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Saphris (Asenapine Maleate) - Drug Interactions, Contraindications, Overdosage, etc



The risks of using SAPHRIS in combination with other drugs have not been extensively evaluated. Given the primary CNS effects of SAPHRIS, caution should be used when it is taken in combination with other centrally acting drugs or alcohol.

Because of its α1-adrenergic antagonism with potential for inducing hypotension, SAPHRIS may enhance the effects of certain antihypertensive agents.

Potential for Other Drugs to Affect SAPHRIS

Asenapine is cleared primarily through direct glucuronidation by UGT1A4 and oxidative metabolism by cytochrome P450 isoenzymes (predominantly CYP1A2). The potential effects of inhibitors of several of these enzyme pathways on asenapine clearance were studied.

Table 5: Summary of Effect of Coadministered Drugs on Exposure to Asenapine in Healthy Volunteers
Coadministered drug
(Postulated effect on CYP450/UGT)
Dose schedules Effect on asenapine pharmacokinetics Recommendation
Coadministered drug Asenapine Cmax AUC0-∞
(CYP1A2 inhibitor)
25 mg twice daily for 8 days 5-mg Single Dose +13% +29% Coadminister with cautionThe full therapeutic dose of fluvoxamine would be expected to cause a greater increase in asenapine plasma concentrations. AUC: Area under the curve.
(CYP2D6 inhibitor)
20 mg once daily for 9 days 5-mg Single Dose –13% –9% No SAPHRIS dose adjustment required [see Drug Interactions]
(CYP1A2/2C19/3A4 inhibitor)
75-mg Single Dose 5-mg Single Dose +17% +10% No SAPHRIS dose adjustment required
(CYP3A4/2D6/1A2 inhibitor)
800 mg twice daily for 8 days 5-mg Single Dose –13% +1% No SAPHRIS dose adjustment required
(CYP3A4 inducer)
400 mg twice daily for 15 days
5-mg Single Dose –16% –16% No SAPHRIS dose adjustment required
(UGT1A4 inhibitor)
500 mg twice daily for 9 days 5-mg Single Dose 2% –1% No SAPHRIS dose adjustment required

A population pharmacokinetic analysis indicated that the concomitant administration of lithium had no effect on the pharmacokinetics of asenapine.

Potential for SAPHRIS to Affect Other Drugs

Coadministration with CYP2D6 Substrates: In vitro studies indicate that asenapine weakly inhibits CYP2D6.

Following coadministration of dextromethorphan and SAPHRIS in healthy subjects, the ratio of dextrorphan/dextromethorphan (DX/DM) as a marker of CYP2D6 activity was measured. Indicative of CYP2D6 inhibition, treatment with SAPHRIS 5 mg twice daily decreased the DX/DM ratio to 0.43. In the same study, treatment with paroxetine 20 mg daily decreased the DX/DM ratio to 0.032. In a separate study, coadministration of a single 75-mg dose of imipramine with a single 5-mg dose of SAPHRIS did not affect the plasma concentrations of the metabolite desipramine (a CYP2D6 substrate). Thus, in vivo, SAPHRIS appears to be at most a weak inhibitor of CYP2D6. Coadministration of a single 20-mg dose of paroxetine (a CYP2D6 substrate and inhibitor) during treatment with 5 mg SAPHRIS twice daily in 15 healthy male subjects resulted in an almost 2-fold increase in paroxetine exposure. Asenapine may enhance the inhibitory effects of paroxetine on its own metabolism.

SAPHRIS should be coadministered cautiously with drugs that are both substrates and inhibitors for CYP2D6.

Valproic acid and lithium pre-dose serum concentrations collected from an adjunctive therapy study were comparable between asenapine treated patients and placebo treated patients indicating a lack of effect of asenapine on valproic and lithium plasma levels.


Human Experience: In pre-marketing clinical studies involving more than 3350 patients and/or healthy subjects, accidental or intentional acute overdosage of SAPHRIS was identified in 3 patients. Among these few reported cases of overdose, the highest estimated ingestion of SAPHRIS was 400 mg. Reported adverse reactions at the highest dosage included agitation and confusion.

Management of Overdosage: There is no specific antidote to SAPHRIS. The possibility of multiple drug involvement should be considered. An electrocardiogram should be obtained and management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms.

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 SAPHRIS-induced alpha blockade). In case of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision and monitoring should continue until the patient recovers.


Hypersensitivity reactions, including anaphylaxis and angioedema, have been observed in patients treated with asenapine. Therefore, SAPHRIS is contraindicated in patients with a known hypersensitivity to the product [see Warnings and Precautions, Adverse Reactions and Patient Counseling Information].


Controlled Substance

SAPHRIS is not a controlled substance.


SAPHRIS has not been systematically studied in animals or humans for its abuse potential or its ability to induce tolerance or physical dependence. Thus, it is not possible to predict the extent to which a CNS-active drug will be misused, diverted and/or abused once it is marketed. Patients should be evaluated carefully for a history of drug abuse, and such patients should be observed carefully for signs that they are misusing or abusing SAPHRIS (e.g., drug-seeking behavior, increases in dose).

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