Sancuso granisetron 3.1 mg/24h Patch, 168-count — NDC 66220-637-72 (Billing 66220-0637-72)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Granisetron is a selective 5-hydroxytryptamine 3 (5-HT 3 ) receptor antagonist with little or no affinity for other serotonin receptors, including 5-HT 1, 5-HT 1A , 5-HT 1B/C , 5-HT 2 ; for alpha 1 -, alpha 2 -, or beta-adrenoreceptors; for dopamine-D 2 ; or for histamine-H 1 ; benzodiazepine; picrotoxin or opioid receptors. Serotonin receptors of the 5-HT 3 type are located peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. During chemotherapy that induces vomiting, mucosal enterochromaffin cells release serotonin, which stimulates 5-HT 3 receptors.

This evokes vagal afferent discharge, inducing vomiting. Animal studies demonstrate that, in binding to 5-HT 3 receptors, granisetron blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as cisplatin. In the ferret animal model, a single granisetron injection prevented vomiting due to high-dose cisplatin or arrested vomiting within 5 to 30 seconds.

12.2Pharmacodynamics The effect of granisetron on QTc prolongation was evaluated in a randomized, single-blind, positive (moxifloxacin 400 mg) - and placebo controlled parallel study in healthy subjects. A total of 120 subjects were administered SANCUSO transdermal system (n=60) or intravenous granisetron (10 mcg/kg over 30 seconds; n=60). In a study with demonstrated ability to detect small effects, the upper bound of the 90% confidence interval for the largest placebo adjusted, baseline corrected QTc based on Fridericia correction method (QTcF) for SANCUSO was below 10 ms.

This study suggests that SANCUSO does not have significant effects on QT prolongation. No evidence of an effect on plasma prolactin or aldosterone concentrations has been found in studies using granisetron. The effect on oro-cecal transit time following application of SANCUSO has not been studied.

Granisetron hydrochloride injection exhibited no effect on oro-cecal transit time in healthy subjects given a single intravenous infusion of 50 mcg/kg or 200 mcg/kg. Single and multiple oral doses of granisetron hydrochloride slowed colonic transit in healthy subjects.

12.3Pharmacokinetics Absorption Granisetron crosses intact skin into the systemic circulation by a passive diffusion process. Following a 7-day application of SANCUSO transdermal system in 24 healthy subjects, high inter- subject variability in systemic exposure was observed. Maximal concentration was reached at approximately 48 hours (range: 24-168 hours) following application.

Mean C max was 5 ng/mL (CV: 170%) and mean AUC 0-168hr was 527 ng-hr/mL (CV: 173%). Mean Plasma Concentration of Granisetron (mean ± SD) Based on the measure of residual content of the transdermal system after removal, approximately 66% (SD: ± 10.9) of granisetron is delivered following transdermal system application for 7 days. Following consecutive application of two SANCUSO transdermal systems, each for seven days, granisetron plasma concentrations were maintained over the study period with evidence of minimal accumulation.

The mean plasma concentration at 24 hours after the second transdermal system application was 1.5-fold higher due to residual granisetron from the first transdermal system. As the plasma concentration increased after the second transdermal system application, the difference decreased and the mean plasma concentration at 48 hours was 1.3-fold higher after application of the second transdermal system compared to that after application of the first transdermal system. In a study designed to assess the effect of heat on the transdermal delivery of granisetron from SANCUSO in healthy subjects, a heat pad generating an average temperature of 42°C (107.6°F) was applied over the transdermal system for 4 hours each day over the 5 day period of wear.

The application of the heat pad was associated with an increase in plasma granisetron concentrations during the period of heat pad appli… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Granisetron is a selective 5-hydroxytryptamine 3 (5-HT 3 ) receptor antagonist with little or no affinity for other serotonin receptors, including 5-HT 1, 5-HT 1A , 5-HT 1B/C , 5-HT 2 ; for alpha 1 -, alpha 2 -, or beta-adrenoreceptors; for dopamine-D 2 ; or for histamine-H 1 ; benzodiazepine; picrotoxin or opioid receptors. Serotonin receptors of the 5-HT 3 type are located peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. During chemotherapy that induces vomiting, mucosal enterochromaffin cells release serotonin, which stimulates 5-HT 3 receptors.

This evokes vagal afferent discharge, inducing vomiting. Animal studies demonstrate that, in binding to 5-HT 3 receptors, granisetron blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as cisplatin. In the ferret animal model, a single granisetron injection prevented vomiting due to high-dose cisplatin or arrested vomiting within 5 to 30 seconds.

12.3Pharmacokinetics Absorption Granisetron crosses intact skin into the systemic circulation by a passive diffusion process. Following a 7-day application of SANCUSO transdermal system in 24 healthy subjects, high inter- subject variability in systemic exposure was observed. Maximal concentration was reached at approximately 48 hours (range: 24-168 hours) following application.

Mean C max was 5 ng/mL (CV: 170%) and mean AUC 0-168hr was 527 ng-hr/mL (CV: 173%). Mean Plasma Concentration of Granisetron (mean ± SD) Based on the measure of residual content of the transdermal system after removal, approximately 66% (SD: ± 10.9) of granisetron is delivered following transdermal system application for 7 days. Following consecutive application of two SANCUSO transdermal systems, each for seven days, granisetron plasma concentrations were maintained over the study period with evidence of minimal accumulation.

The mean plasma concentration at 24 hours after the second transdermal system application was 1.5-fold higher due to residual granisetron from the first transdermal system. As the plasma concentration increased after the second transdermal system application, the difference decreased and the mean plasma concentration at 48 hours was 1.3-fold higher after application of the second transdermal system compared to that after application of the first transdermal system. In a study designed to assess the effect of heat on the transdermal delivery of granisetron from SANCUSO in healthy subjects, a heat pad generating an average temperature of 42°C (107.6°F) was applied over the transdermal system for 4 hours each day over the 5 day period of wear.

The application of the heat pad was associated with an increase in plasma granisetron concentrations during the period of heat pad application. The elevated plasma concentration declined after removal of the heat pad. Mean C max with intermittent heat exposure was 6% higher than without heat.

Mean partial AUCs over 6 hours with 4 hour of heat application (AUC 0-6 , AUC 24-30 , and AUC 48-54 ) were 4.9, 1.4, and 1.1 fold higher, respectively, with heat pad than without heat pad [see Dosage and Administration ( 2 ), Warnings and Precautions ( 5.4 )] . Figure Distribution Plasma protein binding is approximately 65%. Granisetron distributes freely between plasma and red blood cells.

Elimination Metabolism Granisetron metabolism involves N-demethylation and aromatic ring oxidation followed by conjugation. In vitro liver microsomal studies show that granisetron's major route of metabolism is inhibited by ketoconazole, suggestive of metabolism mediated by the cytochrome P-450 3A subfamily. Animal studies suggest that some of the metabolites may also have 5-HT 3 receptor antagonist activity.

Excretion Clearance is predominantly by hepatic metabolism. Based on a study with intravenous injection, approximately 12% of the dose is excreted unchanged in the urine of healthy subjects in 48 hours. The remainder of the dose is excreted as metabolites, 49% in the urine, and 34% in the feces.

Use in Specific Populations Geriatric Patients Following application of SANCUSO transdermal system in healthy subjects, mean AUC 0-z , C max , and C avg were 17%, 15%, and 16% higher, respectively in male and female elderly subjects (≥ 65 years) compared to younger subjects (aged 18-45 years inclusive). These pharmacokinetic parameters were largely overlapped between the two age groups with high variability (CV: >50%). Following a single 40 mcg/kg intravenous dose of granisetron hydrochloride in elderly subjects (mean age 71 years), lower clearance and longer half-life were observed compared to younger healthy subjects.

Male and Female Patients There is evidence to suggest that female subjects had higher granisetron concentrations than males following transdermal system application. However, no statistically significant difference in clinical efficacy outcome was observed between males and females. Racial or Ethnic Groups… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics The effect of granisetron on QTc prolongation was evaluated in a randomized, single-blind, positive (moxifloxacin 400 mg) - and placebo controlled parallel study in healthy subjects. A total of 120 subjects were administered SANCUSO transdermal system (n=60) or intravenous granisetron (10 mcg/kg over 30 seconds; n=60). In a study with demonstrated ability to detect small effects, the upper bound of the 90% confidence interval for the largest placebo adjusted, baseline corrected QTc based on Fridericia correction method (QTcF) for SANCUSO was below 10 ms.

This study suggests that SANCUSO does not have significant effects on QT prolongation. No evidence of an effect on plasma prolactin or aldosterone concentrations has been found in studies using granisetron. The effect on oro-cecal transit time following application of SANCUSO has not been studied.

Granisetron hydrochloride injection exhibited no effect on oro-cecal transit time in healthy subjects given a single intravenous infusion of 50 mcg/kg or 200 mcg/kg. Single and multiple oral doses of granisetron hydrochloride slowed colonic transit in healthy subjects.

14 CLINICAL STUDIES The effectiveness of SANCUSO in the prevention of chemotherapy-induced nausea and vomiting (CINV) was evaluated in a randomized, parallel group, double-blind, double-dummy study conducted in the U.S. and abroad. The study compared the efficacy, tolerability and safety of SANCUSO transdermal system with that of 2 mg oral granisetron once daily in the prevention of nausea and vomiting in a total of 641 patients receiving multi-day chemotherapy. The population randomized into the trial included 48% males and 52% females aged 16 to 86 years receiving moderately emetogenic (ME) or highly emetogenic (HE) multi-day chemotherapy.

Seventy-eight (78%) of patients were White, 12% Asian, 10% Hispanic/Latino and 0% Black. SANCUSO was applied 24 to 48 hours before the first dose of chemotherapy and kept in place for 7 days. Oral granisetron was administered daily for the duration of the chemotherapy regimen, 1hour before each dose of chemotherapy.

Efficacy was assessed from the first administration until 24 hours after the start of the last day's administration of the chemotherapy regimen. The primary endpoint of the trial was the proportion of patients achieving no vomiting and/or retching, no more than mild nausea and no rescue medication from the first administration until 24 hours after the start of the last day's administration of multi-day chemotherapy. Using this definition, the effect of SANCUSO was established in 60.2% of patients in the SANCUSO arm and 64.8% of patients receiving oral granisetron (difference -4.89%; 95% confidence interval – 12.91% to +3.13%).

An assessment of transdermal system adhesion in 621 patients receiving either active or placebo transdermal system showed that less than 1% of transdermal systems became detached over the course of the 7 day period of transdermal system application.

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility In a 24-month carcinogenicity study, rats were treated orally with granisetron 1, 5 or 50 mg/kg/day (6, 30 or 300 mg/m 2 /day). The 50 mg/kg/day dose was reduced to 25 mg/kg/day (150 mg/m 2 /day) during week 59 due to toxicity. For a 50 kg person of average height (1.46 m 2 body surface area), these doses represent about 2.6, 13, and 65 times the recommended clinical dose (3.1 mg/day, 2.3 mg/m 2 /day, delivered by the SANCUSO transdermal system, on a body surface area basis).

There was a statistically significant increase in the incidence of hepatocellular carcinomas and adenomas in males treated with 5 mg/kg/day (30 mg/m 2 /day, about 13 times the recommended human dose with SANCUSO, on a body surface area basis) and above, and in females treated with 25 mg/kg/day (150 mg/m 2 /day, about 65 times the recommended human dose with SANCUSO, on a body surface area basis). No increase in liver tumors was observed at a dose of 1 mg/kg/day (6 mg/m 2 /day, about 2.6 times the recommended human dose with SANCUSO, on a body surface area basis) in males and 5 mg/kg/day (30 mg/m 2 /day, about 13 times the recommended human dose with SANCUSO, on a body surface area basis) in females.

In a 12-month oral toxicity study, treatment with granisetron 100 mg/kg/day (600 mg/m 2 /day, about 261 times the recommended human dose with SANCUSO, on a body surface area basis) produced hepatocellular adenomas in male and female rats while no such tumors were found in the control rats. A 24-month mouse carcinogenicity study of granisetron did not show a statistically significant increase in tumor incidence, but the study was not conclusive. Because of the tumor findings in rat studies, SANCUSO should be prescribed only at the dose and for the indication recommended [see Indications and Usage ( 1 ), Dosage and Administration ( 2 )] .

Granisetron was not mutagenic in an in vitro Ames test and mouse lymphoma cell forward mutation assay, and in vivo mouse micronucleus test and in vitro and ex vivo rat hepatocyte UDS assays. It, however, produced a significant increase in UDS in HeLa cells in vitro and a significant increased incidence of cells with polyploidy in an in vitro human lymphocyte chromosomal aberration test. Granisetron at subcutaneous doses up to 6 mg/kg/day (36 mg/m 2 /day, about 16 times the recommended human dose of SANCUSO, on a body surface area basis), and oral doses up to 100 mg/kg/day (600 mg/m 2 /day, about 261 times the recommended human dose of SANCUSO, on a body surface area basis) was found to have no effect on fertility and reproductive performance of male and female rats.

13.3Phototoxicity When tested for potential photogenotoxicity in vitro in a Chinese hamster ovary (CHO) cell line, at 200 and 300 mcg/mL, granisetron increased the percentage of cells with chromosomal aberration following photoirradiation [see Warnings and Precautions ( 5.5 )] . Granisetron was not phototoxic when tested in vitro in a mouse fibroblast cell line. When tested in vivo in guinea-pigs, SANCUSO transdermal system did not show any potential for photoirritation or photosensitivity.

No phototoxicity studies have been performed in humans.