MECHANISM OF ACTION SECTION.

12.1 Mechanism 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.

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)] . Common adverse reactions (>=3% more than placebo) for the film-coated tablet are respiratory tract infection and anemia (6.1). To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical 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 bosentan tablets 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 bosentan tablets 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 bosentan tablets 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 bosentan tablets (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 bosentan tablets was abnormal liver function.The adverse drug events that occurred in >=3% of the bosentan tablets-treated patients and were more common on bosentan tablets in placebo-controlled trials in PAH at doses of 125 or 250 mg twice daily are shown in Table 3: Table 3: Adverse events occurring in >=3% of patients treated with bosentan tablets 125 to 250 mg twice daily and more common on bosentan tablets in placebo-controlled studies in pulmonary arterial hypertension Adverse Event Bosentan Tablets = 258 Placebo = 172 No. No. Respiratory Tract Infection 56 22% 30 17% Headache 39 15% 25 14% Edema 28 11% 16 9% Chest Pain 13 5% 5% Syncope 12 5% 4% Flushing 10 4% 3% Hypotension 10 4% 2% Sinusitis 4% 2% Arthralgia 4% 2% Serum Aminotransferases, abnormal 4% 2% Palpitations 4% 2% Anemia 3% - Note: 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. Respiratory Tract Infection combines the terms Nasopharyngitis, Upper Respiratory Tract Infection and Respiratory Tract Infection. Combined data from Study 351, BREATHE-1 and EARLYDecreased Sperm CountsAn open-label, single-arm, multicenter, safety study evaluated the effect on testicular function of bosentan tablets 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 bosentan tablets. 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. Bosentan tablets were 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 bosentan tablets have an adverse effect on spermatogenesis.Decreases in Hemoglobin and HematocritTreatment with bosentan tablets 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 bosentan tablets-treated patients was 0.9 g/dL (change to end of treatment). Most of this decrease of hemoglobin concentration was detected during the first few weeks of bosentan tablets treatment and hemoglobin levels stabilized by to 12 weeks of bosentan tablets treatment. In placebo-controlled studies of all uses of bosentan tablets, marked decreases in hemoglobin (> 15% decrease from baseline resulting in values 11 g/dL) were observed in 6% of bosentan tablets-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 bosentan tablets-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 bosentan tablets treatment.During the course of treatment, the hemoglobin concentration remained within normal limits in 68% of bosentan tablets-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. 6.2 Postmarketing Experience. There have been several postmarketing reports of angioedema associated with the use of bosentan tablets. 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 bosentan tablets.The following additional adverse reactions have been reported during the postapproval use of bosentan tablets. 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 bosentan tablets exposure:Unexplained hepatic cirrhosis [see Boxed Warning] Liver failure [see Boxed Warning] Hypersensitivity, DRESS, and anaphylaxis [see Contraindications (4.4)] Thrombocytopenia RashJaundiceAnemia 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, bosentan tablets 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)]. Hepatotoxicity In clinical studies, bosentan tablets 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 bosentan tablets in patients with multiple comorbidities and drug therapies. There have also been reports of liver failure. The contribution of bosentan tablets 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 bosentan tablets. 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 bosentan tablets 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)]. Bosentan tablets should generally be avoided in patients with elevated aminotransferases (> x ULN) 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 >= x ULN, treatment with bosentan tablets should be stopped. There is no experience with the reintroduction of bosentan tablets in these circumstances. Embryo-Fetal ToxicityBosentan tablets are 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 bosentan tablets. Throughout treatment and for one month after stopping bosentan tablets, 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 bosentan tablets [see Drug Interactions (7.2)]. Obtain monthly pregnancy tests.. WARNING: RISKS OF HEPATOTOXICITY and EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. Bosentan tablets are 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 bosentan tablets (5.1). Measure liver aminotransferases prior to initiation of treatment and then monthly (2.1, 5.1). Discontinue bosentan tablets if aminotransferase elevations are accompanied by signs or symptoms of liver dysfunction or injury or increases in bilirubin >=2 ULN (2.4, 5.1). Based on animal data, bosentan tablets are 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 bosentan tablets (4.1, 5.2, 8.1).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis and Mutagenesis Two years of dietary administration of bosentan to mice produced an increased incidence of hepatocellular adenomas and carcinomas in males at doses as low as 450 mg/kg/day (about 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 to 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. 12.1 Mechanism 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. General After oral administration, maximum plasma concentrations of bosentan are attained within to 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. Absorption The 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 Metabolism Bosentan has three metabolites, one of which is pharmacologically active and may contribute 10% to 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% to 65% of those seen after single dose administration, probably the effect of auto-induction of the metabolizing liver enzymes. Steady-state is reached within to days. Excretion Bosentan 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 Hepatic Impairment In 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 bosentan tablets 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 Impairment In patients with severe renal impairment (creatinine clearance 15 to 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 Ketoconazole Co-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 bosentan tablets is necessary, but increased effects of bosentan tablets should be considered. Warfarin Co-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 bosentan tablets 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 bosentan tablets-and placebo-treated patients. Digoxin, Nimodipine, and Losartan Bosentan has no significant pharmacokinetic interactions with digoxin and nimodipine, and losartan has no significant effect on plasma levels of bosentan. Sildenafil In 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. Tadalafil Bosentan (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 drugs Figure 4. Effects of other drugs on Bosentan Figure 3. Figure 4.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Pulmonary Arterial Hypertension. WHO Functional Class III-IV Two 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 bosentan tablets 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, bosentan tablets 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. Bosentan tablets 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 Ability Results of the 6-minute walk distance at months (Study 351) or months (BREATHE-1) are shown in Table 4.Table 4: Effects of bosentan tablets on 6-minute walk distance BREATHE-1 Study 351 Bosentan Tablets 125 mg twice daily (n 74) Bosentan Tablets 250 mg twice daily (n 70) Placebo(n 69)Bosentan Tablets 125 mg twice daily (n 21) Placebo (n 11) Baseline 326 +- 73 333 +- 75 344 +- 76 360 +- 86 355 +- 82 End point353 +- 115 379 +- 101 336 +- 129 431 +- 66 350 +- 147 Change from baseline27 +- 75 46 +- 62 -8 +- 96 70 +- 56 -6 +- 121 Placebo-subtracted 35 (a) 54 (b) 76 (c) Distance in meters: mean +- standard deviation. Changes are to week 16 for BREATHE-1 and to week 12 for Study 351. (a)p=0.01; by Wilcoxon; (b)p=0.0001; by Wilcoxon; (c)p=0.02; by Students t-test.In both trials, treatment with bosentan tablets 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 bosentan (125 mg twice daily and 250 mg twice daily) groups. Values are expressed as mean +- standard error of the mean.Hemodynamic Changes Invasive hemodynamic parameters were assessed in Study 351. Treatment with bosentan tablets 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 Parameters Bosentan Tablets 125 mg twice daily PlaceboCI (L/min/m2) n=20 n=10 Baseline 2.35+-0.73 2.48+-1.03 Absolute Change 0.5+-0.46 -0.52+-0.48 Treatment Effect 1.02(a) Mean PAP (mmHg) n=20 n=10 Baseline 53.7+-13.4 55.7+-10.5 Absolute Change -1.6+-5.1 5.1+-8.8 Treatment Effect -6.7(b) PVR (dynosecocm-5) n=19 n=10 Baseline 896+-425 942+-430 Absolute Change -223+-245 191+-235 Treatment Effect -415(a) Mean RAP (mmHg) n=19 n=10 Baseline 9.7+-5.6 9.9+-4.1 Absolute Change -1.3+-4.1 4.9+-4.6 Treatment Effect -6.2(a) Values shown are means +- SD (a)p<=0.001; (b)p<0.02Symptoms and Functional Status Symptoms 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 bosentan tablets-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 Population BREATHE-1 Study 351 Bosentan Tablets 125/250 mg twice daily (n 144) Placebo (n 69)Bosentan Tablets 125 mg twice daily (n 21) Placebo (n 11)Patients with clinical worsening (6%)(a) 14 (20%) (0%)(b) (27%) [n (%)] Death (1%) (3%) (0%) (0%) Hospitalization for PAH (4%) (13%) (0%) (27%) Discontinuation due to worsening of PAH (3%) (9%) (0%) (27%) Receipt of epoprostenol(c) (3%) (4%) (0%) (27%) Note: Patients may have had more than one reason for clinical worsening. (a)p=0.0015 vs. placebo by log-rank test. There was no relevant difference between the 125 mg and 250 mg twice daily groups. (b)p=0.033 vs. placebo by Fishers exact test. (c)Receipt of epoprostenol was always consequence of clinical worsening.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 bosentan 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 bosentan group and 13 in the placebo group) continued double-blind therapy for up to 28 weeks.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 bosentan tablets 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, bosentan tablets treatment was associated with reduced incidence of worsening of at least one functional class (3% bosentan tablets vs. 13% placebo, = 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 bosentan tablets 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 bosentan tablets compared with placebo (hazard ratio 0.2, = 0.01). Findings were consistent in strata with or without treatment with sildenafil at baseline. Long-term Treatment of PAH Long-term follow-up of patients with Class III and IV PAH who were treated with bosentan tablets 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 bosentan tablets and cannot be used to determine the long-term effect of bosentan tablets on mortality. Pulmonary Arterial Hypertension in Adults related to Congenital Heart Disease with Left-to-Right Shunts 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 bosentan tablets on exercise and safety that were similar to those seen in other trials in patients with PAH (WHO Group 1).. Figure 5. Figure 6. 14.2 Lack of Benefit in Congestive Heart Failure. Bosentan tablets are 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 bosentan tablets (62.5 mg twice daily titrated as tolerated to 125 mg twice daily) and followed for up to 70 weeks. Use of bosentan tablets 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 bosentan tablets were 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 to weeks of treatment with bosentan tablets. 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) 4.1 Pregnancy. Use of bosentan tablets are 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 bosentan tablets [see Boxed Warning, Warnings and Precautions (5.2), Drug Interactions (7.2), Use in Specific Populations (8.1)].. 4.2 Use with Cyclosporine A. Co-administration of cyclosporine and bosentan resulted in markedly increased plasma concentrations of bosentan. Therefore, concomitant use of bosentan tablets and cyclosporine is contraindicated [see Cytochrome P450 Drug Interactions (7.1)]. 4.3 Use with Glyburide. An increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan. Therefore co-administration of glyburide and bosentan tablets is contraindicated [see Cytochrome P450 Drug Interactions (7.1)]. 4.4 Hypersensitivity. Bosentan tablets are 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. 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 569.62 and molecular formula of C27H29N5O6SoH2O. Bosentan is white to yellowish powder. It is soluble in dichloromethane (98.14 mg/mL), freely soluble in acetone (125.1 mg/mL), slightly soluble in methanol (1.44 mg/mL) and practically insoluble in water (<0.10 mg/mL). In the pH range of 1.1 to 7.5 it is practically insoluble. In the solid state, bosentan is very stable, is not hygroscopic and is not light sensitive. Bosentan tablet is available as 62.5 mg and 125 mg film-coated tablets for oral administration, and contains the following excipients: corn starch, pregelatinized starch, povidone K-30, sodium starch glycolate, glyceryl behenate, magnesium stearate, hypromellose, titanium dioxide, triacetin, talc, ethylcellulose, iron oxide yellow, and iron oxide red. Each bosentan tablets 62.5 mg tablet contains 64.541 mg of bosentan, equivalent to 62.5 mg of anhydrous bosentan. Each bosentan tablets 125 mg tablet contains 129.082 mg of bosentan, equivalent to 125 mg of anhydrous bosentan. 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). Reduce the dose and closely monitor patients developing aminotransferase elevations more than X Upper Limit of Normal (ULN) (2.1). 2.1 Required Monitoring. Healthcare professionals who prescribe bosentan tablets must enroll in the Bosentan REMS Program and must comply with the required monitoring to minimize the risks associated with bosentan tablets [see Warnings and Precautions (5.3)]. Obtain pregnancy test in females of reproductive potential prior to bosentan tablets treatment, monthly during treatment and one month after stopping bosentan tablets. Initiate treatment with bosentan tablets 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)].. 2.2 Recommended Dosage. Administer bosentan tablets 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 Recommendations Initial weeks Maintenance (after weeks) Patients >12 years of age and >40 kg 62.5 mg twice daily 125 mg twice daily Patients >12 years of age and <40 kg 62.5 mg twice daily 62.5 mg twice daily 2.3 Administration. Bosentan tablets film-coated tablets should be administered orally twice daily. 2.4 Dosage Adjustments for Aminotransferase Elevations. If aminotransferase levels increase, adjust monitoring and treatment plan according to Table 2. Discontinue bosentan tablets 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 >= x Upper Limit of Normal (ULN). There is no experience with the reintroduction of bosentan tablets in these circumstances. Table 2: Dosage Adjustment and Monitoring in Patients Developing Aminotransferase Elevations >3 ULNALT/AST levels Treatment and monitoring recommendations 3 and <= x ULN Confirm by another aminotransferase test; if confirmed, -in 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 patients >12 years and <40 kg, 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 <= x ULN Confirm 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 patients >12 years, consider reintroduction of treatment at 62.5 mg twice daily, with reassessment of aminotransferase levels within days. 8 ULN Stop treatment permanently. There is no experience with reintroduction of bosentan tablets in these circumstances. 2.5 Use with Ritonavir. Co-administration of Bosentan Tablets in Patients on RitonavirIn patients who have been receiving ritonavir for at least 10 days, start bosentan tablets 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 Bosentan TabletsDiscontinue use of bosentan tablets at least 36 hours prior to initiation of ritonavir. After at least 10 days following the initiation of ritonavir, resume bosentan tablets at the recommended initial dose once daily or every other day based upon individual tolerability [see Cytochrome P450 Drug Interactions (7.1)]. 2.6 Use in Patients with Pre-existing Hepatic Impairment. Avoid initiation of bosentan tablets in patients with aminotransferases >3 ULN. 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: light orange to orange, round, film-coated tablets debossed with 419 on one side and plain on other side. 125 mg tablets: light orange to orange, oval, film-coated tablets debossed with L420 on one side and plain on other side. . Film-coated tablet: 62.5 mg and 125 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Cytochrome P450: Coadministration of bosentan tablets with drugs metabolized by CYP2C9 and CYP3A can increase exposure to bosentan tablets and/or the coadministered drug (4.2, 4.3, 7.1). Hormonal contraceptives: Bosentan tablets use decreases contraceptive exposure and reduces effectiveness (7.2). 7.1 Cytochrome 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 bosentan tablets 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 bosentan tablets are not recommended. Bosentan is an inducer of CYP3A and CYP2C9. Consequently plasma concentrations of drugs metabolized by these two isozymes will be decreased when bosentan tablets are co-administered. Bosentan had no relevant inhibitory effect on any CYP isozyme in vitro (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A). Consequently, bosentan tablets are not expected to increase the plasma concentrations of drugs metabolized by these enzymes. Figure 1. CYP3A induction-mediated effect of bosentan on other drugs Figure 1. Figure 2. 7.2 Hormonal Contraceptives. Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when bosentan tablets are co-administered. Females should practice additional methods of contraception and not rely on hormonal contraception alone when taking bosentan tablets [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.

GERIATRIC USE SECTION.

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

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 62.5 mg, light orange to orange, round, film-coated tablets debossed with 419 on one side and plain on other side. NDC 46708-383-60 Bottle of 60 tabletsNDC 46708-383-10 Carton of 30 (3 10) unit dose tablets. For hospital use. 125 mg, light orange to orange, oval, film-coated tablets debossed with L420 on one side and plain on other side. NDC 46708-384-60 Bottle of 60 tabletsNDC 46708-384-10 Carton of 30 (3 10) unit dose tablets. For hospital use. Store at 25oC (77oF); excursions permitted to 15 to 30C (59to 86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Bosentan tablets are 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)]. Bosentan 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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide). Restricted access Advise the patient that bosentan tablet 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 Bosentan Medication Guide with the patient before initiating bosentan tablets. Instruct patients that the risks associated with bosentan tablets include: Hepatotoxicity Discuss with the patient the requirement to measure serum aminotransferases monthly. Embryo-fetal toxicity Educate and counsel female patients of reproductive potential about the need to use reliable methods of contraception during treatment with bosentan tablets 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 bosentan tablets and for one month after discontinuing bosentan tablets [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 bosentan tablet 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 bosentan tablets. Lactation Advise women not to breastfeed during treatment with bosentan tablets [see Use in Specific Populations (8.2)]. Infertility Advise males of reproductive potential that bosentan tablets may impair fertility [see Warnings and Precautions (5.6), Adverse Reactions (6.1), Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)]. Other Risks Associated with bosentan tablets Instruct patients that the risks associated with bosentan tablets also include the following: Decreases in hemoglobin and hematocrit advise patients of the importance of hemoglobin testing Decreases in sperm count Fluid retention Manufactured by: Alembic Pharmaceuticals Limited (Formulation Division), Village Panelav, P. O. Tajpura, Near Baska, Taluka-Halol, Panchmahal, Gujarat, India. Revised: 12/2019.

LACTATION SECTION.

8.2 Lactation. Risk Summary There are no data on the presence of bosentan in human milk, the effects on the breastfed infant, or the effect on milk production. Because of the potential for serious adverse reactions, such as fluid retention and hepatotoxicity, in breastfed infants from bosentan tablets, advise women not to breastfeed during treatment with bosentan tablets.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis and Mutagenesis Two years of dietary administration of bosentan to mice produced an increased incidence of hepatocellular adenomas and carcinomas in males at doses as low as 450 mg/kg/day (about 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 to 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 bosentan tablets 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL 62.5 mg. NDC 46708-383-60 Bosentan Tablets 62.5 mg Pharmacist: Dispense the accompanying Medication Guide to each patient. Rx only 60 Tablets Alembic 60 tablets.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Juvenile Animal Toxicity Data In 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. General After oral administration, maximum plasma concentrations of bosentan are attained within to 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. Absorption The 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 Metabolism Bosentan has three metabolites, one of which is pharmacologically active and may contribute 10% to 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% to 65% of those seen after single dose administration, probably the effect of auto-induction of the metabolizing liver enzymes. Steady-state is reached within to days. Excretion Bosentan 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 Hepatic Impairment In 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 bosentan tablets 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 Impairment In patients with severe renal impairment (creatinine clearance 15 to 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 Ketoconazole Co-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 bosentan tablets is necessary, but increased effects of bosentan tablets should be considered. Warfarin Co-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 bosentan tablets 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 bosentan tablets-and placebo-treated patients. Digoxin, Nimodipine, and Losartan Bosentan has no significant pharmacokinetic interactions with digoxin and nimodipine, and losartan has no significant effect on plasma levels of bosentan. Sildenafil In 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. Tadalafil Bosentan (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 drugs Figure 4. Effects of other drugs on Bosentan Figure 3. Figure 4.

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary Based on data from animal reproduction studies, bosentan tablets 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 bosentan tablets 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 to 4% and 15 to 20%, respectively.Data Animal Data Bosentan 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.

SPL MEDGUIDE SECTION.

Medication Guide. Bosentan (boe SEN tan) Tablets Read the Medication Guide that comes with bosentan tablets 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 bosentan tabletsBosentan tablets are only available through the Bosentan REMS Program. Before you begin taking bosentan tablets, you must read and agree to all of the instructions in the Bosentan REMS Program. Bosentan tablets 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 bosentan tablets 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 bosentan tablets: nausea vomiting fever unusual tirednesso stomach area (abdominal) pain yellowing of the skin or the whites of your eyes (jaundice) Serious birth defects. Bosentan tablets can cause serious birth defects if taken during pregnancy. You must not be pregnant when you start taking bosentan tablets or during bosentan tablets treatment. Serious birth defects from bosentan tablets can happen early in pregnancy. Females who are able to get pregnant must have negative pregnancy test before starting treatment with bosentan tablets, each month during treatment with bosentan tablets, and month after stopping treatment with bosentan tablets. 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 bosentan tablets, and for one month after stopping bosentan tablets 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 bosentan tablets. 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 bosentan tablets. 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 bosentan tablets 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. See What are the possible side effects of bosentan tablets for more information about side effects. What is bosentan tablet Bosentan tablet 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. Bosentan tablets can improve your ability to exercise and can slow the worsening of your physical condition and symptoms. Bosentan tablets lowers high blood pressure in your lungs and lets your heart pump blood more efficiently. Bosentan tablet 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 bosentan tablets Do not take bosentan tablet if you: are pregnant, plan to become pregnant, or become pregnant during bosentan tablets treatment. Bosentan tablets can cause serious birth defects. All females should read the birth defects section of What is the most important information should know about bosentan tablets take any of these medicines: 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 bosentan tablets. See the end of this Medication Guide for complete list of the ingredients in bosentan tablets. If you have rash, hives or your lips swell after taking bosentan tablets, it may be sign of allergy. You should stop taking your bosentan tablets and talk to your healthcare provider. What should tell my healthcare provider before taking bosentan tablets Bosentan tablets 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 bosentan passes into your milk. You and your healthcare provider should decide if you will take bosentan tablets 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. Bosentan tablets 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 bosentan tablets. 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 There 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 bosentan tablets Your healthcare provider will give you detailed information about the Bosentan REMS Program. Bosentan tablets are only available through certified pharmacies. You will only receive 30-day supply of bosentan tablets at one time. Take bosentan tablets exactly as prescribed. Your healthcare provider will tell you how much bosentan tablets to take and when to take it. In most cases, you will take tablet in the morning and in the evening. You can take bosentan tablets orally with or without food. If you take more than the prescribed dose of bosentan tablets, call your healthcare provider right away. If you miss dose of bosentan tablets, 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 bosentan tablets unless your healthcare provider tells you to. Suddenly stopping your treatment may cause your symptoms to get worse. If you need to stop taking bosentan tablets, speak with your healthcare provider about the right way to stop. What are the possible side effects of bosentan tablets Bosentan tablets can cause serious side effects, including: See What is the most important information should know about bosentan tablets Fluid retention and swelling of your ankles and legs. Bosentan tablets 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 bosentan tablets 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 bosentan tablets. The most common side effects of bosentan tablets include: respiratory tract infection headache fainting flushing low blood pressure inflamed nose passages (sinusitis) joint pain irregular heart beats Tell 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 bosentan tablets. 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 bosentan tablets Store bosentan tablets at 25C (77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature]. Keep bosentan tablets and all medicines out of the reach of children. General information about bosentan tablets Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use bosentan tablets for condition for which it was not prescribed. Do not give bosentan tablets 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 bosentan tablets. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about bosentan tablets that is written for health professionals. What are the ingredients in bosentan tablets Active ingredient: bosentan Inactive ingredients in 62.5 mg and 125 mg film-coated tablets: corn starch, pregelatinized starch, povidone K-30, sodium starch glycolate, glyceryl behenate, magnesium stearate, hypromellose, titanium dioxide, triacetin, talc, ethylcellulose, iron oxide yellow, and iron oxide red. This Medication Guide has been approved by the U.S. Food and Drug Administration.Manufactured by: Alembic Pharmaceuticals Limited (Formulation Division), Village Panelav, P. O. Tajpura, Near Baska, Taluka-Halol, Panchmahal, Gujarat, India.Revised: 12/2019. birth control options.

SPL UNCLASSIFIED SECTION.

2.1 Required Monitoring. Healthcare professionals who prescribe bosentan tablets must enroll in the Bosentan REMS Program and must comply with the required monitoring to minimize the risks associated with bosentan tablets [see Warnings and Precautions (5.3)]. Obtain pregnancy test in females of reproductive potential prior to bosentan tablets treatment, monthly during treatment and one month after stopping bosentan tablets. Initiate treatment with bosentan tablets 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)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Nursing mothers: Choose breastfeeding or bosentan tablets (8.2). 8.1 Pregnancy. Risk Summary Based on data from animal reproduction studies, bosentan tablets 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 bosentan tablets 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 to 4% and 15 to 20%, respectively.Data Animal Data Bosentan 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 Summary There are no data on the presence of bosentan in human milk, the effects on the breastfed infant, or the effect on milk production. Because of the potential for serious adverse reactions, such as fluid retention and hepatotoxicity, in breastfed infants from bosentan tablets, advise women not to breastfeed during treatment with bosentan tablets.. 8.3 Females and Males of Reproductive Potential. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating bosentan tablets, monthly during treatment and one month after stopping treatment with bosentan tablets. 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. Contraception Drug 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 bosentan tablets and should not be used as patients only contraceptive method [see Drug Interactions (7.2)]. Females of reproductive potential using bosentan tablets must use two acceptable methods of contraception during treatment and for month after treatment with bosentan tablets. 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 Males Decreased sperm counts have been observed in patients receiving bosentan tablets. Based on these findings and findings in animals, bosentan tablets 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. Juvenile Animal Toxicity Data In 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 bosentan tablets did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects.. 8.6 Hepatic 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 bosentan tablets 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. Bosentan tablets 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)].. 8.7 Renal 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 bosentan tablets (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). 5.1 Hepatotoxicity. ALT or AST 3 ULN were observed in 11% of bosentan tablets-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 >=3 ULN were associated with aminotransferase increases in of 658 (0.3%) of patients treated with bosentan tablets. The combination of hepatocellular injury (increases in aminotransferases of 3 ULN) and increases in total bilirubin (>= 2x ULN) is marker for potential serious hepatotoxicity.Elevations of AST or ALT associated with bosentan tablets 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 bosentan tablets.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 bosentan tablets 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 >= x ULN.Avoid initiation of bosentan tablets in patients with elevated aminotransferases (> x ULN) 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 bosentan tablets are sufficient to offset the risk of hepatotoxicity, which may preclude future use as their disease progresses. 5.2 Embryo-fetal Toxicity. Based on data from animal reproduction studies, bosentan tablets 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 bosentan tablets 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 bosentan tablets and for at least one month after the last dose [see Dosage and Administration (2), Use in Specific Populations (8.1, 8.3)]. Bosentan tablets are only available for females through restricted program under REMS [see Warnings and Precautions (5.3)]. 5.3 Prescribing and Distribution Program for Bosentan. Because of the risks of hepatotoxicity and birth defects, bosentan tablet 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 bosentan tablets 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 bosentan tablets, all patients must understand the risks and benefits, and complete patient enrollment form.Pharmacies that dispense bosentan tablets must enroll in the program and agree to comply with the Bosentan REMS Program requirements.Further information about Bosentan REMS Program is available at www.BosentanREMSProgram.com or 1-866-359-2612.. Healthcare professionals who prescribe bosentan tablets 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 bosentan tablets, all patients must understand the risks and benefits, and complete patient enrollment form.. Pharmacies that dispense bosentan tablets must enroll in the program and agree to comply with the Bosentan REMS Program requirements.. 5.4 Fluid Retention. Peripheral edema is known clinical consequence of PAH and worsening PAH and is also known effect of bosentan tablets and other endothelin receptor antagonists. In PAH clinical trials with bosentan tablets, 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 bosentan tablets. 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 bosentan tablets or underlying heart failure, and the possible need for treatment or discontinuation of bosentan tablets [see Adverse Reactions (6.1), Clinical Studies (14.2)].. 5.5 Pulmonary Veno-Occlusive Disease. If signs of pulmonary edema occur, consider the possibility of associated pulmonary veno-occlusive disease and consider whether bosentan tablets should be discontinued.. 5.6 Decreased Sperm Counts. Decreased sperm counts have been observed in patients receiving bosentan tablets. Preclinical data also suggest that bosentan tablets, similar to other endothelin receptor antagonists, may have an adverse effect on spermatogenesis [see Adverse Reactions (6.1), Nonclinical Toxicology (13.1)]. 5.7 Decreases in Hemoglobin and Hematocrit. Treatment with bosentan tablets 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)].