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%) [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.

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%) ( 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 ).

6 ADVERSE REACTIONS The following important adverse reactions are described elsewhere in the labeling: Hepatotoxicity [see Boxed Warning , Warnings and Precautions (5.1) ] Embryo-fetal Toxicity [see Boxed Warning , Warnings and Precautions (5.3) ] Fluid Retention [see Warnings and Precautions (5.4) ] Common adverse reactions (≥3% more than placebo) for the film-coated tablet are respiratory tract infection and anemia ( 6.1 ).

Common adverse reactions (≥15%) for the dispersible tablet are upper respiratory tract infections and pyrexia ( 6.1 ).

To report SUSPECTED ADVERSE REACTIONS, contact Actelion at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 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.

6.2 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 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 [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 Autoimmune hepatitis