Temozolomide

Description

Temozolomide is an alkylating drug with the chemical name 3,4-dihydro-3-methyl-4-oxoimidazo5,1d-as-tetrazine-8-carboxamide. It has a molecular formula of C6H6N6O2 and a molecular weight of 194.15. The compound appears as a white to light tan or light pink powder. Temozolomide is stable at acidic pH (<5) and is labile at pH >7, allowing for oral administration. As a prodrug, temozolomide is rapidly hydrolyzed to the active metabolite 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC) at neutral and alkaline pH values, with hydrolysis occurring more rapidly in alkaline conditions.

Uses and Indications

Temozolomide is indicated for the treatment of adults with newly diagnosed glioblastoma, to be administered concomitantly with radiotherapy followed by maintenance treatment. Additionally, it is indicated for the adjuvant treatment of adults with newly diagnosed anaplastic astrocytoma, as well as for the treatment of adults with refractory anaplastic astrocytoma.

There are no specific teratogenic or nonteratogenic effects mentioned in the available data.

Dosage and Administration

Temozolomide may be administered either orally or intravenously, depending on the clinical scenario.

For patients with newly diagnosed glioblastoma, the recommended dosing regimen is as follows: administer 75 mg/m² once daily for a duration of 42 to 49 days in conjunction with focal radiotherapy. Following this initial phase, an initial maintenance dose of 150 mg/m² once daily should be given for Days 1 to 5 of each 28-day cycle for a total of 6 cycles. Based on the patient's tolerance and observed toxicity, the maintenance dose may be escalated to 200 mg/m² for Cycles 2 through 6. It is essential to provide prophylaxis for Pneumocystis pneumonia (PCP) during the concomitant treatment phase and to continue this prophylaxis in patients who develop lymphopenia until their condition resolves to Grade 1 or less.

For the adjuvant treatment of newly diagnosed anaplastic astrocytoma, temozolomide capsules should be administered orally starting 4 weeks after the completion of radiotherapy. The dosing schedule consists of a single daily dose on Days 1 to 5 of a 28-day cycle for a total of 12 cycles. The recommended dosage for Cycle 1 is 150 mg/m² per day. For Cycles 2 to 12, the dosage may be increased to 200 mg/m² per day, provided the patient experienced no or minimal toxicity during Cycle 1.

In cases of refractory anaplastic astrocytoma, the initial dosing regimen consists of 150 mg/m² once daily on Days 1 to 5 of each 28-day cycle.

Contraindications

Use of temozolomide is contraindicated in patients with a history of serious hypersensitivity to temozolomide or any other components of temozolomide capsules and dacarbazine. This contraindication is based on the potential for severe allergic reactions, which may pose significant health risks to affected individuals.

Warnings and Precautions

Myelosuppression is a significant concern associated with the use of temozolomide. Healthcare professionals are advised to monitor the absolute neutrophil count (ANC) and platelet count prior to each treatment cycle and throughout the duration of therapy. It is important to note that geriatric patients and women are at an increased risk for developing myelosuppression.

Hepatotoxicity is another critical warning, as both fatal and severe cases have been reported. Liver function tests should be conducted at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately 2 to 4 weeks after the last dose of temozolomide to ensure patient safety.

Patients should be closely monitored for Pneumocystis pneumonia (PCP), particularly those receiving corticosteroids, as they may be at higher risk for developing lymphopenia and subsequent PCP.

The potential for secondary malignancies, including myelodysplastic syndrome and myeloid leukemia, has been observed in patients receiving temozolomide. This risk should be communicated to patients as part of their treatment plan.

Embryo-fetal toxicity is a significant concern; temozolomide can cause fetal harm. Female patients of reproductive potential should be informed of the risks to a fetus and advised to use effective contraception during treatment. Male patients with partners who are pregnant or of reproductive potential should also be counseled to use condoms to prevent potential exposure.

It is imperative that temozolomide capsules remain intact. They should not be opened, chewed, or dissolved, but rather swallowed whole with a glass of water to avoid exposure to the active ingredient.

In summary, regular monitoring of ANC, platelet counts, and liver function tests is essential for the safe administration of temozolomide, alongside careful consideration of the associated risks of myelosuppression, hepatotoxicity, PCP, secondary malignancies, and embryo-fetal toxicity.

Side Effects

Patients receiving treatment may experience a range of adverse reactions, which can be categorized by seriousness and frequency.

Common adverse reactions observed in clinical trials include alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, and convulsions. These reactions are generally manageable but may impact the quality of life for some patients.

Serious adverse reactions include hematologic laboratory abnormalities, specifically Grade 3 to 4 decreases in lymphocytes, platelets, neutrophils, and leukocytes. Myelosuppression is a significant concern, particularly in geriatric patients and women, who are at a higher risk. It is recommended to monitor absolute neutrophil count (ANC) and platelet count prior to each treatment cycle and throughout the course of therapy.

Hepatotoxicity is another serious adverse reaction, with reports of fatal and severe cases. Liver function tests should be conducted at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately 2 to 4 weeks after the last dose of temozolomide to ensure patient safety.

Patients should also be closely monitored for Pneumocystis pneumonia (PCP), especially those receiving steroids, as lymphopenia can increase the risk of developing this condition. Additionally, there have been observations of secondary malignancies, including myelodysplastic syndrome and myeloid leukemia, in some patients.

Embryo-fetal toxicity is a critical consideration, as the treatment can cause fetal harm. Females of reproductive potential should be informed of the risks and advised to use effective contraception. Male patients with partners who are pregnant or of reproductive potential should also be advised to use condoms to prevent potential harm to the fetus.

A history of serious hypersensitivity to temozolomide or any of its components is a contraindication for treatment. In cases of overdose, dose-limiting toxicity primarily manifests as myelosuppression, which can be severe, particularly at higher doses. An overdose of 2000 mg per day for 5 days has been associated with adverse reactions such as pancytopenia, pyrexia, multi-organ failure, and death. Reports of prolonged treatment, exceeding 5 days (up to 64 days), have also indicated severe and prolonged myelosuppression, infections, and fatalities.

It is essential for healthcare providers to be vigilant in monitoring for these adverse reactions to ensure patient safety and effective management of treatment.

Drug Interactions

No clinically significant differences in the pharmacokinetics of temozolomide or its active metabolite, MTIC, were observed when co-administered with ranitidine. Similarly, the clearance of temozolomide or MTIC is not expected to be significantly affected by co-administration with valproic acid, dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, histamine-2-receptor antagonists, or phenobarbital.

For patients receiving concomitant radiotherapy, it is essential to obtain a complete blood count (CBC) prior to the initiation of treatment and weekly during the treatment period. In the context of 28-day treatment cycles, a CBC should be performed prior to treatment on Day 1 and again on Day 22 of each cycle. If the absolute neutrophil count (ANC) falls below 1.5 x 10^9/L or the platelet count drops below 100 x 10^9/L, weekly CBCs should continue until recovery is achieved.

Liver function tests should be conducted at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately 2 to 4 weeks after the last dose of temozolomide to monitor for potential hepatotoxicity.

Packaging & NDC

The table below lists all NDC Code configurations of Temozolomide, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The safety and effectiveness of temozolomide have not been established in pediatric patients. Two open-label studies assessed the safety and effectiveness of temozolomide capsules in children aged 3 to 18 years, but conclusive results were not achieved.

In the first study, 29 patients with recurrent brain stem glioma and 34 patients with recurrent high-grade astrocytoma were enrolled. The second study, conducted by the Children’s Oncology Group (COG), included 122 patients with various conditions: 29 with medulloblastoma/PNET, 23 with high-grade astrocytoma, 22 with low-grade astrocytoma, 16 with brain stem glioma, 14 with ependymoma, 9 with other CNS tumors, and 9 with non-CNS tumors.

The adverse reaction profile observed in pediatric patients was similar to that seen in adults.

Geriatric Use

Elderly patients, defined as those aged 65 years and older, were represented by 15% of participants in the MK-7365-051 study involving newly diagnosed glioblastoma. However, this study did not include a sufficient number of patients aged 65 years and older to ascertain any differences in effectiveness compared to younger patients. Importantly, no overall differences in safety were observed between patients aged 65 years and older and their younger counterparts.

Similarly, the CATNON trial lacked adequate representation of patients aged 65 years and older, preventing any determination of differences in safety or effectiveness relative to younger patients.

In the MK-7365-006 study, which focused on patients with refractory anaplastic astrocytoma, only 4% of participants were aged 70 years and older. This study also did not provide enough data to evaluate differences in effectiveness for this age group compared to younger patients. Notably, patients aged 70 years and older exhibited a higher incidence of Grade 4 neutropenia (25%) and Grade 4 thrombocytopenia (20%) during the first cycle of therapy compared to patients younger than 70 years.

In the broader safety database encompassing hematologic data (N=932), 7% (4/61) of patients over 70 years experienced Grade 4 neutropenia, while 10% (6/63) experienced Grade 4 thrombocytopenia in the first cycle. In contrast, for patients aged 70 years and younger, the rates were 7% (62/871) for Grade 4 neutropenia and 6% (48/879) for Grade 4 thrombocytopenia during the same period. Additional hematologic complications, including pancytopenia, leukopenia, and anemia, were also reported.

Given these findings, healthcare providers should exercise caution when treating geriatric patients, particularly those aged 70 years and older, and consider close monitoring for hematologic adverse effects. Dose adjustments may be warranted based on individual patient tolerance and response.

Pregnancy

Temozolomide has been shown to cause fetal harm when administered to pregnant women, as evidenced by findings from animal studies and its mechanism of action. Available postmarketing reports indicate cases of spontaneous abortions and congenital malformations, including polymalformations affecting the central nervous system, facial structures, cardiac function, skeletal integrity, and the genitourinary system, associated with exposure to temozolomide during pregnancy. These adverse developmental outcomes are consistent with those observed in animal studies.

In studies involving rats and rabbits, administration of temozolomide during the organogenesis period resulted in numerous external, internal, and skeletal malformations at doses lower than the maximum human dose based on body surface area. Specifically, five consecutive days of oral administration of temozolomide at doses of 75 and 150 mg/m² (0.38 and 0.75 times the human dose of 200 mg/m²) during Gestation Days 8 to 12 led to significant malformations in both species. In rabbits, the 150 mg/m² dose was associated with increased embryolethality, as indicated by a rise in resorptions.

Healthcare professionals should advise pregnant women of the potential risks to the fetus associated with temozolomide. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Given the potential for serious fetal harm, temozolomide should be used during pregnancy only if the potential benefit justifies the risk to the fetus.

Lactation

There are no data on the presence of temozolomide or its metabolites in human milk, nor are there any known effects on a breastfed child or on milk production. Due to the potential for serious adverse reactions, including myelosuppression in breastfed infants, lactating mothers are advised not to breastfeed during treatment with temozolomide and for 1 week after the last dose.

Renal Impairment

Patients with renal impairment should be monitored closely, particularly those with severe renal impairment or end-stage renal disease. No dosage adjustment is recommended for patients with a creatinine clearance (CLcr) of 36 to 130 mL/min/m². However, the recommended dose of temozolomide capsules has not been established for patients with severe renal impairment (CLcr < 36 mL/min/m²) or for those undergoing dialysis. Caution is advised in this population, and clinical judgment should guide treatment decisions.

Hepatic Impairment

Patients with hepatic impairment should be monitored closely due to the potential for hepatotoxicity associated with temozolomide. For patients classified as having mild to moderate hepatic impairment (Child-Pugh class A and B), no dosage adjustment is recommended. However, the recommended dose for patients with severe hepatic impairment (Child-Pugh class C) has not been established, and caution is advised in this population.

It is essential to perform liver function tests at baseline, midway through the first cycle of treatment, prior to each subsequent cycle, and approximately 2 to 4 weeks after the last dose of temozolomide. This monitoring is critical to detect any signs of liver toxicity early and to ensure patient safety during treatment.

Overdosage

In cases of overdosage, dose-limiting toxicity primarily manifests as myelosuppression, which can occur at any administered dose but is anticipated to be more pronounced with higher doses.

Clinical observations have documented a significant overdose scenario involving a patient who ingested 2000 mg per day for a duration of 5 days. This patient experienced severe adverse reactions, including pancytopenia, pyrexia, multi-organ failure, and ultimately, death. Additionally, there have been reports of patients exceeding the recommended treatment duration, with some receiving therapy for as long as 64 days. These patients exhibited adverse reactions such as myelosuppression, which was noted to be severe and prolonged in certain instances, leading to infections and fatalities.

In the event of an overdose, it is crucial to monitor the complete blood count closely. Supportive measures should be implemented as necessary to manage the patient's condition effectively.

Nonclinical Toxicology

Temozolomide has been shown to be carcinogenic in rats at doses less than the maximum recommended human dose. In studies, it induced mammary carcinomas in both male and female rats at doses ranging from 0.13 to 0.63 times the maximum human dose (25 to 125 mg/m²) when administered orally for 5 consecutive days every 28 days over 6 cycles. Additionally, temozolomide was associated with the induction of fibrosarcomas in various tissues, including the heart, eye, seminal vesicles, salivary glands, abdominal cavity, uterus, and prostate. It also caused carcinomas of the seminal vesicles, schwannomas of the heart, optic nerve, and harderian gland, as well as adenomas of the skin, lung, pituitary, and thyroid at doses equivalent to 0.5 times the maximum daily dose. Mammary tumors were also observed following 3 cycles of treatment at the maximum recommended daily dose.

Temozolomide is classified as a mutagen and a clastogen. In a reverse bacterial mutagenesis assay (Ames assay), it increased revertant frequency both in the absence and presence of metabolic activation. Furthermore, temozolomide demonstrated clastogenic effects in human lymphocytes under both conditions of metabolic activation.

In terms of reproductive toxicity, temozolomide has been found to impair male fertility. It caused the formation of syncytial cells and immature sperm at doses of 50 and 125 mg/m² (0.25 and 0.63 times the human dose of 200 mg/m²) in rats and dogs, respectively. Testicular atrophy was also noted in dogs at the dose of 125 mg/m².

Toxicology studies conducted in rats and dogs revealed a low incidence of hemorrhage, degeneration, and necrosis of the retina at temozolomide doses equal to or greater than 125 mg/m² (0.63 times the human dose of 200 mg/m²). These ocular changes were most frequently observed at doses associated with mortality.

Postmarketing Experience

Postmarketing experience has revealed an increased risk of myelodysplastic syndrome and secondary malignancies. These events have been reported voluntarily or identified through surveillance programs.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Patient Information) thoroughly to understand the medication's use and potential risks.

It is important to inform patients that temozolomide can lead to low blood cell counts, necessitating frequent monitoring. Patients should be instructed to contact their healthcare provider immediately if they experience any signs of bleeding, fever, or other indications of infection.

Healthcare providers should also discuss the increased risk of hepatotoxicity associated with temozolomide. Patients must be made aware of the signs and symptoms of hepatotoxicity and should be instructed to report any such occurrences to their healthcare provider without delay. Additionally, patients will undergo periodic liver enzyme tests during treatment and after the last dose of temozolomide.

Patients should be informed about the heightened risk of Pneumocystis pneumonia and advised to seek immediate medical attention for any new or worsening pulmonary symptoms. Healthcare providers may need to discuss the possibility of prophylaxis for Pneumocystis pneumonia with their patients.

It is essential to inform patients about the increased risk of myelodysplastic syndrome and secondary malignancies associated with temozolomide.

Patients should be instructed not to open, chew, or dissolve the capsules. In the event that capsules are accidentally opened or damaged, healthcare providers should advise patients to take rigorous precautions to avoid inhalation or contact with the skin or mucous membranes. If contact with the powder occurs, patients should wash the affected area with water immediately.

Pregnant women and females of reproductive potential should be made aware of the potential risks to a fetus. Healthcare providers should encourage these patients to inform them of any known or suspected pregnancies.

Females of reproductive potential should be advised to use effective contraception during treatment with temozolomide and for 6 months following the last dose. Similarly, male patients with pregnant partners or female partners of reproductive potential should be instructed to use condoms during treatment and for 3 months after the last dose. Furthermore, male patients should be advised against donating semen during treatment and for 3 months following the last dose.

Storage and Handling

Temozolomide capsules are supplied in amber glass bottles equipped with child-resistant polypropylene caps, as well as in child-resistant sachet packs. The National Drug Code (NDC) numbers associated with these products should be referenced for specific packaging details.

For optimal storage, temozolomide capsules should be maintained at a temperature range of 20° to 25°C (68° to 77°F). Temporary excursions are permissible between 15°C to 30°C (59°F to 86°F). Due to the hazardous nature of temozolomide, it is imperative to adhere to all applicable special handling and disposal procedures to ensure safety during use and storage.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Temozolomide as submitted by Accord Healthcare Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)