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

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.)

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.20 21 ASCO states that fixed-combination netupitant and palonosetron plus dexamethasone is an additional treatment option.21

For moderately emetogenic chemotherapy regimens, ASCO recommends a 2-drug antiemetic regimen preferably consisting of palonosetron and dexamethasone.20 21 If palonosetron is not available, a first-generation 5-HT3 receptor antagonist (preferably granisetron or ondansetron) may be substituted.20 Limited evidence suggests that aprepitant may be added to this regimen; in such cases, use of any 5-HT3 receptor antagonist is appropriate.20

For chemotherapy regimens with a low emetogenic risk, ASCO recommends administration of a single dose of dexamethasone prior to chemotherapy.20

For chemotherapy regimens with minimal emetogenic risk, ASCO states that routine antiemetic administration is not necessary.20

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

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

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

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

• 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.)