Included as part of the PRECAUTIONS section.
Letairis 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, and Use in Specific
Letairis is only available for females through a
restricted program under a REMS [see Letairis REMS Program].
Letairis REMS Program
For all females, Letairis is available only through a
restricted program called the Letairis REMS, because of the risk of
embryo-fetal toxicity [see CONTRAINDICATIONS, Embryo-fetal Toxicity, and Use In Specific Populations].
Notable requirements of the Letairis REMS program include
- Prescribers must be certified with the program by
enrolling and completing training.
- All females, regardless of reproductive potential, must
enroll in the Letairis REMS program prior to initiating Letairis. 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
- Pharmacies that dispense Letairis must be certified with
the program and must dispense to female patients who are authorized to receive
Further information is available at www.letairisrems.com
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 Letairis compared
to placebo [see ADVERSE REACTIONS]. Most edema was mild to moderate in
In addition, there have been postmarketing reports of
fluid retention in patients with pulmonary hypertension, occurring within weeks
after starting Letairis. Patients required intervention with a diuretic, fluid
management, or, in some cases, hospitalization for decompensating heart
If clinically significant fluid retention develops, with
or without associated weight gain, further evaluation should be undertaken to
determine the cause, such as Letairis or underlying heart failure, and the
possible need for specific treatment or discontinuation of Letairis therapy.
Peripheral edema/fluid retention is more common with
Letairis plus tadalafil than with Letairis or tadalafil alone.
Pulmonary Edema With Pulmonary Veno-occlusive Disease
If patients develop acute pulmonary edema during
initiation of therapy with vasodilating agents such as Letairis, the
possibility of PVOD should be considered, and if confirmed Letairis should be
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. Letairis may have an adverse effect on
spermatogenesis. Counsel patients about potential effects on fertility [see Use
in Specific Populations and Nonclinical Toxicology].
Decreases in hemoglobin concentration and hematocrit have
followed administration of other endothelin receptor antagonists and were
observed in clinical studies with Letairis. These decreases were observed within
the first few weeks of treatment with Letairis, and stabilized thereafter. The
mean decrease in hemoglobin from baseline to end of treatment for those
patients receiving Letairis in the 12-week placebo-controlled studies was 0.8
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 Letairis (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
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
Measure hemoglobin prior to initiation of Letairis, at
one month, and periodically thereafter. Initiation of Letairis 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 Letairis.
Patient Counseling Information
Advise patients to read the
FDA-approved patient labeling (Medication Guide).
Instruct patients on the risk
of fetal harm when Letairis is used in pregnancy [see WARNINGS AND
PRECAUTIONS and Use In Specific Populations]. Female patients must enroll in the Letairis REMS program.
Instruct females of reproductive potential to immediately contact their physician
if they suspect they may be pregnant.
Letairis REMS Program
For female patients, Letairis
is only available through a restricted program called the Letairis REMS [see CONTRAINDICATIONS,
WARNINGS AND PRECAUTIONS]. Male patients are not enrolled in the Letairis REMS.
Inform female patients (and
their guardians, if applicable) of the following notable requirements:
- All female patients must sign an enrollment form.
- Advise female patients of reproductive potential that
they must comply with the pregnancy testing and contraception requirements [see Use In Specific Populations].
- Educate and counsel females of reproductive potential on
the use of emergency contraception in the event of unprotected sex or known or
suspected contraceptive failure.
- Advise pre-pubertal females to report any changes in
their reproductive status immediately to their prescriber.
Review the Letairis Medication Guide and REMS educational
material with female patients.
A limited number of pharmacies are certified to dispense
Letairis. Therefore, provide patients with the telephone number and website for
information on how to obtain the product.
Advise patients of the symptoms of potential liver injury
and instruct them to report any of these symptoms to their physician.
Advise patients of the importance of hemoglobin testing.
Other Risks Associated with Letairis
Instruct patients that the risks associated with Letairis
also include the following:
- Decreases in sperm count
- Fluid overload
Advise patients not to split, crush, or chew tablets.
Impairment Of Fertility
Oral carcinogenicity studies of
up to two years duration were conducted at starting doses of 10, 30, and 60
mg/kg/day in rats (8 to 48 times the maximum recommended human dose [MRHD] on a
mg/m² basis) and at 50, 150, and 250 mg/kg/day in mice (28 to 140 times
the MRHD). In the rat study, the high-and mid-dose male and female groups had
their doses lowered to 40 and 20 mg/kg/day, respectively, in week 51 because of
effects on survival. The high-dose males and females were taken off drug
completely in weeks 69 and 93, respectively. The only evidence of
ambrisentan-related carcinogenicity was a positive trend in male rats, for the
combined incidence of benign basal cell tumor and basal cell carcinoma of
skin/subcutis in the mid-dose group (high-dose group excluded from analysis),
and the occurrence of mammary fibroadenomas in males in the high-dose group. In
the mouse study, high-dose male and female groups had their doses lowered to
150 mg/kg/day in week 39 and were taken off drug completely in week 96 (males) or
week 76 (females). In mice, ambrisentan was not associated with excess tumors
in any dosed group.
Positive findings of
clastogenicity were detected, at drug concentrations producing moderate to high
toxicity, in the chromosome aberration assay in cultured human lymphocytes.
There was no evidence for genetic toxicity of ambrisentan when tested in vitro
in bacteria (Ames test) or in vivo in rats (micronucleus assay, unscheduled DNA
The development of testicular
tubular atrophy and impaired fertility has been linked to the chronic
administration of endothelin receptor antagonists in rodents. Testicular
tubular degeneration was observed in rats treated with ambrisentan for two
years at doses ≥ 10 mg/kg/day (8-fold MRHD). Increased incidences of
testicular findings were also observed in mice treated for two years at doses
≥ 50 mg/kg/day (28-fold MRHD). Effects on sperm count, sperm morphology,
mating performance, and fertility were observed in fertility studies in which
male rats were treated with ambrisentan at oral doses of 300 mg/kg/day
(236-fold MRHD). At doses of ≥ 10 mg/kg/day, observations of testicular
histopathology in the absence of fertility and sperm effects were also present.
Use In Specific Populations
Pregnancy Category X.
Letairis may cause fetal harm when administered to a
pregnant woman and is contraindicated during pregnancy. Letairis was
teratogenic in rats and rabbits at doses which resulted in exposures of 3.5 and
1.7 times, respectively, the human dose of 10 mg per day. If this drug is used
during pregnancy, or if the patient becomes pregnant while taking this drug,
advise the patient of the potential hazard to a fetus [see CONTRAINDICATIONS,
WARNINGS AND PRECAUTIONS].
Letairis was teratogenic at oral dosages of ≥ 15
mg/kg/day (AUC 51.7 h•μg/mL) in rats and ≥ 7 mg/kg/day (24.7
h•μg/mL) in rabbits; it was not studied at lower dosages. These dosages
are of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day (14.8
h•μg/mL) based on AUC. In both species, there were 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.
A preclinical study in rats has shown decreased survival
of newborn pups (mid and high dosages) and effects on testicle size and
fertility of pups (high dosage) following maternal treatment with ambrisentan
from late gestation through weaning. The mid and high dosages were 51 x, and
170 x (on a mg/m²
body surface area basis) the maximum oral human
dose of 10 mg and an average adult body weight of 70 kg. These effects were
absent at a maternal dosage 17 x the human dose based on mg/m² .
It is not known whether ambrisentan is present in human
milk. Because many drugs are present in human milk and because of the potential
for serious adverse reactions in nursing infants from Letairis, a decision
should be made whether to discontinue nursing or discontinue Letairis, taking into
account the importance of the drug to the mother.
Safety and effectiveness of Letairis in pediatric
patients have not been established.
In the two placebo-controlled clinical studies of
Letairis, 21% of patients were ≥ 65 years old and 5% were ≥ 75 years
old. The elderly (age ≥ 65 years) showed less improvement in walk
distances with Letairis than younger patients did, but the results of such
subgroup analyses must be interpreted cautiously. Peripheral edema was more
common in the elderly than in younger patients.
Females And Males Of Reproductive Potential
Female patients of reproductive potential must have a
negative pregnancy test prior to initiation of treatment, monthly pregnancy
test during treatment, and 1 month after stopping treatment with Letairis.
Advise patients to contact their healthcare provider if they become pregnant or
suspect they may be pregnant. Perform a pregnancy test if pregnancy is
suspected for any reason. For positive pregnancy tests, counsel patient on the
potential risk to the fetus and patient options [see BOXED WARNING and DOSAGE
Female patients of reproductive potential must use
acceptable methods of contraception during treatment with Letairis and for 1
month after stopping treatment with Letairis. Patients may choose one highly
effective form of contraception (intrauterine device (IUD), contraceptive
implant, or tubal sterilization) or a combination of methods (hormone method
with a barrier method or two barrier methods). If a partner's vasectomy is the
chosen method of contraception, a hormone or barrier method must be used along
with this method. Counsel patients on pregnancy planning and prevention,
including emergency contraception, or designate counseling by another
healthcare provider trained in contraceptive counseling [see BOXED WARNING].
In a 6-month study of another endothelin receptor
antagonist, bosentan, 25 male patients with WHO functional class III and IV PAH
and normal baseline sperm count were evaluated for effects on testicular
function. There was a decline in sperm count of at least 50% in 25% of the
patients after 3 or 6 months of treatment with bosentan. One patient developed
marked oligospermia at 3 months, and the sperm count remained low with 2
follow-up measurements over the subsequent 6 weeks. Bosentan was discontinued
and after 2 months the sperm count had returned to baseline levels. In 22 patients
who completed 6 months of treatment, sperm count remained within the normal
range and no changes in sperm morphology, sperm motility, or hormone levels
were observed. Based on these findings and preclinical data [see Nonclinical
Toxicology] from endothelin receptor antagonists, it cannot be excluded
that endothelin receptor antagonists such as Letairis have an adverse effect on
spermatogenesis. Counsel patients about the potential effects on fertility [see
WARNINGS AND PRECAUTIONS].
The impact of renal impairment on the pharmacokinetics of
ambrisentan has been examined using a population pharmacokinetic approach in
PAH patients with creatinine clearances ranging between 20 and 150 mL/min.
There was no significant impact of mild or moderate renal impairment on
exposure to ambrisentan [see CLINICAL PHARMACOLOGY]. Dose adjustment of
Letairis in patients with mild or moderate renal impairment is therefore not
required. There is no information on the exposure to ambrisentan in patients
with severe renal impairment.
The impact of hemodialysis on the disposition of
ambrisentan has not been investigated.
Pre-existing Hepatic Impairment
The influence of pre-existing hepatic impairment on the
pharmacokinetics of ambrisentan has not been evaluated. Because there is in
vitro and in vivo evidence of significant metabolic and biliary contribution to
the elimination of ambrisentan, hepatic impairment might be expected to have
significant effects on the pharmacokinetics of ambrisentan [see CLINICAL
PHARMACOLOGY]. Letairis is not recommended in patients with moderate or
severe hepatic impairment. There is no information on the use of Letairis in
patients with mild pre-existing impaired liver function; however, exposure to
ambrisentan may be increased in these patients.
Elevation of Liver Transaminases
Other endothelin receptor antagonists (ERAs) have been
associated with aminotransferase (AST, ALT) elevations, hepatotoxicity, and
cases of liver failure [see ADVERSE REACTIONS]. In patients who develop
hepatic impairment after Letairis initiation, the cause of liver injury should
be fully investigated. Discontinue Letairis if elevations of liver
aminotransferases are > 5 x ULN or if elevations are accompanied by bilirubin
> 2 x ULN, or by signs or symptoms of liver dysfunction and other causes are