Temozolomide

A to Z Drug Facts

Actions Temozolomide is a pro-drug that undergoes rapid nonenzymatic conversion. Cytotoxicity and antiproliferative activity against tumor cells are thought to be primarily caused by methylation of specific guanine-rich areas of DNA that initiates transcription. Temozolomide is rapidly and completely absorbed after oral administration, demonstrating a 98% oral bioavailability. Peak plasma concentrations occur in 1 hr and has a mean elimination half-life of 1.8 hr.

 Indications Refractory anaplastic astrocytoma.

Metastatic melanoma.

 Contraindications Hypersensitivity to any component of the product; hypersensitivity to dacarbazine; pregnancy.

 Route/Dosage

Anaplastic Astrocytoma, Single Agent Therapy

ADULTS: PO 150 mg/m²/day PO for 5 days; may repeat at 28-day intervals. Based on hematologic response, titrate up to target maintenance dose of 200 mg/m²/day for 5 days of each cycle. Continue therapy until disease progression occurs.

Dosage Adjustment Based on Lowest Post-treatment Blood Counts: If platelets are > 100,000/mm³ and neutrophils are > 1500/mm³ then increase dose by 50 mg/m²/day for next cycle. Do not increase above max dose of 200 mg/m²/day. If platelets are 50,000 to 100,000/mm³ and neutrophils are 1000 to 1500/mm³ then no dosage adjustment is necessary. Delay next course until neutrophils are > 1500/mm³ and platelets > 100,000/mm³. If platelets are < 50,000/mm³ and neutrophils are < 1000/mm³ then reduce dose by 50 mg/m²/day for next cycle. Do not reduce below minimum dose of 100 mg/m²/day. Discontinue therapy if patient cannot tolerate 100 mg/m²/day.

Interactions

Food

Food reduces the rate and extent of temozolomide absorption.

Valproic acid

Valproic acid decreases temozolomide clearance » 5%.

Lab Test Interferences None well documented.

 Adverse Reactions

CARDIOVASCULAR: Peripheral edema. CNS: Headache; fatigue; seizures; hemiparesis; weakness; dizziness; abnormal coordination; amnesia; insomnia; paresthesias. DERMATOLOGIC: Rash; pruritus. GI: Moderate potential for nausea and vomiting; constipation; diarrhea; abdominal pain; anorexia. GU: Fetal malformations in rabbits. HEMATOLOGIC: Dose-limiting bone marrow suppression; neutrophil and platelet nadirs at 26 to 28 days with recovery by day 40 to 42; elderly patients (³ 70 years of age) may experience more severe myelosuppression. MUSCULOSKELETAL: Back pain. OTHER: Fever.

 Precautions

Pregnancy: Category D. Lactation: Undetermined. Patients receiving temozolomide should discontinue nursing. Children: Safety and efficacy have not been established. Elderly: Elderly patients ³ 70 years of age had a higher incidence of Grade 4 neutropenia and Grade 4 thrombocytopenia in the first cycle of therapy; exercise caution when treating. Adjustment in renal/hepatic insufficiency: Dosage reduction may be necessary in severely impaired renal or hepatic function (eg, Ccr < 36 mL/min or Child's-Pugh Class worse than grade I to II). Specific recommendations are not available. Exercise caution when administering to patients with severe renal/hepatic impairment. Carcinogenesis: In rats treated with 200 mg/m² (equivalent to the max recommended daily human dose) on 5 consecutive days, mammary carcinomas were found in males and females. Fertility impairment: Multicycle toxicology studies in rats and dogs have demonstrated testicular toxicity. Mutagenesis: Temozolomide was mutagenic in vitro in bacteria and clastogenic in mammalian cells. Myelosuppression: Prior to dosing, patients must have an absolute neutrophil count (ANC) ³ 1.5 × 10⁹/L and a platelet count ³ 100 × 10⁹/L. Myelosuppression generally occurred late in the treatment. Special populations: Pharmacokinetic analysis indicates that women have an » 5% lower clearance (adjusted for body surface area) for temozolomide than men. Women have higher incidences than men of Grade 4 neutropenia and thrombocytopenia in the first cycle of therapy.

 Administration/Storage

• Store capsules at room temperature.
• Do not open or split capsules. Round the dose to the nearest 5 mg. If capsules are accidentally opened or damaged, take rigorous precautions with the capsule contents to avoid inhalation or contact with the skin or mucous membranes.
• Administer PO.
• To achieve dependable plasma levels, patients should be consistent about the timing of temozolomide with regard to meals. Administration on an empty stomach, or at bedtime, may reduce the risk of nausea and vomiting.
• Follow procedures for proper handling and disposal of anticancer drugs. Wear gloves and avoid skin exposure and inhalation of fumes.
• Do not crush or chew capsules; swallow whole.
• Administer at bedtime. Antiemetic therapy may be administered prior to or following temozolomide administration.

 Assessment/Interventions

• Monitor CBC at baseline, between days 20 and 24 of each cycle, and weekly until the neutrophil count is > 1500/mm³ and platelets are > 100,000/mm³.

 Patient/Family Education

• Inform patients that the most frequently occurring adverse effects are nausea and vomiting. These were usually self-limiting or readily controlled with standard anti-emetic therapy.
• There are no dietary restrictions with temozolomide. To reduce nausea and vomiting, take on an empty stomach.
• Do not open capsules. If capsules are accidentally opened or damaged, take rigorous precautions with the capsule contents to avoid inhalation or contact with the skin or mucous membranes.
• Keep the medication away from children and pets.
• If this drug is used during pregnancy or if patient becomes pregnant while on this drug, inform patient of potential hazard to the fetus.

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Copyright © 2003 Facts and Comparisons
David S. Tatro
A to Z Drug Facts