Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Caution is advised when prescribing TREVICTA with medicinal products known to prolong the QT interval, e.g., class IA antiarrhythmics (e.g., quinidine, disopyramide) and class III antiarrhythmics (e.g., amiodarone, sotalol), some antihistaminics, some antibiotics (e.g., fluoroquinolones), some other antipsychotics and some antimalarials (e.g., mefloquine). This list is indicative and not exhaustive.

Potential for TREVICTA to affect other medicines

Paliperidone is not expected to cause clinically important pharmacokinetic interactions with medicinal products that are metabolised by cytochrome P450 isozymes.

Given the primary central nervous system (CNS) effects of paliperidone (see section 4.8), TREVICTA should be used with caution in combination with other centrally acting medicinal products, e.g., anxiolytics, most antipsychotics, hypnotics, opiates, etc. or alcohol.

Paliperidone may antagonise the effect of levodopa and other dopamine agonists. If this combination is deemed necessary, particularly in end-stage Parkinson’s disease, the lowest effective dose of each treatment should be prescribed.

Because of its potential for inducing orthostatic hypotension (see section 4.4), an additive effect may be observed when TREVICTA is administered with other medicinal products that have this potential, e.g., other antipsychotics, tricyclics.

Caution is advised if paliperidone is combined with other medicinal products known to lower the seizure threshold (i.e., phenothiazines or butyrophenones, tricyclics or SSRIs, tramadol, mefloquine, etc.).

Co-administration of oral paliperidone extended release tablets at steady-state (12 mg once daily) with divalproex sodium prolonged release tablets (500 mg to 2,000 mg once daily) did not affect the steady-state pharmacokinetics of valproate.

No interaction study between TREVICTA and lithium has been performed, however, a pharmacokinetic interaction is not likely to occur.



Potential for other medicines to affect TREVICTA

In vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, but there are no indications in vitro nor in vivo that these isozymes play a significant role in the metabolism of paliperidone. Concomitant administration of oral paliperidone with paroxetine, a potent CYP2D6 inhibitor, showed no clinically significant effect on the pharmacokinetics of paliperidone.

Co-administration of oral paliperidone extended release once daily with carbamazepine 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state Cmax and AUC of paliperidone.
This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone likely as a result of induction of renal P-gp by carbamazepine. A minor decrease in the amount of active substance excreted unchanged in the urine suggests that there was little effect on the CYP metabolism or bioavailability of paliperidone during carbamazepine co-administration. Larger decreases in plasma concentrations of paliperidone could occur with higher doses of carbamazepine.
On initiation of carbamazepine, the dose of TREVICTA should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of TREVICTA should be re-evaluated and decreased if necessary. Consideration should be given to the long-acting nature of TREVICTA.

Co-administration of a single dose of an oral paliperidone extended release tablet 12 mg with divalproex sodium prolonged release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone, likely as a result of increased oral absorption. Since no effect on the systemic clearance was observed, a clinically significant interaction would not be expected between divalproex sodium prolonged release tablets and TREVICTA intramuscular injection. This interaction has not been studied with TREVICTA.

Concomitant use of TREVICTA with risperidone or oral paliperidone

Since paliperidone is the major active metabolite of risperidone, caution should be exercised when TREVICTA is co-administered with risperidone or with oral paliperidone for extended periods of time. Safety data involving concomitant use of TREVICTA with other antipsychotics is limited.

Concomitant use of TREVICTA with psychostimulants

The combined use of psychostimulants (e.g. methylphenidate) with paliperidone can lead to extrapyramidal symptoms upon change of either or both treatments (see section 4.4).