(am bri SEN tan)
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Letairis: 5 mg, 10 mg [contains fd&c red #40 aluminum lake]
Brand Names: U.S.
- Endothelin Receptor Antagonist
Blocks endothelin receptor subtypes ETA and ETB on vascular endothelium and smooth muscle. Stimulation of ETA receptors, located primarily in pulmonary vascular smooth muscle cells is associated with vasoconstriction and cellular proliferation. Stimulation of ETB receptors, located in both pulmonary vascular endothelial cells and smooth muscle cells is associated with vasodilation, antiproliferative effects, and endothelin clearance. Although ambrisentan blocks both ETA and ETB receptors, the affinity is greater for the ETA receptor (>4,000-fold higher affinity).
Hepatic via CYP3A4, CYP2C19, and uridine 5'-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S; in vitro studies also suggest it is a substrate of organic anion transporting polypeptides (OATP) 1B1 and 1B3 and P-glycoprotein (P-gp)
Time to Peak
Special Populations: Hepatic Function Impairment
Influence of hepatic impairment has not been evaluated; however, hepatic impairment would be expected to have significant effects on ambrisentan pharmacokinetics.
Use: Labeled Indications
Pulmonary arterial hypertension: Treatment of pulmonary artery hypertension (PAH) (World Health Organization [WHO] Group I) to improve exercise ability and delay clinical worsening; in combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability. Studies establishing effectiveness included predominantly patients with WHO Functional Class II to III symptoms and etiologies of idiopathic or heritable PAH (60%) or PAH associated with connective tissue diseases (34%).
Note: According to treatment guidelines from the Fifth World Symposium on Pulmonary Hypertension (WSPH), only a small number of PAH patients with WHO-FC IV symptoms (ie, severely ill patients) were included in clinical trials, therefore, most experts consider ambrisentan second-line therapy in these patients (WSPH [Gailè 2013]).
Pregnancy; idiopathic pulmonary fibrosis, including idiopathic pulmonary fibrosis with pulmonary hypertension (WHO Group 3)
Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to ambrisentan or any component of the formulation; severe hepatic impairment (with or without cirrhosis); ALT or AST >3 times ULN at baseline; breastfeeding
Pulmonary arterial hypertension: Adults: Oral: Initial: 5 mg once daily, with or without tadalafil; if tolerated, may increase at 4-week intervals to a maximum of 10 mg/day
Dosage adjustment for concomitant therapy: Coadministration with cyclosporine: Ambrisentan dose should not exceed 5 mg/day
Dosage adjustment in renal impairment:
Mild-to-moderate impairment: No dosage adjustment necessary.
Severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
Canadian labeling: No dosage adjustment necessary.
Dosage adjustment in hepatic impairment:
Mild impairment: There are no dosage adjustments provided in the manufacturer’s labeling; exposure may be increased.
Moderate or severe impairment: Use not recommended.
Mild or moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution and monitor closely.
Severe impairment: Use is contraindicated.
ALT or AST >3 times ULN at baseline: Use is contraindicated.
Impairment developing during therapy:
ALT or AST >5 times ULN: Discontinue therapy.
ALT or AST increased with signs/symptoms of hepatic injury or with bilirubin >2 times ULN: Discontinue therapy.
ALT or AST >3 times ULN: Discontinue therapy.
ALT or AST increased with signs/symptoms of hepatic injury or with bilirubin >2 times ULN: Discontinue therapy.
May consider reinitiation after ALT or AST levels normalize and if there are no signs/symptoms of hepatic injury or jaundice.
Oral: Swallow tablet whole. Do not split, crush, or chew tablets. Administer with or without food. Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).
Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Store in original packaging.
CycloSPORINE (Systemic): May increase the serum concentration of Ambrisentan. Management: Limit ambrisentan dose to 5 mg/day and monitor for ambrisentan adverse reactions in patients receiving systemic cyclosporine. Consider therapy modification
Frequency not always defined.
Cardiovascular: Peripheral edema (14% to 38%), flushing (4%)
Central nervous system: Headache (34%)
Gastrointestinal: Dyspepsia (3%)
Hematologic & oncologic: Decreased hemoglobin (7% to 10%; dose-dependent), anemia (7%), decreased hematocrit
Respiratory: Nasal congestion (6% to 16%), cough (13%), bronchitis (4%), sinusitis (3%)
<1% (Limited to important or life-threatening): Cardiac failure, dizziness, hypersensitivity, hypotension, increased liver enzymes, weakness
Concerns related to adverse effects:
• Fluid retention/peripheral edema: Development of peripheral edema due to treatment and/or disease state (pulmonary arterial hypertension) may occur; a higher incidence is seen with concomitant use of tadalafil and in elderly patients. There have also been postmarketing reports of fluid retention requiring treatment (eg, diuretics, fluid management, hospitalization). Further evaluation may be necessary to determine cause and appropriate treatment or discontinuation of therapy.
• Hematologic changes: A reduction in hematocrit/hemoglobin may be observed within the first few weeks of therapy with subsequent stabilization of levels. Hemoglobin reductions >15% have been observed in some patients. Measure hemoglobin prior to initiating therapy, at 1 month, and periodically thereafter. Significant decreases in hemoglobin in the absence of other causes may warrant the discontinuation of therapy. Use not recommended in patients with clinically significant anemia.
• Hepatic effects: Increases in serum liver aminotransferases have been reported during postmarketing use; however, in the majority of the cases, alternative causes of hepatotoxicity could be identified. Perform liver enzyme testing when clinically indicated. Discontinue therapy if signs/symptoms of hepatic injury appear, if serum liver aminotransferases >5 times ULN (US labeling) or >3 times ULN (Canadian labeling) are observed, or if aminotransferases are increased in the presence of bilirubin >2 times ULN. Hepatotoxicity has been reported with other endothelin receptor antagonists (eg, bosentan); however, ambrisentan may be tried in patients that have experienced asymptomatic increases in liver enzymes caused by another endothelin receptor antagonist after the liver enzymes have returned to normal.
• Spermatogenesis: Sperm count may be reduced in men during treatment (as observed with bosentan). No changes in sperm function or hormone levels have been noted. Fertility issues may require discussion with patient.
• Hepatic impairment: Use caution in patients with mild hepatic impairment; ambrisentan exposure may be increased. The US labeling does not recommend use in patients with moderate or severe impairment. The Canadian labeling recommends use with caution in moderate impairment with monthly monitoring of ALT/AST during therapy and contraindicates use in severe hepatic impairment (with or without cirrhosis) and in patients with ALT or AST >3 times ULN at baseline.
• Pulmonary veno-occlusive disease (PVOD): Discontinue in any patient with pulmonary edema suggestive of PVOD.
• Pregnancy: [US Boxed Warning]: May cause birth defects; use in pregnancy is contraindicated. Exclude pregnancy prior to initiation of therapy and obtain pregnancy tests monthly during treatment and for 1 month after therapy is complete. Reliable contraception must be used during therapy and for 1 month after stopping treatment. Two reliable methods of contraception (eg, hormone method with a barrier method or two barrier methods) must be used throughout treatment and for one month after stopping treatment. Patients who have undergone a tubal ligation or the insertion of a contraceptive implant or intrauterine device (Copper T 380A or LNg 20) do not require additional contraceptive measures. A missed menses or suspected pregnancy should be reported to a healthcare provider and prompt immediate pregnancy testing. Women should also be educated on the appropriate use of emergency contraception if failure of contraceptive is known or suspected or in the event of unprotected sex.
• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).
Concurrent drug therapy issues:
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
• Letairis REMS Program: [US Boxed Warning]: Because of the high likelihood of teratogenic effects, ambrisentan is only available through the Letairis REMS restricted distribution program. Female patients (regardless of reproductive potential), prescribers, and pharmacies must be registered with and meet conditions of the program. Call 1-866-664-5327 or visit www.letairisrems.com for more information.
Monitor for significant peripheral edema and evaluate etiology if it occurs; hepatic enzyme testing when clinically appropriate. The Canadian labeling recommends hepatic function testing at baseline then as clinically indicated (all patients) and monthly during therapy (patients with moderate impairment or other risk factors [eg, significant right heart failure, preexisting hepatic disease or previously elevated transaminases, concurrent medications known to increase transaminases]).
A woman of childbearing potential must have a negative pregnancy test prior to the initiation of therapy, monthly during treatment, and 1 month after stopping treatment. Hemoglobin and hematocrit should be measured at baseline, at 1 month, and periodically thereafter (generally stabilizes after the first few weeks of treatment).
Pregnancy Risk Factor
[US Boxed Warning]: May cause birth defects; use in pregnancy is contraindicated. Exclude pregnancy prior to initiation of therapy and obtain pregnancy tests monthly during treatment and for 1 month after therapy is complete. Reliable contraception must be used during therapy and for 1 month after stopping treatment. Based on animal studies, ambrisentan is likely to produce major birth defects if used by pregnant women. Two reliable methods of contraception (eg, hormone method with a barrier method or 2 barrier methods) must be used throughout treatment and for 1 month after stopping treatment. Patients who have undergone a tubal ligation or the insertion of a contraceptive implant or intrauterine device (Copper T 380A or LNg 20) do not require additional contraceptive measures. A missed menses or suspected pregnancy should be reported to a healthcare provider and prompt immediate pregnancy testing. Sperm counts may be reduced in men during treatment (as observed with bosentan). In general, women with pulmonary hypertension should avoid pregnancy (Badesch, 2007; McLaughlin, 2009).
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience headache, flushing, cough, or rhinorrhea. Have patient report immediately to prescriber signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), dyspnea, excessive weight gain, swelling of arm or leg, or loss of strength and energy (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.
More about ambrisentan
- Other brands: Letairis