Pharmacodynamic interactions: Medicinal products inducing Torsade de Pointes or prolonging QT: Medicinal products inducing Torsade de Pointes: Combined therapy with the following medicinal products which prolong the QT interval is contra-indicated (see Contraindications) due to the increased risk of torsades de pointes; for example: Class 1a anti-arrhythmic substance e.g. quinidine, procainamide, disopyramide; Class III anti-arrhythmic medicinal products e.g. sotalol, bretylium; intravenous erythromycin, co-trimoxazole or pentamidine injection; some anti-psychotics e.g. chlorpromazine, thioridazine, fluphenazine, pimozide, haloperidol, amisulpride and sertindole; lithium and tricyclic antidepressants e.g. doxepin, maprotiline, amitriptyline; certain antihistamines e.g. terfenadine, astemizole, mizolastine; anti-malarials e.g. quinine, mefloquine, chloroquine, halofantrine; moxifloxacin.
Medicinal products prolonging QT interval: Co-administration of amiodarone with medicinal products known to prolong the QT interval (such as clarithromycin) must be based on a careful assessment of the potential risks and benefits for each patient since the risk of torsade de pointes may increase and patients should be monitored for QT prolongation.
Concomitant use of amiodarone with fluoroquinolones should be avoided (concomitant use with moxifloxacin is contra-indicated).
There have been rare reports of QTc interval prolongation, with or without torsades de pointes, in patients taking amiodarone with fluoroquinolones (see Contraindications).
Medicinal products lowering heart rate or causing automaticity or conduction disorders: Combined therapy with the following substances is not recommended: Beta blockers and heart rate lowering calcium channel inhibitors: (diltiazem, verapamil); potentiation of negative chronotropic properties and conduction slowing effects may occur.
Agents which may induce hypokalaemia: Combined therapy with the following substances is not recommended: Stimulant laxatives, which may cause hypokalaemia thus increasing the risk of torsades de pointes; other types of laxatives should be used.
Caution should be exercised over combined therapy with the following medicinal products which may also cause hypokalaemia and/or hypomagnesaemia, e.g. diuretics, systemic corticosteroids, tetracosactide, intravenous amphotericin.
In cases of hypokalaemia, corrective action should be taken and QT interval monitored. In case of torsades de pointes antiarrhythmic agents should not be given; pacing may be instituted and IV magnesium may be used.
General anaesthesia: Caution is advised in patients undergoing general anaesthesia, or receiving high dose oxygen therapy. Potentially severe complications have been reported in patients taking amiodarone undergoing general anaesthesia: bradycardia unresponsive to atropine, hypotension, disturbances of conduction, decreased cardiac output.
A few cases of adult respiratory distress syndrome, sometimes fatal, most often in the period immediately after surgery, have been observed. A possible interaction with a high oxygen concentration may be implicated.
Effect of amiodarone on other medicinal products: Amiodarone and/or its metabolite, desethylamiodarone, inhibit CYP1A1, CYP1A2, CYP3A4, CYP2C9, CYP2D6 and Pglycoprotein and may increase exposure of their substrates.
Due to the long half life of amiodarone, interactions may be observed for several months after discontinuation of amiodarone.
P-gp substrates: Amiodarone is a P-gp inhibitor. Co-administration with P-gp substrates is expected to result in an increase of their exposure.
Digitalis: Administration of amiodarone to a patient already receiving digoxin will bring about an increase in the plasma digoxin concentration and thus precipitate symptoms and signs associated with high digoxin levels. 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.
Dabigatran: Caution should be exercised when amiodarone is co-administered with dabigatran due to the risk of bleeding. It may be necessary to adjust the dose of dabigatran as per its label.
CYP 2C9 substrates: Amiodarone raises the plasma concentrations of oral anticoagulants (e.g. warfarin and phenytoin) by inhibition of CYP 2C9.
Warfarin: The dose of warfarin should be reduced accordingly. More frequent monitoring of prothrombin time both during and after amiodarone treatment is recommended.
Phenytoin: Phenytoin dose should be reduced if signs of overdose appear (resulting in neurological signs), and plasma levels may be measured.
CYP P450 3A4 substrates: When such substances are co-administered with amiodarone, an inhibitor of CYP3A4, this may result in a higher level of their plasma concentrations, which may lead to a possible increase in their toxicity.
Ciclosporin: Plasma levels of ciclosporin may increase as much as 2-fold when used in combination. A reduction in the dose of ciclosporin may be necessary to maintain the plasma concentration within the therapeutic range.
Fentanyl: Amiodarone may potentiate the pharmacological effects of fentanyl and thus may increase the risk of toxic effects.
Statins: The risk of muscular toxicity (e.g. rhabdomyolysis) is increased by concomitant administration of amiodarone with statins metabolised by CYP 3A4 such as simvastatin, atorvastatin and lovastatin. It is recommended to use a statin not metabolised by CYP 3A4 when given with amiodarone.
Other substances metabolised by cytochrome P450 3A4: Examples of such medicinal products are lidocaine, tacrolimus, sildenafil, fentanyl, midazolam, triazolam, dihydroergotamine, ergotamine and colchicine.
CYP 2D6 substrates: Flecainide: Given that flecainide is mainly metabolised by CYP 2D6, by inhibiting this isoenzyme, amiodarone may increase flecainide plasma levels; it is advised to reduce the flecainide dose by 50% and to monitor the patient closely for adverse effects. Monitoring of flecainide plasma levels is strongly recommended in such circumstances.
Effect of other products on amiodarone: CYP3A4 inhibitors and CYP2C8 inhibitors may have a potential to inhibit amiodarone metabolism and to increase its exposure.
It is recommended to avoid CYP 3A4 inhibitors during treatment with amiodarone.
Grapefruit juice inhibits cytochrome P450 3A4 and may increase the plasma concentration of amiodarone. Grapefruit juice should be avoided during treatment with oral amiodarone.
Other medicinal product interactions with amiodarone (see Warnings): Co-administration of amiodarone with sofosbuvir in combination with another HCV direct acting antiviral (such as daclatasvir, simeprevir, or ledipasvir) is not recommended as it may lead to serious symptomatic bradycardia. The mechanism for this bradycardia effect is unknown.
If co-administration cannot be avoided, cardiac monitoring is recommended (see Warnings).