Precautions of Ambrisentan

1. Embryo-Fetal Toxicity

Based on data from animal reproductive studies, ambrisentan may cause fetal harm when administered during pregnancy and is therefore contraindicated in pregnancy. Available human data on endothelin receptor antagonists have not established whether major birth defects associated with ambrisentan use exist. Inform patients who may become pregnant of the potential risk to the fetus. Obtain the results of a pregnancy test before initiating ambrisentan treatment. Advise patients who may become pregnant to use effective contraception to prevent pregnancy before starting treatment, during treatment, and for one month after discontinuing ambrisentan treatment. Discontinue ambrisentan as soon as pregnancy is detected.

2. Fluid Retention

Peripheral edema is a known class effect of endothelin receptor antagonists and a clinical consequence of pulmonary arterial hypertension (PAH) and PAH exacerbation. In placebo-controlled studies, the incidence of peripheral edema was higher in patients treated with ambrisentan 5 mg or 10 mg compared with placebo. Most cases of edema were mild to moderate in severity.

In addition, post-marketing reports have described fluid retention occurring within weeks of ambrisentan initiation in patients with PAH. These patients required intervention with diuretics, fluid management, or in some cases, hospitalization for decompensated heart failure.

If clinically significant fluid retention occurs, with or without associated weight gain, further evaluation should be performed to determine the cause (e.g., ambrisentan or underlying heart failure) and whether specific treatment or discontinuation of ambrisentan is needed.

Peripheral edema/fluid retention is more common when ambrisentan is used in combination with tadalafil than when ambrisentan or tadalafil is used alone.

3. Pulmonary Edema Associated with Pulmonary Veno-Occlusive Disease (PVOD)

If a patient develops acute pulmonary edema during the initiation of treatment with vasodilators such as ambrisentan, the possibility of PVOD should be considered. If PVOD is confirmed, ambrisentan should be discontinued.

4. Decreased Sperm Count

Decreased sperm counts have been observed in human and animal studies of another endothelin receptor antagonist, as well as in animal fertility studies of ambrisentan. Ambrisentan may have an adverse effect on spermatogenesis.

5. Hematologic Changes

Decreases in hemoglobin concentration and hematocrit have been observed with other endothelin receptor antagonists, and this has also been noted in clinical studies of ambrisentan. These decreases occur within the first few weeks of ambrisentan treatment and then tend to stabilize. In 12-week placebo-controlled studies, the mean decrease in hemoglobin from baseline to the end of treatment was 0.8 g/dL in patients treated with ambrisentan.

A significant decrease in hemoglobin (a >15% decrease from baseline resulting in a value below the lower limit of normal) was observed in 7% of all patients receiving ambrisentan (and 10% of patients receiving 10 mg) compared with 4% of patients receiving placebo. The cause of the hemoglobin decrease is unknown, but it does not appear to be due to bleeding or hemolysis.

In long-term open-label extensions of two pivotal clinical studies, the mean decrease in hemoglobin concentration from baseline (ranging from 0.9 to 1.2 g/dL) persisted for up to 4 years of treatment.

Post-marketing reports have described decreases in hemoglobin concentration and hematocrit leading to anemia requiring transfusion.

Measure hemoglobin before initiating ambrisentan treatment, at 1 month, and periodically thereafter. It is not recommended to initiate ambrisentan treatment in patients with clinically significant anemia. If a clinically significant decrease in hemoglobin is observed and other causes are ruled out, consider discontinuing ambrisentan.

FDA，2025.04