Dolasetron (Monograph)

Brand name: Anzemet
Drug class: 5-HT3 Receptor Antagonists
Chemical name: (2α,6α,9aβ)-Octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl ester-1H-indole-3-carboxylic acid monomethanesulfonate
Molecular formula: C₁₉H₂₀N₂O₃•CH₄O₃S
CAS number: 115956-13-3

Medically reviewed by Drugs.com on Jan 9, 2024. Written by ASHP.

Introduction

Antiemetic; selective, first-generation inhibitor of type 3 serotonergic (5-HT₃) receptors.

Uses for Dolasetron

Cancer Chemotherapy-induced Nausea and Vomiting

Prevention of nausea and vomiting associated with emetogenic cancer chemotherapy; may use orally with initial and repeat courses of moderately emetogenic chemotherapy.

In December 2010, FDA informed healthcare professionals that IV dolasetron should no longer be used to prevent nausea and vomiting associated with cancer chemotherapy in pediatric patients and adults because of the risk of prolongation of cardiac conduction intervals and development of abnormal heart rhythms. (See Cardiovascular Effects under Cautions.)

For prevention of nausea and vomiting associated with highly emetogenic chemotherapy regimens (including an anthracycline plus cyclophosphamide), ASCO recommends a 3-drug antiemetic regimen consisting of an NK₁ receptor antagonist (e.g., either oral aprepitant or IV fosaprepitant), a 5-HT₃ receptor antagonist (e.g., dolasetron, granisetron, ondansetron, palonosetron), and dexamethasone. ASCO states that fixed-combination netupitant and palonosetron plus dexamethasone is an additional treatment option.

For moderately emetogenic chemotherapy regimens, ASCO recommends a 2-drug antiemetic regimen preferably consisting of palonosetron and dexamethasone. If palonosetron is not available, a first-generation 5-HT₃ receptor antagonist (preferably granisetron or ondansetron) may be substituted. Limited evidence suggests that aprepitant may be added to this regimen; in such cases, use of any 5-HT₃ receptor antagonist is appropriate.

For chemotherapy regimens with a low emetogenic risk, ASCO recommends administration of a single dose of dexamethasone prior to chemotherapy.

For chemotherapy regimens with minimal emetogenic risk, ASCO states that routine antiemetic administration is not necessary.

Postoperative Nausea and Vomiting

Oral or IV use for prevention and treatment of postoperative nausea and vomiting.

Routine prophylaxis not recommended in patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively.

Recommended for patients who, in the clinician’s judgement, must avoid nausea and/or vomiting postoperatively, even when anticipated incidence is low.

Dolasetron Dosage and Administration

Administration

Administer orally or by IV infusion.

Oral Administration

Administer within 1 hour before chemotherapy or within 2 hours before surgery.

Injection may be mixed in apple or apple-grape juice and used for oral administration in pediatric patients.

IV Administration

For prevention of postoperative nausea and vomiting, administer 15 minutes before cessation of anesthesia. For treatment of nausea and vomiting postoperatively, administer as soon as nausea or vomiting develops.

Dilution

May be diluted in a compatible IV solution to a volume of 50 mL prior to administration. (See Compatibility under Stability.)

Rate of Administration

May administer over as brief a period as 30 seconds.

If diluted to 50 mL in a compatible IV solution, administer over a period of up to 15 minutes.

Dosage

Available as dolasetron mesylate; dosage expressed in terms of the salt.

Pediatric Patients

Cancer Chemotherapy-induced Nausea and Vomiting

Prevention

Oral

Children 2–16 years of age: 1.8 mg/kg (maximum 100 mg) as a single dose within 1 hour before administration of chemotherapy.

If dolasetron mesylate injection is administered orally in children, administer same dosage as for tablets.

Postoperative Nausea and Vomiting

Prevention

Oral

Children 2–16 years of age: 1.2 mg/kg (maximum 100 mg) as a single dose within 2 hours before surgery.

If dolasetron mesylate injection is administered orally in children, administer same dosage as for tablets.

IV

Children 2–16 years of age: 0.35 mg/kg (maximum 12.5 mg) as a single dose approximately 15 minutes before cessation of anesthesia.

Treatment

IV

Children 2–16 years of age: 0.35 mg/kg (maximum 12.5 mg) as a single dose as soon as nausea or vomiting develops.

Adults

Cancer Chemotherapy-induced Nausea and Vomiting

Prevention

Oral

100 mg as a single dose within 1 hour before administration of chemotherapy.

Postoperative Nausea and Vomiting

Prevention

Oral

100 mg as a single dose within 2 hours before surgery. Higher dosages not associated with improved efficacy.

IV

12.5 mg as a single dose administered approximately 15 minutes before cessation of anesthesia. Higher dosages not associated with improved efficacy.

Treatment

IV

12.5 mg as a single dose administered as soon as nausea and/or vomiting develops. Higher dosages not associated with improved efficacy.

Prescribing Limits

Pediatric Patients

Cancer Chemotherapy-induced Nausea and Vomiting

Prevention

Oral

Children 2–16 years of age: 1.8 mg/kg (100 mg maximum) as a single dose.

Postoperative Nausea and Vomiting

Prevention

Oral

Children 2–16 years of age: 1.2 mg/kg (100 mg maximum) as a single dose.

IV

Children 2–16 years of age: 0.35 mg/kg (12.5 mg maximum) as single dose.

Treatment

IV

Children 2–16 years of age: 0.35 mg/kg (12.5 mg maximum) as a single dose.

Adults

Cancer Chemotherapy-induced Nausea and Vomiting

Prevention

Oral

100 mg as a single dose.

Postoperative Nausea and Vomiting

Prevention

Oral

100 mg as a single dose.

IV

12.5 mg as a single dose.

Treatment

IV

12.5 mg as a single dose.

Special Populations

Hepatic Impairment

No dosage adjustments required.

Renal Impairment

No dosage adjustments required.

Geriatric Patients

Dosage adjustments based on age not needed; however, select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Cautions for Dolasetron

Contraindications

• Known hypersensitivity to dolasetron mesylate or any ingredient in the formulation.

• IV dolasetron: Prevention of cancer chemotherapy-induced nausea and vomiting. (See Cardiovascular Effects under Cautions.)

Warnings/Precautions

Warnings

Cardiovascular Effects

Causes dose-dependent prolongation of QT, PR, and QRS intervals. Torsades de pointes, second- or third-degree AV block, cardiac arrest, and serious ventricular arrhythmias, sometimes resulting in death, reported in pediatric patients and adults.

Expected mean increase in QT_cF interval (corrected QT interval, Fridericia’s formula) is 22.5 or 21.2 msec in pediatric or adult cancer patients receiving dolasetron mesylate 1.8 mg/kg IV, 16 msec in renally impaired patients, and 17.9 msec in geriatric patients.

In December 2010, FDA decided that IV dolasetron should no longer be used in any patients for prevention of cancer chemotherapy-induced nausea and vomiting. Cardiac risks are smaller with oral administration and with the smaller IV doses recommended for postoperative nausea and vomiting; therefore, FDA’s decision did not affect oral use of the drug or IV use for postoperative nausea and vomiting.

Patients at particular risk of PR or QRS interval prolongation include those with underlying structural heart disease, preexisting cardiac conduction system abnormalities, sick sinus syndrome, atrial fibrillation with slow ventricular response, or myocardial ischemia; geriatric patients; and those receiving drugs that may cause electrolyte abnormalities or prolong the PR or QRS interval.

Avoid use in patients with or at risk for complete heart block (unless they have an implanted pacemaker) or with congenital long QT syndrome.

Avoid use in patients with underlying structural heart disease, preexisting cardiac conduction system abnormalities, sick sinus syndrome, atrial fibrillation with slow ventricular response, or myocardial ischemia. If dolasetron must be used, use caution and monitor ECG.

Avoid use in patients with uncorrected hypokalemia or hypomagnesemia. Must correct hypokalemia and hypomagnesemia prior to administration. Monitor potassium and magnesium concentrations as clinically indicated during treatment.

Avoid use in geriatric patients. If dolasetron must be used, use caution and monitor ECG.

Avoid use in patients receiving drugs that may cause electrolyte abnormalities (e.g., diuretics) or prolong the PR (e.g., verapamil) or QRS interval (e.g., flecainide, quinidine). If dolasetron must be used, use caution and monitor ECG.

Use with caution in patients receiving drugs that prolong the QT interval and those receiving cumulative high-dose anthracycline therapy.

Monitor ECG in patients with heart failure, bradycardia, or renal impairment and in those at risk of electrolyte abnormalities.

Sensitivity Reactions

Sensitivity reactions, including anaphylactic reaction, facial edema, and urticaria, reported rarely.

Cross-sensitivity reactions reported in patients receiving other selective 5-HT₃ receptor antagonists; not reported to date with dolasetron.

Specific Populations

Pregnancy

Category B.

Lactation

Not known whether dolasetron or its metabolites are distributed into milk. Caution advised if used in nursing women.

Pediatric Use

Safety and efficacy not established in children <2 years of age.

Geriatric Use

No substantial differences in efficacy relative to younger adults when used for prevention of chemotherapy-induced nausea and vomiting; increased sensitivity cannot be ruled out.

Insufficient experience in postoperative patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; select dosage cautiously, usually starting at low end of dosage range.

Geriatric patients are at particular risk for prolongation of PR, QRS, and QT intervals; if drug must be used, use caution and monitor ECG.

Renal Impairment

Monitor ECG during therapy.

Common Adverse Effects

Chemotherapy-induced nausea and vomiting: Headache, fatigue, diarrhea, bradycardia, dizziness, pain, tachycardia, dyspepsia, chills/shivering.

Postoperative nausea and vomiting: Headache, hypotension, dizziness, fever, pruritus, oliguria, drowsiness, pain, hypertension, tachycardia, urinary retention.

Drug Interactions

Hydrodolasetron is metabolized by CYP2D6 and CYP3A.

Drugs that Prolong ECG Intervals

Potential pharmacologic interaction (e.g., additive effect on ECG interval prolongation). (See Cardiovascular Effects under Cautions.)

Avoid concomitant use with drugs that may prolong the PR or QRS interval or may result in electrolyte disorders that may prolong cardiac conduction (e.g., QT) intervals; if concomitant use is necessary, use caution and monitor ECG. Use with caution in patients receiving drugs that prolong the QT interval. (See Specific Drugs under Interactions.)

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (altered dolasetron clearance) with inhibitors or inducers of CYP isoenzymes.

Specific Drugs

Dolasetron Pharmacokinetics

Absorption

Bioavailability

Well absorbed after oral administration, although dolasetron is rarely detected in plasma due to rapid and complete metabolism to active metabolite, hydrodolasetron.

Apparent absolute bioavailability of oral dolasetron, determined by hydrodolasetron concentrations, is approximately 75%.

Peak plasma hydrodolasetron concentrations attained approximately 0.6 or 1 hour following IV or oral administration, respectively.

Orally administered IV solution and tablets are bioequivalent.

Food

Food does not affect bioavailability.

Distribution

Extent

Widely distributed in the body. Not known whether dolasetron or its metabolites are distributed into milk.

Plasma Protein Binding

69–77% (50% bound to α₁-acid glycoprotein).

Elimination

Metabolism

Rapidly and completely metabolized by carbonyl reductase to hydrodolasetron (major active metabolite). Hydrodolasetron is extensively metabolized via CYP2D6, CYP3A, and flavin monooxygenase.

Elimination Route

Approximately two-thirds and one-third of administered dose is excreted in urine and feces, respectively, as hydrodolasetron or other metabolites.

Half-life

For hydrodolasetron, approximately 7.3–8.1 hours.

Special Populations

In children 3–17 years of age, apparent plasma clearance of hydrodolasetron is increased compared with adults (by about 1.8- to 3-fold or 1.4- to 2-fold after oral or IV dolasetron administration, respectively).

In patients with severe hepatic impairment, apparent plasma clearance of hydrodolasetron is reduced (by about 42% after oral dolasetron administration); clearance is not substantially changed after IV administration.

In patients with severe renal impairment, apparent plasma clearance of hydrodolasetron is reduced (by about 44 or 47% after oral or IV dolasetron administration, respectively).

Stability

Storage

Oral

Tablets

20–25°C; protect from light.

Injection

If mixed in apple or apple-grape juice for oral administration, diluted solution may be stored for up to 2 hours at room temperature before use.

Parenteral

Injection, for IV Infusion

20–25°C (may be exposed to 15–30°C); protect from light.

Following dilution with compatible infusion solution, stable under normal lighting conditions at room temperature for 24 hours or under refrigeration for 48 hours.

Compatibility

Parenteral

Solution Compatibility

Drug Compatibility

Manufacturer states that dolasetron mesylate injection and the diluted solution for IV infusion should not be mixed with other drugs.

Actions

• Antiemetic activity appears to be mediated both centrally (in medullary chemoreceptor trigger zone) and peripherally (in GI tract) via inhibition of 5-HT₃ receptors.

• Active metabolite (hydrodolasetron) may block sodium channels and prolong cardiac depolarization and, to a lesser extent, repolarization time.

Advice to Patients

• Risk of serious cardiac arrhythmias, especially in those with personal or family history of abnormal heart rhythms; those with sick sinus syndrome, atrial fibrillation with slow ventricular response, or myocardial ischemia; those receiving drugs that may cause electrolyte disorders or prolong PR or QRS intervals; those with hypokalemia or hypomagnesemia; and geriatric patients.

• Importance of informing clinician of any perceived change in heart rate, feeling of lightheadedness, or syncopal episode.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (especially other drugs that may affect ECG intervals [e.g., antiarrhythmic agents, diuretics, anthracyclines]), as well as any concomitant illnesses (e.g., cardiovascular disease, electrolyte disturbances).

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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