Ambrisentan

Indications

Ambrisentan is used for: Pulmonary Arterial Hypertension

Adult Dose

Indicated for WHO group 1 PAH to 1) improve exercise ability and delay clinical worsening; and 2) in combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability Initiate treatment at 5 mg PO qDay, with or without tadalafil 20 mg PO qDay At 4-week intervals, either ambrisentan or tadalafil dose can be increased, as needed and tolerated, not to exceed ambrisentan 10 mg/day or tadalafil 40 mg/day Coadministration with cyclosporine: Limit ambrisentan to 5 mg/day Hepatic impairment: Ambrisentan is not recommended in patients with moderate or severe hepatic impairment.

Child Dose

Safety and efficacy not established

Renal Dose

Dose adjustment in patients with mild or moderate renal impairment is therefore not required. There is no information on the exposure to ambrisentan in patients with severe renal impairment.

Administration

May be taken with or without food: Swallow whole.

Contra Indications

Ambrisentan may cause fetal harm when administered to a pregnant woman. Ambrisentan is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Pregnancy must be excluded before the initiation of treatment with Ambrisentan and prevented during treatment and for one month after stopping treatment. Ambrisentan is contraindicated in patients with Idiopathic Pulmonary Fibrosis (IPF) including IPF patients with pulmonary hypertension (WHO Group 3).

Precautions

Fluid Retention: Peripheral oedema has been observed with ERAs including ambrisentan. It is also a clinical consequence of PAH and worsening PAH. Pulmonary Veno-occlusive Disease: If patients develop acute pulmonary edema during initiation of therapy with vasodilating agents such as Ambrisentan, the possibility of pulmonary veno-occlusive disease should be considered, and if confirmed. Ambrisentan should be discontinued. Hematological Changes: Decreases in hemoglobin concentration and hematocrit have followed administration of other endothelin receptor antagonists and were observed in clinical studies with Ambrisentan. Lactation: Excretion in milk unknown; not recommended

Pregnancy-Lactation

Pregnancy Based on data from animal reproduction studies, fetal harm may occur when administered to a pregnant woman and is contraindicated during pregnancy There are limited data on use in pregnant women Advise patient of the potential hazard to a fetus Animal data In animal reproduction studies, ambrisentan was teratogenic in rats and rabbits at doses which resulted in exposures of 3.5 and 1.7 times, respectively, the human dose of 10 mg/day Contraception Female patients of reproductive potential must use acceptable methods of contraception during treatment and for 1 month after stopping treatment Patients should choose one highly effective form of contraception (intrauterine device [IUD], contraceptive implant, or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods) If a partner’s vasectomy is one method of contraception, a hormone or barrier method must be used along with this method Counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling Infertility Males: Based on findings and preclinical data, endothelin receptor antagonists have an adverse effect on spermatogenesis; counsel patients about the potential effects on fertility Lactation Unknown whether present in human milk Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

Interactions

Cyclosporine Exposure to ambrisentan may be increased (approximately 2-fold). Limit the dosage of ambrisentan to 5 mg daily with coadministration. Rifampin Coadministration was associated with a 2-fold increase in ambrisentan AUC. Use with caution.

Adverse Effects

Side effects of Ambrisentan : >10% Peripheral edema (17%), Headache (15%) 1-10% Nasal congestion (6%), Palpitations (5%), Constipation (4%), Dyspnea (4%), Flushing (4%), Abdominal pain (3%), Nasopharyngitis (3%), Sinusitis (3%)

Mechanism of Action

High affinity endothelin (ETa) receptor subtype antagonist, resulting in inhibition of vasoconstriction.