Ambrisentan

Class: Vasodilating Agents
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 (PAH)

Management of PAH (WHO group 1 pulmonary hypertension) 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, heritable, or associated with connective tissue diseases).^{1 23}

Endothelin-receptor antagonists (e.g., ambrisentan, bosentan, macitentan) are recommended as one of several treatment options for initial management of PAH in patients with NYHA/WHO functional class II, III, or IV symptoms who are not candidates for calcium-channel blocker therapy or in whom such therapy failed.^{27 38 40}

Individualize choice of therapy; consider factors such as disease severity, route of administration, potential adverse effects, costs of treatment, clinician experience, and patient preference.^{27 38 40}

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}

In patients with inadequate response to initial monotherapy, may consider combination therapy with a prostanoid, phosphodiesterase (PDE) type 5 inhibitor, or soluble guanylate cyclase stimulator (added sequentially).⁴⁰ By targeting different pathophysiologic pathways of the disease, combination therapy may provide additive and/or synergistic benefits.^{25 27 29 38 40 41 42}

Has been designated an orphan drug by FDA for treatment of PAH.^{3 39}

Pulmonary Fibrosis

No clinical benefit observed in a controlled study in patients with pulmonary fibrosis† with or without pulmonary hypertension (WHO group 3); relatively greater risk of disease progression and death observed with ambrisentan versus placebo.^{1 43} (See Contraindications under Cautions.)

Ambrisentan Dosage and Administration

General

Restricted Distribution Program

• Distribution of ambrisentan to female patients is restricted; available only through the Letairis REMS.¹ (See Boxed Warning and also see REMS.)

• All female patients (regardless of childbearing potential), clinicians, and pharmacies must enroll in the program in order to receive, prescribe, and dispense the drug, respectively; in addition, females of childbearing potential must comply with pregnancy testing and contraception requirements.¹ Male patients do not need to enroll.¹ Additional information available at 866-664-5327 or .¹ (See Advice to Patients.)

• Dispense no more than a 30-day supply of ambrisentan at one time; confirm with patients of childbearing potential 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 without regard to meals.¹

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

If a dose is missed, take as soon as it is remembered that day, and take next dose at regularly scheduled time; do not take 2 doses at the same time to make up for a missed dose.¹⁶

Dosage

Adults

PAH

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

PAH

Oral

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

Special Populations

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

• Pregnancy.¹

• Idiopathic pulmonary fibrosis, with or without pulmonary hypertension (WHO group 3).¹ (See Pulmonary Fibrosis under Uses.)

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryotoxicity demonstrated in animals.^{1 6} (See Boxed Warning.)

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 AST/ALT concentrations if clinically indicated.¹ Discontinue therapy if AST/ALT >5 times ULN or if elevations are accompanied by bilirubin concentrations >2 times ULN or by manifestations of liver impairment and alternative causes have been excluded.¹

Specific Populations

Pregnancy

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

Lactation

Not known whether distributed into human milk.¹ Discontinue nursing or the drug.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 No adjustment of cyclosporine dosage required1
Digoxin	Modest increase in digoxin exposure1 35	Not considered clinically important; no dosage adjustments necessary1 35
Hormonal contraceptives	Ethinyl estradiol/norethindrone: No clinically important change in systemic exposure to oral contraceptive1 37	No dosage adjustments necessary1
Ketoconazole	Modest increase in ambrisentan exposure and half-life1 32	Not considered clinically important; no dosage adjustments necessary1 32
Mycophenolate mofetil	Pharmacokinetics of either drug not altered1	No dosage adjustments necessary1
Omeprazole	Peak plasma concentrations and systemic exposure of ambrisentan not substantially altered1	No dosage adjustments necessary1
PDE type 5 inhibitors (sildenafil, tadalafil)	Clinically important pharmacokinetic interaction not observed1 24 31 33	No dosage adjustments necessary1 24 31 33
Rifampin	Increased ambrisentan exposure by twofold, but effect was transient and not considered clinically important1 36	No dosage adjustments necessary1 36
Ritonavir	Peak plasma concentrations and systemic exposure of ambrisentan not altered1	No dosage adjustments necessary1
Tacrolimus	Peak plasma concentrations and systemic exposure of ambrisentan not altered1	No dosage adjustments necessary1
Warfarin	Clinically important interaction not observed1 2 4 9 14 24 30	No dosage adjustments necessary1 24 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

• Risk of fetal harm; importance of advising women of childbearing potential to avoid pregnancy and to use acceptable methods of contraception during and for 1 month following discontinuance of therapy.¹ Acceptable methods of contraception include one highly effective form of contraception (intrauterine device [IUD], progesterone implant, or tubal sterilization) or a combination of methods (either one hormonal and one barrier method or 2 barrier methods where one form is the male condom).^{1 16} Acceptable hormonal methods of contraception include estrogen-progestin combination oral contraceptives or transdermal contraceptive systems, vaginal ring, and progesterone injections.¹⁶ Acceptable barrier methods include male condoms, diaphragms with spermicide, and cervical caps with spermicide.¹⁶ If the partner has had a vasectomy, an additional hormonal or barrier method must be used.^{1 16}

• Importance of advising women to inform their clinician immediately if a menstrual period is missed or pregnancy is suspected; clinicians should perform a pregnancy test if pregnancy is suspected for any reason and provide counseling on the use of emergency contraception in the event of unprotected sexual intercourse or known or suspected contraceptive failure.^{1 16} Apprise patient of potential risk to fetus if pregnancy occurs.¹

• Importance of female patients enrolling in the Letairis REMS program and complying with all contraceptive and pregnancy testing requirements.¹ Importance of monitoring reproductive status of prepubertal females and immediately reporting changes (e.g., breast development, pubic hair) to clinician.¹⁶

• Importance of patients not taking ambrisentan if they have idiopathic pulmonary fibrosis.^{1 16}

• Potential risk of liver toxicity.¹ Importance of patients informing clinicians of any unexplained nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, fever, or itching.¹

• Importance of periodic monitoring of RBC counts during treatment.^{1 16}

• Importance of taking ambrisentan as prescribed and of not interrupting or discontinuing therapy without consulting a 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 advising patients to swallow tablets whole and not to split, chew, or crush tablets.^{1 16}

• Importance of distributing the FDA-approved medication guide to every patient who receives ambrisentan and reviewing the information with the patient.^{1 18} (See REMS.) Importance of patients carefully reading medication guide before initiating therapy and each time prescription is refilled.^{1 16}

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

• Importance of informing clinicians of existing or contemplated concomitant therapy including prescription (e.g., cyclosporine) 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.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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