Dosing & Uses
Dosage Forms & Strengths
tablet
- 5mg
- 10mg
Pulmonary Arterial Hypertension
Indicated for treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability and delay clinical worsening or in combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability
Initiate treatment at 5 mg PO qDay, with or without tadalafil 20 mg PO qDay
At 4-week intervals, either ambrisentan or tadalafil dose can be increased, as needed and tolerated, not to exceed ambrisentan 10 mg/day or tadalafil 40 mg/day
Dosage Modifications
Coadministration with cyclosporine: Limit ambrisentan to 5 mg/day
Renal impairment
- Mild-to-moderate: No dosage adjustment required
- Severe: Not studied
- Hemodialysis: Not studied
Hepatic impairment
Pre-existing
- Mild: No information available
- Moderate-to-severe: Not recommended
Elevated LFTs after initiating
- LFTs >5x ULN: Discontinue
- LFTs increased and accompanied by bilirubin >2x ULN (or signs/symptoms of liver dysfunction): Discontinue
Dosing Considerations
Studies establishing effectiveness included predominantly patients with WHO functional Class II–III symptoms and etiologies of idiopathic or heritable PAH (60%) or PAH associated with connective tissue diseases (34%)
Initiate treatment with ambrisentan in females of reproductive potential only after a negative pregnancy test; obtain monthly pregnancy tests during treatment
Safety and efficacy not established
Interactions
Interaction Checker
No Results

Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor

Adverse Effects
>10%
Peripheral edema (17%)
Headache (15%)
1-10%
Nasal congestion (6%)
Palpitations (5%)
Constipation (4%)
Dyspnea (4%)
Flushing (4%)
Abdominal pain (3%)
Nasopharyngitis (3%)
Sinusitis (3%)
Postmarketing Reports
Anemia
Dizziness
Fatigue
Fluid retention
Heart failure (associated with fluid retention)
Nausea
Vomiting
Increased liver aminotransferases (ALT, AST)
Hypersensitivity (eg, angioedema, rash)
Symptomatic hypotension
Hepatotoxicity
Liver failure
Warnings
Black Box Warnings
Embryo-fetal toxicity
- Do not administer ambrisentan to a pregnant female because it may cause fetal harm
- Females of reproductive potential: Exclude pregnancy before starting treatment, monthly during treatment, and 1 month after stopping treatment
- Prevent pregnancy during treatment and for 1 month after stopping treatment by using acceptable methods of contraception
- For all female patients, Letairis is available only through a restricted program called the Letairis Risk Evaluation and Mitigation Strategy (REMS)
Contraindications
Pregnancy
Idiopathic pulmonary fibrosis
Cautions
Fetal harm when administered during pregnancy and is contraindicated for use in females who are pregnant (see Pregnancy and Black Box Warnings)
Caution with hepatic impairment; may be associated with rare cases of hepatic cirrhosis with prolonged use; not recommended in patients with moderate-to-severe hepatic impairment
Discontinue in patients with elevated aminotransferases >5x ULN, or if elevations are accompanied by bilirubin >2X ULN, or signs/symptoms of liver dysfunction
Reports of decreased hemoglobin concentrations from baseline that persisted for up to 4 yr of treatment
Coadministration with cyclosporine or CYP3A4 or CYP2C19 inhibitors
Peripheral edema is known class effect of endothelin receptor antagonists, and also a clinical consequence of pulmonary arterial hypertension (PAH) and worsening PAH; fluid retention in patients with pulmonary hypertension, occurring within weeks of initiating therapy reported; if clinically significant fluid retention develops, with or without associated weight gain, further evaluate to determine cause, such as ambrisentan or underlying heart failure, possible need for specific treatment or discontinuation of therapy
Risk of fluid retention and peripheral edema; more common in combination with tadalafil, than with ambrisentan or tadalafil alone
Decreased sperm counts observed in human and animal studies with another endothelin receptor antagonist and in animal fertility studies with ambrisentan
Development of acute pulmonary edema during therapy initiation may be associated with pulmonary veno-occlusive disease
Restricted Distribution Program
- Because of risk of birth defects, available only through restricted distribution program called the Ambrisentan REMS, by calling 1-888-417-3172; only prescribers and pharmacies certified with Ambrisentan REMS may prescribe and distribute ambrisentan or the brand Letairis
-
Requirements of the REMS program include the following:
- Prescribers must be certified with the program by enrolling and completing training
- All females, regardless of reproductive potential, must enroll in the Ambrisentan REMS program prior to initiating treatment
- Male patients are not enrolled in the REMS
- Females of reproductive potential must comply with the pregnancy testing and contraception requirements
- Pharmacies that dispense ambrisentan must be certified with the program and must dispense to female patients who are authorized to receive ambrisentan
Pregnancy & Lactation
Pregnancy
Based on data from animal reproduction studies, fetal harm may occur when administered to a pregnant woman and is contraindicated during pregnancy
There are limited data on use in pregnant women
Advise patient of the potential hazard to a fetus
Animal data
- In animal reproduction studies, ambrisentan was teratogenic in rats and rabbits at doses which resulted in exposures of 3.5 and 1.7 times, respectively, the human dose of 10 mg/day
Contraception
- Female patients of reproductive potential must use acceptable methods of contraception during treatment and for 1 month after stopping treatment
- Patients should choose one highly effective form of contraception (intrauterine device [IUD], contraceptive implant, or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods)
- If a partner’s vasectomy is one method of contraception, a hormone or barrier method must be used along with this method
- Counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling
Infertility
- Males: Based on findings and preclinical data, endothelin receptor antagonists have an adverse effect on spermatogenesis; counsel patients about the potential effects on fertility
Lactation
Unknown whether present in human milk
Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
High affinity endothelin (ETa) receptor subtype antagonist, resulting in inhibition of vasoconstriction
Two receptor subtypes, ETA and ETB, mediate the effects of ET-1 in the vascular smooth muscle and endothelium
Primary actions of ETA are vasoconstriction and cell proliferation, while the predominant actions of ETB are vasodilation, antiproliferation, and ET-1 clearance
Absorption
Peak Plasma Time: 2 hr
Distribution
Protein Bound: 99%
Metabolism
Substrate of hepatic CYP3A4, CYP2C19, UGTs (1A9S, 2B7S, and 1A3S)
Elimination
Half-life: 15 hr
Excretion: Predominantly nonrenal
Administration
Oral Administration
Administer with or without food
Swallow whole, do not split, crush, or chew tablets
Storage
Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F)
Images
Patient Handout
Formulary
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