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Dolasetron

Pronunciation

(dol A se tron)

Index Terms

  • Dolasetron Mesylate
  • MDL 73,147EF

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Intravenous, as mesylate:

Anzemet: 20 mg/mL (0.625 mL [DSC], 5 mL [DSC], 25 mL [DSC])

Tablet, Oral, as mesylate:

Anzemet: 50 mg, 100 mg

Brand Names: U.S.

  • Anzemet

Pharmacologic Category

  • Antiemetic
  • Selective 5-HT3 Receptor Antagonist

Pharmacology

Selective serotonin receptor (5-HT3) antagonist, blocking serotonin both peripherally (primary site of action) and centrally at the chemoreceptor trigger zone

Absorption

Oral: Rapid and complete

Distribution

Hydrodolasetron: Children: 5.9 to 7.4 L/kg; Adults: 5.8 L/kg

Metabolism

Hepatic; rapid reduction by carbonyl reductase to hydrodolasetron (active metabolite); further metabolized by CYP2D6, CYP3A, and flavin monooxygenase

Excretion

Urine ~67% (dolasetron: <1% excreted unchanged in urine; hydrodolasetron: 53% to 61% of the total dose); Feces ~33%

Time to Peak

Hydrodolasetron: IV: 0.6 hours; Oral: ~1 hour

Half-Life Elimination

Dolasetron: IV: ≤10 minutes

Hydrodolasetron:

Oral: Children: 5.5 hours; Adolescents: 6.4 hours; Adults: 8.1 hours

IV: Children: 4.8 hours; Adults: 7.3 hours

Severe renal impairment: 11 hours

Severe hepatic impairment: 11 hours

Protein Binding

Hydrodolasetron: 69% to 77% (50% bound to alpha1-acid glycoprotein)

Special Populations: Renal Function Impairment

The apparent clearance of hydrodolasetron decreases 44% (oral) and 47% (IV) with severe renal impairment.

Special Populations: Hepatic Function Impairment

The apparent oral clearance of hydrodolasetron decreases 42% (oral) with severe hepatic impairment.

Use: Labeled Indications

U.S. labeling:

Injection: Prevention and treatment of postoperative nausea and vomiting in adults and children ≥2 years

Oral: Prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy (initial and repeat courses) in adults and children ≥2 years

Canadian labeling: Oral: Prevention of nausea and vomiting associated with emetogenic cancer chemotherapy (initial and repeat courses)

Contraindications

U.S. labeling:

Injection: Hypersensitivity to dolasetron or any component of the formulation; intravenous administration is contraindicated when used for prevention of chemotherapy-associated nausea and vomiting

Tablet: Hypersensitivity to dolasetron or any component of the formulation

Canadian labeling: Hypersensitivity to dolasetron or any component of the formulation; use in children and adolescents <18 years of age; use for the prevention or treatment of postoperative nausea and vomiting; concomitant use with apomorphine

Dosing: Adult

Note: Use of intravenous dolasetron is contraindicated for the prevention of chemotherapy induced nausea and vomiting. In Canada, use of dolasetron is also contraindicated in the prevention and treatment of postoperative nausea and vomiting in adults.

U.S. labeling:

Prevention of chemotherapy-associated nausea and vomiting (including initial and repeat courses): Oral: 100 mg within 1 hour before chemotherapy

Postoperative nausea and vomiting:

Prevention: IV: 12.5 mg ~15 minutes before cessation of anesthesia (do not exceed the recommended dose)

Treatment: IV: 12.5 mg as soon as nausea or vomiting present (do not exceed the recommended dose)

Canadian labeling: Prevention of chemotherapy-associated nausea and vomiting (including initial and repeat courses): Adults: Oral: 100 mg within 1 hour before chemotherapy

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: In Canada, use of dolasetron is contraindicated in children and adolescents <18 years of age.

Prevention of chemotherapy-associated nausea and vomiting (including initial and repeat courses): Children 2-16 years: Oral: 1.8 mg/kg within 1 hour before chemotherapy; maximum: 100 mg/dose

Postoperative nausea and vomiting: Children 2-16 years:

Prevention:

Oral: 1.2 mg/kg within 2 hours before surgery; maximum: 100 mg/dose

IV: 0.35 mg/kg ~15 minutes before cessation of anesthesia; maximum: 12.5 mg/dose

Treatment:

IV: 0.35 mg/kg as soon as nausea or vomiting present; maximum: 12.5 mg/dose

Dosing: Renal Impairment

No dosage adjustment necessary; however, ECG monitoring is recommended in patients with renal impairment.

Dosing: Hepatic Impairment

No dosage adjustment necessary.

Reconstitution

May be administered undiluted, or diluted in 50 mL of a compatible solution (ie, NS, D5W, D51/2NS, D5LR, LR, and 10% mannitol injection).

Extemporaneously Prepared

Dolasetron injection may be diluted in apple or apple-grape juice and taken orally; this dilution is stable for 2 hours at room temperature (Anzemet prescribing information, 2013).

A 10 mg/mL oral suspension may be prepared with tablets and either a 1:1 mixture of Ora-Plus and Ora-Sweet SF or a 1:1 mixture of strawberry syrup and Ora-Plus. Crush twelve 50 mg tablets in a mortar and reduce to a fine powder. Slowly add chosen vehicle to almost 60 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 60 mL. Label "shake well" and "refrigerate". Stable for 90 days refrigerated.

Anzemet® prescribing information, sanofi-aventis U.S. LLC, Bridgewater, NJ, 2013.Johnson CE, Wagner DS, and Bussard WE, "Stability of Dolasetron in Two Oral Liquid Vehicles," Am J Health Syst Pharm, 2003, 60(21):2242-4.14619116

Administration

IV injection may be given either undiluted as an IV push over 30 seconds or diluted in 50 mL of compatible fluid and infused over 15 minutes. Flush line before and after dolasetron administration.

Oral: When unable to administer in tablet form, dolasetron injection may be diluted in apple or apple-grape juice and taken orally; this dilution is stable for 2 hours at room temperature (Anzemet prescribing information, 2013).

Compatibility

Stable in NS, D5W, D51/2NS, D5LR, LR, and mannitol 10% injection.

Storage

Injection: Store intact vials at 20°C to 25°C (68°F to 77°F); excursions are permitted to 15°C to 30°C (59°F to 86°F). Protect from light. Solutions diluted for infusion in NS, D5W, D51/2NS, D5LR, LR, or mannitol 10% are stable under normal lighting conditions at room temperature for 24 hours or under refrigeration for 48 hours.

Tablets: Store at 20°C to 25°C (68°F to 77°F). Protect from light.

Drug Interactions

Apomorphine: Antiemetics (5HT3 Antagonists) may enhance the hypotensive effect of Apomorphine. Avoid combination

Highest Risk QTc-Prolonging Agents: Moderate Risk QTc-Prolonging Agents may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Ivabradine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Mequitazine: Dolasetron may enhance the arrhythmogenic effect of Mequitazine. Management: Concurrent administration of intravenous dolasetron with mequitazine is contraindicated. Avoid combination

MiFEPRIStone: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Moderate Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Panobinostat: Dolasetron may enhance the arrhythmogenic effect of Panobinostat. Monitor therapy

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Serotonin Modulators: Antiemetics (5HT3 Antagonists) may enhance the serotonergic effect of Serotonin Modulators. This could result in serotonin syndrome. Exceptions: Nicergoline. Monitor therapy

Tapentadol: Antiemetics (5HT3 Antagonists) may diminish the analgesic effect of Tapentadol. Monitor therapy

TraMADol: Antiemetics (5HT3 Antagonists) may diminish the analgesic effect of TraMADol. Monitor therapy

Vinflunine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Adverse Reactions

Adverse events may vary according to indication and route of administration.

>10%: Central nervous system: Headache (oral: 18% to 23%; IV: 9%)

1% to 10%:

Cardiovascular: Bradycardia (4% to 5%; may be severe after IV administration), tachycardia (≤3%), edema (<2%), facial edema (<2%), flushing (<2%), hypotension (<2%; may be severe after IV administration), orthostatic hypotension (<2%), peripheral edema (<2%), peripheral ischemia (<2%), phlebitis (<2%), sinus arrhythmia (<2%), thrombophlebitis (<2%)

Central nervous system: Fatigue (oral: 3% to 6%), dizziness (1% to 6%), pain (≤3%), abnormal dreams (<2%), agitation (<2%), anxiety (<2%), ataxia (<2%), chills (≤2%), confusion (<2%), depersonalization (<2%), paresthesia (<2%), shivering (≤2%), sleep disorder (<2%), twitching (<2%), vertigo (<2%)

Dermatologic: Diaphoresis (<2%), skin rash (<2%), urticaria (<2%)

Endocrine & metabolic: Increased gamma-glutamyl transferase (<2%)

Gastrointestinal: Diarrhea (oral: 2% to 5%), dyspepsia (≤3%), abdominal pain (<2%), anorexia (<2%), constipation (<2%), dysgeusia (<2%), pancreatitis (<2%)

Genitourinary: Dysuria (<2%), hematuria (<2%)

Hematologic and oncologic: Anemia (<2%), hematoma (<2%), prolonged prothrombin time (<2%), prolonged partial thromboplastin time (<2%), purpura (<2%), thrombocytopenia (<2%)

Hepatic: Hyperbilirubinemia (<2%), increased serum alkaline phosphatase (<2%)

Hypersensitivity: Anaphylaxis (<2%)

Local: Burning sensation at injection site (IV: <2%), pain at injection site (IV: <2%)

Neuromuscular & skeletal: Arthralgia (<2%), myalgia (<2%), tremor (<2%)

Ophthalmic: Photophobia (<2%), visual disturbance (<2%)

Otic: Tinnitus (<2%)

Renal: Acute renal failure (<2%), polyuria (<2%)

Respiratory: Bronchospasm (<2%), dyspnea (<2%), epistaxis (<2%)

<1% (Limited to important or life-threatening): Abnormal T waves on ECG, appearance of U waves on ECG, atrial fibrillation, atrioventricular block, bundle branch block (left and right), chest pain, extrasystoles (APCs or VPCs), increased serum ALT (transient), increased serum AST (transient), ischemic heart disease, nodal arrhythmia, prolongation P-R interval on ECG (dose-dependent), prolonged Q-T interval on ECG, serotonin syndrome, slow R wave progression, ST segment changes on ECG, supraventricular cardiac arrhythmia, syncope (may be severe after IV administration), torsades de pointes, ventricular arrhythmia (may be serious), ventricular fibrillation cardiac arrest (intravenous), wide complex tachycardia (intravenous), widened QRS complex on ECG (dose-dependent)

Warnings/Precautions

Concerns related to adverse effects:

• Allergic reactions: Use with caution in patients allergic to other 5-HT3 receptor antagonists; cross-reactivity has been reported with other 5-HT3 receptor antagonists.

• ECG effects: Dolasetron is associated with a number of dose-dependent increases in ECG intervals (eg, PR, QRS duration, QT/QTc, JT), usually occurring 1-2 hours after IV administration and lasting 6-8 hours; however, may last ≥24 hours. May rarely lead to heart block or arrhythmia. Clinically relevant QT interval prolongation may occur resulting in torsade de pointes, when used in conjunction with other agents that prolong the QT interval (eg, Class I and III antiarrhythmics). Avoid use in patients at risk of QT prolongation and/or ventricular arrhythmia (eg, patients with congenital long QT syndrome, medications known to prolong QT interval, electrolyte abnormalities [hypokalemia or hypomagnesemia], and cumulative high-dose anthracycline therapy). Correct potassium or magnesium abnormalities prior to initiating therapy. IV formulations of 5-HT3 antagonists have more association with ECG interval changes, compared to oral formulations. Reduction in heart rate may also occur with the 5-HT3 antagonists.

• Serotonin syndrome has been reported with 5-HT3 receptor antagonists, predominantly when used in combination with other serotonergic agents (eg, SSRIs, SNRIs, MAOIs, mirtazapine, fentanyl, lithium, tramadol, and/or methylene blue). Some of the cases have been fatal. The majority of serotonin syndrome reports due to 5-HT3 receptor antagonists have occurred in a post-anesthesia setting or in an infusion center. Serotonin syndrome has also been reported following overdose of another 5-HT3 receptor antagonist. Monitor patients for signs of serotonin syndrome, including mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile blood pressure, diaphoresis, dizziness, flushing, hyperthermia); neuromuscular changes (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination); gastrointestinal symptoms (eg, nausea, vomiting, diarrhea); and/or seizures. If serotonin syndrome occurs, discontinue 5-HT3 receptor antagonist treatment and begin supportive management.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: ECG monitoring is recommended in geriatric patients.

• Pediatric: Use with caution in children and adolescents who have or may develop QTc prolongation; rare cases of supraventricular and ventricular arrhythmias, cardiac arrest, and MI have been reported in this population.

• Renal impairment: ECG monitoring is recommended in patients with renal impairment.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson, 2002; Lucente 2000; Shelley, 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade, 1986; CDC, 1984). See manufacturer’s labeling.

Other warnings/precautions:

• Chemotherapy-related emesis: For chemotherapy-associated nausea and vomiting, should be used on a scheduled basis, not on an "as needed" (PRN) basis, since data support the use of this drug only in the prevention of nausea and vomiting (due to antineoplastic therapy) and not in the rescue of nausea and vomiting. Not intended for treatment of nausea and vomiting or for chronic continuous therapy.

• Postoperative nausea and vomiting: If the prophylaxis dolasetron dose has failed, a repeat dose should not be administered as rescue or treatment for postoperative nausea and vomiting.

Monitoring Parameters

ECG (in patients with cardiovascular disease, elderly, renally impaired, those at risk of developing hypokalemia and/or hypomagnesemia); potassium, magnesium

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, loss of strength and energy, or diarrhea. Have patient report immediately to prescriber severe dizziness, passing out, bradycardia, tachycardia, signs of serotonin syndrome (dizziness, severe headache, agitation, hallucinations, tachycardia, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, severe diarrhea), or abnormal heartbeat (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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