TEMOZOLOMIDE — 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, 250 mg capsules

Temozolomide is an imidazotetrazine alkylating agent that revolutionized the treatment of malignant gliomas, particularly glioblastoma. First approved by the U.S. FDA in 1999 for refractory anaplastic astrocytoma, its indication was expanded in 2005 to include newly diagnosed glioblastoma based on the landmark EORTC/NCIC trial (Stupp regimen). Temozolomide is an oral prodrug that undergoes rapid nonenzymatic conversion at physiologic pH to the active alkylating species MTIC, which methylates DNA at the O6 and N7 positions of guanine, triggering tumor cell death.

Mechanism of action: Temozolomide is not directly active but undergoes rapid nonenzymatic conversion at physiologic pH to the reactive compound MTIC (5-(3-methyltriazen-1-yl)imidazole-4-carboxamide). The cytotoxicity of MTIC is primarily due to alkylation (methylation) at the O6 and N7 positions of guanine in DNA. O6-methylguanine mispairs with thymine during DNA replication, triggering futile cycles of mismatch repair and ultimately leading to DNA double-strand breaks and apoptosis. The DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) can remove the methyl adduct, conferring resistance; thus, methylation of the MGMT promoter is a predictive biomarker for response.

Clinical efficacy: In the pivotal phase 3 trial (Stupp regimen), 573 patients with newly diagnosed glioblastoma were randomized to receive either radiotherapy alone (60 Gy/30 fractions) or radiotherapy plus concomitant temozolomide (75 mg/m² daily for 42 days) followed by up to 6 cycles of adjuvant temozolomide (150-200 mg/m² on days 1-5 of each 28-day cycle). The addition of temozolomide resulted in a statistically significant improvement in overall survival (median survival 14.6 vs 12.1 months) with a hazard ratio of 0.63, corresponding to a 37% reduction in the risk of death. The 2-year survival rate increased from 10.4% to 26.5% [citation:1][citation:8]. For anaplastic astrocytoma, temozolomide is indicated as adjuvant treatment after radiotherapy (12 cycles) and for patients with disease progression on nitrosourea-containing regimens.

Pharmacokinetics: Temozolomide is rapidly and completely absorbed after oral administration, with peak plasma concentrations occurring in approximately 1 hour. Food reduces the rate and extent of absorption (peak concentration decreased by 32%, AUC decreased by 9%, and Tmax increased 2-fold). It is rapidly eliminated with a mean elimination half-life of 1.8 hours and exhibits linear kinetics over the therapeutic dosing range. Temozolomide is weakly bound to human plasma proteins (mean 15%). Approximately 38% of the administered dose is recovered over 7 days (37.7% in urine, 0.8% in feces). Cytochrome P450 enzymes play only a minor role in metabolism.

• History of hypersensitivity reaction to temozolomide or any component of the formulation.
• History of hypersensitivity to dacarbazine (DTIC), since both drugs are metabolized to the same active compound (MTIC).

• Valproic acid: Administration of valproic acid decreases the oral clearance of temozolomide by approximately 5%. The clinical implication is not known.
• Other myelosuppressive drugs: Additive bone marrow suppression; monitor CBC closely.
• Drugs that increase gastric pH (ranitidine, H2-receptor antagonists): In a multiple-dose study, administration of temozolomide with ranitidine did not change Cmax or AUC values for temozolomide or MTIC.
• Phenytoin, carbamazepine, phenobarbital, dexamethasone, prochlorperazine, ondansetron: Population analysis failed to demonstrate any influence on temozolomide clearance [citation:1].
• Anticoagulants (warfarin): Increased INR and bleeding risk due to myelosuppression. Monitor INR regularly.

• Pregnancy: FDA Category D. Based on animal studies, temozolomide can cause fetal harm. Women of reproductive potential should use effective contraception during treatment and for at least 6 months after last dose.
• Lactation: It is not known whether temozolomide is excreted in human milk. Advise women not to breastfeed during treatment and for at least 1 week after last dose due to potential risk of serious adverse reactions in nursing infants.
• Pediatric use: Safety and efficacy have been studied in open-label studies in pediatric patients (aged 3-18 years) with recurrent brain stem glioma and high-grade astrocytoma. The toxicity profile is similar to adults. Common adverse reactions include thrombocytopenia (25% Grade 3-4), neutropenia (20% Grade 3-4), lymphopenia (39% Grade 3-4), and decreased hemoglobin (6% Grade 3-4).
• Geriatric use: Patients 70 years or older have a higher incidence of Grade 4 neutropenia and thrombocytopenia in the first cycle of therapy than younger patients. Dose selection should be cautious, reflecting greater frequency of decreased organ function.
• Gender differences: Women have an approximately 5% lower clearance for temozolomide than men and have higher incidences of Grade 4 neutropenia and thrombocytopenia.
• Hepatic impairment: Mild-to-moderate hepatic impairment (Child-Pugh Class I-II) does not alter pharmacokinetics. Caution in severe hepatic impairment.
• Renal impairment: Creatinine clearance over 36-130 mL/min/m² has no effect on clearance. Not studied in severe renal impairment (CrCl <36 mL/min/m²) or in patients on dialysis. Caution advised.

• Newly diagnosed glioblastoma (concomitant phase): 75 mg/m² once daily for 42-49 days with focal radiotherapy. Provide PCP prophylaxis. Obtain CBC weekly. For ANC 0.5-1.5 x 10⁹/L or platelets 10-100 x 10⁹/L, withhold until recovery then resume at same dose. Discontinue if ANC <0.5 x 10⁹/L or platelets <10 x 10⁹/L or Grade 3-4 non-hematological toxicity.
• Newly diagnosed glioblastoma (maintenance phase): Begin 4 weeks after concomitant phase. Cycle 1: 150 mg/m² once daily on Days 1-5 of each 28-day cycle. Cycles 2-6: May increase to 200 mg/m² on Days 1-5 if no toxicity requiring interruption in Cycle 1. Obtain CBC on Day 22. If ANC <1 x 10⁹/L or platelets <50 x 10⁹/L, withhold and reduce next cycle dose by 50 mg/m². Permanently discontinue if unable to tolerate 100 mg/m².
• Adjuvant treatment of newly diagnosed anaplastic astrocytoma: Begin 4 weeks after radiotherapy. Administer for 12 cycles. Cycle 1: 150 mg/m² once daily on Days 1-5. Cycles 2-12: 200 mg/m² on Days 1-5 if no/minimal toxicity in Cycle 1.
• Refractory anaplastic astrocytoma: Initial dose 150 mg/m² once daily on Days 1-5 of each 28-day cycle. Increase to 200 mg/m² per day if ANC ≥1.5 x 10⁹/L and platelets ≥100 x 10⁹/L at nadir and Day 1 of next cycle. Continue until disease progression or unacceptable toxicity.
• Administration: Take on an empty stomach (at least 1 hour before or 2 hours after food). Swallow capsules whole with a glass of water. Do not open, crush, or chew. If capsules are accidentally opened or damaged, avoid inhalation or contact with skin.

• Symptoms: Expected to include severe myelosuppression (pancytopenia, aplastic anemia), hepatotoxicity, and gastrointestinal toxicity.
• Management: No specific antidote. Hospitalization, supportive care, monitoring of vital signs, CBC, and liver function. Transfusions, antibiotics, and growth factors as needed. Hemodialysis effectiveness unknown.