Темозоломид

Uses

Newly Diagnosed Glioblastoma Multiforme: Темозоломид is used for the treatment of adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment.

Refractory Anaplastic Astrocytoma: Темозоломид is used for the treatment of adult patients with refractory anaplastic astrocytoma, i.e., patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine.

Темозоломид is also used to associated treatment for these conditions: Advanced Melanoma, Glioblastomas, Primary Central Nervous System Lymphoma (PCNSL), Refractory Ewing Sarcoma, Refractory Neuroblastoma, Soft Tissue Sarcoma (STS), Advanced Neuroendocrine tumor, Refractory Anaplastic astrocytoma, Refractory, advanced Mycosis fungoides, Refractory, advanced Sezary Syndrome

How Темозоломид works

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. Темозоломид (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.

Dosage

Темозоломид dosage

Newly diagnosed glioblastoma multiforme: 75 mg/m² for 42 days concomitant with focal radiotherapy followed by initial maintenance dose of 150 mg/m² once daily for Days 1-5 of a 28-day cycle of Темозоломид for 6 cycles

Refractory Anaplastic Astrocytoma: Initial dose 150 mg/m² once daily for 5 consecutive days per 28-day treatment cycle.

The recommended dose for Темозоломид as an intravenous infusion over 90 minutes is the same as the dose for the oral capsule formulation. Bioequivalence has been established only when Темозоломид for Injection was given over 90 minutes

Should be taken on an empty stomach. Take at least 1 hr before meals.

Side Effects

Nausea, vomiting, taste perversion, constipation, diarrhoea, abdominal pain, stomatitis, anorexia, headache, fatigue, convulsions, dizziness, memory impairment, impaired concentration, tremors, blurred vision, hearing impairment, speech disorder, rash, infection, oral candidiasis, dyspnoea, coughing, neutropenia, thrombocytopenia, leucopenia, anaemia, hyperglycemia, decreased wt, insomnia, anxiety, alopecia, muscle weakness, urinary incontinence, increased alanine aminotransferase. Rarely, myelodysplastic syndrome and secondary malignancies.

Toxicity

The primary dose-limiting toxicity of temozolomide is myelosuppression, which can occur with any dose but is more severe at higher doses. Patients taking high doses experienced adverse reactions, including severe and prolonged myelosuppression, infections, and death. One patient who took 2000 mg/day for five days experienced pancytopenia, pyrexia, and multi-organ failure, which resulted in death. Patients experiencing an overdose should have complete blood counts monitored and provided with supportive care as necessary.

Precaution

Severe hepatic and renal impairment. Elderly >70 yr, children. Women of child bearing potential should avoid becoming pregnant during therapy. Males should be advised not to father a child up to 6 mth after treatment and to consider cryoconservation of sperms due to possibility of irreversible infertility. Unknown if distributed into breastmilk, discontinue nursing due to potential risk. May impair ability to drive or operate machinery. Swallow capsules whole with a full glass of water on an empty stomach or at bedtime. Do not take a 2nd dose if capsules are vomited. Monitor CBC wkly during concomitant therapy and on day 22 of each 28 day treatment cycle, followed by wkly blood count until recovery. Hepatitis screening and prophylactic therapy with antiviral agents as clinically indicated to be considered. Prophylaxis for Pneumocystis jiroveci (or Pneumocystis carinii) pneumonia (PCP) needed for all patients receiving concomitant temozolomide and radiation therapy for the 42-day regimen; if patients experience lymphocytopenia during the concomitant phase of therapy, PCP prophylaxis should be continued until recovery from lymphocytopenia. Monitor closely for PCP development in all patients. Anti-emetic prophylaxis recommended.

Interaction

Reduced effectiveness of vaccines and generalised infection may occur in patients immunised with live vaccines. Decreased temozolomide clearance with valproic acid.

Food Interaction

• Take at the same time every day.
• Take on an empty stomach. Food reduces the absorption of temozolomide and taking it on an empty stomach may reduce temozolomide associated nausea and vomiting.

Темозоломид Drug Interaction

Unknown: lorazepam, bevacizumab, sulfamethoxazole / trimethoprim, sulfamethoxazole / trimethoprim, diphenhydramine, celecoxib, docusate, hydromorphone, levetiracetam, levetiracetam, furosemide, pregabalin, polyethylene glycol 3350, acetaminophen / hydrocodone, pantoprazole, levothyroxine, acetaminophen, cyanocobalamin, cholecalciferol, ondansetron

Темозоломид Disease Interaction

Major: urticariaModerate: hepatic impairment, myelosuppression, renal impairment

Volume of Distribution

Темозоломид has a mean apparent volume of distribution (%CV) of 0.4 (13%) L/kg.

Elimination Route

Темозоломид is rapidly and completely absorbed in the gastrointestinal tract and is stable at both acidic and neutral pH. Therefore, temozolomide may be administered both orally and intravenously with a median T_max of one hour. Following a single oral dose of 150 mg/m², temozolomide and its active MTIC metabolite had C_max values of 7.5 μg/mL and 7.5 μg/mL and AUC values of 23.4 μg*hr/mL and 864 ng*hr/mL, respectively. Similarly, following a single 90-minute IV infusion of 150 mg/m², temozolide and its active MTIC metabolite had C_max values of 7.3 μg/mL and 276 ng/mL and AUC values of 24.6 μg*hr/mL and 891 ng*hr/mL, respectively. Темозоломид kinetics are linear over the range of 75-250 mg/m²/day.

Oral temozolomide absorption is affected by food. Administration following a high-fat breakfast of 587 calories caused the mean C_max and AUC to decrease by 32% and 9%, respectively, and the median T_max to increase by 2-fold (from 1-2.25 hours).

Half Life

Темозоломид has a mean elimination half-life of 1.8 hours.

Clearance

Темозоломид has a clearance of approximately 5.5 L/hr/m².

Elimination Route

Roughly 38% of administered temozolomide can be recovered over seven days, with 38% in the urine and only 0.8% in the feces. The recovered material comprises mainly metabolites: unidentified polar metabolites (17%), AIC (12%), and the temozolomide acid metabolite (2.3%). Only 6% of the recovered dose represents unchanged temozolomide.

Pregnancy & Breastfeeding use

Pregnancy Category D. There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and tumorigenicity shown for temozolomide in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of Темозоломид to the mother.

Contraindication

Hypersensitivity to dacarbazine. Severe myelosupression. Pregnancy.

Special Warning

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: Clinical studies of temozolomide did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Renal Impairment: Caution should be exercised when temozolomide is administered to patients with severe renal impairment

Hepatic Impairment: Caution should be exercised when temozolomide is administered to patients with severe hepatic impairment

Acute Overdose

Doses of 500, 750, 1000, and 1250 mg/m2 (total dose per cycle over 5 days) have been evaluated clinically in patients. Dose-limiting toxicity was hematologic and was reported with any dose but is expected to be more severe at higher doses. An overdose of 2000 mg per day for 5 days was taken by one patient and the adverse reactions reported were pancytopenia, pyrexia, multi-organ failure, and death. There are reports of patients who have taken more than 5 days of treatment (up to 64 days), with adverse reactions reported including bone marrow suppression, which in some cases was severe and prolonged, and infections and resulted in death. In the event of an overdose, hematologic evaluation is needed. Supportive measures should be provided as necessary.

Storage Condition

Store at 15-30° C.

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