Interactions between Dronedarone and Lariam

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.

ADJUST DOSING INTERVAL: Food enhances the oral absorption and bioavailability of mefloquine. The proposed mechanism is increased drug solubility in the presence of food. In 20 healthy volunteers, administration of a single 750 mg oral dose of mefloquine 30 minutes following a high-fat meal increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of mefloquine by 73% and 40%, respectively, compared to administration in the fasting state. The Cmax and AUC of the carboxylic acid metabolite were also increased by 35% and 33%, respectively, compared to fasting. In addition, the time to reach peak plasma concentration (Tmax) of mefloquine was significantly shorter after food intake (17 hours) than in the fasting state (36 hours). There was no difference in the elimination half-life of mefloquine and metabolite, or the Tmax for the metabolite.

MANAGEMENT: To ensure maximal oral absorption, mefloquine should be administered immediately after a meal with at least 8 ounces of water.

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 mefloquine for malaria prophylaxis is contraindicated in patients with active depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia, or other major psychiatric disorders. Mefloquine may cause psychiatric symptoms in some patients, including agitation, anxiety, depression, mood changes, panic attacks, paranoia, confusion, hallucinations, aggression, and psychotic behavior. Occasionally, these symptoms have been reported to continue long after mefloquine has been withdrawn due to its long half-life. Rare cases of suicidal ideation and suicide have occurred during mefloquine use, although a causal relationship has not been established. Therapy with mefloquine should be administered cautiously in patients with a previous history of depression. Psychiatric symptoms that occur during prophylactic use such as acute anxiety, depression, restlessness, or confusion should be considered prodromal to a more serious event, and the drug must be discontinued and an alternative medication substituted.

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 mefloquine for malaria prophylaxis is contraindicated in patients with active depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia, or other major psychiatric disorders. Mefloquine may cause psychiatric symptoms in some patients, including agitation, anxiety, depression, mood changes, panic attacks, paranoia, confusion, hallucinations, aggression, and psychotic behavior. Occasionally, these symptoms have been reported to continue long after mefloquine has been withdrawn due to its long half-life. Rare cases of suicidal ideation and suicide have occurred during mefloquine use, although a causal relationship has not been established. Therapy with mefloquine should be administered cautiously in patients with a previous history of depression. Psychiatric symptoms that occur during prophylactic use such as acute anxiety, depression, restlessness, or confusion should be considered prodromal to a more serious event, and the drug must be discontinued and an alternative medication substituted.

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 mefloquine for malaria prophylaxis is contraindicated in patients with active depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia, or other major psychiatric disorders. Mefloquine may cause psychiatric symptoms in some patients, including agitation, anxiety, depression, mood changes, panic attacks, paranoia, confusion, hallucinations, aggression, and psychotic behavior. Occasionally, these symptoms have been reported to continue long after mefloquine has been withdrawn due to its long half-life. Rare cases of suicidal ideation and suicide have occurred during mefloquine use, although a causal relationship has not been established. Therapy with mefloquine should be administered cautiously in patients with a previous history of depression. Psychiatric symptoms that occur during prophylactic use such as acute anxiety, depression, restlessness, or confusion should be considered prodromal to a more serious event, and the drug must be discontinued and an alternative medication substituted.

The use of mefloquine for malaria prophylaxis is contraindicated in patients with active depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia, or other major psychiatric disorders. Mefloquine may cause psychiatric symptoms in some patients, including agitation, anxiety, depression, mood changes, panic attacks, paranoia, confusion, hallucinations, aggression, and psychotic behavior. Occasionally, these symptoms have been reported to continue long after mefloquine has been withdrawn due to its long half-life. Rare cases of suicidal ideation and suicide have occurred during mefloquine use, although a causal relationship has not been established. Therapy with mefloquine should be administered cautiously in patients with a previous history of depression. Psychiatric symptoms that occur during prophylactic use such as acute anxiety, depression, restlessness, or confusion should be considered prodromal to a more serious event, and the drug must be discontinued and an alternative medication substituted.

The use of mefloquine for malaria prophylaxis is contraindicated in patients with a history of seizures. Mefloquine can increase the risk of convulsions in patients with epilepsy and may lower the plasma levels of some anticonvulsant medications. Therefore, it should only be prescribed for curative treatment of malaria in such patients and only if there are compelling medical reasons for its use.

Mefloquine is a myocardial depressant. Animal studies with parenteral mefloquine indicate that the drug possesses 20% of the antifibrillatory action of quinidine and produces 50% of the increase in the PR interval reported with quinine. The effect of mefloquine on the compromised cardiovascular system has not been evaluated. However, transient and asymptomatic ECG alterations have been reported during the use of mefloquine, including sinus bradycardia, sinus arrhythmia, first-degree AV block, prolongation of the QTc interval, and abnormal T waves. In postmarketing use, hypotension, hypertension, flushing, syncope, chest pain, tachycardia, palpitation, bradycardia, irregular pulse, extrasystoles, AV block, and other transient cardiac conduction alterations have been reported rarely. Therapy with mefloquine should be administered cautiously in patients with cardiac disease and only if potential benefits justify the risks.

Mefloquine is primarily metabolized by the liver. Patients with liver disease may be at greater risk for adverse effects from mefloquine due to decreased drug clearance. Therapy with mefloquine should be administered cautiously in patients with liver disease. Periodic evaluation of hepatic function should be performed during prolonged therapy.