Multaq 400 mg
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What Multaq is used for
MULTAQ helps control abnormal heart rate and rhythm called atrial fibrillation and can lower the risk for having to go into the hospital for heart problems or the risk of death.
MULTAQ has not been studied in children.
What Multaq does
MULTAQ is a prescription medicine used in adults to help control abnormal heart rate and rhythm called atrial fibrillation.
When Multaq should not be used
Do not take MULTAQ if:
You have an allergy to dronedarone, the active ingredient in MULTAQ, or anything else in MULTAQ. See “What the important nonmedicinal ingredients are:” for a complete list of ingredients
You have heart problems such as heart block or very slow heart rate (bradycardia), unless you have a pacemaker
Your ECG (electrocardiogram), a record of the electrical activity of your heart shows a heart disorder called “prolonged QT corrected interval” (more than 500 msec).
You have a severe heart problem with severe shortness of breath, swelling of your feet or legs, trouble breathing while lying down or sleeping, shortness of breath while moving around (signs of severe heart failure)
You take certain medicines that can interact with MULTAQ. See the list under the heading “Do not use these medicines with MULTAQ and inform your doctor and pharmacist if you are taking these medications:”
You have severe liver problems
You are pregnant. MULTAQ can harm your baby.
You are breast-feeding. MULTAQ may pass into your milk. Do not take MULTAQ if you are breast-feeding. Do not breast-feed if you take MULTAQ.
Do not use these medicines with MULTAQ and inform your doctor and pharmacist if you are taking these medications
Norvir (ritonavir) for HIV infection
Nizoral (ketoconazole) and Sporanox (itraconazole) for fungal infections
Ketek (telithromycin), Biaxin (clarithromycin) for infections
Cyclosporine for organ transplant
Some medicines that can affect how your heart beats:
Medicines for mental illness called phenothiazines such as chlorpromazine and thioridazine
Medicines for depression such as nortryptyline, Anafranil (chlomipramine)
Medicines for abnormal heart rhythm or fast heartbeat such as sotalol, Cordarone (amiodarone), dofetilide, Tambocor (flecainide), Rythmol (propafenone)
What the medicinal ingredient is
What the important nonmedicinal ingredients for Multaq are
Carnauba wax, colloidal anhydrous silica, crospovidone, hypromellose, lactose monohydrate, macrogol 6000, magnesium stearate, maize starch, poloxamer 407and titanium dioxide.
What dosage forms Multaq comes in
Film coated tablets containing 400 mg dronedarone, as dronedarone hydrochloride.
Warnings and Precautions
BEFORE you use MULTAQ talk to your doctor or pharmacist if you are using
Medicine for high blood pressure, chest pain, or other heart conditions, such as:
Verapamil, diltiazem, nifedipine, metoprolol, propranolol, atenolol, digoxin
benazepril and captopril in a therapeutic class called ACE inhibitors
losartan, and valsartan in a therapeutic class called ARBs
Any of these medicines:
Fexofenadine, a medicine for allergy or hay fever
A medicine to treat cancer (doxorubicin)
Statin medicine to lower blood cholesterol such as atorvastatin (Lipitor) or simvastatin
Rifampicin used for tuberculosis
Phenobarbital, carbamazepine, and phenytoin used for seizure disorders
St. John’s Wort herbal medicine for depression
Sirolimus and tacrolimus used for organ transplants
Tell your doctor about all your heart problems.
Tell your doctor about all your other health problems. Including:
Any health problem that could lead to a low level of potassium or magnesium in your blood.
Tell your doctor if:
You are pregnant, or planning to become pregnant
You are breast-feeding a baby
Blood test and ECG while taking MULTAQ
While you are taking MULTAQ, your doctor may perform heart examination tests such as an ECG or/and may take blood tests to assess your medical condition and how you tolerate the treatment. The results of one of the blood tests for kidney function (blood creatinine) may be changed by MULTAQ and may lead your doctor to take into account another reference for the “normal” value. Please notify any other doctor you may consult for the first time about your new “normal” value for your blood creatinine.
Interactions with Multaq
MULTAQ can interact with certain other medicines and cause serious side effects.
Tell your doctor about all medicines you take. Keep a list of them with you at all times. Show it to your doctor and pharmacist each time you get a new medicine. Do not take any new medicines while you are taking MULTAQ unless you have talked with your doctor. Include all non-prescription medicines, vitamins, and herbal remedies. MULTAQ and certain other medicines can interact with each other, causing serious side effects. Sometimes the dose of other medicines must be changed when they are used with MULTAQ.
Tell your doctor about
Water pills for high blood pressure. They could lower your blood potassium and magnesium.
All heart medicines and blood pressure medicines
Medicines for hay fever, cancer, or high cholesterol
Medicines to treat infections, depression, or seizures
Medicines used in organ transplants
St. John’s Wort
Medication for fungal infections
You should avoid
Drinking grapefruit juice or eating grapefruit.
Proper Use of Multaq
Take MULTAQ as your doctor tells you at the same time each day. Take 1 MULTAQ tablet (400 mg) 2 times a day with meals.
Take the first MULTAQ tablet with your morning meal.
Take the second MULTAQ tablet with your evening meal.
Keep taking MULTAQ even if you feel better. If you stop, your condition may get worse. Keep taking MULTAQ until your doctor tells you to stop. Make sure to observe all appointments with your doctor for check-ups.
If you take too much MULTAQ, call your doctor or regional poison control centre or go to the nearest hospital right away. Taking too much MULTAQ can be dangerous. You may need medical care right away.
If you miss a dose, wait and take your next dose at your regular time. Do not take 2 doses at the same time. Do not make up for a missed dose.
Side Effects for Multaq and What to Do About Them
Co-administration of St John’s Wort, a potent CYP3A4 inducer, is not recommended with dronedarone as this herb decreases its exposure.
|Antidepressants||T||No effect||Dronedarone is a weak inhibitor of CYP2D6 in humans, so it is predicted to have limited interaction on antidepressants that are metabolized by CYP2D6.|
|Proarrhythmic effect||Co-administration of dronedarone with tricyclic antidepressants and other medicinal products inducing torsades de pointes is contraindicated (see Contraindications).|
| Beta-blockers |
(e.g. metoprolol and propranolol
|CT||↑ metoprolol and propranolol exposure||Beta-blockers that are metabolized by CYP 2D6 can have their exposure increased by dronedarone. Moreover, beta-blockers have the potential to interact with dronedarone from a pharmacodynamic point of view. Dronedarone 800 mg daily increased metoprolol exposure by 1.6-fold and propranolol exposure by 1.3-fold (i.e. much below the 6-fold differences observed between poor and extensive CYP 2D6 metabolizers).|
|CT||Bradycardia|| In clinical trials, bradycardia was more frequently observed when dronedarone was given in combination with beta-blockers. |
Due to the pharmacokinetic interaction and possible pharmacodynamic interaction, beta-blockers should be used with caution if taken concomitantly with dronedarone.
| Calcium antagonists |
(e.g. verapamil, diltiazem, nifedipine)
|CT||↑ dronedarone exposure|| Calcium antagonists are substrates and/or moderate inhibitors of CYP3A4. Moreover, calcium antagonists with heart-rate lowering properties have the potential to interact with dronedarone from a pharmacodynamic point of view. |
Repeated doses of diltiazem (240 mg twice daily), verapamil (240 mg once daily) and nifedipine (20 mg twice daily) resulted in an increase in dronedarone exposure of 1.7-, 1.4-, and 1.2-fold, respectively.
|↑ verapamil and nisoldipine exposure|| Calcium antagonists also have their exposure increased by dronedarone (400 mg twice daily) (verapamil by 1.4-fold, and nisoldipine by 1.5-fold). In clinical trials, there was no evidence of safety concerns when dronedarone was co-administered with calcium antagonists with heart rate-lowering effects. |
Overall, due to the pharmacokinetic interaction and possible pharmacodynamic interaction, calcium antagonists with depressant effects on sinus and atrio-ventricular node such as verapamil and diltiazem should be used with caution when associated with dronedarone.
|Digoxin||CT||↑ digoxin exposure|| Dronedarone (400 mg twice daily) increased digoxin exposure by 2.5-fold by inhibiting P-gP transporter. |
Moreover, digitalis has the potential to interact with dronedarone from a pharmacodynamic point of view.
In clinical trials, increased levels of digitalis and/or gastrointestinal disorders were observed when dronedarone was co-administered with digitalis.
Due to the pharmacokinetic interaction and possible pharmacodynamic interaction, digoxin should be used with caution concomitantly with dronedarone and patients should be closely monitored for serum digoxin levels, especially during the first week of co-administration. Clinical and ECG monitoring are also recommended and the digoxin dose should be adjusted as appropriate.
| Drugs prolonging the QT interval |
(e.g. phenothiazines, bepridil, tricyclic antidepressants, certain oral macrolides, Class I and III antiarrhythmics)
|T||Proarrhythmic effect||Co-administration of drugs prolonging the QT interval (inducing torsades de pointes) is contraindicated because of the potential risk of proarrhythmia (see Contraindications).|
| Losartan |
(CYP 2C9 substrate)
|CT||No effect||Although not considered to be a clinically significant interaction, co-administration of losartan 100 mg once daily for 14 days with dronedarone 400 mg bid decreased the Cmax of losartan by 18% and the Cmax and AUC0-24 of the active metabolite by 25% and 21% respectively.|
|Oral contraceptives (e.g. ethinylestradiol and levonorgestrel||CT||No effect||No decreases in ethinylestradiol and levonorgestrel were observed in healthy subjects receiving dronedarone (800 mg twice daily) concomitantly with oral contraceptives. However, an increase of 28% in ethinylestradiol exposure and a 19% increase in levonorgestrel exposure were observed.|
|Pantoprazole||CT||No effect||Pantoprazole (40 mg once daily), a drug increasing gastric pH without any effect on cytochrome P450, had no significant pharmacokinetic interaction with dronedarone.|
| P-glycoprotein substrates |
(e.g. doxorubicin, fexofenadine and talinolol)
|T||↑ P-gp plasma concentration||Dronedarone inhibits P-gP, and interactions may therefore occur with doxorubicin, fexofenadine and talinolol.|
| Potent CYP 3A4 inducers |
(e.g. rifampicin, phenobarbital, carbamazepine, phenytoin)
|CT||↓ dronedarone exposure|| Rifampicin (600 mg once daily) decreased dronedarone exposure by 5-fold with no major change in its active metabolite exposure. |
Co-administration of rifampicin or other potent CYP3A4 inducers are not recommended with dronedarone as they decrease its exposure.
| Potent CYP 3A4 inhibitors |
(e.g. ketoconazole, itraconazole, voriconazole, ritonavir, cyclosporin, telithromycin, clarithromycin)
|CT||↑ dronedarone exposure|| Repeated doses of ketoconazole (200 mg daily), a strong CYP 3A4 inhibitor, resulted in a 17-fold increase in dronedarone exposure. |
Concomitant use of ketoconazole as well as other potent CYP 3A4 inhibitors is contraindicated (see Contraindications).
| Sirolimus and Tacrolimus |
(CYP 3A4 substrates)
|T||↑ sirolimus and tacrolimus exposure||Dronedarone can increase plasma concentrations of tacrolimus and sirolimus (CYP3A4 substrates) when given orally. Monitoring of their plasma concentrations and appropriate dosage adjustment is recommended when these drugs are co-administered with dronedarone|
| Statins |
(Substrates of CYP3A4 and/or P-gP substrates e.g. simvastatin, lovastatin, atorvastatin and pravastatin)
|CT||↑ Simvastatin and simvastatin acid exposure||Dronedarone can increase exposure of statins that are substrates of CYP3A4 and/or P-gP substrates. Dronedarone (400 mg twice daily) increased simvastatin and simvastatin acid exposure by 4-fold and 2-fold respectively.|
|T||↑ lovastatin, atorvastatin and pravastatin|| It is predicted that dronedarone could also increase the exposures of lovastatin, atorvastatin and pravastatin within the same range as simvastatin acid. In clinical trials, there was no evidence of safety concerns when dronedarone was co-administered with statins metabolized by CYP3A4. |
As high doses of statins increase the risk of myopathy, concomitant use of statins which are CYP3A4 substrates and/or P-gP substrates should be undertaken with caution and patients monitored for clinical signs of muscular toxicity.
A significant interaction of dronedarone on statins which are not CYP3A4/P-gP substrates such as fluvastatin and rosuvastatin is unlikely.
| Theophylline |
(CYP 1A2 substrate)
|CT||↓ theophylline exposure||Concomitant administration of dronedarone 400 mg bid with theophylline 400 mg bid resulted in decreased theophylline exposure (18% decrease in AUC0-12 and a 17% decrease in Cmax of theophylline).|
| Warfarin |
(CYP 2C9 substrate)
|CT||↑ S-warfarin exposure||Dronedarone (600 mg twice daily) increased S-warfarin by 1.2-fold with no change in R-warfarin and increased INR by only 1.07-fold. In clinical trials, there was no evidence of safety concerns when dronedarone was co-administered with oral anticoagulants.|
Repeated doses of 300 mL of grapefruit juice (inhibitor of the CYP3A4) three times daily resulted in a 3-fold increase in dronedarone exposure. Therefore, patients should be warned to avoid grapefruit juice beverages while taking dronedarone.
Dronedarone is primarily metabolized by CYP 3A4 (see Action and Clinical Pharmacology, Pharmacokinetics) and is a moderate inhibitor of CYP 3A4 and a mild inhibitor of CYP 2D6. Therefore, inhibitors and inducers of CYP 3A4 have the potential to interact with dronedarone, and dronedarone has the potential to interact with medicinal products that are substrates of CYP 3A4 and CYP 2D6. It also has the potential to inhibit P-glycoprotein (P-gP) transport. Dronedarone has no significant potential to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2C8 and CYP 2B6.
A potential pharmacodynamic interaction can also be expected with beta-blockers, calcium antagonists and digitalis.
Co-administration of drugs prolonging the QT interval (such as phenothiazines, bepridil, tricyclic antidepressants, certain oral macrolides, Class I and III antiarrhythmics, which may induce torsades de pointes) is contraindicated because of the potential risk of proarrhythmia. (See Contraindications).
In clinical trials, patients treated with dronedarone received a variety of concomitant medications including beta-blockers, digitalis, calcium antagonists (including those with heart rate-lowering effects), statins and oral anticoagulants.
Information for the Patient
Dosage and Administration
The recommended dosage 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 (such as flecainide, propafenone, quinidine, disopyramide, dofetilide, sotalol, amiodarone) must be stopped before starting MULTAQ.
Treatment with MULTAQ can be initiated in an outpatient setting.
Multaq is contraindicated in patients with severe hepatic impairment (see Contraindications).
No dose adjustment is required in patients with renal impairment (see Warnings and Precautions, Special Populations and Action and Clinical Pharmacology, Pharmacokinetics).
If a dose of this medication has been missed, the missed dose should be skipped and the patient should go back to the regular dosing schedule. The dose should not be doubled.
The safety profile 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. Of these, 3282 patients were treated with dronedarone 400 mg twice daily, and 2875 received placebo.
The mean exposure across studies was 12 months. In ATHENA, the maximum follow-up was 30 months.
Assessment of intrinsic factors such as race, gender or age on the incidence of any treatment emergent adverse events did not suggest any excess of adverse events in a particular sub-group.
In pooled clinical trials, premature discontinuation due to adverse reactions occurred in 11.8% of the dronedarone-treated patients and in 7.7% in the placebo-treated group. The most common reasons for discontinuation of therapy with MULTAQ were gastrointestinal disorders (3.2 % of patients versus 1.8% in the placebo group).
The most frequent adverse reactions observed with dronedarone 400 mg twice daily in the 5 studies were diarrhea, nausea and vomiting, fatigue and asthenia.
ageusia and dysgeusia.
| Placebo |
| Dronedarone |
400 mg Twice Daily
|Blood creatinine increased ≥10% five days after treatment initiation||20.6%||50.9%|
|QTc Bazett prolonged (>450 msec in male; >470 msec in female)||18.7%||27.6%|
Indications and Clinical Use
No data are available.
For management of a suspected drug overdose, CPhA recommends that you contact your regional Poison Control Centre. See the eCPS Directories section for a list of Poison Control Centres.
In the event of overdosage, the patient’s cardiac rhythm and blood pressure should be monitored in addition to general supportive measures. Treatment should be supportive and based on symptoms.
It is not known whether dronedarone and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis or hemofiltration). There is no specific antidote available.
Dosage Forms, Composition and Packaging
Each white film-coated tablet for oral administration, oblong-shaped, engraved with a double wave marking on one side and “4142” code on the other side contains: dronedarone hydrochloride equivalent to dronedarone 400 mg. Nonmedicinal ingredients: core: colloidal anhydrous silica, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, maize starch and poloxamer 407; coating/polishing: carnauba wax, hypromellose, macrogol 6000 and titanium dioxide. Bottles of 180. Boxes of 4 blisters (15 tablets per blister).
Warnings and Precautions
Dronedarone is contraindicated for use in patients with severe CHF (Stage NYHA IV) (see Contraindications). It should be used with caution in patients with moderate CHF (Stage NYHA III) and only if the benefits are deemed to outweigh the risks involved.
The pharmacological action of dronedarone may induce a moderate (about 10 msec) QTc Bazett prolongation, related to prolonged repolarization. These changes are linked to the therapeutic effect of dronedarone and do not reflect toxicity. Follow up, including ECG, is recommended during treatment. If QTc Bazett interval is ≥500 msec, dronedarone should be stopped (see Contraindications).
Based on clinical experience, dronedarone has a low pro-arrhythmic effect. However, proarrhythmic effects may occur in particular situations such as concomitant use with drugs favoring arrhythmia and/or electrolytic disorders (see Warnings and Precautions and Drug Interactions).
An increase in plasma creatinine has been observed with dronedarone 400 mg twice daily in healthy subjects and in patients. This increase occurs early after treatment initiation and reaches a plateau after 7 days. Mean increase in Atrial Fibrillation (AF) patients is about 10 µmol/L. Values return to baseline within one week after treatment discontinuation. In a specific study in healthy subjects, this increase was shown to be related to inhibition of creatinine secretion at the tubular level, with no effect on glomerular filtration or on renal blood flow. The same mechanism has also been described with other drugs such as cimetidine, trimethoprime or amiodarone. Increased plasma creatinine could be misinterpreted and lead to inappropriate discontinuation of ACE inhibitors or AIIRAs in patients requiring this treatment (see Warnings and Precautions, Monitoring and Laboratory Tests, Management of Plasma Creatinine Increase).
Patients with renal impairment were included in clinical studies. Consistent with the minimal renal excretion of dronedarone, no pharmacokinetic modification was observed in patients with renal impairment in particular in patients with severe renal impairment (see Action and Clinical Pharmacology, Pharmacokinetics) and no particular precaution is needed.
Since antiarrhythmic drugs may be ineffective or may be arrhythmogenic in patients with hypokalemia, any potassium or magnesium deficiency should be corrected before initiation and during dronedarone therapy.
It is not known whether the use of dronedarone during labor or delivery has any immediate or delayed adverse effects. In pre- and post-natal development studies in the rat, at doses up to 50 mg/kg/day, dronedarone induced no effect on the duration of gestation or on parturition.
A large number of elderly patients with AF or AFL have been included in the MULTAQ clinical program (more than 4500 patients aged 65 years or above, of which more than 2000 patients were 75 years or above). Efficacy and safety was comparable in both elderly and younger patients.
It is recommended that baseline values of plasma creatinine be established 7 days after initiation of treatment with dronedarone.
If the result obtained for the plasma creatinine is above the upper limit of normal as provided by the laboratory, this value should be used as the new reference baseline taking into account that this may be expected with dronedarone, since the drug can affect baseline values. An increase in creatinemia should not necessarily lead to the discontinuation of treatment with dronedarone or discontinuation of treatment with ACE-inhibitors or angiotensin receptor blockers (ARBs) (see Warnings and Precautions, Renal).
Further laboratory testing is at the discretion of the attending physician.
Safety and efficacy in children below the age of 18 years has not been established. Therefore use in these patients is not recommended.
Dronedarone and its metabolites are excreted in rat milk. Nursing in lactating rats administered dronedarone was associated with minor reduced body-weight gain in the offspring.
It is not known whether this drug is excreted in human milk. Therefore, when dronedarone therapy is indicated, the mother should be advised to discontinue nursing (see Contraindications).
MULTAQ has been shown to be teratogenic in the rat and is contraindicated in women who are or may become pregnant. Women of childbearing potential should use effective methods of contraception during treatment with MULTAQ. 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 the fetus.
MULTAQ can cause fetal harm when administered to pregnant women. In rats, dronedarone caused marked effects on embryo-fetal development at 100 mg/kg/day such as increased post-implantation losses, reduced fetal and placental weights and various external, visceral and skeletal malformations in most fetuses. At lower dosages, up to 50 mg/kg/day (corresponding to 4.5 times the recommended human therapeutic dose), dronedarone had no effects on the litters (with the exception of a transient minor effect on the bodyweight gain of the pups from D1 to D4 post-partum). Dronedarone had no adverse effects on the mothers and their litters up to 30 mg/kg/day. In rabbits, the high dose level (200 mg/kg/day) did not induce any effects to fetuses.
Storage and Stability
Store at 25°C, with excursion permitted between 15 and 30°C.
Store in the original package.
Action and Clinical Pharmacology
In subjects with moderate hepatic impairment, dronedarone total and unbound exposures are increased by 1.3-fold and by 2-fold respectively. Those of the active metabolite are decreased by 1.6-fold to 1.9-fold. The effect of severe hepatic impairment on the pharmacokinetics of dronedarone was not assessed (see Contraindications).
The in vitro plasma protein binding of dronedarone and its N-debutyl metabolite is >98 % and not saturable. Both compounds bind mainly to albumin. After intravenous (IV) administration the volume of distribution at steady state (Vss) ranges from 1200 to 1400 L.
The pharmacokinetics of dronedarone in patients with atrial fibrillation is consistent with that in healthy subjects. The main sources of variability in dronedarone exposure (age, gender, bodyweight, concomitant treatment with weak to moderate CYP3A4 inhibitors) remain modest in their magnitude (less than 2-fold).
Assessment of intrinsic factors such as race, gender or age on the incidence of any treatment emergent adverse events did not suggest any excess of adverse events in a particular sub-group.
Dronedarone should be taken with food. Following oral administration in fed conditions, dronedarone is well absorbed (at least 70 %) from intestines to blood. However due to presystemic first pass metabolism, the absolute bioavailability of dronedarone (given with food) is 15 %. Concomitant intake of food increases dronedarone bioavailability by on average 2- to 4-fold. After oral administration in fed conditions, peak plasma concentrations of dronedarone and the main circulating active metabolite (N-debutyl metabolite) are reached within 3 to 6 hours. After repeated administration of 400 mg twice daily, steady state is reached within 4 to 8 days of treatment and the mean accumulation ratio for dronedarone ranges from 2.6 to 4.5. The steady state mean dronedarone Cmax is 84-147 ng/mL and the exposure of the main N-debutyl metabolite is similar to that of the parent compound.
The pharmacokinetics of dronedarone and its N-debutyl metabolite both deviate moderately from dose proportionality: a 2-fold increase in dose results in an approximate 2.5- to 3.0-fold increase with respect to Cmax and AUC.
In animals, dronedarone prevents atrial fibrillation or restores normal sinus rhythm depending on the model used. It also prevents ventricular tachycardia and ventricular fibrillation in several animal models. These effects most likely result from its electrophysiological properties belonging to all four Vaughan-Williams classes. Dronedarone is a multichannel blocker inhibiting the potassium currents (including IK(Ach), IKur, IKr, IKs) and thus prolonging cardiac action potential and refractory periods (Class III). It also inhibits the sodium currents (Class Ib) and the calcium currents (Class IV). It non-competitively antagonizes adrenergic activities (Class II).
The pharmacokinetics of dronedarone were not assessed in pediatric patients.
Pharmacokinetic differences due to race were not assessed.
After oral administration, approximately 6 % of the labeled dose is excreted in urine mainly as metabolites (no unchanged compound excreted in urine) and 84 % are excreted in feces mainly as metabolites. After IV administration the plasma clearance of dronedarone ranges from 130 to 150 L/h. The terminal elimination half-life of dronedarone is around 25-30 hours and that of its N-debutyl metabolite around 20-25 hours. In patients, dronedarone and its metabolite are completely eliminated from the plasma within 2 weeks after the end of a 400 mg twice daily-treatment.
Consistent with the very weak renal excretion of dronedarone, no pharmacokinetic modification was observed in patients with renal impairment in particular in patients with severe renal impairment (see Warnings and Precautions, Special Populations).
In female patients, dronedarone exposures are on average 30% higher as compared to male patients (see Adverse Reactions, Adverse Drug Reaction Overview).
Dronedarone is extensively metabolized, mainly by CYP3A4. The major metabolic pathway includes N-debutylation to form the main circulating active metabolite followed by oxidation, oxidative deamination to form the inactive propanoic acid metabolite, followed by oxidation, and direct oxidation. The N-debutyl metabolite exhibits pharmacodynamic activity but is 3 to 10-times less potent than dronedarone.
Of the total number of subjects in clinical studies of dronedarone, 73% were 65 years of age and over and 34% were 75 and over. In patients aged 65 years old and above, dronedarone exposures are 23% higher in comparison with patients aged below 65 years (see Warnings and Precautions, Special Populations).
In animal models, dronedarone reduces heart rate. It prolongs Wenckebach cycle length and AH-, PQ-, QT- intervals; with no marked effect on QTc-, HV- and QRS- intervals. It increases effective refractory periods of the atrium, atrio-ventricular node and ventricle with minimal degree of reverse-use dependency.
Dronedarone decreases arterial blood pressure and myocardial contractility (dP/dtmax) with no change in left ventricular ejection fraction and reduces myocardial oxygen consumption.
Dronedarone has vasodilatory properties, more pronounced in coronary arteries (related to the activation of the nitric oxide pathway) than in peripheral arteries.
Dronedarone displays indirect antiadrenergic effects; it reduces alpha-adrenergic blood pressure response to epinephrine and beta1 and beta2 responses to isoproterenol.
MULTAQ is contraindicated in patients with: