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: Manufacturer of Prequalified Product: Active Pharmaceutical Ingredient (API): Pharmaco-therapeutic group (ATC Code): Therapeutic indication: Abacavir (as sulfate) 300 mg tablets * Hetero Labs Limited, Unit III Module 1- Block B #22-110, IDA, Jeedimetla Rangareddy District Hyderabad 500055 Telangana State, India abacavir (as sulfate) Nucleoside reverse transcriptase inhibitor (J05AF06) Abacavir (as sulfate) 300 mg tablets is indicated for the treatment of HIV infection in combination with other antiretroviral agents. * 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. Page 1 of 5
1. Introduction Abacavir (as sulfate) 300 mg tablets is indicated in combination with another antiretroviral agent for the treatment of Human Immunodeficiency Virus (HIV). Abacavir (as sulfate) 300 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 according to SOP 20 of the WHO Prequalification programme. Active Pharmaceutical Ingredient (API) Based on scientific principles, the WHO Prequalification Team Medicines (PQTm) has identified abacavir (as sulfate) (up to 600mg oral dose) as a BCS class III API, eligible for BCS-based biowaiver applications. The API is thus BCS highly soluble. The APIMF of abacavir sulfate, (1S,4R)-4-[2-Amino-6(cyclopropylamino)-9H-purin-9-yl]-2- cyclopentene-1-methanol sulfate (2:1), has been accepted through WHO s APIMF procedure. The manufacture of abacavir sulfate, which contains two chiral carbon atoms, entails several chemical steps. The desired stereochemistry at the chiral centres (1S,4R) is built into a starting material. The reactions involved in the conversion of this starting material to the API do not involve the chiral centres and hence the original chirality of the starting material is retained throughout the synthesis. The API specifications are pharmacopoeial based and include tests for description, solubility, identification (IR, HPLC and counter ion), water content (KF), residue on ignition, heavy metals, content of sulfate (potentiometric), organic impurities (HPLC), assay (HPLC), enantiomeric content (chiral HPLC; 0.20%), residual solvents and particle size. Cyclopropylamine is controlled at a limit of 30 ppm (GC). Stability testing was conducted according to the requirements of WHO. The proposed re-test period is justified based on the stability results when the API is stored in the original packing material. Other ingredients Other ingredients used in the core tablet formulation include microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide and magnesium stearate. The commercially sourced proprietary film-coating mixture contains HPMC/hypromellose, titanium dioxide, triacetin, iron oxide yellow and polysorbate. TSE / BSE free attestations have been provided for the excipients. Finished Pharmaceutical Product (FPP) Pharmaceutical development and manufacture The multisource product is a yellow coloured, biconvex, capsule shaped, film coated tablet debossed with H on one side and 139 on the other side separating 13 & 9 with a score line. The score line is intended for subdivision of tablets when half a tablet dose is to be administered, as supported by divisibility studies. The tablets are packaged in an HDPE bottles with child resistant or continuous threaded PP caps, with pulp liners. The development of the final composition of the multisource product has been described. The objective was to develop a stable tablet, pharmaceutically equivalent and bioequivalent to the comparator product, Ziagen 300mg Tablets, which is an immediate release solid dosage form for oral administration. The choice of excipients and process (direct compression) was based on the available information on the comparator product. The comparator product was also investigated for various parameters, including impurity profile and in vitro dissolution profiles in BCS related media. The latter profiles were targeted in the optimization studies. Optimization studies were performed for establishing Page 2 of 5
the concentration of disintegrant, diluent, glidant and lubricant. Studies were also performed to optimize process parameters. Satisfactory in-process controls have been established. Product specifications The finished product specifications are pharmacopoeial based and include tests for description, identification (HPLC, TLC), average weight, water content (KF), uniformity of dosage units (by weight variation), dissolution (UV detection), related substances (HPLC), assay (HPLC), residual solvents (GC) and microbial limits. Stability testing Stability studies have been conducted at 30 C/75%RH as long-term storage conditions and for six months at accelerated conditions in the packaging proposed for marketing of the product. The product proved to be quite stable at these storage conditions, with little degradation. 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 2008 according to internationally accepted guidelines. Study Title: A randomized, open label, two treatment, two period, two sequence, single dose, crossover, bioequivalence study of Abacavir Sulfate 300mg tablets of Hetero LabsLtd, India and Ziagen (containing abacavir sulfate 300mg) tablets of GlaxoSmithKline, Research Triangle Park, NC 27709 in healthy adult human subjects under fasting conditions (study no. 08-VIN-186). The objective of the study was to compare the bioavailability of the stated Abacavir sulfate 300 mg tablet manufactured by Hetero Drugs Ltd., India (test drug) with the reference formulation Ziagen (GlaxoSmithKline) and to assess bioequivalence. The comparison was performed as a single centre, open label, randomized, crossover study in healthy subjects under fasting conditions. Each subject was assigned to receive each of the following treatments in a randomized fashion: Treatment T: Test 1 tablet Abacavir sulfate 300 mg (abacavir 300 mg) Batch no. E8048. Treatment R: Reference 1 tablet Ziagen (abacavir 300 mg) Batch no. 1ZP9070 A 7 day wash-out period was observed between administration of test and reference. Serial blood samples (1 pre-dose sample and 19 samples within 12 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 abacavir were analyzed using a validated LC-MS/MS method. The limit of quantification was stated to be about 30 ng/ml for abacavir. The study was performed with 32 participants; data generated from a total of 29 subjects were utilized for analysis to establish pharmacokinetic parameters and assess bioequivalence. Arithmetic mean and geometric mean values of the pharmacokinetic variables for abacavir as well as statistical results are summarised in the following table: Page 3 of 5
Pharmacokinetic Parameter Test formulation (T) arithmetic mean ± SD (*) Abacavir Reference (R) arithmetic mean ± SD (*) log-transformed parameters Ratio Conventional T/R (%) 90% CI (ANOVAlog) t max (h) 0.66 ± 0.46 0.78 ± 0.51 - - C max (ng/ml) 3363 ± 981 3026 ± 891 111.1 100.8 122.4 (3222) (2900) AUC 0-t (ng.h/ml) 7123 ± 2129 6986 ± 2175 101.9 97.0 106.9 (6806) (6682) AUC 0-inf (ng.h/ml) 7227 ± 2127 7082 ± 2182 102.0 97.2 107.1 (6916) (6779) * geometric mean Conclusions: The results of the study show that preset acceptance limits of 80-125 % are met by both AUC and C max values regarding abacavir. Accordingly, the test tablet Abacavir sulfate 300mg meets the criteria for bioequivalence with regard to the rate and extent of absorption and is therefore bioequivalent to the reference Ziagen (GlaxoSmithKline). 4. Summary of Product Safety and Efficacy Abacavir (as sulfate) 300 mg tablets has been shown to conform to the same relevant standards of quality, efficacy and safety as those required of the innovator product. According to the submitted data on quality and bioavailability Abacavir (as sulfate) 300 mg tablets is pharmaceutically and therapeutically equivalent and thus interchangeable with the innovator product Ziagen 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 as stated in the Summary of Product Characteristics are taken into account. Reference is made to the SmPC (WHOPAR part 4) for data on clinical safety. 5. 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 Abacavir (as sulfate) 300 mg tablets is used in accordance with the SmPC. Bioequivalence Abacavir (as sulfate) 300 mg tablets has shown to be bioequivalent with Ziagen 300 mg tablets (GlaxoSmithKline, USA). Efficacy and Safety Regarding clinical efficacy and safety, Abacavir (as sulfate) 300 mg tablets is considered effective and safe to use when the guidance and restrictions in the Summary of Product Characteristics are taken into consideration. Page 4 of 5
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 Abacavir (as sulfate) 300 mg tablets was acceptable for the following indication: treatment of HIV infection in combination with other antiretroviral agents and has advised that the quality, efficacy and safety of Abacavir (as sulfate) 300 mg tablets allow inclusion of Abacavir (as sulfate) 300 mg tablets, manufactured at Hetero Labs Limited, Unit III, Module 1- Block B, #22-110, IDA, Jeedimetla, Rangareddy District Hyderabad 500055 Telangana State Andhra Pradesh, India in the list of prequalified medicinal products Page 5 of 5