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 oral administration of Temozolomide capsules, USP. The prodrug 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 strengths of 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, and 250 mg. The inactive ingredients vary by strength:

• For 5 mg: lactose anhydrous (103.52 mg), colloidal silicon dioxide (0.180 mg), sodium starch glycolate (5.650 mg), tartaric acid (2.260 mg), and stearic acid (3.390 mg).

• For 20 mg: lactose anhydrous (179.0 mg), colloidal silicon dioxide (0.320 mg), sodium starch glycolate (10.350 mg), tartaric acid (4.140 mg), and stearic acid (6.210 mg).

• For 100 mg: lactose anhydrous (73.0 mg), colloidal silicon dioxide (0.280 mg), sodium starch glycolate (9.00 mg), tartaric acid (3.60 mg), and stearic acid (5.40 mg).

• For 140 mg: lactose anhydrous (102.2 mg), colloidal silicon dioxide (0.390 mg), sodium starch glycolate (12.60 mg), tartaric acid (5.040 mg), and stearic acid (7.560 mg).

• For 180 mg: lactose anhydrous (131.4 mg), colloidal silicon dioxide (0.500 mg), sodium starch glycolate (16.20 mg), tartaric acid (6.480 mg), and stearic acid (9.720 mg).

• For 250 mg: lactose anhydrous (182.5 mg), colloidal silicon dioxide (0.700 mg), sodium starch glycolate (22.50 mg), tartaric acid (9.000 mg), and stearic acid (13.50 mg).

The capsule bodies for the 5 mg, 20 mg, 140 mg, 180 mg, and 250 mg strengths are composed of gelatin and titanium dioxide, resulting in a white opaque appearance. The 100 mg capsules have a buff opaque body made of gelatin, titanium dioxide, and ferric oxide yellow. The caps are also made of gelatin, with colors varying by dosage strength: the 5 mg cap is green opaque, the 20 mg cap is rich yellow opaque, the 100 mg cap is peach opaque, the 140 mg cap is blue opaque, the 180 mg cap is red opaque, and the 250 mg cap is white opaque. The capsule body and cap are imprinted with pharmaceutical branding ink, which includes shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, purified water, strong ammonia solution, potassium hydroxide, and Black Iron Oxide.

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.

There are no specific teratogenic or nonteratogenic effects associated with the use of temozolomide as noted in the available data.

Dosage and Administration

The medication is administered orally.

For patients with newly diagnosed glioblastoma, the recommended dosing regimen is 75 mg/m² once daily for 42 days, administered concomitantly with focal radiotherapy. Following this initial phase, the maintenance dose is 150 mg/m² once daily 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 through 6. It is essential to provide prophylaxis for Pneumocystis pneumonia (PCP) during the concomitant treatment phase and to continue this prophylaxis in patients who develop lymphopenia until the condition resolves to grade 1 or less.

For patients with refractory anaplastic astrocytoma, the initial dosing is set at 150 mg/m² once daily for 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 risk associated with the use of Temozolomide capsules, USP. Healthcare professionals are advised to closely 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.

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

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

Hepatotoxicity is a critical risk, with reports of both fatal and severe liver damage. Baseline liver function tests should be conducted, with subsequent evaluations performed midway through the first treatment cycle, prior to each subsequent cycle, and approximately 2 to 4 weeks after the final dose of Temozolomide capsules, USP.

Embryo-fetal toxicity is a notable risk associated with this medication. Female patients of reproductive potential should be informed of the potential for fetal harm 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 potential exposure.

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

Side Effects

Patients receiving treatment with Temozolomide capsules, USP, may experience a range of adverse reactions. Common adverse reactions occurring in 20% or more of participants include alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, and convulsions.

Serious adverse reactions include hematologic laboratory abnormalities, with Grade 3 to 4 incidences of decreased lymphocytes, decreased platelets, decreased neutrophils, and decreased leukocytes observed in 10% or more of subjects. Myelosuppression is a significant concern, necessitating 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.

Additionally, there have been reports of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, in patients undergoing treatment. Pneumocystis pneumonia (PCP) is another serious risk, particularly in patients receiving steroids; therefore, close monitoring for lymphopenia and PCP is advised.

Hepatotoxicity, which can be fatal or severe, has also 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 capsules.

Temozolomide is associated with embryo-fetal toxicity, and it is crucial to inform females of reproductive potential about the potential 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.

A history of hypersensitivity to temozolomide or any other ingredients in Temozolomide capsules, USP, and dacarbazine is also noted as a relevant consideration. Dose-limiting toxicity primarily manifests as myelosuppression, which can occur at any dose but is expected to be more severe at higher doses. An overdose of 2000 mg per day for 5 days resulted in severe adverse reactions, including pancytopenia, pyrexia, multi-organ failure, and death. There are also reports of patients who have undergone treatment for more than 5 days (up to 64 days), experiencing severe and prolonged myelosuppression, infections, and in some cases, resulting in death.

Drug Interactions

Administration of Temozolomide capsules, USP, has been evaluated for potential drug interactions, with the following observations noted:

Pharmacokinetic Interactions:

• The coadministration of ranitidine does not affect the clearance (C) or area under the curve (AUC) values for temozolomide or its active metabolite, MTIC.

• Valproic acid has been shown to decrease the clearance of temozolomide by approximately 5%. Clinicians should consider this interaction when prescribing these medications together, although no specific dosage adjustment is mandated.

• No significant influence on the clearance of orally administered Temozolomide capsules, USP, 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. Geriatric patients and women are at an increased risk for developing these adverse effects.

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

Monitoring Recommendations:

• A complete blood count (CBC) should be obtained prior to treatment initiation and monitored weekly during the course of therapy to detect any signs of myelosuppression.

• Liver function tests should be performed 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 and monitor for potential hepatotoxicity.

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

Pregnancy

Temozolomide can cause fetal harm when administered to pregnant patients, as indicated by its mechanism of action and findings from animal studies. Available postmarketing reports have documented cases of spontaneous abortions and congenital malformations, including polymalformations affecting the central nervous system, facial structures, cardiac system, skeletal system, and genitourinary system in women exposed 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 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 evidenced by a higher incidence of 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 and counseling are warranted for women of childbearing potential who may be exposed to this medication.

Lactation

There is no information available regarding the use of this medication in nursing mothers or its effects on lactation. Consequently, the safety and efficacy of this drug in lactating mothers and its potential impact on breastfed infants remain undetermined. Healthcare professionals should exercise caution and consider the lack of data when prescribing this medication to lactating mothers.

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 an increased risk of hepatotoxicity, including fatal and severe liver damage. 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 capsules, USP.

Monitoring liver function closely is critical to ensure patient safety and to manage any potential adverse effects related to liver function during the course of treatment. Adjustments to dosing or treatment regimens may be necessary based on the results of these liver tests and the overall clinical status of the patient.

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 scenario involving a patient who ingested 2000 mg per day for a duration of 5 days. This patient experienced severe adverse reactions, including pancytopenia, pyrexia, multi-organ failure, and ultimately, death. Additionally, there have been reports of patients exceeding the recommended treatment duration, with some receiving therapy for as long as 64 days. These patients exhibited adverse reactions such as myelosuppression, which was noted to be severe and prolonged in certain instances, leading to infections and fatalities.

In the event of an overdose, it is crucial to monitor the complete blood count closely. Supportive measures should be implemented as necessary to manage the patient's condition effectively.

Nonclinical Toxicology

Temozolomide has been shown to be carcinogenic in rats at doses less than the maximum recommended human dose. In studies, temozolomide 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, the compound induced 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 of 0.5 times the maximum daily dose. Mammary tumors were also observed following 3 cycles of temozolomide 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.

The compound has been shown to impair male fertility. In studies involving rats and dogs, temozolomide 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), respectively, and resulted in testicular atrophy in dogs at the 125 mg/m² 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 ocular changes were most frequently observed at doses associated with mortality.

Postmarketing Experience

No specific postmarketing experience details have been reported. As such, there are no additional adverse events or rare case reports to summarize at this time.

Patient Counseling

Healthcare providers should advise patients to read the FDA-approved patient labeling (Patient Information) to ensure they are well-informed about the medication. 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 instructed to reach out to their healthcare provider promptly if they develop new or worsening pulmonary symptoms. It may be necessary for patients to receive prophylaxis for Pneumocystis pneumonia.

Healthcare providers should also discuss the risk of hepatotoxicity with patients, advising them to seek immediate medical attention if they notice any signs or symptoms indicative of liver damage. Patients must be cautioned against opening capsules, and if a capsule is accidentally opened or damaged, they should take rigorous precautions to avoid inhalation or contact with the skin or mucous membranes. In the event of powder contact, patients should wash their hands thoroughly.

Pregnant women and females of reproductive potential should be informed about the potential risks to a fetus and should notify their healthcare provider if they know or suspect they are pregnant. Females of reproductive potential should be advised 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 counseled to use condoms during treatment and for at least 3 months after the final dose. They should also be advised against donating semen during treatment and for at least 3 months post-treatment. Furthermore, women should be instructed not to breastfeed during treatment with Temozolomide and for at least 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 capsules, USP are supplied in a configuration that adheres to the National Drug Code (NDC) standards. These capsules 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.

It is essential to follow all applicable special handling and disposal procedures to ensure safety and compliance.

Additional Clinical Information

Patients should be advised to read the FDA-approved patient labeling for Temozolomide. Clinicians should inform patients about the potential for myelosuppression, which may lead to low blood cell counts, necessitating regular monitoring. Patients must be instructed to contact their healthcare provider immediately if they experience bleeding, fever, or other signs of infection. Additionally, there is an increased risk of myelodysplastic syndrome and secondary malignancies, as well as Pneumocystis pneumonia; patients should report any new or worsening pulmonary symptoms and may require prophylaxis for Pneumocystis pneumonia.

Patients should also be made aware of the risk of hepatotoxicity and should seek immediate medical attention for any signs or symptoms. It is crucial to instruct patients not to open the capsules, and if they are damaged, to take precautions to avoid inhalation or skin contact with the contents. Pregnant women and females of reproductive potential should be informed of the embryo-fetal toxicity risk and advised to use effective contraception during treatment and for a specified period afterward. Male patients should use condoms and refrain from donating semen during and after treatment. Women are advised against breastfeeding during treatment and for at least one week following the last dose. Lastly, males of reproductive potential should be cautioned that Temozolomide may impair fertility.

FDA Insert (PDF)

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

View full prescribing information (PDF)