Multag

Multag® 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).

Multag is an antiarrhythmic medication that affects the rhythm of heartbeats.

Multag helps keep the heart beating normally in people with life-threatening heart rhythm disorders of the atrium (the upper chambers of the heart that allow blood to flow into the heart) and risk factors such as diabetes, high blood pressure, a history of stroke, or being over 70 years old.

Multag is used to treat certain heart rhythm disorders called atrial fibrillation or atrial flutter. Multag is given to reduce the need for hospitalization due to these heart conditions.

Multag may also be used for purposes not listed in this medication guide.

Usual Adult Dose for Atrial Fibrillation

400 mg orally 2 times a day with a meal

Use: To reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e., age greater than 70 years, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter 50 mm or more, or left ventricular ejection fraction [LVEF] less than 40%), who are in sinus rhythm or who will be cardioverted.

Usual Adult Dose for Atrial Flutter

400 mg orally 2 times a day with a meal

Use: To reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e., age greater than 70 years, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter 50 mm or more, or left ventricular ejection fraction [LVEF] less than 40%), who are in sinus rhythm or who will be cardioverted.

Renal Dose Adjustments

No adjustment recommended.

Liver Dose Adjustments

Mild to moderate liver dysfunction: No adjustment recommended

Severe liver dysfunction: Contraindicated

Precautions

BOXED WARNINGS:

-HEART FAILURE: Multag is contraindicated in patients with symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV heart failure. Multag doubles the risk of death in these patients.

ATRIAL FIBRILLATION (AF): Multag is contraindicated in patients in atrial fibrillation (AF) who cannot be cardioverted into normal sinus rhythm. Multag doubles the risk of death, stroke, and hospitalization for heart failure in patients with permanent AF.

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration advice:

-Administer with food.

-Grapefruit juice should be avoided.

Monitoring:

Cardiovascular: Periodic assessment of heart failure risks or worsening of preexisting NYHA Class I heart failure.

Hepatic: Liver function tests should be performed at baseline and periodically during treatment.

Metabolic: Potassium or magnesium deficiency should be corrected prior to starting treatment.

Renal: Serum creatinine should be monitored prior to and 7 days after treatment initiation.

General: Doses greater than 400 mg daily are not considered more effective and are less well tolerated.

See also:
What is the most important information I should know about Multag?

Multag is used to treat intermittent or "temporary" heart rhythm disorders. In some people with "permanent" atrial fibrillation, Multag increased the risk of stroke, hospitalization due to heart failure, and death. Talk with your doctor about your individual risk. Do not stop taking this medication without first talking to your doctor. Stopping suddenly may make your condition worse.

You should not use Multag if you are allergic to Multag, if you are pregnant or breast-feeding, 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, or if you were recently hospitalized for heart failure.

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

Also 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.

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

You may need regular medical tests to be sure this medication is not causing harmful effects. Visit your doctor regularly.

Use Multag as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Multag comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Multag refilled.
• Take Multag by mouth with food, such as with the morning and evening meals, unless your doctor tells you otherwise.
• Do not eat grapefruit or drink grapefruit juice while you take Multag.
• Take Multag on a regular schedule to get the most benefit from it.
• Continue to take Multag even if you feel well. Do not miss any doses.
• If you miss a dose of Multag, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Multag.

Use: Labeled Indications

Paroxysmal or persistent atrial fibrillation: To reduce the risk of hospitalization for atrial fibrillation (AF) in patients in sinus rhythm with a history of paroxysmal or persistent AF

Off Label Uses

Atrial fibrillation in patients with hypertrophic cardiomyopathy (alternative antiarrhythmic)

Based on the 2011 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline for the diagnosis and treatment of hypertrophic cardiomyopathy (HCM) and the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) guideline for the management of patients with atrial fibrillation (AF), Multag may be considered an alternative to amiodarone or disopyramide (combined with a beta-blocker or a nondihydropyridine calcium channel blocker) for the treatment of AF in patients with HCM, especially in those with an implantable cardioverter-defibrillator (ICD), but clinical experience is limited.

See also:
What other drugs will affect Multag?

Pharmacodynamic Interactions

Drugs prolonging the QT interval (inducing Torsade de Pointes)

Co-administration of drugs prolonging the QT interval (such as certain phenothiazines, tricyclic antidepressants, certain macrolide antibiotics, and Class I and III antiarrhythmics) is contraindicated because of the potential risk of Torsade de Pointes-type ventricular tachycardia.

Digoxin

In the ANDROMEDA (patients with recently decompensated heart failure) and PALLAS (patients with permanent AF) trials baseline use of digoxin was associated with an increased risk of arrhythmic or sudden death in Multag-treated patients compared to placebo. In patients not taking digoxin, no difference in risk of sudden death was observed in the Multag vs. placebo groups..

Digoxin can potentiate the electrophysiologic effects of Multag (such as decreased AV-node conduction). Multag increases exposure to digoxin.

Consider discontinuing digoxin. If digoxin treatment is continued, halve the dose of digoxin, monitor serum levels closely, and observe for toxicity.

Calcium channel blockers

Calcium channel blockers with depressant effects on the sinus and AV nodes could potentiate Multag's effects on conduction.

Give a low dose of calcium channel blockers initially and increase only after ECG verification of good tolerability.

Beta-blockers

In clinical trials, bradycardia was more frequently observed when Multag was given in combination with beta-blockers.

Give a low dose of beta-blockers initially, and increase only after ECG verification of good tolerability.

Effects Of Other Drugs On Multag

Ketoconazole and other potent CYP 3A inhibitors

Concomitant use of ketoconazole as well as other potent CYP 3A inhibitors such as itraconazole, voriconazole, ritonavir, clarithromycin, and nefazodone is contraindicated because exposure to Multag is significantly increased.

Grapefruit juice

Patients should avoid grapefruit juice beverages while taking Multag because exposure to Multag is significantly increased.

Rifampin and other CYP 3A inducers

Avoid rifampin or other CYP 3A inducers such as phenobarbital, carbamazepine, phenytoin, and St John's wort because they decrease exposure to Multag significantly.

Calcium channel blockers

Verapamil and diltiazem are moderate CYP 3A inhibitors and increase Multag exposure. Give a low dose of calcium channel blockers initially and increase only after ECG verification of good tolerability.

Effects Of Multag On Other Drugs

Simvastatin

Multag increased simvastatin/simvastatin acid exposure. Avoid doses greater than 10 mg once daily of simvastatin.

Other statins

Because of multiple mechanisms of interaction with statins (CYPs and transporters), follow statin label recommendations for use with CYP 3A and P-gp inhibitors such as Multag.

Calcium channel blockers

Multag increased the exposure of calcium channel blockers (verapamil, diltiazem or nifedipine). Give a low dose of calcium channel blockers initially and increase only after ECG verification of good tolerability.

Sirolimus, tacrolimus, and other CYP3A substrates with narrow therapeutic range

Multag can increase plasma concentrations of tacrolimus, sirolimus, and other CYP 3A substrates with a narrow therapeutic range when given orally. Monitor plasma concentrations and adjust dosage appropriately.

Beta-blockers and other CYP 2D6 substrates

Multag increased the exposure of propranolol and metoprolol. Give low doses of beta-blockers initially, and increase only after ECG verification of good tolerability. Other CYP 2D6 substrates, including other beta-blockers, tricyclic antidepressants, and selective serotonin reuptake inhibitors (SSRIs) may have increased exposure upon co-administration with Multag.

P-glycoprotein substrates

Digoxin

Multag increased digoxin exposure by inhibiting the P-gp transporter. Consider discontinuing digoxin. If digoxin treatment is continued, halve the dose of digoxin, monitor serum levels closely, and observe for toxicity.

Dabigatran

Exposure to dabigatran is higher when it is administered with Multag than when it is administered alone.

Other P-gp substrates are expected to have increased exposure when co-administered with Multag.

Warfarin

When co-administered with Multag exposure to S-warfarin was slightly higher than when warfarin was administered alone. There were no clinically significant increases in INR.

More patients experienced clinically significant INR elevations ( ≥ 5) usually within 1 week after starting Multag vs. placebo in patients taking oral anticoagulants in ATHENA. However, no excess risk of bleeding was observed in the Multag group.

Postmarketing cases of increased INR with or without bleeding events have been reported in warfarin-treated patients initiated on Multag. Monitor INR after initiating Multag in patients taking warfarin.

See also:
What are the possible side effects of Multag?

The following safety concerns are described elsewhere in the label:

• New or worsening heart failure
• Liver Injury
• Pulmonary toxicity
• Hypokalemia and hypomagnesemia with potassium-depleting diuretics
• QT prolongation

Clinical Trials Experience

The safety evaluation of Multag 400 mg twice daily in patients with AF or AFL is based on 5 placebo controlled studies, ATHENA, EURIDIS, ADONIS, ERATO and DAFNE. In these studies, a total of 6285 patients were randomized and treated, 3282 patients with Multag 400 mg twice daily, and 2875 with placebo. The mean exposure across studies was 12 months. In ATHENA, the maximum follow-up was 30 months.

In clinical trials, premature discontinuation because of adverse reactions occurred in 11.8% of the Multag-treated patients and in 7.7% of the placebo-treated group. The most common reasons for discontinuation of therapy with Multag were gastrointestinal disorders (3.2 % versus 1.8% in the placebo group) and QT prolongation (1.5% versus 0.5% in the placebo group).

The most frequent adverse reactions observed with Multag 400 mg twice daily in the 5 studies were diarrhea, nausea, abdominal pain, vomiting, and asthenia.

Table 1 displays adverse reactions more common with Multag 400 mg twice daily than with placebo in AF or AFL patients, presented by system organ class and by decreasing order of frequency. Adverse laboratory and ECG effects are presented separately in Table 2.

Table 1: Adverse Drug Reactions that Occurred in at Least 1% of Patients and Were More Frequent than Placebo

Photosensitivity reaction and dysgeusia have also been reported at an incidence less than 1% in patients treated with Multag.

The following laboratory data/ECG parameters were reported with Multag 400 mg twice daily.

Table 2: Laboratory data/ECG parameters not necessarily reported as adverse events

Assessment of demographic factors such as gender or age on the incidence of treatment-emergent adverse events did not suggest an excess of adverse events in any particular sub-group.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Multag. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac: New or worsening heart failure Atrial flutter with 1:1 atrioventricular conduction has been reported very rarely.

Hepatic: Liver Injury

Respiratory: Interstitial lung disease including pneumonitis and pulmonary fibrosis

Immune: Anaphylactic reactions including angioedema

Vascular: Vasculitis, including leukocytoclastic vasculitis

Multag is a sinus rhythm controller for management of paroxysmal or persistent atrial fibrillation. Classified as a Class III antiarrhythmic but displays properties of all four Vaughan-Williams classes, Multag blocks a multitude of channels (sodium, potassium, calcium), and demonstrates antiadrenergic properties. Chemically, it is a benzofuran derivative. FDA approved on July 1, 2009.