`
`
`
`
`
`
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`
`
`TRACLEER® safely and effectively. See full prescribing information for
`
`
`TRACLEER.
`
`
`TRACLEER® (bosentan) tablets, for oral use
`
`
`
`Initial U.S. Approval: 2001
`
`
` WARNING: RISKS OF HEPATOTOXICITY and EMBRYO-FETAL
`
`
` TOXICITY
`
`
`
`
`See full prescribing information for complete boxed warning.
` Tracleer is available only through a restricted distribution program called the
`
`
` Tracleer REMS Program because of these risks (5.2):
`
`
`
` Elevations of liver aminotransferases (ALT, AST) and liver failure have been
`
`
` reported with Tracleer (5.1).
`
`
`
`
`
`• Measure liver aminotransferases prior to initiation of treatment and
`
`
`
`then monthly (5.1).
`• Discontinue Tracleer if aminotransferase elevations are
`
`
`
`
`accompanied by signs or symptoms of liver dysfunction or injury or
`
`
`
`
`increases in bilirubin ≥2 x ULN (2.2, 5.1).
`
`
`Based on animal data, Tracleer is likely to cause major birth defects if used
`
`
`during pregnancy (4.1, 8.1).
`
`
`
`• Must exclude pregnancy before and during treatment (4.1, 8.1).
`
`
`• To prevent pregnancy, females of reproductive potential must use
`
`
`
`
`two reliable forms of contraception during treatment and for one
` month after stopping Tracleer (4.1, 8.1).
`
`
`
`RECENT MAJOR CHANGES _________________
`
` _________________
`
`Boxed Warning
`12/2015
`
`
`
`
`
`
`
`
`
`
`Dosage and Administration (2, 2.3)
`12/2015
`
`
`
`
`
`
`
`
`Contraindications (4.1, 4.4)
`10/2016
`
`
`
`
`
`
`
`
`
`Warnings and Precautions (5.2)
`12/2015
`
`
`
`
`
`
`
`
`
`
`INDICATIONS AND USAGE__________________
` _________________
`
`Tracleer is an endothelin receptor antagonist indicated for the treatment of
`
`
`pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise
`
`
`
`ability and to decrease clinical worsening. Studies establishing effectiveness
`
`
`
`
`
`included predominantly patients with NYHA 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%) (1.1).
`
`
`
`
`Considerations for use:
`
`
`Consider whether benefits offset the risk of hepatotoxicity in WHO Class II
`
`
`
`
`
`
`
`
`patients. Early hepatotoxicity may preclude future use as disease progresses (1.1).
`
`
`
`
`
`
`
`
`
`
` ______________
` _______________
`DOSAGE AND ADMINISTRATION
`Initiate at 62.5 mg twice daily with or without food for 4 weeks, and then
`
`
`
`
`•
`increase to 125 mg twice daily (2.1).
`
`
`
`• Patients with low body weight (<40 kg) and >12 years old: Initial and
`
`
`
`
`
`maintenance dose is 62.5 mg twice daily (2.4).
`
`
`
`
`• Reduce the dose and closely monitor patients developing
`
`
`
`
`aminotransferase elevations >3 X ULN (2.2).
`
`
`
`• Discontinue Tracleer 36 hours prior to initiation of ritonavir. Patients on
`
`
`
`
`
`ritonavir: Initiate Tracleer at 62.5 mg once daily or every other day (2.5).
`
`
`
`
`
`
`DOSAGE FORMS AND STRENGTHS______________
` _____________
`
`
`• Tablet: 62.5 mg and 125 mg (3)
`
`
`
`___________________ CONTRAINDICATIONS ___________________
`
`
`
`• Pregnancy (4.1)
`
`
`
`• Use with Cyclosporine A (4.2)
`
`
`
`
`
`• Use with Glyburide (4.3)
`
`
`
`
`• Hypersensitivity (4.4)
`
`
`
`WARNINGS AND PRECAUTIONS _______________
`
` _______________
`
`• Pre-existing hepatic impairment: Avoid use in moderate and severe
`
`
`
`
`impairment (5.3).
`
`
`• Fluid retention: May require intervention (5.4).
`
`
`
`• Pulmonary veno-occlusive disease (PVOD): If signs of pulmonary edema
`
`
`
`
`
`occur, consider the diagnosis of associated PVOD and consider
`
`
`
`
`
`discontinuing Tracleer (5.5)
`
`
`• Decreased sperm counts (5.6)
`
`
`
`
`
`
`• Decreases in hemoglobin and hematocrit: Monitor hemoglobin levels
`
`
`
`
`
`after 1 and 3 months of treatment, then every 3 months thereafter (5.7).
`
`
`
`
`
`
`___________________ ADVERSE REACTIONS ___________________
`
`
`
`
`Common adverse reactions (≥3% more than placebo) are respiratory tract
`
`
`
`
`
`
`
`
`infection and anemia (6.1).
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Actelion at 1-866­
`
`
`228-3546 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`
`
` ___________________
` ___________________
`DRUG INTERACTIONS
`• Hormonal contraceptives: Tracleer use decreases contraceptive exposure
`
`
`
`and reduces effectiveness (7.2).
`
`
`• Simvastatin and other CYP3A-metabolized statins: Combination use
`
`
`
`
`decreases statin exposure and may reduce efficacy (7.6).
`
`
`
`
`
`• Rifampin: Alters bosentan exposure. Monitor hepatic function weekly for
`
`
`
`
`
`4 weeks, followed by normal monitoring (7.7).
`
`
` _______________
` ______________
`USE IN SPECIFIC POPULATIONS
`• Nursing mothers: Choose breastfeeding or Tracleer (8.3).
`
`
`
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`
`
`
`
`
`
`
`Guide
`Revised: 10/2016
`
`
`
`
`8.
`
`
`7.3 Cyclosporine A
`
`
`7.4 Glyburide
`
`
`7.5 Lopinavir/Ritonavir or Other Ritonavir-containing HIV Regimens
`
`
`
`
`7.6
`Simvastatin and Other Statins
`
`
`
`7.7 Rifampin
`
`
`7.8 Tacrolimus
`
`
`7.9 Ketoconazole
`
`
`7.10 Warfarin
`
`
`7.11 Digoxin, Nimodipine, and Losartan
`
`
`
`7.12 Sildenafil
`
`
`7.13
`Iloprost
`
`
`USE IN SPECIFIC POPULATIONS
`
`8.1
`Pregnancy
`
`
`8.3 Nursing Mothers
`
`
`
`8.4
`Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Hepatic Impairment
`
`
`8.7 Renal Impairment
`
`
`10. OVERDOSAGE
`
`
`11. DESCRIPTION
`
`
`12. CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`12.3 Pharmacokinetics
`
`
`13. NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`14. CLINICAL STUDIES
`
`
`Pulmonary Arterial Hypertension
`14.1
`
`
`14.2
`Lack of Benefit in Congestive Heart Failure
`
`
`
`
`16. HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`17. PATIENT COUNSELING INFORMATION
`
`
`
`
`
`1.
`
`
`2.
`
`
`3.
`
`4.
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`WARNING: RISKS OF HEPATOTOXICITY AND EMBRYO-FETAL
`
`TOXICITY
`
`INDICATIONS AND USAGE
`
`
`Pulmonary Arterial Hypertension
`1.1
`
`DOSAGE AND ADMINISTRATION
`
`
`2.1 Adult Dosage
`
`
`
`2.2 Dosage Adjustments for Patients Developing Aminotransferase
`
`Elevations
`
`
`Pregnancy Testing in Females of Reproductive Potential
`2.3
`
`
`
`Patients with Low Body Weight
`2.4
`
`
`
`2.5 Use with Ritonavir
`
`
`2.6 Use in Patients with Pre-existing Hepatic Impairment
`
`
`2.7 Treatment Discontinuation
`
`DOSAGE FORMS AND STRENGTHS
`
`CONTRAINDICATIONS
`
`
`4.1
`Pregnancy
`
`
`
`
`4.2 Use with Cyclosporine A
`
`
`
`4.3 Use with Glyburide
`
`
`4.4 Hypersensitivity
`
`
`5. WARNINGS AND PRECAUTIONS
`
`
`5.1 Hepatotoxicity
`
`
`
`5.2
`Prescribing and Distribution Program for Tracleer
`
`
`5.3
`Patients with Pre-existing Hepatic Impairment
`
`
`5.4
`Fluid Retention
`
`
`5.5
`Pulmonary Veno-Occlusive Disease
`
`
`5.6 Decreased Sperm Counts
`
`
`5.7 Decreases in Hemoglobin and Hematocrit
`
`ADVERSE REACTIONS
`
`
`
`6.1 Clinical Studies Experience
`
`
`6.2
`Postmarketing Experience
`
`DRUG INTERACTIONS
`
`
`7.1 Cytochrome P450 Summary
`
`
`7.2 Hormonal Contraceptives
`
`
`6.
`
`
`7.
`
`Reference ID: 4001651
` *Sections or subsections omitted from the full prescribing information are not listed
`
`
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1139, p. 1 of 27
`
`

`

`
`
`
` WARNING: RISKS OF HEPATOTOXICITY and EMBRYO-FETAL TOXICITY
` Because of the risks of hepatotoxicity and birth defects, Tracleer is available only through a
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` restricted program called the Tracleer REMS Program. The Tracleer REMS Program is a
` component of the Tracleer Risk Evaluation and Mitigation Strategy (REMS). Under the Tracleer
`
`
`
`
`
`
`REMS, prescribers, patients, and pharmacies must enroll in the program. [see Warnings and
`
`
`
`
`
`Precautions (5.2)].
`
`Hepatotoxicity
` In clinical studies, Tracleer caused at least 3-fold upper limit of normal (ULN) elevation of liver
`
`
`
`
`aminotransferases (ALT and AST) in about 11% of patients, accompanied by elevated bilirubin in
` a small number of cases. Because these changes are a marker for potential serious hepatotoxicity,
`
`
`
`
`
` serum aminotransferase levels must be measured prior to initiation of treatment and then monthly
` [see Dosage and Administration (2.2), Warnings and Precautions (5.1)]. In the postmarketing
`
`
` period, in the setting of close monitoring, rare cases of unexplained hepatic cirrhosis were reported
`
` after prolonged (> 12 months) therapy with Tracleer in patients with multiple comorbidities and
`
`
`drug therapies. There have also been reports of liver failure. The contribution of Tracleer in these
`
`
`cases could not be excluded.
`
` In at least one case, the initial presentation (after > 20 months of treatment) included pronounced
`
`
`
` elevations in aminotransferases and bilirubin levels accompanied by non-specific symptoms, all of
` which resolved slowly over time after discontinuation of Tracleer. This case reinforces the
`
`
` importance of strict adherence to the monthly monitoring schedule for the duration of treatment
`
`
`
` and the treatment algorithm, which includes stopping Tracleer with a rise of aminotransferases
`
`
`
`
` accompanied by signs or symptoms of liver dysfunction [see Dosage and Administration (2.2)].
`
`Elevations in aminotransferases require close attention [see Dosage and Administration (2.2)].
`
`Tracleer should generally be avoided in patients with elevated aminotransferases (> 3 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 ≥ 2 x
`
`
`
`
`
`
`
`
`
`ULN, treatment with Tracleer should be stopped. There is no experience with the reintroduction of
`
`
`
`
`Tracleer in these circumstances.
`
`
`Embryo-Fetal Toxicity
`
`
`
`
`
` Tracleer is likely to cause major birth defects if used by pregnant females based on animal data
`
`
` [see Use in Specific Populations (8.1)]. Therefore, pregnancy must be excluded before the start of
`
`
`
` treatment with Tracleer. Throughout treatment and for one month after stopping Tracleer,
`
`
`
`
` females of reproductive potential must use two reliable methods of contraception unless the patient
`
`
`
`
`
`
` has an intrauterine device (IUD) or tubal sterilization, in which case no other contraception is
`
`
`
`
`needed. Hormonal contraceptives, including oral, injectable, transdermal, and implantable
`
`
`
` contraceptives should not be used as the sole means of contraception because these may not be
` effective in patients receiving Tracleer [see Drug Interactions (7.2)]. Obtain monthly pregnancy
`
`
`
`
`
` tests.
`
`
`
`Reference ID: 4001651
`
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1139, p. 2 of 27
`
`

`

`
`
` 1.
`
`
`
` INDICATIONS AND USAGE
`
`
`
` 1.1
` Pulmonary Arterial Hypertension
`
`
`
`
`
` Tracleer® is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to
` improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included
`
`
`
`
` predominantly patients with NYHA 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)].
`
`
`
`
` Considerations for use
`
` Patients with WHO Class II symptoms showed reduction in the rate of clinical deterioration and a trend for
`
`
`
` improvement in walk distance. Physicians should consider whether these benefits are sufficient to offset the
` risk of hepatotoxicity in WHO Class II patients, which may preclude future use as their disease progresses.
`
`
`
`
`
`
`
`
`
`
` 2.
`
` DOSAGE AND ADMINISTRATION
`
`
`
`
`
`
`
` Healthcare professionals who prescribe Tracleer must enroll in the Tracleer REMS Program and must
` comply with the required monitoring to minimize the risks associated with Tracleer [see Warnings and
`
`
`
`
`Precautions (5.2)].
`
`
`
`
` 2.1
`
`
` Adult Dosage
`
`
`
`
`
` Initiate treatment at 62.5 mg twice daily for 4 weeks and then increase to the maintenance dose of 125 mg
`
`
` twice daily. Doses above 125 mg twice daily did not appear to confer additional benefit sufficient to offset the
`
`
`
`
` increased risk of hepatotoxicity.
` Tracleer should be administered in the morning and evening with or without food.
`
`
`
`
`
`
`
`
` 2.2
`
`
` Dosage Adjustments for Patients Developing Aminotransferase Elevations
` Measure liver aminotransferase levels prior to initiation of treatment and then monthly. If aminotransferase
`
`
`
`
` levels increase, revise the monitoring and treatment plan. The table below summarizes the dosage adjustment
` and monitoring recommendations for patients who develop aminotransferase elevations >3 X ULN during
`
`
`
`
`
` therapy with Tracleer. Discontinue Tracleer if liver aminotransferase elevations are accompanied by clinical
`
`
` symptoms of hepatotoxicity (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or
`
` fatigue) or increases in bilirubin ≥ 2 x ULN. There is no experience with the reintroduction of Tracleer in these
`
`
`
`
`
`
` circumstances.
`
`
`
`
`Reference ID: 4001651
`
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1139, p. 3 of 27
`
`

`

`
`
`
`
` Table 1: Dosage Adjustment and Monitoring in Patients Developing Aminotransferase
`
`
` Elevations >3 x ULN
`
`
`
` ALT/AST levels
`
`
`
` > 3 and ≤ 5 x ULN
`
`
`
`
`> 5 and ≤ 8 x ULN
`
`
`> 8 x ULN
`
` Treatment and monitoring recommendations
`
` Confirm by another aminotransferase test; if confirmed, 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, continue or reintroduce the
` treatment as appropriate*.
`
` 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, consider
`
`
`reintroduction of the treatment*.
` Treatment should be stopped and reintroduction of Tracleer should not
`
`
`
`
`
` be considered. There is no experience with reintroduction of Tracleer in
`
` these circumstances.
`
` * If Tracleer is re-introduced it should be at the starting dose; aminotransferase levels should be checked within 3 days and thereafter
`
`
`
` according to the recommendations above.
`
`
`
`
`
`
`
` Pregnancy Testing in Females of Reproductive Potential
` 2.3
`
`
`
` Initiate treatment with Tracleer in females of reproductive potential only after a negative pregnancy test. Obtain
` monthly pregnancy test during treatment [see Use in Specific Populations (8.1)].
`
`
`
`
` Patients with Low Body Weight
` 2.4
`
`
`
`
` In patients with a body weight below 40 kg but who are over 12 years of age, the recommended initial and
`
`
`
`
`
` maintenance dose is 62.5 mg twice daily. There is limited information about the safety and efficacy of Tracleer
` in children between the ages of 12 and 18 years [see Use in Specific Populations (8.4)].
`
`
`
`
`
`
` Use with Ritonavir
` 2.5
`
`
`
`
`
`
`
`
` Coadministration of Tracleer in Patients on Ritonavir
`
` In patients who have been receiving ritonavir for at least 10 days, start Tracleer at 62.5 mg once daily or
`
`
`
`
` every other day based upon individual tolerability [see Drug Interactions (7.5)].
`
`
`
`
`
`
`
` Coadministration of Ritonavir in Patients on Tracleer
`
`
`
`
` Discontinue use of Tracleer at least 36 hours prior to initiation of ritonavir. After at least 10 days
`
`
`
`
` following the initiation of ritonavir, resume Tracleer at 62.5 mg once daily or every other day based upon
`
`
`
`
`
` individual tolerability [see Dosage and Administration (2.7), Drug Interactions (7.5)].
`
`
`
`
`
`
`
`
`
`
`
`
` 2.6
` Use in Patients with Pre-existing Hepatic Impairment
`
`
`
`
` Tracleer should generally be avoided in patients with moderate or severe liver impairment. Initiation of
` Tracleer should generally be avoided in patients with elevated aminotransferases >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)].
`
`
`
`
`
`
`Reference ID: 4001651
`
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1139, p. 4 of 27
`
`

`

`
`
` Treatment Discontinuation
` 2.7
`
`
`
` There is limited experience with abrupt discontinuation of Tracleer. No evidence for acute rebound has been
` observed. Nevertheless, to avoid the potential for clinical deterioration, gradual dose reduction (62.5 mg twice
`
`
`
`daily for 3 to 7 days) should be considered.
`
`
`
` 3.
`
` DOSAGE FORMS AND STRENGTHS
`
` 62.5 mg and 125 mg film-coated, tablets for oral administration.
`
`
`
` 62.5 mg tablets: round, biconvex, orange-white tablets, embossed with identification marking “62,5”
`
` 125 mg tablets: oval, biconvex, orange-white tablets, embossed with identification marking “125”
`
`
`
`
`
` 4.
`
`
`
` CONTRAINDICATIONS
`
` 4.1
` Pregnancy
`
`
`
`
`
`
` Use of Tracleer is contraindicated in females who are or may become pregnant. To prevent pregnancy,
`
`
`
`females of reproductive potential must use two reliable forms of contraception during treatment and for one
`
`
`
`
`month after stopping Tracleer . [see Boxed Warning, Warnings and Precautions (5.2), Drug Interactions (7.2),
`
`Use in Specific Populations (8.1)].
`
`
` Use with Cyclosporine A
` 4.2
`
`
`
`
`
` Coadministration of cyclosporine A and bosentan resulted in markedly increased plasma concentrations of
` bosentan. Therefore, concomitant use of Tracleer and cyclosporine A is contraindicated [see Drug Interactions
`
`
`
`
` (7.3)].
`
`
`
` Use with Glyburide
` 4.3
`
`
`
` An increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly
`
`
`
` with bosentan. Therefore coadministration of glyburide and Tracleer is contraindicated [see Drug Interactions
`
`
` (7.4)].
`
`
`
`
` 4.4
` Hypersensitivity
`
`
`
`
` Tracleer is contraindicated in patients who are hypersensitive to bosentan or any component of the product.
` Observed reactions include Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), anaphylaxis,
`
`
`
`
`
` rash and angioedema [see Adverse Reactions (6.2), Description (11)].
`
`
`
` WARNINGS AND PRECAUTIONS
`
`5
`
` Hepatotoxicity
`
`5.1
`
`
`
` Elevations in ALT or AST by more than 3 x ULN were observed in 11% of Tracleer-treated patients (n =
` 658) compared to 2% of placebo-treated patients (n = 280). Three-fold increases were seen in 12% of 95
`
`
` pulmonary arterial hypertension (PAH) patients on 125 mg twice daily and 14% of 70 PAH patients on 250 mg
`
`
`
`
`
`
`
`
`Reference ID: 4001651
`
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1139, p. 5 of 27
`
`

`

`
`
`
`
` 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 x ULN were associated with aminotransferase
`
` increases in 2 of 658 (0.3%) of patients treated with Tracleer. The combination of hepatocellular injury
`
` (increases in aminotransferases of > 3 x ULN) and increases in total bilirubin (≥ 2x ULN) is a marker for
`
`
`
` potential serious hepatotoxicity.
` Elevations of AST or ALT associated with Tracleer are dose-dependent, occur both early and late in
`
`
`
` treatment, usually progress slowly, are typically asymptomatic, and usually have been reversible after treatment
` interruption or cessation. Aminotransferase elevations also may reverse spontaneously while continuing
`
`
`
`
`
` treatment with Tracleer.
`
`
` Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly and
` therapy adjusted accordingly [see Dosage and Administration (2.2)]. Discontinue Tracleer if liver
`
`
`
`
`
`
`
`
`
` aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting,
` fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 x ULN.
`
`
`
`
`
`
`
`
`
`
`
`
`
` 5.2
` Prescribing and Distribution Program for Tracleer
`
`
`
`
`
`
`
` Because of the risks of hepatotoxicity and birth defects, Tracleer is available only through a restricted
` program called the Tracleer REMS Program. As a component of the Tracleer REMS, prescribers, patients, and
`
`
` pharmacies must enroll in the program. [see Boxed Warning and Contraindications (4.1)].
`
`
` Required components of the Tracleer REMS are:
`
`
`
` • Healthcare professionals who prescribe Tracleer must review the prescriber educational materials,
`
`
` enroll in the Tracleer REMS Program and comply with its requirements.
`
`
` • Healthcare professionals must (1) review serum aminotransferases (ALT/AST) and bilirubin, and
`
`
` agree to order and monitor these tests monthly; and (2) for females of reproductive potential,
`
`
`
`
`
`confirm that the patient is not pregnant, and agree to order and monitor pregnancy tests monthly.
`
` • To receive Tracleer, all patients must understand the risks and benefits, complete a patient
`
`
`enrollment form.
` • Pharmacies that dispense Tracleer must enroll in the program and agree to comply with the Tracleer
`
`
`
` REMS Program requirements.
` Further information about Tracleer and the Tracleer REMS Program is available at www.Tracleerrems.com
`
` or 1-866-228-3546.
`
`
`
`
`
`
`
`
`
`
`
` 5.3
`
`
`
` Patients with Pre-existing Hepatic Impairment
`
`
` Tracleer is not recommended in patients with moderate or severe liver impairment. In addition, initiation of
`
`
` Tracleer should generally be avoided in patients with elevated aminotransferases (> 3 x ULN) prior to drug
`
`
`
`
` initiation because monitoring hepatotoxicity in these patients may be more difficult [see Boxed Warning,
`
`
`
`
`
` Dosage and Administration (2.5) Use in Specific Populations (8.6)].
`
`
`
`
`
` Fluid Retention
` 5.4
`
`
`
` Peripheral edema is a known clinical consequence of PAH and worsening PAH and is also a known effect
` of Tracleer and other endothelin receptor antagonists. In PAH clinical trials with Tracleer, combined adverse
`
`
`
`
`
`
` events of fluid retention or edema were reported in 1.7 percent (placebo-corrected) of patients
`
`
`
`
`
`Reference ID: 4001651
`
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1139, p. 6 of 27
`
`

`

`In addition, there have been numerous postmarketing reports of fluid retention in patients with pulmonary
`
`hypertension occurring within weeks after starting Tracleer. Patients required intervention with 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 Tracleer or underlying heart failure, and the possible need
`
`
`
`for treatment or discontinuation of Tracleer. [see Adverse Reactions (6.1) and Clinical Studies (14.2)].
`
`
`
`
`
`
`
` Pulmonary Veno-Occlusive Disease
` 5.5
`
`
`
`
`
`
` Should signs of pulmonary edema occur, consider the possibility of associated pulmonary veno-occlusive
` disease and consider whether Tracleer should be discontinued.
`
`
`
`
`
`
` 5.6
`
`
` Decreased Sperm Counts
` Decreased sperm counts have been observed in patients receiving Tracleer. Preclinical data also suggest that
`
`
`
` Tracleer, like 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 Tracleer 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].
`
`
`
`
`
`
`
` 6.
`
`
` ADVERSE REACTIONS
` The following important adverse reactions are described elsewhere in the labeling:
`
` • Hepatotoxicity [see Boxed Warning, Warnings and Precautions (5.1)]
`
`
`
`
`
` • Fluid retention [see Warnings and Precautions (5.4)]
`
`
`
`
`
`
` 6.1
`
`
` Clinical Studies 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 Tracleer were obtained from 13 clinical studies (9 placebo-controlled and 4 open-label) in
` 870 patients with pulmonary arterial hypertension 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
` Tracleer 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 pulmonary arterial hypertension patients (n=328) to Tracleer 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 patients with pulmonary arterial hypertension were more frequent on Tracleer (6%; 15/258
`
`
`
`
`
` patients) than on placebo (3%; 5/172 patients). In this database the only cause of discontinuations > 1% and
` occurring more often on Tracleer was abnormal liver function.
`
`
`
`
`
`
`
`
`
`Reference ID: 4001651
`
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1139, p. 7 of 27
`
`

`

` The adverse drug events that occurred in ≥3% of the Tracleer-treated patients and were more common on
`
`
`
`
`
`
` Tracleer in placebo-controlled trials in pulmonary arterial hypertension at doses of 125 or 250 mg twice daily
` are shown in Table 2:
`
`
`Table 2.
`
`
`Adverse events* occurring in ≥3% of patients treated with Tracleer 125-250 mg twice
`
`
`
`
`daily and more common on Tracleer in placebo-controlled studies in pulmonary arterial
`
`
`
`hypertension
`
`
` Adverse Event
`
`
`
`
`
`
` Placebo
`
` Tracleer
`
` n = 172
`
`
`
` n = 258
`
` %
`
` No.
`
` %
`
` No.
`
` Respiratory Tract Infection
`
` 17%
`
` 30
`
` 22%
`
` 56
`
`
` Headache
`
` 14%
`
` 25
`
` 15%
`
` 39
`
`
` Edema
`
` 9%
`
` 16
`
` 11%
`
` 28
`
`
` Chest Pain
`
` 5%
`
` 8
`
` 5%
`
` 13
`
`
` Syncope
`
` 4%
`
` 7
`
` 5%
`
` 12
`
`
` Flushing
`
` 3%
`
` 5
`
` 4%
`
` 10
`
`
` Hypotension
`
` 2%
`
` 3
`
` 4%
`
` 10
`
`
` Sinusitis
`
` 2%
`
` 4
`
` 4%
`
` 9
`
` Arthralgia
`
` 2%
`
` 3
`
` 4%
`
` 9
`
`
`
` 2%
`
` 3
`
` 4%
`
` 9
` Serum Aminotransferases, abnormal
`
`
` 2%
`
` 3
`
` 4%
`
` 9
`
` Palpitations
`
`
`
`
` 3%
`
` 8
`
`
` Anemia
` -
`
`
`
`
`
`
`
` *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.
` 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 Tracleer
`
`
`
` 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 Tracleer. 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.
`
`
`
`Tracleer 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 Tracleer have an adverse effect on spermatogenesis.
`
`Decreases in Hemoglobin and Hematocrit
`
`
`
`Treatment with Tracleer 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 Tracleer-treated patients was 0.9 g/dL (change
`
`
`to end of treatment). Most of this decrease of hemoglobin concentration was detected during the first few weeks
`
`
`
`
`of Tracleer treatment and hemoglobin levels stabilized by 4–12 weeks of Tracleer treatment. In placebo-
`
`controlled studies of all uses of Tracleer, marked decreases in hemoglobin (> 15% decrease from baseline
`
`
`
`resulting in values < 11 g/dL) were observed in 6% of Tracleer-treated patients and 3% of placebo-treated
`
`
`patients. In patients with PAH treated with doses of 125 and 250 mg twice daily, marked decreases in
`
`hemoglobin occurred in 3% compared to 1% in placebo-treated patients.
`
`Reference ID: 4001651
`
`
`WATSON LABORATORIES, INC. , IPR2017-01622, Ex. 1139, p. 8 of 27
`
`

`

` A decrease in hemoglobin concentration by at least 1 g/dL was observed in 57% of Tracleer-treated patients
`
`
`
`
`
` as compared to 29% of placebo-treated patients. In 80% of those patients whose hemoglobin decreased by at
` least 1 g/dL, the decrease occurred during the first 6 weeks of Tracleer treatment.
`
`
`
`
` During the course of treatment the hemoglobin concentration remained within normal limits in 68% of
`
` Tracleer-treated patients compared to 76% of placebo patients. The explanation for the change in hemoglobin is
`
` not known, but it does not appear to be hemorrhage or hemolysis.
`
`
`
`
`
`
`
`
` 6.2
` Postmarketing Experience
`
`
`
`
`
` There have been several postmarketing reports of angioedema associated with the use of Tracleer. The onset
` of the reported cases occurred within a range of 8 hours to 21 days after starting therapy. Some patients were
`
`
`
`
`
` treated with an antihistamine and their signs of angioedema resolved without discontinuing Tracleer.
` The following additional adverse reactions have been reported during the postapproval use of Tracleer.
`
`
`
` 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 Tracleer 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
`
`
`
`
`
`
`
`
` 7.
`
`
`
` DRUG INTERACTIONS
`
`
`
` Cytochrome P450 Summary
` 7.1
`
`
` Bosentan is metabolized by CYP2C9 and CYP3A. Inhibition of these enzymes may increase the plasma
`
`
`
` concentration of bosentan (see ketoconazole). Concomitant administration of both a CYP2C9 inhibitor (such as
` fluconazole or amiodarone) and a strong CYP3A inhibitor (e.g., ketoconazole, itraconazole) or a moderate
`
`
`
`
`
`
`
`
`
`
`
` CYP3A inhibitor (e.g., amprenavir, erythromycin, fluconazole, diltiazem) with Tracleer 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 Tracleer i