AMBRISENTAN Drug Interactions: What You Need to Know

INTERACTIONS Multiple dose coadministration 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 coadministered with cyclosporine [see Clinical Pharmacology (12.3) ]. Cyclosporine increases ambrisentan exposure; limit ambrisentan dose to 5 mg once daily ( 7 ).

Drug Interactions In Vitro Studies

Studies with human liver tissue indicate that ambrisentan is metabolized by CYP3A, CYP2C19, and uridine 5’-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S. In vitro studies suggest that ambrisentan is a substrate of the Organic Anion Transporting Polypeptides OATP1B1 and OATP1B3, and P-glycoprotein (P-gp). Drug interactions might be expected because of these factors; however, a clinically relevant interaction has been demonstrated only with cyclosporine [see Drug Interactions (7) ] . In vitro studies found ambrisentan to have little to no inhibition of human hepatic transporters. Ambrisentan demonstrated weak dose-dependent inhibition of OATP1B1, OATP1B3, and NTCP (IC 50 of 47 μM, 45 μM, and approximately 100 μM, respectively) and no transporter-specific inhibition of BSEP, BRCP, P-gp, or MRP2. Ambrisentan does not inhibit or induce drug metabolizing enzymes at clinically relevant concentrations.

In Vivo Studies

The effects of other drugs on ambrisentan pharmacokinetics and the effects of ambrisentan on the exposure to other drugs are shown in Figure 2 and Figure 3, respectively.

Figure

2 Effects of Other Drugs on Ambrisentan Pharmacokinetics Figure 3 Effects of Ambrisentan on Other Drugs Figure 2 Effects of Other Drugs on Ambrisentan Pharmacokinetics Figure 3 Effects of Ambrisentan on Other Drugs

Pregnancy ( 4.1 )

Idiopathic Pulmonary

Fibrosis ( 4.2 )

4.1 Pregnancy Ambrisentan tablets may cause fetal harm when administered to a pregnant female. Ambrisentan tablets are contraindicated in females who are pregnant. Ambrisentan tablets were consistently shown to have teratogenic effects when administered to animals. 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 ), and Use in Specific Populations ( 8.1 )]</span> .

4.2 Idiopathic Pulmonary Fibrosis Ambrisentan tablets are contraindicated in patients with Idiopathic Pulmonary Fibrosis (IPF), including IPF patients with pulmonary hypertension (WHO Group 3) <span class="opacity-50 text-xs">[see Clinical Studies ( 14.4 )]</span> .

AND PRECAUTIONS Fluid retention may require intervention ( 5.3 ). If patients develop acute pulmonary edema during initiation of therapy with ambrisentan, consider underlying pulmonary veno-occlusive disease and discontinue treatment if necessary ( 5.4 ). Decreases in sperm count have been observed in patients taking endothelin receptor antagonists ( 5.5 ). Decreases in hemoglobin have been observed within the first few weeks; measure hemoglobin at initiation, at 1 month, and periodically thereafter ( 5.6 ). 5.1. Embryo-fetal Toxicity Ambrisentan may cause fetal harm when administered during pregnancy and is contraindicated for use in females who are pregnant. In females of reproductive potential, exclude pregnancy prior to initiation of therapy, ensure use of acceptable contraceptive methods, and obtain monthly pregnancy tests [see Dosage and Administration (2.2) , and Use in Specific Populations ( 8.1 , 8.3 )] . Ambrisentan is only available for females through a restricted program under a REMS [see Warnings and Precautions (5.2) ] . 5.2. Ambrisentan REMS Program For all females, ambrisentan is available only through a restricted program called the Ambrisentan REMS, because of the risk of embryo-fetal toxicity [see Contraindications (4.1) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.1 , 8.3) ] . Notable requirements of the Ambrisentan REMS program include the following: Prescribers must be certified with the program by enrolling and completing training. All females, regardless of reproductive potential, must enroll in the Ambrisentan REMS program prior to initiating ambrisentan. Male patients are not enrolled in the REMS. Females of reproductive potential must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.3) ]. Pharmacies that dispense ambrisentan must be certified with the program and must dispense to female patients who are authorized to receive ambrisentan. Further information is available at www.ambrisentanrems.us.com or 1-888-417-3172. 5.3.

Fluid Retention

Peripheral edema is a known class effect of endothelin receptor antagonists, and is also a clinical consequence of PAH and worsening PAH. In the placebo-controlled studies, there was an increased incidence of peripheral edema in patients treated with doses of 5 or 10 mg ambrisentan compared to placebo [see Adverse Reactions (6.1) ] . Most edema was mild to moderate in severity. In addition, there have been postmarketing reports of fluid retention in patients with pulmonary hypertension, occurring within weeks after starting ambrisentan. Patients required intervention with a diuretic, fluid management, or, in some cases, hospitalization for decompensating heart failure. If clinically significant fluid retention develops, with or without associated weight gain, further evaluation should be undertaken to determine the cause, such as ambrisentan or underlying heart failure, and the possible need for specific treatment or discontinuation of ambrisentan therapy. Peripheral edema/fluid retention is more common with ambrisentan plus tadalafil than with ambrisentan or tadalafil alone. 5.4.

Pulmonary

Edema with Pulmonary Veno-occlusive Disease (PVOD) If patients develop acute pulmonary edema during initiation of therapy with vasodilating agents such as ambrisentan, the possibility of PVOD should be considered, and if confirmed ambrisentan should be discontinued. 5.5.

Decreased Sperm Counts

Decreased sperm counts have been observed in human and animal studies with another endothelin receptor antagonist and in animal fertility studies with ambrisentan. Ambrisentan may have an adverse effect on spermatogenesis. Counsel patients about potential effects on fertility [see Use in Specific Populations (8.6) and Nonclinical Toxicology (13.1) ] . 5.6.

Hematological Changes

Decreases in hemoglobin concentration and hematocrit have followed administration of other endothelin receptor antagonists and were observed in clinical studies with ambrisentan. These decreases were observed within the first few weeks of treatment with ambrisentan, and stabilized thereafter. The mean decrease in hemoglobin from baseline to end of treatment for those patients receiving ambrisentan in the 12-week placebo-controlled studies was 0.8 g/dL. Marked decreases in hemoglobin (>15% decrease from baseline resulting in a value below the lower limit of normal) were observed in 7% of all patients receiving ambrisentan (and 10% of patients receiving 10 mg) compared to 4% of patients receiving placebo. The cause of the decrease in hemoglobin is unknown, but it does not appear to result from hemorrhage or hemolysis. In the long-term open-label extension of the two pivotal clinical studies, mean decreases from baseline (ranging from 0.9 to 1.2 g/dL) in hemoglobin concentrations persisted for up to 4 years of treatment. There have been postmarketing reports of decreases in hemoglobin concentration and hematocrit that have resulted in anemia requiring transfusion. Measure hemoglobin prior to initiation of ambrisentan, at one month, and periodically thereafter. Initiation of ambrisentan therapy is not recommended for patients with clinically significant anemia. If a clinically significant decrease in hemoglobin is observed and other causes have been excluded, consider discontinuing ambrisentan.