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Invega Sustenna (Paliperidone Palmitate) - Drug Interactions, Contraindications, Overdosage, etc



Since paliperidone palmitate is hydrolyzed to paliperidone [see Clinical Pharmacology], results from studies with oral paliperidone should be taken into consideration when assessing drug-drug interaction potential.

Potential for INVEGA SUSTENNA to Affect Other Drugs

Given the primary CNS effects of paliperidone [see Adverse Reactions], INVEGA® SUSTENNA® 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, an additive effect may be observed when INVEGA® SUSTENNA® is administered with other therapeutic agents that have this potential [see Warnings and Precautions].

Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 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.

7.2 Potential for Other Drugs to Affect INVEGA SUSTENNA

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.

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® SUSTENNA® should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of INVEGA® SUSTENNA® should be re-evaluated and decreased if necessary.

Paliperidone is metabolized to a limited extent by CYP2D6 [see Clinical Pharmacology]. In an interaction study in healthy subjects in which a single 3 mg dose of oral paliperidone extended 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 metabolizers. Higher doses of paroxetine have not been studied. The clinical relevance is unknown.

Co-administration of a single dose of an oral paliperidone extended-release 12 mg tablet with divalproex sodium extended-release tablets (two 500 mg tablets once daily at steady-state) resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone. Although this interaction has not been studied with INVEGA® SUSTENNA®, a clinically significant interaction would not be expected between divalproex sodium and INVEGA® SUSTENNA® intramuscular injection.


Human Experience

No cases of overdose were reported in premarketing studies with INVEGA® SUSTENNA®. Because INVEGA® SUSTENNA® is to be administered by health care professionals, the potential for overdosage by patients is low.

While experience with paliperidone overdose is limited, among the few cases of overdose reported in premarketing trials with oral paliperidone, the highest estimated ingestion was 405 mg. Observed signs and symptoms included extrapyramidal symptoms and gait unsteadiness. Other potential signs and symptoms include those resulting from an exaggeration of paliperidone's known pharmacological effects, i.e., drowsiness and sedation, tachycardia and hypotension, and QT prolongation. Torsade de pointes and ventricular fibrillation have been reported in a patient in the setting of overdose with oral paliperidone.

Paliperidone is the major active metabolite of risperidone. Overdose experience reported with risperidone can be found in the OVERDOSAGE section of the risperidone package insert.

Management of Overdosage

There is no specific antidote to paliperidone, therefore, appropriate supportive measures should be instituted and close medical supervision and monitoring should continue until the patient recovers. Consideration should be given to the prolonged-release characteristics of INVEGA® SUSTENNA® and the long apparent half-life of paliperidone when assessing treatment needs and recovery. Multiple drug involvement should also be considered.

In case of acute overdose, establish and maintain an airway and ensure adequate oxygenation and ventilation. The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.

Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with an acute overdose of paliperidone. Similarly the alpha-blocking properties of bretylium might be additive to those of paliperidone, resulting in problematic hypotension.

Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of paliperidone-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered.


Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been observed in patients treated with risperidone and paliperidone. Paliperidone palmitate is converted to paliperidone, which is a metabolite of risperidone and is therefore contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the excipients in the INVEGA® SUSTENNA® formulation.


Controlled Substance

INVEGA® SUSTENNA® (paliperidone) is not a controlled substance.


Paliperidone has not been systematically studied in animals or humans for its potential for abuse.


Paliperidone has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.

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