Pharmacology: Mechanism of Action:
Granisetron is a selective 5–hydroxytryptamine3
) receptor antagonist with little or no affinity for other serotonin receptors, including 5-HT1
; for alpha1
-, 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.
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.
The effectiveness of Sancuso in the prevention of chemotherapy-induced nausea and vomiting (CINV) was evaluated in a Phase 3 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 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 (ME) or highly emetogenic (HE) multi-day chemotherapy. Seventy-eight (78%) of patients were White, 12% Asian, 10% Hispanic/Latino and 0% Black.
The granisetron patch 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, one hour 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 patch adhesion in 621 patients receiving either active or placebo patches showed that less than 1% of patches became detached over the course of the 7 day period of patch application.
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%). (See Figure.)
Click on icon to see table/diagram/image
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.
Plasma protein binding is approximately 65%. Granisetron distributes freely between plasma and red blood cells.
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.
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.
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.
Nonclinical Toxicology: 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 astatistically 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 Dosage & 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.
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.
Granisetron was not phototoxic when tested in vitro
in a mouse fibroblast cell line. When tested in vivo
in guinea-pigs, Sancuso patches did not show any potential for photoirritation or photosensitivity. No phototoxicity studies have been performed in humans.