Ambrisentan (ambrisentan)

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In vitro studies indicate that ambrisentan is metabolized by cytochrome P-450 (CYP) isoenzymes 3A4 and 2C19 and by uridine 5'-diphosphate glucuronosyltransferases (UGTs; uridine diphosphoglucuronosyltransferase, UDP-glucuronate beta-d-glucuronosyltransferase (acceptor-unspecific)) 1A9S, 2B7S, and 1A3S. The drug appears to be a substrate, but not an inhibitor, of the organic anion transport protein (OATP) and the P-glycoprotein (P-gp) transport system. At clinically relevant concentrations, ambrisentan does not inhibit or induce CYP enzymes.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Ace Inhibitors; Arbs; Eras; Aliskiren/Sparsentan

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Sparsentan is an antagonist of the endothelin type A receptor and the angiotensin II type 1 receptor which are thought to contribute to the pathogenesis of IgA nephropathy.(1) Coadministration with renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs) may result in additive inhibition of angiotensin. RAAS inhibitors include ACE inhibitors, angiotensin II receptor blockers (ARBs), and aliskiren.

CLINICAL EFFECTS: Concurrent use of sparsentan with renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs) may result in hypotension, syncope, hyperkalemia, and changes in renal function (including renal failure).(1)

PREDISPOSING FACTORS: Patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion may be at risk of developing acute kidney injury on sparsentan.(1) Patients with advanced kidney disease or taking concomitant potassium-increasing drugs (e.g., potassium supplements, potassium-sparing diuretics), or using potassium-containing salt substitutes are at increased risk for developing hyperkalemia.(1)

PATIENT MANAGEMENT: Do not coadminister sparsentan with renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs). Prior to initiating treatment with sparsentan, discontinue use of renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs).(1) RAAS inhibitors include ACE inhibitors, angiotensin II receptor blockers (ARBs), and aliskiren.

DISCUSSION: The US manufacturer of sparsentan states that concomitant use of sparsentan with renin-angiotensin-aldosterone system (RAAS) inhibitors and endothelin receptor antagonists (ERAs) is contraindicated.(1) RAAS inhibitors include ACE inhibitors, angiotensin II receptor blockers (ARBs), and aliskiren.

Ambrisentan (> 5 MG)/Cyclosporine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Cyclosporine may inhibit the metabolism/transport of ambrisentan by CYP3A4, OATP, and P-gp.(1,2)

CLINICAL EFFECTS: Concurrent use of cyclosporine may result in elevated levels of and toxicity from ambrisentan.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients maintained on cyclosporine should receive a maximum daily dose of 5 mg of ambrisentan.(1,2)

DISCUSSION: In an open-label, parallel-treatment study, 28 healthy subjects had ambrisentan (5 mg daily) added to steady-state cyclosporine (100-150 mg BID) and 24 subjects had cyclosporine (100-150 mg BID) added to steady-state ambrisentan (5 mg daily). All drug levels were evaluated at steady-state. Ambrisentan maximum concentration (Cmax) and area-under-curve (AUC) increased 1.5-fold and 2-fold, respectively, in the presence of cyclosporine. There were no significant effects on cyclosporine levels. The addition of ambrisentan to cyclosporine was less tolerable than the addition of cyclosporine to ambrisentan therapy.(1,2)

There are no severe interactions for this drug.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Ambrisentan (<=5 MG)/Cyclosporine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Cyclosporine may inhibit the metabolism/transport of ambrisentan by CYP3A4, OATP, and P-gp.(1,2)

CLINICAL EFFECTS: Concurrent use of cyclosporine may result in elevated levels of and toxicity from ambrisentan.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients maintained on cyclosporine should receive a maximum daily dose of 5 mg of ambrisentan.(1,2)

DISCUSSION: In an open-label, parallel-treatment study, 28 healthy subjects had ambrisentan (5 mg daily) added to steady-state cyclosporine (100-150 mg BID) and 24 subjects had cyclosporine (100-150 mg BID) added to steady-state ambrisentan (5 mg daily). All drug levels were evaluated at steady-state. Ambrisentan maximum concentration (Cmax) and area-under-curve (AUC) increased 1.5-fold and 2-fold, respectively, in the presence of cyclosporine. There were no significant effects on cyclosporine levels. The addition of ambrisentan to cyclosporine was less tolerable than the addition of cyclosporine to ambrisentan therapy.(1,2)

*Pregnancy.

*Idiopathic pulmonary fibrosis, with or without pulmonary hypertension (WHO group 3).

• Pregnancy
• Pulmonary fibrosis

There are no severe contraindications for this drug.

• Anemia
• Chronic heart failure
• Disease of liver
• Edema

The most common adverse effects (>3%) of ambrisentan in clinical studies were peripheral edema, nasal congestion, sinusitis, and flushing.

When used in combination with tadalafil, the most common adverse effects (>5% compared to either monotherapy) were peripheral edema, headache, nasal congestion, cough, anemia, dyspepsia, and bronchitis.

More Frequent

• Anemia
• Peripheral edema

Rare or Very Rare

• Abnormal hepatic function tests
• Angioedema
• Body fluid retention
• Heart failure
• Hyperbilirubinemia
• Pulmonary edema

More Frequent

• Flushing
• Nasal congestion
• Oligospermia
• Sinusitis

Rare or Very Rare

• Dizziness
• Fatigue
• General weakness
• Nausea
• Skin rash
• Vomiting

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Safety and efficacy of ambrisentan have not been established in children and adolescents younger than 18 years of age. Juvenile animal data revealed a reduction in brain weight, but no morphologic or neurobehavioral changes following drug exposures 1.8 to 7 times the human pediatric exposures at 10 mg (based on AUC).

Based on data from animal reproduction studies, ambrisentan may cause embryofetal toxicity, including birth defects and fetal death, when administered to pregnant females and is contraindicated during pregnancy. Available data from postmarketing reports and published literature over decades of use with ERAs in the same class as ambrisentan have not identified an increased risk of major birth defects; however, these data are limited. If ambrisentan is used during pregnancy, or if the patient becomes pregnant while taking ambrisentan, clinicians should advise the patient of the fetal risk.

It is not known whether ambrisentan is distributed into human milk. Because many drugs are distributed into human milk and because of the potential for serious adverse reactions to ambrisentan in nursing infants, a decision should be made to discontinue nursing or the drug.

The manufacturer makes no specific dosage recommendations for geriatric patients.

A higher incidence of peripheral edema has been observed in geriatric patients 65 years of age or older relative to younger adults. Clinical trials of ambrisentan included 21% of patients >=65 years of age and 5% of patients >=75 years of age. Improvement in walk distance was less in elderly compared to younger patients, although the prescribing information states to interpret this information, which comes from subgroup analysis, with caution.