ADVERSE REACTIONS
ADVERSE EVENTS
See BOX WARNING for discussion of liver injury and PRECAUTIONS for discussion of hemoglobin and hematocrit abnormalities.
Safety data on bosentan were obtained from 12 clinical studies (8 placebo-controlled and 4 open-label) in 777 patients with pulmonary arterial hypertension, and other diseases. Doses up to 8 times the currently recommended clinical dose (125 mg b.i.d.) were administered for a variety of durations. The exposure to bosentan in these trials ranged from 1 day to 4.1 years (N=89 for 1 year; N=61 for 1.5 years and N=39 for more than 2 years). Exposure of pulmonary arterial hypertension patients (N=235) to bosentan ranged from 1 day to 1.7 years (N=126 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 bosentan (5%; 8/165 patients) than on placebo (3%; 2/80 patients). In this database the only cause of discontinuations > 1%, and occurring more often on bosentan was abnormal liver function.
The adverse drug reactions that occurred in >/= 3% of the bosentan-treated patients and were more common on bosentan in placebo-controlled trials in pulmonary arterial hypertension at doses of 125 or 250 mg b.i.d. are shown in Table 4:
Table 4. Adverse events * occurring in >/= 3% of patients treated with bosentan 125-250 mg b.i.d. and more common on bosentanin placebo-controlled studies in pulmonary arterial hypertension
| Adverse Event |
Bosentan
N=165
|
Placebo
N=80
|
| No. |
%
|
No. |
%
|
|
Headache
|
36
|
22%
|
16
|
20%
|
|
Nasopharyngitis
|
18
|
11%
|
6
|
8%
|
|
Flushing
|
15
|
9%
|
4
|
5%
|
Hepatic function
abnormal
|
14
|
8%
|
2
|
3%
|
|
Edema, lower limb
|
13
|
8%
|
4
|
5%
|
|
Hypotension
|
11
|
7%
|
3
|
4%
|
|
Palpitations
|
8
|
5%
|
1
|
1%
|
|
Dyspepsia
|
7
|
4%
|
0
|
0%
|
|
Edema
|
7
|
4%
|
2
|
3%
|
|
Fatigue
|
6
|
4%
|
1
|
1%
|
|
Pruritus
|
6
|
4%
|
0
|
0%
|
| *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. |
|
In placebo-controlled studies of bosentan in pulmonary arterial hypertension and for other diseases (primarily chronic heart failure), a total of 677 patients were treated with bosentan at daily doses ranging from 100 mg to 2000 mg and 288 patients were treated with placebo. The duration of treatment ranged from 4 weeks to 6 months. For the adverse drug reactions that occurred in >/= 3% of bosentan-treated patients, the only ones that occurred more frequently on bosentan than on placebo (>/= 2% difference) were headache (16% vs. 13%), flushing (7% vs. 2%), abnormal hepatic function (6% vs. 2%), leg edema (5% vs. 1%), and anemia (3% vs. 1%).
LABORATORY ABNORMALITIES
Increased Liver Aminotransferases (see BOX WARNING and WARNINGS).
Decreased Hemoglobin and Hematocrit (see PRECAUTIONS).
LONG-TERM TREATMENT
The long-term follow-up of the patients who were treated with TRACLEER® in the two pivotal studies and their open-label extensions (N=235) shows that 93% and 84% of patients were still alive at 1 and 2 years, respectively, after the start of treatment with TRACLEER®. These estimates may be influenced by the presence of epoprostenol treatment, which was administered to 43/235 patients. Without a control group, these data must be interpreted cautiously and cannot be interpreted as an improvement in survival.
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