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Hepsera, INN- Defovir Dipivoxil

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Hepsera, INN- Defovir Dipivoxil SCIENTIFIC DISCUSSION This module reflects the initial scientific discussion for the approval of Hepsera. For information on changes after approvalplease refer to module 8B 1. Chemical, pharmaceutical and biological aspects Composition Hepsera is presented as an immediate release tablet containing 10 mg of adefovir dipivoxil, as active substance. The other ingredients in this formulation are commonly used in tablets Hepsera is supplied in high-density polyethylene bottle (HDPE), with silica gel desiccant canisters or sachets, and polyester fiber packing material. The closure system consists of a child-resistant polypropylene screw cap lined with an induction activated aluminium foil liner. Active substance Adefovir dipivoxil is an ester prodrug of the nucleotide analogue, adefovir. A structural modification of the parent drug has been carried out in order to increase the lipophilicity and to enhance the oral bioavailability of adefovir. The active substance is a white to off-white crystalline powder. It is soluble in ethanol, sparingly soluble in 0.1N HCl and very slightly soluble in water adjusted to pH 7.2 but relatively highly soluble at physiological pH. The active substance does not contain any chiral center and does not exhibit any optical isomerism. In laboratory studies the anhydrate crystal form has been observed to convert gradually into a dihydrate crystal form when adefovir dipivoxil was exposed to high humidity conditions (75% R.H., 25ºC) over an approximately one-month period. However, the only crystal form produced during the active substance synthesis and utilised in non-clinical and clinical studies has been the anhydrous crystal form. Adefovir dipivoxil undergoes also hydrolysis in aqueous solution and to a smaller degree in the solid state after exposure to humidity and heat for extended periods. Adefovir dipivoxil is synthetised from commercially available starting materials. Following crytallisation, the product is dried and milled. Satisfactory specifications and associated methods have been provided for the starting materials, key intermediates, reagents and solvents. The active substance specification includes tests for appearance, identity, clarity of solution, water content, assay, impurity content (HPLC), organic volatile impurities (GC), heavy metals, particle size and additional tests to confirm that the active substance is in the anhydrous form. Impurity limits in specification are justified by toxicology studies. The analytical methods used in routine controls are suitably described and validated. Batch analysis data confirm satisfactory compliance and uniformity with the proposed specification. Batches have been studied under long-term conditions (5°C – samples packed in sealed polyethylene bags placed into tightly capped HDPE bottles) for up to 36 months and under accelerated conditions (25°C/60% RH and 30°C/60% RH – samples packed in sealed polyethylene bags placed into tightly capped HPDE bottles or unsealed polyethylene bags placed into open HDPE bottles) for 6 months. Photostability studies were also performed and showed that the active substance is not light sensitive. The results obtained support the proposed retest period of 2 years under refrigeration at 2-8°C. 1/29 EMEA 2005 Other ingredients All the excipients comply with the Ph. Eur. requirements. The only ingredient from animal origin is the lactose monohydrate using milk and calf rennet of bovine origin during its preparation. The manufacturer has provided confirmation that the milk is sourced from healthy animals in the same conditions as milk collected for human consumption and that the calf rennet complies with the public statement EMEA/CPMP/571/02. The HDPE bottle and the polypropylene cap meet the general Ph. Eur. requirements for plastic primary packaging material. Confirmation has been given that the silica gel desiccant canisters/sachets and the polyester fiber packing material are suitable for contact with food. Product development and finished product The product development was mainly based on the active substance properties and so aimed to minimise the exposure of the active substance to moisture. The tablet formulation is prepared using a conventional wet granulation process and subsequent controlled drying process to reduce the water content of the granules. The effect of environmental moisture on the drug product has also been minimised by adding silica gel as a desiccant to the immediate packaging bottle and also by using a bottle with sufficient wall thickness and an aluminium foil induction seal.All the excipients selected are commonly used in tablet formulations. The function of each excipient and the rationale for its use has been satisfactorily described. The formulation used in the clinical studies and the commercial formulations are similar, the only difference being the dimension and the shape of the tablets. Therefore, no bioequivalence study has been performed. A bioequivalence study has been performed to assess the effect of food on the bioavailability and pharmacokinetic of the intended commercial formulation. The results demonstrate that the absorption of adefovir dipivoxil is unaffected when taken with food. The method of manufacture can be divided into 5 operations: compounding, granulation/drying, milling, final blending (in two steps: extragranular excipients then lubricant), and compression. Validation data have been provided on six primary stability batches and also on 3 full-scale batches prepared using three different active substance lots sourced from the two suppliers. These validation data together with the results obtained during process and formulation optimisation studies showed the robustness of the formulation and that the identified critical parameters are under control. Based on these results, satisfactory in-process controls have been established. The product specification includes tests for appearance, identity, assay, water content, impurity content, content uniformity (Ph. Eur.), dissolution, hardness (Ph. Eur.) and microbial limit (Ph. Eur.). Batch analysis data presented include data for 3 full-scale batches of the finished product manufactured at the intended manufacturing site, comply with the specifications and confirm the robustness and reproducibility of the manufacturing process. Stability of the Product Long term and accelerated stability studies were conducted on six primary stability batches. 36 months data are available for one batch, 24 months for another and 18 months for the four other batches under long term conditions (25ºC/60% R.H – packaging intended for commercialisation). Studies under accelerated conditions (40ºC/75% R.H. – packaging intended for commercialisation) have been performed over a 6-months duration. Additional long-term stability studies have been conducted at the intermediate condition of 30ºC/70% R.H. for a 18-month period. A photostability study has also been performed. The results presented support the proposed shelf life and storage conditions defined in the Summary of Product Characteristics. 2/29 EMEA 2005 2. Toxico-pharmacological aspects Pharmacodynamics Mechanism of action Because adefovir is not well absorbed from the intestine, the prodrug was developed as it was shown in vitro that adefovir dipivoxil enters cells more efficiently than the parent compound, and is rapidly converted into adefovir. Adefovir is actively transported into cells where it is converted by adenylate kinase to the active metabolite adefovir diphosphate through two phosphorylation reactions. Adefovir diphosphate inhibits hepatitis B virus (HBV) polymerase activity by competing with dATP for incorporation into viral DNA. Adefovir diphosphate lacks a 3´-hydroxyl group and therefore causes premature termination of DNA synthesis after incorporation into the DNA chain. Adefovir diphosphate is a potent inhibitor of HBV DNA polymerase; with a Ki value (inhibition constant) equivalent to 0.1 µM. Adefovir diphosphate shows specificity for HBV polymerase with a Ki value 10-700 fold higher than for mammalian DNA polymerases. The half-life of adefovir diphosphate was 16-18 hours in T-lymphocytic MT-4 cells. The half-life of adefovir dipivoxil was 30 hours in quiescent human peripheral blood mononuclear cells (PBMCs) and 12 hours in PHA-stimulated PBMCs. In vivo intracellular half-life of adefovir diphosphate in PBMCs was approximately 36 hours after a single subcutaneous dose of 14C-labeled adefovir to macaques. • In vitro studies Adefovir demonstrated antiviral activity against human HBV, duck HBV (DHBV) and woodchuck HBV (WHV) in cells culture models. Concentrations leading to 50 % inhibition of viral replication (IC50) ranged from 0.2 to 1.2 µM in two different HBV DNA transfected hepatoma cell lines. In different cells types, the cytotoxic concentrations of adefovir ranged from 80 to 500 µM, which revealed a low cytoxicity potential. Adefovir showed additive or synergistic anti-DHBV activity in combination with lamivudine and penciclovir at several molar ratios. There was no antagonism between these three compounds. Adefovir diphosphate was active against lamivudine and famciclovir resistant HBV polymerases with the Ki values increasing by less than 2.3 fold compared with the wild type. In addition, mutations associated with hepatitis B immunoglobulin escape did not reduce sensitivity to adefovir in cell culture. As other nucleotide analogues, adefovir has a nephrotoxic potential. Adefovir was less inhibitory on the growth of human renal proximal tubule epithelial
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