Bosentan

Class: Vasodilating Agents
VA Class: CV900
Chemical Name: 4 - (1,1 - Dimethylethyl) - N - [6 - (2 - hydroxyethoxy) - 5 - (2 - methoxyphenoxy)[2,2′ - bipyrimidin] - 4 - yl] - benzenesulfonamide monohydrate
Molecular Formula: C27H29N5O6S•H2O
CAS Number: 157212-55-0
Brands: Tracleer

Warning(s)

  • Hepatotoxicity
  • Risk of serious hepatic injury.1 Elevations in serum aminotransferase (AST/ALT) concentrations and liver failure reported.1 11 (See Hepatotoxicity under Cautions.)

  • Measure AST/ALT concentrations prior to initiation of therapy and monthly thereafter.1 11

  • Discontinue therapy if AST/ALT elevations are accompanied by manifestations of liver injury (e.g., nausea, vomiting, fever, abdominal pain, jaundice, lethargy, fatigue) or bilirubin concentrations ≥2 times ULN.1 11 (See Patients with Adverse Hepatic Effects under Dosage and Administration.)

  • Generally avoid in patients with elevated aminotransferases (>3 times ULN) at baseline (because monitoring for liver injury may be more difficult) and in those with preexisting moderate to severe hepatic impairment.1

  • Teratogenicity
  • May cause fetal harm; contraindicated in women who are or may become pregnant.1

  • Must exclude pregnancy before start of treatment and prevent thereafter by using 2 reliable forms of contraception during and for 1 month following discontinuance of therapy.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions and also see Advice to Patients.)

  • Oral, injectable, transdermal, and implantable hormonal contraceptives may not be reliable when used concomitantly with bosentan and should not be the sole contraceptive method.1 (See Specific Drugs under Interactions.)

  • Restricted Distribution
  • Distribution of bosentan is restricted because of risks of hepatotoxicity and major birth defects.1 (See Restricted Distribution Program under Dosage and Administration.)

REMS:

FDA approved a REMS for bosentan to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of bosentan 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 (). Also see Restricted Distribution Program under Dosage and Administration: General.

Introduction

Vasodilator; an endothelin receptor antagonist.1

Uses for Bosentan

Pulmonary Arterial Hypertension (PAH)

Management of PAH (WHO group 1 pulmonary hypertension) to improve exercise capacity and slow clinical worsening.1 2 3 6 Efficacy established principally in patients with NYHA/WHO functional class II–IV PAH (idiopathic, heritable, or associated with connective tissue diseases or congenital systemic-to-pulmonary shunts).1

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 has failed.27 38 52 Individualize choice of PAH therapy; consider factors such as disease severity, route of administration, potential adverse effects and costs of treatment, clinician experience, and patient preference.27 38 52

Slideshow: Can Prescription Drugs Lead to Weight Gain?

When considering use in patients with mild (NYHA/WHO class II) PAH, determine whether benefits are sufficient to outweigh risk of hepatotoxicity; liver injury could preclude future use of the drug.1

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).52 By targeting different pathophysiologic pathways of the disease, combination therapy may provide additive and/or synergistic benefits.25 27 29 38 52

Has been designated an orphan drug by FDA for treatment of PAH.12

CHF

Not effective in treatment of CHF with left ventricular dysfunction.1

Bosentan Dosage and Administration

General

Restricted Distribution Program

  • Bosentan can only be obtained through a restricted distribution program (Tracleer Access Program [TAP]); not available through community pharmacies.1 5 6 9 11 16 (See Boxed Warning and also see REMS.) Contact manufacturer at 866-228-3546 for specific information.1 5

  • Dispense no more than a 30-day supply of bosentan at one time; confirm with patient that required pregnancy and liver function tests were completed prior to dispensing.16

  • Distribute medication guide each time bosentan is dispensed and review with patient.1 6

Administration

Oral Administration

Administer orally twice daily (morning and evening) without regard to meals.1

Dosage

Pediatric Patients

PAH
Oral

Patients >12 years of age: Initially, 62.5 mg twice daily for 4 weeks, followed by 125 mg twice daily.1 If patient weighs <40 kg, recommended dosage for both initial and maintenance therapy is 62.5 mg twice daily.1

Whenever therapy is discontinued, consider gradual dosage reduction (e.g., 62.5 mg twice daily for 3–7 days) to minimize risk of clinical deterioration.1 9

Adults

PAH
Oral

Initially, 62.5 mg twice daily for 4 weeks, followed by 125 mg twice daily.1 If patient weighs <40 kg, recommended dosage for both initial and maintenance therapy is 62.5 mg twice daily.1

Whenever therapy is discontinued, consider gradual dosage reduction (e.g., 62.5 mg twice daily for 3–7 days) to minimize risk of clinical deterioration.1 9

Special Populations

Patients with Adverse Hepatic Effects

If elevations in AST and ALT are accompanied by manifestations of hepatic disease (e.g., nausea, vomiting, fever, abdominal pain, jaundice, lethargy, fatigue) or bilirubin are ≥2 times ULN, discontinue bosentan by gradually reducing dosage (e.g., 62.5 mg twice daily for 3–7 days).1 9

If confirmed (i.e., upon a repeat test) AST or ALT elevations of >3 but ≤5 times ULN develop during bosentan therapy, reduce dosage or interrupt therapy.1 9 11

If confirmed AST or ALT concentrations of >5 times ULN, discontinue bosentan by gradually reducing dosage.1 9 11

Monitor serum AST/ALT at least every 2 weeks following dosage reduction or discontinuance.1 11

May consider reinitiation of bosentan at starting dosage of 62.5 mg twice daily following return of AST/ALT to pretreatment levels if AST/ALT elevations did not exceed 8 times ULN; check serum AST/ALT within 3 days of reinitiating therapy and every 2 weeks thereafter.1 9 11

Manufacturer states that reinitiation of bosentan therapy should not be considered if AST/ALT exceeded 8 times ULN.1 11 Clinical experience with reinitiation of bosentan therapy is lacking in such patients, as well as in those with AST/ALT elevations accompanied by manifestations of hepatic disease or by increases in bilirubin concentrations of ≥2 times ULN.1 11

Hepatic Impairment

Dosage adjustment not necessary in patients with preexisting mild hepatic impairment (Child-Pugh class A).1

Avoid use in patients with preexisting moderate or severe hepatic impairment (Child-Pugh class B or C).1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustments necessary.1

Geriatric Patients

No specific dosage recommendations at this time.1

Cautions for Bosentan

Contraindications

  • Known or suspected pregnancy.1

  • Concomitant therapy with cyclosporine or glyburide.1

  • Known hypersensitivity to bosentan or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Hepatotoxicity

With close monitoring, unexplained hepatic cirrhosis and liver failure reported rarely after prolonged (i.e., >12 months) bosentan therapy.1 11 (See Boxed Warning.)

Manufacturer reinforces importance of strict adherence to monthly monitoring schedule and to dosage adjustment and monitoring guidelines throughout bosentan therapy.1 11 (See Patients with Adverse Hepatic Effects under Dosage and Administration.)

Dose-dependent elevations in AST or ALT of >3 times ULN were observed in 11% of patients receiving bosentan (<2 g daily) in clinical trials; occasionally accompanied by elevations in bilirubin,1 9 indicating potentially serious hepatic injury.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.1 Teratogenicity appears to be a class effect of endothelin-receptor antagonists.1 14

Exclude pregnancy (i.e., negative results on a urine or serum pregnancy test performed during the first 5 days of a normal menstrual period and ≥11 days after the last unprotected act of sexual intercourse) prior to initiating bosentan therapy in women of childbearing potential.1 5 6 Perform urine or serum pregnancy tests monthly.1 9 11

Women of childbearing potential must use 2 reliable contraceptive methods (including a nonhormonal method) during and for 1 month following cessation of therapy, unless patient has a Copper T380A or LNg 20 IUD or has undergone tubal sterilization, in which case no other contraceptive method required.1 (See Specific Drugs under Interactions.)

If used during pregnancy or patient becomes pregnant during therapy, apprise of potential fetal hazard.1

Sensitivity Reactions

Hypersensitivity Reactions

Angioedema (occurring 8 hours to 21 days after initiating therapy) reported.1

General Precautions

Fluid Retention

Fluid retention, sometimes requiring intervention (e.g., diuretics, fluid management, hospitalization), reported.1 Peripheral edema a known class effect of endothelin-receptor antagonists and also a consequence of PAH.1 17

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

Fertility in Males

Reduced sperm counts observed in men with PAH receiving usual dosages of bosentan; cannot exclude possibility of adverse effects on spermatogenesis.1

Hematologic Effects

Possible dose-related decreases in hemoglobin and hematocrit.1 9 Monitor hemoglobin 1 and 3 months after initiation of therapy and every 3 months thereafter.1

Pulmonary Effects

Consider possibility of associated pulmonary veno-occlusive disease (PVOD) and discontinue bosentan if manifestations of pulmonary edema occur.1

Specific Populations

Pregnancy

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

Lactation

Not known whether bosentan is distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in children <12 years of age.9 Evaluated in a limited number of pediatric patients 3–15 years of age; safety, efficacy, and pharmacokinetics of bosentan were similar to those parameters reported in adults.35

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1

Hepatic Impairment

Extensively metabolized by liver; hepatic impairment expected to increase exposure to bosentan.1 Use not recommended in patients with preexisting moderate to severe hepatic impairment or AST/ALT >3 times ULN.1 9

Renal Impairment

Minimal effect of severe renal impairment (Scr 15–30 mL/minute) on bosentan pharmacokinetics.1

Common Adverse Effects

Headache,1 nasopharyngitis,1 flushing,1 abnormal hepatic function,1 lower limb edema,1 hypotension,1 palpitations,1 dyspepsia,1 edema,1 fatigue,1 pruritus,1 rash,1 anemia.1

Interactions for Bosentan

Induces and is metabolized by CYP2C9 and CYP3A4; may possibly induce CYP2C19.1

Drugs Affecting Hepatic Microsomal Enzymes

CYP2C9 and CYP3A inhibitors: Potential pharmacokinetic interaction (increased plasma bosentan concentrations).1 Concomitant administration of both a CYP2C9 inhibitor and a potent or moderate CYP3A inhibitor with bosentan is not recommended.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2C9 and CYP3A, and possibly CYP2C19: Potential pharmacokinetic interaction (decreased plasma substrate concentrations).1 9

Does not inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2D6, or 3A in vitro; therefore, not expected to increase plasma concentrations of drugs metabolized by these enzymes.1

Drugs Affecting the Organic Anion Transport Protein (OATP)

Potential pharmacokinetic interaction with drugs that inhibit OATP.1 44

Specific Drugs

Drug

Interaction

Comments

Amiodarone

Potential for increased plasma bosentan concentrations1

Concomitant use of both amiodarone and a potent/moderate CYP3A inhibitor with bosentan not recommended1

Amprenavir (no longer commercially available in the US)

Potential for increased plasma bosentan concentrations1

Concomitant use of both amprenavir and a CYP2C9 inhibitor with bosentan not recommended1

Cyclosporine

Increased plasma bosentan and decreased plasma cyclosporine concentrations1

Concomitant use contraindicated1

Digoxin

Clinically important pharmacokinetic interaction unlikely1 43

Diltiazem

Potential for increased plasma bosentan concentrations1

Concomitant use of both diltiazem and a CYP2C9 inhibitor with bosentan not recommended1

Erythromycin

Potential for increased plasma bosentan concentrations1

Concomitant use of both erythromycin and a CYP2C9 inhibitor with bosentan not recommended1

Fluconazole

Potential for increased plasma bosentan concentrations1

Concomitant use of both fluconazole and a CYP2C9 inhibitor with bosentan not recommended1

Concomitant use of both fluconazole and a potent/moderate CYP3A inhibitor with bosentan not recommended1

Glyburide

Increased risk of elevated serum aminotransferase concentrations; decreased plasma glyburide and bosentan concentrations1

Concomitant use contraindicated; consider alternative hypoglycemic agents1

HIV protease inhibitors (PIs)

Substantially increased plasma trough bosentan concentrations observed with concomitant lopinavir/ritonavir; increases in bosentan concentrations also expected with other PIs1 44 50 51 55

Atazanavir (without ritonavir): Possible decreased atazanavir concentrations50

In patients already receiving a PI for ≥10 days, initiate bosentan at 62.5 mg once daily or every other day based on individual patient tolerance1 50 51 55

In patients currently receiving bosentan, discontinue bosentan for ≥36 hours prior to PI initiation; after ≥10 days of PI therapy, resume bosentan at 62.5 mg once daily or every other day based on individual patient tolerance1 50 51 55

Atazanavir (without ritonavir): Avoid concomitant use with bosentan50 55

HMG-CoA reductase inhibitors (statins)

Simvastatin: Decreased plasma concentrations of simvastatin and active metabolite1

Lovastatin, atorvastatin: Decreased plasma statin concentrations also expected1

Monitor serum cholesterol concentrations when initiating bosentan; adjust statin dosage if necessary1

Hormonal contraceptives

Decreased plasma norethindrone and ethinyl estradiol concentrations and systemic exposure;1 17 39 possible contraceptive failure1

Use concomitant nonhormonal contraceptive method;1 do not use hormonal contraceptive as sole contraceptive method1 17 39

Iloprost

Concomitant therapy appears well tolerated1 20

Combination may be used to therapeutic advantage

Itraconazole

Potential for increased plasma bosentan concentrations1

Concomitant use of both itraconazole and a CYP2C9 inhibitor with bosentan not recommended1

Ketoconazole

Increased plasma bosentan concentrations1 40

Bosentan dosage adjustment not necessary, but consider potential for increased effects1 40

Concomitant use of both ketoconazole and a CYP2C9 inhibitor with bosentan not recommended1

Losartan

Pharmacokinetic interaction unlikely1

Nimodipine

Pharmacokinetic interaction unlikely1

PDE type 5 inhibitors

Sildenafil: Decreased plasma sildenafil and increased plasma bosentan concentrations17 23 46

Tadalafil: Decreased exposure to tadalafil, but no substantial alteration in bosentan exposure48

Sildenafil: Manufacturer states dosage adjustments not necessary1

Rifampin

Healthy individuals: Plasma bosentan concentrations increased by about sixfold after first concurrent dose, then decreased with continued coadministration1 41

If concomitant use necessary, monitor liver function tests weekly for first 4 weeks, then resume usual monthly testing schedule1

Tacrolimus

Markedly increased plasma bosentan concentrations in animals1

Use concomitantly with caution1

Treprostinil

Healthy individuals: Pharmacokinetic interaction not noted with an oral formulation of treprostinil49

Warfarin

Decreased plasma warfarin concentrations and anticoagulant effects1 9 17 42

Monitor INR closely when bosentan is initiated or discontinued17 42

Bosentan Pharmacokinetics

Absorption

Bioavailability

Healthy individuals: Following oral administration, peak plasma concentrations attained within approximately 2–5 hours.1 33 Absolute bioavailability about 50%.1 17 33

Food

Food does not affect bioavailability.1 32

Special Populations

Increased (twofold) exposure to bosentan following oral or IV administration in patients with PAH compared with healthy individuals.1

Distribution

Extent

Does not penetrate into erythrocytes.1

Plasma Protein Binding

>98% (mainly albumin).1 34

Elimination

Metabolism

Metabolized by CYP2C9 and CYP3A4; appears to induce its own metabolism following multiple-dose administration.1

Elimination Route

Biliary excretion following metabolism in the liver.1 33 Less than 3% of dose excreted in urine.1 17 33

Half-life

Healthy adults: Terminal elimination half-life about 5 hours.1 17 33

Special Populations

Because of extensive hepatic metabolism, hepatic impairment may increase exposure to the drug.1

Pharmacokinetics not affected in patients with mild hepatic impairment (Child-Pugh class A).1 Increased exposure to bosentan and its active metabolite observed in patients with moderate hepatic impairment (Child-Pugh class B) and PAH associated with portal hypertension; not evaluated in those with severe hepatic impairment (Class-Pugh class C).1

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

Actions

  • Exhibits specific and competitive antagonism of both endothelin type A and type B receptors in the endothelium and vascular smooth muscle.1 17 33

  • Improves exercise capacity and hemodynamics in patients with PAH by inhibiting vasoconstricting effects of endothelin-1.1

Advice to Patients

  • Risk of liver injury.1 Importance of patients promptly informing clinicians of any nausea, vomiting, fever, unusual tiredness, abdominal pain, or yellowing of the skin or whites of the eyes.1

  • Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Risk of fetal harm.1 10 Importance of avoiding pregnancy; importance of using reliable (including nonhormonal) methods of contraception.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • Importance of monthly monitoring of serum aminotransferases and monthly pregnancy testing.1 11

  • Importance of patients taking bosentan as prescribed.10

  • Importance of not taking a double dose to make up for a missed dose but instead taking the next scheduled dose.10

  • Importance of carefully reading the patient information (medication guide) provided by the manufacturer before initiating therapy and each time the prescription is refilled.1

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

  • Importance of informing patients of other important precautionary information.1 (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 bosentan is restricted.1 5 6 11 (See Restricted Distribution Program under Dosage and Administration.)

Bosentan

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

62.5 mg (of anhydrous bosentan)

Tracleer

Actelion

125 mg (of anhydrous bosentan)

Tracleer

Actelion

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 1, 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. Actelion Pharmaceuticals US. Tracleer (bosentan) tablets prescribing information. South San Francisco, CA; 2012 Oct.

2. Rubin LJ, Badesch DB, Barst RJ et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002; 346:896-903. [IDIS 478525] [PubMed 11907289]

3. Channick RN, Simonneau G, Sitbon O et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet. 2001; 358:1119-23. [IDIS 471290] [PubMed 11597664]

4. Dupuis J. Endothelin-receptor antagonists in pulmonary hypertension. Lancet. 2001; 358:1113-4. [IDIS 471289] [PubMed 11597660]

5. Giaid A, Yanagisawa M, Langleben D et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypersion. N Engl J Med. 1993; 328:1732-9 [PubMed 8497283]

6. FDA approves first oral medication for pulmonary arterial hypertension. FDA Talk Paper. Rockville, MD: Food and Drug Administration; 2001 Nov 20.

7. Newman JH. Treatment of primary pulmonary hypertension—the next generation. N Engl J Med. 2002; 346:933-5. [IDIS 478527] [PubMed 11907295]

8. 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]

9. Actelion, South San Francisco, CA: Personal communication.

10. Actelion Pharmaceuticals US. Tracleer (bosentan) tablets medication guide. South San Francisco, CA: 2012 Oct.

11. Segal ES. Dear healthcare professional letter regarding revisions to the Tracleer (bosentan) prescribing information concerning importance of continued monthly liver function testing. South San Francisco, CA: Actelion Pharmaceuticals US; 2006 Mar 1.

12. 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 .

13. Galiè N, Rubin Lj, Hoeper M et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet. 2008; 371:2093-100. [PubMed 18572079]

14. Gilead Sciences, Inc. Letairis (ambrisentan) tablets prescribing information. Foster City, CA; 2011 Mar.

15. Segal ES. Dear healthcare professional letter regarding important prescribing information for Tracleer (bosentan). South San Francisco, CA: Actelion Pharmaceuticals US; 2006 Mar 1.

16. Tracleer (bosentan) risk evaluation and mitigation strategy (REMS), REMS Modification. Available from FDA web site. Accessed 2011 Apr 29.

17. Mathier MA, Ishizawar D. Bosentan. Expert Opin Pharmacother. 2010; 11:1023-34. [PubMed 20307226]

18. Sitbon O, Badesch DB, Channick RN et al. Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary arterial hypertension: a 1-year follow-up study. Chest. 2003; 124:247-54. [PubMed 12853530]

19. Badesch DB, Barst RJ, Galie N et al. Maintenance of improvement in 6-minute walk distance with long term bosentan treatment: results of the BREATHE-1 open-label extension study. Circulation. 2006; 114: II-578, Abstract 2765.

20. McLaughlin VV, Oudiz RJ, Frost A et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006; 174:1257-63. [PubMed 16946127]

21. Benza RL, Rayburn BK, Tallaj JA et al. Treprostinil-based therapy in the treatment of moderate-to-severe pulmonary arterial hypertension: long-term efficacy and combination with bosentan. Chest. 2008; 134:139-45. [PubMed 18403673]

22. Channick RN, Olschewski H, Seeger W et al. Safety and efficacy of inhaled treprostinil as add-on therapy to bosentan in pulmonary arterial hypertension. J Am Coll Cardiol. 2006; 48:1433-7. [PubMed 17010807]

23. Gruenig E, Michelakis E, Vachiéry JL et al. Acute hemodynamic effects of single-dose sildenafil when added to established bosentan therapy in patients with pulmonary arterial hypertension: results of the COMPASS-1 study. J Clin Pharmacol. 2009; 49:1343-52. [PubMed 19755415]

24. Galiè N, Brundage BH, Ghofrani HA et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009; 119:2894-903. [PubMed 19470885]

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]

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. McLaughlin VV, Benza RL, Rubin LJ et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol. 2010; 55:1915-22. [PubMed 20430262]

31. Seyfarth HJ, Pankau H, Hammerschmidt S et al. Bosentan improves exercise tolerance and Tei index in patients with pulmonary hypertension and prostanoid therapy. Chest. 2005; 128:709-13. [PubMed 16100158]

32. Dingemanse J, Bodin F, Weidekamm E et al. Influence of food intake and formulation on the pharmacokinetics and metabolism of bosentan, a dual endothelin receptor antagonist. J Clin Pharmacol. 2002; 42:283-9. [PubMed 11865964]

33. Weber C, Schmitt R, Birnboeck H et al. Pharmacokinetics and pharmacodynamics of the endothelin-receptor antagonist bosentan in healthy human subjects. Clin Pharmacol Ther. 1996; 60:124-37. [PubMed 8823230]

34. van Giersbergen PL, Popescu G, Bodin F et al. Influence of mild liver impairment on the pharmacokinetics and metabolism of bosentan, a dual endothelin receptor antagonist. J Clin Pharmacol. 2003; 43:15-22. [PubMed 12520623]

35. Barst RJ, Ivy D, Dingemanse J et al. Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension. Clin Pharmacol Ther. 2003; 73:372-82. [PubMed 12709727]

36. Maiya S, Hislop AA, Flynn Y et al. Response to bosentan in children with pulmonary hypertension. Heart. 2006; 92:664-70. [PubMed 16216850]

37. Rosenzweig EB, Ivy DD, Widlitz A et al. Effects of long-term bosentan in children with pulmonary arterial hypertension. J Am Coll Cardiol. 2005; 46:697-704. [PubMed 16098438]

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. van Giersbergen PL, Halabi A, Dingemanse J. Pharmacokinetic interaction between bosentan and the oral contraceptives norethisterone and ethinyl estradiol. Int J Clin Pharmacol Ther. 2006; 44:113-8. [PubMed 16550733]

40. van Giersbergen PL, Halabi A, Dingemanse J. Single- and multiple-dose pharmacokinetics of bosentan and its interaction with ketoconazole. Br J Clin Pharmacol. 2002; 53:589-95. [PubMed 12047483]

41. van Giersbergen PL, Treiber A, Schneiter R et al. Inhibitory and inductive effects of rifampin on the pharmacokinetics of bosentan in healthy subjects. Clin Pharmacol Ther. 2007; 81:414-9. [PubMed 17251982]

42. Weber C, Banken L, Birnboeck H et al. Effect of the endothelin-receptor antagonist bosentan on the pharmacokinetics and pharmacodynamics of warfarin. J Clin Pharmacol. 1999; 39:847-54. [PubMed 10434238]

43. Weber C, Banken L, Birnboeck H et al. The effect of bosentan on the pharmacokinetics of digoxin in healthy male subjects. Br J Clin Pharmacol. 1999; 47:701-6. [PubMed 10383550]

44. Dingemanse J, van Giersbergen PL, Patat A et al. Mutual pharmacokinetic interactions between bosentan and lopinavir/ritonavir in healthy participants. Antivir Ther. 2010; 15:157-63. [PubMed 20386070]

45. van Giersbergen PL, Treiber A, Clozel M et al. In vivo and in vitro studies exploring the pharmacokinetic interaction between bosentan, a dual endothelin receptor antagonist, and glyburide. Clin Pharmacol Ther. 2002; 71:253-62. [PubMed 11956508]

46. Burgess G, Hoogkamer H, Collings L et al. Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil. Eur J Clin Pharmacol. 2008; 64:43-50. [PubMed 18040672]

47. Paul GA, Gibbs JS, Boobis AR et al. Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension. Br J Clin Pharmacol. 2005; 60:107-12. [IDIS 538415] [PubMed 15963102]

48. Wrishko RE, Dingemanse J, Yu A et al. Pharmacokinetic interaction between tadalafil and bosentan in healthy male subjects. J Clin Pharmacol. 2008; 48:610-8. [PubMed 18305126]

49. Gotzkowsky SK, Dingemanse J, Lai A et al. Lack of a pharmacokinetic interaction between oral treprostinil and bosentan in healthy adult volunteers. J Clin Pharmacol. 2010; 50:829-34. [PubMed 20133511]

50. Bristol-Myers Squibb. Reyataz (atazanavir) capsules and oral powder prescribing information. Princeton, NJ; 2014 Jun.

51. Janssen. Prezista (darunavir) oral suspension and tablets prescribing information. Titusville, NJ; 2014 Apr.

52. 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]

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

54. 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]

55. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (May 1, 2014). Updates may be available at HHS AIDS Information (AIDSinfo) website.

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