ambrisentan
Generic Name: ambrisentan
(AM bri SEN tan)
Brand Name: Letairis
Pronunciation
(am bri SEN tan)
Index TermsBSF208075Dosage Forms
Excipient information
presented when available (limited, particularly for generics); consult specific
product labeling.
Tablet, Oral:
Letairis: 5 mg, 10 mg
[contains fd&c red #40 aluminum lake]
Brand Names: U.S.LetairisPharmacologic CategoryEndothelin Receptor AntagonistVasodilatorPharmacology
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).
Metabolism
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)
Excretion
Primarily nonrenal
Time to Peak
~2 hours
Half-Life
Elimination
~9 hours
Protein
Binding
99%
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]).
Contraindications
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
Dosing: Adult
Pulmonary arterial
hypertension: Oral: Initial: 5 mg once daily, with
or without tadalafil; at 4-week intervals, as tolerated and necessary, may
increase either the dose of ambrisentan (maximum dose: 10 mg/day) or tadalafil
(if used concomitantly).
Dosage adjustment for
concomitant therapy: Coadministration with
cyclosporine: Ambrisentan dose should not exceed 5 mg/day
Dosing: Geriatric
Refer to adult dosing.
Dosing: Renal Impairment
US labeling:
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.
Dosing: Hepatic Impairment
Preexisting impairment:
US labeling:
Mild impairment: There are no
dosage adjustments provided in the manufacturer’s labeling; exposure may be
increased.
Moderate or severe impairment:
Use not recommended.
Canadian labeling:
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:
US labeling:
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.
Canadian labeling:
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.
Administration
Oral: Swallow tablet whole. Do
not split, crush, or chew tablets. Administer with or without food.
Storage
Store at 25°C (77°F);
excursions are permitted between 15°C and 30°C (59°F and 86°F). Store in
original packaging.
Drug Interactions
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
Adverse Reactions
Frequency not always defined.
Cardiovascular: Peripheral
edema (14% to 38%), flushing (4%)
Central nervous system:
Headache (34%)
Gastrointestinal: Dyspepsia
(3%)
Genitourinary: Oligospermia
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
ALERT: U.S. Boxed Warning
Pregnancy:
Do not administer ambrisentan
to a pregnant woman because it may cause fetal harm. Ambrisentan is very likely
to produce serious birth defects if used by pregnant women because this effect
has been seen consistently when it is administered to animals. Therefore,
pregnancy must be excluded before the initiation of treatment. Females of
reproductive potential must use acceptable methods of contraception during
treatment and for 1 month after treatment. Obtain monthly pregnancy tests
during treatment and 1 month after discontinuation.
Dispensing program:
Because of the risk of
embryo-fetal toxicity, females can only receive ambrisentan through a
restricted program under a Risk Evaluation and Mitigation Strategy (REMS)
called the Letairis REMS program.
Warnings/Precautions
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.
Disease-related concerns:
• 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.
Special populations:
• 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.
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.
Other warnings/precautions:
• 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.
Monitoring Parameters
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
X
Pregnancy Considerations
[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). Women with pulmonary arterial hypertension are
encouraged to avoid pregnancy (McLaughlin 2009; Taichman 2014).
Patient Education
• 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, fatigue, lack of appetite,
nausea, abdominal pain, light-colored stools, vomiting, or jaundice), shortness
of breath, 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.
