Bosentan

RECENT MAJOR CHANGES Boxed Warning 11/2025 Dosage and Administration ( 2.1 ) 11/2025 Contraindications ( 4.1 ) 11/2025 Warnings and Precautions ( 5.1 , 5.2 , 5.3 ) 11/2025

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 )] . in pediatric patients aged 3 years and older with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), which is expected to result in an improvement in exercise ability. Bosentan tablets are an endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1): in adults to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital heart disease with left-to-right shunts (18%) ( 1 ). in pediatric patients aged 3 years and older with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), which is expected to result in an improvement in exercise ability ( 1 ).

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 4 weeks ( 2.2 ). Patients 12 years of age and younger: dosage is based on weight, see Table 1 ( 2.2 ). Reduce the dose and closely monitor patients developing aminotransferase elevations more than 3 X Upper Limit of Normal (ULN) ( 2.4 ). 2.1 Required Monitoring Healthcare professionals who prescribe bosentan must enroll in the Bosentan REMS and must comply with the required monitoring to minimize the risks associated with bosentan [see Warnings and Precautions ( 5.2 )]. Measure liver aminotransferase levels prior to initiation of treatment and then monthly [see Boxed Warning, Warnings and Precautions ( 5.1 , 5.2 )]. Exclude pregnancy before initiating treatment with bosentan in females of reproductive potential [see Boxed Warning, Contraindications (4.1), Warnings and Precautions (5.3), Use in Specific Populations ( 8.1 , 8.3 )] . 2.2 Recommended Dosage Administer bosentan 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 3 x ULN ALT/AST levels Treatment and monitoring recommendations > 3 and ≤ 5 x ULN Confirm by another aminotransferase test; if confirmed, - in adult and pediatric patients > 12 years and > 40 kg, reduce the daily dose to 62.5 mg twice daily or interrupt treatment, and monitor aminotransferase levels at least every 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 all other pediatric patients, interrupt treatment with no prior dose reduction. If the aminotransferase levels return to pretreatment values, reintroduce at the dose used prior to treatment interruption, with reassessment of aminotransferase levels within 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 adult and pediatric patients > 12 years and >40 kg, consider reintroduction of treatment at 62.5 mg twice daily, with reassessment of aminotransferase levels within 3 days. - in all other pediatric patients, consider reintroduction at the dose used prior to treatment interruption, 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 in Patients on Ritonavir In patients who have been receiving ritonavir for at least 10 days, start bosentan at the recommended initial dose once daily or every other day based upon individual tolerability [see Drug Interactions ( 7.1 )] . Coadministration of Ritonavir in Patients on Bosentan Discontinue use of bosentan at least 36 hours prior to initiation of ritonavir. After at least 10 days following the initiation of ritonavir, resume bosentan at the recommended initial dose once daily or every other day based upon individual tolerability [see Drug Interactions ( 7.1 )] . 2.6 Use in Patients with Pre-existing Hepatic Impairment Avoid initiation of bosentan in patients with aminotransferases > 3 x ULN. No dose adjustment is required in patients with mildly impaired liver function [see Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.6 ), Clinical Pharmacology ( 12.3 )].

3 DOSAGE FORMS AND STRENGTHS Film-coated Tablet: 62.5 mg and 125 mg ( 3 ) 62.5 mg and 125 mg film-coated, tablets for oral administration. 62.5 mg tablets: Peach to light pink colored, coated, round, biconvex, tablets debossed with '446' on one side and plain on other side. 125 mg tablets: Peach to light pink colored, coated, oval, biconvex, tablets debossed with '447' on one side and plain on other side.

4 CONTRAINDICATIONS Pregnancy ( 4.1 ) Use with Cyclosporine A ( 4.2 ) Use with Glyburide ( 4.3 ) Hypersensitivity ( 4.4 ) 4.1 Pregnancy Use of bosentan is contraindicated in females who are pregnant [see Boxed Warning, Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.1 )]. 4.2 Use with Cyclosporine A Coadministration of cyclosporine A and bosentan resulted in markedly increased plasma concentrations of bosentan. Therefore, concomitant use of bosentan and cyclosporine A is contraindicated [see 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 coadministration of glyburide and bosentan is contraindicated [see Drug Interactions ( 7.1) ] . 4.4 Hypersensitivity Bosentan is contraindicated in patients who are hypersensitive to bosentan or any component of the product. Observed reactions include Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), anaphylaxis, rash and angioedema [see Adverse Reactions ( 6.2 ), Description ( 11 )].

6 ADVERSE REACTIONS 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 Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 ( 5.3 )] Fluid Retention [see Warnings and Precautions ( 5.4 )] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 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 were obtained from 13 clinical studies (9 placebo-controlled and 4 open-label) in 870 adult patients with 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 than12 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 > 1% and occurring more often on bosentan was abnormal liver function. The adverse drug events that occurred in ≥ 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 mg to 250 mg Twice Daily and More Common on Bosentan in Placebo-Controlled Studies in Pulmonary Arterial Hypertension *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 Adverse Event Bosentan n = 258 Placebo 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% - Bosentan was evaluated for safety in 119 pediatric patients in uncontrolled studies. The safety profile was similar to that observed in adult patients with PAH. Decreased Sperm 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 obser …

7 DRUG INTERACTIONS Cytochrome P450: Coadministration of bosentan with drugs metabolized by CYP2C9 and CYP3A can increase exposure to bosentan and/or the coadministered drug ( 4.2 , 4.3 , 7.1 ). Hormonal contraceptives: Bosentan 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 Clinical Pharmacology ( 12.3 )] . Concomitant administration of both a CYP2C9 inhibitor (such as fluconazole or amiodarone) and a strong CYP3A inhibitor (e.g. ketoconazole, itraconazole) or a moderate CYP3A inhibitor (e.g. amprenavir, erythromycin, fluconazole, diltiazem) with bosentan will likely lead to large increases in plasma concentrations of bosentan. Coadministration of such combinations of a CYP2C9 inhibitor plus a strong or moderate CYP3A inhibitor with bosentan is not recommended. Bosentan is an inducer of CYP3A and CYP2C9. 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 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. CYP3A induction-mediated effect of bosentan on other drugs CYP3A induction-mediated effect of bosentan on other drugs Effect of other drugs on bosentan

8 USE IN SPECIFIC POPULATIONS Nursing mothers: Choose breastfeeding or bosentan ( 8.2 ). 8.1 Pregnancy Risk Summary Based on data from animal reproduction studies, bosentan may cause fetal harm, including birth defects and fetal death, when administered to a pregnant female and is contraindicated during pregnancy [see Contraindications ( 4.1 )] . Available data from postmarketing reports and published literature over decades of use with endothelin receptor antagonists (ERA) in the same class as bosentan have not identified an increased risk of major birth defects; however, these data are limited. Methodological limitations of these postmarketing reports and published literature include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and missing data. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal ERA use. In animal reproduction studies, oral administration of bosentan to pregnant rats at 2 times the maximum recommended human dose (MRHD) on a mg/m 2 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 a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% 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 Data from a case report describe the presence of bosentan in human milk. There is insufficient information about the effects of bosentan on the breastfed infant and no information on the effects of bosentan 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 Based on data from animal reproductive toxicity studies, bosentan may cause fetal harm, including birth defects and fetal death, when administered to a pregnant patient and is contraindicated during pregnancy [see Contraindications ( 4.1 ), Use in Specific Populations ( 8.1 )]. Pregnancy Testing Verify that females of reproductive potential are not pregnant prior to initiating 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 [see Dosage and Administration (2 .1 ), Contraindications ( 4.1 ), Warnings and Precautions ( 5.3 )] . 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 …

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

11 DESCRIPTION Bosentan is an endothelin receptor antagonist that belongs to a class of highly substituted pyrimidine derivatives, with no chiral centers. It is designated chemically as 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)- [2,2 ́]-bipyrimidin-4-yl]- benzenesulfonamide monohydrate and has the following structural formula: Bosentan has a molecular weight of 569.64 and a molecular formula of C 27 H 29 N 5 O 6 S•H 2 O. Bosentan is a white yellowish powder and it is Soluble in acetonitrile, slightly soluble in methanol and practically insoluble in water. Bosentan is available as 62.5 mg and 125 mg film-coated tablets for oral administration, and contains the following excipients: corn starch, ethylcellulose, glyceryl behenate, hypromellose, iron oxide yellow, iron oxide red, magnesium stearate, povidone, pregelatinized starch, sodium starch glycolate, titanium dioxide, triacetin, and talc. Each bosentan 62.5 mg tablet contains 64.541 mg of bosentan monohydrate, equivalent to 62.5 mg of bosentan. Each bosentan 125 mg tablet contains 129.082 mg of bosentan monohydrate, equivalent to 125 mg of bosentan. Bosentan tablets

10 OVERDOSAGE Bosentan has been given as a single dose of up to 2,400 mg in normal volunteers, or up to 2,000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1,000 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 62.5 mg tablets: Peach to light pink colored, coated, round, biconvex, tablets debossed with '446' on one side and plain on other side. NDC 68382-446-14 in bottle of 60 tablets with child-resistant closure NDC 68382-446-01 in bottle of 100 tablets NDC 68382-446-28 in bottle of 180 tablets NDC 68382-446-05 in bottle of 500 tablets NDC 68382-446-77 in cartons of 100 tablets (10 x 10 unit-dose) for hospital unit-dosing. 125 mg tablets: Peach to light pink colored, coated, oval, biconvex, tablets debossed with '447' on one side and plain on other side. NDC 68382-447-14 in bottle of 60 tablets with child-resistant closure NDC 68382-447-01 in bottle of 100 tablets NDC 68382-447-28 in bottle of 180 tablets NDC 68382-447-05 in bottle of 500 tablets NDC 68382-447-77 in cartons of 100 tablets (10 x 10 unit-dose) for hospital unit-dosing. Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature].