Sancuso (Page 2 of 4)

8.3 Nursing Mothers

It is not known whether granisetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Sancuso is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of Sancuso in pediatric patients under 18 years of age have not been established.

8.5 Geriatric Use

Clinical studies of Sancuso did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, cautious treatment selection for an elderly patient is prudent because of the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Renal Failure or Hepatically-Impaired Patients

Although no studies have been performed to investigate the pharmacokinetics of Sancuso in patients with renal or hepatic impairment, pharmacokinetic information is available for intravenous granisetron (see CLINICAL PHARMACOLOGY: Pharmacokinetics 12.3).

10 OVERDOSAGE

There is no specific antidote for granisetron overdosage. In the case of overdosage, symptomatic treatment should be given.

Overdosage of up to 38.5 mg of granisetron hydrochloride, as a single intravenous injection, has been reported without symptoms or only the occurrence of a slight headache.

In clinical trials there were no reported cases of overdosage with Sancuso.

11 DESCRIPTION

Sancuso contains granisetron, which is an anti-nauseant and antiemetic agent. Chemically it is 1-methyl-N-[(1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]-1H-indazole-3-carboxamide with a molecular weight of 312.4. Its empirical formula is C18 H24 N4 O, while its chemical structure is:


sancuso-01

Granisetron is a white to off-white solid that is insoluble in water. Sancuso is a thin, translucent, matrix-type transdermal patch that is rectangular-shaped with rounded corners, consisting of a backing, the drug matrix and a release liner.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Granisetron is a selective 5-hydroxytryptamine3 (5-HT3 ) receptor antagonist with little or no affinity for other serotonin receptors, including 5-HT1 , 5-HT1A , 5-HT1B/C , 5-HT2 ; for alpha1 -, alpha2 -, or beta-adrenoreceptors; for dopamine-D2 ; or for histamine-H1 ; benzodiazepine; picrotoxin or opioid receptors.

Serotonin receptors of the 5-HT3 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-HT3 receptors. This evokes vagal afferent discharge, inducing vomiting. Animal studies demonstrate that, in binding to 5-HT3 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.

12.2 Pharmacodynamics

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 240 subjects were administered Sancuso patch, intravenous granisetron (10 mcg/kg over 30 seconds). 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, the threshold for regulatory concern.

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.

12.3 Pharmacokinetics

Absorption

Granisetron crosses intact skin into the systemic circulation by a passive diffusion process.

Following a 7-day application of Sancuso 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 patch application. Mean Cmax was 5.0 ng/mL (CV: 170%) and mean AUC0-168hr was 527 ng-hr/mL (CV:173%).

Mean Plasma Concentration of Granisetron (mean ± SD)


sancuso-02
(click image for full-size original)

Based on the measure of residual content of the patch after removal, approximately 66% (SD: ± 10.9) of granisetron is delivered following patch application for 7 days.

Distribution

Plasma protein binding is approximately 65%. Granisetron distributes freely between plasma and red blood cells.

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-HT3 receptor antagonist activity.

Elimination

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.

Subpopulations

Gender

There is evidence to suggest that female subjects had higher granisetron concentrations than males following patch application. However, no statistically significant difference in clinical efficacy outcome was observed between genders.

Pediatrics

No studies have been performed to investigate the pharmacokinetics of Sancuso in pediatrics.

Elderly, and Renal or Hepatic Impairment

Although no studies have been performed to investigate the pharmacokinetics of Sancuso in elderly subjects, and in patients with renal or hepatic impairment, the following pharmacokinetic information is available for intravenous granisetron.

In the elderly, and in patients with renal failure or hepatic impairment, the pharmacokinetics of granisetron were determined following a single 40 mcg/kg intravenous dose of granisetron hydrochloride.

Elderly

In elderly volunteers (mean age 71 years) pharmacokinetic parameters following a single 40 mcg/kg intravenous dose of granisetron hydrochloride, lower clearance and longer half-life were observed compared to younger healthy volunteers.

Renal Failure Patients

Total clearance of granisetron was not affected in patients with severe renal failure who received a single 40 mcg/kg intravenous dose of granisetron hydrochloride.

Hepatically-Impaired Patients

In patients with hepatic impairment due to neoplastic liver involvement, total plasma clearance following a single 40 mcg/kg intravenous dose of granisetron hydrochloride was approximately halved compared to patients without hepatic impairment. Given the wide variability in pharmacokinetic parameters of granisetron and the good tolerance of doses well above the recommended dose, dose adjustment in patients with hepatic functional impairment is not necessary.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis and 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/m2 /day). The 50 mg/kg/day dose was reduced to 25 mg/kg/day (150 mg/m2 /day) during week 59 due to toxicity. For a 50 kg person of average height (1.46 m2 body surface area), these doses represent about 2.6, 13 and 65 times the recommended clinical dose (3.1 mg/day, 2.3 mg/m2 /day, delivered by the Sancuso patch, 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/m2 /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/m2 /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/m2 /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/m2 /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/m2 /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, and DOSAGE AND ADMINISTRATION).

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/m2 /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/m2 /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.

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