Interactions : אינטראקציות

4.5     Interaction with other medicinal products and other forms of interaction

Aminoglycosides
Ataluren should not be co-administered with intravenous aminoglycosides, based on cases of decreased renal function observed in a clinical trial in patients with nmCF (see section 4.3).

Elevations of serum creatinine occurred in several nmCF patients treated with ataluren and intravenous aminoglycosides together with other antibiotics for cystic fibrosis exacerbations. The serum creatinine elevations resolved in all cases, with discontinuation of the intravenous aminoglycoside, and either continuation or interruption of Translarna. These findings suggested that co-administration of Translarna and intravenous aminoglycosides may potentiate the nephrotoxic effect of the aminoglycosides.
Therefore, if treatment with intravenous aminoglycosides is necessary the treatment with Translarna should be stopped and can be resumed 2 days after administration of the aminoglycoside has ended.
The effect of co-administration of ataluren with other nephrotoxic medicinal products is unknown.

Dehydration may be a contributing factor in some of these cases. Patients should maintain adequate hydration while taking ataluren (See section 4.4).

Effect of other medicinal products on ataluren pharmacokinetics
Based on in vitro studies, ataluren is a substrate of UGT1A9. Co-administration of rifampicin, a strong inducer of metabolic enzymes including UGT1A9, decreased ataluren exposure by 29%.
The significance of these findings for humans is unknown. Caution should be exercised when ataluren is co-administered with medicinal products that are inducers of UGT1A9 (e.g. rifampicin).


Effect of ataluren on pharmacokinetics of other medicinal products
Based on in vitro studies, ataluren has the potential to inhibit UGT1A9, organic anion transporter 1 (OAT1), organic anion transporter 3 (OAT3) and organic anion transporting polypeptide 1B3 (OATP1B3).
Co-administration of ataluren with mycophenolate mofetil in healthy subjects did not affect the exposure of its active metabolite, mycophenolic acid (a substrate of UGT1A9).
No dose adjustment is required when ataluren is co-administered with medicinal products that are substrates of UGT1A9.
In a clinical study to evaluate the potential for ataluren to inhibit the OATP1B3 transport system using a single-dose of 80 mg telmisartan, an in-vitro selective OATP1B3 substrate, ataluren increased the exposure to telmisartan by 28%. This effect is considered clinically not relevant. However, the magnitude of this effect could be larger for the 40 mg dose of telmisartan. Therefore caution should be exercised when ataluren is co-administered with medicinal products that are substrates of OAT1 or OATP1B3 because of the risk of increased concentration of these medicinal products (eg, oseltamivir, aciclovir, captopril, furosemide, bumetanide, valsartan, pravastatin, rosuvastatin, atorvastatin, pitavastatin). Caution should also be exercised when ataluren is co-administered with OAT3 substrates (eg, ciprofloxacin), especially those OAT3 substrates with a narrow therapeutic window. In a clinical study, the extent of exposure for ciprofloxacin was 32% higher in the presence of ataluren. In a separate clinical study, the extent of exposure for adefovir was 60% higher in the presence of ataluren. Caution should be exercised when ataluren is co-administered with adefovir.

Based on the in vitro studies, ataluren is not expected to be an inhibitor of neither p-gp mediated transport nor of cytochrome P450 mediated metabolism. Similarly, ataluren is not expected in vivo to be an inducer of cytochrome P450 isoenzymes.

Coadministration of corticosteroids (deflazacort, prednisone, or prednisolone) with ataluren did not affect the plasma concentrations of ataluren. No clinically relevant change in the plasma concentrations of corticosteroids was seen with co-administration of ataluren. These data indicate no apparent drug-drug interaction between corticosteroids and ataluren, and no dose adjustments are required.

Medicinal products that affect the p-glycoprotein transporter
In vitro, ataluren is not a substrate for the p-glycoprotein transporter. The pharmacokinetics of ataluren are unlikely to be affected by medicinal products that inhibit the p-glycoprotein transporter.