Tezolamet

Tezolamet Uses, Dosage, Side Effects, Food Interaction and all others data.

Tezolamet, a triazene, is an inactive prodrug. It is chemically hydrolysed to 3-methyl-(triazen-1-yl) imidazole-4-carboxamide (MTIC), the active metabolite of dacarbazine. The cytotoxicity of MTIC is believed to be due alkylation of DNA, mainly at the O6 and N7 positions of guanine.

Tezolamet 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. Tezolamet 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.

Trade Name Tezolamet
Availability Prescription only
Generic Temozolomide
Temozolomide Other Names Methazolastone, Temozolodida, Temozolomid, Temozolomida, Témozolomide, Temozolomide, Temozolomidum
Related Drugs Avastin, bevacizumab, Temodar, carmustine, Alymsys, Zirabev, procarbazine, Matulane
Type
Formula C6H6N6O2
Weight Average: 194.1508
Monoisotopic: 194.055223466
Protein binding

Temozolomide plasma protein binding varies from 8-36%, with an average of around 15%. In vitro binding experiments revealed approximate dissociation constants of 0.2-0.25 and 0.12 mM for temozolomide with human serum albumin (HSA) and alpha-1-acid glycoprotein (AGP), respectively; despite the slightly higher affinity for AGP, it is likely that temozolomide is predominantly bound to HSA due to its higher serum concentration. In addition, temozolomide binding to HSA results in delayed hydrolysis and a longer half-life than in buffer (1 versus 1.8 hours).

Groups Approved, Investigational
Therapeutic Class Cytotoxic Chemotherapy
Manufacturer
Available Country Netherlands
Last Updated: September 19, 2023 at 7:00 am
Tezolamet
Tezolamet

Uses

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

Refractory Anaplastic Astrocytoma: Tezolamet 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.

Tezolamet 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 Tezolamet 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. Tezolamet (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 Treg 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

Tezolamet dosage

Newly diagnosed glioblastoma multiforme: 75 mg/m<sup>2</sup> for 42 days concomitant with focal radiotherapy followed by initial maintenance dose of 150 mg/m<sup>2</sup> once daily for Days 1-5 of a 28-day cycle of Tezolamet for 6 cycles

Refractory Anaplastic Astrocytoma: Initial dose 150 mg/m<sup>2</sup> once daily for 5 consecutive days per 28-day treatment cycle.

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

Volume of Distribution

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

Elimination Route

Tezolamet 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 Tmax of one hour. Following a single oral dose of 150 mg/m2, temozolomide and its active MTIC metabolite had Cmax 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 Cmax 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. Tezolamet 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 Cmax and AUC to decrease by 32% and 9%, respectively, and the median Tmax to increase by 2-fold (from 1-2.25 hours).

Half Life

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

Clearance

Tezolamet 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 Tezolamet 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.

Innovators Monograph

You find simplified version here Tezolamet

Tezolamet contains Temozolomide see full prescribing information from innovator Tezolamet Monograph, Tezolamet MSDS, Tezolamet FDA label

FAQ

What is Tezolamet used for?

Tezolamet is used to treat certain types of brain tumors. Tezolamet is in a class of medications called alkylating agents. It works by slowing or stopping the growth of cancer cells in your body.

How safe is Tezolamet?

Tezolamet is safe and well tolerated. Twelve patients developed grade 1/2 thrombocytopenia and three patients developed grade 3/4 thrombocytopenia.Tezolamet is safe and effective in the treatment of recurrent AO and AOA.

What are the common side effects of Tezolamet?

The common side effects are include:

  • Fatigue. People have reported feeling tired during treatment and for up to 12 months afterwards.
  • Nausea and vomiting. ...
  • Constipation. ...
  • Loss of appetite. ...
  • Amenorrhoea (an absence of periods) ...
  • Infection

When is the best time to take Tezolamet?

Tezolamet comes as a capsule to take by mouth. It is usually taken once a day in the evening at bedtime. Take Tezolamet capsules on an empty stomach with a glass of water. Take Tezolamet at around the same time every day.

Does Tezolamet make me tired?

Drowsiness Tezolamet may make you drowsy and feel tired.

Is Tezolamet safe during pregnancy?

Do not use Tezolamet if you are pregnant. Use effective birth control to prevent pregnancy while you are using this medicine and for at least 6 months after your last dose.

Is Tezolamet safe during breasfeeding?

Breastfeeding is not recommended during use of this drug.

Can I drink alcohol with Tezolamet?

Do not drink alcohol while you are taking Tezolamet, even on the off days. 

Can I drive after taking alcohol Tezolamet?

    Drowsiness Tezolamet may make you drowsy. Take care if you are driving or operating machinery following this treatment.

Can Tezolamet effects my Fertility?

Fertility Your ability to become pregnant or father a child may be affected by taking this drug.

How long after taking Tezolamet can I eat?

You should take the capsules at least one hour before you eat a meal, or wait until two hours after you have eaten.

Can you eat after taking Tezolamet?

Your shouldn't eat anything one hour before or one hour after taking the capsules. They should be swallowed whole with a glass of water and should not be opened or chewed. You should take the capsules at the same time each day.

How long does Tezolamet work for?

You usually take Tezolamet once a day for between 6 to 7 weeks.

How long can Tezolamet take Tezolamet?

As long as you tolerate the chemotherapy well, and MRIs show no evidence of a growing tumor, then you may take Tezolamet for 12 cycles. It can be used safely for up to 24 cycles.

How long does Tezolamet stay in your body?

The chemotherapy itself stays in the body within 2 -3 days of treatment but there are short-term and long-term side effects that patients may experience.

Does Tezolamet cause depression?

Tezolamet may increase depression in patients.

Why do you have to take on an empty stomach?

Tezolamet should be taken once a day, on an empty stomach. This helps to prevent nausea associated with this medication.

Can I take Tezolamet long time?

Do not take more or less of it and do not take it for a longer time than directed. To do so may increase the chance of unwanted side effects. This medicine should come with a patient information leaflet.

Does Tezolamet reduce immune system?

Tezolamet is able to affect immune function in brain tumor patients through both effects on tumor cells and direct effects on immune cells.

*** Taking medicines without doctor's advice can cause long-term problems.
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