İHALE DÜNYASI
İHALE DÜNYASI
Dronedarone HCl is a benzofuran derivative with the following chemical name: N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl} methanesulfonamide, hydrochloride. Dronedarone HCl is a white fine powder that is practically insoluble in water and freely soluble in methylene chloride and methanol. Its empirical formula is C 31 H 44 N 2 O 5 S, HCl with a relative molecular mass of 593.2. Its structural formula is: MULTAQ is provided as tablets for oral administration. Each tablet of MULTAQ contains 400 mg of dronedarone (expressed as base). The inactive ingredients are: Core of the tablets- hypromellose, starch, crospovidone, poloxamer 407, lactose monohydrate, colloidal silicon dioxide, magnesium stearate. Coating / polishing of the tablets- hypromellose, polyethylene glycol 6000, titanium dioxide, carnauba wax. Chemical Structure
MULTAQ (R) 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) ]. MULTAQ is an antiarrhythmic drug indicated to reduce the risk of hospitalization for atrial fibrillation (AF) in patients in sinus rhythm with a history of paroxysmal or persistent AF ( 1 , 14 ).
The recommended dosage of MULTAQ is 400 mg twice daily in adults. MULTAQ should be taken as one tablet with the morning meal and one tablet with the evening meal. Treatment with Class I or III antiarrhythmics (e.g., amiodarone, flecainide, propafenone, quinidine, disopyramide, dofetilide, sotalol) or drugs that are strong inhibitors of CYP3A (e.g., ketoconazole) must be stopped before starting MULTAQ [see Contraindications (4) ]. One tablet of 400 mg twice a day with morning and evening meals ( 2 )
MULTAQ is contraindicated in patients with: Permanent atrial fibrillation (patients in whom normal sinus rhythm will not or cannot be restored) [see Boxed Warning and Warnings and Precautions (5.2) ] Symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV symptoms [see Boxed Warning and Warnings and Precautions (5.1) ] 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, such as ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, and ritonavir [see Drug Interactions (7.2) ] Concomitant use of drugs or herbal products that prolong the QT interval and might increase the risk of Torsade de Pointes, such as phenothiazine anti-psychotics, tricyclic antidepressants, certain oral macrolide antibiotics, and Class I and III antiarrhythmics Liver toxicity related to the previous use of amiodarone QTc Bazett interval ?500 ms or PR interval >280 ms Severe hepatic impairment Pregnancy (Category X): MULTAQ may cause fetal harm when administered to a pregnant woman. MULTAQ is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1) ] . Nursing mothers [see Use in Specific Populations (8.3) ] Permanent AF (patients in whom normal sinus rhythm will not or cannot be restored) ( Boxed Warning , 4 ) Recently decompensated heart failure requiring hospitalization or Class IV heart failure. ( Boxed Warning , 4 ) Second- or third- degree atrioventicular (AV) block or sick sinus syndrome (except when used in conjunction with a functioning pacemaker) ( 4 ) Bradycardia <50 bpm ( 4 ) Concomitant use of a strong CYP3A inhibitor ( 4 ) Concomitant use of drugs or herbal products that prolong the QT interval and may induce Torsade de Pointes ( 4 ) Liver toxicity related to the previous use of amiodarone ( 4 ) Severe hepatic impairment ( 4 ) QTc Bazett interval ?500 ms ( 4 ) Pregnancy ( 4 , 8.1 ) and Nursing mothers ( 4 , 8.3 )
The following safety concerns are described elsewhere in the label: New or worsening heart failure [see Warnings and Precautions (5.3) ] Liver Injury [see Warnings and Precautions (5.5) ] Hypokalemia and hypomagnesemia with potassium-depleting diuretics [see Warnings and Precautions (5.6) ] QT prolongation [see Warnings and Precautions (5.7) ] Most common adverse reactions (?2%) are diarrhea, nausea, abdominal pain, vomiting, and asthenia ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis U.S. LLC at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience The safety evaluation of dronedarone 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 MULTAQ 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 dronedarone-treated patients and in 7.7% of the placebo-treated group. The most common reasons for discontinuation of therapy with MULTAQ 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 MULTAQ 400 mg twice daily in the 5 studies were diarrhea, nausea, abdominal pain, vomiting, and asthenia. Table 1 displays adverse reactions more common with dronedarone 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 Placebo Dronedarone 400 mg twice daily (N=2875) (N=3282) Gastrointestinal Diarrhea 6% 9% Nausea 3% 5% Abdominal pain 3% 4% Vomiting 1% 2% Dyspeptic signs and symptoms 1% 2% General Asthenic conditions 5% 7% Cardiac Bradycardia 1% 3% Skin and subcutaneous tissue Including rashes (generalized, macular, maculo-papular, erythematous), pruritus, eczema, dermatitis, dermatitis allergic 3% 5% Photosensitivity reaction and dysgeusia have also been reported at an incidence less than 1% in patients treated with MULTAQ. The following laboratory data/ECG parameters were reported with MULTAQ 400 mg twice daily. Table 2: Laboratory data/ECG parameters not necessarily reported as adverse events Placebo MULTAQ 400 mg twice daily (N=2875) (N=3282) Early increases in creatinine ?10% 21% 51% (N=2237) (N=2701) QTc prolonged 19% 28% 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of MULTAQ. 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 [see Warnings and Precautions (5.3) ] Hepatic: Liver Injury [see Warnings and Precautions (5.5) ] Respiratory: Postmarketing cases of interstitial lung disease including pneumonitis and pulmonary fibrosis have been reported.
Determine cardiac rhythm at least once every 3 months. If AF is detected discontinue MULTAQ or cardiovert ( 5.2 ). Liver injury: if hepatic injury is suspected, discontinue MULTAQ ( 5.5 ) Ensure appropriate antithrombotic therapy prior to and throughout MULTAQ use. ( 5.3 ) Hypokalemia and hypomagnesemia: Maintain potassium and magnesium levels within the normal range ( 5.6 ) Increase in creatinine: Monitor serum creatinine periodically ( 5.8 ) 5 ) Teratogen: Women of childbearing potential should use effective contraception while using MULTAQ ( 5.9 ) 5.1 Cardiovascular Death in NYHA Class IV or Decompensated Heart Failure MULTAQ is contraindicated in patients with NYHA Class IV heart failure or symptomatic heart failure with recent decompensation requiring hospitalization because it doubles the risk of death. 5.2 Cardiovascular Death and Heart Failure in Permanent AF MULTAQ doubles the risk of cardiovascular death (largely arrhythmic) and heart failure events in patients with permanent AF. Patients treated with dronedarone should undergo monitoring of cardiac rhythm no less often than every 3 months. Cardiovert patients who are in atrial fibrillation (if clinically indicated) or discontinue MULTAQ. MULTAQ offers no benefit in subjects in permanent AF. 5.3 Increased Risk of Stroke in Permanent AF In a placebo-controlled study in patients with permanent atrial fibrillation, dronedarone was associated with an increased risk of stroke, particularly in the first two weeks of therapy [ see Clinical Studies (14.4) ]. MULTAQ should only be initiated in patients in sinus rhythm who are receiving appropriate antithrombotic therapy [ see Drug interactions (7.3) ]. 5.4 New Onset or Worsening Heart Failure New onset or worsening of heart failure has been reported during treatment with MULTAQ in the postmarketing setting. In a placebo controlled study in patients with permanent AF increased rates of heart failure were observed in patients with normal left ventricular function and no history of symptomatic heart failure, as well as those with a history of heart failure or left ventricular dysfunction. Advise patients to consult a physician if they develop signs or symptoms of heart failure, such as weight gain, dependent edema, or increasing shortness of breath. If heart failure develops or worsens and requires hospitalization, discontinue MULTAQ. 5.5 Liver Injury Hepatocellular liver injury, including acute liver failure requiring transplant, has been reported in patients treated with MULTAQ in the post-marketing setting. Advise patients treated with MULTAQ to report immediately symptoms suggesting hepatic injury (such as anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant pain, jaundice, dark urine, or itching). Consider obtaining periodic hepatic serum enzymes, especially during the first 6 months of treatment, but it is not known whether routine periodic monitoring of serum enzymes will prevent the development of severe liver injury. If hepatic injury is suspected, promptly discontinue MULTAQ and test serum enzymes, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase, as well as serum bilirubin, to establish whether there is liver injury. If liver injury is found, institute appropriate treatment and investigate the probable cause. Do not restart MULTAQ in patients without another explanation for the observed liver injury. 5.6 Hypokalemia and Hypomagnesemia with Potassium-Depleting Diuretics Hypokalemia or hypomagnesemia may occur with concomitant administration of potassium-depleting diuretics. Potassium levels should be within the normal range prior to administration of MULTAQ and maintained in the normal range during administration of MULTAQ. 5.7 QT Interval Prolongation Dronedarone induces a moderate (average of about 10 ms but much greater effects have been observed) QTc (Bazett) prolongation [see Clinical Pharmacology (12.2) and Clinical Studies (14.1) ] . If the QTc Bazett interval is ?500 ms, discontinue MULTAQ [see Contraindications (4) ] . 5.8 Increase in Creatinine after Treatment Initiation Small increases in creatinine levels (about 0.1 mg/dL) following dronedarone treatment initiation have been shown to be a result of inhibition of creatinine's tubular secretion. .. The elevation has a rapid onset, reaches a plateau after 7 days and is reversible after discontinuation. Larger increases in creatinine after dronedarone initiation have been reported in the postmarketing setting. Some cases also reported increases in blood urea nitrogen. In most cases, these effects appear to be reversible upon drug discontinuation. Monitor renal function periodically. 5.9 Women of Childbearing Potential Premenopausal women who have not undergone a hysterectomy or oophorectomy must use effective contraception while using MULTAQ. Dronedarone caused fetal harm in animal studies at doses equivalent to recommended human doses. Counsel women of childbearing potential regarding appropriate contraceptive choices. [see Use in Specific Populations (8.1) ] . --- BOXED WARNING: WARNING: INCREASED RISK OF DEATH, STROKE AND HEART FAILURE IN PATIENTS WITH DECOMPENSATED HEART FAILURE OR PERMANENT ATRIAL FIBRILLATION In patients with symptomatic heart failure and recent decompensation requiring hospitalization or NYHA Class IV heart failure; MULTAQ doubles the risk of death. ( 14.3 ) MULTAQ is contraindicated in patients with symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV heart failure. ( 4 , 5.1 ) In patients with permanent atrial fibrillation, MULTAQ doubles the risk of death, stroke and hospitalization for heart failure. ( 14.4 ). MULTAQ is contraindicated in patients in atrial fibrillation (AF) who will not or cannot be cardioverted into normal sinus rhythm. ( 4 , 5.2 ) WARNING: 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 ( 4 , 5.1 , 14.3 ). MULTAQ is contraindicated in patients in atrial fibrillation (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. ( 4 , 5.2 , 14.4 )
Dronedarone is metabolized primarily by CYP 3A and is a moderate inhibitor of CYP 3A and CYP 2D6 [see Clinical Pharmacology (12.3) ] . Dronedarone's blood levels can therefore be affected by inhibitors and inducers of CYP 3A, and dronedarone can interact with drugs that are substrates of CYP 3A and CYP 2D6. Dronedarone has no significant potential to inhibit CYP 1A2, CYP 2C9, CYP 2C19, CYP 2C8 and CYP 2B6. It has the potential to inhibit P-glycoprotein (P-gP) transport. Pharmacodynamic interactions can be expected with beta-blockers; calcium antagonists and digoxin [see Drug Interactions (7.1) ] . In clinical trials, patients treated with dronedarone received concomitant medications including beta-blockers, digoxin, calcium antagonists (including those with heart rate-lowering effects), statins and oral anticoagulants. Dronedarone is metabolized by CYP 3A and is a moderate inhibitor of CYP 3A and CYP 2D6 and has potentially important pharmacodynamic interactions ( 7 ) Antiarrhythmics: Avoid concomitant use ( 4 , 7.1 ) Digoxin: Consider discontinuation or halve dose of digoxin before treatment and monitor digoxin levels ( 7.1 , 7.3 ) Calcium channel blockers (CCB): Initiate CCB with low dose and increase after ECG verification of tolerability ( 7.1 , 7.2 , 7.3 ) Beta-blockers: May provoke excessive bradycardia, Initiate with low dose and increase after ECG verification of tolerability ( 7.1 , 7.3 ) CYP 3A inducers: Avoid concomitant use ( 7.2 ) Grapefruit juice: Avoid concomitant use ( 7.2 ) Statins: Follow label recommendations for concomitant use of certain statins with a CYP 3A and P-gP inhibitor like dronedarone ( 7.3 ) CYP 3A substrates with a narrow therapeutic index (e.g., sirolimus and tacrolimus): Monitor and adjust dosage of concomitant drug as needed when used with MULTAQ ( 7.3 ) Warfarin: Monitor INR after initiating dronedarone in patients taking warfarin. ( 7.3 ) 7.1 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 [see Contraindications (4) ] . Digoxin Digoxin can potentiate the electrophysiologic effects of dronedarone (such as decreased AV-node conduction). In clinical trials, increased levels of digoxin were observed when dronedarone was co-administered with digoxin. Gastrointestinal disorders were also increased. Because of the pharmacokinetic interaction [see Drug Interaction (7.3) ] and possible pharmacodynamic interaction, consider the need for continued digoxin therapy. 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 dronedarone's effects on conduction. Give low doses of calcium channel blockers initially and increase only after ECG verification of good tolerability [see Drug Interactions (7.3) ] . Beta-blockers In clinical trials, bradycardia was more frequently observed when dronedarone was given in combination with beta-blockers. Give low dose of beta-blockers initially, and increase only after ECG verification of good tolerability [see Drug Interactions (7.3) ] . 7.2 Effects of Other Drugs on Dronedarone Ketoconazole and other potent CYP 3A inhibitors Repeated doses of ketoconazole, a strong CYP 3A inhibitor, resulted in a 17-fold increase in dronedarone exposure and a 9-fold increase in C max . Concomitant use of ketoconazole as well as other potent CYP 3A inhibitors such as itraconazole, voriconazole, ritonavir, clarithromycin, and nefazodone is contraindicated [see Contraindications (4) ] . Grapefruit juice Grapefruit juice, a moderate inhibitor of CYP 3A, resulted in a 3-fold increase in dronedarone exposure and a 2.5-fold increase in C max . Therefore, patients should avoid grapefruit juice beverages while taking MULTAQ. Rifampin and other CYP 3A inducers Rifampin decreased dronedarone exposure by 80%. Avoid rifampin or other CYP 3A inducers such as phenobarbital, carbamazepine, phenytoin, and St John's wort with dronedarone because they decrease its exposure significantly. Calcium channel blockers Verapamil and diltiazem are moderate CYP 3A inhibitors and increase dronedarone exposure by approximately 1.4-to 1.7-fold [see Drug Interactions (7.1 , 7.3) ] . Pantoprazole Pantoprazole, a drug that increases gastric pH, did not have a significant effect on dronedarone pharmacokinetics. 7.3 Effects of Dronedarone on Other Drugs Statins Dronedarone increased simvastatin/simvastatin acid exposure by 4- and 2-fold, respectively. 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 dronedarone. Calcium channel blockers Dronedarone increases calcium channel blocker (verapamil, diltiazem or nifedipine) exposure by 1.4- to 1.5-fold [see Drug Interactions (7.1) ] . Sirolimus, tacrolimus, and other CYP3A substrates with narrow therapeutic range Dronedarone 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 Dronedarone increased propranolol exposure by approximately 1.3-fold following single dose administration. Dronedarone increased metoprolol exposure by 1.6-fold following multiple dose administration [see Drug Interaction (7.1) ]. Other CYP 2D6 substrates, including other beta-blockers, tricyclic antidepressants, and selective serotonin reuptake inhibitors (SSRIs) may have increased exposure upon co-administration with dronedarone. P-glycoprotein substrates Digoxin Dronedarone increased digoxin exposure by 2.5-fold by inhibiting the P-gP transporter [ see Drug Interactions (7.1) ]. Dabigatran Exposure to dabigatran is higher when it is administered with dronedarone than when it is administered alone (1.7- to 2-fold). Other P-gP substrates are expected to have increased exposure when co-administered with dronedarone. Warfarin and losartan (CYP 2C9 substrates) Losartan No interaction was observed between dronedarone and losartan. Warfarin When healthy subjects were administered dronedarone 600 mg twice daily, exposure to S-warfarin was higher than when warfarin was administered alone (1.2-fold). Exposure to R-warfarin was unchanged and there were no clinically significant increases in INR. More patients experienced clinically significant INR elevations (? 5) usually within 1 week after starting dronedarone vs. placebo in patients taking oral anticoagulants in ATHENA. However, no excess risk of bleeding was observed in the dronedarone group. Postmarketing cases of increased INR with or without bleeding events have been reported in warfarin-treated patients initiated on dronedarone. Monitor INR after initiating dronedarone in patients taking warfarin. Theophylline (CYP 1A2 substrate) Dronedarone does not increase steady state theophylline exposure. Oral contraceptives No decreases in ethinylestradiol and levonorgestrel concentrations were observed in healthy subjects receiving dronedarone concomitantly with oral contraceptives.