Temozolomide

Description

Temozolomide is an alkylating drug with the chemical name 3,4-dihydro-3-methyl-4-oxoimidazo5,1-d-tetrazine-8-carboxamide. It appears as a white to light tan or light pink powder, with a molecular formula of C6H6N6O2 and a molecular weight of 194.15 g/mol. The molecule is stable at acidic pH (<5) and labile at pH >7. Each capsule for oral use contains either 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, or 250 mg of temozolomide, USP. The inactive ingredients in temozolomide capsules, USP include lactose anhydrous, sodium starch glycolate, tartaric acid, and stearic acid. The capsule shell is composed of gelatin, titanium dioxide, and sodium lauryl sulfate.

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 treatment of adults with anaplastic astrocytoma, including both adjuvant treatment for those with newly diagnosed anaplastic astrocytoma and treatment for adults with refractory anaplastic astrocytoma.

There are no specific teratogenic or nonteratogenic effects mentioned in 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 for 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 are at an increased risk for developing myelosuppression.

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

Patients should be closely monitored for Pneumocystis pneumonia (PCP), particularly those receiving concurrent steroid therapy, 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 of the long-term risks associated with its use.

Embryo-fetal toxicity is a significant concern; therefore, healthcare providers must inform females of reproductive potential about the risks of fetal harm and the necessity of effective contraception during treatment. Male patients with partners who are pregnant or of reproductive potential should be advised 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 full glass of water to ensure proper dosing and minimize exposure risks.

In summary, regular monitoring of ANC, platelet counts, and liver function tests is essential for the safe administration of temozolomide, alongside appropriate counseling regarding reproductive risks and safe handling of the medication.

Side Effects

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

Common adverse reactions observed in clinical trials include alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, and convulsions, with convulsions occurring in 20% or more of participants. Additionally, hematologic laboratory abnormalities have been noted, including decreased lymphocytes, platelets, neutrophils, and leukocytes, each occurring in 10% or more of patients.

Serious adverse reactions require careful monitoring and management. Myelosuppression is a significant concern, necessitating the 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. Hepatotoxicity has also 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.

Pneumocystis pneumonia (PCP) is another serious risk, particularly in patients receiving steroids, who should be closely monitored for lymphopenia and the development of PCP. There have also been reports of secondary malignancies, including myelodysplastic syndrome and myeloid leukemia.

Embryo-fetal toxicity is a critical consideration, as the treatment 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 pregnant partners or female partners 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 overdose, dose-limiting toxicity primarily manifests as myelosuppression, which can occur at any dose but is expected to be more severe at higher doses. One patient experienced an overdose of 2000 mg per day for 5 days, resulting in pancytopenia, pyrexia, multi-organ failure, and death. Reports of patients exceeding 5 days of treatment (up to 64 days) indicate severe and prolonged myelosuppression, infections, and fatalities. In the event of an overdose, it is essential to monitor complete blood count and provide supportive measures as necessary.

Drug Interactions

There are currently no documented drug interactions associated with this medication. Additionally, there is no information available regarding interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are warranted at this time.

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 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 encompassing hematologic data (N=932), 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 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 system, skeletal system, and 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 period of organogenesis 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, careful consideration should be given to the use of temozolomide in pregnant patients.

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. For patients with a creatinine clearance (CLcr) of 36 to 130 mL/min/m², no dosage adjustment is recommended. 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, 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 overdose, significant adverse reactions have been observed. An overdose of 2000 mg per day for a duration of 5 days has been associated with serious outcomes, including pancytopenia, pyrexia, multi-organ failure, and, in some instances, death.

Patients who have exceeded the recommended treatment duration of 5 days, with some receiving treatment for as long as 64 days, have reported severe and prolonged myelosuppression, leading to increased susceptibility to infections and a heightened risk of mortality.

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. Healthcare professionals are advised to remain vigilant for the aforementioned symptoms and to take appropriate action to mitigate the risks associated with overdose.

Nonclinical Toxicology

Temozolomide has been shown to be carcinogenic in rats at doses lower 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, 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 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.

Impairment of male fertility has been noted with temozolomide. In studies involving rats and dogs, doses of 50 and 125 mg/m² (0.25 and 0.63 times the human dose of 200 mg/m²) resulted in the formation of syncytial cells and immature sperm, as well as testicular atrophy in dogs at the higher dose.

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 retinal changes were most frequently observed at doses associated with mortality.

Postmarketing Experience

Postmarketing experience has identified several adverse events associated with the use of temozolomide capsules, reported voluntarily or through surveillance programs.

Decreased blood cell counts have been observed, with effects on bone marrow leading to reductions in white blood cell, red blood cell, and platelet counts. While these decreases are common, they can be severe and potentially fatal. Hospitalization or transfusions may be required for some patients. Regular blood tests are recommended for monitoring blood cell counts before and during treatment, and dose adjustments may be necessary based on these results. Patients aged 70 years or older and women are noted to have a higher risk of developing decreased blood cell counts during treatment.

Liver problems have also been reported, with some cases being severe and leading to death. Blood tests to assess liver function are advised before initiating treatment, during therapy, and approximately 2 to 4 weeks after the last dose.

Pneumocystis pneumonia (PCP), an infection that can occur in individuals with weakened immune systems, has been associated with temozolomide capsules. The drug's impact on white blood cell counts can compromise immune function, increasing the risk of PCP, particularly in patients receiving steroid medications or those on prolonged treatment. Healthcare providers are advised to monitor patients closely for low blood cell counts and signs of PCP infection, such as shortness of breath, fever, chills, or dry cough.

Additionally, there have been reports of secondary cancers, including myelodysplastic syndrome (MDS) and certain types of leukemia, in patients treated with temozolomide capsules. Ongoing monitoring for these conditions is recommended.

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.

Providers should also discuss the increased risk of hepatotoxicity associated with temozolomide. Patients must be made aware of the symptoms of hepatotoxicity and should be instructed to seek immediate medical attention if they experience any related signs. Additionally, patients will undergo periodic liver enzyme tests during treatment and after the last dose of temozolomide capsules.

Healthcare providers should inform patients about the heightened risk of Pneumocystis pneumonia and advise them to report any new or worsening pulmonary symptoms to their healthcare provider. It may be necessary for patients to receive prophylaxis for Pneumocystis pneumonia.

Patients should be counseled on the increased risk of myelodysplastic syndrome and secondary malignancies associated with temozolomide. Providers should emphasize the importance of not opening, chewing, or dissolving the capsules. In the event that capsules are accidentally opened or damaged, patients should be instructed 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.

For female patients, particularly those who are pregnant or of reproductive potential, it is crucial to discuss the potential risks to a fetus. Patients should be advised to inform their healthcare provider if they know or suspect they are pregnant. Women of reproductive potential should be counseled 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 advised to use condoms during treatment and for 3 months after the last dose. Additionally, male patients should be informed not to donate semen during treatment and for 3 months following the last dose. Women should be counseled against breastfeeding during treatment and for 1 week after the last dose. Lastly, male patients of reproductive potential should be made aware that temozolomide may impair fertility.

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.

The product should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° and 30°C (59° and 86°F) in accordance with USP Controlled Room Temperature guidelines.

Dispensing should occur in tight, light-resistant containers as specified in the USP/NF, or the product may be retained in its original bottle to ensure proper protection from light and environmental factors.

Additional Clinical Information

Clinicians should obtain a complete blood count and monitor absolute neutrophil count (ANC) and platelet counts before initiating treatment with temozolomide, as well as during treatment as clinically indicated. When temozolomide is administered in combination with radiotherapy, a complete blood count should be obtained prior to initiation, weekly during treatment, and as clinically indicated thereafter. Liver function tests are recommended at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately two to four weeks after the last dose.

Patients should be instructed to swallow temozolomide capsules whole with a glass of water and not to open, chew, or dissolve them. In the event of a damaged capsule, contact with the powder should be avoided, and any affected area should be washed with water immediately. If the capsules must be opened or the contents dissolved, this should only be performed by a trained professional using appropriate safety measures. Additionally, healthcare providers should counsel pregnant women and females of reproductive potential about the potential risks to a fetus and recommend effective contraception during treatment and for six months post-treatment. Male patients with female partners of reproductive potential should use condoms during treatment and for three months after, and they should refrain from donating semen during this period.

FDA Insert (PDF)

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

View full prescribing information (PDF)