Temozolomide

Uses and Indications

Temozolomide is indicated for the treatment of adults with:

Glioblastoma

• Newly diagnosed glioblastoma concomitantly with radiotherapy and then as maintenance treatment.

Anaplastic Astrocytoma

• Adjuvant treatment of adults with newly diagnosed anaplastic astrocytoma.

• Treatment of adults with refractory anaplastic astrocytoma, including those who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine.

Limitations of Use

• No specific teratogenic or nonteratogenic effects are mentioned in the provided information.

Dosage and Administration

Temozolomide is administered either orally or intravenously, depending on the formulation used.

Newly Diagnosed Glioblastoma: The recommended dosage is 75 mg/m² once daily for 42 to 49 days in conjunction with focal radiotherapy. Following this initial phase, an initial maintenance dose of 150 mg/m² is to be administered once daily for Days 1 to 5 of each 28-day cycle for a total of 6 cycles. The maintenance dose may be increased to 200 mg/m² for Cycles 2 to 6 based on patient tolerance and toxicity. During the concomitant phase, Pneumocystis pneumonia (PCP) prophylaxis should be provided and continued in patients who develop lymphopenia until resolution to Grade 1 or less.

Adjuvant Treatment of Newly Diagnosed Anaplastic Astrocytoma: Treatment should begin 4 weeks after the conclusion of radiotherapy. Temozolomide is to be administered 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, with the possibility of increasing the dosage to 200 mg/m² for Cycles 2 to 12 if the patient experienced no or minimal toxicity during Cycle 1.

Refractory Anaplastic Astrocytoma: The initial dose is 150 mg/m² once daily on Days 1 to 5 of each 28-day cycle.

Healthcare professionals should ensure that the administration of Temozolomide is in accordance with the outlined dosages and schedules, monitoring for any adverse effects throughout the treatment course.

Contraindications

History of serious hypersensitivity to temozolomide or any other ingredients in temozolomide capsules or dacarbazine is a contraindication for use. Due to the risk of severe allergic reactions, patients with such a history should not be treated with this medication.

Warnings and Precautions

Myelosuppression Temozolomide can cause myelosuppression. It is essential to monitor the absolute neutrophil count (ANC) and platelet count prior to each treatment cycle and throughout the course of therapy. Geriatric patients and women are at a higher risk of developing myelosuppression.

Hepatotoxicity Fatal and severe hepatotoxicity have been reported in patients receiving temozolomide. Liver function tests should be performed at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately 2 to 4 weeks after the last dose.

Pneumocystis Pneumonia (PCP) Patients should be closely monitored for the development of lymphopenia and PCP, particularly those receiving steroids. Prophylaxis for PCP is required for all patients undergoing concomitant temozolomide and radiotherapy for the treatment of newly diagnosed glioblastoma multiforme.

Secondary Malignancies Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed in patients treated with temozolomide.

Embryo-Fetal Toxicity Temozolomide can cause fetal harm. Women of reproductive potential should be advised of the risks and to use effective contraception during treatment. Male patients with pregnant partners or female partners of reproductive potential should also use condoms to prevent exposure.

Exposure to Opened Capsules Temozolomide capsules should not be opened, chewed, or dissolved. They must be swallowed whole with a glass of water to ensure proper dosing.

Laboratory Tests Routine monitoring of the absolute neutrophil count (ANC) and platelet count is required prior to each cycle and during treatment. 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.

Side Effects

Common adverse reactions observed in patients receiving temozolomide include:

• Alopecia

• Fatigue

• Nausea

• Vomiting

• Headache

• Constipation

• Anorexia

• Convulsions

These reactions occur with an incidence of 20% or greater.

Severe or Life-Threatening Adverse Reactions

• Myelosuppression: This includes decreased lymphocytes, platelets, neutrophils, and leukocytes, with monitoring of absolute neutrophil count (ANC) and platelet count recommended prior to each treatment cycle. Geriatric patients and women are at a higher risk of developing myelosuppression.

• Hepatotoxicity: Fatal and severe hepatotoxicity has been reported, necessitating liver function tests at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately 2 to 4 weeks after the last dose.

• Pneumocystis Pneumonia (PCP): Patients, especially those receiving steroids, should be closely monitored for the development of lymphopenia and PCP.

• Secondary Malignancies: Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed.

• Embryo-Fetal Toxicity: Temozolomide can cause fetal harm; females of reproductive potential should be advised of this risk and to use effective contraception.

Adverse Reactions (≥10%) in Specific Patient Populations

In patients with newly diagnosed glioblastoma, the following adverse reactions were noted:

• Alopecia: 69%

• Fatigue: 54%

• Nausea: 36%

• Vomiting: 20%

• Headache: 19%

• Anorexia: 19%

• Rash: 19%

• Convulsions: 6%

In patients with refractory anaplastic astrocytoma, the following adverse reactions were reported:

• Nausea: 53%

• Vomiting: 42%

• Constipation: 33%

• Headache: 41%

• Fatigue: 34%

• Convulsions: 23%

• Hemiparesis: 18%

• Dizziness: 12%

Clinically Relevant Adverse Reactions (<10%)

Additional adverse reactions reported in less than 10% of patients include:

• Central and Peripheral Nervous System: Memory impairment, confusion, dizziness, coordination abnormality, amnesia, insomnia, and somnolence.

• Gastrointestinal System: Stomatitis, abdominal pain, diarrhea.

• General: Weakness, dizziness, asthenia, fever, back pain.

• Musculoskeletal System: Arthralgia, myalgia.

• Psychiatric: Anxiety, depression, insomnia.

• Respiratory System: Coughing, dyspnea, upper respiratory tract infection, pharyngitis, sinusitis.

• Skin and Subcutaneous Tissue: Dry skin, pruritus, erythema, rash.

• Urinary System: Urinary tract infection, increased frequency of micturition.

• Vision: Blurred vision, diplopia, vision abnormal.

Postmarketing Experience

Postmarketing reports have identified additional serious adverse reactions, including:

• Dermatologic: Toxic epidermal necrolysis, Stevens-Johnson syndrome.

• Immune System: Hypersensitivity reactions, including anaphylaxis and erythema multiforme.

• Hematopoietic: Prolonged pancytopenia, which may lead to aplastic anemia and fatal outcomes.

• Hepatobiliary: Severe hepatotoxicity, including elevation of liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis.

• Infections: Serious opportunistic infections, including bacterial, viral (primary and reactivated), fungal, and protozoan infections, with some cases resulting in fatal outcomes.

• Pulmonary: Interstitial pneumonitis, pneumonitis, alveolitis, and pulmonary fibrosis.

Overdosage

In cases of overdose, adverse reactions may include:

• Pancytopenia

• Pyrexia

• Multi-organ failure

• Death

• Severe and prolonged bone marrow suppression

• Infections leading to death

Patients should be monitored closely, and supportive measures should be provided as necessary.

Drug Interactions

Temozolomide, available in capsule form, has limited documented drug interactions. Notably, the concomitant use of valproic acid has been shown to decrease the oral clearance of temozolomide. This interaction may necessitate careful monitoring of temozolomide levels and potential dose adjustments to ensure therapeutic efficacy while minimizing adverse effects.

No additional drug interactions or laboratory test interactions have been reported for temozolomide in the available data. Therefore, healthcare providers should remain vigilant and consider individual patient factors when prescribing temozolomide, particularly in the context of polypharmacy.

Pediatric Use

Safety and effectiveness of temozolomide have not been established in pediatric patients. The safety and effectiveness of temozolomide capsules were assessed in two open-label studies involving pediatric patients aged 3 to 18 years.

In the first study, 29 patients with recurrent brain stem glioma and 34 patients with recurrent high-grade astrocytoma were enrolled. All patients had recurrence following surgery and radiation therapy, with 31% also experiencing 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).

Temozolomide was administered at a dose of 160 to 200 mg/m² daily for 5 days every 28 days. The adverse reaction profile in pediatric patients was found to be similar to that observed in adults.

Geriatric Use

In clinical studies of temozolomide, insufficient numbers of patients aged 65 years and older were included to determine differences in effectiveness compared to younger patients. Specifically, in the MK-7365-051 trial for newly diagnosed glioblastoma, 15% of participants were 65 years or older, and no overall differences in safety were observed between patients aged 65 years and older and younger patients. Similarly, the CATNON trial did not provide adequate data for this age group.

In the MK-7365-006 trial for refractory anaplastic astrocytoma, only 4% of patients were aged 70 years and older. This subgroup 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 a broader safety database encompassing 932 patients, 7% of those over 70 experienced Grade 4 neutropenia, while 10% experienced Grade 4 thrombocytopenia in the first cycle. In contrast, for patients aged 70 years and younger, the rates were 7% and 6%, respectively. Other hematologic issues such as pancytopenia, leukopenia, and anemia were also reported.

Given the greater frequency of decreased hepatic, renal, or cardiac function in elderly patients, dose selection should be approached with caution, taking into account potential concomitant diseases or other drug therapies. Overall, while clinical experience has not identified significant differences in responses between elderly and younger patients, careful monitoring and consideration of individual patient factors are recommended when treating geriatric patients with temozolomide.

Pregnancy

Based on findings from animal studies and its mechanism of action, temozolomide can cause fetal harm when administered to pregnant patients. Available postmarketing reports describe cases of spontaneous abortions and congenital malformations, including polymalformations affecting the central nervous system, facial structures, cardiac function, skeletal integrity, and the genitourinary system, associated with exposure to temozolomide during pregnancy. These cases report adverse developmental outcomes similar to those observed in animal studies.

Administration of temozolomide to rats and rabbits during the period of organogenesis has 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) during gestation days 8 to 12 caused significant malformations in both species. In rabbits, the 150 mg/m² dose was associated with embryolethality, as indicated by increased resorptions.

Pregnant patients should be advised of the potential risks to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is approximately 2% to 4% and 15% to 20%, respectively. There are no adequate and well-controlled studies in pregnant women. Women of childbearing potential should be counseled to avoid becoming pregnant during therapy with temozolomide. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazards to the fetus. Temozolomide is classified as Pregnancy Category D.

Lactation

There are no data available regarding the presence of temozolomide or its metabolites in human milk, nor are there any studies assessing the effects on breastfed infants or milk production. Due to the potential for serious adverse reactions, including myelosuppression in breastfed children, it is advised that lactating mothers refrain from breastfeeding during treatment with temozolomide and for at least one week following the last dose.

Given the lack of specific information on excretion in breast milk and the potential risks to nursing infants, healthcare providers should carefully consider the importance of temozolomide to the mother when advising on breastfeeding options.

Renal Impairment

Patients with renal impairment should be aware that no dosage adjustment of temozolomide is recommended for those with a creatinine clearance (CLcr) ranging from 36 to 130 mL/min/m². However, the recommended dose for patients with severe renal impairment (CLcr < 36 mL/min/m²) or for those with end-stage renal disease on dialysis has not been established.

Due to the lack of specific information regarding dosage adjustments, monitoring, or safety considerations for patients with kidney problems, it is essential for healthcare providers to exercise caution and consider individual patient circumstances when prescribing temozolomide. Regular monitoring of renal function may be warranted in these patients to ensure safety and efficacy of treatment.

Hepatic Impairment

No dosage adjustment is recommended for patients with mild to moderate hepatic impairment (Child-Pugh class A and B). However, the recommended dose of temozolomide has not been established for patients with severe hepatic impairment (Child-Pugh class C).

Fatal and severe hepatotoxicity have been reported in patients receiving temozolomide. It is essential to perform liver function tests at baseline, midway through the first cycle, prior to each subsequent cycle, and approximately 2 to 4 weeks after the last dose of temozolomide to monitor for potential liver toxicity.

Overdosage

In cases of overdose with Temozolomide, particularly at a dosage of 2000 mg per day for 5 consecutive days, significant adverse reactions have been documented. These reactions include pancytopenia, pyrexia, multi-organ failure, and, in some instances, death. Patients who have undergone treatment for more than 5 days, extending up to 64 days, have reported severe and prolonged myelosuppression, alongside infections that have also resulted in fatal outcomes.

The primary dose-limiting toxicity associated with Temozolomide is myelosuppression, which can occur at any dosage but is anticipated to be more severe at higher doses. Therefore, in the event of an overdose, it is crucial to conduct a complete blood count (CBC) to monitor hematologic parameters closely. Supportive measures should be implemented as necessary to manage the patient's condition effectively.

Nonclinical Toxicology

Teratogenic Effects

No specific teratogenic effects have been reported in the available data.

Carcinogenesis

Temozolomide has been identified as carcinogenic in rats at doses less than the maximum recommended human dose. In studies, it induced mammary carcinomas in both male and female rats at doses ranging from 0.13 to 0.63 times the maximum human dose (25-125 mg/m²) when administered orally for 5 consecutive days every 28 days over 6 cycles. Additionally, temozolomide was associated with the induction of fibrosarcomas in various tissues, including the heart, eye, seminal vesicles, salivary glands, abdominal cavity, uterus, and prostate. Other tumors observed included carcinomas of the seminal vesicles, schwannomas of the heart, optic nerve, and harderian gland, as well as adenomas of the skin, lung, pituitary, and thyroid at doses of 0.5 times the maximum daily dose. Mammary tumors were also noted following 3 cycles of treatment at the maximum recommended daily dose.

Mutagenesis

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 Fertility

Temozolomide has been shown to impair male fertility. It 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) in rats and dogs, respectively. Testicular atrophy was also observed in dogs at the dose of 125 mg/m².

Animal Toxicology

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.

Storage and Handling

TEMODAR and temozolomide are supplied in various forms, including capsules, injection, and powder for solution.

TEMODAR capsules and temozolomide capsules, USP should be stored at 25°C (77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F) as per USP Controlled Room Temperature guidelines. Additionally, temozolomide capsules may also be stored at a temperature range of 20°C to 25°C (68°F to 77°F).

TEMODAR for injection must be refrigerated at 2°C to 8°C (36°F to 46°F).

All forms of temozolomide are classified as hazardous drugs, necessitating adherence to applicable special handling and disposal procedures. Care should be exercised during the handling and preparation of temozolomide capsules, which should not be opened. In the event of accidental opening or damage to the capsules, rigorous precautions must be taken to avoid inhalation or contact with skin or mucous membranes. The use of gloves and safety glasses is recommended to prevent exposure in case of breakage.

TEMODAR capsules and temozolomide capsules, USP are supplied in various container types, including amber glass bottles and HDPE plastic bottles, both equipped with child-resistant polypropylene caps. It is essential to dispense these medications in tight, light-resistant containers as defined in USP/NF or retain them in their original packaging.