Ambrisentan is an oral cardiovascular agent that belongs to a class of compounds known as endothelin-receptor antagonists and is indicated as monotherapy or in combination with tadalafil for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I). Unlike bosentan, which is a competitive antagonist for both type A and B endothelin-1 (ET-1) receptors, ambrisentan is a highly selective and potent endothelin-A receptor antagonist. Endothelin-A receptor selectivity is believed to offer advantages by blocking the deleterious vasoconstrictive effects of endothelin-A on pulmonary vasculature while maintaining the vasodilator and ET-1 clearance functions of endothelin-B. In two randomized, double-blind, 12-week, placebo-controlled phase 3 studies (ARIES-1 and ARIES-2), treatment with ambrisentan resulted in a significant improvement in 6-minute walking distances (6MWD) and a significant delay in time to clinical worsening. Ambrisentan is contraindicated in pregnancy and, due to the teratogenic potential, all prescribers, pharmacies, and female patients must enroll in the Ambrisentan REMS program. Pregnancy testing is required in women of reproductive potential before initiating treatment and routinely during therapy. Further information is available at www.ambrisentanrems.us.com.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
NOTE: Due to the risk of birth defects, all prescribers, patients, and pharmacies must enroll in a risk evaluation and mitigation strategy (REMS) program.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 3
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Oral liquid drugs require double chemotherapy gloves and protective gown. Eye/face and respiratory protection may be needed during preparation and administration.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Administer with or without food. Do not split, crush, or chew the tablets.
The safety of ambrisentan was evaluated in 483 patients with PAH during two 12-week, placebo-controlled studies (ARIES-1 and ARIES-2) as well as four non placebo-controlled studies. Doses ranged from 1-10 mg/day PO. Drug exposure ranged from 1 day to 4 years (n = 418 for at least 6 months and n = 343 for at least 1 year). Treatment discontinuations due to adverse events other than those related to pulmonary arterial hypertension were the same between the ambrisentan and placebo groups (2% for both groups). The incidence of serious adverse events other than those related to pulmonary arterial hypertension were similar for ambrisentan (7%) and placebo (5%).
Hypersensitivity reactions, including angioedema and rash (unspecified), have been reported during post-marketing experience with ambrisentan.
Peripheral edema, a clinical consequence of pulmonary arterial hypertension (PAH) and a known-class effect of endothelin receptor antagonists, was reported in 17% of patients taking ambrisentan vs. 11% of patients taking placebo during clinical trials of ambrisentan monotherapy. Most of the cases of peripheral edema were mild to moderate in severity. Peripheral edema is more common with ambrisentan plus tadalafil than with either agent alone. During combination clinical trials, peripheral edema was reported in 45% of patients receiving combined therapy compared to 38% of those receiving ambrisentan alone and 28% of patients in the tadalafil monotherapy group. If clinically significant peripheral edema develops during treatment with ambrisentan, further evaluation should occur to determine the cause and need for specific treatment. Subgroup analyses of ambrisentan monotherapy trials indicate the incidence of peripheral edema was greater in elderly patients (65 years of age and older) receiving ambrisentan compared to placebo (29% for ambrisentan vs. 4% for placebo). The incidence of peripheral edema was similar in patients less than 65 years of age compared to placebo (14% vs. 13%). Among study participants in the combination therapy trial, no difference in the incidence of peripheral edema was observed in elderly patients (65 years and older) compared to younger patients on combination therapy (44% vs. 45%) or ambrisentan monotherapy (37% vs. 39%). Fluid retention requiring intervention (i.e., diuretic therapy, fluid management, or hospitalization for decompensated heart failure) has been reported within weeks of initiation of ambrisentan therapy. If fluid retention with or without associated weight gain develops, patients should be evaluated to determine the cause of fluid retention (e.g., ambrisentan or underlying heart failure) and the necessity of a specific intervention or discontinuation of ambrisentan therapy. If patients develop acute pulmonary edema during initiation of therapy with ambrisentan, consider the possibility of pulmonary veno-occlusive disease (PVOD). Discontinue use of ambrisentan if PVOD is confirmed. Flushing (4% for ambrisentan vs. 1% for placebo) was also reported during clinical trials.
Elevated hepatic enzymes have been reported with ambrisentan; however, in most cases, alternative causes of the liver injury could be identified (e.g., heart failure, hepatic congestion, hepatitis, alcohol use, hepatotoxic medications). Ambrisentan should be discontinued if hepatic enzyme elevations greater than 5 times the ULN are observed, if aminotransferase elevations are accompanied by hyperbilirubinemia (i.e., bilirubin greater than 2 times ULN), or if clinical signs of hepatic impairment or hepatitis (such as anorexia, nausea, vomiting, fever, right upper quadrant abdominal pain, itching, jaundice, fatigue, or malaise) are reported. Other endothelin receptor antagonists have been associated with elevations of aminotransferases, hepatotoxicity, and cases of liver failure. During clinical trials, LFT elevations greater than 3 times ULN occurred in 0% of ambrisentan-treated patients and in 2.3% of placebo-treated patients.
Respiratory-related adverse reactions reported during clinical trials of ambrisentan monotherapy, compared to placebo, include nasal congestion (6% vs. 2%) and sinusitis (3% vs. 0%). During clinical trials of ambrisentan and tadalafil combination therapy, nasal congestion was reported in 19% of those receiving combination therapy, 16% of those receiving ambrisentan monotherapy, and 11% of those receiving tadalafil monotherapy. Cough was reported in 18% of those receiving combination therapy compared to 13% of those receiving ambrisentan monotherapy and 16% of those in the tadalafil monotherapy group. Bronchitis also was reported in the combination therapy clinical trial (10% combination vs. 4% ambrisentan vs. 9% tadalafil).
Decreases in hemoglobin concentration and hematocrit are class effects with endothelin receptor antagonists and were observed in clinical trials with ambrisentan. Decreases in hemoglobin concentration of greater than 15% from baseline were observed in 7% of all patients receiving ambrisentan compared to 4% of patients receiving placebo. Anemia was reported more often in the combination clinical trial involving ambrisentan and tadalafil. Of those receiving combination therapy, anemia was reported in 15% of patients compared to 7% in the ambrisentan monotherapy group and 11% of those receiving tadalafil monotherapy. The decreases in hematocrit and hemoglobin concentrations were observed within the first few weeks of treatment and stabilized thereafter. The mean decrease in hemoglobin from baseline to the end of treatment in the 12-week placebo-controlled, ambrisentan monotherapy studies was 0.8 g/dL. During post-marketing use of ambrisentan, decreases in hemoglobin and hematocrit resulting in anemia requiring transfusion have been reported. Patients should be monitored for signs and symptoms of anemia; hemoglobin must be measured prior to initiation of ambrisentan therapy and periodically thereafter. If a clinically significant decrease in hemoglobin concentration is observed and other causes can not be excluded, discontinuation of therapy should be considered.
Ambrisentan is contraindicated during pregnancy. Ambrisentan may cause fetal harm if administered to a pregnant woman. When administered to animals, ambrisentan caused teratogenesis; effects included abnormalities of the lower jaw and hard and soft palate, malformation of the heart and great vessels, and failure of formation of the thymus and thyroid. There are no data on the use of ambrisentan in pregnant women. Pregnancy must be excluded before and during treatment (including 1 month after discontinuation of therapy) with ambrisentan by the use of 2 reliable methods of contraception including at least one primary form of contraception.
Administration of ambrisentan may be associated with decreased sperm counts (oligospermia). Twenty-five male patients with WHO functional class III and IV primary arterial hypertension and normal baseline sperm count were enrolled in a 6-month, open-label, single arm, multicenter safety study evaluating the effect on testicular function of bosentan, an endothelin receptor antagonist similar to ambrisentan. Of 23 patients who completed the study, 25% experienced a reduction in sperm count of at least 50% at 3 or 6 months. Marked oligospermia occurred in one patient at 3 months with sperm counts remaining low in 2 subsequent measurements over 6 weeks; however, sperm counts returned to baseline levels within 2 months after discontinuation of the drug. In 22 patients who completed 6 months of bosentan therapy, sperm counts remained within the normal range with no observed changes in sperm morphology, sperm motility, or hormone levels. Additionally, testicular atrophy and impaired fertility have been associated with the chronic administration of endothelin-receptor antagonists in rodents. Testicular tubular degeneration was seen in rats treated with ambrisentan for 2 years at doses equivalent to 8 times the maximum recommended human dose. Further effects on sperm count and morphology, fertility, and mating performance were observed in studies in which male rats were treated with oral ambrisentan at doses equivalent to 236 times the maximum recommended human dose.
Asthenia and dizziness were reported during postmarketing use of ambrisentan. A causal relationship has not been established.
During clinical trials of combination therapy with ambrisentan and tadalafil, headache was reported in 41% of patients taking combination therapy compared to 34% of those in the ambrisentan monotherapy group and 35% of those receiving tadalafil monotherapy.
During combination therapy clinical trials including ambrisentan and tadalafil, dyspepsia was reported in 11% of patients taking combination therapy compared to 3% of those in the ambrisentan monotherapy group and 12% of those receiving tadalafil monotherapy.
Symptomatic hypotension has been reported with the post-marketing use of ambrisentan.
Use ambrisentan with caution in patients with hepatic disease. Ambrisentan is not recommended for use in patients with moderate or severe hepatic impairment. There is no information available on the use of ambrisentan in patients with mild hepatic impairment; because hepatic impairment might be expected to have significant effects on the pharmacokinetics of ambrisentan, exposure to ambrisentan may be increased in these patients. Elevations of liver aminotransferases (ALT, AST) have been reported with ambrisentan; however, in most cases, alternative causes of the liver injury could be identified (e.g., 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. During clinical trials, liver function test (LFT) elevations > 3 times the upper limit of normal (ULN) occurred in 0% of ambrisentan-treated patients and in 2.3% of placebo-treated patients. In patients who have previously experienced liver function abnormalities while taking bosentan, ambrisentan may be considered. In an open-label study, 36 patients who had previously discontinued endothelin receptor antagonists due to elevated aminotransferase more than 3 times the ULN were treated with ambrisentan. Patients received ambrisentan 2.5 mg PO once daily for 4 weeks, followed by 5 mg PO once daily for 20 weeks, and then 2.5 mg, 5 mg, or 10 mg PO once daily thereafter. After a median of 13 months of follow-up, 50% of patients were receiving ambrisentan 10 mg PO once daily. One patient receiving 5 mg PO once daily experienced a mild elevation in LFTs that required a temporary dose reduction to 2.5 mg PO once daily; the patient subsequently tolerated 10 mg PO once daily. During this study, no patients discontinued ambrisentan secondary to LFT elevations.
Decreases in hemoglobin concentration and hematocrit are class effects with endothelin receptor antagonists and were observed in clinical trials with ambrisentan. Ambrisentan should not be initiated in patients with clinically significant anemia. The cause of these effects on hemoglobin concentration and hematocrit is unknown; however, it does not appear to be a result of hemorrhage or hemolysis. Decreases in hematocrit and hemoglobin concentrations have been observed within the first few weeks of treatment and have stabilized thereafter. Hemoglobin must be measured prior to initiation of ambrisentan therapy and then periodically. If a clinically significant decrease in hemoglobin concentration is observed and other causes cannot be excluded, discontinuation of therapy should be considered.
Peripheral edema is a known class effect of endothelin receptor antagonists and was reported during ambrisentan clinical trials. In placebo-controlled studies, there was an increased incidence of peripheral edema in patients treated with ambrisentan 5 or 10 mg compared to placebo. In addition, peripheral edema is more common with the combination of ambrisentan and tadalafil then with either medication alone. Most edema was mild to moderate in severity, and it occurred with greater frequency and severity in geriatric patients. If clinically significant fluid retention develops during ambrisentan therapy, further evaluation should occur to determine the cause of fluid retention and whether ambrisentan therapy should be discontinued. Post-marketing reports exist 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. During the 2 placebo-controlled clinical trials of ambrisentan, 21% of patients were 65 years of age or older and 5% were 75 years of age or older. Patients 65 years of age or older showed less improvement in walk distance and had a higher incidence of peripheral edema with ambrisentan than did younger patients. Due to the potential for age-related changes in hepatic function, initiate ambrisentan cautiously in elderly patients, with close monitoring of drug effects.
The possibility of pulmonary veno-occlusive disease (VOD) should be considered in patients who develop acute pulmonary edema during initiation of therapy with ambrisentan. Discontinue use of ambrisentan if pulmonary VOD is confirmed.
Ambrisentan is contraindicated in patients with idiopathic pulmonary fibrosis (IPF), including IPF patients with pulmonary hypertension (WHO Group 3). In a clinical study of patients with IPF, with or without pulmonary hypertension, the risk of disease progression or death was higher in the ambrisentan group compared to placebo. More patients taking ambrisentan died (8% vs. 4%), had a respiratory hospitalization (13% vs. 6%), and had a decrease in FVC/DLCO (17% vs. 12%) than in the placebo group.
Ambrisentan is contraindicated during pregnancy. Data on ambrisentan use during pregnancy is limited; however, it may cause fetal harm if administered to a pregnant woman. When administered to animals, ambrisentan caused teratogenic effects including abnormalities of the lower jaw and hard and soft palate, malformation of the heart and great vessels, and failure of formation of the thymus and thyroid. To prevent ambrisentan exposure during pregnancy, a REMS program has been developed. This program requires prescribers, pharmacists, and patients to comply with certain conditions before prescribing, dispensing, or receiving ambrisentan. If pregnancy does occur during treatment, the prescriber and patient should discuss the potential hazard to a fetus and desirability of continuing the pregnancy. Prescribers should report all cases of pregnancy to the FDA MedWatch program at 800-FDA-1088 and the REMS program.
It is not known whether ambrisentan is excreted in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in a breast-feeding infant from ambrisentan, discontinue breast-feeding or discontinue ambrisentan, taking into account the importance of the drug to the mother. The molecular weight is low enough and elimination half-life is long enough to allow for excretion; however, the low lipid solubility and high plasma binding may reduce the amount in milk. The effect of exposure to a breast-feeding infant is unknown, but the potential for toxicity is a concern. Epoprostenol may be a reasonable alternative in breast-feeding women.
Discuss the reproductive risk of ambrisentan and contraception requirements, including the need for pregnancy testing before and during therapy with the female patient of childbearing potential. For females of childbearing potential, exclude pregnancy prior to initiation of therapy. Follow-up pregnancy tests should occur monthly and for 1 month after stopping treatment. Advise female patients of childbearing potential to contact their physician immediately if they become pregnant or suspect they may be pregnant. If a pregnancy test is positive, counsel the patient on the potential risk to the fetus and discuss options. To prevent pregnancy, females of reproductive potential must use acceptable contraception methods during treatment and for 1 month after discontinuation of ambrisentan therapy. The patient may choose a single highly effective contraceptive form, including an intrauterine device (IUD), contraceptive implant, or tubal sterilization, or a combination of a hormonal contraceptive with a barrier method or 2 barrier methods. If a male partner's vasectomy is chosen as a method of contraception, a hormonal or barrier method must still be used by the female patient. Counsel patients on pregnancy planning and prevention, including emergency contraception. Ambrisentan carries a potential for infertility in males; decreased sperm counts have been observed in male patients receiving endothelin receptor antagonists. Preclinical data also suggest that ambrisentan, like other endothelin receptor antagonists, may have an adverse effect on spermatogenesis.
For the treatment of pulmonary hypertension to improve exercise ability and delay clinical worsening in persons with WHO Group 1 pulmonary hypertension:
Oral dosage:
Adults: 5 mg PO once daily for 4 weeks, with or without tadalafil, then increase dose to 10 mg PO once daily as needed and tolerated.
Children* and Adolescents* 5 to 17 years: 5 to 10 mg PO once daily.
Maximum Dosage Limits:
-Adults
10 mg/day PO.
-Elderly
10 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Ambrisentan is not recommended in patients with moderate or severe hepatic impairment. Information is not available for patients with mild hepatic impairment; however, exposure to ambrisentan may be increased in these patients. Discontinue ambrisentan if aminotransferase elevations are greater than 5 times ULN or if elevations are accompanied by bilirubin greater than 2 times ULN or by signs or symptoms of liver dysfunction and other causes are excluded.
Patients with Renal Impairment Dosing
CrCl 20 mL/min or greater: No dosage adjustment necessary.
CrCl less than 20 mL/min: Pharmacokinetic studies have not been conducted; data on dosage adjustment are not available.
*non-FDA-approved indication
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Acetaminophen; Dextromethorphan; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Acetaminophen; Guaifenesin; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Acetaminophen; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Alfuzosin: (Moderate) The manufacturer warns that the combination of alfuzosin with antihypertensives, such as ambrisentan, has the potential to cause hypotension in some patients.
Amiloride: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Amphetamine: (Minor) Sympathomimetics such as amphetamine or dextroamphetamine can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy of ambrisentan.
Amphetamine; Dextroamphetamine Salts: (Minor) Sympathomimetics such as amphetamine or dextroamphetamine can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy of ambrisentan.
Amphetamine; Dextroamphetamine: (Minor) Sympathomimetics such as amphetamine or dextroamphetamine can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy of ambrisentan.
Articaine; Epinephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Asenapine: (Moderate) Secondary to alpha-blockade, asenapine can produce vasodilation that may result in additive effects during concurrent use of antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of asenapine and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
Benzphetamine: (Minor) Sympathomimetics such as benzphetamine can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy of ambrisentan.
Brompheniramine; Dextromethorphan; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Brompheniramine; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Bupivacaine; Epinephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Cariprazine: (Moderate) Orthostatic vital signs should be monitored in patients who are at risk for hypotension, such as those receiving cariprazine in combination with antihypertensive agents. Atypical antipsychotics may cause orthostatic hypotension and syncope, most commonly during treatment initiation and dosage increases. Patients should be informed about measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning, or rising slowly from a seated position. Consider a cariprazine dose reduction if hypotension occurs.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Chlorpheniramine; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Codeine; Phenylephrine; Promethazine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Co-Enzyme Q10, Ubiquinone: (Moderate) Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10.
Cyclosporine: (Major) When coadministering ambrisentan with cyclosporine, the ambrisentan dose should not be titrated to the recommended maximum daily dose. Limit the adult dose of ambrisentan to 5 mg once daily when coadministered with cyclosporine. Cyclosporine is a strong inhibitor of P-glycoprotein, OATP, and CYP3A4. In vitro data indicate ambrisentan is a substrate of P-glycoprotein, OATP, and CYP3A4. Cyclosporine twice daily (targeting a trough concentration of 150 - 200 ng/mL) and ambrisentan (5 mg once daily) were coadministered in a 14-day repeated dose study in healthy volunteers. The AUC and Cmax of ambrisentan increased approximately 2-fold and 1.5-fold, respectively.
Dexmethylphenidate: (Moderate) Methylphenidate derivatives can reduce the hypotensive effect of antihypertensive agents. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidates and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate derivatives.
Dextroamphetamine: (Minor) Sympathomimetics such as amphetamine or dextroamphetamine can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy of ambrisentan.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Diazoxide: (Major) Additive hypotensive effects can occur with the concomitant administration of diazoxide and ambrisentan. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly. The manufacturer advises that IV diazoxide should not be administered to patients within 6 hours of receiving other antihypertensive agents.
Diethylpropion: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Diphenhydramine; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Dobutamine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Dopamine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Duloxetine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Dutasteride; Tamsulosin: (Minor) Because symptoms of orthostasis (e.g., postural hypotension, dizziness, vertigo) are reported more frequently in tamsulosin-treated vs. placebo patients, there is a potential risk of enhanced hypotensive effects when co-administered with antihypertensive agents.
Ephedrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Ephedrine; Guaifenesin: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Epinephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Eplerenone: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Epoprostenol: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Etomidate: (Minor) General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with ambrisentan may increase the risk of developing hypotension.
General anesthetics: (Minor) General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with ambrisentan may increase the risk of developing hypotension.
Guaifenesin; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Iloperidone: (Moderate) Secondary to alpha-blockade, iloperidone can produce vasodilation that may result in additive effects during concurrent use with antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of iloperidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
Iloprost: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Isocarboxazid: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives or medications with hypotensive properties such as ambrisentan. Careful monitoring of blood pressure is suggested during concurrent therapy.
Isoflurane: (Minor) General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with ambrisentan may increase the risk of developing hypotension.
Isoproterenol: (Moderate) Isoproterenol is not a potent vasopressor; however, it does increase cardiac output. The pharmacologic effects of isoproterenol may cause an increase in blood pressure. If isoproterenol is used concomitantly with antihypertensives, the blood pressure should be monitored as the administration of isoproterenol can compromise the effectiveness of antihypertensive agents.
Ketamine: (Minor) General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with ambrisentan may increase the risk of developing hypotension.
Lidocaine; Epinephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Lisdexamfetamine: (Minor) Sympathomimetics such as lisdexamfetamine can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy of ambrisentan.
Lurasidone: (Moderate) Due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents. If concurrent use of lurasidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
Mepivacaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
Methamphetamine: (Minor) Sympathomimetics such as methamphetamine can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with methamphetamine.
Methylphenidate Derivatives: (Moderate) Methylphenidate derivatives can reduce the hypotensive effect of antihypertensive agents. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidates and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate derivatives.
Methylphenidate: (Moderate) Methylphenidate derivatives can reduce the hypotensive effect of antihypertensive agents. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidates and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate derivatives.
Midodrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Minoxidil: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Monoamine oxidase inhibitors: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives or medications with hypotensive properties such as ambrisentan. Careful monitoring of blood pressure is suggested during concurrent therapy.
Nitroprusside: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Norepinephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Oxymetazoline: (Major) The vasoconstricting actions of oxymetazoline, an alpha adrenergic agonist, may reduce the antihypertensive effects produced by ambrisentan. If these drugs are used together, closely monitor for changes in blood pressure.
Pentoxifylline: (Moderate) Pentoxifylline has been used concurrently with antihypertensive drugs (beta blockers, diuretics) without observed problems. Small decreases in blood pressure have been observed in some patients treated with pentoxifylline; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensives. If indicated, dosage of the antihypertensive agents should be reduced.
Phendimetrazine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Phenelzine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives or medications with hypotensive properties such as ambrisentan. Careful monitoring of blood pressure is suggested during concurrent therapy.
Phenoxybenzamine: (Moderate) Phenoxybenzamine is an antagonist at alpha-receptors. The hypotensive effects of phenoxybenzamine can be additive with those of other antihypertensive agents.
Phentermine: (Major) Sympathomimetics, such as phentermine, can antagonize the effects of vasodilators such as ambrisentan when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Phentermine; Topiramate: (Major) Sympathomimetics, such as phentermine, can antagonize the effects of vasodilators such as ambrisentan when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Phentolamine: (Moderate) Although the duration of action of phentolamine is short, its onset is very rapid. The hypotensive effects of phentolamine can be additive with that of other antihypertensive agents.
Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Potassium-sparing diuretics: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Prazosin: (Moderate) Prazosin is well-known to produce a 'first-dose' phenomenon. The first dose response (acute postural hypotension) of prazosin may be exaggerated in patients who are receiving other antihypertensive agents. Lower dosages of each agent should be used.
Prilocaine; Epinephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Promethazine; Phenylephrine: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
Propofol: (Minor) General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with ambrisentan may increase the risk of developing hypotension.
Rasagiline: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives or medications with hypotensive properties. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with vasodilators. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
Serdexmethylphenidate; Dexmethylphenidate: (Moderate) Methylphenidate derivatives can reduce the hypotensive effect of antihypertensive agents. Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidates and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate derivatives.
Sevoflurane: (Minor) General anesthtics may be associated with hypotension; however the frequency is less than with inhalational anesthetic agents. Concomitant use with ambrisentan may increase the risk of developing hypotension.
Sildenafil: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Silodosin: (Moderate) During clinical trials with silodosin, the incidence of dizziness and orthostatic hypotension was higher in patients receiving concomitant antihypertensive treatment. Thus, caution is advisable when silodosin is administered with antihypertensive agents.
Sotalol: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Sparsentan: (Contraindicated) Concomitant use of sparsentan and endothelin receptor antagonists (ERAs) is contraindicated due to the additive risk for serious adverse effects such as hypotension, syncope, hyperkalemia, and renal dysfunction.
Spironolactone: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Tamsulosin: (Minor) Because symptoms of orthostasis (e.g., postural hypotension, dizziness, vertigo) are reported more frequently in tamsulosin-treated vs. placebo patients, there is a potential risk of enhanced hypotensive effects when co-administered with antihypertensive agents.
Tizanidine: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Tranylcypromine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives or medications with hypotensive properties such as ambrisentan. Careful monitoring of blood pressure is suggested during concurrent therapy.
Triamterene: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Although no specific interactions have been documented, ambrisentan has vasodilatory effects and may contribute additive hypotensive effects when given with other antihypertensive agents. Patients receiving ambrisentan in combination with other antihypertensive agents should be monitored for decreases in blood pressure.
Ambrisentan is a selective endothelin-A receptor antagonist. Endothelin-1 (ET-1), a potent autocrine and paracrine peptide produced primarily by vascular endothelial cells, possesses powerful vasoconstrictor and mitogenic properties. Plasma ET-1 concentrations are elevated in patients with pulmonary arterial hypertension (PAH) and correlate with increased mean right atrial pressure and disease severity. Two receptor subtypes, A and B, have been identified to mediate the effects of ET-1 on vascular smooth muscle cells. Stimulation of the endothelin-A receptor results in vasoconstriction and cell proliferation. Stimulation of the endothelin-B receptor produces vasodilation, antiproliferation, and ET-1 clearance. Ambrisentan antagonizes endothelin-A with high affinity and is highly selective for endothelin-A vs. endothelin-B (> 4000-fold). High selectivity for the endothelin-A receptor is believed to offer advantages in blocking the deleterious vasoconstrictive effects of endothelin-A on pulmonary vasculature, while maintaining the vasodilatory and ET-1 clearance functions of endothelin-B in patients with PAH.
Ambrisentan is administered orally. In healthy subjects, pharmacokinetic parameters are dose proportional. Ambrisentan is highly bound to plasma proteins (99%). It is metabolized by CYP3A, CYP2C19, and uridine 5'-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S. Additionally, in vitro data indicate that it is a substrate of Organic Anion Transport Protein (OATP) and P-glycoprotein (P-gp). Ambrisentan is eliminated primarily by non-renal pathways; however, relative contributions of metabolism and biliary elimination have not been well characterized. The terminal half-life is 15 hours; the effective half-life is 9 hours.
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A, CYP2C19, UGT 1A9S, UGT 2B7S, UGT 1A3S, OATP, P-gp
-Route-Specific Pharmacokinetics
Oral Route
After administration, ambrisentan is rapidly absorbed with maximum plasma concentrations occurring within 2 hours in healthy subjects and patients with pulmonary arterial hypertension (PAH). The absolute bioavailability of ambrisentan is not known; food has no effect on bioavailability. The mean clearance of ambrisentan after oral administration is 38 mL/min in healthy subjects and 19 mL/min in patients with PAH.