GRANISETRON HYDROCHLORIDE injection

Granisetron Hydrochloride by

Drug Labeling and Warnings

Granisetron Hydrochloride by is a Prescription medication manufactured, distributed, or labeled by West-Ward Pharmaceuticals Corp, HIKMA FARMACEUTICA (PORTUGAL), S.A. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 1 INDICATIONS AND USAGE

    Granisetron Hydrochloride Injection, USP is a serotonin-3 (5-HT3) 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.
  • 2 DOSAGE AND ADMINISTRATION

    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-Use Vials for Injection: 1 mg/mL
    Multi-Use Vials for Injection: 4 mg/4 mL (1 mg/mL)

  • 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.

  • 5 WARNINGS AND PRECAUTIONS

    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-HT3 receptor antagonists

    5.4  Benzyl Alcohol

    Granisetron Hydrochloride Injection 1 mg/mL contains benzyl alcohol. Benzyl alcohol, a component of Granisetron Hydrochloride Injection 1 mg/mL, has been associated with serious adverse reactions and death, particularly in neonates. The “gasping syndrome,” characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl  alcohol  and  metabolites  in  blood  and  urine,  has  been  associated  with  benzyl  alcohol  dosages >99 mg/kg/day  in  neonates  and  low  birth-weight  neonates.  Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome,” the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.

    5.5  Serotonin Syndrome

    The development of serotonin syndrome has been reported with 5-HT3 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-HT3 receptor antagonist alone has also been reported. The majority of reports of serotonin syndrome related to 5-HT3 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)].

  • 6 ADVERSE REACTIONS

    QT prolongation has been reported with granisetron hydrochloride [see Warnings and Precautions (5.2) and Drug Interactions (7)].

    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
  • * Metoclopramide/dexamethasone and phenothiazines/dexamethasone.
    		•
    Percent of Patients With Reaction
     Granisetron
    Hydrochloride Injection
    40 mcg/kg (n=1268)    		Comparator*
    (n=422)
     Headache14%6%
     Constipation3%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-HT3 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)].

  • 8 USE IN SPECIFIC POPULATIONS

    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/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.

    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%), postprocedural 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.

  • 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.

  • 11 DESCRIPTION

    Granisetron Hydrochloride Injection, USP is a serotonin-3 (5-HT3) 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 C18H24N4OHCl, while its chemical structure is:

    chemical structure 

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

    Granisetron Hydrochloride Injection, USP 1 mg/mL is available in 1 mL single-use and 4 mL multi-use 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.

  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Granisetron is a selective 5-hydroxytryptamine3  (5-HT3) receptor antagonist with little or no affinity for other serotonin receptors, including 5-HT1; 5-HT1A; 5-HT1B/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-induced vomiting, mucosal enterochromaffin cells release serotonin, which stimulates 5-HT3 receptors. This evokes vagal afferent discharge and may induce vomiting. Animal studies demonstrate that, in binding to 5-HT3 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.

    12.3 Pharmacokinetics

    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.

    Table 2. Pharmacokinetic Parameters in Adult Cancer Patients Undergoing Chemotherapy and in Volunteers, Following a Single Intravenous 40 mcg/kg Dose of Granisetron Hydrochloride Injection
  • *

    5-minute infusion.

  • †

    3-minute infusion.

    		•
     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* 8.95* 0.38* 3.07* 
     Range18.0 to 1760.90 to 31.10.14 to 1.54 0.85 to 10.4 
     Volunteers    
     21 to 42 years    
       Mean64.3† 4.91† 0.79† 3.04† 
       Range11.2 to 1820.88 to 15.20.20 to 2.561.68 to 6.13
     65 to 81 years    
       Mean57.0† 7.69† 0.44† 3.97† 
       Range14.6 to 1532.65 to 17.70.17 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-HT3 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 Cmax 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 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.

  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, 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/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 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/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.

  • 14 CLINICAL STUDIES

    14.1  Chemotherapy-Induced Nausea and Vomiting

    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).

    Table 3. Prevention of Chemotherapy-Induced Nausea and Vomiting - Single-Day Cisplatin Therapy* 
  • *

    Cisplatin administration began within 10 minutes of Granisetron Hydrochloride Injection infusion and continued for 1.5 to 3.0 hours. Mean cisplatin dose was 86 mg/m2 in the Granisetron Hydrochloride Injection group and 80 mg/m2 in the placebo group.

  • † No vomiting and no moderate or severe nausea.
    		•
     

    Granisetron
    Hydrochloride
    Injection

    		PlaceboP-Value
     Number of Patients1414 
     Response Over 24 Hours   
       Complete Response† 93%7%<0.001
       No Vomiting93%14%<0.001
       No More Than Mild Nausea93%7%<0.001

    Granisetron Hydrochloride Injection was also evaluated in a randomized dose response study of cancer patients receiving cisplatin ≥75 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 Hydrochloride 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 Therapy* 
  • *

    Cisplatin administration began within 10 minutes of Granisetron Hydrochloride Injection infusion and continued for 2.6 hours (mean). Mean cisplatin doses were 96 to 99 mg/m2.

  • † No vomiting and no moderate or severe nausea.
    		•
     Granisetron Hydrochloride
    Injection
    (mcg/kg)    		 P-Value
    (vs. 2 mcg/kg)
    210401040
    Number of Patients 525253  
    Response Over 24 Hours     
      Complete Response†31%62%68%<0.002<0.001 
      No Vomiting38%65%74%<0.001<0.001 
      No More Than Mild Nausea58%75%79%NS0.007

    Granisetron Hydrochloride Injection was also evaluated in a double-blind, randomized dose response study of 353 patients stratified for high (≥80 to 120 mg/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 Therapy* 
  • * Cisplatin administration began within 10 minutes of Granisetron Hydrochloride Injection infusion and continued for 2 hours (mean). Mean cisplatin doses were 64 and 98 mg/m2 for low and high strata.
  • †

    No vomiting and no use of rescue antiemetic.

    		•
     Granisetron Hydrochloride
    Injection (mcg/kg)         		 P-Value
    (vs. 5 mcg/kg)
    5102040102040
    High-Dose Cisplatin        
    Number of Patients40494847   
    Response Over 24 Hours       
      Complete Response† 18%41%40%47%0.0180.025 0.004
      No Vomiting28%47%44%53%NSNS0.016
      No Nausea15%35%38%43%0.036 0.0190.005
    Low-Dose Cisplatin        
    Number of Patients 42414046   
    Response Over 24 Hours       
      Complete Response† 29%56%58%41%0.0120.009NS
      No Vomiting36% 63%65%43%0.0120.008NS
      No Nausea29% 56%38%33%0.012NSNS

    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/m2, cisplatin 20 to 50 mg/m2 and cyclophosphamide >600 mg/m2. Granisetron Hydrochloride 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
  • * Patients also received dexamethasone, 12 mg.
  • †

     No vomiting and no moderate or severe nausea.

    		•
      Granisetron
    Hydrochloride
    Injection    		 Chlorpromazine*  P-Value
    Number of Patients  133133  
    Response Over 24 Hours   
      Complete Response† 68%47%<0.001 
      No Vomiting73%53%<0.001 
      No More Than Mild Nausea77%59%<0.001 

    In other studies of moderately emetogenic chemotherapy, no significant difference in efficacy was found between granisetron hydrochloride 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/m2, cytarabine ≥3 g/m2, cyclophosphamide ≥1 g/m2 or nitrogen mustard ≥6 mg/m2 (see Table 7).

    Table 7. Prevention of Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients
  • *

    No vomiting and no moderate or severe nausea.

    		•
     Granisetron Hydrochloride
    Injection Dose (mcg/kg)     
    102040
    Number of Patients 292625
    Median Number of Vomiting Episodes 231
    Complete Response Over 24 Hours* 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/m2/day for two or three days. Granisetron Hydrochloride Injection was administered on each day of ifosfamide treatment. At 24 hours, 22% of Granisetron Hydrochloride 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 Hydrochloride Injection was 1.5; with chlorpromazine it was 7.

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Granisetron Hydrochloride Injection, USP 1 mg/mL (free base), is supplied in 1 mL Single-Use Vials and 4 mL Multi-Use Vials. CONTAINS BENZYL ALCOHOL.

    NDC: 0143-9744-10 (Carton of 10 x 1mL Single-Use Vials)
    NDC: 0143-9745-10 (Carton of 10 x 4 mL Multi-Use Vials)
    NDC: 0143-9745-05 (Carton of 5 x 4 mL Multi-Use Vials)

    Store single-use vials and multi-use 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-use vials.

    Once the multi-use vial is penetrated, its contents should be used within 30 days.

    Do not freeze. Protect from light. Retain in carton until time of use.

  • 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 advised of the risk of allergic reactions if they have a prior allergic reaction to a class of antiemetics known as 5-HT3 receptor antagonists.

    Electrocardiogram changes (QT prolongation) have been reported with the use of granisetron hydrochloide. Patients should be cautioned about the use of this drug if they have heart problems or take medications for heart problems.

    Patients should be informed that Granisetron Hydrochloride Injection (1 mg/mL) contains benzyl alcohol and may cause serious side effects in newborns.

    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 by:
    HIKMA FARMACÊUTICA (PORTUGAL), S.A.
    Estrada do Rio da Mó, nº 8, 8A e 8B - Fervença,
    2705 – 906 Terrugem SNT
    PORTUGAL

    Distributed by:
    WEST-WARD
    A HIKMA COMPANY
    Eatontown, NJ 07724 USA

    Revised: July 2016

    PIN225-WES/6

  • PRINCIPAL DISPLAY PANEL

    NDC: 0143-9744-01
    Granisetron
    Hydrochloride
    Injection, USP
    1 mg/mL
    For Intravenous Use Only
    Rx ONLY
    1 mL Single-Use Vial
    Store at 20º to 25ºC (68º to 77ºF); excursions
    permitted to 15º to 30ºC (59º to 86ºF) [See
    USP Controlled Room Temperature].
    USUAL DOSAGE:     See package insert.
    Do not freeze. Protect from light.

     

    1 mg vial

     

     

    NDC: 0143-9744-10
    10 x 1 mL Single-Use Vials
    Granisetron
    Hydrochloride
    Injection, USP
    1 mg/mL*
    For Intravenous Use Only
    *Each mL contains, in sterile aqueous
    solution, Granisetron Hydrochloride, USP,
    1.12 mg, equivalent to granisetron, 1 mg,
    Sodium Chloride, USP, 9 mg, Citric Acid,
    NF, 2 mg, Benzyl Alcohol, NF, 10 mg, as a
    preservative. pH adjusted with sodium
    hydroxide/hydrochloric acid.

    USUAL DOSAGE: 10 mcg/kg administered
    intravenously either undiluted over
    30 seconds, or diluted with 0.9% sodium
    chloride or 5% dextrose and given over
    5 minutes. See package insert.

    Store at 20º to 25ºC (68º to 77ºF);
    excursions permitted to 15º to 30ºC
    (59º to 86ºF) [See USP Controlled Room
    Temperature].
    Do not freeze.
    Protect from light.
    Retain in carton until time of use.

     

     

     

    1 mg carton

  • PRINCIPAL DISPLAY PANEL

    NDC: 0143-9745-01
    Granisetron
    Hydrochloride
    Injection, USP
    4 mg/4 mL
    (1 mg/mL)
    For Intravenous Use Only
    Rx ONLY
    4 mL Multi-Use Vial
    Store at 20º to 25ºC (68º to 77ºF); excursions
    permitted to 15º to 30ºC (59º to 86ºF) [See
    USP Controlled Room Temperature].
    USUAL DOSAGE:     See package insert.
    Do not freeze. Protect from light.

     

    4 mg vial

     

    NDC: 0143-9745-10
    10 x 4 mL Multi-Use Vials
    Granisetron
    Hydrochloride
    Injection, USP
    4 mg/4 mL
    (1 mg/mL*)
    For Intravenous Use Only
    Rx ONLY
    *Each mL contains, in sterile aqueous
    solution, Granisetron Hydrochloride, USP,
    1.12 mg, equivalent to granisetron, 1 mg,
    Sodium Chloride, USP, 9 mg, Citric Acid,
    NF, 2 mg, Benzyl Alcohol, NF, 10 mg, as a
    preservative. pH adjusted with sodium
    hydroxide/hydrochloric acid.

    USUAL DOSAGE:     See package insert.

    Store at 20º to 25ºC (68º to 77ºF);
    excursions permitted to 15º to 30ºC
    (59º to 86ºF) [See USP Controlled Room
    Temperature].
    Do not freeze.
    Protect from light.
    Retain in carton until time of use.

    NDC: <a href=/NDC/0143-9745-10>0143-9745-10</a> 10 x 4 mL Multi-Use Vials Granisetron Hydrochloride Injection, USP 4 mg/4 mL (1 mg/mL*) For Intravenous Use Only Rx ONLY *Each mL contains, in sterile aqueous solution, Granisetron Hydrochloride, USP, 1.12 mg, equivalent to gransietron, 1 mg, Sodium Chloride, USP, 9 mg, Citric Acid, NF, 2 mg, Benzyl Alcohol, NF, 10 mg, as a preservative. pH adjusted with sodium hydroxide/ hydrochloric acid. USUAL DOSAGE: See package insert. Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15º to 30ºC (59º to 86ºF) [See USP Controlled Room Temperature]. Do not freeze. Protect from light. Retain in carton until time of use.

  • SERIALIZATION IMAGE

    Layout 1

  • INGREDIENTS AND APPEARANCE
    GRANISETRON HYDROCHLORIDE 
    granisetron hydrochloride injection
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 0143-9744
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    GRANISETRON HYDROCHLORIDE (UNII: 318F6L70J8) (GRANISETRON - UNII:WZG3J2MCOL) GRANISETRON1 mg  in 1 mL
    Inactive Ingredients
    Ingredient NameStrength
    SODIUM CHLORIDE (UNII: 451W47IQ8X) 9 mg  in 1 mL
    ANHYDROUS CITRIC ACID (UNII: XF417D3PSL) 2 mg  in 1 mL
    BENZYL ALCOHOL (UNII: LKG8494WBH) 10 mg  in 1 mL
    SODIUM HYDROXIDE (UNII: 55X04QC32I)  
    HYDROCHLORIC ACID (UNII: QTT17582CB)  
    WATER (UNII: 059QF0KO0R)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 0143-9744-1010 in 1 PACKAGE12/23/2009
    1NDC: 0143-9744-011 mL in 1 VIAL, SINGLE-USE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA07862912/23/2009
    GRANISETRON HYDROCHLORIDE 
    granisetron hydrochloride injection
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 0143-9745
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    GRANISETRON HYDROCHLORIDE (UNII: 318F6L70J8) (GRANISETRON - UNII:WZG3J2MCOL) GRANISETRON1 mg  in 1 mL
    Inactive Ingredients
    Ingredient NameStrength
    SODIUM CHLORIDE (UNII: 451W47IQ8X) 9 mg  in 1 mL
    ANHYDROUS CITRIC ACID (UNII: XF417D3PSL) 2 mg  in 1 mL
    BENZYL ALCOHOL (UNII: LKG8494WBH) 10 mg  in 1 mL
    SODIUM HYDROXIDE (UNII: 55X04QC32I)  
    HYDROCHLORIC ACID (UNII: QTT17582CB)  
    WATER (UNII: 059QF0KO0R)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 0143-9745-1010 in 1 CARTON12/23/2009
    1NDC: 0143-9745-014 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product
    2NDC: 0143-9745-055 in 1 CARTON12/23/2009
    2NDC: 0143-9745-014 mL in 1 VIAL, MULTI-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA07862912/23/2009
    Labeler - West-Ward Pharmaceuticals Corp (001230762)
    Establishment
    NameAddressID/FEIBusiness Operations
    HIKMA FARMACEUTICA (PORTUGAL), S.A452742943ANALYSIS(0143-9744, 0143-9745) , LABEL(0143-9744, 0143-9745) , MANUFACTURE(0143-9744, 0143-9745) , PACK(0143-9744, 0143-9745)
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