Dronedarone

Dronedarone is a non iodinated analogue of amiodarone with a shorter half life and fewer thyroid, lung and eye effects. It lowers the risk of hospital admission for cardiovascular causes in paroxysmal or persistent atrial fibrillation, but it is less effective than amiodarone at preventing recurrence, and it increases mortality in permanent atrial fibrillation and in recent or severe heart failure. It is not widely available in East Africa.

Classification. Class III antiarrhythmic with class I to IV properties; benzofuran derivative.

Mechanism. Blocks multiple potassium currents, sodium and calcium channels, and beta adrenoceptors; slows sinus rate and atrioventricular conduction and prolongs the action potential and QT interval.

Pharmacodynamics. Reduces ventricular rate and recurrence of atrial fibrillation; heart rate falls by about 10 beats/minute. Raises serum creatinine by about 10 to 15% by inhibiting tubular secretion without a true fall in filtration.

Pharmacokinetics. Oral bioavailability about 15% alone and 4 times higher with a meal. Half life 13 to 19 hours. Extensive first pass metabolism by CYP3A4; excreted mainly in faeces (about 84%). Inhibits CYP3A4, CYP2D6 and P-glycoprotein.

Maintenance of sinus rhythm after cardioversion in paroxysmal or persistent atrial fibrillation, adult.

• 400 mg twice daily with breakfast and with dinner.

• No loading dose, no titration; maximum 800 mg daily.

• Stop other class I or III antiarrhythmics (amiodarone: wait for the washout) before starting.

• Condition: stable sinus rhythm or planned cardioversion; patients with permanent atrial fibrillation must not be treated.

Children. Not established.

Contraindications.

• Permanent atrial fibrillation (cannot or will not be cardioverted)
• heart failure with NYHA class IV, or class II to III with recent decompensation
• severe left ventricular systolic dysfunction
• second or third degree atrioventricular block or sick sinus syndrome without a pacemaker
• resting heart rate below 50 beats/minute
• QTc 500 ms or more
• liver injury from previous amiodarone
• severe hepatic impairment
• strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir)
• QT prolonging drugs (including some antimalarials and macrolides)
• dabigatran in some labels
• pregnancy and women of child bearing age without contraception
• breastfeeding

Warnings. Liver injury (rare, can be severe; check enzymes); new or worsening heart failure; pulmonary toxicity (interstitial lung disease); serum creatinine rise; bradycardia; QT prolongation; hypokalaemia and hypomagnesaemia; stroke prevention must continue (anticoagulation).

Adverse effects. Diarrhoea, nausea, vomiting, abdominal pain, bradycardia, QT prolongation, raised creatinine, rash, asthenia, photosensitivity.

Interactions. Digoxin: levels double; halve the dose. Dabigatran: raised exposure. Simvastatin: limit to 10 mg daily. Beta blockers and calcium channel blockers (verapamil, diltiazem): bradycardia and atrioventricular block; start at low doses. Strong CYP3A4 inhibitors: contraindicated. CYP3A4 inducers (rifampicin, carbamazepine, St John's wort): lower levels. QT prolonging drugs: contraindicated. Grapefruit juice raises levels.

Special groups.

• Pregnancy: contraindicated; foetal harm in animals.

• Breastfeeding: contraindicated.

• Patients of African ancestry: no dose change; limited data.

• Older adults: no dose adjustment; monitor liver and creatinine.

• Kidney impairment: no adjustment, but creatinine rises early (by about 0.1 mg/dL or 9 micromol/L) and then plateaus; do not stop for that rise alone; avoid with eGFR under 30 mL/min (limited data).

• Liver impairment: contraindicated in severe disease.

Formulations. Tablets 400 mg.

Administration. Oral twice daily with meals (morning and evening). Swallow whole; avoid grapefruit juice.

Baseline. ECG (rhythm, QTc), potassium, magnesium, creatinine, liver enzymes, chest X-ray if lung disease is suspected, pregnancy test.

Monitoring. ECG at least every 3 months (stop if atrial fibrillation becomes permanent or QTc exceeds 500 ms). Liver enzymes at baseline, at 1 week, monthly for 6 months, then at 9 and 12 months, then regularly. Creatinine at 1 week, then occasionally; accept a rise of up to 50 micromol/L. Symptoms of heart failure (weight, breathlessness). Maintain anticoagulation based on stroke risk.

Stopping. Stop for permanent atrial fibrillation, new heart failure, liver enzymes above 3 times the upper limit with symptoms, severe diarrhoea, pulmonary symptoms, or QTc above 500 ms.

Common prescribing errors. Prescribing in permanent atrial fibrillation or heart failure; failing to wait for amiodarone to wash out; combining with clarithromycin, azole antifungals or QT prolonging antimalarials; not halving digoxin; skipping liver tests; mistaking the harmless creatinine rise for kidney injury and stopping an effective drug.