Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction
Caution is advised when prescribing INVEGA with medicines 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 other antipsychotics and some antimalarials (e.g., mefloquine).

Potential for INVEGA to affect other medicines
Paliperidone is not expected to cause clinically important pharmacokinetic interactions with medicines that are metabolised by cytochrome P-450 isozymes. In vitro studies indicate that paliperidone is not an inducer of CYP1A2 activity.

Given the primary CNS effects of paliperidone (see section 4.8), INVEGA should be used with caution in combination with other centrally acting medicines, 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 Invega SPC 9-24
should be prescribed.

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

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

No interaction study between INVEGA and lithium has been performed, however, a pharmacokinetic interaction is unlikely to occur.

Co-administration of INVEGA 12 mg once daily with divalproex sodium prolonged-release tablets (500 mg to 2000 mg once daily) did not affect the steady-state pharmacokinetics of valproate.
Co-administration of INVEGA with divalproex sodium prolonged-release tablets increased the exposure to paliperidone (see below).

Potential for other medicines to affect INVEGA
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 INVEGA with paroxetine, a potent CYP2D6 inhibitor, showed no clinically significant effect on the pharmacokinetics of paliperidone. In vitro studies have shown that paliperidone is a P-glycoprotein (P-gp) substrate.

Co-administration of INVEGA 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 INVEGA should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of INVEGA should be re-evaluated and decreased if necessary. It takes 2-3 weeks for full induction to be achieved and upon discontinuation of the inducer the effect wears off over a similar time period. Other medicinal products or herbals which are inducers, e.g. rifampicin and St John´s wort (Hypericum perforatum) may have similar effects on paliperidone.

Medicinal products affecting gastrointestinal transit time may affect the absorption of paliperidone, e.g., metoclopramide.

Co-administration of a single dose of INVEGA 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.
Dosage reduction for INVEGA should be considered when INVEGA is co-administered with valproate after clinical assessment.

Concomitant use of INVEGA with risperidone
Concomitant use of INVEGA with oral risperidone is not recommended as paliperidone is the active metabolite of risperidone and the combination of the two may lead to additive paliperidone exposure.

Concomitant use of INVEGA with psychostimulants
The combined use of psychostimulants (e.g., methylphenidate) with paliperidone can lead to extrapyramidal Invega SPC 9-24
symptoms upon change of either or both treatments (see section 4.4).

Paediatric population
Interaction studies have only been performed in adults.