Vexplatin-50/Vexplatin-100

Each mL contains: Oxaliplatin USP 2 mg; Water for Injections USP q.s.

Pharmacological Classification: Antineoplastic agent (Platinum Compound).
Pharmacology: Mechanism of Action: Oxaliplatin 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 DACH platinum, which covalently bind with macromolecules. Both inter- and intrastrand Pt-DNA cross/inks 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 cross/inks inhibit DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific.
Pharmacokinetics: The reactive oxaliplatin derivatives are present as a fraction of the unbound platinum in plasma ultrafiltrate. The decline of ultrafilterable platinum levels following oxaliplatin administration is triphasic, characterized by two relatively short distribution phases (t½α; 0.43 hours and t½β; 16.8 hours) and a long terminal elimination phase (t½γ; 391 hours). Pharmacokinetic parameters obtained after a single 2-hour intravenous infusion of Oxaliplatin at a dose of 85 mg/m² expressed as ultrafilterable platinum were Cmax of 0.814 mcg /ml and volume of distribution of 440 L.
Interpatient and intrapatient variability in ultrafilterable platinum exposure (AUC_0-48hr) assessed over 3 cycles was moderate to low (23% and 6%, respectively).
Distribution: At the end of a 2-hour infusion of Oxaliplatin, 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. 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, where it appears to have no relevant activity. No platinum accumulation was observed in plasma ultrafiltrate following 85 mg/m² every two weeks.
Metabolism: Oxaliplatin undergoes rapid and extensive nonenzymatic biotransformation. 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.
Elimination: The major route of platinum elimination is renal excretion. At five days after a single 2-hour infusion of Oxaliplatin, 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 (10 - 17 l/h) that was similar to or exceeded the average human glomerular filtration rate (GFR; 7.5 l/h). There was no significant effect of gender on the clearance of ultrafilterable platinum. The renal clearance of ultrafilterable platinum is significantly correlated with GFR.
Pharmacokinetics in Special Population: Age and Sex: There was no clinically relevant effect of age or sex on the pharmacokinetics in special populations.
Renal Impairment: The AUC_{0-48 hr} of platinum in the plasma ultrafiltrate increases as renal function decreases. The AUC_{0-48 hr} 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).

Oxaliplatin is used in combination with infusional 5-fluorouracil/leucovorin, is indicated for: Adjuvant treatment of stage Ill colon cancer in patients who have undergone complete resection of the primary tumor.
Treatment of advanced colorectal cancer.

Adjuvant therapy in patients with Stage III Colon Cancer: It is recommended for a total of 6 months, i.e. 12 cycles, every 2 weeks, Day 1: Oxaliplatin 85 mg/m² IV infusion in 250 to 500 mL of 5% (50 mg/mL) glucose solution is given at the same time as leucovorin 200 mg/m² IV infusion in 5% glucose solution over 2 to 6 hours in separate bags using a Y-line.
Followed by 5-fluorouracil 400 mg/m² IV bolus given over 2-4 minutes, followed by 5-fluorouracil 600 mg/m² IV infusion in 500 mL of 5% glucose solution (recommended) as a 22-hour continuous infusion.
Day 2: Oxaliplatin 85 mg/m² IV infusion in 250 to 500 mL of 5% (50 mg/mL) glucose solution is given at the same time as leucovorin 200 mg/m² IV infusion in 5% glucose solution over 2 to 6 hours in separate bags using a Y-line.
Followed by 5-fluorouracil 400 mg/m² IV bolus given over 2-4 minutes, followed by 5-fluorouracil 600 mg/m² IV infusion in 500 mL of 5% glucose solution (recommended) as a 22-hour continuous infusion.
Advanced Colorectal Cancer: The recommended dose schedule given every two weeks as follows: Day 1: Oxaliplatin 85 mg/m² IV infusion in 250 to 500 mL of 5% (50 mg/mL) glucose solution is given at the same time as leucovorin 200 mg/m² IV infusion in 5% glucose solution over 2 to 6 hours in separate bags using a Y-line.
Followed by 5-fluorouracil 400 mg/m² IV bolus given over 2-4 minutes, followed by 5-fluorouracil 600 mg/m² IV infusion in 500 mL of 5% glucose solution (recommended) as a 22-hour continuous infusion.
Repeat cycle every 2 weeks.
The administration of Oxaliplatin does not require prehydration. Premedication with antiemetics, including 5-HT₃ blockers with or without dexamethasone is recommended.

Oxaliplatin is contraindicated in patients who have acute, reversible, primarily peripheral, sensory neuropathy that is of early onset, occurring within hours or one to two days of dosing, that resolves within 14 days, and that frequently recurs with further dosing.
A persistent (> 14 days), primarily peripheral, sensory neuropathy that is usually characterized by paresthesias, dysesthesias, hypoesthesias, but may also include deficits in proprioception that can interfere with daily activities (e.g., writing, buttoning, swallowing, and difficulty walking from impaired proprioception).

General: Oxaliplatin should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents.
Neuropathy - Previously Unrated and Previously Treated Patients with Advanced Colorectal Cancer: In the previously treated study, neuropathy information was collected to establish that Oxaliplatin in associated with two types of neuropathy.
Pulmonary Toxicity: Oxaliplatin has been associated with pulmonary fibrosis (< 1% of study patients), which may be fatal.
Hepatotoxicity: Hepatotoxicity as evidenced in the adjuvant study, by increase in transaminases (57% vs. 34%) and alkaline phosphatase (42% vs. 20%) was observed more commonly in the Oxaliplatin combination arm than in the control arm.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term animal studies have not been performed to evaluate the carcinogenic potential of oxaliplatin. Oxaliplatin was not mutagenic to bacteria (Ames test) but was mutagenic to mammalian cells in vitro (L5178Y mouse lymphoma assay). Oxaliplatin was clastogenic both in vitro (chromosome aberration in human lymphocytes) and in vivo (mouse bone marrow micronucleus assay).
In a fertility study, male rats were given oxaliplatin at 0, 0.5, 1, or 2 mg/kg/day for five days every 21 days for a total of three cycles prior to mating with females that received two cycles of oxaliplatin on the same schedule. A dose of 2 mg/kg/day (less than one-seventh the recommended human dose on a body surface area basis) did not affect pregnancy rate, but caused developmental mortality (increased early resorptions, decreased live fetuses, decreased live births) and delayed growth (decreased fetal weight).
Testicular damage, characterized by degeneration, hypoplasia, and atrophy, was observed in dogs administered oxaliplatin at 0.75 mg/kg/day x 5 days every 28 days for three cycles.
Patients with Renal impairment: The exposure (AUC) of unbound platinum in plasma ultrafiltrate tends to increase in renally impaired patients. Caution and close monitoring should be exercised when Oxaliplatin is administered to patients with renal impairment. The starting Oxaliplatin dose does not need to be reduced in patients with mild (creatinine clearance=50-80 mL/min) or moderate (creatinine clearance=30-49 mL/min) renal impairment. However, the starting dose of Oxaliplatin should be reduced in patients with severe renal impairment (creatinine clearance< 30 mL/min).
Use in Pregnancy: Pregnancy Category D: Oxaliplatin may cause fetal harm when administered to a pregnant woman.
Use in Lactation: It is not known whether Oxaliplatin or its derivatives are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Oxaliplatin, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Use in Children: The effectiveness of oxaliplatin in children has not been established.
Use in the Elderly: No significant effect of age on the clearance of ultrafilterable platinum has been observed. No adjustment to starting dose was required in patient's ≥65 years old.

To date there is no available information on safety of use in pregnant women. In animal studies, reproductive toxicity was observed. Consequently, oxaliplatin is not recommended during pregnancy and in women of childbearing potential not using contraceptive measures. The use of oxaliplatin should only be considered after suitably apprising the patient of the risk to the foetus and with the patient's consent.
Appropriate contraceptive measures must be taken during and after cessation of therapy during 4 months for women and 6 months for men. Excretion in breast milk has not been studied. Breast-feeding is contra-indicated during oxaliplatin therapy. Oxaliplatin may have an anti-fertility effect.

Hematopoietic system: Oxaliplatin has low hematological toxicity. During a monochemotherapy course, the administration of oxaliplatin can lead to the following unwanted effects; anaemia, leukopenia, granulocytopenia, thrombocytopenia, sometimes of grade 3 or 4 (Severity of grade; neutrophil count < 500/mm², platelet count <25,000/mm³, hemoglobin <6.5 g/100 mL). The anticipated complications of Oxaliplatin overdose include myelosuppression, nausea, and vomiting, diarrhea and neurotoxicity.

No specific cytochrome P-450-based drug interaction studies have been conducted. No pharmacokinetic interaction between 85 mg/m² Oxaliplatin and 5-fluorouracil/leucovorin has been observed in patients treated every 2 weeks. Increases of 5-fluorouracil plasma concentrations by approximately 20% have been observed with doses of 130 mg/m² Oxaliplatin dosed every 3 weeks. Because 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.

Store at temperatures not exceeding 30°C. Protect from light.
Shelf-Life: 24 months from the date of manufacturing.

Information of patients: The product should not be diluted in sodium chloride solution or in chloride containing solution. Patients and patient's caregivers should be informed of the expected adverse effects of Oxaliplatin particularly its neurologic effects both the acute, reversible effects and the persistent neurosensory toxicity.
Patients should be informed that the acute neurosensory toxicity may be precipitated or exacerbated by exposure to cold or cold objects.
Patients should be instructed to avoid cold drinks, use of ice, and should cover exposed skin prior to exposure to cold temperature or cold objects.
Patients must be adequately informed of the risk of low blood cell counts and instructed to contact their physician immediately should fever, particularly if associated with persistent diarrhea, or evidence of infection develop.
Patients should be instructed to contact their physician if persistent vomiting, diarrhea, signs of dehydration, cough or breathing difficulties occur or signs of allergic reaction appear.
Oxaliplatin is incompatible in solution with alkaline medications or media (such as basic solutions of 5-fluorouracil) and must not be mixed with these or administered simultaneously through the same infusion line. The infusion line should be flushed with 5% glucose solution prior to administration of any concomitant medication.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration and discarded if present.
Needles or intravenous administration sets containing aluminum parts that many come in contact with Oxaliplatin should not be used for preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds.
Have a known history of hypersensitivity to oxaliplatin, pregnancy, breast feeding.
Have myelosuppression prior to starting first course, as evidenced by baseline neutrophils <1.5 x 10⁹/L and or platelet count of <100 x 10⁶/L.
Have a peripheral sensitive neuropathy with functional impairment prior to first course.
Have a severely impaired renal function (creatinine clearance less than 30 mL/min).

Cytotoxic Chemotherapy

L01XA03 - oxaliplatin ; Belongs to the class of platinum-containing antineoplastic agents. Used in the treatment of cancer.

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