Interactions : אינטראקציות

4.5     Interaction with other medicinal products and other forms of interaction

General
The sedative effects of antipsychotics, hypnotics, sedatives, anxiolytics, and antihistaminic drugs may be intensified; dosage reduction is recommended in such instances.

The metabolism of antidepressants is accelerated due to the hepatic effects of oral contraceptives, phenytoin, carbamazepine and barbiturates. The metabolism of antidepressants is inhibited by cimetidine and some other antipsychotics.

CYP3A4 inhibitors
In vitro drug metabolism studies suggest that there is a potential for drug interactions when trazodone is coadministered with cytochrome P4503A4 inhibitors (CYP3A4), such as erythromycin, ketoconazole, itraconazole, ritonavir, indinavir and nefazodone. CYP3A4 inhibitors may lead to a significant increase in the plasma concentration of trazodone. It has been confirmed by in vivo studies in healthy volunteers, that a ritonavir dose of 200 mg BID increases the plasma levels of trazodone greater than two-fold, leading to nausea, syncope and hypotension. Therefore, if trazodone is administered with a potent CYP3A4 inhibitor, a reduction in the dose of trazodone is needed. However, coadministration of trazodone and potent CYP3A4 inhibitors should be avoided where possible.

Carbamazepine
Coadministration of carbamazepine and trazodone results in reduced trazodone plasma concentrations.
Concomitant use of carbamazepine 400 mg daily led to a decrease in plasma levels of trazodone and its active metabolite m-Chlorophenylpiperazine of 76% and 60%, respectively. For this reason, patients taking trazodone in combination with carbamazepine should be closely monitored to assess whether there is a need for an increased dose of trazodone.

Tricyclic antidepressants
Concomitant use with trazodone should be avoided due to the risk of interaction. Carefully evaluate the possibility of onset of serotonin syndrome and cardiovascular adverse effects.

Fluoxetine
Rare cases have been reported of elevated trazodone plasma levels and adverse effects when trazodone had been combined with fluoxetine, a CYP1A2/2D6 cytochrome inhibitor. The mechanism underlying a pharmacokinetic interaction is not fully understood. A pharmacodynamic interaction (serotonin syndrome) cannot be excluded.

Monoamine oxidase inhibitors (MAOIs)
Possible interactions with monoamine oxidase inhibitors (MAOIs) have occasionally been reported.
Although some physicians do give both concurrently, use of trazodone concomitantly with MAOIs, or within two weeks after discontinuation of MAOI treatment, is not recommended. The administration of MAOIs within one week of stopping trazodone treatment is also not recommended.

Phenothiazines
Severe orthostatic hypotension has been observed in the event of concomitant use of phenothiazines, e.g.
chlorpromazine, fluphenazine, levomepromazine, and perphenazine.

Anaesthetics and muscle relaxants
Trazodone hydrochloride may enhance the effects of muscle relaxants and volatile anaesthetics, and caution should be exercised in such instances.

Alcohol
Trazodone intensifies the sedative effects of alcohol. Alcohol intake should be avoided during trazodone therapy.
Levodopa
Antidepressants can accelerate the metabolism of levodopa.

Other
Concomitant use of trazodone with drugs known to prolong the QT interval may increase the risk of e tri ular arrhyth ias, i ludi g torsades de poi tes . Cautio should e take he these drugs are o- administered with trazodone.

Since trazodone is only a weak inhibitor of noradrenaline re-uptake and does not modify the blood pressure response to tyramine, interference with the hypotensive action of guanethidine-like compounds is unlikely. However, studies in laboratory animals suggest that trazodone may inhibit most of the acute actions of clonidine. In the case of other types of antihypertensive drugs, although no clinical interactions have been reported, the possibility of potentiation should be considered.

Undesirable effects may be more frequent during concomitant use of plant-based medicinal preparations o tai i g St Joh s Wort (Hypericum perforatum).

Oral anticoagulant and/or antiplatelet agents: altered anti-coagulant functions (laboratory values and/or clinical signs and symptoms) with increased bleeding have rarely been reported.

There have been reports of changes in prothrombin time in patients receiving trazodone and warfarin.
Combination of trazodone with digoxin and phenytoin may result in elevated levels of these chemicals in the blood. Monitor plasma concentrations in these patients.