Temozolomide

(BAN, USAN, rINN)
Temozolomide Chemical formula
Synonyms: CCRG-81045; M&B-39831; NSC-362856; Sch-52365; Temotsolomidi; Temozolomid; Temozolomida; Témozolomide; Temozolomidum. 3,4-Dihydro-3methyl-4-oxoimidazo[5,1d][1,2,3,5]tetrazine-8-carboxamide.
Cyrillic synonym: Темозоломид.

💊 Chemical information

Chemical formula: C6H6N6O2 = 194.2.
CAS — 85622-93-1.
ATC — L01AX03.
ATC Vet — QL01AX03.

💊 Adverse Effects, Treatment, and Precautions

Myelosuppression is common with temozolomide and is dose-limiting. The nadir of cell counts usually occurs 21 to 28 days after treatment, with recovery within the next 1 to 2 weeks. Patients over 70 years of age are thought to be more susceptible to severe myelosuppression. Prolonged pancytopenia may result in aplastic anaemia, and fatalities have been reported. Opportunistic infections can occur; Pneumocystis jirovecii pneumonia has been reported in patients also given radiotherapy or corticosteroids, or during a longer dosing regimen of temozolomide. Other common adverse effects include gastrointestinal disturbances, anorexia, alopecia, fatigue, headache, rashes, convulsions, and insomnia or somnolence. Anxiety, depression, confusion, dizziness, hemiparesis, aphasia, dysphagia, peripheral neuropathy, paraesthesia, neurological and/or speech disorders, tremor, and concentration or memory impairment can occur, as can visual field defects, blurred vision, diplopia, hearing impairment, or tinnitus. Deafness has been reported. Vascular disorders such as haemorrhage, deep venous thrombosis, and peripheral oedema can occur; pulmonary embolism has been reported. Other commonly reported adverse effects include dyspnoea, coughing, dry skin, pruritus, arthralgia and/or myalgia, urinary incontinence, fever, pain, and dysgeusia. Liver enzyme values can increase, and hyperglycaemia may occur. Cushingoid disorders have occurred uncommonly. Hypersensitivity reactions, including rare cases of anaphylaxis, have been reported. Toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme have been reported rarely. Temozolomide has carcinogenic, mutagenic, and teratogenic potential.

💊 Pharmacokinetics

Temozolomide is rapidly and completely absorbed from the gastrointestinal tract, with peak plasma concentrations occurring 0.5 to 1.5 hours after a dose. Food reduces the rate and extent of absorption. It readily crosses the blood-brain barrier and can be detected in the CSF. The plasma elimination half-life is 1.8 hours. Temozolomide undergoes spontaneous hydrolysis to its active metabolite 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC), which is then further hydrolysed to active and inactive compounds. It is largely eliminated by the kidneys, about 5 to 10% as unchanged drug.

💊 Uses and Administration

Temozolomide is a prodrug that is converted to MTIC (see Pharmacokinetics, above), the active metabolite of dacarbazine. MTIC acts as an alkylating agent. Temozolomide is given orally and is licensed for the treatment of malignant gliomas such as glioblastoma multiforme and anaplastic astrocytoma, and malignant melanoma (below). In adult patients with newly diagnosed glioblastoma multiforme, temozolomide is given initially with focal radiotherapy (the concomitant phase) in an oral dose of 75 mg/m 2 daily for 42 days. Treatment may be interrupted or stopped depending on toxicity. Complete blood counts should be monitored weekly. Four weeks after completing the concomitant phase, temozolomide monotherapy is begun at an oral dose of 150 mg/m 2 once daily for 5 days of a 28-day cycle. In cycle 2, the dose is increased to 200 mg/m 2 for 5 days, if toxicity allows. If the dose cannot be increased in cycle 2, it should not be increased in subsequent cycles. The dose used at cycle 2 is then given every 28 days, toxicity allowing. Up to 6 cycles of temozolomide monotherapy may be given. The usual oral dose for recurrent or progressive malignant gliomas in adults and children over 3 years of age (and previously untreated with chemotherapy) is 200 mg/m 2 daily for 5 days, repeated every 28 days. In patients who have received previous courses of chemotherapy the dose should be reduced to 150 mg/m 2 for the first cycle of therapy, but may be increased to 200 mg/m 2 for subsequent courses if there is no haematological toxicity. A dose of 200 mg/m 2 daily for 5 days every 28 days is
also used for metastatic malignant melanoma.

Malignant neoplasms.

Temozolomide has been studied1-9particularly in the management of malignant neoplasms of the brain. In the UK, guidance has been issued10 on its use in patients with recurrent progressive malignant glioma who have failed first-line chemotherapy treatment with other agents (either because of lack of efficacy or because of adverse effects).
1. Dinnes J, et al. A rapid and systematic review of the effectiveness of temozolomide for the treatment of recurrent malignant glioma. Br J Cancer 2002; 86: 501–5
2. Wick W, et al. One week on/one week off: a novel active regimen of temozolomide for recurrent glioblastoma. Neurology 2004; 62: 2113–15
3. Levin N, et al. Chemotherapy as initial treatment in gliomatosis cerebri: results with temozolomide. Neurology 2004; 63: 354–6
4. Agarwala SS, et al. Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase II study. J Clin Oncol 2004; 22: 2101–7
5. Stupp R, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352: 987–96
6. Athanassiou H, et al. Randomized phase II study of temozolomide and radiotherapy compared with radiotherapy alone in newly diagnosed glioblastoma multiforme. J Clin Oncol 2005; 23: 2372–7
7. Tosoni A, et al. Is protracted low-dose temozolomide feasible in glioma patients? Neurology 2006; 66: 427–9
8. Wick A, et al. Efficacy and tolerability of temozolomide in an alternating weekly regimen in patients with recurrent glioma. J Clin Oncol 2007; 25: 3357–61
9. Sher DJ, et al. The added value of concurrently administered temozolomide versus adjuvant temozolomide alone in newly diagnosed glioblastoma. J Neurooncol 2008; 88: 43–50
10. NICE. Guidance on the use of temozolomide for the treatment of recurrent malignant glioma (brain cancer) (issued April 2001). Available at: http://www.nice.org.uk/nicemedia/pdf/ temozolomideguidance.pdf (accessed 30/07/08)
MELANOMA. Temozolomide has been studied1-3 as a treatment for advanced metastatic melanoma. A phase III trial compared the overall survival-time in 305 patients treated with either oral temozolomide or intravenous dacarbazine in standard doses for up to 12 cycles of therapy. Temozolomide was found to be at least equivalent to dacarbazine in these patients, and there were no major differences in adverse effects.2 However, median survival-times were short in both groups (7.7 months and 6.4 months respectively). Another phase III study comparing temozolomide alone or with interferon alfa in 282 patients also found modest median survivaltimes of 8.4 and 9.7 months respectively.4 Temozolomide has also been investigated in animals for regional therapy of melanoma of the extremities by isolated limb infusion in combination with hyperthermia.5
1. Bleehen NM, et al. Cancer research campaign phase II trial of temozolomide in metastatic melanoma. J Clin Oncol 1995; 13: 910–13
2. Middleton MR, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 2000; 18: 158–66
3. Quirt I, et al. Temozolomide for the treatment of metastatic melanoma: a systematic review. Oncologist 2007; 12: 1114–23
4. Kaufmann R, et al. Temozolomide in combination with interferon-alfa versus temozolomide alone in patients with advanced metastatic melanoma: a randomized, phase III, multicenter study from the Dermatologic Cooperative Oncology Group. J Clin Oncol 2005; 23: 9001–7
5. Ko SH, et al. Optimizing a novel regional chemotherapeutic agent against melanoma: hyperthermia-induced enhancement of temozolomide cytotoxicity. Clin Cancer Res 2006; 12: 289–97.

💊 Preparations

Proprietary Preparations

Arg.: Dralitem; Temodal†; Austral.: Te m o da l; Austria: Te m od al ; Belg.: Te modal; Braz.: Te m od a l ; Canad.: Te m o d a l ; Chile: Te m o d a l ; Cz.: Te m o d a l; Denm.: Te m o d a l ; Fin.: Tem od a l ; Fr.: Te m o d a l ; Ger.: Te mo dal ; Gr.: Te m o dal; Hong Kong: Te m o d a l ; Hung.: Te m o d a l ; Indon.: Te m o d a l ; Irl.: Tem odal; Israel: Te m o d a l ; Ital.: Te m od a l ; Malaysia: Te m o d a l ; Mex.: Te m o d a l ; Neth.: Te m o d a l ; Norw.: Te m o d a l ; NZ: Tem od a l ; Philipp.: Te m o d a l ; Pol.: Te m o d a l ; Port.: Te m o d a l ; Rus.: Tem od a l ( Темодал); S.Afr.: Tem od al ; Te moxol†; Singapore: Te m o d a l ; Spain: Te m o d a l ; Swed.: Te m o da l; Switz.: Te m o d a l ; Thai.: Te m od al; Turk.: Te m o d a l ; UK: Te m o d a l ; USA: Te m o d a r ; Venez.: Te m o d a l .
Published March 03, 2019.