Risk Evaluation and Mitigation Strategy (REMS)
Program for LETAIRIS

A Risk Evaluation and Mitigation Strategy (REMS) is a strategy to manage known or potential serious risks associated with a drug product and is required by the Food and Drug Administration (FDA) to ensure that the benefits of the drug outweigh its risks.

For LETAIRIS, the goals of the REMS program are to:

• Encourage informed benefit-risk decisions regarding the use of LETAIRIS
• Minimize the risk of fetal exposure and adverse fetal outcomes in women of childbearing potential who are prescribed LETAIRIS

In order to ensure that LETAIRIS is prescribed and taken safely, Gilead has worked with the FDA to develop materials for the REMS program to inform prescribers and patients about the risk of serious birth defects.

The 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). LEAP works by:

• Providing information to prescribers on the risks of LETAIRIS
• Providing comprehensive education to patients and assistance with obtaining LETAIRIS
• Enrolling both prescribers and patients into the LEAP program
• Controlling dispensing through Certified Specialty Pharmacies

To learn more about the risk of serious birth defects, read the boxed WARNING provided below and discuss the Medication Guide with your patients.

Overview of LEAP Roles and Responsibilities

The Prescriber:

• Reads the LETAIRIS full prescribing information and understands the risks of LETAIRIS
• Completes a Prescriber Enrollment and Agreement Form and faxes it to LEAP
• Advises the patient that LETAIRIS is only available through a restricted distribution program called LEAP
• Educates the patient about the risks of LETAIRIS using the LETAIRIS Medication Guide and LETAIRIS Patient Enrollment Guide before initiating LETAIRIS treatments, and provides the patient with copies
• Educates and counsels women of childbearing potential on the need to use highly reliable contraception during treatment and for 1 month after stopping treatment, and on the use of emergency contraception in the event of unprotected sex or known or suspected contraception failure
• Orders and reviews pregnancy tests (for women of childbearing potential) prior to initiating treatment and monthly during treatment
• Orders and reviews hemoglobin concentrations and hematocrit prior to initiating treatment with LETAIRIS, at 1 month, and periodically thereafter
• Completes a Patient Enrollment and Consent Form completely and legibly:
  • Confirm patient has agreed to comply with program requirements and has signed the form where indicated
  • As the prescriber, sign the completed form. Fax the completed form, along with all patient insurance information, including prescription drug benefits and medical benefits, to 1-888-882-4035
  • Keep the original form with the patient's records
• Re-enrolls patients annually. You will be reminded when re-enrollment is required
• Counsels patients who fail to comply with the program requirements and notifies LEAP of any adverse events, including death, or if any patient becomes pregnant during LETAIRIS treatment

LEAP Coordinating Center:

• Enters every LETAIRIS prescriber and patient in the LEAP database
• Works with the Certified Specialty Pharmacy to confirm insurance coverage or investigates alternative sources of reimbursement or assistance
• Sends patient information to the chosen Certified Specialty Pharmacy

The Certified Specialty Pharmacy:

• Files the insurance claim
• Contacts all women of childbearing potential receiving LETAIRIS each month to confirm completion of pregnancy testing and counsel on the risk of teratogenicity
• Contacts all patients to make sure they will be available to receive their LETAIRIS shipment
• Provides a copy of the Medication Guide to patients or caregivers each time LETAIRIS is dispensed and instructs patients to read it each time they receive LETAIRIS
• Answers questions and provides information about LETAIRIS
• Ships LETAIRIS to the patient

The following is a list of participating Certified Specialty Pharmacies:

Accredo Aetna Specialty Pharmacy CIGNA Tel-Drug CuraScript CVS Caremark

Kaiser Specialty Pharmacy Walgreens Specialty Pharmacy WellCare Specialty Pharmacy

This list of third-party resources is provided as a convenience to you. Gilead Sciences, LLC, expressly disclaims any and all liability and responsibility for these resources.

INDICATION: LETAIRIS is an endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability and delay clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-III symptoms and etiologies of idiopathic or heritable PAH (64%) or PAH associated with connective tissue diseases (32%).

Clinical worsening was 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.¹

Early escape was defined as meeting two or more of the following criteria: a 20% decrease in the 6-minute walk distance; an increase in WHO functional class; worsening right ventricular failure; rapidly progressing cardiogenic, hepatic, or renal failure, or refractory systolic hypotension.¹

Important Safety Information

BOXED WARNING: CONTRAINDICATED IN PREGNANCY

See full prescribing information for complete boxed WARNING.

Do not administer LETAIRIS to a pregnant woman because it may cause fetal harm. LETAIRIS is very likely to produce serious birth defects if used by a pregnant woman. Because of this risk:

• Exclude pregnancy before the start of treatment and monthly thereafter
• Prevent pregnancy 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 T 380A IUD or LNg 20 IUS, in which case no additional contraception is needed
• 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
• LETAIRIS is available only through a restricted program called the LETAIRIS Education and Access Program (LEAP). Prescribers, patients, and pharmacies must enroll in the program. Further information is available at www.letairisrems.com or 1-866-664-LEAP (5327)

Contraindication

• Do not administer LETAIRIS to a pregnant woman because it can cause fetal harm

Warnings and precautions

• 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
• 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
• 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

Adverse reactions

• During 12-week controlled clinical trials, the incidence of liver aminotransferase (AST, ALT) elevations >3× 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 >5× ULN or if elevations are accompanied by bilirubin >2× ULN or by signs or symptoms of liver dysfunction, and other causes are excluded

Drug interactions

• Multiple-dose coadministration 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 coadministered with cyclosporine

Dosage and administration

• Providers and patients must enroll in the restricted program called LEAP and comply with the required monitoring to ensure safe use
• 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 and should not be split, crushed, or chewed
• Initiate treatment in women of childbearing potential only after a negative pregnancy test and obtain monthly pregnancy tests thereafter
• 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 for complete details.

Reference: 1. LETAIRIS [Prescribing Information]. Foster City, Calif: Gilead Sciences, Inc; February 2012.