Interactions : אינטראקציות

4.5 Interaction with other medicinal products and other forms of interaction
Contraindications of concomitant use
Inhibitors of CYP3A4
Lercanidipine is known to be metabolised by the CYP3A4 enzyme and therefore inhibitors of CYP3A4 administered concurrently may interact with the metabolism and elimination of lercanidipine. An interaction study with a strong CYP3A4 inhibitor, ketoconazole, has shown a considerable increase in plasma levels of lercanidipine (a 15-fold increase of the AUC and an 8-fold increase of the Cmax for the eutomer S- lercanidipine).
Co-prescription of lercanidipine with inhibitors of CYP3A4 (e.g. ketoconazole, itraconazole, ritonavir, erythromycin, troleandomycin, clarithromycin) should be avoided (see section 4.3).
Ciclosporin
Increased plasma levels of both lercanidipine and ciclosporin have been observed following concomitant administration. A study in young healthy volunteers has shown that when ciclosporin was administered 3 hours after the lercanidipine intake, the plasma levels of lercanidipine did not change, while the AUC of ciclosporin increased by 27%. However, the co-administration of lercanidipine with ciclosporin has caused a 3-fold increase of the plasma levels of lercanidipine and a 21% increase of the ciclosporin AUC.
Ciclosporin and lercanidipine should not be administered together (see section 4.3).
Grapefruit or grapefruit juice
As for other dihydropyridines, lercanidipine is sensitive to inhibition of metabolism by grapefruit or grapefruit juice, with a consequent rise in its systemic availability and increased hypotensive effect. Lercanidipine should not be taken with grapefruit or grapefruit juice (see section 4.3).

Concomitant use not recommended
Inducers of CYP3A4
Co-administration of lercanidipine with CYP3A4 inducers like anticonvulsants (e.g. phenytoin, phenobarbital, carbamazepine) and rifampicin should be approached with caution since the antihypertensive effect may be reduced and blood pressure should be monitored more frequently than usual (see section 4.4).

Alcohol
Alcohol should be avoided since it may potentiate the effect of vasodilating antihypertensive drugs (see section 4.4).

Precautions including dose adjustment
Substrates of CYP3A4
Caution should be exercised when lercanidipine is co-prescribed with other substrates of CYP3A4, like terfenadine, astemizole, class III antiarrhythmic drugs such as amiodarone, quinidine, sotalol.
Midazolam
When concomitantly administered at a dose of 20 mg with midazolam p.o. to elderly volunteers, lercanidipine absorption was increased (by approximately 40%) and the rate of absorption was decreased (tmax was delayed from 1.75 to 3 hours). Midazolam concentrations were not modified.
Metoprolol
When lercanidipine was co-administered with metoprolol, a β-blocker eliminated mainly by the liver, the bioavailability of metoprolol was not changed while that of lercanidipine was reduced by 50%. This effect may be due to the reduction in the hepatic blood flow caused by β-blockers and may therefore occur with other drugs of this class. Consequently, lercanidipine may be safely administered with β-adrenoceptor blocking drugs, but dose adjustment may be required.
Digoxin
Co-administration of 20 mg lercanidipine in patients chronically treated with β-methyldigoxin showed no evidence of pharmacokinetic interaction. However, a mean increase of 33% in digoxin Cmax was observed, while AUC and renal clearance were not significantly modified. Patients on concomitant digoxin treatment should be closely monitored clinically for signs of digoxin toxicity.


Concomitant use with other drugs
Fluoxetine
An interaction study with fluoxetine (an inhibitor of CYP2D6 and CYP3A4), conducted in volunteers of an age 

of 65 ± 7 years (mean ± s.d.), has shown no clinically relevant modification of the pharmacokinetics of lercanidipine.
Cimetidine
Concomitant administration of cimetidine 800 mg daily does not cause significant modifications in plasma levels of lercanidipine, but at higher doses caution is required since the bioavailability and the hypotensive effect of lercanidipine may be increased.
Simvastatin
When a dose of 20 mg of lercanidipine was repeatedly co-administered with 40 mg of simvastatin, the AUC of lercanidipine was not significantly modified, while simvastatin AUC increased by 56% and that of its active metabolite β-hydroxyacid by 28%. It is unlikely that such changes are of clinical relevance. No interaction is expected when lercanidipine is administered in the morning and simvastatin in the evening, as indicated for such drug.
Diuretics and ACE inhibitors
Lercanidipine has been safely administered with diuretics and ACE inhibitors.
Other medications affecting blood pressure
As for all antihypertensive medications, an increased hypotensive effects may be observed when lercanidipine is administered with other medications affecting blood pressure, such as alphablockers for the treatment of urinary symptoms, tricyclic antidepressants, neuroleptics. On the contrary, a reduction of the hypotensive effect may be observed with a concomitant use with corticosteroids.