Dronedaron (Dronedaronum)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
Read on
Clinical and pharmacological group: & nbsp

Antiarrhythmics

Included in the formulation
  • Multac®
    pills inwards 
    Sanofi-Aventis France     France
    • АТХ:

    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 rectifier current, activated by acetylcholine (IK (Ach), ultrafast emerging potassium retardation current (IKur), fast outgoing potent current of delayed rectification (IKg) and a slow outgoing potent current of delayed rectification (IKs), thereby prolonging the action potential and the refractory period of the myocardial cells. 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).

    Dronedarone has a vasodilating action associated with the activation of nitric oxide synthesis, and 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 patients receiving dronedaron with the purpose of maintaining sinus rhythm, in the case of recurrence of atrial fibrillation, the latter occurs with a lower frequency of ventricular contraction than that in patients who do not receive dronedaron.

    Pharmacokinetics:

    Suction. When ingested simultaneously with food dronedaron is well absorbed (at least 70%). However, in connection with pre-systemic 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 Cmax dronedarone and its main active metabolite (N-debutylmetabolite) in plasma is achieved within 3-6 hours. With a course of 400 mg twice a day CSS in plasma is achieved 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 AUC of dronedarone and its N-debutylmetabolite also increase, and their increase slightly outstrips the simple proportionality of the dose: an increase in the dose of 2-fold leads to an increase in the corresponding pharmacokinetic parameters by 2.5-3 times.

    Distribution. The connection with the proteins of the plasma of dronedarone and its N-debutylmetabolite in vitro exceeds 98% and is unsaturated. Both substances bind mainly to albumin. After intravenous administration of VSS varies from 1200 to 1400 liters.

    Metabolism. Dronedaron It is intensively metabolized predominantly with the help of the CYP3A4 isoenzyme. 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 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. In patients after completion of 400 mg twice daily dronedaron and its metabolite is completely eliminated from the blood plasma within 2 weeks.

    Indications:

    Atrial fibrillation or atrial flutter in the anamnesis or at present (to reduce the risk of hospitalization for cardiovascular disease).

    ICD-10

    IX.I30-I52.I48   Atrial fibrillation and flutter

    Contraindications:

    - atrioventricular blockade of II or III degree or syndrome of weakness of the sinus node (except for patients with a functioning artificial pacemaker);

    - pronounced bradycardia (heart rate less than 50 beats per minute);

    - the duration of the interval QTc ≥ 500 ms;

    - chronic heart failure IV functional class according to NYHA classification or chronic cardiac insufficiency III functional class according to NYHA classification with recent decompensation,requiring hospitalization or referral to a specialized clinic;

    - simultaneous administration of strong inhibitors of the isoenzyme CYP3A4, such as ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin, nefazodone and ritonavir;

    - simultaneous reception of drugs that can cause the development of paroxysmal tachycardias, including polymorphic ventricular tachycardia such as pirouettes: phenothiazines, cisapride, bepridil, tricyclic antidepressants, terfenadine and some macrolides for oral administration, antiarrhythmics of classes I and III;

    severe hepatic impairment;

    - severe renal failure (creatinine clearance less than 30 ml / min);

    - pregnancy and lactation;

    - hereditary intolerance to galactose, lactase deficiency or glucose-galactose malabsorption (due to the presence of lactose as an auxiliary in the formulation);

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

    - Hypersensitivity to dronedarone or excipients of the drug.
    Carefully:

    With hypokalemia, hypomagnesemia (a deficiency of potassium or magnesium must be mandatoryreplenished before and during drug treatment; while concurrent administration of inhibitors of HMG-CoA reductase (statins) metabolized by the CYP3A4 isoenzyme, such as simvastatin, lovastatin, atorvastatin, pravastatin.

    The use of dronedarone should be limited to patients with paroxysmal and persistent atrial fibrillation if they have sinus rhythm. When relapses occur atrial fibrillation/ atrial flutter on the background of a constant intake of dronedarone should either be quickly restored sinus rhythm, and then the drug can be continued, or dronedaron should be abolished in the case of an ongoing atrial fibrillation.

    Dronedarone can not be recommended for use in patients with permanent form atrial fibrillation/ atrial flutter and as a drug used to reduce heart rate in patients with atrial fibrillationwith atrial flutter. Dronedaron do not prescribe to patients with atrial fibrillation/ atrial flutter, currently having either a history of clinical manifestations of chronic heart failure, and having systolic dysfunction left ventricle with a decline Left ventricular ejection fraction < 40 %.

    Pregnancy and lactation:

    Pregnancy. There is insufficient data on the use of the drug in pregnant women. Studies in animals have demonstrated a teratogenic effect. Pregnant dronedarone is contraindicated.

    Women of childbearing age at the time of taking the drug should use reliable methods of contraception.

    Lactation period. It is not known whether the dronedaron in breast milk. Therefore, if treatment is indicated during lactation, it is necessary to stop breastfeeding or to cancel the drug.

    Dosing and Administration:

    Inside, during meals (during breakfast and dinner), drinking 1/2 cup of water. Treatment can begin on an outpatient basis. Before the start of treatment should stop treatment with antiarrhythmics (such as flecainide, propafenone, quinidine, disopyramide, dofetilide, amiodarone and sotalol).

    Adults. The recommended dose for adults is 400 mg twice a day (800 mg per day) (the first tablet is at breakfast and the second one at dinner time).

    Children and teenagers. Since safety and efficacy in patients younger than 18 years is not established, the use of dronedarone in these patients is not recommended.

    Patients of advanced age. The effectiveness and safety of the drug in elderly patients does not differ from those in younger patients, and dose adjustment in this category of patients is not required.

    Side effects:

    Heart Disease: often - a bradycardia.

    Impaired nervous system: infrequently - dysgeusia (perversion of taste); rarely - agevzia (loss of taste sensitivity).

    Disorders from the digestive tract: often - diarrhea, vomiting, nausea, abdominal pain, dyspepsia.

    Disturbances from the skin and subcutaneous tissues: often - a rash (including generalized, macular, maculopapular), skin itching; infrequently - erythema (including erythema and erythematous rash), eczema, photosensitivity, allergic dermatitis, dermatitis.

    Are common: often - fatigue, fatigue.

    If any of the side effects indicated in the manual are aggravated, or the patient has noticed any other side effects not listed in the instructions, you should notify the doctor.

    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.).

    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 your 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:

    The intake of 300 ml of grapefruit juice 3 times a day resulted in a threefold increase in the systemic exposure of dronedarone. Therefore, patients should refuse to take grapefruit juice in all its forms during the administration of the drug.

    Contraindicated combination of 4-nitro-N - [(1RS) -1- (4-fluorophenyl) -2- (1-ethylpiperidine-4-yl) ethyl] benzamide hydrochloride with dronedarone - Class III antiarrhythmic agent potentially capable of causing polymorphic ventricular tachycardia type "pirouette".

    It should be avoided simultaneous application of Bosutinib with dronedarone - a moderate inhibitor of the isoenzyme CYP3A, as this can lead to an increase in the concentration of Bosutinib in the blood plasma.If it is necessary to simultaneously use bosutinib with dronedarone, consideration should be given to reducing the dosage of bosutinib.

    In studies in vitro shown, that vemurafenib is a substrate and inhibitor of P-glycoprotein. It can not be ruled out that the pharmacokinetic parameters of vemurafenib can be influenced dronedaron, inhibiting P-glycoprotein.

    Verapamil is a substrate and a moderate inhibitor of the CYP3A4 isoenzyme. Furthermore, verapamil, which reduces the heart rate, has the potential for pharmacodynamic interaction with dronedarone.

    Contraindicated concurrent with dronedarone use of voriconazole (a strong inhibitor of the isoenzyme CYP3A4).

    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 and possible pharmacodynamic interactions, 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.

    Diltiazem is a substrate and a moderate inhibitor of the isoenzyme CYP3A4. Furthermore, diltiazem, which reduces the heart rate, has the potential for pharmacodynamic interaction with dronedarone.

    Dronedarone inhibits P-glycoprotein and, possibly, its interaction with doxorubicin (P-glycoprotein substrate), which leads to an increase in the concentration of doxorubicin in the blood serum and an increase in its pharmacodynamic and toxic side effects.

    It is not recommended simultaneous use of dronedarone and drugs containing St. John's wort (the inductors of the isoenzyme CYP3A4), as they reduce the systemic exposure of dronedarone.

    Contraindicated with dronedarone application of itraconazole and / or clarithromycin (strong inhibitors of the isoenzyme CYP3A4).

    It is not recommended simultaneous application of dronedarone and carbamazepine (inductor of isoenzyme CYP3A4), since carbamazepine reduces the system exposure of dronedarone.

    The course of 200 mg of ketoconazole (a strong inhibitor of the isoenzyme CYP3A4) a day caused a 17-fold increase in the systemic exposure of dronedarone. Therefore, the use of ketoconazole, concurrent with dronedarone, is contraindicated.

    Dronedarone may increase the systemic exposure of metoprolol, metabolized by the CYP2D6 isoenzyme. Moreover, in metoprolol there is a potential possibility of pharmacodynamic interaction with dronedarone. Dronedaron in a dose of 800 mg per day increased the system exposure of metoprolol by 1.6 times. It is recommended to use caution metoprolol together with dronedarone because of pharmacokinetic and possible pharmacodynamic interaction (risk of summation of inhibitory effect on sinus and AV-nodes). To start treatment with metoprolol it is necessary from low doses and to increase their dose only under the control of an electrocardiogram. Patients who are already receiving metoprolol, the addition of dronedarone should be performed under ECG monitoring and, if necessary, adjust the dose of metoprolol.

    Nifedipine is a substrate of the isoenzyme CYP3A4. Furthermore, nifedipine, which reduces the heart rate, has the potential for pharmacodynamic interaction with dronedarone.

    Pacireotid should be used with caution at the same time as dronedarone, which can prolong the QT interval.

    Contraindicated with dronedarone application of ritonavir (a strong inhibitor of the isoenzyme CYP3A4).

    Rifampicin (inducer of the isoenzyme CYP3A4) (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 dronedarone and rifampicin is not recommended.

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

    Dronedarone inhibits P-glycoprotein and, possibly, its interaction with talinolol (P-glycoprotein substrate), which leads to an increase in the concentration of talinolol in the blood serum and an increase in its pharmacodynamic and toxic side effects.

    Terfenadine and cisapride may cause prolongation of the QT interval and / or development of paroxysmal tachycardia, including ventricular tachycardia such as pirouette. Simultaneous reception together with dronedaron is contraindicated (there is a potential risk of proarrhythmogenic action).

    Dronedarone inhibits P-glycoprotein and, possibly, its interaction with fexofenadine (P-glycoprotein substrate), leading to an increase in fexofenadine concentration in the serum and an increase in its pharmacodynamic and toxic side effects.

    It is not recommended simultaneous application of dronedarone and phenytoin, phenobarbital (inducers of the isoenzyme CYP3A4), as they reduce the systemic exposure of dronedarone.

    Special instructions:

    Patients should be warned that if they develop symptoms or symptoms of chronic heart failure, such as weight gain, peripheral edema, or dyspnoea, they should immediately consult their doctor.

    Since in patients with hypokalemia, antiarrhythmic agents may be ineffective and even cause arrhythmias, any degree of deficiency of potassium or magnesium ions should be adjusted before and during treatment with the drug.

    After the initiation of dronedarone, the plasma concentration of creatinine increases by an average of 0.1 mg / dL. Its increase occurs immediately at the beginning of treatment, reaches a plateau by the 7th day and is reversible after discontinuation of the drug. In the event that during this time when dronedarone is taken, an increase in the creatinine concentration and then its release to the plateau, this value of the creatinine concentration should be considered a new initial value for comparison with the 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 serve as a basis for the withdrawal of ACE inhibitors and angiotensin II receptor antagonists if the patient needs their admission.

    Elongation of the QT interval. The pharmacological action of dronedarone can cause changes in the ECG, such as a moderate prolongation of the QT interval (associated with an extension of the repolarization period). These changes are associated with the therapeutic effect of dronedarone and are not a sign of toxic effects.During treatment, the drug recommended monitoring, including ECG monitoring. If the duration of the QTc interval is ≥ 500 ms, dronedarone should be discontinued.

    Instructions
    Up