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. 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 dosages 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 132.8 mg of lactose anhydrous, 0.2 mg of colloidal silicon dioxide, 7.5 mg of sodium starch glycolate, 1.5 mg of tartaric acid, and 3 mg of stearic acid. The 20 mg capsule contains 182.2 mg of lactose anhydrous, 0.2 mg of colloidal silicon dioxide, 11 mg of sodium starch glycolate, 2.2 mg of tartaric acid, and 4.4 mg of stearic acid. The 100 mg capsule includes 175.7 mg of lactose anhydrous, 0.3 mg of colloidal silicon dioxide, 15 mg of sodium starch glycolate, 3 mg of tartaric acid, and 6 mg of stearic acid. The 140 mg capsule has 246 mg of lactose anhydrous, 0.4 mg of colloidal silicon dioxide, 21 mg of sodium starch glycolate, 4.2 mg of tartaric acid, and 8.4 mg of stearic acid. The 180 mg capsule contains 316.3 mg of lactose anhydrous, 0.5 mg of colloidal silicon dioxide, 27 mg of sodium starch glycolate, 5.2 mg of tartaric acid, and 10.8 mg of stearic acid. The 250 mg capsule includes 154.3 mg of lactose anhydrous, 0.7 mg of colloidal silicon dioxide, 22.5 mg of sodium starch glycolate, 9 mg of tartaric acid, and 13.5 mg of stearic acid.

The capsule body is made of opaque white gelatin, while the cap color varies according to the dosage strength. The capsule body is imprinted with pharmaceutical branding ink, which contains shellac, propylene glycol, strong ammonia solution, potassium hydroxide, and black iron oxide. The 5 mg capsule features a green cap composed of gelatin, titanium dioxide, iron oxide yellow, and FD&C Blue #2. The 20 mg capsule has a yellow cap made of gelatin, titanium dioxide, and iron oxide yellow. The 100 mg capsule is identified by a pink cap containing gelatin, titanium dioxide, and iron oxide red. The 140 mg capsule has a blue cap made of gelatin, titanium dioxide, and FD&C Blue #2. The 180 mg capsule features an orange cap composed of gelatin, iron oxide red, and titanium dioxide. The 250 mg capsule is marked by a white cap made of gelatin and titanium dioxide. It is important to note that FDA-approved dissolution test specifications differ from those of the USP.

Uses and Indications

Temozolomide Capsules USP is indicated for the treatment of adults with newly diagnosed glioblastoma, to be administered concomitantly with radiotherapy followed by maintenance treatment. Additionally, it is indicated for the adjuvant treatment of adults with newly diagnosed anaplastic astrocytoma, as well as for the treatment of adults with refractory anaplastic astrocytoma.

There are no teratogenic or nonteratogenic effects associated with the use of Temozolomide Capsules USP.

Dosage and Administration

For newly diagnosed glioblastoma, the recommended 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, the maintenance dose should be initiated at 150 mg/m² once daily for Days 1 to 5 of each 28-day cycle, continuing for a total of 6 cycles. Based on patient tolerance and observed toxicity, the maintenance dose may be escalated to 200 mg/m² for cycles 2 through 6.

In the case of adjuvant treatment for newly diagnosed anaplastic astrocytoma, Temozolomide Capsules USP 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 increased 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, taken 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 serious hypersensitivity to temozolomide or any other ingredients in 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 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 Capsules USP.

Patients should be closely monitored for Pneumocystis pneumonia (PCP), particularly those receiving concurrent steroid therapy. Vigilance for the development of lymphopenia and PCP is essential in this population.

The potential for secondary malignancies, including myelodysplastic syndrome and myeloid leukemia, has been observed in patients receiving this treatment. This risk should be communicated to patients as part of their treatment plan.

Embryo-fetal toxicity is a significant concern; Temozolomide Capsules USP can cause fetal harm. Female patients of reproductive potential should be informed of the risks to a fetus and advised to use effective contraception. Male patients with partners who are pregnant or of reproductive potential should be instructed to use condoms to prevent exposure.

It is imperative that Temozolomide Capsules USP are not opened, chewed, or dissolved. They should be swallowed whole with a full glass of water to ensure proper delivery of the medication and to minimize exposure to the active ingredient.

In summary, regular monitoring of ANC, platelet counts, and liver function tests is essential for the safe administration of Temozolomide Capsules USP, alongside careful consideration of the associated risks of myelosuppression, hepatotoxicity, PCP, secondary malignancies, and embryo-fetal toxicity.

Side Effects

Patients receiving Temozolomide Capsules USP 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 are generally manageable but should be monitored throughout treatment.

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.

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; 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 of reproductive potential should also be counseled to use condoms.

Additional important notes include a history of serious hypersensitivity to Temozolomide or its components, as well as dose-limiting toxicity primarily due to 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 has been reported, resulting in severe adverse reactions such as pancytopenia, pyrexia, multi-organ failure, and death. There are also reports of patients undergoing prolonged treatment (up to 64 days) experiencing severe and prolonged myelosuppression, infections, and fatalities.

Temozolomide has been shown to be carcinogenic in animal studies at doses lower than the maximum recommended human dose, inducing mammary carcinomas and fibrosarcomas. Furthermore, it is classified as a mutagen and clastogen, with evidence of impaired male fertility observed in animal studies, including syncytial cell formation, immature sperm, and testicular atrophy.

Patients should be advised that Temozolomide Capsules USP should not be opened, chewed, or dissolved, but rather swallowed whole with a glass of water to ensure proper administration.

Drug Interactions

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

For patients undergoing treatment with temozolomide, it is essential to monitor hematological parameters closely. A complete blood count (CBC) should be obtained prior to the initiation of treatment and weekly during the course of therapy, particularly for those receiving concomitant radiotherapy. In the context of 28-day treatment cycles, a CBC is required on Day 1 and Day 22 of each cycle. If the absolute neutrophil count (ANC) falls below 1.5 x 10^9/L or the platelet count drops below 100 x 10^9/L, weekly CBCs should continue 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 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: 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. 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-7365-0006 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 effectiveness differences in 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 incidence rates were 7% (62/871) for Grade 4 neutropenia and 6% (48/879) for Grade 4 thrombocytopenia during the same period. Additional hematologic events, including pancytopenia, leukopenia, and anemia, were also reported.

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

Pregnancy

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

In animal studies, the 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 increased embryolethality, as indicated by a higher rate 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 should be given to the use of Temozolomide in pregnant patients.

Lactation

There are no data on the presence of Temozolomide or its metabolites in human milk, nor are there any known effects on a breastfed child or on milk production. Due to the potential for serious adverse reactions, including myelosuppression in breastfed infants, lactating mothers are advised not to breastfeed during treatment with Temozolomide and for 1 week after the final dose.

Renal Impairment

Patients with renal impairment should be monitored closely, particularly those with severe renal impairment or end-stage disease. No dosage adjustment is recommended for patients with a creatinine clearance (CLcr) of 36 to 130 mL/min/m². However, the recommended dose of Temozolomide has not been established for patients with severe renal impairment (CLcr <36 mL/min/m²) or for those on dialysis. Caution is advised in this population, and clinical judgment should guide treatment decisions.

Hepatic Impairment

Patients with mild to moderate hepatic impairment (Child Pugh class A and B) do not require any dosage adjustment when receiving Temozolomide. However, the recommended dose for patients with severe hepatic impairment (Child Pugh class C) has not been established.

It is important to note that fatal and severe hepatotoxicity have been reported in some cases. Therefore, liver function tests should be conducted 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. Regular monitoring of liver function is essential to ensure patient safety and to manage any potential adverse effects related to hepatic impairment.

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 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 instances of patients exceeding the recommended treatment duration, with some receiving therapy for as long as 64 days. These cases have similarly reported severe and prolonged myelosuppression, alongside infections, which have also resulted in fatal outcomes.

In the event of an overdose, it is imperative 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 impair male fertility, as evidenced by 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 both rats and dogs. Additionally, testicular atrophy was observed in dogs at the higher dose of 125 mg/m².

In terms of carcinogenicity, temozolomide is classified as carcinogenic in rats at doses below the maximum recommended human dose. 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 six cycles, with five consecutive days of treatment every 28 days. Furthermore, 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 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. Notably, mammary tumors were also induced following three cycles of treatment at the maximum recommended daily dose.

Temozolomide is identified as a mutagen and clastogen. In a reverse bacterial mutagenesis assay (Ames assay), it increased revertant frequency both in the presence and absence of metabolic activation. Additionally, temozolomide was found to be clastogenic in human lymphocytes, again in both the presence and absence of metabolic activation.

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

Postmarketing experience has identified cases of myelosuppression, hepatotoxicity, Pneumocystis pneumonia, and secondary malignancies. Additionally, there is an observed increased risk of myelodysplastic syndrome and secondary malignancies associated with Temozolomide. These events have been reported voluntarily or through surveillance programs, contributing to the understanding of the drug's safety profile.

Patient Counseling

Patients should be advised 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.

Healthcare providers should also inform patients about the increased risk of hepatotoxicity associated with Temozolomide. Patients must be made aware of the symptoms of hepatotoxicity and should be advised to reach out to their healthcare provider without delay if they notice any such signs. Additionally, patients will undergo periodic liver enzyme tests during treatment and after the last dose of Temozolomide.

Patients should be counseled on the heightened risk of Pneumocystis pneumonia and instructed to contact their healthcare provider immediately if they develop new or worsening pulmonary symptoms. It may be necessary for patients to receive prophylaxis for Pneumocystis pneumonia.

It is essential to inform patients about the increased risk of myelodysplastic syndrome and secondary malignancies associated with Temozolomide. Patients should also be advised not to open, chew, or dissolve the capsules. In the event that capsules are accidentally opened or damaged, patients must 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 of 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 six 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 three months after the last dose. Additionally, male patients should be instructed not to donate semen during treatment and for three months following the last dose.

Storage and Handling

Temozolomide capsules USP 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° to 30°C (59° to 86°F).

Due to the hazardous nature of Temozolomide, it is essential to adhere to applicable special handling and disposal procedures to ensure safety during use and management of the product.

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 Areva Pharmaceuticals. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)