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Dolasetron

Medically reviewed on September 10, 2018

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

Dolasetron is a selective serotonin receptor (5-HT3) antagonist which blocks 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

Chemotherapy-associated nausea and vomiting (oral): Prevention of nausea and vomiting associated with initial and repeat course of moderately emetogenic cancer chemotherapy in adults and children ≥2 years

Postoperative nausea and vomiting (injection): Prevention and treatment of postoperative nausea and vomiting (PONV) in adults and children ≥2 years

Limitations of use: Routine PONV prophylaxis is not recommended if there is little expectation that nausea and/or vomiting will occur postoperatively. In patients in whom nausea and/or vomiting must be avoided postoperatively, dolasetron (injection) is recommended even if the anticipated incidence of postoperative nausea and/or vomiting is low. If prophylaxis has failed, a repeat dose should not be utilized as rescue therapy.

Off Label Uses

Chemotherapy-associated nausea and vomiting (high emetic potential) (adults)

In addition to the approved use (prevention of nausea and vomiting associated with moderately emetogenic chemotherapy), antiemetic guidelines from the American Society of Clinical Oncology (ASCO) also recommend offering a 5-HT3 receptor antagonist (including oral dolasetron) in combination with other antiemetic agents for the prevention of highly emetic chemotherapy, including cisplatin-containing chemotherapy or chemotherapy regimens containing an anthracycline and cyclophosphamide.

Chemotherapy-associated nausea and vomiting (low emetic potential) (adults)

In addition to the approved use (prevention of nausea and vomiting associated with moderately emetogenic chemotherapy), antiemetic guidelines from the American Society of Clinical Oncology (ASCO) also recommend offering a 5-HT3 receptor antagonist (including oral dolasetron) as a single agent for the prevention of low emetic chemotherapy.

Contraindications

Tablet: Known hypersensitivity to dolasetron or any component of the formulation

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

Dosing: Adult

Note: Anzemet injection has been discontinued in the US for more than 1 year.

Note: Use of intravenous dolasetron is contraindicated for the prevention of chemotherapy induced nausea and vomiting.

Prevention of chemotherapy-associated nausea and vomiting (moderate emetic potential): Oral: 100 mg within 1 hour before chemotherapy

Guideline recommendations: Prevention of chemotherapy-induced nausea and vomiting: American Society of Clinical Oncology (ASCO [Hesketh 2017]):

High emetic risk, including cisplatin-based and most anthracyclines combined with cyclophosphamide regimens: Oral: 100 mg on the day(s) chemotherapy is administered (antiemetic regimen also includes dexamethasone, an NK1 receptor antagonist, and olanzapine)

Moderate emetic risk: Oral: 100 mg on the day(s) chemotherapy is administered (antiemetic regimen also includes dexamethasone [and an NK1 receptor antagonist for carboplatin AUC ≥4])

Low emetic risk: Oral: 100 mg (as a single agent) prior to chemotherapy on the day(s) chemotherapy is administered

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)

Dosing: Geriatric

Refer to adult dosing. ECG monitoring is also recommended.

Dosing: Pediatric

Note: Anzemet injection has been discontinued in the US for more than 1 year.

Prevention of chemotherapy-associated nausea and vomiting (moderate emetic potential): Children 2 to 16 years: Oral: 1.8 mg/kg within 1 hour before chemotherapy; maximum: 100 mg/dose

Postoperative nausea and vomiting: Children 2 to 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

IV: 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

Oral: Administer within 1 hour prior to chemotherapy. 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).

IV: 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 up to 15 minutes. Flush line before and after dolasetron administration.

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

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

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

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

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

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

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

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

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

QTc-Prolonging Agents (Moderate Risk): May enhance the QTc-prolonging effect of other QTc-Prolonging Agents (Moderate Risk). 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

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 QTc-Prolonging Agents (Moderate Risk). Avoid combination

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

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%, postmarketing, and/or case reports: Abnormal T waves on ECG, appearance of U waves on ECG, atrial fibrillation, atrial flutter, atrioventricular block, bundle branch block (left and right), cardiac arrest, chest pain, extrasystoles (APCs or VPCs), increased serum ALT (transient), increased serum AST (transient), ischemic heart disease, nodal arrhythmia, palpitations, 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, syncope (may be severe after IV administration), torsades de pointes, ventricular arrhythmia , ventricular fibrillation cardiac arrest (IV), ventricular tachycardia (IV), wide complex tachycardia (IV), widened QRS complex on ECG (dose-dependent)

Warnings/Precautions

Concerns related to adverse effects:

• Cardiovascular effects: Dolasetron is associated with dose-dependent QT interval prolongation; torsades de pointes has been reported. Dolasetron has been determined to cause dose-dependent PR and QRS interval prolongation; second- or third-degree atrioventricular block, cardiac arrest, and serious ventricular arrhythmias (with fatalities) have been observed in adult and pediatric patients. The risk for ECG changes is increased in patients with underlying structural heart disease, preexisting conduction system abnormalities, sick sinus syndrome, atrial fibrillation with slow ventricular response, myocardial ischemia, elderly patients, patients receiving drugs known to prolong the QT interval (eg, Class I or II antiarrhythmics), or patients who have received cumulative high-dose anthracycline therapy. Use with caution (and monitor ECG) in patients at risk for ECG changes. Avoid dolasetron use in patients with congenital long QT syndrome, hypokalemia or hypomagnesemia, and complete heart block or in those at risk for complete heart block who do not have an implanted pacemaker. Correct hypokalemia and hypomagnesemia prior to treatment initiation. Following dolasetron administration, monitor serum potassium and magnesium as clinically indicated. Monitor ECG in patients with heart failure, bradycardia, renal impairment, and in elderly patients. The 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.

• Hypersensitivity: Anaphylactic reaction, facial edema, and urticaria have been reported. Use with caution in patients allergic to other 5-HT3 receptor antagonists; cross-reactivity has been reported with other 5-HT3 receptor antagonists.

• Serotonin syndrome: 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 IV 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 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: Antiemetics are most effective when used prophylactically (Roila 2016). If emesis occurs despite optimal antiemetic prophylaxis, reevaluate emetic risk, disease, concurrent morbidities, and medications to assure antiemetic regimen is optimized (ASCO [Hesketh 2017]).

Monitoring Parameters

Monitor serum potassium and magnesium; ECG (in patients with cardiovascular disease, elderly, renally impaired, those at risk of developing hypokalemia and/or hypomagnesemia). Monitor for signs/symptoms of serotonin syndrome.

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, or 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.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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