levels may reverse spontaneously while continuing treatment Discontinue drug if liver aminotransferase elevations accompanied by clinical symptoms of liver injury (eg, nausea, vomiting, fever, abdominal pain, jaundice, unusual lethargy or fatigue) or increases in bilirubin >2X ULN Pregnancy Contraindication Likely to produce serious birth defects if used by pregnant women; this effect has been seen consistently when administered to animals Negative pregnancy test result required before initiating & prevention of pregnancy required thereafter Advise the use of at least 2 reliable methods of contraception (unless tubal sterilization or Copper T 380A IUD or LNg 20 IUD inserted, in which case no other contraception required) Obtain monthly pregnancy tests Restricted Distribution Program Because of risks of liver injury and birth defects, available only through restricted distribution program called the Tracleer REMS program; available at www.Tracleerrems.com or 1-866-228-3546 Healthcare professionals who prescribe bosentan must review educational materials, enroll in the Tracleer REMS program and comply with its requirements Healthcare professionals must review serum ALT/AST and bilirubin; agree to order/monitor tests monthly; confirm females of reproduction potential are no pregnant, and agree to order/monitor pregnancy tests monthly To receive bosentan, all patients must understand the risks and benefits, complete a patient enrollment form Pharmacies that dispense bosentan must enroll in the program and agree to comply with the Tracleer REMS Program requirements Contraindications Hypersensitivity Pregnancy Concomitant cyclosporine or glyburide use Cautions Hypersensitivity of bosentan; observed reactions include Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), anaphylaxis, rash, and angioedema Pulmonary edema may occur; if signs/symptoms arise, consider possibly associated with pulmonary venoocclusive disease and whether treatment should be discontinued Embryo-fetal toxicity reported; see Black Box Warnings and Pregnancy Decreased sperm counts have been observed; preclinical data also suggest bosentan and other endothelin receptor antagonists, may have an adverse effect on spermatogenesis Dose-related decrease in hemoglobin and hematocrit may occur with treatment; it is recommended that hemoglobin concentrations be checked after 1, 3 months, and every 3 months thereafter; if a marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine cause and need for specific treatment Hepatotoxicity ALT or AST > 3 x ULN reported; elevations of AST or ALT associated with this medication are dose-dependent, occur both early and late in treatment, usually progress slowly, are typically asymptomatic, and usually have been reversible after treatment interruption or cessation Aminotransferase elevations may reverse spontaneously while continuing treatment this medication; liver aminotransferase levels must be measured prior to initiation of treatment and then monthly and therapy adjusted accordingly Discontinue therapy if liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 x ULN Avoid initiation of therapy in patients with elevated aminotransferases (> 3 x ULN) prior to drug initiation because monitoring hepatotoxicity in these patients may be more difficult In WHO Functional Class II patients, consider whether the benefits are sufficient to offset risk of hepatotoxicity, which may preclude future use as their disease progresses Fluid retention Peripheral edema is a known clinical consequence of PAH, worsening PAH, and is also a known effect of bosentan and other endothelin receptor antagonists In clinical trials with bosentan, combined adverse events of fluid retention or edema were reported Patients required intervention with a diuretic, fluid management, or hospitalization for decompensating heart failure If clinically significant fluid retention develops, with or without associated weight gain, further evaluation should be undertaken to determine whether treatment-related or possible underlying heart failure, and consider need for treatment or discontinuation of bosentan Monitor hemoglobin levels after 1, 3 months of treatment, then every 3 months thereafter Drug interactions overview Bosentan is metabolized by CYP2C9 and CYP3A; inhibition of these enzymes may increase the plasma concentration of bosentan Concomitant administration of a CYP2C9 inhibitor (eg, fluconazole, amiodarone), a strong CYP3A inhibitor (eg, ketoconazole, itraconazole) or a moderate CYP3A inhibitor (eg, amprenavir, erythromycin, fluconazole, diltiazem) will likely lead to large increases in plasma concentrations of bosentan Coadministration of such combinations of a CYP2C9 inhibitor plus a strong or moderate CYP3A inhibitor with bosentan is not recommended Bosentan is an inducer of CYP3A and CYP2C9; plasma concentrations of drugs metabolized by these two isozymes will be decreased when coadministered bosentan Reduces efficacy of hormonal contraceptives Pregnancy Based on animal data, bosentan may cause fetal harm, including birth defects and fetal death, when administered to a pregnant female and is contraindicated during pregnancy; see Contraindications and Black Box Warnings In animal reproduction studies, oral administration of bosentan to pregnant rats at 2 times the maximum recommended human dose (MRHD) on a mg/m2 basis caused teratogenic effects in rats (eg, malformations of the head, mouth, face, and large blood vessels) Advise pregnant women of the potential risk to a fetus Patient should contact her physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected If the pregnancy test is positive, the physician and patient must discuss the risks to her, the pregnancy, and the fetus Based on findings in animals, bosentan may impair fertility in males of reproductive potential; It is unknown whether effects on fertility would be reversible Contraception, see Black Box Warnings Lactation There are no data on the presence of bosentan in human milk, the effects on the breastfed infant, or the effect on milk production Because of the potential for serious adverse reactions, such as fluid retention and hepatotoxicity, in breastfed infants from bosentan, advise women not to breastfeed during treatment with bosentanPregnancy Categories A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk. B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available. Mechanism of Action Competitive antagonist of endothelin-1; blocks endothelin receptors on vascular endothelium and smooth muscle resulting in inhibition of vasoconstriction Absorption Bioavailability: 50% Peak plasma time: 3-5hr Duration: 24 hr Distribution Protein Bound: >98% (primarily to albumin) Vd: 18L Metabolism Metabolized by hepatic CYP2C9 and CYP3A4 Metabolites: Ro 48-5033 (active metabolite), Ro 47-8634 (inactive metabolite) Enzymes induced: CYP2C9, CYP3A4 Steady-state reached within 3-5 days Elimination Half-Life: 5-8 hr Total clearance: 4L/hr Excretion: Feces (predominantly); urine (minimal) Oral Suspension Preparation If necessary, the 32 mg dispersible tablet can be divided into halves by breaking along the lines cut into the surface Advise patients that bosentan dispersible tablets should not be split into quarters Each 32 mg dispersible tablet, or tablet part, can be dispersed in a minimal amount of water to make a liquid medicine immediately before administration Administer once tablet is fully dispersed Oral Administration Take with or without food If missed a dose, take tablet as soon as possible; do not take 2 doses at the same time; skip the missed dose if close to next administration Storage Film coated and dispersible tablets: Store at 20-25ºC (68-77ºF) Excursions are permitted between 15-30°C (59-86°F) Divided dispersible tablets should be stored under the same conditions and used within 7 days Tablet pieces may be returned to the opened blister and stored there out of reach of children for up to 7 days BRAND FORM. UNIT PRICE PILL IMAGE bosentan oral- 125 mg tabletbosentan oral- 62.5 mg tabletbosentan oral- 125 mg tabletbosentan oral- 62.5 mg tabletbosentan oral- 62.5 mg tabletbosentan oral- 125 mg tabletbosentan oral- 125 mg tabletbosentan oral- 62.5 mg tabletTracleer oral- 32 mg tabletTracleer oral- 125 mg tabletTracleer oral- 62.5 mg tabletCopyright © 2010 First DataBank, Inc.Print Patient Educationbosentan oral BOSENTAN - ORAL (boe-SEN-tan) COMMON BRAND NAME(S): Tracleer WARNING: Bosentan may rarely cause serious (possibly fatal) liver damage. Rarely, liver problems have happened in people after stopping treatment with bosentan. Your doctor will perform liver function tests before you start treatment and once a month during treatment. Tell your doctor right away if you notice nausea/vomiting that doesn't stop, dark urine, loss of appetite, stomach/abdominal pain, or yellowing eyes/skin.Bosentan must not be used during pregnancy because it may cause serious harm (such as birth defects) in an unborn baby. Women of childbearing age must have a negative pregnancy test before starting this medication and monthly during treatment. Use at least two reliable forms of birth control while taking bosentan and for at least one month after stopping bosentan as directed by your doctor to prevent pregnancy. If you become pregnant or think you may be pregnant, tell your doctor right away. (See also Precautions section.)To receive this medication in the United States, you must understand, agree to, and carefully follow the requirements of the Bosentan REMS Program. If you live in Canada or any other country, consult your doctor and pharmacist for your country's regulations. USES: Bosentan is used to treat high blood pressure in the lungs (pulmonary arterial hypertension). This condition is thought to be caused by increased levels of a certain natural substance (endothelin-1). This medication blocks the effects of endothelin-1, thereby helping to decrease the blood pressure in the lungs, slow the worsening of symptoms from the disease, and improve your ability to exercise. HOW TO USE: Read the Medication Guide provided by your pharmacist before you start using bosentan and each time you get a refill. If you have any questions, consult your doctor or pharmacist.Take this medication by mouth with or without food as directed by your doctor, usually twice daily (in the morning and evening).The dosage is based on your medical condition, weight, response to treatment, and other medications you may be taking. Be sure to tell your doctor and pharmacist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products). Your doctor may start you on a lower dose of this medication and then increase the dose after several weeks.Use this medication regularly to get the most benefit from it. To help you remember, take it at the same times each day.Do not stop taking this medication without consulting your doctor. Some conditions may become worse when the drug is suddenly stopped. Your dose may need to be gradually decreased.Women who are pregnant or who may become pregnant should not handle the tablets or breathe the dust from this medication. Do not crush the tablets because doing so will increase exposure to the dust.Tell your doctor if your condition lasts or gets worse. SIDE EFFECTS: See also Warning section.Dizziness, flushing, stuffy nose, or joint pain may occur. If any of these effects last or get worse, tell your doctor or pharmacist promptly.Remember that this medication has been prescribed because your doctor has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.Tell your doctor right away if you have any serious side effects, including: fast/pounding heartbeat, unusual tiredness, swelling ankles/feet, unusual/sudden weight gain, fainting, shortness of breath, coughing up blood.In men, this medication can decrease sperm production, which may affect the ability to father a child. Talk to your doctor for more details.A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: fever, swollen lymph nodes, rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.In the US -Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345. PRECAUTIONS: See also Warning section.Before taking bosentan, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.Before using this medication, tell your