No

Antineoplastic Agent, Alkylating Agent

Ovarian carcinoma, cervical, small cell lung carcinoma, esophageal, testicular, bladder cancer, mesothelioma, pediatric brain tumors, sarcoma, neuroblastoma, osteosarcoma

D

Hypersensitivity to carboplatin or any component (anaphylactic-like reactions may occur), severe bone marrow suppression, or excessive bleeding

The U.S. Food and Drug Administration (FDA) currently recommends that procedures for proper handling and disposal of antineoplastic agents be considered. High doses have resulted in severe abnormalities of liver function tests. Bone marrow suppression, which may be severe, and vomiting are dose related; reduce dosage in patients with bone marrow suppression and impaired renal function. Increased risk of allergic reactions in patients previously exposed to platinum therapy.

>10%:

Endocrine & metabolic: Electrolyte abnormalities such as hypocalcemia and hypomagnesemia, hyponatremia, hypokalemia

Gastrointestinal: Nausea, vomiting, stomatitis

Emetic potential: Moderate

Time course for nausea and vomiting: Onset: 2-6 hours; Duration: 1-48 hours

Hematologic: Neutropenia, leukopenia, thrombocytopenia, anemia

Myelosuppressive: Dose-limiting toxicity

WBC: Severe (dose-dependent)

Platelets: Severe

Nadir: 21-24 days

Recovery: 28-35 days

Hepatic: Abnormal LFTs

Local: Pain at injection site

Neuromuscular & skeletal: Asthenia

1% to 10%:

Dermatologic: Alopecia

Gastrointestinal: Diarrhea, anorexia

Hematologic: Hemorrhagic complications

Neuromuscular & skeletal: Peripheral neuropathy

Otic: Ototoxicity in 1% of patients

<1%: Neurotoxicity has only been noted in patients previously treated with cisplatin, urticaria, rash, blurred vision, nephrotoxicity (uncommon), anaphylaxis, anorexia, malaise, hypertension

Symptoms of overdose include bone marrow suppression, hepatic toxicity

Increased toxicity: Nephrotoxic drugs; aminoglycosides increase risk of ototoxicity

Store intact vials at room temperature (15°C to 30°C/59°F to 86°F) and protect from light

Reconstitute powder to yield a final concentration of 10 mg/mL which is stable for 5 days at room temperature (25°C)

Aluminum needles should not be used for administration due to binding with the platinum ion

Compatible with etoposide

Standard I.V. dilution: Dose/250-1000 mL D₅W

Further dilution to a concentration as low as 0.5 mg/mL is stable at room temperature (25°C) or under refrigeration for 8 days in D₅W

Analogue of cisplatin which covalently binds to DNA; possible cross-linking and interference with the function of DNA

Possible cross-linking and interference with the function of DNA

Metabolism: To aquated and hydroxylated compounds

Protein binding: 0%; however, platinum is 30% irreversibly bound

Half-life: Terminal: 22-40 hours; 2.5-5.9 hours in patients with Cl_cr >60 mL/minute

Elimination: ~60% to 90% is excreted renally in the first 24 hours

IVPB, I.V. infusion, intraperitoneal (refer to individual protocols):

Solid tumor: 300-600 mg/m² once every 4 weeks

Brain tumor: 175 mg/m² once weekly for 4 weeks with a 2-week recovery period between courses; dose is then adjusted on platelet count and neutrophil count values

Adults:

Ovarian cancer: Usual doses range from 360 mg/m² I.V. every 3 weeks single agent therapy to 300 mg/m² every 4 weeks as combination therapy

In general, however, single intermittent courses of carboplatin should not be repeated until the neutrophil count is at least 2000 and the platelet count is at least 100,000

The following dose adjustments are modified from a controlled trial in previously treated patients with ovarian carcinoma. Blood counts were done weekly, and the recommendations are based on the lowest post-treatment platelet or neutrophil value.

Carboplatin dosage adjustment based on pretreatment platelet counts

• Platelets >100,00 cells/mm³ and neutrophils >2000 cells/mm³: Adjust dose 125% from prior course
• Platelets 50-100,000 cells/mm³ and neutrophils 500-2000 cells/mm³: No dose adjustment
• Platelets <50,000 cells/mm³ and neutrophils <500 cells/mm³: Adjust dose 75% from prior course

Carboplatin dosage adjustment based on the Egorin formula (based on platelet counts):

Autologous BMT: I.V.: 1600 mg/m² (total dose) divided over 4 days requires BMT (ie, FATAL without BMT)

Dosing adjustment in hepatic impairment: There are no published studies available on the dosing of carboplatin in patients with impaired liver function. Human data regarding the biliary elimination of carboplatin are not available; however, pharmacokinetic studies in rabbits and rats reflect a biliary excretion of 0.4% to 0.7% of the dose (ie, 0.05 mL/minute/kg biliary clearance).

Dosing adjustment in renal impairment: These dosing recommendations apply to the initial course of treatment. Subsequent dosages should be adjusted according to the patient's tolerance based on the degree of bone marrow suppression.

Cl_cr <60 mL/minute: Increased risk of severe bone marrow suppression. In renally impaired patients who received single agent carboplatin therapy, the incidence of severe leukopenia, neutropenia, or thrombocytopenia has been about 25% when the following dosage modifications have been used:

Cl_cr 41-59 mL/minute: Recommended dose on day 1 is 250 mg/m²

Cl_cr 16-40 mL/minute: Recommended dose on day 1 is 200 mg/m²

Cl_cr <15 mL/minute: The data available for patients with severely impaired kidney function are too limited to permit a recommendation for treatment

or

Dosing adjustment in renal impairment: CALVERT FORMULA

Total dose (mg) = Target AUC (mg/mL/minute) x (GFR [mL/minute] + 25)

Note: The dose of carboplatin calculated is TOTAL mg DOSE not mg/m². AUC is the area under the concentration versus time curve.

Target AUC value will vary depending upon:

Number of agents in the regimen

Treatment status (ie, previously untreated or treated)

For single agent carboplatin/no prior chemotherapy: Total dose (mg): 6-8 (GFR + 25)

For single agent carboplatin/prior chemotherapy: Total dose (mg): 4-6 (GFR + 25)

For combination chemotherapy/no prior chemotherapy: Total dose (mg): 4.5-6 (GFR + 25)

For combination chemotherapy/prior chemotherapy: A reasonable approach for these patients would be to use a target AUC value <5 for the initial cycle

Note: The Jelliffe formula (below) substantially underestimates the creatinine clearance in patients with a serum creatinine <1.5 mg/dL. However, the Jelliffe formula is more accurate in estimating creatinine clearance in patients with significant renal impairment than the Cockroft and Gault formula.

Cl_cr (mL/minute/1.73 m²) for males = 98 - [(0.8) (Age - 20)]/S_cr

Cl_cr (mL/minute/1.73 m²) for females = 98 - [(0.8) (Age - 20)]/S_cr multiplied by 90%

Intraperitoneal: 200-650 mg/m² in 2 L of dialysis fluid have been administered into the peritoneum of ovarian cancer patients

CBC (with differential and platelet count), serum electrolytes, urinalysis, creatinine clearance, liver function tests

None reported

May cause myelosuppression; use caution with clozapine and carbamazepine

No information available to require special precautions

No effects or complications reported

Maintain adequate nutrition (frequent small meals may help) and adequate hydration (2-3 L/day of fluids unless instructed to restrict fluid intake). Nausea and vomiting may be severe; request antiemetic. You will be susceptible to infection; avoid crowds or exposure to infection. Report sore throat, fever, chills, unusual fatigue or unusual bruising/bleeding, difficulty breathing, muscle cramps or twitching, or change in hearing acuity. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Do not get pregnant during or for 1 month following therapy. Male: Do not cause a female to become pregnant. Male/female: Consult prescriber for instruction on appropriate barrier contraceptive measures. This drug may cause severe fetal defects. Do not breast-feed.

Needle or intravenous administration sets containing aluminum parts should not be used in the administration or preparation of carboplatin (aluminum can interact with carboplatin resulting in precipitate formation and loss of potency); administer by I.V. intermittent infusion over 15 minutes to 1 hour, or by continuous infusion (continuous infusion regimens may be less toxic than the bolus route); reconstituted carboplatin 10 mg/mL should be further diluted to a final concentration of 0.5-2 mg/mL with D₅W or NS for administration

Powder for injection, lyophilized: 50 mg, 150 mg, 450 mg

Jeffrey LP, Chairman, National Study Commission on Cytotoxic Exposure. Position Statement. "The Handling of Cytotoxic Agents by Women Who Are Pregnant, Attempting to Conceive, or Breast-Feeding," January 12, 1987.

Lovett D, Kelsen D, Eisenberger M, et al, "A Phase II Trial of Carboplatin and Vinblastine in the Treatment of Advanced Squamous Cell Carcinoma of the Esophagus," Cancer, 1991, 67(2):354-6.

Oguri S, Sakakibara T, Mase H, et al, "Clinical Pharmacokinetics of Carboplatin," J Clin Pharmacol, 1988, 28(3):208-15.

Reece PA, Stafford I, Abbott RI, et al, "Two- Versus 24-Hour Infusion of Cisplatin: Pharmacokinetic Considerations," J Clin Oncol, 1989, 7(2):270-5.

Zeltzer PM, Epport K, Nelson MD Jr, et al, "Prolonged Response to Carboplatin in an Infant With Brain Stem Glioma," Cancer, 1991, 67(1):43-7.