Special Warning : אזהרת שימוש

4.4     Special warnings and precautions for use

Careful monitoring during dronedarone administration is recommended by regular assessment of cardiac, hepatic and pulmonary function (see below). If AF reoccurs discontinuation of dronedarone should be considered. Treatment with dronedarone should be stopped during the course of treatment, in case the patient develops any of the conditions which would lead to a contraindication as mentioned in section 4.3. Monitoring of co-administered medicinal products like digoxin and anti-coagulants is necessary.

Patients developing permanent AF during treatment
A clinical study in patients with permanent AF (AF duration for at least 6 months) and cardiovascular risk factors was stopped early due to an excess of cardiovascular death, stroke and heart failure in patients receiving MULTAQ (see section 5.1). It is recommended to perform ECGs serially, at least every 6 months. If patients treated with MULTAQ develop permanent AF, treatment with MULTAQ should be discontinued.

Patients with history of, or current heart failure or left ventricular systolic dysfunction MULTAQ is contraindicated in patients in unstable hemodynamic conditions, with history of, or current heart failure or left ventricular systolic dysfunction (see section 4.3).
Patients should be carefully evaluated for symptoms of Congestive Heart Failure. There have been spontaneously reported events of new or worsening heart failure during treatment with MULTAQ.
Patients should be advised to consult a physician if they develop or experience signs or symptoms of heart failure, such as weight gain, dependent oedema, or increased dyspnoea. If heart failure develops, treatment with MULTAQ should be discontinued.
Patients should be followed for the development of left ventricular systolic dysfunction during treatment. If left ventricular systolic dysfunction develops, treatment with MULTAQ should be discontinued.

Patients with coronary artery disease
In patients with coronary artery disease, clinical signs of heart failure and ECG should be regularly monitored to detect early signs of heart failure. In ESC and ACC/AHA/HRS guidelines dronedarone has a class IA recommendation in patients with paroxysmal/persistent AF and coronary artery disease.

Elderly
In elderly patients ≥ 75 years with multiple co-morbidities, clinical signs of heart failure and ECG should be monitored on a regular basis (See sections 4.2 and 5.1).

Women of child bearing potential and pregnancy
Dronedarone is not recommended during pregnancy and in women of childbearing potential not using contraception. Women of childbearing potential should use effective methods of contraception during treatment with dronedarone and for 7 days after the final dose. Prior to initiating dronedarone, the prescriber should confirm that women of childbearing potential are not pregnant (see section 4.6).

Liver Injury
Hepatocellular liver injury, including life-threatening acute liver failure, has been reported in patients treated with MULTAQ in the post-marketing setting.
Liver function tests should be performed prior to initiation of treatment with dronedarone after one week and after one month following initiation of treatment and then repeated monthly for six months, at months 9 and 12, and periodically thereafter.
If alanine aminotransferase (ALT) levels are elevated >3 × upper limit of normal (ULN), ALT levels should be re-measured within 48 to 72 hours. If ALT levels are confirmed to be >3 × ULN, treatment with dronedarone should be withdrawn. Appropriate investigation and close observation of patients should continue until normalization of ALT.
Patients should immediately report any symptoms of potential liver injury (such as sustained new- onset abdominal pain, anorexia, nausea, vomiting, fever, malaise, fatigue, jaundice, dark urine or itching) to their physician.

Management of plasma creatinine increase
An increase in plasma creatinine (mean increase 10 μmol/L) has been observed with dronedarone 400 mg twice daily in healthy subjects and in patients. In most patients this increase occurs early after treatment initiation and reaches a plateau after 7 days. It is recommended to measure plasma creatinine values prior to and 7 days after initiation of dronedarone. If an increase in creatininaemia is observed, serum creatinine should be re-measured after a further 7 days. If no further increase in creatininaemia is observed, this value should be used as the new reference baseline taking into account that this may be expected with dronedarone. If serum creatinine continues to rise then consideration should be given to further investigation and discontinuing treatment.
An increase in creatininaemia should not necessarily lead to the discontinuation of treatment with ACE-inhibitors or Angiotensin II Receptors Antagonists (AIIRAs).
Larger increases in creatinine after dronedarone initiation have been reported in the postmarketing setting. Some cases also reported increases in blood urea nitrogen possibly due to hypoperfusion secondary to developing CHF (pre-renal azotaemia). In such cases dronedarone should be stopped (see sections 4.3 and 4.4). It is recommended to monitor renal function periodically and to consider further investigations as needed.

Electrolytes imbalance
Since antiarrhythmic medicinal products may be ineffective or may be arrhythmogenic in patients with hypokalaemia, any potassium or magnesium deficiency should be corrected before initiation and during dronedarone therapy.

QT prolongation
The pharmacological action of dronedarone may induce a moderate QTc Bazett prolongation (about 10 msec), related to prolonged repolarisation. These changes are linked to the therapeutic effect of dronedarone and do not reflect toxicity. Follow up, including ECG (electrocardiogram), is 
recommended during treatment. If QTc Bazett interval is ≥500 milliseconds, dronedarone should be stopped (see section 4.3).
Based on clinical experience, dronedarone has a low pro-arrhythmic effect and has shown a decrease in arrhythmic death in the ATHENA study (see section 5.1).
However, proarrhythmic effects may occur in particular situations such as concomitant use with medicinal products favouring arrhythmia and/or electrolytic disorders (see sections 4.4 and 4.5).

Respiratory, thoracic and mediastinal disorders
Cases of interstitial lung disease including pneumonitis and pulmonary fibrosis have been reported in post-marketing experience. Onset of dyspnoea or non-productive cough may be related to pulmonary toxicity and patients should be carefully evaluated clinically. If pulmonary toxicity is confirmed treatment should be discontinued.

Interactions (see section 4.5)

Digoxin
Administration of dronedarone to patients receiving digoxin will bring about an increase in the plasma digoxin concentration and thus precipitate symptoms and signs associated with digoxin toxicity.
Clinical, ECG and biological monitoring is recommended, and digoxin dose should be halved. A synergistic effect on heart rate and atrioventricular conduction is also possible.

Beta-blockers and calcium antagonists
The co-administration of beta-blockers or calcium antagonists with depressant effect on sinus and atrio-ventricular node should be undertaken with caution. These medicinal products should be initiated at low dose and up titration should be done only after ECG assessment. In patients already on calcium antagonists or beta blockers at time of dronedarone initiation, an ECG should be performed and the dose should be adjusted if needed.

Vitamin K antagonists
Patients should be appropriately anti-coagulated as per clinical AF guidelines. International Normalized Ratio (INR) should be closely monitored after initiating dronedarone in patients taking vitamin K antagonists as per their label.


Potent CYP3A4 inducers
Potent CYP3A4 inducers such as rifampicin, phenobarbital, carbamazepine, phenytoin or St John’s Wort are not recommended.

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

Grapefruit juice
Patients should be warned to avoid grapefruit juice beverages while taking dronedarone.

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

Effects on Driving

4.7   Effects on ability to drive and use machines
MULTAQ has no or negligible influence on the ability to drive and use machines. However, ability to drive and use machines may be affected by adverse reactions such as fatigue.