modified by granisetron hydrochloride in vitro. in in vitro human microsomal studies, ketoconazole inhibited ring oxidation of granisetron. however, the clinical significance of in vivo pharmacokinetic interactions with ketoconazole is not known. in a human pharmacokinetic study, hepatic enzyme induction with phenobarbital resulted in a 25% increase in total plasma clearance of intravenous granisetron. the clinical significance of this change is not known. qt prolongation has been reported with granisetron hydrochloride. use of granisetron hydrochloride in patients concurrently treated with drugs known to prolong the qt interval and/or are arrhythmogenic may result in clinical consequences. serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-ht 3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (ssris) and serotonin and noradrenaline reuptake inhibitors (snris) [see warnings].

erthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, with or without gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). patients should be monitored for the emergence of serotonin syndrome, especially with concomitant use of granisetron and other serotonergic drugs. if symptoms of serotonin syndrome occur, discontinue granisetron and initiate supportive treatment. patients should be informed of the increased risk of serotonin syndrome, especially if granisetron is used concomitantly with other serotonergic drugs (see drug interactions and patient counseling information ).

radiation. pediatric use safety and effectiveness in pediatric patients have not been established. use in the elderly no dosage adjustment is recommended.

of patients with even granisetron hydrochloride tablets * 1 mg twice a day (n=978) granisetron hydrochloride tablets * 2 mg once a day (n=1450) comparator † (n=599) placebo (n=185) headache 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% 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 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 has been reported in a patient treated with granisetron 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 5 gives 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. table 5: principal adverse events in clinical trials — single-day chemotherapy percent of patients with event granisetron hydrochloride injection * 40mcg/kg (n=1268) comparator † (n=422) headache 14% 6% asthenia 5% 6% somnolence 4% 15% diarrhea 4% 6% constipation 3% 3% * adverse events were generally recorded over 7 days post- granisetron hydrochloride injection administration. † metoclopramide/dexamethasone and phenothiazines/dexamethasone. in the absence of a placebo group, there is uncertainty as to how many of these events should be attributed to granisetron, 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 tablets and concurrent radiation were similar to those reported by patients receiving granisetron tablets prior to chemotherapy. the most frequently reported adverse events were diarrhea, asthenia, and constipation. headache, however, was less prevalent in this patient population. postmarketing experience qt prolongation has been reported with granisetron ( see precautions and drug interactions ).

modified by granisetron hydrochloride in vitro. in in vitro human microsomal studies, ketoconazole inhibited ring oxidation of granisetron. however, the clinical significance of in vivo pharmacokinetic interactions with ketoconazole is not known. in a human pharmacokinetic study, hepatic enzyme induction with phenobarbital resulted in a 25% increase in total plasma clearance of intravenous granisetron. the clinical significance of this change is not known. qt prolongation has been reported with granisetron hydrochloride. use of granisetron hydrochloride in patients concurrently treated with drugs known to prolong the qt interval and/or are arrhythmogenic may result in clinical consequences. serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular symptoms) has been described following the concomitant use of 5-ht 3 receptor antagonists and other serotonergic drugs, including selective serotonin reuptake inhibitors (ssris) and serotonin and noradrenaline reuptake inhibitors (snris) [see warnings].

5 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 hydrochloride tablets slowed colonic transit in normal volunteers. however, granisetron hydrochloride had no effect on oro-cecal transit time in normal volunteers when given as a 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 hydrochloride tablets produced mean pharmacokinetic data shown in table 1. table 1: pharmacokinetic parameters (median [range]) following granisetron hydrochloride tablets * 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. peak plasma concentration (ng/ml) terminal phase plasma 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. * 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] absorption when granisetron 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 granisetron hydrochloride tablets have not been studied. however, after intravenous infusion of granisetron hydrochloride, 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 granisetron. elderly the ranges of the pharmacokinetic parameters in elderly volunteers (mean age 71 years), given a 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 a single 40 mcg/kg intravenous dose of granisetron hydrochloride injection. hepatically impaired patients a 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, dosage adjustment in patients with 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 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

0 mg/m 2 /day, 20 times the recommended human dose based on body surface area) in females. in a 12 month oral toxicity study, treatment with granisetron 100 mg/kg/day (600 mg/m 2 /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. 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, 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 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 oral doses up to 100 mg/kg/day (600 mg/m 2 /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.