MULTAQ - PACKAGE LEAFLET - LEAFLETS

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Multaq - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf Life and Storage

Active ingredients: Dronedarone

MULTAQ 400 mg film-coated tablets

Why is Multaq used? What is it for?

MULTAQ contains an active substance called dronedarone. It belongs to a group of medicines called antiarrhythmics that help regulate the heartbeat.

MULTAQ is used if you have a heartbeat problem such as heart beating with an irregular rhythm (atrial fibrillation) and a treatment called cardioversion has brought your heart rate back to normal.

MULTAQ prevents the recurrence of the problem of irregular heartbeats. Your doctor will consider all available treatment options before prescribing MULTAQ.

Contraindications When Multaq should not be used

Do not take MULTAQ:

if you are allergic to dronedarone or any of the other ingredients of this medicine
if you have a problem affecting the nerves of the heart (heart block). Your heart may beat very slowly or you may feel dizzy. If you have been implanted with a pacemaker for this type of problem, you can take MULTAQ
if you have a very slow heart rate (less than 50 beats per minute),
and the "EKG (electrocardiogram) showed a heart problem called" elongated QTc interval "(this interval is greater than 500 milliseconds)
if you have a type of atrial fibrillation (AF) called permanent atrial fibrillation. In permanent atrial fibrillation, AF has been present for a long time (at least 6 months) and the doctor has decided not to restore the heart rhythm to normal atrial rhythm with a treatment called cardioversion
if you have or have had a problem that prevents your heart from pumping blood around your body as it should (a condition called heart failure). You may experience swelling in your feet or legs, breathing problems when lying down or sleeping, or shortness of breath when moving
if the percentage of blood that pumps the heart each time it contracts is too low (a condition called left ventricular dysfunction)
if you have taken amiodarone (another antiarrhythmic medicine) previously and have had lung or liver problems
if you are taking medicines for an "infection (including fungal infections or AIDS), for allergies, for problems with your heart beat, for depression or after a transplant (see" Other medicines and MULTAQ "below. will allow you to get more details on the type of medicines you cannot take together with MULTAQ)
if you have a severe liver problem
if you have a severe kidney problem
if you take dabigatran (see section below "Other medicines and MULTAQ").

If any of the above apply to you, do not take MULTAQ.

Precautions for use What you need to know before you take Multaq

Talk to your doctor or pharmacist before taking MUTAQ if:

have a problem that causes low levels of potassium or magnesium in the blood. This problem must be corrected before starting treatment with MULTAQ
is over 75 years old
have a condition where the coronaries that supply blood to the heart harden and shrink in width (coronary artery disease).

While you are being treated with MULTAQ, tell your doctor if

atrial fibrillation becomes permanent while you are taking MULTAQ. You must stop taking MULTAQ
suffer from swelling of the feet or legs, trouble breathing when lying down or sleeping, shortness of breath when moving or weight gain (which are signs and symptoms of heart failure)
tell your doctor immediately if you develop any of these signs and symptoms of liver problems: stomach (abdominal) pain or discomfort, loss of appetite, nausea, vomiting, yellowing of the skin or whites of the eyes (jaundice), unusual color dark urine, fatigue (especially in association with the other symptoms described above), itching
you have shortness of breath or a dry cough. Tell your doctor who will check your lungs.

If any of the above apply to you (or if you are not sure), talk to your doctor or pharmacist before taking MULTAQ.

Heart, lung and blood tests

Your doctor may carry out tests while you are taking MULTAQ to check your health condition and how the medicine works for you.

The doctor can check the electrical activity of the heart with an ECG (electrocardiogram).
Your doctor will order blood tests to check your liver function before you start taking MULTAQ and during therapy.
If you are taking certain medicines that prevent blood clots such as warfarin, your doctor will order a blood test called INR to check if the medicine is working well
The doctor may also perform other blood tests. The results of one of the blood tests to check kidney function (creatinine levels in the blood) may change following the administration of MULTAQ. Your doctor will take this into account when checking your blood tests and will use another benchmark of "normal" blood creatinine levels.
Your doctor might perform a clinical evaluation of your lungs.

In some cases it may be necessary to discontinue MULTAQ therapy.

Tell any person who checks blood tests that they are taking MULTAQ.

Children and adolescents

MULTAQ is not recommended for children and adolescents under 18 years of age.

Interactions Which drugs or foods may change the effect of Multaq

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Depending on your condition, your doctor may recommend the use of a medicine against the formation of blood clots (anticoagulant).

MULTAQ and some other medicines can interact with each other and cause serious side effects. Your doctor may decide to change the dose of any other medicines you are taking.

You should not take any of the following medicines together with MULTAQ:

other medicines used to control irregular or fast heartbeat such as flecainamide, propafenone, quinidine, disopyramide, dofetilide, sotalol, amiodarone
some medicines used to treat fungal infections such as ketoconazole, voricanozole, itraconazole or posaconazole
some medicines for depression called tricyclic antidepressants
some tranquilizing medicines called phenothiazines
bepridil for chest pain caused by heart disease
telithromycin, erythromycin or clarithromycin (antibiotics for infections)
terfenadine (an allergy medicine)
nefazodone (a medicine for depression)
cisapride (a medicine for the regurgitation of food or acidic fluid from the stomach into the mouth)
ritonavir (an AIDS medicine)
dabigatran (a medicine to prevent blood clots).

You should tell your doctor or pharmacist if you are taking any of the following medicines:

other medicines used for high blood pressure, chest pains caused by heart disease or other heart problems, such as verapamil, diltiazem, nifedipine, metoprolol, propranolol, or digoxin
some medicines used to lower blood cholesterol levels (such as simvastatin, lovastatin, atorvastatin or rosuvastatin)
some medicines against blood clot formation, such as warfarin
some medicines for epilepsy called phenobarbital, carbamazepine or phenytoin
sirolimus, tacrolimus, everolimus and cyclosporine (used after a transplant)
St. John's wort (St. John's wort) - a herbal medicine for depression
rifampicin - for tuberculosis.

MULTAQ with food and drink

Do not drink grapefruit juice while taking MULTAQ. This drink can increase the levels of dronedarone in your blood and the likelihood of having side effects.

Warnings It is important to know that:

Pregnancy and breastfeeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.

MULTAQ is not recommended if you are pregnant or believe you are pregnant.
Do not take MULTAQ if you are a woman who can have children and you are not using effective contraception.
Stop taking the tablets and consult your doctor immediately if you become pregnant while taking MULTAQ.
If you are a mother who is breastfeeding a baby, it is recommended that you consult your doctor before taking MULTAQ.

Driving and using machines

MULTAQ does not usually affect the ability to drive or use machines. However, your ability to drive and use machines can be impaired by undesirable effects such as fatigue (if any).

MULTAQ contains lactose

Lactose is a type of sugar. If you have been told by your doctor that you have an "intolerance to some types of sugars, contact your doctor before taking this medicine.

Dosage and method of use How to use Multaq: Dosage

Treatment with MULTAQ will be under the supervision of a physician experienced in the treatment of heart disease.

Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.

If you need to switch from amiodarone (another drug for irregular heartbeat) to MULTAQ, your doctor will handle that change with caution.

How much medicine to take

The usual dose is one 400 mg tablet twice a day. Take:

one tablet during breakfast e
one tablet during dinner.

If you think the effect of the medicine is too strong or too weak, please tell your doctor or pharmacist.

How to take this medicine

Swallow the tablet whole with a drink of water during a meal. The tablet must not be divided into equal doses.

If you forget to take MULTAQ

Do not take a double dose to make up for a forgotten tablet. Take your next dose at the time of day you usually take it.

If you stop taking MULTAQ

Do not stop taking this medicine without first checking with your doctor or pharmacist.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Overdose What to do if you have taken too much Multaq

Contact your doctor or the nearest emergency department or hospital immediately. Take the medicine pack with you.

Side Effects What are the side effects of Multaq

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The following side effects have been reported with the use of this medicine: Tell your doctor immediately, if you notice any of the following serious side effects - you may need urgent medical help

Very common (affects more than 1 in 10 patients)

ailment caused by the heart not pumping the blood around the body properly as it should (congestive heart failure). In clinical studies, this side effect was observed with similar frequency in patients treated with MULTAQ and in untreated patients. Signs of the disorder include swelling of the feet or legs, trouble breathing when lying down or sleeping, shortness of breath while moving, or weight gain.

Common (affects up to 1 in 10 patients)

Diarrhea, vomiting when excessive as it can lead to kidney problems.
Slow heartbeat.

Uncommon (affects up to 1 in 100 patients)

Inflammation of the lungs (including scarring and thickening of the lungs). The signs include shortness of breath or an unproductive cough.

Rare (affects up to 1 in 1,000 patients)

Liver problems, including life-threatening liver failure condition. The signs include stomach (abdominal area) pain or discomfort, loss of appetite, nausea, vomiting, yellowing of the skin or whites of the eyes (jaundice), abnormal darkening of the urine, tiredness (especially in association with other symptoms listed above) , itch.
Allergic reactions, including swelling of the face, lips, mouth, tongue or throat.

Other side effects include:

Very common (affects more than 1 in 10 patients)

changes in the results of a blood test: your blood creatinine levels
changes in the ECG (electrocardiogram), called prolonged QTc according to Bazett.

Common (affects up to 1 in 10 patients)

digestive problems such as diarrhea, nausea, vomiting and stomach pain
feeling tired
skin problems such as rash or itching
changes in the results of blood tests used to check liver function.

Uncommon (affects up to 1 in 100 patients)

other skin problems such as redness of the skin or eczema (redness, itching, burning or blistering)
skin more sensitive to the sun
change in taste.

Rare (affects up to 1 in 1,000 patients)

loss of taste
inflammation of blood vessels (vasculitis including leukocytoclastic vasculitis).

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

You can also report side effects directly via the national reporting system.

By reporting side effects you can help provide more information on the safety of this medicine

Expiry and Retention

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the blister and carton after "EXP". The expiry date refers to the last day of the month indicated.

This medicine does not require any special storage conditions.

Do not use this medicine if you notice visible signs of deterioration (see section 6 "Description of what MULTAQ looks like and contents of the pack").

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Other Information

What MULTAQ contains

The active ingredient is dronedarone. Each film-coated tablet contains 400 mg of dronedarone (as hydrochloride).
The other ingredients contained in the tablet core are: hypromellose (E464), maize starch, crospovidone (E1202), poloxamer 407, lactose monohydrate, colloidal anhydrous silica, magnesium stearate (E572).
The other ingredients contained in the tablet coating are: hypromellose (E464), macrogol 6000, titanium dioxide (E171), carnauba wax (E903).

Description of what MULTAQ looks like and contents of the package

MULTAQ is a white, oval, film-coated tablet (tablet) debossed with a double wave on one side and the number "4142" on the other side.

MULTAQ film-coated tablets are supplied in opaque PVC and aluminum blister packs of 20, 50, 60 tablets and in packs of 100x1 tablets in opaque PVC and aluminum perforated unit dose blisters.

Not all pack sizes may be marketed.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Multaq can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, ADDITIONAL DETAILED INSTRUCTIONS ON ESTEMPORANEA PREPARATION AND CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

MULTAQ 400 MG TABLETS COATED WITH FILM

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 400 mg of dronedarone (as hydrochloride).

Excipients with known effects:

Each tablet also contains 41.65 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Film-coated tablet (tablet).

White, oblong tablets engraved with a double wave on one side and the number "4142" on the other side.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

MULTAQ is indicated for the maintenance of sinus rhythm following successful cardioversion in clinically stable adult patients with paroxysmal or persistent atrial fibrillation (AF). Given its safety profile (see sections 4.3 and 4.4), MULTAQ should only be prescribed after alternative treatment options have been evaluated.

MULTAQ should not be administered to patients with left ventricular systolic dysfunction or to patients with previous or current heart failure.

04.2 Posology and method of administration

Treatment with MULTAQ should only be initiated and monitored under the supervision of a specialist doctor (see section 4.4).

Treatment with MULTAQ can be initiated in an outpatient setting.

Treatment with class I or III antiarrhythmic drugs (such as flecainide, propafenone, quinidine, disopyramide, dofetilide, sotalol, amiodarone) should be stopped before starting treatment with MULTAQ.

There is limited information on the optimal timing to switch from amiodarone to MULTAQ. It must be considered that amiodarone may have a long duration of action after its discontinuation due to the long half-life. If a switch is planned, this should be done under the supervision of a specialist doctor (see sections 4.3 and 5.1).

Dosage

In adults, the recommended dose is 400 mg twice a day. It is recommended to take

• one tablet during breakfast e

• one tablet during dinner

Grapefruit juice should not be taken at the same time as MULTAQ (see section 4.5).

If a dose is missed, the patient should take the next dose at the usual time of day and should not take a double dose.

Pediatric population

The safety and efficacy of MULTAQ in children under 18 years of age have not yet been established. There are no data available.

Senior citizens

The efficacy and safety of the medicinal product were comparable in elderly patients who did not suffer from other cardiovascular disorders and in younger patients. Care should be taken in patients ≥ 75 years when co-morbidities are present (see sections 4.3, 4.4 and 5.1) Although plasma exposure in elderly female subjects was higher in a pharmacokinetic study in healthy subjects, dose adjustment is not considered necessary (see sections 5.1 and 5.2).

Hepatic insufficiency

Due to lack of data, MULTAQ is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 4.4). No dose adjustment is required in patients with mild or moderate hepatic impairment (see section 5.2).

Kidney failure

MULTAQ is contraindicated in patients with severe renal insufficiency (creatinine clearance (CrCl)

Method of administration

Oral use

It is recommended that the tablet be swallowed whole with a glass of water during a meal. The tablet cannot be divided into equal doses.

04.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• Second or third degree atrioventricular block, complete branch block, distal block, sinus node dysfunction, atrial conduction defects, or sinus node disease (unless the medicine is used in combination with a pacemaker working).

• Bradycardia beats per minute (bpm)

• Permanent atrial fibrillation (AF duration ≥ 6 months or not known) and attempts to restore sinus rhythm no longer considered feasible by the physician

• Unstable hemodynamic conditions

• Previous or current heart failure, or left ventricular systolic dysfunction

• Liver and lung toxicity related to previous use of amiodarone

• Co-administration of potent cytochrome P 450 (CYP) 3A4 inhibitors such as ketoconazole, itraconazole, voriconazole, posaconazole, telithromycin, clarithromycin, nefazodone and ritonavir (see section 4.5)

• Medicines capable of inducing "torsades de pointes" such as phenothiazine, cisapride, bepridil, tricyclic antidepressants, terfenadine and some oral macrolides (such as erythromycin), class I and III antiarrhythmic drugs (see section 4.5)

• QTc interval (Bazett's formula) ≥ 500 milliseconds

• Severe hepatic insufficiency

• Severe renal insufficiency (CrCl

• Co-administration of dabigatran

04.4 Special warnings and appropriate precautions for use

Close monitoring is recommended during dronedarone administration through periodic evaluation of cardiac, liver and lung function (see below). If atrial fibrillation recurs, discontinuation of dronedarone should be considered. Dronedarone treatment should be discontinued if the patient develops any of the conditions that may lead to any of the contraindications mentioned in section 4.3. Co-administration of drugs such as digoxin and anticoagulants should be monitored.

Patients who develop permanent atrial fibrillation during treatment

A clinical study in patients with permanent atrial fibrillation (duration of atrial fibrillation of at least 6 months) and with cardiovascular risk factors was terminated prematurely due to an excess of deaths related to cardiovascular causes, stroke and heart failure in patients who received MULTAQ (see section 5.1). It is recommended that ECG be performed periodically, at least every 6 months. If patients treated with MULTAQ develop permanent atrial fibrillation, treatment with MULTAQ should be discontinued.

Patients with previous or current heart failure, or left ventricular systolic dysfunction.

MULTAQ is contraindicated in patients with haemodynamically unstable conditions, with previous or current heart failure, or left ventricular systolic dysfunction (see section 4.3).

Patients should be carefully evaluated for symptoms of congestive heart failure. New onset or worsening heart failure episodes have been spontaneously reported during treatment with MULTAQ. Patients should be advised to consult their physician if they develop or experience signs or symptoms of heart failure, such as weight gain, heart failure-dependent edema, or increased dyspnoea. If heart failure develops, treatment with MULTAQ should be interrupted.

Patients should be monitored for the development of left ventricular systolic dysfunction during treatment. If left ventricular systolic dysfunction occurs, treatment with MULTAQ should be discontinued.

Patients with coronary artery disease

Caution is needed in patients with coronary artery disease.

Senior citizens

Caution is needed in elderly patients ≥ 75 years with multiple co-morbidities (See sections 4.2 and 5.1).

Liver damage

Cases of hepatocellular injury, including life-threatening acute liver failure, have been reported in patients treated with MULTAQ after its marketing. Liver function tests should be performed before starting dronedarone treatment, after one week and after one week. month from the beginning of the treatment and then repeated monthly for six months, at the 9th and 12th month and thereafter periodically.

If alanine aminotransferase (ALT) levels are equal to or greater than 3 times the upper limit of normal (ULN), ALT levels should be remeasured within 48 to 72 hours. If ALT levels are confirmed to be 3 x ULN or greater, dronedarone treatment should be discontinued.

Appropriate investigation and careful observation of patients should continue until ALT levels normalize.

Patients should immediately report any symptoms of potential liver damage (such as new onset severe abdominal pain, anorexia, nausea, vomiting, fever, malaise, fatigue, jaundice, dark colored urine or itching) to their physician.

Management of the "increase in blood creatinine

An increase in serum creatinine (mean increase 10 μmol / L) was observed in healthy subjects and patients following administration of dronedarone 400 mg twice daily. In most patients, this increase occurs soon after initiation of therapy and reaches a plateau after 7 days. It is recommended that plasma creatinine values be measured before and 7 days after starting dronedarone therapy. If an increase in serum creatinine is observed, serum creatinine should be re-measured after a further 7 days.If no further increase in serum creatinine is observed, this value should be used as a new starting reference value taking into account that this increase could be expected after administration of dronedarone. If serum creatinine continues to rise then further investigation and discontinuation of treatment should be considered.

An increase in blood creatinine need not necessarily lead to discontinuation of treatment with ACE inhibitors or Angiotensin II receptor antagonists (sartans).

Greater increases in creatinine levels after initiation of dronedarone therapy have been reported after its marketing. Some cases also report an increase in blood urea nitrogen possibly due to hypoperfusion secondary to the development of congestive heart failure (pre-stage blood urea nitrogen). renal). In such cases dronedarone should be discontinued (see sections 4.3 and 4.4). It is recommended that renal function be monitored periodically and that further investigations be considered if necessary.

Electrolyte imbalance

Since antiarrhythmic drugs may be ineffective or arrhythmogenic in patients with hypokalaemia, any potassium or magnesium deficiency should be corrected before initiation and during treatment with dronedarone.

Elongation of the QT segment

The pharmacological activity of dronedarone can induce a moderate lengthening of the QTc calculated with Bazett's formula (about 10 milliseconds) related to prolonged repolarization. These variations are related to the therapeutic effect of dronedarone and do not reflect its toxicity. Follow-up, including ECG (electrocardiogram), is recommended during treatment. Dronedarone treatment should be discontinued if QTc interval (Bazett's formula) is ≥ 500 milliseconds (see section 4.3).

Based on clinical experience, dronedarone demonstrated a low proarrhythmic effect and a reduction in arrhythmic death in the ATHENA study (see section 5.1).

However, proarrhythmic effects may occur in particular situations such as with concomitant use of medicinal products that promote arrhythmia and / or electrolyte disturbances (see sections 4.4 and 4.5).

Respiratory, thoracic and mediastinal disorders

Cases of interstitial lung disease including pneumonia and pulmonary fibrosis have been reported in post-marketing experience. The occurrence of dyspnoea or non-productive cough may be related to pulmonary toxicity and patients should be carefully evaluated clinically. pulmonary toxicity is confirmed treatment should be discontinued.

Interactions (see section 4.5)

Digoxin.

Administration of dronedarone to patients on digoxin therapy may lead to increased plasma digoxin concentrations and thereby worsen the symptoms and signs associated with digoxin toxicity.

Clinical, biological and ECG monitoring is recommended and the dose of digoxin be halved. In addition, a synergistic effect on heart rate and atrioventricular conduction may occur.

The co-administration of beta blockers or calcium channel blockers which have a depressive effect on the sinus node and the atrioventricular node should be undertaken with caution. These medicinal products should be administered initially in low doses and the dosage increase should only be decided after evaluation by ECG. It is recommended that ECG be performed and the dosage adjusted if necessary in patients already receiving calcium channel blockers or beta blockers before starting dronedarone treatment.

Anticoagulants

Patients should be appropriately treated with anticoagulant therapy as indicated by clinical guidelines for the treatment of AF. The International Normalized Ratio (INR) should be closely monitored following the initiation of dronedarone therapy in patients taking vitamin K antagonists, as indicated in the printed matter for these products.

The use of inductors is not recommended potent CYP 3A4 such as rifampicin, phenobarbital, carbamazepine, phenytoin or St. John's wort (St. John's wort).

Monoamine oxidase (MAO) inhibitors may reduce the clearance of the active metabolite of dronedarone and therefore should be used with caution.

Statins must be used with caution. Lower starting and maintenance doses for statins should be considered and patients should be monitored for clinical signs of muscle toxicity.

Patients should be advised to avoid drinks containing grapefruit juice while administering dronedarone.

Lactose

This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicine.

04.5 Interactions with other medicinal products and other forms of interaction

Dronedarone is mainly metabolised by CYP 3A4 (see section 5.2). Therefore, CPY 3A4 inhibitors and inducers can interact with dronedarone.

Dronedarone is a moderate inhibitor of CYP 3A4, CYP 2D6 and a potent inhibitor of Pglycoproteins (P-gp). Therefore, dronedarone may interact with medicinal products that are substrates of Pgp, CYP 3A4 or CYP 2D6. Dronedarone and / or its metabolites have also been shown in vitro to inhibit transport proteins belonging to the families of Organic Anion Transporters (OAT), Organic Anion Transport Polypeptides (OATP) and Organic Cation Transporters (OCT).

Dronedarone has no significant potential effect on the inhibition of substrates CYP 1A2, CYP 2C9, CYP 2C19, CYP 2C8 and CYP 2B6.

A potential pharmacodynamic interaction with beta-blockers, calcium channel blockers and digitalis can also be expected.

Medicines capable of inducing "torsades de pointes"

Medicines capable of inducing "torsades de pointes" such as phenothiazines, cisapride, bepridil, tricyclic antidepressants, some oral macrolides (such as erythromycin), terfenadine and class I or III antiarrhythmic drugs are contraindicated due to the potential risk of developing proarrhythmia (see paragraph 4.3). Caution should be exercised when co-administering beta-blockers or digitalis.

Effect of other medicinal products on MULTAQ

Strong CYP 3A4 inhibitors

Repeated daily doses of 200 mg ketoconazole resulted in a 17-fold increase in dronedarone exposure. Therefore, concomitant use of ketoconazole and other potent CYP 3A4 inhibitors such as itraconazole, voriconazole, posaconazole, ritonavir, telithromycin, clarithromycin or nefazodone is contraindicated (see section 4.3).

Moderate / weak inhibitors of CYP 3A4

• Erythromycin

Erythromycin, an oral macrolide, can induce torsades de pointes and, as such, is contraindicated (see section 4.3). Repeated doses of erythromycin (500 mg three times daily for 10 days) resulted in increased exposure to dronedarone at steady state by 3.8 times.

• Calcium antagonists

The calcium channel blockers, diltiazem and verapamil, are moderate substrates and / or inhibitors of CYP 3A4. Furthermore, in consideration of their bradycardising action, verapamil and diltiazem can 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 times respectively. Dronedarone (400 mg twice daily) also resulted in increased exposure to calcium channel blockers (verapamil 1.4 times and nisoldipine 1.5 times). In clinical trials, 13% of patients received calcium channel blockers in combination with dronedarone There was no increased risk of hypotension, bradycardia and heart failure.

In general, due to pharmacokinetic interactions and possible pharmacodynamic interactions, sinus node and atrioventricular node depressant calcium channel blockers such as verapamil and diltiazem should be used with caution when administered in combination with dronedarone. These medicinal products should be given initially in low doses and dose escalation should only be done after evaluation by ECG. It is recommended that an ECG be performed and the calcium channel blocker dose adjusted if necessary in patients already undergoing calcium treatment. antagonists prior to initiation of dronedarone therapy (see section 4.4).

• Other weak / moderate CYP 3A4 inhibitors

Other moderate CYP3A4 inhibitors are also likely to increase dronedarone exposure.

Inducers of CYP 3A4

Rifampicin (600 mg once daily) reduces dronedarone exposure by 80% without substantially changing exposure to its active metabolite. Therefore, co-administration of rifampicin and other potent CYP 3A4 inducers such as phenobarbital, carbamazepine , phenytoin or St. John's wort is not recommended as they reduce exposure to dronedarone.

MAO inhibitors

In a studio in vitro MAOs contributed to the metabolism of the active metabolite of dronedarone.

The clinical relevance of this observation is unknown (see sections 4.4 and 5.2).

Effect of MULTAQ on other medicinal products

Interactions with medicinal products metabolised by CYP 3A4

• Statins

Dronedarone may increase the exposure of statins which are substrates of CYP 3A4 and / or P-gp.

Dronedarone (400 mg twice daily) increases exposure to simvastatin and simvastatin acid 4-fold and 2-fold, respectively. Dronedarone is also expected to increase lovastatin exposure within the same range as simvastatin acid. A weak interaction was observed between dronedarone and atorvastatin (resulting in a 1.7-fold increase in mean exposure to atorvastatin). A weak interaction was observed between dronedarone and statins carried by OATP, such as rovustatin (resulting in an average 1.4-fold increase in rovustatin exposure).

Clinical studies revealed no safety concerns when dronedarone was administered in combination with statins metabolised by CYP 3A4. However, cases of rhabdomyolysis have been spontaneously reported when dronedarone was administered in combination with a statin (particularly simvastatin) and, consequently, concomitant use of statins should be undertaken with caution.

Lower starting and maintenance doses should be considered in accordance with the SmPC of the individual statins and patients should be monitored for clinical signs of muscle toxicity (see section 4.4).

• Calcium antagonists

The interaction of dronedarone with calcium channel blockers is described above (see section 4.4).

• Immunosuppressants

Dronedarone may increase the plasma concentrations of immunosuppressants (tacrolimus, sirolimus, everolimus and cyclosporine). Monitoring of plasma concentrations and appropriate dosage adjustment is recommended when co-administered with dronedarone.

• Oral contraceptives

No reductions in ethinylestradiol and levonorgestrel levels were observed in healthy subjects receiving dronedarone (800 mg twice daily) in combination with oral contraceptives.

Interactions with medicinal products metabolised by CYP 2D6: beta blockers, antidepressants

• Beta blockers

Sotalol should be discontinued prior to initiating therapy with MULTAQ (see sections 4.3 and 4.4).

Exposure to beta-blockers that are metabolised by CYP 2D6 may be increased by dronedarone. Furthermore, beta-blockers may interact with dronedarone from a pharmacodynamic point of view. Dronedarone, given at a dose of 800 mg per day, increases exposure. 1.6-fold metoprolol and 1.3-fold propranolol (i.e. much less than the 6-fold difference observed between poor metabolisers and extensive metabolisers of CYP 2D6). Episodes of bradycardia were observed more frequently in clinical trials when dronedarone was given in combination with beta-blockers.

Due to pharmacokinetic interactions and possible pharmacodynamic interactions, beta-blockers should be used with caution when administered in combination with dronedarone. These medicinal products should be given initially in low doses and dose escalation should only be done after evaluation by ECG. It is recommended to perform an ECG and adjust the dosage of beta blockers, if necessary, in patients already on beta treatment. blockers prior to initiation of dronedarone therapy (see section 4.4).

• Antidepressants

Since dronedarone is a weak inhibitor of CYP 2D6 in humans, it is assumed that the interaction with antidepressant drugs metabolised by CYP 2D6 is limited.

P-gp substrate interactions

• Digoxin

Dronedarone (400 mg twice daily) increases digoxin exposure by 2.5 times by inhibiting P-gp transport function. In addition, digitalis can interact with dronedarone from a pharmacodynamic point of view. It may be found. a synergistic effect on heart rate and atrioventricular conduction. In clinical studies, increased levels of digitalis and / or gastrointestinal disturbances indicators of digitalis toxicity have been observed when dronedarone was given in combination with digitalis.

It is recommended to reduce digoxin dosage by approximately 50%, to closely monitor serum digoxin levels, and to perform clinical and ECG monitoring.

• Dabigatran

When dabigatran etexilate 150 mg once daily was co-administered with dronedarone 400 mg twice daily, dabigatran AUC 0-24 and Cmax increased by 100% and 70%, respectively. No clinical data are available for Concerning the co-administration of these medicinal products in patients with atrial fibrillation Co-administration is contraindicated (see section 4.3).

Interactions with warfarin and losartan (CYP 2C9 substrates)

• Warfarin and other vitamin K antagonists

Dronedarone (600 mg twice daily) increases S-warfarin exposure by 1.2-fold with no changes in R-warfarin and with only an increase in International Normalized Ratio (INR) of only 1.07. times.

However, a clinically significant rise in the INR (≥ 5), usually within 1 week of initiation of dronedarone therapy, has been reported in patients taking oral anticoagulants. Consequently, INR should be closely monitored after initiation of dronedarone therapy in patients treated with vitamin K antagonists in accordance with approved literature.

• Losartan and other AIIRAs (Angiotensin-II Receptor Antagonists)

No interactions were observed between dronedarone and losartan and no interactions are expected between dronedarone and other AIIRAs.

Interactions with theophylline (CYP 1A2 substrate)

Dronedarone given at 400 mg twice daily does not increase steady-state exposure to theophylline.

Interactions with metformin (substate of OCT1 and OCT2)

No interaction was observed between dronedarone and metformin, a substrate of OCT1 and OCT2.

Interactions with omeprazole (substrate of cytochrome CYP 2C19)

Dronedarone does not affect the pharmacokinetics of omeprazole, a substrate of cytochrome CYP 2C19.

Interactions with clopidogrel

Dronedarone does not affect the pharmacokinetics of clopidogrel and its active metabolite.

Other information

Pantoprazole (40 mg once daily), a drug that increases gastric pH without exerting any effect on CYP, does not significantly interact with dronedarone pharmacokinetics.

Grapefruit juice (CYP 3A4 inhibitor)

Repeated doses of 300 ml of grapefruit juice three times a day increased dronedarone exposure 3-fold. Therefore, patients should be advised to avoid grapefruit juice drinks when administering dronedarone (see section 4.4). .

04.6 Pregnancy and breastfeeding

Women of childbearing age and Pregnancy

Data on the use of dronedarone in pregnant women do not exist or are limited in number.

Animal studies have shown reproductive toxicity (see section 5.3).

MULTAQ is not recommended during pregnancy and in women of childbearing potential who are not using contraceptive measures.

Feeding time

It is unknown whether dronedarone and its metabolites are excreted in milk. Available pharmacodynamic / toxicological data in animals have shown excretion of dronedarone and its metabolites in milk. A risk to newborns / infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue / abstain from MULTAQ therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

Animal studies have shown no fertility impairments attributable to dronedarone.

04.7 Effects on ability to drive and use machines

Multaq has no or negligible influence on the ability to drive and use machines.

However, the ability to drive and use machines may be impaired by adverse reactions such as fatigue.

04.8 Undesirable effects

Summary of the safety profile

Assessment of intrinsic factors such as gender or age on the incidence of any adverse reactions that emerged during treatment showed an interaction with sex (female patients) for the incidence of any adverse reactions and serious adverse reactions.

In clinical trials, early discontinuation of treatment due to adverse reactions occurred in 11.8% of dronedarone-treated patients and 7.7% of the placebo-treated group. The most common reasons for discontinuing MULTAQ therapy were gastrointestinal disturbances (3.2% of dronedarone-treated patients versus 1.8% of placebo-treated patients).

The most frequently observed adverse reactions in the 5 studies performed with dronedarone at a dose of 400 mg twice daily were: diarrhea, nausea and vomiting, fatigue and asthenia.

Table of adverse reactions

The safety profile of dronedarone at a dose of 400 mg twice daily given to patients with atrial fibrillation (AF) or atrial flutter (FLA) is based on 5 placebo-controlled studies in which a total of 6,285 were randomized. patients (3,282 patients treated with dronedarone 400 mg twice daily and 2,875 patients treated with placebo). The mean exposure in the studies was 13 months. In the ATHENA study, the maximum follow-up was 30 months. Some adverse reactions were identified during post-marketing surveillance.

Adverse reactions are classified by systems and organs.

Frequencies are defined as follows: very common (≥1 / 10); common (≥1 / 100,

Table 1: Adverse reactions

System and organ classification Very common (≥1 / 10) Common (≥1 / 100, Uncommon (≥ 1 / 1,000 to Rare (≥ 1 / 10,000, Disorders of the immune system Anaphylactic reactions including angioedema Nervous system disorders Dysgeusia Ageusia Cardiac pathologies Congestive heart failure (see below) Bradycardia (see sections 4.3 and 4.4) Vascular pathologies Vasculitis, including leukocytoclastic vasculitis Respiratory, thoracic and mediastinal disorders Interstitial lung disease including pneumonia and pulmonary fibrosis (see below) Gastrointestinal disorders Diarrhea, vomiting, nausea, abdominal pain, dyspepsia Hepatobiliary disorders Abnormal liver function test results Hepatocellular injury, including life-threatening acute hepatic failure (see section 4.4) Skin and subcutaneous tissue disorders Skin rash (including generalized rash, macular rash, maculo-papular rash), pruritus Erythema (including erythema and erythematous rash), eczema, photosensitization, allergic dermatitis, dermatitis General disorders and administration site conditions Fatigue, asthenia Diagnostic tests Blood creatinine increased * QTc elongation ** (Bazett's formula)

* (≥ 10%) 5 days after initiation of therapy (see section 4.4)

** (> 450 ms. Male> 470 ms. Female) (see section 4.4)

Description of selected adverse reactions

In 5 placebo-controlled studies, congestive heart failure was found in the dronedarone group with a comparable incidence to the placebo group (very common, 11.2% versus 10.9%). This percentage should be considered in the context of the underlying high incidence of congestive heart failure in patients with atrial fibrillation. Cases of congestive heart failure have also been reported in post-marketing experience (frequency not known) (see section 4.4).

In 5 placebo-controlled studies, pulmonary events occurred in 0.6% of patients in the dronedarone group versus 0.8% of patients on placebo. Cases of interstitial lung disease including pneumonia and pulmonary fibrosis have been reported in post-marketing experience (frequency not known). A number of patients had previously been exposed to amiodarone (see section 4.4).

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions that occur after authorization of the medicine is important. It allows continuous monitoring of the benefit / risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "Annex V.

04.9 Overdose

It is not known whether dronedarone and / or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis or haemofiltration).

There is no specific antidote. In the event of an overdose, symptomatic supportive therapy aimed at relieving symptoms is recommended.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: cardiac therapy, class III antiarrhythmic.

ATC code: C01BD07.

Mechanism of action

In animals, dronedarone prevents atrial fibrillation or restores normal sinus rhythm depending on the model used. Dronedarone also prevents 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 which inhibits potassium currents (including IK (Ach), IKur, IKr, IKs) thereby prolonging the cardiac action potential and refractory periods (class III). It also inhibits sodium (class Ib) and calcium (class IV) currents. Dronedarone antagonizes adrenergic activity (class II) in a non-competitive way.

Pharmacodynamic properties

In animal models, dronedarone reduces heart rate. It prolongs the length of the Wenckebach cycle and the AH, -PQ and -QT intervals without producing a marked effect or causing a slight increase in the QTc-intervals and without changing the HV and -QRS intervals. Dronedarone increases the effective refractory periods (PRE) of the atrium, atrioventricular node and the ventricular PRE is slightly prolonged with a minimal degree of rate - inverse dependence.

Dronedarone reduces blood pressure and myocardial contractility (dP / dTmax) without changing the left ventricular ejection fraction and decreases myocardial oxygen consumption.

Dronedarone possesses vasodilating properties in the coronary arteries (related to the activation of the nitric oxide pathway) and in the peripheral arteries.

Dronedarone exhibits indirect antiadrenergic effects and partial antagonism to adrenergic stimulation. It reduces the pressure response of the alpha-adrenergic receptors to adrenaline and the responses of the beta1 and beta2 receptors to isoproterenol.

Clinical efficacy and safety

Reduction of the risk of AF-related hospitalization

The efficacy of dronedarone in reducing the risk of AF-related hospitalization was demonstrated in patients with AF or with a history of AF and with additional risk factors in the ATHENA study, a multicentre, multinational, double-blind, randomized, controlled study with placebo.

Patients were required to have at least one risk factor (including age, hypertension, diabetes, previous cerebrovascular event, left atrium diameter ≥ 50 mm or LVEF

Four thousand six hundred twenty-eight (4,628) patients were randomized and treated for up to 30 months (mean follow-up: 22 months) with either dronedarone, 400 mg twice daily (2,301 patients), or placebo (2,327 patients). ), as well as receiving conventional therapy that included beta-blockers (71%), ACE inhibitors or AIIRAs (69%), digitalis (14%), calcium channel blockers (14%), statins (39%), oral anticoagulants (60 %), chronic antiplatelet therapy (6%) and / or diuretics (54%).

The primary endpoint of the study was time to first hospitalization for cardiovascular reasons or death from any cause.

Patients were aged 23 to 97 years and 42% were over 75 years of age. Forty-seven percent (47%) of the patients were female and the majority were Caucasian (89%).

Most patients had hypertension (86%) and structural heart disease (60%) (including coronary heart disease: 30%; congestive heart failure (CHF): 30%; LVEF

Twenty-five percent (25%) of patients had atrial fibrillation at baseline.

Dronedarone reduced the incidence of cardiovascular hospitalization or death from any cause by 24.2% compared to placebo (p

The reduction in cardiovascular hospitalization or death from any cause was comparable in all subgroups, regardless of the initial characteristics or the drug administered (ACE inhibitors or AIIRAs; beta blockers, digitalis, statins, calcium channel blockers, diuretics).

Maintenance of sinus rhythm

In the EURIDIS and ADONIS studies, a total of 1,237 patients with a previous episode of AF or FLA were randomized in an outpatient setting and treated with either dronedarone 400 mg twice daily (n = 828) or placebo (n = 409) in addition to conventional therapies (including oral anticoagulants, beta blockers, ACE inhibitors or AIIRAs, antiplatelet agents used in chronic, diuretics, statins, digitalis and calcium channel blockers). Patients who had had at least one episode of AF / FLA documented by ECG during the past 3 months and who were in sinus rhythm for at least one "hour were monitored for 12 months. Patients on amiodarone were required to undergo ECG approximately 4 hours after the first administration of the drug to verify its good tolerability Other antiarrhythmic drugs had to be suspended for at least 5 plasma half-lives before the drug was administered for the first time.

The age of the patients ranged from 20 to 88 years, predominantly Caucasian (97%), male (69%). The most commonly observed co-morbidities were: hypertension (56.8%) and structural heart disease (41.5%) including coronary heart disease (21.8%).

Pooled data from the EURIDIS and ADONIS studies as well as those from the individual studies showed that dronedarone consistently delays the first relapse of AF / FLA (primary endpoint).

Dronedarone reduced the risk of first AF / FLA relapse during the 12-month study duration by 25% (p = 0.00007) compared to placebo. The median time from randomization to first AF / FLA relapse in the dronedarone group was 116 days, which is 2.2 times longer than that observed in the placebo group (53 days).

The DIONYSOS study compared the efficacy and safety of dronedarone (400 mg twice daily) versus amiodarone (600 mg daily for 28 days, and then 200 mg daily) over a 6-month period. total of 504 patients with documented AF, 249 treated with dronedarone and 255 treated with amiodarone. Patients were aged between 28 and 90 years, 49% were over 65 years. The incidence of the primary efficacy endpoint, defined as first AF relapse or premature discontinuation of study drug due to intolerance or lack of efficacy at 12 months, was 75% in the dronedarone group and 59% in the group. treated with amiodarone (hazard ratio = 1.59, log-rank p-value

AF relapses (including absence of cardioversion) were more frequent in the dronedarone group, while premature discontinuation of study drug due to intolerance was more frequent in the amiodarone group. The incidence of the main safety endpoint, defined as the occurrence of specific thyroid, hepatic, pulmonary, neurological, cutaneous, ocular or gastrointestinal events, or premature discontinuation of study drug following any adverse event, was reduced by 20% in the dronedarone group compared to the group treated with amiodarone (p = 0.129). This reduction was mainly due to the onset of fewer thyroid and neurological events, a tendency for fewer skin and eye disorders, and fewer premature discontinuation of study drug for adverse events compared to the group. treated with amiodarone.

More gastrointestinal adverse events, mainly diarrhea, were observed in the dronedarone group (12.9% vs 5.1%).

Patients with symptoms of heart failure at rest or with minimal exertion within the month prior to hospitalization, or patients hospitalized for heart failure during the month previous.

The ANDROMEDA study was conducted in 627 patients with left ventricular dysfunction, hospitalized with new or aggravated heart failure and who had at least one episode of dyspnoea with minimal exertion or at rest (NYHA class III or IV) or paroxysmal nocturnal dyspnea by the month prior to admission. Patients ranged in age from 27 to 96 years, 68% were over 65 years. The study was terminated prematurely due to an imbalance in the number of deaths observed in the dronedarone group [n = 25 versus 12 (placebo), p = 0.027] (see sections 4.3 and 4.4).

Patients with permanent atrial fibrillation:

The PALLAS study was a randomized placebo-controlled study, which evaluated the clinical benefit of dronedarone 400 mg BID as an adjunct to standard therapy in patients with permanent atrial fibrillation and additional risk factors (patients with congestive heart failure? 69%, coronary heart disease ? 41%, previous stroke or TIA? 27%, LVEF ≤ 40%? 20.7% and patients ≥ 75 years with hypertension and diabetes? 18%). The study was prematurely terminated after randomization of 3,149 patients (placebo = 1,577; dronedarone = 1,572) due to the significant increase in heart failure (placebo = 33; dronedarone = 80; HR = 2.49 (1.66-3, 74)]; of stroke [placebo = 8; dronedarone = 17; HR = 2.14 (0.92-4.96)] and cardiovascular-related deaths [placebo = 6; dronedarone = 15; HR = 2, 53 (0.98-6.53)] (see sections 4.3 and 4.4).

05.2 Pharmacokinetic properties

Absorption

After oral administration, in a fed state, dronedarone is well absorbed (at least 70%). However, the absolute bioavailability of dronedarone (administered with food) is 15% due to the drug's first pass metabolism. Concomitant food intake increases the bioavailability of dronedarone approximately 2-4 times. Peak plasma concentrations of dronedarone and the major circulating active metabolite (the N-debutyl metabolite) are reached within 3-6 hours following oral administration. Steady state is achieved within 4-8 days of treatment following repeated doses of 400 mg twice daily and the mean accumulation ratio of dronedarone ranges from 2.6 to 4.5. The mean Cmax of steady state dronedarone is 84-147 ng / ml and the exposure of the major metabolite N-debutyl is similar to that of the parent compound. Both the pharmacokinetics of dronedarone and that of its metabolite N-debutyl deviate moderately from dose proportionality: a 2-fold increase in dose results in an approximate 2.5-3.0-fold increase in Cmax and "AUC.

Distribution

In vitro, the plasma protein binding of dronedarone and its N-debutyl metabolite is 99.7% and 98.5%, respectively, and is not saturable. Both compounds bind primarily to albumin. The steady state volume of distribution (Vss) ranges from 1,200 to 1,400 L after intravenous (iv) administration.

Biotransformation

Dronedarone is extensively metabolised, mainly by CYP 3A4 (see section 4.5). The most important pathway of metabolism includes the N-debutylation process 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. MAOs contribute in part to the metabolism of the active metabolite of dronedarone (see section 4.5).

The N-debutyl metabolite exhibits a pharmacodynamic activity that is 3-10 times less potent than dronedarone. This metabolite contributes to the pharmacological activity of dronedarone in humans.

Elimination

After oral administration, approximately 6% of the radiolabelled dose is excreted in the urine mainly as metabolites (no compounds are excreted unchanged in the urine) and 84% is excreted in the faeces mainly as metabolites. The plasma clearance of dronedarone varies from 130 to 150 L / h following intravenous administration. The terminal elimination half-life of dronedarone is approximately 25-30 hours and that of its metabolite N-debutyl is around 20-25 hours. In patients, dronedarone and its metabolite are completely cleared from plasma within 2 weeks of stopping therapy at a dose of 400 mg twice daily.

Special populations

The pharmacokinetics of dronedarone in AF patients are comparable to that observed in healthy subjects. Gender, age and body weight are factors influencing the pharmacokinetics of dronedarone.

Each of these factors exerts a "limited influence on dronedarone.

Sex

In female patients, exposures to dronedarone and its metabolite N-debutyl are on average 1.3-1.9 times higher than in male patients.

Senior citizens

The total number of subjects participating in the dronedarone clinical trials consisted of 73% patients aged 65 years (and over) and 34% subjects aged 75 years (and over). Exposures to dronedarone were 23% higher in patients 65 years of age (and older) compared to patients younger than 65 years of age.

Hepatic insufficiency

In subjects with moderate hepatic impairment, exposure to the free fraction of dronedarone was increased by 2-fold; that of the active metabolite was reduced by 47% (see section 4.2).

The effect of severe hepatic impairment on dronedarone pharmacokinetics has not been evaluated (see section 4.3).

Kidney failure

The effect of renal impairment on dronedarone pharmacokinetics has not been evaluated in a specific study. Renal impairment is not expected to alter the pharmacokinetics of dronedarone as no unchanged compounds are excreted in the urine and only approximately 6% of the dose is excreted in the urine as metabolites (see section 4.2).

05.3 Preclinical safety data

Based on an in vivo mouse micronucleus test and four tests in vitro, dronedarone showed no genotoxic effects.

In the two-year carcinogenicity studies, the highest dose of dronedarone administered orally over a 24-month period was 70 mg / kg / day in the rat and 300 mg / kg / day in the rat. mouse.

An increased incidence of mammary gland tumors in female mice, histiocytic sarcoma in mice and haemangioma of the mesenteric lymph nodes in rats were observed only at the highest doses tested (corresponding to a 5-10 times greater exposure. compared to the therapeutic dose in humans).

Hemangiomas are not precancerous changes and do not evolve into malignant hemangiosarcomas either in animals or in humans. None of these observations were considered relevant to humans.

In chronic toxicity studies, reversible and mild phospholipidosis (accumulation of foamy macrophages) was observed in the mesenteric lymph nodes, mainly in the rat. This effect is considered species-specific and not relevant to humans.

Dronedarone caused marked effects on the embryo-fetal development of the rat following administration of high doses, such as increased post-implantation loss, decreased fetal and placental weight, and external, visceral and skeletal malformations.