Embelin 5 mg

INDICATIONS

Ambrisentan is indicated for the treatment of Pulmonary Arterial Hypertension (PAH) (WHO Group 1) to improve exercise ability and delay clinical worsening.

PHARMACOLOGY

Endothelin-1 (ET-1) is a potent autocrine and paracrine peptide. Two receptor subtypes, ETA and ETB, mediate the effects of ET-1 in the vascular smooth muscle and endothelium. The primary actions of ETA are vasoconstriction and cell proliferation, while the predominant actions of ETB are vasodilation, antiproliferation, and ET-1 clearance. Ambrisentan is a high-affinity ETA receptor antagonist with a high selectivity for the ETA versus ETB receptor (>4000-fold). The clinical impact of high selectivity for ETA is not known.The pharmacokinetics of Ambrisentan (S-Ambrisentan) in healthy subjects are dose proportional. The absolute bioavailability of Ambrisentan is not known. Ambrisentan is absorbed with peak concentrations occurring approximately 2 hours after oral administration in healthy subjects and PAH patients. Food does not affect its bioavailability. In vitro studies indicate that Ambrisentan is a substrate of P-gp. Ambrisentan is highly bound to plasma proteins (99%). The elimination of Ambrisentan is predominantly by non-renal pathways, but the relative contributions of metabolism and biliary elimination have not been well characterized. In plasma, the AUC of 4-hydroxymethyl Ambrisentan accounts for approximately 4% relative to parent Ambrisentan AUC. Thein vivo inversion of S-Ambrisentan to R-Ambrisentan is negligible. The mean oral clearance of Ambrisentan is 38 mL/min and 19 mL/min in healthy subjects and in PAH patients, respectively. Although Ambrisentan has a 15-hour terminal half-life, the mean trough concentration of Ambrisentan at steady-state is about 15% of the mean peak concentration and the accumulation factor is about 1.2 after long-term daily dosing, indicating that the effective half-life of Ambrisentan is about 9 hours.

DOSAGE & ADMINISTRATION

Adult dose: Initial treatment is 5 mg once daily, and can be increased to 10 mg once daily if 5 mg is tolerated. Ambrisentan may be administered with or without food.Pediatric patients: The safety and effectiveness of Ambrisentan in pediatric patients have not been established.

INTERACTION

Multiple dose co-administration of Ambrisentan and Cyclosporine resulted in an approximately 2-fold increase in Ambrisentan exposure in healthy volunteers; therefore, limit the dose of Ambrisentan to 5 mg once daily when co-administered with Cyclosporine.

SIDE EFFECTS

Decreases in hemoglobin concentration and hematocrit have followed administration of other endothelin receptor antagonists and were observed in clinical studies with Ambrisentan

PREGNANCY & LACTATION

Pregnancy Category X. It is not known whether Ambrisentan is excreted in human milk. Breastfeeding while receiving Ambrisentan is not recommended.

PRECAUTIONS & WARNINGS

Fluid Retention: Peripheral edema is a known class effect of endothelin receptor antagonists, and 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 con_rmed. 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.Hepatic impairment: Ambrisentan is not recommended in patients with moderate or severe hepatic impairment.

THERAPEUTIC CLASS

Anti-hypertensive, Endothelin receptor antagonist

STORAGE CONDITIONS

Store in a cool and dry place, below 30°C. Protect from light and moisture.