Zolomide

Approved Indications:

• Newly Diagnosed Glioblastoma Multiforme (GBM):
• Used in adult patients concurrently with radiotherapy, followed by adjuvant monotherapy.
• Refractory Anaplastic Astrocytoma:
• Indicated in adult patients with histologically confirmed anaplastic astrocytoma that has progressed despite prior therapy including nitrosourea and procarbazine.

Clinically Accepted Off-label Uses:

• High-Grade Gliomas in Children (e.g., Anaplastic Astrocytoma, GBM):
• Employed under pediatric neuro-oncology protocols, typically in relapsed or progressive disease.
• Aggressive Pituitary Tumors & Pituitary Carcinomas:
• Applied in unresectable or resistant cases after standard therapies fail.
• Neuroendocrine Tumors (e.g., pNETs):
• Used in combination with capecitabine in advanced or unresectable pancreatic neuroendocrine tumors.
• Metastatic Melanoma (with CNS involvement):
• Occasionally used due to blood-brain barrier penetration, although efficacy is limited.
• Recurrent Low-Grade Gliomas (with molecular high-risk features):
• Considered in select high-risk molecular subtypes.

Route: Oral (capsules). Swallowed whole with water. Consistency with meals is preferred (either always with or without food).

Adults:

• Newly Diagnosed Glioblastoma Multiforme (Concomitant Phase):
• 75 mg/m² orally once daily for 42 consecutive days (up to 49 days) with radiotherapy.
• PJP prophylaxis is required during this phase.
• Maintenance Phase (Post-radiotherapy):
• After a 4-week break, 6 cycles of 28 days each:
• Cycle 1: 150 mg/m² once daily on Days 1–5.
• Cycles 2–6: Increase to 200 mg/m²/day for 5 days if no significant toxicity.
• Recurrent/Progressive Gliomas:
• 150 mg/m²/day for 5 consecutive days every 28 days.
• Increase to 200 mg/m²/day from cycle 2 if tolerated.

Pediatric Use (≥3 years):

• Used in high-grade gliomas per oncology protocols.
• Typical dosing: 180–200 mg/m²/day for 5 days every 28 days.

Elderly Patients (≥70 years):

• Increased risk of myelosuppression.
• Start at lowest effective dose with close hematologic monitoring.

Renal Impairment:

• No dose adjustment required in mild to moderate renal dysfunction.
• Use caution in severe impairment due to lack of sufficient data.

Hepatic Impairment:

• No adjustment for mild or moderate hepatic dysfunction.
• Insufficient data in severe hepatic impairment—use with caution.

Temozolomide is a cytotoxic alkylating agent that belongs to the imidazotetrazine class. Once ingested, it undergoes spontaneous hydrolysis at physiological pH to produce the active compound MTIC (monomethyl triazeno imidazole carboxamide). MTIC methylates DNA at the O6 and N7 positions of guanine, causing base mispairing and ultimately DNA strand breaks during replication. This leads to cellular apoptosis, particularly in rapidly dividing tumor cells. Its efficacy is enhanced in tumors with low or absent MGMT (O6-methylguanine-DNA methyltransferase) expression, as MGMT repairs the O6-methylguanine lesions.

• Absorption: Rapid and complete after oral administration; not affected by food, though food delays peak levels.
• Bioavailability: ~100%
• Time to Peak Plasma Concentration (Tmax): ~1 hour (fasted state); delayed if taken with food
• Distribution: Low plasma protein binding (~10–20%); crosses blood-brain barrier effectively
• Metabolism: Undergoes non-enzymatic conversion to MTIC; not reliant on hepatic CYP enzymes
• Half-life:
• Temozolomide: ~1.8 hours
• MTIC: Very short; rapidly cleared
• Elimination: Primarily renal (as parent drug and metabolites); ~38% recovered in urine within 24 hours
• Excretion Route: Urine; minimal fecal excretion

• Pregnancy: Category D – Positive evidence of fetal risk. Based on mechanism and animal data, may cause fetal harm. Not recommended during pregnancy.
• Lactation: Unknown if excreted in human milk. Due to potential for serious adverse effects in nursing infants, breastfeeding should be avoided during therapy and for at least 1 week after the final dose.
• Contraceptive Use:
• Females: Effective contraception during treatment and for at least 6 months after final dose.
• Males: Effective contraception required during treatment and for 3 months post-therapy.

• Primary Class: Antineoplastic Agent
• Pharmacological Class: Alkylating Agent
• Chemical Subclass: Imidazotetrazine derivative

• Known hypersensitivity to temozolomide or dacarbazine
• Severe myelosuppression or bone marrow failure
• Concomitant use with live vaccines
• Pregnancy unless clearly necessary and benefits outweigh risks

• Myelosuppression: Monitor complete blood count (CBC) regularly. Delay or reduce dose in cases of severe neutropenia or thrombocytopenia.
• Pneumocystis jirovecii Pneumonia (PJP): Mandatory prophylaxis during concomitant radiotherapy phase.
• Hepatic Toxicity: Monitor liver enzymes periodically; discontinue if hepatotoxicity develops.
• Infection Risk: Immunosuppression may predispose to serious infections.
• Secondary Malignancy: Risk of therapy-related leukemia and myelodysplasia after long-term use.
• Hypersensitivity Reactions: Risk of anaphylaxis; cross-sensitivity with dacarbazine may occur.
• Fertility Impairment: May lead to temporary or permanent infertility in males and females.

Hematologic:

• Common: Neutropenia, thrombocytopenia, anemia
• Serious: Pancytopenia, aplastic anemia

Gastrointestinal:

• Nausea, vomiting, anorexia, constipation

Neurological:

• Headache, fatigue, seizures, insomnia

Dermatologic:

• Rash, pruritus, alopecia

Respiratory:

• Cough, dyspnea, rare pneumonitis

General:

• Fever, weakness, elevated liver enzymes

Rare/Serious:

• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Opportunistic infections

• Other Myelosuppressants: Increases risk of cumulative bone marrow suppression.
• Live Vaccines: Avoid use during and shortly after treatment; risk of disseminated infection.
• Valproic Acid: May increase hematologic toxicity.
• Enzyme Interaction: Does not significantly affect or rely on CYP450 enzymes; low interaction risk.
• Antiemetics: Often used in combination for nausea control; no direct interaction.

• WHO CNS Tumor Classification (2021): Emphasizes MGMT promoter methylation status as a predictive marker for temozolomide efficacy in glioblastoma.
• NCCN & EANO Guidelines (2024): Continue to recommend temozolomide for glioblastoma, especially when MGMT methylation is present.
• Ongoing Studies: Exploring combinations with immunotherapy and PARP inhibitors in glioblastoma and other CNS tumors.
• No major FDA safety label changes reported in the past year.

• Temperature: Store below 25°C (77°F)
• Moisture Protection: Keep in original container with desiccant; tightly closed
• Light Protection: Store away from direct light
• Handling Precautions:
• Do not crush or open capsules
• Use gloves while handling
• Avoid skin or mucosal exposure
• Disposal: Dispose of as cytotoxic waste following local oncology waste protocols