U.S. FDA Removes Warning about Potential Liver Injury from Boxed Warning of Prescribing Information for Gilead's Letairis

FOSTER CITY, Calif., Mar 04, 2011 (BUSINESS WIRE) -- Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the U.S. Food and Drug Administration (FDA) has approved a change to the prescribing information for Letairis^(R) (ambrisentan 5 mg and 10 mg tablets), the company's once-daily treatment to improve exercise ability and delay clinical worsening in pulmonary arterial hypertension (PAH, WHO Group 1) patients with predominantly WHO Functional Class II-III symptoms. This change removes language concerning the potential risk of liver injury from the Boxed Warning. In conjunction with this label update, PAH patients receiving Letairis are no longer required to obtain monthly liver function tests.

The FDA approved the new labeling based on its review of post-marketing data reflecting use of Letairis over more than 7,800 patient years, which were collected through the Letairis Education and Access Program (LEAP). These data were consistent with clinical trial data used to support the registration of Letairis. During 12-week controlled clinical trials, the incidence of liver function abnormalities was 0 percent on Letairis and 2.3 percent on placebo.

"I am encouraged by these post-marketing data, which reflect the use of ambrisentan since its approval in 2007. These data are consistent with the results we have observed in controlled studies," said Ronald J. Oudiz, MD, Professorof Medicine, David Geffen School of Medicine at UCLA and Director, Liu Center for Pulmonary Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center. "This change will be tremendously helpful to both patients and the staff of specialist centers who diligently support them. Pulmonary arterial hypertension is a very complex disease at the best of times, so any steps to simplify care will be warmly welcomed."

Gilead will continue to offer the full services of LabSync, which manages the administrative requirements associated with laboratory testing, to all patients enrolled in LEAP.

Important Safety Information Including Boxed Warning

Letairis is contraindicated in pregnancy.Because of the risk of birth defects, Letairis continues to have a Boxed Warning and can be prescribed and dispensed only through a special restricted distribution program (Letairis Education and Access Program [LEAP]). Only prescribers and pharmacies registered with LEAP may prescribe and distribute Letairis to patients who are enrolled in and meet all the conditions of LEAP. Because Letairis may cause fetal harm if taken during pregnancy, pregnancy must be excluded before the start of treatment and must be prevented during treatment and for one month after stopping treatment by the use of two acceptable methods of contraception unless the patient has had a tubal sterilization or chooses to use a Copper T380A IUD or LNg 20 IUS, in which case no additional contraception is needed. Monthly pregnancy tests must be obtained. Letairis must not be administered to a pregnant woman.

Peripheral edema occurred more frequently in elderly patients (age greater than or equal to 65 years) receiving Letairis (29 percent; 16/56) compared to placebo (4 percent; 1/28). Peripheral edema is a known class effect of endothelin receptor antagonists. In addition, there have been post-marketing reports of fluid retention occurring within weeks after starting Letairis, which required intervention with a diuretic, fluid management, or, in some cases, hospitalization for decompensating heart failure.

Decreases in sperm count have been observed in patients taking endothelin receptor antagonists.

Decreases in hemoglobin have been observed within the first few weeks of treatment with Letairis. It is recommended to 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 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.

The most common adverse events that occurred at a higher frequency among Letairis-treated patients compared to placebo included (placebo-adjusted frequency): peripheral edema (6 percent), nasal congestion (4 percent), sinusitis (3 percent), flushing (3 percent), palpitations (3 percent), nasal pharyngitis (2 percent), abdominal pain (2 percent), constipation (2 percent), dyspnea (1 percent) and headache (1 percent). During 12-week controlled clinical trials, the incidence of aminotransferases elevations greater than three times the upper limit of normal (ULN) were 0 percent on Letairis and 2.3 percent on placebo. In practice, cases of hepatic injury should be carefully evaluated for cause.

In post-marketing experience, elevations of liver aminotransferases (ALT, AST) have been reported with Letairis use. In most cases alternative causes of the liver injury could be identified (heart failure, hepatic congestion, hepatitis, alcohol use, hepatotoxic medications). Other endothelin receptor antagonists have been associated with elevations of aminotransferases, hepatotoxicity and cases of liver failure. It is recommended to discontinue Letairis if aminotransferase elevations greater than five times the ULN are observed or if aminotransferase elevations are accompanied by bilirubin greater than two times the ULN or if there are signs or symptoms of liver dysfunction and other causes are excluded. Tests for serum liver enzymes should be ordered and reviewed as clinically indicated since some members of this pharmacologic class are hepatotoxic.

Multiple-dose co-administration of Letairis and cyclosporine resulted in an approximately two-fold increase in Letairis exposure in healthy volunteers. Therefore, the dose of Letairis should be limited to 5 mg once-daily when co-administered with cyclosporine.

Studies with human liver tissue indicate that Letairis is metabolized by CYP3A, CYP2C19 and uridine 5'-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S and 1A3S. In vitro studies suggest that Letairis is a substrate of the Organic Anion Transport Protein (OATP) and a substrate, but not an inhibitor of P-glycoprotein (P-gp). Drug interactions might be expected because of these factors. However, a clinically relevant interaction has been demonstrated only with cyclosporine. Letairis does not inhibit or induce phase I or II drug metabolizing enzymes at clinically relevant concentrations.

It is recommended to initiate Letairis treatment at 5 mg once-daily with or without food, and to consider increasing the dose to 10 mg once-daily if 5 mg is tolerated. Tablets should not be split, crushed or chewed. 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 hepatic impairment. However, exposure to Letairis may be increased in these patients.

Full prescribing information for Letairis is available at www.gilead.com and at http://www.letairis.com/downloads/LETAIRIS_prescribing_information.pdf.

About Letairis and Indication and Usage

Letairis is a once-daily treatment for pulmonary arterial hypertension (PAH, WHO Group 1) to improve exercise ability and delay clinical worsening. Studies establishing effectiveness of Letairis included predominantly patients with WHO Functional Class II-III symptoms and etiologies of idiopathic or heritable PAH (64 percent) or PAH associated with connective tissue diseases (32 percent). Clinical worsening is defined as the first occurrence of death, lung transplantation, hospitalization for PAH, atrial septostomy, study withdrawal due to the addition of other PAH therapeutic agents or study withdrawal due to early escape.

Letairis is an endothelin receptor antagonist that has a high affinity for the endothelin type-A (ET_A) receptor. Activation of the ET_A receptor by endothelin-1 (ET-1), a small peptide hormone, leads to vasoconstriction (narrowing of blood vessels) and cell proliferation. The clinical impact of high selectivity for ET_A is not known. Endothelin concentrations are higher in the lung tissue of PAH patients, thus suggesting that ET-1 may play a critical role in the pathogenesis or progression of PAH.

About the Letairis Education and Access Program (LEAP)

Because of the risks of birth defects, Letairis is available only through a special restricted distribution program called the Letairis Education and Access Program (LEAP) by calling 1-866-664-LEAP (1-866-664-5327). Only prescribers and pharmacies registered with LEAP are able to prescribe and distribute Letairis. In addition, Letairis may be dispensed only to patients who are enrolled in and meet all conditions of LEAP.

About LabSync

LabSync is a service that manages the administrative requirements associated with laboratory testing for patients enrolled in LEAP, including assistance with scheduling laboratory appointments, addressing lab-related insurance issues and providing healthcare providers with complete patient histories of LEAP-related laboratory results.

About Pulmonary Arterial Hypertension (WHO Group 1)

PAH is a debilitating disease characterized by constriction of the blood vessels in the lungs leading to high pulmonary arterial pressures. These high pressures make it difficult for the heart to pump blood through the lungs to be oxygenated. Patients with PAH suffer from shortness of breath as the heart struggles to pump against these high pressures, causing such patients to ultimately die of heart failure. PAH can occur with no known underlying cause, or it can occur secondary to diseases such as connective tissue disease, congenital heart defects, cirrhosis of the liver and HIV infection. PAH afflicts approximately 200,000 patients worldwide.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company's mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Asia Pacific.

This press release includes forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995, that are subject to risks, uncertainties and other factors, including risks related to whether or not this label change will impact physicians' decisions to prescribe Letairis over other competing products. As a result, our sales of Letairis may not increase in response to the label change. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead's Annual Report on Form 10-K for the year ended December 31, 2010, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

Letairis is a registered trademark of Gilead Sciences, Inc.

For more information on Gilead Sciences, please visit the company's website at www.gilead.com or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

SOURCE: Gilead Sciences, Inc.

Gilead Sciences, Inc.Susan Hubbard, 650-522-5715 (Investors)Nathan Kaiser, 650-522-1853 (Media)