dronedarone (Rx)

>10%

QTc prolongation (28%)

Early increase in SCr of >10% (51%)

1-10%

Diarrhea (9%)

Asthenia (7%)

Nausea (5%)

Skin reactions (eg, rash, pruritus, eczema, allergic dermatitis) (5%)

Abdominal pain (4%)

Bradycardia (3%)

Vomiting (2%)

Dyspepsia (2%)

Postmarketing Reports

New/worsening HF

Hepatic injury

Cardiac failure

Pulmonary fibrosis

Interstitial lung disease including pneumonitis and PF

Anaphylactic reactions (eg, angioedema)

Vasculitis (eg, leukocytoclastic vasculitis)

Interstitial lung disease, including pneumonitis and pulmonary fibrosis, have been reported

Atrial flutter with 1:1 atrioventricular conduction

Photosensitivity

Dysgeusia

Contraindications

Hypersensitivity

Permanent AF in patients in whom normal sinus rhythm cannot be restored

Symptomatic HF with recent decompensation requiring hospitalization, or symptoms of NYHA class IV HF due to doubled risk of death

Concomitant strong CYP3A4 inhibitors (eg, grapefruit juice, itraconazole, clarithromycin, erythromycin)

Symptomatic HF with recent decompensation requiring hospitalization

NYHA class IV HF

Referral to HF program

2nd or 3rd degree heart block or sick sinus syndrome (unless used with functioning pacemaker)

Bradycardia <50 bpm

QTc interval >500 ms or PR interval >280 ms

Coadministration with drugs that prolong QT interval may cause torsade de Pointes-type ventricular tachycardia (eg, phenothiazine, TCAs, macrolide antibiotics, class I and III antiarrhythmic agents [amiodarone, flecainide, propafenone, quinidine, disopyramide, dofetilide, sotalol])

Liver toxicity related to previous use of amiodarone

Severe hepatic impairment (ie, Child-Pugh Class C)

Pregnancy (category X)

Breastfeeding women

Cautions

Increased risk of stroke, particularly in first two weeks of therapy; should only be initiated in patients in sinus rhythm who are receiving appropriate antithrombotic therapy

Cases of interstitial lung disease including pneumonitis and pulmonary fibrosis reported; onset of dyspnea or non-productive cough may be related to pulmonary toxicity; carefully evaluate patients clinically; if pulmonary toxicity confirmed, discontinue therapy

Postmarketing cases of increased INR with or without bleeding events have been reported in warfarin-treated patients initiated on dronedarone; monitor INR after initiating in patients taking warfarin

Potassium levels should be within normal range prior to administration of therapy and maintained in normal range during administration; increased risk of hypomagnesemia/hypokalemia with potassium-depleting diuretics

Dronedarone induces moderate prolongation of the QT interval; monitor; if QTc Bazett interval is ≥500 ms, discontinue therapy

Marked increase in serum creatinine, prerenal azotemia, and acute renal failure, often in the setting of heart failure or hypovolemia, reported; typically reversible when drug discontinued; monitor renal function

Small increase in SCr following initiation; elevation has a rapid onset, reaches plateau after 7 days, and is reversible upon discontinuation

Women of childbearing potential must exercise caution while on therapy and must be counseled on appropriate contraceptive choices

Heart failure

• New onset or worsening of heart failure has been reported during treatment in postmarketing setting; in a placebo-controlled study in patients with permanent AF increased rates of heart failure were observed in patients with normal left ventricular function and no history of symptomatic heart failure, as well as those with a history of heart failure or left ventricular dysfunction; discontinue if new or worsening HF develops
• Not approved for permanent atrial fibrillation (phase III PALLAS trial halted because preliminary analysis showed 2-fold increase in death, as well as 2-fold increases in stroke and hospitalization for HF)

Hepatotoxicity

Hepatocellular liver injury, including acute liver failure requiring transplant, reported in the postmarketing setting; advise patients to report immediately symptoms suggesting hepatic injury (such as anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant pain, jaundice, dark urine, or itching)

Consider obtaining periodic hepatic serum enzymes, especially during the first 6 months of treatment; not known whether routine periodic monitoring of serum enzymes will prevent development of severe liver injury; if hepatic injury suspected, promptly discontinue therapy and test serum enzymes, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase, as well as serum bilirubin, to establish whether there is liver injury

If liver injury is found, institute appropriate treatment and investigate the probable cause; do not restart therapy in patients without another explanation for observed liver injury

Pregnancy category: X

Lactation: Unknown if distributed in breast milk; contraindicated

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Unknown; noniodinated antiarrhythmic agent structurally related to amiodarone; has properties belonging to all 4 Vaughn-Williams antiarrhythmic classes

Blocks sodium channels, blocks beta1-adrenergic site, and alters adenyl cyclase generation (ie, negative inotropic effects); blocks potassium channels (eg, hERG) and therefore prolongs cardiac repolarization

Absorption

Bioavailability: 4% (without food); 15% (with high-fat meal)

Peak plasma time: 3-6 hr (including major active metabolite); at steady state: 2.6-4.5 hr

Distribution

Protein bound: >98%

Vd: 1400 L (steady state)

Metabolism

CYP3A4 (extensive)

Initial metabolic pathway includes N-debutylation to form active N-debutyl metabolite, oxidative deamination to form the inactive propanoic acid metabolite, and direct oxidation

Metabolites undergo further metabolism to yield over 30 uncharacterized metabolites; N-debutyl metabolite exhibits pharmacodynamic activity (1/10 to 1/3 as potent as dronedarone)

Elimination

Half-life, elimination: 13-19 hr

Clearance: 130-150 L/hr

Excretion: Feces (84%); urine (6%)