Granisetron Hydrochloride Injection: Indications, Dosage, Precautions, Adverse Effects
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Granisetron Hydrochloride Injection - Product Information

Manufacture: Fresenius Kabi USA, LLC
Country: United States
Condition: Nausea/Vomiting, Chemotherapy Induced, Nausea/Vomiting, Postoperative, Nausea/Vomiting, Radiation Induced
Class: 5HT3 receptor antagonists
Form: Liquid solution, Intravenous (IV)
Ingredients: Granisetron Hydrochloride, Sodium Chloride, Citric Acid Monohydrate, Sodium Citrate, Phenol

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.
  • 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.

Dosage and Administration

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]. Pediatric patients under 2 years of age have not been studied.

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.

Dosage Forms and Strengths

Single-Use Vials for Injection: 1 mg/mL, 0.1 mg/mL

Multiple-Use Vials for Injection: 4 mg/4 mL

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.

Warnings and Precautions

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.

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.

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.

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, Patient Counseling Information].

Adverse Reactions

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

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
Granis etron Hydrochloride
Injection
40 mcg/kg
(n=1,268)
Comparator1
(n=422)
Headache 14% 6%
Constipation 3% 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: Advers e Reactions in Controlled Clinical Trials in Pos toperative Naus ea and Vomiting (Reported in ≥ 2% of Adults Receiving Granis etron Hydrochloride Injection 1 mg)
Percent of Patients With Reaction
Granis etron 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%).

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 and Drug Interactions].

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].

Use in Specific Populations

Pregnancy

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.

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.

Pediatric Use

Chemotherapy-Induced Nausea and Vomiting

[See Dosage and Administration] 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.

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.

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.

How Supplied/Storage and Handling

Granisetron Hydrochloride Injection, USP, 0.1 mg/mL (free base), is supplied in 1 mL single-use vials. CONTAINS NO PRESERVATIVE.

Product
No.
NDC
No.
Strength Vial size
361701 63323-317-01 0.1 mg per mL 1 mL single-use vial, packaged in tens.

Granisetron Hydrochloride Injection, USP, 1 mg/mL (free base), is supplied in 1 mL single-use vials. CONTAINS NO PRESERVATIVE.

Product
No.
NDC
No.
Strength Vial size
361801 63323-318-01 1 mg per mL 1 mL single-use vial, packaged individually.

Granisetron Hydrochloride Injection, USP, 1 mg/mL (free base), is supplied in 4 mL multiple-use vials. CONTAINS PRESERVATIVE.

Product
No.
NDC
No.
Strength Vial size
361904 63323-319-04 4 mg per 4 mL
(1 mg per mL)
4 mL multiple-use vial, packaged individually.

Store single-use vials and multiple-use vials at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

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

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

This container closure is not made with natural rubber latex.

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-HT3 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.

Serotonin Syndrome

  • 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.


Fresenius Kabi USA, LLC

Lake Zurich, IL 60047

451080F

Revised: February 2015