Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction
Dronedarone is primarily metabolised by CYP 3A4 (see section 5.2). Therefore, inhibitors and inducers of CYP 3A4 have the potential to interact on dronedarone. Dronedarone is a moderate inhibitor of CYP 3A4, a mild inhibitor of CYP 2D6 and a potent inhibitor of P-glycoproteins (P-gp).
Dronedarone has, therefore the potential to interact on medicinal products substrates of P- glycoproteins, CYP 3A4 or CYP 2D6. Dronedarone and/or its metabolites also have been shown to inhibit transport proteins of the Organic Anion Transporter (OAT); Organic Anion Transporting Polypeptide (OATP) and Organic Cation Transporter (OCT) families in vitro.
Dronedarone has no significant potential to inhibit CYP 1A2, CYP 2C9, CYP 2C19, CYP 2C8 and CYP 2B6.

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

Medicinal products inducing torsades de pointes
Medicinal products inducing torsades de pointes such as phenothiazines, cisapride, bepridil, tricyclic antidepressants, certain oral macrolides (such as erythromycin), terfenadine and Class I and III antiarrhythmics are contraindicated because of the potential risk of proarrhythmia (see section 4.3). In patients already taking beta-blockers at time of dronedarone initiation, an ECG should be performed and the dose of beta-blocker should be adjusted if needed (see section 4.4).
Clinical, ECG and biological monitoring is recommended, and digoxin dose should be halved (see section 4.4).

Effect of other medicinal products on MULTAQ

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

Moderate/weak CYP 3A4 inhibitors

Erythromycin
Erythromycin, an oral macrolide, may induce torsades de pointes and, as such, is contraindicated (see section 4.3). Repeated doses of erythromycin (500 mg three times a day for 10 days) resulted in an increase in steady state dronedarone exposure of 3.8 fold.

Calcium antagonists
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 (see section 4.4).

Other moderate/weak CYP 3A4 Inhibitors
Other moderate inhibitors of CYP3A4 are also likely to increase dronedarone exposure.

CYP 3A4 inducers
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.

MAO inhibitors
In an in vitro study MAO contributed to the metabolism of the active metabolite of dronedarone. The clinical relevance of this observation is not known (see sections 4.4 and 5.2).

Effect of MULTAQ on other medicinal products

Interaction with medicinal products metabolised by CYP 3A4
Dabigatran

When dabigatran etexilate 150 mg once daily was co administered with dronedarone 400 mg twice daily, the dabigatran AUC0 24, and Cmax were increased by 100% and 70%, respectively. No clinical data are available regarding the co-administration of these medicinal products in AF patients. Their co administration is contraindicated (see section 4.3).

Statins
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 (see section 4.4).

Calcium antagonists
The interaction of dronedarone on calcium antagonists is described above (see section 4.4).

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

Oral contraceptives
No decreases in ethinylestradiol and levonorgestrel were observed in healthy subjects receiving dronedarone (800 mg twice daily) concomitantly with oral contraceptives.

Interaction with medicinal products metabolized by CYP 2D6:

Beta blockers
Sotalol must be stopped before starting dronedarone (see sections 4.2 and 4.3). 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 (see section 4.4).

Antidepressants
Since dronedarone is a weak inhibitor of CYP 2D6 in humans, it is predicted to have limited interaction on antidepressant medicinal products metabolized by CYP 2D6.

Interaction with P-gp substrate

Digoxin
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.

Interaction with medicinal products metabolised by CYP 3A4 and P-gp

Rivaroxaban
Dronedarone is likely to increase the exposure of rivaroxaban (a CYP3A4 and P-gp substrate) and consequently concomitant use may increase the risk of bleedings. Concomitant use of rivaroxaban and dronedarone is not recommended.

Apixaban
Dronedarone may increase the exposure of apixaban (a CYP3A4 and P-gp substrate). However, no dose adjustment for apixaban is required when co-administered with agents that are not strong inhibitors of both CYP3A4 and P-gp, such as dronedarone.

Edoxaban
In in vivo studies edoxaban (a CYP3A4 and P-gp substrate) exposure was increased when administered with dronedarone. The edoxaban dose should be reduced according to the edoxaban label recommendations.

Interaction with warfarin and losartan (CYP 2C9 substrates)

Warfarin and other vitamin K antagonists
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).
However, 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.

Losartan and other AIIRAs (Angiotensin II Receptor Antagonists)
No interaction was observed between dronedarone and losartan and an interaction between dronedarone and other AIIRAs is not expected.


Interaction with theophylline (CYP 1A2 substrate)
Dronedarone 400 mg twice daily does not increase the steady state theophylline exposure.
Interaction with metformin (OCT1 and OCT2 substrate)
No interaction was observed between dronedarone and metformin, an OCT1 and OCT2 substrate.

Interaction with omeprazole (CYP 2C19 substrate)
Dronedarone does not affect the pharmacokinetics of omeprazole, a CYP 2C19 substrate.

Interaction with clopidogrel
Dronedarone does not affect the pharmacokinetics of clopidogrel and its active metabolite.
Other information
Pantoprazole (40 mg once daily), a medicinal product which increases gastric pH without any effect on cytochrome P450, did not interact significantly on dronedarone pharmacokinetics.

Grapefruit juice (CYP 3A4 inhibitor)
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 (see section 4.4).