Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Contraindicated combinations (see section 4.3 Contraindications)
+ Colchicine
Colchicine-induced adverse effects are potentiated, which may be fatal.

+ Cisapride
There is an increased risk of ventricular arrhythmias, especially torsades de pointes.

+ Ergotamine/Dihydroergotamine
Ergotism may occur, potentially leading to peripheral necrosis (due to decreased hepatic elimination of ergotamine and inhibition of hepatic elimination of dihydroergotamine).


Inadvisable combinations (see Special warnings, Section 4.4)
+ Dopaminergic ergot alkaloids (bromocriptine, cabergoline, lisuride, pergolide) (see section 4.4).
Plasma concentrations of the dopaminergic agent are increased along with a potential increase in activity or occurrence of signs of overdose.


+ Drugs likely to induce torsades de pointes (see Section 4.4)
(amiodarone, amisulpride, arsenic compounds, bepridil, chlorpromazine, citalopram, cyamemazine, diphemanil, disopyramide, dofetilide, dolasetron, domperidone, dronedarone, droperidol, erythromycin, escitalopram, flupentixol, fluphenazine, halofantrine, haloperidol, hydroquinidine, ibutilide, levofloxacin, levomepromazine, lumefantrine, mequitazine, methadone, mizolastine, moxifloxacin, pentamidine, pimozide, pipamperone, pipotiazine, prucalopride, quinidine, sertindole, sotalol, spiramycin, sulpiride, sultopride, tiapride, toremifene, vandetanib, vincamine, zuclopenthixol).

This serious cardiac rhythm disorder can be caused by a number of antiarrhythmic and non-antiarrhythmic drugs. Hypokalemia (especially induced by potassium-depleting agents) is a promoting factor, as is bradycardia (especially induced by bradycardia- inducing agents) or pre-existing congenital or acquired QT interval prolongation. The medicinal products which cause this adverse effect include class la and III antiarrhythmic agents, and certain neuroleptics. Other agents not belonging to these classes are also involved.

There is an increased risk of ventricular arrhythmias, especially torsades de pointes.

When co-administering these agents, clinical and ECG monitoring are required.
Terfenadine
Certain macrolides are capable of a pharmacokinetic interaction with terfenadine leading to increased serum concentrations of the latter. This may result in severe ventricular arrhythmia, typically torsades de pointes. Although such a reaction has not been demonstrated with roxithromycin and studies in a limited number of healthy volunteers have not shown any pharmacokinetic interaction or relevant ECG changes, the concomitant use of roxithromycin and terfenadine cannot be recommended.

Astemizole and Pimozide

Other drugs, such as astemizole, cisaprid or pimozide, which are metabolized by hepatic CYP3A4 isozyme have been associated with QT interval prolongation and/or cardiac arrhythmias (typically torsades de pointes) as a result of an increased serum concentration subsequent to interaction with significant inhibitors of this isozyme, including some macrolide antibiotics. Roxithromycin has no or limited ability to form a complex with CYP3A4 and therefore to inhibit the metabolism of other drugs that are metabolized by this isozyme. A potential for clinical interaction of roxithromycin with the above mentioned drugs cannot be either ascertained or ruled out in confidence; therefore, simultaneous use of roxithromycin with such drugs is not recommended (see Section 4.4).Class IA and III antiarrhytmic agents
Roxithromycin, like other macrolides, should be used with caution in patients receiving Class IA and III antiarrhythmic agents (see section 4.4).

Combinations requiring precautions for use

+ Bradycardia-inducing agents
There is an increased risk of ventricular arrhythmias, especially torsades de pointes.
Clinical and ECG monitoring are required.

+ Vitamin K antagonists (acenocoumarol, fluindione, phenindione, warfarin) The vitamin K antagonist effect and the risk of haemorrhage are increased. INR should be monitored more frequently. Dose adjustment of the vitamin K antagonist during treatment with the macrolide and after treatment discontinuation may be necessary.

Special INR imbalance-related issues
Numerous cases of increased oral anticoagulant activity have been reported 
in patients receiving antibiotic therapy. The severity of the infection or inflammation, patient’s age and general health status appear to be predisposing risk factors.
Under these circumstances, it seems difficult to determine to what extent the infection itself or its treatment play a role in the INR imbalance.
However, certain classes of antibiotics are more involved, particularly: fluoroquinolones, macrolides, cyclins, cotrimoxazole, and certain cephalosporins.

+ Atorvastatin, simvastatin
There is an increased risk of adverse (concentration-dependent) effects such as rhabdomyolosis.
Lower doses of the cholesterol-lowering drug should be used.



+ Ciclosporin
There is a risk of increased blood ciclosporin and creatinine concentrations.
Blood ciclosporin concentrations should be assayed, kidney function tests carried out and dosage adjustments made during coadministration and after discontinuation of treatment with the macrolide.

+ Disopyramide
An in vitro study has shown that roxithromycin can displace protein-bound disopyramide. Such an effect in vivo may result in increased serum levels of free disopyramide. Consequently, ECG and, if possible, the disopyramide serum levels should be monitored.


+ Digoxin and other digitalis glycosides
Blood digoxin levelsare increased due to increased absorption.
Clinical monitoring (symptoms and ECG) should be performed and, possibly, monitoring of blood digoxin levels during and after treatment with azithromycin.

This clinical monitoring is mandatory if symptoms occur that are suggestive of digitalis glycoside overdose. Cardiac toxicity of digitalis glycosides may cause the following symptomps: nausea, vomiting, diarrhea, headache or vertigo, arrhythmia or heart conduction disorders.

Combinations to be taken into account

+ Midazolam
There is a slight increase in the sedative effects of midazolam.
+ Theophylline (and, by extrapolation, aminophylline)
There is a risk of increased blood theophylline levels, especially in children. However, this generally does not require any adjustment of the usual dose.

+ Roxithromycin is a weak CYP3A inhibitor.
The effect of roxithromycin on exposure to drugs predominantly cleared by CYP3A metabolism would be expected to be 2-fold or less. Caution should be exercised when roxithromycin is concomitantly prescribed with a drug metabolized by CYP3A (such as rifabutin and bromocriptine).