IndicationsFor the prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including high dose cisplatin.
PrecautionsThe potential for clinically significant drug-drug interactions posed by dolasetron and hydrodolasetron appears to be low for drugs commonly used in chemotherapy or surgery (see Warnings for information about potential interaction with other drugs that prolong QTc intervals). Blood levels of hydrodolasetron increased 24% when dolasetron was coadministered with cimetidine (nonselective inhibitor of cytochrome P450) for 7 days, and decreased 28% with coadministration of rifampin (potent inducer of cytochrome P450) for 7 days. Dolasetron injection has been safely coadministered with drugs used in chemotherapy and surgery. In patients taking furosemide, nifedipine, diltiazem, ACE inhibitors, verapamil, glyburide, propranolol, and various chemotherapy agents, no effect was shown on the clearance of hydrodolasetron. Clearance of hydrodolasetron decreased by about 27% when dolasetron was administered concomitantly with atenolol. Dolasetron does not influence anesthesia recovery time in patients. Dolasetron did not inhibit the antitumor activity of 4 chemotherapeutic agents (cisplatin, 5-fluorouracil, doxorubicin, cyclophosphamide) in 4 murine models. Dosage adjustment is not needed in patients over 65. It is not known whether dolasetron is excreted in human milk. Dolasetron should not be administered to a nursing woman. There are no adequate and well-controlled studies in pregnant women. This drug is not recommended for use during pregnancy. Animal reproduction studies have shown no evidence of teratogenicity when dolasetron was administered throughout organogenesis. In a 24-month carcinogenicity study in CD-1 mice, there was a statistically significant (p=0.001) increase in the incidence of combined hepatocellular adenomas and carcinomas in male mice treated orally with 150 mg/kg/day dolasetron and above. 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 carcinogenicity study in Sprague-Dawley rats, oral dolasetron mesylate was not tumorigenic at doses up to 150 mg/kg/day in males and 300 mg/kg/day in females. Dosage adjustment is not necessary in mild to moderate hepatic impairment. The oral formulation of dolasetron is not recommended in patients with severe hepatic impairment because of the possibility of prolonged QTc intervals and other cardiac conduction abnormalities from elevated hydrodolasetron levels. Dosage adjustment is not necessary in mild to moderate renal impairment. However, dolasetron is not recommended in patients with severe renal impairment because of the possibility of prolonged QTc intervals and other cardiac conduction abnormalities from elevated hydrodolasetron levels. Dolasetron (5-HT3 receptor antagonist) should be administered with caution in patients who have or may develop prolongation of cardiac conduction intervals, particularly QTc, due to potential for additive effects (see Warnings, ECG changes and cardiovascular events).
SuppliedEach pale pink, round, film-coated tablet, printed “50” in the center of the tablet and “A” on the other side, contains: dolasetron mesylate monohydrate 50 mg. Nonmedicinal ingredients: carnauba wax, croscarmellose sodium, hydroxypropyl methylcellulose, lactose, magnesium stearate, polyethylene glycol, polysorbate 80, pregelatinized starch, iron oxide, titanium dioxide and white wax. Bottles of 15. Each pink, oval, film-coated tablet, printed with “ANZEMET” on one side and “100” on the other, contains: dolasetron mesylate monohydrate 100 mg. Nonmedicinal ingredients: carnauba wax, croscarmellose sodium, hydroxypropyl methylcellulose, lactose, magnesium stearate, polyethylene glycol, polysorbate 80, pregelatinized starch, iron oxide, titanium dioxide and white wax. Bottles of 15. Store at 15 to 30°C and protect from light. Each mL of clear, colorless, sterile, nonpyrogenic solution for i.v. injection contains: dolasetron mesylate monohydrate 20 mg. Nonmedicinal ingredients: glacial acetic acid, mannitol and sodium acetate trihydrate. pH: 3.2 to 3.8. Clear glass vials of 5 mL.
ContraindicationsIn patients with known hypersensitivity to the drug or any components of its formulations (see Supplied).
Any therapeutic use in children and adolescents under 18 years of age.
The prevention and treatment of post-operative nausea and vomiting in adults.
These contraindications apply to both intravenous (IV) and oral formulations. Warnings Dolasetron can cause ECG interval changes (PR and QTc prolongations and QRS widening) in healthy volunteers and patients. In patients receiving chemotherapy or undergoing surgery, JT prolongations have also been observed following dolasetron, active comparator or placebo. JT prolongations have not been observed in healthy volunteers receiving dolasetron. ECG interval changes are related in magnitude and frequency to blood levels of the active metabolite, hydrodolasetron. These changes are self-limiting with declining blood levels. Some patients have interval prolongations for 24 hours or longer. Interval prolongations could lead to cardiovascular consequences, including heart block or cardiac arrhythmias. These have been rarely reported in patients receiving dolasetron. Complete heart block was observed interoperatively in a 61 year-old woman who received 200 mg dolasetron oral tablet for the prevention of postoperative nausea and vomiting. This patient was also taking verapamil. A 66 year-old man receiving chemotherapy was found dead 6 hours after receiving 1.8 mg/kg (119 mg) i.v. dolasetron injection and concomitant anthracycline therapy. Vital signs taken at 1 and 4.5 hours after dolasetron injection indicated an adequate blood pressure and increasing heart rate. This patient had other potential risk factors including substantial exposure to doxorubicin and concomitant cyclophosphamide. The use of dolasetron mesylate is contraindicated in children and adolescents under 18 years of age and in adults for the prevention and treatment of post-operative nausea and vomiting (see Contraindications) as: -
acute electrocardiographic changes have occurred very commonly in pediatrics aged 2 to 18 years;
-
individual cases of sustained supraventricular and ventricular arrhythmias, myocardial infarction and one case of fatal cardiac arrest have been reported in association with dolasetron in pediatrics. A causal relationship with dolasetron was suspected based on temporal association in all cases. Most of the cases of cardiovascular events occurred in adolescents. In all cases dolasetron was indicated for postoperative nausea and vomiting. They concerned mainly the I.V. route, and in one case oral administration.
Dolasetron (5-HT3 receptor antagonist) should be administered with caution in patients who have or may develop prolongation of cardiac conduction intervals, particularly QTc, due to potential for additive effects. These include, also patients with AV block II-III, bundle branch block, patients receiving concomitant class I and III antiarrythmics and patients with hypokalemia or hypomagnesemia, patients taking diuretics with potential for inducing electrolyte abnormalities, patients with congenital QT syndrome, patients taking anti-arrhythmic drugs or other drugs which lead to QT prolongation, and cumulative high dose anthracycline therapy. Interval prolongation could lead to cardiovascular consequences, including heart block or cardiac arrhythmias. Because dolasetron affects cardiac conductivity, the recommended doses should not be exceeded. Cross hypersensitivity reactions have been reported in patients who have received other selective 5HT3 receptor antagonists. It has not been seen with dolasetron.
Adverse Effectsabdominal pain, anorexia, increased appetite, constipation, eructation, flatulence, nausea. facial edema, increased sweating. Less frequently occurring adverse events: Injection: In controlled and uncontrolled clinical trials the following adverse events occurred at a frequency of 0.3 to 2.0% in patients treated with dolasetron injection at the recommended dose (1.8 mg/kg): agitation, anxiety, confusion, sleep disorder. Cases of local pain and burning on i.v. administration have been observed. In very rare cases, severe hypotension, bradycardia and possibly loss of consciousness may occur immediately or closely following i.v. bolus administration of dolasetron. These events have occurred in patients receiving dolasetron for the prevention of cancer chemotherapy-induced nausea and vomiting. Dolasetron has been shown to cause ECG prolongations, including QTc, PR and QRS intervals. These changes are related in magnitude and frequency to blood levels of the active metabolite; the changes are self-limiting with declining blood levels. Some patients have interval prolongation for 24 hours or longer. Interval prolongation could lead to cardiovascular consequences including heart block or cardiac arrhythmias. There are very rare reports of wide complex tachycardia or ventricular tachycardia and of ventricular fibrillation/cardiac arrest following intravenous administration. Individual cases of sustained supraventricular and ventricular arrhythmias, myocardial infarction and one case of fatal cardiac arrest have been reported in association with dolasetron in pediatrics. A causal relationship with dolasetron was suspected based on temporal association in all cases. Most of the cases of cardiovascular events occurred in adolescents. In all cases dolasetron was indicated for postoperative nausea and vomiting. They concerned mainly the I.V. route, and in one case oral administration. There are rare reports of anaphylactic/anaphylactoid reactions including skin reactions such as rash, puritus, and urticaria, respiratory reactions such as bronchospasm, very rare reports of facial edema/angioedema and shock. bone marrow aplasia, epistaxis. dependent edema, hypotension. atrial arrhythmia, sinus arrhythmia, extrasystoles. dyspnea, nasal irritation, sneezing, throat irritation. urinary retention. Oral Administration: In controlled clinical trials the following adverse events occurred at a frequency of 0.9 to 2.0% in patients treated with oral dolasetron at the recommended dose (100 mg):
OverdoseThere have been reports of overdose. Severe hypotension, dizziness and prolongation of the PR, QRS and QTc intervals were reported after overdose intravenous infusion. Single i.v. doses of dolasetron at 160 mg/kg in male mice and 140 mg/kg in female mice and rats of both sexes were lethal. Symptoms of acute toxicity were tremors, depression and convulsions. It is not known if dolasetron is removed by hemodialysis or peritoneal dialysis. Following a suspected overdose of dolasetron, a patient found to have second-degree or higher AV conduction block should undergo cardiac telemetry monitoring. There is no known specific antidote for dolasetron, and patients with suspected overdose should be managed with supportive therapy. Individual doses as large as 5 mg/kg i.v. or 400 mg orally have been safely given to healthy volunteers or cancer patients.
DosageDolasetron is contraindicated for any therapeutic use in children and adolescents under 18 years of age (see Contraindications). Dolasetron is contraindicated for the prevention and treatment of post-operative nausea and vomiting in adults (see Contraindications). I.V. Administration: The recommended i.v. dosage is 1.8 mg/kg given as a single dose approximately 30 minutes before chemotherapy. Most patients can be adequately treated with 100 mg. For light patients (<56 kg) or heavy patients (>90 kg), 1.8 mg/kg should be used. The injection solution can be infused as rapidly as 100 mg over 30 seconds, or it can be diluted in a compatible i.v. solution such as normal saline or 5% dextrose to 50 mL and infused over 15 minutes. More rapid i.v. administration should be avoided (see Adverse Effects). Dolasetron should not be mixed with other drugs. Flush the infusion line before and after administration of dolasetron. Oral Administration: The recommended oral dosage is one 100 mg tablet given within 1 hour prior to chemotherapy. Stability and Storage of Diluted Solutions: Dilutions of i.v. fluids should be used immediately after preparation or stored for no more than 24 hours at 2 to 8°C.
| 
