Oxaliplatin (Page 5 of 9)

8.5 Geriatric Use

No significant effect of age on the clearance of ultrafilterable platinum has been observed.
In the adjuvant therapy colon cancer randomized clinical trial, [see Clinical Studies ( 14 )] 723 patients treated with oxaliplatin and infusional 5-fluorouracil/leucovorin were <65 years and 400 patients were ≥65 years.
A descriptive subgroup analysis demonstrated that the improvement in DFS for the oxaliplatin combination arm compared to the infusional 5-fluorouracil/leucovorin alone arm appeared to be maintained across genders. The effect of oxaliplatin in patients ≥65 years of age was not conclusive. Insufficient subgroup sizes prevented analysis by race.
Patients ≥65 years of age receiving the oxaliplatin combination therapy experienced more grade 3-4 granulocytopenia than patients < 65 years of age (45% versus 39%).
In the previously untreated for advanced colorectal cancer randomized clinical trial [see Clinical Studies ( 14 )] of oxaliplatin, 160 patients treated with oxaliplatin and 5-fluorouracil/leucovorin were < 65 years and 99 patients were ≥65 years. The same efficacy improvements in response rate, time to tumor progression, and overall survival were observed in the ≥65 year old patients as in the overall study population. In the previously treated for advanced colorectal cancer randomized clinical trial [see Clinical Studies ( 14 )] of oxaliplatin, 95 patients treated with oxaliplatin and 5-fluorouracil/leucovorin were <65 years and 55 patients were ≥65 years. The rates of overall adverse reactions, including grade 3 and 4 events, were similar across and within arms in the different age groups in all studies. The incidence of diarrhea, dehydration, hypokalemia, leukopenia, fatigue and syncope were higher in patients ≥65 years old. No adjustment to starting dose was required in patients ≥65 years old.

8.6 Patients with Renal Impairment

The exposure (AUC) of unbound platinum in plasma ultrafiltrate tends to increase in renally impaired patients [see Pharmacokinetics ( 12.3 )]. 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 to 80 mL/min) or moderate (creatinine clearance=30 to 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) [see Dosage and Administration ( 2.2 )].

10 OVERDOSAGE


There is no known antidote for oxaliplatin overdose. In addition to thrombocytopenia, the anticipated complications of an oxaliplatin overdose include hypersensitivity reaction, myelosuppression, nausea, vomiting, diarrhea and neurotoxicity.
Several cases of overdoses have been reported with oxaliplatin. Adverse reactions observed were Grade 4 thrombocytopenia (<25,000/mm3) without any bleeding, anemia, sensory neuropathy such as paresthesia, dysesthesia, laryngospasm and facial muscle spasms, gastrointestinal disorders such as nausea, vomiting, stomatitis, flatulence, abdomen enlarged and Grade 4 intestinal obstruction, Grade 4 dehydration, dyspnea, wheezing, chest pain, respiratory failure, severe bradycardia and death.Patients suspected of receiving an overdose should be monitored, and supportive treatment should be administered. The maximum dose of oxaliplatin that has been administered in a single infusion is 825 mg.

11 DESCRIPTION

Oxaliplatin Injection, USP is an antineoplastic agent with the molecular formula C8 H14 N2 O4 Pt and the chemical name is cis -[(1 R ,2 R)-1,2-cyclohexanediamine-N,N’ ] [oxalato(2-)-O,O’ ] platinum. Oxaliplatin is an organoplatinum complex in which the platinum atom is complexed with 1,2-diaminocyclohexane (DACH) and with an oxalate ligand as a leaving group.

structure
(click image for full-size original)

The molecular weight is 397.3. Oxaliplatin is slightly soluble in water at 6 mg/mL, very slightly soluble in methanol, and practically insoluble in ethanol and acetone. Oxaliplatin Injection, USP is supplied in vials containing 50 mg or 100 mg of oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 mg per mL. Water for Injection USP is present as an inactive ingredient.

12 CLINICAL PHARMACOLOGY

12.1 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 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. Cytotoxicity is cell-cycle nonspecific.In vivo studies have shown antitumor activity of oxaliplatin against colon carcinoma. In combination with 5-fluorouracil, oxaliplatin exhibits in vitro and in vivo antiproliferative activity greater than either compound alone in several tumor models [HT29 (colon), GR (mammary), and L1210 (leukemia)].

12.3 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 (t1/2α ; 0.43 hours and t1/2β ; 16.8 hours) and a long terminal elimination phase (t1/2γ ; 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 (AUC0-48hr ) 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.
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 to 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 Populations
Pediatric

[See Use in Specific Patient Populations (8.4)].
Renal Impairment
A study was conducted in 38 patients with advanced GI cancer and varying degrees of renal impairment. Patients in the normal (creatinine clearance (CrCL) > 80 mL/min, N=11), mild (CrCL=50 to 80 mL/min, N=13), and moderate (CrCL=30 to 49 mL/min, N=10) groups were treated with 85 mg/m2 oxaliplatin and those in the severe (CrCL < 30 mL/min, N=4) group were treated with 65 mg/m2 oxaliplatin. The mean AUC of unbound platinum was 40%, 95%, and 342% higher in the mild, moderate, and severe groups, respectively, than in the normal group. Mean Cmax of unbound platinum appeared to be similar among the normal, mild and moderate renal function groups, but was 38% higher in the severe group than in the normal group. Caution should be exercised in renally impaired patients [see Use in Specific Populations ( 8.6 )]. The starting dose of oxaliplatin should be reduced in patients with severe renal impairment [see Dosage and Administration ( 2.2 )].

Drug — Drug Interactions
No pharmacokinetic interaction between 85 mg/m2 of oxaliplatin and infusional 5-fluorouracil has been observed in patients treated every 2 weeks, but increases of 5-fluorouracil plasma concentrations by approximately 20% have been observed with doses of 130 mg/m2 of oxaliplatin administered every 3 weeks. In vitro , platinum was not displaced from plasma proteins by the following medications: erythromycin, salicylate, sodium valproate, granisetron, and paclitaxel. In vitro , oxaliplatin 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 co-administration of potentially nephrotoxic compounds, although this has not been specifically studied.

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