ambrisentan (Rx)

>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

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

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.

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

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)