Lyophilized powder for injection

50 mg/vial 100 mg/vial

Solution for injection

5 mg/mL

ATC code: L01X A03

Antineoplastic Agent

sanofi-aventis Canada Inc. 2150 St. Elzear Blvd. West Laval, Quebec H7L 4A8 Date of Revision: July 18, 2008

Submission Control No.: 118553 s-a Version 3.0 dated

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 10 DRUG INTERACTIONS 25 DOSAGE AND ADMINISTRATION 26 OVERDOSAGE 32 ACTION AND CLINICAL PHARMACOLOGY 33 STORAGE AND STABILITY 36 SPECIAL HANDLING INSTRUCTIONS 36 DOSAGE FORMS, COMPOSITION AND PACKAGING 36

PART II: SCIENTIFIC INFORMATION 37

PHARMACEUTICAL INFORMATION 37 CLINICAL TRIALS 38 DETAILED PHARMACOLOGY 52 TOXICOLOGY 55 REFERENCES 60

PART III: CONSUMER INFORMATION. 62

PrELOXATIN(r) Oxaliplatin for injection

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

(see DOSAGE AND ADMINISTRATION section).

CONTRAINDICATIONS

ELOXATIN should not be administered to 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. For a complete listing, see the Dosage Forms, Composition and Packaging section of the Product Monograph. who are breast-feeding. who are pregnant. with severe renal impairment (creatinine clearance ClCr < 30 mL/min).

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

ELOXATIN should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents.

Anaphylactic Reactions -

See WARNINGS AND PRECAUTIONS - Immune section; Cardiovascular section.

Hepatotoxicity -

See WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic section.

Myelosuppression - Neutropenia and Thrombocytopenia

. See WARNINGS AND PRECAUTIONS, Hematologic section.

Neuropathy - Sensory and Motor -

See WARNINGS AND PRECAUTIONS, Neurologic section; ADVERSE REACTIONS, Post-Market Adverse Drug Reactions, Nervous System Disorders.

Respiratory - Interstitial lung disease (including fatalities)

has been reported with ELOXATIN use. See WARNINGS AND PRECAUTIONS, Respiratory section; ADVERSE REACTIONS, Post-Market Adverse Drug Reactions, Respiratory System Disorders.

Carcinogenesis and Mutagenesis

ELOXATIN was shown to be mutagenic and clastogenic in mammalian test systems in vitro and in vivo. The teratogenic potential of ELOXATIN 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. Related compounds with similar mechanism of action and genotoxicity profiles have been reported to be teratogenic. ELOXATIN may increase the risk of genetic defects or fetal malformations. ELOXATIN is contraindicated in pregnancy, and males are advised not to father a child during treatment and up to 6 months thereafter. Because ELOXATIN may cause irreversible infertility, men are advised to seek counseling on sperm storage before starting treatment (see TOXICOLOGY). Carcinogenicity studies have not been performed with ELOXATIN. However given that ELOXATIN is genotoxic, it should be considered a human carcinogen, which should be taken into consideration for the overall risk/benefit in the adjuvant setting.

Cardiovascular

No formal clinical cardiac safety studies have been carried out. Pre-clinical data are limited. No standard hERG or Purkinje fibre tests have been done. Cardiotoxicity was observed in dogs (see TOXICOLOGY). No formal clinical QT studies with ELOXATIN were done. 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. In case of grade 3 or grade 4 hypersensitivity reaction associated with hemodynamic instability (eg. bradycardia, tachycardia, hypotension, hypertension) ECG monitoring should be done.

Gastrointestinal

Gastrointestinal toxicity, which manifests as nausea and vomiting, warrants prophylactic and/or therapeutic antiemetic therapy (see ADVERSE REACTIONS). Dehydration, ileus, intestinal obstruction, hypokalemia, metabolic acidosis, and even renal disorders, may be associated with severe diarrhea/emesis, particularly when combining ELOXATIN with 5-FU. In rare cases, colitis, including Clostridium difficile diarrhea, have occurred (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions). Patients must be adequately informed of the risk of diarrhea/emesis after ELOXATIN/5-FU administration in order to contact urgently their treating physician for appropriate management (see subsection Monitoring and Laboratory Tests below).

Hematologic

Patients must be adequately informed of the risk of neutropenia after ELOXATIN/5-FU administration in order to contact urgently their treating physician for appropriate management (see subsection Monitoring and Laboratory Tests below). Thrombocytopenia is commonly seen with ELOXATIN combination therapy, although the risk of grade 3 or 4 bleeding is low (see ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions). Anemia (rarely presenting as Hemolytic Uremic Syndrome) can also occur.

Hepatic/Biliary/Pancreatic

Routine monitoring of liver function should be performed on all patients receiving ELOXATIN. Hepatotoxicity with the use of ELOXATIN plus 5-FU/LV has been noted in clinical studies (see ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions, "Hepatic Adverse Events" tables 4, 6 and 9. Hepatic vascular disorders should be considered, and if appropriate, should be investigated in cases of abnormal liver function test results or portal hypertension, which cannot be explained by liver metastases. There is evidence that ELOXATIN causes liver sinusoidal obstruction syndrome, also known as veno-occlusive disease of the liver, which, on liver biopsy is manifested as peliosis, nodular regenerative hyperplasia, and perisinusoidal fibrosis. In the literature, there is a case report of fatal hepatic failure following liver metastasis resection in a patient treated pre-operatively with ELOXATIN (see References: Rubbia-Brandt 2004, Vauthey 2006, Hewes 2007, Tisman 2004 and Schouten van der Velden 2006). Very rare cases of hepatic failure, hepatitis and rare cases of pancreatitis have been reported in the post-market setting (see ADVERSE REACTIONS - Post-Market Adverse Drug Reactions).

Immune

Hypersensitivity, anaphylactic reactions, and/or allergic reactions are reported with the use of ELOXATIN. The incidence of grade 3 or 4 events was 2-3% across clinical studies. In the post- marketing experience, some cases of anaphylaxis have been fatal. These allergic reactions can occur within minutes of ELOXATIN administration, and can include rash, urticaria, erythema, pruritis, and, rarely, bronchospasm and hypotension. Patients with a history of allergic reaction to platinum compounds should be monitored for allergic symptoms. In case of an anaphylactic- like reaction to ELOXATIN, the infusion should be immediately discontinued and appropriate symptomatic treatment initiated. These reactions are usually managed with epinephrine, corticosteroid, and antihistamine therapy. ELOXATIN rechallenge is contraindicated (see Serious Warnings and Precautions Box).

Neurologic

ELOXATIN is consistently associated with two types of sensory neuropathy:

An acute, reversible, sensory peripheral neuropathy can develop (reported in 85 to 95% of patients) at the end of the 2-hour ELOXATIN infusion, or within 1 to 2 days of dosing. It usually resolves between cycles, but frequently recurs with further cycles.

Symptoms may be precipitated or exacerbated by exposure to cold temperatures or objects. The symptoms usually present as transient paresthesias, dysesthesias and hypoesthesias in the hands, feet, perioral area, or throat. Other symptoms occasionally observed include, abnormal tongue sensation, dysarthria, eye pain, and throat or chest tightness. In addition, acute motor symptoms, including jaw spasms, muscle spasms, involuntary muscle contractions, ptosis, vocal cord paralysis and cranial nerve dysfunction have been reported. Acute neuropathy (all grades) occurred in 58% of patients with

metastatic colorectal cancer receiving ELOXATIN plus 5-FU/LV 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 occurs in 1-2% of patients, and is 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). Because cold temperatures can precipitate or exacerbate acute neurological symptoms, ice (mucositis prophylaxis) should be avoided during ELOXATIN infusion.

A persistent peripheral sensory neuropathy can develop. It is characterised by paresthesias, dysesthesias, hypoesthesias, and may include deficits in proprioception, thus resulting in difficulties performing activities of daily living (ADLs). This can result in difficulty with delicate movements such as writing or buttoning, as well as difficulty walking due to impaired proprioception.

In adjuvant patients, sensory neuropathy was reported in 92% (all grades) and 13% (grade 3) of patients. The median cycle of onset for grade 3 neuropathy was cycle 9. At the 28 day follow-up after the last treatment cycle, 60% of all patients had neuropathy of any grade (grade 1 - 40%; grade 2 - 16%; grade 3 - 5%) decreasing to 21% at 18 months (grade 1 - 17%; grade 2 - 3%; grade 3 - 1%). At the 48 month follow-up, neuropathy status was as follows: grade 0 - 62%; grade 1 - 9%; grade 2 - 2%; grade 3 - 0.5%; not evaluable - 26.5%. This suggests that there can be partial or complete recovery of sensory neuropathy over time after cessation of therapy. However, in some cases, an increase in severity of the sensory neuropathy was reported years after completion of adjuvant therapy. The long term impact of the neuropathy is difficult to measure, and needs to be considered carefully in the overall risk/benefit ratio during therapy with ELOXATIN. In patients previously untreated for metastatic colorectal cancer, neuropathy was reported in 82% (all grades) and 19% (grade 3/4), and in the previously treated patients in 79% (all grades) and 11% (grade 3/4). 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. NCI CTC grading definitions are as follows:

Sensory peripheral neurotoxicity of ELOXATIN should be carefully monitored, especially if co- administered with other medications with specific neurological toxicity (see Serious Warnings and Precautions Box; ADVERSE REACTIONS section; subsection Monitoring and Laboratory Tests below). The risk factors that make a patient more likely to develop neuropathy have not been identified. One case of posterior reversible encephalopathy syndrome (PRES) has been reported in the literature in a patient treated with oxaliplatin and 5-FU/LV, although the cause/effect relationship cannot be established with certainty (see References - Skelton 2007).

Respiratory

ELOXATIN has been uncommonly associated with pulmonary fibrosis/interstitial lung disease (< 1% of study patients). In the adjuvant trial, the combined incidence of cough and dyspnea in patients receiving ELOXATIN plus 5-FU/LV compared to patients receiving infusional 5- FU/LV alone was 7% vs. 5% (all grades) and 0.8% vs. 0.1% (grade 3-4), respectively. In previously untreated patients with metastatic colorectal cancer, the combined incidence of cough, dyspnea and hypoxia in patients receiving ELOXATIN plus 5-FU/LV vs. irinotecan plus 5- FU/LV was 43% vs. 32% (all grades) and 7% vs. 5% (grade 3-4). In previously treated patients, the combined incidence of cough, dyspnea and hypoxia in patients receiving ELOXATIN plus 5- FU/LV vs. 5-FU/LV alone was 30% vs. 21% (all grades) and 5% vs. 2% (grade 3-4). One fatal case of eosinophilic pneumonia was reported in a patient receiving combination ELOXATIN therapy on study. In case of unexplained respiratory symptoms such as non-productive cough, dyspnea, crackles, or radiological pulmonary infiltrates, ELOXATIN should be discontinued until further pulmonary investigation excludes interstitial lung disease (see Serious Warnings and Precautions Box and ADVERSE REACTIONS). Fatal cases of interstitial lung disease have been reported in the post-market setting.

Skin

In case of ELOXATIN extravasation, the infusion must be stopped immediately and usual local symptomatic treatment initiated. Extravasation of ELOXATIN may result in local pain and inflammation that may be severe and lead to complications, including necrosis, injection site reaction, including redness, swelling, and pain. In the literature, tissue necrosis has been reported with ELOXATIN extravasation (see References: De Lemos 2005).

Special Populations

Geriatrics (>= 65 years of age):

In patients previously untreated for metastatic colorectal cancer, patients >= 65 years (99 of 279 patients) receiving ELOXATIN in combination with 5-FU/LV experienced more fatigue, dehydration, diarrhea, leukopenia, and syncope than patients

< 65 years, although the difference was not statistically significant. Starting doses were the same in both age groups. In the adjuvant trial, patients >= 65 years receiving the ELOXATIN combination therapy (393 of 1108) experienced more grade 3-4 granulocytopenia and diarrhea than patients < 65 years although the difference was not statistically significant.

Pediatrics (<= 22 years of age):

Oxaliplatin single agent has been evaluated in pediatric population in 2 Phase I (69 patients) and 2 Phase II (90 patients) studies. A total of 159 pediatric patients (7 months-22 years of age) with solid tumors have been treated. The effectiveness of oxaliplatin single agent in the pediatric populations treated has not been established. Accrual in both Phase II studies was stopped for lack of tumor response (see INDICATIONS AND CLINICAL USES).

Pregnant Women:

To date, there is no available information on safety of use in pregnant women. Based on preclinical findings, ELOXATIN is likely to be lethal and/or teratogenic to the human foetus at the recommended therapeutic doses. Therefore, ELOXATIN is contraindicated in pregnancy.

As with other cytotoxic agents, effective contraceptive measures should be taken in potentially fertile patients (male and female) prior to initiating chemotherapy with ELOXATIN (see CONTRAINDICATIONS).

Nursing Women:

Excretion in breast milk has not been studied. Breast-feeding is contraindicated during ELOXATIN therapy (see CONTRAINDICATIONS).

Hepatic Insufficiency:

No increase in ELOXATIN acute toxicities was 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.

Renal Insufficiency:

The primary route of platinum elimination is renal. Clearance of ultrafilterable platinum is decreased in patients with mild, moderate and severe renal impairment. A pharmacodynamic relationship between platinum ultrafiltrate levels and clinical safety and effectiveness has not been established (see ACTION AND CLINICAL PHARMACOLOGY).

ELOXATIN has not been studied in patients with severe renal impairment (see CONTRAINDICATIONS). Due to limited information on safety in patients with moderately impaired renal function, administration should be considered after suitable appraisal of the benefit/risk for the patient. In this situation, treatment may be initiated at the normally recommended dose and renal function should be closely monitored and dose adjusted according to toxicity.

Monitoring and Laboratory Tests

Complete blood count with differential, hemoglobin, platelets, and blood chemistries, including ALT, AST, bilirubin, creatinine, magnesium and electrolytes should be performed prior to the start of therapy and before each subsequent course (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment). There have been reports while on study and from post-marketing surveillance of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received ELOXATIN plus 5-FU/LV while on anticoagulants. Patients receiving ELOXATIN plus 5- FU/LV and requiring oral anticoagulants may require closer monitoring (see DRUG INTERACTIONS). Patients receiving ELOXATIN combination therapy should be monitored for diarrhea, vomiting, and mucositis, which can lead to severe/life-threatening dehydration. If this occurs, discontinue ELOXATIN until improvement or resolution (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment). A neurological examination should be performed before each administration and periodically thereafter. See DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment for guidance if neurological symptoms occur.

DRUG INTERACTIONS

Overview

No specific cytochrome P-450-based drug interaction studies have been conducted.

In vitro

, ELOXATIN is not metabolized by, nor does it inhibit, human cytochrome P450 isoenzymes. No P450-mediated drug-drug interactions are therefore anticipated in patients.

Since platinum-containing species are eliminated primarily through the kidney, clearance of these products may be decreased by coadministration of potentially nephrotoxic compounds; although, this has not been specifically studied (see ACTION AND CLINICAL PHARMACOLOGY).

Drug-Drug Interactions

In patients who have received a single dose of 85 mg/m2 of ELOXATIN immediately before administration of 5-FU, no change in the level of exposure to 5-FU has been observed. No pharmacokinetic interaction between 85 mg/m2 ELOXATIN and 5-FU/LV has been observed in patients treated every 2 weeks. Increases of 5-FU plasma concentrations by approximately 20 % have been observed with doses of 130 mg/m2 ELOXATIN administered every 3 weeks. The approved dose of ELOXATIN is 85 mg/m2 every 2 weeks in combination with 5-FU/LV (see DOSAGE AND ADMINISTRATION).

In vitro

, platinum was not displaced from plasma proteins by the following medications: erythromycin, salicylate, sodium valproate, granisetron and paclitaxel.

There have been reports while on study and from post-marketing surveillance of prolonged prothrombin time and INR occasionally associated with hemorrhage in patients who received ELOXATIN plus 5-FU/LV while on anticoagulants. Patients receiving ELOXATIN plus 5- FU/LV and requiring oral anticoagulants may require closer monitoring.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herbs Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Dosing Considerations

Dosage given should be adjusted according to tolerability. If severe/life-threatening diarrhea, neurotoxicity or hematological toxicity occurs, a dose adjustment may be required (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment).

Recommended Dose and Dosage Adjustment

Administer ELOXATIN in combination with 5-FU/LV every 2 weeks. For metastatic disease, treatment is recommended until disease progression or unacceptable toxicity. For adjuvant use, treatment is recommended for a total of 12 cycles (6 months). The recommended dose schedule given every 2 weeks is as follows:

Day 1: ELOXATIN 85 mg/m2 IV infusion in 250 to 500 mL of 5% (50 mg/mL) glucose solution (D5W) is given at the same time as leucovorin 200 mg/m2 IV infusion in 5 % glucose solution (D5W), over 2 to 6 hours in separate bags using a Y-line. Followed by 5-FU 400 mg/m2 IV bolus given over 2-4 minutes, followed by 5-FU 600 mg/m2 IV infusion in 500 mL of 5 % glucose solution (D5W) (recommended) as a 22-hour continuous infusion.

Day 2:

Leucovorin 200 mg/m2 IV infusion over 2 hours. Followed by 5-FU 400 mg/m2 IV bolus given over 2-4 minutes, followed by 5-FU 600 mg/m2 IV infusion in 500 mL of 5 % glucose solution (D5W) (recommended) as a 22-hour continuous infusion.

Geriatrics (>= 65 years of age)

: Starting dose in this age group is the same. In studies of patients with metastatic colorectal cancer, patients >= 65 years receiving ELOXATIN in combination with 5-FU/LV experienced more fatigue, dehydration, diarrhea, leukopenia, and syncope than patients

< 65 years, although the difference was not statistically significant. In the adjuvant trial, patients >= 65 years receiving the ELOXATIN combination therapy experienced more grade 3/4 granulocytopenia and diarrhea than patients < 65 years, although the difference was not statistically significant.

Gastrointestinal:

Adjuvant Stage III colon cancer: If severe/life-threatening gastrointestinal toxicity (NCI CTC grade 3-4) occurs despite prophylactic treatment, ELOXATIN must be discontinued until resolution. A dose reduction of ELOXATIN to 75 mg/m2 and bolus 5-FU to 300 mg/m2 and infusional 5-FU to 500 mg/m2 over 22 hours is recommended at subsequent cycles. Metastatic colorectal cancer: After recovery from grade 3 or 4 gastrointestinal toxicity (despite prophylactic treatment), a dose reduction of ELOXATIN to 65 mg/m2 and 5-FU by 20% (300 mg/m2 bolus and 500 mg/m2 22-hour infusion) is recommended.

Hematologic:

Adjuvant Stage III colon cancer: After recovery from grade 3-4 neutropenia (ANC < 1.0 x 109/L) or grade 3-4 thrombocytopenia (platelets < 50 x 109/L), a dose reduction of ELOXATIN to 75 mg/m2 and bolus 5-FU to 300 mg/m2 and infusional 5-FU to 500 mg/m2 over 22 hours is recommended. The next dose should be delayed until neutrophils >= 1.5 x 109/L and platelets >= 75 x 109/L. Metastatic colorectal cancer: After recovery from grade 3/4 neutropenia (ANC < 1.0 x 109/L) or grade 3/4 thrombocytopenia (platelets < 50 x 109/L), a dose reduction of ELOXATIN to 65 mg/m2 and 5-FU by 20% (300 mg/m2 bolus and 500 mg/m2 22-hour infusion) is recommended. The next dose should be delayed until: neutrophils >= 1.5 x 109/L and platelets >= 75 x 109/L.

Neurologic:

For patients (any indication) who develop acute laryngo-pharyngeal dysesthesia (see ADVERSE REACTIONS), during or within the hours following the 2-hour infusion, the next ELOXATIN infusion should be administered over 6 hours. To prevent such dysesthesia, inform the patient to avoid exposure to cold and to avoid ingesting fresh/cold food or/and beverages during or within the hours following ELOXATIN administration. No dose adjustment is required to the 5-FU/LV regimen for neurotoxicity.

Adjuvant Stage III colon cancer: Neurotoxicity was graded using the NCI CTC grading system (see WARNINGS AND PRECAUTIONS). For patients who experience persistent grade 2 neurotoxicity (mild or moderate objective sensory loss, moderate paresthesias), the ELOXATIN dose should be reduced to 75 mg/m2. For patients with persistent grade 3 neurotoxicity, therapy should be discontinued.

Metastatic colorectal cancer

: In the metastatic colorectal cancer trials, neurotoxicity was graded using a study-specific neurotoxicity scale, and dose adjustments for ELOXATIN were recommended, as follows:

Table 12. Neurologic toxicity scale for oxaliplatin dose adjustments

a

Not resolved by the beginning of the next cycle.

b

May have been cold-induced.

c

May also have been pre-treated with benzodiazepines.

Renal Insufficiency:

ELOXATIN has not been studied in patients with severe renal impairment. In patients with moderate renal impairment, treatment may be initiated at the normally recommended dose and renal function should be closely monitored. Dose should be adjusted according to toxicity (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Special Populations).

Hepatic Insufficiency:

No increase in ELOXATIN acute toxicities was 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.

Administration

ELOXATIN is considered moderately emetogenic. Premedication with antiemetics, including 5- HT3 blockers with or without dexamethasone, is recommended. The administration of ELOXATIN does not require prehydration. ELOXATIN is administered by intravenous infusion. ELOXATIN lyophilized powder must be reconstituted and further diluted before use (see subsections Reconstitution and Dilution Before Infusion). ELOXATIN aqueous solution must be diluted before use (see subsection Dilution Before Infusion). ELOXATIN diluted in 250 to 500 mL of 5 % glucose solution to give a concentration not less than 0.2 mg/mL must be infused via a central venous line or peripheral vein over 2 to 6 hours. In the event of extravasation, administration must be discontinued immediately.

Instruction for use with leucovorin (as calcium folinate or disodium folinate):

ELOXATIN 85 mg/m2 IV infusion in 250 to 500 mL of 5% glucose solution is given at the same time as leucovorin IV infusion in 5% glucose solution, over 2 to 6 hours, using a Y-line placed immediately before infusion. These two drugs should not be combined in the same infusion bag. Leucovorin must not contain trometamol as an excipient and must only be diluted using isotonic 5% glucose solution, never in alkaline solutions or sodium chloride or chloride containing solutions. For information on leucovorin, see the Product Monograph and package insert.

Instruction for use with 5-FU:

ELOXATIN should always be administered before fluoropyrimidines - i.e. 5-FU.

After ELOXATIN administration, flush the line and then administer 5-FU. For information on 5-FU, see the Product Monograph and package insert. Reconstitution

ELOXATIN LYOPHILIZED POWDER

ELOXATIN lyophilized powder must be reconstituted and further diluted before use. Only the recommended diluents should be used to reconstitute and then dilute the freeze-dried product.

Water for injection or 5% glucose solution should be used as solvent to reconstitute the lyophilized powder in solution.

For a vial of 50 mg: add 10 mL of solvent to obtain a concentration of 5 mg oxaliplatin/mL For a vial of 100 mg: add 20 mL of solvent to obtain a concentration of 5 mg oxaliplatin/mL Reconstitution must NEVER be performed with a sodium chloride solution or other chloride- containing solutions.

Do not administer the reconstituted solution without further dilution.

From a microbiological point of view, the reconstituted solution should be diluted immediately with 5 % glucose solution (see the subsection Dilution Before Infusion below). Inspect visually for clarity, particulate matter, precipitate, discoloration and leakage prior to use. Only clear solutions without particles, precipitate, discoloration or leakage should be used. The medicinal product is for single-use only. Any unused solution should be discarded.

ELOXATIN AQUEOUS SOLUTION

ELOXATIN aqueous solution does not need to be reconstituted. The aqueous solution must be diluted with 5% glucose solution before use (see the subsection Dilution Before Infusion below).

Dilution Before Infusion

Only 5% glucose infusion

solution is to be used to dilute the product.

NEVER

use sodium chloride or chloride containing solutions for dilution.

Inspect visually for clarity, particulate matter, precipitate, discoloration and leakage prior to use. Only clear solutions without particles, precipitate, discoloration or leakage should be used. The medicinal product is for single-use only. Any unused solution should be discarded. Needles or intravenous administration sets containing aluminum parts that may come in contact with ELOXATIN should not be used for the preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds. The compatibility of ELOXATIN solution for infusion has been tested with representative, PVC- based, administration sets.

ELOXATIN LYOPHILIZED POWDER

Withdraw the required amount of reconstituted solution from the vial(s) and then dilute with 250 mL to 500 mL of a 5% glucose solution to give an ELOXATIN concentration between not less than 0.2 mg/mL and 0.7 mg/mL (0.70 mg/mL is the highest concentration in clinical practice for an oxaliplatin dose of 85 mg/m2). The concentration range over which the physico-chemical stability of ELOXATIN has been demonstrated is 0.2 mg/mL to 2.0 mg/mL. After dilution in 5% glucose solution, chemical and physical in-use stability has been demonstrated for 24 hours at 2degC to 8degC. From a microbiological point of view, this infusion preparation should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2degC to 8degC unless dilution has taken place in controlled and validated aseptic conditions.

ELOXATIN AQUEOUS SOLUTION

Withdraw the required amount of concentrate from the vial(s) and then dilute with 250 mL to 500 mL of a 5% glucose solution to give an ELOXATIN concentration between not less than 0.2 mg/mL and 0.7 mg/mL (0.70 mg/mL is the highest concentration in clinical practice for an oxaliplatin dose of 85 mg/m2). The concentration range over which the physico-chemical stability of ELOXATIN has been demonstrated is 0.2 mg/mL to 2.0 mg/mL. After dilution in 5% glucose solution, chemical and physical in-use stability has been demonstrated for 24 hours at 25degC and 48 hours at 2degC to 8degC. From a microbiological point of view, this infusion preparation should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2degC to 8degC unless dilution has taken place in controlled and validated aseptic conditions.

Incompatibilities

DO NOT administer undiluted. Only 5% glucose infusion solution is to be used to dilute the product. DO NOT reconstitute or dilute ELOXATIN with saline or other solutions containing chloride ions (including calcium, potassium or sodium chloride). The diluted medicinal product should not be mixed with other medicinal products in the same infusion bag or infusion line. ELOXATIN can be co-administered with leucovorin via a Y- line (see DOSAGE AND ADMINISTRATION, Administration, Instruction for use with leucovorin). DO NOT mix with alkaline medicinal products or solutions, in particular 5-FU, leucovorin preparations containing trometamol as an excipient and trometamol salts of others active substances. Alkaline medicinal products or solutions will adversely affect the stability of ELOXATIN. DO NOT use injection equipment containing aluminium.

Disposal

Remnants of the medicinal product as well as all materials that have been used for reconstitution, for dilution and administration must be destroyed according to hospital standard procedures applicable to cytotoxic agents in accordance with local requirements related to the disposal of hazardous waste.

OVERDOSAGE

The approved dose of ELOXATIN is 85 mg/m2 every 2 weeks in combination with 5-FU/LV (see DOSAGE AND ADMINISTRATION). In cases of overdose, exacerbation of adverse events can be expected. There have been 5 cases of ELOXATIN overdose reported. One patient received two 130 mg/m2 doses of ELOXATIN (cumulative dose of 260 mg/m2) within a 24-hour period. The patient experienced grade 4 thrombocytopenia (< 25 x 109/L) without any bleeding, which resolved. Two other patients were mistakenly administered ELOXATIN instead of carboplatin. One patient received a total ELOXATIN dose of 500 mg and the other received 650 mg. The first patient experienced dyspnea, wheezing, paresthesia, profuse vomiting and chest pain on the day of administration. The patient developed respiratory failure and severe bradycardia, and subsequent resuscitation efforts failed. The other patient also experienced dyspnea, wheezing, paresthesia, and vomiting. The symptoms resolved with supportive care. Another patient who was mistakenly administered a 700 mg dose experienced rapid onset of dysesthesia. Inpatient supportive care was given, including hydration, electrolyte support and platelet transfusion. Recovery occurred 15 days after the overdose. The fifth patient received an overdose of ELOXATIN at 360 mg instead of 120 mg over a 1-hour infusion by mistake. At the end of the infusion, the patient experienced 2 episodes of vomiting, laryngospasm and paresthesia. The patient fully recovered from the laryngospasm within half an hour. At the time of reporting 1 hour after onset of the event, the patient was recovering from paresthesia. There is no known antidote for ELOXATIN overdose. In addition to thrombocytopenia, the anticipated complications of an ELOXATIN overdose include myelosuppression, nausea and vomiting, diarrhea, neurotoxicity and cardiotoxicity. Patients suspected of receiving an overdose should be monitored and supportive treatment should be administered.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

ELOXATIN is a platinum-type alkylating agent. It undergoes nonenzymatic conversion in physiologic solutions to active derivatives via displacement of the labile oxalate ligand. Several transient reactive species are formed, including monoaquo and diaquo 1,2-diaminocyclohexane (DACH) platinum, which covalently bind with macromolecules. Both inter- and intrastrand Pt- DNA crosslinks are formed. Crosslinks are formed between the N7 positions of two adjacent guanines (GG), adjacent adenine-guanines (AG), and guanines separated by an intervening nucleotide (GNG). These crosslinks inhibit DNA replication and transcription leading to cytotoxic and antitumor effects.

Pharmacodynamics

The antitumor activity of oxaliplatin relevant to the proposed indication is confirmed both in vitro and in vivo in human colorectal cancer models. Oxaliplatin demonstrates in vitro cytotoxicity against HT-29, CaCo2 and HEC59 colon cancer cells. Oxaliplatin as a single agent displays only modest in vivo antitumor activity in HT-29 and DLD2 human colon cancer xenografts. Oxaliplatin is additively effective with 5-FU against human colonic tumor xenograft in vivo.

Pharmacokinetics

Absorption:

Maximum platinum concentrations in blood, plasma and plasma ultrafiltrate were reached at the end of 2-hour infusion of oxaliplatin at 85 mg/m2. Low interpatient variability in Cmax values was observed in plasma and whole blood (CV 19% and 16%, respectively). Variability in Cmax in ultrafiltrate was higher (CV 45%). Following biotransformation in vivo, the reactive products from oxaliplatin bind plasma proteins, cellular proteins and DNA. The reactive oxaliplatin derivatives are present as a fraction of the unbound platinum in plasma ultrafiltrate. The Cmax obtained after a single 2-hour IV infusion of ELOXATIN at a dose of 85 mg/m2 expressed as ultrafilterable platinum was 0.814 ug/mL. Interpatient and intrapatient variability in ultrafilterable platinum exposure (AUC0-48) assessed over 3 cycles was moderate to low (23% and 6%, respectively). A pharmacodynamic relationship between platinum ultrafiltrate levels and clinical safety and effectiveness has not been established.

Table 13 - Summary of Pharmacokinetic Parameters in Patients Following Single Dosing of ELOXATIN at 85 mg/m2 q2w (every two weeks)

Distribution: The volume of distribution obtained after a single 2-hour IV infusion of ELOXATIN at a dose of 85 mg/m2 expressed as ultrafilterable platinum was 440 L. At the end of a 2-hour infusion of ELOXATIN, approximately 15% of the administered platinum is present in the systemic circulation. The remaining 85% is rapidly distributed into tissues or eliminated in the urine. The relative distribution ratio of platinum between blood cells, plasma, and plasma ultrafiltrate is approximately 3.1: 3.7: 1.0. In patients, plasma protein binding of platinum is irreversible and is greater than 90%. The main binding proteins are albumin and gamma-globulins. Platinum also binds irreversibly and accumulates (approximately 2-fold) in erythrocytes. Based on AUC values, statistically significant accumulation of platinum was observed in blood cells with a mean terminal-phase half-life of 589 +- 89.8 hrs. No platinum accumulation was observed in plasma ultrafiltrate following 85 mg/m2 every two weeks. Metabolism: Oxaliplatin undergoes extensive nonenzymatic biotransformation in patients and no intact drug was detectable in plasma ultrafiltrate at the end of a 2-hour infusion. There is no evidence of cytochrome P450-mediated metabolism in vitro. Up to 17 platinum-containing derivatives have been observed in plasma ultrafiltrate samples from patients, including several cytotoxic species (monochloro DACH platinum, dichloro DACH platinum, and monoaquo and diaquo DACH platinum) and a number of noncytotoxic, conjugated species. Excretion: The decline of ultrafilterable platinum levels following oxaliplatin administration is triphasic, characterized by two relatively short distribution phases (t1/2a: 0.43 hours and t1/2b: 16.8 hours) and a long terminal elimination phase (t1/2g: 391 hours). The major route of platinum elimination is renal excretion. At five days after a single 2-hour infusion of ELOXATIN, urinary elimination accounted for about 54% of the platinum eliminated, with fecal excretion accounting for only about 2%. Platinum was cleared from plasma at a rate (9 - 19 L/h) that was similar to or exceeded the average human glomerular filtration rate (GFR: 7.5 L/h). The volume of distribution was high with interpatient variability of 33-45%. A significant decrease in clearance of ultrafilterable platinum from 17.6 +- 2.18 L/h to 9.95 +- 1.91 L/h in renal impairment (creatinine clearance 12 - 57 mL/min) was observed together with a statistically significant decrease in distribution volume from 330 +- 40.9 to 241 +- 36.1 L. The renal clearance of ultrafilterable platinum is significantly correlated with GFR (see ADVERSE REACTIONS).

Special Populations and Conditions

Pediatrics:

See INDICATIONS AND CLINICAL USES and WARNINGS and PRECAUTIONS, Special Populations, Pediatrics.

Geriatrics:

There was no significant effect of age (26-72 years) on the clearance of ultrafilterable platinum.

Gender:

There was no significant effect of gender on the clearance of ultrafilterable platinum.

Hepatic Insufficiency:

Mild to moderate hepatic impairment did not affect the clearance of platinum in a clinically significant manner. No increase in ELOXATIN acute toxicities was 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 (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Renal Insufficiency: The primary route of platinum elimination is renal. The AUC0-48 of platinum in the plasma ultrafiltrate increases as renal function decreases. The AUC0-48 of platinum in patients with mild (creatinine clearance, CLcr 50 to 80 mL/min), moderate (CLcr 30 to < 50 mL/min) and severe (CLcr < 30 mL/min) renal impairment is increased by about 60, 140 and 190%, respectively, compared to patients with normal renal function (CLcr > 80 mL/min) (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).

STORAGE AND STABILITY

ELOXATIN LYOPHILIZED POWDER The product should be stored between 15degC to 30degC. Do not freeze. For long-term storage, protect product from light.

ELOXATIN AQUEOUS SOLUTION The product should be stored between 15degC to 30degC. Do not freeze. For long-term storage, protect product from light.

SPECIAL HANDLING INSTRUCTIONS

As with other potentially toxic compounds, care should be exercised in the handling and preparation of ELOXATIN solutions. The handling of this cytotoxic agent by healthcare personnel requires every precaution to guarantee the protection of the handler and his surroundings. If ELOXATIN powder, reconstituted solution, concentrate or solution for infusion contacts the skin, wash immediately and thoroughly with water. If ELOXATIN powder, reconstituted solution, concentrate or solution for infusion contacts the mucous membranes, wash immediately and thoroughly with water. Procedures for the handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published (see References: AMA Council Report 1985, ASHP 1990, ONS 1988 and 1999, OSHA 1986). There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

DOSAGE FORMS, COMPOSITION AND PACKAGING

ELOXATIN LYOPHILIZED POWDER

ELOXATIN is supplied in a clear, single-use, glass vial with a gray stopper and crimping seal with flip-off cap containing 50 mg or 100 mg of oxaliplatin as a sterile, preservative-free lyophilized powder for reconstitution. Lactose monohydrate is present as an inactive ingredient at 450 mg and 900 mg in the 50 mg and 100 mg dosage strengths, respectively.

ELOXATIN AQUEOUS SOLUTION

ELOXATIN is supplied in a clear, glass, single-use vial with a gray stopper and crimping seal with flip-off cap containing 50 mg, 100 mg or 200 mg of oxaliplatin as a sterile, preservative- free, aqueous solution at a concentration of 5 mg/mL. Water for Injection, USP is present as an inactive ingredient.