim in 5 ml ampoule 80 mg per ml Sulfamethoxazole, 16 mg per ml Trimethoprim in 10 ml ampoule.

Requirements

Comply with the monograph for “Parenteral preparations”.

Definition. Sulfamethoxazole and Trimethoprim sterile concentrate is a sterile solution of Sulfamethoxazole and Trimethoprim in water for injections, which, when diluted with a 5% glucose intravenous infusion or a 0.9% sodium chloride intravenous infusion, is suitable for intravenous infusion.

The solution is sterilized by a suitable method (see 5.8 Methods of sterilization).

Sulfamethoxazole and Trimethoprim sterile concentrate contains not less than 90.0 % and not more than 110.0% of the amounts of Sulfamethoxazole (C10H11N3O3S) and Trimethoprim (C14H18N4O3) stated on the label.

[Note from the Secretariat: It is intended to develop Ph.Int. monographs for Glucose intravenous infusion and Sodium chloride intravenous infusion.]

Identity tests

Either tests A and D or tests B and C may be applied.


A.1 Carry out the test as described under 1.14.1. Thin-layer chromatography, using silica gel R6 as the coating substance and a mixture of 100 volumes of dichloro-methane R, 10 volumes of methanol R and 5 volumes of dimethylformamide R as the mobile phase. Apply separately to the plate 5 µl of each of the following two solutions in methanol R. For solution (A) evaporate to dryness a volume of the concentrate containing about 0.16 g of Sulfamethoxazole, shake the residue with 8 ml of methanol R and filter. For solution (B) use 20 mg of sulfamethoxazole RS and 4 mg of trimethoprim RS per ml. After removing the plate from the chromatographic chamber, allow it to dry exhaustively in air or in a current of cool air. Examine the chromatogram in ultraviolet light (254 nm).

The principal spots obtained with solution A correspond in position, appearance and intensity to those obtained with solution B.

A.2. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R5 as the coating substance and the conditions described above under test A.1. Spray the plate with potassium iodobismuthate TS2 solution.

The principal spots obtained with solution A correspond in position, appearance and intensity to those obtained with solution B.

B. Add drop wise to 75 ml of hydrochloric acid (~3.65 g/l) TS a volume of the concen-trate containing about 0.8 g of Sulfamethoxazole, stirring continuously. Allow the


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suspension to stand for 5 minutes and filter through a sintered-glass filter. Wash the residue with 10 ml of water R, recrystallize from ethanol (~750 g/l) TS and dry at 105 °C. Dissolve the residue in the minimum volume of sodium carbonate (~50 g/l) TS, add hydrochloric acid (~36.5 g/l) TS drop wise until precipitation is complete, filter, wash the residue sparingly with water R and dry at 105 °C. The infrared absorption spectrum of the residue is concordant with the reference spectrum of sulfamethoxa-zole RS.

C. To a volume of the concentrate containing about 80 mg of Trimethoprim add 30 ml of sodium hydroxide (~ 4 g/l) TS and extract with two quantities of 50 ml of dichlo-romethane R. Wash the combined extracts with two quantities of 10 ml of sodium hydroxide (~ 4 g/l) TS and then with 10 ml of water R. Shake with 5 g of anhydrous sodium sulfate R, filter and evaporate the filtrate to dryness. Carry out the test as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum of the residue is concordant with the spectrum obtained from trimethoprim RS or with the reference spectrum of Trimethoprim.

D. See the test described under Assay method A. The retention times of the principal peaks in the chromatogram obtained with solution (1) are similar to those in the chro-matogram obtained with solution (2).

pH value (1.13). pH of the solution, 9.5 – 11.0

Bacterial endotoxins. Carry out the test described under 3.4 Test for bacterial endo-toxins. Dilute the sterile concentrate with water BET to obtain a solution containing 1 mg of Trimethoprim and 5 mg of Sulfamethoxazole per ml (solution A). Solution A contains not more than 0.5 IU per ml.

Related substances

Trimethoprim-related substances. Carry out the test as described under 1.14.1. Thin-layer chromatography, using silica gel R4 as the coating substance and a mixture of 97 volumes of chloroform R, 7.5 volumes of methanol R, and 1 volume of ammonia (~ 260 g/l) TS as the mobile phase. Apply separately to the plate 10 µl of each of the following three solutions. For solution (A), transfer an accurately measured volume of concentrate, containing about 48 mg of Trimethoprim and 240 mg of Sulfamethoxa-zole, to a glass-stoppered, 50 ml centrifuge tube. Add 15 ml of hydrochloric acid (~ 2.19 g/l) TS, and mix. Add 15 ml of dichloromethane R, shake for 30 seconds, and centrifuge for 3 minutes. Transfer the supernatant layer to a 125-ml separator. Extract the dichloromethane layer in the centrifuge tube with 15 ml of hydrochloric acid (~ 2.19 g/l) TS, centrifuge and add the extract to the separator. Add 2 ml of sodium hydroxide (~ 100 g/l) TS to the solution in the separator, and extract with three 20 ml portions of dichloromethane R, collecting the organic layer in a 125 ml conical flask. Evaporate the dichloromethane under a stream of nitrogen to dryness. Dissolve the residue in 1 ml of a mixture of equal volumes of dichloromethane R and methanol R (solvent mixture). For solution (B) use 48 mg of sulfamethoxazole RS per ml of the solvent mixture. For solution (C), dilute an accurately measured volume of solution B with the solvent mixture to obtain a solution of 240 µg per ml. After removing the plate from the chromatographic chamber, allow it dry in air, spray with ferric chloride/potassium ferricyanide TS1 and examine the chromatogram in ultraviolet light (254 nm).

Trimethoprim produces a spot at about RF 0.5, and the trimethoprim degradation pro-duct produces a spot at about RF 0.6 to 0.7. Any spot from solution A at about RF 0.6


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to 0.7 is not greater in size and intensity than the spot produced by solution C (0.5%). Disregard any spots due to concentrate excipients at about RF 0.1.

Sulfamethoxazole-related substances. Carry out the test as described under 1.14.1. Thin-layer chromatography, using silica gel R5 as the coating substance. Prepare an ethanol-methanol solution by mixing 95 volumes of dehydrated ethanol R and 5 volumes of methanol R. As the mobile phase, use a mixture of 30 volumes of ethanol-methanol solution, 30 volumes of heptane R, 30 volumes of dichloromethane R and 10 volumes of glacial acetic acid R. Prepare an ammonium hydroxide solution by dilu-ting 1 ml of ammonia (~ 260 g/l) TS in the ethanol-methanol solution, and dilute to 100 ml with the same solution. Apply separately to the plate 10 µl of each of the following five solutions. For solution (A), transfer an accurately measured volume of concen-trate, containing about 32 mg of Trimethoprim and 160 mg of Sulfamethoxazole, to an evaporating dish. Evaporate the sample to dryness using a steam bath. Reconstitute the residue with 16 ml of ammonium hydroxide solution. For solution (B) use 10 mg of sulfamethoxazole RS per ml of ammonium hydroxide solution. For solution (C) use 0.05 mg of sulfanilamide RS per ml of ammonium hydroxide solution. For solution (D) use 0.03 mg of sulfanilic acid RS per ml of ammonium hydroxide solution. For solution (E) dissolve 10 mg of sulfamethoxazole RS in 1 ml of a solution containing 0.05 mg of sulfanilamide RS and 0.03 mg of sulfanilic acid RS per ml of ammonium hydroxide solution. After removing the plate from the chromatographic chamber, allow it dry in air, spray with 4-dimethylaminobenzaldehyde TS7, allow the plate to stand for 15 minutes and examine the chromatogram..

Any spots corresponding to sulfanilamide and sulfanilic acid in the chromatogram obtained with solution A are not greater in size or intensity than the spots obtained with solution C (0.5%) and solution D (0.3%) respectively. The test is not valid unless the chromatogram obtained with solution (E) shows three clearly separated principal spots.

Assay

Either method A or methods B and C may be applied.

A. Carry out the test as described under 1.14.4 High-performance liquid chroma-tography, using a stainless steel column (25 cm x 4.6 mm) packed with particles of base-deactivated silica gel, the surface of which has been modified with chemically bonded octadecylsilyl groups (5 µm). Hypersil BDS C18 has been found suitable. As the mobile phase, use a solution prepared as follows: mix 1400 ml of water R, 400 ml of acetonitrile R, and 2.0 ml of triethylamine R in a 2000-ml volumetric flask. Allow to equilibrate to room temperature, and adjust with acetic acid (~10 g/l) TS to pH 5.9. Dilute to volume with water R, and filter through a 0.45-μm membrane.

Prepare the following solutions. For solution (1) transfer an accurately measured volume of the concentrate containing about 80 mg of Sulfamethoxazole into a 50-ml volumetric flask. Add methanol R to volume and mix. Transfer 5.0 ml of this solution to a 50-ml volumetric flask, dilute with the mobile phase to volume, mix and filter. For solution (2), use 0.32 mg of trimethoprim RS and 1.60 mg of sulfamethoxazole RS per ml of methanol R. Dilute 5.0 ml of this solution to 50.0 ml with the mobile phase.

Operate with a flow rate of 1.0 ml per minute. As a detector use an ultraviolet spectro-photometer set at a wavelength of 254 nm.


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Inject separately 20 µl each of solutions (1) and (2) and record the chromatogram for 1.5 times the retention time of sulfamethoxazole. The test is not valid unless the resolution factor between the peaks due to sulfamethoxazole and to trimethoprim is at least 5.0.

Measure the areas of the peak responses obtained in the chromatograms from solu-tions (1) and (2), and calculate the content of Sulfamethoxazole (C10H11N3O3S) and Trimethoprim (C14H18N4O3) in the tablets.

B. To an accurately measured volume of the concentrate containing about 48 mg of Trimethoprim, add 30 ml of sodium hydroxide (~4 g/l) TS and extract with four quan-tities of 50 ml of dichloromethane R, washing each extract twice with a quantity of 10 ml of sodium hydroxide (~4g/l) TS. Combine the dichloromethane extracts and extract with four quantities of 50 ml of acetic acid (~60 g/l) TS. Wash the combined aqueous extracts with 5 ml of dichloromethane R and dilute to 250.0 ml with acetic acid (~60 g/l). To 10 ml of this solution, add 10 ml of acetic acid (~60 g/l), dilute to 100.0 ml with water R. Measure the absorbance of the resulting solution at the maximum at 271 nm. Calculate the amount of trimethoprim (C14H18N4O3) using the absorptivity value of 20.4 ( = 204).

C. To an accurately measured volume of the concentrate containing about 0.4 g of Sulfamethoxazole add 60 ml of water R and 10 ml of hydrochloric acid (~420 g/l) TS. Add 3 g of potassium bromide R, cool in ice and titrate slowly with sodium nitrite (0.1 mol/l) VS, stirring constantly and determining the end-point potentiometrically.

Each ml of sodium nitrite (0.1 mol/l) VS is equivalent to 25.33 mg of Sulfamethoxazole (C10H11N3O3S).

*****

New reagents needed to be added to Ph.Int.:

Acetic acid (~10 g/l) TSAcetic acid (~300 g/l) TS, diluted with water to contain about 10 g of C2H4O per litre.

Hydrochloric acid (~3.65 g/l) TS Hydrochloric acid (~250 g/l) TS, dilute with water to contain 3.65g of HCl in 1000 ml.

Hydrochloric acid (~ 2.19 g/l) TS Hydrochloric acid (~250 g/l) TS, dilute with water to contain 2.19g of HCl in 1000 ml.

Hydrochloric acid (~36.5 g/l) TS Hydrochloric acid (~250 g/l) TS, dilute with water to contain 36.5g of HCl in 1000 ml.

Sodium hydroxide (~ 4 g/l) TS A solution of sodium hydroxide R containing about 4 g/l of NaOH (approximately 0.1 mol/l).

Sodium hydroxide (~ 100 g/l) TSA solution of sodium hydroxide R containing about 100 g/l of NaOH (approximately 2.5 mol/l).


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Ferric chloride / potassium ferricyanide TS1Procedure. Dissolve 2 g of ferric chloride R and 0.5 g of potassium ferricyanide R in sufficient water to produce 20 ml.

Note. Ferric chloride / potassium ferricyanide TS2 must be freshly prepared.

4-Dimethylaminobenzaldehyde TS7Dissolve 0.1 g of 4-dimethylaminobenzaldehyde R in 1 ml of hydrochloric acid (~420 g/l) TS, dilute with ethanol (~750 g/l) to produce 100 ml.

Sulfamethoxazoli et trimethoprimi solutionum peroralumSulfamethoxazole and trimethoprim oral suspension


Category. Antibacterials.

Storage. The oral suspension should be kept in a tightly closed container, protected from light.

Additional information. Strength in the current WHO Model List of Essential Medi-cines: 200 mg Sulfamethoxazole, 40 mg Trimethoprim per 5 ml. Strength in the current WHO Model List of Essential Medicines for Children: 200 mg Sulfamethoxazole, 40 mg Trimethoprim per 5 ml.

Requirements

Complies with the monograph for “Liquid preparations for oral use”.

Definition. Sulfamethoxazole and Trimethoprim oral suspension is a suspension containing Sulfamethoxazole and Trimethoprim in a suitable vehicle which may be fla-voured. The oral suspension contains not less than 90.0% and not more than 110.0% of Sulfamethoxazole (C10H11N3O3S) and Trimethoprim (C14H18N4O3) stated on the label.

Identity tests

Either test A or B may be applied. Test C may be applied for identification of Trimetho-prim.


A.1 Carry out the test as described under 1.14.1. Thin-layer chromatography, using silica gel R6 as the coating substance and a mixture of 100 volumes of dichlorome-thane R, 10 volumes of methanol R and 5 volumes of dimethylformamide R as the mobile phase. Apply separately to the plate 5 µl of each of the following two solu-tions. For solution (A), add 20 ml of methanol R to 5 ml of the oral suspension, mix,


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shake with 10 g of anhydrous sodium sulfate R, centrifuge and use the supernatant liquid. For solution (B) use 20 mg of sulfamethoxazole RS and 4 mg of trimetho-prim RS per ml methanol R. After removing the plate from the chromatographic chamber, allow it to dry exhaustively in air or in a current of cool air. Examine the chromatogram in ultraviolet light (254 nm).

The principal spots obtained with solution A correspond in position, appearance and intensity to those obtained with solutions B.

A.2 Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R5 as the coating substance and the conditions described above under test A.1. Spray the plate with dilute potassium iodobismuthate solution TS2.

The principal spots obtained with solution A correspond in position, appearance, and intensity to those obtained with solution B.

B. See the test described under Assay method A. The retention times of the principal peaks in the chromatogram obtained with solution (1) are similar to those in the chro-matogram obtained with solution (2).

C. To a quantity of the oral solution containing 50 mg of Trimethoprim add 30 ml of sodium hydroxide (~ 4 g/l) TS and extract with two quantities of 50 ml of dichloro-methane R. Wash the combined dichloromethane extracts with two quantities of 10 ml of sodium hydroxide (~ 4 g/l) TS and then with 10 ml of water R. Shake with 5 g of anhydrous sodium sulfate R, filter and evaporate to dryness. Carry out the test as described under 1.7 Spectrophotometry in the infrared region. The infrared spectrum of the residue is concordant with the reference spectrum of trimethoprim RS.

pH value (1.13). pH of the oral suspension, 5.0 – 6.5.

Related substances

Trimethoprim-related substances. Carry out the test as described under 1.14.1. Thin-layer chromatography, using silica gel R6 as the coating substance and a mixture of 80 volumes of chloroform R, 20 volumes of methanol R and 3 volumes of ammonia (260 g/l) TS as the mobile phase. Prepare a solvent mixture as follows: mix 8 volumes of chloroform R and 2 volumes of methanol R. Apply separately to the plate 5 µl of each of the following three solutions. For solution (A), transfer a volume of oral sus-pension, containing about 40 mg of Trimethoprim to a separation funnel. Extract with three portions of 25 ml of the solvent mixture; collecting the extracts in a 125 ml coni-cal flask. Evaporate to dryness the combined extracts with the aid of a current of air on a steam bath. Dissolve the residue in 2 ml of the solvent mixture, then centrifuge. For solution (B) use 20 mg of trimethoprim RS per ml of the solvent mixture. For solution (C), dilute an accurately measured volume of solution B with the solvent mixture to obtain a solution having a known concentration of 0.1 mg per ml. After removing the plate from the chromatographic chamber, allow it to dry in air, and examine the chro-matogram in ultraviolet light (254 nm).

Trimethoprim produces a spot at about RF 0.7 and the trimethoprim degradation pro-duct produces a spot at about RF 0.3 to 0.5. Any spot obtained with solution A at about RF 0.3 to 0.5 is not greater in size and intensity than the spot obtained with solution C (0.5%).


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Sulfamethoxazole-related substances. Carry out the test as described under 1.14.1. Thin-layer chromatography, using silica gel R5 as the coating substance. Prepare an ethanol-methanol solution by mixing 95 volumes of dehydrated ethanol R and 5 volumes of methanol R. As the mobile phase, use a mixture of 25 volumes of the ethanol-methanol solution, 25 volumes of heptane R, 25 volumes of dichloromethane R and 7 volumes of glacial acetic acid R. Apply separately to the plate 50 µl of each of the following three solutions. For solution (A), transfer a volume of the oral suspension containing 200 mg of Sulfamethoxazole to a 100 ml volumetric flask containing 10 ml of ammonia (260 g/l) TS. Add 50 ml of methanol R, shake for 3 minutes, and dilute to volume with methanol R. Centrifuge a portion of the solution for 3 minutes. For solu-tion (B), transfer 20 mg of sulfamethoxazole RS into a 10 ml volumetric flask, dissolve in 1 ml of ammonia (260 g/l) TS and dilute to volume with methanol. For solution (C), transfer 10 mg of sulfanilamide RS into a 50-ml volumetric flask, dissolve in 5 ml of ammonia (260 g/l) TS and dilute to volume with methanol R. Pipet 5 ml of this solu-tion into a 100 ml volumetric flask, add 10 ml of ammonia (260 g/l) TS and dilute to volume with methanol R. For solution (D), transfer 10 mg of sulfanilic acid RS into a 50 ml volumetric flask, dissolve in 5 ml of ammonia (260 g/l) and dilute to volume with methanol R. Pipet 3 ml of this solution into a 100 ml volumetric flask, add 10 ml of ammonia (260 g/l) TS and dilute to volume with methanol R. For solution (E), transfer 3 mg of sulfamethoxazole N4-glucoside RS into a 50 ml volumetric flask, dissolve in 5 ml of ammonia (260 g/l) TS and dilute to volume with methanol R. For solution (F), transfer 10 mg of sulfanilamide RS, 6 mg of sulfanilic acid RS and 60 mg of sulfame-thoxazole N4-glucoside RS into a 100 ml volumetric flask, dissolve in 10 ml of ammo-nia (260 g/l) TS and dilute to volume with methanol R. Pipet 1 ml of this solution into a 10 ml volumetric flask containing 20 mg of sulfamethoxazole RS, add 1 ml of ammonia (260 g/l) TS and dilute to volume with methanol R to volume.

After removing the plate from the developing chamber, allow it to dry in air, spray with 4-dimethylaminobenzaldhyde TS7 and allow the plate to stand for 15 minutes.

Any spots corresponding to sulfanilamide, sulfanilic acid and sulfamethoxazole N4-glucoside obtained with solution A are not greater in size and intensity than the spots obtained with solution C (0.5%), solution D (0.3%), and solution E (3.0%) respectively. The test is not valid unless the chromatogram obtained with solution F shows four clearly separated principal spots.

Assay

Either method A or methods B and C may be applied.

A. Carry out the test as described under 1.14.4 High-performance liquid chromatogra-phy, using a stainless steel column (25 cm x 4.6 mm) packed with particles of base-deactivated silica gel, the surface of which has been modified with chemically bonded octadecylsilyl groups (5 µm). Hypersil BDS C18 has been found suitable As the mobile phase, use a solution prepared as follows: mix 1400 ml of water R, 400 ml of acetoni-trile R, and 2.0 ml of triethylamine R in a 2000 ml volumetric flask. Allow to equilibrate to room temperature, and adjust with acetic acid (~10 g/l) TS to pH 5.9. Dilute to volume with water R, and filter through a 0.45 μm membrane.

Prepare the following solutions. For solution (1) transfer an accurately weighed quantity of the oral suspension, containing about 80 mg of Sulfamethoxazole, to a 50-ml volumetric flask using about 30 ml of methanol R. Sonicate the mixture for


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about 10 minutes with occasional shaking. Allow to cool to room temperature, make up to volume with methanol R, mix and filter. Transfer 5.0 ml of clear filtrate into a 50 ml volumetric flask, make up to volume with the mobile phase and mix. For solution (2), use 0.32 mg of trimethoprim RS and 1.60 mg of sulfamethoxazole RS per ml of methanol R. Transfer 5.0 ml of this solution into a 50 ml volumetric flask, make up to volume with the mobile phase.

Operate with a flow rate of 1.0 ml per minute. As a detector use an ultraviolet spectro-photometer set at a wavelength of 254 nm. Inject separately 20 µl of solutions (1) and (2) and record the chromatogram for 1.5 times the retention time of sulfamethoxazole. The test is not valid unless the resolution factor between the peaks due to sulfame-thoxazole and to trimethoprim is at least 5.0.

Determine the weight per ml (1.3.1) of the oral suspension and calculate the percen-tage content of Sulfamethoxazole (C10H11N3O3S) and Trimethoprim (C14H18N4O3) in the oral suspension from the declared content of Sulfamethoxazole (C10H-11N3O3S) and Trimethoprim (C14H18N4O3) in sulfamethoxazole RS and trimetho-prim RS.

B. To 8.0 g of the oral suspension, accurately weighed, add 30 ml of sodium hydroxide (~ 4 g/l) TS, shake and extract with four quantities of 50 ml of dichloromethane R, washing each extract with the same two quantities of 10 ml of sodium hydroxide (~4 g/l) TS. Reserve the combined dichloromethane extracts for the Assay method C. Dilute the combined aqueous solution and washings to 250 ml with water R, filter and dilute 5 ml of the filtrate to 200 ml with water R (solution A). Carry out the following procedure protected from light using 2 ml of solution A. Add 0.5 ml of hydrochloric acid (~146 g/l) TS and 1 ml of sodium nitrite (~ 1 g/l) TS and allow to stand for 2 minutes. Add 1 ml of ammonium sulfamate (~ 5 g/l) TS and allow to stand for 3 minutes. Add 1 ml of N-(1-napthyl)ethylenediamine hydrochloride (1 g/l) TS and allow to stand for 10 minutes. Dilute the resulting solution to 25 ml with water R and measure the absor-bance at 538 nm, using in the reference cell a solution prepared in the same manner but using 2 ml of water R in place of solution A. Dissolve 0.25 g of sulfamethoxazole RS in 50 ml of sodium hydroxide (~4 g/l) TS and dilute to 250 ml with water R. Dilute 5 ml of the resulting solution to 200 ml with water R (solution B). Repeat the procedure described above, using 2 ml of solution B and starting at the sentence “Add 0.5 ml of hydrochloric acid (~146 g/l) TS and 1 ml of sodium nitrite (~ 1 g/l) TS …”.

Calculate the content of Sulfamethoxazole (C10H11N3O3S) from the values of the absorbances obtained using the declared content of C10H11N3O3S in sulfamethoxa-zole RS. Determine the weight per ml (1.3.1) of the oral suspension, and calculate the content of Sulfamethoxazole (C10H11N3O3S), weight in volume.

C. Extract the dichloromethane solution reserved in the Assay for sulfamethoxazole with four quantities of 50 ml of acetic acid ( 60 g/l) TS. Wash the combined extracts with 5 ml of dichloromethane R and dilute the aqueous extracts to 250 ml with acetic acid ( 60 g/l) TS. To 10 ml of this solution add 10 ml of acetic acid ( 60 g/l) TS and sufficient water R to produce 100 ml. Measure the absorbance of the resulting solution at the maximum at 271 nm.

Calculate the content of Trimethoprim (C14H18N4O3) using 204 as value for the spe-cific absorbance () at the maximum at 271 nm. Calculate the content of Trimethoprim (C14H18N4O3), weight in volume.


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New reagents to be added in Ph.Int.

Acetic acid (~10 g/l) TSAcetic acid (~300 g/l) TS, diluted with water to contain about 10 g of C2H4O per litre.

Hydrochloric acid (~146 g/l) TSHydrochloric acid (~250 g/l) TS, dilute with water to contain approximately 146 g of HCl in 1000 ml (approximately 4 mol/l).

Sodium hydroxide (~ 4 g/l) TS A solution of sodium hydroxide R containing about 4 g/l of NaOH (approximately 0.1 mol/l).

4-Dimethylaminobenzaldehyde TS7Dissolve 0.1 g of 4-dimethylaminobenzaldehyde R in 1 ml of hydrochloric acid (~420 g/l) TS, dilute with ethanol (~750 g/l) to produce 100 ml.


WHO Drug Information, Vol. 26, No. 2, 2012 Proposed INN: List 107

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International Nonproprietary Names for Pharmaceutical Substances (INN) Notice is hereby given that, in accordance with article 3 of the Procedure for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances, the names given in the list on the following pages are under consideration by the World Health Organization as Proposed International Nonproprietary Names. The inclusion of a name in the lists of Proposed International Nonproprietary Names does not imply any recommendation of the use of the substance in medicine or pharmacy. Lists of Proposed (1–105) and Recommended (1–66) International Nonproprietary Names can be found in Cumulative List No. 14, 2011 (available in CD-ROM only). The statements indicating action and use are based largely on information supplied by the manufacturer. This information is merely meant to provide an indication of the potential use of new substances at the time they are accorded Proposed International Nonproprietary Names. WHO is not in a position either to uphold these statements or to comment on the efficacy of the action claimed. Because of their provisional nature, these descriptors will neither be revised nor included in the Cumulative Lists of INNs.

Dénominations communes internationales des Substances pharmaceutiques (DCI) Il est notifié que, conformément aux dispositions de l'article 3 de la Procédure à suivre en vue du choix de Dénominations communes internationales recommandées pour les Substances pharmaceutiques les dénominations ci-dessous sont mises à l'étude par l'Organisation mondiale de la Santé en tant que dénominations communes internationales proposées. L'inclusion d'une dénomination dans les listes de DCI proposées n'implique aucune recommandation en vue de l'utilisation de la substance correspondante en médecine ou en pharmacie. On trouvera d'autres listes de Dénominations communes internationales proposées (1–105) et recommandées (1–66) dans la Liste récapitulative No. 14, 2011 (disponible sur CD-ROM seulement). Les mentions indiquant les propriétés et les indications des substances sont fondées sur les renseignements communiqués par le fabricant. Elles ne visent qu'à donner une idée de l'utilisation potentielle des nouvelles substances au moment où elles sont l'objet de propositions de DCI. L'OMS n'est pas en mesure de confirmer ces déclarations ni de faire de commentaires sur l'efficacité du mode d'action ainsi décrit. En raison de leur caractère provisoire, ces informations ne figureront pas dans les listes récapitulatives de DCI.

Denominaciones Comunes Internacionales para las Sustancias Farmacéuticas (DCI) De conformidad con lo que dispone el párrafo 3 del "Procedimiento de Selección de Denominaciones Comunes Internacionales Recomendadas para las Sustancias Farmacéuticas", se comunica por el presente anuncio que las denominaciones detalladas en las páginas siguientes están sometidas a estudio por la Organización Mundial de La Salud como Denominaciones Comunes Internacionales Propuestas. La inclusión de una denominación en las listas de las DCI Propuestas no supone recomendación alguna en favor del empleo de la sustancia respectiva en medicina o en farmacia. Las listas de Denominaciones Comunes Internacionales Propuestas (1–105) y Recomendadas (1–66) se encuentran reunidas en Cumulative List No. 14, 2011 (disponible sólo en CD-ROM). Las indicaciones sobre acción y uso que aparecen se basan principalmente en la información facilitada por los fabricantes. Esta información tiene por objeto dar una idea únicamente de las posibilidades de aplicación de las nuevas sustancias a las que se asigna una DCI Propuesta. La OMS no está facultada para respaldar esas indicaciones ni para formular comentarios sobre la eficacia de la acción que se atribuye al producto. Debido a su carácter provisional, esos datos descriptivos no deben incluirse en las listas recapitulativas de DCI.

Proposed INN: List 107 WHO Drug Information, Vol. 26, No. 2, 2012

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Proposed International Nonproprietary Names: List 107 Comments on, or formal objections to, the proposed names may be forwarded by any person to the INN Programme of the World Health Organization within four months of the date of their publication in WHO Drug Information, i.e., for List 107 Proposed INN not later than 31 October 2012 Publication date: 30 June 2012

Dénominations communes internationales proposées: Liste 107 Des observations ou des objections formelles à l'égard des dénominations proposées peuvent être adressées par toute personne au Programme des Dénominations communes internationales de l'Organisation mondiale de la Santé dans un délai de quatre mois à compter de la date de leur publication dans WHO Drug Information, c'est à dire pour la Liste 107 de DCI Proposées le 31 octobre 2012 au plus tard. Date de publication : 30 juin 2012

Denominaciones Comunes Internacionales Propuestas: Lista 107 Cualquier persona puede dirigir observaciones u objeciones respecto de las denominaciones propuestas, al Programa de Denominaciones Comunes Internacionales de la Organización Mundial de la Salud, en un plazo de cuatro meses, contados desde la fecha de su publicación en WHO Drug Information, es decir, para la Lista 107 de DCI Propuestas el 31 de octubre de 2012 a más tardar. Fecha de publicación: 30 de junio de 2012

Proposed INN (Latin, English, French, Spanish) DCI Proposée DCI Propuesta

Chemical name or description: Action and use: Molecular formula Chemical Abstracts Service (CAS) registry number: Graphic formula Nom chimique ou description: Propriétés et indications: Formule brute Numéro dans le registre du CAS: Formule développée Nombre químico o descripción: Acción y uso: Fórmula molecular Número de registro del CAS: Fórmula desarrollada

actoxumabum # actoxumab immunoglobulin G1-kappa, anti-(Clostridium difficile toxin A), Homo

sapiens monoclonal antibody; gamma1 heavy chain (1-449) [Homo sapiens VH (IGHV5-51*01 (94.90%) -(IGHD)-IGHJ3*02) [8.8.12] (1-119) -IGHG1*03 (120-449)], (222-215')-disulfide with kappa light chain (1'-215') [Homo sapiens V-KAPPA (IGKV3-20*01 (100.00%) -IGKJ1*01) [7.3.9] (1'-108') -IGKC*01 (109'-215')]; (228-228'':231-231'')-bisdisulfide dimer immunomodulator

actoxumab immunoglobuline G1-kappa, anti-(Clostridium difficile toxine A), Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-449) [Homo sapiens VH (IGHV5-51*01 (94.90%) -(IGHD)-IGHJ3*02) [8.8.12] (1-119) -IGHG1*03 (120-449)], (222-215')-disulfure avec la chaîne légère kappa (1'-215') [Homo sapiens V-KAPPA (IGKV3-20*01 (100.00%) -IGKJ1*01) [7.3.9] (1'-108') -IGKC*01 (109'-215')]; dimère (228-228'':231-231'')-bisdisulfure immunomodulateur


159

actoxumab inmunoglobulina G1-kappa, anti-(toxina A de Clostridium difficile),

anticuerpo monoclonal de Homo sapiens ; cadena pesada gamma1 (1-449) [Homo sapiens VH (IGHV5-51*01 (94.90%) -(IGHD)-IGHJ3*02) [8.8.12] (1-119) -IGHG1*03 (120-449)], (222-215')-disulfuro con la cadena ligera kappa (1'-215') [Homo sapiens V-KAPPA (IGKV3-20*01 (100.00%) -IGKJ1*01) [7.3.9] (1'-108') -IGKC*01 (109'-215')]; dímero (228-228'':231-231'')-bisdisulfuro inmunomodulador

1245634-25-6 Heavy chain / Chaîne lourde / Cadena pesada

EVQLVQSGAE VKKSGESLKI SCKGSGYSFT SYWIGWVRQM PGKGLEWMGI 50FYPGDSSTRY SPSFQGQVTI SADKSVNTAY LQWSSLKASD TAMYYCARRR 100NWGNAFDIWG QGTMVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200ICNVNHKPSN TKVDKRVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350YTLPPSREEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449

Light chain / Chaîne légère / Cadena ligeraEIVLTQSPGT LSLSPGERAT LSCRASQSVS SSYLAWYQQK PGQAPRLLIY 50GASSRATGIP DRFSGSGSGT DFTLTISRLE PEDFAVYYCQ QYGSSTWTFG 100QGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK 150VDNALQSGNS QESVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ 200GLSSPVTKSF NRGEC 215

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H 22-96 146-202 263-323 369-427 22''-96'' 146''-202'' 263''-323'' 369''-427''Intra-L 23'-89' 135'-195' 23'''-89''' 135'''-195''' Inter-H-L 222-215' 222''-215''' Inter-H-H 228-228'' 231-231''

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilaciónH CH2 N84.4:299, 299''

aladorianum aladorian (7-methoxy-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)oxoacetic acid

antiarrhythmic

aladorian acide (7-méthoxy-2,3-dihydro-1,4-benzothiazépin- 4(5H)-yl)oxoacétique antiarythmique

aladorián ácido (7- metoxi-2,3-dihidro-1,4-benzotiazepin-4(5H)-il)oxoacético antiarrítmico

C12H13NO4S 865433-00-7

N

S

CO2H

O

H3CO


160

alirocumabum # alirocumab immunoglobulin G1-kappa, anti-[Homo sapiens PCSK9 (proprotein

convertase subtilisin/kexin type 9)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-447) [Homo sapiens VH (IGHV3-23*04 (89.80%) -(IGHD)-IGHJ2*01 [8.8.11] (1-118) -IGHG1*01 CHS K2>del (119-447)], (221-220')-disulfide with kappa light chain (1'-220') [Homo sapiens V-KAPPA (IGKV4-1*01 (94.10%) -IGKJ2*01) [12.3.9] (1'-113') -IGKC*01 (114'-220')]; (227-227'':230-230'')-bisdisulfide dimer immunomodulator

alirocumab immunoglobuline G1-kappa, anti-[Homo sapiens PCSK9 (proprotéine convertase subtilisine/kexine type 9)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-447) [Homo sapiens VH (IGHV3-23*04 (89.80%) -(IGHD)-IGHJ2*01 [8.8.11] (1-118) -IGHG1*01 CHS K2>del (119-447)], (221-220')-disulfure avec la chaîne légère kappa (1'-220') [Homo sapiens V-KAPPA (IGKV4-1*01 (94.10%) -IGKJ2*01) [12.3.9] (1'-113') -IGKC*01 (114'-220')]; dimère (227-227'':230-230'')-bisdisulfure immunomodulateur

alirocumab inmunoglobulina G1-kappa, anti-[PCSK9 de Homo sapiens (proproteína convertasa subtilisina/kexina tipo 9)], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-447) [Homo sapiens VH (IGHV3-23*04 (89.80%) -(IGHD)-IGHJ2*01 [8.8.11] (1-118) -IGHG1*01 CHS K2>del (119-447)], (221-220')-disulfuro con la cadena ligera kappa (1'-220') [Homo sapiens V-KAPPA (IGKV4-1*01 (94.10%) -IGKJ2*01) [12.3.9] (1'-113') -IGKC*01 (114'-220')]; dímero (227-227'':230-230'')-bisdisulfuro inmunomodulador


EVQLVESGGG LVQPGGSLRL SCAASGFTFN NYAMNWVRQA PGKGLDWVST 50ISGSGGTTNY ADSVKGRFII SRDSSKHTLY LQMNSLRAED TAVYYCAKDS 100NWGNFDLWGR GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY 150FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI 200CNVNHKPSNT KVDKKVEPKS CDKTHTCPPC PAPELLGGPS VFLFPPKPKD 250TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST 300YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY 350TLPPSRDELT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD 400SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPG 447

Light chain / Chaîne légère / Cadena ligeraDIVMTQSPDS LAVSLGERAT INCKSSQSVL YRSNNRNFLG WYQQKPGQPP 50NLLIYWASTR ESGVPDRFSG SGSGTDFTLT ISSLQAEDVA VYYCQQYYTT 100PYTFGQGTKL EIKRTVAAPS VFIFPPSDEQ LKSGTASVVC LLNNFYPREA 150KVQWKVDNAL QSGNSQESVT EQDSKDSTYS LSSTLTLSKA DYEKHKVYAC 200EVTHQGLSSP VTKSFNRGEC 220


N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilaciónH CH2 N84.4: 298, 298''


161

antithrombinum gamma # antithrombin gamma afucosylated antithrombin;

human antithrombin-III (ATIII, serpin C1) expressed in fucosyl transferase-negative Chinese Hamster Ovary (CHO) cells (glycoform gamma) anticoagulant

antithrombine gamma antithrombine afucosylée; antithrombine-III humaine (ATIII, serpine C1) obtenue à partir de culture de cellules ovariennes d'hamster chinois (CHO) n'exprimant pas la fucosyl transférase (glycoforme gamma) anticoagulant

antitrombina gamma antitrombina afucosilada; antitrombina-III humana (ATIII, serpina C1) obtenida a partir de cultivo de células ováricas de hamster chino (CHO) que no expresan la fucosil transferasa (glicoforma gamma) anticoagulante

1311281-25-0

-Man4--Gl-N4--Gl-NN-Sia3--Gal3--Gl-N2--Man6-

-Sia3--Gal3--Gl-N2--Man3-

HGSPVDICTA KPRDIPMNPM CIYRSPEKKA TEDEGSEQKI PEATNRRVWE 50LSKANSRFAT TFYQHLADSK NDNDNIFLSP LSISTAFAMT KLGACNDTLQ 100QLMEVFKFDT ISEKTSDQIH FFFAKLNCRL YRKANKSSKL VSANRLFGDK 150SLTFNETYQD ISELVYGAKL QPLDFKENAE QSRAAINKWV SNKTEGRITD 200VIPSEAINEL TVLVLVNTIY FKGLWKSKFS PENTRKELFY KADGESCSAS 250MMYQEGKFRY RRVAEGTQVL ELPFKGDDIT MVLILPKPEK SLAKVEKELT 300PEVLQEWLDE LEEMMLVVHM PRFRIEDGFS LKEQLQDMGL VDLFSPEKSK 350LPGIVAEGRD DLYVSDAFHK AFLEVNEEGS EAAASTAVVI AGRSLNPNRV 400TFKANRPFLV FIREVPLNTI IFMGRVANPC VK 432

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro8-128 21-95 247-430

Modified residue / Résidu modifié / Residuo modificadoS36

O-phosphonoSerO

CO2H

NH2H

PO

HO OH

Glycosylation sites (N) / Sites de glycosylation (N) / Posiciones de glicosilación (N)Asn-96 Asn-135 Asn-155 Asn-192

asudemotidum asudemotide human DEP domain-containing protein 1A-(294-302)-peptide

immunological agent for active immunization (antineoplastic)

asudémotide protéine 1A humaine contenant le domaine DEP-(294-302)-peptide agent immunologique d'immunisation active (antineoplasique)

asudemotida proteína 1A humana que contiene el dominio DEP-(294-302)-péptido agente inmunológico para inmunización activa (antineoplásico)

C58H80N10O17 1018833-53-8

H Glu Tyr Tyr Glu Leu Phe Val Asn Ile OH


162

auriclosenum auriclosene 2-(dichloroamino)-2-methylpropane-1-sulfonic acid

antimicrobial

auriclosène acide 2-(dichloroamino)-2-méthylpropane-1-sulfonique antimicrobien

auricloseno ácido 2-(dicloroamino)-2-metilpropano-1-sulfónico antimicrobiano

C4H9Cl2NO3S 846056-87-9

Cl

NCl

CH3H3C

SO3H

avatrombopagum avatrombopag 1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-

1-yl)-1,3-thiazol-2-yl]carbamoyl}pyridin-2-yl)piperidine-4-carboxylic acid thrombopoietin receptor agonist

avatrombopag acide 1-(3-chloro-5-{[4-(4-chlorothiophén-2-yl)- 5-(4-cyclohexylpipérazin-1-yl)-1,3-thiazol-2-yl]carbamoyl}pyridin- 2-yl)pipéridine-4-carboxylique agoniste du récepteur de la thrombopoïétine

avatrombopag ácido 1-(3-cloro-5-{[5-(4-ciclohexilpiperazin-1-il)-4-(4-clorotiofen-2-il)-1,3-tiazol-2-il]carbamoil}piridin-2-il)piperidina-4-carboxílico agonista de los receptores de trombopoyetina

C29H34Cl2N6O3S2 570406-98-3

N

N

S

N

NH

N

N

S

Cl

O

CO2H

Cl

balugrastimum # balugrastim human serum albumin (585 residues) fusion protein with

des-(1-alanine,37-valine,38-serine,39-glutamic acid)-human granulocyte colony-stimulating factor (pluripoietin) granulocyte colony stimulating factor

balugrastim albumine sérique humaine (585 résidus) protéine de fusion avec le dès-(1-alanine,37-valine,38-sérine,39-acide glutamique)-facteur de stimulation des colonies de granulocytes humain (pluripoïétine) facteur de stimulation des colonies de granulocytes


163

balugrastim albumina sérica humana (585 residuos) proteína de fusión con el des-(1-alanina,37-valina,38-serina,39-ácido glutámico)-factor humano estimulante de las colonias de granulocitos (pluripoyetina) factor estimulante de colonias de granulocitos

527698-09-5 DAHKSEVAHR FKDLGEENFK ALVLIAFAQY LQQCPFEDHV KLVNEVTEFA 50

KTCVADESAE NCDKSLHTLF GDKLCTVATL RETYGEMADC CAKQEPERNE 100CFLQHKDDNP NLPRLVRPEV DVMCTAFHDN EETFLKKYLY EIARRHPYFY 150APELLFFAKR YKAAFTECCQ AADKAACLLP KLDELRDEGK ASSAKQRLKC 200ASLQKFGERA FKAWAVARLS QRFPKAEFAE VSKLVTDLTK VHTECCHGDL 250LECADDRADL AKYICENQDS ISSKLKECCE KPLLEKSHCI AEVENDEMPA 300DLPSLAADFV ESKDVCKNYA EAKDVFLGMF LYEYARRHPD YSVVLLLRLA 350KTYETTLEKC CAAADPHECY AKVFDEFKPL VEEPQNLIKQ NCELFEQLGE 400YKFQNALLVR YTKKVPQVST PTLVEVSRNL GKVGSKCCKH PEAKRMPCAE 450DYLSVVLNQL CVLHEKTPVS DRVTKCCTES LVNRRPCFSA LEVDETYVPK 500EFNAETFTFH ADICTLSEKE RQIKKQTALV ELVKHKPKAT KEQLKAVMDD 550FAAFVEKCCK ADDKETCFAE EGKKLVAASQ AALGLTPLGP ASSLPQSFLL 600KCLEQVRKIQ GDGAALQEKL CATYKLCHPE ELVLLGHSLG IPWAPLSSCP 650SQALQLAGCL SQLHSGLFLY QGLLQALEGI SPELGPTLDT LQLDVADFAT 700TIWQQMEELG MAPALQPTQG AMPAFASAFQ RRAGGVLVAS HLQSFLEVSY 750RVLRHLAQP 759

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro53-62 75-91 90-101 124-169 168-177 200-246 245-253265-279 278-289 316-361 360-369 392-438 437-448 461-477476-487 514-559 558-567 621-627 649-659

baricitinibum baricitinib {1-(ethanesulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-

1-yl]azetidin-3-yl}ethanenitrile immunomodulator

baricitinib {1-(éthanesulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azétidin-3-yl}éthanenitrile immunomodulateur

baricitinib {1-(etanosulfonil)-3-[4-(7H-pirrolo[2,3-d]pirimidin-4-il)-1H-pirazol- 1-il]azetidin-3-il}etanonitrilo inmunomodulador

C16H17N7O2S 1187594-09-7

N

N

N N

CN

N

S CH3O

O

HN

bevenopranum bevenopran 5-[2-methoxy-4-({[2-(oxan-

4-yl)ethyl]amino}methyl)phenoxy]pyrazine-2-carboxamide μ-opioid receptor antagonist

bévénopran 5-[2-méthoxy-4-({[2-(oxan- 4-yl)éthyl]amino}méthyl)phénoxy]pyrazine-2-carboxamide antagoniste des récepteurs opioïdes μ

bevenoprán 5-[2-metoxi-4-({[2-(oxan-4-il)etil]amino}metil)fenoxi]pirazina- 2-carboxamida antagonista de los receptores μ de opiáceos


164

C20H26N4O4 676500-67-7

N

NNH2

O

O

OCH3

NH

O

bezlotoxumabum # bezlotoxumab immunoglobulin G1-kappa, anti-[Clostridium difficile toxin B)], Homo

sapiens monoclonal antibody; gamma1 heavy chain (1-449) [Homo sapiens VH (IGHV5-51*01 (94.90%) -(IGHD)-IGHJ3*02) [8.8.12] (1-119) -IGHG1*03 (120-449)], (222-215')-disulfide with kappa light chain (1'-215') [Homo sapiens V-KAPPA (IGKV3-20*01 (100.00%) -IGKJ1*01) [7.3.9] (1'-108') -IGKC*01 (109'-215')]; (228-228'':231-231'')-bisdisulfide dimer immunomodulator

bezlotoxumab immunoglobuline G1-kappa, anti-[Clostridium difficile toxine B)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-449) [Homo sapiens VH (IGHV5-51*01 (94.90%) -(IGHD)-IGHJ3*02) [8.8.12] (1-119) -IGHG1*03 (120-449)], (222-215')-disulfure avec la chaîne légère kappa (1'-215') [Homo sapiens V-KAPPA (IGKV3-20*01 (100.00%) -IGKJ1*01) [7.3.9] (1'-108') -IGKC*01 (109'-215')]; dimère (228-228'':231-231'')-bisdisulfure immunomodulateur

bezlotoxumab inmunoglobulina G1-kappa, anti-[toxina B de Clostridium difficile)], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-449) [Homo sapiens VH (IGHV5-51*01 (94.90%) -(IGHD)-IGHJ3*02) [8.8.12] (1-119) -IGHG1*03 (120-449)], (222-215')-disulfuro con la cadena ligera kappa (1'-215') [Homo sapiens V-KAPPA (IGKV3-20*01 (100.00%) -IGKJ1*01) [7.3.9] (1'-108') -IGKC*01 (109'-215')]; dímero (228-228'':231-231'')-bisdisulfuro inmunomodulador


EVQLVQSGAE VKKSGESLKI SCKGSGYSFT SYWIGWVRQM PGKGLEWMGI 50FYPGDSSTRY SPSFQGQVTI SADKSVNTAY LQWSSLKASD TAMYYCARRR 100NWGNAFDIWG QGTMVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200ICNVNHKPSN TKVDKRVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350YTLPPSREEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449

Light chain / Chaîne légère / Cadena ligeraEIVLTQSPGT LSLSPGERAT LSCRASQSVS SSYLAWYQQK PGQAPRLLIY 50GASSRATGIP DRFSGSGSGT DFTLTISRLE PEDFAVYYCQ QYGSSTWTFG 100QGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK 150VDNALQSGNS QESVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ 200GLSSPVTKSF NRGEC 215




165

birinapantum birinapant N,N'-[(6,6'-difluoro[1H,1'H-2,2'-biindole]-

3,3'-diyl)bis{methylene[(2R,4S)-4-hydroxypyrrolidine-2,1-diyl][(2S)-1-oxobutane-1,2-diyl} bis[(2S)-2-(methylamino)propanamide] antineoplastic

birinapant N,N'-[(6,6'-difluoro[1H,1'H-2,2'-biindole]- 3,3'-diyl)bis{méthylène[(2R,4S)-4-hydroxypyrrolidine-2,1-diyl][(2S)-1-oxobutane-1,2-diyl}]bis[(2S)-2-(méthylamino)propanamide] antinéoplasique

birinapant N,N'-[(6,6'-difluoro[1H,1'H-2,2'-biindol]-3,3'-diil)bis{metileno[(2R,4S)-4-hidroxiporrolidina-2,1-diil][(2S)-1-oxobutano-1,2-diilo}bis[(2S)-2-(metilamino)propanamida] antineoplásico

C42H56F2N8O6 1260251-31-7

H3C

HN

NH

O

N

HHO

HNH

NH

HO

H CH3

CH3

H3CNH

HN

O

N

HHO

H

HO

H CH3

CH3

F

F

blisibimodum # blisibimod B-cell activating factor (BAFF)-binding peptide fragment/human IgG1

Fc fusion protein; glycyl-L-cysteinyl-L-lysyl-L-tryptophyl-{[29-isoleucine(V>I),30-lysine(R>K),31-glutamine(H>Q)]human tumor necrosis factor (TNF) receptor superfamily member 13C (BAFF receptor, CD268)-(26-31)-peptidyl}-L-tryptophyl-L-valyl-L-cysteinyl-L-aspartyl-L-prolyl- L-leucylglycyl-L-serylglycyl-L-seryl-L-alanyl-L-threonylglycylglycyl- L-serylglycyl-L-seryl-L-threonyl-L-alanyl-L-seryl-L-serylglycyl- L-serylglycyl-L-seryl-L-alanyl-L-threonyl-L-histidyl-L-methionyl- L-leucyl-L-prolylglycyl-L-cysteinyl-L-lysyl-L-tryptophyl-{[29-isoleucine(V>I),30-lysine(R>K),31-glutamine(H>Q)]human tumor necrosis factor receptor superfamily member 13C (BAFF receptor, CD268)-(26-31)-peptidyl}-L-tryptophyl-L-valyl-L-cysteinyl-L-aspartyl- L-prolyl-L-leucylpentaglycyl-L-valyl-(human immunoglobulin heavy constant gamma 1 Fc-(6-232)-peptide) dimer (69-69':72-72')-bisdisulfide immunomodulator


166

blisibimod protéine de fusion entre le fragment Fc de l'immunoglobuline G1 humaine et un fragment du peptide se liant au facteur d'activation des cellules B (BAFF); glycyl-L-cystéinyl-L-lysyl-L-tryptophyl-{[29-isoleucine(V>I),30-lysine(R>K),31-glutamine(H>Q)]membre 13C de la superfamille des récepteurs humains du facteur de nécrose tumorale (TNF) (récepteur du BAFF, CD268)-(26-31)-peptidyl}-L-tryptophyl-L-valyl- L-cystéinyl-L-aspartyl-L-prolyl-L-leucylglycyl-L-serylglycyl-L-séryl- L-alanyl-L-thréonylglycylglycyl-L-sérylglycyl-L-séryl-L-thréonyl- L-alanyl-L-séryl-L-sérylglycyl-L-sérylglycyl-L-séryl-L-alanyl-L-thréonyl-L-histidyl-L-méthionyl-L-leucyl-L-prolylglycyl-L-cystéinyl-L-lysyl- L-tryptophyl-{[29-isoleucine(V>I),30-lysine(R>K),31-glutamine(H>Q)]membre 13C de la superfamille des récepteurs humains du TNF (récepteur du BAFF, CD268)-(26-31)-peptidyl}- L-tryptophyl-L-valyl-L-cystéinyl-L-aspartyl-L-prolyl-L-leucylpentaglycyl-L-valyl-(fragment Fc de la chaîne lourde gamma 1 de l'immunoglobuline humaine-(6-232)-peptide), (69-69':72-72')-bisdisulfure du dimère immunomodulateur

blisibimod proteína de fusión entre el fragmento Fc de la inmunoglobulina G1 humana y un fragmento del péptido que se une al factor de activación de las células B (BAFF); glicil-L-cisteinil-L-lisil-L-triptofil-{[29-isoleucina(V>I),30-lisina(R>K),31-glutamina(H>Q)]miembro 13C de la superfamilia de receptores humanos del TNF (receptor del BAFF, CD268)-(26-31)-peptidil}- L-triptofil-L-valil-L-cisteinil-L-aspartil-L-prolil-L-leucilglicil-L-serilglicil- L-seril-L-alanil-L-treonilglicilglicil-L-serilglicil-L-seril-L-treonil-L-alanil- L-seril-L-serilglicil-L-serilglicil-L-seril-L-alanil-L-treonil-L-histidil- L-metionil-L-leucil-L-prolilglicil-L-cisteinil-L-lisil-L-triptofil- {[29-isoleucina(V>I),30-lisina(R>K),31-glutamina(H>Q)]miembro 13C de la superfamilia de receptores humanos del TNF (receptor del BAFF, CD268)-(26-31)-peptidil}-L-triptofil-L-valil-L-cisteinil-L-aspartil-L-prolil-L-leucilpentaglicil-L-valil-(fragmento Fc de la cadena pesada gamma 1 de la inmunoglobulina humana-(6-232)-péptido), (69-69':72-72')-bisdisulfuro del dímero inmunomodulador

1236126-45-6 Monomer / Monomère / Monómero

GCKWDLLIKQ WVCDPLGSGS ATGGSGSTAS SGSGSATHML PGCKWDLLIK 50QWVCDPLGGG GGVDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMISRTP 100EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRVVSVLT 150VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSRDE 200LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY 250SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK 290

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro2-13 2'-13' 43-54 43'-54' 69-69' 72-72' 104-164 104'-164' 210-268 210'-268'

burlulipasum # burlulipase lipase (triacylglycerol lipase, EC-3.1.1.3) which amino acids

sequence is common to Burkholderia plantarii and Burkholderia glumae enzyme


167

burlulipase lipase (triacylglycérol lipase, EC-3.1.1.3) dont la séquence d'acides aminés est commune à Burkholderia plantarii et Burkholderia glumae enzyme

burlulipasa lipasa (triacilglicerol lipasa, EC-3.1.1.3) cuya secuencia de aminoácidos es comune a Burkholderia plantarii y Burkholderia glumae enzima

1261982-91-5 ADTYAATRYP VILVHGLAGT DKFANVVDYW YGIQSDLQSH GAKVYVANLS 50

GFQSDDGPNG RGEQLLAYVK QVLAATGATK VNLIGHSQGG LTSRYVAAVA 100PQLVASVTTI GTPHRGSEFA DFVQDVLKTD PTGLSSTVIA AFVNVFGTLV 150SSSHNTDQDA LAALRTLTTA QTATYNRNFP SAGLGAPGSC QTGAATETVG 200GSQHLLYSWG GTAIQPTSTV LGVTGATDTS TGTLDVANVT DPSTLALLAT 250GAVMINRASG QNDGLVSRCS SLFGQVISTS YHWNHLDEIN QLLGVRGANA 300EDPVAVIRTH VNRLKLQGV 319

Disulfide bridge location / Position du pont disulfure / Posición del puente disulfuro190-269

cebranopadolum cebranopadol trans-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-

3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indol]-4-amine analgesic

cébranopadol trans-6'-fluoro-N,N-diméthyl-4-phényl-4',9'-dihydro- 3'H-spiro[cyclohexane-1,1'-pyrano[3,4-b]indol]-4-amine analgésique

cebranopadol trans-4-fenil-6'-fluoro-N,N-dimetil-4',9'-dihidro- 3'H-espiro[ciclohexano-1,1'-pirano[3,4-b]indol]-4-amina analgésico

C24H27FN2O 863513-91-1 CH3

NH3C

OHN

F

cindunistatum cindunistat S-[2-(acetimidoylamino)ethyl]-2-methyl-L-cysteine

nitric oxide synthase inhibitor

cindunistat S-[2-(acétimidoylamino)éthyl]-2-méthyl-L-cystéine inhibiteur de la NO synthase

cindunistat S-[2-(acetimidoilamino)etil]-2-metil-L-cisteina inhibidor de la NO síntasa

C8H17N3O2S 364067-22-1

H3C NH

SCO2H

NH2H3CNH


168

clazakizumabum # clazakizumab immunoglobulin G1-kappa, anti-[Homo sapiens IL6 (interleukin 6,

IL-6)], humanized monoclonal antibody; gamma1 heavy chain (1-450) [humanized VH (Homo sapiens IGHV3-66*01 (83.50%) -(IGHD)-IGHJ3*02 M123>L (115)) [8.8.14] (1-120) -Homo sapiens IGHG1*03 CH2 N84.4>A (300) (121-450)], (223-217')-disulfide with kappa light chain (1'-217') [humanized V-KAPPA (Homo sapiens IGKV1-39*01 (89.10%) -IGKJ4*01) [6.3.12] (1'-110') -Homo sapiens IGKC*01 (111'-217')]; (229-229":232-232")-bisdisulfide dimer immunomodulator

clazakizumab immunoglobuline G1-kappa, anti-[Homo sapiens IL6 (interleukine 6, IL-6)], anticorps monoclonal humanisé; chaîne lourde gamma1 (1-450) [VH humanisé (Homo sapiens IGHV3-66*01 (83.50%) -(IGHD)-IGHJ3*02 M123>L (115)) [8.8.14] (1-120) -Homo sapiens IGHG1*03 CH2 N84.4>A (300) (121-450)], (223-217')-disulfure avec la chaîne légère kappa (1'-217') [V-KAPPA humanisé (Homo sapiens IGKV1-39*01 (89.10%) -IGKJ4*01) [6.3.12] (1'-110') -Homo sapiens IGKC*01 (111'-217')]; dimère (229-229":232-232")-bisdisulfure immunomodulateur

clazakizumab inmunoglobulina G1-kappa, anti-[IL6 de Homo sapiens (interleukina 6, IL-6)], anticuerpo monoclonal humanizado; cadena pesada gamma1 (1-450) [VH humanizado (Homo sapiens IGHV3-66*01 (83.50%) -(IGHD)-IGHJ3*02 M123>L (115)) [8.8.14] (1-120) -Homo sapiens IGHG1*03 CH2 N84.4>A (300) (121-450)], (223-217')-disulfuro con la cadena ligera kappa (1'-217') [V-KAPPA humanizado (Homo sapiens IGKV1-39*01 (89.10%) -IGKJ4*01) [6.3.12] (1'-110') -Homo sapiens IGKC*01 (111'-217')]; dímero (229-229":232-232")-bisdisulfuro inmunomodulador


EVQLVESGGG LVQPGGSLRL SCAASGFSLS NYYVTWVRQA PGKGLEWVGI 50IYGSDETAYA TSAIGRFTIS RDNSKNTLYL QMNSLRAEDT AVYYCARDDS 100SDWDAKFNLW GQGTLVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK 150DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT 200YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP 250KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYA 300STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ 350VYTLPPSREE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV 400LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK 450

Light chain / Chaîne légère / Cadena ligeraAIQMTQSPSS LSASVGDRVT ITCQASQSIN NELSWYQQKP GKAPKLLIYR 50ASTLASGVPS RFSGSGSGTD FTLTISSLQP DDFATYYCQQ GYSLRNIDNA 100FGGGTKVEIK RTVAAPSVFI FPPSDEQLKS GTASVVCLLN NFYPREAKVQ 150WKVDNALQSG NSQESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT 200HQGLSSPVTK SFNRGEC 217


N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilaciónNone : H CH2 N84.4>A


169

cobimetinibum cobimetinib [3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]{3-hydroxy-

3-[(2S)-piperidin-2-yl]azetidin-1-yl}methanone antineoplastic

cobimétinib [3,4-difluoro-2-(2-fluoro-4-iodoanilino)phényl]{3-hydroxy- 3-[(2S)-pipéridin-2-yl]azétidin-1-yl}méthanone antinéoplasique

cobimetinib [3,4-difluoro-2-(2-fluoro-4-iodoanilino)fenil]{3-hidroxi- 3-[(2S)-piperidin-2-il]azetidin-1-il}metanona antineoplásico

C21H21F3IN3O2 934660-93-2

NH

NO

F

F

F

I

OH

NHH

crisantaspasum # crisantaspase L-asparaginase (EC 3.5.1.1, L-asparagine amidohydrolase) Erwinia

chrysanthemi tetramer α4 antineoplastic

crisantaspase L-asparaginase (EC 3.5.1.1, L-asparagine amidohydrolase) Erwinia chrysanthemi, tétramère α4 antinéoplasique

crisantaspasa L-asparaginasa (EC 3.5.1.1, L-asparagina amidohidrolasa) de Erwinia chrysanthemi, tetrámero α4 antineoplásico

1349719-22-7 Monomer / Monomère / Monómero

ADKLPNIVIL ATGGTIAGSA ATGTQTTGYK AGALGVDTLI AVPEVKKLA 50NVKGEQFSNM ASENMTGDVV LKLSQRVNEL LARDDVDGVV ITHGTDTVEE 100SAYFLHLTVK SDKPVVFVAA MRPATAISAD GPMNLLEAVR VAGDKQSRGR 150GVMVVLNDRI GSARYITKTN ASTLDTFKAN EEGYLGVIIG NRIYYQNRID 200KLHTTRSVFD VRGLTSLPKV DILYGYQDDP EYLYDAAIQH GVKGIVYAGM 250GAGSVSVRGI AGMRKAMEKG VVVIRSTRTG NGIVPPDEEL PGLVSDSLNP 300AHARILLMLA LTRTSDPKVI QEYFHTY 327

dactolisibum dactolisib 2-methyl-2-(4-{3-methyl-2-oxo-8-(quinolin-3-yl)-

2,3-dihydroimidazo[4,5-c]quinolin-1-yl}phenyl)propanenitrile antineoplastic

dactolisib 2-méthyl-2-{4-[3-méthyl-2-oxo-8-(quinoléin-3-yl)- 2,3-dihydroimidazo[4,5-c]quinoléin-1-yl]phényl}propanenitrile antinéoplasique

dactolisib 2-metil-2-(4-{3-metil-2-oxo-8-(quinolin-3-il)-2,3-dihidroimidazo[4,5-c]quinolin-1-il}fenil)propanonitrilo antineoplásico


170

C30H23N5O 915019-65-7

N

N

NN

O

CH3

CNH3C

H3C

danirixinum danirixin 1-(4-chloro-2-hydroxy-3-{[(3S)-piperidine-3-sulfonyl]phenyl}-

3-(3-fluoro-2-methylphenyl)urea interleukin 8 inhibitor

danirixine 1-(4-chloro-2-hydroxy-3-{[(3S)-pipéridine-3-sulfonyl]phényl}- 3-(3-fluoro-2-méthylphényl)urée inhibiteur de l'interleukine 8

danirixina 1-(4-cloro-2-hidroxi-3-{[(3S)-piperidina-3-sulfonil]fenil}-3-(3-fluoro- 2-metilfenil)urea inhibidor de la interleukina 8

C19H21ClFN3O4S 954126-98-8

NH

NH

OH3C

F

OH

S

ClHN

O O

H

demcizumabum # demcizumab immunoglobulin G2-kappa, anti-[Homo sapiens DLL4 (delta-like 4)],

humanized monoclonal antibody; gamma2 heavy chain (1-444) [humanized VH (Homo sapiens IGHV1-18*01 (85.70%) -(IGHD)-IGHJ6*01 T123>L (114) [8.8.12] (1-119) -Homo sapiens IGHG2*01 CHS K2>del (120-444)], (133-218')-disulfide with kappa light chain (1'-218') [humanized V-KAPPA (Homo sapiens IGKV4-1*01 (76.20%) -IGKJ1*01 Q120>G (104)) [10.3.9] (1'-111') -Homo sapiens IGKC*01 (112'-218')]; (221-221":222-222":225-225":228-228")-tetrakisdisulfide dimer immunomodulator, antineoplastic

demcizumab immunoglobuline G2-kappa, anti-[Homo sapiens DLL4 (delta-like 4)], anticorps monoclonal humanisé; chaîne lourde gamma2 (1-444) [VH humanisé (Homo sapiens IGHV1-18*01 (85.70%) -(IGHD)-IGHJ6*01 T123>L (114) [8.8.12] (1-119) -Homo sapiens IGHG2*01 CHS K2>del (120-444)], (133-218')-disulfure avec la chaîne légère kappa (1'-218') [V-KAPPA humanisé (Homo sapiens IGKV4-1*01 (76.20%) -IGKJ1*01 Q120>G (104)) [10.3.9] (1'-111') -Homo sapiens IGKC*01 (112'-218')]; dimère (221-221":222-222":225-225":228-228")-tétrakisdisulfure immunomodulateur, antinéoplasique


171

demcizumab inmunoglobulina G2-kappa, anti-[DLL4 (delta-like 4) de Homo sapiens ], anticuerpo monoclonal humanizado; cadena pesada gamma2 (1-444) [VH humanizado (Homo sapiens IGHV1-18*01 (85.70%) -(IGHD)-IGHJ6*01 T123>L (114) [8.8.12] (1-119) -Homo sapiens IGHG2*01 CHS K2>del (120-444)], (133-218')-disulfuro con la cadena ligera kappa (1'-218') [V-KAPPA humanizado (Homo sapiens IGKV4-1*01 (76.20%) -IGKJ1*01 Q120>G (104)) [10.3.9] (1'-111') -Homo sapiens IGKC*01 (112'-218')]; dímero (221-221":222-222":225-225":228-228")-tetrakisdisulfuro inmunomodulador, antineoplásico


QVQLVQSGAE VKKPGASVKI SCKASGYSFT AYYIHWVKQA PGQGLEWIGY 50ISSYNGATNY NQKFKGRVTF TTDTSTSTAY MELRSLRSDD TAVYYCARDY 100DYDVGMDYWG QGTLVTVSSA STKGPSVFPL APCSRSTSES TAALGCLVKD 150YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSNFGTQTY 200TCNVDHKPSN TKVDKTVERK CCVECPPCPA PPVAGPSVFL FPPKPKDTLM 250ISRTPEVTCV VVDVSHEDPE VQFNWYVDGV EVHNAKTKPR EEQFNSTFRV 300VSVLTVVHQD WLNGKEYKCK VSNKGLPAPI EKTISKTKGQ PREPQVYTLP 350PSREEMTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPMLDSDG 400SFFLYSKLTV DKSRWQQGNV FSCSVMHEAL HNHYTQKSLS LSPG 444

Light chain / Chaîne légère / Cadena ligeraDIVMTQSPDS LAVSLGERAT ISCRASESVD NYGISFMKWF QQKPGQPPKL 50LIYAASNQGS GVPDRFSGSG SGTDFTLTIS SLQAEDVAVY YCQQSKEVPW 100TFGGGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV 150QWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV 200THQGLSSPVT KSFNRGEC 218

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H 22-96 146-202 259-319 365-423 22''-96'' 146''-202'' 259''-319'' 365''-423''Intra-L 23'-92' 138'-198' 23'''-92''' 138'''-198''' Inter-H-L 133-218' 133''-218''' Inter-H-H 221-221'' 222-222'' 225-225'' 228-228''


duligotumabum # duligotumab immunoglobulin G1-kappa, anti-[Homo sapiens ERBB3 (receptor

tyrosine-protein kinase erbB-3, HER3)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-451) [Homo sapiens VH (IGHV3-74*01 (82.70%) -(IGHD)-IGHJ4*01) [8.8.14] (1-121) -IGHG1*03 CH1 R120>K (218) (122-451)], (224-214')-disulfide with kappa light chain (1'-214') [Homo sapiens V-KAPPA (IGKV1-39*01 (87.40%) -IGKJ2*01 L124>V (104)) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; (230-230'':233-233'')-bisdisulfide dimer immunomodulator, antineoplastic

duligotumab immunoglobuline G1-kappa, anti-[Homo sapiens ERBB3 (récepteur tyrosine-protéine kinase erbB3, HER3)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-451) [Homo sapiens VH (IGHV3-74*01 (82.70%) -(IGHD)-IGHJ4*01) [8.8.14] (1-121) -IGHG1*03 CH1 R120>K (218) (122-451)], (224-214')-disulfure avec la chaîne légère kappa (1'-214') [Homo sapiens V-KAPPA (IGKV1-39*01 (87.40%) -IGKJ2*01 L124>V (104)) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dimère (230-230'':233-233'')-bisdisulfure immunomodulateur, antinéoplasique


172

duligotumab inmunoglobulina G1-kappa, anti-[ERBB3 de Homo sapiens (tirosina proteína-kinasa receptora erbB3, HER3)], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-451) [Homo sapiens VH (IGHV3-74*01 (82.70%) -(IGHD)-IGHJ4*01) [8.8.14] (1-121) -IGHG1*03 CH1 R120>K (218) (122-451)], (224-214')-disulfuro con la cadena ligera kappa (1'-214') [Homo sapiens V-KAPPA (IGKV1-39*01 (87.40%) -IGKJ2*01 L124>V (104)) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dímero (230-230'':233-233'')-bisdisulfuro inmunomodulador, antineoplásico


EVQLVESGGG LVQPGGSLRL SCAASGFTLS GDWIHWVRQA PGKGLEWVGE 50ISAAGGYTDY ADSVKGRFTI SADTSKNTAY LQMNSLRAED TAVYYCARES 100RVSFEAAMDY WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV 150KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ 200TYICNVNHKP SNTKVDKKVE PKSCDKTHTC PPCPAPELLG GPSVFLFPPK 250PKDTLMISRT PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY 300NSTYRVVSVL TVLHQDWLNG KEYKCKVSNK ALPAPIEKTI SKAKGQPREP 350QVYTLPPSRE EMTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP 400VLDSDGSFFL YSKLTVDKSR WQQGNVFSCS VMHEALHNHY TQKSLSLSPG 450K 451

Light chain / Chaîne légère / Cadena ligeraDIQMTQSPSS LSASVGDRVT ITCRASQNIA TDVAWYQQKP GKAPKLLIYS 50ASFLYSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ SEPEPYTFGQ 100GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200LSSPVTKSFN RGEC 214



elubrixinum elubrixin 1-(2-chloro-3-fluorophenyl)-3-[4-chloro-2-hydroxy-3-(piperazine-

1-sulfonyl)phenyl]urea interleukin 8 inhibitor

élubrixine 1-(2-chloro-3-fluorophényl)-3-[4-chloro-2-hydroxy-3-(pipérazine- 1-sulfonyl)phényl]urée inhibiteur de l'interleukine 8

elubrixina 1-(2-cloro-3-fluorofenil)-3-[4-cloro-2-hidroxi-3-(piperazina- 1-sulfonil)fenil]urea inhibidor de la interleukina 8

C17H17Cl2FN4O4S 688763-64-6

NH

O

OH

SN

Cl

O O

HN

NH

Cl

F


173

empegfilgrastimum # empegfilgrastim [1-(N-{4-[ω-methoxypoly(oxyethylene)]butyl}-L-methionine)]human

granulocyte colony-stimulating factor (pluripoietin) granulocyte colony stimulating factor

empegfilgrastim [1-(N-{4-[ω-méthoxypoly(oxyéthylène)]butyl}-L-méthionine)]facteur de stimulation des colonies de granulocytes humain (pluripoïétine) facteur de stimulation des colonies de granulocytes

empegfilgrastim [1-(N-{4-[ω-metoxipoli(oxietileno)]butil}-L-metionina)]factor humano de estimulación de las colonias de granulocitos (pluripoyetina) factor estimulante de las colonias de granulocitos

1192706-53-8 MTPLGPASSL PQSFLLKCLE QVRKIQGDGA ALQEKLCATY KLCHPEELVL 50

LGHSLGIPWA PLSSCPSQAL QLAGCLSQLH SGLFLYQGLL QALEGISPEL 100GPTLDTLQLD VADFATTIWQ QMEELGMAPA LQPTQGAMPA FASAFQRRAG 150GVLVASHLQS FLEVSYRVLR HLAQP 175

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro37-43 65-75

Modified residue / Résidu modifié / Residuo modificadoM1PEG-Met

NH

CO2H

H

OO

H3Cn

S CH3

enobosarmum enobosarm (2S)-3-(4-cyanophenoxy)-N-[4-cyano-3-(trifluoromethyl)phenyl]-

2-hydroxy-2- methylpropanamide androgen receptor agonist

énobosarm (2S)-3-(4-cyanophénoxy)-N-[4-cyano-3-(trifluorométhyl)phényl]- 2-hydroxy-2-méthylpropanamide agoniste des récepteurs androgéniques

enobosarm (2S)-3-(4-cianofenoxi)-N-[4-ciano-3-(trifluorometil)fenil]-2-hidroxi- 2-metilpropanamida agonista de los receptores androgénicos

C19H14F3N3O3 841205-47-8

HN

O

CF3

CN

O

CH3HO

NC

enoticumabum # enoticumab immunoglobulin G1-kappa, anti-[Homo sapiens DLL4 (delta-like 4)],

Homo sapiens monoclonal antibody; gamma1 heavy chain (1-452) [Homo sapiens VH (IGHV3-33*01 (90.80%) -(IGHD)-IGHJ5*02) [8.8.16] (1-123) -IGHG1*01 CHS K2>del (124-452)], (226-214')-disulfide with kappa light chain (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (98.90%) -IGKJ4*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; (232-232'':235-235'')-bisdisulfide dimer immunomodulator, antineoplastic


174

énoticumab immunoglobuline G1-kappa, anti-[Homo sapiens DLL4 (delta-like 4)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-452) [Homo sapiens VH (IGHV3-33*01 (90.80%) -(IGHD)-IGHJ5*02) [8.8.16] (1-123) -IGHG1*01 CHS K2>del (124-452)], (226-214')-disulfure avec la chaîne légère kappa (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (98.90%) -IGKJ4*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dimère (232-232'':235-235'')-bisdisulfure immunomodulateur, antinéoplasique

enoticumab inmunoglobulina G1-kappa, anti-[Homo sapiens DLL4 (delta-like 4)], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-452) [Homo sapiens VH (IGHV3-33*01 (90.80%) -(IGHD)-IGHJ5*02) [8.8.16] (1-123) -IGHG1*01 CHS K2>del (124-452)], (226-214')-disulfuro con la cadena ligera kappa (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (98.90%) -IGKJ4*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dímero (232-232'':235-235'')-bisdisulfuro inmunomodulador, antineoplásico


QVQLVESGGG VVQPGRSLRL SCAASGFTFS SYGMHWVRQA PGKGLEWVSF 50LWYDGTNKNY VESVKGRFTI SRDNSKNMLY LEMNSLRAED TAVYYCARDH 100DFRSGYEGWF DPWGQGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC 150LVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG 200TQTYICNVNH KPSNTKVDKK VEPKSCDKTH TCPPCPAPEL LGGPSVFLFP 250PKPKDTLMIS RTPEVTCVVV DVSHEDPEVK FNWYVDGVEV HNAKTKPREE 300QYNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKALPAPIEK TISKAKGQPR 350EPQVYTLPPS RDELTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT 400PPVLDSDGSF FLYSKLTVDK SRWQQGNVFS CSVMHEALHN HYTQKSLSLS 450PG 452

Light chain / Chaîne légère / Cadena ligeraEIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKP GQAPRLLIYD 50ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQH RSNWPPTFGG 100GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200LSSPVTKSFN RGEC 214



ensereptidum ensereptide acetyl(human lactotransferrin-(15-39)-peptidamide)

cicatrisation promoter

enséreptide acétyl(lactotransferrine humaine-(15-39)-peptidamide) promoteur de cicatrisation

ensereptida acetil(lactotransferrina humana-(15-39)-peptidamida) promotor de cicatrización


175

254433-51-7

NH

O

H

H3C

OCO2H

NH

O

H

NH2

HN

NH2

NH

EATKCFQWQR NMRKVRGPPV SCIKR 25

Disulfide bridge location / Position du pont disulfure / Posición del puente disulfuro5 - 22

Modified residues / Résidus modifiés / Residuos modificados

E1

Ac-Glu

R25

Arg-NH2

enzalutamidum enzalutamide 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-

2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide antineoplastic

enzalutamide 4-{3-[4-cyano-3-(trifluorométhyl)phényl]-5,5-diméthyl-4-oxo- 2-sulfanylidèneimidazolidin-1-yl}-2-fluoro-N-méthylbenzamide antinéoplasique

enzalutamida 4-{3-[4-ciano-3-(trifluorometil)fenil]-5,5-dimetil-4-oxo- 2-sulfanilidenoimidazolidin-1-il}-2-fluoro-N-metilbenzamida antineoplásico

C21H16F4N4O2S 915087-33-1

NN

NH

O F

S

OH3CCH3

CF3

CNH3C

ertugliflozinum ertugliflozin (1S,2S,3S,4R,5S)-5-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-

1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol antidiabetic

ertugliflozine (1S,2S,3S,4R,5S)-5-{4-chloro-3-[(4-éthoxyphényl)méthyl]phényl}- 1-(hydroxyméthyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol antidiabétique

ertugliflozina (1S,2S,3S,4R,5S)-5-{4-cloro-3-[(4-etoxifenil)metil]fenil}- 1-(hidroximetil)-6,8-dioxabiciclo[3.2.1]octane-2,3,4-triol hipoglucemiante


176

C22H25ClO7 1210344-57-2

O

O

OH

OH

HO

HO

O

Cl

CH3

etirinotecanum pegolum etirinotecan pegol tetrakis{(4S)-9-([1,4'-bipiperidine]-1'-carbonyloxy)-4,11-diethyl-

3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3’,4’:6,7]indolizino[1,2-b]quinolin-4-yl} N,N′,N′′,N′′′-{methanetetrayltetrakis[methylenepoly(oxyethylene)oxy (1-oxoethylene)]}tetraglycinate antineoplastic

étirinotécan pégol N,N',N'',N'''-{méthanetétrayltétrakis[méthylènepoly(oxyéthylène)oxy (1-oxoéthylène)]}tétraglycinate de tétrakis{(4S)-9-([1,4'-bipipéridine]- 1'-carbonyloxy]-4,11-diéthyl-3,14-dioxo-3,4,12,14-tétrahydro- 1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoléin-4-yle} antinéoplasique

etirinotecán pegol N,N',N'',N'''-{metanotetrailtetrakis[metilenepoli(oxietilene)oxi (1-oxoetileno)]}tetraglicinato de tetrakis{(4S)-9-([1,4'-bipiperidina]- 1'-carboniloxi]-4,11-dietil-3,14-dioxo-3,4,12,14-tetrahidro- 1H-pirano[3',4':6,7]indolizino[1,2-b]quinolin-4-ilo} antineoplásico

C153H176N20O36 [C8H16O4]n 848779-32-8

O

N O

N

O

O

O CH3

O HN

OO

R=

CH3

O

N

N

O

O O

O

n n

n n

R

R

R

R


177

evogliptinum evogliptin (3R)-4-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-

3-(tert-butoxymethyl)piperazin-2-one antidiabetic

évogliptine (3R)-4-[(3R)-3-amino-4-(2,4,5-trifluorophényl)butanoyl]- 3-(tert-butoxyméthyl)pipérazin-2-one antidiabétique

evogliptina (3R)-4-[(3R)-3-amino-4-(2,4,5-trifluorofenil)butanoil]- 3-(terc-butoximetil)piperazin-2-ona hipoglucemiante

C19H26F3N3O3 1222102-29-5

N

HN O

O CH3

H3C CH3

NH2H

F

F

F

O

H

fasiglifamum fasiglifam [(3S)-6-({(2',6'-dimethyl-4'-[3-(methanesulfonyl)propoxy]-[1,1'-

biphenyl]-3-yl)}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid antidiabetic

fasiglifam acide [(3S)-6-({(2',6'-diméthyl-4'-[3-(méthanesulfonyl)propoxy]-[1,1'-biphényl]-3-yl)}méthoxy)-2,3-dihydro-1-benzofuran-3-yl]acétique antidiabétique

fasiglifam ácido [(3S)-6-({(2',6'-dimetil-4'-[3-(metanosulfonil)propoxi]-[1,1'-bifenil]-3-il)}metoxi)-2,3-dihidro-1-benzofuran-3-il]acético hipoglucemiante

C29H32O7S 1000413-72-8 O

H

O

OSH3C CO2H

CH3

CH3

OO

fasinumabum # fasinumab immunoglobulin G4-kappa, anti-[Homo sapiens NGF (nerve growth

factor, nerve growth factor beta polypeptide, NGFB, beta-NGF)], Homo sapiens monoclonal antibody; gamma4 heavy chain (1-446) [Homo sapiens VH (IGHV1-24*01 (95.90%) -(IGHD)-IGHJ5*01) [8.8.12] (1-119) -IGHG4*01 hinge S10>P (227) (120-446)], (133-214')-disulfide with kappa light chain (1'-214') [Homo sapiens V-KAPPA (IGKV1-17*01 (90.50%) -IGKJ1*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; (225-225'':228-228'')-bisdisulfide dimer immunomodulator, analgesic


178

fasinumab immunoglobuline G4-kappa, anti-[Homo sapiens NGF (facteur de croissance du nerf, facteur de croissance du nerf polypeptide bêta, NGFB, bêta-NGF)], Homo sapiens anticorps monoclonal; chaîne lourde gamma4 (1-446) [Homo sapiens VH (IGHV1-24*01 (95.90%) -(IGHD)-IGHJ5*01) [8.8.12] (1-119) -IGHG4*01 charnière S10>P (227) (120-446)], (133-214')-disulfure avec la chaîne légère kappa (1'-214') [Homo sapiens V-KAPPA (IGKV1-17*01 (90.50%) -IGKJ1*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dimère (225-225'':228-228'')-bisdisulfure immunomodulateur, analgésique

fasinumab inmunoglobulina G4-kappa, anti-[NGF de Homo sapiens (factor de crecimiento neuronal, factor de crecimiento neuronal polipéptido beta, NGFB, beta-NGF)], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma4 (1-446) [Homo sapiens VH (IGHV1-24*01 (95.90%) -(IGHD)-IGHJ5*01) [8.8.12] (1-119) -IGHG4*01 bisagra S10>P (227) (120-446)], (133-214')-disulfuro con la cadena ligera kappa (1'-214') [Homo sapiens V-KAPPA (IGKV1-17*01 (90.50%) -IGKJ1*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dímero (225-225'':228-228'')-bisdisulfuro inmunomodulador, analgésico


QVQLVQSGAE VKKPGASVKV SCKVSGFTLT ELSIHWVRQA PGKGLEWMGG 50FDPEDGETIY AQKFQGRVTM TEDTSTDTAY MELTSLRSED TAVYYCSTIF 100GVVTNFDNWG QGTLVTVSSA STKGPSVFPL APCSRSTSES TAALGCLVKD 150YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTKTY 200TCNVDHKPSN TKVDKRVESK YGPPCPPCPA PEFLGGPSVF LFPPKPKDTL 250MISRTPEVTC VVVDVSQEDP EVQFNWYVDG VEVHNAKTKP REEQFNSTYR 300VVSVLTVLHQ DWLNGKEYKC KVSNKGLPSS IEKTISKAKG QPREPQVYTL 350PPSQEEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD 400GSFFLYSRLT VDKSRWQEGN VFSCSVMHEA LHNHYTQKSL SLSLGK 446

Light chain / Chaîne légère / Cadena ligeraDIQMTQSPSS LSASAGDRVT ITCRASQAIR NDLGWYQQKP GKAPKRLIYA 50AFNLQSGVPS RFSGSGSGTE FTLTISSLQP EDLASYYCQQ YNRYPWTFGQ 100GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200LSSPVTKSFN RGEC 214



firtecanum pegolum firtecan pegol tetrakis[(4S)-4,11-diethyl-9-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-

1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl] N,N’,N’’,N’’’-(oxybis{(propane-3,1,2-triyl)bis[poly(oxyethylene)oxy(1-oxoethylene)]})tetraglycinate antineoplastic

firtécan pégol N,N',N'',N'''-(oxybis{(propane-3,1,2-triyl)bis[poly(oxyéthylène)oxy(1-oxoéthylène)]})tétraglycinate de tétrakis[(4S)-4,11-diéthyl-9-hydroxy-3,14-dioxo-3,4,12,14-tétrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinoléin-4-yle] antinéoplasique


179

firtecán pegol N,N',N'',N'''-(oxibis{(propano-3,1,2-triil)bis[poli(oxietileno)oxi(1-

oxoetileno)]})tetraglicinato de tetrakis[(4S)-4,11-dietil-9-hidroxi- 3,14-dioxo-3,4,12,14-tetrahidro-1H-pirano[3',4':6,7]indolizino[1,2-b]quinolin-4-ilo] antineoplásico

C110H106N12O33 (C2H4O)4n 946062-05-1

O

N O

N

O

O

O CH3

O HN

O

H3C

HO

R=

OO

R

OR

O

OR

R n

n

n

n

fluralanerum fluralaner 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-

3-yl]-2-methyl-N-{2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl}benzamide antiparasitic (veterinary use)

fluralaner 4-[(5RS)-5-(3,5-dichlorophényl)-5-(trifluorométhyl)-4,5-dihydro- 1,2-isoxazol-3-yl]-2-méthyl-N-{2-oxo-2-[(2,2,2-trifluoroéthyl)amino]éthyl}benzamide antiparasitaire (usage vétérinaire)

fluralaner 4-[5-(3,5-diclorofenil)-5-(trifluorometil)-4,5-dihidro-1,2-oxazol-3-il]- 2-metil-N-{2-oxo-2-[(2,2,2-trifluoroetil)amino]etil}benzamida antiparasitario (uso veterinario)

C22H17Cl2F6N3O3 864731-61-3

and enantiomeret énantiomèrey enantiómero

CH3

HN

NH

CF3

O

O

NOF3C

Cl

Cl

futuximabum # futuximab immunoglobulin G1-kappa, anti-[Homo sapiens EGFR (epidermal

growth factor receptor, ERBB1, HER1) domain III], chimeric monoclonal antibody; gamma1 heavy chain (1-452) [Mus musculus VH (IGHV1S5*01 -(IGHD)-IGHJ4*01) [8.8.16] (1-123) -Homo sapiens IGHG1*03 CHS K2>del (124-452)], (226-214')-disulfide with kappa light chain (1'-214') [Mus musculus V-KAPPA (IGKV10-96*01 -IGKJ1*02) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; (232-232'':235-235'')-bisdisulfide dimer immunomodulator, antineoplastic


180

futuximab immunoglobuline G1-kappa, anti-[Homo sapiens EGFR (récepteur

du facteur de croissance épidermique ERBB1, HER1) domaine III], anticorps monoclonal chimérique; chaîne lourde gamma1 (1-452) [Mus musculus VH (IGHV1S5*01 -(IGHD)-IGHJ4*01) [8.8.16] (1-123) -Homo sapiens IGHG1*03 CHS K2>del (124-452)], (226-214')-disulfure avec la chaîne légère kappa (1'-214') [Mus musculus V-KAPPA (IGKV10-96*01 -IGKJ1*02) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dimère (232-232'':235-235'')-bisdisulfure immunomodulateur, antinéoplasique

futuximab inmunoglobulina G1-kappa, anti-[EGFR de Homo sapiens (receptor del factor de crecimiento epidérmico ERBB1, HER1) dominio III], anticuerpo monoclonal quimérico; cadena pesada gamma1 (1-452) [Mus musculus VH (IGHV1S5*01 -(IGHD)-IGHJ4*01) [8.8.16] (1-123) -Homo sapiens IGHG1*03 CHS K2>del (124-452)], (226-214')-disulfuro con la cadena ligera kappa (1'-214') [Mus musculus V-KAPPA (IGKV10-96*01 -IGKJ1*02) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dímero (232-232'':235-235'')-bisdisulfuro inmunomodulador, antineoplásico


EVQLQQPGSE LVRPGASVKL SCKASGYTFT SYWMHWVKQR PGQGLEWIGN 50IYPGSRSTNY DEKFKSKATL TVDTSSSTAY MQLSSLTSED SAVYYCTRNG 100DYYVSSGDAM DYWGQGTSVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC 150LVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG 200TQTYICNVNH KPSNTKVDKR VEPKSCDKTH TCPPCPAPEL LGGPSVFLFP 250PKPKDTLMIS RTPEVTCVVV DVSHEDPEVK FNWYVDGVEV HNAKTKPREE 300QYNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKALPAPIEK TISKAKGQPR 350EPQVYTLPPS REEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT 400PPVLDSDGSF FLYSKLTVDK SRWQQGNVFS CSVMHEALHN HYTQKSLSLS 450PG 452

Light chain / Chaîne légère / Cadena ligeraDIQMTQTTSS LSASLGDRVT ISCRTSQDIG NYLNWYQQKP DGTVKLLIYY 50TSRLHSGVPS RFSGSGSGTD FSLTINNVEQ EDVATYFCQH YNTVPPTFGG 100GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200LSSPVTKSFN RGEC 214


N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilaciónH CH2 84.4: 303, 303''

giminabantum giminabant 3-chloro-4-{(2R)-2-(4-chlorophenyl)-4-[(1R)-1-(4-

cyanophenyl)ethyl]piperazin-1-yl}benzonitrile cannabinoid receptor antagonist (veterinary use)

giminabant 3-chloro-4-{(2R)-2-(4-chlorophényl)-4-[(1R)-1-(4-cyanophényl)éthyl]pipérazin-1-yl}benzonitrile antagoniste des récepteurs aux cannabinoïdes (usage vétérinaire)


181

giminabant 3-cloro-4-{(2R)-2-(4-clorofenil)-4-[(1R)-1-(4-cianofenil)etil]piperazin-1-il}benzonitrilo antagonista del receptor de cannabinoides (uso veterinario)

C26H22Cl2N4 890033-57-5

N

N

H CH3

H

CN

Cl

NC

Cl

golvatinibum golvatinib N-[2-fluoro-4-({2-[4-(4-methylpiperazin-1-yl)piperidine-

1-carboxamido]pyridin-4-yl}oxy)phenyl]- N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide antineoplastic

golvatinib N-[2-fluoro-4-({2-[4-(4-méthylpipérazin-1-yl)pipéridine- 1-carboxamido]pyridin-4-yl}oxy)phényl]- N'-(4-fluorophényl)cyclopropane-1,1-dicarboxamide antinéoplasique

golvatinib N-[2-fluoro-4-({2-[4-(4-metilpiperazin-1-il)piperidina- 1-carboxamido]piridin-4-il}oxi)fenil]-N'-(4-fluorofenil)ciclopropano- 1,1-dicarboxamida antineoplásico

C33H37F2N7O4 928037-13-2

O

NH

NH

FO O

F

N

HNN

O

N

NH3C

ibrutinibum ibrutinib 1-{(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-

d]pyrimidin-1-yl]piperidin-1-yl}prop-2-en-1-one antineoplastic

ibrutinib 1-{(3R)-3-[4-amino-3-(4-phénoxyphényl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]pipéridin-1-yl}prop-2-én-1-one antinéoplasique

ibrutinib 1-{(3R)-3-[4-amino-3-(4-fenoxifenil)-1H-pirazolo[3,4-d]pirimidin- 1-il]piperidin-1-il}prop-2-en-1-ona antineoplásico


182

C25H24N6O2 936563-96-1

NCH2

O

N

HN

NN

O

H2N

idelalisibum idelalisib 5-fluoro-3-phenyl-2-{(1S)-1-[(7H-purin-6-yl)amino]propyl}quinazolin-

4(3H)-one antineoplastic

idélalisib 5-fluoro-3-phényl-2-[(1S)-1-(7H-purin-6-ylamino)propyl]quinazolin-4(3H)-one antinéoplasique

idelalisib 5-fluoro-3-fenil-2-[(1S)-1-(7H-purin-6-ilamino)propil]quinazolin- 4(3H)-ona antineoplásico

C22H18FN7O 870281-82-6

N

N

OF

NH

H

N

N

N

HNH3C

imgatuzumabum # imgatuzumab immunoglobulin G1-kappa, anti-[Homo sapiens EGFR (epidermal

growth factor receptor, ERBB1, HER1)], humanized monoclonal antibody; gamma1 heavy chain (1-449) [humanized VH (Homo sapiens IGHV1-46*01 (83.70%) -(IGHD)-IGHJ6*01) [8.8.13] (1-120) -Homo sapiens IGHG1*01 CHS K2>del (121-449)], (223-213')-disulfide with kappa light chain (1'-213') [humanized V-KAPPA (Homo sapiens IGKV1-17*01 (90.50%) -IGKJ2*01) [6.3.8] (1'-106') -Homo sapiens IGKC*01 (107'-213"')]; (229-229":232-232")-bisdisulfide dimer immunomodulator, antineoplastic

imgatuzumab immunoglobuline G1-kappa, anti-[Homo sapiens EGFR (récepteur du facteur de croissance épidermique ERBB1, HER1)], anticorps monoclonal humanisé; chaîne lourde gamma1 (1-449) [VH humanisé (Homo sapiens IGHV1-46*01 (83.70%) -(IGHD)-IGHJ6*01) [8.8.13] (1-120) -Homo sapiens IGHG1*01 CHS K2>del (121-449)], (223-213')-disulfure avec la chaîne légère kappa (1'-213') [V-KAPPA humanisé (Homo sapiens IGKV1-17*01 (90.50%) -IGKJ2*01) [6.3.8] (1'-106') -Homo sapiens IGKC*01 (107'-213"')]; dimère (229-229":232-232")-bisdisulfure immunomodulateur, antinéoplasique


183

imgatuzumab inmunoglobulina G1-kappa, anti-[ EGFR de Homo sapiens (receptor del factor de crecimiento epidérmico ERBB1, HER1)], anticuerpo monoclonal humanizado; cadena pesada gamma1 (1-449) [VH humanizado (Homo sapiens IGHV1-46*01 (83.70%) -(IGHD)-IGHJ6*01) [8.8.13] (1-120) -Homo sapiens IGHG1*01 CHS K2>del (121-449)], (223-213')-disulfuro con la cadena ligera kappa (1'-213') [V-KAPPA humanizado (Homo sapiens IGKV1-17*01 (90.50%) -IGKJ2*01) [6.3.8] (1'-106') -Homo sapiens IGKC*01 (107'-213"')]; dímero (229-229":232-232")-bisdisulfuro inmunomodulador, antineoplásico


QVQLVQSGAE VKKPGSSVKV SCKASGFTFT DYKIHWVRQA PGQGLEWMGY 50FNPNSGYSTY AQKFQGRVTI TADKSTSTAY MELSSLRSED TAVYYCARLS 100PGGYYVMDAW GQGTTVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK 150DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT 200YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP 250KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 300STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ 350VYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV 400LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPG 449

Light chain / Chaîne légère / Cadena ligeraDIQMTQSPSS LSASVGDRVT ITCRASQGIN NYLNWYQQKP GKAPKRLIYN 50TNNLQTGVPS RFSGSGSGTE FTLTISSLQP EDFATYYCLQ HNSFPTFGQG 100TKLEIKRTVA APSVFIFPPS DEQLKSGTAS VVCLLNNFYP REAKVQWKVD 150NALQSGNSQE SVTEQDSKDS TYSLSSTLTL SKADYEKHKV YACEVTHQGL 200SSPVTKSFNR GEC 213



insulinum peglisprum insulin peglispro macrogol 20000 pegylated insulin lispro:

[28B-(6-N-{[ω-methoxypoly(oxyethylene)]carbonyl}-L-lysine), 29B-L-proline]human insulin antidiabetic

insuline péglispro insuline lispro pégylée avec du macrogol 20000: [28B-(6-N-{[ω-méthoxypoly(oxyéthylène)]carbonyl}-L-lysine), 29B-L-proline]insuline humaine antidiabétique

insulina peglispro insulina lispro pegilada con macrogol 20000: [28B-(6-N-{[ω-metoxipoli(oxietileno)]carbonil}-L-lisina), 29B-L-prolina]insulina humana hipoglucemiante

1200440-65-8 CSLYQLENYCGIVEQCCTSI N

LVEALYLVCGFVNQHLCGSH ERGFFYTKPT

O OO

CH3

N6

n


184

lampalizumabum # lampalizumab immunoglobulin Fab G1-kappa, anti-[Homo sapiens CFD

(complement factor D)], humanized monoclonal antibody; VH -(CH1-hinge) gamma1 heavy chain (1-223) [humanized VH (Homo sapiens IGHV7-4-1*02 (88.80%) -(IGHD)-IGHJ5*01) [8.8.8] (1-115) -Homo sapiens IGHG1*01 CH1 (116-213), hinge 1-10 (214-223)], (218-214')-disulfide with kappa light chain (1'-214') [humanized V-KAPPA (Homo sapiens IGKV1-33*01 (77.90%) -IGKJ2*01 L124>V (104) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')] immunomodulator

lampalizumab immunoglobuline Fab G1-kappa, anti-[Homo sapiens CFD (facteur D du complément)], anticorps monoclonal humanisé; chaîne lourde VH -(CH1-charnière) gamma1 (1-223) [VH humanisé (Homo sapiens IGHV7-4-1*02 (88.80%) -(IGHD)-IGHJ5*01) [8.8.8] (1-115) -Homo sapiens IGHG1*01 CH1 (116-213), charnière 1-10 (214-223)], (218-214')-disulfure avec la chaîne légère kappa (1'-214') [V-KAPPA humanisé (Homo sapiens IGKV1-33*01 (77.90%) -IGKJ2*01 L124>V (104) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')] immunomodulateur

lampalizumab inmunoglobulina Fab G1-kappa, anti-[CFD (factor D del complemento) de Homo sapiens], anticuerpo monoclonal humanizado; cadena pesada VH -(CH1-bisagra) gamma1 (1-223) [VH humanizado (Homo sapiens IGHV7-4-1*02 (88.80%) -(IGHD)-IGHJ5*01) [8.8.8] (1-115) -Homo sapiens IGHG1*01 CH1 (116-213), bisagra 1-10 (214-223)], (218-214')-disulfuro con la cadena ligera kappa (1'-214') [V-KAPPA humanizado (Homo sapiens IGKV1-33*01 (77.90%) -IGKJ2*01 L124>V (104) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')] inmunomodulador


EVQLVQSGPE LKKPGASVKV SCKASGYTFT NYGMNWVRQA PGQGLEWMGW 50INTYTGETTY ADDFKGRFVF SLDTSVSTAY LQISSLKAED TAVYYCEREG 100GVNNWGQGTL VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE 150PVTVSWNSGA LTSGVHTFPA VLQSSGLYSL SSVVTVPSSS LGTQTYICNV 200NHKPSNTKVD KKVEPKSCDK THT 223

Light chain / Chaîne légère / Cadena ligeraDIQVTQSPSS LSASVGDRVT ITCITSTDID DDMNWYQQKP GKVPKLLISG 50 GNTLRPGVPS RFSGSGSGTD FTLTISSLQP EDVATYYCLQ SDSLPYTFGQ 100GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200LSSPVTKSFN RGEC 214

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H 22-96 142-198Intra-L 23'-88' 134'-194'Inter-H-L 218-214'

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilaciónNone

latanoprostenum bunodum latanoprostene bunod 4-(nitrooxy)butyl (5Z)-7-{(1R,2R,3R,5S)-3,5-dihydroxy-

2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl}hept-5-enoate antiglaucoma


185

latanoprostène bunod (5Z)-7-{(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy- 5-phénylpentyl]cyclopentyl}hept-5-énoate de 4-(nitrooxy)butyle antiglaucomateux

latanoprosteno bunod (5Z)-7-{(1R,2R,3R,5S)-3,5-dihidroxi-2-[(3R)-3-hidroxi- 5-fenilpentil]ciclopentil}hept-5-enoato de 4-(nitrooxi)butilo antiglaucoma

C27H41NO8 860005-21-6 OH

H

HOH H

H

H OH

O

O

ONO2

latromotidum latromotide human kinesin-like protein KIF20A-(66-75)-peptide

immunological agent for active immunization (antineoplastic)

latromotide membre 20A des protéines de la famille des kinésines humaines-(66-75)-peptide agent immunologique d'immunisation active (antinéoplasique)

latromotida miembro 20A de las proteínas de la familia de las kinesinas humanas-(66-75)-péptido agente inmunológico para inmunización activa (antineoplásico)

C60H105N17O12 1049674-65-8

H Lys Val Tyr Leu Arg Val Arg Pro Leu Leu OH

lifitegrastum lifitegrast (2S)-2-{2-[(1-benzofuran-6-yl)carbonyl)]-5,7-dichloro-

1,2,3,4-tetrahydroisoquinolin-6-carboxamido}- 3-[3-(methanesulfonyl)phenyl]propanoic acid non-steroidal anti-inflammatory

lifitégrast acide (2S)-2-{2-[(1-benzofuran-6-yl)carbonyl)]-5,7-dichloro- 1,2,3,4-tétrahydroisoquinoléin-6-carboxamido}- 3-[3-(méthanesulfonyl)phényl]propanoïque anti-inflammatoire non-stéroïdien

lifitegrast ácido (2S)-2-{2-[(1-benzofuran-6-il)carbonil)]-5,7-dicloro- 1,2,3,4-tetrahidroisoquinolin-6-carboxamido}- 3-[3-(metanosulfonil)fenil]propanoico antiinflamatorio no esteroide


186

C29H24Cl2N2O7S 1025967-78-5

NH

CO2H

H

SCH3

O

O

O

NO

O

Cl

Cl

ligelizumabum # ligelizumab immunoglobulin G1-kappa, anti-[Homo sapiens IGHE

(immunoglobulin constant epsilon (IGHE) region of the heavy chain of IgE) CH3 1.3-9 (12 AA), 108-121 (12 AA) epitope], humanized monoclonal antibody; gamma1 heavy chain (1-453) [humanized VH (Homo sapiens IGHV1-69*11 (80.60%) -(IGHD)-IGHJ4*01) [8.8.16] (1-123) -Homo sapiens IGHG1*01 (124-453)], (226-214')-disulfide with kappa light chain (1'-214') [humanized V-KAPPA (Homo sapiens IGKV3-15*01 (86.30%) -IGKJ4*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; (232-232":235-235")-bisdisulfide dimer immunomodulator

ligélizumab immunoglobuline G1-kappa, anti-[Homo sapiens IGHE (région constante epsilon (IGHE) de la chaîne lourde des immunoglobulines IgE) épitope CH3 1.3-9 (12 AA), 108-121 (12 AA)], anticorps monoclonal humanisé; chaîne lourde gamma1 (1-453) [VH humanisé (Homo sapiens IGHV1-69*11 (80.60%) -(IGHD)-IGHJ4*01) [8.8.16] (1-123) - Homo sapiens IGHG1*01 (124-453)], (226-214')-disulfure avec la chaîne légère kappa (1'-214') [V-KAPPA humanisé (Homo sapiens IGKV3-15*01 (86.30%) -IGKJ4*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dimère (232-232":235-235")-bisdisulfure immunomodulateur

ligelizumab inmunoglobulina G1-kappa, anti-[ IGHE de Homo sapiens (región constante epsilon (IGHE) de la cadena pesada de las inmunoglobulinas IgE) epítopo CH3 1.3-9 (12 AA), 108-121 (12 AA)], anticuerpo monoclonal humanizado; cadena pesada gamma1 (1-453) [VH humanizada (Homo sapiens IGHV1-69*11 (80.60%) -(IGHD)-IGHJ4*01) [8.8.16] (1-123) -Homo sapiens IGHG1*01 (124-453)], (226-214')-disulfuro con la cadena ligera kappa (1'-214') [V-KAPPA humanizado (Homo sapiens IGKV3-15*01 (86.30%) -IGKJ4*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dímero (232-232":235-235")-bisdisulfuro inmunomodulador


187


QVQLVQSGAE VMKPGSSVKV SCKASGYTFS WYWLEWVRQA PGHGLEWMGE 50IDPGTFTTNY NEKFKARVTF TADTSTSTAY MELSSLRSED TAVYYCARFS 100HFSGSNYDYF DYWGQGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC 150LVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG 200TQTYICNVNH KPSNTKVDKK VEPKSCDKTH TCPPCPAPEL LGGPSVFLFP 250PKPKDTLMIS RTPEVTCVVV DVSHEDPEVK FNWYVDGVEV HNAKTKPREE 300QYNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKALPAPIEK TISKAKGQPR 350EPQVYTLPPS RDELTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT 400PPVLDSDGSF FLYSKLTVDK SRWQQGNVFS CSVMHEALHN HYTQKSLSLS 450PGK 453

Light chain / Chaîne légère / Cadena ligeraEIVMTQSPAT LSVSPGERAT LSCRASQSIG TNIHWYQQKP GQAPRLLIYY 50ASESISGIPA RFSGSGSGTE FTLTISSLQS EDFAVYYCQQ SWSWPTTFGG 100GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200LSSPVTKSFN RGEC 214



lirilumabum # lirilumab immunoglobulin G4-kappa, anti-[Homo sapiens KIR2D subgroup

(killer cell immunoglobulin-like receptors from KIRD2 subgroup including KIR2DL1 (nkat1, CD158A), KIR2DL2 (nkat6, CD158B1), KIR2DL3 (nkat2, CD158B2), KIR2DS1 (CD158H) and KIR2DS2 (nkat5, CD158J)], Homo sapiens monoclonal antibody; gamma4 heavy chain (1-450) [Homo sapiens VH (IGHV1-69*01 (95.90%) -(IGHD)-IGHJ6*01) [8.8.16] (1-123) -IGHG4*01 hinge S10>P (231) (124-450)], (137-214')-disulfide with kappa light chain (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (98.90%) -IGKJ2*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; (229-229'':232-232'')-bisdisulfide dimer antineoplastic

lirilumab immunoglobuline G4-kappa, anti-[Homo sapiens KIR2D sous-groupe (récepteurs des cellules tueuses du sous-groupe KIR2D appartenant à la superfamille des immunoglobulines et incluant KIR2DL1 (nkat1, CD158A), KIR2DL2 (nkat6, CD158B1), KIR2DL3 (nkat2, CD158B2), KIR2DS1 (CD158H) et KIR2DS2 (nkat5, CD158J)], Homo sapiens anticorps monoclonal; chaîne lourde gamma4 (1-450) [Homo sapiens VH (IGHV1-69*01 (95.90%) -(IGHD)-IGHJ6*01) [8.8.16] (1-123) -IGHG4*01 charnière S10>P (231) (124-450)], (137-214')-disulfure avec la chaîne légère kappa (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (98.90%) -IGKJ2*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dimère (229-229'':232-232'')-bisdisulfure antinéoplasique


188

lirilumab inmunoglobulina G4-kappa, anti-[subgrupo KIR2D de Homo sapiens

(receptores de células asesinas del subgrupo KIR2D perteneciente a la superfamilia de las inmunoglobulinas y que incluye KIR2DL1 (nkat1, CD158A), KIR2DL2 (nkat6, CD158B1), KIR2DL3 (nkat2, CD158B2), KIR2DS1 (CD158H) et KIR2DS2 (nkat5, CD158J)], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma4 (1-450) [Homo sapiens VH (IGHV1-69*01 (95.90%) -(IGHD)-IGHJ6*01) [8.8.16] (1-123) -IGHG4*01 bisagra S10>P (231) (124-450)], (137-214')-disulfuro con la cadena ligera kappa (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (98.90%) -IGKJ2*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dímero (229-229'':232-232'')-bisdisulfuro antineoplásico


QVQLVQSGAE VKKPGSSVKV SCKASGGTFS FYAISWVRQA PGQGLEWMGG 50FIPIFGAANY AQKFQGRVTI TADESTSTAY MELSSLRSDD TAVYYCARIP 100SGSYYYDYDM DVWGQGTTVT VSSASTKGPS VFPLAPCSRS TSESTAALGC 150LVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG 200TKTYTCNVDH KPSNTKVDKR VESKYGPPCP PCPAPEFLGG PSVFLFPPKP 250KDTLMISRTP EVTCVVVDVS QEDPEVQFNW YVDGVEVHNA KTKPREEQFN 300STYRVVSVLT VLHQDWLNGK EYKCKVSNKG LPSSIEKTIS KAKGQPREPQ 350VYTLPPSQEE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV 400LDSDGSFFLY SRLTVDKSRW QEGNVFSCSV MHEALHNHYT QKSLSLSLGK 450

Light chain / Chaîne légère / Cadena ligeraEIVLTQSPVT LSLSPGERAT LSCRASQSVS SYLAWYQQKP GQAPRLLIYD 50ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ RSNWMYTFGQ 100GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200LSSPVTKSFN RGEC 214



lomibuvirum lomibuvir 5-(3,3-dimethylbut-1-yn-1-yl)-3-{(trans-4-hydroxycyclohexyl)[(trans-

4-methylcyclohexyl)carbonyl]amino}thiophene-2-carboxylic acid antiviral

lomibuvir acide 5-(3,3-diméthylbut-1-yn-1-yl)-3-{(trans- 4-hydroxycyclohexyl)[(trans- 4-méthylcyclohexyl)carbonyl]amino}thiophène-2-carboxylique antiviral

lomibuvir ácido 5-(3,3-dimetilbut-1-in-1-il)-3-{(trans-4-hidroxiciclohexil)[(trans-4-metilciclohexil)carbonil]amino}tiofeno-2-carboxílico antiviral


189

C25H35NO4S 1026785-55-6

S

N

H3C

H3CCH3

CO2H

O

OH

CH3

lucitanibum lucitanib 6-({7-[(1-aminocyclopropyl)methoxy]-6-methoxyquinolin-4-yl}oxy)-

N-methylnaphthalene-1-carboxamide antineoplastic

lucitanib 6-({7-[(1-aminocyclopropyl)méthoxy]-6-méthoxyquinoléin-4-yl}oxy)-N-méthylnaphthalène-1-carboxamide antinéoplasique

lucitanib 6-({7-[(1-aminociclopropil)metoxi]-6-metoxiquinolin-4-il}oxi)- N-metilnaftaleno-1-carboxamida antineoplásico

C26H25N3O4 1058137-23-7

NO

H3CO

O

H2N

NH

CH3

O

momelotinibum momelotinib N-(cyanomethyl)-4-{2-[4-(morpholin-4-yl)anilino]pyrimidin-

4-yl}benzamide antineoplastic

momélotinib N-(cyanométhyl)-4-{2-[4-(morpholin-4-yl)anilino]pyrimidin- 4-yl}benzamide antinéoplasique

momelotinib N-(cianometil)-4-{2-[4-(morfolin-4-il)anilino]pirimidin-4-il}benzamida antineoplásico

C23H22N6O2 1056634-68-4 O

NH

CN

N

N

HN

N

O


190

neceprevirum neceprevir (2R,6R,12Z,13aS,14aR,16aS)-N-(cyclopropanesulfonyl)-6-[2-(3,3-

difluoropiperidin-1-yl)-2-oxoethyl]-2-({7-methoxy-8-methyl- 2-[4-(propan-2-yl)-1,3-thiazol-2-yl]quinolin-4-yl}oxy)-5,16-dioxo-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxamide antiviral

nécéprevir (2R,6R,12Z,13aS,14aR,16aS)-N-(cyclopropanesulfonyl)-6-[2-(3,3-difluoropipéridin-1-yl)-2-oxoéthyl]-2-({7-méthoxy-8-méthyl- 2-[4-(propan-2-yl)-1,3-thiazol-2-yl]quinoléin-4-yl}oxy)-5,16-dioxo-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tétradécahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadécine-14a(5H)-carboxamide antiviral

neceprevir (2R,6R,12Z,13aS,14aR,16aS)-N-(ciclopropanosulfonil)-6-[2-(3,3-difluoropiperidin-1-il)-2-oxoetil]-2-({8-metil-7-metoxi-2-[4-(propan- 2-il)-1,3-tiazol-2-il]quinolin-4-il}oxi)-5,16-dioxo-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahidrociclopropa[e]pirrolo[1,2-a][1,4]diazaciclopentadecina-14a(5H)-carboxamida antiviral

C45H56F2N6O8S2 1229626-28-1

N

NHO O

H

H

H

H

O

N

O

O NH

S

O

O

N

S

N

CH3

OCH3

CH3

CH3

F

F

nivolumabum # nivolumab immunoglobulin G4-kappa, anti-[Homo sapiens PDCD1

(programmed cell death 1, PD-1, PD1, CD279)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-440) [Homo sapiens VH (IGHV3-33*01 (91.80%) -(IGHD)-IGHJ4*01) [8.8.6] (1-113) -IGHG4*01 hinge S10>P (221) (114-440)], (127-214')-disulfide with kappa light chain (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (98.90%) -IGKJ1*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; (219-219'':222-222'')-bisdisulfide dimer immunomodulator


191

nivolumab immunoglobuline G4-kappa, anti-[Homo sapiens PDCD1 (protéine 1 de mort cellulaire programmée, PD-1, PD1, CD279)], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-440) [Homo sapiens VH (IGHV3-33*01 (91.80%) -(IGHD)-IGHJ4*01) [8.8.6] (1-113) -IGHG4*01 charnière S10>P (221) (114-440)], (127-214')-disulfure avec la chaîne légère kappa (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (98.90%) -IGKJ1*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dimère (219-219'':222-222'')-bisdisulfure immunomodulateur

nivolumab inmunoglobulina G4-kappa, anti-[PDCD1 de Homo sapiens (proteína 1 de muerte celular programada, PD-1, PD1, CD279)], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-440) [Homo sapiens VH (IGHV3-33*01 (91.80%) -(IGHD)-IGHJ4*01) [8.8.6] (1-113) -IGHG4*01 bisagra S10>P (221) (114-440)], (127-214')-disulfuro con la cadena ligera kappa (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (98.90%) -IGKJ1*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dímero (219-219'':222-222'')-bisdisulfuro inmunomodulador


QVQLVESGGG VVQPGRSLRL DCKASGITFS NSGMHWVRQA PGKGLEWVAV 50IWYDGSKRYY ADSVKGRFTI SRDNSKNTLF LQMNSLRAED TAVYYCATND 100DYWGQGTLVT VSSASTKGPS VFPLAPCSRS TSESTAALGC LVKDYFPEPV 150TVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG TKTYTCNVDH 200KPSNTKVDKR VESKYGPPCP PCPAPEFLGG PSVFLFPPKP KDTLMISRTP 250EVTCVVVDVS QEDPEVQFNW YVDGVEVHNA KTKPREEQFN STYRVVSVLT 300VLHQDWLNGK EYKCKVSNKG LPSSIEKTIS KAKGQPREPQ VYTLPPSQEE 350MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY 400SRLTVDKSRW QEGNVFSCSV MHEALHNHYT QKSLSLSLGK 440

Light chain / Chaîne légère / Cadena ligeraEIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKP GQAPRLLIYD 50ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ SSNWPRTFGQ 100GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200LSSPVTKSFN RGEC 214


N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilaciónH CH2 84.4:290, 290''

ocaratuzumabum # ocaratuzumab immunoglobulin G1-kappa, anti-[Homo sapiens MS4A1 (membrane-

spanning 4-domains subfamily A member 1, CD20)], humanized monoclonal antibody; gamma1 heavy chain (1-450) [humanized VH (Homo sapiens IGHV5-51*01 (83.70%) -(IGHD)-IGHJ2*01) R120>K (113), L123>T (116) [8.8.14] (1-121) -Homo sapiens IGHG1*01 CH2 P11>I (251), A124>Q (343), CHS K2>del (122-450)], (224-213')-disulfide with kappa light chain (1'-213') [humanized V-KAPPA (Homo sapiens IGKV3-20*01 (85.40%) -IGKJ2*01) [5.3.9] (1'-106') -Homo sapiens IGKC*01 (107'-213')]; (230-230":233-233")-bisdisulfide dimer immunomodulator, antineoplastic


192

ocaratuzumab immunoglobuline G1-kappa, anti-[Homo sapiens MS4A1 (membre 1 de la sous-famille A à 4 domaines transmembranaires, CD20)], anticorps monoclonal humanisé; chaîne lourde gamma1 (1-450) [VH humanisé (Homo sapiens IGHV5-51*01 (83.70%) -(IGHD)-IGHJ2*01) R120>K (113), L123>T (116) [8.8.14] (1-121) -Homo sapiens IGHG1*01 CH2 P11>I (251), A124>Q (343), CHS K2>del (122-450)], (224-213')-disulfure avec la chaîne légère kappa (1'-213') [V-KAPPA humanisé (Homo sapiens IGKV3-20*01 (85.40%) -IGKJ2*01) [5.3.9] (1'-106') -Homo sapiens IGKC*01 (107'-213')]; dimère (230-230":233-233")-bisdisulfure immunomodulateur, antinéoplasique

ocaratuzumab inmunoglobulina G1-kappa, anti-[MS4A1 de Homo sapiens (miembro 1 de la subfamilia A de 4 dominios transmembranarios, CD20)], anticuerpo monoclonal humanizado; cadena pesada gamma1 (1-450) [VH humanizado (Homo sapiens IGHV5-51*01 (83.70%) -(IGHD)-IGHJ2*01) R120>K (113), L123>T (116) [8.8.14] (1-121) -Homo sapiens IGHG1*01 CH2 P11>I (251), A124>Q (343), CHS K2>del (122-450)], (224-213')-disulfuro con la cadena ligera kappa (1'-213') [V-KAPPA humanizado (Homo sapiens IGKV3-20*01 (85.40%) -IGKJ2*01) [5.3.9] (1'-106') -Homo sapiens IGKC*01 (107'-213')]; dímero (230-230":233-233")-bisdisulfuro inmunomodulador, antineoplásico


EVQLVQSGAE VKKPGESLKI SCKGSGRTFT SYNMHWVRQM PGKGLEWMGA 50IYPLTGDTSY NQKSKLQVTI SADKSISTAY LQWSSLKASD TAMYYCARST 100YVGGDWQFDV WGKGTTVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV 150KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ 200TYICNVNHKP SNTKVDKKVE PKSCDKTHTC PPCPAPELLG GPSVFLFPPK 250IKDTLMISRT PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY 300NSTYRVVSVL TVLHQDWLNG KEYKCKVSNK ALPAPIEKTI SKQKGQPREP 350QVYTLPPSRD ELTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP 400VLDSDGSFFL YSKLTVDKSR WQQGNVFSCS VMHEALHNHY TQKSLSLSPG 450

Light chain / Chaîne légère / Cadena ligeraEIVLTQSPGT LSLSPGERAT LSCRASSSVP YIHWYQQKPG QAPRLLIYAT 50SALASGIPDR FSGSGSGTDF TLTISRLEPE DFAVYYCQQW LSNPPTFGQG 100TKLEIKRTVA APSVFIFPPS DEQLKSGTAS VVCLLNNFYP REAKVQWKVD 150NALQSGNSQE SVTEQDSKDS TYSLSSTLTL SKADYEKHKV YACEVTHQGL 200SSPVTKSFNR GEC 213



omarigliptinum omarigliptin (2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methanesulfonyl)-

4,6-dihydropyrrolo[3,4-c]pyrazol-5(2H)-yl]oxan-3-amine antidiabetic

omarigliptine (2R,3S,5R)-2-(2,5-difluorophényl)-5-[2-(méthanesulfonyl)- 4,6-dihydropyrrolo[3,4-c]pyrazol-5(2H)-yl]oxan-3-amine antidiabétique


193

omarigliptina (2R,3S,5R)-2-(2,5-difluorofenil)-5-[2-(metanosulfonil)- 4,6-dihidropirrolo[3,4-c]pirazol-5(2H)-il]oxan-3-amina hipoglucemiante

C17H20F2N4O3S 1226781-44-7

O

H

H

N NN

S

CH3

OOF

FNH2H

oprozomibum oprozomib O-methyl-N-(2-methyl-1,3-thiazol-5-carbonyl)-L-seryl-O-methyl

-N-{(2S)-1-[(2R)-2-methyloxiran-2-yl]-1-oxo-3-phenylpropan-2-yl}- L-serinamide antineoplastic

oprozomib O-méthyl-N-(2-méthyl-1,3-thiazol-5-carbonyl)-L-séryl-O-méthyl- N-{(2S)-1-[(2R)-2-méthyloxiran-2-yl]-1-oxo-3-phénylpropan-2-yl}- L-sérinamide antinéoplasique

oprozomib O-metil-N-(2-metil-1,3-tiazol-5-carbonil)-L-seril-O-metil-N-{(2S)-1-[(2R)-2-metiloxiran-2-il]-1-oxo-3-fenilpropan-2-il}-L-serinamida antineoplásico

C25H32N4O7S 935888-69-0

HN

NH

HN

H

H

HO

O

OO

O

CH3

O

O CH3

H3C

N

SH3C

orticumabum # orticumab immunoglobulin G1-lambda, anti-[Homo sapiens oxLDL (oxidized

low-density lipoprotein (LDL), malondialdehyde (MDA)-modified apolipoprotein (apo) B-100)], Homo sapiens monoclonal antibody; gamma1 heavy chain (1-451) [Homo sapiens VH (IGHV3-23*01 (89.80%) -(IGHD)-IGHJ4*01) [8.8.14] (1-121) -IGHG1*01 (122-451)], (224-215')-disulfide with lambda light chain (1'-216') [Homo sapiens V-LAMBDA (IGLV1-47*02 (89.80%) -IGLJ3*02) [8.3.11] (1'-110') -IGLC2*01 (111'-216')]; (230-230'':233-233'')-bisdisulfide dimer immunomodulator, anti-inflammatory

orticumab immunoglobuline G1-lambda, anti-[Homo sapiens oxLDL (lipoprotéine de faible densité (LDL) oxydée, apolipoprotéine (apo) B-100 modifiée par le malondialdéhyde (MDA))], Homo sapiens anticorps monoclonal; chaîne lourde gamma1 (1-451) [Homo sapiens VH (IGHV3-23*01 (89.80%) -(IGHD)-IGHJ4*01) [8.8.14] (1-121) -IGHG1*01 (122-451)], (224-215')-disulfure avec la chaîne légère lambda (1'-216') [Homo sapiens V-LAMBDA (IGLV1-47*02 (89.80%) -IGLJ3*02) [8.3.11] (1'-110') -IGLC2*01 (111'-216')]; dimère (230-230'':233-233'')-bisdisulfure immunomodulateur, anti-inflammatoire


194

orticumab inmunoglobulina G1-lambda, anti-[oxLDL de Homo sapiens (lipoproteína de baja densidad (LDL) oxidada, apolipoproteína (apo) B-100 modificada por malondialdehído (MDA))], anticuerpo monoclonal de Homo sapiens; cadena pesada gamma1 (1-451) [Homo sapiens VH (IGHV3-23*01 (89.80%) -(IGHD)-IGHJ4*01) [8.8.14] (1-121) -IGHG1*01 (122-451)], (224-215')-disulfuro con la cadena ligera lambda (1'-216') [Homo sapiens V-LAMBDA (IGLV1-47*02 (89.80%) -IGLJ3*02) [8.3.11] (1'-110') -IGLC2*01 (111'-216')]; dímero (230-230'':233-233'')-bisdisulfuro inmunomodulador, antiinflamatorio


EVQLLESGGG LVQPGGSLRL SCAASGFTFS NAWMSWVRQA PGKGLEWVSS 50ISVGGHRTYY ADSVKGRSTI SRDNSKNTLY LQMNSLRAED TAVYYCARIR 100VGPSGGAFDY WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV 150KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ 200TYICNVNHKP SNTKVDKKVE PKSCDKTHTC PPCPAPELLG GPSVFLFPPK 250PKDTLMISRT PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY 300NSTYRVVSVL TVLHQDWLNG KEYKCKVSNK ALPAPIEKTI SKAKGQPREP 350QVYTLPPSRD ELTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP 400VLDSDGSFFL YSKLTVDKSR WQQGNVFSCS VMHEALHNHY TQKSLSLSPG 450K 451

Light chain / Chaîne légère / Cadena ligeraQSVLTQPPSA SGTPGQRVTI SCSGSNTNIG KNYVSWYQQL PGTAPKLLIY 50ANSNRPSGVP DRFSGSKSGT SASLAISGLR SEDEADYYCA SWDASLNGWV 100FGGGTKLTVL GQPKAAPSVT LFPPSSEELQ ANKATLVCLI SDFYPGAVTV 150AWKADSSPVK AGVETTTPSK QSNNKYAASS YLSLTPEQWK SHRSYSCQVT 200HEGSTVEKTV APTECS 216



parsatuzumabum # parsatuzumab immunoglobulin G1-kappa, anti-[Homo sapiens EGFL7 (epidermal

growth factor (EGF)-like repeat superfamily member 7, EGF-like-domains protein 7)], humanized monoclonal antibody; gamma1 heavy chain (1-453) [humanized VH (Homo sapiens IGHV3-74*01 (80.60%) -(IGHD)-IGHJ6*01 T123>L (118) [8.8.16] (1-123) -Homo sapiens IGHG1*03 CH1 R120>K (220) (124-453)], (226-219')-disulfide with kappa light chain (1'-219') [humanized V-KAPPA (Homo sapiens IGKV1-39*01 (81.00%) -IGKJ1*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; (232-232":235-235")-bisdisulfide dimer immunomodulator, antineoplastic


195

parsatuzumab immunoglobuline G1-kappa, anti-[Homo sapiens EGFL7 (membre 7 de la superfamille des protéines à domaines répétés facteur de croissance épidermique (EGF)-like, protéine 7 à domaines EGF-like)], anticorps monoclonal humanisé; chaîne lourde gamma1 (1-453) [VH humanisé (Homo sapiens IGHV3-74*01 (80.60%) -(IGHD)-IGHJ6*01 T123>L (118) [8.8.16] (1-123) -Homo sapiens IGHG1*03 CH1 R120>K (220) (124-453)], (226-219')-disulfure avec la chaîne légère kappa (1'-219') [V-KAPPA humanisé (Homo sapiens IGKV1-39*01 (81.00%) -IGKJ1*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dimère (232-232":235-235")-bisdisulfure immunomodulateur, antinéoplasique

parsatuzumab inmunoglobulina G1-kappa, anti-[ EGFL7 de Homo sapiens (miembro 7 de la superfamilia de proteínas de dominios repetidos factor de crecimiento epidérmico (EGF)-like, proteína 7 de dominios EGF-like)], anticuerpo monoclonal humanizado; cadena pesada gamma1 (1-453) [VH humanizada (Homo sapiens IGHV3-74*01 (80.60%) -(IGHD)-IGHJ6*01 T123>L (118) [8.8.16] (1-123) -Homo sapiens IGHG1*03 CH1 R120>K (220) (124-453)], (226-219')-disulfuro con la cadena ligera kappa (1'-219') [V-KAPPA humanizada (Homo sapiens IGKV1-39*01 (81.00%) -IGKJ1*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dímero (232-232":235-235")-bisdisulfuro inmunomodulador, antineoplásico


EVQLVESGGG LVQPGGSLRL SCAASGYTFI DYYMNWVRQA PGKGLEWVGD 50INLDNSGTHY NQKFKGRFTI SRDKSKNTAY LQMNSLRAED TAVYYCAREG 100VYHDYDDYAM DYWGQGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC 150LVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG 200TQTYICNVNH KPSNTKVDKK VEPKSCDKTH TCPPCPAPEL LGGPSVFLFP 250PKPKDTLMIS RTPEVTCVVV DVSHEDPEVK FNWYVDGVEV HNAKTKPREE 300QYNSTYRVVS VLTVLHQDWL NGKEYKCKVS NKALPAPIEK TISKAKGQPR 350EPQVYTLPPS REEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT 400PPVLDSDGSF FLYSKLTVDK SRWQQGNVFS CSVMHEALHN HYTQKSLSLS 450PGK 453

Light chain / Chaîne légère / Cadena ligeraDIQMTQSPSS LSASVGDRVT ITCRTSQSLV HINAITYLHW YQQKPGKAPK 50LLIYRVSNRF SGVPSRFSGS GSGTDFTLTI SSLQPEDFAT YYCGQSTHVP 100LTFGQGTKVE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200VTHQGLSSPV TKSFNRGEC 219



pefcalcitolum pefcalcitol 2-{[(1S,3R,5Z,7E,20S)-1,3-dihydroxy-9,10-secopregna-

5,7,10(19),16-tetraen-20-yl]oxy}-N-(2,2,3,3,3-pentafluoropropyl)acetamide antipsoriatic


196

pefcalcitol 2-{[(1S,3R,5Z,7E,20S)-1,3-dihydroxy-9,10-sécoprégna-5,7,10(19),16-tetraén-20-yl]oxy}-N-(2,2,3,3,3-pentafluoropropyl)acétamide antipsoriasique

pefcalcitol 2-{[(1S,3R,5Z,7E,20S)-1,3-dihidroxi-9,10-secopregna-5,7,10(19),16-tetraen-20-il]oxi}-N-(2,2,3,3,3-pentafluoropropil)acetamida antipsoriásico

C26H34F5NO4 381212-03-9 H3C

O

NH

CH3

H

H

HO

H H

OH

CH2

O

CF3

F F

perakizumabum # perakizumab immunoglobulin G1-kappa, anti-[Homo sapiens IL17A (interleukin

17A, IL-17A)], humanized monoclonal antibody; gamma1 heavy chain (1-452) [humanized VH (Homo sapiens IGHV3-7*01 (90.80%) -(IGHD)-IGHJ4*01) [8.8.15] (1-122) -Homo sapiens IGHG1*01 CH2 L1.3>A (239), L1.2>A (240) (123-452)], (225-215')-disulfide with kappa light chain (1'-215') [humanized V-KAPPA (Homo sapiens IGKV1-16*01 (82.10%) -IGKJ2*01) [6.3.10] (1'-108') -Homo sapiens IGKC*01 (109'-215')]; (231-231":234-234")-bisdisulfide dimer immunomodulator, anti-inflammatory

pérakizumab immunoglobuline G1-kappa, anti-[Homo sapiens IL17A (interleukine 17A, IL-17A)], anticorps monoclonal humanisé; chaîne lourde gamma1 (1-452) [VH humanisé (Homo sapiens IGHV3-7*01 (90.80%) -(IGHD)-IGHJ4*01) [8.8.15] (1-122) -Homo sapiens IGHG1*01 CH2 L1.3>A (239), L1.2>A (240) (123-452)], (225-215')-disulfure avec la chaîne légère kappa (1'-215') [V-KAPPA humanisé (Homo sapiens IGKV1-16*01 (82.10%) -IGKJ2*01) [6.3.10] (1'-108') -Homo sapiens IGKC*01 (109'-215')]; dimère (231-231":234-234")-bisdisulfure immunomodulateur, anti-inflammatoire

perakizumab inmunoglobulina G1-kappa, anti-[IL17A de Homo sapiens (interleukina 17A, IL-17A)], anticuerpo monoclonal humanizado; cadena pesada gamma1 (1-452) [VH humanizado (Homo sapiens IGHV3-7*01 (90.80%) -(IGHD)-IGHJ4*01) [8.8.15] (1-122) -Homo sapiens IGHG1*01 CH2 L1.3>A (239), L1.2>A (240) (123-452)], (225-215')-disulfuro con la cadena ligera kappa (1'-215') [V-KAPPA humanizado (Homo sapiens IGKV1-16*01 (82.10%) -IGKJ2*01) [6.3.10] (1'-108') -Homo sapiens IGKC*01 (109'-215')]; dímero (231-231":234-234")-bisdisulfuro inmunomodulador, antiinflamatorio


197


EVQLVESGGG LVQPGGSLRL SCAASGFTFS DYTMLWVRQA PGKGLEWVAI 50IKSGGSYSYY PDSVKGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCARDG 100DYGSSYGAMD YWGQGTLVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL 150VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT 200QTYICNVNHK PSNTKVDKKV EPKSCDKTHT CPPCPAPEAA GGPSVFLFPP 250KPKDTLMISR TPEVTCVVVD VSHEDPEVKF NWYVDGVEVH NAKTKPREEQ 300YNSTYRVVSV LTVLHQDWLN GKEYKCKVSN KALPAPIEKT ISKAKGQPRE 350PQVYTLPPSR DELTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP 400PVLDSDGSFF LYSKLTVDKS RWQQGNVFSC SVMHEALHNH YTQKSLSLSP 450GK 452

Light chain / Chaîne légère / Cadena ligeraDIQMTQSPSS LSASVGDRVT ITCRASQDIN SYLSWFQQKP GKAPKSLIVR 50ANRLVDGVPS RFSGSGSGQD YSLTISSLQP EDFATYYCLQ YDAFPPYTFG 100QGTKLEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK 150VDNALQSGNS QESVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ 200GLSSPVTKSF NRGEC 215



placulumabum # placulumab immunoglobulin (V-kappa)2-Fc gamma1, anti-[Homo sapiens TNF

(tumor necrosis factor, TNF superfamily member 2, TNFSF2, TNF-alpha, TNFA)], Homo sapiens monoclonal antibody; V-kappa -(CH1>del) gamma1 chain (1-341) [Homo sapiens V-KAPPA (IGKV1-39*01 (87.40%) -IGKJ1*01) [6.3.9] (1-107) -IGHG1*01 [CH1 1.4-119>del, K120>R (108) (108-109), hinge 1-15 C5>S (114) (110-124), CH2 (125-234), CH3 (235-339), CHS (340-341)]; (120-120':123-123')-bisdisulfide dimer immunomodulator, anti-inflammatory

placulumab immunoglobuline (V-kappa)2-Fc gamma1, anti-[Homo sapiens TNF (facteur de nécrose tumorale, membre 2 de la superfamille du TNF, TNFSF2, TNF-alpha, TNFA)], Homo sapiens anticorps monoclonal; chaîne V-kappa -(CH1>del) gamma1 (1-341) [Homo sapiens V-KAPPA (IGKV1-39*01 (87.40%) -IGKJ1*01) [6.3.9] (1-107) -IGHG1*01 [CH1 1.4-119>del, K120>R (108) (108-109), charnière 1-15 C5>S (114) (110-124), CH2 (125-234), CH3 (235-339), CHS (340-341)]; dimère (120-120':123-123')-bisdisulfure immunomodulateur, anti-inflammatoire

placulumab inmunoglobulina (V-kappa)2-Fc gamma1, anti-[TNF de Homo sapiens (factor de necrosis tumoral, miembro 2 de la superfamilia del TNF, TNFSF2, TNF-alfa, TNFA)], anticuerpo monoclonal de Homo sapiens; cadena V-kappa -(CH1>del) gamma1 (1-341) [Homo sapiens V-KAPPA (IGKV1-39*01 (87.40%) -IGKJ1*01) [6.3.9] (1-107) -IGHG1*01 [CH1 1.4-119>del, K120>R (108) (108-109), bisagra 1-15 C5>S (114) (110-124), CH2 (125-234), CH3 (235-339), CHS (340-341)]; dímero (120-120':123-123')-bisdisulfuro inmunomodulador, antiinflamatorio


198


DIQMTQSPSS LSASVGDRVT ITCRASQAID SYLHWYQQKP GKAPKLLIYS 50ASNLETGVPS RFSGSGSGTD FTLTISSLLP EDFATYYCQQ VVWRPFTFGQ 100GTKVEIKRVE PKSSDKTHTC PPCPAPELLG GPSVFLFPPK PKDTLMISRT 150PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY NSTYRVVSVL 200TVLHQDWLNG KEYKCKVSNK ALPAPIEKTI SKAKGQPREP QVYTLPPSRD 250ELTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP VLDSDGSFFL 300YSKLTVDKSR WQQGNVFSCS VMHEALHNHY TQKSLSLSPG K 341

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H 23-88 155-215 261-319 23'-88' 155'-215' 261'-319'Inter-H-H 120-120' 123-123'

N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilaciónH CH2 N84.4:191, 191'

pocapavirum pocapavir 1,3-dichloro-2-({4-[(2-chloro-

4-methoxyphenoxy)methyl]phenyl}methoxy)benzene antiviral

pocapavir 1,3-dichloro-2-({4-[(2-chloro- 4-méthoxyphénoxy)méthyl]phényl}méthoxy)benzène antiviral

pocapavir 1,3-dicloro-2-({4-[(2-cloro-4-metoxifenoxi)metil]fenil}metoxi)benceno antiviral

C21H17Cl3O3 146949-21-5

O

O

Cl

Cl

ClH3CO

pradimotidum pradimotide human vascular endothelial growth factor receptor 1 (VEGFR-1)-

(1058-1066)-peptide immunological agent for active immunization (antineoplastic)

pradimotide récepteur 1 du facteur de croissance de l'endothélium vasculaire humain (VEGFR-1)-(1058-1066)-peptide agent immunologique d'immunisation active (antinéoplasique)

pradimotida receptor 1 del factor de crecimiento endotelial vascular humano (VEGFR-1)-(1058-1066)-péptido agente inmunológico para inmunización activa (antineoplásico)

C53H78N10O14 908587-83-7

H Ser Tyr Gly Val Leu Leu Trp Glu Ile OH


199

quisinostatum quisinostat N-hydroxy-2-[4-({[(1-methyl-1H-indol-

3-yl)methyl]amino}methyl)piperidin-1-yl]pyrimidine-5-carboxamide antineoplastic

quisinostat N-hydroxy-2-[4-({[(1-méthyl-1H-indol- 3-yl)méthyl]amino}méthyl)pipéridin-1-yl]pyrimidine-5-carboxamide antinéoplasique

quisinostat N-hidroxi-2-[4-({[(1-metil-1H-indol-3-il)metil]amino}metil)piperidin- 1-il]pirimidina-5-carboxamida antineoplásico

C21H26N6O2 875320-29-9

HN

N N N

N NH

OH

O

H3C

rabusertibum rabusertib 1-(2-chloro-3-fluorophenyl)-3-[4-chloro-2-hydroxy-3-(piperazine-

1-sulfonyl)phenyl]urea antineoplastic

rabusertib 1-(5-bromo-4-méthyl-2-{[(2S)-morpholin-2-yl]méthoxy}phényl)- 3-(5-méthylpyrazin-2-yl)urée antinéoplasique

rabusertib 1-(2-cloro-3-fluorofenil)-3-[4-cloro-2-hidroxi-3-(piperazina- 1-sulfonil)fenil]urea antineoplásico

C18H22BrN5O3 911222-45-2 H

NHN

N

N

OCH3O

Br

H3C

O

NH

H

relugolixum relugolix 1-(4-{1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-

3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl}phenyl)-3-methoxyurea gonadotrophin releasing hormone (GnRH) antagonist

rélugolix 1-(4-{1-[(2,6-difluorophényl)méthyl]-5-[(diméthylamino)méthyl]- 3-(6-méthoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tétrahydrothiéno[2,3-d]pyrimidin-6-yl}phényl)-3-méthoxyurea antagoniste de la gonadoréline (GnRH)


200

relugolix 1-(4-{1-[(2,6-difluorofenil)metil]-5-[(dimetilamino)metil]- 3-(6-metoxipiridazin-3-il)-2,4-dioxo-1,2,3,4-tetrahidrotieno[2,3-d]pirimidin-6-il}fenil)-3-metoxiurea antagonista de la gonadorelina (GnRH)

C29H27F2N7O5S 737789-87-6

NF

F

N

S

NN

HN

OO

HN

OH3C

ON

H3C

CH3 OCH3

rilimogenum galvacirepvecum # rilimogene galvacirepvec recombinant replicating vaccinia viral vector expressing a modified

prostate specific antigen (PSA) plus three co-stimulatory molecules, lymphocyte associated function antigen-3 (LFA-3), intracellular adhesion molecule-1 (ICAM-1) and B7.1. gene therapy product (antineoplastic)

rilimogène galvacirépvec vecteur viral recombinant de la vaccine répliquant exprimant un antigène modifié spécifique de la prostate et trois protéines co-stimulantes (antigène 3 associé aux fonctions lymphocytaires (LFA-3), molécule d'adhésion intracellulaire-1 (ICAM-1) et B7.1) produit de thérapie génique (antinéoplasique)

rilimogén galvacirepvec vector viral recombinante de la vacuna replicante que expresa un antígeno modificado especifico prostático y tres proteínas co-stimulantes (antígeno 3 asociado a las funciones limfocitarias (LFA-3), molécula d'adhesión intracelular-1 (ICAM-1) y B7.1) producto para terapia génica (antineoplásico)

1225283-43-1

rilimogenum glafolivecum # rilimogene glafolivec recombinant non-replicating fowlpox viral vector expressing a

modified prostate specific antigen (PSA) plus three co-stimulatory molecules, lymphocyte associated function antigen-3 (LFA-3), intracellular adhesion molecule-1 (ICAM-1) and B7.1 gene therapy product (antineoplastic)

rilimogène glafolivec vecteur viral recombinant non-répliquant de la variole aviaire exprimant un antigène modifié spécifique de la prostate et trois protéines co-stimulantes (antigène 3 associé aux fonctions lymphocytaires (LFA-3), molécule d'adhésion intracellulaire-1 (ICAM-1) et B7.1) produit de thérapie génique (antinéoplasique)


201

rilimogén glafolivec vector viral recombinante no-replicante de la viruela aviar que expresa un antígeno modificado especifico prostático y tres proteínas co-stimulantes (antígeno 3 asociado a las funciones limfocitarias (LFA-3), molécula d'adhesión intracelular-1 (ICAM-1) y B7.1) producto para terapia génica (antineoplásico)

1225283-43-0

saridegibum saridegib N-[(2S,3R,3'R,3aS,4'aR,6S,6'aR,6'bS,7aR,12'aS,12'bS)-3,6,11',12'b-

tetramethyl-2',3',3a,4,4',4'a,5,5',6,6',6'a,6'b,7,7',7a,8',10',12',12'a,12'b-icosahydro-1'H,3H-spiro[furo[3,2-b]pyridine-2,9'-naphtho[2,1-a]azulen]-3'-yl]methanesulfonamide antineoplastic

saridégib N-[(2S,3R,3'R,3aS,4'aR,6S,6'aR,6'bS,7aR,12'aS,12'bS)-3,6,11',12'b-tétraméthyl-2',3',3a,4,4',4'a,5,5',6,6',6'a,6'b,7,7',7a,8',10',12',12'a,12'b-icosahydro-1'H,3H-spiro[furo[3,2-b]pyridine-2,9'-naphto[2,1-a]azulen]-3'-yl]méthanesulfonamide antinéoplasique

saridegib N-[(2S,3R,3'R,3aS,4'aR,6S,6'aR,6'bS,7aR,12'aS,12'bS)-3,6,11',12'b-tetrametil-2',3',3a,4,4',4'a,5,5',6,6',6'a,6'b,7,7',7a,8',10',12',12'a,12'b-icosahidro-1'H,3H-espiro[furo[3,2-b]piridina-2,9'-nafto[2,1-a]azulen]-3'-il]metanosulfonamida antineoplásico

C29H48N2O3S 1037210-93-7

NH

SH3C

OO

CH3

H H

H H

H3C

HO

HNHH3C

H

H

CH3

H

sebelipasum alfa # sebelipase alfa human lysosomal acid lipase/cholesteryl ester hydrolase (cholesteryl

esterase, lipase A, EC=3.1.1.13) glycosylated (produced in transgenic Gallus) enzyme replacement therapy

sébélipase alfa lipase acide lysosomale/hydrolase d'esters de cholesterol (cholestéryl estérase, lipase A, EC=3.1.1.13), enzyme humaine glycosylée produite par Gallus transgénique traitement enzymatique substitutif

sebelipasa alfa lipasa ácida lisosómica/hidrolasa de los ésteres de colesterol (colesteril esterasa, lipasa A, EC=3.1.1.13), enzima humana glicosilada producida por Gallus transgénico tratamiento enzimático de sustitución


202

1276027-63-4 SGGKLTAVDP ETNMNVSEII SYWGFPSEEY LVETEDGYIL CLNRIPHGRK 50

NHSDKGPKPV VFLQHGLLAD SSNWVTNLAN SSLGFILADA GFDVWMGNSR 100GNTWSRKHKT LSVSQDEFWA FSYDEMAKYD LPASINFILN KTGQEQVYYV 150GHSQGTTIGF IAFSQIPELA KRIKMFFALG PVASVAFCTS PMAKLGRLPD 200HLIKDLFGDK EFLPQSAFLK WLGTHVCTHV ILKELCGNLC FLLCGFNERN 250LNMSRVDVYT THSPAGTSVQ NMLHWSQAVK FQKFQAFDWG SSAKNYFHYN 300QSYPPTYNVK DMLVPTAVWS GGHDWLADVY DVNILLTQIT NLVFHESIPE 350WEHLDFIWGL DAPWRLYNKI INLMRKYQ 378

Disulfide bridges location* / Positions* des ponts disulfure / Posiciones* de los puentes disulfuro41-188 227-236 240-244* predicted / prévues / previstas

Glycosylation sites (N) / sites de glycosylation (N)/ posiciones de glicosilación (N)Asn-15 Asn-80 Asn-140 Asn-252 Asn-300

senrebotasum # senrebotase L-methionylglycyl-L-seryl-des-(445-glycine,446-L-tyrosine)-

[2-L-glutamic acid,432,442,444,447-tetra-L-aspartic acid]botulinum neurotoxin A precursor 27-L-alanine variant light chain (433-41')-disulfide with [14-L-arginine,15-L-lysine]human nociceptin fusion protein with L-alanyl-L-leucyl-L-alanyltris(tetraglycyl-L-seryl)- [3-L-valine,4-L-leucine,5-L-glutamine-418-L-leucine,419-L-aspartic acid]botulinum neurotoxin A heavy chain-(1-419)-peptide enzyme

senrébotase L-méthionylglycyl-L-séryl-dès-(445-glycine,446-L-tyrosine)-[2-L-acide glutamique,432,442,444,447-tétra-L-acide aspartique]chaîne légère du 27-L-alanine-variant du précurseur de la neurotoxine A botulique (433-41')-disulfure avec le [14-L-arginine,15-L-lysine]nociceptine humaine protéine de fusion avec le L-alanyl-L-leucyl-L-alanyltris(tétraglycyl-L-seryl)-[3-L-valine,4-L-leucine,5-L-glutamine-418-L-leucine,419-L-acide aspartique]chaîne lourde de la neurotoxine A botulique-(1-419)-peptide enzyme

senrebotasa L-metionilglicil-L-seril-des-(445-glicina,446-L-tirosina)-[2-L-ácido glutámico,432,442,444,447-tetra-L-ácido aspártico]cadena ligera de la 27-L-alanina-variante del precursor de la neurotoxina botulínica A (433-41')-disulfuro con la [14-L-arginina,15-L-lisina]nociceptina humana proteína de fusión con el L-alanil-L-leucil- L-alaniltris(tetraglicil-L-seril)-[3-L-valina,4-L-leucina,5-L-glutamina-418-L-leucina,419-L-ácido aspártico]cadena pesada de la neurotoxina botulínica A–(1-419)-péptido enzima


203

1290102-81-6 Light chain / Chaîne légère / Cadena ligera

MGSMEFVNKQ FNYKDPVNGV DIAYIKIPNA GQMQPVKAFK IHNKIWVIPE 50RDTFTNPEEG DLNPPPEAKQ VPVSYYDSTY LSTDNEKDNY LKGVTKLFER 100IYSTDLGRML LTSIVRGIPF WGGSTIDTEL KVIDTNCINV IQPDGSYRSE 150ELNLVIIGPS ADIIQFECKS FGHEVLNLTR NGYGSTQYIR FSPDFTFGFE 200ESLEVDTNPL LGAGKFATDP AVTLAHELIH AGHRLYGIAI NPNRVFKVNT 250NAYYEMSGLE VSFEELRTFG GHDAKFIDSL QENEFRLYYY NKFKDIASTL 300NKAKSIVGTT ASLQYMKNVF KEKYLLSEDT SGKFSVDKLK FDKLYKMLTE 350IYTEDNFVKF FKVLNRKTYL NFDKAVFKIN IVPKVNYTIY DGFNLRNTNL 400AANFNGQNTE INNMNFTKLK NFTGLFEFYK LLCVDGIITS KTKSDDDDK 449

Heavy chain / Chaîne lourde / Cadena pesadaFGGFTGARKS ARKRKNQALA GGGGSGGGGS GGGGSALVLQ CIKVNNWDLF 50'FSPSEDNFTN DLNKGEEITS DTNIEAAEEN ISLDLIQQYY LTFNFDNEPE 100'NISIENLSSD IIGQLELMPN IERFPNGKKY ELDKYTMFHY LRAQEFEHGK 150'SRIALTNSVN EALLNPSRVY TFFSSDYVKK VNKATEAAMF LGWVEQLVYD 200'FTDETSEVST TDKIADITII IPYIGPALNI GNMLYKDDFV GALIFSGAVI 250'LLEFIPEIAI PVLGTFALVS YIANKVLTVQ TIDNALSKRN EKWDEVYKYI 300'VTNWLAKVNT QIDLIRKKMK EALENQAEAT KAIINYQYNQ YTEEEKNNIN 350'FNIDDLSSKL NESINKAMIN INKFLNQCSV SYLMNSMIPY GVKRLEDFDA 400'SLKDALLKYI YDNRGTLIGQ VDRLKDKVNN TLSTDIPFQL SKYVDNQRLL 450'STLD 454'

Disulfide bridge location / Position du pont disulfure / Posición del puente disulfuro433-41'

sepranolonum sepranolone 3β-hydroxy-5α-pregnan-20-one

GABAA receptor antagonist

sépranolone 3β-hydroxy-5α-prégnan-20-one antagonsite des récepteurs GABAA

sepranolona 3β-hidroxi-5α-pregnan-20-ona antagoniste de los receptores GABAA

C21H34O2 516-55-2

CH3

HCH3

HH

OCH3

H

H

HO H

simtuzumabum # simtuzumab immunoglobulin G4-kappa, anti-[Homo sapiens LOXL2 (lysyl

oxidase-like 2)], humanized monoclonal antibody; gamma4 heavy chain (1-443) [humanized VH (Homo sapiens IGHV1-2*02 (80.60%) -(IGHD)-IGHJ4*01 L123>T (111) [8.8.9] (1-116) -Homo sapiens IGHG4*01 hinge S10>P (224) (117-443)], (130-219')-disulfide with kappa light chain (1'-219') [humanized V-KAPPA (Homo sapiens IGKV2D-29*02 (86.00%) -IGKJ4*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; (222-222":225-225")-bisdisulfide dimer immunomodulator


204

simtuzumab immunoglobuline G4-kappa, anti-[Homo sapiens LOXL2 (protéine 2 lysyl oxidase-like)], anticorps monoclonal humanisé; chaîne lourde gamma4 (1-443) [VH humanisé (Homo sapiens IGHV1-2*02 (80.60%) -(IGHD)-IGHJ4*01 L123>T (111) [8.8.9] (1-116) -Homo sapiens IGHG4*01 charnière S10>P (224) (117-443)], (130-219')-disulfure avec la chaîne légère kappa (1'-219') [V-KAPPA humanisé (Homo sapiens IGKV2D-29*02 (86.00%) -IGKJ4*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dimère (222-222":225-225")-bisdisulfure immunomodulateur

simtuzumab inmunoglobulina G4-kappa, anti-[LOXL2 de Homo sapiens (lysyl oxidase-like 2)], anticuerpo monoclonal humanizado; cadena pesada gamma4 (1-443) [VH humanizado (Homo sapiens IGHV1-2*02 (80.60%) -(IGHD)-IGHJ4*01 L123>T (111) [8.8.9] (1-116) -Homo sapiens IGHG4*01 bisagra S10>P (224) (117-443)], (130-219')-disulfuro con la cadena ligera kappa (1'-219') [V-KAPPA humanizado (Homo sapiens IGKV2D-29*02 (86.00%) -IGKJ4*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dímero (222-222":225-225")-bisdisulfuro inmunomodulador


QVQLVQSGAE VKKPGASVKV SCKASGYAFT YYLIEWVRQA PGQGLEWIGV 50INPGSGGTNY NEKFKGRATI TADKSTSTAY MELSSLRSED TAVYFCARNW 100MNFDYWGQGT TVTVSSASTK GPSVFPLAPC SRSTSESTAA LGCLVKDYFP 150EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTKTYTCN 200VDHKPSNTKV DKRVESKYGP PCPPCPAPEF LGGPSVFLFP PKPKDTLMIS 250RTPEVTCVVV DVSQEDPEVQ FNWYVDGVEV HNAKTKPREE QFNSTYRVVS 300VLTVLHQDWL NGKEYKCKVS NKGLPSSIEK TISKAKGQPR EPQVYTLPPS 350QEEMTKNQVS LTCLVKGFYP SDIAVEWESN GQPENNYKTT PPVLDSDGSF 400FLYSRLTVDK SRWQEGNVFS CSVMHEALHN HYTQKSLSLS LGK 443

Light chain / Chaîne légère / Cadena ligeraDIVMTQTPLS LSVTPGQPAS ISCRSSKSLL HSNGNTYLYW FLQKPGQSPQ 50FLIYRMSNLA SGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCMQHLEYP 100YTFGGGTKVE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200VTHQGLSSPV TKSFNRGEC 219



sonolisibum sonolisib (4E)-4-{[(bis(prop-2-en-1-yl)amino]methylidene}-

6-hydroxy-1α-(methoxymethyl)-3,7,17-trioxo-2-oxaandrosta-5,8-dien-11α-yl acetate antineoplastic

sonolisib acétate de (4E)-4-{[(bis(prop-2-én-1-yl)amino]méthylidène}- 6-hydroxy-1α-(méthoxyméthyl)-3,7,17-trioxo-2-oxaandrosta-5,8-dién-11α-yle antinéoplasique


205

sonolisib acetato de (4E)-4-{[(bis(prop-2-en-1-il)amino]metilideno}- 6-hidroxi-1α-(metoximetil)-3,7,17-trioxo-2-oxaandrosta-5,8-dien- 11α-ilo antineoplásico

C29H35NO5 502632-66-8

O

CH3

CH3O

O

OH

O

NCH2

H2C

OOH3C

CH3O

H

H

H

surotomycinum surotomycin N-[(2E)-3-(4-pentylphenyl)but-2-enoyl]-L-tryptophyl-D-asparaginyl-

L-α-aspartyl-L-threonylglycyl-L-ornithyl-L-α-aspartyl-D-alanyl- L-α-aspartylglycyl-D-seryl-(3R)-3-methyl-L-α-glutamyl- 3-(2-aminobenzoyl)-L-alanine 13→4-lactone antibacterial

surotomycine N-[(2E)-3-(4-pentylphényl)but-2-ènoyl]-L-tryptophyl-D-asparaginyl- L-α-aspartyl-L-thréonylglycyl-L-ornithyl-L-α-aspartyl-D-alanyl- L-α-aspartylglycyl-D-séryl-(3R)-3-méthyl-L-α-glutamyl- 3-(2-aminobenzoyl)-L-alanine 13→4-lactone antibactérien

surotomicina N-[(2E)-3-(4-pentilfenil)but-2-enoil]-L-triptofil-D-asparaginil- L-α-aspartil-L-treonilglicil-L-ornitil-L-α-aspartil-D-alanil- L-α-aspartilglicil-D-seril-(3R)-3-metil-L-α-glutamll-3-(2-aminobenzoil)-L-alanina 13→4-lactona antibacteriano

C77H101N17O26 1233389-51-9

L-Trp D-Asn L-Asp L-Thr Gly

O

HN

HN

H

O

D-Ser

CO2H

H

O

NH2

CH3

H

L-Orn L-Asp D-Ala L-Asp

Gly

O

CH3

CH3

O

technetium (99mTc) etarfolatidum technetium (99mTc) etarfolatide (SPY-5-24)-[N2-(4-{[(2-amino-4-oxo-1,4-dihydropteridin-

6-yl)methyl]amino}benzoyl)-D-γ-glutamyl-(2S)-2-(amino-kN)-β-alanyl-L-α-aspartyl-κN-L-cysteinato-κN,κS]oxido[99mTc]technetate radiodiagnostic agent

technétium (99mTc) étarfolatide (SPY-5-24)-[N2-(4-{[(2-amino-4-oxo-1,4-dihydroptéridin- 6-yl)méthyl]amino}benzoyl)-D-γ-glutamyl-(2S)-2-(amino-kN)-β-alanyl-L-α-aspartyl-κN-L-cystéinato-κN,κS]oxido[99mTc]technétate agent de radiodiagnostique


206

tecnecio (99mTc) etarfolatida (SPY-5-24)-[N2-(4-{[(2-amino-4-oxo-1,4-dihidropteridin-

6-il)metil]amino}benzoil)-D-γ-glutamil--(2S)-2-(amino-kN)-β-alanil- L-α-aspartil-κN-L-cisteinato-κN,κS]oxido[99mTc]tecnetato agente de radiodiagnóstico

C29H32N11O12STc 479410-20-3

N

NH

N

NNH

NH

CO2HH

O

H2N

O

N

N NH2

S

Tc

O

HNO

O

99m

HO2CH

H

O

H

HO2C

tenapanorum tenapanor N,N'-(10,17,-dioxo-3,6,21,24-tetraoxa-9,11,16,18-

tetraazahexacosane-1,26-diyl)bis{[(4S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl]benzenesulfonamide} Na+/H+ exchanger 3 (NHE3) inhibitor

ténapanor N,N'-(10,17,-dioxo-3,6,21,24-tétraoxa-9,11,16,18-tétraazahexacosane-1,26-diyl)bis{[(4S)-6,8-dichloro-2-méthyl-1,2,3,4-tétrahydroisoquinoléin-4-yl]benzènesulfonamide} inhibiteur de l'échangeur Na+/H+3 (NHE3)

tenapanor N,N'-(10,17,-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosano-1,26-diol)bis{[(4S)-6,8-dicloro-2-metil- 1,2,3,4-tetrahidroisoquinolin-4-il]bencenosulfonamida} inhibidor del intercambiador Na+/H+ tipo 3 (NHE3)

C50H66Cl4N8O10S2 1234423-95-0

NCH3

Cl

Cl

SNH

O

O

NH

O O

NHO HN

HN

O

O

HNS

O O

N

Cl

H3C

ClHH

O

trabodenosonum trabodenoson N6-cyclopentyladenosine 5'-nitrate

adenosine A1 receptor agonist

trabodénoson 5'-nitrate de N6-cyclopentyladénosine agoniste du récepteur A1 de l'adénosine

trabodenosón 5'-nitrato de N6-ciclopentiladenosina agonista del receptor A1 de la adenosina


207

C15H20N6O6 871108-05-3

OO

N

N N

N

HN

OHOH

O2N

trempamotidum trempamotide human kinesin-like protein KIF20B (M-phase phosphoprotein 1)-

(278-286)-peptide immunological agent for active immunization (antineoplastic)

trempamotide membre 20B des protéines de la famille des kinésines humaines (phosphoprotéine 1 de la phase M)-(278-286)-peptide agent immunologique d'immunisation active (antinéoplasique)

trempamotida miembro 20B de las proteínas de la familia de las kinesinas humanas (fosfoproteína 1 de la fase M)-(278-286)-péptido agente inmunológico para inmunización activa (antineoplásico)

C58H80N10O18 1018833-44-7

H Ile Tyr Asn Glu Tyr Ile Tyr Asp Leu OH

trenonacogum alfa # trenonacog alfa human coagulation factor IX (EC 3.4.21.22, Christmas factor, plasma

thromboplastin component), 148-threonine variant, produced in Chinese Hamster Ovary (CHO) cells (alfa glycoform) blood coagulation factor

trénonacog alfa variant 148-thréonine du facteur IX humain de coagulation (EC 3.4.21.22, facteur Christmas, facteur antihémophilique B) produit par culture de cellules ovariennes de hamster chinois (CHO) (glycoforme alfa) facteur de coagulation sanguine

trenonacog alfa 148-treonina-variante del factor IX humano de la coagulación sanguínea (EC 3.4.21.22, factor Christmas, factor antihemofílico B) producido por cultivo de células ováricas de hamster chinos (CHO) (glicoforma alfa) factor de coagulación sanguínea


208

1232401-60-3 YNSGKLEEFV QGNLERECME EKCSFEEARE VFENTERTTE FWKQYVDGDQ 50

CESNPCLNGG SCKDDINSYE CWCPFGFEGK NCELDVTCNI KNGRCEQFCK 100NSADNKVVCS CTEGYRLAEN QKSCEPAVPF PCGRVSVSQT SKLTRAETVF 150PDVDYVNSTE AETILDNITQ STQSFNDFTR VVGGEDAKPG QFPWQVVLNG 200KVDAFCGGSI VNEKWIVTAA HCVETGVKIT VVAGEHNIEE TEHTEQKRNV 250IRIIPHHNYN AAINKYNHDI ALLELDEPLV LNSYVTPICI ADKEYTNIFL 300KFGSGYVSGW GRVFHKGRSA LVLQYLRVPL VDRATCLRST KFTIYNNMFC 350AGFHEGGRDS CQGDSGGPHV TEVEGTSFLT GIISWGEECA MKGKYGIYTK 400VSRYVNWIKE KTKLT 415

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro18-23 51-62 56-71 73-82 88-99 95-109111-124 132-289 206-222 336-350 361-389

Modified residues / Résidus modifiés / Residuos modificadosE7-8-15-17-20-21-26-27-30-33-36-404-carboxyGlu

Glycosylation sites (N) / Sites de glycosylation (N) / Posiciones de glicosilación (N)Asn-157 Asn-167

HO2C CO2H

NH2HHO2C

trifarotenum trifarotene 3''-tert-butyl-4'-(2-hydroxyethoxy)-4''-(pyrrolidin-

1-yl)[1,1':3',1'']terphenyl-4-carboxylic acid keratolytic

trifarotène acide 3''-tert-butyl-4'-(2-hydroxyéthoxy)-4''-(pyrrolidin- 1-yl)[1,1':3',1'']terphényl-4-carboxylique kératolytique

trifaroteno ácido 3''-terc-butil-4'-(2-hidroxietoxi)-4''-(pirrolidin- 1-il)[1,1':3',1'']terfenil-4-carboxílico queratolítico

C29H33NO4 895542-09-3

CO2H

OHO

N

H3CCH3

CH3

vercirnonum vercirnon 4-[5-chloro-2-(4-tert-butylbenzenesulfonamido)benzoyl]pyridine

N-oxide anti-inflammatory

vercirnon 4-[5-chloro-2-(4-tert-butylbenzènesulfonamido)benzoyl]pyridine N-oxide anti-inflammatoire

vercirnón N-óxido de 4-[5-cloro-2-(4-terc-butilbencenosulfonamido)benzoil]piridina antiinflamatorio


209

C22H21ClN2O4S 698394-73-9

S

HN

H3C

CH3H3C

O O

O

NO

Cl

vintafolidum vintafolide N-(4-{[(2-amino-4-oxo-1,4-dihydropteridin-

6-yl)methyl]amino}benzoyl)-L-γ-glutamyl-L-α-aspartyl-L-arginyl- L-α-aspartyl-L-α-aspartyl-L-cysteine disulfide with methyl (5S,7R,9S)-5-ethyl-9-[(3aR,4R,5S,5aR,10bR,13aR)-3a-ethyl-4,5-dihydroxy- 8-methoxy-6-methyl-5-({2-[(2-sulfanylethoxy)carbonyl]hydrazinyl}carbonyl)-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazol-9-yl]-5-hydroxy-1,4,5,6,7,8,9,10-octahydro-2H-3,7-methanoazacycloundecino[5,4-b]indol-9-carboxylate antineoplastic

vintafolide N-(4-{[(2-amino-4-oxo-1,4-dihydroptéridin- 6-yl)méthyl]amino}benzoyl)-L-γ-glutamyl-L-α-aspartyl-L-arginyl- L-α-aspartyl-L-α-aspartyl-3-{2-[2-({[2-({(3aR,4R,5S,5aR,10bR,13aR)-3a-éthyl-9-[(5S,7R,9S)-5-éthyl-5-hydroxy-9-(méthoxycarbonyl)-1,4,5,6,7,8,9,10-octahydro-2H-3,7-méthanoazacycloundécino[5,4-b]indol-9-yl]-4,5-dihydroxy-8-méthoxy-6-méthyl-3a,4,5,5a,6,11,12,13a-octahydro-1H-indolizino[8,1-cd]carbazol- 9-yl}carbonyl)hydrazino]carbonyl}oxy)éthyl]disulfanyl}-L-alanine antinéoplasique

vintafolida N-(4-{[(2-amino-4-oxo-1,4-dihidropteridina-6-il)metil]amino}benzoil)-L-γ-glutamil-L-α-aspartil-L-arginil-L-α-aspartil-L-α-aspartil-3-{2-[2-({[2-({(3aR,4R,5S,5aR,10bR,13aR)-3a-etil-9-[(5S,7R,9S)-5-etil-5-hidroxi-9-(metoxicarbonil)-1,4,5,6,7,8,9,10-octahidro-2H-3,7-metanoazacicloundecino[5,4-b]indol-9-il]-4,5-dihidroxi-8-metoxi-6-metil-3a,4,5,5a,6,11,12,13a-octahidro-1H-indolizino[8,1-cd]carbazol-9-il}carbonil)hidrazino]carbonil}oxi)etil]disulfanil}-L-alanina antineoplásico

742092-03-1

Asp Arg Asp Asp NH

CO2H

H

NH

N

H3C

O

O

N

N

OH

OH

H

OH

CH3

CH3

H

H3CO

H

CH3

H

NH

HN

O

O

O

NH

N

N

N

NH

O

NH

O NH2

HO2C

H

O

SS


210

vocimagenum amiretrorepvecum # vocimagene amiretrorepvec recombinant replication-competent retrovirus vector encoding a

human codon optimized yeast cytosine deaminase gene, carrying three stabilizing point mutations (A23L/ V108T/I140L) and translated via an EMCV IRES (encephalomyocarditis virus internal ribosomal entry site) gene therapy product (antineoplastic)

vocimagène amirétrorépvec vecteur rétroviral recombinant répliquant codant le gène de la cytosine désaminase de levure optimisé par des codons humains, comprenant trois points de mutations stabilisants (A23L/ V108T/I140L) et traduit sous le contrôle de la séquence IRES (site d'entrée interne du ribososme) du virus de l'encéphalomyocardite (EMCV) produit de thérapie génique (antinéoplasique)

vocimagén amiretrorepvec vector retroviral recombinante replicante que codifica el gen de la citosina desaminasa de levadura optimizada por codones humanos, que comprende tres puntos de mutaciones estabilizadores (A23L/ V108T/I140L) y traducido bajo el control de la secuencia IRES (sitio de entrada interna del ribososma) del virus de la encefalomiocarditis (EMCV) producto para terapia génica (antineoplásico)

1300724-82-6

vorsetuzumabum # vorsetuzumab immunoglobulin G1-kappa, anti-[Homo sapiens CD70 (tumor

necrosis factor superfamily member 7, TNFSF7, CD27LG, CD27L)], humanized monoclonal antibody; gamma1 heavy chain (1-448) [humanized VH (Homo sapiens IGHV1-2*02 (86.70%) -(IGHD)-IGHJ6*01) [8.8.11] (1-118) -Homo sapiens IGHG1*01 (119-448)], (221-218')-disulfide with kappa light chain (1'-218') [humanized V-KAPPA (Homo sapiens IGKV4-1*01 (79.20%) -IGKJ1*01) [10.3.9] (1'-111') -Homo sapiens IGKC*01 (112'-218')]; (227-227":230-230")-bisdisulfide dimer inmunomodulador, antineoplásico

vorsétuzumab immunoglobuline G1-kappa, anti-[Homo sapiens CD70 (membre 7 de la superfamille du facteur de nécrose tumorale (TNF), TNFSF7, CD27LG, CD27L)], anticorps monoclonal humanisé; chaîne lourde gamma1 (1-448) [VH humanisé (Homo sapiens IGHV1-2*02 (86.70%) -(IGHD)-IGHJ6*01) [8.8.11] (1-118) -Homo sapiens IGHG1*01 (119-448)], (221-218'-disulfure avec la chaîne légère kappa (1'-218') [V-KAPPA humanisé (Homo sapiens IGKV4-1*01 (79.20%) -IGKJ1*01) [10.3.9] (1'-111') -Homo sapiens IGKC*01 (112'-218')]; dimère (227-227":230-230")-bisdisulfure immunomodulateur, antinéoplasique


211

vorsetuzumab inmunoglobulina G1-kappa, anti-[CD70 de Homo sapiens (miembro 7 de la superfamilia del factor de necrosis tumoral (TNF), TNFSF7, CD27LG, CD27L)], anticuerpo monoclonal humanizado; cadena pesada gamma1 (1-448) [VH humanizado (Homo sapiens IGHV1-2*02 (86.70%) -(IGHD)-IGHJ6*01) [8.8.11] (1-118) -Homo sapiens IGHG1*01 (119-448)], (221-218'-disulfuro con la cadena ligera kappa (1'-218') [V-KAPPA humanizada (Homo sapiens IGKV4-1*01 (79.20%) -IGKJ1*01) [10.3.9] (1'-111') -Homo sapiens IGKC*01 (112'-218')]; dímero (227-227":230-230")-bisdisulfuro immunomodulator, antineoplastic


QVQLVQSGAE VKKPGASVKV SCKASGYTFT NYGMNWVRQA PGQGLKWMGW 50INTYTGEPTY ADAFKGRVTM TRDTSISTAY MELSRLRSDD TAVYYCARDY 100GDYGMDYWGQ GTTVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY 150FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI 200CNVNHKPSNT KVDKKVEPKS CDKTHTCPPC PAPELLGGPS VFLFPPKPKD 250TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST 300YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY 350TLPPSRDELT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD 400SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK 448

Light chain / Chaîne légère / Cadena ligeraDIVMTQSPDS LAVSLGERAT INCRASKSVS TSGYSFMHWY QQKPGQPPKL 50LIYLASNLES GVPDRFSGSG SGTDFTLTIS SLQAEDVAVY YCQHSREVPW 100TFGQGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV 150QWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV 200THQGLSSPVT KSFNRGEC 218



vorsetuzumabum mafodotinum # vorsetuzumab mafodotin immunoglobulin G1-kappa auristatin F conjugate, anti-[Homo

sapiens CD70 (tumor necrosis factor superfamily member 7, TNFSF7, CD27LG, CD27L)], humanized monoclonal antibody conjugated to auristatin F; gamma1 heavy chain (1-448) [humanized VH (Homo sapiens IGHV1-2*02 (86.70%) -(IGHD)-IGHJ6*01) [8.8.11] (1-118) -Homo sapiens IGHG1*01 (119-448)], (221-218')-disulfide (if not conjugated) with kappa light chain (1'-218') [humanized V-KAPPA (Homo sapiens IGKV4-1*01 (79.20%) -IGKJ1*01) [10.3.9] (1'-111') -Homo sapiens IGKC*01 (112'-218')]; (227-227":230-230")-bisdisulfide dimer; conjugated, on an average of 3 to 5 cysteinyl, to monomethylauristatin F (MMAF), via a non-cleavable maleimidocaproyl (mc) linker For the mafodotin part, please refer to page 215. immunomodulator, antineoplastic


212

vorsétuzumab mafodotine immunoglobuline G1-kappa conjuguée à l'auristatine F, anti-[Homo sapiens CD70 (membre 7 de la superfamille du TNF, TNFSF7, CD27LG, CD27L)], anticorps monoclonal humanisé conjugué à l'auristatine F; chaîne lourde gamma1 (1-448) [VH humanisé (Homo sapiens IGHV1-2*02 (86.70%) -(IGHD)-IGHJ6*01) [8.8.11] (1-118) -Homo sapiens IGHG1*01 (119-448)], (221-218'-disulfure (si non conjugué) avec la chaîne légère kappa (1'-218') [V-KAPPA humanisé (Homo sapiens IGKV4-1*01 (79.20%) -IGKJ1*01) [10.3.9] (1'-111') -Homo sapiens IGKC*01 (112'-218')]; dimère (227-227":230-230")-bisdisulfure; conjugué, sur 3 à 5 cystéinyl en moyenne, au monométhylauristatine F (MMAF), via un linker maléimidocaproyl (mc) non clivable Pour la partie mafodotine, veuillez-vous référer à la page 215. immunomodulateur, antinéoplasique

vorsetuzumab mafodotina inmunoglobulina G1-kappa conjugada con auristatina F, anti-[CD70 de Homo sapiens (miembro 7 de la superfamilia del TNF, TNFSF7, CD27LG, CD27L)], anticuerpo monoclonal humanizado conjugado con la auristatina F; cadena pesada gamma1 (1-448) [VH humanizado (Homo sapiens IGHV1-2*02 (86.70%) -(IGHD)-IGHJ6*01) [8.8.11] (1-118) -Homo sapiens IGHG1*01 (119-448)], (221-218'-disulfuro (si no está conjugado ) con la cadena ligera kappa (1'-218') [V-KAPPA humanizado (Homo sapiens IGKV4-1*01 (79.20%) -IGKJ1*01) [10.3.9] (1'-111') -Homo sapiens IGKC*01 (112'-218')]; dímero (227-227":230-230")-bisdisulfuro; conjugado en 3 -5 restos cisteinil, por término medio, con monometilauristatina F (MMAF), mediante un enlace maleimidocaproil (mc) no escindible La mafodotina la encontrarán en la pagina 215. inmunomodulador, antineoplásico

1165741-01-4

*Two or three of the inter-chain disulfide bridges are not present, the antibody being conjugated to an average of 3 to 5 drug linkers each via a thioether bond.* Deux ou trois des ponts disulfure ne sont pas présents, l'anticorps étant conjugué à une moyenne de 3 à 5 linker-principe actif chacun via une liaison thioéther.* Faltan dos o tres puentes disulfuro inter-catenarios por estar el anticuerpo conjugado, con sendos enlaces tioéter, a una media de 3 a 5 conectores de principio activo

Heavy chain / Chaîne lourde / Cadena pesadaQVQLVQSGAE VKKPGASVKV SCKASGYTFT NYGMNWVRQA PGQGLKWMGW 50INTYTGEPTY ADAFKGRVTM TRDTSISTAY MELSRLRSDD TAVYYCARDY 100GDYGMDYWGQ GTTVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY 150FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI 200CNVNHKPSNT KVDKKVEPKS CDKTHTCPPC PAPELLGGPS VFLFPPKPKD 250TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST 300YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY 350TLPPSRDELT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD 400SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK 448

Light chain / Chaîne légère / Cadena ligeraDIVMTQSPDS LAVSLGERAT INCRASKSVS TSGYSFMHWY QQKPGQPPKL 50LIYLASNLES GVPDRFSGSG SGTDFTLTIS SLQAEDVAVY YCQHSREVPW 100TFGQGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV 150QWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV 200THQGLSSPVT KSFNRGEC 218

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H 22-96 145-201 262-322 368-426 22''-96'' 145''-201'' 262''-322'' 368''-426''Intra-L 23'-92' 138'-198' 23'''-92''' 138'''-198''' Inter-H-L* 221-218' 221''-218''' Inter-H-H * 227-227'' 230-230''



213

zatuximabum # zatuximab immunoglobulin G1-kappa, anti-[Homo sapiens EGFR (epidermal

growth factor receptor, ERBB1, HER1) domain III], chimeric monoclonal antibody; gamma1 heavy chain (1-448) [Mus musculus VH (IGHV1S81*02 -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -Homo sapiens IGHG1*03 CHS K2>del (120-448)], (222-219')-disulfide with kappa light chain (1'-219') [Mus musculus V-KAPPA (IGKV2-109*01 -IGKJ2*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; (228-228'':231-231'')-bisdisulfide dimer immunomodulator, antineoplastic

zatuximab immunoglobuline G1-kappa, anti-[Homo sapiens EGFR (récepteur du facteur de croissance épidermique ERBB1, HER1) domaine III], anticorps monoclonal chimérique; chaîne lourde gamma1 (1-448) [Mus musculus VH (IGHV1S81*02 -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -Homo sapiens IGHG1*03 CHS K2>del (120-448)], (222-219')-disulfure avec la chaîne légère kappa (1'-219') [Mus musculus V-KAPPA (IGKV2-109*01 -IGKJ2*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dimère (228-228'':231-231'')-bisdisulfure immunomodulateur, antinéoplasique

zatuximab inmunoglobulina G1-kappa, anti-[EGFR de Homo sapiens (receptor del factor de crecimiento epidérmico ERBB1, HER1) dominio III], anticuerpo monoclonal quimérico; cadena ligera gamma1 (1-448) [Mus musculus VH (IGHV1S81*02 -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -Homo sapiens IGHG1*03 CHS K2>del (120-448)], (222-219')-disulfuro con la cadena ligera kappa (1'-219') [Mus musculus V-KAPPA (IGKV2-109*01 -IGKJ2*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dímero (228-228'':231-231'')-bisdisulfuro inmunomodulador, antineoplásico


QVQLQQPGAE LVEPGGSVKL SCKASGYTFT SHWMHWVKQR PGQGLEWIGE 50INPSSGRNNY NEKFKSKATL TVDKSSSTAY MQFSSLTSED SAVYYCVRYY 100GYDEAMDYWG QGTSVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200ICNVNHKPSN TKVDKRVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350YTLPPSREEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPG 448

Light chain / Chaîne légère / Cadena ligeraDIVMTQAAFS NPVTLGTSAS ISCRSSKSLL HSNGITYLYW YLQKPGQSPQ 50LLIYQMSNLA SGVPDRFSSS GSGTDFTLRI SRVEAEDVGV YYCAQNLELP 100YTFGGGTKLE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200VTHQGLSSPV TKSFNRGEC 219




214

zoptarelinum doxorubicinum zoptarelin doxorubicin [6-D-lysine]human gonadoliberin-1 (LHRH) and doxorubicin

covalently linked together with glutaric acid: 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-N6-[5-(2-{(2S,4S)-4-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-2-yl}-2-oxoethoxy)-5-oxopentanoyl]-D-lysine- L-leucyl-L-arginyl-L-prolylglycinamide antineoplastic

zoptaréline doxorubicine [6-D-lysine]gonadolibérine-1 humaine (LHRH) et doxorubicine liées de façon covalente par l'acide glutarique: 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-séryl-L-tyrosyl-N6-[5-(2-{(2S,4S)-4-[(3-amino-2,3,6-tridéoxy-α-L-lyxo-hexopyranosyl)oxy]-2,5,12-trihydroxy-7-méthoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotétracén-2-yl}-2-oxoéthoxy)-5-oxopentanoyl]-D-lysine- L-leucyl-L-arginyl-L-prolylglycinamide antinéoplasique

zoptarelina doxorubicina [6-D-lisina]gonadoliberina-1 humana (LHRH) y doxorubicina unidas covalentemente mediante ácido glutárico: 5-oxo-L-prolil-L-histidil-L-triptofil-L-seril-L-tirosil-N6-[5-(2-{(2S,4S)-4-[(3-amino-2,3,6-tridesoxi-α-L-lixo-hexopiranosil)oxi]-2,5,12-trihidroxi-7-metoxi-6,11-dioxo-1,2,3,4,6,11-hexahidrotetracen-2-il}-2-oxoetoxi)-5-oxopentanoil]-D-lisina-L-leucil-L-arginil-L-prolilglicinamida antineoplásico

139570-93-7

OHO

O

OCH3

H

OH

O

CH3

HO

NH2

O

OH

O

O

NH

His Trp Ser Tyr Leu Arg Pro Gly NH2O

H

O

NH

O

H

O

O

NH

# Electronic structure available on Mednet: http://mednet.who.int/ # Structure électronique disponible sur Mednet: http://mednet.who.int/ # Estructura electrónica disponible en Mednet: http://mednet.who.int/


215

Names for Radicals, Groups and others Dénominations applicables aux radicaux, groupes et autres Denominaciones para radicales, grupos y otros

mafodotinum mafodotin N-{(2R,3R)-3-[(2S)-1-[(3R,4S,5S)-4-({N-[6-(2,5-dioxo-2,5-dihydro-

1H-pyrrol-1-yl)hexanoyl]-N-methyl-L-valyl-L-valyl}methylamino)- 3-methoxy-5-methylheptanoyl]pyrrolidin-2-yl]-3-methoxy- 2-methylpropanoyl}-L-phenylalanine

mafodotine N-{(2R,3R)-3-[(2S)-1-[(3R,4S,5S)-4-({N-[6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoyl]-N-méthyl-L-valyl-L-valyl}méthylamino)- 3-méthoxy-5-méthylheptanoyl]pyrrolidin-2-yl]-3-méthoxy- 2-méthylpropanoyl}-L-phénylalanine

mafodotina N-{(2R,3R)-3-[(2S)-1-[(3R,4S,5S)-4-({N-[6-(2,5-dioxo-2,5-dihidro- 1H-pirrol-1-il)hexanoil]-N-metil-L-valil-L-valil}metilamino)-3-metoxi- 5-metilheptanoil]pirrolidin-2-il]-3-metoxi-2-metilpropanoil}- L-fenilalanina

C49H76N6O11 863971-19-1

H3CN

NH

N

CH3

O

H3C CH3O

H3C CH3

H

HHO

NNH

CO2H

CH3

HHO

H CH3

OO

CH3

H

CH3

CH3

H

H

N

O

O

O

AMENDMENTS TO PREVIOUS LISTS MODIFICATIONS APPORTÉES AUX LISTES ANTÉRIEURES

MODIFICACIONES A LAS LISTAS ANTERIORES Proposed International Non Proprietary Names (Prop. INN): List 36 (Chronicle of the WHO, 1976, Vol. 30, No. 9) p. 16 oxitropii bromidum oxitropium bromide

replace the description and the structure by the following ones

(1R,2R,4S,5S,7s,9s)-9-ethyl-7-{[(2S)-3-hydroxy-2-phenylpropanoyl]oxy}- 9-methyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane bromide

NH

O

H

HH

OH

OCH3

CH3

O

H

H

Br


216

Denominations communes internationales proposées (DCI Prop.): Liste 36(Chronique de l'OMS, Vol. 30, No. 9, 1976) p. 16 oxitropii bromidum bromure d’oxitropium remplacer la description et la structure par les suivantes

bromure de (1R,2R,4S,5S,7s,9s)-9-éthyl-7-{[(2S)-3-hydroxy- 2-phénylpropanoyl]oxy}-9-méthyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane

NH

O

H

HH

OH

OCH3

CH3

O

H

H

Br

Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 36 (Crónica de la OMS, Vol. 30, No. 90, 1976) p. 16 oxitropii bromidum bromuro de oxitropio sustitúyase la descripción y la estructura por las siguientes

bromuro de (1R,2R,4S,5S,7s,9s)-9-etil-7-{[(2S)-2-fenil-3-hidroxipropanoil]oxi}-

9-metil-3-oxa-9-azoniatriciclo[3.3.1.02,4]nonano

NH

O

H

HH

OH

OCH3

CH3

O

H

H

Br

Proposed International Non Proprietary Names (Prop. INN): Lists 90 and 96Dénominations communes internationales proposées (DCI Prop.): Listes 90 et 96Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Listas 90 y 96(WHO Drug Information, Vol. 18, No. 1, 2004 and / et/ y WHO Drug Information, Vol. 20, No. 4, 2006) p. 67 ulipristalum & 300 ulipristal replace the structure by the following ulipristal remplacer la structure par la suivante

ulipristal sustitúyase la estructura por la siguiente

O

NH3C

CH3

OH

H

CH3

H

HCH3

O


217

Proposed International Non Proprietary Names (Prop. INN): List 98Denominations communes internationales proposées (DCI Prop.): Liste 98Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 98 (WHO Drug Information, Vol. 21, No. 4, 2007)

p. 329 conestatum alfa # conestat alfa replace the structure by the following conestat alfa remplacer la structure par la suivante

conestat alfa sustitúyase la estructura por la siguiente

NPNATSSSSQ DPESLQDRGE GKVATTVISK MLFVEPILEV SSLPTTNSTT 50NSATKITANT TDEPTTQPTT EPTTQPTIQP TQPTTQLPTD SPTQPTTGSF 100CPGPVTLCSD LESHSTEAVL GDALVDFSLK LYHAFSAMKK VETNMAFSPF 150SIASLLTQVL LGAGENTKTN LESILSYPKD FTCVHQALKG FTTKGVTSVS 200QIFHSPDLAI RDTFVNASRT LYSSSPRVLS NNSDANLELI NTWVAKNTNN 250KISRLLDSLP SDTRLVLLNA IYLSAKWKTT FDPKKTRMEP FHFKNSVIKV 300PMMNSKKYPV AHFIDQTLKA KVGQLQLSHN LSLVILVPQN LKHRLEDMEQ 350ALSPSVFKAI MEKLEMSKFQ PTLLTLPRIK VTTSQDMLSI MEKLEFFDFS 400YDLNLCGLTE DPDLQVSAMQ HQTVLELTET GVEAAAASAI SVARTLLVFE 450VQQPFLFVLW DQQHKFPVFM GRVYDPRA 478


Glycosylation sites / Sites de glycosylation / Posiciones de glicosilaciónAsn-3 Thr-26 Ser-42 Asn-47 Thr-49 Asn-59 Thr-61Thr-66 Thr-70 Thr-74 Asn-216 Asn-231 Asn-330

Proposed International Non Proprietary Names (Prop. INN): List 99 Denominations communes internationales proposées (DCI Prop.): Liste 99 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 99(WHO Drug Information, Vol. 24, No. 4, 2010) p. 142 macitentanum macitentan replace the chemical name by the following

N-[5-(4-bromophenyl)-6-{2-[(5-bromopyrimidin-2-yl)oxy]ethoxy} pyrimidin-4-yl]-N'-propylsulfuric diamide

Proposed International Non Proprietary Names (Prop. INN): List 100 Denominations communes internationales proposées (DCI Prop.): Liste 100 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 100 (WHO Drug Information, Vol. 242, No. 4, 2008) p. 342 & 343

solanezumabum #

solanezumab replace the description and the structure by the following ones

solanezumab remplacer la description et la structure par les suivantes

solanezumab sustitúyase la descripción y la estructura por las siguientes

immunoglobulin G1-kappa, anti-[Homo sapiens amyloid-beta (Abeta) peptide soluble monomer], humanized monoclonal antibody; gamma1 heavy chain [humanized VH (Homo sapiens IGHV3-23*04 (87.60%) -(IGHD)-IGHJ4*01) [8.8.5] (1-112) -Homo sapiens IGHG1*01 (113-442)], (215-219')-disulfide with kappa light chain (1’-219’) [humanized V-KAPPA (Homo sapiens IGKV2-30*01 (90.00%) -IGKJ1*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; (221-221":224-224")-bisdisulfide dimer


218

immunoglobuline G1-kappa, anti-[Homo sapiens amyloïde-bêta (Abeta) peptide monomère soluble], anticorps monoclonal humanisé; chaîne lourde gamma1 [VH humanisé (Homo sapiens IGHV3-23*04 (87.60%) -(IGHD)-IGHJ4*01) [8.8.5] (1-112) -Homo sapiens IGHG1*01 (113-442)], (215-219')-disulfure avec la chaîne légère kappa (1’-219’) [V-KAPPA humanisé (Homo sapiens IGKV2-30*01 (90.00%) -IGKJ1*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dimère (221-221":224-224")-bisdisulfure

inmunoglobulina G1-kappa, anti-[péptido amiloide-beta (Abeta) monomèrico soluble de Homo sapiens], anticuerpo monoclonal humanizado; cadena pesada gamma1 [VH humanizado (Homo sapiens IGHV3-23*04 (87.60%) -(IGHD)-IGHJ4*01) [8.8.5] (1-112) -Homo sapiens IGHG1*01 (113-442)], (215-219')-disulfuro con la cadena ligera kappa (1’-219’) [V-KAPPA humanizado (Homo sapiens IGKV2-30*01 (90.00%) -IGKJ1*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dímero (221-221":224-224")-bisdisulfuro

Heavy chain / Chaîne lourde / Cadena pesadaEVQLVESGGG LVQPGGSLRL SCAASGFTFS RYSMSWVRQA PGKGLELVAQ 50INSVGNSTYY PDTVKGRFTI SRDNAKNTLY LQMNSLRAED TAVYYCASGD 100YWGQGTLVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT 150VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT QTYICNVNHK 200PSNTKVDKKV EPKSCDKTHT CPPCPAPELL GGPSVFLFPP KPKDTLMISR 250TPEVTCVVVD VSHEDPEVKF NWYVDGVEVH NAKTKPREEQ YNSTYRVVSV 300LTVLHQDWLN GKEYKCKVSN KALPAPIEKT ISKAKGQPRE PQVYTLPPSR 350DELTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP PVLDSDGSFF 400LYSKLTVDKS RWQQGNVFSC SVMHEALHNH YTQKSLSLSP GK 442

Light chain / Chaîne légère / Cadena ligeraDVVMTQSPLS LPVTLGQPAS ISCRSSQSLI YSDGNAYLHW FLQKPGQSPR 50LLIYKVSNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCSQSTHVP 100WTFGQGTKVE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200VTHQGLSSPV TKSFNRGEC 219


N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilaciónH VH CDR2-IMGT N63:56, 56''H CH2 N84.4: 292, 292''

Proposed International Non Proprietary Names (Prop. INN): List 102 Denominations communes internationales proposées (DCI Prop.): Liste 102Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 102(WHO Drug Information, Vol. 23, No. 4, 2009) p. 325 & 326

dalotuzumabum

dalotuzumab replace the description and the structure by the following ones

dalotuzumab sustitúyase la descripción y la estructura por las siguientes

immunoglobulin G1-kappa, anti-[Homo sapiens IGF1R (insulin-like growth factor 1 receptor, IGF1-R, IGF-1R, CD221], humanized monoclonal antibody; gamma1 heavy chain (1-447) [humanized VH (Homo sapiens IGHV4-61*08 (86.90%) -(IGHD)-IGHJ4*01) [9.7.10] (1-117) -Homo sapiens IGHG1*03 (118-447)], (220-219')-disulfide with kappa light chain (1’-219’) [humanized V-KAPPA (Homo sapiens IGKV2-29*03 (84.00%) -IGKJ1*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; (226-226":229-229")-bisdisulfide dimer


219

inmunoglobulina G1-kappa, anti-[Homo sapiens IGF1R (receptor del factor de

crecimiento similar a la insulina 1 (IGF1-R, IGF-1R, CD221)], anticuerpo monoclonal humanizado; cadena pesada gamma1 (1-447) [VH humanizado (Homo sapiens IGHV4-61*08 (86.90%) -(IGHD)-IGHJ4*01) [9.7.10] (1-117) -Homo sapiens IGHG1*03 (118-447)], (220-219')-disulfuro con la cadena ligera kappa (1’-219’) [V-KAPPA humanizado (Homo sapiens IGKV2-29*03 (84.00%) -IGKJ1*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dímero (226-226":229-229")-bisdisulfuro

Heavy chain / Chaîne lourde / Cadena pesadaQVQLQESGPG LVKPSETLSL TCTVSGYSIT GGYLWNWIRQ PPGKGLEWIG 50YISYDGTNNY KPSLKDRVTI SRDTSKNQFS LKLSSVTAAD TAVYYCARYG 100RVFFDYWGQG TLVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF 150PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTQTYIC 200NVNHKPSNTK VDKRVEPKSC DKTHTCPPCP APELLGGPSV FLFPPKPKDT 250LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY 300RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT 350LPPSREEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS 400DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPGK 447

Light chain / Chaîne légère / Cadena ligeraDIVMTQSPLS LPVTPGEPAS ISCRSSQSIV HSNGNTYLQW YLQKPGQSPQ 50LLIYKVSNRL YGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCFQGSHVP 100WTFGQGTKVE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200VTHQGLSSPV TKSFNRGEC 219


N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilaciónH CH2 N84.4297, 297''

Proposed International Non Proprietary Names (Prop. INN): List 103 Denominations communes internationales proposées (DCI Prop.): Liste 103 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 103 (WHO Drug Information, Vol. 24, No. 2 2010) p. 184 dalotuzumabum dalotuzumab remplacer la description par la suivante

immunoglobuline G1-kappa, anti-[Homo sapiens IGF1R (récepteur du facteur

de croissance 1 analogue à l’insuline (IGF1-R, IGF-1R, CD221)], anticorps monoclonal humanisé; chaîne lourde gamma1 (1-447) [VH humanisé (Homo sapiens IGHV4-61*08 (86.90%) -(IGHD)-IGHJ4*01) [9.7.10] (1-117) -Homo sapiens IGHG1*03 (118-447)], (220-219')-disulfure avec la chaîne légère kappa (1’-219’) [V-KAPPA humanisé (Homo sapiens IGKV2-29*03 (84.00%) -IGKJ1*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dimère (226-226":229-229")-bisdisulfure


220

Proposed International Non Proprietary Names (Prop. INN): List 104 Denominations communes internationales proposées (DCI Prop.): Liste 104 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 104 (WHO Drug Information, Vol. 24, No. 4, 2010) p. 369 delete/supprimer/suprimáse insert/insérer/insertese erismodegibum sonidegibum

erismodegib sonidegib

érismodégib sonidégib

erismodegib sonidegib

p. 391 delete/supprimer/suprimáse insert/insérer/insertese ravatirelinum rovatirelinum

ravatirelin rovatirelin

ravatiréline rovatiréline

ravatirelina rovatirelina

p. 391 delete/supprimer/suprimáse insert/insérer/insertese ronomilastum elbimilastum

ronomilast elbimilast



Proposed International Non Proprietary Names (Prop. INN): List 105 Denominations communes internationales proposées (DCI Prop.): Liste 105 Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 105 (WHO Drug Information, Vol. 25, No. 2, 2011) p. 165 daclatasvirum daclatasvir replace the CAS RN by the following

daclatasvir remplacer le numéro de registre du CAS par le suivant

daclatasvir sustitúyase el número de registro del CAS por el siguiente

1009119-64-5

p. 178 lipegfilgrastimum # lipegfilgrastim replace the description and the structure by the following ones

lipegfilgrastim remplacer la description et la structure par les suivantes

lipegfilgrastim sustitúyase la descripción y la estructura por las siguientes

pegylated granulocyte colony stimulating factor (human short isoform); O3.137-[{3,5-dideoxy-5-[(N-{[ω-methoxypoly(oxyethylene)]carbonyl}glycyl)amino]- D-glycero-α-D-galacto-non-2-ulopyranosylonic acid}-(2→6)-2-(acetylamino)-2-deoxy- α-D-galactopyranosyl]-des-(37-39)-[1-methionine]human granulocyte colony-stimulating factor (G-CSF, pluripoietin)

facteur de stimulation de colonie de granulocytes (isoforme court humain) pégylé; O3.137-[{acide 3,5-didéoxy-5-[(N-{[ω-méthoxypoly(oxyéthylène)]carbonyl}glycyl)amino]-D-glycéro-α-D-galacto-non-2-ulopyranosylonique}-(2→6)-2-(acétylamino)-2-déoxy-α-D-galactopyranosyl]-dès-(37-39)-[1-méthionine]facteur humain de stimulation de colonie de granulocytes (G-CSF, pluripoïétine)


221

factor de estimulacin de colonías de granulocitos (isoformo corto humano) pegilado; O3.137-[{acído 3,5-didesoxi-5-[(N-{[ω-metoxipoli(oxietileni)]carbonil}glicil)amino]- D-glicero-α-D-galacto-non-2-ulopiranosilonico}-(2→6)-2-(acetilamino)-2-desoxi- α-D-galactopiranosil]-dès-(37-39)-[1-metionina]factor humano de estimulación de colonías de granulocitos (G-CSF, pluripoyetina)

OCO2H

OH

H

HO OH

HO

HN

O

O

H

H2N CO2H

CH3

O

O

HO

HO NH

HNO

O

O

H3C

n

CH3

O

MTPLGPASSL PQSFLLKCLE QVRKIQGDGA ALQEKL---C ATYKLCHPEE 50LVLLGHSLGI PWAPLSSCPS QALQLAGCLS QLHSGLFLYQ GLLQALEGIS 100PELGPTLDTL QLDVADFATT IWQQMEELGM APALQPTQGA MPAFASAFQR 150RAGGVLVASH LQSFLEVSYR VLRHLAQP 178


Modified residues / Résidu modifié / Residuo modificado

T137

PEG-Gly-Neu-GalNac-Thr

p. 189 delete/supprimer/suprimáse insert/insérer/insertese pictrelisibum pictilisibum

pictrelisib pictilisib

pictrélisib pictilisib

pictrelisib pictilisib

Proposed International Non Proprietary Names (Prop. INN): List 106Denominations communes internationales proposées (DCI Prop.): Liste 106Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 106 (WHO Drug Information, Vol. 25, No. 4, 2011) p. 415 delete/supprimer/suprimáse insert/insérer/insertese ácido florilglutamic (18F) ácido florilglútamico (18F)

p. 416 brexpiprazolum brexpiprazole replace the molecular formula by the following

brexpiprazole remplacer la formule moléculaire brute par la suivante

brexpiprazol sustitúyase la fórmula molecular por la siguiente

C25H27N3O2S

p. 434 delete/supprimer/suprimáse insert/insérer/insertese samidorfán samidorfano


222

ANNEX 1

PROCEDURE FOR THE SELECTION OF RECOMMENDED INTERNATIONAL

NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES1

The following procedure shall be followed by the World Health Organization (hereinafter also referred to as “WHO”) in the selection of recommended international nonproprietary names for pharmaceutical substances, in accordance with resolution WHA3.11 of the World Health Assembly, and in the substitution of such names. Article 1 - Proposals for recommended international nonproprietary names and proposals for substitution of such names shall be submitted to WHO on the form provided therefore. The consideration of such proposals shall be subject to the payment of an administrative fee designed only to cover the corresponding costs of the Secretariat of WHO (“the Secretariat”). The amount of this fee shall be determined by the Secretariat and may, from time to time, be adjusted. Article 2 - Such proposals shall be submitted by the Secretariat to the members of the Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations designated for this purpose, such designated members hereinafter referred to as “the INN Expert Group”, for consideration in accordance with the “General principles for guidance in devising International Nonproprietary Names for Pharmaceutical Substances”, annexed to this procedure2. The name used by the person discovering or first developing and marketing a pharmaceutical substance shall be accepted, unless there are compelling reasons to the contrary. Article 3 - Subsequent to the examination provided for in article 2, the Secretariat shall give notice that a proposed international nonproprietary name is being considered. a) Such notice shall be given by publication in WHO Drug Information3

and by letter to Member States and to national and regional pharmacopoeia commissions or other bodies designated by Member States.

i) Notice shall also be sent to the person who submitted the proposal (“the original applicant”) and other persons known to be concerned with a name under consideration.

b) Such notice shall:

i) set forth the name under consideration; ii) identify the person who submitted the proposal for naming the substance, if so requested by such person; iii) identify the substance for which a name is being considered; iv) set forth the time within which comments and objections will be received and the person and place to whom they should be directed; v) state the authority under which WHO is acting and refer to these rules of procedure.

c) In forwarding the notice, the Secretariat shall request that Member States take such steps as are necessary to prevent the acquisition of proprietary rights in the proposed name during the period it is under consideration by WHO. Article 4 - Comments on the proposed name may be forwarded by any person to WHO within four months of the date of publication, under article 3, of the name in WHO Drug Information.

1 See Annex 1 in WHO Technical Report Series, No. 581, 1975. The original text was adopted by the Executive Board in resolution EB15.R7 and amended in resolutions EB43.R9 and EB115.R4.

2 See Annex 2.

3 Before 1987, lists of international nonproprietary names were published in the Chronicle of the World Health Organization.


223

Article 5 - A formal objection to a proposed name may be filed by any interested person within four months of the date of publication, under article 3, of the name in WHO Drug Information.

Such objection shall:

i) identify the person objecting;

ii) state his or her interest in the name; iii) set forth the reasons for his or her objection to the name proposed. Article 6 - Where there is a formal objection under article 5, WHO may either reconsider the proposed name or use its good offices to attempt to obtain withdrawal of the objection. Without prejudice to the consideration by WHO of a substitute name or names, a name shall not be selected by WHO as a recommended international nonproprietary name while there exists a formal objection thereto filed under article 5 which has not been withdrawn. Article 7 - Where no objection has been filed under article 5, or all objections previously filed have been withdrawn, the Secretariat shall give notice in accordance with subsection (a) of article 3 that the name has been selected by WHO as a recommended international nonproprietary name. Article 8 - In forwarding a recommended international nonproprietary name to Member States under article 7, the Secretariat shall: a) request that it be recognized as the nonproprietary name for the substance; and b) request that Member States take such steps as are necessary to prevent the acquisition of proprietary rights in the name and to prohibit registration of the name as a trademark or trade name. Article 9 a) In the extraordinary circumstance that a previously recommended international nonproprietary name gives rise to errors in medication, prescription or distribution, or a demonstrable risk thereof, because of similarity with another name in pharmaceutical and/or prescription practices, and it appears that such errors or potential errors cannot readily be resolved through other interventions than a possible substitution of a previously recommended international nonproprietary name, or in the event that a previously recommended international nonproprietary name differs substantially from the nonproprietary name approved in a significant number of Member States, or in other such extraordinary circumstances that justify a substitution of a recommended international nonproprietary name, proposals to that effect may be filed by any interested person. Such proposals shall be submitted on the form provided therefore and shall: i) identify the person making the proposal;

ii) state his or her interest in the proposed substitution; and iii) set forth the reasons for the proposal; and

iv) describe, and provide documentary evidence regarding the other interventions undertaken in an effort to resolve the situation, and the reasons why these other interventions were inadequate.

Such proposals may include a proposal for a new substitute international nonproprietary name, devised in accordance with the General principles, which takes into account the pharmaceutical substance for which the new substitute international nonproprietary name is being proposed. The Secretariat shall forward a copy of the proposal, for consideration in accordance with the procedure described in subsection (b) below, to the INN Expert Group and the original applicant or its successor (if different from the person bringing the proposal for substitution and provided that the original applicant or its successor is known or can be found through diligent effort, including contacts with industry associations). In addition, the Secretariat shall request comments on the proposal from:

i) Member States and national and regional pharmacopoeia commissions or other bodies designated by Member States (by including a notice to that effect in the letter referred to in article 3(a), and

ii) any other persons known to be concerned by the proposed substitution.


224

The request for comments shall:

i) state the recommended international nonproprietary name that is being proposed for substitution (and the proposed substitute name, if provided);

ii) identify the person who submitted the proposal for substitution (if so requested by such person);

iii) identify the substance to which the proposed substitution relates and reasons put forward for substitution; iv) set forth the time within which comments will be received and the person and place to whom they should be directed; and v) state the authority under which WHO is acting and refer to these rules of procedure.

Comments on the proposed substitution may be forwarded by any person to WHO within four months of the date of the request for comments. b) After the time period for comments referred to above has elapsed, the Secretariat shall forward any comments received to the INN Expert Group, the original applicant or its successor and the person bringing the proposal for substitution. If, after consideration of the proposal for substitution and the comments received, the INN Expert Group, the person bringing the proposal for substitution and the original applicant or its successor all agree that there is a need to substitute the previously recommended international nonproprietary name, the Secretariat shall submit the proposal for substitution to the INN Expert Group for further processing. Notwithstanding the foregoing, the original applicant or its successor shall not be entitled to withhold agreement to a proposal for substitution in the event the original applicant or its successor has no demonstrable continuing interest in the recommended international nonproprietary name proposed for substitution.

In the event that a proposal for substitution shall be submitted to the INN Expert Group for further processing, the INN Expert Group will select a new international nonproprietary name in accordance with the General principles referred to in article 2 and the procedure set forth in articles 3 to 8 inclusive. The notices to be given by the Secretariat under article 3 and article 7, respectively, including to the original applicant or its successor (if not the same as the person proposing the substitution, and provided that the original applicant or its successor is known or can be found through diligent effort, including contacts with industry associations), shall in such event indicate that the new name is a substitute for a previously recommended international nonproprietary name and that Member States may wish to make transitional arrangements in order to accommodate existing products that use the previously recommended international nonproprietary name on their label in accordance with national legislation.

If, after consideration of the proposal for substitution and the comments received in accordance with the procedure described above, the INN Expert Group, the original applicant or its successor and the person bringing the proposal for substitution do not agree that there are compelling reasons for substitution of a previously recommended international nonproprietary name, this name shall be retained (provided always that the original applicant or its successor shall not be entitled to withhold agreement to a proposal for substitution in the event that the original applicant or its successor has no demonstrable continuing interest in the recommended international nonproprietary name proposed to be substituted). In such an event, the Secretariat shall advise the person having proposed the substitution, as well as the original applicant or its successor (if not the same as the person proposing the substitution, and provided that the original applicant or its successor is known or can be found through diligent effort, including contacts with industry associations), Member States, national and regional pharmacopoeia commissions, other bodies designated by Member States, and any other persons known to be concerned by the proposed substitution that, despite a proposal for substitution, it has been decided to retain the previously recommended international nonproprietary name (with a description of the reason(s) why the proposal for substitution was not considered sufficiently compelling).


225

ANNEX 2

GENERAL PRINCIPLES FOR GUIDANCE IN DEVISING INTERNATIONAL NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES1

1. International Nonproprietary Names (INN) should be distinctive in sound and spelling. They should not be inconveniently long and should not be liable to confusion with names in common use.

2. The INN for a substance belonging to a group of pharmacologically related substances should, where appropriate, show this relationship. Names that are likely to convey to a patient an anatomical, physiological, pathological or therapeutic suggestion should be avoided.

These primary principles are to be implemented by using the following secondary principles:

3. In devising the INN of the first substance in a new pharmacological group, consideration should be given to the possibility of devising suitable INN for related substances, belonging to the new group.

4. In devising INN for acids, one-word names are preferred; their salts should be named without modifying the acid name, e.g. “oxacillin” and “oxacillin sodium”, “ibufenac” and “ibufenac sodium”.

5. INN for substances which are used as salts should in general apply to the active base or the active acid. Names for different salts or esters of the same active substance should differ only in respect of the name of the inactive acid or the inactive base. For quaternary ammonium substances, the cation and anion should be named appropriately as separate components of a quaternary substance and not in the amine-salt style.

6. The use of an isolated letter or number should be avoided; hyphenated construction is also undesirable.

7. To facilitate the translation and pronunciation of INN, “f” should be used instead of “ph”, “t” instead of “th”, “e” instead of “ae” or “oe”, and “i” instead of “y”; the use of the letters “h” and “k” should be avoided.

8. Provided that the names suggested are in accordance with these principles, names proposed by the person discovering or first developing and marketing a pharmaceutical preparation, or names already officially in use in any country, should receive preferential consideration.

9. Group relationship in INN (see General principle 2) should if possible be shown by using a common stem. The following list contains examples of stems for groups of substances, particularly for new groups. There are many other stems in active use.2 Where a stem is shown without any hyphens it may be used anywhere in the name. Latin English -acum -ac anti-inflammatory agents, ibufenac derivatives -adolum -adol } analgesics -adol- -adol-} -astum -ast antiasthmatic, antiallergic substances not acting primarily as antihistaminics -astinum -astine antihistaminics -azepamum -azepam diazepam derivatives bol bol steroids, anabolic -cain- -cain- class I antiarrhythmics, procainamide and lidocaine derivatives -cainum -caine local anaesthetics 1

In its Twentieth report (WHO Technical Report Series, No. 581, 1975), the WHO Expert committee on Nonproprietary Names for Pharmaceutical Substances reviewed the general principles for devising, and the procedures for selecting, INN in the light of developments in pharmaceutical compounds in recent years. The most significant change has been the extension to the naming of synthetic chemical substances of the practice previously used for substances originating in or derived from natural products. This practice involves the use of a characteristic “stem” indicative of a common property of the members of a group. The reason for, and the implications of, the change are fully discussed. The guiding principles were updated during the 13th consultation on nonproprietary names for pharmaceutical substances (Geneva, 27-29 April 1983) (PHARM S/NOM 928 13 May 1983, revised 18 August 1983).

2 A more extensive listing of stems is contained in the working document WHO/EMP/QSM/2011.3 which is regularly updated and can be requested from the INN Programme, WHO, Geneva.


226

cef- cef- antibiotics, cefalosporanic acid derivatives -cillinum -cillin antibiotics, 6-aminopenicillanic acid derivatives -conazolum -conazole systemic antifungal agents, miconazole derivatives cort cort corticosteroids, except prednisolone derivatives -coxibum -coxib selective cyclo-oxygenase inhibitors -entanum -entan endothelin receptor antagonists gab gab gabamimetic agents gado- gado- diagnostic agents, gadolinium derivatives -gatranum -gatran thrombin inhibitors, antithrombotic agents gest gest steroids, progestogens gli gli antihyperglycaemics io- io- iodine-containing contrast media -metacinum -metacin anti-inflammatory, indometacin derivatives -mycinum -mycin antibiotics, produced by Streptomyces strains -nidazolum -nidazole antiprotozoals and radiosensitizers, metronidazole derivatives -ololum -olol β-adrenoreceptor antagonists -oxacinum -oxacin antibacterial agents, nalidixic acid derivatives -platinum -platin antineoplastic agents, platinum derivatives -poetinum -poetin erythropoietin type blood factors -pril(at)um -pril(at) angiotensin-converting enzyme inhibitors -profenum -profen anti-inflammatory agents, ibuprofen derivatives prost prost prostaglandins -relinum -relin pituitary hormone release-stimulating peptides -sartanum -sartan angiotensin II receptor antagonists, antihypertensive (non-peptidic) -vaptanum -vaptan vasopressin receptor antagonists vin- vin- } vinca-type alkaloids -vin- -vin-}

ANNEXE 1

PROCEDURE A SUIVRE EN VUE DU CHOIX DE DENOMINATIONS COMMUNES INTERNATIONALES RECOMMANDEES POUR LES SUBSTANCES

PHARMACEUTIQUES1

L’Organisation mondiale de la Santé (également désignée ci-après sous l’appellation « OMS ») observe la procédure exposée ci-dessous pour l’attribution de dénominations communes internationales recommandées pour les substances pharmaceutiques, conformément à la résolution WHA3.11 de l’Assemblée mondiale de la Santé, et pour le remplacement de telles dénominations. Article 1 - Les propositions de dénominations communes internationales recommandées et les propositions de remplacement de telles dénominations sont soumises à l’OMS sur la formule prévue à cet effet. L’examen de telles propositions est soumis au paiement d’une taxe administrative destinée uniquement à couvrir les coûts correspondants assumés par le Secrétariat de l’OMS (« le Secrétariat »). Le montant de cette taxe est déterminé par le Secrétariat et peut être modifié de temps à autre. Article 2 - Ces propositions sont soumises par le Secrétariat aux experts désignés à cette fin parmi les personnalités inscrites au Tableau d’experts de la Pharmacopée internationale et des Préparations pharmaceutiques, ci-après désignés sous l’appellation « le Groupe d’experts des DCI » ; elles sont examinées par les experts conformément aux « Directives générales pour la formation de dénominations communes internationales pour les substances pharmaceutiques » reproduites ci-après2.

La dénomination acceptée est la dénomination employée par la personne qui découvre ou qui, la première, fabrique et lance sur le marché une substance pharmaceutique, à moins que des raisons majeures n’obligent à s’écarter de cette règle.

1 Voir annexe 1 dans OMS, Série de Rapports techniques, N° 581, 1975. Le texte original a été adopté par le Conseil exécutif dans sa résolution EB15.R7 et amendé dans ses résolutions EB43.R9 et EB115.R4.

2 Voir annexe 2.


227

Article 3 - Après l’examen prévu à l’article 2, le Secrétariat notifie qu’un projet de dénomination commune internationale est à l’étude. a) Cette notification est faite par une insertion dans WHO Drug Information1 et par l’envoi d’une lettre aux Etats Membres et aux commissions nationales et régionales de pharmacopée ou autres organismes désignés par les Etats Membres.

i) Notification est également faite à la personne qui a soumis la proposition (« le demandeur initial ») et à d’autres personnes portant à la dénomination mise à l’étude un intérêt notoire.

b) Cette notification contient les indications suivantes :

i) dénomination mise à l’étude;

ii) nom de l’auteur de la proposition tendant à attribuer une dénomination à la substance, si cette personne le demande ;

iii) définition de la substance dont la dénomination est mise à l’étude ;

iv) délai pendant lequel seront reçues les observations et les objections à l’égard de cette dénomination ; nom et adresse de la personne habilitée à recevoir ces observations et objections ;

v) mention des pouvoirs en vertu desquels agit l’OMS et référence au présent règlement.

c) En envoyant cette notification, le Secrétariat demande aux Etats Membres de prendre les mesures nécessaires pour prévenir l’acquisition de droits de propriété sur la dénomination proposée pendant la période au cours de laquelle cette dénomination est mise à l’étude par l’OMS. Article 4 - Des observations sur la dénomination proposée peuvent être adressées à l’OMS par toute personne, dans les quatre mois qui suivent la date de publication de la dénomination dans WHO Drug Information (voir l’article 3). Article 5 - Toute personne intéressée peut formuler une objection formelle contre la dénomination proposée dans les quatre mois qui suivent la date de publication de la dénomination dans WHO Drug Information (voir l’article 3). Cette objection doit s’accompagner des indications suivantes :

i) nom de l’auteur de l’objection ; ii) intérêt qu’il ou elle porte à la dénomination en cause ; iii) raisons motivant l’objection contre la dénomination proposée. Article 6 - Lorsqu’une objection formelle est formulée en vertu de l’article 5, l’OMS peut soit soumettre la dénomination proposée à un nouvel examen, soit intervenir pour tenter d’obtenir le retrait de l’objection. Sans préjudice de l’examen par l’OMS d’une ou de plusieurs appellations de remplacement, l’OMS n’adopte pas d’appellation comme dénomination commune internationale recommandée tant qu’une objection formelle présentée conformément à l’article 5 n’est pas levée. Article 7 - Lorsqu’il n’est formulé aucune objection en vertu de l’article 5, ou que toutes les objections présentées ont été levées, le Secrétariat fait une notification conformément aux dispositions du paragraphe a) de l’article 3, en indiquant que la dénomination a été choisie par l’OMS en tant que dénomination commune internationale recommandée. Article 8 - En communiquant aux Etats Membres, conformément à l’article 7, une dénomination commune internationale recommandée, le Secrétariat : a) demande que cette dénomination soit reconnue comme dénomination commune de la substance considérée ; et b) demande aux Etats Membres de prendre les mesures nécessaires pour prévenir l’acquisition de droits de propriété sur cette dénomination et interdire le dépôt de cette dénomination comme marque ou appellation commerciale. 1

Avant 1987, les listes de dénominations communes internationales étaient publiées dans la Chronique de l’Organisation mondiale de la Santé.


228

Article 9 - a) Dans le cas exceptionnel où une dénomination commune internationale déjà recommandée donne lieu à des erreurs de médication, de prescription ou de distribution ou en comporte un risque démontrable, en raison d’une similitude avec une autre appellation dans la pratique pharmaceutique et/ou de prescription, et où il apparaît que ces erreurs ou ces risques d’erreur ne peuvent être facilement évités par d’autres interventions que le remplacement éventuel d’une dénomination commune internationale déjà recommandée, ou dans le cas où une dénomination commune internationale déjà recommandée diffère sensiblement de la dénomination commune approuvée dans un nombre important d’Etats Membres, ou dans d’autres circonstances exceptionnelles qui justifient le remplacement d’une dénomination commune internationale recommandée, toute personne intéressée peut formuler une proposition dans ce sens. Cette proposition est présentée sur la formule prévue à cet effet et doit s’accompagner des indications suivantes :

i) nom de l’auteur de la proposition ;

ii) intérêt qu’il ou elle porte au remplacement proposé ;

iii) raisons motivant la proposition ; et

iv) description, faits à l’appui, des autres interventions entreprises pour tenter de régler le problème et exposé des raisons pour lesquelles ces interventions ont échoué.

Les propositions peuvent comprendre une proposition de nouvelle dénomination commune internationale de remplacement, établie conformément aux Directives générales, compte tenu de la substance pharmaceutique pour laquelle la nouvelle dénomination commune internationale de remplacement est proposée. Le Secrétariat transmet une copie de la proposition pour examen, conformément à la procédure exposée plus loin au paragraphe b), au Groupe d’experts des DCI et au demandeur initial ou à son successeur (s’il s’agit d’une personne différente de celle qui a formulé la proposition de remplacement et pour autant que le demandeur initial ou son successeur soit connu ou puisse être retrouvé moyennant des efforts diligents, notamment des contacts avec les associations industrielles). De plus, le Secrétariat demande aux entités et personnes ci-après de formuler des observations sur la proposition :

i) les Etats Membres et les commissions nationales et régionales de pharmacopée ou d’autres organismes désignés par les Etats Membres (en insérant une note à cet effet dans la lettre mentionnée à l’article 3.a), et

ii) toutes autres personnes portant au remplacement proposé un intérêt notoire. La demande d’observations contient les indications suivantes : i) dénomination commune internationale recommandée pour laquelle un remplacement est proposé (et la dénomination de remplacement proposée, si elle est fournie) ; ii) nom de l’auteur de la proposition de remplacement (si cette personne le demande) ; iii) définition de la substance faisant l’objet du remplacement proposé et raisons avancées pour le remplacement ; iv) délai pendant lequel seront reçus les commentaires et nom et adresse de la personne habilitée à recevoir ces commentaires ; et v) mention des pouvoirs en vertu desquels agit l’OMS et référence au présent règlement. Des observations sur la proposition de remplacement peuvent être communiquées par toute personne à l’OMS dans les quatre mois qui suivent la date de la demande d’observations. b) Une fois échu le délai prévu ci-dessus pour la communication d’observations, le Secrétariat transmet les observations reçues au Groupe d’experts des DCI, au demandeur initial ou à son successeur et à l’auteur de la proposition de remplacement. Si, après avoir examiné la proposition de remplacement et les observations reçues, le Groupe d’experts des DCI, l’auteur de la proposition de remplacement et le demandeur initial ou son successeur reconnaissent tous qu’il est nécessaire de remplacer la dénomination commune internationale déjà recommandée, le Secrétariat soumet la proposition de remplacement au Groupe d’experts des DCI pour qu’il y donne suite.


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Nonobstant ce qui précède, le demandeur initial ou son successeur n’est pas habilité à refuser son accord à une proposition de remplacement au cas où il ne peut être démontré qu’il porte un intérêt durable à la dénomination commune internationale recommandée qu’il est proposé de remplacer.

Dans le cas où une proposition de remplacement est soumise au Groupe d’experts des DCI pour qu’il y donne

suite, le Groupe choisit une nouvelle dénomination commune internationale conformément aux Directives générales mentionnées à l’article 2 et selon la procédure décrite dans les articles 3 à 8 inclus. La notification faite par le Secrétariat en vertu de l’article 3 et de l’article 7, respectivement, y compris au demandeur initial ou à son successeur (si ce n’est pas la même personne que celle qui a proposé le remplacement et pour autant que le demandeur initial ou son successeur soit connu ou puisse être retrouvé moyennant des efforts diligents, notamment des contacts avec les associations industrielles), doit dans un tel cas indiquer que la nouvelle dénomination remplace une dénomination commune internationale déjà recommandée et que les Etats Membres peuvent souhaiter prendre des mesures transitoires pour les produits existants qui utilisent la dénomination commune internationale déjà recommandée sur leur étiquette conformément à la législation nationale.

Si, après examen de la proposition de remplacement et des observations communiquées conformément à la

procédure exposée plus haut, le Groupe d’experts des DCI, le demandeur initial ou son successeur et l’auteur de la proposition de remplacement ne s’accordent pas sur le fait qu’il y a des raisons impératives de remplacer une dénomination commune internationale déjà recommandée, cette dernière est conservée (étant entendu toujours que le demandeur initial ou son successeur n’est pas habilité à refuser son accord à une proposition de remplacement au cas où il ne peut être démontré qu’il porte un intérêt durable à la dénomination commune internationale recommandée qu’il est proposé de remplacer). Dans un tel cas, le Secrétariat informe l’auteur de la proposition de remplacement, ainsi que le demandeur initial ou son successeur (s’il s’agit d’une personne différente de celle qui a formulé la proposition de remplacement et pour autant que le demandeur initial ou son successeur soit connu ou puisse être retrouvé moyennant des efforts diligents, notamment des contacts avec les associations industrielles), les Etats Membres, les commissions nationales et régionales de pharmacopée, les autres organismes désignés par les Etats Membres et toutes autres personnes portant un intérêt notoire au remplacement proposé que, malgré une proposition de remplacement, il a été décidé de conserver la dénomination commune internationale déjà recommandée (avec une brève description de la ou des raisons pour lesquelles la proposition de remplacement n’a pas été jugée suffisamment impérative).

ANNEXE 2

DIRECTIVES GENERALES POUR LA FORMATION DE DENOMINATIONS

COMMUNES INTERNATIONALES APPLICABLES AUX SUBSTANCES PHARMACEUTIQUES1

1. Les dénominations communes internationales (DCI) devront se distinguer les unes des autres par leur consonance et leur orthographe. Elles ne devront pas être d’une longueur excessive, ni prêter à confusion avec des appellations déjà couramment employées. 2. La DCI de chaque substance devra, si possible, indiquer sa parenté pharmacologique. Les dénominations susceptibles d’évoquer pour les malades des considérations anatomiques, physiologiques, pathologiques ou thérapeutiques devront être évitées dans la mesure du possible. Outre ces deux principes fondamentaux, on respectera les principes secondaires suivants : 1. Lorsqu’on formera la DCI de la première substance d’un nouveau groupe pharmacologique, on tiendra compte de

la possibilité de former ultérieurement d’autres DCI appropriées pour les substances apparentées du même groupe.

1

Dans son vingtième rapport (OMS, Série de Rapports techniques, N° 581, 1975), le Comité OMS d’experts des Dénominations communes pour les Substances pharmaceutiques a examiné les directives générales pour la formation des dénominations communes internationales et la procédure à suivre en vue de leur choix, compte tenu de l’évolution du secteur pharmaceutique au cours des dernières années. La modification la plus importante a été l’extension aux substances de synthèse de la pratique normalement suivie pour désigner les substances tirées ou dérivées de produits naturels. Cette pratique consiste à employer des syllabes communes ou groupes de syllabes communes (segments-clés) qui sont caractéristiques et indiquent une propriété commune aux membres du groupe des substances pour lequel ces segments-clés ont été retenus. Les raisons et les conséquences de cette modification ont fait l’objet de discussions approfondies. Les directives ont été mises à jour lors de la treizième consultation sur les dénominations communes pour les substances pharmaceutiques (Genève, 27-29 avril 1983) (PHARM S/NOM 928, 13 mai 1983, révision en date du 18 août 1983).


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4. Pour former des DCI des acides, on utilisera de préférence un seul mot. Leurs sels devront être désignés par un terme qui ne modifie pas le nom de l’acide d’origine : par exemple «oxacilline» et «oxacilline sodique», «ibufénac» et «ibufénac sodique».

5. Les DCI pour les substances utilisées sous forme de sels devront en général s’appliquer à la base active (ou à l’acide actif). Les dénominations pour différents sels ou esters d’une même substance active ne différeront que par le nom de l’acide inactif (ou de la base inactive). En ce qui concerne les substances à base d’ammonium quaternaire, la dénomination s’appliquera de façon appropriée au cation et à l’anion en tant qu’éléments distincts d’une substance quaternaire. On évitera de choisir une désignation évoquant un sel aminé.

6. On évitera d’ajouter une lettre ou un chiffre isolé ; en outre, on renoncera de préférence au trait d’union.

7. Pour simplifier la traduction et la prononciation des DCI, la lettre « f » sera utilisée à la place de « ph », « t » à la place de « th », « e » à la place de « ae » ou « oe », et « i » à la place de « y » ; l’usage des lettres « h » et « k » sera aussi évité.

8. On retiendra de préférence, pour autant qu’elles respectent les principes énoncés ici, les dénominations proposées par les personnes qui ont découvert ou qui, les premières, ont fabriqué et lancé sur le marché les préparations pharmaceutiques considérées, ou les dénominations déjà officiellement adoptées par un pays.

9. La parenté entre substances d’un même groupe (voir Directive générale 2) sera si possible indiquée dans les DCI par l’emploi de segments-clés communs. La liste ci-après contient des exemples de segments-clés pour des groupes de substances, surtout pour des groupes récents. Il y a beaucoup d’autres segments-clés en utilisation active. 1 Les segments-clés indiqués sans trait d’union pourront être insérés n’importe où dans une dénomination. Latin Français -acum -ac substances anti-inflammatoires du groupe de l’ibufénac -adolum -adol } analgésiques -adol- -adol- }

-astum -ast antiasthmatiques, antiallergiques n’agissant pas principalement en tant qu’antihistaminiques -astinum -astine antihistaminiques -azepamum -azépam substances du groupe du diazépam bol bol stéroïdes anabolisants -cain- -caïn- antiarythmiques de classe I, dérivés du procaïnamide et de la lidocaïne -cainum -caïne anesthésiques locaux cef- céf- antibiotiques, dérivés de l’acide céphalosporanique -cillinum -cilline antibiotiques, dérivés de l’acide 6-aminopénicillanique -conazolum -conazole agents antifongiques systémiques du groupe du miconazole cort cort corticostéroïdes, autres que les dérivés de la prednisolone -coxibum -coxib inhibiteurs sélectifs de la cyclo-oxygénase -entanum -entan antagonistes du récepteur de l’endothéline gab gab gabamimétiques gado- gado- agents diagnostiques, dérivés du gadolinium -gatranum -gatran antithrombines, antithrombotiques gest gest stéroïdes progestogènes gli gli antihyperglycémiants io- io- produits de contraste iodés -metacinum -métacine anti-inflammatoires du groupe de l’indométacine -mycinum -mycine antibiotiques produits par des souches de Streptomyces -nidazolum -nidazole antiprotozoaires et radiosensibilisants, du groupe du métronidazole -ololum -olol antagonistes des récepteurs β-adrénergiques -oxacinum -oxacine substances antibactériennes du groupe de l’acide nalidixique -platinum -platine antinéoplasiques, dérivés du platine -poetinum -poétine facteurs sanguins de type érythropoïétine -pril(at)um -pril(ate) inhibiteurs de l’enzyme de conversion de l’angiotensine -profenum -profène anti-inflammatoires du groupe de l’ibuprofène prost prost prostaglandines

1

Une liste plus complète de segments-clés est contenue dans le document de travail WHO/EMP/QSM/2011.3 qui est régulièrement mis à jour et qui peut être demandé auprès du programme des DCI, OMS, Genève.


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-relinum -réline peptides stimulant la libération d’hormones hypophysaires -sartanum -sartan antagonistes d’un récepteur de l’angiotensine II, antihypertenseurs (non peptidiques) -vaptanum -vaptan antagonistes du récepteur de la vasopressine vin- vin- } alcaloïdes du type vinca -vin- -vin- }

ANEXO 1

PROCEDIMIENTO DE SELECCIÓN DE DENOMINACIONES COMUNES INTERNACIONALES RECOMENDADAS PARA SUSTANCIAS FARMACÉUTICAS1

La Organización Mundial de la Salud (OMS) seguirá el procedimiento que se expone a continuación tanto para seleccionar denominaciones comunes internacionales recomendadas para las sustancias farmacéuticas, de conformidad con lo dispuesto en la resolución WHA3.11, como para sustituir esas denominaciones. Artículo 1 - Las propuestas de denominaciones comunes internacionales recomendadas y las propuestas de sustitución de esas denominaciones se presentarán a la OMS en los formularios que se proporcionen a estos efectos. El estudio de estas propuestas estará sujeto al pago de una tasa destinada a sufragar los costos de administración que ello suponga para la Secretaría de la OMS («la Secretaría»). La Secretaría establecerá la cuantía de esa tasa y podrá ajustarla periódicamente. Artículo 2 - Estas propuestas serán sometidas por la Secretaría a los miembros del Cuadro de Expertos en Farmacopea Internacional y Preparaciones Farmacéuticas encargados de su estudio, en adelante designados como «el Grupo de Expertos en DCI», para que las examinen de conformidad con los «Principios generales de orientación para formar denominaciones comunes internacionales para sustancias farmacéuticas», anexos a este procedimiento.2 A menos que haya poderosas razones en contra, la denominación aceptada será la empleada por la persona que haya descubierto o fabricado y comercializado por primera vez esa sustancia farmacéutica. Artículo 3 - Tras el examen al que se refiere el artículo 2, la Secretaría notificará que está en estudio un proyecto de denominación internacional. a) Esa notificación se hará mediante una publicación en Información Farmacéutica OMS3

y el envío de una carta a los Estados Miembros y a las comisiones nacionales y regionales de las farmacopeas u otros organismos designados por los Estados Miembros.

i) La notificación será enviada también a la persona que haya presentado la propuesta («el solicitante inicial») y a otras personas que tengan un interés especial en una denominación objeto de estudio.

b) En esa notificación se incluirán los siguientes datos: i) la denominación sometida a estudio; ii) la identidad de la persona que ha presentado la propuesta de denominación de la sustancia, si lo pide esa persona; iii) la identidad de la sustancia cuya denominación está en estudio; iv) el plazo fijado para recibir observaciones y objeciones, así como el nombre y la dirección de la persona a quien deban dirigirse; y v) los poderes conferidos para el caso a la OMS y una referencia al presente procedimiento.

1 Véase el anexo 1 en OMS, Serie de Informes Técnicos, Nº 581, 1975. El texto vigente fue adoptado por el Consejo Ejecutivo en su resolución EB15.R7 y modificado en las resoluciónes EB43.R9 y EB115.R4..

2 Véase el anexo 2.

3 Hasta 1987 las listas de DCI se publicaban en la Crónica de la Organización Mundial de la Salud.


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c) Al enviar esa notificación, la Secretaría solicitará de los Estados Miembros la adopción de todas las medidas necesarias para impedir la adquisición de derechos de patente sobre la denominación propuesta, durante el periodo en que la OMS la tenga en estudio. Artículo 4 - Toda persona puede formular a la OMS observaciones sobre la denominación propuesta dentro de los cuatro meses siguientes a su publicación en Información Farmacéutica OMS, conforme a lo dispuesto en el artículo 3. Artículo 5 - Toda persona interesada puede presentar una objeción formal a una denominación propuesta dentro de los cuatro meses siguientes a su publicación en Información Farmacéutica OMS, conforme a lo dispuesto en el artículo 3. Esa objeción deberá acompañarse de los siguientes datos:

i) la identidad de la persona que formula la objeción; ii) las causas que motivan su interés por la denominación; y iii) las causas que motivan su objeción a la denominación propuesta.

Artículo 6 - Cuando se haya presentado una objeción formal en la forma prevista en el artículo 5, la OMS podrá reconsiderar el nombre propuesto o utilizar sus buenos oficios para intentar lograr que se retire la objeción. La OMS no seleccionará como denominación común internacional una denominación a la que se haya hecho una objeción formal, presentada según lo previsto en el artículo 5, que no haya sido retirada, todo ello sin perjuicio de que la Organización examine otra denominación o denominaciones sustitutivas. Artículo 7 - Cuando no se haya formulado ninguna objeción en la forma prevista en el artículo 5, o cuando todas las objeciones presentadas hayan sido retiradas, la Secretaría notificará, conforme a lo dispuesto en el párrafo a) del artículo 3, que la denominación ha sido seleccionada por la OMS como denominación común internacional recomendada. Artículo 8 - Al comunicar a los Estados Miembros una denominación común internacional, conforme a lo previsto en el artículo 7, la Secretaría: a) solicitará que esta denominación sea reconocida como denominación común para la sustancia de que se trate; y b) solicitará a los Estados Miembros que adopten todas las medidas necesarias para impedir la adquisición de derechos de patente sobre la denominación, y prohíban que sea registrada como marca de fábrica o como nombre comercial. Artículo 9 a) En el caso excepcional de que, debido a su semejanza con otra denominación utilizada en las prácticas farmacéuticas y/o de prescripción, una denominación común internacional recomendada anteriormente ocasione errores de medicación, prescripción o distribución, o suponga un riesgo manifiesto de que esto ocurra, y parezca que tales errores o potenciales errores no sean fácilmente subsanables con otras medidas que no sean la posible sustitución de esa denominación común internacional recomendada anteriormente; en el caso de que una denominación común internacional recomendada anteriormente difiera considerablemente de la denominación común aprobada en un número importante de Estados Miembros, o en otras circunstancias excepcionales que justifiquen el cambio de una denominación común internacional recomendada, cualquier persona interesada puede presentar propuestas en este sentido. Esas propuestas se presentarán en los formularios que se proporcionen a estos efectos e incluirán los siguientes datos:

i) la identidad de la persona que presenta la propuesta;

ii) las causas que motivan su interés en la sustitución propuesta;

iii) las causas que motivan la propuesta; y

iv) una descripción, acompañada de pruebas documentales, de las otras medidas que se hayan adoptado con el fin de resolver la situación y de los motivos por los cuales dichas medidas no han sido suficientes.

Entre esas propuestas podrá figurar una relativa a una nueva denominación común internacional sustitutiva,

formulada con arreglo a los Principios generales y que tenga en cuenta la sustancia farmacéutica para la que se proponga la nueva denominación común internacional sustitutiva.


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La Secretaría enviará al Grupo de Expertos en DCI y al solicitante inicial o a su sucesor (en el caso de que sea una persona diferente de la que ha presentado la propuesta de sustitución y siempre que el solicitante inicial o su sucesor sean conocidos o puedan ser encontrados mediante esfuerzos diligentes, como el contacto con las asociaciones industriales) una copia de la propuesta, para que sea examinada de conformidad con el procedimiento descrito en el párrafo b) infra. Además, la Secretaría solicitará observaciones sobre la propuesta:

i) a los Estados Miembros y a las comisiones nacionales y regionales de las farmacopeas u otros organismos designados por los Estados Miembros (ello se hará incluyendo una notificación a tal efecto en la carta a la que se refiere el párrafo a) del artículo 3), y

ii) a cualquier persona que tenga un interés especial en la sustitución propuesta.

Al solicitar que se formulen estas observaciones se facilitarán los siguientes datos: i) la denominación común internacional recomendada que se propone sustituir (y la denominación sustitutiva propuesta, si se ha facilitado);

ii) la identidad de la persona que ha presentado la propuesta de sustitución (si lo pide esa persona); iii) la identidad de la sustancia a la que se refiere la sustitución propuesta y las razones para presentar la propuesta de sustitución; iv) el plazo fijado para recibir observaciones, así como el nombre y la dirección de la persona a quien deban dirigirse; y

v) los poderes conferidos para el caso a la OMS y una referencia al presente procedimiento.

Toda persona puede formular a la OMS observaciones sobre la sustitución propuesta dentro de los cuatro meses siguientes a la fecha en que se realizó la solicitud de observaciones. b) Una vez agotado el mencionado plazo para la formulación de observaciones, la Secretaría enviará todos los comentarios recibidos al Grupo de Expertos en DCI, al solicitante inicial o a su sucesor, y a la persona que haya presentado la propuesta de sustitución. Si después de examinar la propuesta de sustitución y las observaciones recibidas, el Grupo de Expertos en DCI, la persona que haya presentado la propuesta de sustitución y el solicitante inicial, o su sucesor, están de acuerdo en la necesidad de sustituir la denominación común internacional recomendada anteriormente, la Secretaría remitirá la propuesta de sustitución al Grupo de Expertos en DCI para que la tramite. No obstante lo anterior, el solicitante inicial o su sucesor no tendrán derecho a impedir el acuerdo sobre una propuesta de sustitución en el caso de que hayan dejado de tener un interés demostrable en la denominación común internacional cuya sustitución se propone.

En caso de que la propuesta de sustitución sea presentada al Grupo de Expertos en DCI para que la tramite, este grupo seleccionará una nueva denominación común internacional de conformidad con los Principios generales a los que se refiere el artículo 2 y al procedimiento establecido en los artículos 3 a 8 inclusive. En ese caso, en las notificaciones que la Secretaría ha de enviar con arreglo a los artículos 3 y 7, respectivamente, incluida la notificación al solicitante inicial o a su sucesor (en el caso de que no sea la misma persona que propuso la sustitución y siempre que el solicitante inicial o su sucesor sean conocidos o puedan ser encontrados mediante esfuerzos diligentes, como el contacto con las asociaciones industriales), se indicará que la nueva denominación sustituye a una denominación común internacional recomendada anteriormente y que los Estados Miembros podrán, si lo estiman oportuno, adoptar disposiciones transitorias aplicables a los productos existentes en cuya etiqueta se utilice, con arreglo a la legislación nacional, la denominación común internacional recomendada anteriormente que se haya sustituido.

En caso de que, después de haber estudiado la propuesta de sustitución y los comentarios recibidos de conformidad con el procedimiento descrito anteriormente, el Grupo de Expertos en DCI, el solicitante inicial o su sucesor y la persona que haya presentado la propuesta de sustitución no lleguen a un acuerdo sobre la existencia de razones poderosas para sustituir una denominación común internacional recomendada anteriormente, esta denominación se mantendrá (siempre en el entendimiento de que el solicitante inicial o su sucesor no tendrán derecho a impedir el acuerdo sobre una propuesta de sustitución en el caso de que hayan dejado de tener un interés demostrable en la denominación común internacional cuya sustitución se propone). En ese caso, la Secretaría comunicará a la persona que haya propuesto la sustitución, así como al solicitante inicial o a su sucesor (en el caso de que no sea la misma persona que propuso la sustitución y siempre que el solicitante inicial o su sucesor sean conocidos o puedan ser encontrados mediante esfuerzos diligentes, como el contacto con las asociaciones industriales), a los Estados Miembros, a las comisiones nacionales y regionales de las farmacopeas o


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a otros organismos designados por los Estados Miembros y a cualquier otra persona que tenga interés en la sustitución propuesta, que, pese a la presentación de una propuesta de sustitución, se ha decidido mantener la denominación común internacional recomendada anteriormente (con una descripción de la o las razones por las que se ha considerado que la propuesta de sustitución no estaba respaldada por razones suficientemente poderosas).

ANEXO 2

PRINCIPIOS GENERALES DE ORIENTACIÓN PARA FORMAR DENOMINACIONES

COMUNES INTERNACIONALES PARA SUSTANCIAS FARMACÉUTICAS1

1. Las denominaciones comunes internacionales (DCI) deberán diferenciarse tanto fonética como ortográficamente. No deberán ser incómodamente largas, ni dar lugar a confusión con denominaciones de uso común.

2. La DCI de una sustancia que pertenezca a un grupo de sustancias farmacológicamente emparentadas deberá mostrar apropiadamente este parentesco. Deberán evitarse las denominaciones que puedan tener connotaciones anatómicas, fisiológicas, patológicas o terapéuticas para el paciente.

Estos principios primarios se pondrán en práctica utilizando los siguientes principios secundarios:

3. Al idear la DCI de la primera sustancia de un nuevo grupo farmacológico, deberá tenerse en cuenta la posibilidad de poder formar DCI convenientes para las sustancias emparentadas que se agreguen al nuevo grupo.

4. Al idear DCI para ácidos, se preferirán las de una sola palabra; sus sales deberán denominarse sin modificar el nombre del ácido: p. ej. «oxacilina» y «oxacilina sódica», «ibufenaco» y «ibufenaco sódico».

5. Las DCI para las sustancias que se usan en forma de sal deberán en general aplicarse a la base activa o al ácido activo. Las denominaciones para diferentes sales o esteres de la misma sustancia activa solamente deberán diferir en el nombre del ácido o de la base inactivos. En los compuestos de amonio cuaternario, el catión y el anión deberán denominarse adecuadamente por separado, como componentes independientes de una sustancia cuaternaria y no como sales de una amina.

6. Deberá evitarse el empleo de letras o números aislados; también es indeseable el empleo de guiones.

7. Para facilitar la traducción y la pronunciación, se emplearán de preferencia las letras «f» en lugar de «ph», «t» en lugar de «th», «e» en lugar de «ae» u «oe», e «i» en lugar de «y»; se deberá evitar el empleo de las letras «h» y «k».

8. Siempre que las denominaciones propuestas estén de acuerdo con estos principios, recibirán una consideración preferente las denominaciones propuestas por la persona que haya descubierto las sustancias, o que fabrique y comercialice por primera vez una sustancia farmacéutica, así como las denominaciones ya adoptadas oficialmente en cualquier país.

9. El parentesco entre sustancias del mismo grupo se pondrá de manifiesto en las DCI (véase el Principio 2) utilizando una partícula común. En la lista que figura a continuación se indican ejemplos de partículas para grupos de sustancias, en particular para grupos nuevos. Existen muchas otras partículas que se usan habitualmente.2 Cuando una partícula aparece sin guión alguno, puede utilizarse en cualquier lugar de la palabra.

1 En su 20º informe (OMS, Serie de Informes Técnicos, Nº 581, 1975), el Comité de Expertos de la OMS en Denominaciones Comunes para las Sustancias Farmacéuticas revisó los Principios generales para formar denominaciones comunes internacionales (DCI), y su procedimiento de selección, a la luz de las novedades registradas en los últimos años en materia de compuestos farmacéuticos. El cambio más importante había consistido en hacer extensivo a la denominación de sustancias químicas sintéticas el método utilizado hasta entonces para las sustancias originadas en productos naturales o derivadas de éstos. Dicho método conlleva la utilización de una «partícula» característica que indica una propiedad común a los miembros de un grupo. En el citado informe se examinan en detalle las razones y consecuencias de este cambio. Los Principios generales de orientación se actualizaron durante la 13ª consulta sobre denominaciones comunes para sustancias farmacéuticas (Ginebra, 27 a 29 de abril de 1983) (PHARM S/NOM 928, 13 de mayo de 1983, revisado el 18 de agosto de 1983). 2 En el documento de trabajo WHO/EMP/QSM/2011.3, que se actualiza periódicamente y puede solicitarse al Programa sobre Denominaciones Comunes Internacionales, OMS, Ginebra, figura una lista más amplia de partículas.


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Latin Español -acum -aco antiinflamatorios derivados del ibufenaco -adolum -adol ) analgésicos -adol- -adol- ) -astum -ast antiasmáticos, sustancias antialérgicas cuya acción principal no es la antihistamínica -astinum -astina antihistamínicos -azepamum -azepam derivados del diazepam bol bol esteroides anabolizantes -cain- -caína- antiarrítmicos de clase I, derivados de procainamida y lidocaína -cainum -caína- anestésicos locales cef- cef- antibióticos, derivados del ácido cefalosporánico -cillinum - cilina antibióticos derivados del ácido 6-aminopenicilánico -conazolum -conazol antifúngicos sistémicos derivados del miconazol cort cort corticosteroides, excepto derivados de prednisolona -coxibum -coxib inhibidores selectivos de ciclooxigenasa -entanum -entán antagonistas del receptor de endotelina gab gab gabamiméticos gado- gado- agentes para diagnóstico derivados de gadolinio -gartranum -gatrán inhibidores de la trombina antitrombóticos gest gest esteroides progestágenos gli gli hipoglucemiantes, antihiperglucémicos io- io- medios de contraste iodados -metacinum -metacina antiinflamatorios derivados de indometacina -mycinum -micina antibióticos producidos por cepas de Streptomyces -nidazolum -nidazol antiprotozoarios y radiosensibilizadores, derivados de metronidazol -ololum -olol antagonistas de receptores -adrenérgicos -oxacinum -oxacino antibacterianos derivados del ácido nalidíxico -platinum -platino antineoplásicos derivados del platino -poetinum -poetina factores sanguíneos similares a la eritropoyetina -pril(at)um -pril(at) inhibidores de la enzima conversora de la angiotensina -profenum -profeno antiinflamatorios derivados del ibuprofeno prost prost prostaglandinas -relinum -relina péptidos estimulantes de la liberación de hormonas hipofisarias -sartanum -sartán antihipertensivos (no peptídicos) antagonistas del receptorde angiotensina II -vaptanum -vaptán antagonistas del receptor de vasopresina vin- vin- ) alcaloides de la vinca -vin- -vin- )

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