Ambrisentan

Class: Vasodilating Agents, Miscellaneous
VA Class: CV900
Chemical Name: (+)-(2S)-2-[(4,6-Diamethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid
Molecular Formula: C₂₂H₂₂N₂O₄
CAS Number: 177036-94-1
Brands: Letairis

Introduction

Vasodilator; a propionic-acid,^{2 3 12 14 17} endothelin-1 (ET-1) type A receptor-selective antagonist.^{1 2 4 9 12 14}

Uses for Ambrisentan

Pulmonary Arterial Hypertension

Management of pulmonary arterial hypertension (PAH, WHO group 1) to improve exercise capacity and delay clinical worsening.^{1 2 3 4 9 23} Efficacy established principally in patients with NYHA/WHO functional class II or III PAH (idiopathic, familial, or PAH associated with connective tissue diseases).^{1 23}

Recommended by the American College of Chest Physicians (ACCP) and other experts as one of several treatment options for management of PAH in patients with NYHA functional class II, III, or IV symptoms who are not candidates for calcium-channel blocker therapy or in whom such therapy failed.^{27 28 38}

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Individualize choice of therapy; consider factors such as disease severity, route of administration, potential adverse effects, and patient preference.^{27 28 38}

Ambrisentan appears to have a low potential for hepatotoxicity; limited data suggest that the drug may be tried in patients who have experienced asymptomatic aminotransferase elevations while receiving other endothelin-receptor antagonists, after aminotransferase levels have normalized.^{1 6 11 19 20 22}

Limited information available on use of endothelin-receptor antagonists in conjunction with other PAH therapies.^{25 27 29 38} May be beneficial in patients who deteriorate or fail to improve on monotherapy; however, additional studies needed to fully establish role of combination therapy.^{25 27 28 29 38}

Designated an orphan drug by FDA for treatment of PAH.^{3 39}

Ambrisentan Dosage and Administration

General

Restricted Distribution Program

Ambrisentan can be obtained only through a restricted distribution program (see Boxed Warning and REMS); available only through specialty pharmacies registered with the Letairis Education and Access Program (LEAP).^{1 3 13 18} Contact LEAP at 866-664-LEAP (5327) or visit www.letairis.com for additional information.¹

Dispense no more than a 30-day supply of ambrisentan at one time; confirm with patient that required pregnancy testing was completed prior to dispensing.²¹

Distribute medication guide each time ambrisentan is dispensed and review with patient.^{1 3 16 18 21}

Administration

Oral Administration

Administer orally once daily without regard to meals.¹

Do not split, chew, or crush tablets.^{1 3}

Dosage

Adults

Pulmonary Arterial Hypertension

Oral

Initially, 5 mg once daily; may increase to 10 mg once daily if tolerated.¹

Do not exceed 5 mg once daily if administered concomitantly with cyclosporine.^{1 34} (See Specific Drugs under Interactions.)

Prescribing Limits

Adults

Pulmonary Arterial Hypertension

Oral

Safety and efficacy of dosages >10 mg daily not established.¹

Special Populations

Patients with Adverse Hepatic Effects

Monitor serum aminotransferase (AST/ALT) concentrations if clinically indicated.¹ (See Hepatic Effects under Cautions.) Discontinue therapy if AST or ALT >5 times ULN or if elevated aminotransferase concentrations are accompanied by bilirubin concentrations >2 times ULN.¹ Also discontinue if manifestations of liver impairment (e.g., nausea, vomiting, fever, abdominal pain, jaundice, lethargy, fatigue) develop and alternative causes have been excluded.¹

Hepatic Impairment

Avoid use in patients with preexisting moderate or severe hepatic impairment.¹

Renal Impairment

Dosage adjustment not required in patients with mild or moderate renal impairment; not studied in patients with severe renal impairment.¹

Geriatric Patients

No specific dosage recommendations at this time.¹

Cautions for Ambrisentan

Contraindications

• Known, anticipated, or suspected pregnancy.^{1 3}

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity demonstrated in animals and appears to be a class effect of endothelin-receptor antagonists.^{1 6} (See Boxed Warning.)

Exclude pregnancy prior to initiation of therapy and perform monthly pregnancy tests during therapy.¹

Women of childbearing potential must use 2 acceptable methods of contraception during and for 1 month following cessation of therapy; if patient has had a Copper T380A or LNg 20 IUD inserted or has undergone tubal sterilization, no other contraceptive method is required.^{1 3 16 18}

If ambrisentan used during pregnancy or patient becomes pregnant during therapy, apprise of potential fetal hazard.¹ (See Advice to Patients.)

Fluid Retention

Peripheral edema reported, usually mild to moderate in severity; occurred with greater frequency and severity in geriatric patients.^{1 26} Peripheral edema is a known class effect of endothelin-receptor antagonists and also a consequence of PAH.^{1 26}

Fluid retention, sometimes requiring intervention (e.g., diuretics, fluid management, hospitalization), reported.¹

If clinically important fluid retention occurs, further evaluate to determine cause; initiate appropriate treatment or discontinue ambrisentan if necessary.¹

Fertility in Males

Reduced sperm counts observed in some men with PAH following treatment with another endothelin receptor antagonist (bosentan); possibility of adverse effects on spermatogenesis with ambrisentan cannot be excluded.¹

Hematologic Effects

Decreases in hemoglobin and hematocrit reported within first few weeks of treatment, followed by stabilization; hemoglobin decreases do not appear to be related to hemorrhage or hemolysis.^{1 3 4 9 26}

Monitor hemoglobin concentrations prior to initiation, at 1 month, and periodically during therapy.^{1 3 13}

Not recommended in patients with clinically important anemia.¹ Consider discontinuance of therapy if clinically important, otherwise unexplained reductions in hemoglobin occur.^{1 3}

Pulmonary Effects

If acute pulmonary edema occurs, consider possibility of pulmonary veno-occlusive disease; if confirmed, discontinue therapy.¹

Hepatic Effects

Serious hepatotoxicity (e.g., cirrhosis, liver failure) reported with some endothelin-receptor antagonists (e.g., bosentan, sitaxsentan [not commercially available in the US]).^{1 20 22} Hepatotoxicity was previously thought to be a class effect of these drugs;^{3 6 10 11 14 19 20 22} however, further evaluation of data indicate that risk of liver injury with ambrisentan is low.^{1 19}

Monitor liver function tests as clinically indicated; discontinue therapy if severe elevations of hepatic enzymes or manifestations of liver injury occur.¹ (See Patients with Adverse Hepatic Effects under Dosage and Administration.) Carefully evaluate causative factors in those who develop hepatic injury.¹

Specific Populations

Pregnancy

Category X.¹ (See Fetal/Neonatal Morbidity and Mortality and also Contraindications, under Cautions.)

Lactation

Decreased survival in newborn rats following maternal exposure to ambrisentan.¹ Not known whether ambrisentan is distributed into human milk.¹ Use not recommended during breast-feeding.¹

Pediatric Use

Safety and efficacy not established in children and adolescents <18 years of age.^{1 3}

Geriatric Use

Higher incidence of peripheral edema observed in patients ≥65 years of age relative to younger adults.¹

Hepatic Impairment

Substantially metabolized and eliminated by the liver and biliary system.¹ Avoid use in patients with moderate to severe hepatic impairment.¹ No information on use in patients with mild hepatic impairment; possible increased systemic exposure.¹

Renal Impairment

Not studied in patients with severe renal impairment or in those undergoing hemodialysis.¹

No clinically important effect of mild or moderate renal impairment on ambrisentan disposition.¹ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Peripheral edema,^{1 23 24 26} nasal congestion,^{1 23 24} sinusitis,^{1 24} flushing,^{1 24} palpitations,^{1 24} nasopharyngitis,^{1 24} abdominal pain,^{1 24} constipation,^{1 24} dyspnea,¹ headache.^{1 3 23 24 26}

Interactions for Ambrisentan

Metabolized by UGT enzymes 1A9S, 2B7S, and 1A3S and by CYP3A4 and CYP2C19 isoenzymes in vitro.^{1 3 14 32}

Appears to be a substrate of P-glycoprotein and organic anion transport protein (OATP).^{1 3}

Does not inhibit P-glycoprotein.^{1 3}

Does not inhibit or induce CYP enzymes at clinically relevant concentrations.^{1 31}

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP2C19: Pharmacokinetic interaction possible but not likely to be clinically important.^{1 3}

Inhibitors or inducers of CYP3A4: Pharmacokinetic interaction possible but clinically important interaction demonstrated to date only with cyclosporine (a CYP3A4 inhibitor).^{1 34}

Drugs Affecting the Organic Anion Transport Protein (OATP)

Potential pharmacokinetic interaction with drugs that inhibit OATP.^{1 34}

Drugs Affecting the P-glycoprotein Transport System

Pharmacokinetic interactions possible with inhibitors or inducers of P-glycoprotein.^{1 34 36}

Drugs Affecting Uridine Diphosphate Glucuronosyltransferase Enzymes

Pharmacokinetic interactions possible with drugs that induce UGT but not likely to be clinically important.¹

Specific Drugs

Drug	Interaction	Comments
Cyclosporine	Increased AUC and peak plasma ambrisentan concentrations by 2- and 1.5-fold, respectively; no change in cyclosporine exposure1 34	Limit ambrisentan dosage to 5 mg once daily1 34
Digoxin	Modest increase in digoxin exposure1 35	Not considered clinically important1 35
Hormonal contraceptives	Ethinyl estradiol/norethindrone: No clinically important change in systemic exposure to oral contraceptive1 37
Ketoconazole	Modest increase in ambrisentan exposure and half-life1 32	Not considered clinically important; ambrisentan dosage adjustment should not be necessary32
Omeprazole	Clinically important interaction not observed
Phosphodiesterase (PDE) type 5 inhibitors (sildenafil, tadalafil)	Clinically important pharmacokinetic interaction not observed1 24 31 33	Dosage adjustments should not be necessary24 31 33
Rifampin	Increased ambrisentan exposure by twofold, but effect was transient and not considered clinically important1 36	Ambrisentan dosage adjustment should not be necessary36
Warfarin	Clinically important interaction not observed1 2 4 9 14 24 30	Dosage adjustments should not be necessary24 30

Ambrisentan Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration,^{1 3 9 31 33 34} with peak plasma concentrations occurring within approximately 2 hours.^{1 9 12 31 33 34} Absolute bioavailability unknown.^{1 3 14}

Food

Food does not affect absorption.^{1 3}

Distribution

Extent

Detected in liver and plasma 2–4 hours after administration.^{3 14}

Plasma Protein Binding

99%.¹

Elimination

Metabolism

Undergoes hepatic metabolism, principally by glucuronidation and to a lesser extent by hydroxylation.^{1 14 31 32}

Elimination Route

Predominantly nonrenal pathways; contributions of metabolism and biliary excretion not well characterized.^{1 3 34} Most of radiolabeled dose recovered in feces as unchanged drug or glucuronide metabolite.^{1 12 14} Undergoes enterohepatic recycling.³⁴

Half-life

Terminal half-life 15 hours; effective half-life approximately 9 hours.^{1 3 9 33}

Special Populations

Potential for increased exposure to ambrisentan in patients with hepatic impairment.¹ (See Hepatic Effects under Cautions.)

Serum ambrisentan concentrations not affected in patients with mild or moderate renal impairment (based on studies in individuals with Cl_cr 20–150 mL/minute).¹

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C) in original package.¹

Actions

• Exhibits specific, selective antagonism of ET-1 type A receptor in the endothelium and vascular smooth muscle.^{1 3 14} Increased concentrations of ET-1, a potent vasoconstrictor, have been detected in the plasma and lung tissue of patients with PAH, suggesting a pathogenic role for ET-1 in this disorder.^{5 7}

• Pharmacologically related to other ET-1 receptor antagonists (e.g., bosentan), but exhibits 4000-fold greater selectivity for ET-1 type A receptor versus type B receptor.^{1 3 6 17} Clinical implications of receptor selectivity currently not established.^{1 14 15}

• Improves exercise capacity in PAH patients by inhibiting ET-1 type A receptor-mediated vasoconstriction and cell proliferation.^{1 2 4 9}

Advice to Patients

• Importance of taking ambrisentan as prescribed and of not interrupting or discontinuing therapy without consulting clinician.¹⁶

• Importance of not taking a double dose to make up for a missed dose but instead taking the next scheduled dose.¹⁶

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.^{1 16}

• Importance of advising women of childbearing potential to avoid pregnancy and to use 2 highly reliable forms of contraception (either one hormonal and one barrier method or 2 barrier methods, one of which is the male condom) simultaneously during and for 1 month following therapy.^{1 16 18} Acceptable hormonal methods include progesterone injections, progesterone implants, estrogen-progestin combination oral contraceptives, transdermal contraceptive systems, and vaginal ring.¹ Acceptable barrier methods include diaphragms with spermicide, cervical caps with spermicide, and male condoms.¹ No additional contraception is necessary if patient has undergone tubal sterilization or chooses to use a Copper T380A or LNg 20 IUD.¹ If the partner has had a vasectomy, an additional hormonal or barrier method must be used.^{1 18} Advise women to inform their clinician immediately if a menstrual period is missed or pregnancy suspected.^{1 16} Apprise patient of potential risk to fetus if pregnancy occurs.^{1 16}

• Importance of monthly pregnancy testing.^{1 16}

• Importance of periodic monitoring of red blood cell counts during treatment.^{1 16}

• Importance of advising patients to swallow tablets whole and not to split, chew, or crush tablets.^{1 16}

• Importance of distributing patient information (medication guide) to every patient who receives ambrisentan and of reviewing the information with the patient.^{1 18}

• Importance of patients carefully reading medication guide before initiating therapy and each time prescription is refilled.^{1 16}

• Importance of informing clinicians of existing or contemplated concomitant therapy including prescription and OTC drugs, as well as any concomitant illnesses.^{1 16}

• Importance of informing patients of other important precautionary information.^{1 16} (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Distribution of ambrisentan is restricted.¹ (See Restricted Distribution Program under Dosage and Administration.)

Ambrisentan

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	5 mg	Letairis	Gilead
		10 mg	Letairis	Gilead