TEMOZOLOMIDE
Clinical safety rating: avoid
Contraindicated (not allowed)
Temozolomide is an alkylating agent that causes DNA methylation at O6 and N7 positions of guanine, leading to DNA damage and apoptosis. It is converted to the active metabolite MTIC under physiological conditions.
| Metabolism | Hydrolyzed spontaneously at physiologic pH to the active metabolite MTIC (monomethyl triazenoimidazole carboxamide). Metabolism occurs primarily in the liver via non-enzymatic processes; CYP450 enzymes do not play a significant role. |
| Excretion | Approximately 38% of total radioactivity is excreted in urine over 7 days (5.6% as unchanged temozolomide, 12% as AIC metabolite, 21% as other polar metabolites), and less than 1% is excreted in feces. |
| Half-life | 1.8 hours (range 1.3–2.5 hours) for temozolomide; the active monomethyl triazeno imidazole carboxamide (MTIC) metabolite has a half-life of approximately 2.0 hours. |
| Protein binding | Approximately 15% bound to plasma proteins (primarily albumin); weak and reversible binding. |
| Volume of Distribution | 0.4 L/kg (range 0.3–0.5 L/kg), indicating distribution primarily into total body water; crosses the blood-brain barrier achieving cerebrospinal fluid concentrations 30–40% of plasma levels. |
| Bioavailability | Oral: ~100% (rapid and complete absorption; food reduces peak concentration by 33% but does not affect AUC). |
| Onset of Action | Oral: Median time to peak plasma concentration (Tmax) is 1 hour (range 0.5–1.5 hours) after a single dose; clinical response (tumor shrinkage) typically observed within 2–4 weeks of continuous daily dosing. |
| Duration of Action | Plasma levels decline rapidly after absorption; clinical effect duration is linked to treatment cycle (e.g., 42–56 days for concomitant radiotherapy phase, then up to 6–12 cycles of maintenance therapy). |
| Molecular Weight | 194.15 |
150 mg/m2 orally once daily for 5 consecutive days of a 28-day cycle; for first cycle, then increase to 200 mg/m2/day if tolerated.
| Dosage form | CAPSULE |
| Renal impairment | No specific dose adjustment recommended for mild to moderate renal impairment (CrCl ≥36 mL/min). For severe impairment (CrCl <36 mL/min), not recommended due to lack of data. |
| Liver impairment | Child-Pugh class A: No adjustment. Child-Pugh class B: Use with caution; consider dose reduction. Child-Pugh class C: Not recommended. |
| Pediatric use | In pediatric patients (≥3 years), 150 mg/m2/day orally for 5 days of a 28-day cycle for first cycle, then increase to 200 mg/m2/day if tolerated. For refractory or recurrent disease, alternative dosing of 200 mg/m2/day for 5 days every 28 days may be used. |
| Geriatric use | No specific dose adjustment required; increased risk of myelosuppression, especially neutropenia and thrombocytopenia. Monitor blood counts closely. |
| 1st trimester | Contraindicated due to teratogenicity; may cause fetal harm based on animal studies and its mechanism of action (alkylating agent). |
| 2nd trimester | Contraindicated; risk of fetal toxicity outweighs potential benefit. Use effective contraception. |
| 3rd trimester | Contraindicated; avoid in third trimester unless maternal benefit justifies risk to fetus. |
Clinical note
Valproic acid may decrease clearance Can cause severe myelosuppression and pneumocystis pneumonia prophylaxis is required.
| Placental transfer | Yes; temozolomide crosses the placenta in animal models. Low molecular weight and lipophilicity suggest potential for human placental transfer. |
| Breastfeeding | No data on presence in human milk; due to potential serious adverse reactions in nursing infants (e.g., bone marrow suppression, carcinogenicity), breastfeeding is not recommended during therapy and for at least 2 weeks after last dose. |
■ FDA Black Box Warning
None
| Common Effects | Myelosuppression |
| Serious Effects |
Hypersensitivity to temozolomide or any component of the formulationHypersensitivity to dacarbazine (DTIC)Severe myelosuppression (e.g., absolute neutrophil count <1.5 x 10^9/L, platelet count <100 x 10^9/L)
| Precautions | Myelosuppression (neutropenia, thrombocytopenia, anemia) - dose-limiting, Pneumocystis jirovecii pneumonia risk during prolonged therapy, Hepatotoxicity - monitor LFTs, Fetal harm if used during pregnancy, Secondary malignancies (rare) |
| Food/Dietary | Avoid food for at least 2 hours before and 1 hour after administration to minimize variability in absorption. No specific food-drug interactions; however, grapefruit juice has no known interaction. Maintain adequate hydration to prevent constipation. |
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| Lactation Rating | L5 (Contraindicated) |
| Teratogenic Risk | Pregnancy Category D. Temozolomide is teratogenic and embryotoxic in animal studies. First trimester exposure is associated with major congenital malformations including CNS, skeletal, and visceral defects. Second and third trimester exposure may cause intrauterine growth restriction, preterm birth, and fetal myelosuppression. Use is contraindicated in pregnancy unless no safer alternative exists. |
| Fetal Monitoring | Monitor complete blood count (CBC) with differential weekly during treatment and at least 2 weeks after discontinuation due to risk of myelosuppression. Monitor liver function tests (AST, ALT, alkaline phosphatase, bilirubin) prior to each cycle. Perform pregnancy test before initiation and monthly during therapy. Fetal ultrasound for growth and anatomy if inadvertent exposure occurs. |
| Fertility Effects | Temozolomide is gonadotoxic. In males, may cause oligospermia, azoospermia, and irreversible infertility. In females, may cause ovarian failure, premature menopause, and reduced fertility. Pre-treatment fertility preservation counseling (sperm banking, oocyte/embryo cryopreservation) is recommended. |
| Clinical Pearls | Administer on an empty stomach (at least 2 hours after and 1 hour before food) to reduce variability. Antiemetic prophylaxis (e.g., ondansetron) is recommended before each dose due to high emetogenic potential. Monitor CBC weekly during the first cycle and then monthly; dose adjustments required for severe neutropenia or thrombocytopenia. Capsules must not be opened or crushed; if damaged, avoid inhalation or skin contact. Pneumocystis jirovecii pneumonia prophylaxis is necessary during concurrent radiotherapy. Use with caution in patients with severe hepatic impairment (AST/ALT >3x ULN) or severe renal impairment. |
| Patient Advice | Take temozolomide at the same time each day on an empty stomach with a glass of water. Do not eat for at least 2 hours before or 1 hour after taking. · Swallow capsules whole. Do not open, crush, or chew them. If you vomit after taking a dose, do not take another dose; wait until the next scheduled dose. · Wash hands thoroughly after handling the medication. If a capsule breaks, avoid contact with skin or eyes; clean surfaces with soap and water. · Use effective contraception during treatment and for at least 6 months after the last dose. Do not breastfeed. · Report signs of infection (fever, sore throat), unusual bruising or bleeding, severe nausea or vomiting, or dark urine immediately. · Avoid live vaccines and close contact with people who have recently received a live vaccine. |