temozolomide 5 MG Oral Capsule

1. INDICATIONS AND USAGE TEMOZOLOMIDE Capsules, USP are an alkylating drug indicated for the treatment of adult patients with: • Newly diagnosed glioblastoma concomitantly with radiotherapy and then as maintenance treatment. ( 1.1 ) • Refractory anaplastic astrocytoma who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine. ( 1.2 ) 1.1 Newly Diagnosed Glioblastoma TEMOZOLOMIDE Capsules, USP is indicated for the treatment of adult patients with newly diagnosed glioblastoma concomitantly with radiotherapy and then as maintenance treatment. 1.2 Refractory Anaplastic Astrocytoma TEMOZOLOMIDE Capsules , USP is indicated for the treatment of adult patients with refractory anaplastic astrocytoma who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine.

DOSAGE AND ADMINISTRATION Administer either orally or intravenously. ( 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 TEMODAR orally in a single dose on days 1-5 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 TEMODAR 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 TEMODAR either orally or intravenously 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 TEMODAR is 75 mg/m 2 either orally or intravenously 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 . TABLE 1: Dosage Modifications Due to Adverse Reactions During Concomitant Use Phase Adverse Reaction Interruption Discontinuation Absolute Neutrophil Count Withhold TEMODAR if ANC is greater than or equal to 0.5 × 10 9 /L and less than 1.5 × 10 9 /L. Discontinue TEMODAR if ANC is less than 0.5 × 10 9 /L. Resume TEMODAR at the same dose when ANC is greater than or equal to 1.5 × 10 9 /L. Platelet Count Withhold TEMODAR if platelet count is greater than or equal to 10 × 10 9 /L and less than 100 × 10 9 /L. Discontinue TEMODAR if platelet count is less than 10 × 10 9 /L. Resume TEMODAR at the same dose when platelet count is greater than or equal to 100 × 10 9 /L. Non-hematological Adverse Reaction (except for alopecia, nausea, vomiting) Withhold TEMODAR if Grade 2 adverse reaction occurs. Discontinue TEMODAR if Grade 3 or 4 adverse reaction occurs. Resume TEMODAR at the same dose when resolution to Grade 1 or less. Single Agent Maintenance Use Phase: Beginning 4 weeks after concomitant use phase completion, administer TEMODAR either orally or intravenously once daily on Days 1 to 5 of each 28-day cycle for 6 cycles. The recommended dosage of TEMODAR 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 × 10 9 /L and the platelet count is above 100 × 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 TEMODAR is withheld, reduce the dose for the next cycle by 50 mg/m 2 per day. Permanently discontinue TEMODAR in patients who are unable to tolerate a dose of 100 mg/m 2 per day. TABLE 2: Dosage Modifications Due to Adverse Reactions During Maintenance and Adjuvant Treatment Adverse Reactions Interruption and Dose Reduction Discontinuation Absolute Neutrophil Count Withhold TEMODAR if ANC less than 1 × 10 9 /L. Discontinue TEMODAR if unable to tolerate a dose of 100 mg/m 2 per day. When ANC is above 1.5 × 10 9 /L, resume TEMODAR at reduced dose for the next cycle. Platelet Count Withhold TEMODAR if platelet less than 50 × 10 9 /L. Discontinue TEMODAR if unable to tolerate a dose of 100 mg/m 2 per day. When platelet count is above 100 × 10 9 /L, resume TEMODAR at reduced dose for the next cycle. Nonhematological Adverse Reactions (except for alopecia, nausea, vomiting) Withhold TEMODAR if Grade 3 adverse reaction occurs. Discontinue TEMODAR if recurrent Grade 3 adverse reaction occurs after dose reduction, if Grade 4 adverse reaction occurs, or if unable to tolerate a dose of 100 mg/m 2 per day. When resolved to Grade 1 or less, resume TEMODAR at reduced dose for the next cycle. 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 TEMODAR orally in a single dose on days 1 to 5 of a 28-day cycle for 12 cycles. The recommended dosage of TEMODAR 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 TEMODAR is 150 mg/m 2 once daily on Days 1 to 5 of each 28-day cycle. Increase the TEMODAR 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 × 10 9 /L, and Platelet count is greater than or equal to 100 × 10 9 /L. Continue TEMODAR 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 × 10 9 /L or the platelet count is less than 50 × 10 9 /L during any cycle, reduce the TEMODAR dose for the next cycle by 50 mg/m 2 per day. Permanently discontinue TEMODAR in patients who are unable to tolerate a dose of 100 mg/m 2 per day. 2.4 Preparation and Administration TEMODAR is a hazardous drug. Follow applicable special handling and disposal procedures. 1 TEMODAR capsules Take TEMODAR at the same time each day. Administer TEMODAR consistently with respect to food (fasting vs. nonfasting) [see Clinical Pharmacology (12.3) ] . To reduce nausea and vomiting, take TEMODAR on an empty stomach or at bedtime and consider antiemetic therapy prior to and following TEMODAR administration. Swallow TEMODAR capsules whole with water. Advise patients not t

WARNINGS AND PRECAUTIONS • Myelosuppression: Monitor absolute neutrophil count (ANC) and platelet count prior to each cycle and during treatment. Geriatric patients and women have a higher risk of developing myelosuppression. ( 5.1 , 8.5 ) • Hepatotoxicity: Fatal and severe hepatotoxicity have been reported. Perform liver 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. ( 5.2 ) • Pneumocystis Pneumonia (PCP): Closely monitor all patients, particularly those receiving steroids, for the development of lymphopenia and PCP. ( 5.3 ) • Secondary Malignancies: Myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed. ( 5.4 ) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. Advise male patients with pregnant partners or female partners of reproductive potential to use condoms. ( 5.5 , 8.1 , 8.3 ) • Exposure to Opened Capsules: Temozolomide capsules should not be opened, chewed, or dissolved but should be swallowed whole with a glass of water. ( 5.6 ) 5.1 Myelosuppression Myelosuppression, including pancytopenia, leukopenia, and anemia, some with fatal outcomes, have occurred with temozolomide [see Adverse Reactions (6.1 , 6.2) ] . In MK-7365-006, myelosuppression usually occurred during the first few cycles of therapy and was generally not cumulative. The median nadirs occurred at 26 days for platelets (range: 21 to 40 days) and 28 days for neutrophils (range: 1 to 44 days). Approximately 10% of patients required hospitalization, blood transfusion, or discontinuation of therapy due to myelosuppression. Geriatric patients and women have been shown in clinical trials to have a higher risk of developing myelosuppression. Obtain a complete blood count and monitor ANC and platelet counts before initiation of treatment and as clinically indicated during treatment. When temozolomide is used in combination with radiotherapy, obtain a complete blood count prior to initiation of treatment, weekly during treatment, and as clinically indicated [see Dosage and Administration (2.1 , 2.2 , 2.3) ] . For severe myelosuppression, withhold temozolomide and then resume at same or reduced dose, or permanently discontinue, based on occurrence [see Dosage and Administration (2.1 , 2.2 , 2.3) ] . 5.2 Hepatotoxicity Fataland severe hepatotoxicity have been reported in patients receiving temozolomide. Perform liver 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. 5.3 Pneumocystis Pneumonia Pneumocystis pneumonia (PCP) has been reported in patients receiving temozolomide. The risk of PCP is increased in patients receiving steroids or with longer treatment regimens of temozolomide. For patients with newly diagnosed glioblastoma, provide PCP prophylaxis for all patients during the concomitant phase. Continue PCP prophylaxis in patients who experience lymphopenia, until resolution to Grade 1 or less [see Dosage and Administration (2.1) ] . Monitor all patients receiving temozolomide for the development of lymphopenia and PCP. 5.4 Secondary Malignancies Theincidence of secondary malignancies is increased in patients treated with temozolomide -containing regimens. Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed following temozolomide administration. 5.5 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, temozolomide can cause fetal harm when administered to a pregnant woman. Adverse developmental outcomes have been reported in both pregnant patients and pregnant partners of male patients. Oral administration of temozolomide to rats and rabbits during the period of organogenesis resulted in embryolethality and polymalformations at doses less than the maximum human dose based on body surface area. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with temozolomide and for 6 months after the last dose. Because of potential risk of genotoxic effects on sperm, advise male patients with female partners of reproductive potential to use condoms during treatment with temozolomide and for 3 months after the last dose. Advise male patients not to donate semen during treatment with temozolomide and for 3 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ] . 5.6 Exposure to Opened Capsules Advisepatients not to open, chew or dissolve the contents of the temozolomide capsules. Swallow capsules whole with a glass of water. If a capsule becomes damaged, avoid contact of the powder contents with skin or mucous membranes. In case of powder contact, wash affected area with water immediately [see Dosage and Administration (2.4) ] . If temozolomide capsules must be opened or the contents must be dissolved, this should be done by a professional trained in safe handling of hazardous drugs using appropriate equipment and safety procedures.

CONTRAINDICATIONS Temozolomide capsules, USP is contraindicated in patients with a history of hypersensitivity reactions to: temozolomide or any other ingredients in Temozolomide capsules, USP; 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 hypersensitivity to temozolomide or any other ingredients in Temozolomide capsules, USP and dacarbazine. ( 4.1 )

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Temozolomide is not directly active but undergoes rapid nonenzymatic conversion at physiologic pH to the reactive compound 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC). The cytotoxicity of MTIC is thought to be primarily due to DNA alkylation, mainly at the O 6 and N 7 positions of guanine, which causes DNA double strand breaks and results in programmed cell death. 12.2 Pharmacodynamics Temozolomide exposure-response relationships and the time course of pharmacodynamic response are unknown. 12.3 Pharmacokinetics Following a single oral dose of 150 mg/m 2 , the mean C max is 7.5 mcg/mL for temozolomide and 282 ng/mL for MTIC. The mean AUC is 23.4 mcg·hr/mL for temozolomide and 864 ng·hr/mL for MTIC. Following a single 90-minute intravenous infusion of 150 mg/m 2 , the mean C max is 7.3 mcg/mL for temozolomide and 276 ng/mL for MTIC. The mean AUC is 24.6 mcg·hr/mL for temozolomide and 891 ng·hr/mL for MTIC. Temozolomide exhibits linear kinetics over the therapeutic dosing range of 75 mg/m 2 /day to 250 mg/m 2 /day. Absorption The median T max is 1 hour. Effect of Food The mean temozolomide C max and AUC decreased by 32% and 9%, respectively, and median T max increased by 2-fold (from 1 to 2.25 hours) when temozolomide capsules were administered after a modified high-fat breakfast (587 calories comprised of 1 fried egg, 2 strips of bacon, 2 slices of toast, 2 pats of butter, and 8 oz whole milk). Distribution Temozolomide has a mean (CV%) apparent volume of distribution of 0.4 L/kg (13%). The mean percent bound of drug-related total radioactivity is 15%. Elimination Clearance of temozolomide is approximately 5.5 L/hr/m 2 and the mean elimination half-life is 1.8 hours. Metabolism Temozolomide is spontaneously hydrolyzed at physiologic pH to the active species, MTIC and to temozolomide acid metabolite. MTIC is further hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC), which is known to be an intermediate in purine and nucleic acid biosynthesis, and to methylhydrazine, which is believed to be the active alkylating species. Cytochrome P450 enzymes play a minor role in the metabolism of temozolomide and MTIC. Relative to the AUC of temozolomide, the exposure to MTIC and AIC is 2.4% and 23%, respectively. Excretion Approximately 38% of the administered temozolomide total radioactive dose is recovered over 7 days: 38% in urine and 0.8% in feces. The majority of the recovered radioactivity in urine is unchanged temozolomide (6%), AIC (12%), temozolomide acid metabolite (2.3%), and unidentified polar metabolite(s) (17%). Specific Populations No clinically significant differences in the pharmacokinetics of temozolomide were observed based on age (range: 19 to 78 years), gender, smoking status (smoker vs. non-smoker), creatinine clearance (CLcr) of 36 to 130 mL/min/m 2 , or mild to moderate hepatic impairment (Child Pugh class A and B). The pharmacokinetics of temozolomide has not been studied in patients with CLcr <36 mL/min/m 2 , end-stage renal disease on dialysis, or severe hepatic impairment (Child-Pugh class C). Drug Interaction Studies Clinical Studies and Model-Informed Approaches No clinically significant differences in the pharmacokinetics of temozolomide or MTIC were observed when co-administered with ranitidine. No clinically significant differences in the clearance of temozolomide or MTIC were predicted when co-administered with the following drugs: valproic acid, dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, histamine-2-receptor antagonists, or phenobarbital.