Temozolomide

Description

Temozolomide is an alkylating agent with the chemical name 3,4-dihydro-3-methyl-4-oxoimidazo5,1-d-as-tetrazine-8-carboxamide. Its molecular formula is C6H6N6O2, and it has a molecular weight of 194.15. The compound appears as a white to light pink or light tan powder. Temozolomide is stable at acidic pH (<5) and is labile at pH >7, allowing for oral administration of temozolomide capsules.

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. Temozolomide capsules, USP, are available in various strengths: 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, and 250 mg.

The capsules contain inactive ingredients including anhydrous lactose, colloidal silica, sodium starch glycolate, stearic acid, and tartaric 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 black iron oxide, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, shellac, and strong ammonia solution.

Specific capsule formulations include:

• 5 mg: Opaque green cap containing FD&C Blue #2, gelatin, iron oxide yellow, sodium lauryl sulfate, and titanium dioxide.

• 20 mg: Opaque yellow cap containing gelatin, iron oxide yellow, sodium lauryl sulfate, and titanium dioxide.

• 100 mg: Opaque pink cap containing gelatin, iron oxide red, sodium lauryl sulfate, and titanium dioxide.

• 140 mg: Opaque blue cap containing FD&C Blue #2, gelatin, sodium lauryl sulfate, and titanium dioxide.

• 180 mg: Opaque orange cap containing gelatin, iron oxide red, sodium lauryl sulfate, and titanium dioxide.

• 250 mg: Opaque white cap containing gelatin, sodium lauryl sulfate, 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 followed by maintenance treatment. Additionally, this drug is indicated for the treatment of adults with anaplastic astrocytoma, including both the adjuvant treatment of newly diagnosed cases and the treatment of refractory anaplastic astrocytoma.

There are no teratogenic or nonteratogenic effects associated with temozolomide capsules.

Dosage and Administration

For patients with newly diagnosed glioblastoma, the recommended initial dosage is 75 mg/m² administered once daily for a duration of 42 to 49 days, in conjunction with focal radiotherapy. Following this initial treatment phase, an initial maintenance dose of 150 mg/m² should be given once daily for Days 1 to 5 of each 28-day cycle, continuing for a total of 6 cycles. Based on the patient's tolerance and observed toxicity, the maintenance dose may be increased to 200 mg/m² for Cycles 2 through 6.

In the case of adjuvant treatment for newly diagnosed anaplastic astrocytoma, temozolomide capsules should be administered orally as a single dose on Days 1 to 5 of a 28-day cycle, commencing 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 escalated to 200 mg/m² per day, provided the patient has experienced no or minimal toxicity during Cycle 1.

For patients with refractory anaplastic astrocytoma, the initial dosage is set at 150 mg/m², to be taken 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 of its components, as well as to dacarbazine. This contraindication is based on the potential for severe allergic reactions in susceptible 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 course of therapy. It is important to note that geriatric patients and women are at an increased risk of 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 treated with 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 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 risk.

In summary, regular monitoring of ANC and platelet counts, as well as liver function tests, is essential for the safe administration of temozolomide. Awareness of the associated risks, including myelosuppression, hepatotoxicity, PCP, secondary malignancies, and embryo-fetal toxicity, is crucial for healthcare professionals managing patients on this therapy.

Side Effects

Common adverse reactions observed in patients receiving treatment include alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, and convulsions, with an incidence of 20% or greater.

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 recommended to monitor absolute neutrophil count (ANC) and platelet count prior to each treatment cycle and during 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 lymphopenia may develop. The occurrence of secondary malignancies, including myelodysplastic syndrome and myeloid leukemia, has also been noted 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 be counseled to use condoms to prevent potential exposure.

In cases of overdose, dose-limiting toxicity primarily manifests as myelosuppression, which can be severe at higher doses. An overdose of 2000 mg per day for 5 days resulted in adverse reactions such as pancytopenia, pyrexia, multi-organ failure, and death. Reports indicate that patients who exceeded 5 days of treatment (up to 64 days) experienced severe and prolonged myelosuppression, infections, and in some cases, death.

Additionally, a history of serious hypersensitivity to temozolomide or any of its components is a contraindication. Limited data suggest that male patients may experience changes in sperm parameters during treatment; however, the duration and reversibility of these changes remain unclear.

Drug Interactions

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

Patients receiving temozolomide are at an increased risk for Pneumocystis pneumonia (PCP), particularly those on steroid therapy or those undergoing prolonged treatment regimens. It is recommended that all patients with newly diagnosed glioblastoma receive PCP prophylaxis during the concomitant treatment phase. This prophylaxis should be continued in patients who develop lymphopenia until their lymphocyte count resolves to Grade 1 or less.

Monitoring for lymphopenia and the development of PCP is advised for all patients undergoing treatment with temozolomide. Additionally, there is an increased incidence of secondary malignancies associated with temozolomide-containing regimens, including cases of myelodysplastic syndrome and secondary malignancies such as myeloid leukemia.

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 did not establish conclusive results.

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: medulloblastoma/PNET (29), high-grade astrocytoma (23), low-grade astrocytoma (22), brain stem glioma (16), ependymoma (14), other CNS tumors (9), and non-CNS tumors (9).

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. Notably, 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. However, it was noted that 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 assessments and tolerance.

Pregnancy

Temozolomide can cause fetal harm when administered to pregnant patients, as evidenced by findings from animal studies and its mechanism of action. Available postmarketing reports have documented 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 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 8-12 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 potential risk to the fetus.

Lactation

Temozolomide can cause fetal harm when administered to a pregnant woman. Therefore, it is advised that lactating mothers exercise caution when considering the use of temozolomide. There is no available data on the excretion of temozolomide in human breast milk or its effects on breastfed infants.

Given the potential for embryofetal toxicity and genotoxic effects on sperm cells, healthcare professionals should advise females of reproductive potential to use effective contraception during treatment with temozolomide and for 6 months after the last dose. Additionally, male patients with pregnant partners or female partners of reproductive potential should be counseled to use condoms during treatment and for 3 months following the last dose. Male patients are also advised against donating semen during this treatment period and for 3 months thereafter.

It is important to note that temozolomide may impair male fertility, with limited data indicating changes in sperm parameters during treatment. However, there is no information available regarding the duration or reversibility of these changes.

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 these patients to ensure safety and efficacy.

Hepatic Impairment

Patients with hepatic impairment may experience fatal and severe hepatotoxicity. 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 dosage but is anticipated to be more pronounced with higher doses.

A specific instance of overdose involved 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 up to 64 days. These cases also exhibited adverse reactions such as myelosuppression, which was 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 symptoms and complications arising from the 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 found to induce fibrosarcomas in various tissues, including the heart, eye, seminal vesicles, salivary glands, abdominal cavity, uterus, and prostate. Other tumors observed included 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 also noted 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 presence and absence of metabolic activation. Furthermore, temozolomide demonstrated clastogenic effects in human lymphocytes under similar conditions.

Impairment of male fertility has been observed 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. Testicular atrophy was also noted in dogs at the higher 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 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. Cases of myelosuppression, hepatotoxicity, Pneumocystis pneumonia, and secondary malignancies have been reported voluntarily or through surveillance programs.

There is an observed increased risk of myelodysplastic syndrome and secondary malignancies. Reports indicate the necessity for frequent monitoring of blood cell counts due to the potential for low blood cell counts. Patients are advised to contact their healthcare provider immediately if they experience signs of bleeding, fever, or other indications of infection.

Additionally, hepatotoxicity has been reported, highlighting the importance of immediate communication with healthcare providers upon noticing any signs or symptoms of liver issues. An increased risk of Pneumocystis pneumonia has also been noted, with recommendations for patients to seek medical advice for any new or worsening pulmonary symptoms. Based on postmarketing experience, prophylaxis for Pneumocystis pneumonia may be warranted.

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 patients.

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 about the potential risks to a fetus. They should be advised to notify their healthcare provider if they know or suspect they are pregnant. Furthermore, females 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 with temozolomide and for 3 months after the last dose. Additionally, male patients should be instructed not to donate semen during treatment and for 3 months following the last dose.

Storage and Handling

Temozolomide capsules, USP, are supplied in various package configurations. It is essential to store the capsules at a temperature range of 20°C to 25°C (68°F to 77°F). Temporary excursions are permissible between 15°C to 30°C (59°F to 86°F), in accordance with USP Controlled Room Temperature guidelines.

As temozolomide is classified as a hazardous drug, healthcare professionals must 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 Camber Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)