Temodar

Description

Temozolomide is an alkylating drug 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 g/mol. The substance appears as a white to light tan or light pink powder. Temozolomide is stable at acidic pH (<5) and labile at pH >7.

TEMODAR capsules for oral use are available in strengths of 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, and 250 mg of temozolomide. The inactive ingredients vary by strength: the 5 mg capsules contain 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 capsules contain 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 capsules contain 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 capsules contain 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 capsules contain 316.3 mg of lactose anhydrous, 0.5 mg of colloidal silicon dioxide, 27 mg of sodium starch glycolate, 5.4 mg of tartaric acid, and 10.8 mg of stearic acid; and the 250 mg capsules contain 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 body of the capsules is made of opaque white gelatin, and the cap is also made of gelatin, with colors varying based on dosage strength.

TEMODAR for injection is intended for intravenous use and contains 100 mg of sterile and pyrogen-free lyophilized powder. The inactive ingredients in the injection formulation include 600 mg of mannitol, 160 mg of L-threonine, 120 mg of polysorbate 80, 235 mg of sodium citrate dihydrate, and 160 mg of hydrochloric acid.

Uses and Indications

TEMODAR is indicated for the treatment of adults with newly diagnosed glioblastoma, to be administered concomitantly with radiotherapy followed by maintenance treatment. Additionally, TEMODAR 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 specific teratogenic or nonteratogenic effects mentioned in the available data.

Dosage and Administration

TEMODAR may be administered either orally or intravenously, depending on the clinical scenario.

For patients with Newly Diagnosed Glioblastoma, the recommended dosing regimen is as follows: Administer 75 mg/m² once daily for a duration of 42 to 49 days in conjunction with focal radiotherapy. Following this initial phase, an initial maintenance dose of 150 mg/m² once daily should be given for Days 1 to 5 of each 28-day cycle for a total of 6 cycles. Based on the patient's tolerance and observed toxicity, the maintenance dose may be escalated to 200 mg/m² for Cycles 2 through 6. It is essential to provide Pneumocystis pneumonia (PCP) prophylaxis during the concomitant phase and to continue this prophylaxis in patients who develop lymphopenia until their condition resolves to Grade 1 or less.

For the Adjuvant Treatment of Newly Diagnosed Anaplastic Astrocytoma, TEMODAR should be initiated 4 weeks after the completion of radiotherapy. The dosing schedule consists of administering TEMODAR orally in a single dose on Days 1 to 5 of a 28-day cycle for a total of 12 cycles. The recommended dosage for Cycle 1 is 150 mg/m² per day. For Cycles 2 to 12, the dosage may be increased to 200 mg/m² per day, provided the patient has experienced no or minimal toxicity during Cycle 1.

In the case of Refractory Anaplastic Astrocytoma, the initial dosing regimen consists of 150 mg/m² once daily on Days 1 to 5 of each 28-day cycle.

Contraindications

Use of TEMODAR is contraindicated in patients with a history of serious 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 TEMODAR. 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 both 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 TEMODAR to ensure patient safety.

Patients should be closely monitored for Pneumocystis pneumonia (PCP), particularly those receiving corticosteroids, as they may be at higher risk for developing lymphopenia and subsequent PCP.

The potential for secondary malignancies, including myelodysplastic syndrome and myeloid leukemia, has been observed in patients receiving TEMODAR. This necessitates careful consideration and monitoring throughout treatment.

Embryo-fetal toxicity is a significant risk associated with TEMODAR. Female patients of reproductive potential should be informed of the potential risks to a fetus and advised to utilize effective contraception. Male patients with partners who are pregnant or of reproductive potential should be instructed to use condoms to prevent exposure.

It is imperative that TEMODAR capsules remain intact; they should not be opened, chewed, or dissolved. Patients should be instructed to swallow the capsules whole with a full glass of water to ensure proper administration and minimize risk.

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

Side Effects

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

Common adverse reactions occurring in 20% or more of patients include alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, and convulsions. Among these, fatigue is reported in 54% of patients with newly diagnosed glioblastoma, while convulsions occur in 6% of this population. In patients with refractory anaplastic astrocytoma, nausea (53%), vomiting (42%), and headache (41%) are also prevalent.

Severe or life-threatening adverse reactions have been noted, including fatigue (13%), convulsions (6%), headache (5%), and thrombocytopenia (5%). In clinical trials, thrombocytopenia has been observed in patients, necessitating careful monitoring of blood counts.

In patients with newly diagnosed glioblastoma, additional adverse reactions occurring at a frequency of 10% or greater include skin reactions such as alopecia (69%) and rash (19%), as well as gastrointestinal symptoms like nausea (36%) and vomiting (20%). Participants also reported anorexia (19%) and headache (19%). For those with refractory anaplastic astrocytoma, gastrointestinal symptoms such as constipation (33%) and diarrhea (16%) were also significant, alongside central nervous system effects like convulsions (23%) and dizziness (12%).

Clinically relevant adverse reactions occurring in less than 10% of patients include memory impairment, confusion, blurred vision, stomatitis, abdominal pain, weakness, dizziness, allergic reactions, and various skin reactions such as dry skin and pruritus.

Postmarketing experiences have revealed serious dermatologic reactions, including toxic epidermal necrolysis and Stevens-Johnson syndrome. Immune system reactions such as hypersensitivity, including anaphylaxis and erythema multiforme, have also been reported. Hematopoietic complications, including prolonged pancytopenia that may lead to aplastic anemia, have been observed, as well as severe hepatotoxicity characterized by elevated liver enzymes and hyperbilirubinemia.

Patients are at risk for serious opportunistic infections, including bacterial, viral, fungal, and protozoan infections, some of which have resulted in fatal outcomes. Pulmonary complications such as interstitial pneumonitis and pulmonary fibrosis have also been documented. Endocrine disorders, including diabetes insipidus, have been noted as well.

It is essential to monitor patients for myelosuppression, particularly in geriatric patients and women, who are at increased risk. Additionally, the potential for embryo-fetal toxicity necessitates advising females of reproductive potential to use effective contraception. Patients should be informed that TEMODAR capsules should not be opened, chewed, or dissolved, but should be swallowed whole with a glass of water to ensure proper administration.

Drug Interactions

There are currently no documented drug interactions associated with this medication. Additionally, there are no known interactions with laboratory tests. As such, no specific recommendations for dosage adjustments or monitoring are warranted at this time.

Packaging & NDC

The table below lists all NDC Code configurations of Temodar (temozolomide), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The safety and effectiveness of TEMODAR have not been established in pediatric patients. Two open-label studies assessed the safety and effectiveness of TEMODAR 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 conditions: 29 with medulloblastoma/PNET, 23 with high-grade astrocytoma, 22 with low-grade astrocytoma, 16 with brain stem glioma, 14 with ependymoma, 9 with other CNS tumors, and 9 with non-CNS tumors.

The adverse reaction profile observed in pediatric patients was similar to that seen in adults.

Geriatric Use

Elderly patients, defined as those aged 65 years and older, were represented by 15% of participants in the MK-7365-051 study involving newly diagnosed glioblastoma. However, this study did not include a sufficient number of patients aged 65 years and older to ascertain any differences in effectiveness compared to younger patients. Importantly, no overall differences in safety were observed between patients aged 65 years and older and their younger counterparts.

Similarly, the CATNON trial lacked adequate representation of patients aged 65 years and older, preventing any conclusions regarding differences in safety or effectiveness relative to younger patients.

In the MK-7365-006 study, which focused on patients with refractory anaplastic astrocytoma, only 4% of participants were aged 70 years and older. This study also did not provide enough data to determine effectiveness differences for this age group compared to younger patients. Notably, patients aged 70 years and older exhibited a higher incidence of Grade 4 neutropenia (25%) and Grade 4 thrombocytopenia (20%) during the first cycle of therapy compared to those younger than 70 years.

In the broader safety database, which included hematologic data from 932 patients, 7% (4 out of 61) of patients over 70 years experienced Grade 4 neutropenia, while 10% (6 out of 63) experienced Grade 4 thrombocytopenia in the first cycle. In contrast, for patients aged 70 years and younger, the rates were 7% (62 out of 871) for Grade 4 neutropenia and 6% (48 out of 879) for Grade 4 thrombocytopenia. Additionally, occurrences of pancytopenia, leukopenia, and anemia were noted.

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

Based on findings from animal studies and its mechanism of action, TEMODAR 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 TEMODAR during pregnancy. These cases report similar adverse developmental outcomes to those observed in animal studies.

Administration of TEMODAR to rats and rabbits during the period of organogenesis resulted in 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) in rats and rabbits, respectively, during the period of organogenesis (Gestation Days 8-12), caused significant malformations of the external and internal organs and skeleton in both species. In rabbits, temozolomide at the 150 mg/m² dose (0.75 times the human dose of 200 mg/m²) led to 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.

Lactation

There are no data on the presence of TEMODAR 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 TEMODAR and for 1 week after the last dose.

Renal Impairment

Patients with creatinine clearance (CLcr) of 36 to 130 mL/min/m² do not require dosage adjustments. However, the recommended dose of TEMODAR has not been established for patients with severe renal impairment (CLcr <36 mL/min/m²) or for those with end-stage renal disease on dialysis. It is important for healthcare professionals to monitor these patients closely due to the lack of established dosing guidelines in this population.

Hepatic Impairment

Patients with mild to moderate hepatic impairment (Child-Pugh class A and B) do not require any dosage adjustment for TEMODAR. 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 TEMODAR to monitor liver health and detect any potential adverse effects.

Overdosage

In cases of overdose, significant adverse reactions have been observed. An overdose of 2000 mg per day for a duration of 5 days has been associated with severe outcomes, including pancytopenia, pyrexia, multi-organ failure, and, in some instances, death.

Furthermore, patients who have extended their treatment beyond 5 days, with some receiving doses for up to 64 days, have reported experiencing severe and prolonged myelosuppression, increased susceptibility to infections, and mortality.

In the event of an overdose, it is crucial to monitor the complete blood count (CBC) closely. Supportive measures should be implemented as necessary to manage the symptoms and complications arising from the overdose. Healthcare professionals are advised to remain vigilant and provide appropriate care to mitigate the risks associated with 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 six cycles, with five consecutive days of treatment every 28 days. 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 three 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 noted with temozolomide. In studies involving rats and dogs, the drug 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. Testicular atrophy was also observed in dogs at the higher dose of 125 mg/m².

Toxicology studies conducted in rats and dogs revealed a low incidence of hemorrhage, degeneration, and necrosis of the retina at temozolomide doses equal to or greater than 125 mg/m² (0.63 times the human dose of 200 mg/m²). These retinal changes were most frequently observed at doses associated with mortality.

Postmarketing Experience

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

Dermatologic Reactions Cases of toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported.

Immune System Reactions Hypersensitivity reactions, including anaphylaxis, have been observed. Additionally, erythema multiforme was reported, which resolved after discontinuation of TEMODAR and, in some instances, recurred upon rechallenge.

Hematopoietic Reactions Prolonged pancytopenia has been noted, which may lead to aplastic anemia and potentially fatal outcomes.

Hepatobiliary Reactions Reports of severe and fatal hepatotoxicity have been documented, including elevation of liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis.

Infectious Complications Serious opportunistic infections have occurred, some with fatal outcomes, involving bacterial, viral (both primary and reactivated), fungal, and protozoan organisms.

Pulmonary Reactions Instances of interstitial pneumonitis, pneumonitis, alveolitis, and pulmonary fibrosis have been reported.

Endocrine Reactions Diabetes insipidus has been identified as a potential adverse reaction.

Patient Counseling

Patients should be advised to read the FDA-approved patient labeling (Patient Information) to understand the medication fully. It is important to inform patients that TEMODAR 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 also be made aware of the increased risk of hepatotoxicity associated with TEMODAR. They should be advised to report any signs or symptoms of hepatotoxicity to their healthcare provider without delay. Additionally, patients will undergo periodic liver enzyme tests during treatment and after the last dose of TEMODAR.

The risk of Pneumocystis pneumonia should be communicated to patients, along with the recommendation to seek immediate medical attention for any new or worsening pulmonary symptoms. Prophylaxis for Pneumocystis pneumonia may be necessary, and patients should be informed of this possibility.

Patients should be counseled about the increased risk of myelodysplastic syndrome and secondary malignancies associated with TEMODAR. They should also be instructed 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 risk 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 TEMODAR and for 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 with TEMODAR and for 3 months after the last dose. They should also be advised against donating semen during treatment and for 3 months following the last dose.

Women should be advised not to breastfeed during treatment with TEMODAR and for 1 week after the last dose. Lastly, males of reproductive potential should be informed that TEMODAR may impair fertility.

Storage and Handling

TEMODAR Capsules are supplied in a configuration that allows for convenient storage and handling. 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.

For TEMODAR for injection, it is essential to maintain refrigeration, storing the product at temperatures between 2°C to 8°C (36°F to 46°F).

As TEMODAR is classified as a hazardous drug, healthcare professionals must adhere to all applicable special handling and disposal procedures to ensure safety during use and management.

Additional Clinical Information

Postmarketing experience has revealed several serious adverse reactions associated with the use of TEMODAR. Dermatologic events include toxic epidermal necrolysis and Stevens-Johnson syndrome. Clinicians should be aware of potential immune system reactions, such as hypersensitivity, anaphylaxis, and erythema multiforme, which may resolve upon discontinuation but can recur upon rechallenge.

Hematopoietic complications may manifest as prolonged pancytopenia, potentially leading to aplastic anemia and fatal outcomes. Hepatobiliary issues have been noted, including severe hepatotoxicity, elevated liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis. Additionally, patients may experience serious opportunistic infections from bacterial, viral (both primary and reactivated), fungal, and protozoan sources, some of which have resulted in fatalities. Pulmonary complications such as interstitial pneumonitis, pneumonitis, alveolitis, and pulmonary fibrosis have also been reported. Lastly, endocrine effects may include diabetes insipidus.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Temodar as submitted by Merck Sharp & Dohme LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)