Granisetron

DESCRIPTION

Kytril (granisetron hydrochloride) is an antinauseant and antiemetic agent. Chemically it is endo-N-(9-methyl-9-azabicyclo [3.3.1] non-3-yl)-1-methyl-1H-indazole-3-carboxamide hydrochloride with a molecular weight of 348.9 (312.4 free base). Its empirical formula is C₁₈H₂₄N₄O·HCl.

Granisetron hydrochloride is a white to off-white solid that is readily soluble in water and normal saline at 20°C. Granisetron HCl injection is a clear, colorless, sterile, nonpyrogenic, aqueous solution for intravenous administration.

Each 1 ml of preservative-free aqueous solution contains 1.12 mg granisetron hydrochloride equivalent to granisetron, 1.0 mg and sodium chloride, 9.0 mg. The solution's pH ranges from 4.7 to 7.3.

Tablets for Oral Administration: Each white, triangular, biconvex, film-coated Kytril Tablet contains 1.12 mg granisetron hydrochloride equivalent to granisetron, 1 mg. Inactive ingredients are: hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate and titanium dioxide.

CLINICAL PHARMACOLOGY

Granisetron is a selective 5-hydroxytryptamine₃(5-HT₃) receptor antagonist with little or no affinity for other serotonin receptors, including 5-HT₁; 5-HT_1A; 5-HT_1B/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-HT₃receptors. This evokes vagal afferent discharge, inducing vomiting. Animal studies demonstrate that, in binding to 5-HT₃receptors, 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.

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 slowed colonic transit in normal volunteers. However, granisetron HCl 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

Injection

In adult cancer patients undergoing chemotherapy and in volunteers, infusion of a single 40 mcg/kg dose of granisetron HCl injection produced the following mean pharmacokinetic data ( TABLE 1):

TABLE 1 - Pharmacokinetic Parameters in Adult Cancer Patients Undergoing Chemotherapy and in Volunteers, Following a Single Intravenous 40 mcg/kg Dose of Granisetron HCl Injection

There was high inter and intrasubject variability noted in these studies. No difference in mean AUC was found between males and females, although males had a higher C_max generally.

Granisetron metabolism involves N-demethylation and aromatic ring oxidation followed by conjugation. Animal studies suggest that some of the metabolites may also have 5-HT₃ receptor antagonist activity.

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.

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.

Plasma protein binding is approximately 65% and granisetron distributes freely between plasma and red blood cells. Tablets

In healthy volunteers and adult cancer patients undergoing chemotherapy, administration of oral granisetron HCl produced the following mean pharmacokinetic data ( TABLES 2A and 2B):

TABLE 2A - Pharmacokinetic Parameters (Median [range]) Following Granisetron Hydrochloride

TABLE 2B - Pharmacokinetic Parameters (Median [range]) Following Granisetron Hydrochloride

The effects of gender on the pharmacokinetics of oral granisetron HCl 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 a higher C_max generally.

When oral granisetron HCl was 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.

Granisetron metabolism involves N-demethylation and aromatic ring oxidation followed by conjugation. Animal studies suggest that some of the metabolites may also have 5-HT₃ receptor antagonist activity.

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.

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.

Plasma protein binding is approximately 65% and granisetron distributes freely between plasma and red blood cells.

In the elderly and in patients with renal failure or hepatic impairment, the pharmacokinetics of granisetron was determined following administration of intravenous granisetron HCl:

Elderly: The ranges of the pharmacokinetic parameters in elderly volunteers (mean age 71 years), given a single 40 mcg/kg intravenous dose of granisetron HCl 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 HCl injection.

Hepatically Impaired Patients: A pharmacokinetic study with intravenous granisetron HCl 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 1.0 mg b.i.d. dose, dosage adjustment in patients with possible hepatic functional impairment is not necessary.

Pediatrics: The pharmacokinetics of granisetron has not been adequately studied in children.

CLINICAL STUDIES Injection

Granisetron HCl injection has been shown to prevent nausea and vomiting associated with single-day and repeat cycle cancer chemotherapy. Single-Day Chemotherapy

Cisplatin-Based Chemotherapy: In a double-blind, placebo-controlled study in 28 cancer patients, granisetron HCl injection, administered as a single intravenous infusion of 40 mcg/kg, was significantly more effective than placebo in preventing nausea and vomiting induced by cisplatin chemotherapy. (See TABLE 3.)

TABLE 3 - Prevention of Chemotherapy-Induced Nausea and Vomiting--Single-Day

Cisplatin Therapy¹

Granisetron HCl injection was also evaluated in a randomized dose response study of cancer patients receiving cisplatin ³75 mg/m². Additional chemotherapeutic agents included: anthracyclines, carboplatin, cytostatic antibiotics, folic acid derivatives, methylhydrazine, nitrogen mustard analogs, podophyllotoxin derivatives, pyrimidine analogs and vinca alkaloids. Granisetron HCl 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 4.)

TABLE 4 - Prevention of Chemotherapy-Induced Nausea and Vomiting--Single-Day

High-Dose Cisplatin Therapy¹

Granisetron HCl injection was also evaluated in a double-blind, randomized dose response study of 353 patients stratified for high (³80 to 120 mg/m²) or low (50 to 79 mg/m²) cisplatin dose. Response rates of patients for both cisplatin strata are given in TABLE 5.

TABLE 5 - Prevention of Chemotherapy-Induced Nausea and Vomiting--Single-Day

High-Dose and Low-Dose Cisplatin Therapy¹

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 was at least as effective as the higher doses.

Moderately Emetogenic Chemotherapy: Granisetron HCl 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/m², cisplatin 20 to 50 mg/m² and cyclophosphamide >600 mg/m². Granisetron HCl injection was superior to the chlorpromazine regimen in preventing nausea and vomiting. (See TABLE 6.)

TABLE 6 - Prevention of Chemotherapy-Induced Nausea and Vomiting--Single-Day

Moderately Emetogenic Chemotherapy

In other studies of moderately emetogenic chemotherapy, no significant difference in efficacy was found between granisetron HCl doses of 40 mcg/kg and 160 mcg/kg doses.

Repeat-Cycle Chemotherapy: In an uncontrolled trial, 512 cancer patients received granisetron HCl 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 HCl 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: A randomized double-blind study evaluated the 24-hour response of 80 pediatric cancer patients (age 2 to 16 years) to granisetron HCl injection 10, 20 or 40 mcg/kg. Patients were treated with cisplatin ³60 mg/m², cytarabine ³3 g/m², cyclophosphamide ³1 g/m² or nitrogen mustard ³6 mg/m². (See TABLE 7.)

TABLE 7 - Prevention of Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients

A second pediatric study compared granisetron HCl injection 20 mcg/kg to chlorpromazine plus dexamethasone in 88 patients treated with ifosfamide ³3 g/m²/day for two or three days. Granisetron HCl injection was administered on each day of ifosfamide treatment. At 24 hours, 22% of granisetron HCl 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 HCl injection was 1.5; with chlorpromazine it was 7.0.

Tablets

Oral granisetron HCl prevents nausea and vomiting associated with emetogenic cancer therapy as shown by 24-hour efficacy data from three double-blind studies. The first trial compared oral granisetron HCl doses of 0.25 to 2.0 mg b.i.d. in 930 cancer patients receiving, principally, cyclophosphamide, carboplatin and cisplatin (20 mg/m² to 50 mg/m²). Efficacy was based on: complete response (i.e., no vomiting, no moderate or severe nausea, no rescue medication), no vomiting and no nausea. TABLE 8 summarizes the results of this study.

TABLE 8 - Prevention of Nausea and Vomiting 24 Hours Post-Chemotherapy¹

A second double-blind, randomized trial compared oral granisetron HCl 1.0 mg b.i.d. with prochlorperazine sustained release capsules 10.0 mg b.i.d., in 230 cancer patients receiving moderately emetogenic chemotherapeutic agents. Oral granisetron HCl was significantly better than prochlorperazine in preventing nausea and vomiting (see TABLE 9.)

TABLE 9 - Prevention of Nausea and Vomiting 24 Hours Post-Chemotherapy¹

Percentage of Patients Antiemetic Regimen

INDICATIONS

Granisetron HCl is indicated for the prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin.

DOSAGE AND ADMINISTRATION

Injection

The recommended dosage for granisetron HCl injection is 10 mcg/kg infused intravenously over 5 minutes, beginning within 30 minutes before initiation of chemotherapy, and only on the day(s) chemotherapy is given.

Pediatric Use: The recommended dose in children 2 to 16 years of age is 10 mcg/kg (see CLINICAL PHARMACOLOGY, CLINICAL STUDIES.) Children under 2 years of age have not been studied.

Use in the Elderly, Renal Failure Patients or Hepatically Impaired Patients: No dosage adjustment is recommended. (See CLINICAL PHARMACOLOGY, Pharmacokinetics.)

Infusion Preparation: Granisetron HCl injection should be diluted in 0.9% Sodium Chloride or 5% Dextrose to a total volume of 20 to 50 ml.

Stability: Intravenous infusion of granisetron HCl injection should be prepared at the time of administration. However, granisetron HCl 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 HCl 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.

Tablets

The recommended adult dosage of oral granisetron HCl is 1 mg twice daily. The first 1 mg tablet is given up to 1 hour before chemotherapy, and the second tablet, 12 hours after the first, 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: Data on oral granisetron HCl are not available.

HOW SUPPLIED

Injection: Kytril (granisetron hydrochloride) Injection, 1 mg/ml (free base), is supplied in 1 ml Single-Use Vials.

Store vials at 30°C (86°F) or below. Do not freeze. Protect from light.

Tablets: White, triangular, biconvex, film-coated tablets debossed K1 on one face.

Store between 15° and 30°C (59° and 86°F). Protect from light.

SIDE EFFECTS

Injection

TABLE 10 gives the comparative frequencies of the five most commonly reported adverse events ( ≥3%) in patients receiving granisetron HCl injection, in single-day chemotherapy trials. These patients received chemotherapy, primarily cisplatin, and intravenous fluids during the 24-hour period following granisetron HCl injection administration. Events were generally recorded over seven days post-granisetron HCl injection administration. In the absence of a placebo group, there is uncertainty as to how many of these events should be attributed to granisetron HCl, except for headache, which was clearly more frequent than in comparison groups.

TABLE 10 - Principal Adverse Events in Clinical Trials--Single-Day Chemotherapy

In over 3,000 patients receiving granisetron HCl injection (2 to 160 mcg/kg) in single-day and multiple-day clinical trials with emetogenic cancer therapies, adverse events, other than those in TABLE 10, were observed; attribution of many of these events to granisetron HCl 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 HCl 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 anaphylactoid reactions, other allergic reactions and skin rashes have been reported.

Other: Taste disorder (2%), fever (3%). In multiple-day comparative studies, fever occurred more frequently with granisetron HCl injection (8.6%) than with comparative drugs (3.4%, P<0.014), which usually included dexamethasone.

Tablets

Over 2,600 patients have received oral granisetron HCl in clinical trials with emetogenic cancer therapies consisting primarily of cyclophosphamide or cisplatin regimens.

In patients receiving oral granisetron HCl 1 mg b.i.d. for 1, 7 or 14 days, the following table ( TABLE 11) lists adverse experiences reported in more than 5% of the patients with comparator and placebo incidences.

TABLE 11 - Principal Adverse Events in Clinical Trials

Gastrointestinal: In single-day dosing studies in which adverse events were collected for 7 days, nausea (15%) and vomiting (9%) 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 oral granisetron HCl 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 (3%), insomnia (3%), anxiety (2%), somnolence (1%). One case compatible with but not diagnostic of extrapyramidal symptoms has been reported in a patient treated with oral granisetron HCl.

Hypersensitivity: Rare cases of hypersensitivity reactions, sometimes severe (e.g., anaphylaxis, shortness of breath, hypotension, urticaria) have been reported.

Other: Fever (5%). Events often associated with chemotherapy also have been reported: leukopenia (11%), decreased appetite (5%), anemia (4%), alopecia (3%), thrombocytopenia (3%).

Over 5,000 patients have received injectable granisetron HCl in clinical trials.

TABLE 12 gives the comparative frequencies of the five commonly reported adverse events ( ≥3%) in patients receiving granisetron HCl 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 HCl injection administration.

TABLE 12 - Principal Adverse Events in Clinical Trials--Single-Day Chemotherapy

In the absence of a placebo group, there is uncertainty as to how many of these events should be attributed to granisetron HCl, except for headache, which was clearly more frequent than in comparison groups.

DRUG INTERACTIONS

Granisetron does not induce or inhibit the cytochrome P-450 drug- metabolizing enzyme system. There have been no definitive drug-drug interaction studies to examine pharmacokinetic or pharmacodynamic interaction with other drugs but, in humans, granisetron HCl injection has been safely administered with drugs representing benzodiazepines, neuroleptics and anti-ulcer medications commonly prescribed with antiemetic treatments. Granisetron HCl 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.

WARNINGS

No information provided.

PRECAUTIONS

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Injection

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 16, 81 and 405 times the recommended clinical dose (0.37 mg/m², IV) on a body surface area basis. There was a statistically significant increase in the incidence of hepatocellular carcinomas and adenomas in males treated with 5 mg/kg/day (30 mg/m²/day, 81 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, 405 times the recommended human dose based on body surface area). No increase in liver tumors was observed at a dose of 1 mg/kg/day (6 mg/m²/day, 16 times the recommended human dose based on body surface area) in males and 5 mg/kg/day (30 mg/m²/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/m²/day, 1622 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 HCl injection 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 subcutaneous doses up to 6 mg/kg/day (36 mg/m²/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.

Tablets

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 4, 20 and 101 times the recommended clinical dose (1.48 mg/m², oral) on a body surface area basis. There was a statistically significant increase in the incidence of hepatocellular carcinomas and adenomas in males treated with 5 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 a dose of 1 mg/kg/day (6 mg/m²/day, 4 times the recommended human dose based on body surface area) in males and 5 mg/kg/day (30 mg/m²/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/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. 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 tablets 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/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

Injection: Reproduction studies have been performed in pregnant rats at intravenous doses up to 9 mg/kg/day (54 mg/m²/day, 146 times the recommended human dose based on body surface area) and pregnant rabbits at intravenous doses up to 3 mg/kg/day (35.4 mg/m²/day, 96 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.

Tablets: 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 a nursing woman.

Pediatric Use

Injection: See DOSAGE AND ADMINISTRATION for use in children 2 to 16 years of age. Safety and effectiveness in children under 2 years of age have not been established.

Tablets: Safety and effectiveness in children have not been established. Geriatric Use

Injection: During clinical trials, 713 patients 65 years of age or older received granisetron HCl injection. Effectiveness and safety were similar in patients of various ages.

Tablets: During clinical trials, 325 patients 65 years of age or older received oral granisetron HCl; 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.