Anastrozole 1 mg Film-coated Tablets PL 18727/0014 · version of Arimidex 1 mg Film-coated Tablets...

MHRA PAR; ANASTROZOLE 1 MG FILM-COATED TABLETS, PL 18727/0014

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Anastrozole 1 mg Film-coated Tablets

PL 18727/0014

UKPAR

TABLE OF CONTENTS

Lay summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

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Steps taken after initial procedure

Page 14

Summary of product characteristics

Page 15

Patient information leaflet

Page 28

Labelling

Page 30

Annex 1

Page 32


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ANASTROZOLE 1 MG FILM-COATED TABLETS

PL 18727/0014

LAY SUMMARY

The Medicines and Healthcare products Regulatory Agency (MHRA) granted a Marketing Authorisation (licence) for the medicinal product Anastrozole 1 mg Film-coated Tablets (Product Licence number: PL 18727/0014) on 7 January 2011. Anastrozole belongs to a group of medicines called aromatase inhibitors. This means that it interferes with some of the actions of aromatase, an enzyme within the body which affects the level of certain female sex hormones such as oestrogens. Anastrozole 1 mg Film-coated Tablets are used to treat breast cancer in post-menopausal women. Anastrozole 1 mg Film-coated Tablets raised no clinically significant safety concerns and it was, therefore, judged that the benefits of using this product outweigh the risks; hence a Marketing Authorisation has been granted.


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PL 18727/0014

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS Introduction

Page 4

Pharmaceutical assessment

Page 5

Preclinical assessment

Page 8

Clinical assessment

Page 9

Overall conclusions and risk benefit assessment

Page 12


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INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the UK granted a Marketing Authorisation for the medicinal product Anastrozole 1 mg Film-coated Tablets to Fresenius Kabi Oncology Plc. on 7 January 2011. This medicine is only available on prescription. Anastrozole 1 mg Film-coated Tablets are used in the: - Treatment of advanced breast cancer in postmenopausal women (efficacy has not been demonstrated in oestrogen receptor negative patients unless they had a previous positive clinical response to tamoxifen)

- Adjuvant treatment of postmenopausal women with hormone receptor positive early invasive breast cancer

- Adjuvant treatment of early breast cancer in hormone receptor positive postmenopausal women who have received 2 to 3 years of adjuvant tamoxifen. This application is submitted under Article 10.1 of Directive 2001/83/EC, as amended. The applicant claims that Anastrozole 1 mg Film-coated Tablets is a generic version of Arimidex 1 mg Film-coated Tablets (PL 17901/0002). Arimidex 1 mg Film-coated Tablets have been authorised in the EEA for over 10 years (since 11 August 1995), the legal basis of this application is, therefore, acceptable and the ten year rule is complied with. Assurance has been provided that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture, assembly and batch release of this product. No new preclinical studies were conducted, which is acceptable given that the application is for a generic version of an originator product that has been licensed for over 10 years. No new clinical studies were conducted, which is acceptable given that the application is for a generic version of an originator product that has been licensed for over 10 years. The bioequivalence study was carried out in accordance with Good Clinical Practice (GCP).


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PHARMACEUTICAL ASSESSMENT DRUG SUBSTANCE: ANASTROZOLE General information

INN: Anastrozole

Chemical names:

CAS number: 120511-73-1

Structure:

Molecular formula: C17H19N5

Relative molecular mass: 293.37 g/mol

General properties Anastrozole is a white to off-white crystalline powder, which is soluble in methylene chloride and ethyl acetate, very slightly soluble in water (0.53 mg/mL at 25 °C, dependent on pH from pH 1-4 but independent thereafter) and insoluble in N-hexane. No polymorphic forms are reported. Anastrozole has a melting point of 81-84 °C and a pKa of 1.4. Manufacture Synthesis of the drug substance from the designated starting materials has been adequately described and appropriate in-process controls and intermediate specifications are applied. Satisfactory specification tests are in place for all starting materials and reagents and these are supported by relevant certificates of analysis. Control An appropriate specification is provided for the active substance. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. Appropriate proof-of-structure data have been supplied for the active pharmaceutical ingredient. All potential known impurities have been identified and characterised. Satisfactory certificates of analysis have been provided for all working standards. Batch analysis data are provided and comply with the proposed specification.


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Container closure system Suitable specifications have been provided for all packaging used. The primary packaging has been shown to comply with current guidelines concerning contact with food. Stability Appropriate stability data have been generated supporting a suitable retest period when stored in the proposed packaging. DRUG PRODUCT: ANASTROZOLE 1 MG FILM-COATED TABLETS Anastrozole 1 mg Film-coated Tablets contain the pharmaceutical excipients lactose monohydrate, sodium starch glycollate, povidone, magnesium stearate and opadry white Y-1-7000 (containing hypromellose, polyethylene glycol and titanium dioxide). All excipients comply with their respective European Pharmacopoeia monographs, with the exception of opadry white which is controlled by a suitable in-house specification, in the absence of a European Pharmacopoeia monograph for this excipient this is acceptable. Satisfactory certificates of analysis have been provided for all excipients. Pharmaceutical development The objective of the pharmaceutical development programme was to formulate a robust, stable, solid oral dosage form equivalent to the reference product, Arimidex 1 mg Film-coated Tablets and exhibiting the same bioavailability in order to comply with the regulations pertaining to generic medicinal product applications. Suitable pharmaceutical development data have been provided for this application. The physico-chemical properties of the drug product have been compared with those of the originator product. These data demonstrate that the proposed product can be considered a generic version of Arimidex 1 mg Film-coated Tablets. Manufacture A description and flow-chart of the manufacturing method have been provided. In-process controls are satisfactory, based on process validation data and controls on the finished product. Process validation has been carried out on batches of the product. The results are satisfactory. Finished product specification The finished product specifications are satisfactory. Test methods have been described and adequately validated, as appropriate. Batch data have been provided and comply with the release specifications. Certificates of analysis have been provided for any working standards used. Container closure system The tablets are sealed in blisters of clear PVC film and heat sealable aluminium blister foil. The finished product is available in packs of 14, 28, 30, 90, 98 or 100 tablets. Specifications and certificates of analysis for all packaging materials have been provided. These are satisfactory. All primary packaging complies with EU legislation regarding contact with food.


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Stability Finished product stability studies have been conducted in accordance with current guidelines and in the packaging proposed for marketing. Based on the results, a shelf-life of 2 years has been set for the product. Bioequivalence/bioavailability Satisfactory certificates of analysis have been provided for the test and reference batches used in the bioequivalence study. The bio-analytical methods used have been satisfactorily validated. Bioequivalence has been demonstrated between the test and reference products. Expert report A satisfactory expert report is provided from an appropriately qualified author. Product literature The SmPC, PIL and labels are pharmaceutically acceptable. A package leaflet has been submitted to the MHRA along with results of consultations with target patient groups ("user testing"), in accordance with Article 59 of Council Directive 2001/83/EC. The results indicate that the package leaflet is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains. Pharmaceutical conclusion It is recommended that a Marketing Authorisation is granted for this application.


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PRECLINICAL ASSESSMENT As the pharmacodynamic, pharmacokinetic and toxicological properties of anastrozole are well-known, no further preclinical studies are required and none have been provided. The applicant’s preclinical expert report has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the product’s pharmacology and toxicology. A suitable justification has been provided for non-submission of an environmental risk assessment. There are no objections to the approval of this product from a preclinical viewpoint.


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CLINICAL ASSESSMENT Pharmacokinetics In support of this application a bioequivalence study comparing the test and reference products was performed. The major metabolite of anastrozole in plasma is triazole, which does not inhibit aromatase. Anastrozole was the only substance monitored in the pharmacokinetic study. Methods The study was an open-labelled, balanced, randomised, two treatment, two sequence, single dose, two way crossover comparative oral bioavailability study carried out in 31 healthy adult human male subjects under fasting conditions. The products were administered orally with water. A washout period of 28 days was applied between doses. Blood samples were collected prior to drug administration and up to 240 hours post drug administration. The design of the study is adequate. As the formulation is immediate release, a single dose study is appropriate. Considering the tmax and half life of anastrozole, the dosing schedule and washout period are also satisfactory. Subjects aged 18-55 years were checked-in for the trial, including two standby subjects who were included in order to account for any dropouts prior to dosing in period II. Thirty subjects were dosed in period I of the trial, as per the protocol. Twenty-six subjects completed the trial successfully. One subject was withdrawn from the trial on medical grounds prior to dosing in period I, he was replaced by a standby subject. The reasons for the non-completion of four of the subjects were: one subject did not report for three consecutive ambulatory sampling times; two subjects did not report for the check-in of period II and one subject consumed alcohol during the 240 hour ambulatory sampling time in period II. Given that none of the dropouts were for safety reasons, their omission from the statistical analysis is acceptable. Details of missing samples are stated. The subject populations studied is satisfactory. Bioanalytical methods have been described and validated satisfactorily. The primary variables monitored were AUC0-t, AUC0-inf and Cmax, which were estimated based on anastrozole plasma levels for each subject included in the statistical analysis. The secondary variables calculated were Tmax, the elimination rate constant λz, t½ and the residual AUC. Values below the lower limit of quantification were set to zero. The pharmacokinetic variables are considered satisfactory. Analysis of variance (ANOVA) was carried out on the log-transformed AUC0-t, AUC0-inf and Cmax. Other parameters were analysed by a non-parametric approach. Ratios of the geometric means of the test product versus reference for AUC and Cmax were calculated, together with the 90% confidence intervals of the ratios. The statistical methods are considered adequate.


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Results

Formulation effects for the data were found to be insignificant. Period and sequence effects were found to be statistically significant, however, these were attributed to the long washout period. The intra-subject CV for Cmax, AUC0-t and AUC0-inf were 7.3, 7.6 and 7.8 %, respectively. This is acceptable. Adverse events in the study subjects are listed, all were deemed unlikely to be related to the administration of the products. This is accepted. No deaths occurred in the trial. The 90% confidence intervals of the relative mean AUC and Cmax of the test to reference product are within the accepted range of 80-125%, in line with CPMP/EWP/QWP/1401/98 Note for guidance on the investigation of bioavailability and bioequivalence.. Pharmacokinetic conclusion Based on the submitted bioequivalence study the applicant’s Anastrozole 1 mg film-coated tablet is considered bioequivalent to Arimidex 1 mg Film-coated Tablets.


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Efficacy No new data on the efficacy of this product have been submitted and none are required for this type of application. Safety No new or unexpected safety issues were raised by the bioequivalence study. Product literature The SmPC, PIL and labels are medically acceptable. The SmPC is consistent with that for the originator product. Pharmacovigilance system The Pharmacovigilance System, as described by the applicant, fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person 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. Risk management plan The applicant has not submitted an RMP, nor is one needed for an application of this kind. Clinical Expert report The clinical expert report has been written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier. Conclusion The grant of a Marketing Authorisation is recommended.


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OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT

QUALITY The important quality characteristics of Anastrozole 1 mg Film-coated Tablets 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 risk-benefit balance. PRECLINICAL No new preclinical data were submitted and none are required for applications of this type. EFFICACY The efficacy of anastrozole is well established. Bioequivalence has been demonstrated between the applicant’s product and the reference product. SAFETY No new or unexpected safety concerns arise from this application. The SmPC, PIL and labelling are satisfactory and consistent with those for the reference product. RISK-BENEFIT ASSESSMENT The quality of the product is acceptable, and no new preclinical or clinical safety concerns have been identified. The bioequivalence study supports the claim that the applicant’s product and the originator product are interchangeable. Extensive clinical experience with anastrozole is considered to have demonstrated the therapeutic value of the compound. The risk: benefit ratio is, therefore, considered to be acceptable for this product and a Marketing Authorisation may be granted.


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PL 18727/0014

STEPS TAKEN FOR ASSESSMENT

1 The MHRA received the Marketing Authorisation application on 4 January 2008

2 Following standard checks and communication with the applicant the MHRA considered the application valid on 28 January 2008

3 Following assessment of the application the MHRA requested further information relating to the quality and clinical dossiers on 22 August 2008

4 The applicant responded to the MHRA’s request, providing further information on the quality and clinical dossiers on 17 November 2008

5 Following assessment of the response the MHRA requested further information relating to the quality dossier on 15 June 2009

6 The applicant responded to the MHRA’s request, providing further information on the quality dossier on 10 September 2009

7 Following assessment of the response the MHRA requested further information relating to the quality dossier on 10 June 2010

8 The applicant responded to the MHRA’s request, providing further information on the quality dossier on 6 July 2010

9 Following assessment of the response the MHRA requested further information relating to the quality dossier on 28 September 2010

10 The applicant responded to the MHRA’s request, providing further information on the quality dossier on 8 October 2010

11 The application was determined on 7 January 2011


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PL 18727/0014

STEPS TAKEN AFTER INITIAL PROCEDURE

The following table lists non-safety updates to the Marketing Authorisation for this product that have been approved by the MHRA since the product was first licensed. The updates have been added as annexes to this PAR. This is not a complete list of the post-authorisation changes that have been made to this Marketing Authorisation.

Date submitted

Application type

Scope Outcome

19/10/2011 Medical Type II

To update sections 1, 2, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.1, 5.2, 5.3, 6.1, 6.3, 6.5, 6.6 of the SmPC to bring it in line with an MR procedure (UK-H-4949-001-MR). As a consequence, the label and leaflet have been updated.

Granted 31/01/2012


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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT Anastrozole 1 mg Film-coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 1 mg anastrozole. Also contains lactose monohydrate. For excipients, see 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet. White to off white, circular, film coated biconvex tablets, debossed with ‘DB02’ on one side and plain on other side.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications Treatment of advanced breast cancer in postmenopausal women. Efficacy has not been demonstrated in oestrogen receptor negative patients unless they had a previous positive clinical response to tamoxifen. Adjuvant treatment of postmenopausal women with hormone receptor positive early invasive breast cancer. Adjuvant treatment of early breast cancer in hormone receptor positive postmenopausal women who have received 2 to 3 years of adjuvant tamoxifen.

4.2 Posology and method of administration Adults including the elderly: One 1 mg tablet to be taken orally once a day Children: Not recommended for use in children (see sections 5.1 and 5.2). Renal impairment: No dose change is recommended in patients with mild or moderate renal impairment Hepatic impairment: No dose change is recommended in patients with mild hepatic disease. For early disease, the recommended duration of treatment should be 5 years.

4.3 Contraindications

Anastrozole is contraindicated in: - premenopausal women. - pregnant or lactating women. - patients with severe renal impairment (creatinine clearance less than 20

ml/min). - patients with moderate or severe hepatic disease.


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- patients with known hypersensitivity to anastrozole or to any of the excipients as referenced in section 6.1.

Oestrogen-containing therapies should not be co-administered with Anastrozole 1 mg Film-coated Tablets as they would negate its pharmacological action. Concurrent tamoxifen therapy (see section 4.5).

4.4 Special warnings and precautions for use

Anastrozole Tablets is not recommended for use in children as safety and efficacy have not been established in this group of patients (see sections 5.1 and 5.2). The menopause should be defined biochemically in any patient where there is doubt about hormonal status. There are no data to support the safe use of Anastrozole Tablets in patients with moderate or severe hepatic impairment, or patients with severe impairment of renal function (creatinine clearance less than 20 ml/min). Women with osteoporosis or at risk of osteoporosis, should have their bone mineral density formally assessed by bone densitometry e.g. DEXA scanning at the commencement of treatment and at regular intervals thereafter. Treatment or prophylaxis for osteoporosis should be initiated as appropriate and carefully monitored. There are no data available for the use of anastrozole with LHRH analogues. This combination should not be used outside clinical trials. As Anastrozole Tablets lowers circulating oestrogen levels it may cause a reduction in bone mineral density with a possible consequent increased risk of fracture. The use of bisphosphonates may stop further bone mineral loss caused by anastrozole in postmenopausal women and could be considered. This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Antipyrine and cimetidine clinical interaction studies indicate that the co-administration of Anastrozole Tablets with other drugs is unlikely to result in clinically significant drug interactions mediated by cytochrome P450. A review of the clinical trial safety database did not reveal evidence of clinically significant interaction in patients treated with Anastrozole Tablets who also received other commonly prescribed drugs. There were no clinically significant interactions with bisphosphonates (see section 5.1). Oestrogen-containing therapies should not be co-administered with Anastrozole Tablets as they would negate its pharmacological action. Tamoxifen should not be co-administered with Anastrozole Tablets, as this may diminish its pharmacological action (see section 4.3).


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4.6 Pregnancy and lactation Anastrozole Tablets is contraindicated in pregnant or lactating women.

4.7 Effects on ability to drive and use machines

Anastrozole Tablets is unlikely to impair the ability of patients to drive and operate machinery. However, asthenia and somnolence have been reported with the use of Anastrozole Tablets and caution should be observed when driving or operating machinery while such symptoms persist.

4.8 Undesirable effects

Unless specified, the following frequency categories were calculated from the number of adverse events reported in a large phase III study conducted in 9366 postmenopausal women with operable breast cancer treated for five years (ATAC study). Frequency System Organ Class Adverse reaction

Very common ( 10%)

Vascular Hot flushes, mainly mild or moderate in nature

General Asthenia, mainly mild or moderate in nature

Musculoskeletal, connective tissue and bone

Joint pain/stiffness, mainly mild or moderate in nature

Nervous system Headache, mainly mild or moderate in nature

Gastrointestinal Nausea, mainly mild or moderate in nature

Skin and subcutaneous tissue

Rash, mainly mild or moderate in nature

Common ( 1% and <10%)


Hair thinning (Alopecia), mainly mild or moderate in nature Allergic reactions

Gastrointestinal Diarrhoea, mainly mild or moderate in nature Vomiting, mainly mild or moderate in nature

Nervous system Somnolence, mainly mild or moderate in nature Carpal Tunnel Syndrome

Hepatobiliary disorders Increases in alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase

Reproductive system and breast

Vaginal dryness, mainly mild or moderate in nature


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Vaginal bleeding, mainly mild or moderate in nature*

Metabolism and nutrition Anorexia, mainly mild in nature Hypercholesterolaemia, mainly mild or moderate in nature

Uncommon ( 0.1% and <1%)

Hepatobiliary disorders Increases in gamma-GT and bilirubin Hepatitis


Urticaria

Musculoskeletal, connective tissue and bone

Trigger finger

Rare ( 0.01% and <0.1%)


Erythema multiforme Anaphylactoid reaction

Not known Skin and subcutaneous tissue

Stevens-Johnson syndrome** Angioedema**

*Vaginal bleeding has been reported commonly, mainly in patients with advanced breast cancer during the first few weeks after changing from existing hormonal therapy to treatment with Anastrozole Tablets. If bleeding persists, further evaluation should be considered. **Cannot be estimated from the available data. As Anastrozole Tablets lowers circulating oestrogen levels, it may cause a reduction in bone mineral density placing some patients at a higher risk of fracture (see section 4.4). The table below presents the frequency of pre-specified adverse events in the ATAC study, irrespective of causality, reported in patients receiving trial therapy and up to 14 days after cessation of trial therapy.

Adverse effects Anastrozole 1 mg Film-coated

Tablet (N=3092)

Tamoxifen (N=3094)

Hot flushes 1104 (35.7%) 1264 (40.9%) Joint pain/stiffness 1100 (35.6%) 911 (29.4%) Mood disturbances 597 (19.3%) 554 (17.9%) Fatigue/asthenia 575 (18.6%) 544 (17.6%) Nausea and vomiting 393 (12.7%) 384 (12.4%) Fractures 315 (10.2%) 209 (6.8%) Fractures of the spine, hip, or wrist/Colles

133 (4.3%) 91 (2.9%)


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Adverse effects Anastrozole 1 mg Film-coated

Tablet (N=3092)

Tamoxifen (N=3094)

Wrist/Colles fractures 67 (2.2%) 50 (1.6%) Spine fractures 43 (1.4%) 22 (0.7%) Hip fractures 28 (0.9%) 26 (0.8%) Cataracts 182 (5.9%) 213 (6.9%) Vaginal bleeding 167 (5.4%) 317 (10.2%) Ischaemic cardiovascular disease 127 (4.1%) 104 (3.4%) Angina pectoris 71 (2.3%) 51 (1.6%) Myocardial infarct 37 (1.2%) 34 (1.1%) Coronary artery disorder 25 (0.8%) 23 (0.7%) Myocardial ischaemia 22 (0.7%) 14 (0.5%) Vaginal discharge 109 (3.5%) 408 (13.2%) Any venous thromboembolic event 87 (2.8%) 140 (4.5%) Deep venous thromboembolic events including PE

48 (1.6%) 74 (2.4%)

Ischaemic cerebrovascular events 62 (2.0%) 88 (2.8%) Endometrial cancer 4 (0.2%) 13 (0.6%) Fracture rates of 22 per 1000 patient-years and 15 per 1000 patient-years were observed for the Anastrozole Tablets and tamoxifen groups, respectively, after a median follow-up of 68 months. The observed fracture rate for Anastrozole Tablets is similar to the range reported in age-matched postmenopausal populations. It has not been determined whether the rates of fracture and osteoporosis seen in ATAC in patients on anastrozole treatment reflect a protective effect of tamoxifen, a specific effect of anastrozole, or both. The incidence of osteoporosis was 10.5% in patients treated with Anastrozole Tablets and 7.3% in patients treated with tamoxifen.

4.9 Overdose

There is limited clinical experience of accidental overdosage. In animal studies, anastrozole demonstrated low acute toxicity. Clinical trials have been conducted with various dosages of Anastrozole Tablets, up to 60 mg in a single dose given to healthy male volunteers and up to 10 mg daily given to postmenopausal women with advanced breast cancer; these dosages were well tolerated. A single dose of Anastrozole Tablets that results in life-threatening symptoms has not been established. There is no specific antidote to overdosage and treatment must be symptomatic. In the management of an overdose, consideration should be given to the possibility that multiple agents may have been taken. Vomiting may be induced if the patient is alert. Dialysis may be helpful because Anastrozole is not highly protein bound. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.

5 PHARMACOLOGICAL PROPERTIES


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5.1 Pharmacodynamic properties ATC Code: L02B G03 (Enzyme inhibitors) Anastrozole is a potent and highly selective non-steroidal aromatase inhibitor. In postmenopausal women, estradiol is produced primarily from the conversion of androstenedione to estrone through the aromatase enzyme complex in peripheral tissues. Estrone is subsequently converted to estradiol. Reducing circulating estradiol levels has been shown to produce a beneficial effect in women with breast cancer. In postmenopausal women, Anastrozole Tablets at a daily dose of 1 mg produced estradiol suppression of greater than 80% using a highly sensitive assay. Anastrozole does not possess any progestogenic, androgenic or oestrogenic activity. Daily doses of Anastrozole Tablets up to 10 mg do not have any effect on cortisol or aldosterone secretion, measured before or after standard ACTH challenge testing. Corticoid supplements are therefore not needed. Primary adjuvant treatment of early breast cancer In a large phase III study conducted in 9366 postmenopausal women with operable breast cancer treated for 5 years, Anastrozole Tablets was shown to be statistically superior to tamoxifen in disease-free survival. A greater magnitude of benefit was observed for disease-free survival in favour of Anastrozole Tablets versus tamoxifen for the prospectively defined hormone receptor positive population. Anastrozole Tablets was statistically superior to tamoxifen in time to recurrence. The difference was of even greater magnitude than in disease free survival for both the Intention To Treat (ITT) population and hormone receptor positive population. Anastrozole was statistically superior to tamoxifen in terms of time to distant recurrence. The incidence of contralateral breast cancer was statistically reduced for Anastrozole Tablets compared to tamoxifen. Following 5 years of therapy, anastrozole is at least as effective as tamoxifen in terms of overall survival. However, due to low death rates, additional follow-up is required to determine more precisely the long-term survival for anastrozole relative to tamoxifen. With 68 months median follow-up, patients in the ATAC study have not been followed up for sufficient time after 5 years of treatment, to enable a comparison of long-term post treatment effects of Anastrozole Tablets relative to tamoxifen.

ATAC endpoint summary: 5-year treatment completion analysis Efficacy endpoints Number of events (frequency) Intention-to-treat

population Hormone-receptor-positive tumour status

Anastrozole1 mg Film-

coated Tablet(N=3125)

Tamoxifen (N=3116)

Anastrozole 1 mg Film-

coated Tablet (N=2618)

Tamoxifen(N=2598)

Disease-free survival a 575 (18.4) 651 (20.9) 424 (16.2) 497 (19.1) Hazard ratio 0.87 0.83 2-sided 95% CI 0.78 to 0.97 0.73 to 0.94 p-value 0.0127 0.0049


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Distant disease-free survival b

500 (16.0) 530 (17.0) 370 (14.1) 394 (15.2)

Hazard ratio 0.94 0.93 2-sided 95% CI 0.83 to 1.06 0.80 to 1.07 p-value 0.2850 0.2838 Time to recurrence c 402 (12.9) 498 (16.0) 282 (10.8) 370 (14.2) Hazard ratio 0.79 0.74 2-sided 95% CI 0.70 to 0.90 0.64 to 0.87 p-value 0.0005 0.0002 Time to distant recurrence d

324 (10.4) 375 (12.0) 226 (8.6) 265 (10.2)

Hazard ratio 0.86 0.84 2-sided 95% CI 0.74 to 0.99 0.70 to 1.00 p-value 0.0427 0.0559 Contralateral breast primary

35 (1.1) 59 (1.9) 26 (1.0) 54 (2.1)

Odds ratio 0.59 0.47 2-sided 95% CI 0.39 to 0.89 0.30 to 0.76 p-value 0.0131 0.0018 Overall survival e 411 (13.2) 420 (13.5) 296 (11.3) 301 (11.6) Hazard ratio 0.97 0.97 2-sided 95% CI 0.85 to 1.12 0.83 to 1.14 p-value 0.7142 0.7339 a Disease-free survival includes all recurrence events and is defined as the first occurrence of loco-regional recurrence, contralateral new breast cancer, distant recurrence or death (for any reason). b Distant disease-free survival is defined as the first occurrence of distant recurrence or death (for any reason). c Time to recurrence is defined as the first occurrence of loco-regional recurrence, contralateral new breast cancer, distant recurrence or death due to breast cancer. d Time to distant recurrence is defined as the first occurrence of distant recurrence or death due to breast cancer. e Number (%) of patients who had died.

As with all treatment decisions, women with breast cancer and their physician should assess the relative benefits and risks of the treatment. When Anastrozole Tablets and tamoxifen were co-administered, the efficacy and safety were similar to tamoxifen when given alone, irrespective of hormone receptor status. The exact mechanism of this is not yet clear. It is not believed to be due to a reduction in the degree of estradiol suppression produced by Anastrozole Tablets. Adjuvant treatment of early breast cancer for patients being treated with adjuvant tamoxifen In a phase III trial (ABCSG 8) conducted in 2579 postmenopausal women with hormone receptor positive early breast cancer who had received surgery with or without radiotherapy and no chemotherapy, switching to Anastrozole Tablets after 2 years adjuvant treatment with tamoxifen was statistically


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superior in disease-free survival when compared to remaining on tamoxifen, after a median follow-up of 24 months. Time to any recurrence, time to local or distant recurrence and time to distant recurrence confirmed a statistical advantage for Anastrozole Tablets, consistent with the results of disease-free survival. The incidence of contralateral breast cancer was very low in the two treatment arms with a numerical advantage for Anastrozole. Overall survival was similar for the two treatment groups.

ABCSG 8 trial endpoint and results summary Efficacy endpoints Number of events (frequency)

Anastrozole 1 mg Film-coated

Tablet (N=1297)

Tamoxifen (N=1282)

Disease-free survival 65 (5.0) 93 (7.3) Hazard ratio 0.67 2-sided 95% CI 0.49 to 0.92 p-value 0.014 Time to any recurrence 36 (2.8) 66 (5.1) Hazard ratio 0.53 2-sided 95% CI 0.35 to 0.79 p-value 0.002 Time to local or distant recurrence

29 (2.2) 51 (4.0)

Hazard ratio 0.55 2-sided 95% CI 0.35 to 0.87 p-value 0.011 Time to distant recurrence 22 (1.7) 41(3.2) Hazard ratio 0.52 2-sided 95% CI 0.31 to 0.88 p-value 0.015 New contralateral breast cancer

7 (0.5) 15 (1.2)

Odds ratio 0.46 2-sided 95% CI 0.19 to 1.13 p-value 0.090 Overall survival 43(3.3) 45 (3.5) Hazard ratio 0.96 2-sided 95% CI 0.63 to 1.46 p-value 0.840

Two further similar trials (GABG/ARNO 95 and ITA), in one of which patients had received surgery and chemotherapy, as well as a combined analysis of ABCSG 8 and GABG/ARNO 95, supported these results. The Anastrozole Tablets safety profile in these 3 studies was consistent with the known safety profile established in postmenopausal women with hormone receptor positive early breast cancer.


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Study of anastrozole with the bisphosphonate risedronate (SABRE) Bone Mineral Density (BMD) In the phase III/IV SABRE study, 234 postmenopausal women with hormone receptor positive early breast cancer scheduled for treatment with Anastrozole 1 mg/day were stratified to low, moderate and high risk groups according to their existing risk of fragility fracture. The primary efficacy parameter was the analysis of lumbar spine bone mass density using DEXA scanning. All patients received treatment with vitamin D and calcium. Patients in the low risk group received Anastrozole alone (N=42), those in the moderate group were randomised to Anastrozole plus risedronate 35 mg once a week (N=77) or Anastrozole plus placebo (N=77) and those in the high risk group received Anastrozole plus risedronate 35 mg once a week (N=38). The primary endpoint was change from baseline in lumbar spine bone mass density at 12 months. The 12-month main analysis has shown that patients already at moderate to high risk of fragility fracture showed no decrease in their bone mass density (assessed by lumbar spine bone mineral density using DEXA scanning) when managed by using Anastrozole 1 mg/day in combination with risedronate 35 mg once a week. In addition, a decrease in BMD which was not statistically significant was seen in the low risk group treated with Anastrozole 1 mg/day alone. These findings were mirrored in the secondary efficacy variable of change from baseline in total hip BMD at 12 months. This study provides evidence that the use of bisphosphonates should be considered in the management of possible bone mineral loss in postmenopausal women with early breast cancer scheduled to be treated with Anastrozole. Lipids In the SABRE study there was a neutral effect on plasma lipids in those patients treated with Anastrozole plus risedronate. Paediatrics Three clinical trials were conducted in paediatric patients (2 in pubertal boys with gynaecomastia and 1 in girls with McCune-Albright Syndrome). Gynaecomastia studies Trial 0006 was a randomised, double-blind, multi-centre study of 82 pubertal boys (aged 11-18 years inclusive) with gynaecomastia of greater than 12 months duration treated with Anastrozole 1 mg/day or placebo daily for up to 6 months. No significant difference in the number of patients who had a 50% or greater reduction in total breast volume after 6 months of treatment was observed between the anastrozole 1 mg treated group and the placebo group. Trial 0001 was an open-label, multiple-dose pharmacokinetic study of Anastrozole 1 mg/day in 36 pubertal boys with gynaecomastia of less than 12 months duration. The secondary objectives were to evaluate the proportion of


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patients with reductions from baseline in the calculated volume of gynaecomastia of both breasts combined of at least 50% between day 1 and after 6 months of study treatment, and patient tolerability and safety. A pharmacodynamic subpopulation of 25 boys was selected in this study to explore the potential benefits of anastrozole. It was noted a decrease in total breast volume of 50% or greater at 6 months was seen in 55.6% (as measured by ultrasound) and 77.8% (as measured by caliper) of the boys (observational data only, no statistical analysis conducted on these results). McCune-Albright Syndrome study Trial 0046 was an international, multi-centre, open-label exploratory trial of Anastrozole in 28 girls (aged 2 to 10 years) with McCune-Albright Syndrome (MAS). The primary objective was to evaluate the safety and efficacy of anastrozole 1 mg/day in patients with MAS. The efficacy of study treatment was based on the proportion of patients fulfilling defined criteria relating to vaginal bleeding, bone age, and growth velocity. No statistically significant change in the frequency of vaginal bleeding days on treatment was observed. There were no clinically significant changes in Tanner staging, mean ovarian volume or mean uterine volume. No statistically significant change in the rate of increase in bone age on treatment compared to the rate during baseline was observed. Growth rate (in cm/year) was significantly reduced (p<0.05) from pre-treatment through month 0 to month 12, and from pre-treatment to the second 6 months (month 7 to month 12). Of the patients with baseline vaginal bleeding, 28% experienced a 50% reduction in the frequency of bleeding days on treatment; 40% experienced a cessation over a 6-month period, and 12% experienced a cessation over a 12-month period. The overall assessment of the adverse events in children less than 18 years of age raised no safety or tolerability concerns.

5.2 Pharmacokinetic properties

Absorption of anastrozole is rapid and maximum plasma concentrations typically occur within two hours of dosing (under fasted conditions). Anastrozole is eliminated slowly with a plasma elimination half-life of 40 to 50 hours. Food slightly decreases the rate but not the extent of absorption. The small change in the rate of absorption is not expected to result in a clinically significant effect on steady-state plasma concentrations during once daily dosing of Anastrozole Tablets. Approximately 90 to 95% of plasma anastrozole steady-state concentrations are attained after 7 daily doses. There is no evidence of time or dose-dependency of anastrozole pharmacokinetic parameters. Anastrozole pharmacokinetics are independent of age in postmenopausal women. In boys with pubertal gynaecomastia, anastrozole was rapidly absorbed, was widely distributed, and was eliminated slowly with a half-life of approximately 2 days. Clearance of anastrozole was lower in girls than in boys


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and exposure higher. Anastrozole in girls was widely distributed and slowly eliminated, with an estimated half-life of approximately 0.8 days. Anastrozole is only 40% bound to plasma proteins. Anastrozole is extensively metabolised by postmenopausal women with less than 10% of the dose excreted in the urine unchanged within 72 hours of dosing. Metabolism of anastrozole occurs by N-dealkylation, hydroxylation and glucuronidation. The metabolites are excreted primarily via the urine. Triazole, the major metabolite in plasma, does not inhibit aromatase. The apparent oral clearance of anastrozole in volunteers with stable hepatic cirrhosis or renal impairment was in the range observed in healthy volunteers.

5.3 Preclinical safety data

Acute toxicity In acute toxicity studies in rodents, the median lethal dose of anastrozole was greater than 100 mg/kg/day by the oral route and greater than 50 mg/kg/day by the intraperitoneal route. In an oral acute toxicity study in the dog, the median lethal dose was greater than 45 mg/kg/day. Chronic toxicity Multiple dose toxicity studies utilized rats and dogs. No no-effect levels were established for anastrozole in the toxicity studies, but those effects that were observed at the low doses (1 mg/kg/day) and mid doses (dog 3 mg/kg/day; rat 5 mg/kg/day) were related to either the pharmacological or enzyme-inducing properties of anastrozole and were unaccompanied by significant toxic or degenerative changes. Mutagenicity Genetic toxicology studies with anastrozole show that it is not a mutagen or a clastogen. Reproductive toxicology Oral administration of anastrozole to female rats produced a high incidence of infertility at 1 mg/kg/day and increased pre-implantation loss at 0.02 mg/kg/day. These effects occurred at clinically relevant doses. An effect in man cannot be excluded. These effects were related to the pharmacology of the compound and were completely reversed after a 5-week compound withdrawal period. Oral administration of anastrozole to pregnant rats and rabbits caused no teratogenic effects at doses up to 1.0 and 0.2 mg/kg/day respectively. Those effects that were seen (placental enlargement in rats and pregnancy failure in rabbits) were related to the pharmacology of the compound. The survival of litters born to rats given anastrozole at 0.02 mg/kg/day and above (from day 17 of pregnancy to day 22 post-partum) was compromised. These effects were related to the pharmacological effects of the compound on parturition. There were no adverse effects on behaviour or reproductive performance of the first generation offspring attributable to maternal treatment with anastrozole.


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Carcinogenicity A two year rat oncogenicity study resulted in an increase in incidence of hepatic neoplasms and uterine stromal polyps in females and thyroid adenomas in males at the high dose (25 mg/kg/day) only. These changes occurred at a dose which represents 100-fold greater exposure than occurs at human therapeutic doses, and are considered not to be clinically relevant to the treatment of patients with anastrozole. A two year mouse oncogenicity study resulted in the induction of benign ovarian tumours and a disturbance in the incidence of lymphoreticular neoplasms (fewer histiocytic sarcomas in females and more deaths as a result of lymphomas). These changes are considered to be mouse-specific effects of aromatase inhibition and not clinically relevant to the treatment of patients with anastrozole.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate Sodium Starch Glycolate Povidone Magnesium Stearate Opadry White Y-1-7000 (hypromellose, polyethylene glycol and titanium dioxide)

6.2 Incompatibilities

Not applicable. 6.3 Shelf life

The shelf-life of Anastrozole 1 mg Film-coated Tablets is 2 years. 6.4 Special precautions for storage

This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container

Blisters of clear PVC film / heat sealable aluminium blister foil. Pack size: 14 tablets (1 x14), 28 tablets (2 x14), 30 tablets (3 x10), 90 tablets (9 x10), 98 tablets (7 x14) and 100 tablets (10 x10). Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Fresenius Kabi Oncology Plc. Lion Court, Farnham Road Bordon, Hampshire GU35 0NF, United Kingdom.


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8 MARKETING AUTHORISATION NUMBER(S)

PL 18727/0014

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 07/01/2011 10 DATE OF REVISION OF THE TEXT

07/01/2011


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PATIENT INFORMATION LEAFLET


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30

LABELLING

Blister:


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Carton:


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Annex 1

Reference: PL 18727/0014; application 0006 Product: Anastrozole 1 mg film-coated tablets MAH: Fresenius Kabi Oncology Plc. Active Ingredient: Anastrozole Reason: To update sections 1, 2, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.1, 5.2, 5.3, 6.1, 6.3, 6.5, 6.6 of the SmPC to bring it in line with an MR procedure (UK/H/4949/001/MR). As a consequence, the label and leaflet have been updated. Supporting evidence: The applicant has submitted the following updated documents: Sections 1, 2, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.1, 5.2, 5.3, 6.1, 6.3, 6.5, 6.6 of the SmPC. Consequently, updated mock-ups of the PIL and labelling have been provided. Evaluation SmPC: The updated SmPC fragments are in line with the outgoing D90 MRP SmPC. Consequential updates to the PIL and labelling have been evaluated and are in line with the texts agreed at D90. Conclusion All submitted documents the applicant has provided (UK SmPC fragments, PIL and labelling mock-ups) are in line with the agreed D90 texts for the MR procedure UK/H/4949/001/MR. The variation was approved on 31 January 2012 and the following updated SmPC fragments, PIL and labelling have been incorporated into this Marketing Authorisation.


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Summary of Product Characteristics – updated sections Only the sections updated in view of the stated variation are reproduced below: 1 NAME OF THE MEDICINAL PRODUCT

Anastrozole 1 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 1 mg anastrozole. Excipients Each film-coated tablet contains 91.25 mg of lactose monohydrate (see section 4.4). For a full list of excipients, see section 6.1.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Anastrozole is indicated for the: • Treatment of hormone receptor-positive advanced breast cancer in

postmenopausal women.

• Adjuvant treatment of hormone receptor-positive early invasive breast cancer in postmenopausal women.

• Adjuvant treatment of hormone receptor-positive early invasive breast cancer in postmenopausal women who have received 2 to 3 years of adjuvant tamoxifen.

4.2 Posology and method of administration

Posology The recommended dose of anastrozole for adults including the elderly is one 1 mg tablet once a day. For postmenopausal women with hormone receptor-positive early invasive breast cancer, the recommended duration of adjuvant endocrine treatment is 5 years. Special populations Paediatric population Anastrozole is not recommended for use in children and adolescents due to insufficient data on safety and efficacy (see sections 4.4 and 5.1). Renal impairment No dose change is recommended in patients with mild or moderate renal impairment. In patients with severe renal impairment, administration of anastrozole should be performed with caution (see section 4.4 and 5.2). Hepatic impairment No dose change is recommended in patients with mild hepatic disease. Caution is advised in patients with moderate to severe hepatic impairment (see section 4.4).


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Method of administration Anastrozole should be taken orally.

4.3 Contraindications

Anastrozole is contraindicated in: - Pregnant or breast-feeding women. - Patients with known hypersensitivity to anastrozole or to any of the excipients as referenced in section 6.1.

4.4 Special warnings and precautions for use

General Anastrozole should not be used in premenopausal women. The menopause should be defined biochemically (luteinizing-hormone [LH], follicle stimulating hormone [FSH], and/or oestradiol levels) in any patient where there is doubt about hormonal status. There are no data to support the use of anastrozole with LHRH analogues. Co-administration of tamoxifen or oestrogen-containing therapies with anastrozole should be avoided as this may diminish its pharmacological action (see section 4.5 and 5.1). Effect on bone mineral density As anastrozole lowers circulating oestrogen levels it may cause a reduction in bone mineral density with a possible consequent increased risk of fracture (see section 4.8). Women with osteoporosis or at risk of osteoporosis, should have their bone mineral density formally assessed at the commencement of treatment and at regular intervals thereafter. Treatment or prophylaxis for osteoporosis should be initiated as appropriate and carefully monitored. The use of specific treatments, e.g., bisphosphonates, may stop further bone mineral loss caused by anastrozole in postmenopausal women and could be considered (see section 4.8). Hepatic impairment Anastrozole has not been investigated in breast cancer patients with moderate or severe hepatic impairment. Exposure to anastrozole can be increased in subjects with hepatic impairment (see section 5.2); administration of anastrozole in patients with moderate and severe hepatic impairment should be performed with caution (see section 4.2). Treatment should be based on a benefit-risk evaluation for the individual patient. Renal impairment Anastrozole has not been investigated in breast cancer patients with severe renal impairment. Exposure to anastrozole is not increased in subjects with severe renal impairment (GRF <30 ml/min, see section 5.2); in patients with severe renal impairment, administration of anastrozole should be performed with caution (see section 4.2).


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Paediatric population Anastrozole is not recommended for use in children and adolescents as safety and efficacy have not been established in this group of patients (see section 5.1). Anastrozole should not be used in boys with growth hormone deficiency in addition to growth hormone treatment. In the pivotal clinical trial, efficacy was not demonstrated and safety was not established (see section 5.1). Since anastrozole reduces oestradiol levels, anastrozole must not be used in girls with growth hormone deficiency in addition to growth hormone treatment. Long-term safety data in children and adolescents are not available. Hypersensitivity to lactose This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Anastrozole inhibits CYPs 1A2, 2C8/9 and 3A4 in vitro. Clinical studies with antipyrine and warfarin showed that anastrozole at a 1 mg dose did not significantly inhibit the metabolism of antipyrine and R– and S-warfarin indicating the co-administration of anastrozole with other medicinal products is unlikely to result in clinically significant medicinal product interactions mediated by CYP enzymes. The enzymes mediating metabolism of anastrozole have not been identified. Cimetidine, a weak, unspecific inhibitor of CYP enzymes, did not affect the plasma concentrations of anastrozole. The effect of potent CYP inhibitors is unknown. A review of the clinical trial safety database did not reveal evidence of clinically significant interaction in patients treated with anastrozole who also received other commonly prescribed medicinal products. There were no clinically significant interactions with bisphosphonates (see section 5.1). Co-administration of tamoxifen or oestrogen-containing therapies with anastrozole should be avoided as this may diminish its pharmacological action (see section 4.4 and 5.1).

4.6 Fertility, pregnancy and lactation

Pregnancy There are no data from the use of anastrozole in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Anastrozole is contraindicated during pregnancy (see section 4.3). Breast-feeding There are no data on the use of anastrozole during lactation. Anastrozole is contraindicated during breast-feeding (see section 4.3).


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Fertility The effects of anastrozole on fertility in humans have not been studied. Studies in animals have shown reproductive toxicity (see section 5.3).

4.7 Effects on ability to drive and use machines

Anastrozole has no or negligible influence on the ability to drive and use machines. However, asthenia and somnolence have been reported with the use of anastrozole and caution should be observed when driving or operating machinery while such symptoms persist.

4.8 Undesirable effects

The following table presents adverse reactions from clinical trials, post-marketing studies or spontaneous reports. Unless specified, the frequency categories were calculated from the number of adverse events reported in a large phase III study conducted in 9,366 postmenopausal women with operable breast cancer given adjuvant treatment for five years (the Anastrozole, Tamoxifen, Alone or in Combination [ATAC] study). Adverse reactions listed below are classified according to frequency and System Organ Class (SOC). Frequency groupings are defined according to the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to <1/1,000), and very rare (<1/10,000), not known (cannot be estimated from the available data). The most frequently reported adverse reactions were headache, hot flushes, nausea, rash, arthralgia, joint stiffness, arthritis, and asthenia. Table 1 Adverse reactions by System Organ Class and frequency Adverse reactions by SOC and frequency Metabolism and nutrition disorders

Common

Anorexia Hypercholesterolaemia

Very common Headache Nervous system disorders Common

Somnolence Carpal Tunnel Syndrome*

Vascular disorders Very common Hot flushes Very common Nausea Gastrointestinal disorders

Common

Diarrhoea Vomiting

Common

Increases in alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase

Hepatobiliary disorders

Uncommon

Increases in gamma-GT and bilirubin Hepatitis

Very common Rash Common

Hair thinning (alopecia) Allergic reactions

Uncommon Urticaria

Skin and subcutaneous tissue disorders

Rare

Erythema multiforme Anaphylactoid reaction Cutaneous vasculitis (including some


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reports of Henoch-Schönlein purpura)**

Very rare

Stevens-Johnson syndrome Angioedema

Very common

Arthralgia/joint stiffness Arthritis Osteoporosis

Common Bone pain

Musculoskeletal and connective tissue disorders

Uncommon Trigger finger Reproductive system and breast disorders

Common Vaginal dryness Vaginal bleeding ***

General disorders and administration site conditions

Common Asthenia

* Events of Carpal Tunnel Syndrome have been reported in patients receiving anastrozole treatment in clinical trials in greater numbers than those receiving treatment with tamoxifen. However, the majority of these events occurred in patients with identifiable risk factors for the development of the condition. ** Since cutaneous vasculitis and Henoch-Schönlein purpura was not observed in ATAC, the frequency category for these events can be considered as ‘Rare’ (≥ 0.01% and < 0.1%) based on the worst value of the point estimate. *** Vaginal bleeding has been reported commonly, mainly in patients with advanced breast cancer during the first few weeks after changing from existing hormonal therapy to treatment with Anastrozole. If bleeding persists, further evaluation should be considered. The table below presents the frequency of pre-specified adverse events in the ATAC study after a median follow-up of 68 months, irrespective of causality, reported in patients receiving trial therapy and up to 14 days after cessation of trial therapy. Table 2 ATAC study pre-specified adverse events Adverse events Anastrozole

(N=3,092) Tamoxifen (N=3,094)

Hot flushes 1,104 (35.7%) 1,264 (40.9%) Joint pain/stiffness 1,100 (35.6%) 911 (29.4%) Mood disturbances 597 (19.3%) 554 (17.9%) Fatigue/asthenia 575 (18.6%) 544 (17.6%) Nausea and vomiting 393 (12.7%) 384 (12.4%) Fractures 315 (10.2%) 209 (6.8%) Fractures of the spine, hip, or wrist/Colles’ 133 (4.3%) 91 (2.9%) Wrist/Colles’ fractures 67 (2.2%) 50 (1.6%) Spine fractures 43 (1.4%) 22 (0.7%) Hip fractures 28 (0.9%) 26 (0.8%) Cataracts 182 (5.9%) 213 (6.9%) Vaginal bleeding 167 (5.4%) 317 (10.2%) Ischaemic cardiovascular disease 127 (4.1%) 104 (3.4%) Angina pectoris 71 (2.3%) 51 (1.6%) Myocardial infarct 37 (1.2%) 34 (1.1%) Coronary artery disorder 25 (0.8%) 23 (0.7%) Myocardial ischaemia 22 (0.7%) 14 (0.5%) Vaginal discharge 109 (3.5%) 408 (13.2%)


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Adverse events Anastrozole (N=3,092)

Tamoxifen (N=3,094)

Any venous thromboembolic event 87 (2.8%) 140 (4.5%) Deep venous thromboembolic events including PE (pulmonary embolism)

48 (1.6%) 74 (2.4%)

Ischaemic cerebrovascular events 62 (2.0%) 88 (2.8%) Endometrial cancer 4 (0.2%) 13 (0.6%) Fracture rates of 22 per 1,000 patient-years and 15 per 1,000 patient-years were observed for the anastrozole and tamoxifen groups, respectively, after a median follow-up of 68 months. The observed fracture rate for anastrozole is similar to the range reported in age-matched postmenopausal populations. The incidence of osteoporosis was 10.5% in patients treated with anastrozole and 7.3% in patients treated with tamoxifen. It has not been determined whether the rates of fracture and osteoporosis seen in ATAC in patients on anastrozole treatment reflect a protective effect of tamoxifen, a specific effect of anastrozole, or both.

4.9 Overdose

There is limited clinical experience of accidental overdose. In animal studies, anastrozole demonstrated low acute toxicity. Clinical trials have been conducted with various dosages of anastrozole, up to 60 mg in a single dose given to healthy male volunteers and up to 10 mg daily given to postmenopausal women with advanced breast cancer; these dosages were well tolerated. A single dose of anastrozole that results in life-threatening symptoms has not been established. There is no specific antidote to overdose and treatment must be symptomatic. In the management of an overdose, consideration should be given to the possibility that multiple agents may have been taken. Vomiting may be induced if the patient is alert. Dialysis may be helpful because anastrozole is not highly protein bound. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Enzyme inhibitors, ATC Code: L02B G03 Mechanism of action and pharmacodynamic effects Anastrozole is a potent and highly selective non-steroidal aromatase inhibitor. In postmenopausal women, oestradiol is produced primarily from the conversion of androstenedione to oestrone through the aromatase enzyme complex in peripheral tissues. Oestrone is subsequently converted to oestradiol. Reducing circulating oestradiol levels has been shown to produce a beneficial effect in women with breast cancer. In postmenopausal women, anastrozole at a daily dose of 1 mg produced oestradiol suppression of greater than 80% using a highly sensitive assay. Anastrozole does not possess any progestogenic, androgenic or oestrogenic activity.


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Daily doses of anastrozole up to 10 mg do not have any effect on cortisol or aldosterone secretion, measured before or after standard adrenocorticotrophic hormone (ACTH) challenge testing. Corticoid supplements are therefore not needed. Clinical efficacy and safety Advanced breast cancer First-line therapy in postmenopausal women with advanced breast cancer Two double-blind, controlled clinical studies of similar design (Study 1033IL/0030 and Study 1033IL/0027) were conducted to assess the efficacy of anastrozole compared with tamoxifen as first-line therapy for hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer in postmenopausal women. A total of 1,021 patients were randomised to receive 1 mg of anastrozole once daily or 20 mg of tamoxifen once daily. The primary endpoints for both trials were time to tumour progression, objective tumour response rate, and safety. For the primary endpoints, Study 1033IL/0030 showed that anastrozole had a statistically significant advantage over tamoxifen for time to tumour progression (Hazard ratio (HR) 1.42, 95% Confidence Interval (CI) [1.11, 1.82], Median time to progression 11.1 and 5.6 months for anastrozole and tamoxifen respectively, p=0.006); objective tumour response rates were similar for anastrozole and tamoxifen. Study 1033IL/0027 showed that anastrozole and tamoxifen had similar objective tumour response rates and time to tumour progression. Results from the secondary endpoints were supportive of the results of the primary efficacy endpoints. There were too few deaths occurring across treatment groups of both trials to draw conclusions on overall survival differences. Second-line therapy in postmenopausal women with advanced breast cancer anastrozole was studied in two controlled clinical trials (Study 0004 and Study 0005) in postmenopausal women with advanced breast cancer who had disease progression following tamoxifen therapy for either advanced or early breast cancer. A total of 764 patients were randomised to receive either a single daily dose of 1 mg or 10 mg of anastrozole or megestrol acetate 40 mg four times a day. Time to progression and objective response rates were the primary efficacy variables. The rate of prolonged (more than 24 weeks) stable disease, the rate of progression, and survival were also calculated. In both studies there were no significant differences between treatment arms with respect to any of the efficacy parameters. Adjuvant treatment of early invasive breast cancer for hormone receptor-positive patients In a large phase III study conducted in 9,366 postmenopausal women with operable breast cancer treated for 5 years (see below), anastrozole was shown to be statistically superior to tamoxifen in disease-free survival. A greater magnitude of benefit was observed for disease-free survival in favour of anastrozole versus tamoxifen for the prospectively defined hormone receptor positive population. Table 3 ATAC endpoint summary: 5-year treatment completion analysis

Number of events (frequency) Efficacy endpoints

Intention-to-treat population Hormone-receptor-positive tumour status


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Anastrozole (N=3,125)

Tamoxifen (N=3,116)

Anastrozole (N=2,618)

Tamoxifen (N=2,598)

Disease-free survival a 575 (18.4) 651 (20.9) 424 (16.2) 497 (19.1) Hazard ratio 0.87 0.83 2-sided 95% CI 0.78 to 0.97 0.73 to 0.94 p-value 0.0127 0.0049

Distant disease-free survival b 500 (16.0) 530 (17.0) 370 (14.1) 394 (15.2) Hazard ratio 0.94 0.93 2-sided 95% CI 0.83 to 1.06 0.80 to 1.07 p-value 0.2850 0.2838

Time to recurrence c 402 (12.9) 498 (16.0) 282 (10.8) 370 (14.2) Hazard ratio 0.79 0.74 2-sided 95% CI 0.70 to 0.90 0.64 to 0.87 p-value 0.0005 0.0002

Time to distant recurrence d 324 (10.4) 375 (12.0) 226 (8.6) 265 (10.2) Hazard ratio 0.86 0.84 2-sided 95% CI 0.74 to 0.99 0.70 to 1.00 p-value 0.0427 0.0559

Contralateral breast primary 35 (1.1) 59 (1.9) 26 (1.0) 54 (2.1) Odds ratio 0.59 0.47 2-sided 95% CI 0.39 to 0.89 0.30 to 0.76 p-value 0.0131 0.0018

Overall survival e 411 (13.2) 420 (13.5) 296 (11.3) 301 (11.6) Hazard ratio 0.97 0.97 2-sided 95% CI 0.85 to 1.12 0.83 to 1.14 p-value 0.7142 0.7339

a Disease-free survival includes all recurrence events and is defined as the first occurrence of loco-regional recurrence, contralateral new breast cancer, distant recurrence or death (for any reason).

b Distant disease-free survival is defined as the first occurrence of distant recurrence or death (for any reason).

c Time to recurrence is defined as the first occurrence of loco-regional recurrence, contralateral new breast cancer, distant recurrence or death due to breast cancer.

d Time to distant recurrence is defined as the first occurrence of distant recurrence or death due to breast cancer.

e Number (%) of patients who had died. The combination of anastrozole and tamoxifen did not demonstrate any efficacy benefits in comparison with tamoxifen in all patients as well as in the hormone receptor-positive population. This treatment arm was discontinued from the study. With an updated follow-up at a median of 10 years, long term comparison of the treatment effects of anastrozole relative to tamoxifen were shown to be consistent with previous analyses. Adjuvant treatment of early invasive breast cancer for hormone receptor-positive patients being treated with adjuvant tamoxifen In a phase III trial (Austrian Breast and Colorectal Cancer Study Group[ABCSG] 8) conducted in 2,579 postmenopausal women with hormone receptor positive early


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breast cancer who had received surgery with or without radiotherapy and no chemotherapy (see below), switching to anastrozole after 2 years adjuvant treatment with tamoxifen was statistically superior in disease-free survival when compared to remaining on tamoxifen, after a median follow-up of 24 months. Table 4 ABCSG 8 trial endpoint and results summary

Number of events (frequency) Efficacy endpoints Anastrozole (N=1,297)

Tamoxifen (N=1,282)

Disease-free survival 65 (5.0) 93 (7.3) Hazard ratio 0.67 2-sided 95% CI 0.49 to 0.92 p-value 0.014

Time to any recurrence 36 (2.8) 66 (5.1) Hazard ratio 0.53 2-sided 95% CI 0.35 to 0.79 p-value 0.002

Time to distant recurrence 22 (1.7) 41(3.2) Hazard ratio 0.52 2-sided 95% CI 0.31 to 0.88 p-value 0.015

New contralateral breast cancer

7 (0.5) 15 (1.2)

Odds ratio 0.46 2-sided 95% CI 0.19 to 1.13 p-value 0.090

Overall survival 43(3.3) 45 (3.5) Hazard ratio 0.96 2-sided 95% CI 0.63 to 1.46 p-value 0.840

Two further similar trials (GABG/ARNO 95 and ITA), in one of which patients had received surgery and chemotherapy, as well as a combined analysis of ABCSG 8 and GABG/ARNO 95, supported these results. The anastrozole safety profile in these 3 studies was consistent with the known safety profile established in postmenopausal women with hormone receptor positive early breast cancer. Bone mineral density (BMD) In the phase III/IV (Study of Anastrozole with the Bisphosphonate Risedronate [SABRE]), 234 postmenopausal women with hormone receptor positive early breast cancer scheduled for treatment with anastrozole 1 mg/day were stratified to low, moderate and high risk groups according to their existing risk of fragility fracture. The primary efficacy parameter was the analysis of lumbar spine bone mass density using DEXA scanning. All patients received treatment with vitamin D and calcium. Patients in the low risk group received anastrozole alone (N=42), those in the moderate group were randomised to anastrozole plus risedronate 35 mg once a week (N=77) or anastrozole plus placebo (N=77) and those in the high risk group received anastrozole plus risedronate 35 mg once a week (N=38). The primary endpoint was change from baseline in lumbar spine bone mass density at 12 months.


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The 12-month main analysis has shown that patients already at moderate to high risk of fragility fracture showed no decrease in their bone mass density (assessed by lumbar spine bone mineral density using DEXA scanning) when managed by using anastrozole 1 mg/day in combination with risedronate 35 mg once a week. In addition, a decrease in BMD which was not statistically significant was seen in the low risk group treated with anastrozole 1 mg/day alone. These findings were mirrored in the secondary efficacy variable of change from baseline in total hip BMD at 12 months. This study provides evidence that the use of bisphosphonates could be considered in the management of possible bone mineral loss in postmenopausal women with early breast cancer scheduled to be treated with anastrozole. Paediatrics population Anastrozole is not indicated for use in children and adolescents. Efficacy has not been established in the paediatric populations studied (see below). The number of children treated was too limited to draw any reliable conclusions on safety. No data on the potential long-term effects of anastrozole treatment in children and adolescents are available (see also section 5.3). The European Medicines Agency has waived the obligation to submit the results of studies with anastrozole in one or several subsets of the paediatric population in short stature due to growth hormone deficiency (GHD), testotoxicosis, gynaecomastia, and McCune-Albright syndrome (see section 4.2). Short stature due to Growth Hormone Deficiency A randomised, double-blind, multi-centre study evaluated 52 pubertal boys (aged 11 to 16 years inclusive) with GHD treated for 12 to 36 months with anastrozole 1 mg/day or placebo in combination with growth hormone. Only 14 subjects on anastrozole completed 36 months. No statistically significant difference from placebo was observed for the growth related parameters of predicted adult height, height, height SDS (standard deviation score), and height velocity. Final height data were not available. While the number of children treated was too limited to draw any reliable conclusions on safety, there was an increased fracture rate and a trend towards reduced bone mineral density in the anastrozole arm compared to placebo. Testotoxicosis An open-label, non-comparative, multi-centre study evaluated 14 male patients (aged 2 to 9 years) with familial male-limited precocious puberty, also known as testotoxicosis, treated with combination of anastrozole and bicalutamide. The primary objective was to assess the efficacy and safety of this combination regimen over 12 months. Thirteen out of the 14 patients enrolled completed 12 months of combination treatment (one patient was lost to follow-up). There was no significant difference in growth rate after 12 months of treatment, relative to the growth rate during the 6 months prior to entering the study. Gynaecomastia studies Trial 0006 was a randomised, double-blind, multi-centre study of 82 pubertal boys (aged 11-18 years inclusive) with gynaecomastia of greater than 12 months duration treated with anastrozole 1 mg/day or placebo daily for up to 6 months. No significant difference in the number of patients who had a 50% or greater reduction in total breast volume after 6 months of treatment was observed between the anastrozole 1 mg treated group and the placebo group.


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Trial 0001 was an open-label, multiple-dose pharmacokinetic study of anastrozole 1 mg/day in 36 pubertal boys with gynaecomastia of less than 12 months duration. The secondary objectives were to evaluate the proportion of patients with reductions from baseline in the calculated volume of gynaecomastia of both breasts combined of at least 50% between day 1 and after 6 months of study treatment, and patient tolerability and safety. A decrease in 50% or more of total breast volume was seen in 56% (20/36) of the boys after 6 months. McCune-Albright Syndrome study Trial 0046 was an international, multi-centre, open-label exploratory trial of anastrozole in 28 girls (aged 2 to 10 years) with McCune-Albright Syndrome (MAS). The primary objective was to evaluate the safety and efficacy of anastrozole 1 mg/day in patients with MAS. The efficacy of study treatment was based on the proportion of patients fulfilling defined criteria relating to vaginal bleeding, bone age, and growth velocity. No statistically significant change in the frequency of vaginal bleeding days on treatment was observed. There were no clinically significant changes in Tanner staging, mean ovarian volume or mean uterine volume. No statistically significant change in the rate of increase in bone age on treatment compared to the rate during baseline was observed. Growth rate (in cm/year) was significantly reduced (p<0.05) from pre-treatment through month 0 to month 12, and from pre-treatment to the second 6 months (month 7 to month 12).

5.2 Pharmacokinetic properties

Absorption of anastrozole is rapid and maximum plasma concentrations typically occur within two hours of dosing (under fasted conditions). Food slightly decreases the rate but not the extent of absorption. The small change in the rate of absorption is not expected to result in a clinically significant effect on steady-state plasma concentrations during once daily dosing of anastrozole tablets. Approximately 90 to 95% of plasma anastrozole steady-state concentrations are attained after 7 daily doses, and accumulation is 3- to 4-fold. There is no evidence of time or dose-dependency of anastrozole pharmacokinetic parameters. Anastrozole pharmacokinetics are independent of age in postmenopausal women. Anastrozole is only 40% bound to plasma proteins. Anastrozole is eliminated slowly with a plasma elimination half-life of 40 to 50 hours. Anastrozole is extensively metabolised by postmenopausal women with less than 10% of the dose excreted in the urine unchanged within 72 hours of dosing. Metabolism of anastrozole occurs by N-dealkylation, hydroxylation and glucuronidation. The metabolites are excreted primarily via the urine. Triazole, the major metabolite in plasma, does not inhibit aromatase. Renal or hepatic impairment The apparent clearance (CL/F) of anastrozole, following oral administration, was approximately 30% lower in volunteers with stable hepatic cirrhosis than in matched controls (Study 1033IL/0014). However, plasma anastrozole concentrations in the volunteers with hepatic cirrhosis were within the range of concentrations seen in normal subjects in other trials. Plasma anastrozole concentrations observed during


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long-term efficacy trials in patients with hepatic impairment were within the range of plasma anastrozole concentrations seen in patients without hepatic impairment. The apparent clearance (CL/F) of anastrozole, following oral administration, was not altered in volunteers with severe renal impairment (GFR <30 ml/min) in Study 1033IL/0018, consistent with the fact that anastrozole is eliminated primarily by metabolism. Plasma anastrozole concentrations observed during long-term efficacy trials in patients with renal impairment were within the range of plasma anastrozole concentrations seen in patients without renal impairment. In patients with severe renal impairment, administration of anastrozole should be performed with caution (see section 4.2 and 4.4). Paediatric population In boys with pubertal gynaecomastia (10-17 years), anastrozole was rapidly absorbed, was widely distributed, and was eliminated slowly with a half-life of approximately 2 days. Clearance of anastrozole was lower in girls (3-10 years) than in the older boys and exposure higher. Anastrozole in girls was widely distributed and slowly eliminated.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction for the indicated population. Acute toxicity In animal studies toxicity was only seen at high doses. In acute toxicity studies in rodents, the median lethal dose of anastrozole was greater than 100 mg/kg/day by the oral route and greater than 50 mg/kg/day by the intraperitoneal route. In an oral acute toxicity study in the dog, the median lethal dose was greater than 45 mg/kg/day. Chronic toxicity In animal studies adverse effects were only seen at high doses. Multiple dose toxicity studies utilized rats and dogs. No no-effect levels were established for anastrozole in the toxicity studies, but those effects that were observed at the low doses (1 mg/kg/day) and mid doses (dog 3 mg/kg/day; rat 5 mg/kg/day) were related to either the pharmacological or enzyme-inducing properties of anastrozole and were unaccompanied by significant toxic or degenerative changes. Mutagenicity Genetic toxicology studies with anastrozole show that it is not a mutagen or a clastogen. Reproductive toxicology In a fertility study weanling male rats were dosed orally with 50 or 400 mg/l anastrozole via their drinking water for 10 weeks. Measured mean plasma concentrations were 44.4 (±14.7) ng/ml and 165 (±90) ng/ml respectively. Mating indices were adversely affected in both dose groups, whilst a reduction in fertility was evident only at the 400 mg/l dose level. The reduction was transient as all mating and


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fertility parameters were similar to control group values following a 9 week treatment-free recovery period. Oral administration of anastrozole to female rats produced a high incidence of infertility at 1 mg/kg/day and increased pre-implantation loss at 0.02 mg/kg/day. These effects occurred at clinically relevant doses. An effect in man cannot be excluded. These effects were related to the pharmacology of the compound and were completely reversed after a 5-week compound withdrawal period. Oral administration of anastrozole to pregnant rats and rabbits caused no teratogenic effects at doses up to 1.0 and 0.2 mg/kg/day respectively. Those effects that were seen (placental enlargement in rats and pregnancy failure in rabbits) were related to the pharmacology of the compound. The survival of litters born to rats given anastrozole at 0.02 mg/kg/day and above (from Day 17 of pregnancy to Day 22 post-partum) was compromised. These effects were related to the pharmacological effects of the compound on parturition. There were no adverse effects on behaviour or reproductive performance of the first generation offspring attributable to maternal treatment with anastrozole. Carcinogenicity A two year rat oncogenicity study resulted in an increase in incidence of hepatic neoplasms and uterine stromal polyps in females and thyroid adenomas in males at the high dose (25 mg/kg/day) only. These changes occurred at a dose which represents 100-fold greater exposure than occurs at human therapeutic doses, and are considered not to be clinically relevant to the treatment of patients with anastrozole. A two year mouse oncogenicity study resulted in the induction of benign ovarian tumours and a disturbance in the incidence of lymphoreticular neoplasms (fewer histiocytic sarcomas in females and more deaths as a result of lymphomas). These changes are considered to be mouse-specific effects of aromatase inhibition and not clinically relevant to the treatment of patients with anastrozole.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate Sodium Starch Glycolate (Type A) Povidone K-30 (E1201) Magnesium Stearate (E572) Hypromellose 5 cP (E464) Macrogol 400 Titanium dioxide (E171)

6.3 Shelf life

3 years.

6.5 Nature and contents of container

PVC / Aluminium blister of 10 and 14 tablets. Pack sizes of 14, 28, 30, 90, 98 and 100 film-coated tablets.


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Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Any unused product or waste material should be disposed of in accordance with local requirements.

10 DATE OF REVISION OF THE TEXT

27/01/2012


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Patient Information Leaflet - updated


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Anastrozole 1 mg Film-coated Tablets PL 18727/0014 · version of Arimidex 1 mg Film-coated Tablets...

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