Usual Adult Dose for Pulmonary Hypertension

Initial dose: 62.5 mg orally twice a day for 4 weeks
Maintenance dose: Following initial dose, increase to 125 mg orally twice a day

Comments:

• Doses above 125 mg twice a day did not appear to confer additional benefit sufficient enough to offset increased risk of hepatotoxicity.

Use: For the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability and to decrease clinical worsening.

Usual Pediatric Dose for Pulmonary Hypertension

3 to 12 years:
4 kg to 8 kg: 16 mg orally twice a day
Greater than 8 kg to 16 kg: 32 mg orally twice a day
Greater than 16 kg to 24 kg: 48 mg orally twice a day
Greater than 24 kg to 40 kg: 64 mg orally twice a day

Greater than 12 years:

• Less than 40 kg: 62.5 mg orally twice a day
• Greater than 40 kg: 62.5 mg orally twice a day for 4 weeks, then increase to 125 mg orally twice a day

Use: For use in pediatric patients 3 years or older with idiopathic or congenital PAH to improve pulmonary vascular resistance, which is expected to result in an improvement in exercise ability

Renal Dose Adjustments

No adjustment recommended.

Liver Dose Adjustments

Mild liver dysfunction: No adjustment recommended.
Moderate to severe liver dysfunction and/or elevated aminotransferases greater than 3 times the upper limit of normal: Use should be avoided.

Dose Adjustments

Patients Developing Aminotransferase Elevations:

• Discontinue this drug if liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (e.g., nausea, vomiting, fever, abdominal pain, jaundice, unusual lethargy, or fatigue) or bilirubin 2 times the upper limit of normal.

Adults and Pediatric Patients Greater Than 12 Years and Greater than 40 kg:

• ALT/AST greater than 3 times the upper limit of normal (3 x ULN) and less than or equal to 5 x ULN: Confirm by another aminotransferase test; if confirmed, reduce daily dose to 62.5 mg orally twice a day or interrupt treatment, and monitor aminotransferase levels at least every 2 weeks. If aminotransferase levels return to pretreatment values, continue or reintroduce the treatment as appropriate. If this drug is reintroduced it should be at 62.5 mg orally twice a day; aminotransferase levels should be checked within 3 days and thereafter according to the recommendations above.
• ALT/AST greater than 5 x ULN but less than or equal to 8 x ULN: Confirm by another aminotransferase test; if confirmed, stop treatment and monitor aminotransferase levels at least every 2 weeks. Once the aminotransferase levels return to pretreatment values, consider reintroduction of treatment at 62.5 mg orally twice a day; aminotransferase levels should be checked within 3 days and thereafter according to the recommendations above.
• ALT/AST greater than 8 x ULN: Treatment should be stopped and reintroduction should not be considered due to lack of experience with reintroduction in these circumstances.

All Other Pediatric Patients:

• ALT/AST greater than 3 times the upper limit of normal (3 x ULN) and less than or equal to 5 x ULN: Confirm by another aminotransferase test; if confirmed, interrupt treatment with no prior dose reduction. If aminotransferase levels return to pretreatment values, reintroduce at the dose used prior to treatment interruption; aminotransferase levels should be checked within 3 days and thereafter according to the recommendations above.
• ALT/AST greater than 5 x ULN but less than or equal to 8 x ULN: Confirm by another aminotransferase test; if confirmed, stop treatment and monitor aminotransferase levels at least every 2 weeks. Once the aminotransferase levels return to pretreatment values, consider reintroduction of treatment at the dose used prior to treatment interruption; aminotransferase levels should be checked within 3 days and thereafter according to the recommendations above.
• ALT/AST greater than 8 x ULN: Treatment should be stopped and reintroduction should not be considered due to lack of experience with reintroduction in these circumstances.

Body weight below 40 kg in patients 12 years of age or older:

• Initial and maintenance dose: 62.5 mg orally twice a day; limited information on safety and efficacy of this drug in children between the ages of 12 and 18 years.

Coadministration of bosentan in patients who have been receiving ritonavir for at least 10 days:

• Initial dose: 62.5 mg orally once a day or every other day based upon individual tolerability

Coadministration of ritonavir in patients on bosentan: Discontinue bosentan at least 36 hours prior to initiation of ritonavir; after at least 10 days following initiation of ritonavir, resume bosentan at 62.5 mg orally once a day or every other day based upon individual tolerability

Pregnancy testing in females of reproductive potential: Initiate therapy only after a negative pregnancy test; obtain monthly pregnancy tests during treatment.

Treatment discontinuation: To avoid the potential for clinical deterioration, gradual dose reduction (62.5 mg orally twice a day for 3 to 7 days) should be considered.

Precautions

The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for bosentan. It includes elements to assure safe use and an implementation system. For additional information: http://www.accessdata.fda.gov/scripts/cder/rems/index.cfm

US BOXED WARNINGS:

• HEPATOTOXICITY: Elevations of ALT and AST of 3 x ULN can occur and are occasionally accompanied by elevated bilirubin; these changes are a marker for potential serious hepatotoxicity.
• Serum aminotransferase levels must be measured prior to initiation of treatment and then monthly thereafter.
• Elevations in aminotransferases require close attention; this drug should generally be avoided in patients with elevated aminotransferases (greater than 3 x ULN) at baseline because monitoring for hepatotoxicity may be more difficult.
• If liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (e.g., nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin 2 x ULN or greater, treatment should be stopped. There is no experience with the reintroduction of this drug in these circumstances.
• EMBRYOFETAL TOXICITY: This drug is likely to cause major birth defects if used by pregnant females based on animal data.
• Females of reproductive potential must have pregnancy ruled out prior to initiating therapy and must use 2 acceptable forms of contraception (unless the patient has an intrauterine device [IUD] or tubal sterilization, in which case no other contraception is needed) every month for the duration of therapy and for one month following discontinuation of therapy; hormonal contraceptives, including oral, injectable, transdermal, and implantable contraceptives should not be used as the sole means of contraception because these may not be effective in patients receiving this drug.
• Monthly pregnancy tests must also be obtained.

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration advice:

• Take orally twice a day in the morning and evening with or without food.
• Disperse tablets for oral suspension, or dispersible tablet half, in a minimal amount of water immediately prior to administration.

Storage requirements:

• Store divided dispersible tablets at 20C to 25C (68F to 77F) in the opened blister for up to 7 days.

General:

• Studies establishing effectiveness included predominately patients with New York Heart Association (NYHA) Functional Class II through IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital heart disease with left to right shunts (18%).
• Patients with WHO Class II symptoms showed reduction in the rate of clinical deterioration and a trend for improvement in walk distance; consider whether these benefits are sufficient to offset the risk of hepatotoxicity in WHO Class II patients, which may preclude future use as their disease progresses.
• Healthcare professionals who prescribe this drug must enroll in the REMS program and must comply with the required monitoring to minimize risks associated with this drug.

Monitoring:

• Genitourinary: Initiate treatment in females of reproductive potential only after a negative pregnancy test and obtain monthly pregnancy tests during treatment; a negative pregnancy test must also be obtained 1 month after stopping treatment.
• Hematologic: Measure hemoglobin concentrations after 1 and 3 months, and every 3 months thereafter.
• Hepatic: Measure liver aminotransferase levels prior to initiation of treatment and then monthly and thereafter; adjust therapy accordingly.

Patient advice:

• Contact your physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected.