Ataluren

Caution should be exercised when ataluren is co-administered with medicinal products that are inducers of UGT1A9, or substrates of OAT1 or OAT3.

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 (e.g. oseltamivir, aciclovir, captopril, furosemide, bumetanide, valsartan, pravastatin, rosuvastatin, atorvastatin, pitavastatin).

Caution should also be exercised when ataluren is co-administered with OAT3 substrates (e.g. 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.

Because hypertension with use of concomitant systemic corticosteroids was reported for some patients in clinical trials, it is recommended that resting systolic and diastolic blood pressure be monitored every 6 months in nmDMD patients receiving ataluren concomitantly with corticosteroids, or more frequently as needed based on the patient’s clinical status.

There are no adequate data from the use of ataluren in pregnant women. Studies in animals have shown reproductive toxicity only at doses that resulted in maternal toxicity. As a precautionary measure, it is recommended to avoid the use of ataluren during pregnancy.

It is unknown whether ataluren/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of ataluren/metabolites in milk. A risk to the breastfed new-borns/infants cannot be excluded.

Breast-feeding should be discontinued during treatment with ataluren.

Fertility

Non-clinical data revealed no hazard for humans based on a standard male and female fertility study in rats.

The effect of ataluren on driving, on cycling, or on using machines has not been tested. Patients who experience dizziness should use caution when driving, cycling or using machines.