Temozolomide

Description

Temozolomide 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 is stable at acidic pH (<5) and is labile at pH >7, allowing for both oral and intravenous 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.

Temozolomide is available in capsule form for oral use, with strengths of 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, and 250 mg. Each capsule contains inactive ingredients including lactose anhydrous, colloidal silicon dioxide, sodium starch glycolate, tartaric acid, and stearic acid. The capsule body is made of opaque white gelatin, while the cap color varies by dosage strength. The imprinted pharmaceutical branding ink on the capsule body and cap includes shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, purified water, strong ammonia solution, potassium hydroxide, and ferric oxide.

Specific cap colors and their corresponding formulations are as follows: the 5 mg capsule has a green cap, the 20 mg capsule has a yellow cap, the 100 mg capsule has a pink cap, the 140 mg capsule has a blue cap, the 180 mg capsule has an orange cap, and the 250 mg capsule has a white cap. The FDA-approved dissolution test specifications for temozolomide differ from those established by the USP.

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 teratogenic or nonteratogenic effects associated with temozolomide as per the available data.

Dosage and Administration

Temozolomide is administered orally.

For patients with newly diagnosed glioblastoma, the recommended dosage is 75 mg/m² once daily for a duration of 42 to 49 days, administered concomitantly with focal radiotherapy. Following this initial treatment 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 toxicity assessments, the maintenance dose may be increased to 200 mg/m² for Cycles 2 to 6.

During the concomitant treatment phase, it is essential to provide prophylaxis for Pneumocystis pneumonia (PCP) 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 should be initiated 4 weeks after the completion of radiotherapy. The recommended regimen consists of a single oral dose on Days 1 to 5 of a 28-day cycle for a total of 12 cycles. The dosage for Cycle 1 is 150 mg/m² per day, with an increase to 200 mg/m² for Cycles 2 to 12 if the patient experienced no or minimal toxicity during Cycle 1.

In cases of refractory anaplastic astrocytoma, the initial dosage is 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 risk 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 may have an increased susceptibility to myelosuppression.

Hepatotoxicity is another critical concern, with reports of both fatal and severe liver damage. Baseline liver function tests should be conducted, followed by assessments midway through the first cycle, prior to each subsequent cycle, and approximately 2 to 4 weeks after the final 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 treated with temozolomide. This necessitates careful consideration and monitoring during treatment.

Embryo-fetal toxicity is a significant risk associated with temozolomide. Female patients of reproductive potential should be informed of the potential risks to a fetus and advised to use effective contraception. Male patients with partners who are pregnant or of reproductive potential should also be counseled to use condoms to prevent 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 avoid potential 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 appropriate counseling regarding the risks of myelosuppression, hepatotoxicity, PCP, secondary malignancies, and embryo-fetal toxicity.

Side Effects

Common adverse reactions observed in patients include alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, and convulsions.

Serious adverse reactions necessitate careful monitoring and management. Myelosuppression is a significant concern, particularly in geriatric patients and women, who are at an increased risk. It is essential to monitor the absolute neutrophil count (ANC) and platelet count prior to each treatment cycle and throughout the course of therapy.

Hepatotoxicity has been reported, with instances of fatal and severe liver damage. 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), especially those receiving steroids, as they may develop lymphopenia and be at higher risk for this infection.

There is also a risk of secondary malignancies, including myelodysplastic syndrome and myeloid leukemia, which have been observed in some patients.

Embryo-fetal toxicity is a critical consideration; the medication can cause fetal harm. Females of reproductive potential should be informed of the potential risks to a fetus 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.

Additional important notes include a history of serious hypersensitivity to temozolomide or any of its components. Myelosuppression is dose-limiting and can occur at any dosage, with more severe effects expected at higher doses. In one reported case, a patient experienced an overdose of 2000 mg per day for 5 days, resulting in pancytopenia, pyrexia, multi-organ failure, and death. There have been reports of patients undergoing treatment for extended periods (up to 64 days), experiencing severe and prolonged myelosuppression, infections, and subsequent death. In the event of an overdose, it is crucial to monitor the complete blood count and provide supportive measures as necessary.

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 concomitant use of valproic acid, dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, histamine-2-receptor antagonists, or phenobarbital.

In terms of laboratory test interactions, it is essential to withhold temozolomide capsules until patients achieve an absolute neutrophil count (ANC) of 1.5 x 10^9/L or greater and a platelet count of 100 x 10^9/L or greater prior to dosing. For patients undergoing concomitant radiotherapy, a complete blood count should be obtained prior to the initiation of treatment and weekly during the course of treatment.

During the 28-day treatment cycles, a complete blood count must be performed prior to treatment on Day 1 and on Day 22 of each cycle. If the ANC falls below 1.5 x 10^9/L or the platelet count falls below 100 x 10^9/L, complete blood counts should be conducted weekly until recovery is achieved. Additionally, for patients receiving focal radiotherapy, a complete blood count should be obtained weekly and as clinically indicated.

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 use of temozolomide capsules in children and adolescents aged 3 to 18 years, but did not establish definitive outcomes.

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, the 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 conclusions regarding 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 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.

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, for patients aged 70 years and younger, 7% (62 out of 871) experienced Grade 4 neutropenia, and 6% (48 out of 879) experienced 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 events. 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 has not been established for patients with CLcr less than 36 mL/min/m² or for those undergoing dialysis. Caution is advised in this population due to the lack of established dosing guidelines.

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 of temozolomide has not been established for patients with severe hepatic impairment (Child-Pugh class C).

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 crucial to detect any signs of liver dysfunction or hepatotoxicity, which can be fatal or severe.

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 are reports of patients who have exceeded 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 of 0.5 times the maximum daily dose. Mammary tumors were 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 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. 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 identified cases of myelosuppression, hepatotoxicity, Pneumocystis pneumonia, and secondary malignancies associated with temozolomide. Additionally, reports of myelodysplastic syndrome and secondary malignancies have been noted in the postmarketing data. These events were reported voluntarily or 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 capsules 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 informed to report any signs or symptoms of hepatotoxicity promptly. Additionally, patients will undergo periodic liver enzyme tests during treatment and after the last dose of temozolomide capsules.

Patients should be made aware of the heightened risk of Pneumocystis pneumonia and instructed to contact their healthcare provider if they develop new or worsening pulmonary symptoms. Prophylaxis for Pneumocystis pneumonia may be necessary, and this should be discussed with patients.

It is essential to inform patients about the increased risk of myelodysplastic syndrome and secondary malignancies associated with temozolomide. Furthermore, patients should be advised not to open, chew, or dissolve the capsules. In the event that capsules are accidentally opened or damaged, patients must 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.

Healthcare providers should counsel pregnant women and females of reproductive potential about the potential risks to a fetus. Females should be encouraged to inform their healthcare provider if they know or suspect they are pregnant. Additionally, females of reproductive potential should be advised to use effective contraception during treatment with temozolomide and for 6 months following the last dose.

Male patients with pregnant partners or female partners of reproductive potential should be instructed to use condoms during treatment with temozolomide 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 is classified as a hazardous drug, and it is essential to adhere to all applicable special handling and disposal procedures when managing this medication.

Temozolomide Capsules should be stored at a temperature of 25°C (77°F), with permissible excursions between 15°C and 30°C (59°F to 86°F) in accordance with USP Controlled Room Temperature guidelines.

These capsules are supplied in high-density polyethylene (HDPE) plastic bottles, which are equipped with child-resistant polypropylene caps to ensure safety and compliance with storage requirements.

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 Rising Pharma Holdings, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)