Multaq

Multaq is a prescription medication used to lower the chance of hospitalization from an atrial fibrillation (irregular heart rhythm).  This medication is used in adults who have had atrial fibrillation in the past but now have a normal heart rhythm.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Tell your doctor about all of the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• certain medicines that can change the amount of Multaq that gets into your body. Do not use these medicines with Multaq:
  • Nefazodone for depression
  • Norvir (ritonavir) for HIV infection
  • Nizoral (ketoconazole), and Sporanox (itraconazole), and Vfend (voriconazole) for fungal infections
  • Ketek (telithromycin), Biaxin (clarithromycin) for bacterial infections
  • Cyclosporine for organ transplant
• You take certain medicines that can lead to a dangerous abnormal heart rhythm:
  • Some medicines for mental illness called phenothiazines
  • Some medicines for depression called tricyclic antidepressants
  • Some medicines for abnormal heart rhythm or fast heartbeat
  • Some medicines for bacterial infection

Ask your doctor if you are not sure if your medicine is one that is listed above.

Tell your doctor if you are breastfeeding or plan to breastfeed. It is not known if Multaq  passes into your breast milk. You and your doctor should decide if you will take Multaq or breastfeed. You should not do both.

• Mechanism of antiarrhythmic action not fully elucidated; exact contribution of activities in each of the 4 Vaughan-Williams antiarrhythmic classes to the clinical effect of the drug unknown.1 5

• Benzofuran derivative structurally related to amiodarone, but with structural modifications that include removal of the iodine group and addition of a methane-sulfonyl group.1 2 3 5 6 7 8 16

• Removal of the iodine group intended to reduce risk of nontarget organ (e.g., thyroid, pulmonary) adverse effects associated with amiodarone therapy; addition of the methane-sulfonyl group aimed at reducing lipophilicity, decreasing risk of neurotoxic adverse effects, and shortening half-life of dronedarone.2 3 5 6 8 16

• Electrophysiologic profile similar to amiodarone, but with different relative effects on individual ion channels.2 3 4 5 6

• Prolongs action potential duration (APD) mainly by inhibition of potassium channels, including transmembrane delayed rectifier, ultrarapid delayed rectifier, inward rectifier, and transient outward potassium currents.5 6

• Inhibits sodium currents (at rapid pacing rates), calcium channels and slow L-type calcium currents, and demonstrates noncompetitive, antiadrenergic (α- and β-blocking) activity.5 6 8 16

• Prolongs PR interval and slows sinus rate by prolonging atrial and ventricular refractory periods.1 8

• Prolongs RR and QT intervals.5 6

• Produces a dose-dependent increase in PR interval and a moderate prolongation of the QTc interval similar to amiodarone.1 5 8

In the U.S.

• Multaq

Available Dosage Forms:

• Tablet

Therapeutic Class: Antiarrhythmic

Chemical Class: Benzofuran

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Chest pain or discomfort
• lightheadedness, dizziness, or fainting
• shortness of breath
• slow or irregular heartbeat
• unusual tiredness

• Abdominal or stomach pain, severe
• chills
• cough
• dark urine
• fever
• general feeling of discomfort or illness
• loss of appetite
• nausea or vomiting
• thickening of bronchial secretions
• unusual tiredness or weakness
• yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Diarrhea
• lack or loss of strength

• Acid or sour stomach
• belching
• blistering, crusting, irritation, itching, or reddening of the skin
• cracked, dry, or scaly skin
• heartburn
• indigestion
• itching skin
• rash
• redness or discoloration of the skin
• skin rash, encrusted, scaly, and oozing
• skin rash, hives, itching, or redness
• stomach discomfort, upset, or pain
• swelling

• Change in taste
• increased sensitivity of the skin to sunlight
• loss of taste
• severe sunburn

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Multaq® is indicated to reduce the risk of hospitalization for atrial fibrillation in patients in sinus rhythm with a history of paroxysmal or persistent atrial fibrillation (AF) [see Clinical Studies (14)].

ATHENA

ATHENA was a multicenter, multinational, double blind, and randomized placebo-controlled study of dronedarone in 4628 patients with a recent history of AF/AFL who were in sinus rhythm or who were to be converted to sinus rhythm. The objective of the study was to determine whether dronedarone could delay death from any cause or hospitalization for cardiovascular reasons.

Initially patients were to be ≥70 years old, or <70 years old with at least one risk factor (including hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≥50 mm or LVEF <0.40). The inclusion criteria were later changed such that patients were to be ≥75 years old, or ≥70 years old with at least one risk factor. Patients had to have both AF/AFL and sinus rhythm documented within the previous 6 months. Patients could have been in AF/AFL or in sinus rhythm at the time of randomization, but patients not in sinus rhythm were expected to be either electrically or chemically converted to normal sinus rhythm after anticoagulation.

Subjects were randomized and treated for up to 30 months (median follow-up: 22 months) with either Multaq 400 mg twice daily (2301 patients) or placebo (2327 patients), in addition to conventional therapy for cardiovascular diseases that included beta-blockers (71%), ACE inhibitors or angiotensin II receptor blockers (ARBs) (69%), digoxin (14%), calcium antagonists (14%), statins (39%), oral anticoagulants (60%), aspirin (44%), other chronic antiplatelet therapy (6%) and diuretics (54%).

The primary endpoint of the study was the time to first hospitalization for cardiovascular reasons or death from any cause. Time to death from any cause, time to first hospitalization for cardiovascular reasons, and time to cardiovascular death and time to all causes of death were also explored.

Patients ranged in age from 23 to 97 years; 42% were 75 years old or older. Forty-seven percent (47%) of patients were female and a majority was Caucasian (89%). Seventy-one percent (71%) of those enrolled had no history of heart failure. The median ejection fraction was 60%. Twenty-nine percent (29%) of patients had heart failure, mostly NYHA class II (17%). The majority had hypertension (86%) and structural heart disease (60%).

Results are shown in Table 3. Multaq reduced the combined endpoint of cardiovascular hospitalization or death from any cause by 24.2% when compared to placebo. This difference was entirely attributable to its effect on cardiovascular hospitalization, principally hospitalization related to AF.

Other endpoints, death from any cause and first hospitalization for cardiovascular reasons, are shown in Table 3. Secondary endpoints count all first events of a particular type, whether or not they were preceded by a different type of event.

The Kaplan-Meier cumulative incidence curves showing the time to first event are displayed in Figure 3. The event curves separated early and continued to diverge over the 30 month follow-up period.

Figure 3: Kaplan-Meier Cumulative Incidence Curves from Randomization to First Cardiovascular Hospitalization or Death from Any Cause

Reasons for hospitalization included major bleeding (1% in both groups), syncope (1% in both groups), and ventricular arrhythmia (<1% in both groups).

The reduction in cardiovascular hospitalization or death from any cause was generally consistent in all subgroups based on baseline characteristics or medications (ACE inhibitors or ARBs; beta-blockers, digoxin, statins, calcium channel blockers, diuretics) (see Figure 4).

Figure 4: Relative Risk (Multaq versus Placebo) Estimates with 95% Confidence Intervals According to Selected Baseline Characteristics: First Cardiovascular Hospitalization or Death from Any Cause.

(a) Determined from Cox regression model
(b) P-value of interaction between baseline characteristics and treatment based on Cox regression model
(c) Calcium antagonists with heart rate lowering effects restricted to diltiazem, verapamil and bepridil

EURIDIS and ADONIS

In EURIDIS and ADONIS, a total of 1237 patients in sinus rhythm with a prior episode of AF or AFL were randomized in an outpatient setting and treated with either Multaq 400 mg twice daily (n=828) or placebo (n=409) on top of conventional therapies (including oral anticoagulants, beta-blockers, ACE inhibitors or ARBs, chronic antiplatelet agents, diuretics, statins, digoxin, and calcium channel blockers). Patients had at least one ECG-documented AF/AFL episode during the 3 months prior to study entry but were in sinus rhythm for at least one hour. Patients ranged in age from 20 to 88 years, with the majority being Caucasian (97%), male (70%) patients. The most common comorbidities were hypertension (56.8%) and structural heart disease (41.5%), including coronary heart disease (21.8%). Patients were followed for 12 months.

In the pooled data from EURIDIS and ADONIS as well as in the individual trials, dronedarone delayed the time to first recurrence of AF/AFL (primary endpoint), lowering the risk of first AF/AFL recurrence during the 12-month study period by about 25%,with an absolute difference in recurrence rate of about 11% at 12 months.

ANDROMEDA

Patients recently hospitalized with symptomatic heart failure and severe left ventricular systolic dysfunction (wall motion index ≤1.2) were randomized to either Multaq 400 mg twice daily or matching placebo, with a primary composite end point of all-cause mortality or hospitalization for heart failure. Patients enrolled in ANDROMEDA were predominantly NYHA Class II (40%) and III (57%), and only 25% had AF at randomization. After enrolment of 627 patients and a median follow-up of 63 days, the trial was terminated because of excess mortality in the dronedarone group. Twenty-five (25) patients in the dronedarone group died versus 12 patients in the placebo group (hazard ratio 2.13; 95% CI: 1.07 to 4.25). The main reason for death was worsening heart failure. Baseline digoxin therapy was reported in 6/16 dronedarone patients versus 1/16 placebo patients who died of arrhythmia. In patients without baseline use of digoxin, no excess risk of arrhythmic death was observed in the dronedarone versus placebo groups.

There were also excess hospitalizations for cardiovascular reasons in the dronedarone group (71 vs 51 for placebo) [see Boxed Warning, Contraindications (4)].

PALLAS

Patients with permanent AF (AF documented in 2 weeks prior to randomization and at least 6 months prior to randomization in whom cardioversion had failed or was not planned) and additional risk factors for thromboembolism (coronary artery disease, prior stroke or TIA, symptomatic heart failure, LVEF <40%, peripheral arterial occlusive disease, or age >75 with hypertension and diabetes) were randomized to dronedarone 400 mg twice daily or placebo.

After enrollment of 3236 patients (placebo=1617 and dronedarone=1619) and a median follow up of 3.7 months for placebo and 3.9 for dronedarone, the study was terminated because of a significant increase in

• Mortality: 25 dronedarone versus 13 placebo (HR, 1.94; CI: 0.99 to 3.79). The majority of deaths in the dronedarone group were classified as arrhythmic/sudden deaths (HR, 3.26; CI: 1.06 to 10.0). Baseline digoxin therapy was reported in 11/13 dronedarone patients who died of arrhythmia. None of the arrhythmic deaths on placebo (4) reported use of digoxin. In patients without baseline use of digoxin, no excess risk of arrhythmic death was observed in the dronedarone versus placebo groups.
• Stroke: 23 dronedarone versus 10 placebo (HR, 2.32; CI: 1.11 to 4.88). The increased risk of stroke observed with dronedarone was observed in the first two weeks of therapy (10 dronedarone vs 1 placebo), most of the subjects treated with dronedarone did not have an INR of 2.0 to 3.0 [see Warnings and Precautions (5.3)].
• Hospitalizations for heart failure in the dronedarone group: 43 dronedarone versus 24 placebo (HR, 1.81; CI: 1.10 to 2.99).

Do not stop taking Multaq without first talking to your doctor. Stopping suddenly may make your condition worse.

You should not use Multaq if you were recently hospitalized for heart failure, or if you now have symptoms of heart failure (shortness of breath, swelling, rapid weight gain). You also should not use this medicine if you have a "permanent" heart rhythm disorder called atrial fibrillation. Multaq can double your risk of death if you have any of these heart conditions.

Multaq can harm an unborn baby or cause birth defects. Do not use dronedarone if you are pregnant.

You should not breast-feed while using this medicine.

You should not use Multaq if you have severe liver disease or certain serious heart conditions such as "AV block" or sick sinus syndrome (unless you have a pacemaker). You should not use Multaq if you have a history of very slow heart beats, or if you have ever used amiodarone and it caused you to have lung problems or liver problems.

There are many other medicines that can cause serious medical problems if you take them together with Multaq. You may need to stop taking certain drugs while you are taking Multaq. Tell your doctor about all other medicines you use.

Multaq is used to treat intermittent or "temporary" heart rhythm disorders. In some people with "permanent" atrial fibrillation, Multaq increased the risk of stroke, hospitalization due to heart failure, and death. Multaq can double your risk of death if you have any of these heart conditions:

• if you were recently hospitalized for heart failure;

• if you now have symptoms of heart failure (shortness of breath, swelling, rapid weight gain); or

• you have a "permanent" atrial fibrillation that cannot be changed back to a normal rhythm.

You also should not use Multaq if you are allergic to dronedarone, or if you have:

• severe liver disease;

• certain serious heart conditions, especially severe heart failure, "AV block" or sick sinus syndrome (unless you have a pacemaker);

• a history of slow heart beats that have caused you to faint;

• if you are pregnant or breast-feeding; or

• if you have ever used amiodarone and it caused you to have lung problems or liver problems.

Some medicines can cause unwanted or dangerous effects when used with Multaq. You may need to stop taking certain drugs while you are taking this medicine. Tell your doctor about all other medicines you use, especially:

• cyclosporine;

• ritonavir;

• antifungal medicine - ketoconazole, itraconazole, voriconazole;

• an antibiotic - clarithromycin, telithromycin;

• an antidepressant;

• medicine to treat a psychiatric disorder; or

• other heart rhythm medicines.

To make sure Multaq is safe for you, tell your doctor if you have:

• kidney disease;

• liver disease;

• a history of heart failure;

• an electrolyte imbalance (such as low levels of potassium or magnesium in your blood); or

• if you have a pacemaker or defibrillator implanted in your chest.

FDA pregnancy category X. This medicine can harm an unborn baby or cause birth defects. Do not use Multaq if you are pregnant. Tell your doctor right away if you become pregnant during treatment. Use effective birth control while you are using this medicine.

It is not known whether dronedarone passes into breast milk or if it could harm a nursing baby. You should not breast-feed while taking Multaq.

Take Multaq exactly as prescribed by your doctor. Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Multaq works best if you take it with your morning and evening meals.

Your heart function may need to be checked using an electrocardiograph or ECG (sometimes called an EKG) every 3 months. This will help your doctor determine how long to treat you with Multaq. Your liver and kidney function may also need to be checked.

Use Multaq regularly even if you feel fine or have no symptoms. Get your prescription refilled before you run out of medicine completely.

You should not stop using Multaq suddenly. Stopping suddenly may make your condition worse.

Store at room temperature away from heat and moisture.