Dronedarone

Dronedarone is an antiarrhythmic Class III agent belonging to a multi-channel blocker.

Dronedarone is used in the management of atrial fibrillation (AF) in patients in sinus rhythm with a history of paroxysmal or persistent AF to reduce the risk of hospitalization.

The absolute bioavailability of dronedarone is approx 4% (w/o food) and approx 15% (w/ food). The volume of distribution was approx 20 L/kg. The Plasma protein binding was >98% (mainly albumin). The hepatic metabolism was mainly via CYP3A4 isoenzyme to N-butyl metabolite. The initial metabolic pathway includes N-debutylation, oxidative deamination, and direct oxidation. It gets excreted Via faeces: Approx 84% (as metabolites and unchanged drug); urine: Approx 6% (as metabolites) with elimination half-life: 13-19 hr.

The common side effects are Hypokalaemia, hypomagnesemia, bradycardia, diarrhea, Nausea, vomiting, abdominal pain, and dyspepsia, rashes and asthenia, pneumonitis and pulmonary fibrosis, etc.

Dronedarone is available in the form of a dosage form, such as tablets.

Dronedarone is available in the USA, UK, Canada, Australia, Germany, Denmark, India.

Dronedarone moderately prolongs the QTc interval by about 10 ms on average. Dronedarone decreases arterial blood pressure and reduces oxygen consumption. It reduces myocardial contractility with no change in left ventricular ejection fraction. Dronedarone vasodilates coronary arteries through activation of the nitric oxide pathway.

Dronedarone is an antiarrhythmic agent structurally related to Dronedarone but w/o the iodine moiety to reduce the risk of non-target organ adverse effects associated w/ Dronedarone . It exhibits all the properties of the 4 antiarrhythmic classes. It prolongs cardiac action potential duration and refractory periods by inhibiting K channels, inhibits Na and Ca channels, and has noncompetitive antiadrenergic activity

The Duration of Action of Dronedarone was13–19 hours.

The Tmax was about 3 to 6 hours. and Cmax was about 1.87 ± 1.65 mg/mL

Dronedarone is used in the management of atrial fibrillation (AF) in patients in sinus rhythm with a history of paroxysmal or persistent AF to reduce the risk of hospitalization.

Dronedarone is an antiarrhythmic agent structurally related to Dronedarone but w/o the iodine moiety to reduce the risk of non-target organ adverse effects associated w/ Dronedarone . It exhibits all the properties of the 4 antiarrhythmic classes.

Dronedarone is used in the management of atrial fibrillation (AF) in patients in sinus rhythm with a history of paroxysmal or persistent AF to reduce the risk of hospitalization.

Paroxysmal or persistent atrial fibrillation:

To reduce the risk of hospitalization for atrial fibrillation (AF) in patients in sinus rhythm with a history of paroxysmal or persistent AF.

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

Dronedarone is available in various dosage strengths : 400 mg.

Dronedarone is available in the form of a dosage form such as tablets.

Dronedarone is used in the management of atrial fibrillation (AF) in patients in sinus rhythm with a history of paroxysmal or persistent AF to reduce the risk of hospitalization.

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.

Dronedarone may be contraindicated in the following

• Hypersensitivity to Dronedarone or any component of the formulation; permanent atrial fibrillation (patients in whom normal sinus rhythm will not or cannot be restored); symptomatic heart failure (heart failure with recent [within the last 4 weeks] decompensation requiring hospitalization or NYHA Class III or IV symptoms); liver or lung toxicity related to previous Dronedarone use; second-degree or third-degree atrioventricular block or sick sinus syndrome (except when used in conjunction with a functioning artificial pacemaker); bradycardia <50 bpm; concomitant use of strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, ritonavir); concomitant use of drugs or herbal products known to prolong the QT interval increasing the risk for torsade de pointes (eg, phenothiazine antipsychotics, tricyclic antidepressants, certain oral macrolide antibiotics, class I and III antiarrhythmics); QTc (Bazett) interval ≥500 msec or PR interval >280 msec; severe hepatic impairment; pregnancy; breastfeeding
• Canadian labeling: Additional contraindications (not in US labeling): Permanent atrial fibrillation of any duration where sinus rhythm cannot be restored and further attempts to restore it are no longer considered; history of or current heart failure regardless of NYHA class; left ventricular systolic dysfunction; complete bundle branch block, distal block, sinus node dysfunction, or atrial conduction defects (except when used in conjunction with a functioning pacemaker); unstable hemodynamic condition

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

Concerns related to adverse effects:

• Renal effects: Dronedarone may produce a slight increase in serum creatinine (~0.1 mg/dL) within 7 days of initiation due to inhibition of tubular secretion; glomerular filtration rate is not affected. Effect is reversible upon discontinuation. Marked increase in serum creatinine, prerenal azotemia and acute renal failure have been reported; usually in the setting of heart failure or hypovolemia. The effects appear to be reversible upon drug discontinuation and with appropriate medical treatment; monitor renal function periodically. Discontinue use in the setting of heart failure as this is a contraindication.

Disease-related concerns:

• Cardiac devices (eg, implanted defibrillators): One trial conducted during ischemia in a closed-chest animal (porcine) model demonstrated that Dronedarone does not affect defibrillation threshold of implantable cardioverter defibrillators (ICD) compared to Dronedarone (Chevalier 2012). However, prospective human studies are necessary to confirm these results in humans. Assess defibrillation threshold when initiating Dronedarone and during therapy.

• Electrolyte imbalance: Correct electrolyte disturbances, especially hypokalemia or hypomagnesemia, prior to use and throughout therapy.

• Hepatic impairment: Use with caution in patients with mild to moderate hepatic impairment; use is contraindicated in severe hepatic impairment. Use is also contraindicated in patients with previous liver toxicity with Dronedarone.

• Permanent atrial fibrillation (AF): Cardiovert patients who are in AF (if clinically indicated) or discontinue Dronedarone.

Special populations:

• Older adult: In the treatment of atrial fibrillation, avoid antiarrhythmics as first-line treatment. In older adults, data suggests rate control may provide more benefits than risks compared to rhythm control for most patients.

• Women of childbearing potential: Should use effective contraceptive methods during treatment.

Other warnings/precautions:

• Appropriate use: Initiate only in patients in sinus rhythm who are receiving appropriate antithrombotic therapy.

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

Dronedarone use in breastfeeding patients is not recommended.

Pregnancy Category X

Dronedarone may cause fetal harm when administered to a pregnant woman. In animal studies, Dronedarone was teratogenic in rats at the maximum recommended human dose (MRHD), and in Rabbits at half the MRHD. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. When pregnant rats received Dronedarone at oral doses greater than or equal to the MRHD (on a Mg/m2 Basis), fetuses had increased rates of external, visceral and skeletal malformations (cranioschisis, cleft palate, incomplete evagination of pineal body, brachygnathia, partially fused Carotid arteries, truncus arteriosus, abnormal location of the liver, partially duplicated inferior Vena cava, brachydactyly, ectrodactylia, syndactyly, and anterior and/or posterior club feet). When pregnant rabbits received Dronedarone, at a dose approximately half the MRHD (on a Mg/m2 basis), fetuses had an increased rate of skeletal abnormalities (anomalous ribcage and Vertebrae, pelvic asymmetry) at doses ≥20 mg/kg (the lowest dose tested and approximately half the MRHD on a mg/m2 Basis). Actual animal doses: rat (≥80 mg/kg/day); rabbit (≥20 mg/kg)

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

The adverse reactions related to molecule Dronedarone 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 Dronedarone is briefly summarized here.

Increased risk of bradycardia w/ β-blockers, Ca channel blockers and other antiarrhythmics. May increase plasma concentrations of statins, sirolimus and tacrolimus, vit K antagonists, warfarin and digoxin.

Potentially Fatal: Increased risk of QT prolongation and torsade de pointes w/ phenothiazines antipsychotics, tricyclic antidepressants, class I and III antiarrhythmics, some macrolides (e.g. erythromycin), bepridil and terfenadine. Decreased plasma concentration w/ CYP3A4 inducers (e.g., phenytoin, phenobarbital, rifampicin, carbamazepine). Increased plasma concentration w/ CPY3A4 inhibitor (e.g. ciclosporin, cimetidine, clarithromycin, ketoconazole, HIV-protease inhibitors, nefazodone).

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

No dose adjustment is required.

In the event of overdosage, monitor the patient’s cardiac rhythm and blood pressure. Treatment should be supportive and based on symptoms.

It is not known whether Dronedarone or its metabolites can be removed by dialysis (hemodialysis, Peritoneal dialysis or hemofiltration). There is no specific antidote available.

Pharmacodynamics:

Dronedarone is an antiarrhythmic agent that restores normal sinus rhythm and reduces heart rate in atrial fibrillation. In another model, it prevents ventricular tachycardia and ventricular fibrillation.Dronedarone moderately prolongs the QTc interval by about 10 ms on average. Dronedarone decreases arterial blood pressure and reduces oxygen consumption. It reduces myocardial contractility with no change in left ventricular ejection fraction. Dronedarone vasodilates coronary arteries through activation of the nitric oxide pathway. In clinical studies, Dronedarone reduced incidence of hospitalizations for acute coronary syndromes and reduced incidence of stroke.Dronedarone exhibits antiadrenergic effects by reducing alpha-adrenergic blood pressure response to epinephrine and beta 1 and beta 2 responses to isoproterenol. Dronedarone was shown to inhibit triiodothyronine (T3) signalling by binding to TRα1 but much less so to TRβ1. The treatment of Dronedarone in patients with severe heart failure and left ventricular systolic dysfunction was associated with increased early mortality related to the worsening of heart failure.

In animal studies, the use of Dronedarone at doses equivalent to the recommended human doses was associated with fetal harm. In clinical studies and postmarketing reports, Dronedarone was shown to cause hepatocellular liver injury and pulmonary toxicities, such as interstitial lung disease, pneumonitis, and pulmonary fibrosis

Pharmacokinetics:

• Absorption

Dronedarone is well absorbed after oral administration (>70%). It displays low systemic bioavailability due to extensive first-pass metabolism. The absolute bioavailability of Dronedarone without and with a high-fat meal is 4% and 15%, respectively. The peak plasma concentrations of Dronedarone and its main circulating N-dibutyl metabolite are reached within 3 to 6 hours after administration with food. Following repeated administration of 400 mg dronedarone twice daily, the steady-state was reached within 4 to 8 days of initial treatment. The steady-state Cmax and systemic exposure to the N-dibutyl metabolite are similar to that of the parent compound.

• Distribution

The volume of distribution at steady-state ranges from 1200 to 1400 L following intravenous administration.

• Metabolism:

Hepatic metabolism mainly via CYP3A4 isoenzyme to N-butyl metabolite. Initial metabolic pathway includes N-debutylation, oxidative deamination and direct oxidation.

• Excretion:

Via faeces: Approx 84% (as metabolites and unchanged drug); urine: Approx 6% (as metabolites). Elimination half-life: 13-19 hr.

1. https://reference.medscape.com/drug/multaq-dronedarone-999201
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2922784/
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3201110/
4. https://www.sciencedirect.com/science/article/pii/S2221618916000044
5. https://www.nejm.org/doi/full/10.1056/nejmoa1109867