Tracleer

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

Studies establishing effectiveness included predominantly patients with WHO Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital heart disease with left-to-right shunts (18%). 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.

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. Patients 12 years of age and younger: dosage is based on weight, see Table 1. Reduce the dose and closely monitor patients developing aminotransferase elevations more than 3×Upper Limit of Normal (ULN).

2.1Required Monitoring Healthcare

professionals who prescribe TRACLEER must enroll in the Bosentan REMS and must comply with the required monitoring to minimize the risks associated with TRACLEER . Measure liver aminotransferase levels prior to initiation of treatment and then monthly . Exclude pregnancy before initiating treatment with TRACLEER in females of reproductive potential .

2.2Recommended Dosage Administer

TRACLEER orally following the dosing recommendations in Table 1. Doses above 125 mg twice daily did not appear to confer additional benefit sufficient to offset the increased risk of hepatotoxicity. Table 1: Dosing 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 Patients ≤12 years of age ≥4–8 kg 16 mg twice daily 16 mg twice daily >8–16 kg 32 mg twice daily 32 mg twice daily >16–24 kg 48 mg twice daily 48 mg twice daily >24–40 kg 64 mg twice daily 64 mg twice daily

2.3Administration

TRACLEER film-coated tablets and tablets for oral suspension (dispersible tablets) should be administered orally twice daily. Disperse tablets for oral suspension, or dispersible tablet half, in a minimal amount of water immediately before administration. Store divided dispersible tablet pieces at 20 ºC to 25 ºC (68 ºF to 77 ºF) in the opened blister for up to 7 days.

2.4Dosage Adjustments for Aminotransferase Elevations If

aminotransferase levels increase, adjust monitoring and treatment plan according to Table 2. Discontinue TRACLEER if liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or bilirubin ≥2 × Upper Limit of Normal (ULN). There is no experience with the reintroduction of TRACLEER in these circumstances.

Table 2: Dosage Adjustment and Monitoring in Patients Developing Aminotransferase Elevations >3×ULN ALT/AST levels Treatment and monitoring recommendations >3 and ≤5 × ULN Confirm by another aminotransferase test; if confirmed, in adults and pediatric patients >12 years and >40 kg , reduce the daily dose to 62.5 mg twice daily or interrupt treatment, and monitor aminotransferase levels at least every 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 × 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 adults and pediatric patients >12 years and >40 kg , consider reintroduction of treatment at 62.5 mg twice daily, with reassessment of aminotransferase levels within 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 × ULN Stop treatment permanently. There is no experience with reintroduction of TRACLEER in these circumstances.

2.5Use with Ritonavir Co-administration of

TRACLEER in Patients on Ritonavir In patients who have been receiving ritonavir for at least 10 days, start TRACLEER at the recommended initial dose once daily or every other day based upon individual tolerability . Co-administration 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 the recommended initial dose once daily or every other day based upon individual tolerability .

2.6Use in Patients with Pre-existing Hepatic Impairment

Avoid initiation of TRACLEER in patients with aminotransferases >3 × ULN. No dose adjustment is required in patients with mildly impaired liver function .

Fluid retention: May require intervention. Pulmonary veno-occlusive disease (PVOD): If signs of pulmonary edema occur, consider the diagnosis of associated PVOD and consider discontinuing TRACLEER. Decreased sperm counts. Decreases in hemoglobin and hematocrit: Monitor hemoglobin levels after 1 and 3 months of treatment, then every 3 months thereafter.

5.1Hepatotoxicity

ALT or AST >3 × 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 twice daily. Eight-fold increases were seen in 2% of PAH patients on 125 mg twice daily and 7% of PAH patients on 250 mg twice daily.

Bilirubin increases to ≥3 × ULN were associated with aminotransferase increases in 2 of 658 (0.3%) of patients treated with TRACLEER. In a pooled analysis of four pediatric studies conducted in PAH (n=100), elevations in liver aminotransferases ≥3×ULN were observed in 2% of patients. The combination of hepatocellular injury (increases in aminotransferases of >3 × ULN) and increases in total bilirubin (≥2 × 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 . 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 × ULN. Avoid initiation of TRACLEER in patients with elevated aminotransferases (>3 × ULN) prior to drug initiation because monitoring hepatotoxicity in these patients may be more difficult . In WHO Functional Class II patients, consider whether the benefits of TRACLEER are sufficient to offset the risk of hepatotoxicity, which may preclude future use as their disease progresses. TRACLEER is only available through a restricted program under REMS .

5.2Bosentan

REMS Because of the risks of hepatotoxicity , TRACLEER is available only through a restricted program called the Bosentan REMS. As a component of the Bosentan REMS, prescribers, patients, and pharmacies must enroll in the program . Required components of the Bosentan REMS are: Healthcare professionals who prescribe TRACLEER must review the prescriber educational materials, enroll in the Bosentan REMS and comply with its requirements. Healthcare professionals must review serum aminotransferases (ALT/AST) and bilirubin, and agree to order and monitor these tests monthly. To receive TRACLEER, all patients must understand the risks and benefits, and complete a patient enrollment form with their prescriber.

Pharmacies that dispense TRACLEER must enroll in the program and agree to comply with the Bosentan REMS requirements. Further information about TRACLEER and the Bosentan REMS is available at www.BosentanREMSProgram.com or 1-866-359-2612.

5.3Embryo-Fetal Toxicity Based on

data from animal reproduction studies, TRACLEER may cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. The available human data for endothelin receptor antagonists do not establish the presence or absence of major birth defects related to the use of TRACLEER. Advise females of reproductive potential about the potential risk to a fetus. Exclude pregnancy prior to TRACLEER treatment.

Advise females of reproductive potential to use effective contraception prior to initiation of treatment with TRACLEER, during treatment, and for at least one month after the last dose. When pregnancy is detected, discontinue TRACLEER as soon as possible .

5.4Fluid Retention 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% (placebo-corrected) of patients. In addition, there have been numerous postmarketing reports of fluid retention in patients with pulmonary hypertension occurring within weeks after starting TRACLEER. Patients required intervention with 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 .

5.5Pulmonary Veno-Occlusive Disease If

signs of pulmonary edema occur, consider the possibility of associated pulmonary veno-occlusive disease and consider whether TRACLEER should be discontinued.

5.6Decreased Sperm Counts Decreased

sperm counts have been observed in patients receiving TRACLEER. Preclinical data also suggest that TRACLEER, similar to other endothelin receptor antagonists, may have an adverse effect on spermatogenesis .

5.7Decreases 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 .

Pregnancy. Use with Cyclosporine A. Use with Glyburide. Hypersensitivity.

4.1Pregnancy Use of

TRACLEER is contraindicated in females who are pregnant .

4.2Use with Cyclosporine A Co-administration of

cyclosporine A and bosentan resulted in markedly increased plasma concentrations of bosentan. Therefore, concomitant use of TRACLEER and cyclosporine A is contraindicated .

4.3Use with Glyburide An

increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan. Therefore co-administration of glyburide and TRACLEER is contraindicated .

4.4Hypersensitivity

TRACLEER is contraindicated in patients who are hypersensitive to bosentan or any component of the product. Observed reactions include Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), anaphylaxis, rash, and angioedema .

8.1Pregnancy Risk Summary Based on

data from animal reproduction studies, TRACLEER may cause fetal harm, including birth defects and fetal death, when administered to a pregnant female and is contraindicated during pregnancy . Available data from postmarketing reports and published literature over decades of use with endothelin receptor antagonists (ERA) in the same class as TRACLEER 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 . 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 2–4% and 15–20%, 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.

The following important adverse reactions are described elsewhere in the labeling: Hepatotoxicity Embryo-fetal Toxicity Fluid Retention Common adverse reactions (≥3% more than placebo) for the film-coated tablet are respiratory tract infection and anemia. Common adverse reactions (≥15%) for the dispersible tablet are upper respiratory tract infections and pyrexia. To report SUSPECTED ADVERSE REACTIONS, contact Actelion at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 TRACLEER 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 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 PAH 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 adult patients with PAH were more frequent on TRACLEER (6%; 15/258 patients) than on placebo (3%; 5/172 patients).

In this database the only cause of discontinuations >1% and occurring more often on TRACLEER was abnormal liver function. The adverse drug events that occurred in ≥3% of the TRACLEER-treated patients and were more common on TRACLEER in placebo-controlled trials in PAH at doses of 125 or 250 mg twice daily are shown in Table 3: Table 3: Adverse Events 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.

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 TRACLEER n=258 Placebo n=172 No. % No. % Respiratory Tract Infection Respiratory Tract Infection combines the terms "Nasopharyngitis", "Upper Respiratory Tract Infection" and "Respiratory Tract Infection". Combined data from Study 351, BREATHE-1 and EARLY 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% - - TRACLEER was evaluated for safety in 119 pediatric patients in uncontrolled studies. The safety profile was similar to that observed in adult patients with PAH. Decreased Sperm 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 adult TRACLEER-treated patients was 0.9 g/dL (change to end of treatment). Most of this decrease of hemoglobin concentration was detected during the first few weeks of TRACLEER treatment and hemoglobin levels stabilized by 4–12 weeks of TRACLEER treatment. In placebo-controlled studies of all uses of TRACLEER, marked decreases in hemoglobin (>15% decrease from baseline resulting in values <11 g/dL) were observed in 6% of TRACLEER-treated patients and 3% of placebo-treated patients.

In patients with PAH treated with doses of 125 and 250 mg twice daily, marked decreases in hemoglobin occurred in 3% compared to 1% in placebo-treated patients. A decrease in hemoglobin concentration by at least 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. In a pooled analysis of pediatric patients (N=100) with PAH treated with TRACLEER, a decrease in hemoglobin levels to <10 g/dL from baseline was reported in 11% of patients.

There was no decrease to <8 g/dL.

6.2Postmarketing Experience There

have been several postmarketing reports of angioedema associated with the use of TRACLEER. The onset of the reported cases occurred within 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 post approval 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 Liver failure Hypersensitivity, DRESS, and anaphylaxis Thrombocytopenia Rash Jaundice Anemia requiring transfusion Neutropenia and leukopenia Nasal congestion Autoimmune hepatitis