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Dolasetron Mesylate

Pronunciation: doe-LAS-e-tron MES-i-late
Class: 5-HT ₃ receptor antagonist

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Trade Names

Anzemet
- Injection 20 mg/mL
- Tablets, oral 50 mg
- Tablets, oral 100 mg

Pharmacology

Selective serotonin (5-HT ₃ ) receptor antagonist that inhibits serotonin receptors in the GI tract and chemoreceptor zone.

Pharmacokinetics

Absorption

Parent drug is rapidly eliminated and completely metabolized to hydrodolasetron (active). T _max for hydrodolasetron is approximately 1 h (oral) and approximately 0.6 h (IV). Bioavailability is approximately 75% (determined by hydrodolasetron).

Distribution

Vd approximately 5.8 L/kg (hydrodolasetron). Hydrodolasetron is 69% to 77% protein bound.

Metabolism

Reduced to hydrodolasetron by carbonyl reductase. Subsequent hydroxylation due to CYP2D6 and N-oxidation due to CYP3A and flavin monooxygenase.

Elimination

Approximately 67% of dose is recovered in the urine (61% as hydrodolasetron) and approximately 33% recovered in the feces.

Half-life is less than 10 min for dolasetron (IV), approximately 7.3 h for hydrodolasetron (IV), and approximately 8.1 h (oral).

Cl is approximately 9.4 mL/min/kg (IV) and approximately 13.4 mL/min/kg (oral) for hydrodolasetron.

Special Populations

Renal Function Impairment

The apparent Cl of hydrodolasetron decreases 44% (oral) and 47% (IV) with severe renal impairment. No dose adjustment is necessary for patients with renal impairment; however, ECG monitoring is recommended.

Hepatic Function Impairment

The apparent oral Cl of hydrodolasetron decreases 42% with severe hepatic impairment. No dosage adjustment is necessary for patients with hepatic impairment.

Elderly

The pharmacokinetics of hydrodolasetron are similar in adult (young and elderly) healthy volunteers. No dosage adjustment is necessary for elderly patients; however, ECG monitoring is recommended.

Children

The apparent Cl of hydrodolasetron following oral administration is approximately 1.6- to 3.4-fold (oral) and 1.4- to 2-fold (IV) higher in children and adolescents than in adults. For children receiving dolasetron injection diluted in apple or apple-grape juice and administered orally, the mean apparent Cl was 34% greater and half-life was 21% shorter than in adults.

Indications and Usage

Injection

Prevention and treatment of postoperative nausea and/or vomiting.

Oral

Prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy; prevention of postoperative nausea and vomiting.

Unlabeled Uses

Radiotherapy-induced nausea and vomiting.

Contraindications

Known hypersensitivity to the drug; for the prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy caused by dose-dependent QT prolongation (injection only).

Dosage and Administration

Prevention of Cancer Chemotherapy–Induced Nausea and Vomiting
Adults and Children older than 16 y

PO 100 mg within 1 h before chemotherapy (max, 100 mg/dose).

Children 2 to 16 y of age

PO 1.8 mg/kg (max, 100 mg/dose) within 1 h before chemotherapy.

Prevention of Postoperative Nausea and Vomiting
Adults and Children older than 16 y

PO 100 mg within 2 h before surgery (max, 100 mg/dose).

IV 12.5 mg 15 min before cessation of anesthesia (max, 12.5 mg/dose).

Children 2 to 16 y of age

PO 1.2 mg/kg (max, 100 mg/dose) within 2 h before surgery.

IV 0.35 mg/kg (max, 12.5 mg/dose) 15 min before cessation of anesthesia.

Treatment of Postoperative Nausea and/or Vomiting
Adults and Children older than 16 y

IV 12.5 mg as a single dose as soon as nausea and vomiting presents (max, 12.5 mg/dose).

Children 2 to 16 y of age

IV 0.35 mg/kg (max, 12.5 mg/dose) as a single dose as soon as nausea and vomiting presents.

General Advice

Dolasetron injection may be mixed with apple or apple-grape juice for oral administration in children. Use within 2 h of dilution.
Infuse IV as rapidly as 30 sec or diluted in a compatible IV solution to 50 mL and infused over a period of up to 15 min.
Injection solution may be administered undiluted or may be diluted in a compatible IV solution to 50 mL.
Compatible IV fluids include sodium chloride 0.9%, dextrose 5%, dextrose 5% and sodium chloride 0.45%, dextrose 5% and Ringer's lactate injection, and Ringer's lactate injection and mannitol 10% injection.
Do not mix dolasetron injection with other drugs.
Flush infusion line before and after administration.
Inspect injection solution for particulate matter or discoloration before use.

Storage/Stability

Store injection vials between 59° to 86°F and tablets between 68° and 77°F. Protect from light. Diluted injection is stable for 24 h at room temperature or for 48 h if refrigerated. After oral dilution with apple or apple-grape juice, store at room temperature and do not use beyond 2 h.

Drug Interactions

Apomorphine

Serious adverse reactions, including profound hypotension and loss of consciousness, may occur when apomorphine is administered with dolasetron. Coadministration is contraindicated.

Atenolol

Increased serum levels of active metabolite, hydrodolasetron (IV only).

Cimetidine

Increased serum levels of active metabolite, hydrodolasetron.

Drugs that prolong the QTc interval (eg, quinidine)

Additive effects on conduction, increasing the risk of life-threatening cardiac arrhythmias, including torsades de pointes.

Rifampin

Decreased serum levels of active metabolite, hydrodolasetron.

Adverse Reactions

Cardiovascular

Bradycardia (5%); tachycardia (3%); flushing, hypotension, orthostatic hypotension, sinus arrhythmia; wide complex tachycardia or ventricular fibrillation cardiac arrest following IV administration (postmarketing).

CNS

Headache (23%); dizziness, fatigue (6%); chills/shivering (2%); agitation, depersonalization, paresthesia, sleep disorder, tremor, vertigo.

Dermatologic

Increased sweating, rash.

EENT

Abnormal vision, taste perversion.

GI

Diarrhea (5%); dyspepsia (3%); abdominal pain, anorexia, constipation.

Genitourinary

Oliguria (3%).

Local

Local pain or burning on IV administration.

Miscellaneous

Fever (4%); pain (3%).

Precautions

Monitor

Monitor serum potassium and magnesium levels; correct hypokalemia and hypomagnesemia prior to administration and monitor during therapy as clinically indicated. Use ECG monitoring in elderly patients and patients with CHF, bradycardia, and renal impairment.

Pregnancy

Category B .

Lactation

Undetermined.

Children

Safety and efficacy in children younger than 2 y not established.

Hypersensitivity

Cross-hypersensitivity may occur.

Special Risk Patients

Use with caution in conditions predisposing to prolongation of cardiac conduction intervals (eg, electrolyte abnormalities, congenital QT syndrome, class 1A antiarrhythmics).

CV effects

May cause dose-dependent prolongation of the QT, PR, and QRS intervals; reports of second or third-degree AV block, cardiac arrest, and serious ventricular arrhythmias, including fatalities in adults and children.

Patient Information

Advise patient that headache is a common adverse reaction.
Advise patient that medication will greatly reduce likelihood of nausea and vomiting, but that these are still possible.
Inform patients that dolasetron may cause serious cardiac arrhythmias, such as QT prolongation or heart block. Instruct patients to tell their health care provider right away if they perceive a change in their heart rate, feel light-headed, or if they have a syncopal episode.
Advise patients that dolasetron tablets may be taken without regard to food.
Advise patient and/or patient caregiver that in children for whom the tablet is not appropriate, the injection solution may be mixed in apple or apple-grape juice for oral dosing.