Letairis

Pronunciation

Generic Name: 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

Warning(s)

  • Teratogenicity
  • May cause fetal harm; contraindicated in pregnant women.1 18

    Exclude pregnancy in females of childbearing potential before initiation of treatment and prevent thereafter by using acceptable methods of contraception during and for 1 month following discontinuance of therapy.1 3 18 (See Fetal/Neonatal Morbidity and Mortality under Cautions and also see Advice to Patients.)

  • Distribution of ambrisentan is restricted in all female patients.1 3 13 18 (See Restricted Distribution Program under Dosage and Administration.)

REMS:

FDA approved a REMS for ambrisentan to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of ambrisentan and consists of the following: medication guide, elements to assure safe use, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center (). See also Restricted Distribution Program under Dosage and Administration: General.

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 Letairis

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

Slideshow: Flashback: FDA Drug Approvals 2013

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.)

Letairis 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 Letairis

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 Letairis

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

Letairis 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 Clcr 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.

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

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 4, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Gilead Sciences, Inc. Letairis (ambrisentan) tablets prescribing information. Foster City, CA; 2014 Jan.

2. Oudiz RJ, Torres F, Frost AE et al. A placebo-controlled, efficacy and safety study of ambrisentan in patients with pulmonary arterial hypertension (ARIES-1). Chest. 2006; 130(4 suppl):121S.

3. Gilead Sciences: Personal communication.

4. Oudiz RJ, Olschewski H, Galie N et al. Ambrisentan improves exercise capacity and time to clinical worsening in patients with pulmonary arterial hypertension: results of the ARIES-2 study. Poster presented at the 7th International Pulmonary Hypertension Association (PHA) Conference. Minneapolis, MN: 2006 June 23-25.

5. Giaid A, Yanagisawa M, Langleben D et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993; 328:1732-39. [PubMed 8497283]

6. Actelion Pharmaceuticals US. Tracleer (bosentan) tablets prescribing information. South San Francisco, CA: 2007 Feb 15

7. Stewart DJ, Levy RD, Cernacek P et al. Increased plasma endothelin-1 in pulmonary hypertension: Marker or mediator of disease. Ann Intern Med. 1991; 114:464-9. [PubMed 1994793]

8. Benigni A, Remuzzi G. Endothelin antagonists. Lancet. 1999; 353:133-38. [PubMed 10023915]

9. Galie N, Badesch D, Oudiz R et al. Ambrisentan therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2005; 46:529-35. [PubMed 16053970]

10. Channick RN, Sitbon O, Barst RJ et al. Endothelin receptor antagonists in pulmonary arterial hypertension. J Am Coll Cardiol. 2004; 43 (Suppl S):62-7.

11. Barst RJ, Langleben D, Badesch D et al. Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan. J Am Coll Cardiol. 2006; 47:2049-56. [PubMed 16697324]

12. Vatter H, Seifert V. Ambrisentan, a non-peptide endothelin receptor antagonist. Cardiovasc Drug Rev. 2006; 24:63-76. [PubMed 16939634]

13. Gilead Sciences. Letairis education and access program (LEAP) prescriber information. Foster City, CA; 2007 Jun.

14. Barst RJ. A review of pulmonary arterial hypertension: role of ambrisentan. Vasc Health Risk Manag. 2007; 3:11-22. [PubMed 17583171]

15. Jacobs A, Preston IR, Gomberg-Maitland M. Endothelin receptor antagonism in pulmonary arterial hypertension-a role for selective ETAinhibition? Curr Med Res Opin. 2006; 22:2567-74.

16. Gilead Sciences, Inc. Letairis (ambrisentan) tablets medication guide. Foster City, CA; 2014 Jan.

17. McGoon M, Frost A, Rubin L et al. Ambrisentan therapy in patients with pulmonary arterial hypertension who discontinued bosentan or sitaxsentan due to liver function abnormalities: 1 year follow-up. Presented at the 103nd American Thoracic Society annual international conference. San Francisco, CA: 2007 May 18-23.

18. Food and Drug Administration. Medwatch-Safety-Related drug labeling changes: Letairis (ambrisentan) 5 and 10 mg tablets [May 2009]. From FDA website http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm165575.htm.

19. Food and Drug Administration. FDA drug safety communication: Liver injury warning to be removed from Letairis (ambrisentan) tablets. Rockville, MD; 2011 Mar 4. Available from FDA website. Accessed 2011 Apr 1.

20. Food and Drug Administration. Questions and answers: Liver injury warning to be removed from Letairis (ambrisentan) tablets. Rockville, MD; 2011 Mar 4. Available from FDA website. Accessed 2011 Apr 1.

21. Gilead Sciences Inc. NDA 22-081 Letairis (ambrisentan) risk evaluation and mitigation strategy (REMS). Foster City, CA. Initial approval 2009 May; revised 2014 Jan. Available from FDA website. Accessed 2014 Apr 4.

22. McGoon MD, Frost AE, Oudiz RJ et al. Ambrisentan therapy in patients with pulmonary arterial hypertension who discontinued bosentan or sitaxsentan due to liver function test abnormalities. Chest. 2009; 135:122-9. [PubMed 18812445]

23. Galiè N, Olschewski H, Oudiz RJ et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation. 2008; 117:3010-9. [PubMed 18506008]

24. Cheng JW. Ambrisentan for the management of pulmonary arterial hypertension. Clin Ther. 2008; 30:825-33. [PubMed 18555930]

25. Abraham T, Wu G, Vastey F et al. Role of combination therapy in the treatment of pulmonary arterial hypertension. Pharmacotherapy. 2010; 30:390-404. [PubMed 20334459]

26. Oudiz RJ, Galiè N, Olschewski H et al. Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009; 54:1971-81. [PubMed 19909879]

27. Barst RJ, Gibbs JS, Ghofrani HA et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009; 54(1 Suppl):S78-84.

29. Gokhman R, Smithburger PL, Kane-Gill SL et al. Pharmacologic and Pharmacokinetic Rationale for Combination Therapy in Pulmonary Arterial Hypertension. J Cardiovasc Pharmacol. 2010; :. [PubMed 20838230]

30. Walker G, Mandagere A, Dufton C et al. The pharmacokinetics and pharmacodynamics of warfarin in combination with ambrisentan in healthy volunteers. Br J Clin Pharmacol. 2009; 67:527-34. [PubMed 19552747]

31. Spence R, Mandagere A, Dufton C et al. Pharmacokinetics and safety of ambrisentan in combination with sildenafil in healthy volunteers. J Clin Pharmacol. 2008; 48:1451-9. [PubMed 18832294]

32. Richards DB, Walker GA, Mandagere A et al. Effect of ketoconazole on the pharmacokinetic profile of ambrisentan. J Clin Pharmacol. 2009; 49:719-24. [PubMed 19389876]

33. Spence R, Mandagere A, Harrison B et al. No clinically relevant pharmacokinetic and safety interactions of ambrisentan in combination with tadalafil in healthy volunteers. J Pharm Sci. 2009; 98:4962-74. [PubMed 19455620]

34. Spence R, Mandagere A, Richards DB et al. Potential for pharmacokinetic interactions between ambrisentan and cyclosporine. Clin Pharmacol Ther. 2010; 88:513-20. [PubMed 20811346]

35. Richards DB, Spence R, Mandagere A et al. Effects of multiple doses of ambrisentan on the pharmacokinetics of a single dose of digoxin in healthy volunteers. J Clin Pharmacol. 2011; 51:102-6. [PubMed 20350954]

36. Harrison B, Magee MH, Mandagere A et al. Effects of rifampicin (rifampin) on the pharmacokinetics and safety of ambrisentan in healthy subjects: a single-sequence, open-label study. Clin Drug Investig. 2010; 30:875-85. [PubMed 20923245]

37. Spence R, Mandagere A, Walker G et al. Effect of steady-state ambrisentan on the pharmacokinetics of a single dose of the oral contraceptive norethindrone (norethisterone) 1 mg/ethinylestradiol 35 microg in healthy subjects: an open-label, single-sequence, single-centre study. Clin Drug Investig. 2010; 30:313-24. [PubMed 20384387]

38. McLaughlin VV, Archer SL, Badesch DB et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009; 53:1573-619. [PubMed 19389575]

39. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; [March 9, 2010]. From FDA web site .

40. Galiè N, Corris PA, Frost A et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013; 62(25 Suppl):D60-72. [PubMed 24355643]

41. Channick RN. Combination therapy in pulmonary arterial hypertension. Am J Cardiol. 2013; 111(8 Suppl):16C-20C. [PubMed 23558025]

42. Zhu B, Wang L, Sun L et al. Combination therapy improves exercise capacity and reduces risk of clinical worsening in patients with pulmonary arterial hypertension: a meta-analysis. J Cardiovasc Pharmacol. 2012; 60:342-6. [PubMed 22691882]

43. Raghu G, Behr J, Brown KK et al. Treatment of idiopathic pulmonary fibrosis with ambrisentan. Ann Intern Med. 2013; 158:641-9.

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