Granisetron Hydrochloride

Granisetron hydrochloride injection is a serotonin-3 (5-HT 3 ) receptor antagonist indicated for:

• The prevention of nausea and/or vomiting associated with initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin.
• The prevention and treatment of postoperative nausea and vomiting in adults. As with other antiemetics, routine prophylaxis is not recommended in patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients where nausea and/or vomiting must be avoided during the postoperative period, granisetron hydrochloride injection is recommended even where the incidence of postoperative nausea and/or vomiting is low. Granisetron hydrochloride injection is a serotonin-3 (5-HT3) receptor antagonist indicated for:
• Prevention of nausea and/or vomiting associated with initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin. ( 1 )
• Prevention and treatment of postoperative nausea and vomiting in adults. ( 1 )

Prevention of chemotherapy-induced nausea and vomiting ( 2.1 ):

• Recommended dosage is 10 mcg/kg intravenously within 30 minutes before initiation of chemotherapy
• Pediatric patients (2 to 16 years): Recommended dosage is 10 mcg/kg Prevention of postoperative nausea and vomiting ( 2.2 ):
• Recommended dosage is 1 mg, undiluted, administered intravenously over 30 seconds, before anesthetic induction or immediately before reversal of anesthesia. Treatment of postoperative nausea and vomiting ( 2.2 ):
• Recommended dosage is 1 mg, undiluted, administered intravenously over 30 seconds 2.1 Prevention of Chemotherapy-Induced Nausea and Vomiting Adult Patients The recommended dosage for granisetron hydrochloride injection is 10 mcg/kg administered intravenously within 30 minutes before initiation of chemotherapy, and only on the day(s) chemotherapy is given. Infusion Preparation Granisetron hydrochloride injection may be administered intravenously either undiluted over 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, 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, undiluted, administered intravenously over 30 seconds.

• Injection 1 mg per mL (free base). ( 3 )
• Injection 0.1 mg per mL (free base). ( 3 ) Multiple-Dose Vials for Injection: 4 mg per 4 mL (1 mg per mL) Single-Dose Vials for Injection: 1 mg per mL, 0.1 mg per mL

Granisetron hydrochloride injection is contraindicated in patients with known hypersensitivity (eg. anaphylaxis, shortness of breath, hypotension, urticaria) to the drug or to any of its components.

• Hypersensitivity to granisetron or to any of its components. ( 4 )

5 WARNINGS AND PRECAUTIONS

• Granisetron hydrochloride does not stimulate gastric or intestinal peristalsis and should not be used instead of nasogastric suction. ( 5.1 )
• QT prolongation has been reported with granisetron hydrochloride. Use with caution in patients with pre-existing arrhythmias or cardiac conduction disorders. ( 5.2 )
• Hypersensitivity reactions, such as anaphylaxis, shortness of breath, hypotension, and urticaria, may occur in patients with known hypersensitivity to other selective 5-HT 3 receptor antagonists. ( 5.3 )
• Serotonin syndrome has been reported with granisetron products, alone but particularly with concomitant use of serotonergic drugs. ( 5.4 )

5.1 Gastric or Intestinal Peristalsis Granisetron hydrochloride is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction. The use of granisetron hydrochloride in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a 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) ].

Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system in vitro . There have been no definitive drug-drug interaction studies to examine pharmacokinetic or pharmacodynamic interaction with other drugs; however, in humans, granisetron hydrochloride injection has been safely administered with drugs representing benzodiazepines, neuroleptics and anti-ulcer medications commonly prescribed with antiemetic treatments. Granisetron hydrochloride injection also does not appear to interact with emetogenic cancer chemotherapies. Because granisetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes, inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of granisetron. No specific interaction studies have been conducted in anesthetized patients. In addition, the activity of the cytochrome P-450 subfamily 3A4 (involved in the metabolism of some of the main narcotic analgesic agents) is not modified by granisetron hydrochloride in vitro . In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of granisetron 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 norepinephrine 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 with drugs known to prolong the QT interval and/or are arrhythmogenic may result in clinical consequences. ( 7 )

There is no specific antidote for granisetron hydrochloride injection overdosage. In case of overdosage, symptomatic treatment should be given. Overdosage of up to 38.5 mg of granisetron hydrochloride injection has been reported without symptoms or only the occurrence of a slight headache.

• Pregnancy: Use only if clearly needed. ( 8.1 )
• Nursing mothers: Caution should be exercised when administered to a nursing woman. ( 8.3 )
• Pediatric use: Safety and efficacy in pediatric patients have not been established for use in postoperative nausea and vomiting. ( 8.4 )
• Geriatric use: No differences in responses between the elderly and younger patients were observed in reported clinical experience. ( 8.5 )

8.1 Pregnancy Teratogenic Effects Pregnancy Category B Reproduction studies have been performed in pregnant rats at intravenous doses up to 9 mg/kg/day (54 mg/m 2 /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/m 2 /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.

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.

Teratogenic Effects Pregnancy Category B Reproduction studies have been performed in pregnant rats at intravenous doses up to 9 mg/kg/day (54 mg/m 2 /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/m 2 /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.

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.

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.

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.

Granisetron Hydrochloride Injection, USP is a serotonin-3 (5-HT 3 ) receptor antagonist. 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 C 18 H 24 N 4 O

• HCl, while its chemical structure is: Granisetron hydrochloride, USP Granisetron hydrochloride, USP is a white to off-white solid that is readily soluble in water and normal saline at 20ºC. Granisetron Hydrochloride Injection, USP is a clear, colorless, sterile, nonpyrogenic, aqueous solution for intravenous administration. Granisetron hydrochloride injection, USP 1 mg per mL is available in a 4 mL multiple-dose vial. Each 1 mL contains granisetron hydrochloride, USP 1.12 mg; equivalent to granisetron, 1 mg; sodium chloride, 9 mg; citric acid anhydrous, 2 mg; methyl paraben, 1.8 mg; and propyl paraben, 0.2 mg as preservatives. Water for injection, q.s.; Sodium hydroxide and/or hydrochloric acid may be added to adjust the pH.The solution’s pH ranges from 4 to 6. Granisetron Hydrochloride Injection, USP 1 mg per mL is available in a 1 mL single-dose vial. Granisetron Hydrochloride Injection, USP 0.1 mg per mL is available in a 1 mL single-dose vial. 0.1 mg per mL: Each 1 mL contains granisetron hydrochloride USP, 0.112 mg equivalent to granisetron, 0.1 mg; sodium chloride, 9 mg; and citric acid, 2 mg. Contains no preservative. Sodium hydroxide and/or hydrochloric acid may be added to adjust the pH. 1 mg per mL: Each 1 mL contains granisetron hydrochloride USP, 1.12 mg equivalent to granisetron, 1 mg; sodium chloride, 9 mg; and citric acid, 2 mg. Contains no preservative. Sodium hydroxide and/or hydrochloric acid may be added to adjust the pH. chemical structure

Granisetron is a selective 5-hydroxytryptamine 3 (5-HT 3 ) receptor antagonist with little or no affinity for other serotonin receptors, including 5-HT 1 ; 5-HT 1A ; 5-HT 1B/C ; 5-HT 2 ; for alpha 1 -, alpha 2 - or beta-adrenoreceptors; for dopamine-D 2 ; or for histamine-H 1 ; benzodiazepine; picrotoxin or opioid receptors. Serotonin receptors of the 5-HT 3 type are located peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. During chemotherapy-induced vomiting, mucosal enterochromaffin cells release serotonin, which stimulates 5-HT 3 receptors. This evokes vagal afferent discharge and may induce vomiting. Animal studies demonstrate that, in binding to 5-HT 3 receptors, 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. 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.

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 5-minute infusion 8.95 0.38 3.07 Range 18 to 176 0.90 to 31.1 0.14 to 1.54 0.85 to 10.4 Volunteers 21 to 42 years Mean 64.3 3- minute infusion 4.91 0.79 3.04 Range 11.2 to 182 0.88 to 15.2 0.20 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 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 Single Intravenous 1 mg Dose of Granisetron Hydrochloride Injection Terminal Phase Plasma Half-Life (h) TotalClearance (L/h/kg) Volume ofDistribution (L/kg) Mean 8.63 0.28 2.42 Range 1.77 to 17.73 0.07 to 0.71 0.71 to 4.13 The pharmacokinetics of granisetron in patients undergoing surgery were similar to those seen in cancer patients undergoing chemotherapy.

, Mutagenesis, Impairment of Fertility In a 24-month carcinogenicity study, rats were treated orally with granisetron 1, 5 or 50 mg/kg/day (6, 30 or 300 mg/m 2 /day). The 50 mg/kg/day dose was reduced to 25 mg/kg/day (150 mg/m 2 /day) during week 59 due to toxicity. For a 50 kg person of average height (1.46 m 2 body surface area), these doses represent 16, 81 and 405 times the recommended clinical dose (0.37 mg/m 2 , 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/m 2 /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/m 2 /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/m 2 /day, 16 times the recommended human dose based on body surface area) 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, 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 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.

17 PATIENT COUNSELING INFORMATION Patients should be informed that the most common adverse reactions for the indication of chemotherapy induced nausea and vomiting are headache and constipation (see Table 1). Patients should be informed that the most common adverse reactions for the indication of postoperative nausea and vomiting are pain, headache, fever, abdominal pain and hepatic enzyme increased (see Table 2). Patients should be advised of the risk of allergic reactions if they have a prior allergic reaction to a class of antiemetics known as 5-HT 3 receptor antagonists. Electrocardiogram changes (QT prolongation) have been reported with the use of granisetron hydrochloride. Patients should be cautioned about the use of this drug if they have heart problems or take medications for heart problems. Advise patients of the possibility of serotonin syndrome with concomitant use of granisetron and another serotonergic agent such as medications to treat depression and migraines. Advise patients to seek immediate medical attention if the following symptoms occur: changes in mental status, autonomic instability, neuromuscular symptoms with or without gastrointestinal symptoms. Manufactured for: Mylan Institutional LLC Rockford, IL 61103 U.S.A. Manufactured by: Mylan Laboratories Limited Bangalore, India AUGUST 2017