Interactions between Cycloset and Dronedarone

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of dronedarone. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. According to the product labeling, administration with grapefruit juice resulted in a 2.5-fold increase in dronedarone peak plasma concentration and a 3-fold increase in systemic exposure. Because dronedarone is associated with concentration-dependent prolongation of the QT interval, increased levels may potentiate the risk of ventricular arrhythmias such as torsade de pointes and sudden death.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of dronedarone. The mechanism of interaction is unknown. According to the product labeling, the absolute bioavailability of dronedarone increases from about 4% when administered in the fasted state to approximately 15% when administered with a high-fat meal.

MANAGEMENT: Patients treated with dronedarone should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. Dronedarone should be taken twice daily with the morning and evening meals.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

MONITOR: Nicotine may cause vasoconstriction in some patients and potentiate the ischemic response to ergot alkaloids.

MANAGEMENT: Caution may be advisable when ergot alkaloids are used in combination with nicotine products. Patients should be advised to seek immediate medical attention if they experience potential symptoms of ischemia such as coldness, pallor, cyanosis, numbness, tingling, or pain in the extremities; muscle weakness; severe or worsening headache; visual disturbances; severe abdominal pain; chest pain; and shortness of breath.

Cardiac irregularities occur infrequently in patients on dopamine agonists. The initial administration and titration is recommended to occur under close cardiac monitoring in a facility equipped for intensive cardiac care. Adverse cardiac affects may include palpitation, sinus tachycardia, ventricular tachycardia, extrasystole, atrial flutter or fibrillation, or block of AV conduction.

Dronedarone has shown to double the risk of death in patients with symptomatic heart failure and recent decompensation requiring hospitalization or NYHA Class IV heart failure. It has also shown to double the risk of stroke and death and hospitalization due to heart failure in patients with atrial fibrillation. Other patients at risk include patients with second or third degree AV block, or sick sinus syndrome (except when used in conjunction with a functioning pacemaker), patients with bradycardia < 50 bpm, and patients with QT interval prolongation. The use of dronedarone is contraindicated in these patients.

Dronedarone has shown to double the risk of death in patients with symptomatic heart failure and recent decompensation requiring hospitalization or NYHA Class IV heart failure. It has also shown to double the risk of stroke and death and hospitalization due to heart failure in patients with atrial fibrillation. Other patients at risk include patients with second or third degree AV block, or sick sinus syndrome (except when used in conjunction with a functioning pacemaker), patients with bradycardia < 50 bpm, and patients with QT interval prolongation. The use of dronedarone is contraindicated in these patients.

Dronedarone is extensively metabolized by the liver. There is little clinical experience with moderate hepatic impairment and none in patients with severe hepatic impairment. No dosage adjustment is recommended for patients with moderate hepatic impairment, however its use is contraindicated in patients with severe hepatic impairment. Additionally hepatocellular liver injury, including acute liver failure has been reported in patients using dronedarone in the postmarketing setting. Patients should be advised to report immediately any symptoms suggesting hepatic injury, such as anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant pain, jaundice, dark urine or itching.

Dronedarone has shown to double the risk of death in patients with symptomatic heart failure and recent decompensation requiring hospitalization or NYHA Class IV heart failure. It has also shown to double the risk of stroke and death and hospitalization due to heart failure in patients with atrial fibrillation. Other patients at risk include patients with second or third degree AV block, or sick sinus syndrome (except when used in conjunction with a functioning pacemaker), patients with bradycardia < 50 bpm, and patients with QT interval prolongation. The use of dronedarone is contraindicated in these patients.

The use of dopamine agonists has been associated with psychiatric effects such as hallucinations, psychosis, confusion, anxiety, mania, hypomania, depression, rapid mood cycling, nightmares, and hypersexuality. Therapy with dopamine agonists should be administered cautiously in psychotic patients and all patients should be carefully observed for development of depression and suicidal tendencies.

Dopamine agonists may impair the systemic regulation of blood pressure, with resultant orthostatic hypotension at any time, but especially during dose escalation. Additionally, patients with Parkinson's disease may have an impaired capacity to respond to an orthostatic challenge. For these reasons, patients with Parkinson's disease (or restless legs syndrome) who are being treated with dopaminergic agonists typically require careful monitoring for signs/symptoms of orthostatic hypotension, especially during dose escalation, and should be advised of this risk.

Ordinarily, patients with major psychotic disorder should not be treated with dopaminergic antiparkinsonian agents, because of the risk of exacerbating psychosis. Hallucinations and psychotic-like behavior have been reported with dopaminergic medications. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of these drugs. The use of bromocriptine in patients with severe psychotic disorders is not recommended.