Dofetilide

Dofetilide is an antiarrhythmic Class III agent belonging to a cardiac ion channel blocker.

Dofetilide is used to treat the symptoms of Atrial Fibrillation/Flutter. It is also used to treat supraventricular tachycardia.

It is well absorbed with bioavailability: >90%. The Volume of distribution was about 3 L/kg. With plasma protein binding of 60-70%. It underwent limited metabolism and was mediated to some extent by CYP3A4 isoenzyme to form metabolites via N-dealkylation and N-oxidation. It gets excreted via urine (80%, mainly as an unchanged drug and the remaining as inactive or minimally active metabolites) with a terminal half-life of approx 10 hr.

The common side effects are Headache, chest pain, Dizziness, resp tract infection, dyspnoea, Nausea, flu syndrome, insomnia, accidental injury, diarrhea, rash, back/abdominal pain., etc.

Dofetilide is available in the form of a dosage form, such as capsules.

Dofetilide is available in the USA, UK, Canada, Australia, and India.

Dofetilide selectively inhibits the rapidly activating component of the K channel involved in the repolarisation of cardiac cells, thereby prolonging the action potential duration and effective refractory period in both atrial and ventricular cardiac tissue.

The onset of Action of Dofetilide was 2 to 3 hours.

The Duration of Action of Dofetilide was 10 hours .

The Tmax was about 2-3 hr. and Cmax was about 2.40 to 3.43 ng/ml

Dofetilide is available in the form of a dosage form such as capsules.

Dofetilide is used to treat the symptoms of Atrial Fibrillation/Flutter. It is also used to treat supraventricular tachycardia.

Dofetilide is used to correct irregular heartbeat of patients with atrial fibrillation or atrial flutter to a normal heart rhythm. Dofetilide belongs to the group of medicines known as antiarrhythmics. It works by slowing nerve impulses in the heart.

Dofetilide is available in various dosage strengths : 125mcg, 250mcg, 500mcg. Dofetilide is used to treat the symptoms of Atrial Fibrillation/Flutter. It is also used to treat supraventricular tachycardia.

Atrial fibrillation/atrial flutter:

Maintenance of normal sinus rhythm in patients with chronic atrial fibrillation/atrial flutter of longer than 1-week duration who have been converted to normal sinus rhythm; conversion of atrial fibrillation and atrial flutter to normal sinus rhythm.

Although not approved there have been certain off label use documented for Dofetilide which includes:-

Supraventricular tachycardia

The dosage and the duration of treatment should be as per the clinical judgment of the treating physician

Dofetilide is available in various dosage strengths : 125mcg, 250mcg, 500mcg

Dofetilide is available in the form of a dosage form such as capsules.

Dose Adjustment in Kidney patient:

● CrCl >60 mL/minute: Initial: No dosage adjustment necessary.

● CrCl 40 to 60 mL/minute: Initial: 250 mcg twice daily.

● CrCl 20 to 39 mL/minute: Initial: 125 mcg twice daily.

● CrCl <20 mL/minute: Use is contraindicated

Dose Adjustment in Hepatic Impairment Patient

Mild or moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe hepatic impairment (Child-Pugh class C): There are no dosage adjustments provided.

Dose Adjustment in Pediatric Patient.

No dosage adjustment is necessary.

Dofetilide is used to treat the symptoms of Atrial Fibrillation/Flutter. It is also used to treat supraventricular tachycardia.

Atrial Fibrillation :-Diets high in processed foods, such as fast food, and items high in added sugar, like soda and sugary baked goods, have been linked to increased heart disease risk.

Drinking too much alcohol can increase the risk of developing AFib.It may also trigger AFib episodes in people who already have AFib, especially if patients have existing cardiovascular disease or diabetes.

The dietary restriction should be individualized as per the patient's requirements.

Dofetilide may be contraindicated in the following

Dofetilide contraindications include patients with long QT syndrome. It is also contraindicated in patients on kidney dialysis or with renal diseases.

Dofetilide is contraindicated in patients with a low potassium level in the blood, vomiting and/or diarrhea, sweating, loss of appetite, decreased thirst, and whether the patients have ever had heart or liver disease. Dofetilide is contraindicated in patients planning to become pregnant, pregnant, or breastfeeding.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows.

Concerns related to adverse effects:

• Proarrhythmic effects: May cause serious ventricular arrhythmias, primarily torsades de pointes (TdP). Watch for proarrhythmic effects; monitor and adjust dose to prevent QTc prolongation; reduced CrCl or certain dofetilide drug interactions will increase dofetilide plasma concentration. Risk of TdP significantly increases with doses greater than the maximum dose of 500 mcg twice daily. The risk of TdP may be higher in certain patient subgroups (eg, patients with heart failure). Most episodes of TdP occur within the first 3 days of therapy.

Disease-related concerns:

• Arrhythmias: Appropriate use: Reserve for patients who are highly symptomatic with atrial fibrillation/atrial flutter. Must be initiated (or reinitiated) in a setting that can provide continuous monitoring of CrCl and ECG monitoring and cardiac resuscitation with staff familiar with the recognition and treatment of life-threatening arrhythmias for a minimum of 3 days, or for a minimum of 12 hours after electrical or pharmacological cardioversion to normal sinus rhythm, whichever is greater. Patients should be readmitted for continuous monitoring if dosage is later increased.

• Conduction disturbances:

Use with caution in patients with second or third-degree heart block and/or sick sinus syndrome unless a functional pacemaker is in place; these patients were not included in phase 3 clinical trials. However, no effect on AV nodal conduction seen in patients with normal conduction and those with first-degree heart block. Defibrillation threshold is reduced in patients with ventricular tachycardia or ventricular fibrillation undergoing implantation of a cardioverter-defibrillator device.

• Electrolyte imbalance:

Correct electrolyte disturbances, especially hypokalemia or hypomagnesemia, prior to use and throughout therapy.

Alcohol consumption with Dofetilide may increase the risk of low blood pressure and cause adverse effects, such as Dizziness, fainting, light-headedness, or Headache.

Dofetilide use in breastfeeding patients is not recommended.

US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Do not consume grapefruit or grapefruit juice during treatment with Dofetilide unless directed otherwise by your doctor. Grapefruit juice can increase the blood levels of Dofetilide to dangerous levels.

The adverse reactions related to molecule Dofetilide can be categorized as

● Common Adverse effects:

Cardiac conduction disorder (e.g. slows AV conduction), CNS effects (e.g., dizziness, blurred vision, fatigue), agranulocytosis, elevated antinuclear antibody (ANA) titre, hepatic abnormalities, fulminant hepatitis.

● Less Common adverse effects:

Thrombocytopenia, leucopenia, granulocytopenia. Cardiac disorders: Palpitations, bradycardia, tachycardia, Nausea, vomiting, dry mouth, dysgeusia, constipation, diarrhoea, abdominal pain, flatulence.

Rare adverse effects:

Hypotension, orthostatic hypotension, Erectile dysfunction. Respiratory, thoracic and mediastinal disorders: Dyspnoea.

The clinically relevant drug interactions of Dofetilide is briefly summarized here.

Increased plasma concentration when used w/ drugs secreted by renal tubular cationic transport (e.g. amiloride, metformin, triamterene). Increased risk of toxicity when used w/ QT-prolonging agents (e.g. class I/III antiarrhythmics, bepridil, cisapride, phenothiazines, TCAs, certain fluoroquinolones and oral macrolides).

Potentially Fatal: Increased risk of torsade de pointes when used w/ hydrochlorothiazide (w/ or w/o triamterene), verapamil, and renal cation transport inhibitors (e.g. cimetidine, dolutegravir, trimethoprim, ketoconazole, prochlorperazine, megestrol).

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

No dose adjustment is required..

Symptoms: Torsade de Pointes.

Management: Supportive and symptomatic treatment. Administer charcoal slurry w/in 15 min of dofetilide admin. Admin of isoproterenol infusion and IV Mg sulfate may be useful in managing torsade de points.

Pharmacodynamics:

Dofetilide is an antiarrhythmic drug with Class III (cardiac action potential duration prolonging) properties and is indicated for the maintenance of normal sinus rhythm. Dofetilide increases the monophasic action potential duration in a predictable, concentration-dependent manner, primarily due to delayed repolarization. At concentrations covering several orders of magnitude, Dofetilide blocks only IKr with no relevant block of the other repolarizing potassium currents (e.g., IKs, IK1). At clinically relevant concentrations, Dofetilide has no effect on sodium channels (associated with Class I effect), adrenergic alpha-receptors, or adrenergic beta-receptors.

Pharmacokinetics:

Absorption:

Well absorbed. Bioavailability: >90%. Time to peak plasma concentration: 2-3 hr.

Distribution:

Volume of distribution: 3 L/kg. Plasma protein binding: 60-70%.

Metabolism:

Undergoes limited metabolism; mediated to some extent by CYP3A4 isoenzyme to form metabolites via N-dealkylation and N-oxidation.

Excretion:

Via urine (80%, mainly as unchanged drug and the remaining as inactive or minimally active metabolites). Terminal half-life: Approx 10 hr.

1. https://go.drugbank.com/drugs/DB00204

2. https://www.ncbi.nlm.nih.gov/books/NBK459154/

3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823191/

4. https://www.ahajournals.org/doi/full/10.1161/01.cir.102.21.2665

5. https://reference.medscape.com/drug/tikosyn-dofetilide-342298