Included as part of the PRECAUTIONS section.

LETAIRIS Education and Access Program (LEAP)

Because of the risk of birth defects, LETAIRIS is available only through a restricted program called the LETAIRIS Education and Access Program (LEAP).

Required components of LEAP:

• Healthcare professionals who prescribe LETAIRIS must complete the LEAP Prescriber Enrollment and Agreement Form, enroll in the program, and comply with the REMS requirements.
• To receive LETAIRIS, all patients must complete a patient enrollment form and be re-enrolled annually by their prescriber. For women of childbearing potential, (1) a pregnancy test must be ordered and reviewed by the prescriber prior to initiation of LETAIRIS treatment and monthly during treatment, (2) she must agree to be contacted prior to each shipment to confirm that a pregnancy test was completed, (3) she must agree to be counseled on the requirements of the REMS program and the risks of LETAIRIS, and (4) she must agree to be contacted by Gilead if she becomes pregnant while on Letairis or within 30 days of treatment discontinuation.
• Pharmacies that dispense LETAIRIS must enroll in the program and agree to comply with the REMS requirements.

Further information is available at www.letairisrems.com or 1-866-664-LEAP (5327).

Fluid Retention

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 severity, and it occurred with greater frequency and severity in elderly patients.

In addition, there have been post-marketing 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 failure.

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.

Pulmonary Veno-occlusive Disease

If patients develop acute pulmonary edema during initiation of therapy with vasodilating agents such as LETAIRIS, the possibility of pulmonary veno-occlusive disease should be considered, and if confirmed LETAIRIS should be discontinued.

Decreased Sperm Counts

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.

Hematological Changes

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 g/dL.

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 hemolysis.

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 transfusion.

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

See FDA-approved patient labeling (Medication Guide).

Letairis Education and Access Program (LEAP)

Advise the patient that LETAIRIS is available only through a restricted program called LEAP.

As a component of LEAP, prescribers must review the contents of the LETAIRIS Medication Guide and the Letairis Patient Enrollment Guide before initiating treatment with Letairis.

Inform the patient that LETAIRIS is available only from Certified Specialty Pharmacies enrolled in LEAP. Provide patients with a list of Certified Specialty Pharmacies.

As a component of LEAP, Certified Specialty Pharmacies must provide a copy of the Medication Guide to patients or caregivers each time LETAIRIS is dispensed. Patients must be instructed to read the Medication Guide each time they receive LETAIRIS because new information may be available. In addition, Certified Specialty Pharmacies must contact patients before each shipment to confirm that the patient will be available to receive the LETAIRIS shipment, and, in the case of women of childbearing potential, to confirm that a pregnancy test has been completed.

Patients must complete a patient enrollment form and be re-enrolled annually by their prescribers using the LEAP Patient Enrollment and Consent form to confirm that they understand the risks of LETAIRIS.

Patients may be asked to participate in a survey to evaluate the effectiveness of LEAP.

Pregnancy

Instruct patients that the risks associated with Letairis include serious birth defects if used by pregnant women:

• Educate and counsel women of childbearing potential to use highly reliable contraception during LETAIRIS treatment and for one month after stopping treatment. If the patient has had a tubal sterilization or chooses to use a Copper T 380A IUD or LNg 20 IUS for pregnancy prevention, no additional contraception is needed. Women who do not choose one of these methods should always use two acceptable forms of contraception: one hormone method and one barrier method, or two barrier methods where one method is the male condom.
• Acceptable hormone methods include: progesterone injectables, progesterone implants, combination oral contraceptives, transdermal patch, and vaginal ring.
• Acceptable barrier methods include: diaphragm (with spermicide), cervical cap (with spermicide), and the male condom.
• Partner's vasectomy must be used along with a hormone method or a barrier method.
• Educate and counsel women of childbearing potential on the use of emergency contraception in the event of unprotected sex or known or suspected contraceptive failure [see BOXED WARNING, CONTRAINDICATIONS].

Instruct patient to immediately contact their physician if they suspect they may be pregnant.

Hepatic Effects

Some members of this pharmacological class are hepatotoxic. Patients should be educated on the symptoms of potential liver injury (such as anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant abdominal discomfort, jaundice, dark urine or itching) and instructed to report any of these symptoms to their physician.

Hematological Change

Patients should be advised 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 hemoglobin and hematocrit
• Decreases in sperm count
• Fluid overload

Administration

Patients should be advised not to split, crush, or chew tablets.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, 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 synthesis assay).

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

Pregnancy Category X [see CONTRAINDICATIONS]. Treat women of childbearing potential only after a negative pregnancy test and treat only women who are using acceptable methods of contraception. Pregnancy tests should be obtained monthly in women of childbearing potential taking LETAIRIS [see WARNINGS AND PRECAUTIONS].

Nursing Mothers

It is not known whether ambrisentan is excreted in human milk. Breastfeeding while receiving LETAIRIS is not recommended. A preclinical study in rats has shown decreased survival of newborn pups (mid and high doses) and effects on testicle size and fertility of pups (high dose) following maternal treatment with ambrisentan from late gestation through weaning. Doses tested were 17x, 51x, and 170x (low, mid, high dose, respectively) the maximum oral human dose of 10 mg on a mg/mm² basis.

Pediatric Use

Safety and effectiveness of LETAIRIS in pediatric patients have not been established.

Geriatric Use

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.

Renal Impairment

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.

Hepatic Impairment

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 would 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 aminotransferase elevations > 5x ULN or if elevations are accompanied by bilirubin > 2x ULN, or by signs or symptoms of liver dysfunction and other causes are excluded.

Last reviewed on RxList: 2/24/2012
This monograph has been modified to include the generic and brand name in many instances.