Brand and Other Names:Letairis
- Classes: PAH, Endothelin Antagonists
Dosing & Uses
Dosage Forms & Strengths
Pulmonary Arterial Hypertension (PAH)
Indicated for WHO group 1 PAH to 1) improve exercise ability and delay clinical worsening; and 2) 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
Coadministration with cyclosporine: Limit ambrisentan to 5 mg/day
- Mild-to-moderate: No dosage adjustment required
- Severe: Not studied
- Mild: No information available
- Moderate-to-severe: Not recommended
- Elevated LFTs after initiating
- LFTs >5 xULN: Discontinue
- LFTs increased and accompanied by bilirubin >2 xULN (or signs/symptoms of liver dysfunction): Discontinue
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
Serious - Use Alternative
Significant - Monitor Closely
Peripheral edema (17%)
Nasal congestion (6%)
Abdominal pain (3%)
Heart failure (associated with fluid retention)
Increased liver aminotransferases (ALT, AST)
Hypersensitivity (eg, angioedema, rash)
Black Box Warnings
- Likely to produce serious birth defects if used by pregnant women; this effect has been seen consistently when administered to animals
- Exclude pregnancy before the initiating treatment; obtain monthly pregnancy tests during treatment and 1 month after discontinuing treatment
- Females of reproductive potential must use acceptable methods of contraception during treatment and for 1 month after treatment
- Acceptable methods of contraception include: 1 highly effective form of contraception (IUD, contraceptive implant (including progesterone implant), or tubal sterilization), or a combination of methods (hormone method with a barrier method, or 2 barrier methods)
- If a partner’s vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method
Restricted Distribution Program
- Because of risk of birth defects, available only through restricted distribution program called the LETAIRIS Education and Access Program (LEAP), by calling 1-866-664-LEAP (5327); only prescribers and pharmacies registered with LEAP may prescribe and distribute ambrisentan
- May be dispensed only to patients enrolled in and meet all conditions of LEAP
Idiopathic pulmonary fibrosis (IPF) including patients with pulmonary hypertension (WHO Group 3)
Pregnancy; see Black Box Warnings
Available only through a special restricted distribution program (see 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
Adverse effect on spermatogenesis for endotheling receptor antagonists reported
Development of acute pulmonary edema during therapy initiation may be associated with pulmonary veno-occlusive disease
Pregnancy & Lactation
Pregnancy Category: X; Consistently shown to have teratogenic effects when administered to animals
Decreased sperm counts observed in human and animal studies with another endothelin receptor antagonist and in animal fertility studies with ambrisentan; may have an adverse effect on spermatogenesis
Lactation: Excretion in milk unknown; not recommended
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.
Mechanism of Action
High affinity endothelin (ETa) receptor subtype antagonist, resulting in inhibition of vasoconstriction
Peak Plasma Time: 2 hr
Protein Bound: 99%
Substrate of hepatic CYP3A4, CYP2C19, UGTs (1A9S, 2B7S, and 1A3S)
Half-Life: 9 hr
Excretion: Predominantly nonrenal
May take with or without food
Swallow whole, do not split, crush, or chew tablets
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