Temozolomide 20 mg Capsule, 15-count — NDC 47335-891-72 (Billing 47335-0891-72)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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 O6 and N7 positions of guanine, which causes DNA double strand breaks and results in programmed cell death.

12.2Pharmacodynamics Temozolomide exposure-response relationships and the time course of pharmacodynamic response are unknown.

12.3Pharmacokinetics 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

0.4L/kg (13%). The mean percent bound of drug-related total radioactivity is 15%. Elimination Clearance of temozolomide is approximately

5.5L/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 coadministered with ranitidine. No clinically significant differences in the clearance of temozolomide or MTIC were predicted when coadministered with the following drugs: valproic acid, dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, histamine-2-receptor antagonists, or phenobarbital.

12.1Mechanism 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 O6 and N7 positions of guanine, which causes DNA double strand breaks and results in programmed cell death.

12.3Pharmacokinetics 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

0.4L/kg (13%). The mean percent bound of drug-related total radioactivity is 15%. Elimination Clearance of temozolomide is approximately

5.5L/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 coadministered with ranitidine. No clinically significant differences in the clearance of temozolomide or MTIC were predicted when coadministered with the following drugs: valproic acid, dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, histamine-2-receptor antagonists, or phenobarbital.

12.2Pharmacodynamics Temozolomide exposure-response relationships and the time course of pharmacodynamic response are unknown.

14 CLINICAL STUDIES

14.1Newly Diagnosed Glioblastoma The efficacy of temozolomide was evaluated in MK-7365-051 ( NCT00006353 ), a randomized (1:1), multicenter, open-label trial. Eligible patients were required to have newly diagnosed glioblastoma. Patients were randomized to receive either radiation therapy alone or concomitant temozolomide 75 mg/m 2 once daily starting the first day of radiation therapy and continuing until the last day of radiation therapy for 42 days (with a maximum of 49 days), followed by temozolomide 150 mg/m 2 or 200 mg/m 2 once daily on Days 1 to 5 of each 28-day cycle, starting 4 weeks after the end of radiation therapy and continuing for 6 cycles.

In both arms, focal radiation therapy was delivered as 60 Gy/30 fractions and included radiation to the tumor bed or resection site with a 2-to 3-cm margin. PCP prophylaxis was required during the concomitant phase regardless of lymphocyte count and continued until recovery of lymphocyte count to Grade 1 or less. The major efficacy outcome measure was overall survival.

A total of 573 patients were randomized, 287 to temozolomide and radiation therapy and 286 to radiation therapy alone. At the time of disease progression, temozolomide was administered as salvage therapy in 161 patients of the 282 (57%) in the radiation therapy alone arm and 62 patients of the 277 (22%) in the temozolomide and radiation therapy arm. The addition of concomitant and maintenance temozolomide to radiation therapy for the treatment of patients with newly diagnosed glioblastoma showed a statistically significant improvement in overall survival compared to radiotherapy alone ( Figure 1 ).

The hazard ratio (HR) for overall survival was 0.63 (95% CI: 0.52, 0.75) with a log-rank P <0.0001 in favor of the temozolomide arm. The median overall survival was 14.6 months in the temozolomide arm and 12.1 months for radiation therapy alone arm. FIGURE 1: Kaplan-Meier Curves for Overall Survival (ITT Population) in Patients with Newly Diagnosed Glioblastoma in MK-7365-051 spl-temozolomide-figure-1

14.2Anaplastic Astrocytoma Newly Diagnosed Anaplastic Astrocytoma The efficacy of temozolomide for the adjuvant treatment of newly diagnosed anaplastic astrocytoma was derived from studies of temozolomide in the published literature. Temozolomide was evaluated in CATNON (NCT00626990), a randomized, open-label, multicenter trial, where the major efficacy outcome measure was overall survival. Refractory Anaplastic Astrocytoma The efficacy of temozolomide was evaluated in Study MK-7365-006, a single-arm, multicenter trial.

Eligible patients had anaplastic astrocytoma at first relapse and a baseline Karnofsky performance status (KPS) of 70 or greater. Patients had previously received radiation therapy and may also have previously received a nitrosourea with or without other chemotherapy. Fifty-four patients had disease progression on prior therapy with both a nitrosourea and procarbazine and their malignancy was considered refractory to chemotherapy (refractory anaplastic astrocytoma population).

Temozolomide capsules were given on Days 1 to 5 of each 28-day cycle at a starting dose of 150 mg/m2/day. If ANC was ≥1.5 x 109/L and platelet count was ≥100 x 109/L at the nadir and on Day 1 of the next cycle, the temozolomide dose was increased to 200 mg/m2/day. The major efficacy outcome measure was progression-free survival at 6 months and the additional efficacy outcome measures were overall survival and overall response rate.

In the refractory anaplastic astrocytoma population (n=54), the median age was 42 years (range: 19 to 76); 65% were male; and 72% had a KPS of >80. Sixty-three percent of patients had surgery other than a biopsy at the time of initial diagnosis. Of those patients undergoing resection, 73% underwent a subtotal resection and 27% underwent a gross total resection.

Eighteen percent of patients had surgery at the time of first relapse. The median time from initial diagnosis to first rela… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Temozolomide is carcinogenic in rats at doses less than the maximum recommended human dose. Temozolomide induced mammary carcinomas in both males and females at doses 0.13 to 0.63 times the maximum human dose (25 to 125 mg/m 2 ) when administered orally on 5 consecutive days every 28 days for 6 cycles. Temozolomide also induced fibrosarcomas of the heart, eye, seminal vesicles, salivary glands, abdominal cavity, uterus, and prostate, 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 0.5 times the maximum daily dose.

Mammary tumors were also induced following 3 cycles of temozolomide at the maximum recommended daily dose. Temozolomide is a mutagen and a clastogen. In a reverse bacterial mutagenesis assay (Ames assay), temozolomide increased revertant frequency in the absence and presence of metabolic activation.

Temozolomide was clastogenic in human lymphocytes in the presence and absence of metabolic activation. Temozolomide impairs male fertility. Temozolomide caused syncytial cells/immature sperm formation at doses of 50 and 125 mg/m 2 (0.25 and 0.63 times the human dose of 200 mg/m 2 ) in rats and dogs, respectively, and testicular atrophy in dogs at 125 mg/m 2 .

13.2Animal Toxicology and/or Pharmacology Toxicology studies in rats and dogs identified a low incidence of hemorrhage, degeneration, and necrosis of the retina at temozolomide doses equal to or greater than 125 mg/m 2 (0.63 times the human dose of 200 mg/m 2 ). These changes were most commonly seen at doses where mortality was observed.