TEMOTERO 20 20MG CAPSULE

Indications

• Newly diagnosed glioblastoma multiforme in adults, in combination with radiotherapy
• Second-line treatment of malignant glioma in adults

Dosage

Children: Refer to the BNF for Children for pediatric dosing information.

Adults: Refer to the BNF and product literature for specific dosing guidelines.

Mechanism of action

Temozolomide undergoes spontaneous nonenzymatic breakdown at physiological pH to produce 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC), which generates a methyl diazonium cation. This cation methylates DNA, primarily at the N7 position of guanine, leading to DNA damage. Tumor tissue, such as glioblastoma, has a higher pH than healthy tissue, enhancing the activation of temozolomide within the tumor.

Pharmacodynamics

As a prodrug, temozolomide requires hydrolysis to exert its effects, resulting in the alkylation of DNA and subsequent cellular damage. Myelosuppression is a common side effect, especially in vulnerable populations such as older patients and females. Close monitoring of blood counts is essential during treatment due to the risk of severe myelosuppression and potential progression to secondary malignancies.

Pharmacokinetics

Temozolomide is well absorbed following oral administration and exhibits linear pharmacokinetics. The drug has a volume of distribution of approximately 20-30 L/m² and is eliminated primarily through renal excretion. The half-life is around 1.8 hours, with peak plasma concentrations occurring approximately 1 hour after dosing. It is advised to monitor renal and liver functions throughout the treatment course.

Adverse effects

• nausea
• vomiting
• diarrhoea
• anaemia
• lethargy
• anxiety
• confusion
• decreased appetite
• arthralgia
• asthenia
• cognitive impairment
• hypoalbuminaemia
• fever
• acute kidney injury
• myelosuppression
• hepatotoxicity
• pneumocystis jirovecii pneumonia

Interactions

• alkylating agents
• melphalan

Precautions

• Caution in renal impairment, particularly with eGFR below 30 mL/minute/1.73 m2.
• Monitor renal function, liver function tests, blood glucose levels, and complete blood counts regularly.
• Antiemetic pre-medication recommended.
• Risk of extravasation; avoid if possible.
• Prophylaxis for Pneumocystis pneumonia should be considered during treatment.

Pregnancy

Temozolomide should only be used in pregnancy if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Breastfeeding should be discontinued during treatment with temozolomide.

Storage

Store in a refrigerator (2–8°C) and protect from light. Consult product literature for specific storage conditions after reconstitution and dilution.

Formulations

• Powder and solvent for solution for injection

Mechanism of action

Glioblastoma (glioblastoma multiforme) is the most common and aggressive adult primary brain tumour, accounting for 45.6% of all primary malignant brain tumours. Primarily defined histopathologically by necrosis and microvascular proliferation (WHO grade IV classification), glioblastomas are commonly treated through radiotherapy and concomitant alkylation-based chemotherapy with temozolomide. Temozolomide (TMZ) is a small (194 Da) lipophilic alkylating agent of the imidazotetrazine class that is stable at acidic pH, allowing for both oral and intravenous dosing, and can cross the blood-brain barrier to affect CNS tumours. After absorption, TMZ undergoes spontaneous nonenzymatic breakdown at physiological pH to form 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC), which then reacts with water to produce 5-aminoimidazole-4-carboxamide (AIC) and a highly reactive methyl diazonium cation. Brain tumours such as glioblastoma typically possess a more alkaline pH than healthy tissue, favouring TMZ activation within tumour tissue. The methyl diazonium cation is highly reactive and methylates DNA at the N7 position of guanine (N7-MeG, 70%), the N3 position of adenine (N3-MeA, 9%), and the O6 position of guanine (O6-MeG, 6%). Although more prevalent, N7-MeG and N3-MeA are rapidly repaired by the base excision repair pathway and are not primary mediators of temozolomide toxicity, although N3-MeA lesions are lethal if not repaired. By comparison, repair of O6-MeG requires action by the suicide enzyme methylguanine-DNA methyltransferase (MGMT), which removes the methyl group to restore guanine. If not repaired by MGMT, O6-MeG mispairs with thymine, activating the DNA mismatch repair (MMR) pathway that removes the thymine (not the O6-MeG), resulting in futile cycles of repair and eventual DNA strand breaks leading to apoptosis. As MMR activity is crucial for temozolomide cytotoxicity, cells that have reduced or absent MGMT function and an intact MMR pathway are the most sensitive to temozolomide treatment. Glioblastomas that upregulate MGMT downregulate MMR or alter both are resistant to TMZ, leading to treatment failure. More recently, increased interest has also been shown in the immunomodulatory effects of TMZ, related to its myelosuppressive effects. Counterintuitively, lymphodepletion may enhance the antitumour effects of cellular immunotherapy and improve the dynamics of memory cells by altering tumour-specific versus tumour-tolerant populations. The depletion of tumour-localized immunosuppressive T_reg cells may contribute to an improved response to immunotherapy. Hence, TMZ treatment may also form the backbone of immunotherapy strategies against glioblastoma in the future.

Pharmacodynamics

Temozolomide is a prodrug of the imidazotetrazine class that requires nonenzymatic hydrolysis at physiological pH _in vivo_ to perform alkylation of adenine/guanine residues, leading to DNA damage through futile repair cycles and eventual cell death. Temozolomide treatment is associated with myelosuppression, which is likely to be more severe in females and geriatric patients. Patients must have an ANC of ≥1.5 x 10⁹/L and a platelet count of ≥100 x 10⁹/L before starting therapy and must be monitored weekly during the concomitant radiotherapy phase, on days one and 22 of maintenance cycles, and weekly at any point where the ANC/platelet count falls below the specified values until recovery. Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed following temozolomide administration. Pneumocystis pneumonia may occur in patients undergoing treatment, and prophylaxis should be provided for patients in the concomitant phase of therapy with monitoring at all stages. Severe hepatotoxicity has also been reported, and liver testing should be performed at baseline, midway through the first cycle, before each subsequent cycle, and approximately two to four weeks after the last dose. Animal studies suggest that temozolomide has significant embryo-fetal toxicity; male and female patients should practice contraception up to three and six months following the last dose of temozolomide, respectively.