Bosentan (Page 3 of 8)

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)].

6 ADVERSE REACTIONS

The following important adverse reactions are described elsewhere in the labeling:

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 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.

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