Caution is advised when prescribing INVEGA TRINZA with drugs known to prolong the QT interval.
Since paliperidone palmitate is hydrolyzed to paliperidone (see Pharmacology: Pharmacokinetics under Actions), results from studies with oral paliperidone should be taken into consideration when assessing drug-drug interaction potential.
Potential for INVEGA TRINZA to Affect Other Drugs: Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P-450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized 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 metabolized 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 antagonize the effect of levodopa and other dopamine agonists.
Because of its potential for inducing orthostatic hypotension (see Orthostatic Hypotension under 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, CYP2C19, and CYP3A5. This suggests 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, there are no indications in vitro nor in vivo that these isozymes play a significant role in the metabolism of paliperidone. In vitro studies have shown that paliperidone is a P-gp substrate.
Paliperidone is metabolized to a limited extent by CYP2D6 (see Pharmacology: Pharmacokinetics: Metabolism and Elimination under Actions). In an interaction study in healthy subjects in which oral paliperidone was administered concomitantly with paroxetine, a potent CYP2D6 inhibitor, no clinically relevant effects on the pharmacokinetics of paliperidone were observed.
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 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, likely the result of an increased oral absorption. Since no significant effect on the systemic clearance was observed, 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.
Concomitant Use of INVEGA TRINZA with Risperidone or with oral paliperidone: Since paliperidone is the active metabolite of risperidone, caution should be exercised when INVEGA TRINZA is coadministered with risperidone or with oral paliperidone for extended periods of time. Safety data involving concomitant use of INVEGA TRINZA with other antispychotics is limited.