Interactions : אינטראקציות

7       DRUG INTERACTIONS
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.

7.1     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
Effect on asenapine
Coadministered drug                     Dose schedules                                           Recommendation pharmacokinetics
(Postulated effect on
Coadministered
CYP450/UGT)                                             Asenapine      Cmax        AUC0-∞ drug

Fluvoxamine               25 mg twice daily for        5-mg Single                            Coadminister with +13%        +29%
(CYP1A2 inhibitor)                8 days                    Dose                                    caution* 
No SAPHRIS dose
Paroxetine               20 mg once daily for         5-mg Single                                adjustment –13%         –9%
(CYP2D6 inhibitor)                9 days                    Dose                               required [see Drug Interactions (7.2)]

Imipramine                                                                                   No SAPHRIS dose 5-mg Single
(CYP1A2/2C19/3A4             75-mg Single Dose                           +17%        +10%          adjustment Dose inhibitor)                                                                                      required 

No SAPHRIS dose
Cimetidine                 800 mg twice daily          5-mg Single
–13%         +1%          adjustment
(CYP3A4/2D6/1A2 inhibitor)           for 8 days                 Dose required


21
400 mg twice daily                                                                                 No SAPHRIS dose Carbamazepine                                                            5-mg Single for 15 days                                                 –16%               –16%                adjustment (CYP3A4 inducer)                                                             Dose required


No SAPHRIS dose
Valproate                         500 mg twice daily                   5-mg Single 2%                –1%                adjustment
(UGT1A4 inhibitor)                       for 9 days                          Dose required
*The full therapeutic dose of fluvoxamine would be expected to cause a greater increase in asenapine plasma concentrations. AUC: Area under the curve.


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

7.2   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.