Granisetron Hydrochloride (Page 3 of 4)

Pregnancy


Teratogenic Effects 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.

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.

Geriatric Use

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

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 bid 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 in Table 4.
Table 4: Principal Adverse Events in Clinical Trials

* 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. Metoclopramide/dexamethasone; phenothiazines/dexamethasone; dexamethasone alone; prochlorperazine. Usually mild to moderate in severity.
Percent of Patients With Even
Granisetron hydrochloride Tablets* 1 mg twice a day (n=978) Granisetron hydrochloride Tablets* 2 mg once a day (n=1450) Comparator (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%

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 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.Table 5: Principal Adverse Events in Clinical Trials — Single-Day Chemotherapy

Percent of Patients with Event
Granisetron hydrochloride Injection* 40mcg/kg (n=1268) Comparator (n=422)
Headache 14% 6%
Asthenia 5% 6%
Somnolence 4% 15%
Diarrhea 4% 6%
Constipation 3% 3%
* Adverse events were generally recorded over 7 days post- granisetron hydrochloride injection administration. 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, except for headache, which was clearly more frequent than in comparison groups.

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