ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Chemotherapy-Induced Nausea and Vomiting. Over 3700 patients have received Granisetron HCl Tablets in clinical trials with emetogenic cancer therapies consisting primarily of cyclophosphamide or cisplatin regimens. In patients receiving GranisetronHCl Tablets mg bid for 1, or 14 days, or mg qd for day, adverse experiences reported in more than 5% of the patients with comparator and placebo incidences are listed in Table 4.Other adverse events reported in clinical trials were:Table Principal Adverse Events in Clinical Trials Percent of Patients With Event Granisetron HClAdverse events were recorded for days when granisetron hydrochloride tablets were given on single day and for up to 28 days when granisetron hydrochloride tablets were administered for or 14 days. tablets1 mg bid(n=978)Granisetron HCl tablets2mg qd(n=1450)ComparatorMetoclopramide/dexamethasone; phenothiazines/dexamethasone; dexamethasone alone; prochlorperazine. (n=599)Placebo(n=185)HeadacheUsually mild to moderate in severity. 21% 20% 13% 12% Constipation 18% 14% 16% 8% Asthenia 14% 18% 10% 4% Diarrhea 8% 9% 10% 4% Abdominal pain 6% 4% 6% 3% Dyspepsia 4% 6% 5% 4% Gastrointestinal:In single-day dosing studies in which adverse events were collected for days, nausea (20%) and vomiting (12%) were recorded as adverse events after the 24-hour efficacy assessment period.Hepatic:In comparative trials, elevation of AST and ALT (>2 times the upper limit of normal) following the administration of granisetron hydrochloride tablets occurred in 5% and 6% of patients, respectively. These frequencies were not significantly different from those seen with comparators (AST: 2%; ALT: 9%).Cardiovascular:Hypertension (1%); hypotension, angina pectoris, atrial fibrillation, and syncope have been observed rarely.Central Nervous System:Dizziness (5%), insomnia (5%), anxiety (2%), somnolence (1%). One case compatible with, but not diagnostic of, extrapyramidal symptoms have been reported in patient treated with Granisetron HCl Tablets.Hypersensitivity:Rare cases of hypersensitivity reactions, sometimes severe (eg, anaphylaxis, shortness of breath, hypotension, urticaria) have been reported.Other:Fever (5%). Events often associated with chemotherapy also have been reported: leukopenia(9%), decreased appetite (6%), anemia (4%), alopecia (3%), thrombocytopenia (2%).Over 5000 patients have received injectable granisetron hydrochloride in clinical trials.Table 5gives the comparative frequencies of the five commonly reported adverse events (>=3%) in patients receiving granisetron hydrochloride Injection, 40 mcg/kg, in single-day chemotherapy trials. These patients received chemotherapy, primarily cisplatin, and intravenous fluids during the 24-hour period following granisetron hydrochloride Injection administration. Percent of Patients with Event Granisetron hydrochlorideAdverse events were generally recorded over days post- granisetron hydrochloride Injection administration Injection40 mcg/kg(n=1268)ComparatorMetoclopramide/dexamethasone and phenothiazines/dexamethasone. (n=422)Headache 14% 6% Asthenia 5% 6% Somnolence 4% 15% Diarrhea 4% 6% Constipation 3% 3% In the absence of placebo group, there is uncertainty as to how many of these events should be attributed to granisetron hydrochloride, except for headache, which was clearly more frequent than in comparison groups.. Radiation-Induced Nausea and Vomiting. In controlled clinical trials, the adverse events reported by patients receiving Granisetron HCl Tablets and concurrent radiation were similar to those reported by patients receiving Granisetron HCl Tablets prior to chemotherapy. The most frequently reported adverse events were diarrhea, asthenia, and constipation. Headache, however, was less prevalent in this patient population.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment Of Fertility. In 24-month carcinogenicity study, rats were treated orally with granisetron 1, or 50 mg/kg/day (6, 30 or 300 mg/m2/day). The 50mg/kg/day dose was reduced to 25 mg/kg/day (150 mg/m2/day) during week 59 due to toxicity. For 50 kg person of average height (1.46 m2 body surface area), these doses represent 4, 20, and 101 times the recommended clinical dose (1.48 mg/m2, oral) on body surface area basis. There was statistically significant increase in the incidence of hepatocellular carcinomas and adenomas in males treated with mg/kg/day (30 mg/m2/day, 20 times the recommended human dose based on body surface area) and above, and in females treated with 25 mg/kg/day (150 mg/m2/day, 101 times the recommended human dose based on body surface area). No increase in liver tumors was observed at dose of mg/kg/day (6 mg/m2/day, times the recommended human dose based on body surface area) in males and mg/kg/day (30 mg/m2/day, 20 times the recommended human dose based on body surface area) in females. In 12-month oral toxicity study, treatment with granisetron 100 mg/kg/day (600 mg/m2/day, 405 times the recommended human dose based on body surface area) produced hepatocellular adenomas in male and female rats while no such tumors were found in the control rats. 24-month mouse carcinogenicity study of granisetron did not show statistically significant increase in tumor incidence, but the study was not conclusive.Because of the tumor findings in rat studies, granisetron hydrochloride 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 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 significant increase in UDS in HeLa cells in vitro and significant increased incidence of cells with polyploidy in an in vitro human lymphocyte chromosomal aberration test. Granisetron at oral doses up to 100 mg/kg/day (600 mg/m2/day, 405 times the recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Granisetron is 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, single granisetron injection prevented vomiting due to high-dose cisplatin or arrested vomiting within to 30 seconds. In most human studies, granisetron has had little effect on blood pressure, heart rate or ECG. No evidence of an effect on plasma prolactin or aldosterone concentrations has been found in other studies. Following single and multiple oral doses, Granisetron HCl Tablets slowed colonic transit in normal volunteers. However, Granisetron HCl had no effect on oro-cecal transit time in normal volunteers when given as single intravenous (IV) infusion of 50 mcg/kg or 200 mcg/kg. Pharmacokinetics. In healthy volunteers and adult cancer patients undergoing chemotherapy, administration of Granisetron HCl Tablets produced mean pharmacokinetic data shown in Table 1.Table Pharmacokinetic Parameters (Median [range]). Following Granisetron HCl Tablets Not determined after oral administration; following single intravenous dose of 40 mcg/kg, terminal phase half-life was determined to be 8.95 hoursN.D. Not determined Peak Plasma Concentration(ng/mL)Terminal Phase Plasma Half-Life(h)Volume of Distribution(L/kg)Total Clearance(L/h/kg)Cancer Patients mg bid, days(n=27)5.99[0.63 to 30.9] N.D. N.D. 0.52[0.09 to 7.37] Volunteers single mg dose(n=39)3.63[0.27 to 9.14] 6.23[0.96 to 19.9] 3.94[1.89 to 39.4] 0.41[0.11 to 24.6] AbsorptionWhen Granisetron hydrochloride tablets were administered with food, AUC was decreased by 5% and Cmax increased by 30% in non-fasted healthy volunteers who received single dose of 10 mg.DistributionPlasma protein binding is approximately 65% and granisetron distributes freely between plasma and red blood cells.MetabolismGranisetron metabolism involves N-demethylation and aromatic ring oxidation followed by conjugation. In vitro liver microsomal studies show that granisetrons 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. In normal volunteers, approximately 11% of the orally administered dose is eliminated unchanged in the urine in 48 hours. The remainder of the dose is excreted as metabolites, 48% in the urine and 38% in the feces. Subpopulation. GenderThe effects of gender on the pharmacokinetics of Granisetron HCl Tablets have not been studied. However, after intravenous infusion of Granisetron HCl, no difference in mean AUC was found between males and females, although males had higher Cmax generally. In elderly and pediatric patients and in patients with renal failure or hepatic impairment, the pharmacokinetics of granisetron was determined following administration of intravenous granisetron hydrochloride. Elderly The ranges of the pharmacokinetic parameters in elderly volunteers (mean age 71 years), given single 40 mcg/kg intravenous dose of granisetron hydrochloride injection, were generally similar to those in younger healthy volunteers; mean values were lower for clearance and longer for half-life in the elderly. Renal Failure Patients Total clearance of granisetron was not affected in patients with severe renal failure who received single 40 mcg/kg intravenous dose of granisetron hydrochloride Injection. Hepatically Impaired Patients: pharmacokinetic study with intravenous granisetron hydrochloride in patients with hepatic impairment due to neoplastic liver involvement showed that total clearance was approximately halved compared to patients without hepatic impairment. Given the wide variability in pharmacokinetic parameters noted in patients and the good tolerance of doses well above the recommended dose, dosage adjustment in patients with possible hepatic functional impairment is not necessary. Pediatric Patients: pharmacokinetic study in pediatric cancer patients (2 to 16 years of age), given single 40 mcg/kg intravenous dose of granisetron hydrochloride Injection, showed that volume of distribution and total clearance increased with age. No relationship with age was observed for peak plasma concentration or terminal phase plasma half-life. When volume of distribution and total clearance are adjusted for body weight, the pharmacokinetics of granisetron are similar in pediatric and adult cancer patients.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE ADMINISTRATION. Emetogenic Chemotherapy The recommended adult dosage of oral Granisetron HCl (granisetron hydrochloride) is mg once daily or mg twice daily. In the mg once-daily regimen, two mg tablets are given up to hour before chemotherapy. In the mg twice-daily regimen, the first mg tablet is given up to hour before chemotherapy, and the second tablet 12 hours after the first. Either regimen is administered only on the day(s) chemotherapy is given. Continued treatment, while not on chemotherapy, has not been found to be useful.Use in the Elderly, Pediatric Patients, Renal Failure Patients or Hepatically Impaired PatientsNo dosage adjustment is recommended (see CLINICAL PHARMACOLOGY: Pharmacokinetics ). Radiation (Either Total Body Irradiation or Fractionated Abdominal Radiation)The recommended adult dosage of oral granisetron hydrochloride is mg once daily. Two mg tablets are taken within hour of radiation.Pediatric UseThere is no experience with oral Granisetron HCl in the prevention of radiation-induced nausea and vomiting in pediatric patients.Use in the ElderlyNo dosage adjustment is recommended.

DRUG INTERACTIONS SECTION.

Drug Interactions. Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system in vitro. There have been no definitive drug-drug interaction studies to examine pharmacokinetic or pharmacodynamic interaction with other drugs; however, in humans, Granisetron hydrochloride Injection has been safely administered with drugs representing benzodiazepines, neuroleptics, and anti-ulcer medications commonly prescribed with antiemetic treatments. Granisetron hydrochloride Injection also does not appear to interact with emetogenic cancer chemotherapies. Because granisetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes, inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of granisetron. No specific interaction studies have been conducted in anesthetized patients. In addition, the activity of the cytochrome P-450 subfamily 3A4 (involved in the metabolism of some of the main narcotic analgesic agents) is not modified by granisetron hydrochloride in vitro. In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of Granisetron HCl. However, the clinical significance of in vivo pharmacokinetic interactions with ketoconazole is not known. In human pharmacokinetic study, hepatic enzyme induction with phenobarbital resulted in 25% increase in total plasma clearance of intravenous Granisetron HCl. The clinical significance of this change is not known.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Granisetron Hydrochloride Tablets-20 Tablets. RX Only NDC67877-184-20 Each tablet contains 1.12 mg of granisetron Hydrochloride equivalent to granisetron, mg. This unit-dose package is not-child-resistant. For institutional use only. Dosage: Chemotherapy: mg once daily or 1mg twice daily. In the mg once daily regimen, two mg tablets are given up to hour before chemotherapy. In the mg twice daily regimen, the first mg tablet is given up to hour before chemotherapy and the second tablet 12 hours after the first. Radiation: Two 1mg tablets are taken within hour of radiation. See accompanying prescribing information. Store between 20o and 25oC (68o and 77oF) [see USP Controlled Room Temperature]. Protect from light. Retain in carton until time of use. M.L.: 164/MN/AP/95/F/R Mfd for: Ascend Laboratories,Montvale, NJ07645. Mfd by: Natco Pharma Limited,Kothur 509 228, AP, India. Blister Art Work. carton label 20tablets. blister art work 20 tablets.

PRECAUTIONS SECTION.

PRECAUTIONS. Granisetron HCl is not drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction. The use of Granisetron HCl in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask progressive ileus and/or gastric distention.. Drug Interactions. Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system in vitro. There have been no definitive drug-drug interaction studies to examine pharmacokinetic or pharmacodynamic interaction with other drugs; however, in humans, Granisetron hydrochloride Injection has been safely administered with drugs representing benzodiazepines, neuroleptics, and anti-ulcer medications commonly prescribed with antiemetic treatments. Granisetron hydrochloride Injection also does not appear to interact with emetogenic cancer chemotherapies. Because granisetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes, inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of granisetron. No specific interaction studies have been conducted in anesthetized patients. In addition, the activity of the cytochrome P-450 subfamily 3A4 (involved in the metabolism of some of the main narcotic analgesic agents) is not modified by granisetron hydrochloride in vitro. In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of Granisetron HCl. However, the clinical significance of in vivo pharmacokinetic interactions with ketoconazole is not known. In human pharmacokinetic study, hepatic enzyme induction with phenobarbital resulted in 25% increase in total plasma clearance of intravenous Granisetron HCl. The clinical significance of this change is not known.. Carcinogenesis, Mutagenesis, Impairment Of Fertility. In 24-month carcinogenicity study, rats were treated orally with granisetron 1, or 50 mg/kg/day (6, 30 or 300 mg/m2/day). The 50mg/kg/day dose was reduced to 25 mg/kg/day (150 mg/m2/day) during week 59 due to toxicity. For 50 kg person of average height (1.46 m2 body surface area), these doses represent 4, 20, and 101 times the recommended clinical dose (1.48 mg/m2, oral) on body surface area basis. There was statistically significant increase in the incidence of hepatocellular carcinomas and adenomas in males treated with mg/kg/day (30 mg/m2/day, 20 times the recommended human dose based on body surface area) and above, and in females treated with 25 mg/kg/day (150 mg/m2/day, 101 times the recommended human dose based on body surface area). No increase in liver tumors was observed at dose of mg/kg/day (6 mg/m2/day, times the recommended human dose based on body surface area) in males and mg/kg/day (30 mg/m2/day, 20 times the recommended human dose based on body surface area) in females. In 12-month oral toxicity study, treatment with granisetron 100 mg/kg/day (600 mg/m2/day, 405 times the recommended human dose based on body surface area) produced hepatocellular adenomas in male and female rats while no such tumors were found in the control rats. 24-month mouse carcinogenicity study of granisetron did not show statistically significant increase in tumor incidence, but the study was not conclusive.Because of the tumor findings in rat studies, granisetron hydrochloride 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 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 significant increase in UDS in HeLa cells in vitro and significant increased incidence of cells with polyploidy in an in vitro human lymphocyte chromosomal aberration test. Granisetron at oral doses up to 100 mg/kg/day (600 mg/m2/day, 405 times the recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.. Pregnancy. Teratogenic Effects Pregnancy Category B. Reproduction studies have been performed in pregnant rats at oral doses up to 125 mg/kg/day (750 mg/m2/day, 507 times the recommended human dose based on body surface area) and pregnant rabbits at oral doses up to 32 mg/kg/day (378 mg/m2/day, 255 times the recommended human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to granisetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.. 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 Granisetron HCl is administered to nursing woman.. Pediatric Use. Safety and effectiveness in pediatric patients have not been established.. Geriatric Use. During clinical trials, 325 patients 65 years of age or older received Granisetron HCl Tablets; 298 were 65 to 74 years of age, and 27 were 75 years of age or older. Efficacy and safety were maintained with increasing age.