Translarna

/ Medison

Treatment with Translarna should only be initiated by specialist physicians with experience in the management of Duchenne/Becker muscular dystrophy.
Ataluren should be administered orally every day in 3 doses.
The first dose should be taken in the morning, the second at midday, and the third in the evening. Recommended dosing intervals are 6 hours between morning and midday doses, 6 hours between midday and evening doses, and 12 hours between the evening dose and the first dose on the next day.
The recommended dose is 10 mg/kg body weight in the morning, 10 mg/kg body weight at midday, and 20 mg/kg body weight in the evening (for a total daily dose of 40 mg/kg body weight).
Translarna is available in sachets of 125 mg, 250 mg or 1000 mg. Please refer to table 1 at the attached doctor’s leaflet for information on which sachet strength(s) to use in the preparation of the recommended dose by body weight range.
Delayed or missed dose: If there is a delay in the administration of ataluren of less than 3 hours after the morning or midday doses or less than 6 hours after the evening dose, the dose should be taken with no changes to the subsequent dose schedules. If there is a delay of more than 3 hours after the morning or midday doses or more than 6 hours after the evening dose, the dose should not be taken, and patients should resume their usual dosing schedule. Patients should not take a double or extra dose if a dose is missed. It is important to administer the correct dose.
Increasing the dose above the recommended dose may be associated with reduced effectiveness.
Elderly: The safety and efficacy of ataluren in patients aged 65 and older have not yet been established.
Renal impairment: Safety and efficacy of ataluren in patients with renal impairment has not been established.
Hepatic impairment: No dosage adjustment is required for patients with mild, moderate or severe hepatic impairment.
Paediatric population: Paediatric patients with body weight ≥12 kg are treated as per the dosing recommendations by body weight range (see dosing table). The recommended dose is the same for all age ranges, i.e. 10 mg/kg body weight in the morning, 10 mg/kg body weight at midday, and 20 mg/kg body weight in the evening (for a total daily dose of 40 mg/kg body weight).
The safety and efficacy of Translarna in children <12kg and aged 6 months to 2 years have not yet been established. No data are available.
Method of administration: Translarna should be administered orally after mixing it to a suspension in liquid or in semisolid food. Sachets should only be opened at the time of dose preparation. The full contents of each sachet should be mixed with, at least 30 ml of liquid (water, milk, fruit juice) or 3 tablespoons of semi-solid food (yoghurt or apple sauce). The prepared dose should be mixed well before administration. The amount of the liquid or semi-solid food can be increased based on patient preference. Patients should take the entire dose.

Translarna is indicated for the treatment of Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene, in ambulatory patients aged 2 years and older. Efficacy has not been demonstrated in non-ambulatory patients.
The presence of a nonsense mutation in the dystrophin gene should be determined by genetic testing.

Hypersensitivity to the active substance or to any of the excipients.
Concomitant use of intravenous aminoglycosides.

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: Patients with renal impairment should be closely monitored.
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 oncomitantly 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 OAT1or OAT3.
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. 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.

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.
See prescribing information for full details.

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.
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.
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.

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.
As a precautionary measure, it is recommended to avoid the use of ataluren during pregnancy.
Lactation: 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.

Healthy volunteers receiving a single oral dose of 200 mg/kg of ataluren experienced transient, low-grade symptoms of headache, nausea, vomiting, and diarrhoea. No serious adverse reactions were observed in these subjects. In the event of a suspected overdose, supportive medical care should be provided including consulting with a healthcare professional and close observation of the clinical status of the patient.

Shelf-life: Each prepared dose is best administered immediately after preparation. The prepared dose should be discarded if not consumed within 24 hours of preparation if kept refrigerated (2-8°C), or within 3 hours at room temperature (15-30°C).