TRACLEER®
[bosentan]

TRACLEER® causes at least 3-fold (upper limit of normal; ULN) elevation of liver aminotransferases (ALT and AST) in about 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 (see WARNINGS: Potential Liver Injury and DOSAGE AND ADMINISTRATION). In the post-marketing period, in the setting of close monitoring, rare cases of unexplained hepatic cirrhosis were reported after prolonged (> 12 months) therapy with TRACLEER® in patients with multiple co-morbidities and drug therapies. There have also been rare reports of liver failure. The contribution of TRACLEER® in these cases could not be excluded.

In at least one case the initial presentation (after > 20 months of treatment) included pronounced elevations in aminotransferases and bilirubin levels accompanied by non-specific symptoms, all of which resolved slowly over time after discontinuation of TRACLEER®. This case reinforces the importance of strict adherence to the monthly monitoring schedule for the duration of treatment and the treatment algorithm, which includes stopping TRACLEER® with a rise of aminotransferases accompanied by signs or symptoms of liver dysfunction. (see DOSAGE AND ADMINISTRATION).

Elevations in aminotransferases require close attention (see DOSAGE AND ADMINISTRATION). TRACLEER® should generally be avoided in patients with elevated aminotransferases (> 3 × ULN) at baseline because monitoring liver injury may be more difficult. If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 × ULN, treatment should be stopped. There is no experience with the re-introduction of TRACLEER® in these circumstances.

TRACLEER® (bosentan) is very likely to produce major birth defects if used by pregnant women, as this effect has been seen consistently when it is administered to animals (see CONTRAINDICATIONS). Therefore, pregnancy must be excluded before the start of treatment with TRACLEER® and prevented thereafter by the use of a reliable method of contraception. 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 TRACLEER® (see Precautions: Drug Interactions). Therefore, effective contraception through additional forms of contraception must be practiced. Monthly pregnancy tests should be obtained.

Because of potential liver injury and in an effort to make the chance of fetal exposure to TRACLEER® (bosentan) as small as possible, TRACLEER® may be prescribed only through the TRACLEER® Access Program by calling 1 866 228 3546. Adverse events can also be reported directly via this number.

Bosentan is the first of a new drug class, an endothelin receptor antagonist.

TRACLEER® (bosentan) belongs to a class of highly substituted pyrimidine derivatives, with no chiral centers. It is designated chemically as 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2']-bipyrimidin-4-yl]- benzenesulfonamide monohydrate and has the following structural formula:

Bosentan has a molecular weight of 569.64 and a molecular formula of C₂₇H₂₉N₅O₆S•H₂O. Bosentan is a white to yellowish powder. It is poorly soluble in water (1.0 mg/100 mL) and in aqueous solutions at low pH (0.1 mg/100 mL at pH 1.1 and 4.0; 0.2 mg/100 mL at pH 5.0). Solubility increases at higher pH values (43 mg/100 mL at pH 7.5). In the solid state, bosentan is very stable, is not hygroscopic and is not light sensitive.

TRACLEER® is available as 62.5 mg and 125 mg film-coated tablets for oral administration, and contains the following excipients: corn starch, pregelatinized starch, sodium starch glycolate, povidone, glyceryl behenate, magnesium stearate, hydroxypropylmethylcellulose, triacetin, talc, titanium dioxide, iron oxide yellow, iron oxide red, and ethylcellulose. Each TRACLEER® 62.5 mg tablet contains 64.541 mg of bosentan, equivalent to 62.5 mg of anhydrous bosentan. Each TRACLEER® 125 mg tablet contains 129.082 mg of bosentan, equivalent to 125 mg of anhydrous bosentan.

Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ET_A and ET_B receptors in the endothelium and vascular smooth muscle. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this disease. Bosentan is a specific and competitive antagonist at endothelin receptor types ET_A and ET_B. Bosentan has a slightly higher affinity for ET_A receptors than for ET_B receptors.

It is not known whether bosentan's pharmacokinetics is influenced by gender, body weight, race, or age.

TRACLEER® is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in patients with WHO Class III or IV symptoms, to improve exercise ability and decrease the rate of clinical worsening (see Clinical Studies).

See BOX WARNING for CONTRAINDICATION to use in pregnancy.

TRACLEER® is expected to cause fetal harm if administered to pregnant women. Bosentan was teratogenic in rats given oral doses ≥ 60 mg/kg/day (twice the maximum recommended human oral dose of 125 mg, b.i.d., on a mg/ m² basis). In an embryo-fetal toxicity study in rats, bosentan showed dose-dependent teratogenic effects, including malformations of the head, mouth, face and large blood vessels. Bosentan increased stillbirths and pup mortality at oral doses of 60 and 300 mg/kg/day (2 and 10 times, respectively, the maximum recommended human dose on a mg/m² basis). Although birth defects were not observed in rabbits given oral doses of up to 1500 mg/kg/day, plasma concentrations of bosentan in rabbits were lower than those reached in the rat. The similarity of malformations induced by bosentan and those observed in endothelin-1 knockout mice and in animals treated with other endothelin receptor antagonists indicates that teratogenicity is a class effect of these drugs. There are no data on the use of TRACLEER® in pregnant women.

Pregnancy must be excluded before the start of treatment with TRACLEER® and prevented thereafter by use of reliable contraception. It has been demonstrated that hormonal contraceptives, including oral, injectable, transdermal, and implantable contraceptives may not be reliable in the presence of TRACLEER® and should not be used as the sole contraceptive method in patients receiving TRACLEER® (see Drug Interactions: Hormonal Contraceptives, Including Oral, Injectable, Transdermal and Implantable Contraceptives). Input from a gynecologist or similar expert on adequate contraception should be sought as needed.

TRACLEER® should be started only in patients known not to be pregnant. For female patients of childbearing potential, a prescription for TRACLEER® should not be issued by the prescriber unless the patient assures the prescriber that she is not sexually active or provides negative results from a urine or serum pregnancy test performed during the first 5 days of a normal menstrual period and at least 11 days after the last unprotected act of sexual intercourse.

Follow-up urine or serum pregnancy tests should be obtained monthly in women of childbearing potential taking TRACLEER®. The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, she must notify the physician immediately for pregnancy testing. If the pregnancy test is positive, the physician and patient must discuss the risk to the pregnancy and to the fetus.

Co-administration of cyclosporine A and bosentan resulted in markedly increased plasma concentrations of bosentan. Therefore, concomitant use of TRACLEER® and cyclosporine A is contraindicated.

An increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan. Therefore co-administration of glyburide and TRACLEER® is contraindicated.

TRACLEER® is also contraindicated in patients who are hypersensitive to bosentan or any component of the medication.

(see BOX WARNING)

Elevations in ALT or AST by more than 3 × ULN were observed in 11% of bosentan-treated patients (N = 658) compared to 2% of placebo-treated patients (N = 280). Three-fold increases were seen in 12% of 95 PAH patients on 125 mg b.i.d. and 14% of 70 PAH patients on 250 mg b.i.d. Eight-fold increases were seen in 2% of PAH patients on 125 mg b.i.d. and 7% of PAH patients on 250 mg b.i.d. Bilirubin increases to ≥3 × ULN were associated with aminotransferase increases in 2 of 658 (0.3%) of patients treated with bosentan.

The combination of hepatocellular injury (increases in aminotransferases of > 3 × ULN) and increases in total bilirubin (≥ 3 × ULN) is a marker for potential serious liver injury.¹

Elevations of AST and/or ALT associated with bosentan 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 also may reverse spontaneously while continuing treatment with TRACLEER®.

Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly. If elevated aminotransferase levels are seen, changes in monitoring and treatment must be initiated (see DOSAGE AND ADMINISTRATION). If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 × ULN, treatment should be stopped. There is no experience with the re-introduction of TRACLEER® in these circumstances.

Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly. TRACLEER® should generally be avoided in patients with moderate or severe liver impairment (see Clinical Pharmacology and DOSAGE AND ADMINISTRATION). In addition, TRACLEER® should generally be avoided in patients with elevated aminotransferases (> 3 × ULN) because monitoring liver injury in these patients may be more difficult (see BOX WARNING).

Treatment with TRACLEER® caused a dose-related decrease in hemoglobin and hematocrit. Hemoglobin levels should be monitored after 1 and 3 months of treatment and then every 3 months. The overall mean decrease in hemoglobin concentration for bosentan-treated patients was 0.9 g/dL (change to end of treatment). Most of this decrease of hemoglobin concentration was detected during the first few weeks of bosentan treatment and hemoglobin levels stabilized by 4–12 weeks of bosentan treatment. In placebo-controlled studies of all uses of bosentan, marked decreases in hemoglobin (> 15% decrease from baseline resulting in values < 11 g/dL) were observed in 6% of bosentan-treated patients and 3% of placebo-treated patients. In patients with pulmonary arterial hypertension treated with doses of 125 and 250 mg b.i.d., marked decreases in hemoglobin occurred in 3% compared to 1% in placebo-treated patients.

A decrease in hemoglobin concentration by at least 1 g/dL was observed in 57% of bosentan-treated patients as compared to 29% of placebo-treated patients. In 80% of those patients whose hemoglobin decreased by at least 1 g/dL, the decrease occurred during the first 6 weeks of bosentan treatment.

During the course of treatment the hemoglobin concentration remained within normal limits in 68% of bosentan-treated patients compared to 76% of placebo patients. The explanation for the change in hemoglobin is not known, but it does not appear to be hemorrhage or hemolysis.

It is recommended that hemoglobin concentrations be checked after 1 and 3 months, and every 3 months thereafter. If a marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and need for specific treatment.

In a placebo-controlled trial of patients with severe chronic heart failure, there was an increased incidence of hospitalization for CHF associated with weight gain and increased leg edema during the first 4-8 weeks of treatment with TRACLEER®. In addition, there have been numerous post-marketing reports of fluid retention in patients with pulmonary hypertension, occurring within weeks after starting TRACLEER®. Patients required intervention with a diuretic, fluid management, or hospitalization for decompensating heart failure (see CLINICAL STUDIES; Congestive Heart Failure).

Should signs of pulmonary edema occur when TRACLEER® is administered the possibility of associated PVOD should be considered and TRACLEER® should be discontinued.

Patients are advised to consult the TRACLEER® Medication Guide on the safe use of TRACLEER®.

The physician should discuss with the patient the importance of monthly monitoring of serum aminotransferases and urine or serum pregnancy testing and of avoidance of pregnancy. The physician should discuss options for effective contraception and measures to prevent pregnancy with their female patients. Input from a gynecologist or similar expert on adequate contraception should be sought as needed.

Bosentan is metabolized by CYP2C9 and CYP3A4. Inhibition of these enzymes may increase the plasma concentration of bosentan (see ketoconazole). Concomitant administration of both a CYP2C9 inhibitor (such as fluconazole or amiodarone) and a CYP3A4 inhibitor (such as ketoconazole, itraconazole, or ritonavir) with bosentan will likely lead to large increases in plasma concentrations of bosentan. Co-administration of such combinations of a potent CYP2C9 inhibitor plus a CYP3A4 inhibitor with TRACLEER® is not recommended.

Bosentan is an inducer of CYP3A4 and CYP2C9. Consequently plasma concentrations of drugs metabolized by these two isozymes will be decreased when TRACLEER® is co-administered. Bosentan had no relevant inhibitory effect on any CYP isozyme in vitro (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4). Consequently, TRACLEER® is not expected to increase the plasma concentrations of drugs metabolized by these enzymes.

Two years of dietary administration of bosentan to mice produced an increased incidence of hepatocellular adenomas and carcinomas in males at doses as low as 450 mg/kg/day (about 8 times the maximum recommended human dose [MRHD] of 125 mg b.i.d., on a mg/m² basis). In the same study, doses greater than 2000 mg/kg/day (about 32 times the MRHD) were associated with an increased incidence of colon adenomas in both males and females. In rats, dietary administration of bosentan for two years was associated with an increased incidence of brain astrocytomas in males at doses as low as 500 mg/kg/day (about 16 times the MRHD). In a comprehensive battery of in vitro tests (the microbial mutagenesis assay, the unscheduled DNA synthesis assay, the V-79 mammalian cell mutagenesis assay, and human lymphocyte assay) and an in vivo mouse micronucleus assay, there was no evidence for any mutagenic or clastogenic activity of bosentan.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, breastfeeding while taking TRACLEER® is not recommended.

Safety and efficacy in pediatric patients have not been established. (See DOSAGE AND ADMINISTRATION).

Clinical experience with TRACLEER® in subjects aged 65 or older has not included a sufficient number of such subjects to identify a difference in response between elderly and younger patients (see DOSAGE AND ADMINISTRATION).

See BOX WARNING for discussion of liver injury and PRECAUTIONS for discussion of hemoglobin and hematocrit abnormalities.

Safety data on bosentan were obtained from 12 clinical studies (8 placebo-controlled and 4 open-label) in 777 patients with pulmonary arterial hypertension, and other diseases. Doses up to 8 times the currently recommended clinical dose (125 mg b.i.d.) were administered for a variety of durations. The exposure to bosentan in these trials ranged from 1 day to 4.1 years (N=89 for 1 year; N=61 for 1.5 years and N=39 for more than 2 years). Exposure of pulmonary arterial hypertension patients (N=235) to bosentan ranged from 1 day to 1.7 years (N=126 more than 6 months and N=28 more than 12 months).

Treatment discontinuations due to adverse events other than those related to pulmonary hypertension during the clinical trials in patients with pulmonary arterial hypertension were more frequent on bosentan (5%; 8/165 patients) than on placebo (3%; 2/80 patients). In this database the only cause of discontinuations > 1%, and occurring more often on bosentan was abnormal liver function.

The adverse drug reactions that occurred in ≥ 3% of the bosentan-treated patients and were more common on bosentan in placebo-controlled trials in pulmonary arterial hypertension at doses of 125 or 250 mg b.i.d. are shown in Table 4:

In placebo-controlled studies of bosentan in pulmonary arterial hypertension and for other diseases (primarily chronic heart failure), a total of 677 patients were treated with bosentan at daily doses ranging from 100 mg to 2000 mg and 288 patients were treated with placebo. The duration of treatment ranged from 4 weeks to 6 months. For the adverse drug reactions that occurred in ≥ 3% of bosentan-treated patients, the only ones that occurred more frequently on bosentan than on placebo (≥ 2% difference) were headache (16% vs. 13%), flushing (7% vs. 2%), abnormal hepatic function (6% vs. 2%), leg edema (5% vs. 1%), and anemia (3% vs. 1%).

Hypersensitivity, Rash, Thrombocytopenia.

There have been several post-marketing reports of angioneurotic edema associated with the use of bosentan. The onset of the reported cases occurred within a range of 8 hours to 21 days after starting therapy. Some patients were treated with an antihistamine and their signs of angioedema resolved without discontinuing TRACLEER®.

In the post-marketing period, in the setting of close monitoring, rare cases of unexplained hepatic cirrhosis were reported after prolonged (> 12 months) therapy with TRACLEER® in patients with multiple co-morbidities and drug therapies. There have also been rare reports of liver failure. The contribution of TRACLEER® in these cases could not be excluded (see BOX WARNING).

Increased Liver Aminotransferases (see BOX WARNING and WARNINGS).

Decreased Hemoglobin and Hematocrit (see PRECAUTIONS)

Bosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg b.i.d. of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed.

There is no specific experience of overdosage with bosentan beyond the doses described above. Massive overdosage may result in pronounced hypotension requiring active cardiovascular support.

TRACLEER® treatment should be initiated at a dose of 62.5 mg b.i.d. for 4 weeks and then increased to the maintenance dose of 125 mg b.i.d. Doses above 125 mg b.i.d. did not appear to confer additional benefit sufficient to offset the increased risk of liver injury.

Tablets should be administered morning and evening with or without food.

If TRACLEER® is re-introduced it should be at the starting dose; aminotransferase levels should be checked within 3 days and thereafter according to the recommendations above.

If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 × ULN, treatment should be stopped. There is no experience with the re-introduction of TRACLEER® in these circumstances.

TRACLEER® treatment should only be initiated in women of child-bearing potential following a negative pregnancy test and only in those who practice adequate contraception that does not rely solely upon hormonal contraceptives, including oral, injectable, transdermal, or implantable contraceptives (see DRUG INTERACTIONS: Hormonal Contraceptives, Including Oral, Injectable, Transdermal, and Implantable Contraceptives). Input from a gynecologist or similar expert on adequate contraception should be sought as needed. Urine or serum pregnancy tests should be obtained monthly in women of childbearing potential taking TRACLEER®.

The effect of renal impairment on the pharmacokinetics of bosentan is small and does not require dosing adjustment.

Clinical studies of TRACLEER® did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Clinical experience has not identified differences in responses between elderly and younger patients. In general, caution should be exercised in dose selection for elderly patients given the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in this age group.

Because there is in vitro and in vivo evidence that the main route of excretion of bosentan is biliary, liver impairment could be expected to increase exposure (C_max and AUC) of bosentan. Mild liver impairment was shown not to impact the pharmacokinetics of bosentan. The influence of moderate or severe liver impairment on the pharmacokinetics of TRACLEER® has not been evaluated. There are no specific data to guide dosing in hepatically impaired patients (See WARNINGS); caution should be exercised in patients with mildly impaired liver function. TRACLEER® should generally be avoided in patients with moderate or severe liver impairment.

Safety and efficacy in pediatric patients have not been established.

In patients with a body weight below 40 kg but who are over 12 years of age the recommended initial and maintenance dose is 62.5 mg b.i.d.

There is limited experience with abrupt discontinuation of TRACLEER®. No evidence for acute rebound has been observed. Nevertheless, to avoid the potential for clinical deterioration, gradual dose reduction (62.5 mg b.i.d. for 3 to 7 days) should be considered.

62.5 mg film-coated, round, biconvex, orange-white tablets, embossed with identification marking "62,5", packaged in a white high-density polyethylene bottle and a white polypropylene child-resistant cap.

NDC 66215-101-06: Bottle containing 60 tablets.

125 mg film-coated, oval, biconvex, orange-white tablets, embossed with identification marking "125", packaged in a white high-density polyethylene bottle and a white polypropylene child-resistant cap.

NDC 66215-102-06: Bottle containing 60 tablets.

Rx only.

Store at 20°C – 25°C (68°F – 77°F). Excursions are permitted between 15°C and 30°C (59°F and 86°F). [See USP Controlled Room Temperature].

Tracleer (tra-KLEER) Tablets
(bosentan)

Read this information carefully before you start taking Tracleer tablets. Read the information you get with Tracleer each time you refill your prescription. There may be new information. This information does not take the place of talking with your doctor.

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

•Liver damage.

•  Tracleer can cause liver damage if liver problems are not found early. Therefore, you must have a blood test to check your liver function before you start Tracleer and each month after that. (See "What are the possible side effects of Tracleer?" for information about the signs of liver problems.)

•Major birth defects.

•  Tracleer can cause major birth defects if taken during pregnancy. Therefore, women must not be pregnant when they start taking Tracleer or during Tracleer treatment. Women who are sexually active must have a negative pregnancy test before beginning treatment. A negative test means you are not pregnant. The test should be during the first five days of a normal menstrual period and at least 11 days after the last unprotected sexual intercourse. Pregnancy tests must be done each month during Tracleer treatment, if you are sexually active.
•  Women who are able to get pregnant must use effective birth control while taking Tracleer. Birth control pills, shots, patches, implants, or other hormone-based birth control may not be enough when Tracleer is used. Talk with your doctor and, if needed, with a gynecologist (a doctor who specializes in female reproduction) or another doctor who knows about birth control, to find out how to avoid pregnancy. Tell your doctor right away if you miss a period or think you may be pregnant.

What is Tracleer?

Tracleer is a medicine to treat pulmonary arterial hypertension, which is high blood pressure in the lung arteries. You take it by mouth.

Tracleer can improve your ability to exercise and can slow the worsening of your physical condition and symptoms. Tracleer lowers high blood pressure in your lungs and lets your heart pump blood more effectively.

Who should not take Tracleer?

Do not take Tracleer if:

• you are pregnant, plan to become pregnant, or become pregnant during Tracleer treatment. Tracleer can cause major birth defects. All women should read the birth defects section of "What is the most important information I should know about Tracleer?" Severe birth defects from Tracleer happen early in pregnancy. Therefore, you must not be pregnant while taking Tracleer.
• your blood test shows possible liver injury
• you are taking cyclosporine-A, (used for psoriasis and rheumatoid arthritis, and to prevent rejection of heart or kidney transplants) or glyburide (used for diabetes)
• you are allergic to any ingredients in Tracleer. The active ingredient is bosentan. Ask your doctor or pharmacist if you need to know the inactive ingredients.

Tell your doctor if you have moderate or severe liver problems. Tracleer may not be right for you.

Tell your doctor about all the medicines you use. They may affect how Tracleer works, or Tracleer may affect how the other medicines work. Be sure to tell your doctor if you take

• ketoconazole, fluconazole, itraconazole or voriconazole (used for fungal infections)
• hormone-based birth control, such as pills, shots, patches, and implants
• cyclosporine A (used for psoriasis and rheumatoid arthritis, and to prevent rejection of heart or kidney transplants)
• tacrolimus (used to prevent rejection of liver or kidney transplants)
• rifampicin (used for tuberculosis)
• glyburide (used for diabetes)
• cholesterol lowering medicines
• warfarin (used to prevent blood clots)
• ritonavir (used to treat HIV).

How should I take Tracleer?

Tracleer will be mailed to you by a central pharmacy. Your doctor will give you complete details:

• In most cases, you will take 1 tablet in the morning and 1 in the evening.
• You can take it with or without food.
• Your doctor will tell you how much to take.
• It will be easier to remember to take Tracleer if you do it at the same time each morning and evening. If you have trouble remembering, ask a family member to remind you, or put written notes where you will be sure to see them.
• If you take more than the prescribed dose of Tracleer, call your doctor right away.
• If you miss a dose, take your tablet as soon as you remember. However, do not take 2 doses to make up for a missed dose. Take your next tablet at the regular time.
• Do not stop taking Tracleer unless your doctor tells you to do so. Suddenly stopping your treatment may cause your symptoms to get worse. If you need to stop taking Tracleer, your doctor may tell you to reduce the dose over a few days before stopping completely.

During treatment your doctor will test your blood for signs of side effects to your liver and red blood cells.

What should I avoid while taking Tracleer?

• Do not get pregnant while taking Tracleer. (See the birth defect section of "What is the most important information I should know about Tracleer?") If you miss a period, call your doctor.
• Breast feeding is not recommended while taking Tracleer. It is not known if Tracleer can pass through your milk and harm the baby.
• Do not use hormone-based birth control (pills, shots, patches, implants) as your only method of birth control. These may not work when used with Tracleer. Ask your doctor about effective birth control choices.
• Do not take cyclosporine-A. This medicine can cause too much Tracleer in your blood and increase your chance of liver damage.
• Do not take glyburide. This medicine can increase your chance of liver damage.

What are the possible side effects of Tracleer?

Tracleer can have serious side effects:

• Liver damage. Tracleer can cause liver damage if it is not found early. Because this side effect may not cause symptoms at first, only a blood test can show that you have early liver damage. Regular blood tests let your doctor change or stop your therapy before there is permanent damage. Therefore, it is very important that you have a liver function blood test before you start treatment and every month after that.
  Call your doctor right away if you have any of these symptoms of liver problems: nausea, vomiting, fever, unusual tiredness, abdominal (stomach area) pain, or yellowing of the skin or the whites of your eyes (jaundice).
• Major birth defects. All females should read the birth defects section of "What is the most important information I should know about Tracleer?"
• Low sperm count. Drugs like Tracleer lower sperm count in animals. If this happens in men taking Tracleer, they may lose the ability to father children.

Other possible side effects

The most common side effects of Tracleer are:

• low red blood cell levels (anemia)
• headache
• inflamed throat and irritated nose passages
• flushing (hot flashes)
• ankle and leg swelling
• low blood pressure
• irregular heart beats
• upset stomach
• tiredness
• rash
• itching

General advice about prescription medicines

Medicines are sometimes prescribed for purposes other than those uled in a Medication Guide. If you have any concerns or questions about Tracleer, ask your doctor or other healthcare provider. This Medication Guide is only a summary of some important information about Tracleer. Your doctor can give you information about Tracleer that was written for healthcare professionals. Do not use Tracleer for a condition for which it was not prescribed. Do not share Tracleer with other people.

This Medication Guide has been approved by the US Food and Drug Administration.

February 15, 2007

©2007 Actelion Pharmaceuticals US, Inc.