Summary Basis of Decision for Eloxatin ®
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Eloxatin®
Oxaliplatin, 50 mg/vial and 100 mg/vial, Powder for solution; 5 mg/mL, solution, Intravenous
sanofi-aventis Canada Inc.
Submission control no: 109965
Date issued: 2009-02-19
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02296268 - 50 mg/vial, powder for solution
- 02296276 - 100 mg/vial, powder for solution
- 02296284 - 5 mg/mL, solution
Therapeutic Classification:
Non-medicinal ingredients:
Solution: Water for injection
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On June 15, 2007, Health Canada issued a Notice of Compliance to sanofi-aventis Canada Inc. for the drug product Eloxatin.
Eloxatin contains the medicinal ingredient oxaliplatin which is an antineoplastic agent.
Eloxatin is indicated for use in combination with 5-fluorouracil (5-FU) and leucovorin (LV) as treatment for patients with metastatic colorectal cancer. Metastatic colorectal cancer is a leading cause of cancer-related morbidity and mortality in the Western world. Eloxatin undergoes non-enzymatic conversion in physiologic solutions to active derivatives via displacement of the labile oxalate ligand. Several transient reactive species are formed that generate both inter- and intra-strand Pt-DNA crosslinks. These crosslinks inhibit DNA replication and transcription, leading to cytotoxic and antitumour effects.
The market authorization was based on submitted data from quality (chemistry and manufacturing) studies, as well as data from non-clinical and clinical studies. Clinical safety and efficacy were supported by four Phase III trials, ten Periodic Safety Update Reports (PSURs), and five Cumulative Reviews of relevant safety issues. Treatment with Eloxatin in combination with 5-FU/LV in previously-treated patients demonstrated significant improvements in response rate and time to tumour progression compared to 5-FU/LV alone. There was no significant improvement in median overall survival. In previously-untreated patients, Eloxatin in combination with 5-FU/LV compared to irinotecan plus 5-FU/LV resulted in a significantly longer time to tumour progression, improvement in overall survival, and a higher response rate. Toxicities were common. There are very serious risks associated with the use of Eloxatin (see Product Monograph for full listing), however the benefit/risk ratio is favourable given the indication.
Eloxatin (50 mg/vial, 100 mg/vial, 5 mg/mL, oxaliplatin) is presented as lyophilized powder for injection and solution for injection. The recommended dose schedule given every 2 weeks is as follows: Day 1 - Eloxatin 85 mg/m2 IV infusion and LV 200 mg/m2 IV infusion given over 2-6 hours, followed by an IV bolus of 5-FU 400 mg/m2 given over 2-4 minutes, followed by a 22-hour continuous infusion of 5-FU 600 mg/m2; Day 2 - LV 200 mg/m2 IV infusion given over 2 hours, followed by an IV bolus of 5-FU 400 mg/m2 given over 2-4 minutes, followed by a 22-hour continuous infusion of 5-FU 600 mg/m2. The dosage given should be adjusted according to tolerability. If severe/life-threatening diarrhea, neurotoxicity, or hematological toxicity occurs, a dose adjustment may be required. Dosing guidelines are available in the Product Monograph.
Eloxatin is contraindicated for patients with a history of known allergy to Eloxatin or other platinum compounds or to any ingredient in the formulation or component of the container, patients who are breast feeding or pregnant, and patients with severe renal impairment (creatinine clearance <30 mL/min). Eloxatin should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Eloxatin are described in the Product Monograph.
Priority Review status was granted for the evaluation of Eloxatin as it demonstrated an advantageous safety profile over existing standard therapy (IFL - irinotecan/5-FU/LV) for metastatic colorectal cancer, a serious, life-threatening illness not adequately managed by a drug marketed in Canada.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Eloxatin is favourable for use in combination with 5-fluorouracil (5-FU) and leucovorin (LV) as treatment for patients with metastatic colorectal cancer.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Oxaliplatin, the medicinal ingredient of Eloxatin, is an antineoplastic agent belonging to a new class of platinum-based compounds in which the platinum (Pt) is complexed with 1, 2-diaminocyclohexane and an oxalate group. Eloxatin is indicated for use in combination with 5-fluorouracil (5-FU) and leucovorin (LV) as treatment for patients with metastatic colorectal cancer. Metastatic colorectal cancer is a leading cause of cancer-related morbidity and mortality in the Western world. Eloxatin undergoes non-enzymatic conversion in physiologic solutions to active derivatives via displacement of the labile oxalate ligand. Several transient reactive species are formed that generate both inter- and intra-strand Pt-DNA crosslinks. These crosslinks inhibit DNA replication and transcription, leading to cytotoxic and antitumour effects.
Manufacturing Process and Process Controls
Oxaliplatin is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:
- The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance.
- The drug substance specifications are found to be satisfactory. Impurity limits meet International Conference on Harmonisation (ICH) requirements.
- The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
The materials used in the manufacture of the drug substance are considered to be suitable and/or meet standards appropriate for their intended use. The manufacturing process is considered to be adequately controlled within justified limits.
Characterization
Oxaliplatin is a white to off-white crystalline powder. Detailed characterization studies were performed.
The structure of oxaliplatin is considered to be adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
Comparability studies of oxaliplatin lots produced by different manufacturers were performed and comparable physicochemical characteristics were demonstrated.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within ICH established limits and/or were qualified from batch analysis and therefore, are considered to be acceptable.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of oxaliplatin are considered acceptable.
Copies of the analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing of oxaliplatin.
Results from process validation reports indicated that the impurities of the drug substance were adequately controlled. The level of impurities reported for the drug substance was found to be within the established limits.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The drug substance packaging is considered acceptable.
Stability
Based on the long-term and accelerated stability data submitted, the proposed retest period and storage conditions for the drug substance are supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Eloxatin powder for solution is a sterile freeze-dried product with two presentations: 50 mg oxaliplatin/vial and 100 mg oxaliplatin/vial. After reconstitution in water for injection or 5% glucose solution, a concentrate for solution for infusion containing 5 mg of oxaliplatin per mL is formed. Each vial of Eloxatin also contains lactose monohydrate as a bulking agent. The lyophilized Eloxatin powder is packaged in Type I clear glass vials and sealed with chlorobutyl rubber stoppers and aluminium crimping seals with coloured flip-off caps.
Eloxatin solution is a sterile, preservative-free, aqueous solution for injection containing 5 mg of oxaliplatin per mL of water for injection. The solution is available in three presentations: 50 mg/vial (nominal 10 mL fill), 100 mg/vial (nominal 20 mL fill), and 200 mg/vial (nominal 40 mL fill). Eloxatin solution is packaged in Type I clear glass vials and sealed with bromobutyl rubber stoppers and aluminium crimping seals with coloured flip-off caps.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of oxaliplatin with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the development are considered acceptable upon review.
Manufacturing Process and Process Controls
The Eloxatin drug product is compounded, sterile filtered, filled, and freeze-dried (lyophilized powder only) using conventional pharmaceutical equipment and facilities.
All manufacturing equipment, in-process manufacturing steps and detailed operating parameters were adequately described in the submitted documentation and are found to be acceptable. The manufacturing process is considered to be adequately controlled within justified limits.
The specifications for all of the ingredients are approved in accordance with United States Pharmacopeia National Formulary (USP/NF) or Ph. Eur. standards.
Control of Drug Product
Eloxatin is tested to verify that the identity, appearance, content uniformity, particulate matter, levels of degradation products and microbiological impurities, as well as the formulation-relevant parameters pH and water content, are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products, are within acceptable limits.
Copies of the analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing of Eloxatin.
Batch analysis results were reviewed and are considered to be acceptable according to the specifications of the drug product.
Although impurities and degradation products arising from manufacturing and/or storage were reported and characterized, these were found to be within ICH established limits and/or were qualified from toxicological studies and therefore, are considered to be acceptable.
Stability
Based on the long-term and accelerated stability data submitted, the proposed 36-month shelf-life at 15-30°C for both Eloxatin powder and solution is considered acceptable. The products should be protected from light and not frozen.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies.
3.1.3 Facilities and Equipment
The design, operations and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured.
All of the proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations. All sites are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
N/A
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Eloxatin has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
The pharmacodynamic effects of oxaliplatin were investigated both in vitro and in vivo. In vitro cytotoxicity and cell clonogenic assays were conducted using a variety of murine and human cell lines. In vivo antitumour activity of oxaliplatin was evaluated in various murine tumour models and in human xenograft models. The antitumour activity of oxaliplatin relevant to the proposed indication was confirmed both in vitro in colon cancer cells and in vivo in human colorectal cancer models.
Oxaliplatin strongly demonstrated in vitro cytotoxicity against HT-29, Caco-2 and HEC59 colorectal cancer cells. However, oxaliplatin displayed only modest in vivo antitumour activity against HT-29 and DLD2 human colon cancer xenografts. Despite the fact that synergy was not observed when oxaliplatin was combined with 5-FU in HT-29 cell culture in vitro, oxaliplatin was additively effective with 5-FU against human colonic tumour xenografts in vivo.
Similar to other platinum cytotoxic agents, oxaliplatin forms DNA-Pt addicts disrupting DNA replication and transcription. However, oxaliplatin has a different cytotoxic/antitumour profile. Based on numerous in vitro and in vivo studies, oxaliplatin was found effective against some, but not all, cisplatin-resistant cell lines.
Oxaliplatin is synthesized as a water soluble compound and readily undergoes non-enzymatic biotransformation in biological fluids to form more reactive products. Following biotransformation in vivo, the reactive products from oxaliplatin bind plasma proteins, cellular proteins, and DNA.
3.2.2 Pharmacokinetics
Absorption
Absorption of oxaliplatin was studied in mice, rats, rabbits (males only), and dogs. The pharmacokinetic (PK) profiles of blood platinum were similar to that observed in plasma with a bi-phasic elimination and evidence of a long terminal half-life. The conditions relevant to the drug formulation and administration in clinical settings were only used in the dog studies. The main findings were as follows:
- Maximum concentrations of oxaliplatin-derived platinum in blood and plasma were observed at the end of the infusion, between 1.5 and 2 hours after the start of the IV infusion.
- In dogs, platinum exposure in PUF generally increased as the dose increased (AUC = 11.7 µg.h/mL for 150 mg/m2 and 14.3 ug.h/mL for 200 mg/m2) and was similar to a human exposure at a dose of 130 mg/m2 (AUC = 11.9 ug.h/mL).
- The PK profiles of dog blood and plasma Pt were similar, with a terminal t1/2 of approximately 5 days.
- Oxaliplatin, when administered intravenously (IV) or intraperitoneally (IP), is extensively protein bound (approximately 85%), but only the ultrafiltrable free fraction is considered active.
- Oxaliplatin red blood cell (RBC) binding was rapid, reaching 37-53% in mice and humans.
- Studies using human blood showed that platinum cellular uptake into the blood cells reached a maximum concentration within 2 hours after the start of the IV infusion. The extent of the uptake by the blood cells at the maximum concentration was approximately 40% of total blood. Blood cell-associated platinum did not act as a reservoir for platinum in the plasma compartment. In addition, in vitro human plasma protein binding reached up to 85% (of total plasma binding) after 5 hours incubation.
Distribution
Distribution of oxaliplatin was determined in male rodents: mouse, rat, and rabbit. In mice, extensive tissue distribution of platinum was observed in all tissues with the exception of the brain, where levels were negligible. The highest platinum levels were found in the spleen, a consequence of a strong incorporation into the RBC and in the kidney.
In rats bearing colonic tumours, there was some evidence of platinum uptake into tumours after administration of oxaliplatin. In rabbits, platinum from oxaliplatin was widely distributed into tissues. The highest platinum levels were also detected in the kidney and spleen.
In all rodents, platinum accumulation in the spleen was high (up to 55% in mice). Platinum levels in the kidney and liver were high, but generally lower with oxaliplatin as compared to other platinum drugs. Platinum concentrations were not detected in the brain of rabbits and rats, indicating that oxaliplatin and its products either do not penetrate the blood brain barrier or are not retained in the central nervous system (CNS).
Metabolism
Oxaliplatin undergoes rapid and extensive non-enzymatic biotransformation. There is no evidence of cytochrome P450-mediated metabolism in vitro. The oxalate group is displaced by a variety of nucleophiles to give a mixture of diaminocyclohexane (DACH), chloro, or aquo derivatives, as well as amino acid derivatives, e.g. methionine DACH platin. Most of these biotransformed products of oxaliplatin were common across all species tested. Many of these products were also detected in biological fluids in vitro. Several biotransformation products were not characterized.
In the dog, only 10% of the unchanged oxaliplatin was found in the plasma ultrafiltrate after 1.5 hours infusion. Four major biotransformation products were observed, two of which were identified as monochloro DACH platin and dichloro DACH platin. At 2 hours post-infusion, most of the radioactivity was distributed between two unknown components. Four major, and at least seven minor, components were observed in dog urine. The major product appeared to be devoid of platinum and was identified as DACH.
The reaction pathway via the diaquo and related derivatives is thought to produce the activated species that interacts with cellular DNA.
Excretion
Renal elimination was the major route of excretion of oxaliplatin and total platinum in dogs and rabbits; approximately 70% dose was eliminated within 24 hours. Overall excretion in the dog over 7 days accounted for 76.5%, with ~ 6% contribution from fecal excretion. The terminal phase of excretion was slow, presumably due to the known irreversible binding of this class of compounds to proteins. There are no data on the excretion of oxaliplatin via the milk of animals or humans.
3.2.3 Toxicology
Acute Toxicity
Acute toxicity of oxaliplatin in mice and rats was similar. Dyspnea, ptosis, vasodilation (10 min) and stereotypy were observed in rats immediately after injection. The frequency and longevity of symptoms were dose-related. Statistically significant growth retardation was reported in all treatment groups; there was a clear correlation between the growth retardation and dose. Rodents that died after a single dose presented significant weight loss and poor general health.
In mice, the LD10 values ranged from 43.2 to 60 mg/m2. The LD10, calculated for the aqueous solution formulation, was 51 mg/m2. There were no biologically significant differences in the acute toxicity of oxaliplatin as bulk substance in 5% glucose compared to oxaliplatin lyophilized with lactose or with mannitol. In rats, IP oxaliplatin injection resulted in the LD10 = 84 mg/m2.
In rats, a single-dose IV injection of oxaliplatin in 5% glucose resulted in an LD05 = 113 mg/m2. Mortality was immediate for the high dose and generally delayed for the lower doses. Statistically significant growth retardation was reported in the dose range of 84-240 mg/m2. There was a clear dose-effect relationship in the frequency and longevity of symptoms such as dyspnea, ptosis, vasodilation, stereotypy, and growth retardation.
In dogs, the single IV doses =150 mg/m2 oxaliplatin were lethal. Animals treated with 300 mg/m2 showed increased creatine kinase (CK). One oxaliplatin-treated dog died due to ventricular fibrillation (300 mg/m2). Oxaliplatin cardiotoxicity was the most frequent cause of lethal events observed in the dog studies. Cardiotoxicity of oxaliplatin was observed from decreased heart rate, arrhythmias, and ECG changes such as tachycardia, bradycardia, extrasystoles, ectopic beats, abnormal T waves, and decreased ST segment. Oxaliplatin toxicities were dose-dependent and included emesis, diarrhea, decreases in food consumption and body weight, and decreases in white blood cell (WBC) count. Head twitches, salivation, hypertension, and metabolic acidosis were observed at higher doses. Blood analysis indicated hypokaleamia, and increases in hematocrit. Nephrotoxicity was evident from the decreased urine volume, proteins, and blood in the urine.
Repeat-Dose Toxicity
In dogs treated for 5 days at 15, 30, 45, or 60 mg/m2, the dose limiting toxicity was the lethal cardiac toxicity. Five daily doses of oxaliplatin produced emesis, a decrease in food consumption and body weight, and a slight decrease in WBC. The main clinical chemistry findings were protein, blood, and bilirubin in the urine; and increases in ALT and AST. The toxic effects such as anorexia, vomiting, and decreased heart rate were more severe at higher doses. Autopsy revealed mammary gland hypertrophy, inguinal hypertrophy, and multiple adhesions (liver, pancreas, genitals) in one animal dosed 5 x 15 mg/m2. Decreased heart rate, arrhythmias, and ECG changes, such as tachycardia, bradycardia, extrasystoles, ectopic beats, abnormal T waves, and decreased ST segment indicated cardiotoxicity. The 60 mg/m2 daily dose induced the death of the animal after the 4th treatment (total dose of 240 mg/m2). The sudden death due to ventricular fibrillation occurred when the animal appeared to be in good condition. Transitory bradycardia was recorded 1 hour after treatment. The toxic effects were similar at all doses. As such, the margins between low toxic dose, high toxic dose, and lethal dose were not established.
In the dose-finding study, single IV doses =100 mg/m2, or 5 daily IV doses of 40 mg/m2 were lethal. The mortality rate was 87.5% (14/16). The deaths occurred on Days 1 and 2 after administration. One dog treated with 300 mg/m2 died of ventricular fibrillation. No deaths were observed at the dose of 5 x 30 mg/m2 every three weeks. Significant dose-dependent toxicities included emesis, diarrhea, myelosuppression, ECG changes such as ventricular extrasystoles, and ventricular fibrillation. The main finding was that the fractioning of the oxaliplatin doses into the five consecutive administrations was better tolerated.
No mortalities occurred in dogs during the 84-day period when treated with oxaliplatin over three cycles of 0, 15, 25, or 35 mg/m2 dosing followed by 23 days treatment-free. The observed toxicities were dose-dependent and included: pancreatitis; myelosuppression; testicular hypoplasia /atrophy; degeneration in the kidney proximal tubules; sialadenitis; congestion of the conjunctiva; and increase in the caliber of the retinal veins.
The maximum tolerated dose (MTD) in dogs was 35 mg/m2 given on a cycle of daily dosing for five days, followed by three weeks recovery, repeated three times.
Abnormalities of various types were detected in dogs administered a single dose of oxaliplatin IV at 0, 50, 100, or 150 mg/m2 every 3 weeks for three cycles. Two of six animals (150 mg/m2 group) died at 3 hours and 8 hours post-infusion. ECG were reported as being normal, but the monitoring time (pre-treatment, before the 2nd and the 3rd infusions, and at the end of the study) was not considered adequate. Thus, the results are non-conclusive. The following findings indicated toxic effects of oxaliplatin:
- Strongly contracted rigid hearts with large blood clots;
- Renal lesions, observed at the high dose level in the form of nephrocytic hypertrophy;
- Cell hypoplasia lesions in the organs characterized by active cell renewal:
- lymph organs, primary (thymus) and secondary (spleen and nodes);
- gonads: hypoplasia present in all groups, severe at doses =100 mg/m2.
In rats, the repeat-dose toxicity study included three cycles of 5-day treatment followed by 16 days with no treatment. The 5-daily doses of oxaliplatin were 3, 6, and 12 mg/m2. The 63-day observations revealed that the target organs were the bone marrow and kidney. Decreased bone marrow cellular count was mainly due to erythroblastic and myeloblastic depletions. Decreases in WBC (mostly lymphocytes) and RBC were dose-related. Nephrotoxicity was observed from the increased levels of blood urea nitrogen and creatinine. Histopathological examinations of the kidney confirmed necrosis and degeneration of the tubules.
Cardiotoxicity
Based on non-clinical studies, oxaliplatin has cardiotoxic potential in dogs. In the dog, a single dose of =150 mg/m2 oxaliplatin caused serious cardiovascular reactions such as increased blood pressure, arrhythmia, and ventricular ectopic events, followed by fatal ventricular fibrillation. Oxaliplatin cardiotoxicity was the most frequent cause of lethal events observed in dogs; however, the mechanism of the dose-dependent cardiotoxicity of oxaliplatin remains unknown. Based on the non-clinical data and the similarities in the drug biotransformation and exposure in dogs and humans, there is a safety concern for patients treated with oxaliplatin at a dose =130 mg/m2. It should be anticipated that, if overdosed, oxaliplatin may possibly cause cardiac dysfunction that may lead to the death of the patient.
Genotoxicity
The positive mutagenic and clastogenic activity of oxaliplatin was expected based on the biochemical and pharmacological aspects of its interaction with cellular DNA resulting in DNA damage and repair. The standard battery of genetic toxicology studies were conducted. Oxaliplatin was not genotoxic in the Ames test. Positive mutagenic effects were obtained for oxaliplatin in an in vitro mouse lymphoma cell test. Significant clastogenic activity was seen both in vitro (human lymphocyte clastogenic test) and in vivo (mouse micronucleus assay). The clastogenic effect of oxaliplatin was observed at a dose of 12 mg/m2 (proposed clinical dose is 85 mg/m2). Based on the genetic toxicity study results, oxaliplatin is considered mutagenic and clastogenic.
Carcinogenicity
Carcinogenicity studies have not been conducted with oxaliplatin. However, the genotoxic activity of oxaliplatin indicates that oxaliplatin may be a carcinogen.
Myelotoxicity
Based on the results from in vitro bone marrow experiments, oxaliplatin exhibited myelotoxicity. Thus, oxaliplatin has a potential to produce myelosuppression in cancer patients.
Neurotoxicity
In vitro and in vivo mechanistic studies investigated the different mechanisms that could underlie oxaliplatin's acute and persistent neurotoxicities noted in colorectal cancer (CRC) patients. The results suggested that the acute neurotoxic effects are most likely due to effects on sodium channels, whereas persistent neurotoxic effects are related to damage to dorsal root ganglia. Oxaliplatin was capable of altering the voltage-gated sodium channels through a pathway involving Ca2+. The infusion of Ca2+ and Mg2+ for preventing acute neurotoxicity in patients was suggested.
Oxaliplatin was shown to increase the sodium current in dorsal root ganglion neurons, thus altering the voltage-response relationship. This effect was not dependent on intracellular calcium. The effect of oxaliplatin on action potential could be antagonized by the anti-epileptic drug carbamazepine. Based on these findings, it was suggested that the Na+ channel blocker carbamazepine could be used to reduce side effects of oxaliplatin therapy in patients.
In vivo neurotoxicity studies in rats demonstrated that oxaliplatin causes damage to nucleoli of dorsal root ganglia. The damage occurred a few hours after treatment and recovery was taking a few months. Functional neurotoxicity was observed as decreased sensory nerve conduction velocity, and required 3 months to recover.
Reproductive and Developmental Toxicity
In a fertility study, oxaliplatin administered daily for 5 consecutive days followed by a 16-day interval for 2-3 cycles did not affect fertility in either male or female rats. Maternal toxicity was manifested by a decrease in weight gain and dose-dependent increase in post-implantation loss. Fetotoxicity in rats was dose-dependent and reached up to 100% at a dose of 12 mg/m2.
Oxaliplatin had no teratogenic activity in rats or rabbits at IV doses up to 6 and 9.6 mg/m2/day, respectively. Oxaliplatin administered during the first days of the rat gestation (Days 1-5) did not produce any fetal malformations. However, a low dose of 6 mg/m2/day oxaliplatin administered over Days 6-10 or Days 11-15 of gestation resulted in delayed ossification and a significant decrease in fetal weight. Study findings in oxaliplatin-treated rats also included a dose-related increase in embryonic deaths. Thus, possible risks of miscarriage and congenital malformations exist. Related compounds with similar mechanisms of action have been reported to be teratogenic. It is very likely that oxaliplatin is toxic to the human fetus, and should therefore be contraindicated during pregnancy. In male dogs administered oxaliplatin at 15 mg/m2/day for 5 days every 28 days for 3 cycles, testicular degeneration, hypoplasia, and atrophy were observed. A no-effect level was not identified. This daily dose is approximately one-sixth of the recommended human dose.
3.2.4 Summary and Conclusion
Pharmacodynamic studies demonstrated in vitro cytotoxicity and in vivo antitumour activity of oxaliplatin in a variety of tumour model systems, including human colorectal cancer models. A synergistic cytotoxic action has been observed with the combination of oxaliplatin and fluorouracil, both in vitro and in vivo.
Pharmacokinetic studies determined the disposition of oxaliplatin in mice, rats, rabbits, and dogs. Extensive distribution of platinum was observed in all tissues except the brain. The highest platinum levels were seen in the spleen, kidney and liver. The plasma profile of oxaliplatin was generally multi-phasic, with several declines and a long terminal half-life. There is no evidence of cytochrome P450-mediated metabolism in vitro. Oxaliplatin undergoes rapid biotransformation via non-enzymatic degradation both in vitro and in vivo. Most of the biotransformed products of oxaliplatin are common across all species tested. Oxaliplatin and its derivates are excreted mainly in the urine.
Toxicology studies demonstrated 10% lethality at a single dose of 51 mg/m2 and 84 mg/m2 in mice and rats, respectively. In animals, the main toxicities included cardiotoxicity (dogs), nephrotoxicity, lympho-hematopoietic, gastrointestinal, and reproductive organ (testes) toxicities. The teratogenic potential of oxaliplatin was manifested by the embryonic mortality, decreased fetal weight, and delayed ossifications in rats at doses up to 12 mg/m2/day. This daily dose is approximately one-sixth of the recommended human dose.
Oxaliplatin caused cardiotoxicity in dogs characterized by decreased heart rate, arrhythmias, and ECG changes, (such as tachycardia, bradycardia, extrasystoles, ectopic beats, abnormal T waves, and decreased ST segment), ventricular fibrillation, and death of the animals at doses =150 mg/m2. Based on the similarities in the drug biotransformation and exposure in dogs and humans, there is a safety concern for patients treated with oxaliplatin at a dose =130 mg/m2. It should be anticipated that, in the case of oxaliplatin overdose in humans, oxaliplatin may possibly cause cardiac dysfunction that may lead to the death of the patient. It is therefore indicated in the Product Monograph that oxaliplatin was cardiotoxic in dogs. No cardiac safety studies have been carried out in humans.
Based on the animal toxicology findings, kidney, and cardiac function are targets of oxaliplatin. There is a potential hazard to the human fetus if oxaliplatin is used during pregnancy, therefore pregnancy was added to the list of contraindications. Oxaliplatin is genotoxic in mammalian test systems and should be considered a human carcinogen. These warnings and precautions are included in the Product Monograph.
3.3 Clinical basis for decision
3.3.1 Human Pharmacology
Following oxaliplatin IV administration, oxaliplatin-derived platinum is extensively distributed in the plasma. The relative distribution ratio of platinum between blood cells, plasma, and plasma ultrafiltrate is approximately 3.1: 3.7: 1.0. Maximum platinum concentrations (Cmax) were reached at the end of the 2 hour infusion of 85 mg/m2 oxaliplatin. Plasma protein binding was 90% by the end of the 2 hour infusion. Low interpatient variability in Cmax values was observed in plasma and whole blood (%CV of 19% and 16%, respectively). Variability in Cmax in ultrafiltrate was higher (%CV of 45%). Moderate interpatient variability in drug exposure values (AUC 0-48) were observed in all matrices (%CV of 19% to 34%). The interpatient variability of other calculated AUC parameters was of a similar order of magnitude.
The volume of distribution of platinum at steady state (Vss) was high in all matrices. Moderate to high interpatient variability in Vss values (%CV of 33% to 45%) and in clearance (CL) values (%CV of 31% to 41%) was seen in all matrices. The plasma protein binding of oxaliplatin was evaluated in vitro using concentrations ranging from 0.3-20 µg/mL oxaliplatin. The serum protein binding of oxaliplatin was 79-87%, at equilibrium after 6 hours. The main serum binding proteins were albumin and gamma-globulins. Most of the platinum was covalently bound. No binding saturation was observed in the concentration range 0.3-20 µg/mL. In plasma, 85-88% of oxaliplatin-derived radioactivity was bound within 5 hours. In the whole blood, 37.1% of oxaliplatin was bound to blood erythrocytes within 2 hours in vitro.
Based on AUC values, statistically significant accumulation of platinum was observed in blood cells and plasma following administration of 130 mg/m2 oxaliplatin every three weeks for 1 to 2 cycles. The inter- and intra-patient variability in ultrafilterable platinum exposure AUC0-48 assessed over three cycles was moderate to low (23% and 6%, respectively). There was no evidence of platinum accumulation in plasma ultrafiltrate.
Biotransformation of [3H]-oxaliplatin was investigated in vitro using human liver microsomal fractions. In the presence and absence of NADPH, 67% and 71% of unchanged drug was found, respectively. In both cases, the second major product, diaquo DACH accounted for 17% of radioactivity. Several other minor products represented less than 1-3% of the radioactivity each. Once liver enzymes were inactivated, 82% of the radioactivity co-eluted as oxaliplatin and 12% as diaquo DACH platin. The elution profiles were similar in all cases. Thus, there was no evidence of cytochrome P450-mediated metabolism of DACH ring. In plasma, oxaliplatin (50 µg/ml) remained unchanged at 37°C for 30 min. After 1 hour, 30% was transformed into dichloro DACH platin. At 2 hours no unchanged oxaliplatin was detectable in plasma samples in vitro.
Oxaliplatin undergoes extensive biotransformation in patients, and no intact drug was detectable in plasma ultrafiltrate at the end of a 2-hour infusion. Several cytotoxic biotransformation products including the monochloro, dichloro, and diaquo DACH platinum species have been identified in the systemic circulation, together with a number of inactive conjugates at later time points. There was no evidence of hepatic metabolism via cytochrome P450-mediated enzymatic reactions. Thus, no metabolism- or protein displacement-based drug-drug interactions are anticipated in patients treated with oxaliplatin.
Biotransformation is the major route of oxaliplatin clearance in patients. Platinum is predominantly excreted via urinary elimination. Within 48 hours of dosing, 46% of the total platinum is excreted in the urine and 2.1% in the feces. Smaller amounts (0.4-1.9%) 1of the administered dose per day continued to be eliminated after 48 hours. By Day 5 after a single 2-hour infusion of Eloxatin, approximately 54% of the total dose was recovered in the urine and approximately 2% in the feces. The pharmacokinetics of individual active compounds have not been determined.
In patients with renal impairment, a significant decrease in clearance of ultrafilterable platinum from 17.6±2.18 L/h to 9.95±1.91 L/h (creatinine clearance 12-57 mL/min) was observed together with a statistically significant decrease in distribution volume from 330±40.9 L to 241±36.1 L. The effect of severe renal impairment on platinum clearance has not been evaluated. The drug exposure increased by 60, 140, and 190% in patients with mild, moderate, and severe renal impairment, respectively, compared to patients with normal renal function. The pharmacodynamic relationship between platinum levels and clinical safety has not been established. Oxaliplatin should not be administered to the patients with severe renal impairment.
In adult cancer patients with impaired liver function, a significant decrease in the beta half-life and a corresponding increase in the AUC of ultrafilterable platinum was seen in patients with severe hepatic impairment (total bilirubin 3.1 mg/dL to 6.0 mg/dL). Clinical indicators of hepatic function such as bilirubin, alkaline phosphatase, and serum glutamic oxaloacetic transaminase (SGOT) were not correlated with ultrafilterable platinum elimination. However, increasing levels of serum creatinine were significantly correlated with decreasing ultrafilterable platinum clearance. No increase in oxaliplatin acute toxicities were observed in the subset of patients with abnormal liver function tests at baseline. No specific dose adjustment for patients with abnormal liver function tests was performed during clinical development.
3.3.2 Clinical Efficacy
In support of clinical efficacy and safety, the sponsor submitted: four Phase III studies (two for first line metastatic colorectal cancer (MCRC) therapy, one for second line MCRC therapy, and one study which, although an adjuvant therapy study, was reviewed for the safety data relevant to the MCRC indication); ten Periodic Safety Update Reports (PSURs); and five Cumulative Reviews of relevant safety issues.
Study EFC7462-9741 was a Phase III, randomized, open-label study conducted in 795 patients that demonstrates that in previously untreated patients with MCRC, the use of Eloxatin with 5-FU and LV led to a statistically significant improvement in median time to tumour progression (TTP), the primary efficacy endpoint. Patients treated with Eloxatin plus 5-FU/LV had a median TTP of 8.7 months compared to 6.9 months in patients receiving the reference standard IFL (irinotecan + 5-FU/LV). This is a difference in TTP of 1.8 months, which in a patient with metastatic colorectal cancer, would be considered a clinically meaningful benefit. It is recognized that metastatic colorectal cancer has a poor prognosis, with a median survival of 1 year.
This demonstration of efficacy is supported by the secondary efficacy endpoints. After a median follow-up time of 20 months, when over 80% of patients had progressed, the median overall survival (OS) in patients treated with Eloxatin plus 5-FU/LV was 19.4 months compared to 14.6 months in patients receiving IFL. This difference of 4.8 months was statistically significant, with the hazard ratio (HR) for death (Eloxatin plus 5-FU/LV relative to IFL) being 0.65, with 95% confidence limits of 0.53 to 0.80. Again, the improvement of median OS by 4.8 months in patients receiving Eloxatin plus 5-FU/LV vs. IFL is most definitely a clinically meaningful benefit in a disease that is uniformly fatal, with a median survival of one year. There was also a statistically significant improvement in secondary efficacy endpoints: median OS 19.4 months vs. 14.6 months; and response rate (RR) 45% vs. 33%. The efficacy within the Eloxatin plus 5-FU/LV arm was similar in all subgroups.
The supportive study for first-line therapy of MCRC was Study EFC2962, designed as a Phase II-III, open-label, multi-centre study in 420 patients to compare progression-free survival (PFS, primary efficacy endpoint) of MCRC patients treated with either 5-FU/LV alone or in combination with oxaliplatin. Based on expert radiologic assessment, median PFS in patients on the oxaliplatin-containing arm was statistically significantly better than in patients on the 5-FU/LV arm (8.2 months vs. 6.0 months). There was also a significantly better RR for the oxaliplatin-containing arm (49% vs. 22%). There was no improvement in OS (15.9 months vs. 14.7 months; a difference of 1.2 months); nevertheless, Study EFC2962 was considered to be supportive of the pivotal Study EFC7462 because the primary efficacy endpoint (PFS) was significantly better and the secondary efficacy endpoint of RR was significantly better.
A Quality of Life (QoL) assessment of patients in Study EFC2962 was inconclusive due to a low percentage of patients completing a baseline and at least one more QoL questionnaire (both arms).
Study EFC4584 was a Phase III multicenter, open-label, randomized three-arm study (816 patients) comparing overall survival (primary endpoint) of patients treated with 5-FU/LV, oxaliplatin, or both, in the second line MCRC setting. Median overall survival in patients receiving oxaliplatin plus 5-FU/LV was 9.9 months compared to 8.8 months with 5-FU/LV alone, which was not statistically significant; however, there was considered to be a trend towards longer survival for the oxaliplatin-containing arm compared to the 5-FU/LV arm. Secondary endpoints were statistically significantly better in the oxaliplatin plus 5-FU/LV arm compared to 5-FU/LV alone (RR 11% vs. 1%; TTP 5.3 months vs. 2.6 months). These results were similar in all subgroups.
3.3.3 Clinical Safety
Across the main studies reviewed in this submission (EFC7462, EFC2962, EFC4584 for the metastatic indication, as well as Study EFC3313 which was an adjuvant study for the purpose of safety assessment only), some common features were noted:
- The addition of Eloxatin to 5-FU/LV led to an increase in toxicity compared to 5-FU/LV alone.
- Eloxatin was associated with hepatotoxicity, manifested primarily by elevation of hepatic enzymes. In the clinical studies reviewed, levels of transaminases, specifically ALT, which is the main drug-induced hepatotoxity marker, were elevated in 6% (all grades) and 1% (grade 3/4) of patients in the Eloxatin plus 5-FU/LV treatment arm for previously untreated metastatic colorectal cancer patients. Alkaline phosphatase was also elevated in 16% (all grades) and 0% (grade 3/4) of these patients. For patients who were previously treated for metastatic colorectal cancer, ALT was elevated in 36% (all grades) and 0% (grade 3/4) of patients, while alkaline phosphatase was elevated in 60% (all grades) and 4% (grade 3/4) of patients.
- In addition, there was evidence (as noted in the PSURs reviewed) that Eloxatin causes liver sinusoidal obstruction syndrome, also known as veno-occlusive disease of the liver. On liver biopsy, this was manifested as peliosis, nodular regenerative hyperplasia, and perisinusoidal fibrosis. Because Eloxatin causes elevated liver function tests, clinicians need to be aware to monitor for the development of veno-occlusive disease. This warning is included in the Product Monograph (Serious Warnings and Precautions Box).
- Eloxatin in combination with 5-FU/LV was myelosuppressive. Neutropenia was very common (observed in approximately 80% of patients), although it was not usually associated with febrile neutropenia. The incidence of febrile neutropenia was relatively low across the studies, usually less than 5%.
- Thrombocytopenia was very common with the Eloxatin plus 5-FU/LV combination (observed in approximately 70% of patients), although bleeding events were infrequent. Most bleeding events were epistaxis; however, there were infrequent cases of rectal bleeding, hemoptysis, and hematuria. In addition, there were reports of prolonged prothrombin time and International Normalized Ratio (INR) that were associated with hemorrhage in patients on anticoagulants. Close monitoring of anticoagulation status is needed in patients taking oral anticoagulants.
- Eloxatin in combination with 5-FU/LV was toxic to the gastrointestinal tract. Approximately 65% of patients experienced diarrhea (all grades), which can lead to dehydration and associated electrolyte imbalance. Also, vomiting and mucositis were common, thus possibly interfering with oral hydration efforts. Usually, the use of pre-chemotherapy 5-HT3 blockers with or without dexamethasone can control chemotherapy-related nausea and vomiting. In the clinical trials, standard anti-diarrheals were used (e.g. loperamide). Despite these measures, grade 3/4 vomiting occurred in approximately 6% of patients, grade 3/4 diarrhea in approximately 12%, and grade 3/4 dehydration in less than 5% of patients.
- Eloxatin was neurotoxic, and was associated with two types of neuropathy:
(1) An acute sensory peripheral neuropathy that developed at the end of the 2-hour Eloxatin infusion, or within 1 to 2 days of dosing. It usually resolved between cycles, but frequently recurred with further cycles. Symptoms may be precipitated or exacerbated by exposure to cold temperatures or objects. Symptoms usually presented as transient paresthesias, dysesthesias, and hypoesthesias in the hands, feet, perioral area, or throat. Other symptoms occasionally observed included jaw spasm, abnormal tongue sensation, dysarthria, eye pain, and throat or chest tightness. Acute neuropathy (all grades) occurred in 58% of patients with advanced/metastatic colorectal cancer receiving Eloxatin plus 5-FU/LV in the metastatic study, but grade 3/4 events occurred in only 4% of patients. In any individual cycle, acute neurotoxicity was observed in about one third of patients. An acute syndrome of pharyngolaryngeal dysesthesia occured in 1-2% of patients, and was characterized by subjective sensations of dysphagia or dyspnea, feeling of suffocation, without any evidence of respiratory distress (no cyanosis or hypoxia) or of laryngospasm or bronchospasm (no stridor or wheezing).
(2) A persistent peripheral sensory neuropathy that was characterized by paresthesias, dysesthesias, hypoesthesias, and may include deficits in proprioception, thus resulting in difficulties performing activities of daily living (ADLs) including those involving delicate movements such as writing or buttoning, as well as difficulty walking. In patients previously untreated for metastatic colorectal cancer, neuropathy was reported in 82% (all grades) and 19% (grade 3/4) of patients, and in the previously-treated patients neuropathy was reported in 79% (all grades) and 11% (grade 3/4) of patients. The probability of developing peripheral sensory neuropathy is dependant upon the cumulative dose of oxaliplatin administered. These symptoms may improve in some patients upon discontinuation of Eloxatin.
One case of posterior reversible encephalopathy syndrome (PRES) has been reported in the literature, although the cause/effect relationship cannot be established with certainty. - Eloxatin administration can cause hypersensitivity reactions. Across the clinical studies, the incidence of Grade 3/4 events was 2-3%. Some cases (in post marketing) were fatal. These reactions were managed with epinephrine, corticosteroids, and antihistamines. A warning has been included in the Product Monograph.
- The combined incidence of cough, dyspnea, and hypoxia in patients receiving Eloxatin plus 5-FU/LV was 30% and 43% (all grades) in the metastatic clinical studies, although the incidence of interstitial lung disease (ILD), or pulmonary fibrosis, was rare. One fatal case of eosinophilic pneumonia was reported in a patient receiving Eloxatin combination therapy on study.
- Based on non-clinical data, Eloxatin is cardiotoxic in dogs. In the clinical situation, cardiovascular events were reported in association with the combination therapy of Eloxatin plus 5-FU/LV, although most of these events were low-grade, and not much higher than in the control arm. In patients previously untreated in metastatic colorectal cancer, oedema and thrombosis were reported in 15% and 6% (all grades), and 0% and 5% (grade 3/4) of the patients, respectively. In previously treated patients, leg and peripheral oedema were reported in 8% and 6% (all grades) and <1% and 0% (grade 3/4) of the patients, respectively. The number of deaths due to cardiac events was low in all arms of the reviewed studies. However, given the patient population, there are a variety of confounding factors such as co-morbidities and concomitant medications, which make it very difficult to conclusively implicate Eloxatin. The Sponsor intends to continue to closely monitor myocardial (and cerebrovascular) ischemic disorders. No formal clinical cardiac safety studies have been done. Additionally, the effect of Eloxatin in combination with 5-HT3 blocker anti-emetics (given as pre-medication in clinical studies) on QTc has not been formally studied. A warning has been included in the Product Monograph.
- Based on the Periodic Safety Update Report (PSUR) data reviewed, there is evidence that Eloxatin, although less nephrotoxic than cisplatin, can cause acute tubular necrosis, acute interstitial nephritis, and acute renal failure. This is of particular importance in the patient who develops diarrhea and dehydration related to treatment with Eloxatin plus 5-FU/LV. Study POP5347 is an ongoing study in patients with gastrointestinal cancers and varying degrees of renal impairment.
- Hemolytic Uremic Syndrome was rarely reported with the use of Eloxatin in clinical studies and in the post-market setting.
- In the event of extravasation, Eloxatin may result in irritation. Cases of necrosis were reported in the post-market setting, thus Eloxatin may be considered to have vesicant properties. There does not appear to be a recommended approach to Eloxatin extravasation, other than to stop the infusion. The rationale for which local treatment to apply (i.e. heat or cold) varies based on physiological perspectives and individual institutions are recommended to deal with this as per local practice.
- In metastatic colorectal cancer studies, patients =65 years old receiving Eloxatin in combination with 5-FU/LV experienced more fatigue, dehydration, diarrhea, leukopenia, and syncope than patients <65 years old, although the difference was not statistically significant. The starting dose for elderly patients does not require adjustment, however a warning has been included in the Product Monograph indicating the above findings.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
In previously untreated patients with metastatic colorectal cancer, the use of Eloxatin plus 5-FU/LV provides clinical benefit in the form of longer overall survival, time to tumour progression, and better response rate compared to the current standard IFL (irinotecan/5-FU/LV) regimen. In previously treated patients with metastatic colorectal cancer, when compared to 5-FU/LV alone, which had been the standard therapy of metastatic colorectal cancer for several years prior to the use of IFL, Eloxatin plus 5-FU/LV provides a longer time to tumour progression and response rate, with a trend toward improved overall survival. Quality of life data is inconclusive.
The clinical benefit of Eloxatin is associated with a risk of toxicity. Patients receiving Eloxatin plus 5-FU/LV for their metastatic disease can expect to have: myelosuppression, with a possibility of bleeding and/or infection, that may be life-threatening; gastrointestinal toxicity which includes nausea, vomiting, and diarrhea, which can lead to severe/life-threatening dehydration; peripheral sensory neuropathy, which usually does develop, can be dose-limiting and may cause disabling effects in approximately 10% of patients after a cumulative dose of approximately 800 mg/m2, and may be persistent for several weeks or months after cessation of therapy; liver dysfunction, that has a small chance of being severe or life-threatening; hypersensitivity reactions (including fatal anaphylaxis, although rarely); and other, rare toxicities (interstitial lung disease, hemolytic uremic syndrome, renal toxicity). A unique feature of Eloxatin is the cold-induced neuropathy, transient paresthesias, or acute pharyngolaryngeal dysesthesias. Patient education will be very important in this regard.
Priority Review status was granted for the evaluation of Eloxatin as it demonstrated an advantageous safety profile over existing standard therapy (IFL) for metastatic colorectal cancer, a serious, life-threatening illness that was not adequately managed by the drugs marketed in Canada.
Based on the review of this submission, it is clear that the benefits of Eloxatin plus 5-FU/LV use in patients with metastatic colorectal cancer do outweigh the risks. The efficacy of this combination demonstrated in this submission is clinically meaningful to this patient population, and would likely be considered by these individuals to be worth the toxicity of the therapy. Granted, Eloxatin is a toxic drug, but with patient education and usual oncology practice, this therapy should become part of the oncology armamentarium in Canada for the treatment of metastatic colorectal cancer.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and effectiveness, Health Canada considers that the benefit/risk profile of Eloxatin is favourable for use in combination with 5-fluorouracil (5-FU) and leucovorin (LV) as treatment for patients with metastatic colorectal cancer. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: Eloxatin®
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2006-08-01 |
| Request for priority status | |
| Filed | 2006-10-16 |
| Approval issued by Director, Bureau of Metabolism, Oncology and Reproductive Sciences (BMORS) | 2006-11-17 |
| Submission filed | 2006-11-20 |
| Screening | |
| Screening Acceptance Letter issued | 2006-12-22 |
| Review | |
| Quality Evaluation complete | 2007-06-04 |
| Clinical Evaluation complete | 2007-06-15 |
| Biostatistics Evaluation complete | 2007-04-24 |
| Labelling Review complete | 2007-06-13 |
| Notice of Compliance issued by Director General | 2007-06-15 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| ELOXATIN | 02296268 | SANOFI-AVENTIS CANADA INC | OXALIPLATIN 50 MG / VIAL |
| ELOXATIN | 02296276 | SANOFI-AVENTIS CANADA INC | OXALIPLATIN 100 MG / VIAL |