Mylan Laboratories Limited F-4 & F-12, Malegaon MIDC, Sinnar Nashik Maharashtra State, India

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1 This part reflects the scientific knowledge and the information about this product available at the time of prequalification. Thereafter, updates may have become necessary which are included in parts 1 to 5 and, if related to pharmaceutical issues, also documented in part 8 of this WHOPAR SCIENTIFIC DISCUSSION Name of the Finished Pharmaceutical Product: M anufacturer of Prequalified Product: Ritonavir 25 mg Tablets * Mylan Laboratories Limited F-4 & F-12, Malegaon MIDC, Sinnar Nashik Maharashtra State, India Active Pharmaceutical I ngredient (API ): Pharmaco-therapeutic group (ATC Code): Therapeutic indication: Ritonavir Antiviral for systemic use, protease inhibitor (J05AE03). Ritonavir 25 mg Tablets is indicated as a pharmacokinetic enhancer for protease inhibitors in a combination therapy with other antiretroviral agents for the treatment of HIV-1 infected patients. * Trade names are not prequalified by WHO. This is the national medicines regulatory authority s (NMRA) responsibility. Throughout this WHOPAR the proprietary name is given as an example only.

2 1. Introduction Ritonavir 25 mg Tablets is indicated as a pharmacokinetic enhancer for protease inhibitors in a combination therapy with other antiretroviral agents for the treatment of HIV-1 infected patients. Ritonavir 25 mg Tablets should be initiated by a health care provider experienced in the management of HIV infection. 2. Assessment of Quality The assessment was done in accordance with the requirements of WHO s Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part. Active pharmaceutical Ingredient (API) Ritonavir has been prequalified by WHO according to WHO s Procedure for assessing the acceptability, in principle, of active pharmaceutical ingredients for use in pharmaceutical products (WHO Technical Report Series No. 953, 2009, Annex 4). This procedure provides an assurance that the API, used in the manufacture of Ritonavir 25 mg Tablets, is of good quality and manufactured in accordance with WHO Good Manufacturing Practices. API prequalification consists of a comprehensive evaluation procedure that has two components: Assessment of the API master file (APIMF) to verify compliance with WHO norms and standards, and inspection of the sites of API manufacture to verify compliance with WHO GMP requirements. Other ingredients Other ingredients used in the core tablet formulation include sorbitan monolaurate, copovidone, colloidal silicon dioxide, sodium chloride and sodium stearyl fumarate, all being pharmacopoeial controlled. The commercially sourced proprietary film-coating mixture contains hypromellose, titanium dioxide, polyethylene glycol, hydroxypropyl cellulose, talc, colloidal anhydrous silica and polysorbate. BSE/TSE compliance declarations were provided. Finished pharmaceutical product (FPP) Pharmaceutical development and manufacture Ritonavir 25 mg Tablets are white, film-coated, round, biconvex, bevelled edge tablets debossed with RT on one side of the tablet and 25 on the other side. The tablets are packaged in HDPE bottles. A desiccant, comprising of a plastic canister with perforation for breathing, containing silica gel, is included in the bottle pack for protection from moisture. The objective of the project was to develop Ritonavir 25 mg Tablets with a robust manufacturing process and which is stable and bioequivalent to Mylan s reference strength, Ritonavir 100 mg Tablets. In order to increase the dissolution rate of the poorly soluble ritonavir and to enhance its bioavailability from the tablet dosage form, it has to be in the form of a solid dispersion in the tablet. Initially a solvent evaporation process was used to manufacture the solid dispersion of the reference strength (HA467). However, recently a melt extrusion process was introduced by the manufacturer and through a variation, Page 2 of 5

3 which included a bioequivalence study against the WHO comparator product Norvir 100 mg film-coated tablets, accepted for the reference strength. The 25 mg tablet is a direct scale down of the latter product, using melt extrusion. The critical steps of the manufacturing process were optimized and appropriate inprocess controls were set to ensure batch-to-batch reproducibility. Specifications The finished product specifications include appropriate tests for description, identification of the API (HPLC and TLC) and of titanium dioxide, dissolution (2-point; HPLC), uniformity of dosage units (by content uniformity), related substances (HPLC), assay (HPLC), water (KF), retention of amorphous form (XRPD) and microbial limits. The test procedures have been adequately validated. Stability testing Stability studies have been performed on three batches at 30 C/75%RH (zone IVb) as long-term storage conditions and for six months at accelerated conditions in the packaging proposed for marketing of the product. The data showed slight increase for some of the degradation products, though within the agreed limits at both storage conditions. The absence of the crystalline form of the API was demonstrated by XRPD up to 6 months at accelerated conditions and up to end-of-shelf at long-term conditions. Based on the available stability data, the proposed shelf life and storage conditions as stated in the SmPC are acceptable. Conclusions The quality part of the dossier is accepted. 3. Assessment of Bio-Equivalence The following bioequivalence study has been performed in 2013 according to internationally accepted guidelines. Study Title: A randomized, open label, balanced, single center, two treatment, two period, two sequence, single dose, crossover bioequivalence study of Ritonavir tablets 100 mg of Mylan Laboratories Limited, India and Norvir (ritonavir) tablets 100 mg of Abbott Laboratories, North Chicago, IL 60064, U.S.A, in healthy human adult subjects, under fed conditions. (study no. S ). The objective of the study was to compare the bioavailability of the stated Ritonavir 100 mg tablet manufactured for/by Mylan Laboratories Ltd., India (test drug) with the reference formulation Norvir (Abbot Laboratories) and to assess bioequivalence. The comparison was performed as a single centre, open label, randomized, crossover study in healthy subjects under fed conditions. Each subject was assigned to receive each of the following treatments in a randomized fashion: Treatment T: Test 1 tablet Ritonavir 100 mg (ritonavir 100 mg) Batch no Treatment R: Reference 1 tablet Norvir Page 3 of 5

4 (ritonavir 100 mg) Batch no A minimal 7 day wash-out period was observed between administration of test and reference. Serial blood samples (1 pre-dose sample and 19 samples within 36 h post dose) were taken during each study period to obtain bioavailability characteristics AUC, C max and t max for bioequivalence evaluation. Drug concentrations for ritonavir were analyzed using a validated LC-MS/MS method. The limit of quantification was stated to be about 10 ng/ml for ritonavir. The study was performed with 48 participants; data generated from a total of 42 subjects were utilized for analysis to establish pharmacokinetic parameters and assess bioequivalence. Arithmetic mean and geometric mean values of the pharmacokinetic variables for ritonavir as well as statistical results are summarised in the following table: Pharmacokinetic Parameter Test formulation (T) arithmetic mean ± SD (*) Ritonavir Reference (R) arithmetic mean ± SD (*) log-transformed parameters Ratio Conventional T/R (%) 90% CI (ANOVAlog) t max (h) 5.44 ± ± C max (ng/ml) 594 ± ± (523) (531) AUC 0-t (ng.h/ml) 5238 ± ± (4743) (4650) * geometric mean Conclusions The results of the study show that preset acceptance limits of % are met by both AUC and C max values regarding ritonavir. Accordingly, the test tablet Ritonavir 100 mg meets the criteria for bioequivalence with regard to the rate and extent of absorption and is therefore bioequivalent to the reference Norvir (Abbot Laboratories). A biowaiver was granted for the additional 25 mg tablet strength (Mylan Laboratories Ltd, India) in accordance to WHO guideline. In comparison with the strength of the test product used in the bioequivalence study, the Ritonavir 25 mg tablet was determined to be qualitative essential the same, the ratio of active ingredient and excipients between the strengths is considered essential the same and the dissolution profiles between the formulations for the API was determined the same. 4. Summary of Product Safety and Efficacy According to the submitted data on quality Ritonavir 25 mg Tablets is a direct scale-down of Ritonavir 100 mg Tablets. The latter is pharmaceutically and therapeutically equivalent and thus interchangeable Page 4 of 5

5 with the innovator product Norvir, for which benefits have been proven in terms of virological and immunological efficacy. The clinical safety of this product is considered to be acceptable when guidance and restrictions presented in the summary of product characteristics are taken into consideration. Reference is made to the SmPC (WHOPAR part 4) for data on clinical safety. 4. Benefit risk assessment and overall conclusion Quality Physicochemical and biological aspects relevant to the uniform pharmaceutical characteristics have been investigated and are controlled in a satisfactory way. The quality of this product is considered to lead to an acceptable clinical performance when Ritonavir 25 mg Tablets is used in accordance with the SmPC. Bioequivalence Ritonavir 25 mg Tablets fulfilled all criteria for waiving an in-vivo bioequivalence study as per relevant WHO guidance. Hence, Ritonavir 25 mg Tablets and Norvir (Abbot Laboratories) can be considered bioequivalent. Efficacy and Safety Regarding clinical efficacy and safety, Ritonavir 25 mg Tablets is considered effective and safe to use when the guidance and restrictions in the summary of product characteristics are taken into consideration. Benefit Risk Assessment Based on WHO's assessment of data on quality, bioequivalence, safety and efficacy the team of assessors considered that the benefit risk profile of Ritonavir 25 mg Tablets was acceptable for the following indication: as a pharmacokinetic enhancer for protease inhibitors in a combination therapy with other antiretroviral agents for the treatment of HIV-1 infected patients. and has advised that the quality, efficacy and safety of Ritonavir 25 mg Tablets allow inclusion of Ritonavir 25 mg Tablets, manufactured at Mylan Laboratories Ltd, F-4 & F-12 Malegaon MIDC, Nashik, Maharashtra, India in the list of prequalified medicinal products. Page 5 of 5