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Overview
Granisetron (tablet) is an antinauseant and antiemetic agent that is FDA approved for the prevention of nausea and vomiting associated with:1) initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin;2) radiation, including total body irradiation and fractionated abdominal radiation. Common adverse reactions include asthenia, headache, somnolence, and fever.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Indications
Granisetron hydrochloride tablets are indicated for the prevention of:
Nausea and vomiting associated with initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin.
Nausea and vomiting associated with radiation, including total body irradiation and fractionated abdominal radiation.
Dosage
Emetogenic Chemotherapy
The recommended adult dosage of oral granisetron hydrochloride tablets is 2 mg once daily or 1 mg twice daily. In the 2 mg once-daily regimen, two 1 mg tablets are given up to 1 hour before chemotherapy. In the 1 mg twice-daily regimen, the first 1 mg tablet is given up to 1 hour before chemotherapy, and the second tablet 12 hours after the first. Either regimen is administered only on the day(s) chemotherapy is given. Continued treatment, while not on chemotherapy, has not been found to be useful.
Radiation
The recommended adult dosage of oral granisetron hydrochloride tablets is 2 mg once daily. Two 1 mg tablets are taken within 1 hour of radiation.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Granisetron (tablet) in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Granisetron (tablet) in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Indications
Granisetron hydrochloride tablets are indicated for the prevention of:
Nausea and vomiting associated with initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin.
Nausea and vomiting associated with radiation, including total body irradiation and fractionated abdominal radiation.
Dosage
Safety and effectiveness in pediatric patients have not been established.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Granisetron (tablet) in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Granisetron (tablet) in pediatric patients.
Contraindications
Granisetron hydrochloride tablets are contraindicated in patients with known hypersensitivity to the drug or any of its components.
Warnings
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
Adverse Reactions
Clinical Trials Experience
Chemotherapy-Induced Nausea and Vomiting
In patients receiving granisetron hydrochloride tablets 1 mg twice a day for 1, 7 or 14 days, or 2 mg once a day for 1 day, adverse experiences reported in more than 5% of the patients with comparator and placebo incidences are listed in Table 4.
This image is provided by the National Library of Medicine.
Other adverse events reported in clinical trials were:
Gastrointestinal: In single-day dosing studies in which adverse events were collected for 7 days, nausea (20%) and vomiting (12%) were recorded as adverse events after the 24-hour efficacy assessment period.
Hepatic: In comparative trials, elevation of AST and ALT (>2 times the upper limit of normal) following the administration of granisetron hydrochloride tablets occurred in 5% and 6% of patients, respectively. These frequencies were not significantly different from those seen with comparators (AST: 2%; ALT: 9%).
Cardiovascular: Hypertension (1%); hypotension, angina pectoris, atrial fibrillation, and syncope have been observed rarely.
Central Nervous System: Dizziness (5%), insomnia (5%), anxiety (2%), somnolence (1%). One case compatible with, but not diagnostic of, extrapyramidal symptoms has been reported in a patient treated with granisetron hydrochloride tablets.
Hypersensitivity: Rare cases of hypersensitivity reactions, sometimes severe (eg, anaphylaxis, shortness of breath, hypotension, urticaria) have been reported.
Other: Fever (5%). Events often associated with chemotherapy also have been reported: leukopenia (9%), decreased appetite (6%), anemia (4%), alopecia (3%), thrombocytopenia (2%).
Over 5000 patients have received injectable granisetron hydrochloride in clinical trials.
Table 5 gives the comparative frequencies of the five commonly reported adverse events (≥ 3%) in patients receiving granisetron hydrochloride injection, 40 mcg/kg, in single-day chemotherapy trials. These patients received chemotherapy, primarily cisplatin, and intravenous fluids during the 24-hour period following granisetron hydrochloride injection administration.
This image is provided by the National Library of Medicine.
In the absence of a placebo group, there is uncertainty as to how many of these events should be attributed to granisetron hydrochloride, except for headache, which was clearly more frequent than in comparison groups.
Radiation-Induced Nausea and Vomiting
In controlled clinical trials, the adverse events reported by patients receiving granisetron hydrochloride tablets and concurrent radiation were similar to those reported by patients receiving granisetron hydrochloride tablets prior to chemotherapy. The most frequently reported adverse events were diarrhea, asthenia, and constipation. Headache, however, was less prevalent in this patient population.
Postmarketing Experience
QT prolongation has been reported with granisetron hydrochloride.
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, this 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).
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): B
Teratogenic Effect:
Reproduction studies have been performed in pregnant rats at oral doses up to 125 mg/kg/day (750 mg/m2/day, 507 times the recommended human dose based on body surface area) and pregnant rabbits at oral doses up to 32 mg/kg/day (378 mg/m2/day, 255 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.
Pregnancy Category (AUS): B1
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Granisetron (tablet) in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Granisetron (tablet) during labor and delivery.
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 is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatic Use
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.
During clinical trials, 325 patients 65 years of age or older received granisetron hydrochloride tablets; 298 were 65 to 74 years of age, and 27 were 75 years of age or older. Efficacy and safety were maintained with increasing age.
For the prevention of nausea and vomiting of both metogenic chemotherapy and radiation, no dosage adjustment is recommended.
Gender
The effects of gender on the pharmacokinetics of granisteron hydrochloride tablets have not been studied. However, after intravenous infusion of granisetron hydrochloride, no difference in mean AUC was found between males and females, although males had a higher Cmax generally.
Race
There is no FDA guidance on the use of Granisetron (tablet) with respect to specific racial populations.
Renal Impairment
*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.
For the prevention of nausea and vomiting of both metogenic chemotherapy, no dosage adjustment is recommended.
Hepatic Impairment
A pharmacokinetic study with intravenous granisetron hydrochloride 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.
For the prevention of nausea and vomiting of both metogenic chemotherapy, no dosage adjustment is recommended.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Granisetron (tablet) in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Granisetron (tablet) in patients who are immunocompromised.
Administration and Monitoring
Administration
Oral
Monitoring
There is limited information regarding Monitoring of Granisetron (tablet) in the drug label.
Description
IV Compatibility
There is limited information regarding IV Compatibility of Granisetron (tablet) in the drug label.
Overdosage
Acute Overdose
Signs and Symptoms
Description
Management
Description
Chronic Overdose
There is limited information regarding Chronic Overdose of Granisetron (tablet) in the drug label.
Pharmacology
There is limited information regarding Granisetron (tablet) Pharmacology in the drug label.
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