t modified by granisetron hydrochloride in vitro . in in vitro human microsomal studies, ketoconazole inhibited ring oxidation of granisetron hydrochloride. 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 hydrochloride. 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 and precautions (5.4) ] . granisetron hydrochloride injection has been administered safely with benzodiazepines, neuroleptics, and anti-ulcer medications. ( 7 ) does not appear to interact with emetogenic cancer chemotherapies. ( 7 ) inducers or inhibitors of cyp450 enzymes may change the clearance and therefore the half-life of granisetron. ( 7 ) coadministration of granisetron hydrochloride injection with drugs known to prolong the qt interval and/or are arrhythmogenic may result in clinical consequences. ( 7 )

nd treatment of postoperative nausea and vomiting in adults. ( 1 )

progressive ileus and/or gastric distention. 5.2 cardiovascular events an adequate qt assessment has not been conducted, but qt prolongation has been reported with granisetron hydrochloride. therefore, granisetron hydrochloride should be used with caution in patients with pre-existing arrhythmias or cardiac conduction disorders, as this might lead to clinical consequences. patients with cardiac disease, on cardio-toxic chemotherapy, with concomitant electrolyte abnormalities and/or on concomitant medications that prolong the qt interval are particularly at risk. 5.3 hypersensitivity reactions hypersensitivity reactions (e.g., anaphylaxis, shortness of breath, hypotension, urticaria) may occur in patients who have exhibited hypersensitivity to other selective 5-ht 3 receptor antagonists. 5.4 serotonin syndrome the development of serotonin syndrome has been reported with 5-ht 3 receptor antagonists. most reports have been associated with concomitant use of serotonergic drugs (e.g., selective serotonin reuptake inhibitors (ssris), serotonin and norepinephrine reuptake inhibitors (snris), monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol, and intravenous methylene blue). some of the reported cases were fatal. serotonin syndrome occurring with overdose of another 5-ht 3 receptor antagonist alone has also been reported. the majority of reports of serotonin syndrome related to 5-ht 3 receptor antagonist use occurred in a post-anesthesia care unit or an infusion center. symptoms associated with serotonin syndrome may include the following combination of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), 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 (7) , patient counseling information (17) ] .

mia), 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 (7) , patient counseling information (17) ] .

30 seconds, or diluted with 0.9% sodium chloride or 5% dextrose and infused over 5 minutes. stability intravenous infusion of granisetron hydrochloride injection should be prepared at the time of administration. however, granisetron hydrochloride injection has been shown to be stable for at least 24 hours when diluted in 0.9% sodium chloride or 5% dextrose and stored at room temperature under normal lighting conditions. as a general precaution, granisetron hydrochloride injection should not be mixed in solution with other drugs. parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit. pediatric patients the recommended dose in pediatric patients 2 to 16 years of age is 10 mcg/kg [see clinical studies (14) ] . pediatric patients under 2 years of age have not been studied. 2.2 prevention and treatment of postoperative nausea and vomiting adult patients the recommended dosage for prevention of postoperative nausea and vomiting is 1 mg of granisetron hydrochloride injection, undiluted, administered intravenously over 30 seconds, before induction of anesthesia or immediately before reversal of anesthesia. the recommended dosage for the treatment of nausea and/or vomiting after surgery is 1 mg of granisetron hydrochloride injection, undiluted, administered intravenously over 30 seconds.

and discoloration before administration whenever solution and container permit. pediatric patients the recommended dose in pediatric patients 2 to 16 years of age is 10 mcg/kg [see clinical studies (14) ] . pediatric patients under 2 years of age have not been studied.

are based on clinical trial experience only. table 1 gives the comparative frequencies of the two most commonly reported adverse reactions (≥3%) in patients receiving granisetron hydrochloride injection, in single-day chemotherapy trials. these patients received chemotherapy, primarily cisplatin, and intravenous fluids during the 24-hour period following granisetron hydrochloride injection administration. reactions were generally recorded over seven days post-granisetron hydrochloride injection administration. table 1: principal adverse reactions in clinical trials — single-day chemotherapy percent of patients with reaction granisetron hydrochloride injection 40 mcg/kg (n=1,268) comparator 1 (n=422) headache constipation 14% 3% 6% 3% 1 metoclopramide/dexamethasone and phenothiazines/dexamethasone. additional adverse events reported in clinical trials were asthenia, somnolence and diarrhea. in over 3,000 patients receiving granisetron hydrochloride injection (2 to 160 mcg/kg) in single-day and multiple-day clinical trials with emetogenic cancer therapies, adverse events, other than those adverse reactions listed in table 1, were observed; attribution of many of these events to granisetron hydrochloride is uncertain. hepatic: in comparative trials, mainly with cisplatin regimens, elevations of ast and alt (>2 times the upper limit of normal) following administration of granisetron hydrochloride injection occurred in 2.8% and 3.3% of patients, respectively. these frequencies were not significantly different from those seen with comparators (ast: 2.1%; alt: 2.4%). cardiovascular: hypertension (2%); hypotension, arrhythmias such as sinus bradycardia, atrial fibrillation, varying degrees of a-v block, ventricular ectopy including non-sustained tachycardia, and ecg abnormalities have been observed rarely. central nervous system: agitation, anxiety, cns stimulation and insomnia were seen in less than 2% of patients. extrapyramidal syndrome occurred rarely and only in the presence of other drugs associated with this syndrome. hypersensitivity: rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylaxis, shortness of breath, hypotension, urticaria) have been reported. other: fever (3%), taste disorder (2%), skin rashes (1%). in multiple-day comparative studies, fever occurred more frequently with granisetron hydrochloride injection (8.6%) than with comparative drugs (3.4%, p <0.014), which usually included dexamethasone. postoperative nausea and vomiting the adverse reactions listed in table 2 were reported in ≥ 2% of adults receiving granisetron hydrochloride injection 1 mg during controlled clinical trials. table 2: adverse reactions in controlled clinical trials in postoperative nausea a nd vomiting (reported in ≥ 2% of adults receiving granisetron hydrochloride injection 1 mg) percent of patients with reaction granisetron hydrochloride injection 1 mg (n=267) placebo (n=266) pain 10.1 8.3 headache 8.6 7.1 fever 7.9 4.5 abdominal pain 6 6 hepatic enzymes increased 5.6 4.1 dizziness 4.1 3.4 diarrhea 3.4 1.1 flatulence 3 3 dyspepsia 3 1.9 oliguria 2.2 1.5 coughing 2.2 1.1 additional adverse events reported in clinical trials were constipation, anemia, insomnia, bradycardia, leukocytosis, anxiety, hypotension, infection, hypertension, and urinary tract infection. in a clinical study conducted in japan, the types of adverse events differed notably from those reported above in table 2. the adverse events in the japanese study that occurred in ≥ 2% of patients and were more frequent with granisetron hydrochloride injection 1 mg than with placebo were: fever (56% to 50%), sputum increased (2.7% to 1.7%), and dermatitis (2.7% to 0%). 6.2 postmarketing experience the following adverse reactions have been identified during post approval use of granisetron hydrochloride. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to granisetron hydrochloride exposure. qt prolongation has been reported with granisetron hydrochloride [see warnings and precautions (5.2) and drug interactions (7) ].

incipal adverse reactions in clinical trials — single-day chemotherapy percent of patients with reaction granisetron hydrochloride injection 40 mcg/kg (n=1,268) comparator 1 (n=422) headache constipation 14% 3% 6% 3% 1 metoclopramide/dexamethasone and phenothiazines/dexamethasone. additional adverse events reported in clinical trials were asthenia, somnolence and diarrhea. in over 3,000 patients receiving granisetron hydrochloride injection (2 to 160 mcg/kg) in single-day and multiple-day clinical trials with emetogenic cancer therapies, adverse events, other than those adverse reactions listed in table 1, were observed; attribution of many of these events to granisetron hydrochloride is uncertain. hepatic: in comparative trials, mainly with cisplatin regimens, elevations of ast and alt (>2 times the upper limit of normal) following administration of granisetron hydrochloride injection occurred in 2.8% and 3.3% of patients, respectively. these frequencies were not significantly different from those seen with comparators (ast: 2.1%; alt: 2.4%). cardiovascular: hypertension (2%); hypotension, arrhythmias such as sinus bradycardia, atrial fibrillation, varying degrees of a-v block, ventricular ectopy including non-sustained tachycardia, and ecg abnormalities have been observed rarely. central nervous system: agitation, anxiety, cns stimulation and insomnia were seen in less than 2% of patients. extrapyramidal syndrome occurred rarely and only in the presence of other drugs associated with this syndrome. hypersensitivity: rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylaxis, shortness of breath, hypotension, urticaria) have been reported. other: fever (3%), taste disorder (2%), skin rashes (1%). in multiple-day comparative studies, fever occurred more frequently with granisetron hydrochloride injection (8.6%) than with comparative drugs (3.4%, p <0.014), which usually included dexamethasone. postoperative nausea and vomiting the adverse reactions listed in table 2 were reported in ≥ 2% of adults receiving granisetron hydrochloride injection 1 mg during controlled clinical trials. table 2: adverse reactions in controlled clinical trials in postoperative nausea a nd vomiting (reported in ≥ 2% of adults receiving granisetron hydrochloride injection 1 mg) percent of patients with reaction granisetron hydrochloride injection 1 mg (n=267) placebo (n=266) pain 10.1 8.3 headache 8.6 7.1 fever 7.9 4.5 abdominal pain 6 6 hepatic enzymes increased 5.6 4.1 dizziness 4.1 3.4 diarrhea 3.4 1.1 flatulence 3 3 dyspepsia 3 1.9 oliguria 2.2 1.5 coughing 2.2 1.1 additional adverse events reported in clinical trials were constipation, anemia, insomnia, bradycardia, leukocytosis, anxiety, hypotension, infection, hypertension, and urinary tract infection. in a clinical study conducted in japan, the types of adverse events differed notably from those reported above in table 2. the adverse events in the japanese study that occurred in ≥ 2% of patients and were more frequent with granisetron hydrochloride injection 1 mg than with placebo were: fever (56% to 50%), sputum increased (2.7% to 1.7%), and dermatitis (2.7% to 0%).

t modified by granisetron hydrochloride in vitro . in in vitro human microsomal studies, ketoconazole inhibited ring oxidation of granisetron hydrochloride. 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 hydrochloride. 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 and precautions (5.4) ] . granisetron hydrochloride injection has been administered safely with benzodiazepines, neuroleptics, and anti-ulcer medications. ( 7 ) does not appear to interact with emetogenic cancer chemotherapies. ( 7 ) inducers or inhibitors of cyp450 enzymes may change the clearance and therefore the half-life of granisetron. ( 7 ) coadministration of granisetron hydrochloride injection with drugs known to prolong the qt interval and/or are arrhythmogenic may result in clinical consequences. ( 7 )

studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. 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 granisetron hydrochloride injection is administered to a nursing woman. 8.4 pediatric use chemotherapy-induced nausea and vomiting [see dosage and administration ( 2 )] for use in chemotherapy-induced nausea and vomiting in pediatric patients 2 to 16 years of age. safety and effectiveness in pediatric patients under 2 years of age have not been established. postoperative nausea and vomiting safety and efficacy have not been established in pediatric patients for the prevention of postoperative nausea and vomiting (ponv). granisetron has been evaluated in a pediatric patient clinical trial for use in the prevention of ponv. due to the lack of efficacy and the qt prolongation observed in this trial, use of granisetron for the prevention of ponv in children is not recommended. the trial was a prospective, multicenter, randomized, double-blind, parallel-group trial that evaluated 157 children aged 2 to 16 years who were undergoing elective surgery for tonsillectomy or adenotonsillectomy. the purpose of the trial was to assess two dose levels (20 mcg/kg and 40 mcg/kg) of intravenous granisetron in the prevention of ponv. there was no active comparator or placebo. the primary endpoint was total control of nausea and vomiting (defined as no nausea, vomiting/retching, or use of rescue medication) in the 24 hours following surgery. efficacy was not established due to lack of a dose response. the trial also included standard 12 lead ecgs performed pre-dose and after the induction of anesthesia. ecgs were repeated at the end of surgery after the administration of granisetron and just prior to reversal of anesthesia. qt prolongation was seen at both dose levels. five patients in this trial experienced an increase of ≥ 60 msec in qtcf. in addition, there were two patients whose qtcf was ≥ 500 msec. interpretation of the qtcf prolongation was confounded by multiple factors, including the use of concomitant medication and the lack of either a placebo or active control. a thorough qt trial in adults has not been performed. other adverse events that occurred in the study included: vomiting (5 to 8%), post-procedural hemorrhage (3 to 5%), and dehydration (0 to 5%). pediatric patients under 2 years of age have not been studied. 8.5 geriatric use during chemotherapy clinical trials, 713 patients 65 years of age or older received granisetron hydrochloride injection. the safety and effectiveness were similar in patients of various ages. during postoperative nausea and vomiting clinical trials, 168 patients 65 years of age or older, of which 47 were 75 years of age or older, received granisetron hydrochloride injection. clinical studies of granisetron hydrochloride injection did not include sufficient numbers of subjects aged 65 years 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.

cg/kg) of intravenous granisetron in the prevention of ponv. there was no active comparator or placebo. the primary endpoint was total control of nausea and vomiting (defined as no nausea, vomiting/retching, or use of rescue medication) in the 24 hours following surgery. efficacy was not established due to lack of a dose response. the trial also included standard 12 lead ecgs performed pre-dose and after the induction of anesthesia. ecgs were repeated at the end of surgery after the administration of granisetron and just prior to reversal of anesthesia. qt prolongation was seen at both dose levels. five patients in this trial experienced an increase of ≥ 60 msec in qtcf. in addition, there were two patients whose qtcf was ≥ 500 msec. interpretation of the qtcf prolongation was confounded by multiple factors, including the use of concomitant medication and the lack of either a placebo or active control. a thorough qt trial in adults has not been performed. other adverse events that occurred in the study included: vomiting (5 to 8%), post-procedural hemorrhage (3 to 5%), and dehydration (0 to 5%). pediatric patients under 2 years of age have not been studied.

or arrested vomiting within 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. granisetron hydrochloride injection exhibited no effect on oro-cecal transit time in normal volunteers given a single intravenous infusion of 50 mcg/kg or 200 mcg/kg. single and multiple oral doses slowed colonic transit in normal volunteers. 12.3 pharmacokinetics chemotherapy-induced nausea and vomiting in adult cancer patients undergoing chemotherapy and in volunteers, mean pharmacokinetic data obtained from an infusion of a single 40 mcg/kg dose of granisetron hydrochloride injection are shown in table 3. table 3: pharmacokinetic parameters in adult cancer patients undergoing chemotherapy and in volunteers, following a single intravenous 40 mcg/kg dose of granisetron hydrochloride injection peak plasma concentration (ng/ml) terminal phase plasma half-life (h) total clearance (l/h/kg) volume of distribution (l/kg) cancer patients mean 63.8 * 8.95 * 0.38 * 3.07 * range 18 to 176 0.9 to 31.1 0.14 to 1.54 0.85 to 10.4 volunteers 21 to 42 years mean 64.3 † 4.91 † 0.79 † 3.04 † range 11.2 to 182 0.88 to 15.2 0.2 to 2.56 1.68 to 6.13 65 to 81 years mean 57 † 7.69 † 0.44 † 3.97 † range 14.6 to 153 2.65 to 17.7 0.17 to 1.06 1.75 to 7.01 * 5-minute infusion. † 3-minute infusion. 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 12% of the administered dose is eliminated unchanged in the urine in 48 hours. the remainder of the dose is excreted as metabolites, 49% in the urine, and 34% in the feces. subpopulations gender there was high inter- and intra-subject variability noted in these studies. no difference in mean auc was found between males and females, although males had a higher c max generally. 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 patients (see table 3). 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. 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 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. postoperative nausea and vomiting in adult patients (age range, 18 to 64 years) recovering from elective surgery and receiving general balanced anesthesia, mean pharmacokinetic data obtained from a single 1 mg dose of granisetron hydrochloride injection administered intravenously over 30 seconds are shown in table 4. table 4: pharmacokinetic parameters in 16 adult surgical patients following a s ingle intravenous 1 mg dose of granisetron hydrochloride injection terminal phase plasma half-life (h) total clearance (l/h/kg) volume of distribution (l/kg) mean range 8.63 1.77 to 17.73 0.28 0.07 to 0.71 2.42 0.71 to 4.13 the pharmacokinetics of granisetron in patients undergoing surgery were similar to those seen in cancer patients undergoing chemotherapy.

ution 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 12% of the administered dose is eliminated unchanged in the urine in 48 hours. the remainder of the dose is excreted as metabolites, 49% in the urine, and 34% in the feces. subpopulations gender there was high inter- and intra-subject variability noted in these studies. no difference in mean auc was found between males and females, although males had a higher c max generally. 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 patients (see table 3). 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. 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 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. postoperative nausea and vomiting in adult patients (age range, 18 to 64 years) recovering from elective surgery and receiving general balanced anesthesia, mean pharmacokinetic data obtained from a single 1 mg dose of granisetron hydrochloride injection administered intravenously over 30 seconds are shown in table 4. table 4: pharmacokinetic parameters in 16 adult surgical patients following a s ingle intravenous 1 mg dose of granisetron hydrochloride injection terminal phase plasma half-life (h) total clearance (l/h/kg) volume of distribution (l/kg) mean range 8.63 1.77 to 17.73 0.28 0.07 to 0.71 2.42 0.71 to 4.13 the pharmacokinetics of granisetron in patients undergoing surgery were similar to those seen in cancer patients undergoing chemotherapy.

ea) in males and 5 mg/kg/day (30 mg/m 2 /day, 81 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, 1,622 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 injection should be prescribed only at the dose and for the indication recommended [see indications and usage (1) and dosage and administration (2) ] . 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/m 2 /day, 97 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.

ay (30 mg/m 2 /day, 81 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, 1,622 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 injection should be prescribed only at the dose and for the indication recommended [see indications and usage (1) and dosage and administration (2) ] . 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/m 2 /day, 97 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.

evere nausea. granisetron hydrochloride injection was also evaluated in a randomized dose response study of cancer patients receiving cisplatin ≥75 mg/m 2 . additional chemotherapeutic agents included: anthracyclines, carboplatin, cytostatic antibiotics, folic acid derivatives, methylhydrazine, nitrogen mustard analogs, podophyllotoxin derivatives, pyrimidine analogs, and vinca alkaloids. granisetron hydrochloride injection doses of 10 and 40 mcg/kg were superior to 2 mcg/kg in preventing cisplatin-induced nausea and vomiting, but 40 mcg/kg was not significantly superior to 10 mcg/kg (see table 6). table 6: prevention of chemotherapy-induced nausea and vomiting — single-day high-dose cisplatin therapy 1 granisetron hydrochloride injection (mcg/kg) p-value (vs. 2 mcg/kg) 2 10 40 10 40 number of patients 52 52 53 response over 24 hours complete response 2 31% 62% 68% <0.002 <0.001 no vomiting 38% 65% 74% <0.001 <0.001 no more than mild nausea 58% 75% 79% ns 0.007 1 cisplatin administration began within 10 minutes of granisetron hydrochloride injection infusion and continued for 2.6 hours (mean). mean cisplatin doses were 96 to 99 mg/m 2 . 2 no vomiting and no moderate or severe nausea. granisetron hydrochloride injection was also evaluated in a double-blind, randomized dose response study of 353 patients stratified for high (≥80 to 120 mg/m 2 ) or low (50 to 79 mg/m 2 ) cisplatin dose. response rates of patients for both cisplatin strata are given in table 7. table 7: prevention of chemotherapy-induced nausea and vomiting — single-day high-dose and low-dose cisplatin therapy 1 granisetron hydrochloride injection (mcg/kg) p-value (vs. 5 mcg/kg) 5 10 20 40 10 20 40 high-dose cisplatin number of patients 40 49 48 47 response over 24 hours complete response 2 18% 41% 40% 47% 0.018 0.025 0.004 no vomiting 28% 47% 44% 53% ns ns 0.016 no nausea 15% 35% 38% 43% 0.036 0.019 0.005 low-dose cisplatin number of patients 42 41 40 46 response over 24 hours complete response 2 29% 56% 58% 41% 0.012 0.009 ns no vomiting 36% 63% 65% 43% 0.012 0.008 ns no nausea 29% 56% 38% 33% 0.012 ns ns 1 cisplatin administration began within 10 minutes of granisetron hydrochloride injection infusion and continued for 2 hours (mean). mean cisplatin doses were 64 and 98 mg/m 2 for low and high strata. 2 no vomiting and no use of rescue antiemetic. for both the low and high cisplatin strata, the 10, 20, and 40 mcg/kg doses were more effective than the 5 mcg/kg dose in preventing nausea and vomiting within 24 hours of chemotherapy administration. the 10 mcg/kg dose was at least as effective as the higher doses. moderately emetogenic chemotherapy granisetron hydrochloride injection, 40 mcg/kg, was compared with the combination of chlorpromazine (50 to 200 mg/24 hours) and dexamethasone (12 mg) in patients treated with moderately emetogenic chemotherapy, including primarily carboplatin >300 mg/m 2 , cisplatin 20 to 50 mg/m 2 and cyclophosphamide >600 mg/m 2 . granisetron hydrochloride injection was superior to the chlorpromazine regimen in preventing nausea and vomiting (see table 8). table 8: prevention of chemotherapy-induced nausea and vomiting—single-day moderately emetogenic chemotherapy granisetron hydrochloride injection chlorpromazine 1 p-value number of patients 133 133 response over 24 hours complete response 2 68% 47% <0.001 no vomiting 73% 53% <0.001 no more than mild nausea 77% 59% <0.001 1 patients also received dexamethasone, 12 mg. 2 no vomiting and no moderate or severe nausea. in other studies of moderately emetogenic chemotherapy, no significant difference in efficacy was found between granisetron hydrochloride doses of 40 mcg/kg and 160 mcg/kg. repeat-cycle chemotherapy in an uncontrolled trial, 512 cancer patients received granisetron hydrochloride injection, 40 mcg/kg, prophylactically, for two cycles of chemotherapy, 224 patients received it for at least four cycles, and 108 patients received it for at least six cycles. granisetron hydrochloride injection efficacy remained relatively constant over the first six repeat cycles, with complete response rates (no vomiting and no moderate or severe nausea in 24 hours) of 60% to 69%. no patients were studied for more than 15 cycles. pediatric studies a randomized double-blind study evaluated the 24-hour response of 80 pediatric cancer patients (age 2 to 16 years) to granisetron hydrochloride injection 10, 20 or 40 mcg/kg. patients were treated with cisplatin ≥60 mg/m 2 , cytarabine ≥3 g/m 2 , cyclophosphamide ≥ 1 g/m 2 or nitrogen mustard ≥6 mg/m 2 (see table 9). table 9: prevention of chemotherapy-induced nausea and vomiting in pediatric patients granisetron hydrochloride injection dose (mcg/kg) 10 20 40 number of patients 29 26 25 median number of vomiting episodes 2 3 1 complete response over 24 hours 1 21% 31% 32% 1 no vomiting and no moderate or severe nausea. a second pediatric study compared granisetron hydrochloride injection 20 mcg/kg to chlorpromazine plus dexamethasone in 88 patients treated with ifosfamide ≥3 g/m 2 /day for two or three days. granisetron hydrochloride injection was administered on each day of ifosfamide treatment. at 24 hours, 22% of granisetron hydrochloride injection patients achieved complete response (no vomiting and no moderate or severe nausea in 24 hours) compared with 10% on the chlorpromazine regimen. the median number of vomiting episodes with granisetron hydrochloride injection was 1.5; with chlorpromazine it was 7. 14.2 postoperative nausea and vomiting prevention of postoperative nausea and vomiting the efficacy of granisetron hydrochloride injection for prevention of postoperative nausea and vomiting was evaluated in 868 patients, of which 833 were women, 35 men, 484 caucasians, 348 asians, 18 blacks, 18 other, with 61 patients 65 years or older. granisetron hydrochloride injection was evaluated in two randomized, double-blind, placebo-controlled studies in patients who underwent elective gynecological surgery or cholecystectomy and received general anesthesia. patients received a single intravenous dose of granisetron hydrochloride injection (0.1 mg, 1 mg or 3 mg) or placebo either 5 minutes before induction of anesthesia or immediately before reversal of anesthesia. the primary endpoint was the proportion of patients with no vomiting for 24 hours after surgery. episodes of nausea and vomiting and use of rescue antiemetic therapy were recorded for 24 hours after surgery. in both studies, granisetron hydrochloride injection (1 mg) was more effective than placebo in preventing postoperative nausea and vomiting (see table 10). no additional benefit was seen in patients who received the 3 mg dose. table 10: prevention of postoperative nausea and vomiting in adult patients study and efficacy endpoint placebo granisetron hydrochloride injection 0.1 mg granisetron hydrochloride injection 1 mg granisetron hydrochloride injection 3 mg study 1 number of patients 133 132 134 128 no vomiting 0 to 24 hours 34% 45% 63%** 62%** no nausea 0 to 24 hours 22% 28% 50%** 42%** no nausea or vomiting 0 to 24 hours 18% 27% 49%** 42%** no use of rescue antiemetic therapy 0 to 24 hours 60% 67% 75%* 77%* study 2 number of patients 117 — 110 114 no vomiting 0 to 24 hours 56% — 77%** 75%* no nausea 0 to 24 hours 37% — 59%** 56%* *p<0.05 **p<0.001 versus placebo note: no vomiting = no vomiting and no use of rescue antiemetic therapy; no nausea = no nausea and no use of rescue antiemetic therapy gender/race there were too few male and black patients to adequately assess differences in effect in either population. treatment of postoperative nausea and vomiting the efficacy of granisetron hydrochloride injection for treatment of postoperative nausea and vomiting was evaluated in 844 patients, of which 731 were women, 113 men, 777 caucasians, 6 asians, 41 blacks, 20 other, with 107 patients 65 years or older. granisetron hydrochloride injection was evaluated in two randomized, double-blind, placebo-controlled studies of adult surgical patients who received general anesthesia with no prophylactic antiemetic agent, and who experienced nausea or vomiting within 4 hours postoperatively. patients received a single intravenous dose of granisetron hydrochloride injection (0.1 mg, 1 mg or 3 mg) or placebo after experiencing postoperative nausea or vomiting. episodes of nausea and vomiting and use of rescue antiemetic therapy were recorded for 24 hours after administration of study medication. granisetron hydrochloride injection was more effective than placebo in treating postoperative nausea and vomiting (see table 11). no additional benefit was seen in patients who received the 3 mg dose. table 11: treatment of postoperative nausea and vomiting in adult patients study and efficacy endpoint placebo granisetron hydrochloride injection 0.1 mg granisetron hydrochloride injection 1 mg granisetron hydrochloride injection 3 mg study 3 number of patients 133 128 133 125 no vomiting 0 to 6 hours 26% 53%*** 58%*** 60%*** 0 to 24 hours 20% 38%*** 46%*** 49%*** no nausea 0 to 6 hours 17% 40%*** 41%*** 42%*** 0 to 24 hours 13% 27%** 30%** 37%*** no use of rescue antiemetic therapy 0 to 6 hours — — — — 0 to 24 hours 33% 51%** 61%*** 61%*** study 4 number of patients (all patients) 162 163 — — no vomiting 0 to 6 hours 20% 32%* — — 0 to 24 hours 14% 23%* — no nausea 0 to 6 hours 13% 18% — — 0 to 24 hours 9% 14% — — no nausea or vomiting 0 to 6 hours 13% 18% — — 0 to 24 hours 9% 14% — — no use of rescue antiemetic therapy 0 to 6 hours — 0 to 24 hours 24% 34%* — — number of patients (treated for vomiting) 1 86 103 — — no vomiting 0 to 6 hours 21% 27% — — 0 to 24 hours 14% 20% — — *p<0.05 **p<0.01 ***p<0.001 versus placebo 1 protocol specified analysis: patients who had vomiting prior to treatment note: no vomiting = no vomiting and no use of rescue antiemetic therapy; no nausea = no nausea and no use of rescue antiemetic therapy gender/race there were too few male and black patients to adequately assess differences in effect in either population.

etron hydrochloride injection was also evaluated in a randomized dose response study of cancer patients receiving cisplatin ≥75 mg/m 2 . additional chemotherapeutic agents included: anthracyclines, carboplatin, cytostatic antibiotics, folic acid derivatives, methylhydrazine, nitrogen mustard analogs, podophyllotoxin derivatives, pyrimidine analogs, and vinca alkaloids. granisetron hydrochloride injection doses of 10 and 40 mcg/kg were superior to 2 mcg/kg in preventing cisplatin-induced nausea and vomiting, but 40 mcg/kg was not significantly superior to 10 mcg/kg (see table 6). table 6: prevention of chemotherapy-induced nausea and vomiting — single-day high-dose cisplatin therapy 1 granisetron hydrochloride injection (mcg/kg) p-value (vs. 2 mcg/kg) 2 10 40 10 40 number of patients 52 52 53 response over 24 hours complete response 2 31% 62% 68% <0.002 <0.001 no vomiting 38% 65% 74% <0.001 <0.001 no more than mild nausea 58% 75% 79% ns 0.007 1 cisplatin administration began within 10 minutes of granisetron hydrochloride injection infusion and continued for 2.6 hours (mean). mean cisplatin doses were 96 to 99 mg/m 2 . 2 no vomiting and no moderate or severe nausea. granisetron hydrochloride injection was also evaluated in a double-blind, randomized dose response study of 353 patients stratified for high (≥80 to 120 mg/m 2 ) or low (50 to 79 mg/m 2 ) cisplatin dose. response rates of patients for both cisplatin strata are given in table 7. table 7: prevention of chemotherapy-induced nausea and vomiting — single-day high-dose and low-dose cisplatin therapy 1 granisetron hydrochloride injection (mcg/kg) p-value (vs. 5 mcg/kg) 5 10 20 40 10 20 40 high-dose cisplatin number of patients 40 49 48 47 response over 24 hours complete response 2 18% 41% 40% 47% 0.018 0.025 0.004 no vomiting 28% 47% 44% 53% ns ns 0.016 no nausea 15% 35% 38% 43% 0.036 0.019 0.005 low-dose cisplatin number of patients 42 41 40 46 response over 24 hours complete response 2 29% 56% 58% 41% 0.012 0.009 ns no vomiting 36% 63% 65% 43% 0.012 0.008 ns no nausea 29% 56% 38% 33% 0.012 ns ns 1 cisplatin administration began within 10 minutes of granisetron hydrochloride injection infusion and continued for 2 hours (mean). mean cisplatin doses were 64 and 98 mg/m 2 for low and high strata. 2 no vomiting and no use of rescue antiemetic. for both the low and high cisplatin strata, the 10, 20, and 40 mcg/kg doses were more effective than the 5 mcg/kg dose in preventing nausea and vomiting within 24 hours of chemotherapy administration. the 10 mcg/kg dose was at least as effective as the higher doses. moderately emetogenic chemotherapy granisetron hydrochloride injection, 40 mcg/kg, was compared with the combination of chlorpromazine (50 to 200 mg/24 hours) and dexamethasone (12 mg) in patients treated with moderately emetogenic chemotherapy, including primarily carboplatin >300 mg/m 2 , cisplatin 20 to 50 mg/m 2 and cyclophosphamide >600 mg/m 2 . granisetron hydrochloride injection was superior to the chlorpromazine regimen in preventing nausea and vomiting (see table 8). table 8: prevention of chemotherapy-induced nausea and vomiting—single-day moderately emetogenic chemotherapy granisetron hydrochloride injection chlorpromazine 1 p-value number of patients 133 133 response over 24 hours complete response 2 68% 47% <0.001 no vomiting 73% 53% <0.001 no more than mild nausea 77% 59% <0.001 1 patients also received dexamethasone, 12 mg. 2 no vomiting and no moderate or severe nausea. in other studies of moderately emetogenic chemotherapy, no significant difference in efficacy was found between granisetron hydrochloride doses of 40 mcg/kg and 160 mcg/kg. repeat-cycle chemotherapy in an uncontrolled trial, 512 cancer patients received granisetron hydrochloride injection, 40 mcg/kg, prophylactically, for two cycles of chemotherapy, 224 patients received it for at least four cycles, and 108 patients received it for at least six cycles. granisetron hydrochloride injection efficacy remained relatively constant over the first six repeat cycles, with complete response rates (no vomiting and no moderate or severe nausea in 24 hours) of 60% to 69%. no patients were studied for more than 15 cycles. pediatric studies a randomized double-blind study evaluated the 24-hour response of 80 pediatric cancer patients (age 2 to 16 years) to granisetron hydrochloride injection 10, 20 or 40 mcg/kg. patients were treated with cisplatin ≥60 mg/m 2 , cytarabine ≥3 g/m 2 , cyclophosphamide ≥ 1 g/m 2 or nitrogen mustard ≥6 mg/m 2 (see table 9). table 9: prevention of chemotherapy-induced nausea and vomiting in pediatric patients granisetron hydrochloride injection dose (mcg/kg) 10 20 40 number of patients 29 26 25 median number of vomiting episodes 2 3 1 complete response over 24 hours 1 21% 31% 32% 1 no vomiting and no moderate or severe nausea. a second pediatric study compared granisetron hydrochloride injection 20 mcg/kg to chlorpromazine plus dexamethasone in 88 patients treated with ifosfamide ≥3 g/m 2 /day for two or three days. granisetron hydrochloride injection was administered on each day of ifosfamide treatment. at 24 hours, 22% of granisetron hydrochloride injection patients achieved complete response (no vomiting and no moderate or severe nausea in 24 hours) compared with 10% on the chlorpromazine regimen. the median number of vomiting episodes with granisetron hydrochloride injection was 1.5; with chlorpromazine it was 7.

tients to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms with or without gastrointestinal symptoms.