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Dolasetron Mesylate

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
Brands: Anzemet

Introduction

Antiemetic; selective inhibitor of type 3 serotonergic (5-HT3) receptors.1 2 3

Uses for Dolasetron Mesylate

Cancer Chemotherapy-induced Nausea and Vomiting

Prevention of nausea and vomiting associated with emetogenic cancer chemotherapy;2 3 4 5 6 7 8 may use orally with initial and repeat courses of moderately emetogenic chemotherapy.2 3

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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.17 (See Cardiovascular Effects under Cautions.)

Postoperative Nausea and Vomiting

Oral or IV use for prevention and treatment of postoperative nausea and vomiting.1 2 3

Routine prophylaxis not recommended in patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively.1

Recommended for patients who, in the clinician’s judgement, must avoid nausea and/or vomiting postoperatively, even when anticipated incidence is low.1 8

Dolasetron Mesylate Dosage and Administration

Administration

Administer orally or by IV infusion.1 2

Oral Administration

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

Injection may be mixed in apple or apple-grape juice and used for oral administration in pediatric patients.1

IV Administration

For prevention of postoperative nausea and vomiting, administer 15 minutes before cessation of anesthesia.1 For treatment of nausea and vomiting postoperatively, administer as soon as nausea or vomiting develops.1

Dilution

May be diluted in a compatible IV solution to a volume of 50 mL prior to administration.1 (See Compatibility under Stability.)

Rate of Administration

May administer over as brief a period as 30 seconds.1

If diluted to 50 mL in a compatible IV solution, administer over a period of up to 15 minutes.1

Dosage

Available as dolasetron mesylate; dosage expressed in terms of the salt.1 2

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.2

If dolasetron mesylate injection is administered orally in children, administer same dosage as for tablets.1 2

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.2

If dolasetron mesylate injection is administered orally in children, administer same dosage as for tablets.1 2

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.1

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.1

Adults

Cancer Chemotherapy-induced Nausea and Vomiting
Prevention
Oral

100 mg as a single dose within 1 hour before administration of chemotherapy.2

Postoperative Nausea and Vomiting
Prevention
Oral

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

IV

12.5 mg as a single dose administered approximately 15 minutes before cessation of anesthesia.1 Higher dosages not associated with improved efficacy.1

Treatment
IV

12.5 mg as a single dose administered as soon as nausea and/or vomiting develops.1 Higher dosages not associated with improved efficacy.1

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.1 2

Postoperative Nausea and Vomiting
Prevention
Oral

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

IV

Children 2–16 years of age: 0.35 mg/kg (12.5 mg maximum) as single dose.1

Treatment
IV

Children 2–16 years of age: 0.35 mg/kg (12.5 mg maximum) as a single dose.1

Adults

Cancer Chemotherapy-induced Nausea and Vomiting
Prevention
Oral

100 mg as a single dose.2

Postoperative Nausea and Vomiting
Prevention
Oral

100 mg as a single dose.2

IV

12.5 mg as a single dose.1

Treatment
IV

12.5 mg as a single dose.1

Special Populations

Hepatic Impairment

No dosage adjustments required.1 2

Renal Impairment

No dosage adjustments required.1 2

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.1 2

Cautions for Dolasetron Mesylate

Contraindications

  • Known hypersensitivity to dolasetron mesylate or any ingredient in the formulation.1 2

  • IV dolasetron: Prevention of cancer chemotherapy-induced nausea and vomiting.1 (See Cardiovascular Effects under Cautions.)

Warnings/Precautions

Warnings

Cardiovascular Effects

Causes dose-dependent prolongation of QT, PR, and QRS intervals.1 2 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.1 2

Expected mean increase in QTcF 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,1 16 msec in renally impaired patients,2 and 17.9 msec in geriatric patients.2

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.17 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.1 2 17

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.1 2

Avoid use in patients with or at risk for complete heart block (unless they have an implanted pacemaker) or with congenital long QT syndrome.1 2

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.1 2 18 If dolasetron must be used, use caution and monitor ECG.1 2 18

Avoid use in patients with uncorrected hypokalemia or hypomagnesemia.1 2 Must correct hypokalemia and hypomagnesemia prior to administration.1 2 Monitor potassium and magnesium concentrations as clinically indicated during treatment.1 2

Avoid use in geriatric patients.1 2 18 If dolasetron must be used, use caution and monitor ECG.1 2 18

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).1 2 18 If dolasetron must be used, use caution and monitor ECG.1 2 18

Use with caution in patients receiving drugs that prolong the QT interval and those receiving cumulative high-dose anthracycline therapy.1 2

Monitor ECG in patients with heart failure, bradycardia, or renal impairment and in those at risk of electrolyte abnormalities.1 2 17 18

Sensitivity Reactions

Sensitivity reactions, including anaphylactic reaction, facial edema, and urticaria, reported rarely.1 2

Cross-sensitivity reactions reported in patients receiving other selective 5-HT3 receptor antagonists; not reported to date with dolasetron.1 2

Specific Populations

Pregnancy

Category B.1 2

Lactation

Not known whether dolasetron or its metabolites are distributed into milk.1 2 Caution advised if used in nursing women.1 2

Pediatric Use

Safety and efficacy not established in children <2 years of age.1 2

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.2

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.1 2

Geriatric patients are at particular risk for prolongation of PR, QRS, and QT intervals; if drug must be used, use caution and monitor ECG.1 2 18

Renal Impairment

Monitor ECG during therapy.1 2

Common Adverse Effects

Chemotherapy-induced nausea and vomiting: Headache,2 4 fatigue,2 diarrhea,2 4 bradycardia,2 dizziness,2 pain,2 tachycardia,2 dyspepsia,2 chills/shivering.2 4

Postoperative nausea and vomiting: Headache,1 2 hypotension,2 dizziness,1 2 fever,2 pruritus,2 oliguria,2 drowsiness,1 pain,1 hypertension,2 tachycardia,2 urinary retention.1

Interactions for Dolasetron Mesylate

Hydrodolasetron is metabolized by CYP2D6 and CYP3A.1 2 3

Drugs that Prolong ECG Intervals

Potential pharmacologic interaction (e.g., additive effect on ECG interval prolongation).1 2 (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.1 2 18 Use with caution in patients receiving drugs that prolong the QT interval.1 2 (See Specific Drugs under Interactions.)

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (altered dolasetron clearance) with inhibitors or inducers of CYP isoenzymes.1 2

Specific Drugs

Drug

Interaction

Comments

ACE inhibitors

Alteration of hydrodolasetron clearance unlikely1 2

 

Antineoplastic agents

No inhibition of antineoplastic activity of cisplatin, fluorouracil, doxorubicin, or cyclophosphamide in murine models2

 

Atenolol

Decreased clearance of hydrodolasetron1 2

 

Cimetidine

Increased serum hydrodolasetron concentrations and AUC1 2

 

Diltiazem

Alteration of hydrodolasetron clearance unlikely1 2

 

Diuretics

May induce electrolyte disorders and increase risk of QT interval prolongation1 2

Avoid concomitant use; if concomitant use is necessary, use caution and monitor ECG1 2 18

Flecainide

Increased risk of QRS interval prolongation1 2

Avoid concomitant use; if concomitant use is necessary, use caution and monitor ECG1 2 18

Furosemide

Alteration of hydrodolasetron clearance unlikely1 2

 

Glyburide

Alteration of hydrodolasetron clearance unlikely1 2

 

Nifedipine

Alteration of hydrodolasetron clearance unlikely1 2

 

Pimozide

Increased risk of QT interval prolongation19

Concomitant use contraindicated19

Propranolol

Alteration of hydrodolasetron clearance unlikely1 2

 

Quinidine

Increased risk of QRS interval prolongation1 2

Avoid concomitant use; if concomitant use is necessary, use caution and monitor ECG1 2 18

Rifampin

Decreased serum hydrodolasetron concentrations and AUC1 2

 

Verapamil

Increased risk of PR interval prolongation1 2

Alteration of hydrodolasetron clearance unlikely1 2

Avoid concomitant use; if concomitant use is necessary, use caution and monitor ECG1 2 18

Ziprasidone

Increased risk of QT interval prolongation16

Concomitant use contraindicated16

Dolasetron Mesylate 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.2

Apparent absolute bioavailability of oral dolasetron, determined by hydrodolasetron concentrations, is approximately 75%.2

Peak plasma hydrodolasetron concentrations attained approximately 0.6 or 1 hour following IV or oral administration, respectively.1 2

Orally administered IV solution and tablets are bioequivalent.2

Food

Food does not affect bioavailability.2

Distribution

Extent

Widely distributed in the body.2 Not known whether dolasetron or its metabolites are distributed into milk.1 2

Plasma Protein Binding

69–77% (50% bound to α1-acid glycoprotein).1 2

Elimination

Metabolism

Rapidly and completely metabolized by carbonyl reductase to hydrodolasetron (major active metabolite).1 2 Hydrodolasetron is extensively metabolized via CYP2D6, CYP3A, and flavin monooxygenase.1 2

Elimination Route

Approximately two-thirds and one-third of administered dose is excreted in urine and feces, respectively, as hydrodolasetron or other metabolites.1 2

Half-life

For hydrodolasetron, approximately 7.3–8.1 hours.1 2

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).1 2

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.1 2

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).1 2

Stability

Storage

Oral

Tablets

20–25°C; protect from light.2

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.1

Parenteral

Injection, for IV Infusion

20–25°C (may be exposed to 15–30°C); protect from light.1

Following dilution with compatible infusion solution, stable under normal lighting conditions at room temperature for 24 hours or under refrigeration for 48 hours.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible

Dextrose 5% in Ringer’s injection, lactated1

Dextrose 5% in sodium chloride 0.45% 1

Dextrose 5% in water1

Mannitol 10%1

Ringer’s injection, lactated1

Sodium chloride 0.9%1

Drug Compatibility

Manufacturer states that dolasetron mesylate injection and the diluted solution for IV infusion should not be mixed with other drugs.1

Y-site CompatibilityHID

Compatible

Azithromycin

Caspofungin acetate

Dexmedetomidine HCl

Fenoldopam mesylate

Hetastarch in lactated electrolyte injection (Hextend)

Oxaliplatin

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.1 2 3

  • Active metabolite (hydrodolasetron) may block sodium channels and prolong cardiac depolarization and, to a lesser extent, repolarization time.1 2 8

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.1 2

  • Importance of informing clinician of any perceived change in heart rate, feeling of lightheadedness, or syncopal episode.1 2

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 2

  • 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).1 2

  • 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.

Dolasetron Mesylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

50 mg

Anzemet

Sanofi-Aventis

100 mg

Anzemet

Sanofi-Aventis

Parenteral

Injection, for IV use

12.5 mg/0.625 mL

Anzemet (available as Carpuject cartridges and vials)

Sanofi-Aventis

20 mg/mL

Anzemet

Sanofi-Aventis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Anzemet 100MG Tablets (SANOFI-AVENTIS U.S.): 5/$355.96 or 10/$699.96

Anzemet 20MG/ML Solution (SANOFI-AVENTIS U.S.): 5/$49.99 or 15/$135.96

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 12, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Sanofi-Aventis. Anzemet (dolasetron mesylate) injection prescribing information. Bridgewater, NJ; 2011 Jan.

2. Sanofi-Aventis. Anzemet (dolasetron mesylate) tablets prescribing information. Bridgewater, NJ; 2011 Jan.

3. Balfour JA, Goa KL. Dolasetron: a review of its pharmacology and therapeutic potential in the management of nausea and vomiting induced by chemotherapy, radiotherapy or surgery. Drugs. 1997; 54:273-98. [PubMed 9257083]

4. Rubenstein EB, Gralla RJ, Hainsworth JD et al for the Oral Dolasetron Dose-response Study Group. Randomized, double-blind, dose-response trial across four oral doses of dolasetron for the prevention of acute emesis after moderately emetogenic chemotherapy. Cancer. 1997; 79:1216-24. [IDIS 383153] [PubMed 9070501]

5. Yielding A, Bertoli L, Eisenberg P et al. Antiemetic efficacy of two different single intravenous doses of dolasetron in patients receiving high-dose cisplatin-containing chemotherapy. Am J Clin Oncol. 1996; 19:619-23. [IDIS 377400] [PubMed 8931684]

6. Hesketh P, Gandara D, Hesketh A et al. Dose-ranging evaluation of the antiemetic efficacy of intravenous dolasetron in patients receiving chemotherapy with doscorubicin or cyclophosphamide. Support Care Cancer. 1996; 4:141-6. [PubMed 8673351]

7. Audhuy B, Cappelaere P, Martin M et al. A double-blind, randomised comparison of the anti-emetic efficacy of two intravenous doses of dolasetron mesilate and granisetron in patients receiving high dose cisplatin chemotherapy. Eur J Cancer. 1996; 32A:807-13. [PubMed 9081358]

8. Aventis Pharmaceuticals Inc, Kansas City, MO: Personal communication.

9. Graczyk SG, McKenzie R, Kallar S et al. Intravenous dolasetron for the prevention of postoperative nausea and vomiting after outpatient laparoscopic gynecologic surgery. Anesth Analg. 1997; 84:325-30. [IDIS 381725] [PubMed 9024022]

10. Kovac AL, Scuderi PE, Boerner TF et al on behalf of the Dolasetron Mesylate PONV Treatment Study Group. Treatment of postoperative nausea and vomiting with single intravenous doses of dolasetron mesylate: a multicenter trial. Anesth Analg. 1997; 85:546-52. [IDIS 400396] [PubMed 9296407]

11. McKeage MJ. Comparative adverse effect profile of platinum drugs. Drug Saf. 1995; 13:228-44. [PubMed 8573296]

12. Cubeddu LX, Hoffmann IS. Participation of serotonin on early and delayed emesis induced by initial and subsequent cycles of cisplatinum-based chemotherapy: effects of antiemetics. J Clin Pharmacol. 1993; 33:691-7. [IDIS 319277] [PubMed 7691898]

13. Hesketh PJ, Gandara DR. Serotonin antagonists: a new class of antiemetic agents. J Natl Cancer Inst. 1991; 83:613-20. [PubMed 1850806]

14. Gralla RJ. Adverse effects of treatment: antiemetic therapy. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 4th ed. Philadelphia: J.B. Lippincott Company; 1993:2338-48.

16. Pfizer Inc. Geodon (ziprasidone) prescribing information. New York, NY; 2020 Dec.

17. US Food and Drug Administration. Drug safety communcation: Abnormal heart rhythms associated with use of Anzemet (dolasetron mesylate). 2010 Dec. From FDA website.

18. Sanofi-Aventis. Personal communication. Bridgwater, NJ; 2011 Sep.

19. Gate Pharmaceuticals. Orap (pimozide) tablets prescribing information. Sellersville, PA; 2010 Aug.

HID. Trissel LA. Handbook on injectable drugs. 16th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2011:528-9.

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