DRONEDARONE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for DRONEDARONE (DRONEDARONE).
Dronedarone is a multichannel blocker that inhibits potassium (IKr, IKs, IKur), sodium (INa), and calcium (ICaL) currents, and exhibits antiadrenergic effects via noncompetitive antagonism of beta-1 and beta-2 receptors. It also prolongs atrial refractoriness and slows atrioventricular conduction.
| Metabolism | Extensively metabolized via CYP3A4 and to a lesser extent CYP2D6. Major metabolite is SR-35021. |
| Excretion | Primarily fecal (≥84%) via biliary excretion; renal excretion accounts for <6% as unchanged drug. |
| Half-life | Terminal half-life is 13–19 hours; steady state achieved within 4–8 days. |
| Protein binding | >98% bound, primarily to albumin. |
| Volume of Distribution | Approximately 12–20 L/kg, indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is 15–20% due to extensive first-pass metabolism; increases 2- to 3-fold with food. |
| Onset of Action | Oral: clinical effect (e.g., reduction in atrial fibrillation recurrence) typically observed within 1–2 weeks. |
| Duration of Action | Sustained antiarrhythmic effect with consistent dosing; therapeutic effect persists over 24 hours with twice-daily administration. |
400 mg orally twice daily after meals
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for GFR >30 mL/min. Dronedarone is contraindicated in patients with GFR <30 mL/min (creatinine clearance <30 mL/min or serum creatinine >2.5 mg/dL) due to increased mortality observed in clinical trials. |
| Liver impairment | Contraindicated in Child-Pugh class B and C (moderate to severe hepatic impairment). No dose adjustment for Child-Pugh class A. Monitor hepatic enzymes periodically. |
| Pediatric use | Safety and efficacy not established in pediatric patients; no approved pediatric dosing. |
| Geriatric use | No specific dose adjustment required based on age alone. However, elderly patients may have age-related renal or hepatic impairment; consider contraindications for severe renal impairment and monitor hepatic function. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for DRONEDARONE (DRONEDARONE).
| Breastfeeding | Unknown if excreted in human breast milk. No M/P ratio available. Due to potential for serious adverse reactions in nursing infants, including proarrhythmic effects and hepatic toxicity, breastfeeding should be discontinued during dronedarone therapy or avoid its use in nursing mothers. |
| Teratogenic Risk | FDA Category X. Dronedarone is contraindicated in pregnant women. Animal studies have shown embryofetal toxicity and teratogenicity, including cardiovascular and skeletal malformations, at doses below human exposure. There are no adequate and well-controlled studies in pregnant women. Use during pregnancy is not recommended; if exposure occurs, notify the patient of potential fetal harm and consider alternative therapy. |
■ FDA Black Box Warning
Increased risk of death, stroke, and hospitalization for heart failure in patients with NYHA Class IV heart failure or decompensated heart failure. Dronedarone is contraindicated in such patients.
| Serious Effects |
["NYHA Class IV heart failure or decompensated heart failure","Second- or third-degree atrioventricular block, sick sinus syndrome (unless pacemaker present)","Bradycardia <50 bpm","Concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin)","Concomitant use of Class I or Class III antiarrhythmic drugs (e.g., quinidine, procainamide, amiodarone, dofetilide, sotalol)","QTc interval >500 ms","Severe hepatic impairment","Pregnancy"]
| Precautions | ["Increased risk of cardiovascular death in patients with severe heart failure","Increased risk of stroke and hospitalization for heart failure","Hepatotoxicity: severe liver injury including acute hepatic failure reported","Interstitial lung disease including pneumonitis and pulmonary fibrosis","Proarrhythmia: can increase QT interval, Torsade de Pointes risk","Electrolyte disturbances: hypokalemia, hypomagnesemia should be corrected before use"] |
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| Fetal Monitoring | Monitor maternal ECG, liver function tests (LFTs), renal function, and electrolytes periodically. In pregnancy, monitor fetal heart rate and growth via ultrasound, and assess for signs of fetal distress due to potential placental hypoperfusion. May need to monitor maternal thyroid function as dronedarone can increase thyroid hormone levels. |
| Fertility Effects | Animal studies at high doses have shown reduced fertility in female rats (increased estrous cycle length, decreased implantation) and testicular toxicity in male rats (reduced sperm motility and count). Human fertility effects are unknown; advise patients planning pregnancy to consider alternative therapy. |