Ambrisentan

Pronunciation: (AM-bri-SEN-tan)
Class: Endothelin receptor antagonist

Trade Names

Letairis
- Tablets, oral 5 mg
- Tablets, oral 10 mg

Pharmacology

Antagonizes endothelin receptor by binding to endothelin A.

Pharmacokinetics

Absorption

Rapidly absorbed. T _max is 2 h.

Distribution

Plasma protein binding is 99%.

Metabolism

Metabolized by CYP2C19, CYP3A4, and uridine 5′-diphosphate glucuronosyltransferases 1A3S, 1A9S, and 2B7S. Substrate for P-glycoprotein.

Elimination

Elimination is primarily nonrenal. Terminal half-life is 15 h; effective half-life is approximately 9 h.

Special Populations

Renal Function Impairment

No significant impact on patients with mild or moderate impairment. No information on exposure in patients with severe renal impairment or who are on hemodialysis.

Hepatic Function Impairment

Influence of hepatic impairment has not been evaluated; however, hepatic impairment would be expected to have significant effects on ambrisentan pharmacokinetics.

Indications and Usage

Treatment of pulmonary arterial hypertension to improve exercise capacity and delay clinical worsening.

Contraindications

Women who are or may become pregnant.

Dosage and Administration

Adults

PO 5 mg once daily initially. Consider increasing the dosage to 10 mg once daily if 5 mg is tolerated.

General Advice

• May be taken with or without food.
• Do not split, crush, or chew tablets.

Storage/Stability

Store between 59° and 86°F in the original packaging.

Drug Interactions

Cyclosporine

Exposure to ambrisentan may be increased (approximately 2-fold). Limit the dosage of ambrisentan to 5 mg daily with coadministration.

Rifampin

Coadministration was associated with a 2-fold increase in ambrisentan AUC. Use with caution.

Adverse Reactions

Cardiovascular

Palpitations (5%); flushing (4%); heart failure associated with fluid retention (postmarketing).

CNS

Headache (15%).

EENT

Nasal congestion (6%); nasopharyngitis (3%).

GI

Constipation (4%); abdominal pain (3%); elevated liver aminotransferases (ALT, AST), nausea, vomiting (postmarketing).

Hematologic

Hgb decreased (10%); anemia (postmarketing).

Hypersensitivity

Hypersensitivity, including angioedema or rash (postmarketing).

Respiratory

Dyspnea (4%); sinusitis (3%).

Miscellaneous

Peripheral edema (17%); fluid retention (postmarketing).

Precautions

Warnings Pregnancy Because serious birth defects were seen consistently when ambrisentan was administered to animals, use is contraindicated in pregnancy. Pregnancy must be excluded before initiation of treatment and prevented during treatment and for 1 mo after stopping treatment by the use of 2 acceptable methods of contraception, unless patient has had a tubal sterilization or Copper T 380A intrauterine device (IUD) or levonorgestrel 20 intrauterine system inserted. Obtain monthly pregnancy tests. Dispensing program Ambrisentan is available only through a special restricted distribution program called the Letairis Education and Access Program (LEAP) by calling 1-866-664-5327. Only prescribers and pharmacies registered with LEAP may prescribe and distribute ambrisentan. Ambrisentan may be dispensed only to patients who are enrolled in and meet all conditions of LEAP.

Monitor Monitor LFTs periodically. Measure Hgb prior to initiation of treatment, 1 month after initiation, and periodically thereafter. For women of childbearing potential, order and review a pregnancy test prior to initiation of treatment and monthly during treatment.

Pregnancy

Category X . May cause fetal harm.

Lactation

Undetermined. Breast-feeding is not recommended while receiving ambrisentan.

Children

Safety and efficacy not established.

Elderly

Peripheral edema was more common in elderly patients.

Hepatic Function

Not recommended in patients with moderate or severe hepatic impairment. There is no information on use in patients with mild preexisting liver impairment; however, exposure to ambrisentan may be increased in these patients.

Fertility impairment

Decreased sperm counts have been reported with other endothelin receptor antagonists. It cannot be excluded that ambrisentan may have a similar adverse effect.

Fluid retention

Peripheral edema may occur.

Hematologic effects

Hgb concentrations and Hct may decrease within the first few weeks of treatment and stabilize thereafter. Initiation of therapy is not recommended for patients with clinically significant anemia.

Pulmonary edema

If signs of pulmonary edema occur, consider the possibility of associated pulmonary veno-occlusive disease and discontinue therapy.

Overdosage

Symptoms

Dizziness, flushing, headache, hypotension, nasal congestion, nausea.

Patient Information

• Advise patient to read the Medication Guide before using product the first time and with each refill.
• Advise patients that ambrisentan may cause fetal harm. Instruct women of childbearing potential that reliable contraceptive measures must be used during treatment and for 1 mo after treatment is stopped. Advise patients to use at least 2 reliable methods (1 hormonal method and 1 barrier method) of contraception unless they have had a tubal sterilization, or Copper T 380A IUD or levonorgestrel 20 intrauterine system inserted. Acceptable hormone methods include progesterone injectables or implants, combination oral contraceptives, transdermal patches, and vaginal rings. Acceptable barrier methods include diaphragm (with spermicide), cervical cap (with spermicide), and the male condom. Partner's vasectomy must be used along with a hormone method or a barrier method.
• Advise patients that monthly pregnancy tests (in women of childbearing potential) will be required to use this medication safely.
• Advise patients of the importance of Hgb testing.
• Instruct patients to immediately report any symptoms of potential liver injury (eg, anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant abdominal discomfort, jaundice, dark urine, itching) to their health care provider.
• Advise patients that tablets may be taken without regard to meals, and that tablets should not be split, crushed, or chewed.
• Instruct women who become pregnant or miss a menstrual period during therapy to notify their health care provider immediately.

Copyright © 2009 Wolters Kluwer Health.