INDICATIONS AND USAGE 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.

WARNINGS Serotonin Syndrome The development of serotonin syndrome has been reported with 5-HT 3 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-HT 3 receptor antagonist alone has also been reported.

The majority of reports of serotonin syndrome related to 5-HT 3 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 PRECAUTIONS and Drug Interactions ).

Chemotherapy-Induced Nausea and Vomiting 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.

Table 4 Principal Adverse Events in Clinical Trials Percent of Patients With Event Granisetron Hydrochloride 1 Tablets 1 mg twice a day (n=978) Granisetron Hydrochloride 1 Tablets 2 mg once a day (n=1450) Comparator 2 (n=599) Placebo (n=185) Headache 21% 20% 13% 12% Constipation 18% 14% 16% 8% Asthenia 14% 18% 10% 4% Diarrhea 8% 9% 10% 4% Abdominal pain 6% 4% 6% 3% Dyspepsia 4% 6% 5% 4% 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.

Table 5 Principal Adverse Events in Clinical Trials - Single-Day Chemotherapy Percent of Patients with Event Granisetron Hydrochloride Injection 1 40 mcg/kg (n=1268) Comparator 2 (n=422) Headache 14% 6% Asthenia 5% 6% Somnolence 4% 15% Diarrhea 4% 6% Constipation 3% 3% 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.

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 (see PRECAUTIONS and Drug Interactions ).