Total Body Irradiation
In a double-blind randomized study, 18 patients receiving granisetron hydrochloride tablets, 2 mg daily, experienced significantly greater antiemetic protection compared to patients in a historical negative control group who received conventional (non-5-HT3 antagonist) antiemetics. Total body irradiation consisted of 11 fractions of 120 cGy administered over 4 days, with three fractions on each of the first 3 days, and two fractions on the fourth day. Granisetron hydrochloride tablets were given one hour before the first radiation fraction of each day.
Twenty-two percent (22%) of patients treated with granisetron hydrochloride tablets did not experience vomiting or receive rescue antiemetics over the entire 4 day dosing period, compared to 0% of patients in the historical negative control group (P<0.01).
In addition, patients who received granisetron hydrochloride tablets also experienced significantly fewer emetic episodes during the first day of radiation and over the 4 day treatment period, compared to patients in the historical negative control group. The median time to the first emetic episode was 36 hours for patients who received granisetron hydrochloride tablets.
Fractionated Abdominal Radiation
The efficacy of granisetron hydrochloride tablets, 2 mg daily, was evaluated in a double-blind, placebo-controlled randomized trial of 260 patients. Granisetron hydrochloride tablets were given 1 hour before radiation, composed of up to 20 daily fractions of 180 to 300 cGy each. The exceptions were patients with seminoma or those receiving whole abdomen irradiation who initially received 150 cGy per fraction. Radiation was administered to the upper abdomen with a field size of at least 100 cm2.
The proportion of patients without emesis and those without nausea for granisetron hydrochloride tablets, compared to placebo, was statistically significant (P<0.0001) at 24 hours after radiation, irrespective of the radiation dose. Granisetron hydrochloride was superior to placebo in patients receiving up to 10 daily fractions of radiation, but was not superior to placebo in patients receiving 20 fractions.
Patients treated with granisetron hydrochloride tablets (n=134) had a significantly longer time to the first episode of vomiting (35 days vs. 9 days, P<0.001) relative to those patients who received placebo (n=126), and a significantly longer time to the first episode of nausea (11 days vs. 1 day, P<0.001). Granisetron hydrochloride provided significantly greater protection from nausea and vomiting than placebo.
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.
Granisetron hydrochloride is contraindicated in patients with known hypersensitivity to the drug or any of its components.
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 conbination 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 ).
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.
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.
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) (see WARNINGS).
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 4, 20, and 101 times the recommended clinical dose (1.48 mg/m2 , oral) 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, 20 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, 101 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, 4 times the recommended human dose based on body surface area) in males and 5 mg/kg/day (30 mg/m2 /day, 20 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, 405 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 should be prescribed only at the dose and for the indication recommended (see INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION).
Granisetron was not mutagenic in 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 oral doses up to 100 mg/kg/day (600 mg/m2 /day, 405 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.
Pregnancy Category B.
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.
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.
Safety and effectiveness in pediatric patients have not been established.
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.
Adverse Reactions to Granisetron Hydrochloride
Over 3700 patients have received granisetron hydrochloride tablets in clinical trials with emetogenic cancer therapies consisting primarily of cyclophosphamide or cisplatin regimens. In patients receiving granisetron hydrochloride tablets 1 mg twice a day for 1, 7 or 14 days, or 2 mg daily for 1 day, adverse experiences reported in more than 5% of the patients with comparator and placebo incidences are listed inTable 4.
|Percent of Patients With Event|
|Granisetron Hydrochloride1 Tablets 1 mg twice a day (n=978)||Granisetron Hydrochloride1 Tablets 2 mg once a day (n=1450)||Comparator2 (n=599)||Placebo (n=185)|
1 Adverse events were recorded for 7 days when granisetron hydrochloride tablets were given on a single day and for up to 28 days when granisetron hydrochloride tablets were administered for 7 or 14 days.
2 Metoclopramide/dexamethasone; phenothiazines/dexamethasone; dexamethasone alone; prochlorperazine.
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 (e.g., 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.
|Percent of Patients with Event|
|Granisetron Hydrochloride Injection1 40 mcg/kg (n=1268)||Comparator2 (n=422)|
1 Adverse events were generally recorded over 7 days post-granisetron hydrochloride injection administration.
2 Metoclopramide/dexamethasone and phenothiazines/dexamethasone.
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.
RxDrugLabels.com provides trustworthy package insert and label information about marketed prescription drugs as submitted by manufacturers to the U.S. Food and Drug Administration. Package information is not reviewed or updated separately by RxDrugLabels.com. Every individual prescription drug label and package insert entry contains a unique identifier which can be used to secure further details directly from the U.S. National Institutes of Health and/or the FDA.