Dolasetron (Anzemet) is a 5 HT-3 receptor antagonist that inhibits the central and peripheral receptors responsible for inducing vomiting.

Dolasetron Uses:

• Chemotherapy-associated nausea and vomiting:

  • The oral form is quite effective in preventing nausea and vomiting due to the initial and repeat course of moderate chemotherapy in adults and children ≥2 years.

• Postoperative nausea and vomiting:

  • The injectable form is effective in preventing and treating postoperative nausea and vomiting in adults and children ≥2 years.

• Limitations of use:

  • Routine postoperative nausea and vomiting prophylaxis is not advised if there is a lesser chance of nausea/vomiting postoperatively.
  • In patients in whom nausea/vomiting must be avoided postoperatively, the injection form of dolasetron is prescribed despite the low incidence of postoperative nausea and/or vomiting. If prophylaxis is not successful, a repeat dose should not be used as rescue therapy.

• Off-label USe in Adults:

  • Chemotherapy-associated nausea and vomiting (high /low emetic potential)

Dolasetron dosage in adults:

Note:

• Anzemet injection has been discontinued in the US for more than 1 year.
• I/V  dolasetron is contraindicated for preventing chemotherapy-induced nausea and vomiting.

Dolasetron Dose in the Prevention of chemotherapy-associated nausea and vomiting (moderate emetic potential):

• 100 mg per oral within 60 minutes before chemotherapy.

Dolasetron Guideline recommendations:

• Prevention of chemotherapy-induced nausea and vomiting: American Society of Clinical Oncology:

  • High emetic risk, including cisplatin-based and most anthracyclines combined with cyclophosphamide regimens:

    • 100 mg per oral  on the day of  chemotherapy administration (including dexamethasone, an NK receptor antagonist, and olanzapine)

  • Moderate emetic risk:

    • 100 mg per oral  on the day of chemotherapy administration (including dexamethasone and an NK receptor antagonist for carboplatin area under the curve (AUC) ≥4]

  • Low emetic risk:

    • A single dose of 100 mg per oral before chemotherapy on the day of chemotherapy administration.

Dolasetron Dose in Postoperative nausea and vomiting:

• Prevention:

  • 12.5 mg  intravenously in 15 minutes before the cessation of anesthesia (do not exceed the recommended dose)

• Treatment:

  • I12.5 mg intravenously  at the onset of nausea or vomiting (do not exceed the recommended dose)

Donasetron dosage in children:

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

Donasetron Dose in the prevention of Chemotherapy-induced nausea and vomiting:

Note:

Intravenous administration of dolasetron for chemotherapy-induced nausea/vomiting is contraindicated due to increase risk of QT prolongation. The parenteral formula is advised orally if the patients cannot swallow tablets or the tablet strength is an inappropriate dose.

• Children ≥2 years and Adolescents ≤16 years:

  • Tablet or using the parenteral formulation: 1.8 mg/kg per oral as a single dose within 60 minutes prior to chemotherapy
  • The maximum dose is 100 mg/dose

• Adolescents >16 years:

  • 100 mg per oral  as a single dose within 60 minutes prior to  chemotherapy

Dolasetron Dose in Postoperative nausea and vomiting:

Note: A repeat dose should not be given as rescue therapy in case of prophylaxis failure.

• Prevention:

  • Oral (using parenteral formulation administered orally):

  • Children and adolescents 2 - 16 years of age:

    • 2 mg/kg per oral given within 120 minutes before the surgery
    • The maximum dose is 100 mg

  • Children ≥2 years and Adolescents ≤16 years:

    • 35 mg/kg intravenously in 15 minutes before the cessation of anesthesia
    • maximum dose: 12.5 mg/dose

  • Adolescents >16 years:

    • 5 mg intravenously in 15 minutes before the cessation of anesthesia (do not exceed the recommended dose)

• Treatment:

  • Children ≥2 years and Adolescents ≤16 years:

    • 35 mg/kg  intravenous at the onset of nausea /
    • vomiting maximum dose: 12.5 mg/dose

  • Adolescents >16 years:

    • 5 mg intravenous at the onset of  nausea /vomiting (do not exceed the recommended dose)

Donasetron Pregnancy Risk Factor: B

• Studies on animal reproduction did not show any adverse effects.

Dolasetron is not recommended for use while breastfeeding

• It is unclear if dolasetron is secreted into breast milk.
• Dolasetron should not be administered to nursing mothers without caution, according to the manufacturer.

Donasetron dose adjustment in renal disease:

No dosage adjustment required. But  Electrocardiogram monitoring is advised in patients with renal impairment. 

Donasetron dose adjustment in liver disease:

No dosage adjustment necessary.

Donasetron Side effects:

Adverse events depend on its indication and  administration route

Common Side Effects of Dolasetron:

• Central nervous system:

  • Headache

Less Common Side Effects of Dolasetron:

• Cardiovascular:

  • Bradycardia
  • Tachycardia
  • Edema
  • Facial Edema
  • Flushing
  • Hypotension
  • Orthostatic Hypotension
  • Peripheral Edema
  • Peripheral Ischemia
  • Phlebitis
  • Sinus Arrhythmia
  • Thrombophlebitis

• Central Nervous System:

  • Fatigue
  • Dizziness
  • Pain
  • Abnormal Dreams
  • Agitation
  • Anxiety
  • Ataxia
  • Chills
  • Confusion
  • Depersonalization
  • Paresthesia
  • Shivering
  • Sleep Disorder
  • Twitching
  • Vertigo

• Dermatologic:

  • Diaphoresis
  • Skin Rash
  • Urticaria

• Endocrine & Metabolic:

  • Increased Gamma-Glutamyl Transferase

• Gastrointestinal:

  • Diarrhea
  • Dyspepsia
  • Abdominal Pain
  • Anorexia
  • Constipation
  • Dysgeusia
  • Pancreatitis

• Genitourinary:

  • Dysuria
  • Hematuria

• Hematologic And Oncologic:

  • Anemia
  • Hematoma
  • Prolonged Prothrombin Time
  • Prolonged Partial Thromboplastin Time
  • Purpura
  • Thrombocytopenia

• Hepatic:

  • Hyperbilirubinemia
  • Increased Serum Alkaline Phosphatase

• Hypersensitivity:

  • Anaphylaxis

• Local:

  • Burning Sensation At Injection Site
  • Pain At Injection Site

• Neuromuscular & Skeletal:

  • Arthralgia
  • Myalgia
  • Tremor

• Ophthalmic:

  • Photophobia
  • Visual Disturbance

• Otic:

  • Tinnitus

• Renal:

  • Acute Renal Failure
  • Polyuria

• Respiratory:

  • Bronchospasm
  • Dyspnea
  • Epistaxis

Contraindication to Dolasetron:

• Dolasetron and any other component of the formulation may cause hypersensitivity in individuals who are sensitive to oral tablets.
• Injections may cause hypersensitivity.
• It is also contraindicated in case of prevention of chemotherapy-associated nausea and vomiting

Warnings and precautions

• Cardiovascular effects

  • In some cases, dose-dependent QT interval lengthening and torsades des pointes were observed.
  • Dolasetron can cause a dose-dependent prolongation of PR/QRS interval, second/third-degree AV block, cardiac arrhythmias, and fatal ventricular arrhythmias in children and adults.
  • In patients with underlying structural heart disease, preexisting conduction system abnormalities, sick sinus syndrome, AF with a slow ventricular response, MI, old age, concurrent drugs causing QT interval prolongation (eg, Class I or II antiarrhythmics), PR interval (eg, verapamil), or QRS interval (eg, flecainide or quinidine), diuretics causing electrolyte abnormalities, or patients who had high dose anthracyclines the risk of cardiac ECG changes is significantly increased.
  • Patients with congenital long QT syndrome/low potassium/low magnesium/complete or potential heart block/risk of complete heart block, who don't have an implanted pacemaker, should not take Dolasetron.
  • Before starting treatment, it is important to correct hypokalemia and hypermagnesemia.
  • Monitor serum potassium and magnesium levels after dolasetron administration.
  • ECG should always be performed in patients with heart disease, bradycardia and renal impairment as well as elderly.
  • Intranavenous 5-HT antagonists are more associated with ECG interval changes than the oral form.
  • Bradycardia could lead to 5-HT antagonists.

• Hypersensitivity

  • Dolasetron can cause facial edema and anaphylaxis.
  • Patients who are allergic to other 5-HT antagonists should be cautious as cross-reactivity can occur with other 5-HT antagonists.

• Serotonin syndrome:

  • Serotonin syndrome can be observed when 5-HT-3 receptor antagonists are used, Especially in combination therapy with serotonergic drugs (eg, selective Serotonin Uptake Inhibitors, SNRIs and Monoamine Oxase Inhibitors, Mirtazapine or Intravenous methylene Blue).
  • Serotonin syndrome caused by 5-HT receptor antagonists is most commonly seen in a post-anesthesia setting, or in an infusion centre.
  • Serotonin syndrome may also be caused by an overdose of another 5-HT antagonist.
  • Serotonin syndrome symptoms include mental changes such as agitation, hallucinations and delirium, coma, autonomic instability (eg tachycardia and labile BP, diaphoresis and flushing, hyperthermia), neuromuscular disorders (eg tremors, rigidity and myoclonus, hyperreflexia and incoordination), and GI symptoms (eg nausea, vomiting and diarrhea).
  • Serotonin syndrome should not be treated with 5HT-3 receptor antagonist therapy. Supportive treatment should be started.

Dolasetron: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• Monitoring of serum potassium and magnesium.
• ECG should be checked in patients with heart failure, bradycardia, old age, renal impairment, those at risk of developing hypokalemia, or hypomagnesemia.
• Signs and symptoms of serotonin syndrome should also be taken into account.

How to administer Dolasetron?

• Oral administration should be done within 60 minutes before chemotherapy.
• When unable to swallow tablet form, diluted injection in apple / apple-grape juice can be given orally this dilution is stable for 2 hours at room temperature.
• Intravenous injection is administered either undiluted as an Intravenous push over 30 seconds or diluted in 50 mL of compatible fluid and infused over up to 15 minutes.
• The line should be flushed prior to and after dolasetron administration.

Dolasetron mechanism of action:

Dolasetron, a selective serotonin antagonist (5-HT-3), acts peripherally at the primary action site and centrally in the chemoreceptor trigger area. Absorption via the oral route is rapid and complete

Protein binding: Hydrodolasetron: 69% to 77% (~50% bound to alpha -acid glycoprotein)

Metabolism: Occurs in liver, carbonyl reductase cause rapid reduction to hydrodolasetron (active metabolite); further metabolized by CYP2D6, CYP3A, and flavin monooxygenase Bioavailability: Not affected by food if taken orally Children: 59% (formulation not specified); Adults: ~75% Half-life elimination: The half-life of Dolasetron if given I/V ≤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

Time to peak, plasma: Hydrodolasetron: IV: 0.6 hours; Oral: ~1 hour Excretion: Urine ~67% (dolasetron: <1% excreted unchanged in urine; hydrodolasetron: 53% to 61% of the total dose); Feces ~33%  

Dolasetron Brand Names (International):

• Anzemet
• Anemet

Dolasetron Brand Names in Pakistan: