ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following important adverse reactions are described elsewhere in the labeling:Hepatotoxicity [see Boxed Warning, Warnings and Precautions (5.1)] Embryo-fetal Toxicity [see Boxed Warning, Warnings and Precautions (5.2)] Fluid Retention [see Warnings and Precautions (5.4)] Hepatotoxicity [see Boxed Warning, Warnings and Precautions (5.1)] Embryo-fetal Toxicity [see Boxed Warning, Warnings and Precautions (5.2)] Fluid Retention [see Warnings and Precautions (5.4)] Common adverse reactions (>=3% more than placebo) for the film-coated tablet are respiratory tract infection and anemia (6.1).Common adverse reactions (>=15%) for the dispersible tablet are upper respiratory tract infections and pyrexia (6.1).To report SUSPECTED ADVERSE REACTIONS, contact Janssen at 1-800-526-7736 (1-800-JANSSEN) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Common adverse reactions (>=3% more than placebo) for the film-coated tablet are respiratory tract infection and anemia (6.1).. Common adverse reactions (>=15%) for the dispersible tablet are upper respiratory tract infections and pyrexia (6.1).. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Safety data on TRACLEER were obtained from 13 clinical studies (9 placebo-controlled and open-label) in 870 adult patients with PAH and other diseases. Doses up to times the currently recommended clinical dose (125 mg twice daily) were administered for variety of durations. The exposure to TRACLEER in these trials ranged from day to 4.1 years (n=94 for year; n=61 for 1.5 years; and n=39 for more than years). Exposure of PAH patients (n=328) to TRACLEER ranged from day to 1.7 years (n=174 more than 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 adult patients with PAH were more frequent on TRACLEER (6%; 15/258 patients) than on placebo (3%; 5/172 patients). In this database the only cause of discontinuations >1% and occurring more often on TRACLEER was abnormal liver function.The adverse drug events that occurred in >=3% of the TRACLEER-treated patients and were more common on TRACLEER in placebo-controlled trials in PAH at doses of 125 or 250 mg twice daily are shown in Table 3:Table 3:Adverse eventsNote: only AEs with onset from start of treatment to calendar day after end of treatment are included. All reported events (at least 3%) are included except those too general to be informative, and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population. occurring in >=3% of patients treated with TRACLEER 125-250 mg twice daily and more common on TRACLEER in placebo-controlled studies in pulmonary arterial hypertensionAdverse EventTRACLEERn=258Placebon=172No.%No.% Respiratory Tract InfectionRespiratory Tract Infection combines the terms Nasopharyngitis, Upper Respiratory Tract Infection and Respiratory Tract Infection. Combined data from Study 351, BREATHE-1 and EARLY 5622%3017% Headache3915%2514% Edema2811%169% Chest Pain135%85% Syncope125%74% Flushing104%53% Hypotension104%32% Sinusitis94%42% Arthralgia94%32% Serum Aminotransferases, abnormal94%32% Palpitations94%32% Anemia83%--TRACLEER was evaluated for safety in 119 pediatric patients in uncontrolled studies. The safety profile was similar to that observed in adult patients with PAH. Decreased Sperm CountsAn open-label, single-arm, multicenter, safety study evaluated the effect on testicular function of TRACLEER 62.5 mg twice daily for weeks, followed by 125 mg twice daily for months. Twenty-five male patients with WHO functional class III and IV PAH and normal baseline sperm count were enrolled. Twenty-three completed the study and discontinued due to adverse events not related to testicular function. There was decline in sperm count of at least 50% in 25% of the patients after or months of treatment with TRACLEER. Sperm count remained within the normal range in all 22 patients with data after months and no changes in sperm morphology, sperm motility, or hormone levels were observed. One patient developed marked oligospermia at months and the sperm count remained low with follow-up measurements over the subsequent weeks. TRACLEER was discontinued and after months the sperm count had returned to baseline levels. Based on these findings and preclinical data from endothelin receptor antagonists, it cannot be excluded that endothelin receptor antagonists such as TRACLEER have an adverse effect on spermatogenesis.. Decreases in Hemoglobin and HematocritTreatment with TRACLEER can cause dose-related decrease in hemoglobin and hematocrit. It is recommended that hemoglobin concentrations be checked after and months, and every months thereafter. If marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and need for specific treatment.The overall mean decrease in hemoglobin concentration for adult TRACLEER-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 TRACLEER treatment and hemoglobin levels stabilized by 4-12 weeks of TRACLEER treatment. In placebo-controlled studies of all uses of TRACLEER, marked decreases in hemoglobin (>15% decrease from baseline resulting in values <11 g/dL) were observed in 6% of TRACLEER-treated patients and 3% of placebo-treated patients. In patients with PAH treated with doses of 125 and 250 mg twice daily, marked decreases in hemoglobin occurred in 3% compared to 1% in placebo-treated patients.A decrease in hemoglobin concentration by at least g/dL was observed in 57% of TRACLEER-treated patients as compared to 29% of placebo-treated patients. In 80% of those patients whose hemoglobin decreased by at least g/dL, the decrease occurred during the first weeks of TRACLEER treatment.During the course of treatment, the hemoglobin concentration remained within normal limits in 68% of TRACLEER-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.In pooled analysis of pediatric patients (N=100) with PAH treated with TRACLEER, decrease in hemoglobin levels to <10 g/dL from baseline was reported in 11% of patients. There was no decrease to <8 g/dL.. 6.2Postmarketing Experience. There have been several postmarketing reports of angioedema associated with the use of TRACLEER. The onset of the reported cases occurred within range of hours to 21 days after starting therapy. Some patients were treated with an antihistamine and their signs of angioedema resolved without discontinuing TRACLEER.The following additional adverse reactions have been reported during the postapproval use of TRACLEER. Because these adverse reactions are reported from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to TRACLEER exposure:Unexplained hepatic cirrhosis [see Boxed Warning] Liver failure [see Boxed Warning] Hypersensitivity, DRESS, and anaphylaxis [see Contraindications (4.4)] ThrombocytopeniaRashJaundiceAnemia requiring transfusionNeutropenia and leukopeniaNasal congestion. Unexplained hepatic cirrhosis [see Boxed Warning] Liver failure [see Boxed Warning] Hypersensitivity, DRESS, and anaphylaxis [see Contraindications (4.4)] Thrombocytopenia. Rash. Jaundice. Anemia requiring transfusion. Neutropenia and leukopenia. Nasal congestion.

BOXED WARNING SECTION.

WARNING: RISKS OF HEPATOTOXICITY and EMBRYO-FETAL TOXICITY. Because of the risks of hepatotoxicity and birth defects, TRACLEER is available only through restricted program called the Bosentan REMS Program. Under the Bosentan REMS, prescribers, patients, and pharmacies must enroll in the program [see Warnings and Precautions (5.3)]. WARNING: RISKS OF HEPATOTOXICITY and EMBRYO-FETAL TOXICITYSee full prescribing information for complete boxed warning.TRACLEER is available only through restricted distribution program called the Bosentan REMS Program because of these risks (5.3):Elevations of liver aminotransferases (ALT, AST) and liver failure have been reported with TRACLEER (5.1).Measure liver aminotransferases prior to initiation of treatment and then monthly (2.1, 5.1).Discontinue TRACLEER if aminotransferase elevations are accompanied by signs or symptoms of liver dysfunction or injury or increases in bilirubin >=2xULN (2.4, 5.1).Based on animal data, TRACLEER is likely to cause major birth defects if used during pregnancy (4.1, 5.2, 8.1).Must exclude pregnancy before and during treatment (2.1, 4.1, 8.1).To prevent pregnancy, females of reproductive potential must use two reliable forms of contraception during treatment and for one month after stopping TRACLEER (4.1, 5.2, 8.1).. Measure liver aminotransferases prior to initiation of treatment and then monthly (2.1, 5.1).. Discontinue TRACLEER if aminotransferase elevations are accompanied by signs or symptoms of liver dysfunction or injury or increases in bilirubin >=2xULN (2.4, 5.1).. Must exclude pregnancy before and during treatment (2.1, 4.1, 8.1).. To prevent pregnancy, females of reproductive potential must use two reliable forms of contraception during treatment and for one month after stopping TRACLEER (4.1, 5.2, 8.1).. HepatotoxicityIn clinical studies, TRACLEER caused 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 small number of cases. Because these changes are marker for potential serious hepatotoxicity, serum aminotransferase levels must be measured prior to initiation of treatment and then monthly [see Dosage and Administration (2.4), Warnings and Precautions (5.1)]. In the postmarketing 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 comorbidities and drug therapies. There have also been 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 rise of aminotransferases accompanied by signs or symptoms of liver dysfunction [see Dosage and Administration (2.4)]. Elevations in aminotransferases require close attention [see Dosage and Administration (2.4)]. TRACLEER should generally be avoided in patients with elevated aminotransferases (>3xULN) at baseline because monitoring for hepatotoxicity may be more difficult. 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 >=2xULN, treatment with TRACLEER should be stopped. There is no experience with the reintroduction of TRACLEER in these circumstances.. Embryo-Fetal ToxicityTRACLEER is likely to cause major birth defects if used by pregnant females based on animal data [see Warnings and Precautions (5.2), Use in Specific Populations (8.1)]. Therefore, pregnancy must be excluded before the start of treatment with TRACLEER. Throughout treatment and for one month after stopping TRACLEER, females of reproductive potential must use two reliable methods of contraception unless the patient has an intrauterine device (IUD) or tubal sterilization, 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 TRACLEER [see Drug Interactions (7.2)]. Obtain monthly pregnancy tests.

STORAGE AND HANDLING SECTION.

Store at 20oC to 25oC (68oF to 77oF). Excursions are permitted between 15C and 30C (59F and 86F). [See USP Controlled Room Temperature]. These storage temperatures apply to both film-coated and dispersible tablets. Divided dispersible tablets should be stored under the same conditions and used within days. Tablet pieces may be returned to the opened blister and stored there out of reach of children for up to days.Keep out of reach of children.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Nursing mothers: Choose breastfeeding or TRACLEER (8.2).. Nursing mothers: Choose breastfeeding or TRACLEER (8.2).. 8.1 Pregnancy. Risk SummaryBased on data from animal reproduction studies, TRACLEER may cause fetal harm, including birth defects and fetal death, when administered to pregnant female and is contraindicated during pregnancy [see Contraindications (4.1)]. There are limited data on TRACLEER use in pregnant women. In animal reproduction studies, oral administration of bosentan to pregnant rats at 2-times the maximum recommended human dose (MRHD) on mg/m2 basis caused teratogenic effects in rats, including malformations of the head, mouth, face, and large blood vessels [see Animal Data]. Advise pregnant women of the potential risk to fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Data. Animal DataBosentan was teratogenic in rats given oral doses two times the MRHD (on 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 and 10 times the MRHD (on mg/m2 basis). Although birth defects were not observed in rabbits given oral doses of up to the equivalent of 10.5 g/day in 70 kg person, 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 embryo-fetal toxicity is class effect of these drugs.. 8.2 Lactation. Risk SummaryThere 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 TRACLEER, advise women not to breastfeed during treatment with TRACLEER.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating TRACLEER, monthly during treatment and one month after stopping treatment with TRACLEER. The 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.. ContraceptionDrug interaction studies show that bosentan reduces serum levels of the estrogen and progestin in oral contraceptives. Based on these findings, hormonal contraceptives (including oral, injectable, transdermal, and implantable contraceptives) may be less effective for preventing pregnancy in patients using TRACLEER and should not be used as patients only contraceptive method [see Drug Interactions (7.2)]. Females of reproductive potential using TRACLEER must use two acceptable methods of contraception during treatment and for month after treatment with TRACLEER. Patients may choose one highly effective form of contraception (intrauterine devices (IUD) or tubal sterilization) or combination of methods (hormone method with barrier method or two barrier methods). If partners vasectomy is the chosen method of contraception, hormone or barrier method must be used along with this method. Counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling [see Boxed Warning].. Infertility. MalesDecreased sperm counts have been observed in patients receiving TRACLEER. Based on these findings and findings in animals, TRACLEER may impair fertility in males of reproductive potential. It is not known whether effects on fertility would be reversible [see Warnings and Precautions (5.6), Adverse Reactions (6.1), Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use. The efficacy of TRACLEER in patients <18 years is supported by data from an uncontrolled trial in which 19 pediatric patients were treated with TRACLEER. In this study, cardiopulmonary hemodynamic improvements were similar to those seen in adults treated with TRACLEER [see Pulmonary Arterial Hypertension (14.1)]. Safety in pediatric patients is supported by data from 100 pediatric patients treated with TRACLEER for median of 17 months [see Clinical Studies Experience (6.1), Pulmonary Arterial Hypertension (14.1)].. Juvenile Animal Toxicity DataIn juvenile rat toxicity study, rats were treated from Day postpartum to adulthood (Day 69 postpartum). Decreased body weights, absolute weights of testes and epididymides, and reduced number of sperm in epididymides were observed after weaning. No effect on testis histology or sperm morphology and function was seen. The NOAEL was times (at Day postpartum) and times (Day 69 postpartum) the human therapeutic exposure, respectively.No effects on general development, sensory, cognitive function and reproductive performance were detected at the highest dose tested in juvenile rats, times the therapeutic exposure in children with PAH.. 8.5 Geriatric Use. Clinical studies of TRACLEER did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects.. 8.6Hepatic Impairment. 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 (Cmax and AUC) of bosentan. The pharmacokinetics of TRACLEER have not been evaluated in patients with severe liver impairment (Child-Pugh Class C). In patients with moderate hepatic impairment (Child-Pugh Class B), the systemic exposures to bosentan and its active metabolite increased significantly. TRACLEER should generally be avoided in patients with moderate or severe liver impairment. Pharmacokinetics of bosentan were not altered in patients with mild impairment of hepatic function (Child-Pugh Class A) [see Dosage and Administration (2.6), Warnings and Precautions (5.1), Pharmacokinetics (12.3)].. 8.7Renal Impairment. The effect of renal impairment on the pharmacokinetics of bosentan is small and does not require dosing adjustment [see Pharmacokinetics (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Fluid retention: May require intervention (5.4).Pulmonary veno-occlusive disease (PVOD): If signs of pulmonary edema occur, consider the diagnosis of associated PVOD and consider discontinuing TRACLEER (5.5).Decreased sperm counts (5.6).Decreases in hemoglobin and hematocrit: Monitor hemoglobin levels after and months of treatment, then every months thereafter (5.7).. Fluid retention: May require intervention (5.4).. Pulmonary veno-occlusive disease (PVOD): If signs of pulmonary edema occur, consider the diagnosis of associated PVOD and consider discontinuing TRACLEER (5.5).. Decreased sperm counts (5.6).. Decreases in hemoglobin and hematocrit: Monitor hemoglobin levels after and months of treatment, then every months thereafter (5.7).. 5.1Hepatotoxicity. ALT or AST >3xULN were observed in 11% of TRACLEER-treated patients (n=658) compared to 2% of placebo-treated patients (n=280). Three-fold increases were seen in 12% of 95 pulmonary arterial hypertension (PAH) patients on 125 mg twice daily and 14% of 70 PAH patients on 250 mg twice daily. Eight-fold increases were seen in 2% of PAH patients on 125 mg twice daily and 7% of PAH patients on 250 mg twice daily. Bilirubin increases to >=3xULN were associated with aminotransferase increases in of 658 (0.3%) of patients treated with TRACLEER. In pooled analysis of four pediatric studies conducted in PAH (n =100), elevations in liver aminotransferases >=3xULN were observed in 2% of patients. The combination of hepatocellular injury (increases in aminotransferases of >3xULN) and increases in total bilirubin (>=2xULN) is marker for potential serious hepatotoxicity.Elevations of AST or ALT associated with TRACLEER 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 and therapy adjusted accordingly [see Dosage and Administration (2.1, 2.4)]. Discontinue TRACLEER 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 >=2xULN.Avoid initiation of TRACLEER in patients with elevated aminotransferases (>3xULN) prior to drug initiation because monitoring hepatotoxicity in these patients may be more difficult [see Boxed Warning, Dosage and Administration (2.6), Use in Specific Populations (8.6)].In WHO Functional Class II patients, consider whether the benefits of TRACLEER are sufficient to offset the risk of hepatotoxicity, which may preclude future use as their disease progresses.. 5.2Embryo-fetal Toxicity. Based on data from animal reproduction studies, TRACLEER may cause fetal harm when administered to pregnant female and is contraindicated in females who are pregnant. Advise females of reproductive potential of the potential risk to fetus. Obtain pregnancy test prior to TRACLEER treatment, monthly during treatment and for one month after stopping treatment. Advise females of reproductive potential to use two reliable forms of contraception during treatment with TRACLEER and for at least one month after the last dose [see Dosage and Administration (2), Use in Specific Populations (8.1, 8.3)].TRACLEER is only available for females through restricted program under REMS [see Warnings and Precautions (5.3)]. 5.3Prescribing and Distribution Program for Bosentan. Because of the risks of hepatotoxicity and birth defects, TRACLEER is available only through restricted program called the Bosentan REMS Program. As component of the Bosentan REMS, prescribers, patients, and pharmacies must enroll in the program [see Boxed Warning, Warnings and Precautions (5.1, 5.2), Contraindications (4.1)].Required components of the Bosentan REMS are:Healthcare professionals who prescribe TRACLEER must review the prescriber educational materials, enroll in the Bosentan REMS Program and comply with its requirements.Healthcare professionals must (1) review serum aminotransferases (ALT/AST) and bilirubin, and agree to order and monitor these tests monthly; and (2) for females of reproductive potential, confirm that the patient is not pregnant, and agree to order and monitor pregnancy tests monthly.To receive TRACLEER, all patients must understand the risks and benefits, and complete patient enrollment form.Pharmacies that dispense TRACLEER must enroll in the program and agree to comply with the Bosentan REMS Program requirements.Further information about TRACLEER and the Bosentan REMS Program is available at www.BosentanREMSProgram.com or 1-866-359-2612.. Healthcare professionals who prescribe TRACLEER must review the prescriber educational materials, enroll in the Bosentan REMS Program and comply with its requirements.. Healthcare professionals must (1) review serum aminotransferases (ALT/AST) and bilirubin, and agree to order and monitor these tests monthly; and (2) for females of reproductive potential, confirm that the patient is not pregnant, and agree to order and monitor pregnancy tests monthly.. To receive TRACLEER, all patients must understand the risks and benefits, and complete patient enrollment form.. Pharmacies that dispense TRACLEER must enroll in the program and agree to comply with the Bosentan REMS Program requirements.. 5.4Fluid Retention. Peripheral edema is known clinical consequence of PAH and worsening PAH and is also known effect of TRACLEER and other endothelin receptor antagonists. In PAH clinical trials with TRACLEER, combined adverse events of fluid retention or edema were reported in 1.7% (placebo-corrected) of patients.In addition, there have been numerous postmarketing reports of fluid retention in patients with pulmonary hypertension occurring within weeks after starting TRACLEER. Patients required intervention with 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 the cause, such as TRACLEER or underlying heart failure, and the possible need for treatment or discontinuation of TRACLEER [see Adverse Reactions (6.1), Clinical Studies (14.2)].. 5.5Pulmonary Veno-Occlusive Disease. If signs of pulmonary edema occur, consider the possibility of associated pulmonary veno-occlusive disease and consider whether TRACLEER should be discontinued.. 5.6Decreased Sperm Counts. Decreased sperm counts have been observed in patients receiving TRACLEER. Preclinical data also suggest that TRACLEER, similar to other endothelin receptor antagonists, may have an adverse effect on spermatogenesis [see Adverse Reactions (6.1), Nonclinical Toxicology (13.1)]. 5.7Decreases in Hemoglobin and Hematocrit. Treatment with TRACLEER can cause dose-related decrease in hemoglobin and hematocrit. There have been postmarketing reports of decreases in hemoglobin concentration and hematocrit that have resulted in anemia requiring transfusion. It is recommended that hemoglobin concentrations be checked after and months, and every months thereafter. If marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and need for specific treatment [see Adverse Reactions (6.1)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis and MutagenesisTwo 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 times the maximum recommended human dose [MRHD] of 125 mg twice daily, on 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 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.. Impairment of Fertility/Testicular FunctionThe development of testicular tubular atrophy and impaired fertility has been linked with the chronic administration of certain endothelin receptor antagonists in rodents.Treatment with bosentan at oral doses of up to 1500 mg/kg/day (50 times the MRHD on mg/m2 basis) or intravenous doses up to 40 mg/kg/day had no effects on sperm count, sperm motility, mating performance or fertility in male and female rats. An increased incidence of testicular tubular atrophy was observed in rats given bosentan orally at doses as low as 125 mg/kg/ day (about times the MRHD and the lowest doses tested) for two years but not at doses as high as 1500 mg/kg/day (about 50 times the MRHD) for months. Effects on sperm count and motility were evaluated only in the much shorter duration fertility studies in which males had been exposed to the drug for 4-6 weeks. An increased incidence of tubular atrophy was not observed in mice treated for years at doses up to 4500 mg/kg/day (about 75 times the MRHD) or in dogs treated up to 12 months at doses up to 500 mg/kg/day (about 50 times the MRHD).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. Bosentan is specific and competitive antagonist at endothelin receptor types ETA and ETB. Bosentan has slightly higher affinity for ETA receptors than for ETB receptors. The clinical impact of dual endothelin blockage is unknown.Endothelin-1 (ET-1) is neurohormone, the effects of which are mediated by binding to ETA and ETB receptors in the endothelium and vascular smooth muscle. ET-1 concentrations are elevated in plasma and lung tissue of patients with PAH, suggesting pathogenic role for ET-1 in this disease.. 12.3 Pharmacokinetics. GeneralAfter oral administration, maximum plasma concentrations of bosentan are attained within 3-5 hours and the terminal elimination half-life is about hours in healthy adult subjects. The exposure to bosentan after intravenous and oral administration is about twice as high in adult patients with PAH as it is in healthy adult subjects.In relative bioavailability study in healthy adults, the peak plasma concentration and area under the plasma concentration-time curve for bosentan are on an average 14% and 11%, respectively, lower following administration of the oral dispersible tablet compared to the film-coated tablet.. AbsorptionThe absolute bioavailability of bosentan in normal volunteers is about 50% and is unaffected by food.Bosentan is highly bound (>98%) to plasma proteins, mainly albumin. Bosentan does not penetrate into erythrocytes. The volume of distribution is about 18 L.. Elimination. MetabolismBosentan has three metabolites, one of which is pharmacologically active and may contribute 10%-20% of the effect of bosentan. Bosentan is an inducer of CYP2C9 and CYP3A and possibly also of CYP2C19. Upon multiple oral dosing, plasma concentrations in healthy adults decrease gradually to 50-65% of those seen after single dose administration, probably the effect of auto-induction of the metabolizing liver enzymes. Steady-state is reached within 3-5 days.. ExcretionBosentan is eliminated by biliary excretion following metabolism in the liver. Less than 3% of an administered oral dose is recovered in urine. Total clearance after single intravenous dose is about L/h in patients with PAH.. Specific Populations. PediatricsThe average plasma exposure to bosentan at steady state (AUCss) in pediatric patients with PAH aged to 15 years treated with 31.25, 62.5 or 125 mg (approximately mg/kg) film-coated tablet twice daily is 37% lower than that observed in adult patients with PAH receiving 125 mg film-coated tablet twice daily. Following administration of mg/kg twice daily doses of dispersible tablet in patients with PAH aged to 11 years, the average systemic exposure to bosentan at steady state is similar to that observed with mg/kg. The average exposure to bosentan in these pediatric patients was approximately half the exposure in adult patients treated with 125 mg film-coated tablets twice daily.The exposure to bosentan at mg/kg three times daily dosing of dispersible tablet is similar to that of mg/kg twice daily dosing in patients with PAH aged months to 12 years.Based on these findings, exposure to bosentan reaches plateau at lower doses in pediatric patients than in adults, and doses higher than mg/kg twice daily do not increase the exposure to bosentan in pediatric patients.. Hepatic ImpairmentIn vitro and in vivo evidence showing extensive hepatic metabolism of bosentan suggests that liver impairment could significantly increase exposure to bosentan. In study comparing patients with mild liver impairment (Child-Pugh Class A) to controls, the single- and multiple-dose pharmacokinetics of bosentan were not altered in patients with mild hepatic impairment.In another small (N=8) pharmacokinetic study, the steady-state AUC of bosentan was on average 4.7 times higher and the active metabolite Ro 48-5033 was 12.4 times higher in patients with moderately impaired liver function (Child-Pugh Class B) and PAH associated with portal hypertension than in patients with normal liver function and PAH of other etiologies.The pharmacokinetics of TRACLEER have not been evaluated in patients with severe liver impairment (Child-Pugh Class C) [see Dosage and Administration (2.2), Warnings and Precautions (5.1), Use in Specific Populations (8.6)]. Renal ImpairmentIn patients with severe renal impairment (creatinine clearance 15-30 mL/min), plasma concentrations of bosentan were essentially unchanged and plasma concentrations of the three metabolites were increased about 2-fold compared to subjects with normal renal function. These differences do not appear to be clinically important.. Drug Interactions. KetoconazoleCo-administration of bosentan 125 mg twice daily and ketoconazole, potent CYP3A inhibitor, increased the plasma concentrations of bosentan by approximately 100% in normal volunteers. No dose adjustment of TRACLEER is necessary, but increased effects of TRACLEER should be considered.. WarfarinCo-administration of bosentan 500 mg twice daily for days in normal volunteers decreased the plasma concentrations of both S-warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A substrate) by 29 and 38%, respectively. Clinical experience with concomitant administration of TRACLEER and warfarin in patients with PAH did not show clinically relevant changes in INR or warfarin dose (baseline vs. end of the clinical studies), and the need to change the warfarin dose during the trials due to changes in INR or due to adverse events was similar among TRACLEER- and placebo-treated patients.. Digoxin, Nimodipine, and LosartanBosentan has no significant pharmacokinetic interactions with digoxin and nimodipine, and losartan has no significant effect on plasma levels of bosentan.. SildenafilIn normal volunteers, co-administration of multiple doses of 125 mg twice daily bosentan and 80 mg three times daily sildenafil resulted in reduction of sildenafil plasma concentrations by 63% and increased bosentan plasma concentrations by 50%. The changes in plasma concentrations were not considered clinically relevant and dose adjustments are not necessary. This recommendation holds true when sildenafil is used for the treatment of PAH or erectile dysfunction.. TadalafilBosentan (125 mg twice daily) reduced tadalafil (40 mg once per day) systemic exposure (AUC) by 42% and Cmax by 27% following multiple dose co-administration. Tadalafil did not affect the exposure (AUC and Cmax) of bosentan or its metabolites.Figure 3. CYP Induction-mediated effect of bosentan on other drugsFigure 4. Effects of other drugs on bosentan. Figure 3. Figure 4.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Pulmonary Arterial Hypertension. WHO Functional Class III-IVTwo randomized, double-blind, multi-center, placebo-controlled trials were conducted in 32 and 213 patients. The larger study (BREATHE-1) compared doses (125 mg twice daily and 250 mg twice daily) of TRACLEER with placebo. The smaller study (Study 351) compared 125 mg twice daily with placebo. Patients had severe (WHO functional Class III-IV) PAH: idiopathic or heritable PAH (72%) or PAH associated with scleroderma or other connective tissue diseases (21%), or to autoimmune diseases (7%). There were no patients with PAH associated with other conditions such as HIV disease or recurrent pulmonary emboli.In both studies, TRACLEER or placebo was added to patients current therapy, which could have included combination of digoxin, anticoagulants, diuretics, and vasodilators (e.g., calcium channel blockers, ACE inhibitors), but not epoprostenol. TRACLEER was given at dose of 62.5 mg twice daily for weeks and then at 125 mg twice daily or 250 mg twice daily for either 12 (BREATHE-1) or (Study 351) additional weeks. The primary study endpoint was 6-minute walk distance. In addition, symptoms and functional status were assessed. Hemodynamic measurements were made at 12 weeks in Study 351.The mean age was about 49 years. About 80% of patients were female, and about 80% were Caucasian. Patients had been diagnosed with pulmonary hypertension for mean of 2.4 years.. Submaximal Exercise AbilityResults of the 6-minute walk distance at months (Study 351) or months (BREATHE-1) are shown in Table 4.Table 4: Effects of TRACLEER on 6-minute walk distanceBREATHE-1Study 351TRACLEER125 mg twice daily(n=74)TRACLEER250 mg twice daily(n=70)Placebo(n=69)TRACLEER125 mg twice daily(n=21)Placebo(n=11)Distance in meters: mean +- standard deviation. Changes are to week 16 for BREATHE-1 and to week 12 for Study 351.Baseline326 +- 73333 +- 75344 +- 76360 +- 86355 +- 82End point353 +- 115379 +- 101336 +- 129431 +- 66350 +- 147Change from baseline27 +- 7546 +- 62-8 +- 9670 +- 56-6 +- 121Placebo subtracted35 p=0.01; by Wilcoxon; 54 p=0.0001; by Wilcoxon; 76 p=0.02; by Students t-test. In both trials, treatment with TRACLEER resulted in significant increase in exercise ability. The improvement in walk distance was apparent after month of treatment (with 62.5 mg twice daily) and fully developed by about months of treatment (Figure 5). It was maintained for up to months of double-blind treatment. Walking distance was somewhat greater with 250 mg twice daily, but the potential for increased hepatotoxicity causes this dose not to be recommended [see Dosage and Administration (2.1)]. There were no apparent differences in treatment effects on walk distance among subgroups analyzed by demographic factors, baseline disease severity, or disease etiology, but the studies had little power to detect such differences.Figure 5.Mean Change in 6-min Walk Distance (BREATHE-1)Change from baseline in 6-minute walking distance from start of therapy to week 16 in the placebo and combined TRACLEER (125 mg twice daily and 250 mg twice daily) groups. Values are expressed as mean +- standard error of the mean.. Figure 5. Hemodynamic ChangesInvasive hemodynamic parameters were assessed in Study 351. Treatment with TRACLEER led to significant increase in cardiac index (CI) associated with significant reduction in pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), and mean right atrial pressure (RAP) (Table 5).The relationship between hemodynamic effects and improvements in 6-minute walk distance is unknown.Table 5:Change from Baseline to Week 12: Hemodynamic ParametersTRACLEER125 mg twice dailyPlaceboValues shown are means +- SDCI (L/min/m2)n=20n=10Baseline2.35+-0.732.48+-1.03Absolute Change0.50+-0.46-0.52+-0.48Treatment Effect1.02p<=0.001; Mean PAP (mmHg)n=20n=10Baseline53.7+-13.455.7+-10.5Absolute Change-1.6+-5.15.1+-8.8Treatment Effect-6.7p<0.02 PVR (dynseccm-5)n=19n=10Baseline896+-425942+-430Absolute Change-223+-245191+-235Treatment Effect-415 Mean RAP (mmHg)n=19n=10Baseline9.7+-5.69.9+-4.1Absolute Change-1.3+-4.14.9+-4.6Treatment Effect-6.2 Symptoms and Functional StatusSymptoms of PAH were assessed by Borg dyspnea score, WHO functional class, and rate of clinical worsening. Clinical worsening was assessed as the sum of death, hospitalizations for PAH, discontinuation of therapy because of PAH, and need for epoprostenol. There was significant reduction in dyspnea during walk tests (Borg dyspnea score), and significant improvement in WHO functional class in TRACLEER-treated patients. There was significant reduction in the rate of clinical worsening (Table and Figure 6). Figure shows the log-rank test reflecting clinical worsening over 28 weeks.Table 6:Incidence of Clinical Worsening, Intent To Treat PopulationBREATHE-1Study 351TRACLEER125/250 mg twice daily(n=144)Placebo(n=69)TRACLEER125 mg twice daily(n=21)Placebo(n=11)Note: Patients may have had more than one reason for clinical worsening.Patients with clinical worsening[n (%)]9 (6%)p=0.0015 vs. placebo by log-rank test. There was no relevant difference between the 125 mg and 250 mg twice daily groups. 14 (20%)0 (0%)p=0.033 vs. placebo by Fishers exact test. (27%)Death1 (1%)2 (3%)0 (0%)0 (0%)Hospitalization for PAH6 (4%)9 (13%)0 (0%)3 (27%)Discontinuation due to worsening of PAH5 (3%)6 (9%)0 (0%)3 (27%)Receipt of epoprostenolReceipt of epoprostenol was always consequence of clinical worsening. (3%)3 (4%)0 (0%)3 (27%)Figure 6. Time to Clinical Worsening (BREATHE-1)Time from randomization to clinical worsening with Kaplan-Meier estimate of the proportions of failures in BREATHE-1. All patients (n=144 in the TRACLEER group and n=69 in the placebo group) participated in the first 16 weeks of the study. subset of this population (n=35 in the TRACLEER group and 13 in the placebo group) continued double-blind therapy for up to 28 weeks.. Figure 6. WHO Functional Class II In randomized, double-blind, multicenter, placebo-controlled trial, 185 mildly symptomatic PAH patients with WHO Functional Class II (mean baseline 6-minute walk distance of 443 meters) received TRACLEER 62.5 mg twice daily for weeks followed by 125 mg twice daily (n=93), or placebo (n=92) for months. Enrolled patients were treatment-naive (n=156) or on stable dose of sildenafil (n=29). The coprimary endpoints were change from baseline to month in PVR and 6-minute walk distance. Time to clinical worsening (assessed as the sum of death, hospitalization due to PAH complications, or symptomatic progression of PAH), Borg dyspnea index, change in WHO functional class and hemodynamics were assessed as secondary endpoints.Compared with placebo, TRACLEER treatment was associated with reduced incidence of worsening of at least one functional class (3% TRACLEER vs. 13% placebo, p=0.03), and improvement in hemodynamic variables (PVR, mPAP, TPR, cardiac index, and SVO2; <0.05). The +19 mean (+14 median) increase in 6-minute walk distance with TRACLEER vs. placebo was not significant (p=0.08). There was significant delay in time to clinical worsening (first seen primarily as symptomatic progression of PAH) with TRACLEER compared with placebo (hazard ratio 0.2, p=0.01). Findings were consistent in strata with or without treatment with sildenafil at baseline.. Long-term Treatment of PAHLong-term follow-up of patients with Class III and IV PAH who were treated with TRACLEER in open-label extensions of trials (N=235) showed that 93% and 84% of patients were still alive at and years, respectively, after the start of treatment.These uncontrolled observations do not allow comparison with group not given TRACLEER and cannot be used to determine the long-term effect of TRACLEER on mortality.. Pediatric StudiesThe efficacy of bosentan was evaluated in an open-label, uncontrolled study in 19 pediatric patients with PAH aged to 15 years. Patients had primary pulmonary hypertension (n=10) or PAH related to congenital heart diseases (9 patients) and were WHO functional class II (n=15, 79%) or class III (n=4; 21%) at baseline. Patients were dosed with bosentan at approximately mg/kg twice daily (body weight adjusted dose, corresponding to the recommended adult dose) [see Dosage and Administration (2.1)] for 12 weeks. Half of the patients in each group were already being treated with intravenous epoprostenol and the dose of epoprostenol remained constant for the duration of the study.Hemodynamics were measured in 17 patients (Table 7). The mean decrease in PVR was 389 dynseccm-5, which was similar to the effect seen in adults. Hemodynamic improvements from baseline were similar with or without co-administration of epoprostenol.Table 7:Change from Baseline to Week 12: Hemodynamic ParametersTRACLEER2 mg/kg twice dailyValues shown are means +- SDCI (L/min/m2)n=17Baseline4.0+-1.5Absolute Change0.5+-1.4Mean PAP (mmHg)n=18Baseline60+-18Absolute Change-8+-9PVR (dynseccm-5)n=17Baseline1195+-755Absolute Change-389+-616Mean RAP (mmHg)n=18Baseline6.1+-2.7Absolute Change-0.5+-2.3. Pulmonary Arterial Hypertension in Adults related to Congenital Heart Disease with Left-to-Right ShuntsA small study (N=54) and its open-label extension (N=37) of up to 40 weeks in adult patients with Eisenmenger physiology demonstrated effects of TRACLEER on exercise and safety that were similar to those seen in other trials in patients with PAH (WHO Group 1).. 14.2Lack of Benefit in Congestive Heart Failure. TRACLEER is not effective in the treatment of congestive heart failure with left ventricular dysfunction. In pair of studies, 1613 subjects with NYHA Class III-IV heart failure, left ventricular ejection fraction <35%, on diuretics, ACE inhibitor, and other therapies, were randomized to placebo or TRACLEER (62.5 mg twice daily titrated as tolerated to 125 mg twice daily) and followed for up to 70 weeks. Use of TRACLEER was associated with no benefit on patient global assessment (the primary end point) or mortality. However, hospitalizations for heart failure were more common during the first to weeks after TRACLEER was initiated. In 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. Patients required intervention with diuretic, fluid management, or hospitalization for decompensating heart failure.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Pregnancy (4.1)Use with Cyclosporine (4.2)Use with Glyburide (4.3)Hypersensitivity (4.4). Pregnancy (4.1). Use with Cyclosporine (4.2). Use with Glyburide (4.3). Hypersensitivity (4.4). 4.1Pregnancy. Use of TRACLEER is contraindicated in females who are or may become pregnant. To prevent pregnancy, females of reproductive potential must use two reliable forms of contraception during treatment and for one month after stopping TRACLEER [see Boxed Warning, Warnings and Precautions (5.2), Drug Interactions (7.2), Use in Specific Populations (8.1)].. 4.2Use with Cyclosporine A. Co-administration of cyclosporine and bosentan resulted in markedly increased plasma concentrations of bosentan. Therefore, concomitant use of TRACLEER and cyclosporine is contraindicated [see Cytochrome P450 Drug Interactions (7.1)]. 4.3Use with Glyburide. 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 [see Cytochrome P450 Drug Interactions (7.1)]. 4.4Hypersensitivity. TRACLEER is contraindicated in patients who are hypersensitive to bosentan or any component of the product. Observed reactions include Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), anaphylaxis, rash, and angioedema [see Adverse Reactions (6.2), Description (11)].

DESCRIPTION SECTION.

11 DESCRIPTION. TRACLEER(R) is the proprietary name for bosentan, an endothelin receptor antagonist that belongs to 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 molecular weight of 569.64 and molecular formula of C27H29N5O6SH2O. Bosentan is 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, ethylcellulose, glyceryl behenate, hydroxypropylmethylcellulose, iron oxide red, iron oxide yellow, magnesium stearate, povidone, pregelatinized starch, sodium starch glycolate, talc, titanium dioxide, and triacetin. Each TRACLEER 62.5 mg tablet contains 64.54 mg of bosentan monohydrate, equivalent to 62.5 mg of anhydrous bosentan. Each TRACLEER 125 mg tablet contains 129.08 mg of bosentan monohydrate, equivalent to 125 mg of anhydrous bosentan.TRACLEER is also available as 32 mg tablet for oral suspension and contains the following excipients: acesulfame potassium, aspartame (E951), calcium hydrogen phosphate anhydrous, cellulose microcrystalline, croscarmellose sodium, magnesium stearate, silica colloidal anhydrous, tartaric acid, and tutti frutti flavor. Each dispersible tablet contains 1.87 mg of phenylalanine. Each dispersible tablet contains 33.045 mg of bosentan monohydrate, equivalent to 32 mg anhydrous bosentan.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Patients older than 12 years of age: initiate at 62.5 mg orally twice daily; for patients weighing greater than 40 kg, increase to 125 mg orally twice daily after weeks (2.2).Patients 12 years of age and younger: dosage is based on weight, see Table (2.2).Reduce the dose and closely monitor patients developing aminotransferase elevations more than 3xUpper Limit of Normal (ULN) (2.1).. Patients older than 12 years of age: initiate at 62.5 mg orally twice daily; for patients weighing greater than 40 kg, increase to 125 mg orally twice daily after weeks (2.2).. Patients 12 years of age and younger: dosage is based on weight, see Table (2.2).. Reduce the dose and closely monitor patients developing aminotransferase elevations more than 3xUpper Limit of Normal (ULN) (2.1).. 2.1Required Monitoring. Healthcare professionals who prescribe TRACLEER must enroll in the Bosentan REMS Program and must comply with the required monitoring to minimize the risks associated with TRACLEER [see Warnings and Precautions (5.3)].Obtain pregnancy test in females of reproductive potential prior to TRACLEER treatment, monthly during treatment and one month after stopping TRACLEER. Initiate treatment with TRACLEER in females of reproductive potential only after negative pregnancy test [see Boxed Warning, Contraindications (4.1), Warnings and Precautions (5.3), Use in Specific Populations (8.1, 8.3)].Measure liver aminotransferase levels prior to initiation of treatment and then monthly [see Warnings and Precautions (5.1)].. 2.2Recommended Dosage. Administer TRACLEER orally following the dosing recommendations in Table 1. Doses above 125 mg twice daily did not appear to confer additional benefit sufficient to offset the increased risk of hepatotoxicity.Table 1: Dosing RecommendationsInitial weeksMaintenance (after weeks)Patients >12 years of age and >40 kg62.5 mg twice daily125 mg twice dailyPatients >12 years of age and <40 kg62.5 mg twice daily62.5 mg twice dailyPatients <=12 years of age >=4-8 kg16 mg twice daily16 mg twice daily >8-16 kg32 mg twice daily32 mg twice daily >16-24 kg48 mg twice daily48 mg twice daily >24-40 kg64 mg twice daily64 mg twice daily. 2.3Administration. TRACLEER film-coated tablets and tablets for oral suspension (dispersible tablets) should be administered orally twice daily.Disperse tablets for oral suspension, or dispersible tablet half, in minimal amount of water immediately before administration.Store divided dispersible tablet pieces at 20oC to 25oC (68oF to 77oF) in the opened blister for up to days.. 2.4Dosage Adjustments for Aminotransferase Elevations. If aminotransferase levels increase, adjust monitoring and treatment plan according to Table 2.Discontinue TRACLEER 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 bilirubin >=2xUpper Limit of Normal (ULN). There is no experience with the reintroduction of TRACLEER in these circumstances.Table 2:Dosage Adjustment and Monitoring in Patients Developing Aminotransferase Elevations >3xULNALT/AST levelsTreatment and monitoring recommendations>3 and <=5xULNConfirm by another aminotransferase test; if confirmed,in adults and pediatric patients >12 years and >40 kg, reduce the daily dose to 62.5 mg twice daily or interrupt treatment, and monitor aminotransferase levels at least every weeks. If the aminotransferase levels return to pretreatment values, treatment may continue or be reintroduced at 62.5 mg twice daily, with reassessment of aminotransferase levels within days.in all other pediatric patients, interrupt treatment with no prior dose reduction. If the aminotransferase levels return to pretreatment values, reintroduce at the dose used prior to treatment interruption, with reassessment of aminotransferase levels within days. >5 and <=8xULNConfirm by another aminotransferase test; if confirmed, stop treatment and monitor aminotransferase levels at least every weeks. Once the aminotransferase levels return to pretreatment values,in adults and pediatric patients >12 years and >40 kg, consider reintroduction of treatment at 62.5 mg twice daily, with reassessment of aminotransferase levels within days.in all other pediatric patients, consider reintroduction at the dose used prior to treatment interruption, with reassessment of aminotransferase levels within days. >8xULNStop treatment permanently. There is no experience with reintroduction of TRACLEER in these circumstances.. in adults and pediatric patients >12 years and >40 kg, reduce the daily dose to 62.5 mg twice daily or interrupt treatment, and monitor aminotransferase levels at least every weeks. If the aminotransferase levels return to pretreatment values, treatment may continue or be reintroduced at 62.5 mg twice daily, with reassessment of aminotransferase levels within days.. in all other pediatric patients, interrupt treatment with no prior dose reduction. If the aminotransferase levels return to pretreatment values, reintroduce at the dose used prior to treatment interruption, with reassessment of aminotransferase levels within days.. in adults and pediatric patients >12 years and >40 kg, consider reintroduction of treatment at 62.5 mg twice daily, with reassessment of aminotransferase levels within days.. in all other pediatric patients, consider reintroduction at the dose used prior to treatment interruption, with reassessment of aminotransferase levels within days.. 2.5Use with Ritonavir. Co-administration of TRACLEER in Patients on RitonavirIn patients who have been receiving ritonavir for at least 10 days, start TRACLEER at the recommended initial dose once daily or every other day based upon individual tolerability [see Cytochrome P450 Drug Interactions (7.1)].. Co-administration of Ritonavir in Patients on TRACLEERDiscontinue use of TRACLEER at least 36 hours prior to initiation of ritonavir. After at least 10 days following the initiation of ritonavir, resume TRACLEER at the recommended initial dose once daily or every other day based upon individual tolerability [see Cytochrome P450 Drug Interactions (7.1)].. 2.6Use in Patients with Pre-existing Hepatic Impairment. Avoid initiation of TRACLEER in patients with aminotransferases >3xULN. No dose adjustment is required in patients with mildly impaired liver function [see Warnings and Precautions (5.3), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. 62.5 mg tablets: round, biconvex, orange-white tablets, debossed with identification marking 62,5125 mg tablets: oval, biconvex, orange-white tablets, debossed with identification marking 12532 mg tablets for oral suspension:quadrisected: clover-shaped, quadrisected, pale yellow to off-white tablets, debossed with identification marking 32 on the side opposite the quadrisection lines,bisected: round, pale yellow to off-white tablets, bisected on one side and debossed with identification marking 32 on the other side.. quadrisected: clover-shaped, quadrisected, pale yellow to off-white tablets, debossed with identification marking 32 on the side opposite the quadrisection lines,. bisected: round, pale yellow to off-white tablets, bisected on one side and debossed with identification marking 32 on the other side.. Film-coated tablet: 62.5 mg and 125 mg (3)Tablet for oral suspension: 32 mg (3). Film-coated tablet: 62.5 mg and 125 mg (3). Tablet for oral suspension: 32 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Cytochrome P450: Coadministration of TRACLEER with drugs metabolized by CYP2C9 and CYP3A can increase exposure to TRACLEER and/or the coadministered drug (4.2, 4.3, 7.1).Hormonal contraceptives: TRACLEER use decreases contraceptive exposure and reduces effectiveness (7.2).. Cytochrome P450: Coadministration of TRACLEER with drugs metabolized by CYP2C9 and CYP3A can increase exposure to TRACLEER and/or the coadministered drug (4.2, 4.3, 7.1).. Hormonal contraceptives: TRACLEER use decreases contraceptive exposure and reduces effectiveness (7.2).. 7.1Cytochrome P450 Drug Interactions. Bosentan is metabolized by CYP2C9 and CYP3A. Inhibition of these enzymes may increase the plasma concentration of bosentan [see Pharmacokinetics (12.3)]. Concomitant administration of both CYP2C9 inhibitor (such as fluconazole or amiodarone) and strong CYP3A inhibitor (e.g., ketoconazole, itraconazole) or moderate CYP3A inhibitor (e.g., amprenavir, erythromycin, fluconazole, diltiazem) with TRACLEER will likely lead to large increases in plasma concentrations of bosentan. Co-administration of such combinations of CYP2C9 inhibitor plus strong or moderate CYP3A inhibitor with TRACLEER is not recommended.Bosentan is an inducer of CYP3A 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, CYP3A). Consequently, TRACLEER is not expected to increase the plasma concentrations of drugs metabolized by these enzymes.Figure 1.CYP3A induction-mediated effect of bosentan on other drugsFigure 2.Effect of other drugs on bosentan. Figure 1. Figure 2. 7.2Hormonal Contraceptives. Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when TRACLEER is co-administered. Females should practice additional methods of contraception and not rely on hormonal contraception alone when taking TRACLEER [see Use in Specific Populations (8.3)].An interaction study demonstrated that co-administration of bosentan and combination oral hormonal contraceptive produced average decreases of norethindrone and ethinyl estradiol levels of 14% and 31%, respectively. However, decreases in exposure were as much as 56% and 66%, respectively, in individual subjects.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating TRACLEER, monthly during treatment and one month after stopping treatment with TRACLEER. The 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.. ContraceptionDrug interaction studies show that bosentan reduces serum levels of the estrogen and progestin in oral contraceptives. Based on these findings, hormonal contraceptives (including oral, injectable, transdermal, and implantable contraceptives) may be less effective for preventing pregnancy in patients using TRACLEER and should not be used as patients only contraceptive method [see Drug Interactions (7.2)]. Females of reproductive potential using TRACLEER must use two acceptable methods of contraception during treatment and for month after treatment with TRACLEER. Patients may choose one highly effective form of contraception (intrauterine devices (IUD) or tubal sterilization) or combination of methods (hormone method with barrier method or two barrier methods). If partners vasectomy is the chosen method of contraception, hormone or barrier method must be used along with this method. Counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling [see Boxed Warning].. Infertility. MalesDecreased sperm counts have been observed in patients receiving TRACLEER. Based on these findings and findings in animals, TRACLEER may impair fertility in males of reproductive potential. It is not known whether effects on fertility would be reversible [see Warnings and Precautions (5.6), Adverse Reactions (6.1), Nonclinical Toxicology (13.1)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of TRACLEER did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects.

HEPATIC IMPAIRMENT SUBSECTION.

8.6Hepatic Impairment. 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 (Cmax and AUC) of bosentan. The pharmacokinetics of TRACLEER have not been evaluated in patients with severe liver impairment (Child-Pugh Class C). In patients with moderate hepatic impairment (Child-Pugh Class B), the systemic exposures to bosentan and its active metabolite increased significantly. TRACLEER should generally be avoided in patients with moderate or severe liver impairment. Pharmacokinetics of bosentan were not altered in patients with mild impairment of hepatic function (Child-Pugh Class A) [see Dosage and Administration (2.6), Warnings and Precautions (5.1), Pharmacokinetics (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 62.5 mg film-coated, round, biconvex, orange-white tablets, debossed with identification marking 62,5, packaged in white high-density polyethylene bottle and white polypropylene child-resistant cap or in foil blister-strips for hospital unit-dosing.NDC 66215-101-06: Bottle containing 60 tablets.NDC 66215-101-03: Carton of 30 tablets in 10 blister strips of tablets.125 mg film-coated, oval, biconvex, orange-white tablets, debossed with identification marking 125, packaged in white high-density polyethylene bottle and white polypropylene child-resistant cap or in foil blister-strips for hospital unit-dosing.NDC 66215-102-06: Bottle containing 60 tablets.NDC 66215-102-03: Carton of 30 tablets in 10 blister strips of tablets.32 mg tablets for oral suspension, pale yellow to off-white, clover-shaped, quadrisected on one side and debossed with identification marking 32 on the other side, packaged in child resistant Aluminum/Aluminum peel-push blisters.NDC 66215-103-56: Carton of 56 tablets for oral suspension in blister-strips of 14 tablets.NDC 66215-103-14: Blister strip of 14 tablets for oral suspension.32 mg tablets for oral suspension, pale yellow to off-white, round, bisected on one side and debossed with identification marking 32 on the other side, packaged in child resistant Aluminum/Aluminum peel-push blisters.NDC 66215-232-56: Carton of 56 tablets for oral suspension in blister-strips of 14 tablets.NDC 66215-232-14: Blister strip of 14 tablets for oral suspension.. Store at 20oC to 25oC (68oF to 77oF). Excursions are permitted between 15C and 30C (59F and 86F). [See USP Controlled Room Temperature]. These storage temperatures apply to both film-coated and dispersible tablets. Divided dispersible tablets should be stored under the same conditions and used within days. Tablet pieces may be returned to the opened blister and stored there out of reach of children for up to days.Keep out of reach of children.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. TRACLEER is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1):in adults to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital heart disease with left-to-right shunts (18%) [see Clinical Studies (14.1)].in pediatric patients aged years and older with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), which is expected to result in an improvement in exercise ability.. in adults to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital heart disease with left-to-right shunts (18%) [see Clinical Studies (14.1)].. in pediatric patients aged years and older with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), which is expected to result in an improvement in exercise ability.. TRACLEER is an endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1):in adults to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital heart disease with left-to-right shunts (18%) (1).in pediatric patients aged years and older with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), which is expected to result in an improvement in exercise ability (1).. in adults to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital heart disease with left-to-right shunts (18%) (1).. in pediatric patients aged years and older with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), which is expected to result in an improvement in exercise ability (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide). Restricted accessAdvise the patient that TRACLEER is only available through restricted access program called the Bosentan REMS Program.As component of the Bosentan REMS, prescribers must review the contents of the TRACLEER Medication Guide with the patient before initiating TRACLEER.Instruct patients that the risks associated with TRACLEER include:HepatotoxicityDiscuss with the patient the requirement to measure serum aminotransferases monthly.Embryo-fetal toxicityEducate and counsel female patients of reproductive potential about the need to use reliable methods of contraception during treatment with TRACLEER and for one month after treatment discontinuation. Females of reproductive potential must have monthly pregnancy tests and must use two different forms of contraception while taking TRACLEER and for one month after discontinuing TRACLEER [see Use in Specific Populations (8.1)].Females who have intrauterine devices (IUD) or tubal sterilization can use these contraceptive methods alone. Patients should be instructed to immediately contact their physician if they suspect they may be pregnant. Patients should seek additional contraceptive advice from gynecologist or similar expert as needed.Educate and counsel females of reproductive potential on the use of emergency contraception in the event of unprotected sex or contraceptive failure.Advise pre-pubertal females to report any changes in their reproductive status immediately to her prescriber.Advise patients to contact their gynecologist or healthcare provider if they want to change the form of birth control which is used to ensure that another acceptable form of birth control is selected.Advise the patient that TRACLEER is available only from certified pharmacies that are enrolled in the Bosentan REMS Program.Patients must sign the Bosentan REMS Program Patient Enrollment Form to confirm that they understand the risks of TRACLEER.LactationAdvise women not to breastfeed during treatment with TRACLEER [see Use in Specific Populations (8.2)].InfertilityAdvise males of reproductive potential that TRACLEER may impair fertility [see Warnings and Precautions (5.6), Adverse Reactions (6.1), Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].PhenylketonuricsTRACLEER dispersible tablets contain phenylalanine, component of aspartame. Each dispersible tablet contains 1.87 mg of phenylalanine.. HepatotoxicityDiscuss with the patient the requirement to measure serum aminotransferases monthly.. Embryo-fetal toxicityEducate and counsel female patients of reproductive potential about the need to use reliable methods of contraception during treatment with TRACLEER and for one month after treatment discontinuation. Females of reproductive potential must have monthly pregnancy tests and must use two different forms of contraception while taking TRACLEER and for one month after discontinuing TRACLEER [see Use in Specific Populations (8.1)].Females who have intrauterine devices (IUD) or tubal sterilization can use these contraceptive methods alone. Patients should be instructed to immediately contact their physician if they suspect they may be pregnant. Patients should seek additional contraceptive advice from gynecologist or similar expert as needed.Educate and counsel females of reproductive potential on the use of emergency contraception in the event of unprotected sex or contraceptive failure.Advise pre-pubertal females to report any changes in their reproductive status immediately to her prescriber.Advise patients to contact their gynecologist or healthcare provider if they want to change the form of birth control which is used to ensure that another acceptable form of birth control is selected.Advise the patient that TRACLEER is available only from certified pharmacies that are enrolled in the Bosentan REMS Program.Patients must sign the Bosentan REMS Program Patient Enrollment Form to confirm that they understand the risks of TRACLEER.. LactationAdvise women not to breastfeed during treatment with TRACLEER [see Use in Specific Populations (8.2)].. InfertilityAdvise males of reproductive potential that TRACLEER may impair fertility [see Warnings and Precautions (5.6), Adverse Reactions (6.1), Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].. PhenylketonuricsTRACLEER dispersible tablets contain phenylalanine, component of aspartame. Each dispersible tablet contains 1.87 mg of phenylalanine.. Other Risks Associated with TRACLEERInstruct patients that the risks associated with TRACLEER also include the following:Decreases in hemoglobin and hematocrit advise patients of the importance of hemoglobin testing,Decreases in sperm count,Fluid retention.. Decreases in hemoglobin and hematocrit advise patients of the importance of hemoglobin testing,. Decreases in sperm count,. Fluid retention.. Administration ConsiderationsAdvise patients that TRACLEER dispersible tablets should not be split into quarters.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 TRACLEER, advise women not to breastfeed during treatment with TRACLEER.

MECHANISM OF ACTION SECTION.

12.1Mechanism of Action. Bosentan is specific and competitive antagonist at endothelin receptor types ETA and ETB. Bosentan has slightly higher affinity for ETA receptors than for ETB receptors. The clinical impact of dual endothelin blockage is unknown.Endothelin-1 (ET-1) is neurohormone, the effects of which are mediated by binding to ETA and ETB receptors in the endothelium and vascular smooth muscle. ET-1 concentrations are elevated in plasma and lung tissue of patients with PAH, suggesting pathogenic role for ET-1 in this disease.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis and MutagenesisTwo 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 times the maximum recommended human dose [MRHD] of 125 mg twice daily, on 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 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.. Impairment of Fertility/Testicular FunctionThe development of testicular tubular atrophy and impaired fertility has been linked with the chronic administration of certain endothelin receptor antagonists in rodents.Treatment with bosentan at oral doses of up to 1500 mg/kg/day (50 times the MRHD on mg/m2 basis) or intravenous doses up to 40 mg/kg/day had no effects on sperm count, sperm motility, mating performance or fertility in male and female rats. An increased incidence of testicular tubular atrophy was observed in rats given bosentan orally at doses as low as 125 mg/kg/ day (about times the MRHD and the lowest doses tested) for two years but not at doses as high as 1500 mg/kg/day (about 50 times the MRHD) for months. Effects on sperm count and motility were evaluated only in the much shorter duration fertility studies in which males had been exposed to the drug for 4-6 weeks. An increased incidence of tubular atrophy was not observed in mice treated for years at doses up to 4500 mg/kg/day (about 75 times the MRHD) or in dogs treated up to 12 months at doses up to 500 mg/kg/day (about 50 times the MRHD).

OVERDOSAGE SECTION.

10 OVERDOSAGE. Bosentan has been given as single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine interaction study, in which doses of 500 and 1000 mg twice daily 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.In the postmarketing period, there was one reported overdose of 10,000 mg of TRACLEER taken by an adolescent male patient. He had symptoms of nausea, vomiting, hypotension, dizziness, sweating, and blurred vision. He recovered within 24 hours with blood pressure support.Bosentan is unlikely to be effectively removed by dialysis due to the high molecular weight and extensive plasma protein binding.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 62.5 mg Tablet Bottle Carton. NDC 66215-101-06Tracleer(R) (bosentan) tablets 62.5 mgAttention: Dispense with enclosed Medication Guide.Rx only60 film-coated tabletsjanssen. PRINCIPAL DISPLAY PANEL 62.5 mg Tablet Bottle Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The efficacy of TRACLEER in patients <18 years is supported by data from an uncontrolled trial in which 19 pediatric patients were treated with TRACLEER. In this study, cardiopulmonary hemodynamic improvements were similar to those seen in adults treated with TRACLEER [see Pulmonary Arterial Hypertension (14.1)]. Safety in pediatric patients is supported by data from 100 pediatric patients treated with TRACLEER for median of 17 months [see Clinical Studies Experience (6.1), Pulmonary Arterial Hypertension (14.1)].. Juvenile Animal Toxicity DataIn juvenile rat toxicity study, rats were treated from Day postpartum to adulthood (Day 69 postpartum). Decreased body weights, absolute weights of testes and epididymides, and reduced number of sperm in epididymides were observed after weaning. No effect on testis histology or sperm morphology and function was seen. The NOAEL was times (at Day postpartum) and times (Day 69 postpartum) the human therapeutic exposure, respectively.No effects on general development, sensory, cognitive function and reproductive performance were detected at the highest dose tested in juvenile rats, times the therapeutic exposure in children with PAH.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. GeneralAfter oral administration, maximum plasma concentrations of bosentan are attained within 3-5 hours and the terminal elimination half-life is about hours in healthy adult subjects. The exposure to bosentan after intravenous and oral administration is about twice as high in adult patients with PAH as it is in healthy adult subjects.In relative bioavailability study in healthy adults, the peak plasma concentration and area under the plasma concentration-time curve for bosentan are on an average 14% and 11%, respectively, lower following administration of the oral dispersible tablet compared to the film-coated tablet.. AbsorptionThe absolute bioavailability of bosentan in normal volunteers is about 50% and is unaffected by food.Bosentan is highly bound (>98%) to plasma proteins, mainly albumin. Bosentan does not penetrate into erythrocytes. The volume of distribution is about 18 L.. Elimination. MetabolismBosentan has three metabolites, one of which is pharmacologically active and may contribute 10%-20% of the effect of bosentan. Bosentan is an inducer of CYP2C9 and CYP3A and possibly also of CYP2C19. Upon multiple oral dosing, plasma concentrations in healthy adults decrease gradually to 50-65% of those seen after single dose administration, probably the effect of auto-induction of the metabolizing liver enzymes. Steady-state is reached within 3-5 days.. ExcretionBosentan is eliminated by biliary excretion following metabolism in the liver. Less than 3% of an administered oral dose is recovered in urine. Total clearance after single intravenous dose is about L/h in patients with PAH.. Specific Populations. PediatricsThe average plasma exposure to bosentan at steady state (AUCss) in pediatric patients with PAH aged to 15 years treated with 31.25, 62.5 or 125 mg (approximately mg/kg) film-coated tablet twice daily is 37% lower than that observed in adult patients with PAH receiving 125 mg film-coated tablet twice daily. Following administration of mg/kg twice daily doses of dispersible tablet in patients with PAH aged to 11 years, the average systemic exposure to bosentan at steady state is similar to that observed with mg/kg. The average exposure to bosentan in these pediatric patients was approximately half the exposure in adult patients treated with 125 mg film-coated tablets twice daily.The exposure to bosentan at mg/kg three times daily dosing of dispersible tablet is similar to that of mg/kg twice daily dosing in patients with PAH aged months to 12 years.Based on these findings, exposure to bosentan reaches plateau at lower doses in pediatric patients than in adults, and doses higher than mg/kg twice daily do not increase the exposure to bosentan in pediatric patients.. Hepatic ImpairmentIn vitro and in vivo evidence showing extensive hepatic metabolism of bosentan suggests that liver impairment could significantly increase exposure to bosentan. In study comparing patients with mild liver impairment (Child-Pugh Class A) to controls, the single- and multiple-dose pharmacokinetics of bosentan were not altered in patients with mild hepatic impairment.In another small (N=8) pharmacokinetic study, the steady-state AUC of bosentan was on average 4.7 times higher and the active metabolite Ro 48-5033 was 12.4 times higher in patients with moderately impaired liver function (Child-Pugh Class B) and PAH associated with portal hypertension than in patients with normal liver function and PAH of other etiologies.The pharmacokinetics of TRACLEER have not been evaluated in patients with severe liver impairment (Child-Pugh Class C) [see Dosage and Administration (2.2), Warnings and Precautions (5.1), Use in Specific Populations (8.6)]. Renal ImpairmentIn patients with severe renal impairment (creatinine clearance 15-30 mL/min), plasma concentrations of bosentan were essentially unchanged and plasma concentrations of the three metabolites were increased about 2-fold compared to subjects with normal renal function. These differences do not appear to be clinically important.. Drug Interactions. KetoconazoleCo-administration of bosentan 125 mg twice daily and ketoconazole, potent CYP3A inhibitor, increased the plasma concentrations of bosentan by approximately 100% in normal volunteers. No dose adjustment of TRACLEER is necessary, but increased effects of TRACLEER should be considered.. WarfarinCo-administration of bosentan 500 mg twice daily for days in normal volunteers decreased the plasma concentrations of both S-warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A substrate) by 29 and 38%, respectively. Clinical experience with concomitant administration of TRACLEER and warfarin in patients with PAH did not show clinically relevant changes in INR or warfarin dose (baseline vs. end of the clinical studies), and the need to change the warfarin dose during the trials due to changes in INR or due to adverse events was similar among TRACLEER- and placebo-treated patients.. Digoxin, Nimodipine, and LosartanBosentan has no significant pharmacokinetic interactions with digoxin and nimodipine, and losartan has no significant effect on plasma levels of bosentan.. SildenafilIn normal volunteers, co-administration of multiple doses of 125 mg twice daily bosentan and 80 mg three times daily sildenafil resulted in reduction of sildenafil plasma concentrations by 63% and increased bosentan plasma concentrations by 50%. The changes in plasma concentrations were not considered clinically relevant and dose adjustments are not necessary. This recommendation holds true when sildenafil is used for the treatment of PAH or erectile dysfunction.. TadalafilBosentan (125 mg twice daily) reduced tadalafil (40 mg once per day) systemic exposure (AUC) by 42% and Cmax by 27% following multiple dose co-administration. Tadalafil did not affect the exposure (AUC and Cmax) of bosentan or its metabolites.Figure 3. CYP Induction-mediated effect of bosentan on other drugsFigure 4. Effects of other drugs on bosentan. Figure 3. Figure 4.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on data from animal reproduction studies, TRACLEER may cause fetal harm, including birth defects and fetal death, when administered to pregnant female and is contraindicated during pregnancy [see Contraindications (4.1)]. There are limited data on TRACLEER use in pregnant women. In animal reproduction studies, oral administration of bosentan to pregnant rats at 2-times the maximum recommended human dose (MRHD) on mg/m2 basis caused teratogenic effects in rats, including malformations of the head, mouth, face, and large blood vessels [see Animal Data]. Advise pregnant women of the potential risk to fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.. Data. Animal DataBosentan was teratogenic in rats given oral doses two times the MRHD (on 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 and 10 times the MRHD (on mg/m2 basis). Although birth defects were not observed in rabbits given oral doses of up to the equivalent of 10.5 g/day in 70 kg person, 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 embryo-fetal toxicity is class effect of these drugs.

RENAL IMPAIRMENT SUBSECTION.

8.7Renal Impairment. The effect of renal impairment on the pharmacokinetics of bosentan is small and does not require dosing adjustment [see Pharmacokinetics (12.3)].

SPL MEDGUIDE SECTION.

Medication GuideTRACLEER(R) (TRA-KLEER)(BOSENTAN)TABLETSThis Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: 07/2021Read the Medication Guide that comes with TRACLEER before you start taking it and each time you get refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment.What is the most important information should know about TRACLEERTRACLEER is only available through the Bosentan REMS Program. Before you begin taking TRACLEER, you must read and agree to all of the instructions in the Bosentan REMS Program.TRACLEER can cause serious side effects including:Liver damage.Liver damage may not cause symptoms at first. Only blood test can show if you have early liver damage. You must have your blood tested to check your liver function before you start TRACLEER and each month after that. Your healthcare provider will order these tests. Regular blood tests are important because they will help your healthcare provider adjust or stop your treatment before there is permanent damage.Tell your healthcare provider if you have had liver problems, including liver problems while taking other medicines. Call your healthcare provider right away if you have any of these symptoms of liver problems while taking TRACLEER:nauseavomitingfeverunusual tirednessstomach area (abdominal) painyellowing of the skin or the whites of your eyes (jaundice) Serious birth defects.TRACLEER can cause serious birth defects if taken during pregnancy. You must not be pregnant when you start taking TRACLEER or during TRACLEER treatment. Serious birth defects from TRACLEER can happen early in pregnancy. Females who are able to get pregnant must have negative pregnancy test before starting treatment with TRACLEER, each month during treatment with TRACLEER, and month after stopping treatment with TRACLEER.Talk to your healthcare provider about your menstrual cycle. Your healthcare provider will decide when to do pregnancy test and will order pregnancy test for you depending on your menstrual cycle.Females who are able to get pregnant are females who:have entered puberty, even if they have not started their menstrual period, and have uterus, and have not gone through menopause. Menopause means that you have not had menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed. Females who are not able to get pregnant are females who:have not yet entered puberty, or do not have uterus, or have gone through menopause. Menopause means that you have not had menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed or are infertile for other medical reasons and this infertility is permanent and cannot be reversed. Females who are able to get pregnant must use two acceptable forms of birth control during treatment with TRACLEER, and for one month after stopping TRACLEER because the medicine may still be in the body.If you have had tubal sterilization or have an IUD (intrauterine device), these methods can be used alone and no other form of birth control is needed.Talk with your healthcare provider or gynecologist (a doctor who specializes in female reproduction) to find out about options for acceptable birth control that you may use to prevent pregnancy during treatment with TRACLEER.If you decide that you want to change the form of birth control that you use, talk with your healthcare provider or gynecologist to be sure that you choose another acceptable form of birth control.See the chart below for Acceptable Birth Control Options during treatment with TRACLEER.Do not have unprotected sex. Talk to your healthcare provider or pharmacist right away if you have unprotected sex or if you think your birth control has failed. Your healthcare provider may talk with you about using emergency birth control.Tell your healthcare provider right away if you miss menstrual period or think you may be pregnant. If you are the parent or caregiver of female child who started taking TRACLEER before reaching puberty, you should check your child regularly to see if she is developing signs of puberty. Tell your healthcare provider right away if you notice that she is developing breast buds or any pubic hair. Your healthcare provider should decide if your child has reached puberty. Your child may reach puberty before having her first menstrual period. Acceptable birth control optionsOption 1Option 2Option 3Option 4One method from this list:orOne method from this list:orOne method from this list:orOne method from this list:Standard intrauterine device (Copper 380A IUD)Intrauterine system (LNg 20 IUS: progesterone IUS)Tubal sterilizationEstrogen and progesterone oral contraceptives (the pill)Estrogen and progesterone transdermal patchVaginal ringProgesterone injectionProgesterone implantDiaphragm with spermicideCervical cap with spermicidePartners vasectomyPLUSOne method from this list:PLUSOne method from this list:Male condomDiaphragm with spermicideCervical cap with spermicide Estrogen and progesterone oral contraceptives (the pill)Estrogen and progesterone transdermal patchVaginal ringProgesterone injectionProgesterone implantMale condomPLUSOne method from this list:Male condomDiaphragm with spermicideCervical cap with spermicideTRACLEER 32 mg dispersible tablets contain Aspartame. Phenylketonurics: Contains Phenylalanine 1.87 mg per 32 mg dispersible tablet. See What are the possible side effects of TRACLEER for more information about side effects.What is TRACLEERTRACLEER is prescription medicine used to treat people with certain types of pulmonary arterial hypertension (PAH), which is high blood pressure in the vessels of the lungs.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 efficiently.TRACLEER is only:Prescribed by healthcare providers who are enrolled in the Bosentan REMS Program.Available to people who understand and agree to enroll in the Bosentan REMS Program.Who should not take TRACLEERDo not take TRACLEER if you:are pregnant, plan to become pregnant, or become pregnant during TRACLEER treatment. TRACLEER can cause serious birth defects. All females should read the birth defects section of What is the most important information should know about TRACLEER take any of these medicines:cyclosporine used to treat psoriasis and rheumatoid arthritis, and to prevent rejection of heart, liver, and kidney transplantsglyburide used to treat diabetes are allergic to bosentan or any of the ingredients in TRACLEER. See the end of this Medication Guide for complete list of the ingredients in TRACLEER. If you have rash, hives or your lips swell after taking TRACLEER, it may be sign of allergy. You should stop taking your TRACLEER and talk to your healthcare provider.What should tell my healthcare provider before taking TRACLEERTRACLEER may not be right for you. Tell your healthcare provider about all your medical conditions, including if you: have liver problems.are breast-feeding or plan to breast feed. It is not known if TRACLEER passes into your milk. You and your healthcare provider should decide if you will take TRACLEER or breastfeed. You should not do both.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. TRACLEER and other medicines may affect how each other works and cause side effects. Especially tell your healthcare provider if you take:hormone-based birth control, such as pills, shots, patches, and implants. These birth control methods may not work as well when taken with TRACLEER.simvastatin or other -statin medicines used to lower cholesterolrifampin used for tuberculosisketoconazole, fluconazole, itraconazole, or voriconazole used for fungal infectionswarfarin sodium used to prevent blood clotsritonavir used to treat HIVThere may be more than one brand name medicine. Ask your healthcare provider if you are not sure if your medicine is one that is listed above.Know the medicines you take. Keep list of them and show it to your healthcare provider or pharmacist when you get new medicine.How should take TRACLEERYour healthcare provider will give you detailed information about the Bosentan REMS Program.TRACLEER is only available through certified pharmacies. You will only receive 30-day supply of TRACLEER at one time.Take TRACLEER exactly as prescribed.Your healthcare provider will tell you how much TRACLEER to take and when to take it.In most cases, you will take tablet in the morning and in the evening.You can take TRACLEER orally with or without food.If you take more than the prescribed dose of TRACLEER, call your healthcare provider right away.If you miss dose of TRACLEER, take your tablet as soon as you remember. Do not take doses at the same time. If it is almost time for your next dose, skip the missed dose. Just take the next dose at your regular time.Do not stop taking TRACLEER unless your healthcare provider tells you to. Suddenly stopping your treatment may cause your symptoms to get worse. If you need to stop taking TRACLEER, speak with your healthcare provider about the right way to stop.If necessary, the 32 mg dispersible tablet can be divided into halves by breaking along line cut into the surface. Hold the tablet between the thumb and index finger on either side of the line, with the line facing upwards, and break the tablet along the line (see figure below). The dispersible tablet should not be broken into quarters. Each 32 mg dispersible tablet, or tablet part, can be dispersed in minimal amount of water to make liquid medicine immediately before administration. When the tablet has fully dispersed, the liquid should be administered to the patient.What are the possible side effects of TRACLEERTRACLEER can cause serious side effects, including:See What is the most important information should know about TRACLEERFluid retention and swelling of your ankles and legs. TRACLEER can cause your body to hold too much water, and you may get swelling of your ankles and legs. Tell your healthcare provider if you have swelling of your ankles and legs that happens either with or without weight gain, or if you have more trouble with your breathing than normal. Your healthcare provider will look for the cause of this.Lower Sperm Count. Some men who take TRACLEER may have lower sperm counts. This may affect your ability to father child. Tell your healthcare provider if fertility is concern for you.Low red blood cell levels (anemia). Your healthcare provider will do blood tests to check your red blood cells during treatment with TRACLEER.The most common side effects of TRACLEER include:respiratory tract infectionheadachefaintingflushinglow blood pressureinflamed nose passages (sinusitis)joint painirregular heart beatsTell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of TRACLEER. For more information, ask your doctor or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store TRACLEERStore TRACLEER at room temperature between 68F to 77F (20C to 25C).Dispersible tablets that have been broken to adjust the dose of medicine can be stored at room temperature, between 68F to 77F (20C to 25C), and should be used within days of having been broken. Tablet pieces may be returned to the opened blister and stored there out of reach of children for up to days.Keep TRACLEER and all medicines out of the reach of children.General information about TRACLEERMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use TRACLEER for condition for which it was not prescribed. Do not give TRACLEER to other people, even if they have the same symptoms that you have. It may harm them.This Medication Guide summarizes the most important information about TRACLEER. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about TRACLEER that is written for health professionals. For more information call 1-800-526-7736 (1-800-JANSSEN), go to www.TRACLEER.com.What are the ingredients in TRACLEERActive ingredient: bosentanInactive ingredients in 62.5 mg and 125 mg film-coated tablets: corn starch, ethylcellulose, glyceryl behenate, hydroxypropylmethylcellulose, iron oxide red, iron oxide yellow, magnesium stearate, povidone, pregelatinized starch, sodium starch glycolate, talc, titanium dioxide, and triacetin.Inactive ingredients in 32 mg dispersible tablets: acesulfame potassium, aspartame (E951), calcium hydrogen, cellulose microcrystalline, croscarmellose sodium, magnesium stearate, phosphate anhydrous, silica colloidal anhydrous, tartaric acid, and tutti frutti flavor.Manufactured for:Actelion Pharmaceuticals US, Inc.a Janssen Pharmaceutical Company South San Francisco, CA 94080, USAJN20210120 (C) 2001 2019 Actelion Pharmaceuticals US, Inc.. Liver damage may not cause symptoms at first. Only blood test can show if you have early liver damage. You must have your blood tested to check your liver function before you start TRACLEER and each month after that. Your healthcare provider will order these tests. Regular blood tests are important because they will help your healthcare provider adjust or stop your treatment before there is permanent damage.. Tell your healthcare provider if you have had liver problems, including liver problems while taking other medicines. Call your healthcare provider right away if you have any of these symptoms of liver problems while taking TRACLEER:nauseavomitingfeverunusual tirednessstomach area (abdominal) painyellowing of the skin or the whites of your eyes (jaundice) nausea. vomiting. fever. unusual tiredness. stomach area (abdominal) pain. yellowing of the skin or the whites of your eyes (jaundice). TRACLEER can cause serious birth defects if taken during pregnancy. You must not be pregnant when you start taking TRACLEER or during TRACLEER treatment. Serious birth defects from TRACLEER can happen early in pregnancy. Females who are able to get pregnant must have negative pregnancy test before starting treatment with TRACLEER, each month during treatment with TRACLEER, and month after stopping treatment with TRACLEER.Talk to your healthcare provider about your menstrual cycle. Your healthcare provider will decide when to do pregnancy test and will order pregnancy test for you depending on your menstrual cycle.Females who are able to get pregnant are females who:have entered puberty, even if they have not started their menstrual period, and have uterus, and have not gone through menopause. Menopause means that you have not had menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed. Females who are not able to get pregnant are females who:have not yet entered puberty, or do not have uterus, or have gone through menopause. Menopause means that you have not had menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed or are infertile for other medical reasons and this infertility is permanent and cannot be reversed. Talk to your healthcare provider about your menstrual cycle. Your healthcare provider will decide when to do pregnancy test and will order pregnancy test for you depending on your menstrual cycle.Females who are able to get pregnant are females who:have entered puberty, even if they have not started their menstrual period, and have uterus, and have not gone through menopause. Menopause means that you have not had menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed. Females who are not able to get pregnant are females who:have not yet entered puberty, or do not have uterus, or have gone through menopause. Menopause means that you have not had menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed or are infertile for other medical reasons and this infertility is permanent and cannot be reversed. Females who are able to get pregnant are females who:have entered puberty, even if they have not started their menstrual period, and have uterus, and have not gone through menopause. Menopause means that you have not had menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed. have entered puberty, even if they have not started their menstrual period, and have uterus, and have not gone through menopause. Menopause means that you have not had menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed.. Females who are not able to get pregnant are females who:have not yet entered puberty, or do not have uterus, or have gone through menopause. Menopause means that you have not had menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed or are infertile for other medical reasons and this infertility is permanent and cannot be reversed. have not yet entered puberty, or do not have uterus, or have gone through menopause. Menopause means that you have not had menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed or are infertile for other medical reasons and this infertility is permanent and cannot be reversed.. Females who are able to get pregnant must use two acceptable forms of birth control during treatment with TRACLEER, and for one month after stopping TRACLEER because the medicine may still be in the body.If you have had tubal sterilization or have an IUD (intrauterine device), these methods can be used alone and no other form of birth control is needed.Talk with your healthcare provider or gynecologist (a doctor who specializes in female reproduction) to find out about options for acceptable birth control that you may use to prevent pregnancy during treatment with TRACLEER.If you decide that you want to change the form of birth control that you use, talk with your healthcare provider or gynecologist to be sure that you choose another acceptable form of birth control.See the chart below for Acceptable Birth Control Options during treatment with TRACLEER.Do not have unprotected sex. Talk to your healthcare provider or pharmacist right away if you have unprotected sex or if you think your birth control has failed. Your healthcare provider may talk with you about using emergency birth control.Tell your healthcare provider right away if you miss menstrual period or think you may be pregnant.. If you have had tubal sterilization or have an IUD (intrauterine device), these methods can be used alone and no other form of birth control is needed.. Talk with your healthcare provider or gynecologist (a doctor who specializes in female reproduction) to find out about options for acceptable birth control that you may use to prevent pregnancy during treatment with TRACLEER.. If you decide that you want to change the form of birth control that you use, talk with your healthcare provider or gynecologist to be sure that you choose another acceptable form of birth control.. Do not have unprotected sex. Talk to your healthcare provider or pharmacist right away if you have unprotected sex or if you think your birth control has failed. Your healthcare provider may talk with you about using emergency birth control.. Tell your healthcare provider right away if you miss menstrual period or think you may be pregnant.. are pregnant, plan to become pregnant, or become pregnant during TRACLEER treatment. TRACLEER can cause serious birth defects. All females should read the birth defects section of What is the most important information should know about TRACLEER take any of these medicines:cyclosporine used to treat psoriasis and rheumatoid arthritis, and to prevent rejection of heart, liver, and kidney transplantsglyburide used to treat diabetes cyclosporine used to treat psoriasis and rheumatoid arthritis, and to prevent rejection of heart, liver, and kidney transplants. glyburide used to treat diabetes. are allergic to bosentan or any of the ingredients in TRACLEER. See the end of this Medication Guide for complete list of the ingredients in TRACLEER. If you have rash, hives or your lips swell after taking TRACLEER, it may be sign of allergy. You should stop taking your TRACLEER and talk to your healthcare provider.. have liver problems.. are breast-feeding or plan to breast feed. It is not known if TRACLEER passes into your milk. You and your healthcare provider should decide if you will take TRACLEER or breastfeed. You should not do both.. hormone-based birth control, such as pills, shots, patches, and implants. These birth control methods may not work as well when taken with TRACLEER.. simvastatin or other -statin medicines used to lower cholesterol. rifampin used for tuberculosis. ketoconazole, fluconazole, itraconazole, or voriconazole used for fungal infections. warfarin sodium used to prevent blood clots. ritonavir used to treat HIV. TRACLEER is only available through certified pharmacies. You will only receive 30-day supply of TRACLEER at one time.. Take TRACLEER exactly as prescribed.. Your healthcare provider will tell you how much TRACLEER to take and when to take it.. In most cases, you will take tablet in the morning and in the evening.. You can take TRACLEER orally with or without food.. If you take more than the prescribed dose of TRACLEER, call your healthcare provider right away.. If you miss dose of TRACLEER, take your tablet as soon as you remember. Do not take doses at the same time. If it is almost time for your next dose, skip the missed dose. Just take the next dose at your regular time.. Do not stop taking TRACLEER unless your healthcare provider tells you to. Suddenly stopping your treatment may cause your symptoms to get worse. If you need to stop taking TRACLEER, speak with your healthcare provider about the right way to stop.. If necessary, the 32 mg dispersible tablet can be divided into halves by breaking along line cut into the surface. Hold the tablet between the thumb and index finger on either side of the line, with the line facing upwards, and break the tablet along the line (see figure below). The dispersible tablet should not be broken into quarters. Each 32 mg dispersible tablet, or tablet part, can be dispersed in minimal amount of water to make liquid medicine immediately before administration. When the tablet has fully dispersed, the liquid should be administered to the patient.. See What is the most important information should know about TRACLEER. Fluid retention and swelling of your ankles and legs. TRACLEER can cause your body to hold too much water, and you may get swelling of your ankles and legs. Tell your healthcare provider if you have swelling of your ankles and legs that happens either with or without weight gain, or if you have more trouble with your breathing than normal. Your healthcare provider will look for the cause of this.. Lower Sperm Count. Some men who take TRACLEER may have lower sperm counts. This may affect your ability to father child. Tell your healthcare provider if fertility is concern for you.. Low red blood cell levels (anemia). Your healthcare provider will do blood tests to check your red blood cells during treatment with TRACLEER.. respiratory tract infection. headache. fainting. flushing. low blood pressure. inflamed nose passages (sinusitis). joint pain. irregular heart beats. Store TRACLEER at room temperature between 68F to 77F (20C to 25C).. Dispersible tablets that have been broken to adjust the dose of medicine can be stored at room temperature, between 68F to 77F (20C to 25C), and should be used within days of having been broken. Tablet pieces may be returned to the opened blister and stored there out of reach of children for up to days.. Figure.

SPL UNCLASSIFIED SECTION.

HepatotoxicityIn clinical studies, TRACLEER caused 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 small number of cases. Because these changes are marker for potential serious hepatotoxicity, serum aminotransferase levels must be measured prior to initiation of treatment and then monthly [see Dosage and Administration (2.4), Warnings and Precautions (5.1)]. In the postmarketing 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 comorbidities and drug therapies. There have also been 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 rise of aminotransferases accompanied by signs or symptoms of liver dysfunction [see Dosage and Administration (2.4)]. Elevations in aminotransferases require close attention [see Dosage and Administration (2.4)]. TRACLEER should generally be avoided in patients with elevated aminotransferases (>3xULN) at baseline because monitoring for hepatotoxicity may be more difficult. 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 >=2xULN, treatment with TRACLEER should be stopped. There is no experience with the reintroduction of TRACLEER in these circumstances.