Granisetron Hydrochloride

INDICATIONS AND USAGE Granisetron is indicated for the prevention of: Nausea and vomiting associated with initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin. Nausea and vomiting associated with radiation, including total body irradiation and fractionated abdominal radiation.

DOSAGE AND ADMINISTRATION Emetogenic Chemotherapy The recommended adult dosage of oral granisetron hydrochloride is 2 mg once daily or 1 mg twice daily. In the 2 mg once-daily regimen, 10 mL of GRANISOL oral solution (2 teaspoonfuls, equivalent to 2 mg of granisetron) are given up to 1 hour before chemotherapy. In the 1 mg twice-daily regimen, the first teaspoonful (5 mL) of GRANISOL oral solution is given up to 1 hour before chemotherapy, and the second teaspoonful (5 mL) of GRANISOL oral solution, 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, Renal Failure Patients or Hepatically Impaired Patients No dosage adjustment is recommended (see CLINICAL PHARMACOLOGY: Pharmacokinetics ). Pediatric Use Safety and effectiveness in pediatric patients have not been established. Radiation (Either Total Body Irradiation or Fractionated Abdominal Radiation) The recommended adult dosage of oral granisetron hydrochloride is 2 mg once daily. Ten milliliters of GRANISOL oral solution (2 teaspoonfuls, equivalent to 2 mg of granisetron) are taken within 1 hour of radiation. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Use in the Elderly No dosage adjustment is recommended.

ADVERSE REACTIONS QT prolongation has been reported with granisetron (see PRECAUTIONS and Drug Interactions ). Chemotherapy-Induced Nausea and Vomiting Over 3700 patients have received Kytril tablets in clinical trials with emetogenic cancer therapies consisting primarily of cyclophosphamide or cisplatin regimens. In patients receiving Kytril tablets 1 mg bid for 1, 7 or 14 days, or 2 mg daily for 1 day, adverse experiences reported in more than 5% of the patients with comparator and placebo incidences are listed in Table 4 . Table 4 Principal Adverse Events in Clinical Trials Percent of Patients With Event Kytril 1 Tablets 1 mg twice a day (n=978) Kytril 1 Tablets 2 mg once a day N=1450) Comparator 2 (n=599) Placebo (n=185) Headache 3 21% 20% 13% 12% Constipation 18% 14% 16% 8% Asthenia 14% 18% 10% 45 Diarrhea 8% 9% 10% 4% Abdominal Pain 6% 4% 6% 3% Dyspepsia 4% 6% 5% 4% 1 Adverse events were recorded for 7 days when Kytril tablets were given on a single day and for up to 28 days when Kytril tablets were administered for 7 or 14 days. 2 Metoclopramide/dexamethasone; phenothiazines/dexamethasone; dexamethasone alone; prochlorperazine. 3 Usually mild to moderate in severity. Other adverse events reported in clinical trials were: Gastrointestinal : In single-day dosing studies in which adverse events were collected for 7 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 Kytril 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 has been reported in a patient treated with Kytril 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 Kytril in clinical trials. Table 5 gives the comparative frequencies of the five commonly reported adverse events (≥3%) in patients receiving Kytril injection, 40 mcg/kg, in single-day chemotherapy trials. These patients received chemotherapy, primarily cisplatin, and intravenous fluids during the 24-hour period following Kytril injection administration. Table 5 Principal Adverse Events in Clinical Trials - Single-Day Chemotherapy Percent of Patients With Event Kytril Injection 1 40 mcg/kg (n=1268) Comparator 2 (n=422) Headache 14% 6% Asthenia 5% 6% Somnolence 4% 15% Diarrhea 4% 6% Constipation 3% 3% 1 Adverse events were generally recorded over 7 days post-Kytril injection administration. 2 Metoclopramide/dexamethasone and phenothiazines/dexamethasone.

Pharmacokinetics In healthy volunteers and adult cancer patients undergoing chemotherapy, administration of Kytril tablets produced mean pharmacokinetic data shown in Table 1 . Table 1 Pharmacokinetic Parameters (Median [range]) Following Kytril Tablets 1 Not determined after oral administration; following a single intravenous dose of 40 mcg/kg, terminal phase half-life was determined to be 8.95 hours. N.D. Not determined. Peak Plasma Concentration (ng/mL) Terminal Phase Half-Life (h) Volume of Distribution (L/kg) Total Clearance (L/h/kg) Cancer Patients 1 mg bid, 7 days (n=27) 5.99 [0.63 to 30.9] N.D. 1 N.D. 0.52 [0.09 to 7.37] Volunteers Single 1 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] A 2 mg dose of GRANISOL oral solution is bioequivalent to the corresponding dose of Kytril tablets (1 mg x 2) and may be used interchangeably. Absorption When Kytril tablets were administered with food, AUC was decreased by 5% and C max increased by 30% in non-fasted healthy volunteers who received a single dose of 10 mg. Distribution Plasma protein binding is approximately 65% and 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-HT 3 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. Subpopulations Gender The effects of gender on the pharmacokinetics of Kytril tablets have not been studied. However, after intravenous infusion of granisetron, no difference in mean AUC was found between males and females, although males had a higher C max 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 Kytril. Elderly The ranges of the pharmacokinetic parameters in elderly volunteers (mean age 71 years), given a single 40-mcg/kg intravenous dose of Kytril 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 a single 40 mcg/kg intravenous dose of Kytril injection. Hepatically Impaired Patients A pharmacokinetic study with intravenous Kytril 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, dosage adjustment in patients with possible hepatic functional impairment is not necessary. Pediatric Patients A pharmacokinetic study in pediatric cancer patients (2 to 16 years of age), given a single 40 mcg/kg intravenous dose of Kytril 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.