Public Assessment Report Decentralised Procedure - GOV.UK · strength for paracetamol from 1000 mg...

PAR Ratiopharm Cold & Flu Lemon Flavour 500 mg/12.2 mg powder for oral solution UK/H/4743/001/DC

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Public Assessment Report

Decentralised Procedure

Ratiopharm Cold & Flu Lemon Flavour 500mg/12.2 mg Powder for Oral Solution

(paracetamol, phenylephrine hydrochloride)

UK/H/4743/001/DC

UK licence numbers: PL 15773/0912

Ratiopharm GmbH


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LAY SUMMARY On 15 August 2012, the MHRA granted Ratiopharm GmbH a Marketing Authorisation (licence) for the medicinal product, Ratiopharm Cold & Flu Lemon Flavour 500 mg/12.2 mg powder for oral solution (PL 15773/0912). This is a P licensed medicine, available only from pharmacies, under the supervision of a pharmacist. Ratiopharm Cold & Flu Lemon Flavour 500 mg/12.2 mg powder for oral solution contains paracetamol, an analgesic which relieves aches and reduces fever, and phenylephrine, a decongestant to relieve a blocked up nose. Ratiopharm Cold & Flu Lemon Flavour 500 mg/12.2 mg powder for oral solution is used in adults and adolescents over 16 years of age for the relief of the symptoms of colds and influenza, including the relief of aches, headache, nasal congestion and lowering of temperature. Only patients who have colds and flu accompanied by stuffy nose should use this medicine. Patients who do not have symptoms of stuffy nose should preferably take a monocomponent product containing only paracetamol. No new or unexpected safety concerns arose from this application. It was judged that the benefits of Ratiopharm Cold & Flu Lemon Flavour 500 mg/12.2 mg powder for oral solution outweigh the risks; hence a Marketing Authorisation has been granted.


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TABLE OF CONTENTS

Module 1: Information about initial procedure Page 4 Module 2: Summary of Product Characteristics Page 5 Module 3: Product Information Leaflet Page 6 Module 4: Labelling Page 7 Module 5: Scientific discussion during initial procedure Page 11 I Introduction Page 11

II About the product Page 13

III Scientific Overview and discussion Page 14

III.1 Quality aspects Page 14

III.2 Non-clinical aspects Page 17

III.3 Clinical aspects Page 17

IV Overall conclusions and benefit-risk assessment Page 22 Module 6: Steps taken after initial procedure Page 23


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Module 1

Information about Initial Procedure

Product Name

Ratiopharm Cold & Flu Lemon Flavour 500 mg/12.2 mg powder for oral solution

Type of Application

Hybrid, Article 10(3)

Active Substance

Paracetamol, phenylephrine hydrochloride

Form

Powder for oral solution

Strength

Paracetamol 500 mg Phenylephrine hydrochloride 12.2 mg

MA Holder

Ratiopharm GmbH, Graf-Arco-Strasse 3, 89079 Ulm, GERMANY

Reference Member State (RMS)

UK

Concerned Member States (CMS)

Austria, Belgium, Czech Republic, Estonia, Germany, Hungary, Lithuania, Portugal, Romania

Procedure Number

UK/H/4743/001/DC

Timetable

End of Procedure: Day 210 – 06 June 2012


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Module 2

Summary of Product Characteristics In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPC) and Patient Information Leaflets (PIL) for products granted Marketing Authorisations at a national level are available on the MHRA website.


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Module 3

Patient Information Leaflet

The MAH has submitted a text version only and has committed to submitting mock-up livery to the relevant regulatory authorities, as appropriate. In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPC) and Patient Information Leaflets (PIL) for products granted Marketing Authorisations at a national level are available on the MHRA website.


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Module 4

Labelling

The MAH has submitted a text version only and has committed to submitting mock-up livery to the relevant regulatory authorities, as appropriate.


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Module 5

Scientific discussion during initial procedure I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the MHRA granted Ratiopharm GmbH a Marketing Authorisation for the medicinal product, Ratiopharm Cold & Flu Lemon Flavour 500 mg/12.2 mg powder for oral solution (PL 15773/0912; UK/H/4743/001/DC) on 15 August 2012. The product is a P licensed medicine. This is an application for Ratiopharm Cold & Flu Lemon Flavour 500 mg/12.2 mg powder for oral solution, submitted under Article 10(3) of Directive 2001/83 EC, as amended. The application refers to the UK originator product, Lemsip Max Cold & Flu Lemon (00063/0069), authorised to Reckitt Benckiser Healthcare (UK) Limited on 24 April 1995 through a Change of Ownership (CoA) procedure from the original licence, PL 00044/0146 (authorised to Reckitt & Colman in November 1991). The originator product has been authorised in the UK for more than 10 years, thus the period of data exclusivity has expired. Lemsip Max Cold & Flu Lemon sachets contain 1000 mg paracetamol and 12.2 mg phenylephrine hydrochloride (equivalent to 10 mg phenylephrine base). Therefore, the difference between the proposed product and the reference medicinal product is a change in strength for paracetamol from 1000 mg to 500 mg. With the UK as the Reference Member State (RMS) in this Decentralised Procedure, Ratiopharm GmbH applied for a Marketing Authorisation for Ratiopharm Cold & Flu Lemon Flavour 500 mg/12.2 mg powder for oral solution in Austria, Belgium, Czech Republic, Estonia, Germany, Hungary, Lithuania, Portugal and Romania. Ratiopharm Cold & Flu Lemon Flavour 500 mg/12.2 mg powder for oral solution is indicated in adults and children over 16 years of age for the short term symptomatic treatment of colds and influenza (aches, fever) when associated with nasal congestion. In vivo, paracetamol has both analgesic and anti-pyretic activity, which is believed to be mediated through inhibition of the cyclooxygenase (COX) pathway within the central nervous system. Although this mechanism is shared with the non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol does not have significant anti-inflammatory activity nor does it inhibit production of pro-clotting thromboxanes. Additional pathways such as the serotonergic descending pain pathways may be involved in the anti-nociceptive effect of paracetamol. Phenylephrine is a potent alpha1-adrenoceptor agonist. Its action on the peripheral alpha1 receptors induces vasoconstriction, which in the nasal mucosa, reduces oedema and nasal swelling. The orally administered drug has not demonstrated consistent cardiovascular effects at the recommended doses of 10 – 12.2 mg four times a day; oral doses of 40 to 60 mg are needed to elicit clinically meaningful cardiovascular effects such as increased diastolic blood pressure and reflex cardiac slowing. Phenylephrine retains activity as a nasal decongestant when given orally, the drug distributing through the systemic circulation to the vascular bed of nasal mucosa. No new non-clinical or clinical efficacy studies were conducted for this application, which is acceptable given that the application cross-refers to a product that has been licensed for over


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10 years. Bioequivalence studies are not necessary to support this application for a powder for oral solution. The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place for this product type at all sites responsible for the manufacture and assembly of this product. Evidence of compliance with GMP has been provided for the named manufacturing and assembly sites. For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites. For manufacturing sites outside the community, the RMS has accepted copies of current GMP Certificates or satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’ issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites. The RMS considers that the pharmacovigilance system as described by the Marketing Authorisation Holder (MAH) fulfils the requirements and provides adequate evidence that the MAH has the services of a Qualified Person (QP) responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. The MAH has provided adequate justification for not submitting a detailed Risk Management Plan (RMP). As the application refers to an already authorised reference product, for which safety concerns requiring additional risk minimisation have not been identified, routine pharmacovigilance activities are proposed and a risk minimisation system is not considered necessary. The reference product has been in use for many years and the safety profiles of the actives are well-established.


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II. ABOUT THE PRODUCT Name of the product in the Reference Member State

Ratiopharm Cold & Flu Lemon Flavour 500 mg/12.2 mg powder for oral solution

Name(s) of the active substance(s) (INN)

Paracetamol, phenylephrine hydrochloride

Pharmacotherapeutic classification (ATC code)

paracetamol combinations excl. psycholeptics (N02BE51)

Pharmaceutical form and strength(s)

Powder for oral solution Paracetamol 500 mg Phenylephrine hydrochloride 12.2 mg

Reference numbers for the Decentralised Procedure

UK/H/4743/001/DC

Reference Member State

United Kingdom

Member States concerned

AT, BE, CZ, DE, EE, HU, LT, PT, RO

Marketing Authorisation Number(s)

PL 15773/0912

Name and address of the authorisation holder

Ratiopharm GmbH, Graf-Arco-Strasse 3, 89079 Ulm, GERMANY


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III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS ACTIVE SUBSTANCE

Paracetamol

Nomenclature:

INN: Paracetamol

Chemical names: i) N-(4-Hydroxyphenyl)acetamide

ii) N-Acetyl-4-aminophenol

iii) N-acetyl-para-aminophenol Structure:

Molecular formula: C8H9NO2

Molecular weight: 151.2 g/mol

CAS No: 103-90-2

Physical form: A white or almost white crystalline powder

Solubility: Sparingly soluble in water, freely soluble in alcohol, very slightly soluble in methylene chloride

The active substance, paracetamol, is the subject of a European Pharmacopeia (Ph. Eur) monograph. All aspects of the manufacture and control of paracetamol are supported by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability (CEP). The certificate is accepted as confirmation of the suitability of paracetamol for inclusion in this medicinal product. ACTIVE SUBSTANCE

Phenylephrine hydrochloride

Nomenclature:

INN: Phenylephrine hydrochloride

Chemical names: i) (R)-3-[1-Hydroxy-2-methylaminoethyl]phenol hydrochloride

ii) (1R)-1-(3-Hydroxyphenyl)-2-(methylamino)ethanol hydrochloride Structure:


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Molecular formula: C9H14ClNO2

Molecular weight: 203.7 g/mol

CAS No: 61-76-7

Physical form: A white or almost white crystalline powder

Solubility: Freely soluble in water and in ethanol (96 %) The active substance, phenylephrine hydrochloride, is the subject of a European Pharmacopeia (Ph. Eur) monograph. All aspects of the manufacture and control of phenylephrine hydrochloride are supported by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability (CEP). The certificate is accepted as confirmation of the suitability of phenylephrine hydrochloride for inclusion in this medicinal product. FINISHED PRODUCT

Description and Composition

Ratiopharm Cold & Flu Lemon Flavour 500 mg/12.2 mg powder for oral solution is presented as a single-dose sachet containing a free-flowing white powder. Each sachet contains 500 mg of paracetamol and 12.2 mg of phenylephrine hydrochloride, equivalent to 10 mg phenylephrine base. Other ingredients consist of pharmaceutical excipients, namely ascorbic acid, sucrose, aspartame (E951), lemon flavours, saccharin sodium, silica colloidal anhydrous, citric acid anhydrous and sodium citrate. Appropriate justification for the inclusion of each excipient has been provided. All excipients comply with their respective European Pharmacopoeia monographs, with the exception of the lemon flavours, which comply with satisfactory in-house specifications. Satisfactory Certificates of Analysis have been provided for all excipients. The applicant has provided a declaration confirming that there are no materials of human or animal origin contained in or used in the manufacturing process for the proposed products. None of the excipients are sourced from genetically modified organisms. There were no novel excipients used. Pharmaceutical development

Details of the pharmaceutical development of the medicinal product have been supplied and are satisfactory. The objective was to develop a stable powder for oral solution formulation containing 500 mg of paracetamol and 12.2 mg of phenylephrine hydrochloride. Comparative dissolution data were provided for batches of the test and reference products. The dissolution profiles were satisfactory. Manufacture

A description and flow-chart of the manufacturing method has been provided. In-process controls are appropriate considering the nature of the products and the method of manufacture. Process validation studies were conducted and the results were satisfactory. The validation data demonstrate consistency of the manufacturing process.


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Finished product specification

Finished product specifications are provided for release and shelf-life and are satisfactory. Acceptance limits have been justified with respect to conventional pharmaceutical requirements and, where appropriate, safety. Test methods have been described and have been adequately validated, as appropriate. Satisfactory batch analysis data are provided and accepted. The data demonstrate that the batches are compliant with the proposed specifications. Certificates of Analysis have been provided for any reference standards used. Container Closure System

Ratiopharm Cold & Flu Lemon Flavour 500 mg/12.2 mg powder for oral solution are licensed for marketing in laminated aluminium -paper foil sachets, which are packaged with the Patient Information Leaflet (PIL) into cardboard outer cartons in pack sizes of 6, 8, 10, 12, 14, 16 or 20 sachets. The MAH has stated that not all pack sizes may be marketed. Satisfactory specifications and Certificates of Analysis for all packaging components used have been provided. All primary product packaging complies with EU legislation, Directive 2002/72/EC (as amended), and is suitable for contact with foodstuffs. Stability

Finished product stability studies have been conducted in accordance with current guidelines, using product stored in the packaging proposed for marketing. These data support the applied shelf-life of 2 years, with storage instructions “Store in the original container in order to protect from light and moisture”. The reconstituted solution in hot water is stable for 60 minutes at room temperature. Quality Overall Summary

A satisfactory quality overall summary is provided, which has been prepared by an appropriately qualified expert. The CV of the expert has been supplied. Product Information

The approved Summary of Product Characteristics (SmPC) and Patient Information Leaflet (PIL) and labelling texts are satisfactory. The labelling fulfils the statutory requirements for Braille. The MAH has submitted text versions of the PIL and labelling only and has committed to submitting mock-up livery to the relevant regulatory authorities, as appropriate. The PIL text is in line with the SmPC and is satisfactory. User-testing of the PIL text has been accepted based on bridging to the successful user-testing of the ‘parent’ PIL for Paracetephrine Hermes (Hermes Arzneimittel GmbH), containing 1000 mg of paracetamol and 12.2 mg of phenylephrine hydrochloride. The text, content, key safety messages and layout of the proposed PIL are considered to be sufficiently similar to the approved PIL for the stated product. The bridging is accepted. Conclusion

All pharmaceutical issues have been resolved and the quality grounds for this application are considered adequate. There are no objections to approval of Ratiopharm Cold & Flu Lemon Flavour 500 mg/12.2 mg powder for oral solution from a pharmaceutical point of view.


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III.2 NON-CLINICAL ASPECTS

INTRODUCTION

Specific non-clinical studies have not been performed, which is acceptable considering that this is a hybrid application, cross-referring to a product that has been licensed for more than 10 years. The non-clinical overview provides a satisfactory review of the pharmacodynamic, pharmacokinetic, and toxicological properties of paracetamol and phenylephrine hydrochloride individually and in combination. The active ingredients are widely-used and well-known actives. The CV of the non-clinical expert has been supplied. For applications of this nature, the need for repetitive tests on animals and humans is avoided. Reference is made to the originator product, Lemsip Max Cold & Flu Lemon (Reckitt Benckiser Healthcare (UK) Limited). The MAH has provided adequate justification for not submitting a detailed Environmental Risk Assessment (ERA). The product is intended to substitute market shares of other similar products. It is not expected that additional patients will be treated with paracetamol or phenylephrine based on the new marketing authorization. There is, therefore, no reason to conclude that marketing of this product will change the overall use pattern of the existing market. There are no environmental concerns associated with the method of manufacture or formulation of the product. There are no objections to approval of Ratiopharm Cold & Flu Lemon Flavour 500 mg/12.2 mg powder for oral solution from a non-clinical point of view. III.3 CLINICAL ASPECTS

INDICATIONS

Ratiopharm Cold & Flu Lemon Flavour 500 mg/12.2 mg powder for oral solution are indicated in adults and children over 16 years of age for the short term symptomatic treatment of colds and influenza (aches, fever) when associated with nasal congestion. The indications are consistent with those of the reference product and are satisfactory. POSOLOGY AND METHOD OF ADMINISTRATION

The adult dose is one sachet, dissolved by stirring in hot water. The dose may be repeated every 4-6 hours, although no more than four doses should be taken in 24 hours. Full details concerning the posology are provided in the SmPCs. The posology is satisfactory. CLINICAL PHARMACOLOGY

The clinical pharmacology of paracetamol and phenylephrine hydrochloride is well-known. No new pharmacodynamic or pharmacokinetic data are supplied and none are required for this application. Pharmacodynamics

Both paracetamol and phenylephrine are well-known active ingredients with a long history of clinical use. Paracetamol possesses both analgesic and antipyretic properties. It is a non-steroidal anti-inflammatory drug (NSAID) that acts by inhibiting the prostaglandin G/H synthase enzymes known as cyclooxygenases. The inhibition of cyclooxygenase 2 (COX-2) is thought to


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mediate mainly the antipyretic, analgesic and anti-inflammatory actions of NSAIDs, while the simultaneous inhibition of cyclooxygenase-1 (COX-1) largely but not exclusively accounts for unwanted adverse effects in the gastrointestinal tract. Paracetamol is a weak anti-inflammatory drug which is effective as an antipyretic and analgesic agent at typical doses that partly inhibit the cyclooxygenases, but is known to have fewer gastrointestinal side effects than the other NSAIDs. The antipyretic effect appears to result from a central action on the hypothalamus to reduce the sensitivity of heat-regulating centres to endogenous pyrogens. Phenylephrine is a sympathomimetic agent (α-receptor agonist) and is used primarily as a nasal decongestant. It causes an effective constriction of vascular beds, which is the basis for its decongestant action. Paracetamol and phenylephrine have been used in combination for many years for the treatment of symptoms associated with common cold and influenza-like infections such as fever, headache, and nasal congestion. Assessor's comment: No new pharmacodynamic (PD) studies have been performed. The applicant has provided bibliographic references to support the PD. The data is acceptable. Pharmacokinetics

Paracetamol

In man, paracetamol is rapidly absorbed from the gastrointestinal tract (small intestine), and rapidly and relatively uniformly distributed throughout the body tissues. Binding to plasma proteins is insignificant. At therapeutic doses, paracetamol protein binding is low (<5-24%). No clinically significant interactions based on plasma protein binding displacement have been identified to date. Paracetamol is extensively metabolised with only 2-5 % of a therapeutic dose excreted unchanged in urine. The major metabolites of paracetamol are the 4-sulphate and 4-glucuronide conjugates, but a minor fraction is converted by hepatic mixed function oxidase to N-acetyl-p-benzoquinoneimine, a highly reactive alkylating metabolite. This metabolite is normally rapidly inactivated by conjugation with reduced glutathione and eventually excreted in the urine as cysteine and mercapturic acid conjugates. Large doses of paracetamol cause acute hepatic necrosis as a result of depletion of glutathione and of covalent binding of the excess reactive metabolite to vital cell constituents. Paracetamol causes acute renal tubular necrosis by a similar mechanism and its toxicity is dependent on microsomal enzyme activity and glutathione availability. The kidney is a major site for conversion of the 3-glutathionyl conjugate to the 3-cysteinyl conjugate, and this reaction also occurs in the gastrointestinal wall. Other minor metabolites of paracetamol include conjugates of 3-methoxy-, 3-hydroxy-, and 3- thiomethylparacetamol. Urinary excretion is the predominant pathway of elimination for all paracetamol metabolites, although substantial quantities of both the 4-glucuronide and 3-glutathione conjugates are excreted initially in bile. At higher doses, there is a shift to the glucuronidation pathway, resulting in a higher biliary excretion.


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Phenylephrine hydrochloride

Phenylephrine hydrochloride is absorbed after oral administration and is rapidly distributed, metabolised and excreted, mainly in the urine. Phenylephrine is thought to undergo oxidative deamination by monoamine oxidase to the aldehyde, which can be further oxidised by aldehyde oxidase to metahydroxymandelic acid or reduced by aldehyde dehydrogenase to meta-hydroxyphenylglycol. Combination

Gastric emptying changes could affect paracetamol absorption. However, phenylephrine has no effect on gastric emptying (rat animal model). Additionally, no risk for transport protein interactions in the absorption site is expected as phenylephrine is not an evident substrate of transport proteins. After oral dosing, phenylephrine is rapidly absorbed in the GIT being highly conjugated by sulphation and glucuronidation during first pass. The majority of this phenylephrine metabolism takes place within the enterocytes. The minor hepatic metabolism occurs via MAO. The final systemic availability of active parent is ~1%. At therapeutic oral doses of 12.2 mg phenylephrine hydrochloride (parent) levels are systemically very low (<1 ng/mL) after first pass. In contrast, paracetamol metabolism is hepatic during and after first pass with bioavailability >75%. Competition for the sulphation/ glucuronidation pathways with paracetamol is not an issue as the phenylephrine is metabolized by enterocytes and paracetamol in the liver. The differentiation between metabolism in enterocytes (phenylephrine) vs. the liver (paracetamol) mitigates the risk of shunting to the P450 (NAPQI) pathway for paracetamol. On the other hand, paracetamol is not known to saturate the pre-systemic sulphation or glucuronidation paths (being highly bioavailable) thus an effect of increased phenylephrine levels when concomitant paracetamol at therapeutic doses is also ruled out. At therapeutic doses, paracetamol protein binding is low (<5-24%). No clinically significant interactions based on plasma protein binding displacement have been identified to date. If displacement of bound paracetamol occurred by phenylephrine with concomitant increase of free paracetamol, as the drug’s elimination is not rate limited then paracetamol would eliminate faster and also compensate by distributing further and equilibrium would be re-established. Therefore, no interaction effects are foreseeable at drug distribution. Assessor's comment: No new pharmacokinetic (PK) studies have been performed. The applicant has provided bibliographic references to support the PK. The data is acceptable. Biowaiver

Ratiopharm Cold & Flu Lemon Flavour 500 mg/12.2 mg powder for oral solution is to be administered orally and each sachet contains 500 mg of paracetamol and 12.2 mg of phenylephrine hydrochloride. The composition of the proposed product is essentially similar to that of the reference product, Lemsip® Max Cold & Flu. No excipients, different from those of the reference Lemsip product, are contained in the proposed product that would influence the gastrointestinal transit, absorption, in-vivo solubility or in-vivo stability of the active substances. Additionally it has been clearly demonstrated that the proposed and reference products are true solutions at the time of administration.


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Assessor's comment: The justification for biowaiver is acceptable. CLINICAL EFFICACY

No new data are submitted and none are required for this type of application. Efficacy is reviewed in the clinical overview. The efficacy of paracetamol and phenylephrine hydrochloride is well-established from their extensive use in clinical practice. No clinical studies could be identified in publicly available databases testing the combination of paracetamol 500 mg and phenylephrine hydrochloride 12.2 mg. However, this combination closely corresponds to combinations that are already in widespread use in different EU markets. Furthermore, the pharmacodynamic activity of both compounds is distinct (paracetamol has no vasoconstrictive properties and phenylephrine is not analgesic/ antipyretic), so that it can be reasonably assumed that the efficacy of the combination is not less than the efficacy of the separate active ingredients given separately. CLINICAL SAFETY

No new data have been submitted and none are required for applications of this type. No new or unexpected safety concerns arose from this application. Safety is reviewed in the clinical overview. The safety profiles of paracetamol and phenylephrine hydrochloride are well-known. Paracetamol

Paracetamol is the most commonly used medication and the fact that it has been available over-the-counter for so many years is testimony to its benign safety profile. The product is considered to be very well tolerated at the adult recommended doses of 1,000 mg up to 4 times daily, and this excellent tolerability is probably a major factor in its wide usage. Nevertheless, paracetamol has been associated with serious adverse reactions, the most important of which is certainly its hepatotoxicity. Phenylephrine hydrochloride

Phenylephrine hydrochloride is generally well-tolerated and its wide usage in the OTC setting is testimony to its excellent overall safety profile. Phenylephrine hydrochloride should not be used during pregnancy since it may cause fetal hypoxia at high doses. Common side effects include tachycardia, palpitations, nausea, headache and changes in blood pressure. The safety profile of phenylephrine hydrochloride has been studied in a number of early studies. In these studies, the orally administered drug has not demonstrated consistent cardiovascular effects at single doses of 10 – 15 mg. Single oral doses of 40 to 60 mg are needed to consistently produce cardiovascular effects: at these doses, there is a decline in pulse rate and a slight increase in blood pressure. The controlled clinical studies did not reveal any consistent cardiovascular effects for the 10 and 15 mg doses. Combination

As already discussed, no clinical studies could be identified in publicly available databases testing the combination of paracetamol 500 mg and phenylephrine 12.2 mg. However as mentioned in the pharmacokinetic and pharmacodynamic sections on the combination product, it is highly unlikely that meaningful pharmacokinetic or


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pharmacodynamic interactions exist between paracetamol and phenylephrine. Therefore, the expected safety profile of the combination (when taken as directed) should not be different from what can be expected from the separate compounds. The individual substances of the combination product are intended to relieve simultaneously different symptoms of colds and influenza and therefore the doses which have been selected for the combination product are commonly used for the treatment of these symptoms with the mono-substances. Therefore the benefit/risk assessment with regard to safety of the fixed combination is equal to that of each substance taken alone. Furthermore, this combination closely corresponds to combinations that are already safely in widespread use in different EU markets. There may be a concern that patients exceed the maximum number of daily doses. This is a situation that may happen when insufficient decongestant activity is experienced. The concern here would be that as a result, higher (maybe toxic) doses of paracetamol will be ingested. Given the characteristics of phenylephrine hydrochloride, it seems unlikely that re-dosing would occur more than 4 times daily. This would result in a total daily paracetamol dose of 2 g and the maximum package size of 20 sachets contains only 10 g paracetamol, which is well within safety limits for adults. Safety conclusion: Both paracetamol and phenylephrine are well established OTC products with well-established safety profiles. No new concerns are expected at the doses proposed or in this combination. CLINICAL OVERVIEW

A satisfactory clinical overview is provided and has been prepared by an appropriately qualified expert. The CV of the clinical expert has been supplied. PRODUCT INFORMATION:

Summary of Product Characteristics (SmPC)

The approved SmPC is consistent with that of the reference product and is acceptable. Patient Information Leaflet

The final PIL text is in line with the approved SmPC and is satisfactory. Labelling

The labelling text is satisfactory. CONCLUSIONS

Sufficient clinical information has been submitted to support this application. The risk-benefit of the product is considered favourable from a clinical perspective. The grant of a Marketing Authorisation was, therefore, recommended.


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IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY

The important quality characteristics of Ratiopharm Cold & Flu Lemon Flavour 500 mg/12.2 mg powder for oral solution are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. NON-CLINICAL

No new non-clinical data were submitted and none are required for applications of this type. CLINICAL

No new data are submitted and none are required for this type of application. Efficacy is reviewed in the clinical overview. The efficacy of paracetamol and phenylephrine hydrochloride is well-established from their extensive use in clinical practice. This combination closely corresponds to combinations that are already in widespread use in different EU markets. Furthermore, the pharmacodynamic activity of both compounds is distinct, so that it can be reasonably assumed that the efficacy of the combination is not less than the efficacy of the separate active ingredients given separately. No new or unexpected safety concerns arise from this application. PRODUCT LITERATURE

The approved Summary of Product Characteristics (SmPC), and Patient Information Leaflet (PIL) and labelling texts are satisfactory. The PIL text is in line with the SmPC and is satisfactory. User-testing of the PIL text has been accepted based on bridging to the successful user-testing of the ‘parent’ PIL for Paracetephrine Hermes (Hermes Arzneimittel GmbH). The results show that the leaflet meets the criteria for readability as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use. The MAH has submitted text versions of the PIL and labelling only and has committed to submitting mock-up livery to the relevant regulatory authorities, as appropriate. The labelling fulfils the statutory requirements for Braille. BENEFIT-RISK ASSESSMENT

The quality of the product is acceptable and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with paracetamol and phenylephrine hydrochloride is considered to have demonstrated the therapeutic value of Ratiopharm Cold & Flu Lemon Flavour 500 mg/12.2 mg powder for oral solution. The benefit: risk ratio is considered to be positive.


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Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY Date submitted

Application type

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