TRANSLARNA Granules for oral suspension Ref.[7623] Active ingredients: Ataluren

Patients who do not have a nonsense mutation

Patients must have a nonsense mutation in the dystrophin gene as part of their underlying disease state, as determined by genetic testing. Patients who do not have a nonsense mutation should not receive ataluren.

Renal impairment

An increase in ataluren exposure and in ataluren metabolite has been reported in patients with severe renal impairment (eGFR <30 ml/min). The toxicity of the metabolite is unknown. Higher ataluren exposure was associated with potential decrease in efficacy. Therefore, patients with severe renal impairment or end-stage renal disease should be treated with ataluren only if the anticipated clinical benefit outweighs the potential risk, and should be closely monitored for possible metabolite toxicity and decrease in efficacy. A lower ataluren dose should be considered.

Treatment should not be initiated in previously untreated patients with eGFR <30 ml/min (see sections 4.2 and 5.2).

Changes in lipid profile

Because changes in lipid profile (increased triglycerides and cholesterol) were reported for some patients in clinical trials, it is recommended that total cholesterol, LDL, HDL, and triglycerides be monitored on an annual basis in nonsense mutation Duchenne muscular dystrophy (nmDMD) patients receiving ataluren, or more frequently as needed based on the patient’s clinical status.

Hypertension with use of concomitant systemic corticosteroids

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.

Renal function monitoring

Because small increases in mean serum creatinine, blood urea nitrogen (BUN), and cystatin C were observed in the controlled studies of nmDMD, it is recommended that serum creatinine, BUN, and cystatin C be monitored every 6 to 12 months in nmDMD patients receiving ataluren, or more frequently as needed based on the patient’s clinical status.

Potential interactions with other medicinal products

Caution should be exercised when ataluren is co-administered with medicinal products that are inducers of UGT1A9, or substrates of OAT1 or OAT3 (see section 4.5).

Aminoglycosides

Aminoglycosides have been shown to reduce the readthrough activity of ataluren in vitro. In addition, ataluren was found to increase nephrotoxicity of intravenous aminoglycosides. The co-administration of these medicinal products with ataluren should be avoided (see section 4.3). Since the mechanism by which ataluren increases nephrotoxicity of intravenous aminoglycosides is not known, concomitant use of other nephrotoxic medicinal products with ataluren is not recommended. If this is unavoidable (e.g. vancomycin to treat MRSA) careful monitoring of renal function is advised (see section 4.5).

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 (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.

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.

Pregnancy

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 (see section 5.3). As a precautionary measure, it is recommended to avoid the use of ataluren during pregnancy.

Breastfeeding

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 (see section 5.3). 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 (see section 5.3).

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.

Summary of the safety profile

The safety profile of ataluren is based on pooled data from two randomised, double-blind, 48-week placebo-controlled studies conducted in a total of 232 male patients with Duchenne muscular dystrophy (nmDMD) caused by a nonsense mutation treated at the recommended dose of 40 mg/kg/day (10, 10, 20 mg/kg; n=172) or at a dose of 80 mg/kg/day (20, 20, 40 mg/kg; n=60), as compared to placebo-treated patients (n=172).

The most common adverse reactions in the 2 placebo-controlled studies were vomiting, diarrhoea, nausea, headache, upper abdominal pain, and flatulence, all occurring in ≥5% of all ataluren-treated patients. In both studies, 1/232 (0.43%) patients treated with ataluren discontinued due to an adverse reaction of constipation and 1/172 (0.58%) placebo patients discontinued treatment due to an adverse reaction of disease progression (loss of ambulation).

An open-label study was performed including patients aged 2-5 years (n=14) to evaluate the PK and safety of ataluren. A higher frequency of malaise (7.1%), pyrexia (42.9%), ear infection (28.6%), and rash (21.4%) were reported in patients aged 2-5 years compared with patients 5 years of age and older. However, these conditions are reported more frequently in the younger children in general. Safety data from 28 weeks of therapy showed a similar safety profile of ataluren in patients 2-5 years as compared with patients aged 5 years and older.

Adverse reactions were generally mild or moderate in severity, and no treatment-related serious adverse events were reported among ataluren-treated patients in these 2 studies.

Tabulated list of adverse reactions

The adverse reactions reported in patients with nmDMD treated with the recommended daily dose of 40 mg/kg/day ataluren in the 2 placebo-controlled studies are presented in Table 1. Adverse reactions reported in >1 patient in the 40 mg/kg/day group at a frequency greater than that of the placebo group are presented by MedDRA System Organ Class, Preferred Term, and frequency. Frequency groupings are defined to the following convention: very common (≥1/10) and common (≥1/100 to <1/10).

Table 1. Adverse reactions reported in >1 ataluren-treated patients with nmDMD at a frequency greater than placebo in the 2 placebo-controlled studies (pooled analysis):

In a 48-week open-label extension study in patients with nmDMD patients who were ambulant or non-ambulant demonstrated a similar safety profile. Long term safety data is not available.

Description of selected adverse reactions (laboratory abnormalities)

Serum lipids

An increase in serum lipids, i.e. cholesterol and triglycerides, was observed. There have been cases reported where this increase to abnormal high values was already observed after 4 weeks.

Renal function tests

During the randomised, placebo-controlled studies, small increases in mean serum creatinine, BUN, and cystatin C were observed. The values tended to stabilize early in the study and did not increase further with continued treatment.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.