Interactions : אינטראקציות

4.5            Interaction with other medicinal products and other forms of interaction

Due to its α 1 -adrenergic receptor antagonism, aripiprazole has the potential to enhance the effect of 5TR   R5T


 certain antihypertensive agents.

Given the primary CNS effects of aripiprazole, caution should be used when aripiprazole is taken in combination with alcohol or other CNS medicinal products with overlapping adverse reactions such as sedation (see section 4.8).

If aripiprazole is administered concomitantly with medicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used.

U   Potential for other medicinal products to affect aripiprazole    U28TU 


A gastric acid blocker, the H 2 antagonist famotidine, reduces aripiprazole rate of absorption but this R   R


 effect is deemed not clinically relevant. Aripiprazole is metabolised by multiple pathways involving the CYP2D6 and CYP3A4 enzymes but not CYP1A enzymes. Thus, no dosage adjustment is required for smokers.

Quinidine and other CYP2D6 inhibitors
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In a clinical trial in healthy subjects, a potent inhibitor of CYP2D6 (quinidine) increased aripiprazole AUC by 107 %, while C max was unchanged. The AUC and C max of dehydro-aripiprazole, the active 26TR     R26T                   26TR   R2 6T


 metabolite, decreased by 32 % and 47 %, respectively. Aripiprazole dose should be reduced to approximately one-half of its prescribed dose when concomitant administration of aripiprazole with quinidine occurs. Other potent inhibitors of CYP2D6, such as fluoxetine and paroxetine, may be expected to have similar effects and similar dose reductions should therefore be applied.

Ketoconazole and other CYP3A4 inhibitors
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In a clinical trial in healthy subjects, a potent inhibitor of CYP3A4 (ketoconazole) increased aripiprazole AUC and C max by 63 % and 37 %, respectively. The AUC and C max of dehydro- 26TR    R2 6T                                   26TR   R26T


 aripiprazole increased by 77 % and 43 %, respectively. In CYP2D6 poor metabolisers, concomitant use of potent inhibitors of CYP3A4 may result in higher plasma concentrations of aripiprazole compared to that in CYP2D6 extensive metabolizers.

When considering concomitant administration of ketoconazole or other potent CYP3A4 inhibitors with aripiprazole, potential benefits should outweigh the potential risks to the patient. When concomitant administration of ketoconozole with aripiprazole occurs, aripiprazole dose should be reduced to approximately one-half of its prescribed dose. Other potent inhibitors of CYP3A4, such as itraconazole and HIV protease inhibitors, may be expected to have similar effects and similar dose reductions should therefore be applied.

Upon discontinuation of the CYP2D6 or CYP3A4 inhibitor, the dosage of aripiprazole should be increased to the level prior to the initiation of the concomitant therapy.

When weak inhibitors of CYP3A4 (e.g., diltiazem or escitalopram) or CYP2D6 are used concomitantly with aripiprazole, modest increases in aripiprazole concentrations might be expected.

Carbamazepine and other CYP3A4 inducers
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Following concomitant administration of carbamazepine, a potent inducer of CYP3A4, the geometric means of C max and AUC for aripiprazole were 68 % and 73 % lower, respectively, compared to when 26TR          R26T


 aripiprazole (30 mg) was administered alone. Similarly, for dehydro-aripiprazole the geometric means of C max and AUC after carbamazepine co-administration were 69 % and 71 % lower, respectively,         26TR    R26T


 than those following treatment with aripiprazole alone.
Aripiprazole dose should be doubled when concomitant administration of aripiprazole occurs with carbamazepine. Other potent inducers of CYP3A4 (such as rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine and St. John's Wort) may be expected to have similar effects and similar dose increases should therefore be applied. Upon discontinuation of potent CYP3A4 inducers, the dosage of aripiprazole should be reduced to the recommended dose.

Valproate and lithium
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When either valproate or lithium were administered concomitantly with aripiprazole, there was no clinically significant change in aripiprazole concentrations.

Serotonin syndrome
Cases of serotonin syndrome have been reported in patients taking aripiprazole, and possible signs and symptoms for this condition can occur especially in cases of concomitant use with other serotonergic medicinal products, such as SSRI/SNRI, or with medicinal products that are known to increase aripiprazole concentrations (see section 4.8).

U   Potential for aripiprazole to affect other medicinal products

In clinical studies, 10-30 mg/day doses of aripiprazole had no significant effect on the metabolism of substrates of CYP2D6 (dextromethorphan/3-methoxymorphinan ratio), CYP2C9 (warfarin), CYP2C19 (omeprazole), and CYP3A4 (dextromethorphan). Additionally, aripiprazole and dehydro- aripiprazole did not show potential for altering CYP1A2-mediated metabolism in vitro. Thus, aripiprazole is unlikely to cause clinically important medicinal product interactions mediated by these enzymes.

When aripiprazole was administered concomitantly with either valproate, lithium or lamotrigine, there was no clinically important change in valproate, lithium or lamotrigine concentrations.