4.1. Therapeutic indications

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 (see section 5.1).

The presence of a nonsense mutation in the dystrophin gene should be determined by genetic testing (see section 4.4).

4.2. Posology and method of administration

Treatment with Translarna should only be initiated by specialist physicians with experience in the management of Duchenne/Becker muscular dystrophy.

Posology

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. The table below provides information on which sachet strength(s) to use in the preparation of the recommended dose by body weight range.

Weight Range (kg)

Number of sachets

Morning

Midday

Evening

125 mg sachets

250 mg sachets

1000 mg sachets

125 mg sachets

250 mg sachets

1000 mg sachets

125 mg sachets

250 mg sachets

1000 mg sachets

12

14

1

0

0

1

0

0

0

1

0

15

16

1

0

0

1

0

0

1

1

0

17

20

0

1

0

0

1

0

0

1

0

21

23

0

1

0

0

1

0

1

1

0

24

26

0

1

0

0

1

0

0

2

0

27

31

0

1

0

0

1

0

1

2

0

32

35

1

1

0

1

1

0

1

2

0

36

39

1

1

0

1

1

0

0

3

0

40

44

1

1

0

1

1

0

1

3

0

45

46

0

2

0

0

2

0

1

3

0

47

55

0

2

0

0

2

0

0

0

1

56

62

0

2

0

0

2

0

0

1

1

63

69

0

3

0

0

3

0

0

1

1

70

78

0

3

0

0

3

0

0

2

1

79

86

0

3

0

0

3

0

0

3

1

87

93

0

0

1

0

0

1

0

3

1

94

105

0

0

1

0

0

1

0

0

2

106

111

0

0

1

0

0

1

0

1

2

112

118

0

1

1

0

1

1

0

1

2

119

125

0

1

1

0

1

1

0

2

2

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.

Special populations

Elderly

The safety and efficacy of ataluren in patients aged 65 and older have not yet been established (see section 5.2).

Renal impairment

No dosage adjustment is required for patients with mild or moderate renal impairment. Treatment of patients with severe renal impairment (eGFR <30 ml/min) or end-stage renal disease is not recommended (see sections 4.4 and 5.2).

Hepatic impairment

No dosage adjustment is required for patients with mild, moderate or severe hepatic impairment (see section 5.2).

Paediatric population

Paediatric patients with body weight ≥12 kg are treated as per the dosing recommendations by body weight range (see above 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 been established. No data are available. Currently available safety and pharmacokinetic data are described in section 4.8 and 5.2.

Method of administration

Translarna should be administered orally after mixing it to a suspension in liquid or in semi-solid 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.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Concomitant use of intravenous aminoglycosides (see sections 4.4 and 4.5).

4.4. Special warnings and precautions for use

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).

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 (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.

4.6. Fertility, pregnancy and lactation

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).

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

Summary of the safety profile

The safety profile of ataluren is based on pooled data from 1 randomised, double-blind, 72-week placebo-controlled study and 2 randomised, double-blind, 48‑week placebo-controlled studies conducted in a total of 764 male patients with nmDMDat the recommended dose of 40 mg/kg/day (10, 10, 20 mg/kg; n=356) or at a dose of 80 mg/kg/day (20, 20, 40 mg/kg; n=60), as compared to placebo-treated patients (n=348).

The most common adverse reactions in the 3 placebo-controlled studies was vomiting, occurring in ≥5% of all ataluren-treated patients. In the 3 studies, 1/416 (0.24%) patients treated with ataluren discontinued due to an adverse reaction of constipation and 1/348 (0.29%) placebo patients discontinued treatment due to an adverse reaction of disease progression (loss of ambulation).

Adverse reactions were generally mild or moderate in severity. Two treatment-related serious adverse events of upper abdominal pain and vomiting were reported in ataluren-treated patients in the 72-week placebo-controlled study; both events were moderate in severity and resolved without the need for permanent discontinuation of treatment. No treatment-related serious adverse events were reported in ataluren-treated patients in the two 48-week placebo-controlled studies

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.

The safety and PK of ataluren was evaluated in a 24-week open-label study in 6 nmDMD patients aged ≥6 months to <2 years of age (mean age was 14 months, age range 7 – 23 months). In this study, the safety profile was comparable to that seen in nmDMD patients aged >2 years of age.

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 3 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 3 placebo-controlled studies (pooled analysis)

System Organ Class

Very common

Common

Frequency not known

Metabolism and nutrition disorders

Decreased appetite, hypertriglyceridaemia

Change in lipid profile (increased triglycerides and cholesterol)

Nervous system disorders

Headache

Vascular disorders

Hypertension

Respiratory, thoracic, and mediastinal disorders

Cough, epistaxis

Gastrointestinal disorders

Vomiting

Nausea, upper abdominal pain, flatulence, abdominal discomfort, constipation

Skin and subcutaneous tissue disorders

Rash erythematous

Musculoskeletal and connective tissue disorders

Pain in extremity, musculoskeletal chest pain

Renal and urinary disorders

Haematuria, enuresis

Change in renal function tests (increased creatinine, blood urea nitrogen, cystatin C)

General disorders and administration site conditions

Pyrexia, weight decreased

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 Yellow Card Scheme.

Website: https://yellowcard.mhra.gov.uk or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

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.