Multac® (Multaq)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceDronedaronDronedaron
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  • Multac®
    pills inwards 
    Sanofi-Aventis France     France
    • Dosage form: & nbspfilm-coated tablets
    Composition:

    One tablet contains:

    active substance: dronedarone hydrochloride - 426 mg (in terms of dronedarone - 400 mg);

    Excipients: hypromellose (6 mPa.s) - 26.00 mg, corn starch - 45.50 mg, crospovidone (type A) - 65.00 mg, poloxamer 407-f 40.00 mg, lactose monohydrate - 41.65 mg, silicon colloidal dioxide 2.60 mg, magnesium stearate 3.25 mg, hypromellose (6 mPa.s) 7.25 mg, titanium dioxide (E 171) 1.00 mg, macrogol-6000 1.75 mg, wax carnauba - traces.

    Description:Oblong tablets covered with a white film shell, with the engraving of the code "4142" on one side and the double-wave sign on the other side.
    Pharmacotherapeutic group:Antiarrhythmic agent.
    ATX: & nbsp

    C.01.B.D.07   Dronedaron

    Pharmacodynamics:

    Dronedarone has electrophysiological properties characteristic of all four classes of antiarrhythmics according to the Vogen-Williams classification. Dronedaron is a blocker of several ion channels inhibiting potassium currents (the effect of class III antiarrhythmics), including the output potassium delayed-delayed potassium current, activated by acetylcholine (IK (Ach)), the ultrafast fasted potassium retardation current (IKur) ) and a slow outgoing potent current of delayed rectification (IKs).Due to this, the action potential and the refractory period of the myocardial cells elongate. Dronedaron also inhibits sodium currents (anti-arrhythmic effect of IB class) and calcium currents (effect of antiarrhythmics IV class). Dronedaron is a noncompetitive antagonist of adrenergic activity (effect of class II antiarrhythmics).

    In animals, depending on the experimental model used, dronedaron prevents the development of atrial fibrillation or restores the normal sinus rhythm. It also prevents the development of ventricular tachycardia or ventricular fibrillation in some experimental models in animals. Dronedaron reduces the heart rate, lengthens the duration of the Wenkebach period and the intervals of the AH, PQ, QT, without affecting or causing a weak elongation of the QTc intervals (QT corrected by the Bazett formula), HV and QRS. It increases the effective refractory period of the atria, atrioventricular node and ventricles with a minimum degree of inverse dependence of this increase on the heart rate. Dronedaron reduces arterial pressure, myocardial contractility (dP / dt max) without changing the fraction of the left ventricular ejection, as well as oxygen consumption by the myocardium.

    Dronedarone has a vasodilating effect associated with the activation of nitric oxide synthesis and is more pronounced in the coronary than in the peripheral arteries.

    Dronedarone has an indirect anti-adrenergic effect, reduces the response of the arterial pressure to the alpha-adrenergic receptors epinephrine (epinephrine) and mediated via beta1 - and beta2 -adrenergic receptors for the reaction to isoproterenol.

    In healthy volunteers, when 400 mg of dronedarone was taken 2 times a day and at higher doses, a moderate increase in the duration of the PR and QTc interval was observed. Even when taking dronedarone in a dose of 1600 mg 2 times a day, the duration of the QTc interval did not exceed 500 ms.

    Reducing the risk of hospitalization and mortality for cardiovascular disease

    When taken in a dose of 400 mg 2 times a day dronedaron compared with placebo and regardless of concomitant therapy (angiotensin-converting enzyme or angiotensin II receptor antagonists, antagonists, beta-blockers, digoxin, statins, blockers of "slow" calcium channels (BCC), diuretics) reduces by 24.2% the risk of hospitalization forcardiovascular disease or mortality for any reason in patients with atrial fibrillation / atrial flutter or atrial fibrillation / atrial fibrillation in history with additional risk factors, including age, arterial hypertension, diabetes mellitus, previous cerebral circulation disorder, left atrial size> 50 mm or a fraction of the ejection of the left ventricle less than 0.40. In particular, dronedaron reduces the risk of cardiovascular mortality by 30%, sudden death due to cardiovascular causes, by 59.5% and death by stroke by 38.3%.

    Maintaining Sinus Rhythm

    Dronedarone helps maintain sinus rhythm, reducing the risk of recurrence of atrial fibrillation / atrial flutter by 55% for six months and 25% over 12 months compared with placebo.

    Effect on heart rate

    With a constant form of atrial fibrillation (lasting more than 6 months) with dronedarone, in addition to conventional therapy, on the 14th day of treatment, the heart rate (HR) is at rest (an average of about 9 bpm) and during the maximum physical exertion (an average of 25 beats per minute).This effect does not depend on standard therapy aimed at controlling heart rate.

    In patients receiving dronedaron with the purpose of maintaining sinus rhythm, in case of recurrence of atrial fibrillation, the latter occurs with a lower frequency of ventricular contraction than that of non-recipients dronedaron patients.

    Pharmacokinetics:

    Suction

    When ingested simultaneously with food dronedaron is well absorbed (at least 70%). However, in connection with presystemic metabolism at the "first passage" through the liver, the absolute bioavailability of dronedarone (taken with food) is 15%. Simultaneous food intake increases the bioavailability of dronedarone by 2-4 times. After ingestion with food, the maximum plasma concentrations (Cmax) dronedarone and its main active metabolite (N-debutyl metabolite) is achieved within 3-6 hours. With a course of 400 mg twice a day, the equilibrium plasma concentration is reached in 4-8 days of treatment and the average value of the accumulation factor of dronedarone is 2.6-4.5. Average value of Cmax dronedarone in the equilibrium state is 84-147 ng / ml, the concentration of the basic N-debutylmetabolite has the same average values. With increasing dronedarone doses, the Cmax and the area under the concentration-time curve (AUC) of dronedarone and its N-debutylmetabolite also increase, and their increase slightly outstrips the simple proportionality of the dose: a 2-fold increase in the dose leads to a 2.5-3-fold increase in the corresponding pharmacokinetic indices.

    Distribution

    The association with the proteins of the blood plasma of dronedarone and its N-debutylmetabolite in vitro exceeds 98% and is unsaturated. Both substances bind mainly to albumin. After intravenous administration, the volume of distribution in the equilibrium state (Vss) ranges from 1200 to 1400 liters.

    Metabolism

    Dronedarone is intensively metabolized, mainly with the help of the CYP3A4 isoenzyme (see section "Interaction with Other Drugs"). The main pathway of metabolism consists of N-debutilization with the formation of the main active metabolite present in the blood with its subsequent oxidation, oxidative deamination with the formation of an inactive metabolite of propionic acid with its further oxidation. Monoamine oxidases contribute in part to the metabolism of the active metabolite of dronedarone.The pharmacodynamic activity of N-debutylmetabolite is 3-10 times lower than the pharmacodynamic activity of dronedarone.

    Excretion

    After ingestion, approximately 6% of radon-labeled dronedarone is excreted by the kidneys, mainly in the form of metabolites (unchanged dronedaron in urine is not determined) and 84% is released through the intestine, also mainly in the form of metabolites. After intravenous injection, the clearance of dronedarone from the blood plasma is 130-150 l / h. The final half-life of dronedarone is about 25-30 hours, and its N-debutylmetabolite is about 20-25 hours. At patients after the termination of reception dronedarona on 400 mg 2 times a day dronedaron and its metabolite is completely eliminated from the blood plasma for 2 weeks.

    Pharmacokinetics in specific patient groups

    The pharmacokinetics of dronedarone in patients with atrial fibrillation does not differ from that of healthy volunteers. The main sources of variability in plasma concentrations of dronedarone (age, gender, body weight, concomitant intake of weak and moderate inhibitors of the isoenzyme CYP3A4) affect its plasma concentrations quite weakly (change less than 2-fold).

    Floor

    Plasma concentrations of dronedarone in women are on average 30% higher than in men.

    Elderly age

    In patients aged 65 years and older, plasma dronedarone concentrations are 23% higher than those in patients younger than 65 years of age.

    Impaired liver function

    In patients with moderate impairment of liver function, the plasma concentrations of total and unbound dronedarone increase by 1.3 and 2 times, respectively, and the active metabolite decreases 1.6 - 1.9 times (see the section "Dosing and Administration").

    The effect of severe liver dysfunction on the pharmacokinetics of dronedarone has not been studied (see the section "Contraindications").

    Impaired renal function

    Patients with renal dysfunction, including those with severe renal lesions, did not change pharmacokinetics, which is due to a very low excretion of dronedarone through the kidneys (see the section "Dosing and Administration").

    Indications:

    Persistent or paroxysmal atrial fibrillation (atrial fibrillation) or atrial flutter in patients with sinus rhythm or in patients undergoing cardioversion (restoration of sinus rhythm):

    - to maintain sinus rhythm and / or

    - to reduce the risk of cardiovascular hospitalization or mortality (see the section "Pharmacodynamics").

    Contraindications:

    - Hypersensitivity to dronedarone or excipients of the drug.

    - atrioventricular block II or III degree, complete bundle branch block, the distal block atrioventricular conduction, sinus node dysfunction, disorders of intraatrial conduction or sick sinus syndrome (except for use in patients with a functioning artificial pacemaker).

    - Expressed bradycardia (heart rate less than 50 beats per minute).

    - The duration of the QTc interval is ≥ 500 ms.

    - permanent atrial fibrillation (AF duration ≥6 months or unknown) when making the decision to terminate the doctor further attempts to restore sinus rhythm.

    - Instability of hemodynamics.

    - Heart failure or left ventricular dysfunction, including, in the anamnesis.

    - Simultaneous reception of strong inhibitors of the isoenzyme CYP3A4, such as ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin, nefazodone and ritonavir (see the section "Interaction with other medicinal products").

    - Simultaneous reception of drugs that can cause the development of paroxysmal tachycardias, including polymorphic ventricular "pirouette" tachycardia: phenothiazines, cisapride, bepridil, tricyclic antidepressants, terfenadine and some macrolides for oral administration, antiarrhythmics of I and III classes (see "Interaction with other medicinal preparations ").

    - Severe hepatic insufficiency (more than 9 points on the Child-Pugh scale).

    - Phenomena of hepatotoxicity or pulmonary toxicity when taking amiodarone.

    - Pregnancy (see the section "Application during pregnancy and during breast-feeding").

    - Lactation period (see section "Application during pregnancy and during breast-feeding").

    - Hereditary lactose intolerance (lactase deficiency), galactose intolerance, glucose-galactose malabsorption (due to the presence of lactose in the formulation as an auxiliary substance).

    - Children under 18 years of age (lack of clinical experience with dronedarone).

    Carefully:

    - With hypokalemia, hypomagnesemia (a deficiency of potassium or magnesium should be necessarily replenished before and during treatment with the drug Multak®).

    - With the simultaneous use of indirect anticoagulants (requires careful monitoring of the international normalized relationship - MNO).

    - With ischemic heart disease.

    - In patients older than 75 years with a large number of concomitant diseases.

    - With the simultaneous administration of HMG-CoA reductase (statin) inhibitors metabolized by the CYP3A4 isoenzyme, such as simvastatin, lovastatin, atorvastatin, pravastatin (see the section "Interaction with other medicinal products").

    Pregnancy and lactation:

    Pregnancy

    There is insufficient data on the use of the drug Multak® in pregnant women. Studies in animals have demonstrated a teratogenic effect.

    Pregnant reception of the drug Multak® is contraindicated (see section "Contraindications").

    Women of childbearing age should take reliable methods of contraception while taking Multac®.

    Breastfeeding period

    It is not known whether the dronedaron in breast milk.Therefore, if treatment with Multac® is indicated during lactation, it is necessary to stop breastfeeding or to cancel the Multac® product.

    Dosing and Administration:

    Treatment with Multac® can begin on an outpatient basis. The drug should be taken orally during meals (during breakfast and dinner), drinking 1/2 cup of water.

    Before starting the preparation of Multac®, discontinue treatment with antiarrhythmic drugs of I or III class (such as flecainide, propafenone, quinidine, disopyramide, dofetilide, amiodarone and sotalol). There is limited information regarding the optimal timing of the transition from amiodarone to the administration of the drug Multak®. It should be borne in mind that amiodarone, which has a long half-life, can last for a long time after its discontinuation. If you plan to transfer such a patient to receive the drug Multak®, this should be done with caution and under the supervision of a specialist (see section "Contraindications").

    Adults

    The recommended adult dose is 1 tablet of Multac® (400 mg) twice a day (800 mg per day) (one tablet at breakfast and the second tablet at dinner).

    Children and teens

    Since safety and efficacy in patients younger than 18 years of age have not been established, the use of Multak® in these patients is not recommended.

    Elderly patients

    The efficacy and safety of the Multal® drug in elderly patients does not differ from those in younger patients. Caution should be exercised in patients older than 75 years with a large number of concomitant diseases.

    Liver failure

    When used in patients with mild (5-6 points on the Child-Pugh scale) and moderately expressed (7-9 points on the Child-Pugh scale), liver failure is not required to correct the dose (see the section "Pharmacokinetics"). In connection with the lack of clinical data for patients with severe hepatic insufficiency (more than 9 points on the Child-Pugh scale), the preparation of the drug Multak® is contraindicated (see the section "Contraindications"),

    Renal insufficiency

    With renal failure, dose adjustment is not required (see the section "Pharmacokinetics").

    Side effects:

    Data from clinical trials

    The data presented in this section are based on the results of 5 placebo-controlled studies (ATHENA, EURIDIS, ADONIS, ERATO and DAFNE).In these studies, a total of 6,285 patients participated, of which 3,282 patients received dronedaron 400 mg twice a day and 2,875 patients received a placebo.

    The average duration of follow-up in these studies was 12 months, and in the ATHENA study, the maximum follow-up period was 30 months.

    The incidence of treatment-related adverse effects was independent of sex, race or age of the patients.

    In clinical trials, premature discontinuation of the drug as a result of adverse events was observed in 11.8% of patients taking dronedaron, and in 7.7% of patients taking placebo. The most common reasons for stopping dronedarone were digestive disorders (3.2% of patients compared to 1.8% of patients receiving placebo).

    The undesirable phenomena listed below are given in accordance with the following gradations of their occurrence frequency: very frequent (≥10%); frequent (≥1% - <10%); infrequent (≥0.1% - <1%); rare (≥0.01% - <0.1%); very rare (<0.01%) (including individual cases); the frequency is unknown (according to the available data, the frequency of occurrence of the side effect can not be established).

    Heart Disease

    Frequent

    Bradycardia.

    Disturbances from the nervous system

    Infrequent

    Dysgeusia (perversion of taste).

    Rare

    Agevzia (loss of taste sensitivity).

    Disorders from the gastrointestinal tract

    Frequent

    Diarrhea, vomiting, abdominal pain, nausea, dyspepsia.

    Disturbances from the skin and subcutaneous tissues

    Frequent

    Rash (including generalized, macular, maculate-papular), itchy skin.

    Infrequent

    Erythema (including erythema and erythematous rash), eczema, photosensitivity, allergic dermatitis, dermatitis.

    Are common

    Frequent

    Increased fatigue, weakness.

    From the laboratory indicators

    Very Frequent

    The prolongation of the QTc interval (> 450 ms for men,> 470 ms for women) (in 27.6% of patients with dronedarone and in 18.7% of patients on placebo).

    An increase in plasma creatinine concentration by ≥10% on the fifth day after the start of treatment, reaching a plateau by day 7, reversible after the cancellation of dronedarone, and associated with inhibition of creatinine secretion at the level of the tubules without the effect of the drug on the glomerular filtration rate or renal blood flow.

    Data obtained during post-marketing use of the drug

    Heart Disease

    Frequency unknown

    Heart failure (heart failure may be a complication of heart disease, including flickering and fluttering of the atria, but one can not exclude the relationship with dronedarone intake). Several cases of atrial flutter with atrioventricular conduction of 1: 1 have been reported.

    Disturbances from the liver and bile ducts

    Frequency unknown

    Deviation from the norm of indicators of functional "hepatic" samples. Hepatocellular insufficiency, including life-threatening acute liver failure (see section "Special instructions").

    Vascular disorders

    Frequency unknown

    Vasculitis, including leukocytoclastic vasculitis.

    Disturbances from the respiratory system, chest and mediastinal organs

    Frequency unknown

    Interstitial lung involvement, including pulmonitis and pulmonary fibrosis (a number of patients with these undesirable effects before taking dronedarone took amiodarone) (see section "Special instructions").

    Immune system disorders

    Frequency unknown

    Anaphylactic reactions, including angioedema.

    Overdose:

    Symptoms

    In case of overdose, it is possible to expect the development of more pronounced known undesirable phenomena (pronounced bradycardia, significant prolongation of the QT interval, nausea, vomiting, etc.) (see "Side effect" section).

    Treatment

    In case of an overdose, the drug should be discontinued. If, after taking an excessive dose, no more than a few hours have elapsed, you can try to induce vomiting or rinse the stomach. In case of an overdose, you should constantly monitor heart rate and blood pressure. In case of an overdose, treatment should be supportive of the body's basic functions and symptomatic.

    The possibility of excretion of dronedarone and its metabolites by dialysis (hemodialysis, peritoneal dialysis or hemofiltration) has not been studied. There is no specific antidote.

    Interaction:

    Dronedarone is metabolized predominantly with the CYP3A4 isoenzyme (see the section "Pharmacokinetics") and is a moderate inhibitor of the CYP3A4 isoenzyme and a weak inhibitor of the CYP2D6 isoenzyme. Therefore inhibitors and inducers of the isoenzyme CYP3A4 have the potential to interact with dronedarone, and dronedaron has the potential to interact with pharmacological agents that are substrates of CYP3A4 and CYP2D6 isoenzymes. It also has the potential to inhibit P-glycoprotein transport. In vitro dronedaron and / or its metabolites have the potential to inhibit the transport of organic anions and cations by means of an organic anion carrier (PAO), a transport polypeptide for organic anions (TPOA) and an organic cation carrier (POC). Dronedaron does not have a significant inhibition potential of the isoenzymes CYP1A2, CYP2C9, CYP2C19, CYP2C8 and CYP2B6.

    Potential pharmacodynamic interaction with beta-blockers, slow calcium channel blockers and digoxin can also be expected.

    In clinical trials, patients who took dronedaron, received various concomitant therapy, including beta-blockers, digoxin, BCCC (including reducing heart rate verapamil and diltiazem), inhibitors of HMG-CoA reductase (statins) and anticoagulants.

    The effect of other drugs on Multak®

    - Medications that can induce prolongation of the QT interval and / or development of paroxysmal tachycardias, including ventricular "pirouette" tachycardia - such as antipsychotics,which are derivatives of phenothiazine, cisapride, bepridil, tricyclic antidepressants, terfenadine, individual macrolides for oral administration, antiarrhythmics of I and III classes.

    There is a potential risk of developing proarhythmogenic action. Simultaneous reception of these drugs in conjunction with the drug Multak® is contraindicated (see the section "Contraindications").

    - Strong inhibitors of the isoenzyme CYP3A4: ketoconazole, itraconazole, voriconazole, ritonavir, telithromycin, clarithromycin, nefazodone.

    Course intake 200 mg ketoconazole and a day caused a 17-fold increase in the systemic exposure of dronedarone. Therefore, concurrent with dronedarone, ketoconazole, as well as other strong inhibitors of the CYP3A4 isoenzyme, such as itraconazole, voriconazole, ritonavir, clarithromycin, nefazodone.

    - Moderate or weak inhibitors of the isoenzyme CYP3A4: BCCI

    BCCIs are substrates and / or moderate inhibitors of the isoenzyme ZA4. Moreover, BCCs, which reduce heart rate (such as verapamil, diltiazem), have the potential for pharmacodynamic interaction with dronedarone.

    Course reception diltiazem (240 mg twice daily), verapamil (240 mg 1 time per day) and nifedipine in retarded form (20 mg twice daily) resulted in an increase in systemic exposure dronedarone 1.7, 1.4 and 1.2 times, respectively. Systemic exposure of BCCI also increased with dronedarone (400 mg twice daily) (verapamil 1.4 times and nisoldipine 1.5 times). In clinical studies, there was no pharmacodynamic interaction in the joint use of dronedarone and BCCC, which reduce the heart rate.

    However, given the pharmacokinetic interaction and possible pharmacodynamic interactions (risk summation inhibitory action on the sinus and the atrioventricular node), caution should be exercised in the combined use of dronedarone and BCCI oppressing sinoatrial node and the atrioventricular such as verapamil and diltiazem. Treatment with these drugs should begin with low doses, and a gradual increase in the dose should only be carried out under ECG monitoring. In patients who are already receiving BCCI at the time of dronedarone treatment, ECG monitoring is required and, if necessary, the dose of BCCM should be reduced.

    - Erythromycin

    Other moderate inhibitors of the CYP3A4 isoenzyme also appear to increase the systemic exposure of dronedarone. The course reception of erythromycin (500 mg 3 times a day for 10 days) resulted in an increase in systemic exposure of dronedarone in the equilibrium state by 3.8 times.

    - Inductors of the isoenzyme CYP3A4: rifampicin, phenobarbital, carbamazepine, phenytoin; preparations containing St. John's wort.

    Rifampicin (600 mg once a day) reduced the system exposure of dronedarone by a factor of 5, without significantly affecting the systemic exposure of its active metabolite. Therefore, simultaneous use of rifampicin and other potential inducers of the CYP3A4 isoenzyme, such as phenobarbital, carbamazepine, phenytoin, preparations containing St. John's wort, as they reduce the systemic exposure of dronedarone.

    Effect of Multak® on other drugs

    Interaction with drugs metabolized by the CYP3A4 isoenzyme

    Inhibitors of HMG-CoA reductase (statins)

    Dronedarone may increase the systemic exposure of HMG-CoA reductase inhibitors, as they are substrates for the isoenzyme CYP3A4 and P-glycoprotein. Dronedaron (400 mg twice daily) increased the systemic exposure of simvastatin and simvastatin acid by 4 and 2 times, respectively. It is assumed that dronedaron can also increase the systemic exposure of lovastatin, atorvastatin and pravastatin to the same extent as simvastatin acid. There was a weak interaction between dronedarone and atorvastatin (the system exposure of atorvastatin increased 1.7-fold). In clinical studies, no data were obtained on the significant interaction of dronedarone with HMG-CoA reductase inhibitors metabolized by the CYP3A4 isoenzyme. There was a weak interaction between dronedarone and statins, which are transferred by TPOA, such as rosuvastatin (1,4-fold increase in the systemic exposure of rosuvastatin).

    Given that large doses of HMG-CoA reductase inhibitors increase the risk of developing myopathy, caution should be exercised while using HMG-CoA reductase inhibitors that are a substrate of the CYP3A4 and / or P-glycoprotein isoenzyme such as simvastatin, lovastatin, atorvastatin and pravastatin, and to conduct constant monitoring of patients for clinical manifestations of toxic damage to muscles.Lower starting and maintenance doses of HMG-CoA reductase inhibitors should be used as recommended in the instructions for the use of a particular HMG-CoA reductase inhibitor.

    Significant interaction of dronedarone and HMG-CoA reductase inhibitors that are not substrates of the CYP3A4 and / or glycoprotein-P isoenzymes, such as fluvastatin and rosuvastatin, it is unlikely.

    - BMMC (see above)

    - Sirolimus, tacrolimus

    Dronedarone can increase plasma concentrations of sirolimus and tacrolimus. When combined with dronedarone, regular monitoring of their plasma concentrations and appropriate dose adjustment of sirolimus and tacrolimus are recommended.

    - Oral contraceptives

    In healthy women who received oral contraceptives with dronedarone (800 mg twice daily), there was no decrease in the concentrations of ethinyl estradiol or levonorgestrel.

    Interaction with drugs metabolized by the CYP2D6 isoenzyme

    Beta-blockers: metoprolol, propranolol

    Dronedarone may increase the systemic exposure of beta-adrenoblockers metabolized by the CYP2D6 isoenzyme.Moreover, beta-blockers have the potential for pharmacodynamic interaction with dronedarone. Dronedaron in a dose of 800 mg per day increased the system exposure of metoprolol 1.6 times and the system exposure of propranolol - 1.3 times. In clinical studies using a combination of dronedarone with beta-blockers, bradycardia was more often observed.

    It is recommended to use with caution beta-blockers in conjunction with dronedarone because of the pharmacokinetic interaction and possible pharmacodynamic interaction (risk of summation of the inhibitory effect on the sinus and atrioventricular nodes). It is necessary to start treatment with beta-blockers from low doses and increase their dose only under ECG control. Patients who are already receiving beta-blockers, the addition of dronedarone should be performed under ECG monitoring and, if necessary, adjust the dose of beta-blockers.

    Interaction with drugs that are substrates of P-glycoprotein

    - Digoxin

    Dronedarone (400 mg twice daily) increased the systemic exposure of digoxin by 2.5 times by inhibiting the P-glycoprotein transporter. Besides, digoxin has the potential for pharmacodynamic interaction with dronedarone. In clinical studies in cases where dronedaron was taken together with digoxin, there was an increase in serum digoxin concentration and / or undesirable effects on the part of the digestive system.

    Due to pharmacokinetic interaction and possible pharmacodynamic interaction, care should be taken if digoxin Together with dronedarone. If treatment with digoxin continues, then its dose should be reduced by a factor of 2, regular serum digoxin concentration should be monitored and patients monitored for signs of glycosidic intoxication.

    - Dabigatran

    With the simultaneous use of dabigatran with a course of dronedarone 400 mg twice daily, the area under the pharmacokinetic curve of dabigatran AUC0.24 and Stach increased by 100% and 70%, respectively. There was no effect of dronedarone on the renal clearance of dabigatran.

    - Other substrates of P-glycoprotein: doxorubicin, fexofenadine and talinolol

    Dronedarone inhibits P-glycoprotein and, possibly, its interaction with doxorubicin, fexofenadine and talinolol, leading to an increase in the concentrations of these drugs in the blood serum and an increase in their pharmacodynamic and toxic side effects.

    Interaction with substrates of the isoenzyme CYP2C9

    - Warfarin and other indirect anticoagulants

    Dronedarone (600 mg twice daily) increased 1.2 times the concentration of S-warfarin, without affecting the concentrations of R-warfarin, and only 1.07 times increased INR (the international normalized ratio). In the ATHENA clinical trial, a larger number of patients taking indirect anticoagulants had a clinically significant (≥5%) increase in INR after treatment with dronedarone compared with placebo. However, there was no additional risk of bleeding in patients taking indirect anticoagulants and dronedaron Simultaneously.

    Postmarketing observations recorded cases of an increase in INR with bleeding or no bleeding in patients treated with indirect anticoagulants who were treated with dronedarone.After adherence to treatment with dronedarone, INR should be monitored in patients taking indirect anticoagulants as indicated in the instructions for their use.

    - Losartan and other angiotensin II receptor antagonists

    No interaction of dronedarone with losartan has been observed. The interaction of dronedarone with other angiotensin II receptor antagonists is not expected.

    Interaction with theophylline (substrate of the isoenzyme CYP1A2)

    Dronedarone in a dose of 400 mg twice a day did not cause an increase in the systemic exposure of theophylline in a state of reaching an equilibrium concentration in the blood plasma.

    Interaction with metformin (Substrate POK1 and POK2)

    There was no interaction of dronedarone with metformin (substrate PK1 and PKK2).

    Interaction with omeprazole (substrate of the isoenzyme CYP2C19)

    No interaction was observed between dronedarone and omeprazole (substrate of the isoenzyme CYP2C19).

    Interaction with clopidogrel

    There was no interaction between dronedarone and clopidogrel.

    Other information

    Pantoprazole (40 mg once a day), a drug that increases the pH of the stomach without affecting the isoenzymes of the cytochrome P450 system, did not have a significant effect on the pharmacokinetics of dronedarone.

    Grapefruit juice (inhibitor of the isoenzyme CYP3A4)

    The intake of 300 ml of grapefruit juice 3 times a day resulted in a 3-fold increase in the systemic exposure of dronedarone. Therefore, patients should be warned not to take grapefruit juice in all its forms while taking Multac®.

    Special instructions:

    Patients who, during treatment, develop a permanent form of atrial fibrillation

    A clinical trial in patients with persistent atrial fibrillation (duration of atrial fibrillation for at least 6 months) and risk factors for cardiovascular complications was terminated prematurely due to an increase in cardiovascular mortality, stroke and unscheduled hospitalization for cardiovascular reasons.

    It is recommended that ECG monitoring be performed at least every 6 months while the patient receives the Multac® drug. If patients receiving the Multac® drug develop a permanent form of atrial fibrillation, treatment with Multac® should be discontinued.

    Patients with heart failure or systolic dysfunction of the left ventricle, developed during treatment with the drug Multak®

    The drug Multak® is contraindicated in patients with unstable hemodynamics; heart failure or systolic dysfunction of the left ventricle, including, in the anamnesis.

    Patients should be warned about the need to inform the attending physician about the development of symptoms of heart failure, such as weight gain, swelling, and an increase in dyspnea. If heart failure develops, treatment with Multac® should be discontinued.

    Patients should be observed for the development of systolic dysfunction of the left ventricle during treatment. If systolic dysfunction of the left ventricle develops, treatment with Multac® should be stopped.

    Impaired liver function

    In the post-marketing application of the drug, hepatocellular liver failure was reported in several patients, including life-threatening acute hepatic impairment.

    Before the application of the drug Multak®, then one week and one month after the commencement of treatment with the Multac® drug, a study of liver function,after which they should be monitored monthly for 6 months of taking the drug, then every 3 months of treatment (during the 9th and 12th months) and periodically thereafter. If the activity of alanine aminotransferase (ALT) in the blood rises to a level 3 times higher than the upper limit of the norm, this study should be repeated. If a three-fold excess of the upper limit of normal for ALT activity in the blood is confirmed, stop taking Multac®. Careful observation of the patient prior to the normalization of ALT activity is necessary, as well as a survey to identify possible causes of increased ALT activity in the blood, including those related to the underlying heart disease. In patients who have not been found to have another explanation for liver dysfunction, you can not resume taking Multac®.

    Patients are advised to immediately tell their doctor of any symptoms suspected of a violation of liver function (such as anorexia, nausea, vomiting, fever, malaise, weakness, discomfort in the upper right abdomen, jaundice, darkening of urine or itching).

    Disturbances from the respiratory organs

    During post-marketing use of the drug, cases of interstitial lung lesions, including pneumonitis and pulmonary fibrosis, were reported (see "Side effect" section). The appearance of dyspnea or unproductive cough may be associated with pulmonary toxicity, and such patients require a thorough clinical examination. When confirming pulmonary toxicity, treatment with Multac® should be discontinued.

    Violation of the water-electrolyte balance

    Since in patients with hypokalemia, antiarrhythmic drugs may be ineffective and even cause arrhythmias, hypokalemia and hypomagnesemia should be corrected before beginning and, if necessary, corrected during treatment with the Multac® preparation.

    Simultaneous use of indirect anticoagulants

    If necessary, patients should undergo anticoagulant therapy. When dronedarone was added to treatment with indirect anticoagulants, an increase in INR was observed in clinical trials, but there was no additional risk of bleeding,At the same time, in cases of postmarketing surveillance with simultaneous use of indirect anticoagulants and dronedarone, cases of increase in INR, including those with development of bleeding, have been reported. Therefore, in patients taking indirect anticoagulants, the INR should be carefully monitored after the use of the Multac® drug.

    Increase in the concentration of creatinine in the blood plasma

    After starting the preparation of Multak®, the plasma concentration of creatinine increases by an average of 0.1 mg / dL. Its increase occurs immediately at the beginning of treatment and reaches a plateau by day 7 and is reversible after discontinuation of the drug. If during this time period, when the preparation of Multak® is taken, creatinine concentration is increased and then its output on the "plateau", then this value of creatinine concentration should be considered a new initial value for comparison with values ​​of plasma creatinine concentration in the future. This increase in plasma creatinine is associated with inhibition of creatinine secretion at the level of the tubules and is not due to the effect of the drug on the glomerular filtration rate or renal blood flow and should not be grounds for withdrawalACE inhibitors and angiotensin II receptor antagonists if the patient needs them.

    In the post-marketing application of the drug Multac®, a more pronounced increase in creatinine concentration was recorded, including cases of development of prerenal azotemia, which arose secondary, as a result of chronic heart failure, kidney hypoperfusion, or hypovolemia. Several cases of increased blood urea nitrogen concentrations have also been reported.

    In most cases, these phenomena were reversible after drug withdrawal. Periodically monitor the function of the kidneys and, if necessary, conduct additional examinations.

    Increasing the duration of the QT interval

    The pharmacological action of the drug Multac® can cause ECG changes, such as a moderate increase in the duration of the QT interval (associated with an increase in the duration of the repolarization period). These changes are associated with the therapeutic effect of the drug Multak® and are not a sign of toxic effects. During the treatment with the Multac® preparation, an observation including ECG monitoring is recommended.If the duration of the QTc interval is ≥ 500 ms, reception of the Multac® preparation should be discontinued (see "Contraindications").

    The results of clinical study showed that the drug Multak® has a mildly pronounced pro-rhythmogenic effect. A clinical study of ATHENA showed a decrease in the death rate due to cardiac rhythm disturbances (see the section "Pharmacodynamics"). Nevertheless, it is impossible to completely exclude the possibility of developing pro-arrhythmogenic action in individual cases, especially when using drugs that contribute to the occurrence of arrhythmia and / or disturbances in the water-electrolyte balance.

    Effect on the ability to drive transp. cf. and fur:Special studies to assess the effect on the ability to drive vehicles have not been carried out, however, based on the pharmacodynamic properties of dronedarone, there is no reason to assume that it may violate the ability to drive vehicles or work with other mechanisms, engage in other potentially hazardous activities requiring increased concentration.
    Form release / dosage:Tablets, film-coated, 400 mg.
    Packaging:

    For 10 tablets in a blister of PVC and aluminum foil.

    For 1, 2, 6 or 10 blisters together with instructions for use in a cardboard box.

    Storage conditions:

    Store at a temperature not exceeding 30 ° C.

    Keep out of the reach of children.

    Shelf life:

    3 years.

    Do not use the product after the expiry date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-000061
    Date of registration:02.12.2010
    Expiration Date:02.12.2015
    The owner of the registration certificate:Sanofi-Aventis FranceSanofi-Aventis France France
    Manufacturer: & nbsp
    Representation: & nbspSanofi Aventis GroupSanofi Aventis Group
    Information update date: & nbsp20.05.2018
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