Granisetron Hydrochloride

1 INDICATIONS AND USAGE Granisetron Hydrochloride Injection, USP 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. Granisetron Hydrochloride Injection, USP is a serotonin-3 (5-HT 3 ) 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 )

2 DOSAGE AND ADMINISTRATION 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 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.

3 DOSAGE FORMS AND STRENGTHS Single Dose Vials for Injection: 1 mg/mL Multiple Dose Vials for Injection: 4 mg/4 mL (1 mg/mL) Injection 1 mg/mL (free base). ( 3 )

4 CONTRAINDICATIONS Granisetron Hydrochloride Injection is contraindicated in patients with known hypersensitivity (e.g. 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 )

6 ADVERSE REACTIONS QT prolongation has been reported with granisetron hydrochloride [see Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7 )] . Most common adverse reactions: Chemotherapy-induced nausea and vomiting (≥3%): Headache, and constipation ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 or FDA at 1-800-FDA-1088 or www . fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in patients. Chemotherapy-Induced Nausea and Vomiting The following have been reported during controlled clinical trials or in the routine management of patients. The percentage figures 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=1268) Comparator Metoclopramide/dexamethasone and phenothiazines/dexamethasone. (n=422) Headache 14% 6% Constipation 3% 3% 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 (eg, 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. 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 )] .

7 DRUG INTERACTIONS 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 noradrenaline reuptake inhibitors (SNRIs) [see Warnings and Precautions ( 5.5 )]. Granisetron Hydrochloride Injection, USP 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 )

8 USE IN SPECIFIC POPULATIONS 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. Benzyl alcohol may cross the placenta. Granisetron Hydrochloride Injection 1 mg/mL is preserved with benzyl alcohol and should be used in pregnancy only if the benefit outweighs the potential risk. 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 Benzyl alcohol, a component of Granisetron Hydrochloride Injection 1 mg/mL, has been associated with serious adverse reactions and death, particularly in neonates [see Warnings and Precautions ( 5.4 )] . 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 …

12.1 Mechanism of Action 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.

11 DESCRIPTION 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 C18H24N4O•HCl, while its chemical structure is: Granisetron hydrochloride is a white to off-white solid that is readily soluble in water and normal saline at 20°C. Granisetron Hydrochloride Injection, USP is a clear, colorless, sterile, nonpyrogenic, aqueous solution for intravenous administration. Granisetron Hydrochloride Injection, USP 1 mg/mL is available in 1 mL single dose and 4 mL multiple dose vials. 1 mg/mL: Each mL contains 1.12 mg granisetron hydrochloride equivalent to granisetron, 1 mg; sodium chloride, 9 mg; citric acid anhydrous, 2 mg; and benzyl alcohol, 10 mg, as a preservative. The solution’s pH ranges from 4.0 to 6.0; pH adjusted with sodium hydroxide/hydrochloric acid. chemical structure

10 OVERDOSAGE 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Granisetron Hydrochloride Injection, USP 1 mg/mL (free base), is supplied in 1 mL Single Dose Vials and 4 mL Multiple Dose Vials. CONTAINS BENZYL ALCOHOL. NDC 0143-9744-10 (Carton of 10 x 1 mL Single Dose Vials) NDC 0143-9745-10 (Carton of 10 x 4 mL Multiple Dose Vials) NDC 0143-9745-05 (Carton of 5 x 4 mL Multiple Dose Vials) Store single dose vials and multiple dose vials at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature] Discard unused portion for the single dose vials. Once the multiple dose vial is penetrated, its contents should be used within 30 days. Do not freeze. Protect from light. Retain in carton until time of use.