The US Food and Drug Administration (FDA) has approved bosentan (Tracleer, Actelion Pharmaceuticals US Inc) for children aged 3 years and older with idiopathic or congenital pulmonary arterial hypertension (PAH). This is the first FDA-approved medication for children with PAH.
The drug will be available in a new 32-mg tablet that is scored to allow weight-based dose adjustment for younger patients. It can be dispersed in a teaspoon of water before being given orally. Bosentan is expected to improve exercise ability by improving pulmonary vascular resistance.
The FDA approved bosentan for pulmonary arterial hypertension in November 2001.
“Actelion has focused on the needs of the PAH community since Tracleer, our first treatment for PAH, was approved in 2001,” Gary Palmer, MD, MBA, senior vice president, medical, Actelion Pharmaceuticals, said in a company news release. “We’re pleased our portfolio of treatments continues to grow and pediatric PAH patients will now have an FDA-approved treatment option available.”
Bosentan is an endothelin receptor antagonist indicated for the treatment of adults with PAH (World Health Organization [WHO] group 1) to improve exercise ability and reduce clinical worsening. Endothelin occurs naturally in the body and is involved in blood circulation; too much of the chemical can tighten the blood vessels, reducing blood flow and making the heart work less effectively.
Bosentan blocks the effects of excess endothelin produced in patients with PAH.
Clinical trials that demonstrated effectiveness included primarily those with WHO functional class II to IV symptoms and causes of idiopathic or heritable PAH (60%), PAH associated with connective tissue disorders (21%), and PAH associated with congenital heart disease and left-to-right shunting (18%).
In addition to the existing 62.5- and 125-mg dosages for adults, the 32-mg tablets are expected to be available by the fourth quarter of 2017.
Adverse Events, Boxed Warning
Bosentan can cause hepatotoxicity and birth defects; therefore, it is available only through the Tracleer risk evaluation and mitigation strategy program. The program requires enrollment of prescribers, patients, and pharmacies.
Bosentan is contraindicated in women who are or who may become pregnant, with cyclosporine A, with glyburide, and in patients with hypersensitivity to bosentan or any component of Tracleer. Drug reaction with eosinophilia and systemic symptoms, anaphylaxis, rash, and angioedema have been observed in patients taking bosentan.
In clinical trials, elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (more than 3 times the upper limit of normal [ULN]) were seen in 11% of those treated with bosentan, along with elevated bilirubin in a few patients. In a pooled analysis of studies conducted in pediatric patients with PAH, 2% of patients experienced elevations in liver aminotransferases at least 3 times ULN. Patients should have aminotransferase levels measured before beginning treatment and monthly thereafter. The drug should not be used in patients with moderate or severe liver impairment or elevated ALT/AST more than 3 times ULN before beginning treatment.
The most common adverse events occurring more often in patients taking bosentan compared with placebo were respiratory tract infection (22% vs 17%), headache (15% vs 14%), edema (11% vs 9%), chest pain (5% vs 5%), syncope (5% vs 4%), flushing (4% vs 3%), hypotension (4% vs 2%), sinusitis (4% vs 2%), arthralgia (4% vs 2%), abnormal serum aminotransferases (4% vs 2%), heart palpitations (4% vs 2%), and anemia (3% vs 0%).
Patients should be monitored closely for clinically significant fluid retention, which could indicate underlying heart failure. Patients with signs of pulmonary edema may have associated pulmonary veno-occlusive disease and may need to discontinue bosentan.
Patients can experience a dose-related drop in hemoglobin and hematocrit; therefore, hemoglobin should be measured after 1 and 3 months and every 3 months thereafter. The cause and need for specific treatment should be determined in patients whose hemoglobin decreases markedly.
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