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

• Hepatotoxicity


• 
  

  Potential risk of developing hepatic injury.^{1 3 18} Elevated serum aminotransferase (AST/ALT) concentrations to at least 3 times the upper limit of normal (ULN) reported.^{1 9} A class effect of endothelin-receptor antagonists;^{1 6 10 11 14} during postmarketing experience, unexplained hepatic cirrhosis and liver failure reported rarely after prolonged therapy (>12 months) with another endothelin-receptor antagonist (bosentan).^{1 6}

  
  


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  Serum aminotransferases and bilirubin (if aminotransferase concentrations are elevated)³ must be measured prior to initiation of therapy and monthly thereafter.¹ (See Hepatic Effects under Cautions.)

  
  


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  In patients with adverse hepatic effects, dosage reduction, interruption of therapy, or discontinuance of the drug may be necessary.^{1 3} (See Patients with Adverse Hepatic Effects under Dosage and Administration.)

  
  


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  Ambrisentan generally should be avoided in patients with elevated aminotransferases (>3 × ULN) at baseline (because monitoring for liver injury may be more difficult).¹

  
  

• Fetotoxicity


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  May cause fetal harm; contraindicated in pregnant women.^{1 18} Pregnancy must be excluded before start of treatment and prevented thereafter by use of 2 acceptable methods of contraception during and for one month following treatment unless patient has undergone tubal sterilization or chooses to use a Copper T380A or LNg 20 IUD, in which case no additional contraceptive method is required.^{1 3 18} (See Fetal/Neonatal Morbidity and Mortality under Cautions and also see Advice to Patients.)

  
  

REMS:

FDA approved a REMS for ambrisentan to ensure that the benefits of a drug 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 ().

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

Treatment of pulmonary arterial hypertension (PAH), WHO group 1, in patients with WHO class II or III symptoms to improve exercise capacity and to delay clinical worsening.^{1 2 3 4 9}

Ambrisentan has been used in a limited number of PAH patients in whom therapy with other endothelin-receptor antagonists was discontinued due to aminotransferase elevations.^{1 14 17} In an uncontrolled, open-label study, no patient who previously had aminotransferase elevations (ALT and/or AST >3 × ULN) on bosentan or another investigational endothelin-receptor antagonist (sitaxsentan) required discontinuance of ambrisentan due to aminotransferase elevations (>3 × ULN) during limited long-term follow-up (median of 13 months), and escalation of ambrisentan dosage up to 10 mg daily in 50% of patients.^{1 3 14 17}

Manufacturer suggests that ambrisentan therapy may be tried in patients who have experienced asymptomatic aminotransferase elevations while receiving other endothelin-receptor antagonists, after aminotransferase levels in such patients have normalized.¹

Additional studies needed to clarify the role of selective ET-1 receptor antagonists versus dual ET-1 type A/type B receptor antagonists (e.g., bosentan) in patients with PAH,^{14 15} and to establish the efficacy of ambrisentan used in conjunction with other PAH therapies (e.g., prostanoids [epoprostenol, iloprost, treprostinil], phosphodiesterase type 5 inhibitors [e.g., sildenafil]).^{10 14}

Ambrisentan Dosage and Administration

General

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  A risk management plan (Risk Evaluation and Mitigation Strategy, REMS) has been developed for ambrisentan to minimize adverse effects and ensure that benefits outweigh risks of therapy.¹⁸ Ambrisentan can only be obtained through a restricted distribution program because of potential hepatotoxicity and fetotoxicity (see Boxed Warning); available only through physicians and specialty pharmacies registered with the Letairis Education and Access Program (LEAP).^{1 3 13 18}

  
  


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  Patients must enroll in and meet all conditions of LEAP to obtain ambrisentan, and reenroll after 12 months of treatment and annually thereafter.^{1 18} Contact LEAP at 866-664-LEAP (5327) for specific information.¹

  
  


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  FDA-approved medication guide must be distributed with each 30-day supply of ambrisentan dispensed and reviewed with every patient.^{1 3 16 18}

  
  

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 maximum of 10 mg once daily if tolerated.¹

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

If AST or ALT concentrations >8 × ULN, discontinue ambrisentan and do not reinitiate therapy with the drug.^{1 3} In addition, discontinue ambrisentan if AST or ALT concentrations >3 × ULN and are accompanied by manifestations of hepatic disease (e.g., nausea, vomiting, fever, abdominal pain, jaundice, lethargy, fatigue) or bilirubin concentrations >2 × ULN; there is no experience with reinitiation of ambrisentan therapy in these circumstances.^{1 3}

If confirmed (i.e., upon a repeat test) AST or ALT elevations >3 but ≤5 × ULN, reduce dosage or interrupt therapy and continue to monitor AST/ALT concentrations at least every 2 weeks until levels are <3 × ULN.^{1 3}

If AST or ALT concentrations >5 but ≤8 × ULN, discontinue therapy and continue to monitor AST/ALT concentrations at least every 2 weeks until levels are <3 × ULN.^{1 3}

May consider reinitiation of ambrisentan therapy following return of AST/ALT concentrations to pretreatment levels if AST/ALT elevations did not exceed 8 × ULN; monitor aminotransferase concentrations more frequently after reinitiation.¹

Manufacturer states that reinitiation of ambrisentan therapy should not be considered if AST/ALT concentrations exceed 8 × ULN.¹ Clinical experience with reinitiation of therapy is lacking in such patients, as well as in those with AST/ALT elevations accompanied by manifestations of hepatic injury or increases in bilirubin concentrations of >2 × ULN.¹

Hepatic Impairment

Consider reduced dosage in patients with preexisting mild hepatic impairment.¹

Avoid use in patients with preexisting moderate or severe hepatic impairment or with AST/ALT concentrations >3 x ULN.¹ (See Boxed Warning.)

Renal Impairment

Mild or moderate renal impairment: Dosage adjustment not required.¹

Severe renal impairment: Not studied.¹

Patients on hemodialysis: Not studied.^{1 3}

Cautions for Ambrisentan

Contraindications

• 
  

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

  
  

Warnings/Precautions

Hepatic Effects

Risk of elevated serum aminotransferases (AST or ALT) and/or bilirubin concentrations.¹ (See Boxed Warning.) AST/ALT concentrations exceeding 3 × ULN observed in 0.8% of patients after 12 weeks of ambrisentan therapy and 2.8% of patients treated with ambrisentan for 1 year in clinical trials.^{1 3}

In at least one patient, concomitant bilirubin elevations exceeding 2 × ULN also reported.¹

Hepatotoxicity appears to be a class effect of endothelin-receptor antagonists.^{1 3 6 10 11 14} Rare cases of hepatic cirrhosis and liver failure reported with other drug in this class (e.g., bosentan).⁶ In at least one patient receiving bosentan, marked elevations in liver function test results accompanied by nonspecific symptoms developed after >20 months of therapy, with gradual resolution following drug discontinuance.^{1 6}

Use in patients with preexisting moderate or severe hepatic impairment not recommended; (see Boxed Warning) use caution in patients with mild hepatic impairment.^{1 3}

Perform liver function tests (e.g., AST, ALT, bilirubin) prior to initiation and monthly during therapy.^{1 13}

Manufacturer recommends strict adherence to monthly monitoring schedule and dosage adjustment guidelines.^{1 13} (See Patients with Adverse Hepatic Effects under Dosage and Administration.)

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}

Contraindicated in women who are or may become pregnant.^{1 18} (See Boxed Warning.)

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

Must use 2 acceptable methods of contraception during and for 1 month following cessation of therapy; alternatively, 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} (See Advice to Patients.)

Fertility in Males

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

Hematologic Effects

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

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

Discontinue ambrisentan if clinically important, otherwise unexplained reductions in hemoglobin observed.^{1 3}

Fluid Retention

Peripheral edema reported, usually mild to moderate in severity; occurred with greater frequency and severity in geriatric patients.¹ Peripheral edema is a known class effect of endothelin-receptor antagonists and also a consequence of PAH.¹ Fluid retention, sometimes requiring intervention (e.g., diuretics, fluid management, hospitalization), reported during postmarketing surveillance.¹

Monitor patients for clinically important fluid retention and initiate appropriate treatment or discontinue ambrisentan if necessary.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 or with AST/ALT concentrations >3 × ULN.¹ Use with caution in patients with mild hepatic impairment and consider reduced dosage.¹

Renal Impairment

Safety and efficacy not established in patients with severe renal impairment.¹

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

Common Adverse Effects

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

Interactions for Ambrisentan

Interaction potential of ambrisentan not well characterized; lack of in vivo interaction studies with strong inhibitors/inducers of CYP 3A4 or 2C19, strong inhibitors of p-glycoprotein or organic anion transport protein (OATP), or with inducers of CYPs, uridine diphosphate glucuronosyltransferase (UGT) or p-glycoprotein.^{1 3}

In vitro evidence suggests metabolism by UGT enzymes 1A9, 2B7, and 1A3 and by CYP3A4 and CYP2C19.^{1 3 14}

Substrate of p-glycoprotein and OATP.^{1 3}

Ambrisentan does not inhibit p-glycoprotein,^{1 3}

Drugs Affecting Hepatic Microsomal Enzymes

Strong inhibitors of CYP3A4 or CYP2C19: Potential pharmacokinetic interactions (increased plasma concentrations of ambrisentan).^{1 3}

Drugs Affecting the p-Glycoprotein Transport System

Pharmacokinetic interactions possible with strong inhibitors or inducers of p-glycoprotein.¹

Drugs Affecting Uridine Diphosphate Glucuronosyltransferase Enzymes

Pharmacokinetic interactions possible with drugs that induce UGT 1A9, 2B7, or 1A3.¹ Use concomitantly with caution.¹

Specific Drugs

Drug	Interaction	Comments
Antibiotics, macrolide (e.g., clarithromycin, telithromycin)	Possible increased ambrisentan concentrations; in vivo studies with specific drugs lacking1 3	Use with caution1
Antifungals, azole (e.g., itraconazole, ketoconazole)	Possible increased ambrisentan concentrations; in vivo studies with specific drugs lacking1 3	Use with caution1
Antiretrovirals (e.g., atazanavir, indinavir, nelfinavir, ritonavir, saquinavir)	Possible increased ambrisentan concentrations; in vivo studies with specific drugs lacking1 3	Use with caution1
Cyclosporine	Possible increased ambrisentan concentrations; in vivo studies with specific drugs lacking1 3	Use with caution1
Nefazodone	Possible increased ambrisentan concentrations; in vivo studies with specific drugs lacking1 3	Use with caution1
Omeprazole	Possible increased ambrisentan concentrations; in vivo studies with specific drugs lacking1 3	Use with caution1
Rifampin	Possible pharmacokinetic interaction through induction of p-glycoprotein and hepatic microsomal enzymes (CYP3A4 and CYP2C19) and inhibition of OATP transport systems; in vivo studies with specific drugs lacking1 3	Use with caution1
Sildenafil	Clinically important interaction not observed1 14	No dosage adjustment of ambrisentan or sildenafil required1
Warfarin	Clinically important interaction not observed1 2 4 9 14	No dosage adjustment of ambrisentan or warfarin required1

Ambrisentan Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration,^{1 3 9} with peak plasma concentrations attained within approximately 2 hours after oral administration.^{1 9 12} 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}

Elimination Route

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

Half-life

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

Special Populations

Potential for increased exposure to ambrisentan in patients with hepatic impairment.¹ (See Hepatic Impairment 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

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  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}

  
  


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  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}

  
  


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  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

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

  
  


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

  
  


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  Risk of liver injury.^{1 16} Importance of patient promptly informing clinician of any nausea, vomiting, appetite loss, fever, unusual tiredness, abdominal pain, dark urine, itching, or yellowing of the skin or white of the eyes.^{1 16}

  
  


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

  
  


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  Importance of avoiding pregnancy and using 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}

  
  


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  Importance of monthly monitoring of liver function tests and monthly pregnancy testing.^{1 16}

  
  


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

  
  


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

  
  


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  Importance of distributing FDA-approved medication guide to every patient who receives ambrisentan and reviewing the information with the patient.^{1 18}

  
  


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

  
  


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

  
  


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  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 General under Dosage and Administration.)

Ambrisentan

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

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Gilead Sciences, Inc. Letairis (ambrisentan) tablets prescribing information. Foster City, CA; 2009 July.

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 7^th 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 ET_Ainhibition? Curr Med Res Opin. 2006; 22:2567-74.

16. Gilead Sciences, Inc. Letairis (ambrisentan) tablets medication guide. Foster City, CA; 2007 Jun.

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 103^nd 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.

More Ambrisentan resources

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• Ambrisentan Drug Interactions
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• Ambrisentan MedFacts Consumer Leaflet (Wolters Kluwer)


• Ambrisentan Professional Patient Advice (Wolters Kluwer)


• ambrisentan Advanced Consumer (Micromedex) - Includes Dosage Information


• Letairis Prescribing Information (FDA)


• Letairis Consumer Overview

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