Temozolomide

Description

Temozolomide is an alkylating drug 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 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 values, with hydrolysis occurring more rapidly in alkaline conditions.

Temozolomide is available in capsule form for oral use, with dosages of 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, and 250 mg. Each capsule contains specific inactive ingredients, which vary by dosage strength. For the 5 mg capsule, the inactive ingredients include 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 has 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 made of gelatin and titanium dioxide, resulting in an opaque white appearance. The cap is also composed of gelatin, with colors varying according to 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 5 mg capsule features an opaque green cap, the 20 mg capsule has an opaque yellow cap, the 100 mg capsule is topped with an opaque flesh cap, the 140 mg capsule has a transparent blue cap, the 180 mg capsule features an opaque orange cap, and the 250 mg capsule has an opaque white cap.

Uses and Indications

TEMOZOLOMIDE Capsules, USP are indicated for the treatment of adult patients with newly diagnosed glioblastoma, to be administered concomitantly with radiotherapy followed by maintenance treatment. Additionally, this drug is indicated for patients with refractory anaplastic astrocytoma who have experienced disease progression on a regimen that includes nitrosourea and procarbazine.

No teratogenic or nonteratogenic effects have been reported.

Dosage and Administration

The medication 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: an initial dose of 75 mg/m² should be administered once daily for 42 days in conjunction with focal radiotherapy. Following this initial phase, the maintenance dose is set at 150 mg/m² once daily for Days 1 to 5 of each subsequent 28-day cycle, continuing for a total of 6 cycles. Based on patient tolerance and observed toxicity, the maintenance dose may be increased to 200 mg/m² for cycles 2 through 6. It is essential to provide prophylaxis for Pneumocystis pneumonia (PCP) during the concomitant phase and to continue this prophylaxis in patients who experience lymphopenia until their condition resolves to grade 1 or less.

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, USP 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 concern associated with the use of this medication. 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.

The potential for myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, has been observed in patients receiving this treatment. Therefore, vigilance in monitoring for these conditions is warranted.

Pneumocystis pneumonia (PCP) is another serious risk, particularly in patients receiving corticosteroids. All patients should be closely monitored for the development of lymphopenia and PCP during treatment.

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

Embryo-fetal toxicity is a significant risk associated with this medication. Female patients 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 counseled to use condoms to prevent potential fetal harm.

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

Side Effects

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

Common adverse reactions observed in clinical trials include alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, and convulsions. These reactions are generally manageable but may impact the quality of life for some patients.

Serious adverse reactions include hematologic laboratory abnormalities, specifically grade 3 to 4 decreases in lymphocytes, platelets, neutrophils, and leukocytes. Myelosuppression is a significant concern, necessitating close monitoring of absolute neutrophil count (ANC) and platelet count prior to each treatment cycle and during the course of therapy. Geriatric patients and women are at an increased risk for developing myelosuppression.

Additionally, there have been reports of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, in patients treated with TEMOZOLOMIDE. Pneumocystis pneumonia (PCP) is another serious risk, particularly in patients receiving steroids; therefore, all patients should be closely monitored for lymphopenia and the development of PCP.

Hepatotoxicity is a critical adverse reaction, with instances of fatal and severe liver damage reported. Liver function tests should be conducted at baseline, midway through the first treatment cycle, prior to each subsequent cycle, and approximately 2 to 4 weeks after the last dose.

Embryo-fetal toxicity is a significant concern, as TEMOZOLOMIDE can cause fetal harm. Females of reproductive potential should be advised of the 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 overdose, 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 accounts of patients who have exceeded 5 days of treatment (up to 64 days), experiencing severe and prolonged myelosuppression, infections, and resulting fatalities.

Patients with a history of hypersensitivity to temozolomide or any other components of TEMOZOLOMIDE capsules, USP, and dacarbazine should not receive this treatment.

Drug Interactions

Administration of TEMOZOLOMIDE Capsules has been evaluated for potential drug interactions, with the following findings:

Pharmacokinetic Interactions:

• The coadministration of TEMOZOLOMIDE with ranitidine does not affect the pharmacokinetics of temozolomide or its active metabolite, MTIC, as evidenced by unchanged Cmax and AUC values.

• A population analysis indicates that valproic acid may reduce the clearance of temozolomide by approximately 5%. Clinicians should consider this interaction when prescribing these medications, although no specific dosage adjustment is mandated.

• No significant influence on the clearance of orally administered TEMOZOLOMIDE was observed with dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, histamine-2-receptor antagonists, or phenobarbital.

Pharmacodynamic Interactions:

• Myelosuppression, including conditions such as pancytopenia, leukopenia, and anemia, has been reported in patients receiving TEMOZOLOMIDE, with some cases resulting in fatal outcomes.

Laboratory Test Interactions:

• Prior to initiating treatment with TEMOZOLOMIDE, it is essential to ensure that patients have an absolute neutrophil count (ANC) of at least 1.5 x 10^9/L and a platelet count of at least 100 x 10^9/L.

• During the concomitant phase with radiotherapy, a complete blood count (CBC) should be obtained prior to the start of treatment and weekly throughout the treatment period.

• For patients undergoing 28-day treatment cycles, a CBC should be performed prior to treatment on Day 1 and again 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.

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. Caution is advised when considering the use of temozolomide in this population due to the lack of established safety and efficacy.

Geriatric Use

In clinical trials for newly diagnosed glioblastoma, specifically Study MK-7365-051, 15% of participants were aged 65 years and older. However, the study did not include a sufficient number of elderly patients to ascertain any differences in effectiveness compared to younger cohorts. Notably, no overall differences in safety were observed between patients aged 65 years and older and their younger counterparts.

In the context of refractory anaplastic astrocytoma, Study MK-7365-0006 included 4% of patients aged 70 years and older. Similar to the glioblastoma study, this trial lacked adequate representation of patients aged 70 years and older to evaluate effectiveness differences relative to younger patients. It is important to note 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 those younger than 70 years of age.

Given these findings, healthcare providers should exercise caution when treating geriatric patients, particularly those aged 70 years and older, and consider close monitoring for hematological adverse effects. Dose adjustments may be warranted based on individual patient tolerance and response to therapy.

Pregnancy

Based on its mechanism of action and findings from animal studies, TEMOZOLOMIDE can cause fetal harm when administered to a pregnant woman. Available postmarketing reports describe 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 cases report adverse developmental outcomes similar to those observed in animal studies.

Administration of TEMOZOLOMIDE to rats and rabbits during the period of organogenesis has demonstrated numerous external, internal, and skeletal malformations at doses less 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 resulted in 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 warranted for women of childbearing potential.

Lactation

There is no specific information available regarding the use of this medication in nursing mothers. Additionally, there is no data on the potential for excretion of this medication in breast milk or its 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. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

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 therapy.

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 increased 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 patients exhibited severe and prolonged myelosuppression, alongside infections, which also led to 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 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 - 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. 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 equivalent to 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, 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 reported voluntarily or through surveillance programs.

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

Hematopoietic effects have been noted, including prolonged pancytopenia, which may lead to aplastic anemia and potentially fatal outcomes. Hepatobiliary events include severe and fatal hepatotoxicity, characterized by elevated liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis.

Infections reported include serious opportunistic infections, some of which have resulted in fatal outcomes, involving bacterial, viral (both primary and reactivated), fungal, and protozoan organisms.

Pulmonary complications consist of interstitial pneumonitis, pneumonitis, alveolitis, and pulmonary fibrosis. Additionally, endocrine disorders such as diabetes insipidus have been observed.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Patient Information) to ensure they are well-informed about their treatment with TEMOZOLOMIDE.

It is important to inform patients that TEMOZOLOMIDE can cause low blood cell counts, necessitating frequent monitoring of these counts. 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 be made aware of the increased risk of myelodysplastic syndrome and secondary malignancies associated with TEMOZOLOMIDE. Additionally, they should be informed about the heightened risk of Pneumocystis pneumonia and advised to reach out to their healthcare provider promptly if they develop new or worsening pulmonary symptoms. Prophylaxis for Pneumocystis pneumonia may be required.

Healthcare providers should also discuss the risk of hepatotoxicity with patients, advising them to contact their healthcare provider immediately if they notice any signs or symptoms indicative of liver damage.

Patients must be instructed not to open the capsules. In the event that a capsule is accidentally opened or damaged, they 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 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 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 with TEMOZOLOMIDE and for at least 3 months after the final dose. They should also be cautioned against donating semen during treatment and for at least 3 months after the last dose.

Women should be advised not to breastfeed during treatment with TEMOZOLOMIDE and for at least 1 week after the final dose. Lastly, male patients of reproductive potential should be informed that TEMOZOLOMIDE may impair fertility.

Storage and Handling

TEMOZOLOMIDE Capsules are supplied in various package configurations. They 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.

Due to the cytotoxic nature of TEMOZOLOMIDE, it is essential to adhere to all applicable special handling and disposal procedures to ensure safety during storage and administration.

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.

For patient counseling, it is important to inform females of reproductive potential about the potential risks to a fetus and the necessity of using effective contraception. Male patients with pregnant partners or female partners of reproductive potential should be advised to use condoms to prevent potential exposure.

FDA Insert (PDF)

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

View full prescribing information (PDF)