Dolasetron

Pregnancy Category B.

Teratology studies have not revealed evidence of impaired fertility or harm to the fetus due to dolasetron mesylate. These studies have been performed in pregnant rats at intravenous doses up to 60 mg/kg/day (5.4 times the recommended human dose based on body surface area) and pregnant rabbits at intravenous doses up to 20 mg/kg/day (3.2 times the recommended human dose based on body surface area). 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 dolasetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when dolasetron injection is administered to a nursing woman.

In a 24-month carcinogenicity study, there was a statistically significant (P<0.001) increase in the incidence of combined hepatocellular adenomas and carcinomas in male mice treated with 150 mg/kg/day and above. In this study, mice (CD-1) were treated orally with dolasetron mesylate 75, 150 or 300 mg/kg/day (225, 450 or 900 mg/m²/day). For a 50 kg person of average height (1.46 m² body surface area), these doses represent 3.4, 6.8 and 13.5 times the recommended clinical dose (66.6 mg/m², intravenous) on a body surface area basis. No increase in liver tumors was observed at a dose of 75 mg/kg/day in male mice and at doses up to 300 mg/kg/day in female mice.

In a 24-month rat (Sprague-Dawley) carcinogenicity study, oral dolasetron mesylate was not tumorigenic at doses up to 150 mg/kg/day (900 mg/m²/day, 13.5 times the recommended human dose based on body surface area) in male rats and 300 mg/kg/day (1800 mg/m²/day, 27 times the recommended human dose based on body surface area) in female rats.

Dolasetron mesylate was not genotoxic in the Ames test, the rat lymphocyte chromosomal aberration test, the Chinese hamster ovary (CHO) cell (HGPRT) forward mutation test, the rat hepatocyte unscheduled DNA synthesis (UDS) test or the mouse micronucleus test.

Dolasetron mesylate was found to have no effect on fertility and reproductive performance at oral doses up to 100 mg/kg/day (600 mg/m²/day, 9 times the recommended human dose based on body surface area) in female rats and up to 400 mg/kg/day (2400 mg/m²/day, 36 times the recommended human dose based on body surface area) in male rats.

Postoperative Patients

In controlled clinical trials with 2,550 adult patients, headache and dizziness were reported more frequently with 12.5 mg dolasetron Injection than with placebo. Rates of other adverse events were similar. Following is a listing of all adverse events reported in ≥2% of patients receiving either placebo or 12.5 mg dolasetron Injection for the prevention or treatment of postoperative nausea and vomiting in controlled clinical trials (Table).

Adverse Events ≥2% from Placebo-Controlled Postoperative Nausea and Vomiting Studies:

In clinical trials, the following reported adverse events, assessed by investigators as treatmentrelated or causality unknown, occurred following oral or intravenous administration of dolasetron in <2% of adult patients undergoing surgery:

Body as a Whole: Chills/shivering.

Cardiovascular: Sinus arrhythmia, hypotension, orthostatic hypotension. The following events also occurred and with a similar frequency as placebo and/or active comparator: Mobitz I AV block, chest pain, syncope, severe bradycardia, and palpitations.

In addition, the following asymptomatic treatment-emergent ECG changes were seen at rates less than or equal to those for active or placebo controls: bradycardia, tachycardia, T wave change, ST-T wave change, extrasystole (APCs or VPCs), bundle branch block (left and right).

Furthermore, severe hypotension, bradycardia and syncope have been reported immediately or closely following IV administration.

Dermatologic: Rash.

Gastrointestinal System: Constipation, dyspepsia, abdominal pain.

Hearing, Taste and Vision: Taste perversion, abnormal vision.

Hypersensitivity: Anaphylactic reaction, urticaria.

Liver and Biliary System: Transient increases in AST (SGOT) and/or ALT (SGPT). The increases did not appear to be related to dose or duration of therapy and were not associated with symptomatic hepatic disease. Similar increases were seen with patients receiving active comparator.

Musculoskeletal: Myalgia, arthralgia.

Nervous System: Vertigo; flushing, paraesthesia.

Psychiatric: Agitation, anxiety, abnormal dreaming.

Respiratory System: Bronchospasm.

Vascular (Extracardiac): Local pain or burning on IV administration.

Postmarketing Experience

There are reports of wide complex tachycardia or ventricular tachycardia and of ventricular fibrillation cardiac arrest following intravenous administration.