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Public Assessment Report

Scientific discussion

Sildenafil Amneal 20 mg film-coated tablets

(sildenafil citrate)

NL/H/3654/001/DC

Date: 14 November 2017

This module reflects the scientific discussion for the approval of Sildenafil Amneal 20 mg film-coated tablets. The procedure was finalised on 2 May 2017. For information on changes after this date please refer to the ‘steps taken after finalisation’ at the end of this PAR. C B G

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CEP Certificate of Suitability to the monographs of the European Pharmacopoeia CHMP Committee for Medicinal Products for Human Use CMD(h) Coordination group for Mutual recognition and Decentralised procedure for human medicinal products CMS Concerned Member State EDQM European Directorate for the Quality of Medicines EEA European Economic Area ERA Environmental Risk Assessment ICH International Conference of Harmonisation MAH Marketing Authorisation Holder Ph.Eur. European Pharmacopoeia PL Package Leaflet RH Relative Humidity RMP Risk Management Plan SmPC Summary of Product Characteristics TSE Transmissible Spongiform Encephalopathy

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I. INTRODUCTION

Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Sildenafil Amneal 20 mg film-coated tablets from Amneal Pharma Europe Limited.

The product is indicated for:

Adults Treatment of adult patients with pulmonary arterial hypertension classified as WHO functional class II and III, to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease.

Paediatric population Treatment of paediatric patients aged 1 year to 17 years old with pulmonary arterial hypertension. Efficacy in terms of improvement of exercise capacity or pulmonary haemodynamics has been shown in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart disease.

A comprehensive description of the indications and posology is given in the SmPC.

This decentralised procedure concerns a generic application claiming essential similarity with the innovator product Revatio 20 mg, film-coated tablets which has been registered in the EU through centralised procedure EU/1/05/318/001 by Pfizer Ltd. The date of authorisation was on 28 October 2005.

The concerned member states (CMS) involved in this procedure were Germany, Denmark, Spain, Finland, Norway, Sweden and the United Kingdom.

The marketing authorisation has been granted pursuant to Article 10(1) of Directive 2001/83/EC.

Similarity assessment in view of the orphan drug legislation The MAH claims an indication for which an orphan designation has been granted, i.e. treatment of Pulmonary Arterial Hypertension (PAH). The MAH provided a similarity report. In this report Sildenafil Amneal is compared with 4 other products for which orphan designation has been granted: - Revatio 20 mg film-coated tablets (active substance sildenafil; orphan designation has been granted, but is currently expired) - Adempas 0.5/1.0/1.5/2.0/2.5 mg film-coated tablets (active substance riociguat) - Opsumit 10 mg film-coated tablets (active substance macitentan) - Volibris 5 mg film-coated tablets (active substance ambrisentan)

The MAH concludes that that only Revatio 20 mg is similar to the generic medicinal product (Sildenafil Amneal 20 mg) according to Article 3 of Commission Regulation (EC) No. 847/2000. Other products (Adempas, Opsumit and Volibris) are not similar to Sildenafil Amneal 20 mg. The molecular structure and mechanism of action of sildenafil are different. The conclusions of the MAH are supported by the member states. Overall, the generic product applied for is considered non similar to all orphan medicinal products with the indication PAH currently authorised in EU. Thus the application of Sildenafil Amneal 20 mg film-coated tablets for marketing authorization for the indication PAH can be accepted in view of the orphan drug legislation.

II. QUALITY ASPECTS

II.1 Introduction

Sildenafil Amneal 20 mg is a white to off white, round shaped film-coated tablets, with debossing ‘AN 1017’ on one side and plain on the other side. Each film-coated tablet contains 20 mg of sildenafil (as citrate).

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The film-coated tablets are packed in PVC-PVdC/Aluminium blisters.

The excipients are: Tablet core - anhydrous calcium hydrogen phosphate, microcrystalline cellulose, croscarmellose sodium, hypromellose, magnesium stearate Tablet coating - polyvinyl alcohol-partially hydrolyzed, titanium dioxide (E171), macrogol 4000, talc (E553b)

II.2 Drug Substance

The active substance is sildenafil citrate, an established active substance described in the European Pharmacopoeia (Ph.Eur.). Sildenafil citrate is a white or almost white and slightly hygroscopic powder. It is slightly soluble in water and in methanol and practically insoluble in hexane. Sildenafil citrate has no chiral centres and does not exhibit stereoisomerism. The drug substance is a crystalline powder and is consistently manufactured having the same polymorphic form.

The CEP procedure is used for the active substance. Under the official Certification Procedures of the EDQM of the Council of Europe, manufacturers or suppliers of substances for pharmaceutical use can apply for a certificate of suitability concerning the control of the chemical purity and microbiological quality of their substance according to the corresponding specific monograph, or the evaluation of reduction of Transmissible Spongiform Encephalopathy (TSE) risk, according to the general monograph, or both. This procedure is meant to ensure that the quality of substances is guaranteed and that these substances comply with the European Pharmacopoeia.

Manufacturing process A CEP has been submitted; therefore no details on the manufacturing process have been included.

Quality control of drug substance The drug substance specification of the MAH is in line with the Ph.Eur. monograph on sildenafil citrate and CEP and with the specification from the active substance manufacturer, with additional tests for microbiological quality, particle size distribution and identity. The drug substance specification is acceptable. Batch analytical data by the drug product manufacturer, demonstrating compliance with the drug substance specification have been provided for two batches.

Stability of drug substance Stability data on the active substance have been provided for at least three full scaled batches stored at 25°C/60% RH (60 months) and 40°C/75% RH (6 months). No clear trends or changes were observed for any of the tested parameters at both storage conditions. The proposed retest period of 60 months for the drug substance with storage condition ‘Store in a well closed container below 25°C’ is justified.

II.3 Medicinal Product

Pharmaceutical development The development of the product has been described, the choice of excipients is justified and their functions explained. The main development studies performed were the characterisation of the reference product Revatio, selection and optimization of the components and the performance of comparative dissolution studies. The choices of the packaging and manufacturing process are justified. A bioequivalence study has been performed versus the reference product. The test batch used in the bioequivalence study has been manufactured according to the finalized formulation and manufacturing process. Comparative dissolution data between the test and reference batch show similar profiles at pH 1.2, pH 4.5 and pH 6.8 media (>85% in 15 minutes or f2 >50). The pharmaceutical development has been adequately performed.

Manufacturing process The main steps in the manufacturing process are wet granulation (of intragranular ingredients), blending with the extragranular ingredients, lubrication, compression and film-coating. The manufacturing process has been adequately validated on two production scale batches of common blend that were used for the compression of two pilot scale batches of finished product. The product is

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E B M manufactured using conventional manufacturing techniques. Process validation for full scaled batches will be performed post authorisation.

Control of excipients The excipients comply with Ph.Eur. or in-house specifications. These specifications are acceptable.

Quality control of drug product The product specification includes tests for appearance, identification, disintegration time, dissolution, assay, uniformity of dosage units, related substances, loss on drying and microbiological quality. Except for loss on drying, the release and shelf-life requirements are identical. The specification is acceptable. The analytical methods have been adequately described and validated. Batch analysis data have been provided on two pilot scale batches of the drug product, demonstrating compliance with the drug product release specification.

Stability of drug product Stability data on the product has been provided on two pilot scaled batches stored at 25°C/60% RH (24 months) and 40°C/75% RH (6 months). The conditions used in the stability studies are according to the ICH stability guideline. The batches were stored in PVC-PVdC/Al-blisters. Except for an increase in loss on drying at both storage conditions, no clear changes or trends were observed in any of the tested parameters. Results of a photostability study showed that the drug product is not sensitive to light exposure. The proposed shelf-life of 2 years without any special storage requirements is justified.

Specific measures for the prevention of the transmission of animal spongiform encephalopathies There are no substances of ruminant animal origin present in the product nor have any been used in the manufacturing of this product, so a theoretical risk of transmitting TSE can be excluded.

II.4 Discussion on chemical, pharmaceutical and biological aspects

Based on the submitted dossier, the member states consider that Sildenafil Amneal 20 mg has a proven chemical-pharmaceutical quality. Sufficient controls have been laid down for the active substance and finished product. No post-approval commitments were made.

III. NON-CLINICAL ASPECTS

III.1 Ecotoxicity/environmental risk assessment (ERA)

Since Sildenafil Amneal is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary.

III.2 Discussion on the non-clinical aspects

This product is a generic formulation of Revatio, which is available on the European market. Reference is made to the preclinical data obtained with the innovator product. A non-clinical overview on the pharmacology, pharmacokinetics and toxicology has been provided, which is based on up-to- date and adequate scientific literature. The overview justifies why there is no need to generate additional non-clinical pharmacology, pharmacokinetics and toxicology data. Therefore, the member states agreed that no further non-clinical studies are required.

IV. CLINICAL ASPECTS

IV.1 Introduction

Sildenafil citrate is a well-known active substance with established efficacy and tolerability.

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E B M A clinical overview has been provided, which is based on scientific literature. The overview justifies why there is no need to generate additional clinical data. Therefore, the member states agreed that no further clinical studies are required.

For this generic application, the MAH has submitted a bioequivalence study, which is discussed below.

IV.2 Pharmacokinetics

The MAH conducted a bioequivalence study in which the pharmacokinetic profile of the test product Sildenafil Amneal 20 mg (Amneal Pharma Europe Limited, Ireland) is compared with the pharmacokinetic profile of the reference product Revatio 20 mg film-coated tablets (Pfizer Ltd, UK).

The choice of the reference product in the bioequivalence study is accepted, as has been registered trough a centralised procedure. The formula and preparation of the bioequivalence batch is identical to the formula proposed for marketing.

Bioequivalence study Design A single-dose, randomised, two-period, two-treatment, two-sequence, crossover bioequivalence study was carried out under fasted conditions in 48 healthy male subjects, aged 18-41 years. Each subject received a single dose (20 mg) of one of the 2 sildenafil formulations. The tablet was orally administered with 240 ml water after an overnight fast of 10 hours. There were 2 dosing periods, separated by a washout period of 8 days.

Blood samples were collected pre-dose and at 0.17, 0.33, 0.5, 00.67, 0.83, 1.00, 1.25, 1.5, 1.75, 2., 2.25, 2.5, 3., 3.5, 4, 6, 8, 10, 12, 16, 20 and 24 hours after administration of the products.

The design of the study is acceptable. The wash-out period and sampling period are long enough, and the sampling scheme is adequate. Fasting conditions are acceptable as sildenafil can be taken with and without food. Next to sildenafil, the active metabolite piperazine N-desmethyl sildenafil has been analysed. As the data on the parent are pivotal, the metabolite data are considered supportive.

Analytical/statistical methods The analytical method has been adequately validated and is considered acceptable for analysis of the plasma samples. The methods used in this study for the pharmacokinetic calculations and statistical evaluation are considered acceptable.

Results One subject was withdrawn due to an adverse event (emesis). The remaining 47 subjects completed the study and were eligible for pharmacokinetic analysis.

Table 1. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax (median, range)) of sildenafil under fasted conditions.

Treatment AUC0-t AUC0-∞ Cmax tmax N=47 ng.h/ml ng.h/ml ng/ml h 0.8 Test 369 ± 123 378 ± 125 127 ± 50 (0.3 - 3.0) 0.8 Reference 396 ± 145 406 ± 148 138 ± 56 (0.3 - 2.0) *Ratio 0.94 0.92 -- -- (90% CI) (0.88 – 0.99) (0.82 – 1.02) CV (%) 17 -- 31 --

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E B M AUC0-∞ area under the plasma concentration-time curve from time zero to infinity AUC0-t area under the plasma concentration-time curve from time zero to t hours Cmax maximum plasma concentration tmax time for maximum concentration CV coefficient of variation *ln-transformed values

Table 2. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax (median, range)) of piperazine N-desmethyl sildenafil under fasted conditions.

Treatment AUC0-t AUC0-∞ Cmax tmax N=47 ng.h/ml ng.h/ml ng/ml h Test 271 ± 96 281 ± 101 62 ± 18 1.0 (0.5 - 3.0)

Reference 291 ± 119 303 ± 126 65 ± 22 1.0 (0.5 - 2.3)

AUC0-∞ area under the plasma concentration-time curve from time zero to infinity AUC0-t area under the plasma concentration-time curve from time zero to t hours Cmax maximum plasma concentration tmax time for maximum concentration *ln-transformed values

Conclusion on bioequivalence study The 90% confidence intervals calculated for AUC0-t and Cmax are within the bioequivalence acceptance range of 0.80 – 1.25. Based on the submitted bioequivalence study Sildenafil Amneal 20 mg is considered bioequivalent with Revatio 20 mg film-coated tablets.

The MEB has been assured that the bioequivalence study has been conducted in accordance with acceptable standards of Good Clinical Practice (GCP, see Directive 2005/28/EC) and Good Laboratory Practice (GLP, see Directives 2004/9/EC and 2004/10/EC).

IV.3 Risk Management Plan

The MAH has submitted a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to Sildenafil Amneal.

- Summary table of safety concerns as approved in RMP Important identified risks - Drug interactions with organic nitrate, bosentan (and other CYP3A4 inducers) - Vaso-occlusive crisis in patients with sickle cell disease - Increased relative mortality in the paediatric population - Epistaxis/bleeding events Important potential risks - Hypotension - Non-arteritic anterior ischaemic optic neuropathy (NAION) - Hearing loss - Pulmonary haemorrhage in off-label paediatric patients - Drug interactions with epoprostenol, iloprost, guanylate cyclase stimulators, and PDE5 inhibitors Missing information - Long-term ocular safety - Safety in pregnancy - Safety in patients with renal impairment - Safety in patients with cardiovascular diseases - Long-term mortality

The member states agreed that routine pharmacovigilance activities and routine risk minimisation measures are sufficient for the risks and areas of missing information.

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E B M IV.4 Discussion on the clinical aspects

For this authorisation, reference is made to the clinical studies and experience with the innovator product Revatio. No new clinical studies were conducted. The MAH demonstrated through a bioequivalence study that the pharmacokinetic profile of the product is similar to the pharmacokinetic profile of this reference product. Risk management is adequately addressed. This generic medicinal product can be used instead of the reference product.

V. USER CONSULTATION

The package leaflet has been evaluated via a user consultation study in accordance with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The test consisted of a pilot test with 4 participants, followed by two rounds with 10 participants each. The questions covered the following areas sufficiently: traceability, comprehensibility and applicability. The results show that the package 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.

VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION

Sildenafil Amneal 20 mg, film-coated tablets has a proven chemical-pharmaceutical quality and is a generic form of Revatio 20 mg, film-coated tablets. Revatio is a well-known medicinal product with an established favourable efficacy and safety profile.

Bioequivalence has been shown to be in compliance with the requirements of European guidance documents.

The Board followed the advice of the assessors.

There was no discussion in the CMD(h). Agreement between member states was reached during a written procedure. The member states, on the basis of the data submitted, considered that essential similarity has been demonstrated for Sildenafil Amneal with the reference product, and have therefore granted a marketing authorisation. The decentralised procedure was finalised with a positive outcome on 2 May 2017.

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STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE - SUMMARY

Procedure Scope Product Date of end of Approval/ Summary/ number Information the procedure non Justification for affected approval refuse

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