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Bosentan

Bosentan

Pronunciation: boe-SEN-tan

Class: Endothelin receptor antagonist

For ProfessionalsSide EffectsDosageInteractionsMore…

Trade Names

Tracleer

– Tablets, oral 62.5 mg

– Tablets, oral 125 mg

Pharmacology

Antagonizes endothelin receptor by binding to endothelin A and endothelin B receptors in the endothelium and vascular smooth muscle.

Pharmacokinetics

Absorption

T max is 3 to 5 h. Absolute bioavailability is approximately 50%. Steady state is reached in 3 to 5 days.

Distribution

Vd is approximately 18 L. More than 98% protein bound (mainly albumin).

Metabolism

Metabolized in the liver. There are 3 metabolites, one of which contributes 10% to 20% of bosentan’s effects. Bosentan induces CYP2C9, CYP3A4, and possibly CYP2C19; it may induce its own metabolism.

Elimination

Half-life is approximately 5 h. Eliminated by biliary excretion; less than 3% is recovered in urine. Cl is 4 L/h.

Special Populations

Renal Function Impairment

In patients with severe renal impairment (CrCl 15 to 30 mL/min), concentrations of the 3 metabolites may increase 2-fold, although it is not clinically significant.

Hepatic Function Impairment

Exposure to bosentan would be significantly increased; avoid use in those with moderate or severe liver impairment or elevated aminotransferases more than 3 times the ULN.

Elderly

It is not known whether bosentan pharmacokinetics are influenced by age.

Children

It is not known whether bosentan pharmacokinetics are influenced by age.

Gender

It is not known whether bosentan pharmacokinetics are influenced by gender.

Race

It is not known whether bosentan pharmacokinetics are influenced by race.

Body weight It is not known whether bosentan pharmacokinetics are influenced by body weight.

Indications and Usage

Treatment of pulmonary arterial hypertension (WHO group 1) to improve exercise ability and decrease the rate of clinical worsening.

Unlabeled Uses

Prevention of digital ulcers in systemic sclerosis; prevention of Raynaud phenomenon.

Contraindications

Coadministration of cyclosporine or glyburide; hypersensitivity to bosentan or any component of the product; pregnancy.

Dosage and Administration

Pulmonary Arterial Hypertension

Adults PO 62.5 mg twice daily for 4 wk, then increase to maintenance dosage of 125 mg twice daily. In patients with a body weight less than 40 kg, the recommended maintenance dosage is 62.5 mg twice daily.

Dosage adjustment If ALT/AST is more than 3 and 5 or less times the ULN, confirm by another aminotransferase test. If confirmed, reduce the daily dosage to 62.5 mg twice daily or interrupt treatment and monitor aminotransferase levels at least every 2 wk. If the aminotransferase levels return to pretreatment values, continue or reintroduce the treatment as appropriate. If ALT/AST is more than 5 and 8 or less times the ULN, confirm by another aminotransferase test. If confirmed, stop treatment and monitor aminotransferase levels at least every 2 wk. Once the aminotransferase levels return to pretreatment values, consider reintroduction of the treatment. If ALT/AST is more than 8 times the ULN, treatments should be stopped and reintroduction of bosentan should not be considered.

Discontinuation of therapy When discontinuing therapy, consider a gradual dose reduction (62.5 mg twice daily for 3 to 7 days) to avoid the potential for clinical deterioration.

Concomitant therapy

Adults PO Discontinue use of bosentan at least 36 h prior to initiation of ritonavir. After at least 10 days following the initiation of ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability. In patients who have been receiving ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability.

General Advice

  • This medication is available only through the Tracleer Access Program.
  • May be taken with or without food.
  • If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (eg, abdominal pain, fever, jaundice, nausea, unusual lethargy or fatigue, vomiting) or increases in bilirubin of 2 times the ULN or more, stop treatment.
  • If therapy is reintroduced, it should be at the starting dose and aminotransferase levels should be checked within 3 days and thereafter at least every 2 wk.

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

Clarithromycin The risk of bosentan hepatotoxicity may be increased. Close clinical and laboratory monitoring is warranted. If an interaction is suspected, stop one or both drugs.

Cyclosporine Bosentan trough concentrations may be increased, while cyclosporine plasma levels may be decreased; coadministration is contraindicated.

Glyburide Plasma concentrations of both glyburide and bosentan may be decreased; coadministration is contraindicated.

HMG-CoA reductase inhibitors (eg, atorvastatin, lovastatin, simvastatin) Plasma concentrations of simvastatin and its metabolite may be decreased when coadministered with bosentan. Bosentan is also expected to reduce plasma concentrations of other HMG-CoA reductase inhibitors metabolized by CYP3A4 (ie, atorvastatin, lovastatin). Monitor cholesterol levels and adjust the HMG-CoA reductase inhibitor dose accordingly.

Hormonal contraceptives (ie, implantable, injectable, oral, transdermal) Plasma concentrations may be reduced by bosentan, decreasing the effectiveness. Women should not rely on hormonal contraception alone when taking bosentan.

Ketoconazole Plasma concentrations of bosentan may be increased. No dosage adjustment is necessary, but consider increased effects of bosentan. Addition monitoring is warranted.

Phosphodiesterase type 5 inhibitors (eg, sildenafil) Coadministration may elevate bosentan plasma concentrations, increasing the pharmacologic effects and risk of toxicity. Phosphodiesterase type 5 inhibitor concentrations may be reduced, decreasing the pharmacologic effects. Coadminister these agents with caution. Closely monitor the clinical response and for adverse reactions. Adjust therapy as needed.

Rifampin Coadministration may increase bosentan trough concentrations after the first concomitant dose and decrease bosentan trough concentrations at steady state. Measure liver function weekly for the first 4 wk of concurrent use before reverting to normal monitoring.

Ritonavir-containing regimens Coadministration may increase bosentan trough concentrations. In patients receiving ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on tolerability. In patients receiving bosentan, stop bosentan at least 36 h before starting ritonavir. At least 10 days after starting ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon tolerability.

Tacrolimus Although not studied in humans, coadministration resulted in markedly increased plasma concentrations of bosentan in animals. Use with caution.

Warfarin Warfarin plasma concentrations may be decreased by bosentan. Clinically important changes in INR or warfarin dose were not seen in patients with pulmonary arterial hypertension during clinical trials. Because warfarin has a narrow therapeutic index, monitor coagulation parameters and adjust the warfarin dose as needed.

Adverse Reactions

Cardiovascular

Syncope (5%); flushing, hypotension, palpitations (4%).

CNS

Headache (15%).

Dermatologic

Rash (postmarketing).

Hematologic

Anemia (3%); anemia requiring transfusion, leukopenia, neutropenia, thrombocytopenia (postmarketing).

Hepatic

Abnormal hepatic function test (4%); hepatic cirrhosis, jaundice, liver failure (postmarketing).

Respiratory

Respiratory tract infection (22%); sinusitis (4%).

Miscellaneous

Edema (11%); arthralgia (4%); angioneurotic edema, hypersensitivity (postmarketing).

Precautions

Warnings

Distribution program Because of the risk of liver injury and birth defects, bosentan is available only through a special restricted distribution program called the Tracleer Access Program (TAP), by calling 1-866-228-3546. Only health care providers and pharmacies registered with TAP may prescribe and distribute bosentan. In addition, bosentan may be dispensed only to patients who are enrolled in and meet all conditions of TAP.

Liver injury At least a 3-fold ULN elevation of liver aminotransferases (ALT and AST) occurred in approximately 11% of patients, accompanied by elevated bilirubin in a small number of cases. Because these changes are a marker for potential serious liver injury, serum aminotransferase levels must be measured prior to initiation of treatment and then monthly. Rare cases of unexplained hepatic cirrhosis were reported after prolonged (more than 12 mo) therapy with bosentan in patients with multiple comorbidities and drug therapies. There have also been rare reports of liver failure.

Avoid using bosentan in patients with elevated aminotransferases (greater than 3 times the ULN) at baseline because monitoring liver injury may be more difficult. Stop treatment if liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (eg, abdominal pain, fever, jaundice, nausea, unusual lethargy or fatigue, vomiting) or increases in bilirubin 2 times or more the ULN.

Pregnancy Bosentan is likely to cause major birth defects if used by pregnant women based on animal data. Pregnancy must be excluded before the start of treatment with bosentan. Throughout treatment and for 1 mo after stopping bosentan, women of childbearing potential must use 2 reliable methods of contraception unless the patient has a tubal sterilization or Copper T 380A intrauterine device or levonorgestrel 20 mcg/day intrauterine system inserted, in which case no other contraception is needed. Hormonal contraceptives, including oral, injectable, transdermal, and implantable contraceptives, should not be used as the sole means of contraception because these may not be effective in patients receiving bosentan. Obtain monthly pregnancy tests.

Monitor

Ensure that liver enzymes are measured before starting therapy and monthly during treatment. Ensure that Hgb is measured after 1 and 3 mo of therapy and then every 3 mo for duration of treatment. Obtain monthly follow-up urine or serum pregnancy tests in women of childbearing potential.

Pregnancy

Category X . May cause fetal harm. Pregnancy must be excluded before starting bosentan.

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Select dose with caution, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and comorbidity.

Hypersensitivity

May occur, including rash and angioedema.

Hepatic Function

Avoid use in patients with moderate or severe hepatic impairment or elevated aminotransferases (more than 3 times the ULN); use with caution in patients with mild hepatic impairment.

Fertility

There was a decline in sperm count of at least 50% in 25% of patients after 3 or 6 mo of treatment with bosentan.

Fluid retention

Fluid retention or edema may occur.

Hematologic

Dose-related decreases in Hgb and Hct may occur.

Pulmonary edema

If signs of pulmonary edema occur, consider the possibility of associated pulmonary veno-occlusive disease and discontinue bosentan.

Overdosage

Symptoms

Blurred vision, decreased BP, dizziness, headache, increased heart rate, nausea, sweating, vomiting.

Patient Information

  • Advise patient to read the Medication Guide before beginning therapy and with each refill.
  • Advise patient to take in the morning and evening as prescribed, without regard to meals.
  • Advise patient that monthly liver enzyme tests and pregnancy tests (in women of childbearing potential) will be required to use this medication safely.
  • Caution patient that if drug is stopped for any period of time and then restarted, the lower initial dose should be used again.
  • Instruct women of childbearing potential that reliable contraceptive measures must be used during treatment. Advise patient using hormonal contraception (eg, oral, implantable, injectable) that another nonhormonal contraceptive needs to be used.
  • Instruct women to notify health care provider immediately if pregnancy is suspected (eg, delay in menses, any other reason to suspect pregnancy), they are planning on becoming pregnant, or they are breast-feeding.
  • Instruct patient to stop taking drug and immediately report any of these symptoms to health care provider: abdominal pain, fatigue, fever, nausea, jaundice, unusual lethargy, vomiting.

Copyright © 2009 Wolters Kluwer Health.

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Bosentan

Bosentan

Generic Name: bosentan (boe-SEN-tan)

Brand Name: Tracleer

Bosentan may cause serious liver problems. Liver function tests should be done before and during treatment with bosentan to monitor for side effects. Be sure to keep all doctor and lab appointments. You should usually not take bosentan if you have abnormal liver function tests. Contact your doctor immediately if you experience nausea, vomiting, fever, stomach pain, yellowing of the skin or eyes, dark urine, pale stools, or unusual tiredness.

Bosentan may cause serious birth defects if taken during pregnancy. Do not take bosentan if you are pregnant or planning to become pregnant. You will need to have a negative pregnancy test before you start bosentan, and monthly while you take it. You must also use 2 effective forms of birth control while you take bosentan and for 1 month after you stop taking it. Talk with your doctor about the use of effective birth control while you take bosentan.

Bosentan is only available through a special program called Tracleer Access Program. Talk to your doctor to be sure you are enrolled in this program and that you meet all of its requirements.

OverviewSide EffectsInteractionsFor ProfessionalsMore…

Bosentan is used for:

Treating high blood pressure in the lungs (pulmonary arterial hypertension) in certain patients.

Bosentan is an endothelin receptor antagonist. It works by blocking a certain substance in the lungs, which helps to decrease blood pressure in the lungs.

Do NOT use bosentan if:

  • you are allergic to any ingredient in bosentan
  • you are pregnant or may become pregnant
  • you have moderate to severe liver problems
  • you are taking bosutinib, cabazitaxel, cyclosporine, or glyburide

Contact your doctor or health care provider right away if any of these apply to you.

Before using bosentan:

Some medical conditions may interact with bosentan. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

  • if you are pregnant, planning to become pregnant, or are breast-feeding
  • if you are able to become pregnant
  • if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement
  • if you have allergies to medicines, foods, or other substances
  • if you have a history of liver problems, abnormal liver function tests, heart problems (eg, congestive heart failure), or blood problems (eg, anemia)
  • if you have fluid retention (eg, unusual swelling of the arms, hands, legs, or feet)
  • if you drink alcohol or take medicines that may harm the liver (eg, acetaminophen, methotrexate, isoniazid, certain medicines for HIV infection). Ask your doctor if you are unsure if any of your medicines might harm the liver

Some MEDICINES MAY INTERACT with bosentan. Tell your health care provider if you are taking any other medicines, especially any of the following:

  • Amiodarone, azole antifungals (eg, fluconazole, itraconazole, ketoconazole, voriconazole), cobicistat, cyclosporine, diltiazem, HIV protease inhibitors (eg, ritonavir), macrolide antibiotics (eg, erythromycin), or tacrolimus because they may increase the risk of bosentan’s side effects
  • Glyburide or rifampin because the risk of liver problems may be increased
  • Anticoagulants (eg, warfarin), axitinib, bosutinib, cabazitaxel, HMG-CoA reductase inhibitors (statins) (eg, simvastatin), hormonal contraceptives (eg, oral, injected, patch, implanted birth control), or ulipristal because their effectiveness may be decreased by bosentan

This may not be a complete list of all interactions that may occur. Ask your health care provider if bosentan may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use bosentan:

Use bosentan as directed by your doctor. Check the label on the medicine for exact dosing instructions.

  • Bosentan comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get bosentan refilled.
  • Take bosentan by mouth with or without food.
  • Do not suddenly stop taking bosentan without checking with your doctor. Your condition may become worse if bosentan is suddenly stopped. If you need to stop bosentan, your doctor may gradually lower your dose.
  • Take bosentan on a regular schedule to get the most benefit from it. Taking bosentan at the same times each day will help you to remember to take it.
  • Continue to take bosentan even if you feel well. Do not miss any doses.
  • If you miss a dose of bosentan, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use bosentan.

Important safety information:

  • Bosentan may cause dizziness or light-headedness. These effects may be worse if you take it with alcohol or certain medicines. Use bosentan with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.
  • Do not take more than the recommended dose or change your dose of bosentan without checking with your doctor.
  • Serious liver problems may occur while taking bosentan. Contact your doctor right away if you develop symptoms of liver problems, such as nausea, vomiting, loss of appetite, fever, stomach pain, yellowing of the skin or eyes, dark urine, pale stools, itching, or unusual tiredness or achiness. Discuss any questions or concerns with your doctor.
  • Women who are able to become pregnant must have a negative pregnancy test before starting bosentan. This test must occur during the first 5 days of a normal menstrual period and at least 11 days after the last unprotected sexual intercourse. Pregnancy tests must also be done each month during treatment with bosentan.
  • Bosentan may decrease the effectiveness of hormonal birth control pills, injections, patches, and implants. Women who are able to become pregnant must use 2 effective forms of birth control while they take bosentan and for 1 month after they stop taking it. Talk with your doctor about the use of effective birth control while you use bosentan.
  • Bosentan may decrease sperm count in men, which could impair the ability to father a child. Contact your doctor with any questions or concerns.
  • Tell your doctor or dentist that you take bosentan before you receive any medical or dental care, emergency care, or surgery.
  • Lab tests, including liver function and complete blood cell counts, may be performed while you use bosentan. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.
  • Bosentan should be used with extreme caution in CHILDREN younger than 12 years old; safety and effectiveness in these children have not been confirmed.
  • PREGNANCY and BREAST-FEEDING: Bosentan may cause harm to the fetus. Do not become pregnant while you are using it. If you think you may be pregnant or you miss your menstrual period, contact your doctor right away. It is not known if bosentan is found in breast milk. Do not breast-feed while taking bosentan.

Possible side effects of bosentan:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Flushing; headache; nose or throat irritation; symptoms of respiratory tract infection (eg, cough, runny or stuffy nose, sneezing).

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing or swallowing; tightness in the chest; swelling of the mouth, face, lips, throat, or tongue; unusual hoarseness); chest pain; dizziness; fainting; fever, chills, or persistent sore throat; irregular heartbeat; joint pain; light-headedness; new or worsening swelling of the arms, hands, legs, or feet; shortness of breath; sudden, unexplained weight gain; symptoms of liver problems (eg, dark urine; pale stools; persistent loss of appetite; stomach pain; unusual nausea, vomiting, or tiredness; yellowing of the skin or eyes); unusual bruising or bleeding; unusual tiredness or weakness.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include dizziness; fainting; fast heartbeat; light-headedness; nausea; severe or persistent headache; vomiting.

Proper storage of bosentan: Store bosentan at room temperature, between 68 and 77 degrees F (20 and 25 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep bosentan out of the reach of children and away from pets.

General information:

  • If you have any questions about bosentan, please talk with your doctor, pharmacist, or other health care provider.
  • Bosentan is to be used only by the patient for whom it is prescribed. Do not share it with other people.
  • If your symptoms do not improve or if they become worse, check with your doctor.
  • Check with your pharmacist about how to dispose of unused medicine.

This information should not be used to decide whether or not to take bosentan or any other medicine. Only your health care provider has the knowledge and training to decide which medicines are right for you. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about bosentan. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to bosentan. This information is not specific medical advice and does not replace information you receive from your health care provider. You must talk with your healthcare provider for complete information about the risks and benefits of using bosentan.

Issue Date: March 6, 2013 Database Edition 13.1.1.003 Copyright © 2013 Wolters Kluwer Health, Inc.

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Bosentan

Bosentan

Class: Vasodilating Agents, Miscellaneous

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

For ProfessionalsSide EffectsDosageInteractionsMore…

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 use of 2 reliable forms of contraception during and for one month following treatment.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

Management of pulmonary arterial hypertension (PAH) (WHO group 1) 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, familial, or PAH associated with connective tissue diseases or congenital systemic-to-pulmonary shunts).1

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

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

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

Has been used in conjunction with other PAH therapies (e.g., iloprost, treprostinil, sildenafil).17 20 21 22 23 24 25 27 29 30 31 38 May be beneficial in patients who deteriorate or fail to improve on monotherapy; however, additional studies needed to fully establish role of combination therapy.25 27 28 29 38

Designated an orphan drug by FDA for treatment of PAH.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 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

Pulmonary Arterial Hypertension
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

Pulmonary Arterial Hypertension
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 but ≤8 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

No specific data available to guide dosing in patients with preexisting hepatic impairment.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 bosentan therapy (i.e., >12 months).1 11 (See Boxed Warning.)

Marked elevations in liver function test results accompanied by nonspecific symptoms developed after >20 months of bosentan therapy in at least 1 patient.1 11 Following drug discontinuance, AST/ALT remained elevated and bilirubin continued to increase; liver failure and biopsy-confirmed cirrhosis developed.1 11 Causality to the drug could not be excluded.1 11 Liver failure later abated and liver function tests slowly resolved (7 months after discontinuance).11

Manufacturer reinforces importance of strict adherence to monthly monitoring schedule and to dosage adjustment and monitoring guidelines for the duration of 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 (up to 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 prior to initiating therapy in women of childbearing potential (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).1 5 6 Perform urine or serum pregnancy tests monthly.1 9 11

Women of childbearing potential must use 2 reliable contraceptive methods during and for 1 month following cessation of therapy.1 If patient has had a Copper T380A or LNg 20 IUD inserted or has undergone tubal sterilization, 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 is a known class effect of endothelin-receptor antagonists and also a consequence of PAH.1 17

If clinically important fluid retention occurs, further evaluate 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; therefore, 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

Use not recommended in patients with preexisting moderate to severe hepatic impairment or AST/ALT >3 times ULN.1 9 Use with caution in patients with mild hepatic impairment.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, 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, it is 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

Do not use concomitantly with bosentan and a potent/moderate CYP3A inhibitor1

Amprenavir

Potential for increased plasma bosentan concentrations1

Do not use concomitantly with bosentan and a CYP2C9 inhibitor1

Cyclosporine

Increased plasma bosentan and decreased plasma cyclosporine concentrations1

Concomitant use contraindicated1

Digoxin

Pharmacokinetic interaction unlikely1 43

Diltiazem

Potential for increased plasma bosentan concentrations1

Do not use concomitantly with bosentan and a CYP2C9 inhibitor1

Erythromycin

Potential for increased plasma bosentan concentrations1

Do not use concomitantly with bosentan and a CYP2C9 inhibitor1

Fluconazole

Potential for increased plasma bosentan concentrations1

Do not use concomitantly with bosentan and a CYP2C9 inhibitor1

Do not use concomitantly with bosentan and a potent/moderate CYP3A inhibitor1

Glyburide

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

Concomitant use contraindicated; consider use of alternative hypoglycemic agents1

HMG-CoA reductase inhibitors (statins)

Simvastatin: Decreased plasma simvastatin concentrations1

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;1 17 39 possible contraceptive failure1

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

Iloprost

Limited data indicate that concomitant therapy is well tolerated1 20

Itraconazole

Potential for increased plasma bosentan concentrations1

Do not use concomitantly with bosentan and a CYP2C9 inhibitor1

Ketoconazole

Increased plasma bosentan concentrations1 40

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

Do not use concomitantly with bosentan and a CYP2C9 inhibitor1

Losartan

Pharmacokinetic interaction unlikely1

Nimodipine

Pharmacokinetic interaction unlikely1

Phosphodiesterase (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: Dosage adjustments not necessary1

Rifampin

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

Ritonavir

Increased plasma bosentan concentrations1 44

In patients already receiving ritonavir (including low-dose ritonavir [i.e., ritonavir-boosted antiretroviral regimen]) for ≥10 days, initiate bosentan at 62.5 mg once daily or every other day based on individual patient tolerance1 50 51

In patients currently receiving bosentan, discontinue bosentan for ≥36 hours prior to initiating ritonavir (including low-dose ritonavir); after ≥10 days of ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual patient tolerance1 50 51

Tacrolimus

Increased plasma bosentan concentrations in animals1

Use concomitantly with caution1

Treprostinil

Pharmacokinetic interaction not noted with an oral formulation of treprostinil49

Warfarin

Decreased plasma warfarin concentrations1 9 17 42

Monitor INR closely when bosentan is initiated or discontinued17 42

Bosentan Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentrations attained within approximately 2–5 hours.1 33 Absolute bioavailability in healthy individuals 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 Approximately 1% excreted in urine.17 33

Half-life

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; not evaluated in those with moderate or severe hepatic impairment.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

  • Importance of patients taking bosentan as prescribed. Importance of not taking a double dose to make up for a missed dose but instead taking the next scheduled dose.

  • 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
  • Importance of avoiding pregnancy; importance of using reliable 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 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

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, 1959-2013, Selected Revisions January 27, 2012. 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; 2011 Feb.

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: 2005 Nov 14.

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.

28. Badesch DB, Abman SH, Simonneau G et al. Medical therapy for pulmonary arterial hypertension: Updated ACCP evidence-based clinical practice guidelines. Chest. 2007; 131:1917-28. [PubMed 17565025]

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 sulfate) capsules prescribing information. Princeton, NJ; 2011 Oct.

51. Tibotec. Prezista (darunavir) tablets prescribing information. Raritan, NJ; 2011 Oct.

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bosentan

bosentan

Generic Name: bosentan (boe SEN tan)

Brand Name: Tracleer

OverviewSide EffectsDosageInteractionsFor ProfessionalsMore…

What is Bosentan?

Bosentan prevents thickening of the blood vessels, especially those in the lungs and heart. Bosentan also lowers blood pressure in your lungs, helping your heart pump blood more efficiently.

Bosentan is used to treat pulmonary arterial hypertension (PAH). It improves your ability to exercise and prevents your condition from getting worse.

Bosentan may also be used for other purposes not listed in this medication guide.

What is the most important information I should know about bosentan?

This medication can cause birth defects in an unborn baby. Do not use if you are pregnant. Tell your doctor right away if you become pregnant during treatment. Use an effective barrier form of birth control (such as a condom or diaphragm with spermicide gel or inserts). Hormonal forms of contraception (such as birth control pills, injections, implants, skin patches, and vaginal rings) may not be effective enough to prevent pregnancy during your treatment.

Your doctor may have you take a pregnancy test before you start using this medicine, to make sure you are not pregnant. You may also be re-tested each month during your treatment.

Do not use this medication if you are allergic to bosentan, or if you are also taking cyclosporine (Sandimmune, Neoral, Gengraf), glyburide (Micronase, DiaBeta, Glynase Pres Tab), or HIV/AIDS medication that contains lopinavir or ritonavir (Kaletra, Norvir).

Bosentan can cause severe liver problems. Symptoms include nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes). Call your doctor at once if you have any of these symptoms. Your liver function will need to be tested before you start taking bosentan, and again each month during your treatment.

Do not stop taking bosentan without first talking to your doctor. You may need to use less and less before you stop the medication completely.

What should I discuss with my healthcare provider before taking bosentan?

Do not use this medication if you are allergic to bosentan, or if you:

  • are also taking HIV/AIDS medication that contains lopinavir or ritonavir (Kaletra, Norvir);

  • are also taking using glyburide (Micronase, DiaBeta, Glynase Pres Tab);
  • are pregnant or might become pregnant during treatment; or
  • are also using cyclosporine (Sandimmune, Neoral, Gengraf).

Bosentan can cause severe liver problems. Symptoms include nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes). Call your doctor at once if you have any of these symptoms. Your liver function will need to be tested before you start taking bosentan, and again each month during your treatment.

FDA pregnancy category X. This medication can cause birth defects. Do not use bosentan if you are pregnant. Tell your doctor right away if you become pregnant during treatment. Use an effective barrier form of birth control (such as a condom or diaphragm with spermicide gel or inserts). Hormonal forms of contraception (such as birth control pills, injections, implants, skin patches, and vaginal rings) may not be effective enough to prevent pregnancy during your treatment.

Your doctor may have you take a pregnancy test before you start using this medicine, to make sure you are not pregnant. You may also be re-tested each month during your treatment.

It is not known whether bosentan passes into breast milk or if it could harm a nursing baby. Do not take this medication without telling your doctor if you are breast-feeding a baby.

How should I take bosentan?

Take bosentan exactly as it was prescribed for you. Do not take the medication in larger or smaller amounts, or take it for longer than recommended by your doctor. Follow the directions on your prescription label.

Take each dose with a full glass (8 ounces) of water.

Bosentan can be taken with or without food.

Bosentan is usually taken twice a day, morning and evening.

Do not stop taking bosentan without first talking to your doctor. You may need to use less and less before you stop the medication completely.

Store bosentan at room temperature away from moisture and heat.

See also: Bosentan dosage (in more detail)

What happens if I miss a dose?

Take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention if you think you have used too much of this medicine.

Overdose can cause headache, nausea, vomiting, increased heart rate and fainting or dizziness (low blood pressure).

What should I avoid while using bosentan?

Follow your doctor’s instructions about any restrictions on food, beverages, or activity while you are using bosentan.

Bosentan side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have any of these serious side effects:

  • nausea, stomach pain, loss of appetite;

  • dark urine, clay-colored stools; or
  • jaundice (yellowing of the skin or eyes).

Less serious side effects may include:

  • headache;

  • flushing;
  • swelling of the feet, ankles, or legs;
  • dizziness;
  • upset stomach;
  • fatigue; or
  • itching.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

See also: bosentan side effects (in more detail)

Bosentan Dosing Information

Usual Adult Dose for Pulmonary Hypertension:

greater than or equal to 40 kg:

Initial dose: 62.5 mg twice daily for 4 weeks

Maintenance dose: increase to a maintenance dose of 125 mg twice daily

less than 40 kg:

Initial dose: 62.5 mg twice daily for 4 weeks

Maintenance dose: continue dosing of 62.5 mg twice daily

Usual Pediatric Dose for Pulmonary Hypertension:

Full Term Neonate: Oral: 1 mg/kg/dose orally twice daily short-term use (2 to 16 days) in three full term neonates has been reported. In the initial report, two full term neonates (8 days and 14 days old) with persistent pulmonary hypertension of the newborn (PPHN) and transposition of the great arteries received bosentan prior to cardiac surgery; patients also received other therapies. A case report describes the use of bosentan monotherapy for PPHN in a full term neonate as primary course of treatment initiated at 29 hours of life; therapy was weaned after 72 hours through the following dose reductions: 0.5 mg/kg/dose orally twice daily followed by 0.5 mg/kg once daily and subsequent discontinuation at 96 hours of treatment.

1 month to 12 years:

less than 10 kg: Initial: 1 to 2 mg/kg orally twice daily for 4 weeks; increase to maintenance dose of 2 to 4 mg/kg orally twice daily.

10 to 20 kg: Initial: 31.25 mg orally daily for 4 weeks; increase to maintenance dose of 31.25 mg orally twice daily.

over 20 to 40 kg: Initial: 31.25 mg orally twice daily for 4 weeks; increase to maintenance dose of 62.5 mg orally twice daily.

over 40 kg: Initial: 62.5 mg orally twice daily for 4 weeks; increase to maintenance dose of 125 mg orally twice daily.

over 12 years:

less than 40 kg: 62.5 mg orally twice daily.

40 kg or more: 62.5 mg orally twice daily for 4 weeks; increase to maintenance dose of 125 mg twice daily.

What other drugs will affect bosentan?

Do not take bosentan without first talking to your doctor if you are taking any of the following medicines:

  • amiodarone (Cordarone, Pacerone);

  • diltiazem (Tiazac, Cartia, Cardizem);
  • erythromycin (E.E.S., EryPed, Ery-Tab, Erythrocin);
  • rifampin (Rifadin, Rifater, Rifamate, Rimactane);
  • tacrolimus (Prograf);
  • an antifungal medication such as ketoconazole (Nizoral), fluconazole (Diflucan), or itraconazole (Sporanox);
  • a blood thinner such as warfarin (Coumadin); or
  • a cholesterol-lowering medicine such as simvastatin (Zocor), lovastatin (Mevacor), or atorvastatin (Lipitor).

This list is not complete and there may be other drugs not listed that can affect bosentan. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

Next Page → Side Effects

More bosentan resources

  • Side Effects
  • Recommended Dosage
  • Pregnancy Warnings
  • Drug Interactions
  • Support Group
  • 0 Reviews - Add your own review/rating
  • bosentan MedFacts Consumer Leaflet (Wolters Kluwer)
  • bosentan Advanced Consumer (Micromedex) – Includes Dosage Information
  • Bosentan Professional Patient Advice (Wolters Kluwer)
  • Bosentan Monograph (AHFS DI)
  • Tracleer Prescribing Information (FDA)

Compare bosentan with other medications

  • Pulmonary Arterial Hypertension

Where can I get more information?

  • Your doctor or pharmacist can provide more information about bosentan.

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