Temozolomide

Description

Temozolomide, USP is an alkylating agent with the chemical name 3,4-dihydro-3-methyl-4-oxoimidazo5,1-d-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/light pink powder. Temozolomide, USP is stable at acidic pH (< 5) and is labile at pH > 7, allowing for oral administration. As a prodrug, it is rapidly hydrolyzed to the active metabolite 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC) at neutral and alkaline pH, with hydrolysis occurring more rapidly in alkaline conditions.

Each capsule for oral use contains one of the following strengths: 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, or 250 mg of temozolomide, USP. The inactive ingredients in the capsules include colloidal silicon dioxide, ethyl alcohol, lactose anhydrous, sodium starch glycolate, stearic acid, and tartaric acid. The capsule bodies are composed of gelatin and titanium dioxide, presenting a white opaque color. The caps are also made of gelatin, with colors varying according to dosage strength. The capsule body and cap are imprinted with pharmaceutical branding ink, which contains alcohol, D&C Yellow #10, FD&C Blue #1, FD&C Blue #2, FD&C Red #40, iron oxide black, n-butyl alcohol, propylene glycol, and shellac.

Specific cap colors and their corresponding ingredients are as follows: the green cap for the 5 mg capsule contains FD&C Blue #2; the yellow cap for the 20 mg capsule contains D&C Yellow #10 and FD&C Yellow #6; the pink cap for the 100 mg capsule contains FD&C Blue #1, FD&C Red #3, and FD&C Red #40; the blue cap for the 140 mg capsule contains FD&C Blue #1; the red cap for the 180 mg capsule contains FD&C Blue #1 and FD&C Red #40; and the white cap for the 250 mg capsule contains only gelatin and titanium dioxide.

Uses and Indications

Temozolomide capsules are indicated for the treatment of adults with newly diagnosed glioblastoma, to be administered concomitantly with radiotherapy and subsequently as maintenance treatment. This drug is also indicated for the treatment of adults with anaplastic astrocytoma, including its use as an adjuvant treatment for 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 associated with temozolomide mentioned in the provided data.

Dosage and Administration

Temozolomide is administered orally.

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

For the adjuvant treatment of newly diagnosed anaplastic astrocytoma, temozolomide capsules should be administered orally in a single dose on Days 1 to 5 of a 28-day cycle, starting 4 weeks after the conclusion of radiotherapy. The recommended dosage for Cycle 1 is 150 mg/m² per day. For Cycles 2 through 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.

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 undergoing treatment. Therefore, vigilance in monitoring for any signs of these conditions is warranted.

Hepatotoxicity is another critical risk associated with temozolomide, with reports of both fatal and severe liver damage. Liver function tests should be conducted at baseline, midway through the first treatment cycle, prior to each subsequent cycle, and approximately 2 to 4 weeks following the last dose of temozolomide to ensure patient safety.

Embryo-fetal toxicity is a serious consideration, as 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. Patients should be instructed to swallow the capsules whole with a full glass of water to ensure proper administration and minimize risks associated with exposure to the drug.

In summary, careful monitoring of ANC, platelet counts, and liver function tests is essential for the safe use of temozolomide, alongside appropriate counseling regarding the risks of myelosuppression, PCP, secondary malignancies, hepatotoxicity, and embryo-fetal toxicity.

Side Effects

Patients receiving treatment may experience a range of adverse reactions, which can be categorized into common and serious reactions.

Common adverse reactions occurring in 20% or more of patients include alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, and convulsions. These reactions are generally manageable and should be monitored throughout the treatment course.

Serious adverse reactions require immediate attention and monitoring. Myelosuppression is a significant concern, necessitating regular monitoring of absolute neutrophil count (ANC) and platelet count prior to each treatment cycle and during therapy. Geriatric patients and women are at an increased risk for developing myelosuppression. Additionally, Pneumocystis pneumonia (PCP) has been reported, particularly in patients receiving steroids; therefore, close monitoring for lymphopenia and PCP is essential.

The development of secondary malignancies, including myelodysplastic syndrome and myeloid leukemia, has also been observed in some patients. Hepatotoxicity, which can be severe or fatal, has been reported; thus, 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.

Embryo-fetal toxicity is another critical consideration, as the treatment can cause fetal harm. Female patients 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.

Additional important notes include a history of serious hypersensitivity to temozolomide or any of its components. In cases of overdosage, dose-limiting toxicity primarily manifests as myelosuppression, which can occur at any dose but is expected to be more severe at higher doses. A reported overdose of 2000 mg per day for 5 days resulted in adverse reactions such as pancytopenia, pyrexia, multi-organ failure, and death. There have been instances of patients undergoing treatment for extended periods (up to 64 days), leading to severe and prolonged myelosuppression, infections, and fatalities. In the event of an overdose, it is crucial to monitor the complete blood count and provide supportive measures as necessary.

Drug Interactions

Co-administration of temozolomide or its active metabolite, MTIC, with ranitidine does not result in clinically significant alterations in pharmacokinetics. Similarly, no clinically significant differences in the clearance of temozolomide or MTIC are anticipated when these agents are used alongside valproic acid, dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, histamine-2-receptor antagonists, or phenobarbital.

For patients undergoing treatment with temozolomide, it is essential to monitor hematological parameters closely. A complete blood count (CBC) should be obtained prior to the initiation of treatment and weekly during the course of therapy, particularly for those receiving concomitant radiotherapy. In the context of 28-day treatment cycles, a CBC is required on Day 1 and Day 22 of each cycle.

In instances where the absolute neutrophil count (ANC) falls below 1.5 x 10^9/L or the platelet count drops below 100 x 10^9/L, it is imperative to continue performing complete blood counts weekly until recovery is achieved. This monitoring is crucial to ensure patient safety and to manage potential hematological toxicities effectively.

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 and adolescents 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 diagnoses: 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, indicating comparable safety concerns across age groups.

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

In the MK-7365-006 study, only 4% of patients with refractory anaplastic astrocytoma were aged 70 years and older. This study also did not provide enough data to determine effectiveness differences 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 those younger than 70 years of age.

In the broader safety database, which included hematologic data from 932 patients, 7% (4 out of 61) of patients over 70 years experienced Grade 4 neutropenia, while 10% (6 out of 63) experienced Grade 4 thrombocytopenia in the first cycle. In contrast, among patients aged 70 years or younger, 7% (62 out of 871) experienced Grade 4 neutropenia, and 6% (48 out of 879) experienced Grade 4 thrombocytopenia during the same period. Additionally, occurrences of pancytopenia, leukopenia, and anemia were noted.

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 to therapy.

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 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, the use of temozolomide during pregnancy should be approached with caution.

Lactation

There are no specific statements regarding the use of this medication in lactating mothers or its effects on breastfed infants. Healthcare professionals should consider the absence of data when advising lactating mothers about the use of this medication.

Renal Impairment

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

Hepatic Impairment

Patients with hepatic impairment may experience an increased risk of hepatotoxicity, including fatal and severe outcomes. 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. Monitoring liver function closely is critical to ensure patient safety and to manage any potential adverse effects related to compromised liver function.

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 instances of patients undergoing treatment for extended periods, exceeding 5 days and reaching up to 64 days, who also reported severe and prolonged myelosuppression. These cases were frequently accompanied by infections and, in some instances, resulted in fatal outcomes.

In the event of an overdose, it is imperative 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 mg/m² to 125 mg/m²) when administered orally on five consecutive days every 28 days for six cycles. Additionally, temozolomide induced fibrosarcomas in various tissues, including the heart, eye, seminal vesicles, salivary glands, abdominal cavity, uterus, and prostate, as well as carcinomas of the seminal vesicles, schwannomas of the heart, optic nerve, and harderian gland, and adenomas of the skin, lung, pituitary, and thyroid at doses of 0.5 times the maximum daily dose. Mammary tumors were also observed following three cycles of temozolomide 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 was found to be clastogenic in human lymphocytes under both conditions of metabolic activation.

In terms of reproductive toxicity, temozolomide impairs 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, and resulted in testicular atrophy in dogs at a 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 commonly observed at doses associated with mortality.

Postmarketing Experience

Postmarketing experience has indicated 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.

Patients should also be made aware of the increased risk of hepatotoxicity associated with temozolomide. They should be advised to report any signs or symptoms of liver issues to their healthcare provider promptly. Additionally, patients will undergo periodic liver enzyme tests during treatment and after the last dose of temozolomide.

Healthcare providers should inform patients about the heightened risk of Pneumocystis pneumonia and instruct them to seek immediate medical attention for any new or worsening pulmonary symptoms. Prophylaxis for Pneumocystis pneumonia may be necessary, and this should be discussed with the patient.

Patients should be counseled on the increased risk of myelodysplastic syndrome and secondary malignancies associated with temozolomide.

It is crucial to advise patients not to open, chew, or dissolve the capsules. In the event that capsules are accidentally opened or damaged, patients should 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 informed of the potential risks to a fetus. They should be advised to notify their healthcare provider if they know or suspect they are pregnant.

Females of reproductive potential should be counseled 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 advised to use condoms during treatment and for 3 months after the last dose. Furthermore, male patients should be instructed not to donate semen during treatment with temozolomide and for 3 months after the last dose.

Storage and Handling

Temozolomide capsules USP are supplied in various package configurations. The product should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) as defined by USP Controlled Room Temperature guidelines.

As temozolomide is classified as a hazardous drug, it is essential to adhere to all applicable special handling and disposal procedures to ensure safety during storage and administration.

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 Amneal Pharmaceuticals LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)