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 for ambrisentan tablets are presented from two 12-week, placebo-controlled studies (ARIES-1 and ARIES-2) in patients with pulmonary arterial hypertension (PAH).
The exposure to ambrisentan in these studies ranged from 6 days to 100 days. In ARIES-1 and ARIES-2, a total of 261 patients received ambrisentan tablets at doses of 2.5, 5, or 10 mg once daily and 132 patients received placebo. The adverse reactions that occurred in > 3% more patients receiving ambrisentan tablets than receiving placebo are shown in Table 1. Table 1 Adverse Reactions with Placebo-Adjusted Rates > 3% in ARIES-1 and ARIES-2 Placebo (N = 132) Ambrisentan Tablets (N = 261) Adverse Reaction n (%) n (%) Placebo-adjusted (%) Peripheral edema 14 (11) 45 (17) 6 Nasal congestion 2 (2) 15 (6) 4 Sinusitis 0 (0) 8 (3) 3 Flushing 1 (1) 10 (4) 3 Most adverse drug reactions were mild to moderate and only nasal congestion was dose-dependent.
Few notable differences in the incidence of adverse reactions were observed for patients by age or sex. Peripheral edema was similar in younger patients (< 65 years) receiving ambrisentan tablets (14%; 29/205) or placebo (13%; 13/104), and was greater in elderly patients (≥ 65 years) receiving ambrisentan tablets (29%; 16/56) compared to placebo (4%; 1/28). The results of such subgroup analyses must be interpreted cautiously.
The incidence of treatment discontinuations due to adverse events other than those related to PAH during the clinical trials in patients with PAH was similar for ambrisentan tablets (2%; 5/261 patients) and placebo (2%; 3/132 patients). The incidence of patients with serious adverse events other than those related to PAH during the clinical trials in patients with PAH was similar for placebo (7%; 9/132 patients) and for ambrisentan tablets (5%; 13/261 patients).
During 12-week controlled clinical trials, the incidence of aminotransferase elevations > 3 x upper limit of normal (ULN) were 0% on ambrisentan tablets and 2.3% on placebo. In practice, cases of hepatic injury should be carefully evaluated for cause. Use in Patients with Prior Endothelin Receptor Antagonist (ERA) Related Serum Liver Enzyme Abnormalities In an uncontrolled, open-label study, 36 patients who had previously discontinued endothelin receptor antagonists (ERAs: bosentan, an investigational drug, or both) due to aminotransferase elevations > 3 x ULN were treated with ambrisentan tablets.
Prior elevations were predominantly moderate, with 64% of the ALT elevations < 5 x ULN, but 9 patients had elevations > 8 x ULN. Eight patients had been re-challenged with bosentan and/or the investigational ERA and all eight had a recurrence of aminotransferase abnormalities that required discontinuation of ERA therapy. All patients had to have normal aminotransferase levels on entry to this study. Twenty-five of the 36 patients were also receiving prostanoid and/or phosphodiesterase type 5 (PDE5) inhibitor therapy.
Two patients discontinued early (including one of the patients with a prior 8 x ULN elevation). Of the remaining 34 patients, one patient experienced a mild aminotransferase elevation at 12 weeks on ambrisentan tablets 5 mg that resolved with decreasing the dosage to 2.5 mg, and that did not recur with later escalations to 10 mg. With a median follow-up of 13 months and with 50% of patients increasing the dose of ambrisentan tablets to 10 mg, no patients were discontinued for aminotransferase elevations.
While the uncontrolled study design does not provide information about what would have occurred with re-administration of previously used ERAs or show that ambrisentan tablets led to fewer aminotransferase elevations than would have been seen with those drugs, the study indicates that ambrisentan tablets may be tried in patients who have experienced asymptomatic aminotransferase elevations on other ERAs after aminotransferase levels have returned to normal.
6.2Postmarketing Experience
The following adverse reactions were identified during post-approval use of ambrisentan tablets. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to estimate reliably the frequency or to establish a causal relationship to drug exposure: anemia requiring transfusion [see Warnings and Precautions (5.5) ] , heart failure (associated with fluid retention), symptomatic hypotension, and hypersensitivity (e.g., angioedema, rash).
Elevations of liver aminotransferases (ALT, AST) have been reported with ambrisentan tablets use; in most cases alternative causes of the liver injury could be identified (heart failure, hepatic congestion, hepatitis, alcohol use, hepatotoxic medications). Other endothelin receptor antagonists have been associated with elevations of aminotransferases, hepatotoxicity, and cases of liver failure [see Adverse Reactions (6.1) ].
