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 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. The inactive ingredients vary by dosage strength. For the 5 mg capsule, the formulation includes lactose anhydrous (132.8 mg), colloidal silicon dioxide (0.2 mg), sodium starch glycolate (7.5 mg), tartaric acid (1.5 mg), and stearic acid (3.0 mg). The 20 mg capsule contains lactose anhydrous (182.2 mg), colloidal silicon dioxide (0.2 mg), sodium starch glycolate (11 mg), tartaric acid (2.2 mg), and stearic acid (4.4 mg). The 100 mg capsule includes lactose anhydrous (175.7 mg), colloidal silicon dioxide (0.3 mg), sodium starch glycolate (15 mg), tartaric acid (3.0 mg), and stearic acid (6.0 mg). The 140 mg capsule formulation consists of lactose anhydrous (246 mg), colloidal silicon dioxide (0.4 mg), sodium starch glycolate (21 mg), tartaric acid (4.2 mg), and stearic acid (8.4 mg). The 180 mg capsule contains lactose anhydrous (316.3 mg), colloidal silicon dioxide (0.5 mg), sodium starch glycolate (27 mg), tartaric acid (5.4 mg), and stearic acid (10.8 mg). The 250 mg capsule includes lactose anhydrous (154.3 mg), colloidal silicon dioxide (0.7 mg), sodium starch glycolate (22.5 mg), tartaric acid (9.0 mg), and stearic acid (13.5 mg).

The capsule body is composed of gelatin and titanium dioxide, resulting in an opaque white appearance. The cap is also made of gelatin, with color variations based on dosage strength. The capsule body and cap are imprinted with pharmaceutical branding ink, which contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, purified water, strong ammonia solution, potassium hydroxide, and ferric oxide. The specific colors for the caps are as follows: the 5 mg capsule has an opaque green cap, the 20 mg capsule has an opaque yellow cap, the 100 mg capsule has an opaque flesh cap, the 140 mg capsule has a transparent blue cap, the 180 mg capsule has an opaque orange cap, and the 250 mg capsule has an opaque white cap. The FDA-approved dissolution test specifications for temozolomide differ from those of the USP.

Uses and Indications

TEMOZOLOMIDE Capsules are indicated for the treatment of adult patients with newly diagnosed glioblastoma, to be administered concomitantly with radiotherapy followed by maintenance treatment. Additionally, TEMOZOLOMIDE 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.

No teratogenic or nonteratogenic effects have been reported.

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 treatment 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 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 initiated 4 weeks after the completion of radiotherapy. The recommended dosing is 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 set at 150 mg/m² per day, with the potential to escalate to 200 mg/m² for Cycles 2 to 12, provided the patient has experienced no or minimal toxicity during Cycle 1.

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

Contraindications

Use of TEMOZOLOMIDE capsules is contraindicated in patients with a history of hypersensitivity to temozolomide or any other components of the formulation, 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 risk associated with TEMOZOLOMIDE therapy. 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 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 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 undergoing treatment with TEMOZOLOMIDE. This necessitates careful consideration and monitoring throughout the treatment course.

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 utilize 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 ensure proper administration and minimize risks associated with exposure to the drug.

In summary, rigorous 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, secondary malignancies, and embryo-fetal toxicity.

Side Effects

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

Common adverse reactions reported include alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, and convulsions. These reactions were observed in clinical trials and may vary in intensity among individuals.

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 during the course of therapy.

Hepatotoxicity is another serious adverse reaction associated with TEMOZOLOMIDE, 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.

Patients should also be closely monitored for Pneumocystis pneumonia (PCP), especially those receiving steroids, due to the risk of lymphopenia and subsequent development of PCP.

Additionally, there have been observations of secondary malignancies, including myelodysplastic syndrome and myeloid leukemia, in patients treated with TEMOZOLOMIDE.

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

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 including pancytopenia, pyrexia, multi-organ failure, and death. There are also reports of patients who have undergone extended treatment (up to 64 days), experiencing severe and prolonged myelosuppression, infections, and fatalities.

Finally, a history of hypersensitivity to TEMOZOLOMIDE or any of its components, including dacarbazine, should be noted as a contraindication. In the safety database encompassing 932 patients with hematologic data, additional adverse reactions such as pancytopenia, leukopenia, and anemia were also documented.

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 alterations 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 of developing 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 experience lymphopenia until their lymphocyte count resolves to Grade 1 or less.

Additionally, there is an observed increase in the incidence of secondary malignancies in patients treated with temozolomide-containing regimens. Notable cases include myelodysplastic syndrome and secondary malignancies, such as myeloid leukemia, following the administration of temozolomide. Monitoring for these potential adverse effects is advised in patients undergoing treatment.

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 its safety and effectiveness.

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.

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, 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, caution is advised when treating geriatric patients, particularly those aged 70 years and older, due to the increased risk of severe hematologic adverse events. Monitoring of blood counts and appropriate dose adjustments may be necessary to mitigate these risks.

Pregnancy

TEMOZOLOMIDE can cause fetal harm when administered to a pregnant woman. Available postmarketing reports have described cases of spontaneous abortions and congenital malformations, including polymalformations with central nervous system, facial, cardiac, skeletal, and genitourinary system anomalies associated with exposure to TEMOZOLOMIDE during pregnancy. These adverse developmental outcomes are consistent with findings from animal studies.

In animal studies, administration of TEMOZOLOMIDE to rats and rabbits 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 caused significant malformations in both species. In rabbits, the 150 mg/m² dose was associated with embryolethality, as indicated by increased resorptions.

Healthcare professionals should advise pregnant women of the potential risk to a fetus. 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 risks associated with TEMOZOLOMIDE, careful consideration and counseling are recommended for women of childbearing potential.

Lactation

There is no specific information available regarding the use of this medication in nursing mothers or its effects on lactation. Additionally, no data are provided concerning the excretion of the drug in breast milk or its potential effects on breastfed infants. Healthcare professionals should consider the lack of information when advising lactating mothers about the use of this medication.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. As such, healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, given the absence of detailed guidance on this population. Regular monitoring of renal function may be warranted 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. Close monitoring of liver function is critical to ensure patient safety and to manage any potential adverse effects related to liver function during the course of 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 incident 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. Furthermore, there are additional reports of patients who exceeded the recommended treatment duration, with some undergoing treatment for as long as 64 days. These cases have also been associated with severe and prolonged myelosuppression, leading to infections and, in certain instances, fatal outcomes.

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 - 125 mg/m²) when administered orally for 5 consecutive days every 28 days over 6 cycles. Additionally, temozolomide induced 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 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 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. 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

During post-approval use of TEMOZOLOMIDE, the following adverse reactions have been identified. These reactions were reported voluntarily from a population of uncertain size, making it challenging to reliably estimate their frequency or establish a causal relationship to the drug exposure.

Dermatologic reactions include toxic epidermal necrolysis and Stevens-Johnson syndrome. Immune system-related events consist of hypersensitivity reactions, including anaphylaxis, as well as erythema multiforme, which resolved after discontinuation of TEMOZOLOMIDE and, in some instances, recurred upon rechallenge.

Hematopoietic adverse events include prolonged pancytopenia, which may lead to aplastic anemia and potentially fatal outcomes. Hepatobiliary reactions reported include severe and fatal hepatotoxicity, elevation of liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis.

Infections reported include serious opportunistic infections, some of which resulted in fatal outcomes, involving bacterial, viral (both primary and reactivated), fungal, and protozoan organisms. Pulmonary adverse reactions encompass interstitial pneumonitis, pneumonitis, alveolitis, and pulmonary fibrosis. Additionally, endocrine-related events include diabetes insipidus.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Patient Information) to understand the medication fully. 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 discuss with patients the increased risk of myelodysplastic syndrome and secondary malignancies associated with TEMOZOLOMIDE. Additionally, patients should be made aware of the heightened risk of Pneumocystis pneumonia and instructed to reach out to their healthcare provider if they develop new or worsening pulmonary symptoms. Prophylaxis for Pneumocystis pneumonia may be required.

Patients should also be informed about the risk of hepatotoxicity. They should be advised to contact their healthcare provider immediately if they notice any signs or symptoms indicative of liver damage.

It is crucial to instruct patients not to open the capsules. In the event that a capsule is 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 their hands thoroughly.

Pregnant women and females of reproductive potential should be made aware of the potential risks to a fetus. They should be advised to inform 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 at least 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 at least 3 months after the final dose. They should also be informed not to donate semen during treatment and for at least 3 months after the last dose.

Lastly, women should be advised against breastfeeding during treatment with TEMOZOLOMIDE and for at least 1 week after the final dose. Male patients of reproductive potential should be informed 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 to ensure safety.

TEMOZOLOMIDE Capsules, USP should be stored at a controlled room temperature of 25°C (77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) as defined by USP guidelines.

These capsules are supplied in amber glass bottles, which are equipped with child-resistant polypropylene caps to enhance safety and prevent accidental ingestion.

Additional Clinical Information

Clinicians should monitor patients' absolute neutrophil count (ANC) and platelet count prior to each treatment cycle and during therapy. Liver function tests are recommended at baseline, midway through the first cycle, before each subsequent cycle, and approximately 2 to 4 weeks after the final dose of TEMOZOLOMIDE.

TEMOZOLOMIDE capsules must be swallowed whole with a glass of water and should not be opened, chewed, or dissolved. It is important to counsel females of reproductive potential about the risks to a fetus and the necessity of effective contraception. Male patients with pregnant partners or female partners of reproductive potential should be advised to use condoms.

FDA Insert (PDF)

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

View full prescribing information (PDF)