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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 crosslinking 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.