Usage
Temozolomide is an alkylating agent indicated for the treatment of:
- Adults:
- Newly diagnosed glioblastoma multiforme (GBM) concomitantly with radiotherapy and then as maintenance treatment.
- Refractory anaplastic astrocytoma who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine.
- Children (3 years and older): Malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy. It is also used to treat aggressive pituitary tumors and pituitary cancer.
Pharmacological Classification: Alkylating antineoplastic agent.
Mechanism of Action: Temozolomide is an imidazotetrazine derivative that undergoes rapid chemical conversion at physiologic pH to the active metabolite, monomethyl triazenoimidazole carboxamide (MTIC). MTIC methylates/alkylates DNA primarily at the N-7 and O-6 positions of guanine. This methylation damages the DNA of tumor cells, leading to cell death.
Alternate Names
- International Nonproprietary Name (INN): Temozolomide
- Brand Name: Temodar
How It Works
Pharmacodynamics: Temozolomide causes DNA damage in tumor cells. The cytotoxicity is believed to be due to alkylation at the O6 position of guanine. Methylation at other DNA sites may also contribute to cell death.
Pharmacokinetics:
- Absorption: Temozolomide is rapidly and completely absorbed after oral administration. Taking it with a high-fat meal may decrease the maximum concentration reached.
- Distribution: Widely distributed in the body. Low protein binding suggests minimal interactions with other highly protein-bound medications.
- Metabolism: Undergoes spontaneous, non-enzymatic conversion at physiologic pH to its active metabolite, MTIC. Hepatic metabolism is negligible.
- Elimination: Primarily renal excretion of temozolomide and its metabolites. A smaller portion of the dose is eliminated via fecal excretion.
Mode of Action: Alkylation of DNA, primarily at the O-6 position of guanine.
Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: Does not have any known significant receptor binding or specific enzyme inhibition related to its anticancer action. Its activity is based on direct DNA alkylation.
Elimination Pathways: Primarily renal excretion.
Dosage
Standard Dosage
Adults:
-
Newly Diagnosed Glioblastoma Multiforme:
- Concomitant with Radiotherapy: 75 mg/m² orally once daily for 42 days with focal radiotherapy (may extend to 49 days if radiotherapy is interrupted).
- Maintenance: 150 mg/m² orally once daily on days 1-5 of a 28-day cycle for 6 cycles. The dose may be escalated to 200 mg/m² in subsequent cycles if tolerated.
-
Refractory Anaplastic Astrocytoma: 150 mg/m² orally once daily on days 1-5 of each 28-day treatment cycle. Subsequent cycles may be increased to 200 mg/m² daily if there is no hematologic toxicity.
-
Metastatic Malignant Melanoma: 200 mg/m² orally once daily on days 1-5 of a 28-day cycle.
Children:
- Malignant Glioma (≥ 3 years): 200 mg/m² orally once daily for 5 days per 28-day cycle. Previously treated patients may start at 150 mg/m² and escalate to 200 mg/m² in subsequent cycles if tolerated.
Special Cases:
- Elderly Patients: Increased risk of myelosuppression. Close monitoring and possible dose adjustments are required.
- Patients with Renal Impairment: Close monitoring and possible dose adjustment are necessary for severe renal impairment.
- Patients with Hepatic Dysfunction: Monitor closely; dose adjustments might be needed for severe hepatic dysfunction.
- Patients with Comorbid Conditions: Careful consideration and dose modification are warranted based on specific conditions.
Clinical Use Cases
Temozolomide’s primary use is for specific brain tumors and melanoma. It is not indicated for conditions requiring intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
Dose reductions or treatment delays may be necessary based on hematological toxicity (neutropenia, thrombocytopenia), other adverse effects, or intercurrent illnesses. Detailed guidelines are available in product information sheets.
Side Effects
Common Side Effects
Nausea, vomiting, constipation, fatigue, headache, rash, alopecia, myelosuppression (neutropenia, thrombocytopenia, anemia), and lymphopenia.
Rare but Serious Side Effects
Pneumocystis jirovecii pneumonia (PCP), myelodysplastic syndrome (MDS), secondary malignancies (including myeloid leukemia), tumor lysis syndrome, hepatotoxicity, and severe myelosuppression.
Long-Term Effects
Risk of secondary malignancies, including myeloid leukemia, and infertility.
Adverse Drug Reactions (ADR)
Severe myelosuppression, hypersensitivity reactions, severe hepatotoxicity, and PCP.
Contraindications
Hypersensitivity to temozolomide or dacarbazine. Severe myelosuppression. Pregnancy. Breastfeeding.
Drug Interactions
- Valproic Acid: May decrease temozolomide clearance.
- Myelosuppressive Agents: Increased risk of myelosuppression.
- Other Interactions: Limited data available. Interactions through CYP450 metabolism are unlikely.
Pregnancy and Breastfeeding
Pregnancy Safety Category: D (US FDA); X (Australian classification)
Fetal Risks: Temozolomide is teratogenic and can cause fetal harm. Contraception is mandatory during treatment and for several months after the last dose for both males and females.
Breastfeeding: Temozolomide is likely excreted in breast milk. Breastfeeding should be discontinued during treatment and for a period after the last dose.
Drug Profile Summary
- Mechanism of Action: Alkylation of DNA, primarily at O-6 of guanine, leading to cell death.
- Side Effects: Nausea, vomiting, constipation, fatigue, myelosuppression, hepatotoxicity.
- Contraindications: Hypersensitivity, severe myelosuppression, pregnancy, breastfeeding.
- Drug Interactions: Valproic acid, myelosuppressive agents.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Varies by indication and patient factors. See detailed dosage section.
- Monitoring Parameters: Complete blood counts (CBC) including ANC and platelet counts, liver function tests, and monitoring for signs of infection.
Popular Combinations
- Radiotherapy: For newly diagnosed GBM.
Precautions
- Monitor blood counts and liver function.
- PCP prophylaxis, especially during concomitant radiotherapy and in lymphopenic patients.
- Contraception for both men and women.
- Caution in elderly patients and those with renal or hepatic impairment.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Temozolomide?
A: The dosage varies depending on the indication and patient characteristics. See detailed dosage section above.
Q2: How should Temozolomide be administered?
A: Administer orally, preferably on an empty stomach at least one hour before or two hours after a meal. Capsules should be swallowed whole with water. Do not crush or chew. Intravenous administration is also possible, as a 90-minute infusion.
Q3: What are the most common side effects of Temozolomide?
A: Nausea, vomiting, constipation, fatigue, myelosuppression, headache, alopecia.
Q4: What are the contraindications for Temozolomide use?
A: Hypersensitivity to temozolomide or dacarbazine, severe myelosuppression, pregnancy, breastfeeding.
Q5: Does Temozolomide interact with other medications?
A: It can interact with valproic acid, and concomitant use with other myelosuppressive agents can worsen myelosuppression. Consult drug interaction checkers for other potential interactions.
Q6: Can Temozolomide be used in pregnant or breastfeeding women?
A: No, it is contraindicated in both pregnancy and breastfeeding due to potential fetal harm and excretion in breast milk.
Q7: What monitoring parameters are essential during Temozolomide therapy?
A: Regular monitoring of complete blood counts, including ANC and platelet counts, liver function tests, and close observation for signs of infection are essential.
Q8: What precautions should be taken in elderly patients receiving Temozolomide?
A: Elderly patients are at higher risk of myelosuppression and require close monitoring. Dose adjustment might be required.
Q9: Are there any long-term risks associated with Temozolomide use?
A: Yes, there’s a risk of secondary malignancies, including myeloid leukemia, and infertility.
Q10: Is Temozolomide safe for use in children?
A: Yes, it can be used for children aged 3 and over. Adjust the dose based on weight and monitor them carefully.
