"The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has recommended the marketing of selexipag (Uptravi, Actelion Registration Ltd) for the treatment of adults with pulmonary arterial hypertension (PAH)./"...
Letairis may cause fetal harm when administered during pregnancy and is contraindicated for use in females who are pregnant. In females of reproductive potential, exclude pregnancy prior to initiation of therapy, ensure use of acceptable contraceptive methods, and obtain monthly pregnancy tests [see DOSAGE AND ADMINISTRATION, and Use in Specific Populations].
Letairis is only available for females through a restricted program under a REMS [see Letairis REMS Program].
Letairis REMS Program
For all females, Letairis is available only through a restricted program called the Letairis REMS, because of the risk of embryo-fetal toxicity [see CONTRAINDICATIONS, Embryo-fetal Toxicity, and Use In Specific Populations].
Notable requirements of the Letairis REMS program include the following:
- 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.
- Females of reproductive potential must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations].
- Pharmacies that dispense Letairis must be certified with the program and must dispense to female patients who are authorized to receive Letairis.
Further information is available at www.letairisrems.com or 1-866-664-5327.
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]. Most edema was mild to moderate in severity.
In addition, there have been postmarketing 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.
Peripheral edema/fluid retention is more common with Letairis plus tadalafil than with Letairis or tadalafil alone.
Pulmonary Edema With Pulmonary Veno-occlusive Disease (PVOD)
If patients develop acute pulmonary edema during initiation of therapy with vasodilating agents such as Letairis, the possibility of PVOD should be considered, and if confirmed Letairis should be discontinued.
Decreased Sperm Counts
Decreased sperm counts have been observed in human and animal studies with another endothelin receptor antagonist and in animal fertility studies with ambrisentan. Letairis may have an adverse effect on spermatogenesis. Counsel patients about potential effects on fertility [see Use in Specific Populations and Nonclinical Toxicology].
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.
In the long-term open-label extension of the two pivotal clinical studies, mean decreases from baseline (ranging from 0.9 to 1.2 g/dL) in hemoglobin concentrations persisted for up to 4 years of treatment.
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 a clinically significant decrease in hemoglobin is observed and other causes have been excluded, consider discontinuing Letairis.
Patient Counseling Information
Advise patients to read the FDA-approved patient labeling (Medication Guide).
Instruct patients on the risk of fetal harm when Letairis is used in pregnancy [see WARNINGS AND PRECAUTIONS and Use In Specific Populations]. Female patients must enroll in the Letairis REMS program. Instruct females of reproductive potential to immediately contact their physician if they suspect they may be pregnant.
Letairis REMS Program
For female patients, Letairis is only available through a restricted program called the Letairis REMS [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS]. Male patients are not enrolled in the Letairis REMS.
Inform female patients (and their guardians, if applicable) of the following notable requirements:
- All female patients must sign an enrollment form.
- Advise female patients of reproductive potential that they must comply with the pregnancy testing and contraception requirements [see Use In Specific Populations].
- Educate and counsel females of reproductive potential on the use of emergency contraception in the event of unprotected sex or known or suspected contraceptive failure.
- Advise pre-pubertal females to report any changes in their reproductive status immediately to their prescriber.
Review the Letairis Medication Guide and REMS educational material with female patients.
A limited number of pharmacies are certified to dispense Letairis. Therefore, provide patients with the telephone number and website for information on how to obtain the product.
Advise patients of the symptoms of potential liver injury and instruct them to report any of these symptoms to their physician.
Advise patients of the importance of hemoglobin testing.
Other Risks Associated with Letairis
Instruct patients that the risks associated with Letairis also include the following:
- Decreases in sperm count
- Fluid overload
Advise patients not to split, crush, or chew tablets.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Oral carcinogenicity studies of up to two years duration were conducted at starting doses of 10, 30, and 60 mg/kg/day in rats (8 to 48 times the maximum recommended human dose [MRHD] on a mg/m² basis) and at 50, 150, and 250 mg/kg/day in mice (28 to 140 times the MRHD). In the rat study, the high-and mid-dose male and female groups had their doses lowered to 40 and 20 mg/kg/day, respectively, in week 51 because of effects on survival. The high-dose males and females were taken off drug completely in weeks 69 and 93, respectively. The only evidence of ambrisentan-related carcinogenicity was a positive trend in male rats, for the combined incidence of benign basal cell tumor and basal cell carcinoma of skin/subcutis in the mid-dose group (high-dose group excluded from analysis), and the occurrence of mammary fibroadenomas in males in the high-dose group. In the mouse study, high-dose male and female groups had their doses lowered to 150 mg/kg/day in week 39 and were taken off drug completely in week 96 (males) or week 76 (females). In mice, ambrisentan was not associated with excess tumors in any dosed group.
Positive findings of clastogenicity were detected, at drug concentrations producing moderate to high toxicity, in the chromosome aberration assay in cultured human lymphocytes. There was no evidence for genetic toxicity of ambrisentan when tested in vitro in bacteria (Ames test) or in vivo in rats (micronucleus assay, unscheduled DNA synthesis assay).
The development of testicular tubular atrophy and impaired fertility has been linked to the chronic administration of endothelin receptor antagonists in rodents. Testicular tubular degeneration was observed in rats treated with ambrisentan for two years at doses ≥ 10 mg/kg/day (8-fold MRHD). Increased incidences of testicular findings were also observed in mice treated for two years at doses ≥ 50 mg/kg/day (28-fold MRHD). Effects on sperm count, sperm morphology, mating performance, and fertility were observed in fertility studies in which male rats were treated with ambrisentan at oral doses of 300 mg/kg/day (236-fold MRHD). At doses of ≥ 10 mg/kg/day, observations of testicular histopathology in the absence of fertility and sperm effects were also present.
Use In Specific Populations
Pregnancy Category X.
Letairis may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy. Letairis was teratogenic in rats and rabbits at doses which resulted in exposures of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential hazard to a fetus [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS].
Letairis was teratogenic at oral dosages of ≥ 15 mg/kg/day (AUC 51.7 h•μg/mL) in rats and ≥ 7 mg/kg/day (24.7 h•μg/mL) in rabbits; it was not studied at lower dosages. These dosages are of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day (14.8 h•μg/mL) based on AUC. In both species, there were abnormalities of the lower jaw and hard and soft palate, malformation of the heart and great vessels, and failure of formation of the thymus and thyroid.
A preclinical study in rats has shown decreased survival of newborn pups (mid and high dosages) and effects on testicle size and fertility of pups (high dosage) following maternal treatment with ambrisentan from late gestation through weaning. The mid and high dosages were 51 x, and 170 x (on a mg/m² body surface area basis) the maximum oral human dose of 10 mg and an average adult body weight of 70 kg. These effects were absent at a maternal dosage 17 x the human dose based on mg/m² .
It is not known whether ambrisentan is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from Letairis, a decision should be made whether to discontinue nursing or discontinue Letairis, taking into account the importance of the drug to the mother.
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.
Females And Males Of Reproductive Potential
Female patients of reproductive potential must have a negative pregnancy test prior to initiation of treatment, monthly pregnancy test during treatment, and 1 month after stopping treatment with Letairis. Advise patients to contact their healthcare provider if they become pregnant or suspect they may be pregnant. Perform a pregnancy test if pregnancy is suspected for any reason. For positive pregnancy tests, counsel patient on the potential risk to the fetus and patient options [see BOXED WARNING and DOSAGE AND ADMINISTRATION].
Female patients of reproductive potential must use acceptable methods of contraception during treatment with Letairis and for 1 month after stopping treatment with Letairis. Patients may choose one highly effective form of contraception (intrauterine device (IUD), contraceptive implant, or tubal sterilization) or a combination of methods (hormone method with a barrier method or two barrier methods). If a partner's vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method. Counsel patients on pregnancy planning and prevention, including emergency contraception, or designate counseling by another healthcare provider trained in contraceptive counseling [see BOXED WARNING].
In a 6-month study of another endothelin receptor antagonist, bosentan, 25 male patients with WHO functional class III and IV PAH and normal baseline sperm count were evaluated for effects on testicular function. There was a decline in sperm count of at least 50% in 25% of the patients after 3 or 6 months of treatment with bosentan. One patient developed marked oligospermia at 3 months, and the sperm count remained low with 2 follow-up measurements over the subsequent 6 weeks. Bosentan was discontinued and after 2 months the sperm count had returned to baseline levels. In 22 patients who completed 6 months of treatment, sperm count remained within the normal range and no changes in sperm morphology, sperm motility, or hormone levels were observed. Based on these findings and preclinical data [see Nonclinical Toxicology] from endothelin receptor antagonists, it cannot be excluded that endothelin receptor antagonists such as Letairis have an adverse effect on spermatogenesis. Counsel patients about the potential effects on fertility [see WARNINGS AND PRECAUTIONS].
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.
Pre-existing Hepatic Impairment
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 might 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. There is no information on the use of Letairis in patients with mild pre-existing impaired liver function; however, exposure to ambrisentan may be increased in these patients.
Elevation of Liver Transaminases
Other endothelin receptor antagonists (ERAs) have been associated with aminotransferase (AST, ALT) elevations, hepatotoxicity, and cases of liver failure [see ADVERSE REACTIONS]. In patients who develop hepatic impairment after Letairis initiation, the cause of liver injury should be fully investigated. Discontinue Letairis if elevations of liver aminotransferases are > 5 x ULN or if elevations are accompanied by bilirubin > 2 x ULN, or by signs or symptoms of liver dysfunction and other causes are excluded.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 10/16/2015
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