Pharmaceutical Approval Update: Ambrisentan (Letairis) part 2
Peripheral edema: Peripheral edema is a known effect of the class of endothelin receptor antagonists, and it is a clinical consequence of PAH and worsening PAH. In the placebo-controlled studies, the incidence of peripheral edema increased in patients receiving ambrisentan 5 or 10 mg, compared to those receiving placebo. Most edema was mild to moderate in severity. If clinically significant peripheral edema develops, with or without associated weight gain, further evaluation should be undertaken to determine the cause, such as heart failure, and the possible need for specific treatment.
Coadministration of cyclosporine A: Cyclosporine is a strong inhibitor of P-glycoprotein (P-gp), organic anion transport protein (OATP), and CYP 3A4. In vitro data indicate that ambrisentan is a substrate of P-gp, OATP, and CYP 3A. Therefore, caution is recommended when ambrisentan is taken with cyclosporine A, because cyclosporine A may cause increased exposure to ambrisentan.
Coadministration of strong CYP 3A and 2C19 inhibitors: Caution is necessary when ambrisentan is administered with strong CYP 3A-inhibitors and CYP 2C19-inhibitors (e.g., AstraZenecaj).
Prescribing and Distribution Program: Because of the risks of liver injury and birth defects, ambrisentan is available only via a program called the Letairis Education and Access Program (LEAP). To enroll in LEAP, prescribers must complete the LEAP Prescriber Enrollment and Agreement Form. All patients who receive this drug must be enrolled in LEAP and must be re-enrolled after the first six months of treatment and annually thereafter. Prescribers should review the ambrisentan medication guide and patient education brochure with all patients. All patients should be informed about the drug’s risks, including possible hepatotoxicity and terato-genicity.
Women of childbearing age should be instructed to use two different forms of contraception, including at least one primary form during ambrisentan treatment, and for one month after they stop treatment. If the patient has undergone a tubal sterilization or has the Copper T 380A IUD or the levoi norgestrel-20 IUD, no additional contraception is needed. The primary forms of contraception include tubal sterilization, hormonal therapy (combination oral contraceptives, transdermal patch, injectables, implantables, or vaginal ring), an IUD, and a partner’s vasectomy. The IUD can be used alone without a secondary form of contraception, as can tubal sterilization.
Secondary forms of contraception include barrier methods such as latex condoms, diaphragms, and cervical caps.
For women of childbearing age, a pregnancy test is necessary before ambrisentan treatment begins and then the test should be given monthly during treatment. Patients who do not comply with LEAP requirements should be counseled. Pre-scribers should notify LEAP of any adverse events, including liver injury, or if any patient becomes pregnant during ambri-sentan treatment.
Liver function tests (including aminotransferases and bili-rubin) should be reviewed before ambrisentan therapy is begun and then monthly during treatment.
Dosage and Administration: Treatment is initiated at 5 mg once daily with or without food. Prescribers should consider increasing the dose to 10 mg once daily if 5 mg is tolerated. Tablets may be administered with or without food, and they should not be split, crushed, or chewed. Doses higher than 10 mg once daily have not been studied in patients with PAH. Liver function tests should be measured before and during treatment with ambrisentan.
Women of Childbearing Age: Ambrisentan should be prescribed for women of childbearing age only after a negative pregnancy test and only if patients are using two reliable methods of contraception (unless the patient has had a tubal sterilization or has the Copper T 380A or LNg-20 IUD). In these cases, no other contraception is needed. Pregnancy tests should be performed monthly in these patients.
Pre-existing Hepatic Impairment: Ambrisentan is not recommended for patients with moderate or severe hepatic impairment. Caution should be used for patients with mild hepatic impairment.
Commentary: The FDA approved ambrisentan as an orphan drug for patients with PAH. PAH is characterized by elevated blood pressure within the pulmonary arteries. If these small arteries become narrowed or blocked, the heart must work harder to pump the blood through them. Over time, the overworked heart muscle may become weak and lose its ability to pump enough blood through the lungs. Symptoms include shortness of breath, fatigue, chest pain, dizzy spells, and fainting. About 100,000 people in the U.S. have PAH. canada pharmacy mall
In two clinical studies, ambrisentan significantly improved physical activity capacity, compared with placebo, as shown by a standard six-minute walking test, and it also delayed the worsening of PAH.
Bosentan, an earlier endothelin receptor antagonist, was approved for the treatment of PAH, but ambrisentan produces fewer drug interactions. Prostacyclin as a continuous IV infusion has also been used.