Translarna^® (Powder) Instructions for Use

Marketing Authorization Holder

PTC Therapeutics International Ltd. (Ireland)

Manufactured By

Pharmaceutical Manufacturing Research Services, Inc. (USA)

Labeled By

ANDERSONBRECON, Inc. (USA)

Or

ALMAC PHARMA SERVICES, Limited (United Kingdom)

Quality Control Release

ANDERSONBRECON, Inc. (USA)

Or

ALMAC PHARMA SERVICES, Limited (United Kingdom)

ATC Code

M09AX03 (Ataluren)

Active Substance

Ataluren (Rec.INN registered by WHO)

Dosage Forms

	Translarna®	Powder for oral administration 125 mg: sachet 30 pcs.
		Powder for oral administration 250 mg: sachet 30 pcs.
		Powder for oral administration 1000 mg: sachet 30 pcs.

Dosage Form, Packaging, and Composition

Powder for oral administration white or almost white, granular, with a vanilla odor.

Excipients: polydextrose (E1200) – 128.25 mg, macrogol 3350 – 50 mg, poloxamer 407 – 18.5 mg, mannitol (E421) – 132 mg, crospovidone – 25 mg, hydroxyethylcellulose – 7.5 mg, colloidal silicon dioxide (E551) – 5 mg, magnesium stearate – 5 mg, artificial flavor “Vanillin” (corn maltodextrin, propylene glycol, flavoring agent) – 3.75 mg.

500 mg – sachets (30) – cardboard packs with a first-opening control sticker.

Powder for oral administration white or almost white, granular, with a vanilla odor.

Excipients: polydextrose (E1200) – 256.5 mg, macrogol 3350 – 100 mg, poloxamer 407 – 37 mg, mannitol (E421) – 264 mg, crospovidone – 50 mg, hydroxyethylcellulose – 15 mg, colloidal silicon dioxide (E551) – 10 mg, magnesium stearate – 10 mg, artificial flavor “Vanillin” (corn maltodextrin, propylene glycol, flavoring agent) – 7.5 mg.

1000 mg – sachets (30) – cardboard packs with a first-opening control sticker.

Powder for oral administration white or almost white, granular, with a vanilla odor.

Excipients: polydextrose (E1200) – 1026 mg, macrogol 3350 – 400 mg, poloxamer 407 – 148 mg, mannitol (E421) – 1056 mg, crospovidone – 200 mg, hydroxyethylcellulose – 60 mg, colloidal silicon dioxide (E551) – 40 mg, magnesium stearate – 40 mg, artificial flavor “Vanillin” (corn maltodextrin, propylene glycol, flavoring agent) – 30 mg.

4000 mg – sachets (30) – cardboard packs with a first-opening control sticker.

Clinical-Pharmacological Group

Gene therapy drug used for Duchenne muscular dystrophy

Pharmacotherapeutic Group

Other preparations for the treatment of musculoskeletal system disorders

Pharmacological Action

A treatment for Duchenne muscular dystrophy (DMD). A nonsense DNA mutation causes a premature stop codon in the mRNA. As a result, the synthesis of the full-length protein stops.

Ataluren allows the translating ribosome to read through the mRNA containing the premature stop codon and synthesize the full-length protein.

Pharmacokinetics

Although Ataluren is practically insoluble in water, after oral administration it is rapidly absorbed from the gastrointestinal tract.

The mean C_max of ataluren in plasma is reached 1.5 hours after administration and is dose-dependent. The mean relative bioavailability of ataluren is at least 55% when taken 30 minutes after a meal.

The binding of ataluren to plasma proteins is 99.6%, and the degree of binding is independent of plasma concentration. Ataluren does not bind to erythrocytes.

In studies in healthy volunteers, the relative bioavailability of ataluren upon repeated administration was approximately 40% lower than after the first dose. The decrease in relative bioavailability occurs approximately 60 hours after the first dose.

The C_ss of ataluren in plasma at the recommended dosage regimen is established in approximately 2 weeks. No accumulation of ataluren is observed with repeated doses.

Ataluren is metabolized by conjugation via the UGT1A9 enzyme, predominantly in the liver and intestine.

In in vivo studies after oral administration of radiolabeled ataluren, a single metabolite was detected in plasma – Ataluren-O-1β-acyl-glucuronide. The concentration of this metabolite in plasma is about 8% of the AUC_Ataluren.

The T_1/2 of ataluren is 2-6 hours and depends more on the functional state of the liver and kidneys than on the administered dose.

After a single administration of radiolabeled Ataluren, it was detected in equal proportions in feces and urine. Also, in urine, in addition to ataluren at a concentration of <1%, its metabolite is detected at a concentration of 49%.

No cumulative effect is observed with repeated oral administration of ataluren at doses from 10 to 50 mg/kg.

Indications

Congenital Duchenne muscular dystrophy (DMD) caused by a nonsense mutation in the dystrophin gene, in adults and children over 2 years of age.

ICD codes

Dosage Regimen

Administer orally three times daily, morning, midday, and evening.

Calculate the daily dose based on the patient’s actual body weight.

The recommended daily dosage is 40 mg/kg divided into three approximately equal doses.

Take each dose following a specific meal schedule: the morning and midday doses must be taken within 30 minutes after the start of a meal.

Take the evening dose immediately following the evening meal, ideally on an empty stomach or with a very small amount of food.

This meal schedule is critical for optimal absorption.

For dose preparation, empty the entire contents of the prescribed sachet(s) into a clean container.

Add a minimum of 120 mL (approximately 4 ounces) of liquid—water, milk, or fruit juice—and stir vigorously.

Consume the entire suspension immediately after preparation; do not store for later use.

Available strengths are 125 mg, 250 mg, and 1000 mg sachets.

Combine different strength sachets as needed to achieve the precise prescribed dose.

Initiate treatment under the supervision of a physician experienced in managing Duchenne muscular dystrophy.

Regularly monitor renal function, lipid profile, and blood pressure during therapy.

Discontinue treatment during intravenous administration of aminoglycoside antibiotics.

Adverse Reactions

Metabolism and nutrition disorders common – decreased appetite, hypertriglyceridemia, hyperthermia, weight loss; frequency unknown – changes in lipid profile (increased levels of cholesterol and triglycerides).

Nervous system disorders common – headache.

Cardiac disorders common – arterial hypertension.

Respiratory, thoracic and mediastinal disorders common – cough, epistaxis.

Gastrointestinal disorders very common – vomiting; common – nausea, upper abdominal pain, abdominal discomfort, flatulence, constipation.

Skin and subcutaneous tissue disorders common – erythematous rash.

Musculoskeletal and connective tissue disorders common – pain in extremity, musculoskeletal chest pain.

Renal and urinary disorders common – hematuria, enuresis.

Contraindications

Hypersensitivity to ataluren; concomitant use with intravenous administration of aminoglycoside antibiotics; pregnancy, breastfeeding; children under 2 years of age.

With caution

Renal impairment.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

No dose adjustment is required in patients with hepatic impairment.

Use in Renal Impairment

Use with caution in patients with renal impairment.

Pediatric Use

Used in children over 2 years of age.

Special Precautions

Before using ataluren, genetic testing for the presence of a nonsense mutation in the dystrophin gene should be performed.

During treatment, it is recommended to perform a blood test for total cholesterol, LDL, HDL, and triglyceride levels at least once a year.

It is recommended to monitor blood pressure at least once every 6 months.

Since ataluren may increase the average serum creatinine, blood urea nitrogen, and cystatin C levels, a blood test for these parameters should be performed at least once a year.

Concomitant use of ataluren with intravenously administered aminoglycosides and other nephrotoxic drugs (e.g., vancomycin) increases the nephrotoxic effect of the latter.

If it is not possible to avoid simultaneous administration of ataluren with a nephrotoxic drug, renal function should be regularly monitored.

Due to the possible development of dehydration during the use of ataluren, patients are recommended to take a sufficient amount of fluid.

Effect on ability to drive vehicles and operate machinery

No specific studies have been conducted, but if adverse events occur that may affect these abilities, it is recommended to avoid driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions (until these symptoms disappear).

Drug Interactions

Concomitant use of ataluren and intravenous administration of aminoglycosides is not recommended, as it enhances the nephrotoxic effect of the latter.

Also, with such a treatment regimen, an increase in serum creatinine levels is possible. After discontinuation of the concomitant use of ataluren and aminoglycosides, the creatinine level returns to normal.

During treatment with intravenously administered aminoglycosides, it is recommended to discontinue ataluren and resume it 2 days after the end of aminoglycoside administration.

Since the mechanism of enhancement of the nephrotoxic effect of aminoglycosides in the presence of ataluren is unknown, the use of other drugs with nephrotoxicity together with ataluren is not recommended.

Ataluren is a substrate of UGT1A9. In in vitro studies, with the concomitant use of ataluren and inducers of metabolic enzymes, including UGT1A9, a 29% decrease in ataluren exposure was observed.

Caution is recommended when using ataluren concomitantly with UGT1A9 inducers (rifampicin).

In in vitro studies, Ataluren inhibited the activity of UGT1A9, organic anion transporter 1 (OAT1), organic anion transporter 3 (OAT3), and organic anion transporting polypeptide 1B3 (OATP1B3).

Caution should be exercised when co-administering ataluren and substrates of OAT1 or OATP1B3 (oseltamivir, acyclovir, captopril, furosemide, bumetanide, valsartan, pravastatin, rosuvastatin, atorvastatin, pitavastatin) due to the risk of increased concentrations of these drugs.

Caution should be exercised when co-administering ataluren and substrates of OAT3 (ciprofloxacin). In clinical studies, the exposure of ciprofloxacin in the presence of ataluren increased by 32%, and the exposure of adefovir by 60%.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.