PRESCRIBING ALERT

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1 PRESCRIBING ALERT Dear Healthcare Professional, At MPR we strive to bring you important drug information in a concise and timely fashion. In keeping with this goal, we are pleased to bring you this PRESCRIBING ALERT announcing the availability of MULTAQ (dronedarone) 400 mg Tablets from sanofi-aventis U.S. LLC. MULTAQ is an antiarrhythmic indicated to reduce the risk of cardiovascular hospitalization of patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL). 1 MULTAQ is also indicated for use in patients with a recent episode of AF/AFL and associated cardiovascular risk factors (ie, age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter 50 mm or left ventricular ejection fraction [LVEF] <40%), who are in sinus rhythm or who will be cardioverted. 1 MULTAQ should not be used in patients with NYHA Class IV heart failure or NYHA Class II-III heart failure with recent decompensation requiring hospitalization or referral to a specialized heart failure clinic. 1 In a landmark clinical trial, MULTAQ demonstrated its ability to reduce hospitalizations or death from any cardiovascular cause by 24% which was entirely attributable to its effect on cardiovascular hospitalization. 1 In pooled data from two other trials, MULTAQ delayed the time to the first recurrence of AF/AFL, lowering the risk of first recurrence during the 12 month study period by about 25%, with an absolute difference in recurrence rate of about 11% at 12 months. 1 The most common adverse reactions in patients taking MULTAQ were diarrhea, nausea, abdominal pain, vomiting, and asthenia. 1 Contraindications IMPORTANT SAFETY INFORMATION WARNING: HEART FAILURE MULTAQ is contraindicated in patients with NYHA Class IV heart failure, or NYHA Class II III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic. In a placebo-controlled study in patients with severe heart failure requiring recent hospitalization or referral to a specialized heart failure clinic for worsening symptoms (the ANDROMEDA Study), patients given MULTAQ had a greater than two-fold increase in mortality. Such patients should not be given MULTAQ. MULTAQ is also contraindicated in patients with second- or third-degree atrioventricular (AV) block or sick sinus syndrome (except when used in conjunction with a functioning pacemaker), bradycardia <50 bpm, QTc Bazett interval 500 msec or PR interval >280 msec, and severe hepatic impairment. MULTAQ should not be given to patients who are or may become pregnant (Category X) or nursing. MULTAQ may cause fetal harm when administered to a pregnant woman. MULTAQ should not be coadministered with strong CYP 3A inhibitors, such as ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, ritonavir, or (Important Safety Information continued on back)

2 drugs or herbal products that prolong the QT interval and might increase the risk of Torsade de Pointes, such as phenothiazine antipsychotics, tricyclic antidepressants, certain macrolide antibiotics, and Class I and III antiarrhythmics. New or Worsening Heart Failure There are limited data available for AFib/AFL patients who develop worsening heart failure during treatment with MULTAQ. If heart failure develops or worsens, consider the suspension or discontinuation of MULTAQ. Advise patients to consult a physician if they develop signs and symptoms of heart failure, such as weight gain, dependent edema, or increasing shortness of breath. Hypokalemia and Hypomagnesemia with Potassium-Depleting Diuretics Hypokalemia and hypomagnesemia may occur with concomitant administration of potassiumdepleting diuretics. Potassium levels should be within the normal range prior to administration of MULTAQ and maintained in the normal range during administration of MULTAQ. QT Interval Prolongation MULTAQ induces a moderate (average of about 10 msec but much greater effects have been observed) QTc (Bazett) prolongation. If the QTc Bazett interval is 500 msec, MULTAQ should be stopped. Increase in Creatinine Serum creatinine levels increase by about 0.1 mg/dl following MULTAQ treatment initiation. The elevation has a rapid onset, reaches a plateau after 7 days and is reversible after discontinuation. If an increase in serum creatinine occurs and plateaus, this increased value should be used as the patient s new baseline. The change in creatinine levels has been shown to be the result of an inhibition of creatinine s tubular secretion, with no effect upon the glomerular filtration rate. Drug-Drug Interactions Treatment with Class I or III antiarrhythmics or drugs that are strong inhibitors of CYP 3A must be stopped before starting MULTAQ (see Contraindications). Patients should be instructed to avoid grapefruit juice beverages while taking MULTAQ. Calcium channel blockers and beta-blockers could potentiate the effects of MULTAQ on conduction. Increased digoxin levels and gastrointestinal disorders have been observed when MULTAQ was coadministered with digoxin. Digoxin can also potentiate the electrophysiologic effects of MULTAQ (such as decreased AV-node conduction); the need for digoxin therapy should be reconsidered when prescribing MULTAQ. If digoxin treatment is continued, halve the dose of digoxin, monitor serum levels closely, and observe for toxicity. Please see accompanying full Prescribing Information, including boxed WARNING, and MULTAQ Medication Guide. More information about the use of MULTAQ is available in the current edition of MPR. Sincerely, Grace L. McBride Editorial Director MPR Custom Programs Reference 1. MULTAQ [package insert]. Bridgewater, NJ; sanofi-aventis U.S. LLC: sanofi-aventis U.S. LLC US.DRO /February 2010 sanofi-aventis U.S. LLC

3 Company: sanofi-aventis U.S. LLC Pharmacologic Class: Antiarrhythmic Active Ingredient: Dronedarone Indications: To reduce 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 cardiovascular risk factors (age >70 yrs, HTN, diabetes, prior cerebrovascular accident, left atrial diameter 50 mm or LVEF <40%), who are in sinus rhythm or who will be cardioverted. Adults: 18 yrs: 400 mg twice daily (AM & PM) with meals. Children: <18 yrs: not recommended. Contraindications MULTAQ is contraindicated in patients with NYHA Class IV heart failure, or NYHA Class II-III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic. In the ANDROMEDA study, a greater than two-fold increase in mortality was observed in this unstable population. Second-or third-degree atrioventricular (AV) block or sick sinus syndrome (except when used in conjunction with a functioning pacemaker). Bradycardia <50 bpm. Concomitant use of strong CYP 3A inhibitors. Concomitant use of drugs or herbal products that prolong the QT interval and might induce Torsade de Pointes. QTc Bazett interval 500 ms. Severe hepatic impairment. Pregnancy. Nursing mothers. Warnings & Precautions: Heart failure: If heart failure develops or worsens, consider suspension or discontinuation of MULTAQ. Hypokalemia and hypomagnesemia: Maintain potassium and magnesium levels within the normal range. QT prolongation: Stop MULTAQ if QTc Bazett 500 ms. Increase in Prescribing Alert MULTAQ (dronedarone) Tablets Available to treat atrial fibrillation creatinine: Within a week, MULTAQ causes a small increase in serum creatinine that does not reflect a change in underlying renal function. Teratogen: Women of childbearing potential should use effective contraception while using MULTAQ. Interactions: Dronedarone is metabolized by CYP 3A and is a moderate inhibitor of CYP 3A and CYP 2D6 and has potentially important pharmacodynamic interactions: Antiarrhythmics, grapefruit juice, CYP 3A inducers: avoid concomitant use. Digoxin: consider discontinuation or halve dose of digoxin before treatment and monitor. Calcium channel blockers (CCB): initiate CCB with low dose and increase after ECG verification of tolerability. Beta-blockers: may provoke excessive bradycardia; initiate with low dose and increase after ECG verification of tolerability. Statins: follow label recommendations for concomitant use of certain statins with a CYP 3A and P-gP inhibitor like dronedarone. CYP 3A substrates with a narrow therapeutic index (eg, sirolimus and tacrolimus): monitor and adjust dosage of concomitant drug as needed. Adverse Reactions: GI upset, asthenia, rash, increased serum creatinine. How supplied: Tabs 60, 180, 500 MULTAQ is the first antiarrhythmic drug proven to reduce the risk of cardiovascular hospitalization in AF patients as indicated 1 Reduces the risk of cardiovascular hospitalization in patients with paroxysmal or persistent AF/AFL, with a recent episode of AF/AFL and associated cardiovascular risk factors (ie, age >70 years, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter 50 mm or left ventricular ejection fraction [LVEF] <40%) who are in sinus rhythm or who will be cardioverted Please see Important Safety Information, including boxed WARNING, on page 5 and accompanying full Prescribing Information and MULTAQ Medication Guide. 1 (continued on next page)

4 Prescribing Alert MULTAQ has been evaluated in key clinical trials 1 summary of trials STUDY DESIGN END POINT(S)/RESULTS Athena Euridis/ adonis Andromeda Cardiovascular outcomes 400 mg bid vs placebo N=2301/2327 (multinational study) Minimum/maximum follow-up: 12 and 30 months respectively (median 22 months) Antiarrhythmic efficacy and safety Pooled data of 2 trials 400 mg bid vs placebo (1 year) N = 828/409 (EURIDIS/ADONIS) Median follow-up: 12 months All-cause mortality in severe or recently decompensated HF 400 mg bid vs placebo (1 year) N = 627/1000 (310 and 317, MULTAQ and placebo, respectively) Median follow-up: 63 days For the combined primary end point of time to cardio vascular hospitalization or death from any cause, MULTAQ demonstrated a 24.2% relative risk reduction (RRR) vs placebo (P<0.0001), entirely attributable to its effect on cardiovascular hospitalization* Secondary end points included all-cause mortality (RRR: 14%, P=NS) and cardiovascular hospitalization (RRR: 26%, P<0.0001), principally related to AF For the primary end point of time to first recurrence of AF/ AFL, MULTAQ demonstrated 25% risk reduction (RR) vs placebo (P<0.001) with an absolute difference in recurrence rate of about 11% at 12 months (pooled data) Trial terminated early due to excess mortality in the MULTAQ group vs placebo: 25 (8.1%) vs 12 (3.8%) (HR=2.13; 95% Cl: ; P=0.027) The excess mortality was predominantly related to worsening of heart failure, with 10 deaths in the MULTAQ group and 2 in the placebo group * Reduction in cardiovascular hospitalization or death consistent in all subgroups based on baseline characteristics or medications. 1 ATHENA = A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg BID for the Prevention of Cardiovascular Hospitalization of Death From Any Cause in PatiENts With Atrial Fibrillation/Atrial Flutter. EURIDIS = EURopean Trial In Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the MaIntenance of Sinus Rhythm. ADONIS = American-Australian-African Trial With DronedarONe In Atrial Fibrillation/Flutter Patients for the Maintenance of Sinus Rhythm. ANDROMEDA = ANtiarrhythmic Trial with DROnedarone in Moderate-to-Severe Congestive Heart Failure Evaluating Morbidity DecreAse. Source: MULTAQ [package insert]. 1 Please see Important Safety Information, including boxed WARNING, on page 5 and accompanying full Prescribing Information and MULTAQ Medication Guide. 2 (continued on next page)

5 Prescribing Alert Reduces cardiovascular hospitalization Time to First Cardiovascular Hospitalization or Death Results Entirely Attributable to Effect on CV Hospitalization Cumulative Incidence (%) RRR=24% P< Placebo Months Number at risk: Placebo: MULTAQ: Median follow-up: 22 months. CV = Cardiovascular. RRR = Relative risk reduction. Sources: MULTAQ [package insert] 1 ; Data on file. 2 MULTAQ In the ATHENA trial, MULTAQ reduced the combined primary end point of CV hospitalization or death from any cause by 24% vs placebo 1 Most cardiovascular hospitalizations were related to atrial fibrillation Event curves separated early and continued to diverge over the 30-month follow-up period Efficacy established in additional conventional background CV therapies Prolongs time to first recurrence of AF/AFL Median Time to Recurrence of Atrial Fibrillation or Atrial Flutter Time (Days) days 116 days Placebo MULTAQ EURIDIS/ADONIS Primary End point 1,2 MULTAQ prolonged time to first recurrence vs placebo at 12 months (pooled data) Reduced risk of first recurrence by 25% (P<0.001) Absolute difference in recurrence rate of 11% n=409 n= months study duration Pooled Data Sources: MULTAQ [package insert] 1 ; Data on file. 2 Please see Important Safety Information, including boxed WARNING, on page 5 and accompanying full Prescribing Information and MULTAQ Medication Guide. 3 (continued on next page)

6 Prescribing Alert Throughout clinical trials, MULTAQ was administered in addition to conventional cardiovascular therapies for common comorbidities 1 Beta-blockers, ACE inhibitors or ARBs, digoxin, calcium channel blockers, statins, oral anticoagulants, aspirin, and diuretics 1 MULTAQ was administered following discontinuation of antiarrhythmics MULTAQ demonstrated its safety profile throughout the clinical program 1 Adverse Reactions Observed In Clinical Trials Gastrointestinal disorders Photosensitivity reaction and dysgeusia have also been reported at an incidence less than 1% in patients treated with MULTAQ Please refer to the Risk Mitigation Program, MPACT*, when prescribing MULTAQ for your patients The MPACT Program was developed to assist healthcare professionals in the identification of appropriate patients and to ensure safe use of MULTAQ while minimizing risk *MPACT = MULTAQ Partnership for Appropriate Care and Treatment Placebo (n=2875) MULTAQ 400 mg bid (n=3282) Diarrhea 6% 9% Nausea 3% 5% Abdominal pain 3% 4% Vomiting 1% 2% Dyspeptic signs and symptoms 1% 2% General disorders & administration-site conditions Asthenic conditions 5% 7% Cardiac disorders Bradycardia 1% 3% Skin and subcutaneous tissue disorders Including rashes (generalized, macular, maculopapular, erythematous), pruritus, eczema, dermatitis, dermatitis allergic 3% 5% Adverse drug reactions that occurred in at least 1% of patients and were more frequent than placebo in the pooled data from all 5 studies in the clinical program. Source: MULTAQ [package insert]. 1 Please see Important Safety Information, including boxed WARNING, on page 5 and accompanying full Prescribing Information and MULTAQ Medication Guide. 4 (continued on next page)

7 Contraindications Prescribing Alert IMPORTANT SAFETY INFORMATION WARNING: HEART FAILURE MULTAQ is contraindicated in patients with NYHA Class IV heart failure, or NYHA Class II III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic. In a placebo-controlled study in patients with severe heart failure requiring recent hospitalization or referral to a specialized heart failure clinic for worsening symptoms (the ANDROMEDA Study), patients given MULTAQ had a greater than two-fold increase in mortality. Such patients should not be given MULTAQ. MULTAQ is also contraindicated in patients with second- or third-degree atrioventricular (AV) block or sick sinus syndrome (except when used in conjunction with a functioning pacemaker), bradycardia <50 bpm, QTc Bazett interval 500 msec or PR interval >280 msec, and severe hepatic impairment. MULTAQ should not be given to patients who are or may become pregnant (Category X) or nursing. MULTAQ may cause fetal harm when administered to a pregnant woman. MULTAQ should not be coadministered with strong CYP 3A inhibitors, such as keto conazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, ritonavir, or drugs or herbal products that prolong the QT interval and might increase the risk of Torsade de Pointes, such as phenothiazine antipsychotics, tricyclic antidepressants, certain macrolide antibiotics, and Class I and III antiarrhythmics. New or Worsening Heart Failure There are limited data available for AFib/AFL patients who develop worsening heart failure during treatment with MULTAQ. If heart failure develops or worsens, consider the suspension or discontinuation of MULTAQ. Advise patients to consult a physician if they develop signs and symptoms of heart failure, such as weight gain, dependent edema, or increasing shortness of breath. Hypokalemia and Hypomagnesemia with Potassium-Depleting Diuretics Hypokalemia and hypomagnesemia may occur with concomitant administration of potassiumdepleting diuretics. Potassium levels should be within the normal range prior to administration of MULTAQ and maintained in the normal range during administration of MULTAQ. QT Interval Prolongation MULTAQ induces a moderate (average of about 10 msec but much greater effects have been observed) QTc (Bazett) prolongation. If the QTc Bazett interval is 500 msec, MULTAQ should be stopped. Increase in Creatinine Serum creatinine levels increase by about 0.1 mg/dl following MULTAQ treatment initiation. The elevation has a rapid onset, reaches a plateau after 7 days and is reversible after discontinuation. If an increase in serum creatinine occurs and plateaus, this increased value should be used as the patient s new baseline. The change in creatinine levels has been shown to be the result of an inhibition of creatinine s tubular secretion, with no effect upon the glomerular filtration rate. Drug-Drug Interactions Treatment with Class I or III antiarrhythmics or drugs that are strong inhibitors of CYP 3A must be stopped before starting MULTAQ (see Contraindications). Patients should be instructed to avoid grapefruit juice beverages while taking MULTAQ. Calcium channel blockers and beta-blockers could potentiate the effects of MULTAQ on conduction. Increased digoxin levels and gastrointestinal disorders have been observed when MULTAQ was coadministered with digoxin. Digoxin can also potentiate the electrophysiologic effects of MULTAQ (such as decreased AV-node conduction); the need for digoxin therapy should be reconsidered when prescribing MULTAQ. If digoxin treatment is continued, halve the dose of digoxin, monitor serum levels closely, and observe for toxicity. Please see accompanying full Prescribing Information, including boxed WARNING and MULTAQ Medication Guide. 5 (continued on next page)

8 Choose the Appropriate Patient for MULTAQ Do not prescribe MULTAQ for Patients with NYHA Class IV heart failure NYHA Class II-III heart failure with recent decompensation requiring hospitalization or referral to a specialized heart failure clinic One study in the MULTAQ clinical program, ANDROMEDA, was terminated early due to a greater than two-fold increase in risk of death in such patients (P=0.027). 1 There were also excess hospitalizations for cardiovascular reasons in the MULTAQ group (71 vs 51 for placebo). Note: These patients may have been clinically improved at the time of enrollment and it is the history of decompensation that characterized them. Patients enrolled into ANDROMEDA were predominantly NYHA Class II (40%) and III (57%), and only 38% had a history of AF/AFL (25% had AF at randomization). MULTAQ can be prescribed for Prescribing Alert Patients with paroxysmal or persistent AF or AFL with a recent episode of AF/AFL and associated cardiovascular risk factors (ie, age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter 50 mm or LVEF <40%), who are in sinus rhythm or who will be cardioverted MULTAQ is an antiarrhythmic drug indicated to reduce the risk of cardiovascular hospitalization If heart failure develops or worsens, consider the suspension or discontinuation of MULTAQ Please see Important Safety Information, including boxed WARNING, on page 5 and accompanying full Prescribing Information and MULTAQ Medication Guide. ReferenceS 1. MULTAQ [package insert]. Bridgewater, NJ; sanofi-aventis U.S. LLC: Data on file, sanofi-aventis U.S. LLC sanofi-aventis U.S. LLC US.DRO /February 2010 sanofi-aventis U.S. LLC