ataluren

Ataluren is an investigational drug used to delay disease progression in ambulatory patients with Duchenne muscular dystrophy (DMD), a progressive and fatal neuromuscular disease. The medication is not yet approved by the FDA and is not available in the U.S., however, it received conditional marketing authorization on July 31, 2014, valid throughout the European Union (EU). The drug is currently under additional monitoring by the European Medicines Agency (EMA), and is available in some European countries, Brazil, Chile, Israel and the Republic of Korea.

Duchenne muscular dystrophy is an X-linked genetic disease that, almost exclusively, male offspring inherit from a carrier mother, who usually has no symptoms or rarely, mild symptoms. Duchenne muscular dystrophy is a severe muscle wasting disease caused by the complete absence of dystrophin, a protein that is vital for the integrity of muscle cells, due to mutations in the dystrophin gene. Absence of this protein results in progressive loss of skeletal muscle tissue that affects walking ability and eventually the respiratory and cardiac muscles.

DMD symptoms usually appear by 3 to 5 years of life, the patient is typically wheelchair-bound by age 14, and death occurs before the third decade due to cardiorespiratory complications. Becker muscular dystrophy (BMD) is a rarer disease similar to DMD, but a less severe form with milder symptoms and better life expectancy. Until now, there is no cure for either disease and they are managed with corticosteroids, cardiac medications and assistive devices. Ataluren is the first drug that targets treatment by enabling the production of a modified dystrophin protein.

Ataluren is indicated for DMD that results from a specific mutation known as nonsense mutation in the dystrophin gene, present in approximately 13% of DMD patients. The presence of the nonsense mutation is determined by genetic testing. Nonsense mutation results in a premature ‘stop codon’ in the messenger RNA (mRNA), which terminates the translation before a full-length protein is generated. Ataluren enables readthrough of the defective mRNA, prevents premature termination and helps generate a full-length, functional protein.

• Do not use ataluren in patients with hypersensitivity to any of its components.
• Do not use ataluren to treat DMD patients who do not have a nonsense mutation of the dystrophin gene. Presence of nonsense mutation must be determined by genetic testing before initiating treatment.
• Do not use concurrently with intravenous (IV) aminoglycosides, antibiotics that work by inhibiting protein synthesis. Aminoglycosides reduce the efficacy of ataluren. In addition, ataluren increases nephrotoxicity from aminoglycosides.
• Do not use ataluren concurrently with any other drug that is nephrotoxic. If it is unavoidable, monitor the patient’s kidney function closely.
• Exposure to ataluren and its metabolite can be increased in patients with severe renal impairment. Higher exposure to ataluren reduces its efficacy and the toxicity of ataluren metabolite is unknown. Use ataluren to treat patients with severe renal impairment and end-stage renal disease only if potential benefit outweighs potential risk, monitor the patient closely, and consider reducing ataluren dosage.
• Changes in the lipid profile were reported in ataluren clinical trials. Monitor the patient’s triglycerides and cholesterol levels annually, or more frequently if necessary.
• Concomitant administration with corticosteroids has been reported to cause hypertension in some patients. Monitor the patient’s blood pressure levels every 6 months or more frequently, if needed.
• There have been small increases in serum creatinine, blood urea nitrogen (BUN) and cystatin C in some patients receiving ataluren. Monitor the patient’s kidney function, and creatinine, BUN and cystatin C levels every 6 to 12 months or more frequently, based on the patient’s clinical status.

Common side effects of ataluren include:

• Headache
• Nausea
• Vomiting
• Diarrhea
• Upper abdominal pain
• Gas (flatulence)
• Abdominal discomfort
• Constipation
• Decrease in appetite
• Increase in cholesterol and triglyceride levels in blood
• Fever (pyrexia)
• Ear infection
• Red rash (erythematous rash)
• Feeling unwell (malaise)
• Weight loss
• High blood pressure (hypertension)
• Cough
• Nasal bleeding (epistaxis)
• Pain in extremity
• Musculoskeletal chest pain
• Urinary incontinence (enuresis)
• Blood in urine (hematuria)
• Increase in:
  • Creatinine
  • Blood urea nitrogen (BUN)
  • Cystatin C

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Granules for oral suspension

• 125 mg
• 250 mg
• 1000 mg

Pediatric:

Duchenne Muscular Dystrophy (DMD)

• Indicated for the treatment of Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene, in ambulatory patients aged 2 years (5 years in some countries) and older
• Granules are to be taken by mouth after mixing them with liquid or semi-solid food (such as yogurt).
• Ataluren is taken three times a day, and the recommended dose is 10 mg/kg (10 mg per kilogram body weight) in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening (for a total daily dose of 40 mg/kg).
• The safety and efficacy of ataluren in children weighing less than 12 kg and aged below 2 years have not yet been established

Overdose

• Overdose of 200 mg/kg ataluren in healthy individuals did not cause serious symptoms.
• Overdose symptoms included transient, low-grade nausea, vomiting, diarrhea, and headache.
• Ataluren overdose may be treated with symptomatic and supportive care.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

Interactions with ataluren include:

• aminoglycosides
• rifampicin
• oseltamivir
• acyclovir
• captopril
• furosemide
• bumetanide
• valsartan
• pravastatin
• rosuvastatin
• atorvastatin
• pitavastatin
• ciprofloxacin

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• There are no data on the use of ataluren in pregnant women. Animal reproductive studies show toxicity to fetus at doses that cause maternal toxicity.
• It is not known if ataluren is present in breastmilk, however, the drug and its metabolites were excreted in animal milk. Avoid breastfeeding during ataluren therapy.

• Take ataluren exactly as directed.
• Drink adequate fluids to avoid dehydration.
• Do not drive or operate heavy machinery if you feel dizzy.
• You will need periodic lab tests. Follow up with your physician and do not miss your appointments.
• Store ataluren safely out of reach of children.
• In case of overdose, contact your physician or Poison Control.