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
Special Alerts:
[Posted 12/17/2010] ISSUE: FDA notified healthcare professionals that a contraindication is being added to the prescribing information advising that the injection form of dolasetron mesylate (Anzemet) should no longer be used to prevent nausea and vomiting associated with cancer chemotherapy (CINV) in pediatric and adult patients. New data demonstrate that dolasetron injection can increase the risk of developing torsade de pointes, an abnormal heart rhythm, which in some cases can be fatal. Patients at particular risk are those with underlying heart conditions or those who have existing heart rate or rhythm problems. Dolasetron causes a dose-dependant prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
BACKGROUND: FDA previously noted cardiovascular safety concerns which suggested dolasetron could cause QT prolongation. However, limitations of the previous data did not clearly establish the degree to which dolasetron may cause QT prolongation. FDA recommended that the drug sponsor conduct a thorough QT study in adults in order to determine the degree of the prolongation. A pediatric study was not recommended due to the wide variability in heart rate and, thus, QTc interval in the pediatric population. See the Data Summary section of the Drug Safety Communication (DSC) for information that supports this change in the prescribing information.
RECOMMENDATION: Dolasetron should not be used in patients with congenital long-QT syndrome. Hypokalemia and hypomagnesemia should be corrected before administering dolasetron. These electrolytes should be monitored after administration as clinically indicated. Use electrocardiogram monitoring in patients with congestive heart failure, patients with bradycardia, patients with underlying heart disease, the elderly and in patients who are renally impaired who are taking dolasetron. Dolasetron injection may still be used for the prevention and treatment of postoperative nausea and vomiting because the lower doses used are less likely to affect the electrical activity of the heart and result in abnormal heart rhythms.
Dolasetron tablets may still be used to prevent CINV because the risk of developing an abnormal heart rhythm with the oral form of this drug is less than that seen with the injection form. However, a stronger warning about this potential risk is being added to the Warnings and Precautions sections of the dolasetron tablet label. For more information visit the FDA website at: and .
Introduction
Antiemetic; selective inhibitor of type 3 serotonergic (5-HT3) receptors.1 2 3
Uses for Dolasetron Mesylate
Cancer Chemotherapy-induced Nausea and Vomiting
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Prevention of nausea and vomiting associated with emetogenic cancer chemotherapy;1 2 3 may use orally with initial and repeat courses of moderately emetogenic chemotherapy2 3 or IV with initial and repeat courses of emetogenic chemotherapy, including high-dose cisplatin.1 3
Postoperative Nausea and Vomiting
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
Administer approximately 30 minutes before chemotherapy.1
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 as rapidly as 100 mg over 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
IV
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Children 2–16 years of age: 1.8 mg/kg (maximum 100 mg) as a single dose approximately 30 minutes before administration of chemotherapy.1
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
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
IV
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
1.8 mg/kg as a single dose (given by IV infusion) approximately 30 minutes before administration of chemotherapy.1 Alternatively, a single 100-mg dose administered over 30 seconds.1
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 or IV
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
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
IV
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
1.8 mg/kg or 100 mg as a single dose.1
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
Cautions for Dolasetron Mesylate
Contraindications
Warnings/Precautions
Warnings
Cardiovascular Effects
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Risk of acute, usually reversible ECG alterations (PR, QTc, JT prolongation and QRS widening) related to plasma concentrations of active metabolite (hydrodolasetron); interval prolongation rarely results in heart block or cardiac arrhythmias.1 2 3 7 9
Use with caution in patients who have or may develop prolongation of cardiac conduction intervals (particularly QTc), including those with congenital QT syndrome, those with uncorrected hypokalemia or hypomagnesemia, patients receiving diuretics that may induce electrolyte abnormalities, patients receiving antiarrhythmic agents or other drugs that alter cardiac conduction (e.g., prolong QT interval), and those receiving cumulative high-dose anthracycline therapy.1 2
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.1 2
Common Adverse Effects
Headache,1 2 3 4 7 10 diarrhea,1 2 3 4 7 hypotension, 2 fatigue,1 2 3 dizziness,1 2 3 bradycardia2 .
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 QT-interval prolongation).1 2 (See Cardiovascular Effects under Cautions and also 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 models1 2
|
|
Atenolol
|
Decreased clearance of hydrodolasetron1 2
|
|
Cimetidine
|
Increased serum hydrodolasetron concentrations1 2
|
|
Diltiazem
|
Alteration of hydrodolasetron clearance unlikely1 2
|
|
Furosemide
|
Alteration of hydrodolasetron clearance unlikely1 2
|
|
Glyburide
|
Alteration of hydrodolasetron clearance unlikely1 2
|
|
Nifedipine
|
Alteration of hydrodolasetron clearance unlikely1 2
|
|
Propranolol
|
Alteration of hydrodolasetron clearance unlikely1 2
|
|
Rifampin
|
Decreased serum hydrodolasetron concentrations1 2
|
|
Verapamil
|
Alteration of hydrodolasetron clearance unlikely1 2
|
|
Ziprasidone
|
Increased risk of QT interval prolongationc
|
Concomitant use contraindicatedc
|
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 1.6- to 3.4-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
|
Dexmedetomidine HCl
|
Fenoldopam mesylate
|
Hetastarch in lactated electrolyte injection (Hextend)
|
Oxaliplatin
|
ActionsActions
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
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
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 QT interval [e.g., antiarrhythmic agents]), as well as any concomitant illnesses (e.g., cardiovascular disease).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 (single-use ampuls and Carpuject cartridges; preservative-free)
|
Sanofi-Aventis
|
|
|
20 mg/mL
|
Anzemet (multiple-dose vials with phenol; single-dose vials preservative-free)
|
Sanofi-Aventis
|
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. 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
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions January 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
References
1. Aventis Pharmaceuticals Inc. Anzemet (dolasetron mesylate injection) prescribing information. Kansas City, MO; 1999 Feb.
2. Aventis Pharmaceuticals. Anzemet (dolasetron mesylate tablets) prescribing information. Kansas City, MO; 2000 Jun.
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 on behalf of the European Dolasetron Comparative Study Group. Eur J Cancer. 1996; 32A:807-13.
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.
a. Aventis Pharmaceuticals. Anzemet (dolasetron mesylate tablets) prescribing information. Kansas City, MO; 2003 Oct.
b. Aventis Pharmaceuticals Inc. Anzemet (dolasetron mesylate injection) prescribing information. Kansas City, MO; 2003 Oct.
c. Pfizer Inc. Geodon (ziprasidone) prescribing information. New York, NY; 2002 July.
HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:562-3.
More Dolasetron Mesylate resources
- Dolasetron Mesylate Side Effects (in more detail)
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- Dolasetron Mesylate Support Group
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