TEMODAR
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TEMODAR (TEMODAR).
Temozolomide is a prodrug that undergoes rapid nonenzymatic conversion at physiological pH to the active alkylating agent MTIC (monomethyl triazenoimidazole carboxamide). MTIC methylates DNA at the O6 position of guanine, leading to DNA mismatch repair-dependent cytotoxicity and apoptosis.
| Metabolism | Metabolized via nonenzymatic hydrolysis to MTIC and further to the inactive metabolites AIC (aminoimidazole carboxamide) and methylhydrazine; also undergoes minor hepatic metabolism via CYP450 isoenzymes (CYP1A1, CYP2A6, CYP2E1, and CYP3A4) with no significant drug interactions. |
| Excretion | Renal: ~38% of total dose recovered in urine over 7 days, primarily as unchanged temozolomide (5.6%) and metabolites (including AIC, a major metabolite). Fecal excretion is minimal (<1%). Biliary excretion is negligible. |
| Half-life | Terminal elimination half-life is approximately 1.8 hours. Clinically, the short half-life supports once-daily dosing; no accumulation occurs with repeated doses. The active metabolite MTIC has a half-life of about 2 hours. |
| Protein binding | Approximately 15% bound to plasma proteins, primarily albumin. Low binding minimizes drug interactions via protein displacement. |
| Volume of Distribution | Mean Vd is 0.4 L/kg (range 0.1-1.1 L/kg). This moderate distribution indicates partial tissue penetration, including crossing the blood-brain barrier (CSF concentration ~30% of plasma). |
| Bioavailability | Oral bioavailability is nearly 100% (mean 100%, range 96-104%). Food reduces peak concentration by 33% and delays absorption but does not affect AUC; thus, temozolomide can be taken with or without food. |
| Onset of Action | Oral: Clinical response (tumor shrinkage) typically observed after 2-4 weeks of continuous daily dosing. Intravenous: Not applicable as no IV formulation; oral only. |
| Duration of Action | Duration of therapeutic effect is sustained over the treatment cycle (42 days for concomitant phase with radiotherapy, then 28-day cycles). Each daily dose provides systemic exposure for ~12 hours; myelosuppression nadir occurs at 21-28 days post-cycle. |
| Molecular Weight | 194.15 |
150-200 mg/m² orally once daily for 5 consecutive days of a 28-day cycle for anaplastic astrocytoma; 75 mg/m² orally daily for 42 days with radiotherapy for glioblastoma.
| Dosage form | POWDER |
| Renal impairment | No dose adjustment required for GFR ≥30 mL/min; temozolomide is contraindicated in severe renal impairment (CrCl <36 mL/min) as per manufacturer. |
| Liver impairment | For mild to moderate hepatic impairment (Child-Pugh A/B), standard dose; severe (Child-Pugh C) has not been studied; use with caution. |
| Pediatric use | In pediatric patients (≥3 years), 150 mg/m² orally once daily for 5 days per 28-day cycle; may escalate to 200 mg/m² if tolerated. For high-grade glioma with radiotherapy, 90 mg/m² daily during RT. |
| Geriatric use | No specific geriatric dose adjustment; monitor for myelosuppression, especially in patients >70 years due to increased risk of neutropenia and thrombocytopenia. |
| 1st trimester | Contraindicated due to teratogenicity; causes fetal malformations and developmental toxicity in animal studies. |
| 2nd trimester | Contraindicated; risk of fetal harm outweighs potential benefit; consider alternative therapy. |
| 3rd trimester | Contraindicated; may cause fetal harm; avoid use during third trimester. |
Clinical note
Comprehensive clinical and safety monograph for TEMODAR (TEMODAR).
| Placental transfer | Temozolomide crosses the placenta in animal models; human data limited but expected to cross due to low molecular weight and lipophilicity. |
| Breastfeeding | Temozolomide is excreted in animal milk; not recommended during breastfeeding due to potential serious adverse reactions in nursing infants. Discontinue breastfeeding or drug, considering importance of drug to mother. |
■ FDA Black Box Warning
TEMODAR can cause myelosuppression, including prolonged pancytopenia, which may result in aplastic anemia. Geriatric patients and women have been shown in clinical trials to have a higher risk of developing myelosuppression. Prescribe with caution and monitor blood counts frequently.
| Serious Effects |
History of hypersensitivity to temozolomide or any component of formulationSevere myelosuppression (e.g., absolute neutrophil count <1.5 x 10^9/L, platelet count <100 x 10^9/L)
| Precautions | Myelosuppression (monitor CBC weekly; may require dose reduction or discontinuation); Pneumocystis jirovecii pneumonia (prophylaxis required during concomitant radiotherapy); hepatotoxicity; secondary malignancies (myelodysplastic syndrome, acute myeloid leukemia); embryo-fetal toxicity; hypersensitivity reactions including Stevens-Johnson syndrome; seizures with brain tumors. |
| Food/Dietary | Take on an empty stomach (no food for at least 2 hours before and 1 hour after). Avoid alcohol and grapefruit juice due to potential hepatotoxicity. |
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| Lactation Rating |
| L5 (Contraindicated) |
| Teratogenic Risk | Teratogenic in animals (rat, rabbit) at doses below human therapeutic levels. First trimester: high risk of major malformations (central nervous system, skeletal). Second and third trimesters: risk of fetal growth restriction, low birth weight, and potential neurodevelopmental deficits. All trimesters: increased risk of fetal death. Avoid use in pregnancy unless no safer alternative. |
| Fetal Monitoring | Monitor complete blood count with differential weekly during therapy (neutropenia, thrombocytopenia). Assess liver and renal function periodically. Fetal monitoring: serial ultrasound for growth restriction and anatomy if exposed during pregnancy. Consider neonatal hematologic assessment at birth. |
| Fertility Effects | Temozolomide causes ovarian and testicular suppression. In males: oligospermia, azoospermia (may be permanent). In females: amenorrhea, premature ovarian failure, reduced fertility. Preclinical evidence of gonadal toxicity. Pre-treatment fertility preservation consultation recommended. |
| Clinical Pearls | Temozolomide is an alkylating agent requiring activation at physiological pH; it is used primarily for glioblastoma multiforme and anaplastic astrocytoma. Administer on an empty stomach with a glass of water to reduce nausea; consider prophylactic antiemetics. Monitor for myelosuppression, especially thrombocytopenia and neutropenia, typically occurring 21-28 days post-cycle. Dose adjustments are necessary for ANC <1.5 × 10^9/L or platelets <100 × 10^9/L. Prophylaxis for Pneumocystis jirovecii pneumonia is recommended during the concomitant phase with radiotherapy. Avoid concurrent use with valproic acid due to increased risk of hepatotoxicity. |
| Patient Advice | Take this medication on an empty stomach at the same time each day with a full glass of water. · Do not open or chew the capsules; swallow whole. If vomiting occurs, do not take a replacement dose. · Use effective contraception during treatment and for at least 6 months after stopping. · Avoid live vaccines while on treatment and for 6 months after the last dose. · Report any signs of infection (fever, sore throat), unusual bruising or bleeding, or severe fatigue to your doctor immediately. |