Temozolomide Drug Information

1. INDICATIONS AND USAGE TEMOZOLOMIDE Capsules are an alkylating drug indicated for the treatment of adult patients with: Newly diagnosed glioblastoma concomitantly with radiotherapy and then as maintenance treatment. Anaplastic astrocytoma Adjuvant treatment of adults with newly diagnosed anaplastic astrocytoma.

2. DOSAGE AND ADMINISTRATION Administer either orally or intravenously. Provide Pneumocystis pneumonia (PCP) prophylaxis during concomitant phase and continue in patients who develop lymphopenia until resolution to grade 1 or less.

Adjuvant Treatment of Newly Diagnosed Anaplastic Astrocytoma: Beginning 4 weeks after the end of radiotherapy, administer TEMOZOLOMIDE Capsules orally in a single dose on days 1-5 of a 28-day cycle for 12 cycles. For concomitant radiotherapy, obtain a complete blood count prior to initiation of treatment and weekly during treatment. For the 28-day treatment cycles, obtain a complete blood count prior to treatment on Day 1 and on Day 22 of each cycle.

For concomitant use with focal radiotherapy, obtain a complete blood count weekly and as clinically indicated. 2.2 Recommended Dosage and Dosage Modifications for Newly Diagnosed Glioblastoma Administer TEMOZOLOMIDE either orally or intravenously once daily for 42 to 49 consecutive days during the concomitant phase with focal radiotherapy and then once daily on Days 1 to 5 of each 28-day cycle for 6 cycles during the maintenance phase. Focal radiotherapy includes the tumor bed or resection site with a 2 to 3 cm margin. Other administration schedules have been used.

Obtain a complete blood count weekly. The recommended dosage modifications due toadverse reactions during concomitant use phase are provided in Table 1. Do not start the next cycle until the ANC and platelet count exceed these levels.

The recommended dosage modifications due to adverse reactions during the maintenance use phase are provided in Table 2. If TEMOZOLOMIDE is withheld, reduce the dose for the next cycle by 50 mg/m 2 per day. Permanently discontinue TEMOZOLOMIDE in patients who are unable to tolerate a dose of 100 mg/m 2 per day.

Cycles per day on days 1 to 5 if patient experienced no or minimal toxicity in Cycle 1. If the dose was not escalated at the onset of Cycle 2, do not increase the dose during Cycles 3 to 6. The recommended complete blood count testing and dosage modifications due to adverse reactions during adjuvant treatment are provided above and in Table 2.

Continue TEMOZOLOMIDE until disease progression or unacceptable toxicity. Follow applicable special handling and disposal procedures. 1 TEMOZOLOMIDE capsules Take TEMOZOLOMIDE at the same time each day. Administer TEMOZOLOMIDE consistently with respect to food (fasting vs. nonfasting).

To reduce nausea and vomiting, take TEMOZOLOMIDE on an empty stomach or at bedtime and consider antiemetic therapy prior to and following TEMOZOLOMIDE administration. Swallow TEMOZOLOMIDE capsules whole with water. Advise patients not to open, chew, or dissolve the contents of the capsules.

If capsules are accidentally opened or damaged, take precautions to avoid inhalation or contact with the skin or mucous membranes. In case of powder contact, wash the affected area with water immediately.

6. ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Myelosuppression. Hepatotoxicity.

Pneumocystis Pneumonia. Secondary Malignancies. The most common adverse reactions (≥ 20% incidence) are: alopecia, fatigue, nausea, vomiting, headache, constipation, anorexia, and convulsions.

The most common Grade 3 to 4 hematologic laboratory abnormalities (≥ 10% incidence) in patients with anaplastic astrocytoma are: decreased lymphocytes, decreased platelets, decreased neutrophils, and decreased leukocytes. To report SUSPECTED ADVERSE REACTIONS, contact Devatis Inc. at 1-833-534-4406 or [email protected] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch or www.devatis.com. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Newly Diagnosed Glioblastoma The safety of TEMOZOLOMIDE was evaluated in Study MK-7365-051.

The most common adverse reactions (≥20%) in patients treated with TEMOZOLOMIDE were alopecia, fatigue, nausea, anorexia, headache, constipation, and vomiting. Note: Grade 5 (fatal) adverse reactions are included in the Grade ≥3 column. One patient who was randomized to radiation therapy-only arm received radiation therapy and TEMOZOLOMIDE. Clinically relevant adverse reactions in <10% of patients are presented below: Central & Peripheral Nervous System: memory impairment, confusion Eye: vision blurred Gastrointestinal System: stomatitis, abdominal pain General: weakness, dizziness Immune System: allergic reaction Injury: radiation injury not otherwise specified Musculoskeletal System: arthralgia Platelet, Bleeding, & Clotting: thrombocytopenia Psychiatric: insomnia Respiratory System: coughing, dyspnea Special Senses Other: taste perversion Skin & Subcutaneous Tissue: dry skin, pruritus, erythema When laboratory abnormalities and adverse reactions were combined, Grade 3 or Grade 4 neutrophil abnormalities including neutropenic reactions were observed in 8% of patients, and Grade 3 or Grade 4 platelet abnormalities including thrombocytopenic reactions, were observed in 14% of patients.

Newly Diagnosed Anaplastic Astrocytoma The safety of TEMOZOLOMIDE for the adjuvant treatment of adults with newly diagnosed anaplastic astrocytoma was derived from published literature. The safety of TEMOZOLOMIDE for the adjuvant treatment of patients with newly diagnosed anaplastic astrocytoma was consistent with the known safety profile of TEMOZOLOMIDE. Refractory Anaplastic Astrocytoma The safety of TEMOZOLOMIDE was evaluated in Study MK-7365-006.

Tables 4 and 5 summarize the adverse reactions and hematological laboratory abnormalities in MK-7365-006. TABLE 4: Adverse Reactions (≥10%) in Patients with Refractory Anaplastic Astrocytoma Trial 0 Clinically relevant adverse reactions in <10% of patients are presented below: Central and Peripheral Nervous System: paresthesia, somnolence, paresis, urinary incontinence, ataxia, dysphasia, convulsions local, gait abnormal, confusion Endocrine: adrenal hypercorticism Gastrointestinal System: abdominal pain, anorexia General: back pain Metabolic: weight increase Musculoskeletal System: myalgia Psychiatric: anxiety, depression Reproductive Disorders: breast pain female Respiratory System: upper respiratory tract infection, pharyngitis, sinusitis, coughing Skin & Appendages: rash, pruritus Urinary System: urinary tract infection, micturition increased frequency Vision: diplopia, vision abnormal 1 1 This term includes blurred vision; visual deficit; vision changes; and vision troubles. In the entire safety database for which hematologic data exist (N=932), of patients > 70 years experienced Grade 4 neutropenia or thrombocytopenia in the first cycle, respectively.

Pancytopenia, leukopenia, and anemia also occurred. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of TEMOZOLOMIDE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug exposure. Dermatologic: Toxic epidermal necrolysis and Stevens-Johnson syndrome Immune System: Hypersensitivity reactions, including anaphylaxis.

Erythema multiforme, which resolved after discontinuation of TEMOZOLOMIDE and, in some cases, recurred upon rechallenge. Hematopoietic: Prolonged pancytopenia, which may result in aplastic anemia and fatal outcomes. Hepatobiliary: Fatal and severe hepatotoxicity, elevation of liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis Infections: Serious opportunistic infections, including some cases with fatal outcomes, with bacterial, viral (primary and reactivated), fungal, and protozoan organisms.

Pulmonary: Interstitial pneumonitis, pneumonitis, alveolitis, and pulmonary fibrosis. Endocrine: Diabetes insipidus

Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action Temozolomide 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 with exposure to Temozolomide during pregnancy. These cases report similar adverse developmental outcomes to those observed in animal studies.

Administration of Temozolomide to rats and rabbits during the period of organogenesis caused numerous external, internal, and skeletal malformations at doses less than the maximum human dose based on body surface area (see Data). 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 respectively.

Data Animal Data Five consecutive days of oral administration of temozolomide at doses of times the human dose of 200 mg/m 2 in rats and rabbits, respectively, during the period of organogenesis (Gestation Days 8-12) caused numerous malformations of the external and internal organs and skeleton in both species.

Pediatric Use Safety and effectiveness of TEMOZOLOMIDE have not been established in pediatric patients. Safety and effectiveness of TEMOZOLOMIDE capsules were assessed, but not established, in 2 open-label studies in pediatric patients aged 3 to 18 years. In one study, 29 patients with recurrent brain stem glioma and 34 patients with recurrent high-grade astrocytoma were enrolled.

In a second study conducted by the Children’s Oncology Group (COG), 122 patients were enrolled, including patients with medulloblastoma/PNET, high grade astrocytoma, low grade astrocytoma, brain stem glioma, ependymoma, other CNS tumors, and non-CNS tumors. The adverse reaction profile in pediatric patients was similar to adults.

• 4. CONTRAINDICATIONS Temozolomide is contraindicated in patients with a history of hypersensitivity reactions to:
• Temozolomide or any other ingredients in Temozolomide; and
• Dacarbazine, since both temozolomide and dacarbazine are metabolized to the same active metabolite 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide. Reactions to Temozolomide have included anaphylaxis. History of hypersensitivity to temozolomide or any other ingredients in Temozolomide capsules and dacarbazine.

10. OVERDOSAGE Dose-limiting toxicity was myelosuppression and was reported with any dose but is expected to be more severe at higher doses. An overdose of 2000 mg per day for 5 days was taken by one patient and the adverse reactions reported were pancytopenia, pyrexia, multi-organ failure, and death.

There are reports of patients who have taken more than 5 days of treatment (up to 64 days), with adverse reactions reported including myelosuppression, which in some cases was severe and prolonged, and infections and resulted in death. In the event of an overdose, monitor complete blood count and provide supportive measures as necessary.