Caution is advised when prescribing INVEGA TRINZA with drugs known to prolong the QT interval. Since paliperidone palmitate is hydrolysed to paliperidone (see Pharmacology: Pharmacokinetics under Actions), results from studies with oral paliperidone should be taken into consideration when assessing drug-drug interaction potential.
Concomitant use of INVEGA TRINZA with risperidone or with oral paliperidone: Since paliperidone is the major active metabolite of risperidone, the co-administration of INVEGA TRINZA with oral risperidone or paliperidone is likely to result in an increase in the paliperidone concentration, within the bloodstream. Caution should be exercised when INVEGA TRINZA is co-administered with risperidone or with oral paliperidone for extended periods of time. Safety data involving concomitant use of INVEGA TRINZA with other antispychotics is limited.
Concomitant use of INVEGA TRINZA with psychostimulants: The combined use of psychostimulants (e.g. methylphenidate) with paliperidone can lead to the emergence of extrapyramidal symptoms upon change of either or both treatments (see Precautions).
Potential for INVEGA TRINZA to Affect Other Drugs: Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolised by cytochrome P-450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolised by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolised by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties.
Paliperidone is a weak inhibitor of P-glycoprotein (P-gp) at high concentrations. No in vivo data are available and the clinical relevance is unknown.
Given the primary CNS effects of paliperidone (see Adverse Reactions), INVEGA TRINZA should be used with caution in combination with other centrally acting drugs and alcohol. Paliperidone may antagonise the effect of levodopa and other dopamine agonists.
Because of its potential for inducing orthostatic hypotension (see Precautions), an additive effect may be observed when INVEGA TRINZA is administered with other therapeutic agents that have this potential.
Co-administration of oral paliperidone extended-release tablets at steady-state (12 mg once daily) with divalproex sodium extended-release tablets (500 mg to 2000 mg once daily) did not affect the steady-state pharmacokinetics of valproate.
Pharmacokinetic interaction between INVEGA TRINZA and lithium is unlikely.
Potential for Other Drugs to Affect INVEGA TRINZA: Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies do not show decreased elimination by these isozymes and they contribute to only a small fraction of total body clearance. In vitro studies have shown that paliperidone is a P-gp substrate.
Paliperidone is metabolised to a limited extent by CYP2D6 (see Pharmacology: Pharmacokinetics under Actions). In an interaction study in healthy subjects in which a single 3 mg dose of oral paliperidone modified release was administered concomitantly with 20 mg per day of paroxetine (a potent CYP2D6 inhibitor), paliperidone exposures were on average 16% (90% CI: 4, 30) higher in CYP2D6 extensive metabolisers. Higher doses of paroxetine have not been studied. The clinical relevance is unknown.
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. A minor decrease in the amount of drug excreted unchanged in the urine suggests that there was little effect on the CYP metabolism or bioavailability of paliperidone during carbamazepine co-administration. On initiation of carbamazepine, the dose of INVEGA TRINZA should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of INVEGA TRINZA should be re-evaluated and decreased if necessary. Consideration should be given to the long-acting nature of INVEGA TRINZA.
Paliperidone, a cation under physiological pH, is primarily excreted unchanged by the kidneys, approximately half via filtration and half via active secretion. Concomitant administration of trimethoprim, a drug known to inhibit active renal cation drug transport, did not influence the pharmacokinetics of paliperidone.
Co-administration of a single dose of an oral paliperidone extended-release tablet 12 mg with divalproex sodium extended-release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone. Although this interaction has not been studied with INVEGA TRINZA a clinically significant interaction would not be expected between divalproex sodium extended-release tablets and INVEGA TRINZA intramuscular injection. This interaction has not been studied with INVEGA TRINZA.
Pharmacokinetic interaction between lithium and INVEGA TRINZA is unlikely.