FDA Uses Bridging Analyses of Pediatric Hemodynamic Data to Adult Exercise Capacity in the Approval of Tracleer® (Bosentan) for Pediatric Pulmonary Arterial Hypertension Patients 3 Years of Age and Older 

On September 5, 2017, the US Food & Drug Administration (FDA) approved Tracleer (bosentan) for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) in pediatric patients aged 3 years and older. This is the first approval of a drug for the treatment of pediatric PAH with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), which is expected to result in an improvement in exercise ability. FDA’s efficacy evaluation relied on the findings from one of the trials − BREATHE-3, an open-label, uncontrolled study in 19 pediatric patients with PAH aged 3 to 15 years which measured PVR, a cardio-pulmonary hemodynamic variable. FDA conducted analyses using data from previously approved programs in adults that established the relationship between improvements in the 6-minute walk distance (6MWD) and PVR in adults and showed that the relationship was consistent across different approved drug classes (e.g., endothelin receptor antagonist, prostanoids, PDE5 inhibitor, and soluble guanylate cyclase stimulator). The observed reduction in PVR in pediatrics from the BREATHE-3 study was used to bridge the bosentan efficacy findings in adults. 

Safety in pediatric patients is supported by data from 100 pediatric patients treated with bosentan for a median of 17 months.

The new Tracleer oral dispersible tablet was also approved to facilitate use in adults and pediatric patients who cannot swallow the previously approved film-coated tablet. Although this new dosage form contains two cross-sectional scores, the approved recommended dosage regimen for patients 3-12 years of age is tailored so as to allow only a bisection of the dosage form. 

The approved recommended dosage regimen for Tracleer is based on age and body weight.  
For patients > 12 years of age and: 
> 40 kg: The approved recommended initial dosage is 62.5 mg orally twice daily.  After 4 weeks, increase to a maintenance dosage of 125 mg orally twice daily.  
< 40 kg: The approved recommended dosage is 62.5 mg orally twice daily.
For patients 3-12 years of age and: 
≥ 4-8 kg: The approved recommended dosage is 16 mg orally twice daily.
> 8-16 kg: The approved recommended dosage is 32 mg orally twice daily.
> 16-24 kg: The approved recommended dosage is 48 mg orally twice daily.
> 24-40 kg: The approved recommended dosage is 64 mg orally twice daily.

Reduce dosage and closely monitor patients developing aminotransferase elevations more than 3 times the upper limit of normal. Additional dosage recommendations and modification information are described in the full prescribing information linked below.

Common adverse reactions (≥ 3% more than placebo) for the film-coated tablet are respiratory tract infection and anemia. Common adverse reactions (≥ 15%) for the dispersible tablet are upper respiratory tract infections and pyrexia. 

Tracleer is also indicated for the treatment of PAH (WHO Group 1) in adults to improve exercise ability and to decrease clinical worsening. 

Full prescribing information is available at https://go.usa.gov/xRtpn

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products which are often available shortly following approval.