Multaq - Dronedarone

Question 1

Antiarrhythmic class

Answer 1

Has effects from all 4 classes but contribution of each to the clinical effect is unknown

Question 2

Mechanism of action

Answer 2

Mechanism of action unknown • Clear dose-dependent ↑ in PR Interval • Moderate dose-related ↑ QTc Interval

Question 3

Indications

Answer 3

MULTAQ is an antiarrhythmic drug indicated to reduce the risk of hospitalization for AF in patients in sinus rhythm with a history of paroxysmal or persistent AF

Question 4

Oral Dosing Strengths

Answer 4

400 mg

Question 5

Dosing

Answer 5

• 400 mg BID • One tablet twice a day (with morning and evening meals) No adjustment recommended for moderate hepatic impairment

Question 6

Treatment setting

Answer 6

No requirement

Question 7

Monitoring requirements at initiation

Answer 7

No monitoring required during initiation; monitor INR (in patients taking warfarin), renal function, liver serum enzymes and heart rhythm per PI

Question 8

Pharmacokinetics

Answer 8

Moderate deviation from dose proportionality: 2-fold increase in dose results in ~2.5- to 3.0-fold increase in Cmax and AUC

Question 9

Bioavailability/ absorption

Answer 9

Low systemic bioavailability, which is ↑ by meals — Without food (4%) — With high-fat meal (15%) • With food, peak plasma levels reached in 3-6 hours • Steady state within 4-8 days

Question 10

Half-life

Answer 10

13-19 hrs.

Question 11

Protein binding

Answer 11

98%

Question 12

Metabolism

Answer 12

Extensively metabolized, mainly by CYP3A

Question 13

Major active metabolite

Answer 13

N-debutyl metabolite — With food, plasma levels reached in 3-6 hours — One-tenth to one-third as potent as dronedarone

Question 14

Route of elimination

Answer 14

• ~6% renal excretion • 84% excreted in feces

Question 15

Overdosage

Answer 15

• Monitor cardiac rhythm and BP
• No specific antidote available; treatment should be supportive and based on symptoms

Question 16

Contraindications

Answer 16

• Permanent AF (patients in whom normal sinus rhythm will not or cannot be restored)
• Recently decompensated HF requiring hospitalization or Class IV HF symptoms
• 2nd- or 3rd-degree AV block or SSS (except when used in conjunction with a functioning pacemaker)
• Bradycardia <50 bpm
• Concomitant use of a strong CYP3A inhibitor
• Concomitant use of drugs or herbal products that prolong the QT interval and may induce TdP
• Liver or lung toxicity related to the previous use of amiodarone
• Severe hepatic impairment
• QTc Bazett interval ≥500 ms or PR interval >280 ms
• Pregnancy and nursing mothers
• Hypersensitivity to drug

Question 17

Boxed Warning

Answer 17

INCREASED RISK OF DEATH, STROKE, AND HEART FAILURE IN PATIENTS WITH DECOMPENSATED HEART FAILURE OR PERMANENT ATRIAL FIBRILLATION

• MULTAQ is contraindicated in patients with symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV heart failure. MULTAQ doubles the risk of death in these patients
• MULTAQ is contraindicated in patients in AF who will not or cannot be cardioverted into normal sinus rhythm. In patients with permanent AF, MULTAQ doubles the risk of death, stroke, and hospitalization for heart failure

Question 18

Warnings (except boxed warning—see above)

Answer 18

Warnings and Precautions

• Determine cardiac rhythm at least once every 3 months. If AF is detected, discontinue MULTAQ or cardiovert
• Liver injury: if hepatic injury is suspected, discontinue MULTAQ
• MULTAQ should only be initiated in patients who are receiving appropriate antithrombotic therapy
• Hypokalemia and hypomagnesemia: Maintain potassium and magnesium levels within the normal range
• ↑ in creatinine: Monitor renal function periodically
• Fetal harm: Women of childbearing potential should use effective contraception while using MULTAQ

Question 19

Precautions

Answer 19

See Warnings

Question 20

Drug interactions

Answer 20

• Potential pharmacodynamic interactions: — Drugs or herbal products that prolong the QT interval, eg, Class I and III AADs, certain oral macrolide antibiotics, certain phenothiazine antipsychotics, or tricyclic antidepressants (all contraindicated)

— Digoxin

— CCBs

— b-blockers

— Potassium-depleting diuretics

• Drugs that affect dronedarone exposure:

— Potent CYP3A inhibitors (ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, ritonavir)

— Grapefruit juice

— CYP3A inducers (rifampin, phenobarbital, carbamazepine, phenytoin, and St John’s wort)

— CCBs (verapamil, diltiazem)

• Drugs that may be affected by dronedarone:

— Statins (simvastatin, simvastatin acid); avoid doses >10 mg once daily

— CCBs (verapamil, diltiazem, nifedipine)

— CYP3A substrates with a narrow therapeutic index (sirolimus, tacrolimus)

— b-blockers and other CYP2D6 substrates (tricyclic antidepressants, selective serotonin reuptake inhibitors)

— P-gP substrates (digoxin [2.5-fold↑], dabigatran [1.7 to 2-fold ↑])

— Warfarin: monitor INR after initiating MULTAQ in patients taking warfarin

Question 21

Adverse Reactions

Answer 21

• Safety evaluated in 3282 patients given dronedarone (400 mg BID); most common AEs (dronedarone vs placebo):

— Diarrhea (9% vs 6%)

— Nausea (5% vs 3%)

— Abdominal pain (4% vs 3%)

— Vomiting (2% vs 1%)

— Dyspepsia (2% vs 1%)

— Asthenia (7% vs 5%)

— Bradycardia (3% vs 1%)

— Skin rash (5% vs 3%)

• Laboratory data

— Early ↑ in creatinine ≥10% (51% vs 21%)

— QTc prolonged (28% vs 19%)