WARNINGS AND PRECAUTIONS
Potential Liver Injury
(SEE BOXED WARNING)
Treatment with endothelin receptor antagonists has been associated with dose-dependent liver injury manifested primarily by elevation of serum aminotransferases (ALT or AST), but sometimes accompanied by abnormal liver function (elevated bilirubin). The combination of aminotransferases greater than 3-times the upper limit of normal (>3 x ULN) and total bilirubin >2 x ULN is a marker for potentially serious hepatic injury.
Liver function tests were closely monitored in all clinical studies with LETAIRIS. For all LETAIRIS-treated patients (N=483), the 12-week incidence of aminotransferases >3 x ULN was 0.8% and >8 x ULN was 0.2%. For placebo-treated patients, the 12-week incidence of aminotransferases >3 x ULN was 2.3% and >8 x ULN was 0.0%. The 1-year rate of aminotransferase elevations >3 x ULN with LETAIRIS was 2.8% and >8 x ULN was 0.5%. One case of aminotransferase elevations >3 x ULN has been accompanied by bilirubin elevations >2 x ULN.
Liver chemistries must be measured prior to initiation of LETAIRIS and at least every month thereafter. If there are aminotransferase elevations >3 x ULN and ≤5 x ULN, they should be re-measured. If the confirmed level is >3 x ULN and ≤5 x ULN, reduce the daily dose or interrupt treatment and continue to monitor every two weeks until the levels are <3 x ULN. If there are aminotransferase elevations >5 x ULN and ≤8 x ULN, LETAIRIS should be discontinued and monitoring should continue until the levels are <3 x ULN. LETAIRIS can then be re-initiated with more frequent measurement of aminotransferase levels. If there are aminotransferase elevations >8 x ULN, treatment should be stopped and re-initiation should not be considered.
LETAIRIS is not recommended in patients with elevated aminotransferases (>3 x ULN) at baseline because monitoring liver injury may be more difficult. If aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant abdominal discomfort, itching, or jaundice) or increases in bilirubin >2 x ULN, LETAIRIS treatment should be stopped. There is no experience with the re-introduction of LETAIRIS in these circumstances.
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.
Hemoglobin must be measured prior to initiation of LETAIRIS and should be measured at one month and periodically thereafter. If a clinically significant decrease in hemoglobin is observed and other causes have been excluded, discontinuation of treatment should be considered.
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 (6)]. 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.
Co-administration of LETAIRIS and Cyclosporine A
Cyclosporine is a strong inhibitor of P-glycoprotein (P-gp), Organic Anion Transport Protein (OATP), and CYP3A4. In vitro data indicate ambrisentan is a substrate of P-gp, OATP and CYP3A. Therefore, use caution when LETAIRIS is co-administered with cyclosporine A because cyclosporine A may cause increased exposure to LETAIRIS [see Drug Interactions (7)].
Co-administration of LETAIRIS and Strong CYP3A and 2C19 Inhibitors
Use caution when LETAIRIS is co-administered with strong CYP3A-inhibitors (e.g., ketoconazole) and CYP2C19-inhibitors (e.g., omeprazole) [see Drug Interactions (7)].
Prescribing and Distribution Program for LETAIRIS
Because of the risks of liver injury and birth defects, LETAIRIS is available only through a special restricted distribution program called the LETAIRIS Education and Access Program (LEAP). Only prescribers and pharmacies registered with LEAP may prescribe and distribute LETAIRIS. In addition, LETAIRIS may be dispensed only to patients who are enrolled in and meet all conditions of LEAP.
To enroll in LEAP, prescribers must complete the LEAP Prescriber Enrollment and Agreement Form indicating agreement to (see LEAP Prescriber Enrollment and Agreement Form for full prescribing physician agreement):
- Read the Prescribing Information (PI) and Medication Guide for LETAIRIS.
- Enroll all patients in LEAP and re-enroll patients after the first 6 months of treatment and annually thereafter.
- Review the LETAIRIS Medication Guide and patient education brochure(s) with every patient.
- Educate patients on the risks of LETAIRIS, including the risks of hepatotoxicity and teratogenicity [see Boxed Warning ].
- Educate and counsel women of childbearing potential to use two different forms of contraception including at least one primary form during LETAIRIS treatment and for one month following treatment discontinuation. If the patient has had a tubal sterilization or a Copper T 380A IUD or LNg 20 IUD inserted, no additional contraception is needed [see Boxed Warning, Contraindication ].
Primary forms of contraception include tubal sterilization, hormonal (combination oral contraceptives, transdermal patch, injectables, implantables, or vaginal ring), IUD, and a partner's vasectomy. A Copper T 380A IUD or LNg 20 IUD can be used alone, i.e. without a secondary form of contraception, as can tubal sterilization.
Secondary forms of contraception include barrier contraceptives such as latex condoms, diaphragms, and cervical caps.
- Order and review liver function tests (including aminotransferases and bilirubin) prior to initiation of LETAIRIS treatment and monthly during treatment.
- For women of childbearing potential, order and review a pregnancy test prior to initiation of LETAIRIS treatment and monthly during treatment.
- Counsel patients who fail to comply with the program requirements.
- Notify LEAP of any adverse events, including liver injury, or if any patient becomes pregnant during LETAIRIS treatment.
Use in Specific Populations
Pregnancy Category X [see Contraindications].
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.
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.
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.
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. Use caution when administering LETAIRIS to patients with mild pre-existing impaired liver function who may require reduced doses of LETAIRIS [see Dosage and Administration].