Temozolomide

Description

Temozolomide capsules contain temozolomide, an imidazotetrazine derivative with the chemical name 3,4-dihydro-3-methyl-4-oxoimidazo5,1-as-tetrazine-8-carboxamide. The molecular formula is C6H6N6O2, and the molecular weight is 194.15. The active ingredient is a white to light tan/light pink powder that is stable at acidic pH (less than 5) and labile at pH greater than 7, allowing for both oral and intravenous administration. Temozolomide acts as a prodrug, rapidly hydrolyzing 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.

Each capsule is available in various strengths, containing either 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, or 250 mg of temozolomide. The inactive ingredients include mannitol, croscarmellose sodium, stearic acid, citric acid anhydrous, colloidal silicon dioxide, and sodium lauryl sulfate. The capsule body is made of opaque white gelatin, while the cap is also gelatin-based, with colors varying according to dosage strength. The capsule body and cap are imprinted with pharmaceutical branding ink, which includes shellac glaze in ethanol, iron oxide black, n-butyl alcohol, propylene glycol, ethanol, methanol, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, and D&C Yellow No. 10 Aluminum Lake.

Specific cap colors for each dosage strength are as follows: the 5 mg capsule has an olive cap containing gelatin, titanium dioxide, yellow iron oxide, black iron oxide, and FD&C Blue No. 1; the 20 mg capsule has an orange cap with gelatin, titanium dioxide, yellow iron oxide, and red iron oxide; the 100 mg capsule features a flesh cap with gelatin, titanium dioxide, and FD&C Red No. 40; the 140 mg capsule has an aqua blue cap containing gelatin, titanium dioxide, and FD&C Blue No. 1; the 180 mg capsule is characterized by a swedish orange cap with gelatin, titanium dioxide, FD&C Red No. 40, and FD&C Blue No. 1; and the 250 mg capsule has a white cap made of gelatin and titanium dioxide.

Uses and Indications

Temozolomide is indicated for the treatment of adult patients with newly diagnosed glioblastoma multiforme (GBM) in conjunction with radiotherapy, followed by maintenance treatment. Additionally, it 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 mentioned in the available data.

Dosage and Administration

For patients with newly diagnosed glioblastoma multiforme (GBM), the recommended dosage is 75 mg/m² administered daily for 42 days in conjunction with focal radiotherapy. Following this initial treatment phase, an initial maintenance dose of 150 mg/m² should be given once daily for Days 1-5 of a 28-day cycle of temozolomide, continuing for a total of 6 cycles.

In the case of refractory anaplastic astrocytoma, the initial dosage is 150 mg/m² administered once daily for 5 consecutive days within each 28-day treatment cycle.

Healthcare professionals should ensure proper calculation of the dosage based on the patient's body surface area and monitor for any potential adverse effects throughout the treatment regimen.

Contraindications

Use of this product is contraindicated in patients with known hypersensitivity to any component of temozolomide or to dacarbazine (DTIC). This contraindication is based on the potential for severe allergic reactions in susceptible individuals.

Warnings and Precautions

Myelosuppression is a significant concern associated with the use of temozolomide. Healthcare professionals are advised to monitor the Absolute Neutrophil Count (ANC) and platelet count prior to dosing and throughout the treatment course. It is important to note that geriatric patients and women are at an increased risk of developing myelosuppression. Additionally, there have been reports of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, in patients receiving this treatment.

Pneumocystis pneumonia (PCP) prophylaxis is mandatory for all patients undergoing concomitant temozolomide and radiotherapy as part of the 42-day regimen for the treatment of newly diagnosed glioblastoma multiforme. All patients, especially those receiving corticosteroids, should be closely monitored for the development of lymphopenia and PCP. Complete blood counts must be obtained throughout the treatment course as specified to ensure patient safety.

Hepatotoxicity is another critical risk associated with temozolomide, with reports of both fatal and severe cases. Liver function tests should be performed at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately two to four weeks after the last dose of temozolomide to monitor for potential liver damage.

It is essential to inform women of childbearing potential that fetal harm may occur if temozolomide is administered during pregnancy. Women should be counseled to avoid becoming pregnant while receiving this medication.

Furthermore, it is important to adhere to the established infusion protocol, as bioequivalence has only been confirmed when temozolomide is administered over a 90-minute period. Infusion over a shorter or longer duration may lead to suboptimal dosing and could increase the risk of infusion-related adverse reactions.

Side Effects

Patients receiving temozolomide may experience a range of adverse reactions. Common adverse reactions, occurring in 10% or more of participants, include alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, convulsions, rash, hemiparesis, diarrhea, asthenia, fever, dizziness, coordination abnormalities, viral infections, amnesia, and insomnia.

Serious adverse reactions include myelosuppression, which necessitates monitoring of Absolute Neutrophil Count (ANC) and platelet count prior to dosing and throughout treatment. Geriatric patients and women are at an increased risk for developing myelosuppression. Common Grade 3 to 4 hematologic laboratory abnormalities observed in 10% or more of subjects include lymphopenia, thrombocytopenia, neutropenia, and leukopenia.

Additionally, cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been reported. Patients receiving concomitant temozolomide and radiotherapy for the treatment of newly diagnosed glioblastoma multiforme are required to have prophylaxis for Pneumocystis pneumonia (PCP). All patients, particularly those on steroids, should be closely monitored for the development of lymphopenia and PCP.

Hepatotoxicity, which can be fatal or severe, has also been reported. It is recommended to perform liver function tests at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately two to four weeks after the last dose of temozolomide.

Fetal harm may occur if temozolomide is administered to a pregnant woman; therefore, women should be advised to avoid becoming pregnant during treatment.

In cases of overdosage, adverse reactions may include pancytopenia, pyrexia, multi-organ failure, death, severe and prolonged bone marrow suppression, and infections leading to death. Known hypersensitivity to any component of temozolomide or to dacarbazine (DTIC) has also been documented. Allergic reactions have been reported in some patients.

Drug Interactions

The interaction between valproic acid and temozolomide is characterized as a pharmacokinetic interaction. Valproic acid has been shown to decrease the oral clearance of temozolomide.

Clinicians should consider monitoring temozolomide levels and adjusting the dosage accordingly to avoid potential toxicity, particularly in patients receiving both medications concurrently.

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

Safety and effectiveness of temozolomide in pediatric patients have not been established. The drug has been evaluated in two open-label studies involving pediatric patients aged 3 to 18 years, administered at doses ranging from 160 to 200 mg/m² daily for 5 days every 28 days.

In the first study, 29 patients with recurrent brain stem glioma and 34 patients with recurrent high-grade astrocytoma were enrolled. All participants had experienced recurrence following surgery and radiation therapy, with 31% also having disease progression after chemotherapy.

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 toxicity profile of temozolomide in pediatric patients appears to be similar to that observed in adults.

Geriatric Use

Clinical studies of temozolomide did not include a sufficient number of subjects aged 65 and over to determine whether they respond differently from younger patients. However, other reported clinical experiences have not identified significant differences in responses between elderly patients and their younger counterparts.

In general, dose selection for geriatric patients should be approached with caution. This is due to the increased likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies that may affect treatment outcomes.

In a study involving patients with anaplastic astrocytoma, those aged 70 years and older exhibited a higher incidence of Grade 4 neutropenia and Grade 4 thrombocytopenia during the first cycle of therapy, with rates of 25% and 20%, respectively. These findings suggest that elderly patients may be at an increased risk for severe hematologic adverse effects.

Conversely, in newly diagnosed patients with glioblastoma multiforme, the adverse reaction profile was found to be similar between younger patients (less than 65 years) and older patients (65 years and older). This indicates that while caution is warranted in dose selection and monitoring for elderly patients, their overall response to treatment may not differ significantly from that of younger patients in this specific context.

Pregnancy

Temozolomide is classified as Pregnancy Category D, indicating that there is positive evidence of risk to the fetus based on human data. Administration of temozolomide to pregnant patients can result in fetal harm. Animal studies have demonstrated that oral administration of temozolomide at doses of 0.38 and 0.75 times the highest recommended human dose (75 and 150 mg/m²) during the organogenesis period led to significant malformations of both external and internal soft tissues and skeletal structures in rats and rabbits. Furthermore, doses equivalent to 0.75 times the highest recommended human dose (150 mg/m²) were associated with increased embryolethality, as evidenced by a rise in resorptions in these animal models.

Due to the lack of adequate and well-controlled studies in pregnant women, the potential risks associated with temozolomide use during pregnancy remain uncertain. Healthcare providers should counsel pregnant patients or those who may become pregnant about the potential hazards to the fetus if temozolomide is administered during pregnancy or if pregnancy occurs while on this medication. Women of childbearing potential are advised to avoid becoming pregnant during treatment with temozolomide.

Lactation

It is not known whether this drug is excreted in human milk. Due to the potential for serious adverse reactions in nursing infants and the tumorigenicity demonstrated for temozolomide in animal studies, lactating mothers should make a decision regarding the continuation of breastfeeding or the discontinuation of the drug. This decision should consider the importance of temozolomide to the mother’s health.

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 two to four weeks after the last dose of temozolomide. Monitoring liver function closely is critical to ensure patient safety and to manage any potential adverse effects related to compromised liver function.

Overdosage

In clinical evaluations, doses of 500, 750, 1000, and 1250 mg/m² administered over a 5-day cycle have been assessed in patients. Dose-limiting toxicity primarily manifests as hematologic complications, which can occur at any dosage but are anticipated to be more pronounced at elevated doses.

A specific case of overdose involved a patient who ingested 2000 mg per day for 5 consecutive 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 up to 64 days. These cases have been associated with significant adverse effects, notably severe and prolonged bone marrow suppression, as well as infections that have led to fatal outcomes.

In the event of an overdose, it is imperative to conduct a thorough hematologic evaluation to assess the extent of toxicity. Supportive measures should be implemented as necessary to manage symptoms and complications arising from the overdose.

Nonclinical Toxicology

Temozolomide has been shown to be carcinogenic in rats at doses less than the maximum recommended human dose. Specifically, 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 found to induce 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 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 demonstrated clastogenic effects in human lymphocytes under both conditions of metabolic activation.

Impairment of male fertility has been noted with temozolomide. In studies involving rats and dogs, the drug caused the formation of syncytial cells and immature sperm at doses of 0.25 and 0.63 times the maximum recommended human dose (50 and 125 mg/m², respectively). Testicular atrophy was also observed in dogs at the higher dose of 0.63 times the maximum recommended human dose (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 0.63 times the maximum recommended human dose (125 mg/m²). These retinal changes were most frequently observed at doses associated with mortality.

Postmarketing Experience

Nausea and vomiting are the most frequently reported adverse reactions associated with temozolomide, typically self-limiting or manageable with standard antiemetic therapy. Decreased blood cell counts have been observed, particularly affecting rapidly growing cells such as those in the bone marrow. Monitoring of blood cell levels is recommended, as reductions in white blood cells, including neutrophils and lymphocytes, can increase the risk of serious infections. Low platelet counts may also occur, which can lead to bleeding; patients are advised to report any unusual bruising or bleeding to their healthcare provider.

Patients aged 70 years or older and women may be at a higher risk for blood cell count alterations. Pneumocystis pneumonia (PCP), an infection that can arise in immunocompromised individuals, has been reported in patients receiving temozolomide. Vigilant monitoring for signs and symptoms of PCP, such as shortness of breath, fever, chills, and dry cough, is essential, especially in patients concurrently using steroids.

There have been reports of secondary cancers, including myelodysplastic syndrome and certain types of leukemia, in individuals treated with temozolomide. Additionally, convulsions, which may be severe or life-threatening, have been documented. Rare instances of liver side effects have also been reported, with some cases resulting in death.

Common side effects include nausea and vomiting, headache, fatigue, loss of appetite, hair loss, constipation, bruising, rash, unilateral paralysis, diarrhea, weakness, fever, dizziness, coordination difficulties, viral infections, sleep disturbances, memory loss, pain, and localized irritation or swelling at the infusion site, as well as bruising or petechiae. Regular blood monitoring is advised to detect these potential side effects early.

Patient Counseling

Healthcare providers should advise patients that nausea and vomiting are the most frequently occurring adverse reactions associated with temozolomide. These symptoms are typically self-limiting or can be effectively managed with standard antiemetic therapy.

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 occurs, patients should flush the affected area with water.

It is essential to keep the medication out of reach of children and pets. Additionally, healthcare providers should inform patients that temozolomide may cause birth defects. Both male and female patients taking temozolomide capsules should utilize effective birth control methods. Female patients and female partners of male patients should avoid becoming pregnant during treatment.

Patients should be encouraged to disclose all medical conditions to their healthcare provider, particularly if they have a history of allergies to dacarbazine (DTIC) or severe allergic reactions to temozolomide, as well as any kidney or liver problems. Pregnant or breastfeeding patients should discuss their situation with their doctor, as it is not known whether temozolomide passes into breast milk.

Patients should maintain an updated list of all medications they are taking and present this list to their healthcare provider and pharmacist when receiving new prescriptions. It is crucial for patients to take temozolomide capsules exactly as prescribed, at the same time each day, with a full glass of water. Capsules should be swallowed whole and not chewed, opened, or split.

To minimize nausea, patients may be advised to take temozolomide on an empty stomach or at bedtime. Healthcare providers may prescribe additional medications to prevent or treat nausea or to alleviate other side effects associated with temozolomide.

Patients should be reminded to see their doctor regularly to monitor their progress and to check for any side effects that may not be immediately noticeable. If a dose of temozolomide is missed, patients should consult their healthcare provider for guidance on when to take the next dose.

In the case of vomiting after taking temozolomide capsules, patients should not take any additional capsules and should wait until the next scheduled dose. It is critical that patients do not exceed the prescribed amount of temozolomide; they should contact their doctor immediately if they suspect they have taken more than the recommended dose.

Storage and Handling

Temozolomide capsules are supplied in various package configurations, with specific NDC numbers available for identification. These capsules should be stored at a controlled room temperature of 25°C (77°F), with permissible excursions between 15-30°C (59-86°F) in accordance with USP guidelines.

Care must be taken during the handling and preparation of temozolomide capsules. It is imperative that the capsules remain unopened. In the event that a capsule is accidentally opened or damaged, stringent precautions should be implemented to prevent inhalation or contact with the contents, which may pose a risk to skin or mucous membranes. The use of gloves and safety glasses is strongly recommended to minimize exposure in case of breakage. Additionally, healthcare professionals should adhere to established procedures for the proper handling and disposal of anticancer drugs to ensure safety.

Additional Clinical Information

Prior to the initiation of treatment, clinicians should obtain a complete blood count (CBC) for patients, which must be monitored weekly during the concomitant treatment phase with radiotherapy (RT). For patients undergoing 28-day treatment cycles, a CBC is required on Day 1 and again on Day 22 of each cycle, which is 21 days after the first dose. 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, blood counts should be performed weekly until recovery is achieved.

It is important to note that the route, method, and frequency of administration can affect dosing efficacy; infusing the treatment over a shorter or longer period may lead to suboptimal dosing outcomes.

FDA Insert (PDF)

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

View full prescribing information (PDF)