Three major pathways are involved in abnormal cell proliferation and function associated with PAH.3
Important Safety Information
BOXED WARNING: EMBRYO-FETAL TOXICITY
Do not administer Letairis to a pregnant female because it may cause fetal harm. Letairis is very likely to produce serious birth defects if used by pregnant females, as this effect has been seen consistently when it is administered to animals.
Exclude pregnancy before the initiation of treatment with Letairis. Females of reproductive potential must use acceptable methods of contraception during treatment with Letairis and for one month after treatment. Obtain monthly pregnancy tests during treatment and 1 month after discontinuation of treatment.
Because of the risk of embryo-fetal toxicity birth defects, females can only receive Letairis through a restricted program called the Letairis REMS program.
- Do not administer Letairis to a pregnant woman because it can cause fetal harm.
- Letairis is contraindicated in patients with Idiopathic Pulmonary Fibrosis (IPF) including IPF patients with pulmonary hypertension (WHO Group 3)
Warnings and precautions
- Embryo-fetal Toxicity: Letairis may cause fetal harm when administered during pregnancy.
Letairis REMS Program: For all females, Letairis is only available through a restricted program called Letairis REMS. Some requirements of the Letairis REMS Program include:
Further information is available at www.letairisrems.com or 1-866-664-5327
- 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.
- Pharmacies that dispense Letairis must be certified with the program and must dispense to female patients who are authorized to receive Letairis
- Mild to moderate peripheral edema: Peripheral edema occurred more frequently in elderly patients (age ≥65 years) receiving Letairis (29%; 16/56) compared to placebo (4%; 1/28). Peripheral edema is a known class effect of endothelin receptor antagonists. In addition, there have been postmarketing reports of fluid retention occurring within weeks after starting Letairis that required intervention with a diuretic, fluid management, or, in some cases, hospitalization for decompensating heart failure.
- Pulmonary Edema with PVOD: If patients develop acute pulmonary edema during initiation of therapy with vasodilating agents such as Letairis, pulmonary veno-occlusive disease should be considered, and if confirmed, Letairis should be discontinued.
- Decreases in sperm count have been observed in patients taking endothelin receptor antagonists and in animal fertility studies with ambrisentan. Counsel patients about potential effects on fertility
- Hematologic changes: Decreases in hemoglobin have been observed within the first few weeks of treatment with Letairis, and may persist during treatment. There have been postmarketing reports of anemia requiring transfusion. Measure hemoglobin prior to initiation, at 1 month, and periodically thereafter. Initiation of Letairis therapy is not recommended for patients with clinically significant anemia.
- During 12-week controlled clinical trials, the incidence of liver aminotransferase (AST, ALT) elevations >3x ULN was 0% for Letairis and 2.3% for placebo
- In postmarketing experience, elevations of aminotransferases have been reported with Letairis use; in most cases alternative causes of liver injury could be identified (heart failure, hepatic congestion, hepatitis, alcohol use, hepatotoxic medications). In practice, cases of hepatic injury should be carefully evaluated for cause
- Other ERAs have been associated with aminotransferase elevations, hepatotoxicity, and cases of liver failure
- Discontinue Letairis if aminotransferase elevations are >5x ULN or if elevations are accompanied by bilirubin >2x ULN or by signs or symptoms of liver dysfunction, and other causes are excluded
- Multiple-dose co-administration of Letairis and cyclosporine resulted in an approximately 2-fold increase in Letairis exposure in healthy volunteers. Limit the dose of Letairis to 5 mg once daily when co-administered with cyclosporine
Dosage and administration
Adult Dosage: Initiate treatment at 5 mg once daily, and consider increasing the dose to 10 mg once daily if 5 mg is tolerated. Tablets may be taken with or without food. Tablets should not be split, crushed, or chewed. Doses higher than 10 mg once daily have not been studied in patients with pulmonary arterial hypertension (PAH).
Pregnancy Testing in Females of Reproductive Potential: Initiate treatment with Letairis in females of reproductive potential only after a negative pregnancy test. Obtain monthly pregnancy tests during treatment
Not recommended in patients with moderate or severe hepatic impairment. There is no information on the use of Letairis in patients with mild hepatic impairment; however, exposure to Letairis may be increased in these patients
Please see full Prescribing Information, including BOXED WARNING on the risk of embryo-fetal toxicity.
References: 1. Channick RN, Sitbon O, Barst RJ, Manes A, Rubin LJ. Endothelin receptor antagonists in pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(12, suppl S):62S-67S. 2. Austin ED, Loyd JE. Genetics and mediators in pulmonary arterial hypertension. Clin Chest Med. 2007;28(1):43-57. 3. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351(14):1425-1436. 4. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. J Am Coll Cardiol. 2009;53(17):1573-1619. 5. Galiè N, Manes A, Branzi A. The endothelin system in pulmonary arterial hypertension. Cardiovasc Res. 2004;61(2):227-237. 6. McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation. 2006;114(13):1417-1431.
© 2013 Gilead Sciences, Inc. All rights reserved. LETP0057 September 2013
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