Interactions : אינטראקציות

4.5 Interaction with other medicinal products and other forms of interaction

Drugs inducing “torsade de pointes” or prolonging the QT interval Some of the more important drugs that interact with amiodarone include warfarin, digoxin, phenytoin and any drug which prolongs the QT interval.
Combined therapy with the following drugs which prolong the QT interval is contra-indicated (see section  4.3) due to the increased risk of torsade de pointes; for example:
• class Ia anti-arrhythmic drugs e.g. quinidine, procainamide, disopyramide 
• class III anti-arrhythmic drugs e.g. sotalol, bretylium
• intravenous erythromycin, co-trimoxazole or pentamidine injection 
• some anti-psychotics e.g. chlorpromazine, thioridazine, fluphenazine, pimozide, haloperidol, amisulpiride and sertindole
• lithium and tricyclic anti-depressants e.g. doxepin, maprotiline, amitriptyline • certain antihistamines e.g. terfenadine, astemizole, mizolastine
• anti-malarials e.g. quinine, mefloquine, chloroquine, halofantrine • moxifloxacin

Fluoroquinoles
There have been rare reports of QTc interval prolongation, with or without torsade de pointes, in patients taking amiodarone with fluoroquinolones. Concomitant use of amiodarone with fluoroquinolones should be avoided (concomitant use with moxifloxacin is contra-indicated, see above).
Drugs lowering heart rate, causing automaticity or conduction disorders

Combined therapy with the following drugs is not recommended:
• Beta blockers and certain calcium channel inhibitors (diltiazem, verapamil); potentiation of negative chronotropic properties and conduction slowing effects may occur.
• Stimulant laxatives, which may cause hypokalaemia thus increasing the risk of torsade de pointes; other types of laxatives should be used.
Caution should be exercised over combined therapy with the following drugs which may also cause hypokalaemia and/or hypomagnesaemia, e.g. diuretics, systemic corticosteroids, tetracosactide, intravenous amphotericin B.
In cases of hypokalaemia, corrective action should be taken, and QT interval monitored. In case of torsade 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.

Very rare cases of severe respiratory complications (adult acute respiratory distress syndrome), sometimes fatal, have been observed usually in the period immediately following surgery. A possible interaction with a high oxygen concentration may be implicated.
Effect of Amiodacore Injection on other medicinal products
Amiodarone and/or its metabolite, desethylamiodarone, inhibit CYP1A1, CYP1A2, CYP3A4, CYP2C9, CYP2D6 and P- glycoprotein 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.
PgP substrates
Amiodarone is a P-gp inhibitor. Co administration with P-gp substrates is expected to result in an increase in their exposure.
Digoxin
Administration of Amiodacore Injection 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; disturbances in automaticity (excessive bradycardia), a synergistic effect on heart rate and atrioventricular conduction may occur. Clinical, ECG and biological monitoring is recommended to observe for signs of digitalis toxicity and digoxin dosage should be halved.
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 dosage of dabigatran as per its label.
CYP2C9 substrates:
Amiodarone raises the plasma concentrations of CYP2C9 substrates such as oral anticoagulants (warfarin) and phenytoin by inhibition of the cytochrome P4502C9.
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 dosage should be reduced if signs of overdosage appear, and plasma levels may be measured.
CYP2D6 substrates
Flecainide
Given that flecainide is mainly metabolised by CYP2D6, 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.
CYP P450 3A4 substrates
When drugs 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.
• Statins: the risk of muscular toxicity (e.g. rhabdomyolysis) is increased by concomitant administration of amiodarone with statins metabolised by CYP3A4 such as simvastatin, atorvastatin and lovastatin. It is recommended to use a statin not metabolised by CYP3A4 when given with amiodarone.
• Other drugs metabolised by cytochrome P4503A4: examples of such drugs are lidocaine, sirolimus, tacrolimus, sildenafil, fentanyl, midazolam, triazolam, dihydroergotamine and ergotamine and colchicine.
Interaction with substrates of other CYP 450 isoenzymes
In vitro studies show that amiodarone also has the potential to inhibit CYP1A2, CYP2C19 and CYP2D6 through its main metabolite. When co-administered, amiodarone would be expected to increase the plasma concentration of drugs whose metabolism is dependent upon CYP1A2, CYP2C19 and CYP2D6.

Effect of other products on Amiodacore Injection
CYP3A4 inhibitors and CYP2C8 inhibitors may have a potential to inhibit amiodarone metabolism and to increase its exposure.
It is recommended to avoid CYP3A4 inhibitors (e.g. grapefruit juice and certain medicinal products) during treatment with amiodarone.
Grapefruit juice inhibits cytochrome P4503A4 and may increase the plasma concentration of amiodarone. Grapefruit juice should be avoided during treatment with oral amiodarone.
Other drug interactions with amiodarone (see section 4.4)
Co-administration of amiodarone with sofosbuvir-containing regimens 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 section 4.4).