9. consequently plasma concentrations of drugs metabolized by these two isozymes will be decreased when bosentan is coadministered. bosentan had no relevant inhibitory effect on any cyp isozyme in vitro (cyp1a2, cyp2c9, cyp2c19, cyp2d6, cyp3a). consequently, bosentan is 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 2. effect of other drugs on bosentan 1 2 7.2 hormonal contraceptives hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when bosentan is coadministered. females should practice additional methods of contraception and not rely on hormonal contraception alone when taking bosentan [see use in specific populations (8.3) ] . an interaction study demonstrated that coadministration of bosentan and a 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.

with left-to-right shunts (18%) ( 1 ).

eated with bosentan. the combination of hepatocellular injury (increases in aminotransferases of greater than 3 x uln) and increases in total bilirubin (greater than or equal to 2 x uln) is a marker for potential serious hepatotoxicity. elevations of ast or alt associated with bosentan are dose-dependent, occur both early and late in treatment, usually progress slowly, are typically asymptomatic, and usually have been reversible after treatment interruption or cessation. aminotransferase elevations also may reverse spontaneously while continuing treatment with bosentan. 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 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 greater than or equal to 2 x uln. avoid initiation of bosentan in patients with elevated aminotransferases (greater than 3 x uln) prior to drug initiation because monitoring hepatotoxicity in these patients may be more difficult [see boxed warning , d osage and administration (2.6) , use in specific populations (8.6) ] . in who functional class ii patients, consider whether the benefits of bosentan 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 may cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. advise females of reproductive potential of the potential risk to a fetus. obtain a pregnancy test prior to bosentan 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 and for at least one month after the last dose [see dosage and administration (2) , use in specific populations (8.1 , 8.3) ] . bosentan is only available for females through a restricted program under rems [see warnings and precautions (5.3) ] . 5.3 prescribing and distribution program for bosentan tablets because of the risks of hepatotoxicity and birth defects, bosentan tablets are available only through a restricted program called the bosentan rems program. as a 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 a 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 tablets and the bosentan rems program is available at www.bosentanremsprogram.com or 1-866-359-2612. 5.4 fluid retention peripheral edema is a known clinical consequence of pah and worsening pah and is also a known effect of bosentan and other endothelin receptor antagonists. in pah clinical trials with bosentan, 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. patients required intervention with a diuretic, fluid management, or hospitalization for decompensating heart failure. if clinically significant fluid retention develops, with or without associated weight gain, further evaluation should be undertaken to determine the cause, such as bosentan or underlying heart failure, and the possible need for treatment or discontinuation of bosentan [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 should be discontinued. 5.6 decreased sperm counts decreased sperm counts have been observed in patients receiving bosentan. preclinical data also suggest that bosentan, 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 can cause a 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 1 and 3 months, and every 3 months thereafter. if a marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and need for specific treatment [see adverse reactions (6.1) ] .

er 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 4 weeks maintenance (after 4 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 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 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 greater than or equal to 2 x upper limit of normal (uln). there is no experience with the reintroduction of bosentan in these circumstances. table 2: dosage adjustment and monitoring in patients developing aminotransferase elevations > 3 x uln alt/ast levels treatment and monitoring recommendations > 3 and ? 5 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 2 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 3 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 3 days. > 5 and ? 8 x uln confirm by another aminotransferase test; if confirmed, stop treatment and monitor aminotransferase levels at least every 2 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 3 days. > 8 x uln stop treatment permanently. there is no experience with reintroduction of bosentan in these circumstances. 2.5 use with ritonavir coadministration of bosentan tablets in patients on ritonavir in 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) ] . coadministration of ritonavir in patients on bosentan tablets discontinue 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 greater than 3 x 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) ] .

th pah and other diseases. doses up to 8 times the currently recommended clinical dose (125 mg twice daily) were administered for a variety of durations. the exposure to bosentan in these trials ranged from 1 day to 4.1 years (n=94 for 1 year; n=61 for 1.5 years; and n=39 for more than 2 years). exposure of pah patients (n=328) to bosentan ranged from 1 day to 1.7 years (n=174 more than 6 months and n=28 more than 12 months). treatment discontinuations due to adverse events other than those related to pulmonary hypertension during the clinical trials in adult patients with pah were more frequent on bosentan (6%; 15/258 patients) than on placebo (3%; 5/172 patients). in this database the only cause of discontinuations greater than 1% and occurring more often on bosentan was abnormal liver function. the adverse drug events that occurred in greater than or equal to 3% of the bosentan-treated patients and were more common on bosentan 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 125 to 250 mg twice daily and more common on bosentan in placebo-controlled studies in pulmonary arterial hypertension bosentan placebo adverse event n = 258 n = 172 no. % no. % respiratory tract infection** 56 22% 30 17% headache 39 15% 25 14% edema 28 11% 16 9% chest pain 13 5% 8 5% syncope 12 5% 7 4% flushing 10 4% 5 3% hypotension 10 4% 3 2% sinusitis 9 4% 4 2% arthralgia 9 4% 3 2% serum aminotransferases, abnormal 9 4% 3 2% palpitations 9 4% 3 2% anemia 8 3% - - *note: only aes with onset from start of treatment to 1 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 early decreased sperm counts an open-label, single-arm, multicenter, safety study evaluated the effect on testicular function of bosentan 62.5 mg twice daily for 4 weeks, followed by 125 mg twice daily for 5 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 2 discontinued due to adverse events not related to testicular function. there was a decline in sperm count of at least 50% in 25% of the patients after 3 or 6 months of treatment with bosentan. sperm count remained within the normal range in all 22 patients with data after 6 months and no changes in sperm morphology, sperm motility, or hormone levels were observed. one patient developed marked oligospermia at 3 months and the sperm count remained low with 2 follow-up measurements over the subsequent 6 weeks. bosentan was discontinued and after 2 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 have an adverse effect on spermatogenesis. decreases in hemoglobin and hematocrit treatment with bosentan can cause a dose-related decrease in hemoglobin and hematocrit. it is recommended that hemoglobin concentrations be checked after 1 and 3 months, and every 3 months thereafter. if a marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and need for specific treatment. the overall mean decrease in hemoglobin concentration for adult bosentan-treated patients was 0.9 g/dl (change to end of treatment). most of this decrease of hemoglobin concentration was detected during the first few weeks of bosentan treatment and hemoglobin levels stabilized by 4 to 12 weeks of bosentan treatment. in placebo-controlled studies of all uses of bosentan, marked decreases in hemoglobin (greater than 15% decrease from baseline resulting in values less than 11 g/dl) were observed in 6% of bosentan-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 1 g/dl was observed in 57% of bosentan-treated patients as compared to 29% of placebo-treated patients. in 80% of those patients whose hemoglobin decreased by at least 1 g/dl, the decrease occurred during the first 6 weeks of bosentan treatment. during the course of treatment, the hemoglobin concentration remained within normal limits in 68% of bosentan-treated patients compared to 76% of placebo patients. the explanation for the change in hemoglobin is not known, but it does not appear to be hemorrhage or hemolysis. 6.2 postmarketing experience there have been several postmarketing reports of angioedema associated with the use of bosentan. the onset of the reported cases occurred within a range of 8 hours to 21 days after starting therapy. some patients were treated with an antihistamine and their signs of angioedema resolved without discontinuing bosentan. the following additional adverse reactions have been reported during the postapproval use of bosentan. because these adverse reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to bosentan exposure: 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

9. consequently plasma concentrations of drugs metabolized by these two isozymes will be decreased when bosentan is coadministered. bosentan had no relevant inhibitory effect on any cyp isozyme in vitro (cyp1a2, cyp2c9, cyp2c19, cyp2d6, cyp3a). consequently, bosentan is 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 2. effect of other drugs on bosentan 1 2 7.2 hormonal contraceptives hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when bosentan is coadministered. females should practice additional methods of contraception and not rely on hormonal contraception alone when taking bosentan [see use in specific populations (8.3) ] . an interaction study demonstrated that coadministration of bosentan and a 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.

isk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. data animal data bosentan was teratogenic in rats given oral doses two times the mrhd (on a mg/m 2 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 2 and 10 times the mrhd (on a mg/m 2 basis). although birth defects were not observed in rabbits given oral doses of up to the equivalent of 10.5 g/day in a 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 a 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, advise women not to breastfeed during treatment with bosentan. 8.3 females and males of reproductive potential pregnancy testing verify the pregnancy status of females of reproductive potential prior to initiating bosentan, monthly during treatment and one month after stopping treatment with bosentan. 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 and should not be used as a patient’s only contraceptive method [see drug interactions (7.2) ] . females of reproductive potential using bosentan must use two acceptable methods of contraception during treatment and for 1 month after treatment with bosentan. patients may choose one highly effective form of contraception (intrauterine devices (iud) or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods). if a partner’s vasectomy is the chosen method of contraception, a 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. based on these findings and findings in animals, bosentan 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 a juvenile rat toxicity study, rats were treated from day 4 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 4 times (at day 4 postpartum) and 2 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, 7 times the therapeutic exposure in children with pah. 8.5 geriatric use clinical studies of bosentan 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 (c max and auc) of bosentan. the pharmacokinetics of bosentan 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 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) ] .

4% and 15% to 20%, respectively. data animal data bosentan was teratogenic in rats given oral doses two times the mrhd (on a mg/m 2 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 2 and 10 times the mrhd (on a mg/m 2 basis). although birth defects were not observed in rabbits given oral doses of up to the equivalent of 10.5 g/day in a 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 a class effect of these drugs.

an in normal volunteers is about 50% and is unaffected by food. bosentan is highly bound (greater than 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 3 to 5 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 a single intravenous dose is about 4 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 a study comparing 8 patients with mild liver impairment (child-pugh class a) to 8 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 5 patients with moderately impaired liver function (child-pugh class b) and pah associated with portal hypertension than in 3 patients with normal liver function and pah of other etiologies. the pharmacokinetics of bosentan 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 coadministration of bosentan 125 mg twice daily and ketoconazole, a potent cyp3a inhibitor, increased the plasma concentrations of bosentan by approximately 100% in normal volunteers. no dose adjustment of bosentan is necessary, but increased effects of bosentan should be considered. warfarin coadministration of bosentan 500 mg twice daily for 6 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 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- 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, coadministration of multiple doses of 125 mg twice daily bosentan and 80 mg three times daily sildenafil resulted in a 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 c max by 27% following multiple dose coadministration. tadalafil did not affect the exposure (auc and c max ) of bosentan or its metabolites. figure 3. cyp induction-mediated effect of bosentan on other drugs figure 4. effects of other drugs on bosentan 1 1

le dose administration, probably the effect of auto-induction of the metabolizing liver enzymes. steady-state is reached within 3 to 5 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 a single intravenous dose is about 4 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 a study comparing 8 patients with mild liver impairment (child-pugh class a) to 8 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 5 patients with moderately impaired liver function (child-pugh class b) and pah associated with portal hypertension than in 3 patients with normal liver function and pah of other etiologies. the pharmacokinetics of bosentan 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 coadministration of bosentan 125 mg twice daily and ketoconazole, a potent cyp3a inhibitor, increased the plasma concentrations of bosentan by approximately 100% in normal volunteers. no dose adjustment of bosentan is necessary, but increased effects of bosentan should be considered. warfarin coadministration of bosentan 500 mg twice daily for 6 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 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- 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, coadministration of multiple doses of 125 mg twice daily bosentan and 80 mg three times daily sildenafil resulted in a 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 c max by 27% following multiple dose coadministration. tadalafil did not affect the exposure (auc and c max ) of bosentan or its metabolites. figure 3. cyp induction-mediated effect of bosentan on other drugs figure 4. effects of other drugs on bosentan 1 1

r any mutagenic or clastogenic activity of bosentan. impairment of fertility/testicular function the 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 1,500 mg/kg/day (50 times the mrhd on a mg/m 2 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 4 times the mrhd and the lowest doses tested) for two years but not at doses as high as 1,500 mg/kg/day (about 50 times the mrhd) for 6 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 to 6 weeks. an increased incidence of tubular atrophy was not observed in mice treated for 2 years at doses up to 4,500 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).

enic activity of bosentan. impairment of fertility/testicular function the 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 1,500 mg/kg/day (50 times the mrhd on a mg/m 2 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 4 times the mrhd and the lowest doses tested) for two years but not at doses as high as 1,500 mg/kg/day (about 50 times the mrhd) for 6 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 to 6 weeks. an increased incidence of tubular atrophy was not observed in mice treated for 2 years at doses up to 4,500 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).

4 weeks and then at 125 mg twice daily or 250 mg twice daily for either 12 (breathe-1) or 8 (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 a mean of 2.4 years. submaximal exercise ability results of the 6-minute walk distance at 3 months (study 351) or 4 months (breathe-1) are shown in table 4. table 4. effects of bosentan on 6-minute walk distance breathe-1 study 351 bosentan bosentan placebo bosentan placebo 125 mg twice daily 250 mg twice daily 125 mg twice daily (n = 74) (n = 70) (n = 69) (n = 21) (n = 11) baseline 326 ± 73 333 ± 75 344 ± 76 360 ± 86 355 ± 82 end point 353 ± 115 379 ± 101 336 ± 129 431 ± 66 350 ± 147 change from baseline 27 ± 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 student’s t-test. in both trials, treatment with bosentan resulted in a significant increase in exercise ability. the improvement in walk distance was apparent after 1 month of treatment (with 62.5 mg twice daily) and fully developed by about 2 months of treatment (figure 5). it was maintained for up to 7 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 led to a significant increase in cardiac index (ci) associated with a 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 125 mg twice daily placebo ci (l/min/m 2 ) n=20 n=10 baseline 2.35±0.73 2.48±1.03 absolute change 0.50±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 (dyn•sec•cm -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<0.02 symptoms 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 a significant reduction in dyspnea during walk tests (borg dyspnea score), and significant improvement in who functional class in bosentan-treated patients. there was a significant reduction in the rate of clinical worsening (table 6 and figure 6). figure 6 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 bosentan 125/250 mg twice daily placebo 125 mg twice daily placebo (n = 144) (n = 69) (n = 21) (n = 11) patients with clinical worsening 9 (6%) (a) 14 (20%) 0 (0%) (b) 3 (27%) [n (%)] death 1 (1%) 2 (3%) 0 (0%) 0 (0%) hospitalization for pah 6 (4%) 9 (13%) 0 (0%) 3 (27%) discontinuation due to worsening of pah 5 (3%) 6 (9%) 0 (0%) 3 (27%) receipt of epoprostenol (c) 4 (3%) 3 (4%) 0 (0%) 3 (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 fisher’s exact test. (c) receipt of epoprostenol was always a 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. a 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 a 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 62.5 mg twice daily for 4 weeks followed by 125 mg twice daily (n = 93), or placebo (n = 92) for 6 months. enrolled patients were treatment-naïve (n = 156) or on a stable dose of sildenafil (n = 29). the coprimary endpoints were change from baseline to month 6 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 treatment was associated with a reduced incidence of worsening of at least one functional class (3% bosentan vs. 13% placebo, p = 0.03), and improvement in hemodynamic variables (pvr, mpap, tpr, cardiac index, and svo 2 ; p < 0.05). the +19 m mean (+14 m median) increase in 6-minute walk distance with bosentan vs . placebo was not significant (p = 0.08). there was a significant delay in time to clinical worsening (first seen primarily as symptomatic progression of pah) with bosentan 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 pah long-term follow-up of patients with class iii and iv pah who were treated with bosentan in open-label extensions of trials (n=235) showed that 93% and 84% of patients were still alive at 1 and 2 years, respectively, after the start of treatment. these uncontrolled observations do not allow comparison with a group not given bosentan and cannot be used to determine the long-term effect of bosentan on mortality. pulmonary arterial hypertension in adults related to congenital heart disease with left-to-right shunts a 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 on exercise and safety that were similar to those seen in other trials in patients with pah (who group 1). 5 6 14.2 lack of benefit in congestive heart failure bosentan is not effective in the treatment of congestive heart failure with left ventricular dysfunction. in a pair of studies, 1,613 subjects with nyha class iii-iv heart failure, left ventricular ejection fraction less than 35%, on diuretics, ace inhibitor, and other therapies, were randomized to placebo or bosentan (62.5 mg twice daily titrated as tolerated to 125 mg twice daily) and followed for up to 70 weeks. use of bosentan 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 4 to 8 weeks after bosentan was initiated. in a placebo-controlled trial of patients with severe chronic heart failure, there was an increased incidence of hospitalization for chf associated with weight gain and increased leg edema during the first 4 to 8 weeks of treatment with bosentan. patients required intervention with a diuretic, fluid management, or hospitalization for decompensating heart failure.

iscontinuing 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 a 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 tablets are available only from certified pharmacies that are enrolled in the bosentan rems program. patients must sign the bosentan rems program patient enrollment and consent 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 in india by: watson pharma private ltd. verna, salcette goa 403 722 india distributed by: actavis pharma, inc. parsippany, nj 07054 usa rev. a 5/2019