Granisetron

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. 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, USP is recommended even where the incidence of postoperative nausea and/or vomiting is low. 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 ) Prevention and treatment of postoperative nausea and vomiting in adults. ( 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 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 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.

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 hydrochloride injection or to any of its components. ( 4 )

Not available.

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 ) Postoperative nausea and vomiting (≥ 2%): Pain, headache, fever, abdominal pain and hepatic enzymes increased ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 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=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) ].