Dronedarone

Rifampicin (600 mg once daily) decreased dronedarone exposure by 80% with no major change on its active metabolite exposure. 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 decrease dronedarone exposure.

Repeated doses of 300 ml of grapefruit juice three times daily resulted in a 3-fold increase in dronedarone exposure. Therefore, patients should be warned to avoid grapefruit juice beverages while taking dronedarone.

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

Clinically significant INR elevations (≥5) usually within 1 week after starting dronedarone were reported in patients taking oral anticoagulants. Consequently, INR should be closely monitored after initiating dronedarone in patients taking vitamin K antagonists as per their label.

Beta blockers that are metabolized by CYP 2D6 can have their exposure increased by dronedarone. Moreover, beta blockers have the potential to interact with dronedarone from a pharmacodynamic point of view. Dronedarone 800 mg daily increased metoprolol exposure by 1.6-fold and propranolol exposure by 1.3-fold (i.e. much below the 6-fold differences observed between poor and extensive CYP 2D6 metabolisers). In clinical studies, bradycardia was more frequently observed when dronedarone was given in combination with beta-blockers.

Due to the pharmacokinetic interaction and possible pharmacodynamic interaction, beta blockers should be used with caution concomitantly with dronedarone. These medicinal products should be initiated at low dose and up-titration should be done only after ECG assessment. In patients already taking beta blockers at time of dronedarone initiation, an ECG should be performed and the beta blocker dose should be adjusted if needed.

Dronedarone can increase exposure of statins that are substrates of CYP 3A4 and/or P-gp substrates. Dronedarone (400 mg twice daily) increased simvastatin and simvastatin acid exposure by 4-fold and 2-fold respectively. It is predicted that dronedarone could also increase the exposure of lovastatin within the same range as simvastatin acid. There was a weak interaction between dronedarone and atorvastatin (which resulted in a mean 1.7-fold increase in atorvastatin exposure). There was a weak interaction between dronedarone and statins transported by OATP, such as rosuvastatin (which resulted in a mean 1.4-fold increase in rosuvastatin exposure).

In clinical trials, there was no evidence of safety concerns when dronedarone was co-administered with statins metabolized by CYP 3A4. However, spontaneously reported cases of rhabdomyolysis when dronedarone was given in combination with a statin (simvastatin in particular) have been reported, and, therefore, concomitant use of statins should be undertaken with caution. Lower starting dose and maintenance doses of statins should be considered according to the statin label recommendations and patients monitored for clinical signs of muscular toxicity.

Dronedarone (400 mg twice daily) increased digoxin exposure by 2.5-fold by inhibiting P-gp transporter. Moreover, digitalis has the potential to interact with dronedarone from a pharmacodynamic point of view. A synergistic effect on heart rate and atrio-ventricular conduction is possible. In clinical studies, increased levels of digitalis and/or gastrointestinal disorders indicating digitalis toxicity were observed when dronedarone was co-administered with digitalis.

The digoxin dose should be reduced by approximately 50%, serum levels of digoxin should be closely monitored and clinical and ECG monitoring is recommended.

Calcium antagonists, diltiazem and verapamil, are substrates and/or moderate inhibitors of CYP 3A4. Moreover, due to their heart rate-lowering properties, verapamil and diltiazem have the potential to interact with dronedarone from a pharmacodynamic point of view.

Repeated doses of diltiazem (240 mg twice daily), verapamil (240 mg once daily) and nifedipine (20 mg twice daily) resulted in an increase in dronedarone exposure of 1.7-, 1.4- and 1.2-fold, respectively. Calcium antagonists also have their exposure increased by dronedarone (400 mg twice daily) (verapamil by 1.4-fold, and nisoldipine by 1.5-fold). In clinical studies, 13% of patients received calcium antagonists concomitantly with dronedarone. There was no increased risk of hypotension, bradycardia and heart failure.

Overall, due to the pharmacokinetic interaction and possible pharmacodynamic interaction, calcium antagonists with depressant effects on sinus and atrio-ventricular node such as verapamil and diltiazem should be used with caution when associated with dronedarone. 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 at time of dronedarone initiation, an ECG should be performed and the calcium antagonist dose should be adjusted if needed.

Dronedarone could increase plasma concentrations of immunosupressants (tacrolimus, sirolimus, everolimus and cyclosporine). Monitoring of their plasma concentrations and appropriate dose adjustment is recommended in case of coadministration with dronedarone.

Dronedarone (600 mg twice daily) increased by 1.2-fold S-warfarin with no change in R-warfarin and only a 1.07 increase in International Normalized Ratio (INR).

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.

Based on clinical experience, dronedarone has a low pro-arrhythmic effect and has shown a decrease in arrhythmic death in the ATHENA study.

However, proarrhythmic effects may occur in particular situations such as concomitant use with medicinal products favouring arrhythmia and/or electrolytic disorders.

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 creatininemia is observed, serum creatinine should be re-measured after a further 7 days. If no further increase in creatinaemia 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 creatininemia 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. In most cases, these effects appear to be reversible upon drug discontinuation.

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.

Hepatocellular liver injury, including life-threatening acute liver failure, has been reported in patients treated with dronedarone 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.

Caution is needed in patients with coronary artery disease.

There are no or limited amount of data from the use of dronedarone in pregnant women.

Dronedarone is not recommended during pregnancy.

It is unknown whether dronedarone and its metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of dronedarone and its metabolites in milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from dronedarone therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Women of child bearing potential and Pregnancy

Studies in animals have shown reproductive toxicity. Dronedarone is not recommended in women of childbearing potential not using contraception.

Fertility

Dronedarone was not shown to alter fertility in animal studies.

Dronedarone 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.

Summary of the safety profile

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

In clinical studies, premature discontinuation due to adverse reactions occurred in 11.8% of the dronedarone-treated patients and in 7.7% in the placebo-treated group. The most common reasons for discontinuation of therapy with dronedarone were gastrointestinal disorders (3.2% of patients versus 1.8% in the placebo group).

The most frequent adverse reactions observed with dronedarone 400 mg twice daily in the 5 studies were diarrhoea, nausea and vomiting, fatigue and asthenia.

List of adverse reactions

The safety profile of dronedarone 400 mg twice daily in patients with atrial fibrillation (AF) or atrial flutter (AFL) is based on 5 placebo controlled studies, in which a total of 6,285 patients were randomised (3,282 patients received dronedarone 400 mg twice daily, and 2,875 received placebo).

The mean exposure across studies was 13 months. In ATHENA study, the maximum follow-up was 30 months. Some adverse reactions were also identified during post marketing surveillance. Adverse reactions are presented by system organ class.

Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse reactions:

Immune system disorders

Rare: Anaphylactic reactions including angioedema

Nervous system disorders

Uncommon: Dysgeusia

Rare: Ageusia

Cardiac disorders

Very Common: Congestive heart failure (see below)

Common: Bradycardia

Vascular disorders

Rare: Vasculitis, including leukocytoclastic vasculitis

Respiratory, thoracic and mediastinal disorders

Uncommon: Interstitial lung disease including pneumonitis and pulmonary fibrosis (see below)

Gastrointestinal disorders

Common: Diarrhoea, Vomiting, Nausea, Abdominal pain, Dyspepsia

Hepatobiliary disorders

Common: Liver function test abnormalities

Rare: Hepatocellular liver injury, including life-threatening acute liver failure

Skin and subcutaneous tissue disorders

Common: Rashes (including generalised, macular, maculo-papular), Pruritus

Uncommon: Erythemas (including erythema and rash erythematous), Eczema, Photosensitivity reaction, Dermatitis allergic, Dermatitis

General disorders and administration site conditions

Common: Fatigue, Asthenia

Investigations

Very Common: Blood creatinine increased*, QTc Bazett prolonged#

* ≥10% five days after treatment initiation
^# >450 msec in male >470 msec in female

Description of selected adverse reactions

In the 5 placebo controlled studies, CHF occurred in the dronedarone group with rates comparable with placebo (very commonly, 11.2% versus 10.9%). This rate should be considered in the context of the underlying elevated incidence of CHF in AF patients. Cases of CHF have also been reported in post-marketing experience (frequency not known).

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