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Ambrisentan

Pronunciation: (am-bree-SEN-tan)
Class: Endothelin receptor antagonist

Trade Names:
Letairis
- Tablets 5 mg
- Tablets 10 mg

Pharmacology

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Antagonizes endothelin receptor by binding to endothelin A.

Pharmacokinetics

Absorption

Rapidly absorbed. T _max is 2 h.

Distribution

Plasma protein binding is 99%.

Metabolism

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

Elimination

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

Indications and Usage

Treatment of pulmonary arterial hypertension in patients with WHO class II or III symptoms to improve exercise capacity and delay clinical worsening.

Contraindications

Pregnancy.

Dosage and Administration

Adults

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

General Advice

Take with or without food.
Do not split, crush, or chew tablets.

Storage/Stability

Store at 59° to 86°F.

Drug Interactions

Cyclosporine

Exposure to ambrisentan may be increased; use with caution.

Inducers of P-gp, CYPs, and UGTs

Use ambrisentan with caution.

Strong inhibitors of CYP2C19 (eg, omeprazole) and CYP3A (eg, ketoconazole)

Ambrisentan concentrations may be increased; use with caution.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Palpitations (5%).

CNS

Headache (15%).

Dermatologic

Flushing (4%).

EENT

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

GI

Constipation (4%); abdominal pain (3%).

Respiratory

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

Miscellaneous

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

Precautions

Warnings

Hepatotoxicity

At least a 3-fold increase in ALT or AST occurs in some patients and requires close monitoring.

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 thereafter by use of at least 2 reliable methods of contraception unless patient has had a tubal sterilization or Copper T 380A intrauterine device (IUD) or levonorgestrel (LNg) 20 IUD inserted.

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 may be dispensed only to patients who are enrolled in and meet all conditions of LEAP.

Monitor

Monitor serum aminotransferase levels (and bilirubin if aminotransferase levels are elevated) prior to starting treatment and monthly for the duration of treatment. Measure hemoglobin prior to initiation of treatment, at 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 .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Peripheral edema was more common in elderly patients.

Renal Function

No information available regarding use in patients with severe renal impairment.

Hepatic Function

Use with caution in patients with mild hepatic impairment. Not recommended in patients with moderate or severe hepatic impairment. Avoid use in patients with elevated aminotransferases (more than 3 times ULN) at baseline. If liver aminotransferases are accompanied by clinical symptoms of liver injury (eg, abdominal pain, fever, jaundice, nausea, unusual lethargy or fatigue, vomiting) or if increases in bilirubin of more than 2 times ULN occur, stop treatment.

Hematologic effects

Hemoglobin concentration and hematocrit may decrease within the first few weeks of treatment and stabilize thereafter.

Fluid retention

Peripheral edema may occur.

Overdosage

Symptoms

Hypotension.

Patient Information

Advise patient to read the Medication Guide before using product the first time and with each refill.
Instruct women of childbearing potential that reliable contraceptive measures must be used during treatment. Advise patients to use at least 2 reliable methods of contraception unless they have had a tubal sterilization or Copper T 380A IUD or LNg 20 IUD inserted.
Advise patients that monthly liver enzyme tests and pregnancy tests (in women of childbearing potential) will be required to use this medication safely.
Inform patients that, during treatment, their health care provider will test their blood for signs of adverse reactions to the liver and RBC.
Advise patients that product may be taken without regard to meals.
Advise patients not to split, crush, or chew tablets.
Instruct women who become pregnant or miss a menstrual period during therapy to notify health care provider.