Usual Adult Dose for Pulmonary Hypertension

Initial dose: 5 mg orally once a day.

Comments:

• Consider increasing the dose to 10 mg orally once a day if 5 mg is tolerated.
• When used with tadalafil, the dose of either drug can be increased as needed and tolerated at 4-week intervals.

• For the treatment of pulmonary arterial hypertension (WHO Group 1) to improve exercise ability and delay clinical worsening.
• For the treatment of pulmonary arterial hypertension (WHO Group 1) in combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening pulmonary arterial hypertension, and to improve exercise ability.

Renal Dose Adjustments

• Mild or moderate impairment: No adjustment recommended.
• Severe renal impairment: Caution is recommended.

Liver Dose Adjustments

• Mild impairment: Dose adjustment may be required; however, no specific guidelines have been suggested. Caution is recommended.
• Moderate or severe impairment: Use not recommended.

• ALT or AST elevations are greater than 5 times the upper limit of normal (ULN)
• ALT or AST elevations are accompanied by bilirubin elevations of greater than 2 times the ULN
• ALT or AST elevations are accompanied by signs or symptoms of liver dysfunction and other causes have been excluded

Dose Adjustments

When coadministered with cyclosporine, the dose of ambrisentan should be limited to 5 mg once a day.

Precautions

The US FDA requires a Risk Evaluation and Mitigation Strategy (REMS) for ambrisentan. 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 WARNING:
Embryo-Fetal Toxicity:

• Do not administer to pregnant females because it may cause fetal harm.
• Drug is very likely to produce serious birth defects as this effect has been consistently seen in animal studies.

• Exclude pregnancy before treatment initiation.
• Acceptable methods of contraception should be used during treatment and for 1 month following discontinuation of treatment.
• A negative pregnancy test must be obtained prior to each prescription and 1 month following discontinuation of treatment.
• Because of the risk of embryo-fetal toxicity, females can only receive drug through a restricted program called the Letairis REMS program.

Dialysis

Data not available

Other Comments

Administration Advice:

• May be taken with or without food.
• Tablets should not be crushed, split, or chewed.

• Drug is contraindicated in patients with idiopathic pulmonary fibrosis (IPF) including IPF patients with pulmonary hypertension (WHO group 3); a randomized controlled study in this population was terminated for lack of efficacy and a greater risk of disease progression or death associated with drug use.
• Efficacy studies included predominantly WHO functional class II and III patients with idiopathic or heritable pulmonary arterial hypertension (PAH) or PAH associated with connective tissue disease.

• Pregnancy testing should be performed before the initiation of treatment, monthly while on treatment, and for 1 month after stopping treatment.
• Measure hemoglobin at baseline, at 1 month, and periodically thereafter.
• Monitor blood pressure closely in patients with preexisting hypotension.
• Monitor for signs and symptoms of hepatic injury, including monthly monitoring of AST and ALT.

• Advise patients to use effective contraception during therapy and for 1 month following discontinuation of therapy; patients should immediately contact healthcare provider if they suspect they may be pregnant.
• Advise patients to report symptoms of potential hepatotoxicity.