Source: Drug labeling information submitted to the Food and Drug Administration (FDA), updated by the National Library of Medicine (NLM) .
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.
|
Coadministered drug (Postulated effect on CYP450/UGT) |
Dose schedules |
Effect on asenapine pharmacokinetics |
Recommendation |
||
|
Coadministered drug |
Asenapine |
Cmax |
AUC0-∞ |
||
|
Fluvoxamine (CYP1A2 inhibitor) |
25 mg twice daily for 8 days |
5-mg Single Dose |
13% |
29% |
Coadminister with caution* |
|
Paroxetine (CYP2D6 inhibitor) |
20 mg once daily for 9 days |
5-mg Single Dose |
–13% |
–9% |
No SAPHRIS dose adjustment required [see Drug Interactions (7.2)] |
|
Imipramine (CYP1A2/2C19/3A4 inhibitor) |
75-mg Single Dose |
5-mg Single Dose |
17% |
10% |
No SAPHRIS dose adjustment required |
|
Cimetidine (CYP3A4/2D6/1A2 inhibitor) |
800 mg twice daily for 8 days |
5-mg Single Dose |
–13% |
1% |
No SAPHRIS dose adjustment required |
|
Carbamazepine (CYP3A4 inducer) |
400 mg twice daily for 15 days |
5-mg Single Dose |
–16% |
–16% |
No SAPHRIS dose adjustment required |
|
Valproate (UGT1A4 inhibitor) |
500 mg twice daily for 9 days |
5-mg Single Dose |
2% |
–1% |
No SAPHRIS dose adjustment 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.
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.
