GRANISETRON HYDROCHLORIDE- granisetron hydrochloride_injection

Granisetron is a selective 5-hydroxytryptamine 3 3 1 1A 1B/C 2 1 2 2 1 Serotonin receptors of the 5-HT 3 3 3 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 2. Table2PharmacokineticParametersinAdultCancerPatientsUndergoingChemotherapyandinVolunteers , FollowingaSingleIntravenous40mcg/kgDoseofGranisetronHydrochlorideInjection * 5-minute infusion. dagger 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. 07* Range 18. 4 Volunteers 21 to 42 years Mean 64. 91 dagger 0. 79 dagger 3. 04 dagger Range 11. 13 65 to 81 years Mean 57. 69 dagger 0. 44 dagger 3. 97 dagger Range 14. 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 3 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 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 2). 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.

Granisetron hydrochloride injection is a serotonin-3 (5-HT 3 Prevention of nausea and/or vomiting associated with initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin. ( 1 Granisetron hydrochloride injection is a serotonin-3 (5-HT 3 The prevention of nausea and/or vomiting associated with initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin.

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 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).

Most common adverse reactions: Chemotherapy-induced nausea and vomiting (>=3%): Headache, and constipation ( 6. 1 To report SUSPECTED ADVERSE REACTIONS, contact Wockhardt USA LLC. at 1-800-346-6854 or FDA at 1-800-FDA-1088 or www. gov/medwatch. QT prolongation has been reported with granisetron hydrochloride injection [see Warnings and Precautions ( 5. 2 and Drug Interactions ( 7 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. Table1PrincipalAdverseReactionsinClinicalTrials-Single-DayChemotherapy 1 Percent of Patients With Reaction Granisetron Hydrochloride Injection 40 mcg/kg (n=1268) Comparator 1 (n=422) Headache 14% 6% 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 injection is uncertain. Hepatic: Cardiovascular: Central Nervous System: Hypersensitivity: Other: The following adverse reactions have been identified during post approval use of granisetron hydrochloride injection. 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 injection exposure. 2 and Drug Interactions ( 7.

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

Pregnancy: Use only if clearly needed. 1 Nursing mothers: Caution should be exercised when administered to a nursing woman. 3 Geriatric use: No differences in responses between the elderly and younger patients were observed in reported clinical experience. 5 Pregnancy Category B Reproduction studies have been performed in pregnant rats at intravenous doses up to 9 mg/kg/day (54 mg/m 2 2 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 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.

RECENT MAJOR CHANGES
Warnings and Precautions Serotonin Syndrome ( 5.4
DRUG INTERACTIONS
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 Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system in vitro in vitro In in vitro in vivo QT prolongation has been reported with granisetron hydrochloride injection. Use of granisetron hydrochloride injection 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 see Warnings and Precautions (5.

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.
NONCLINICAL TOXICOLOGY
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 2 2 2 2 2 2 2 2 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 in vivo in vitro ex vivo in vitro in vitro Granisetron at subcutaneous doses up to 6 mg/kg/day (36 mg/m 2
CLINICAL STUDIES
Single-Day Chemotherapy Cisplatin-Based Chemotherapy In a double-blind, placebo-controlled study in 28 cancer patients, granisetron hydrochloride 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). Table3PreventionofChemotherapy-InducedNauseaandVomiting - Single-DayCisplatinTherapy 1 1 2 2 2 Granisetron Hydrochloride Injection Placebo P-Value Number of Patients 14 14 Response Over 24 Hours Complete Response 2 93% 7% <0.001 No Vomiting 93% 14% <0.001 No More Than Mild Nausea 93% 7% <0.001 Granisetron hydrochloride injection was also evaluated in a randomized dose response study of cancer patients receiving cisplatin >=75 mg/m 2 Table4PreventionofChemotherapy-InducedNauseaandVomiting-Single-DayHigh-DoseCisplatinTherapy 1 1 2 2 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 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 2 Table5PreventionofChemotherapy-InducedNauseaandVomiting - Single-DayHigh-DoseandLow-DoseCisplatinTherapy 1 1 2 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 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 2 2 Table6PreventionofChemotherapy-InducedNauseaandVomiting - Single-DayModeratelyEmetogenicChemotherapy 1 2 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 In other studies of moderately emetogenic chemotherapy, no significant difference in efficacy was found between granisetron hydrochloride injection 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 2 2 2 Table7PreventionofChemotherapy-InducedNauseaandVomitinginPediatricPatients 1 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% 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

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