Temozolomide

Brand names: TEMODAR, Temozolomide, temozolomide, TEMOZOLOMIDE

Boxed warning

IMPORTANT DISPENSING INFORMATION For every patient, dispense Temozolomide capsules, USP in a separate vial or in its original package, making sure each container lists the strength per capsule and that patients take the appropriate number of capsules from each package or vial. Please see the dispensing instructions below for more information.

Warnings

BOXED WARNING: Myelosuppression - "Myelosuppression, including pancytopenia, leukopenia...and anemia, some with fatal outcomes, have occurred," with approximately 10% of patients requiring hospitalization or transfusion; blood counts must be monitored, with nadirs typically around day 26-28. Hepatotoxicity - "Fatal and severe hepatotoxicity have been reported" and liver function should be checked at baseline, mid-cycle, and after each cycle. Secondary malignancies, including myelodysplastic syndrome and secondary leukemias, have been observed. Contraindicated in patients with prior serious hypersensitivity to temozolomide or dacarbazine (shared metabolite). Also warns of Pneumocystis pneumonia risk, especially with concurrent steroid use, and embryo-fetal toxicity.

Contraindications

4 CONTRAINDICATIONS Temozolomide is contraindicated in patients with a history of serious hypersensitivity reactions to: temozolomide or any other ingredients in temozolomide capsules; 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 [see Adverse Reactions (6.2) ] . History of serious hypersensitivity to temozolomide or any other ingredients in temozolomide capsules and dacarbazine. ( 4 )

Overdose

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.

Uses

Indicated for adults with "newly diagnosed glioblastoma concomitantly with radiotherapy and then as maintenance treatment," and for "adjuvant treatment of adults with newly diagnosed anaplastic astrocytoma" as well as "treatment of adults with refractory anaplastic astrocytoma."

Dosage forms & strengths

Capsule CAPSULE POWDER INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION

TEMOZOLOMIDE 100 mg TEMOZOLOMIDE 140 mg TEMOZOLOMIDE 180 1 TEMOZOLOMIDE 180 mg TEMOZOLOMIDE 20 mg TEMOZOLOMIDE 250 mg TEMOZOLOMIDE 5 mg Temozolomide 100 mg Anhydrous Lactose 175.7 mg Silicon Dioxide 0.3 mg Sodium Starch Glycolate Type A Potato 15 mg Tartaric Acid 3 mg Stearic Acid 6 mg anhydrous lactose 175.7 mg silicon dioxide 0.3 mg sodium starch glycolate type A potato 15 mg tartaric acid 3 mg stearic acid 6 mg Temozolomide 140 mg Anhydrous Lactose 246 mg Silicon Dioxide 0.4 mg Sodium Starch Glycolate Type A Potato 21 mg Tartaric Acid 4.2 mg Stearic Acid 8.4 mg anhydrous lactose 246 mg silicon dioxide 0.4 mg sodium starch glycolate type A potato 21 mg tartaric acid 4.2 mg stearic acid 8.4 mg Temozolomide 180 mg Anhydrous Lactose 316.3 mg Silicon Dioxide 0.5 mg Sodium Starch Glycolate Type A Potato 27 mg Tartaric Acid 5.2 mg Stearic Acid 10.8 mg anhydrous lactose 316.3 mg silicon dioxide 0.5 mg sodium starch glycolate type A potato 27 mg tartaric acid 5.4 mg stearic acid 10.8 mg Temozolomide 20 mg Anhydrous Lactose 182.2 mg Silicon Dioxide 0.2 mg Sodium Starch Glycolate Type A Potato 11 mg Tartaric Acid 2.2 mg Stearic Acid 4.4 mg anhydrous lactose 182.2 mg silicon dioxide 0.2 mg sodium starch glycolate type A potato 11 mg tartaric acid 2.2 mg stearic acid 4.4 mg Temozolomide 250 mg Anhydrous Lactose 154.3 mg Silicon Dioxide 0.7 mg Sodium Starch Glycolate Type A Potato 22.5 mg Tartaric Acid 9 mg Stearic Acid 13.5 mg anhydrous lactose 154.3 mg silicon dioxide 0.7 mg sodium starch glycolate type A potato 22.5 mg tartaric acid 9 mg stearic acid 13.5 mg Temozolomide 5 mg Anhydrous Lactose 132.8 mg Sodium Starch Glycolate Type A Potato 7.5 mg Tartaric Acid 1.5 mg Stearic Acid 3 mg anhydrous lactose 132.8 mg sodium starch glycolate type A potato 7.5 mg tartaric acid 1.5 mg stearic acid 3 mg TEMOZOLOMIDE 20 mg/1 TEMOZOLOMIDE 180 mg/1 TEMOZOLOMIDE 140 mg/1 TEMOZOLOMIDE 1 kg/kg TEMOZOLOMIDE 100 mg/1 TEMOZOLOMIDE 250 mg/1 TEMOZOLOMIDE 5 mg/1 TEMOZOLOMIDE 25 kg/25kg TEMOZOLOMIDE 2.5 mg/mL

2 DOSAGE AND ADMINISTRATION Administer orally. ( 2.4 ) Newly Diagnosed Glioblastoma : 75 mg/m 2 once daily for 42 to 49 days concomitant with focal radiotherapy followed by initial maintenance dose of 150 mg/m 2 once daily for Days 1 to 5 of each 28-day cycle for 6 cycles. May increase maintenance dose to 200 mg/m 2 for Cycles 2 to 6 based on toxicity. ( 2.1 ) Provide Pneumocystis pneumonia (PCP) prophylaxis during concomitant phase and continue in patients who develop lymphopenia until resolution to Grade 1 or less. ( 2.1 ) Adjuvant Treatment of Newly Diagnosed Anaplastic Astrocytoma : Beginning 4 weeks after the end of radiotherapy, administer temozolomide orally in a single dose on days 1 to 5 of a 28-day cycle for 12 cycles. The recommended dosage for Cycle 1 is 150 mg/m 2 per day and for Cycles 2 to 12 is 200 mg/m 2 if patient experienced no or minimal toxicity in Cycle 1. ( 2.2 ) Refractory Anaplastic Astrocytoma: Initial dose of 150 mg/m 2 once daily on Days 1 to 5 of each 28-day cycle. ( 2.2 ) 2.1 Monitoring to Inform Dosage and Administration Prior to dosing, withhold temozolomide capsules until patients have an absolute neutrophil count (ANC) of 1.5 x 10 9 /L or greater and a platelet count of 100 x 10 9 /L or greater. 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. Perform complete blood counts weekly until recovery if the ANC falls below 1.5 x 10 9 /L and the platelet count falls below 100 x 10 9 /L. 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 capsules once daily for 42 to 49 consecutive days during the concomitant use phase with focal radiotherapy, and then once daily on Days 1 to 5 of each 28-day cycle for 6 cycles during the maintenance use phase. Provide Pneumocystis pneumonia (PCP) prophylaxis during the concomitant use phase and continue in patients who develop lymphopenia until resolution to Grade 1 or less [see Warnings and Precautions (5.3) ] . Concomitant Use Phase: The recommended dosage of temozolomide capsules is 75 mg/m 2 once daily for 42 to 49 days in combination with focal radiotherapy. 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 to adverse reactions during concomitant use phase are provided in Table 1 . Single Agent Maintenance Use Phase: Beginning 4 weeks after concomitant use phase completion, administer temozolomide capsules once daily on Days 1 to 5 of each 28-day cycle for 6 cycles. The recommended dosage of temozolomide capsules in the maintenance use phase is: • Cycle 1: 150 mg/m 2 per day on days 1 to 5. • Cycles 2 to 6: May increase to 200 mg/m 2 per day on days 1 to 5 before starting Cycle 2 if no dosage interruptions or discontinuations are required (Table 1). If the dose is not escalated at the onset of Cycle 2, do not increase the dose for Cycles 3 to 6. Obtain a complete blood count on Day 22 and then weekly until the ANC is above 1.5 x 10 9 /L and the platelet count is above 100 x 10 9 /L. 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 capsules are withheld, reduce the dose for the next cycle by 50 mg/m 2 per day. Permanently discontinue temozolomide capsules in patients who are unable to tolerate a dose of 100 mg/m 2 per day. temozolomide-table1 temozolomide-table2 2.3 Recommended Dosage and Dosage Modifications for Anaplastic Astrocytoma 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 to 5 of a 28-day cycle for 12 cycles. The recommended dosage of temozolomide capsules is: • Cycle 1: 150 mg/m 2 per day on days 1 to 5. • Cycles 2 to 12: 200 mg/m 2 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 [see Dosage and Administration (2.2) ]. Refractory Anaplastic Astrocytoma The recommended initial dosage of temozolomide capsules is 150 mg/m 2 once daily on Days 1 to 5 of each 28-day cycle. Increase the temozolomide dose to 200 mg/m 2 per day if the following conditions are met at the nadir and on Day 1 of the next cycle: • ANC is greater than or equal to 1.5 x 10 9 /L, and • Platelet count is greater than or equal to 100 x 10 9 /L. Continue temozolomide capsules until disease progression or unacceptable toxicity. Obtain a complete blood count on Day 22 and then weekly until the ANC is above 1.5 x 10 9 /L and the platelet count is above 100 x 10 9 /L. Do not start the next cycle until the ANC and platelet count exceed these levels. If the ANC is less than 1 x 10 9 /L or the platelet count is less than 50 x 10 9 /L during any cycle, reduce the temozolomide dose for the next cycle by 50 mg/m 2 per day. Permanently discontinue temozolomide capsules in patients who are unable to tolerate a dose of 100 mg/m 2 per day. 2.4 Preparation and Administration Temozolomide is a hazardous drug. Follow applicable special handling and disposal procedures. 1 Temozolomide capsules Take temozolomide capsules at the same time each day. Administer temozolomide capsules consistently with respect to food (fasting vs. nonfasting) [ see Clinical Pharmacology (12.3) ]. To reduce nausea and vomiting, take temozolomide capsules on an empty stomach or at bedtime and consider antiemetic therapy prior to and following temozolomide capsule administration. Swallow temozolomide capsules whole with water. Advise patients not to open, chew, or dissolve the contents of the capsules [ see Warnings and Precautions (5.6) ]. 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.