Public Assessment Report



Public Assessment Report

Scientific discussion

Oxaliplatin Pliva 5 mg/ml

oxaliplatin

powder for solution for infusion

MRP CZ/H/146/01/MR

Applicant:

Pliva s.r.o., Czech Republic

This module reflects the scientific discussion for the approval of Oxaliplatin 5mg/ml 50 and 100mg powder for solution for infusion. The procedure was finalised on 01-10-2007.

Introduction

This generic application for marketing authorisation concerns Oxaliplatin, Pliva a.s. 5mg/ml 50 and 100mg. The application was approved in a Mutual Recognition Procedure on 1st October 2007. The national marketing authorization was granted on 11th November, 2006.

The objective was to develop a generic equivalent to originator product Eloxatin, marketed by Sanofi Synthelabo France. Oxaliplatin is a third generation anti-cancer platinum derivative and the first approval was granted in France on 12th April, 1996.

Oxaliplatin in combination with 5-fluorouracil (5-FU) and folinic acid (FA) is indicated for:

Adjuvant treatment of stage III (Duke's C) colon cancer after complete resection of primary tumour.

Treatment of metastatic colorectal cancer.

Since oxaliplatin is administered by the i.v. route, bioequivalence studies are not necessary and information regarding them is not provided in literature. No new preclinical and clinical studies were conducted. This is acceptable for this abridged application

QUALITY ASPECTS

Introduction

Oxaliplatin Pliva 5 mg/ml is presented in the form of powder for solution for infusion.

It contains oxaliplatin as the active substance. The only excipient is mannitol.

The primary packaging consists of a colourless type I glass vial closed with a bromobutyl rubber stopper and aluminium cap with a polypropylene cover (flip-off).

The approved shelf life of the product is 2 years.

Active Substance

Oxaliplatin is described in the European Pharmacopoeia. Oxaliplatin is a white or almost white crystalline powder, solubility at 25 °C is: in water 8 mg/ml, in dimethylformamide 9.92 mg/ml, in ethanol 0.28 mg/ml. Melting point: about 200°C, decomposition starts at about 250°C. Specific optical rotation: [α20] is +74.5° to +78.0° (0.5% water solution). Under given conditions of crystallisation, there is no evidence of polymorphism.

The scientific information has been submitted in the Active Substance Master File. A satisfactory letter of access was provided by the manufacturer. Manufacture has been described in detail. A flow chart of the synthetic route is included. Tests and acceptance criteria performed at critical steps in the manufacturing process have been identified. Process validation was performed on five production batches.

Batch analyses results from three consecutive production scale batches that confirm compliance with the proposed specification and demonstrate that the manufacturing method is capable of consistently producing material of an acceptable quality were provided.

Analytical methods have been described and validated when non-compendial in accordance with ICH requirements.

The substance is packed in brown glass bottles, Type III glass, with screw caps and PE fixing inset. The bottles and PE fixing are stated to comply with the Ph.Eur. requirements.

The stability data provided are acceptable, results remain well within specification for all characteristics, throughout the study period for which data have been provided, and under all conditions. A re-test period of 24 months for product stored in brown glass bottles with screw caps and PE lining as primary packaging material at a temperature below 25°C, protected from light, can be approved.

Medicinal Product

Oxaliplatin Pliva 5 mg/ml, powder for solution for infusion, is a white freeze-dried powder. It is a sterile lyophilised product marketed in two presentations, 50 mg/vial and 100 mg/vial. Oxaliplatin Pliva is reconstituted with 10 ml or 20 ml solvent (water for injection or 5% glucose) to obtain 5 mg/ml of oxaliplatin.

Pharmaceutical Development

The aim of development studies was to obtain a generic product with oxaliplatin in a form of powder for solution for infusion. The only excipient in the lyophilised product is mannitol used as the inert constituent and diluent. Water for injection is used as a solvent and is removed during freeze drying. Nitrogen is used as the protective gas during the manufacture. All the excipients are commonly used in pharmaceutical preparations and are of Ph.Eur. quality. No antioxidant or preservative was used. None of the ingredients is of animal origin.

The comparison of impurity profile of Oxaliplatin Pliva 50 mg and innovator product Eloxatin

50 mg, Sanofi, was provided and the tested batches of both products exhibit almost identical levels of impurities.

Manufacturing of the product

Sterilisation method was chosen according to NfG CPMP/QWP/054/98 Decision Trees for Selection of Sterilisation Methods. The method is assessed as non standard and it is adequately validated.

Product specification

The proposed specifications at release and end of shelf life are satisfactory, including all of the required tests relevant to the intended dosage form. Limits for related substances comply with ICH guidelines. Analytical methods are well described, non pharmacopoeial methods have been validated.

The packaging material colourless glass vial (type I) with bromobutyl rubber stopper complies with the Ph.Eur.

Stability of the product

The stability of the drug product was tested and evaluated in several stability studies in accordance with the predefined stability protocol.

A shelf life of 2 years and special storage condition “Keep the vial in the outer carton to protect the product from light” is acceptable.

Discussion on chemical and pharmaceutical aspects

Information on development, manufacture and control of the drug substance and drug product has been presented in a satisfactory manner. The results of tests carried out indicate satisfactory consistency and uniformity of important product quality characteristics, and these in turn lead to the conclusion that the product should have a satisfactory and uniform performance in the clinic.

Steps taken after authorisation

The quality of the product, in particular in respect of control, has been regularly updated to take account of technical and scientific progress and necessary changes were made by variation procedures.

CLINICAL ASPECTS

Oxaliplatin is an antineoplastic agent belonging to the new class of platinum derivates. Oxaliplatin contains platinum atom complexed with oxalate group and 1,2 – diaminocyclohexane. It differs from cisplatin and carboplatin in not having free amino-groups bound to platinum, but rigid cyclic structure. These reactive platinum complexes are believed to inhibit DNA synthesis by forming interstrand cross-linking of DNA molecules.

Compared to cisplatin and carboplatin, oxaliplatin exhibits a much greater volume of distribution, probably due to enhanced tissue penetration and altered cell membrane permeability. The oxaliplatin PK are similar to those of cisplatin, with a bicompartemental distribution for both total and ultrafiltrable PT and linearity in the dose range studies. The recommended dose and administration are 130-135 mg/m2 administered over two hours in three weeks intervals. The dose limiting toxicity is cumulative neurotoxicity. There are no differences between Cmax platinum in plasma and ultrafiltartes, however, ultrafiltrate AUC is significantly increased in renally impaired patients. Thus, oxaliplatin can be safely administered without dose modification to the patients with moderately impaired renal function.

85% of plasma oxaliplatin is bound to proteins, 37% of the infused oxaliplatin is sequestered in the erythrocytes within 2-5 hours. Plasmatic half-life alpha is 7.3 hours.

Approximately half of the platinum dose is discovered in the urine within 3 days after the administration, whereas the faecal excretion is minimal. Urinary excretion of oxaliplatin is higher compared to cisplatin and carboplatin.

The cumulative PK shows that there is no meaningful accumulation of PT after even 7 courses of chemotherapy with oxaliplatin.

The pharmacokinetic profile of oxaliplatin with high clearance rates, high volume of distribution and faster elimination than cisplatin, results in no nephrotoxicity.

Similarly to cisplatin, the main mechanism of action of oxaliplatin is mediated through the formation of DNA-adducts. Since the intrastrand adducts are the mostly abundant adducts and are capable of both DNA replication and transcription, they are considered the major cytotoxic lesion. The other types of adducts are represented by interstrand crosslinks, and DNA protein crosslinks appear to represent minor species.

The cytotoxic activity is at least that of cisplatin and carboplatin in neuroblastomal, leukaemia, melanoma, breast, ovarian endometrial, NSCLC, gastric and colonic cancer cell lines. Oxaliplatin has demonstrated additive or synergistic cytotoxic properties with many other cytotoxic agents, such as fluoropyrimidines, cyclophosphamide, cisplatin, irinotecan, paclitaxel, nolatrexed, gemcitabine.

Although oxaliplatin has a different spectrum of activity against human tumours than cisplatin and carboplatin, the resistance emerges with kinetics resembling those for the first and second generation platinum-containing chemotherapeutic agents. The resistance may be mediated by enhanced tolerance to adducts in DNA. This tolerance is commonly found in cells with acquired oxaliplatin resistance. Further studies are needed to clarify the involvement of mitochondrial apoptosis in oxaliplatin resistance.

Oxaliplatin is an antineoplastic drug belonging to a new generation of platinum-based compounds, which contains a platinum atom complexed with oxalate and 1,2-diaminocyclohexane. Specifically, these complexes are believed to inhibit DNA synthesis by forming interstrand and intrastrand cross-linking of DNA molecules. Unlike other platinum-based agents, oxaliplatin shows clinical activity in colorectal cancer. Its dose-limiting toxicity is cumulative peripheral sensoric neuropathy.

Oxaliplatin 5 mg/ml powder for solution for infusion is indicated for the treatment of metastatic carcinoma of the colon and adjuvant treatment of stage III (Duke's C) colon cancer after complete resection of primary in combination with 5-fluorouracil (5-FU) and folinic acid (FA).

Pharmacodynamic and pharmacokinetic properties of oxaliplatin are well known. As it is a widely used, well-known active substance, no further studies are required and the applicant provides none. Overview based on literature review is, thus, appropriate.

Since oxaliplatin is administered by the i.v. route, bioequivalence studies are not necessary and information regarding them is not provided in literature.

No new preclinical studies and no clinical studies were conducted, which is acceptable given that the applications were based on essential similarity to the product licensed for more than 6 years. The application contains an adequate review of published clinical data.

The MAH has submitted EU-RMP on the current template. According to this EU-RMP, no safety concerns requiring additional risk minimization activities have been identified. The MAH is convinced that routine pharmacovigilance activities are completely sufficient to identify actual or potential risks.

Conclusion:

No activities were taken for safety reasons by regulatory authorities. Based on the available information, is concluded that there is no important new safety information which alter the favourable benefit/risk assessment of the product.

The proposed wording of SPC of Oxaliplatin Pliva reflects up to date knowledge and recommendations. The applicant has performed a readability testing of the package information leaflet.

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