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Letairis

Letairis(ambrisentan) – Gilead

BOXED WARNING

Contraindicated in pregnancy; may cause serious birth defects. Exclude pregnancy before treatment and prevent during treatment and for 1 month after stopping treatment by using 2 acceptable methods of contraception, unless the patient has had tubal sterilization or chooses to use Copper T 380A IUD or LNg 20 IUS, in which case no additional contraception is needed. Obtain monthly pregnancy tests. Available only through a restricted program under a Risk Evaluation and Mitigation Strategy called the Letairis Education and Access Program (LEAP); prescribers, patients, and pharmacies must enroll in the program.

View FDA-Approved Full Prescribing Information for Letairis

THERAPEUTIC CLASS

Endothelin receptor antagonist

INDICATIONS

Treatment of pulmonary arterial HTN (World Health Organization [WHO] Group 1) to improve exercise ability and delay clinical worsening.

ADULT DOSAGE

Adults: Initial: 5mg qd. Titrate: May increase to 10mg qd if 5mg is tolerated. Max: 10mg qd.

HOW SUPPLIED

Tab: 5mg, 10mg

CONTRAINDICATIONS

Women who are or may become pregnant. Idiopathic pulmonary fibrosis (IPF), including IPF patients with pulmonary HTN (WHO Group 3).

WARNINGS/PRECAUTIONS

May cause peripheral edema; reported with greater frequency and severity in elderly patients. If clinically significant fluid retention develops, evaluate further to determine cause and possible need for treatment or d/c of therapy. If acute pulmonary edema occurs during initiation, consider the possibility of pulmonary veno-occlusive disease; d/c if confirmed. May decrease sperm count. Decreases in Hgb and Hct that may result in anemia requiring transfusion reported; measure Hgb prior to initiation, at 1 month, and periodically thereafter. Not recommended with clinically significant anemia. Consider d/c if clinically significant Hgb decrease is observed and other causes have been excluded. Not recommended with moderate/severe hepatic impairment. Investigate for the cause of liver injury if hepatic impairment develops; d/c if aminotransferase elevations >5X ULN or if elevations are accompanied by bilirubin >2X ULN, or by signs/symptoms of liver dysfunction and other causes are excluded.

ADVERSE REACTIONS

Peripheral edema, nasal congestion, flushing, sinusitis.

DRUG INTERACTIONS

Cyclosporine may increase exposure; limit dose to 5mg qd when coadministered with cyclosporine. Rifampin may increase area under the curve; no dose adjustment required.

PREGNANCY

Category X, not for use in nursing.

MECHANISM OF ACTION

Endothelin receptor antagonist; selective for endothelin type-A receptor, blocks the vasoconstriction and cell proliferation effects of endothelin-1 in vascular smooth muscle and endothelium.

PHARMACOKINETICS

Absorption: Tmax=2 hrs. Distribution: Plasma protein binding (99%). Metabolism: Liver via CYP3A, 2C19, and UGTs 1A9S, 2B7S, and 1A3S. Elimination: T1/2=15 hrs.

ASSESSMENT

Assess for IPF, anemia, hepatic impairment, pregnancy/nursing status, and possible drug interactions. Obtain baseline Hgb levels.

MONITORING

Monitor for fluid retention, pulmonary edema, pulmonary veno-occlusive disease, hepatic impairment, and for improvements in WHO class symptoms and exercise ability. Obtain monthly pregnancy tests. Measure Hgb at 1 month and periodically thereafter.

PATIENT COUNSELING

Advise that drug is available only through a restricted program called LEAP and from Certified Specialty Pharmacies enrolled in LEAP. Advise to complete a patient enrollment form. Inform that drug may cause serious birth defects if used by pregnant women. Educate and counsel women of childbearing potential to use highly reliable contraception during and for 1 month after stopping treatment. If IUD or tubal sterilization is used, inform that additional contraception is not needed. Instruct to contact physician if pregnancy is suspected. Instruct to report to physician if symptoms of liver injury (eg, anorexia, N/V, fever, malaise, fatigue, right upper quadrant abdominal discomfort, jaundice, dark urine, itching) occur. Advise of the importance of Hgb testing. Inform of other risks associated with therapy (eg, decreases in Hgb, Hct, and sperm count, fluid overload).

ADMINISTRATION/STORAGE

Administration: Oral route. Do not split, crush, or chew tabs. May be taken with or without food. Storage: 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Store in original packaging.


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    Letairis

    Letairis

    Generic Name: ambrisentan

    Dosage Form: tablet, film coated

    For ProfessionalsSide EffectsDosageInteractionsMore…

    WARNING: CONTRAINDICATED IN PREGNANCY 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 pregnant women, as this effect has been seen consistently when it is administered to animals [see Contraindications (4.1)].

    Pregnancy must therefore be excluded before the initiation of treatment with Letairis and 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 T 380A IUD or LNg 20 IUS, in which case no additional contraception is needed. Obtain monthly pregnancy tests [see Warnings and Precautions (5.1)].

    Because of the risk of birth defects, Letairis is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Letairis Education and Access Program (LEAP). As a component of the Letairis REMS, prescribers, patients, and pharmacies must enroll in the program [see Warnings and Precautions (5.1)].

    Indications and Usage for Letairis

    Letairis is 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%).

    Letairis Dosage and Administration

    Healthcare professionals who prescribe Letairis must enroll in the restricted program called LEAP and must comply with the required monitoring to ensure safe use of Letairis [see Warnings and Precautions (5.1)].

    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 administered 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).

    Women of Childbearing Potential

    Initiate treatment with Letairis in women of childbearing potential only after a negative pregnancy test [see Contraindications (4.1) and Warnings and Precautions (5.1)].

    Dosage Forms and Strengths

    5 mg and 10 mg film-coated tablets for oral administration

    • Each 5 mg tablet is square convex, pale pink, with “5″ on one side and “GSI” on the other side.
    • Each 10 mg tablet is oval convex, deep pink, with “10″ on one side and “GSI” on the other side.

    Contraindications

    Pregnancy

    Letairis may cause fetal harm when administered to a pregnant woman. Ambrisentan was teratogenic at oral doses of ≥15 mg/kg/day in rats and ≥7 mg/kg/day in rabbits; it was not studied at lower doses. 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. Teratogenicity is a class effect of endothelin receptor antagonists. There are no data on the use of Letairis in pregnant women.

    Letairis is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Pregnancy must be excluded before the initiation of treatment with Letairis and prevented during treatment and for one month after stopping treatment [see Dosage and Administration (2.2), Warnings and Precautions (5.1)].

    Idiopathic Pulmonary Fibrosis

    Letairis is contraindicated in patients with Idiopathic Pulmonary Fibrosis (IPF) including IPF patients with pulmonary hypertension (WHO Group 3) [see Clinical Studies (14.3)].

    Warnings and Precautions

    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).

    Required components of LEAP:

    • Healthcare professionals who prescribe Letairis must complete the LEAP Prescriber Enrollment and Agreement Form, enroll in the program, and comply with the REMS requirements.
    • To receive Letairis, all patients must complete a patient enrollment form and be re-enrolled annually by their prescriber. For women of childbearing potential, (1) a pregnancy test must be ordered and reviewed by the prescriber prior to initiation of Letairis treatment and monthly during treatment, (2) she must agree to be contacted prior to each shipment to confirm that a pregnancy test was completed, (3) she must agree to be counseled on the requirements of the REMS program and the risks of Letairis, and (4) she must agree to be contacted by Gilead if she becomes pregnant while on Letairis or within 30 days of treatment discontinuation.
    • Pharmacies that dispense Letairis must enroll in the program and agree to comply with the REMS requirements.

    Further information is available at www.Letairisrems.com or 1-866-664-LEAP (5327).

    Fluid Retention

    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 (6.1)]. Most edema was mild to moderate in severity, and it occurred with greater frequency and severity in elderly patients.

    In addition, there have been post-marketing 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.

    Pulmonary Veno-occlusive Disease

    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.

    Decreased Sperm Counts

    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 (13.1)] from endothelin receptor antagonists, it cannot be excluded that endothelin receptor antagonists such as Letairis have an adverse effect on spermatogenesis.

    Hematological Changes

    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.

    There have been postmarketing reports of decreases in hemoglobin concentration and hematocrit that have resulted in anemia requiring transfusion.

    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.

    Adverse Reactions

    See Warnings and Precautions (5.5) for discussion of hematological changes.

    Clinical Trials Experience

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

    Safety data for Letairis were obtained from two 12-week, placebo-controlled studies in patients with pulmonary arterial hypertension (PAH) (ARIES-1 and ARIES-2) and four nonplacebo-controlled studies in 483 patients with PAH who were treated with doses of 1, 2.5, 5, or 10 mg once daily. The exposure to Letairis in these studies ranged from 1 day to 4 years (N=418 for at least 6 months and N=343 for at least 1 year).

    In ARIES-1 and ARIES-2, a total of 261 patients received Letairis at doses of 2.5, 5, or 10 mg once daily and 132 patients received placebo. The adverse reactions that occurred in >3% more patients receiving Letairis than receiving placebo are shown in Table 1.

    Table 1 Adverse Reactions with Placebo-Adjusted Rates >3%
    Placebo

    (N=132)

    Letairis

    (N=261)

    Adverse reaction n (%) n (%) Placebo-adjusted (%)
    Peripheral edema 14 (11) 45 (17) 6
    Nasal congestion 2 (2) 15 (6) 4
    Sinusitis 0 (0) 8 (3) 3
    Flushing 1 (1) 10 (4) 3

    Most adverse drug reactions were mild to moderate and only nasal congestion was dose-dependent.

    Few notable differences in the incidence of adverse reactions were observed for patients by age or sex. Peripheral edema was similar in younger patients (<65 years) receiving Letairis (14%; 29/205) or placebo (13%; 13/104), and was greater in elderly patients (≥65 years) receiving Letairis (29%; 16/56) compared to placebo (4%; 1/28). The results of such subgroup analyses must be interpreted cautiously.

    The incidence of treatment discontinuations due to adverse events other than those related to PAH during the clinical trials in patients with PAH was similar for Letairis (2%; 5/261 patients) and placebo (2%; 3/132 patients). The incidence of patients with serious adverse events other than those related to PAH during the clinical trials in patients with PAH was similar for placebo (7%; 9/132 patients) and for Letairis (5%; 13/261 patients).

    During 12-week controlled clinical trials, the incidence of aminotransferase elevations >3 × upper limit of normal (ULN) were 0% on Letairis and 2.3% on placebo. In practice, cases of hepatic injury should be carefully evaluated for cause.

    Use in Patients with Prior Endothelin Receptor Antagonist (ERA) Related Serum Liver Enzyme Abnormalities

    In an uncontrolled, open-label study, 36 patients who had previously discontinued endothelin receptor antagonists (ERAs: bosentan, an investigational drug, or both) due to aminotransferase elevations >3 × ULN were treated with Letairis. Prior elevations were predominantly moderate, with 64% of the ALT elevations <5 × ULN, but 9 patients had elevations >8 × ULN. Eight patients had been re-challenged with bosentan and/or the investigational ERA and all eight had a recurrence of aminotransferase abnormalities that required discontinuation of ERA therapy. All patients had to have normal aminotransferase levels on entry to this study. Twenty-five of the 36 patients were also receiving prostanoid and/or phosphodiesterase type 5 (PDE5) inhibitor therapy. Two patients discontinued early (including one of the patients with a prior 8 × ULN elevation). Of the remaining 34 patients, one patient experienced a mild aminotransferase elevation at 12 weeks on Letairis 5 mg that resolved with decreasing the dosage to 2.5 mg, and that did not recur with later escalations to 10 mg. With a median follow-up of 13 months and with 50% of patients increasing the dose of Letairis to 10 mg, no patients were discontinued for aminotransferase elevations. While the uncontrolled study design does not provide information about what would have occurred with re-administration of previously used ERAs or show that Letairis led to fewer aminotransferase elevations than would have been seen with those drugs, the study indicates that Letairis may be tried in patients who have experienced asymptomatic aminotransferase elevations on other ERAs after aminotransferase levels have returned to normal.

    Postmarketing Experience

    The following adverse reactions were identified during postapproval use of Letairis. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to estimate reliably the frequency or to establish a causal relationship to drug exposure: anemia [see Warnings and Precautions (5.5)], asthenia, dizziness, fatigue, fluid retention [see Warnings and Precautions (5.2)], heart failure (associated with fluid retention), hypersensitivity (e.g., angioedema, rash), nausea, and vomiting.

    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 [see Adverse Reactions (6.1)].

    Drug Interactions

    Multiple dose co-administration of ambrisentan and cyclosporine resulted in an approximately 2-fold increase in ambrisentan exposure in healthy volunteers; therefore, limit the dose of ambrisentan to 5 mg once daily when co-administered with cyclosporine [see Clinical Pharmacology (12.3)].

    USE IN SPECIFIC POPULATIONS

    Pregnancy

    Pregnancy Category X [see Contraindications (4.1)]. Treat women of childbearing potential only after a negative pregnancy test and treat only women who are using acceptable methods of contraception. Pregnancy tests should be obtained monthly in women of childbearing potential taking Letairis [see Warnings and Precautions (5.1)].

    Nursing Mothers

    It is not known whether ambrisentan is excreted in human milk. Breastfeeding while receiving Letairis is not recommended. A preclinical study in rats has shown decreased survival of newborn pups (mid and high doses) and effects on testicle size and fertility of pups (high dose) following maternal treatment with ambrisentan from late gestation through weaning. Doses tested were 17×, 51×, and 170× (low, mid, high dose, respectively) the maximum oral human dose of 10 mg on a mg/mm2 basis.

    Pediatric Use

    Safety and effectiveness of Letairis in pediatric patients have not been established.

    Geriatric Use

    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.

    Renal Impairment

    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 (12.3)]. 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.

    Hepatic Impairment

    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 would be expected to have significant effects on the pharmacokinetics of ambrisentan [see Clinical Pharmacology (12.3)]. 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 (6.1, 6.2)]. In patients who develop hepatic impairment after Letairis initiation, the cause of liver injury should be fully investigated. Discontinue Letairis if aminotransferase elevations >5× ULN or if elevations are accompanied by bilirubin >2× ULN, or by signs or symptoms of liver dysfunction and other causes are excluded.

    Overdosage

    There is no experience with overdosage of Letairis. The highest single dose of Letairis administered to healthy volunteers was 100 mg and the highest daily dose administered to patients with PAH was 10 mg once daily. In healthy volunteers, single doses of 50 mg and 100 mg (5 to 10 times the maximum recommended dose) were associated with headache, flushing, dizziness, nausea, and nasal congestion. Massive overdosage could potentially result in hypotension that may require intervention.

    Letairis Description

    Letairis is the brand name for ambrisentan, an endothelin receptor antagonist that is selective for the endothelin type-A (ETA) receptor. The chemical name of ambrisentan is (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid. It has a molecular formula of C22H22N2O4 and a molecular weight of 378.42. It contains a single chiral center determined to be the (S) configuration and has the following structural formula:

    Figure 1 Ambrisentan Structural Formula

    Ambrisentan is a white to off-white, crystalline solid. It is a carboxylic acid with a pKa of 4.0. Ambrisentan is practically insoluble in water and in aqueous solutions at low pH. Solubility increases in aqueous solutions at higher pH. In the solid state ambrisentan is very stable, is not hygroscopic, and is not light sensitive.

    Letairis is available as 5 mg and 10 mg film-coated tablets for once daily oral administration. The tablets include the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate and microcrystalline cellulose. The tablets are film-coated with a coating material containing FD&C Red #40 aluminum lake, lecithin, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Each square, pale pink Letairis tablet contains 5 mg of ambrisentan. Each oval, deep pink Letairis tablet contains 10 mg of ambrisentan. Letairis tablets are unscored.

    Letairis – Clinical Pharmacology

    Mechanism of Action

    Endothelin-1 (ET-1) is a potent autocrine and paracrine peptide. Two receptor subtypes, ETA and ETB, mediate the effects of ET-1 in the vascular smooth muscle and endothelium. The primary actions of ETA are vasoconstriction and cell proliferation, while the predominant actions of ETB are vasodilation, antiproliferation, and ET-1 clearance.

    In patients with PAH, plasma ET-1 concentrations are increased as much as 10-fold and correlate with increased mean right atrial pressure and disease severity. ET-1 and ET-1 mRNA concentrations are increased as much as 9-fold in the lung tissue of patients with PAH, primarily in the endothelium of pulmonary arteries. These findings suggest that ET-1 may play a critical role in the pathogenesis and progression of PAH.

    Ambrisentan is a high affinity (Ki=0.011 nM) ETA receptor antagonist with a high selectivity for the ETA versus ETB receptor (>4000-fold). The clinical impact of high selectivity for ETA is not known.

    Pharmacodynamics

    Cardiac Electrophysiology

    In a randomized, positive- and placebo-controlled, parallel-group study, healthy subjects received either Letairis 10 mg daily followed by a single dose of 40 mg, placebo followed by a single dose of moxifloxacin 400 mg, or placebo alone. Letairis 10 mg daily had no significant effect on the QTc interval. The 40 mg dose of Letairis increased mean QTc at tmax by 5 ms with an upper 95% confidence limit of 9 ms. For patients receiving Letairis 5–10 mg daily and not taking metabolic inhibitors, no significant QT prolongation is expected.

    Pharmacokinetics

    The pharmacokinetics of ambrisentan (S-ambrisentan) in healthy subjects are dose proportional. The absolute bioavailability of ambrisentan is not known. Ambrisentan is absorbed with peak concentrations occurring approximately 2 hours after oral administration in healthy subjects and PAH patients. Food does not affect its bioavailability. In vitro studies indicate that ambrisentan is a substrate of P-gp. Ambrisentan is highly bound to plasma proteins (99%). The elimination of ambrisentan is predominantly by non-renal pathways, but the relative contributions of metabolism and biliary elimination have not been well characterized. In plasma, the AUC of 4-hydroxymethyl ambrisentan accounts for approximately 4% relative to parent ambrisentan AUC. The in vivo inversion of S-ambrisentan to R-ambrisentan is negligible. The mean oral clearance of ambrisentan is 38 mL/min and 19 mL/min in healthy subjects and in PAH patients, respectively. Although ambrisentan has a 15-hour terminal half-life, the mean trough concentration of ambrisentan at steady-state is about 15% of the mean peak concentration and the accumulation factor is about 1.2 after long-term daily dosing, indicating that the effective half-life of ambrisentan is about 9 hours.

    Drug Interactions

    In vitro studies

    Studies with human liver tissue indicate that ambrisentan is metabolized by CYP3A, CYP2C19, and uridine 5′-diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S. In vitro studies suggest that ambrisentan is a substrate of the Organic Anion Transporting Polypeptides OATP1B1 and OATP1B3, 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 [see Drug Interactions (7)]. Ambrisentan does not inhibit or induce drug metabolizing enzymes at clinically relevant concentrations.

    In vivo studies

    The effects of other drugs on ambrisentan pharmacokinetics and the effects of ambrisentan on the exposure to other drugs are shown in Figure 2 and Figure 3, respectively.

    Figure 2 Effects of Other Drugs on Ambrisentan Pharmacokinetics

    * Omeprazole: based on population pharmacokinetic analysis in PAH patients

    ** Rifampin: AUC and Cmax were measured at steady-state. On Day 3 of co-administration a transient 2-fold increase in AUC was noted that was no longer evident by Day 7. Day 7 results are presented.

    Figure 3 Effects of Ambrisentan on Other Drugs

    * Active metabolite of mycophenolate mofetil

    ** GMR (95% CI) for INR

    Nonclinical Toxicology

    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.

    Clinical Studies

    Pulmonary Arterial Hypertension (PAH)

    Two 12-week, randomized, double-blind, placebo-controlled, multicenter studies were conducted in 393 patients with PAH (WHO Group 1). The two studies were identical in design except for the doses of Letairis and the geographic region of the investigational sites. ARIES-1 compared once-daily doses of 5 mg and 10 mg Letairis to placebo, while ARIES-2 compared once-daily doses of 2.5 mg and 5 mg Letairis to placebo. In both studies, Letairis or placebo was added to current therapy, which could have included a combination of anticoagulants, diuretics, calcium channel blockers, or digoxin, but not epoprostenol, treprostinil, iloprost, bosentan, or sildenafil. The primary study endpoint was 6-minute walk distance. In addition, clinical worsening, WHO functional class, dyspnea, and SF-36® Health Survey were assessed.

    Patients had idiopathic or heritable PAH (64%) or PAH associated with connective tissue diseases (32%), HIV infection (3%), or anorexigen use (1%). There were no patients with PAH associated with congenital heart disease.

    Patients had WHO functional class I (2%), II (38%), III (55%), or IV (5%) symptoms at baseline. The mean age of patients was 50 years, 79% of patients were female, and 77% were Caucasian.

    Submaximal Exercise Ability

    Results of the 6-minute walk distance at 12 weeks for the ARIES-1 and ARIES-2 studies are shown in Table 2 and Figure 4.

    Table 2 Changes from Baseline in 6-Minute Walk Distance (meters)
    ARIES-1 ARIES-2
    Placebo

    (N=67)

    5 mg

    (N=67)

    10 mg

    (N=67)

    Placebo

    (N=65)

    2.5 mg

    (N=64)

    5 mg

    (N=63)

    Mean ± standard deviation
    *
    p-values are Wilcoxon rank sum test comparisons of Letairis to placebo at Week 12 stratified by idiopathic or heritable PAH and non-idiopathic, non-heritable PAH patients
    Baseline 342 ± 73 340 ± 77 342 ± 78 343 ± 86 347 ± 84 355 ± 84
    Mean change from baseline -8 ± 79 23 ± 83 44 ± 63 -10 ± 94 22 ± 83 49 ± 75
    Placebo-adjusted mean change from baseline _ 31 51 _ 32 59
    Placebo-adjusted median change from baseline _ 27 39 _ 30 45
    p-value* _ 0.008 <0.001 _ 0.022 <0.001
    Mean change from baseline in 6-minute walk distance in the placebo and Letairis groups

    Values are expressed as mean ± standard error of the mean.

    Figure 4 Mean Change in 6-Minute Walk Distance

    In both studies, treatment with Letairis resulted in a significant improvement in 6-minute walk distance for each dose of Letairis and the improvements increased with dose. An increase in 6-minute walk distance was observed after 4 weeks of treatment with Letairis, with a dose-response observed after 12 weeks of treatment. Improvements in walk distance with Letairis were smaller for elderly patients (age ≥65) than younger patients and for patients with secondary PAH than for patients with idiopathic or heritable PAH. The results of such subgroup analyses must be interpreted cautiously.

    The effects of Letairis on walk distances at trough drug levels are not known. Because only once daily dosing was studied in the clinical trials, the efficacy and safety of more frequent dosing regimens for Letairis are not known. If exercise ability is not sustained throughout the day in a patient, consider other PAH treatments that have been studied with more frequent dosing regimens.

    Clinical Worsening

    Time to clinical worsening of PAH 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. 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. The clinical worsening events during the 12-week treatment period of the Letairis clinical trials are shown in Table 3 and Figure 5.

    Table 3 Time to Clinical Worsening
    ARIES-1 ARIES-2
    Placebo

    (N=67)

    Letairis

    (N=134)

    Placebo

    (N=65)

    Letairis

    (N=127)

    Intention-to-treat population

    Note: Patients may have had more than one reason for clinical worsening.

    Nominal p-values

    Clinical worsening, no. (%) 7 (10%) 4 (3%) 13 (22%) 8 (6%)
    Hazard ratio _ 0.28 _ 0.30
    p-value, Fisher exact test _ 0.044 _ 0.006
    p-value, Log-rank test _ 0.030 _ 0.005

    There was a significant delay in the time to clinical worsening for patients receiving Letairis compared to placebo. Results in subgroups such as the elderly were also favorable.

    Time from randomization to clinical worsening with Kaplan-Meier estimates of the proportions of failures in ARIES-1 and ARIES-2

    p-values shown are the log-rank comparisons of Letairis to placebo stratified by idiopathic or heritable PAH and non-idiopathic, non-heritable PAH patients.

    Figure 5 Time to Clinical Worsening

    Long-term Treatment of PAH

    In long-term follow-up of patients who were treated with Letairis (2.5 mg, 5 mg, or 10 mg once daily) in the two pivotal studies and their open-label extension (N=383), Kaplan-Meier estimates of survival at 1, 2, and 3 years were 93%, 85%, and 79%, respectively. Of the patients who remained on Letairis for up to 3 years, the majority received no other treatment for PAH. These uncontrolled observations do not allow comparison with a group not given Letairis and cannot be used to determine the long-term effect of Letairis on mortality.

    Adverse Effects in Idiopathic Pulmonary Fibrosis (IPF)

    A randomized controlled study in patients with IPF, with or without pulmonary hypertension (WHO Group 3), compared Letairis (n=329) to placebo (n=163). The study was terminated after 34 weeks for lack of efficacy, and was found to demonstrate a greater risk of disease progression or death on Letairis. More patients taking Letairis died (8% vs. 4%), had a respiratory hospitalization (13% vs. 6%), and had a decrease in FVC/DLCO (17% vs. 12%) [see Contraindications (4.2)].

    How Supplied/Storage and Handling

    Letairis is available only through the Letairis Education and Access Program (LEAP) by calling 1-866-664-LEAP (5327) or by logging on to www.Letairis.com.

    Letairis film-coated, tablets are supplied as follows:

    Tablet Strength Package Configuration NDC No. Description of Tablet;

    Debossed on Tablet;

    Size

    5 mg 30 count blister 61958-0801-2 Square convex; pale pink;

    “5″ on side 1 and

    “GSI” on side 2;

    6.6 mm Square

    10 count blister 61958-0801-3    
    10 mg 30 count blister 61958-0802-2 Oval convex; deep pink;

    “10″ on side 1 and

    “GSI” on side 2;

    9.8 mm × 4.9 mm Oval

    10 count blister 61958-0802-3    

    Store at 25 °C (77 °F); excursions permitted to 1530 °C (5986 °F) [see USP controlled room temperature]. Store Letairis in its original packaging.

    Patient Counseling Information

    See FDA-approved patient labeling (Medication Guide).

    Letairis Education and Access Program (LEAP)

    Advise the patient that Letairis is available only through a restricted program called LEAP.

    As a component of LEAP, prescribers must review the contents of the Letairis Medication Guide and the Letairis Patient Enrollment Guide before initiating treatment with Letairis.

    Inform the patient that Letairis is available only from Certified Specialty Pharmacies enrolled in LEAP. Provide patients with a list of Certified Specialty Pharmacies.

    As a component of LEAP, Certified Specialty Pharmacies must provide a copy of the Medication Guide to patients or caregivers each time Letairis is dispensed. Patients must be instructed to read the Medication Guide each time they receive Letairis because new information may be available. In addition, Certified Specialty Pharmacies must contact patients before each shipment to confirm that the patient will be available to receive the Letairis shipment, and, in the case of women of childbearing potential, to confirm that a pregnancy test has been completed.

    Patients must complete a patient enrollment form and be re-enrolled annually by their prescribers using the LEAP Patient Enrollment and Consent form to confirm that they understand the risks of Letairis.

    Patients may be asked to participate in a survey to evaluate the effectiveness of LEAP.

    Pregnancy

    Instruct patients that the risks associated with Letairis include serious birth defects if used by pregnant women:

    • Educate and counsel women of childbearing potential to use highly reliable contraception during Letairis treatment and for one month after stopping treatment. If the patient has had a tubal sterilization or chooses to use a Copper T 380A IUD or LNg 20 IUS for pregnancy prevention, no additional contraception is needed. Women who do not choose one of these methods should always use two acceptable forms of contraception: one hormone method and one barrier method, or two barrier methods where one method is the male condom.
    • Acceptable hormone methods include: progesterone injectables, progesterone implants, combination oral contraceptives, transdermal patch, and vaginal ring.
    • Acceptable barrier methods include: diaphragm (with spermicide), cervical cap (with spermicide), and the male condom.
    • Partner’s vasectomy must be used along with a hormone method or a barrier method.
    • 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 [see Boxed Warning, Contraindications (4)].

    Instruct patient to immediately contact their physician if they suspect they may be pregnant.

    Hepatic Effects

    Some members of this pharmacological class are hepatotoxic. Patients should be educated on the symptoms of potential liver injury (such as anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant abdominal discomfort, jaundice, dark urine or itching) and instructed to report any of these symptoms to their physician.

    Hematological Change

    Patients should be advised 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 hemoglobin and hematocrit
    • Decreases in sperm count
    • Fluid overload

    Administration

    Patients should be advised not to split, crush, or chew tablets.

    Gilead Sciences, Inc., Foster City, CA 94404

    Letairis is a registered trademark of Gilead Sciences, Inc. Gilead and the Gilead logo are trademarks of Gilead Sciences, Inc. Other brands noted herein are the property of their respective owners.

    © 2012 Gilead Sciences, Inc.

    GS22-081-010

    Medication Guide

    Letairis® (le-TAIR-is)

    (ambrisentan)

    Tablets

    Read this Medication Guide before you start taking Letairis and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or your treatment.

    What is the most important information I should know about Letairis?

    • Serious birth defects.

      Letairis can cause serious birth defects if taken during pregnancy.

      • Women must not be pregnant when they start taking Letairis or become pregnant during treatment.
      • Women who are able to get pregnant must have a negative pregnancy test before beginning treatment with Letairis and each month during treatment. Your doctor will decide when to do the test, depending on your menstrual cycle.

      Women who are able to get pregnant must use two acceptable forms of birth control, during Letairis treatment and for one month after stopping Letairis.

      • If you have had a tubal sterilization or have an IUD, these methods can be used alone and no other form of birth control is needed.
      • Talk with your doctor or gynecologist (a doctor who specializes in female reproduction) to find out about how to prevent pregnancy.
      • Do not have unprotected sex. Talk to your doctor or pharmacist right away if you have unprotected sex or if you think your birth control has failed. Your doctor may tell you to use emergency birth control.
      • Tell your doctor right away if you miss a menstrual period or think you may be pregnant.

    Letairis is available only through a restricted program called the Letairis Education and Access Program (LEAP). To receive Letairis, you must talk to your doctor, understand the benefits and risks of Letairis, and agree to all of the instructions in the LEAP program.

    What is Letairis?

    Letairis is a prescription medicine to treat pulmonary arterial hypertension (PAH), which is high blood pressure in the arteries of your lungs.

    Letairis can improve your ability to exercise and it can help slow down the worsening of your physical condition and symptoms.

    Who should not take Letairis?

    Do not take Letairis if:

    • you are pregnant, plan to become pregnant, or become pregnant during treatment with Letairis. Letairis can cause serious birth defects. (See “What is the most important information I should know about Letairis?”) Serious birth defects from Letairis happen early in pregnancy.
    • you have a condition called Idiopathic Pulmonary Fibrosis (IPF).

    Tell your doctor about all your medical conditions and all the medicines you take including prescription and nonprescription medicines. Letairis and other medicines may affect each other causing side effects. Do not start any new medicines until you check with your doctor.

    Especially tell your doctor if you take the medicine cyclosporine (Gengraf, Neoral, Sandimmune). Your doctor may need to change your dose of Letairis. You should not take more than 5 mg of Letairis each day if you also take cyclosporine.

    Letairis has not been studied in children.

    How should I take Letairis?

    Letairis will be mailed to you by a specialty pharmacy. Your doctor will give you complete details.

    • Take Letairis exactly as your doctor tells you. Do not stop taking Letairis unless your doctor tells you.
    • You can take Letairis with or without food.
    • Do not split, crush or chew Letairis tablets.
    • It will be easier to remember to take Letairis if you take it at the same time each day.
    • If you take more than your regular dose of Letairis, call your doctor right away.
    • If you miss a dose, take it as soon as you remember that day. Take your next dose at the regular time. Do not take two doses at the same time to make up for a missed dose.

    What should I avoid while taking Letairis?

    • Do not get pregnant while taking Letairis. (See the serious birth defects section of “What is the most important information I should know about Letairis?”) If you miss a menstrual period, or think you might be pregnant, call your doctor right away.
    • Breastfeeding is not recommended while taking Letairis. It is not known if Letairis can pass through your milk and harm your baby.

    What are the possible side effects of Letairis?

    Serious side effects of Letairis include:

    • Serious birth defects. (See “What is the most important information I should know about Letairis?”)
    • Swelling all over the body (fluid retention) can happen within weeks after starting Letairis. Tell your doctor right away if you have any unusual weight gain, tiredness, or trouble breathing while taking Letairis. These may be symptoms of a serious health problem. You may need to be treated with medicine or need to go to the hospital.
    • Sperm count reduction. Reduced sperm counts have been observed in some men taking a drug similar to Letairis, an effect which might impair their ability to father a child. Tell your doctor if remaining fertile is important to you.
    • Low red blood cell levels (anemia) can happen during the first weeks after starting Letairis. If this happens, you may need a blood transfusion. Your doctor will do blood tests to check your red blood cells before starting Letairis. Your doctor may also do these tests during treatment with Letairis.

    The most common side effects of Letairis are:

    • Swelling of hands, legs, ankles and feet (peripheral edema)
    • Stuffy nose (nasal congestion)
    • Inflamed nasal passages (sinusitis)
    • Hot flashes or getting red in the face (flushing)

    Some medicines that are like Letairis can cause liver problems. Tell your doctor if you get any of these symptoms of a liver problem while taking Letairis:

    • loss of appetite
    • nausea or vomiting
    • fever
    • achiness
    • generally do not feel well
    • pain in the upper right stomach (abdominal) area
    • yellowing of your skin or the whites of your eyes
    • dark urine
    • itching

    Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of Letairis. For more information, ask your doctor or pharmacist.

    Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    How should I store Letairis?

    Store Letairis at 68 °F to 77 °F (20 °C to 25 °C), in the package it comes in.

    Keep Letairis and all medicines out of the reach of children.

    General information about Letairis

    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Letairis for a condition for which it was not prescribed. Do not give Letairis to other people, even if they have the same symptoms that you have. It may harm them.

    This Medication Guide summarizes the most important information about Letairis. If you would like more information, ask your doctor. You can ask your doctor or pharmacist for information about Letairis that is written for healthcare professionals.

    For more information, call 1-866-664-LEAP (5327) or visit www.Letairis.com or www.gilead.com.

    What are the ingredients in Letairis?

    Active ingredient: ambrisentan

    Inactive Ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate and microcrystalline cellulose. The tablets are film-coated with a coating material containing FD&C Red #40 aluminum lake, lecithin, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

    This Medication Guide has been approved by the U.S. Food and Drug Administration.

    Gilead Sciences, Inc., Foster City, CA 94404

    Revised October 2012

    Letairis is a registered trademark of Gilead Sciences, Inc. Gilead and the Gilead logo are trademarks of Gilead Sciences, Inc. Other brands noted herein are the property of their respective owners.

    © 2012 Gilead Sciences, Inc.

    GS22-081-010

    PRINCIPAL DISPLAY PANEL – 5 mg Tablet Carton

    NDC 61958-0801-3

    Letairis®

    (ambrisentan) Tablets, 5 mg

    Rx only

    Each tablet contains 5 mg of ambrisentan.

    10 tablets

    Note to Authorized Dispenser: Provide a copy of the Letairis Medication

    Guide included in this carton to each patient.

    GILEAD

    PRINCIPAL DISPLAY PANEL – 10 mg Tablet Carton

    NDC 61958-0802-3

    Letairis®

    (ambrisentan) Tablets, 10 mg

    Rx only

    Each tablet contains 10 mg of ambrisentan.

    10 tablets

    Note to Authorized Dispenser: Provide a copy of the Letairis Medication

    Guide included in this carton to each patient.

    GILEAD

    Letairis 

    ambrisentan tablet, film coated

    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:61958-0801
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    AMBRISENTAN (AMBRISENTAN) AMBRISENTAN 5 mg
    Inactive Ingredients
    Ingredient Name Strength
    CROSCARMELLOSE SODIUM  
    LACTOSE MONOHYDRATE  
    MAGNESIUM STEARATE  
    CELLULOSE, MICROCRYSTALLINE  
    FD&C RED NO. 40  
    ALUMINUM OXIDE  
    LECITHIN, SOYBEAN  
    POLYETHYLENE GLYCOL 3350  
    POLYVINYL ALCOHOL  
    TALC  
    TITANIUM DIOXIDE  
    Product Characteristics
    Color PINK Score no score
    Shape SQUARE Size 7mm
    Flavor Imprint Code GSI;5
    Contains         
    Packaging
    # Item Code Package Description
    1 NDC:61958-0801-2 3 BLISTER PACK in 1 CARTON
    1 10 TABLET, FILM COATED in 1 BLISTER PACK
    2 NDC:61958-0801-3 1 BLISTER PACK in 1 CARTON
    2 10 TABLET, FILM COATED in 1 BLISTER PACK
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA022081 06/15/2007
    Letairis 

    ambrisentan tablet, film coated

    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:61958-0802
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    AMBRISENTAN (AMBRISENTAN) AMBRISENTAN 10 mg
    Inactive Ingredients
    Ingredient Name Strength
    CROSCARMELLOSE SODIUM  
    LACTOSE MONOHYDRATE  
    MAGNESIUM STEARATE  
    CELLULOSE, MICROCRYSTALLINE  
    FD&C RED NO. 40  
    ALUMINUM OXIDE  
    LECITHIN, SOYBEAN  
    POLYETHYLENE GLYCOL 3350  
    POLYVINYL ALCOHOL  
    TALC  
    TITANIUM DIOXIDE  
    Product Characteristics
    Color RED Score no score
    Shape OVAL Size 10mm
    Flavor Imprint Code GSI;10
    Contains         
    Packaging
    # Item Code Package Description
    1 NDC:61958-0802-2 3 BLISTER PACK in 1 CARTON
    1 10 TABLET, FILM COATED in 1 BLISTER PACK
    2 NDC:61958-0802-3 1 BLISTER PACK in 1 CARTON
    2 10 TABLET, FILM COATED in 1 BLISTER PACK
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    NDA NDA022081 06/15/2007
    Labeler - Gilead Sciences, Inc (185049848)

    Revised: 10/2012   Gilead Sciences, Inc

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    Letairis

    Letairis

    Generic Name: ambrisentan (AM-bri-SEN-tan)

    Brand Name: Letairis

    Letairis may cause serious birth defects if you take it while you are pregnant. Women who are pregnant should not take Letairis. You must have a negative pregnancy test before you start to take Letairis, and monthly while you take it. You must also use 2 effective forms of birth control while you take Letairis and for 1 month after you stop taking it. Talk with your doctor about the use of effective birth control while you use Letairis.

    Letairis is only available through a special program called Letairis Education and Access Program (LEAP). Talk to your doctor to be sure you are enrolled in this program and that you meet all of its requirements.

    OverviewSide EffectsInteractionsFor ProfessionalsMore…

    Letairis is used for:

    Treating high blood pressure in the lungs (pulmonary arterial hypertension [PAH]) in certain patients.

    Letairis is an endothelin receptor antagonist. It works by blocking a certain substance in the lungs, which helps to decrease blood pressure in the lungs.

    Do NOT use Letairis if:

    • you are allergic to any ingredient in Letairis
    • you are pregnant, may become pregnant, or plan to become pregnant
    • you have moderate to severe liver problems
    • you have a certain type of lung problem called idiopathic pulmonary fibrosis

    Contact your doctor or health care provider right away if any of these apply to you.

    Before using Letairis:

    Some medical conditions may interact with Letairis. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

    • if you are pregnant, planning to become pregnant, or are breast-feeding
    • if you are able to become pregnant
    • if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement
    • if you have allergies to medicines, foods, or other substances
    • if you have a history of liver problems, heart failure, or anemia
    • if you have fluid retention (eg, unusual swelling of the arms, hands, legs, or feet) or a certain lung problem (pulmonary veno-occlusive disease)
    • if you have had abnormal liver function tests while taking another endothelin receptor antagonist (eg, bosentan)
    • if you drink alcohol or take medicines that may harm the liver (eg, acetaminophen, methotrexate, ketoconazole, isoniazid, certain medicines for HIV infection). Ask your doctor if you are unsure if any of your medicines might harm the liver

    Some MEDICINES MAY INTERACT with Letairis. Tell your health care provider if you are taking any other medicines, especially any of the following:

    • Cyclosporine because it may increase the risk of Letairis’s side effects

    This may not be a complete list of all interactions that may occur. Ask your health care provider if Letairis may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

    How to use Letairis:

    Use Letairis as directed by your doctor. Check the label on the medicine for exact dosing instructions.

    • Letairis comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Letairis refilled.
    • Take Letairis by mouth with or without food.
    • Swallow Letairis whole. Do not break, split, crush, or chew before swallowing.
    • Take Letairis on a regular schedule to get the most benefit from it. Taking Letairis at the same times each day will help you to remember to take it.
    • Continue to take Letairis even if you feel well. Do not miss any doses.
    • If you miss a dose of Letairis, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

    Ask your health care provider any questions you may have about how to use Letairis.

    Important safety information:

    • Do NOT take more than the recommended dose without checking with your doctor.
    • Do not stop taking Letairis unless your doctor tells you to.
    • Serious liver problems have been reported with other medicines that are similar to Letairis (eg, bosentan). Contact your doctor right away if you develop symptoms of liver problems, such as nausea, vomiting, loss of appetite, fever, stomach pain, yellowing of the skin or eyes, dark urine, pale stools, itching, or unusual tiredness or achiness. Discuss any questions or concerns with your doctor.
    • Some men taking another medicine similar to Letairis (bosentan) have experienced a decrease in sperm count. A low sperm count may decrease the ability to father a child. It is not known if Letairis may cause the same effect on sperm count. Discuss any questions or concerns with your doctor.
    • Women who are able to become pregnant must have a negative pregnancy test before they start to take Letairis, and monthly while they are taking it. Talk with your doctor for more information.
    • Women who are able to become pregnant must use 2 effective forms of birth control while they take Letairis and for at least 1 month after they stop taking it. Talk with your doctor about the use of effective birth control while you use Letairis. Talk with your doctor right away if you miss a menstrual period, have unprotected sex, think your birth control has failed, or think you may be pregnant.
    • Tell your doctor or dentist that you take Letairis before you receive any medical or dental care, emergency care, or surgery.
    • Lab tests, including liver function, hemoglobin levels, and hematocrit levels, may be performed while you use Letairis. These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.
    • Use Letairis with caution in the ELDERLY; they may be more sensitive to its effects, especially swelling of the arms, hands, legs, or feet.
    • Letairis should be used with extreme caution in CHILDREN; safety and effectiveness in children have not been confirmed.
    • PREGNANCY and BREAST-FEEDING: Do not take Letairis if you are pregnant. It may cause harm to the fetus. Avoid becoming pregnant while you are taking it. If you think you may be pregnant, contact your doctor right away. It is not known if Letairis is found in breast milk. Do not breast-feed while taking Letairis.

    Possible side effects of Letairis:

    All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

    Flushing; nose or throat irritation; stuffy nose.

    Seek medical attention right away if any of these SEVERE side effects occur:

    Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); new or worsening shortness of breath; new or worsening swelling of the hands, legs, ankles, and feet; sudden or unusual weight gain; unusual tiredness or weakness.

    This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

    If OVERDOSE is suspected:

    Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include fainting; flushing; headache; light-headedness; nausea; severe dizziness; stuffy nose.

    Proper storage of Letairis: Store Letairis between 68 and 77 degrees F (20 and 25 degrees C) in the original package. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Letairis out of the reach of children and away from pets.

    General information:

    • If you have any questions about Letairis, please talk with your doctor, pharmacist, or other health care provider.
    • Letairis is to be used only by the patient for whom it is prescribed. Do not share it with other people.
    • If your symptoms do not improve or if they become worse, check with your doctor.
    • Check with your pharmacist about how to dispose of unused medicine.

    This information should not be used to decide whether or not to take Letairis or any other medicine. Only your health care provider has the knowledge and training to decide which medicines are right for you. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Letairis. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Letairis. This information is not specific medical advice and does not replace information you receive from your health care provider. You must talk with your healthcare provider for complete information about the risks and benefits of using Letairis.

    Issue Date: March 6, 2013 Database Edition 13.1.1.003 Copyright © 2013 Wolters Kluwer Health, Inc.

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    Letairis

    Letairis

    Generic Name: ambrisentan (Oral route)

    am-bri-SEN-tan

    OverviewSide EffectsDosageInteractionsFor ProfessionalsMore… Oral route(Tablet) Ambrisentan should not be administered during pregnancy as it may cause serious birth defects which have been consistently seen in animal studies. Pregnancy must be excluded before the treatment initiation, and prevented during treatment and for 1 month after treatment discontinuation with 2 reliable methods of contraception. If the patient has had a tubal sterilization or chooses to use a Copper T 380A intrauterine device or LNg 20 intrauterine system, no additional contraception is needed. Monthly pregnancy tests are recommended. Letairis(R) is only available through a restricted distribution program under a Risk Evaluation and Mitigation (REMS), called the Letairis Education and Access Program (LEAP). As a component of the Letairis REMS, prescribers, patients, and pharmacies must enroll in the program .

    Commonly used brand name(s)

    In the U.S.

    • Letairis

    Available Dosage Forms:

    • Tablet

    Therapeutic Class: Antihypertensive

    Pharmacologic Class: Endothelin Receptor Antagonist

    Uses For Letairis

    Ambrisentan is used to treat symptoms of pulmonary hypertension, which is high blood pressure in the main artery that carries blood from the right side of the heart (the ventricle) to the lungs. When the small blood vessels in the lungs become more resistant to blood flow, the right ventricle must work harder to pump enough blood through the lungs. Ambrisentan works by relaxing these blood vessels and increasing the supply of blood to the lungs, which reduces the workload of the heart.

    This medicine is available only with your doctor’s prescription and through a special restricted distribution program called the Letairis Education and Access Program (LEAP).

    Before Using Letairis

    In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

    Allergies

    Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

    Pediatric

    Appropriate studies have not been performed on the relationship of age to the effects of ambrisentan in the pediatric population. Safety and efficacy have not been established.

    Geriatric

    Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of ambrisentan in the elderly. However, elderly patients are more likely to have peripheral edema than younger patients, which may require caution in patients receiving ambrisentan.

    Pregnancy

    Pregnancy Category Explanation
    All Trimesters X Studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. This drug should not be used in women who are or may become pregnant because the risk clearly outweighs any possible benefit.

    Breast Feeding

    There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

    Interactions with Medicines

    Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

    Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

    • Cyclosporine

    Interactions with Food/Tobacco/Alcohol

    Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

    Other Medical Problems

    The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

    • Anemia (low red blood cells) or
    • Edema (swelling in the hands, lower legs, or feet) or
    • Heart failure or
    • Liver disease, mild or
    • Lung problems—Use with caution. May make these conditions worse.
    • Liver disease, moderate or severe—Should not be used in patients with this condition.

    Proper Use of Letairis

    Take this medicine exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. Also, do not stop taking this medicine without checking with your doctor first.

    It is very important that you understand the rules of the LEAP® program. Read the patient Medication Guide. Ask your doctor or pharmacist if you have any questions. You might be asked to sign a form to show that you understand the information.

    You may take this medicine with or without food.

    Swallow the tablet whole. Do not crush, break, or chew it.

    Dosing

    The dose of this medicine will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

    The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

    • For oral dosage form (tablets):
      • For pulmonary hypertension:
        • Adults—At first, 5 milligrams (mg) once a day. Your doctor may increase your dose to 10 mg once a day, if needed.
        • Children—Use and dose must be determined by your doctor.

    Missed Dose

    If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

    Storage

    Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

    Keep out of the reach of children.

    Do not keep outdated medicine or medicine no longer needed.

    Ask your healthcare professional how you should dispose of any medicine you do not use.

    Precautions While Using Letairis

    It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly and to check for unwanted effects. Blood tests may be needed to check for unwanted effects.

    Using this medicine while you are pregnant can cause very serious birth defects. Use two forms of effective birth control to keep from getting pregnant while you are using this medicine (even if the medicine is temporarily stopped), and for at least one month after you stop taking the medicine. The most effective forms of birth control are hormone birth control pills, patches, shots, vaginal rings, or implants, or a vasectomy (for men). One of these forms of birth control should be combined with a condom, a diaphragm, or a cervical cap. If a woman has had a tubal ligation or has an IUD, she does not need to use a second form of birth control. If you think you have become pregnant while using this medicine, tell your doctor right away.

    If you are a woman who can get pregnant, you must have a negative pregnancy test before you will be allowed to take this medicine. You will also be required to have a pregnancy test every month during your treatment. If you miss a period while you are using this medicine, tell your doctor right away.

    This medicine may cause fluid retention (edema) in some patients. Check with your doctor right away if you are gaining weight rapidly; have swelling in your hands, ankles, feet, or all over the body; or if you have trouble breathing while you are using this medicine.

    Stop using this medicine and call your doctor right away if you start to have nausea, vomiting, fever, dark-colored urine or pale stools, a loss of appetite, pain in your upper stomach, or yellow eyes or skin. These could be signs of liver injury.

    This medicine may decrease the amount of sperm men make and affect their ability to have children. If you plan to have children, talk with your doctor before using this medicine.

    Pulmonary edema may occur with this medicine. Check with your doctor right away if you have chest pain; difficult, fast, or noisy breathing, sometimes with wheezing; blue lips and fingernails; pale skin; increased sweating; coughing that sometimes produces a pink frothy sputum; or shortness of breath.

    Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

    Letairis Side Effects

    Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

    Check with your doctor immediately if any of the following side effects occur:

    More common

    • Bloating or swelling of the face, arms, hands, lower legs, or feet
    • rapid weight gain
    • tingling of the hands or feet
    • unusual weight gain or loss

    Less common

    • Cough
    • fast, irregular, pounding, or racing heartbeat or pulse
    • fever
    • headache
    • muscle aches
    • pain or tenderness around the eyes and cheekbones
    • shortness of breath or troubled breathing
    • sore throat
    • stuffy or runny nose
    • tightness of the chest or wheezing
    • unusual tiredness or weakness

    Incidence not known

    • Chest pain
    • decrease in the amount of urine
    • dilated neck veins
    • extreme fatigue
    • irregular breathing
    • noisy, rattling breathing
    • pale skin
    • troubled breathing at rest
    • troubled breathing with exertion

    Get emergency help immediately if any of the following symptoms of overdose occur:

    Symptoms of overdose

    • Blurred vision
    • confusion
    • dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
    • sweating

    Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

    Less common

    • Difficulty having a bowel movement (stool)
    • feeling of warmth
    • redness of the face, neck, arms and occasionally, upper chest
    • stomach pain

    Incidence not known

    • Large, hive-like swelling on face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
    • nausea
    • rash
    • vomiting

    Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

    Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

    See also: Letairis side effects (in more detail)

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    Letairis

    Letairis

    Generic Name: Ambrisentan
    Class: Vasodilating Agents, Miscellaneous

    VA Class: CV900

    Chemical Name: (+)-(2S)-2-[(4,6-Diamethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid

    Molecular Formula: C22H22N2O4

    CAS Number: 177036-94-1

    For ProfessionalsSide EffectsDosageInteractionsMore…

    Warning(s)

    • Teratogenicity
    • May cause fetal harm; contraindicated in women who are or may become pregnant.1 18

      Exclude pregnancy before start of treatment and prevent thereafter by use of 2 acceptable methods of contraception during and for one month following treatment.1 3 18 (See Fetal/Neonatal Morbidity and Mortality under Cautions and also see Advice to Patients.)

    • Distribution of ambrisentan is restricted because of risk of major birth defects.1 3 13 18 (See Restricted Distribution Program under Dosage and Administration.)

    REMS:

    FDA approved a REMS for ambrisentan to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of ambrisentan and consists of the following: medication guide, elements to assure safe use, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center (). See also Restricted Distribution Program under Dosage and Administration: General.

    Introduction

    Vasodilator; a propionic-acid,2 3 12 14 17 endothelin-1 (ET-1) type A receptor-selective antagonist.1 2 4 9 12 14

    Uses for Letairis

    Pulmonary Arterial Hypertension

    Management of pulmonary arterial hypertension (PAH, WHO group 1) to improve exercise capacity and delay clinical worsening.1 2 3 4 9 23 Efficacy established principally in patients with NYHA/WHO functional class II or III PAH (idiopathic, familial, or PAH associated with connective tissue diseases).1 23

    Recommended by the American College of Chest Physicians (ACCP) and other experts as one of several treatment options for management of PAH in patients with NYHA functional class II, III, or IV symptoms who are not candidates for calcium-channel blocker therapy or in whom such therapy failed.27 28 38

    Individualize choice of therapy; consider factors such as disease severity, route of administration, potential adverse effects, and patient preference.27 28 38

    Ambrisentan appears to have a low potential for hepatotoxicity; limited data suggest that the drug may be tried in patients who have experienced asymptomatic aminotransferase elevations while receiving other endothelin-receptor antagonists, after aminotransferase levels have normalized.1 6 11 19 20 22

    Limited information available on use of endothelin-receptor antagonists in conjunction with other PAH therapies.25 27 29 38 May be beneficial in patients who deteriorate or fail to improve on monotherapy; however, additional studies needed to fully establish role of combination therapy.25 27 28 29 38

    Designated an orphan drug by FDA for treatment of PAH.3 39

    Letairis Dosage and Administration

    General

    Restricted Distribution Program

    Ambrisentan can be obtained only through a restricted distribution program (see Boxed Warning and REMS); available only through specialty pharmacies registered with the Letairis Education and Access Program (LEAP).1 3 13 18 Contact LEAP at 866-664-LEAP (5327) or visit www.letairis.com for additional information.1

    Dispense no more than a 30-day supply of ambrisentan at one time; confirm with patient that required pregnancy testing was completed prior to dispensing.21

    Distribute medication guide each time ambrisentan is dispensed and review with patient.1 3 16 18 21

    Administration

    Oral Administration

    Administer orally once daily without regard to meals.1

    Do not split, chew, or crush tablets.1 3

    Dosage

    Adults

    Pulmonary Arterial Hypertension
    Oral

    Initially, 5 mg once daily; may increase to 10 mg once daily if tolerated.1

    Do not exceed 5 mg once daily if administered concomitantly with cyclosporine.1 34 (See Specific Drugs under Interactions.)

    Prescribing Limits

    Adults

    Pulmonary Arterial Hypertension
    Oral

    Safety and efficacy of dosages >10 mg daily not established.1

    Special Populations

    Patients with Adverse Hepatic Effects

    Monitor serum aminotransferase (AST/ALT) concentrations if clinically indicated.1 (See Hepatic Effects under Cautions.) Discontinue therapy if AST or ALT >5 times ULN or if elevated aminotransferase concentrations are accompanied by bilirubin concentrations >2 times ULN.1 Also discontinue if manifestations of liver impairment (e.g., nausea, vomiting, fever, abdominal pain, jaundice, lethargy, fatigue) develop and alternative causes have been excluded.1

    Hepatic Impairment

    Avoid use in patients with preexisting moderate or severe hepatic impairment.1

    Renal Impairment

    Dosage adjustment not required in patients with mild or moderate renal impairment; not studied in patients with severe renal impairment.1

    Geriatric Patients

    No specific dosage recommendations at this time.1

    Cautions for Letairis

    Contraindications

    • Known, anticipated, or suspected pregnancy.1 3

    Warnings/Precautions

    Fetal/Neonatal Morbidity and Mortality

    May cause fetal harm; teratogenicity demonstrated in animals and appears to be a class effect of endothelin-receptor antagonists.1 6 (See Boxed Warning.)

    Exclude pregnancy prior to initiation of therapy and perform monthly pregnancy tests during therapy.1

    Women of childbearing potential must use 2 acceptable methods of contraception during and for 1 month following cessation of therapy; if patient has had a Copper T380A or LNg 20 IUD inserted or has undergone tubal sterilization, no other contraceptive method is required.1 3 16 18

    If ambrisentan used during pregnancy or patient becomes pregnant during therapy, apprise of potential fetal hazard.1 (See Advice to Patients.)

    Fluid Retention

    Peripheral edema reported, usually mild to moderate in severity; occurred with greater frequency and severity in geriatric patients.1 26 Peripheral edema is a known class effect of endothelin-receptor antagonists and also a consequence of PAH.1 26

    Fluid retention, sometimes requiring intervention (e.g., diuretics, fluid management, hospitalization), reported.1

    If clinically important fluid retention occurs, further evaluate to determine cause; initiate appropriate treatment or discontinue ambrisentan if necessary.1

    Fertility in Males

    Reduced sperm counts observed in some men with PAH following treatment with another endothelin receptor antagonist (bosentan); possibility of adverse effects on spermatogenesis with ambrisentan cannot be excluded.1

    Hematologic Effects

    Decreases in hemoglobin and hematocrit reported within first few weeks of treatment, followed by stabilization; hemoglobin decreases do not appear to be related to hemorrhage or hemolysis.1 3 4 9 26

    Monitor hemoglobin concentrations prior to initiation, at 1 month, and periodically during therapy.1 3 13

    Not recommended in patients with clinically important anemia.1 Consider discontinuance of therapy if clinically important, otherwise unexplained reductions in hemoglobin occur.1 3

    Pulmonary Effects

    If acute pulmonary edema occurs, consider possibility of pulmonary veno-occlusive disease; if confirmed, discontinue therapy.1

    Hepatic Effects

    Serious hepatotoxicity (e.g., cirrhosis, liver failure) reported with some endothelin-receptor antagonists (e.g., bosentan, sitaxsentan [not commercially available in the US]).1 20 22 Hepatotoxicity was previously thought to be a class effect of these drugs;3 6 10 11 14 19 20 22 however, further evaluation of data indicate that risk of liver injury with ambrisentan is low.1 19

    Monitor liver function tests as clinically indicated; discontinue therapy if severe elevations of hepatic enzymes or manifestations of liver injury occur.1 (See Patients with Adverse Hepatic Effects under Dosage and Administration.) Carefully evaluate causative factors in those who develop hepatic injury.1

    Specific Populations

    Pregnancy

    Category X.1 (See Fetal/Neonatal Morbidity and Mortality and also Contraindications, under Cautions.)

    Lactation

    Decreased survival in newborn rats following maternal exposure to ambrisentan.1 Not known whether ambrisentan is distributed into human milk.1 Use not recommended during breast-feeding.1

    Pediatric Use

    Safety and efficacy not established in children and adolescents <18 years of age.1 3

    Geriatric Use

    Higher incidence of peripheral edema observed in patients ≥65 years of age relative to younger adults.1

    Hepatic Impairment

    Substantially metabolized and eliminated by the liver and biliary system.1 Avoid use in patients with moderate to severe hepatic impairment.1 No information on use in patients with mild hepatic impairment; possible increased systemic exposure.1

    Renal Impairment

    Not studied in patients with severe renal impairment or in those undergoing hemodialysis.1

    No clinically important effect of mild or moderate renal impairment on ambrisentan disposition.1 (See Renal Impairment under Dosage and Administration.)

    Common Adverse Effects

    Peripheral edema,1 23 24 26 nasal congestion,1 23 24 sinusitis,1 24 flushing,1 24 palpitations,1 24 nasopharyngitis,1 24 abdominal pain,1 24 constipation,1 24 dyspnea,1 headache.1 3 23 24 26

    Interactions for Letairis

    Metabolized by UGT enzymes 1A9S, 2B7S, and 1A3S and by CYP3A4 and CYP2C19 isoenzymes in vitro.1 3 14 32

    Appears to be a substrate of P-glycoprotein and organic anion transport protein (OATP).1 3

    Does not inhibit P-glycoprotein.1 3

    Does not inhibit or induce CYP enzymes at clinically relevant concentrations.1 31

    Drugs Affecting Hepatic Microsomal Enzymes

    Inhibitors or inducers of CYP2C19: Pharmacokinetic interaction possible but not likely to be clinically important.1 3

    Inhibitors or inducers of CYP3A4: Pharmacokinetic interaction possible but clinically important interaction demonstrated to date only with cyclosporine (a CYP3A4 inhibitor).1 34

    Drugs Affecting the Organic Anion Transport Protein (OATP)

    Potential pharmacokinetic interaction with drugs that inhibit OATP.1 34

    Drugs Affecting the P-glycoprotein Transport System

    Pharmacokinetic interactions possible with inhibitors or inducers of P-glycoprotein.1 34 36

    Drugs Affecting Uridine Diphosphate Glucuronosyltransferase Enzymes

    Pharmacokinetic interactions possible with drugs that induce UGT but not likely to be clinically important.1

    Specific Drugs

    Drug

    Interaction

    Comments

    Cyclosporine

    Increased AUC and peak plasma ambrisentan concentrations by 2- and 1.5-fold, respectively; no change in cyclosporine exposure1 34

    Limit ambrisentan dosage to 5 mg once daily1 34

    Digoxin

    Modest increase in digoxin exposure1 35

    Not considered clinically important1 35

    Hormonal contraceptives

    Ethinyl estradiol/norethindrone: No clinically important change in systemic exposure to oral contraceptive1 37

    Ketoconazole

    Modest increase in ambrisentan exposure and half-life1 32

    Not considered clinically important; ambrisentan dosage adjustment should not be necessary32

    Omeprazole

    Clinically important interaction not observed

    Phosphodiesterase (PDE) type 5 inhibitors (sildenafil, tadalafil)

    Clinically important pharmacokinetic interaction not observed1 24 31 33

    Dosage adjustments should not be necessary24 31 33

    Rifampin

    Increased ambrisentan exposure by twofold, but effect was transient and not considered clinically important1 36

    Ambrisentan dosage adjustment should not be necessary36

    Warfarin

    Clinically important interaction not observed1 2 4 9 14 24 30

    Dosage adjustments should not be necessary24 30

    Letairis Pharmacokinetics

    Absorption

    Bioavailability

    Rapidly absorbed following oral administration,1 3 9 31 33 34 with peak plasma concentrations occurring within approximately 2 hours.1 9 12 31 33 34 Absolute bioavailability unknown.1 3 14

    Food

    Food does not affect absorption.1 3

    Distribution

    Extent

    Detected in liver and plasma 2–4 hours after administration.3 14

    Plasma Protein Binding

    99%.1

    Elimination

    Metabolism

    Undergoes hepatic metabolism, principally by glucuronidation and to a lesser extent by hydroxylation.1 14 31 32

    Elimination Route

    Predominantly nonrenal pathways; contributions of metabolism and biliary excretion not well characterized.1 3 34 Most of radiolabeled dose recovered in feces as unchanged drug or glucuronide metabolite.1 12 14 Undergoes enterohepatic recycling.34

    Half-life

    Terminal half-life 15 hours; effective half-life approximately 9 hours.1 3 9 33

    Special Populations

    Potential for increased exposure to ambrisentan in patients with hepatic impairment.1 (See Hepatic Effects under Cautions.)

    Serum ambrisentan concentrations not affected in patients with mild or moderate renal impairment (based on studies in individuals with Clcr 20–150 mL/minute).1

    Stability

    Storage

    Oral

    Tablets

    25°C (may be exposed to 15–30°C) in original package.1

    Actions

    • Exhibits specific, selective antagonism of ET-1 type A receptor in the endothelium and vascular smooth muscle.1 3 14 Increased concentrations of ET-1, a potent vasoconstrictor, have been detected in the plasma and lung tissue of patients with PAH, suggesting a pathogenic role for ET-1 in this disorder.5 7

    • Pharmacologically related to other ET-1 receptor antagonists (e.g., bosentan), but exhibits 4000-fold greater selectivity for ET-1 type A receptor versus type B receptor.1 3 6 17 Clinical implications of receptor selectivity currently not established.1 14 15
    • Improves exercise capacity in PAH patients by inhibiting ET-1 type A receptor-mediated vasoconstriction and cell proliferation.1 2 4 9

    Advice to Patients

    • Importance of taking ambrisentan as prescribed and of not interrupting or discontinuing therapy without consulting clinician.16

    • Importance of not taking a double dose to make up for a missed dose but instead taking the next scheduled dose.16
    • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 16
    • Importance of advising women of childbearing potential to avoid pregnancy and to use 2 highly reliable forms of contraception (either one hormonal and one barrier method or 2 barrier methods, one of which is the male condom) simultaneously during and for 1 month following therapy.1 16 18 Acceptable hormonal methods include progesterone injections, progesterone implants, estrogen-progestin combination oral contraceptives, transdermal contraceptive systems, and vaginal ring.1 Acceptable barrier methods include diaphragms with spermicide, cervical caps with spermicide, and male condoms.1 No additional contraception is necessary if patient has undergone tubal sterilization or chooses to use a Copper T380A or LNg 20 IUD.1 If the partner has had a vasectomy, an additional hormonal or barrier method must be used.1 18 Advise women to inform their clinician immediately if a menstrual period is missed or pregnancy suspected.1 16 Apprise patient of potential risk to fetus if pregnancy occurs.1 16
    • Importance of monthly pregnancy testing.1 16
    • Importance of periodic monitoring of red blood cell counts during treatment.1 16
    • Importance of advising patients to swallow tablets whole and not to split, chew, or crush tablets.1 16
    • Importance of distributing patient information (medication guide) to every patient who receives ambrisentan and of reviewing the information with the patient.1 18
    • Importance of patients carefully reading medication guide before initiating therapy and each time prescription is refilled.1 16
    • Importance of informing clinicians of existing or contemplated concomitant therapy including prescription and OTC drugs, as well as any concomitant illnesses.1 16
    • Importance of informing patients of other important precautionary information.1 16 (See Cautions.)

    Preparations

    Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

    Distribution of ambrisentan is restricted.1 (See Restricted Distribution Program under Dosage and Administration.)

    Ambrisentan
    Routes

    Dosage Forms

    Strengths

    Brand Names

    Manufacturer

    Oral

    Tablets, film-coated

    5 mg

    Letairis

    Gilead

    10 mg

    Letairis

    Gilead

    Disclaimer

    This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

    The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug’s actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

    AHFS Drug Information. © Copyright, 1959-2013, Selected Revisions January 30, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

    References

    1. Gilead Sciences, Inc. Letairis (ambrisentan) tablets prescribing information. Foster City, CA; 2009 July.

    2. Oudiz RJ, Torres F, Frost AE et al. A placebo-controlled, efficacy and safety study of ambrisentan in patients with pulmonary arterial hypertension (ARIES-1). Chest. 2006; 130(4 suppl):121S.

    3. Gilead Sciences: Personal communication.

    4. Oudiz RJ, Olschewski H, Galie N et al. Ambrisentan improves exercise capacity and time to clinical worsening in patients with pulmonary arterial hypertension: results of the ARIES-2 study. Poster presented at the 7th International Pulmonary Hypertension Association (PHA) Conference. Minneapolis, MN: 2006 June 23-25.

    5. Giaid A, Yanagisawa M, Langleben D et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993; 328:1732-39. [PubMed 8497283]

    6. Actelion Pharmaceuticals US. Tracleer (bosentan) tablets prescribing information. South San Francisco, CA: 2007 Feb 15

    7. Stewart DJ, Levy RD, Cernacek P et al. Increased plasma endothelin-1 in pulmonary hypertension: Marker or mediator of disease. Ann Intern Med. 1991; 114:464-9. [PubMed 1994793]

    8. Benigni A, Remuzzi G. Endothelin antagonists. Lancet. 1999; 353:133-38. [PubMed 10023915]

    9. Galie N, Badesch D, Oudiz R et al. Ambrisentan therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2005; 46:529-35. [PubMed 16053970]

    10. Channick RN, Sitbon O, Barst RJ et al. Endothelin receptor antagonists in pulmonary arterial hypertension. J Am Coll Cardiol. 2004; 43 (Suppl S):62-7.

    11. Barst RJ, Langleben D, Badesch D et al. Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan. J Am Coll Cardiol. 2006; 47:2049-56. [PubMed 16697324]

    12. Vatter H, Seifert V. Ambrisentan, a non-peptide endothelin receptor antagonist. Cardiovasc Drug Rev. 2006; 24:63-76. [PubMed 16939634]

    13. Gilead Sciences. Letairis education and access program (LEAP) prescriber information. Foster City, CA; 2007 Jun.

    14. Barst RJ. A review of pulmonary arterial hypertension: role of ambrisentan. Vasc Health Risk Manag. 2007; 3:11-22. [PubMed 17583171]

    15. Jacobs A, Preston IR, Gomberg-Maitland M. Endothelin receptor antagonism in pulmonary arterial hypertension-a role for selective ETAinhibition? Curr Med Res Opin. 2006; 22:2567-74.

    16. Gilead Sciences, Inc. Letairis (ambrisentan) tablets medication guide. Foster City, CA; 2007 Jun.

    17. McGoon M, Frost A, Rubin L et al. Ambrisentan therapy in patients with pulmonary arterial hypertension who discontinued bosentan or sitaxsentan due to liver function abnormalities: 1 year follow-up. Presented at the 103nd American Thoracic Society annual international conference. San Francisco, CA: 2007 May 18-23.

    18. Food and Drug Administration. Medwatch-Safety-Related drug labeling changes: Letairis (ambrisentan) 5 and 10 mg tablets [May 2009]. From FDA website http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm165575.htm.

    19. Food and Drug Administration. FDA drug safety communication: Liver injury warning to be removed from Letairis (ambrisentan) tablets. Rockville, MD; 2011 Mar 4. Available from FDA website. Accessed 2011 Apr 1.

    20. Food and Drug Administration. Questions and answers: Liver injury warning to be removed from Letairis (ambrisentan) tablets. Rockville, MD; 2011 Mar 4. Available from FDA website. Accessed 2011 Apr 1.

    21. Letairis (ambrisentan) risk evaluation and mitigation strategy (REMS). Available from FDA web site. Accessed 2011 Apr 13.

    22. McGoon MD, Frost AE, Oudiz RJ et al. Ambrisentan therapy in patients with pulmonary arterial hypertension who discontinued bosentan or sitaxsentan due to liver function test abnormalities. Chest. 2009; 135:122-9. [PubMed 18812445]

    23. Galiè N, Olschewski H, Oudiz RJ et al. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation. 2008; 117:3010-9. [PubMed 18506008]

    24. Cheng JW. Ambrisentan for the management of pulmonary arterial hypertension. Clin Ther. 2008; 30:825-33. [PubMed 18555930]

    25. Abraham T, Wu G, Vastey F et al. Role of combination therapy in the treatment of pulmonary arterial hypertension. Pharmacotherapy. 2010; 30:390-404. [PubMed 20334459]

    26. Oudiz RJ, Galiè N, Olschewski H et al. Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009; 54:1971-81. [PubMed 19909879]

    27. Barst RJ, Gibbs JS, Ghofrani HA et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009; 54(1 Suppl):S78-84.

    28. Badesch DB, Abman SH, Simonneau G et al. Medical therapy for pulmonary arterial hypertension: Updated ACCP evidence-based clinical practice guidelines. Chest. 2007; 131:1917-28. [PubMed 17565025]

    29. Gokhman R, Smithburger PL, Kane-Gill SL et al. Pharmacologic and Pharmacokinetic Rationale for Combination Therapy in Pulmonary Arterial Hypertension. J Cardiovasc Pharmacol. 2010; :. [PubMed 20838230]

    30. Walker G, Mandagere A, Dufton C et al. The pharmacokinetics and pharmacodynamics of warfarin in combination with ambrisentan in healthy volunteers. Br J Clin Pharmacol. 2009; 67:527-34. [PubMed 19552747]

    31. Spence R, Mandagere A, Dufton C et al. Pharmacokinetics and safety of ambrisentan in combination with sildenafil in healthy volunteers. J Clin Pharmacol. 2008; 48:1451-9. [PubMed 18832294]

    32. Richards DB, Walker GA, Mandagere A et al. Effect of ketoconazole on the pharmacokinetic profile of ambrisentan. J Clin Pharmacol. 2009; 49:719-24. [PubMed 19389876]

    33. Spence R, Mandagere A, Harrison B et al. No clinically relevant pharmacokinetic and safety interactions of ambrisentan in combination with tadalafil in healthy volunteers. J Pharm Sci. 2009; 98:4962-74. [PubMed 19455620]

    34. Spence R, Mandagere A, Richards DB et al. Potential for pharmacokinetic interactions between ambrisentan and cyclosporine. Clin Pharmacol Ther. 2010; 88:513-20. [PubMed 20811346]

    35. Richards DB, Spence R, Mandagere A et al. Effects of multiple doses of ambrisentan on the pharmacokinetics of a single dose of digoxin in healthy volunteers. J Clin Pharmacol. 2011; 51:102-6. [PubMed 20350954]

    36. Harrison B, Magee MH, Mandagere A et al. Effects of rifampicin (rifampin) on the pharmacokinetics and safety of ambrisentan in healthy subjects: a single-sequence, open-label study. Clin Drug Investig. 2010; 30:875-85. [PubMed 20923245]

    37. Spence R, Mandagere A, Walker G et al. Effect of steady-state ambrisentan on the pharmacokinetics of a single dose of the oral contraceptive norethindrone (norethisterone) 1 mg/ethinylestradiol 35 microg in healthy subjects: an open-label, single-sequence, single-centre study. Clin Drug Investig. 2010; 30:313-24. [PubMed 20384387]

    38. 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 and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009; 53:1573-619. [PubMed 19389575]

    39. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; [March 9, 2010]. From FDA web site .

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    Letairis

    Letairis

    Generic Name: ambrisentan (am bri SEN tan)

    Brand Name: Letairis

    OverviewSide EffectsDosageInteractionsFor ProfessionalsMore…

    What is ambrisentan?

    Ambrisentan prevents thickening of the blood vessels, especially those in the lungs and heart. Ambrisentan also lowers blood pressure in your lungs, helping your heart pump blood more efficiently.

    Ambrisentan is used to treat pulmonary arterial hypertension (PAH). It improves your ability to exercise and prevents your condition from getting worse.

    Ambrisentan may also be used for purposes not listed in this medication guide.

    What is the most important information I should know about ambrisentan?

    Ambrisentan can harm an unborn baby or cause birth defects. Do not use if you are pregnant.

    If you are a woman of child-bearing potential, you will need to have a negative pregnancy test before you start treatment with ambrisentan. You will also be re-tested each month during your treatment.

    You will be required to use two forms of birth control to prevent pregnancy during your treatment, and for at least 1 month after your treatment ends. If you have had a tubal ligation or are using a copper IUD, you will not need to use a second form of birth control.

    Do not stop taking ambrisentan without first talking to your doctor. You may need to use less and less before you stop the medication completely.

    Ambrisentan is available only under a special program called LEAP (Letairis Education and Access Program). You must be registered in the program and sign agreements to use birth control and undergo pregnancy and blood testing as required by the program. Read all program brochures and agreements carefully.

    What should I discuss with my healthcare provider before taking ambrisentan?

    Your should not use this medication if you are allergic to ambrisentan, or if you are pregnant.

    To make sure you can safely take ambrisentan, tell your doctor if you have any of these other conditions:

    • anemia (low red blood cell counts);

    • a history of liver problems; or
    • if you are pregnant or plan to become pregnant while taking ambrisentan.

    FDA pregnancy category X. This medication can harm an unborn baby or cause birth defects. Do not use ambrisentan if you are pregnant. Tell your doctor right away if you become pregnant during treatment.

    If you are a woman of child-bearing potential, you will need to have a negative pregnancy test before you start treatment with ambrisentan. You will also be re-tested each month during your treatment.

    You will be required to use two forms of birth control to prevent pregnancy during your treatment, and for at least 1 month after your treatment ends. If you have had a tubal ligation or are using a copper IUD (intrauterine device), you will not need to use a second form of birth control.

    Recommended combinations of birth control forms include:

    • 1 hormone form (birth control pill, skin patch, implant, vaginal ring, or injection) plus 1 barrier form (condom, diaphragm with spermicide, or cervical cap with spermicide).

    • a condom and a female barrier form together (diaphragm with spermicide, or cervical cap with spermicide).
    • a partner’s vasectomy plus 1 hormone form or 1 barrier form.

    Talk with your doctor about the use of emergency contraception if you have unprotected sex or if you believe your form of contraception has failed.

    It is not known whether ambrisentan passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using ambrisentan.

    Ambrisentan may lower a man’s sperm count and could affect fertility (your ability to have children).

    How should I take ambrisentan?

    Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

    Ambrisentan is available only under a special program called LEAP (Letairis Education and Access Program). You must be registered in the program and sign agreements to use birth control and undergo pregnancy and blood testing as required by the program. Read all program brochures and agreements carefully.

    Before you start treatment with ambrisentan, your doctor may perform blood tests to make sure it is safe for you to take this medication. Your blood will need to be tested often during treatment. Visit your doctor regularly.

    Ambrisentan is usually taken once daily. Take the medicine at the same time each day.

    Ambrisentan can be taken with or without food.

    Do not crush, chew, or split the tablet. Swallow the pill whole.

    Do not stop taking ambrisentan without first talking to your doctor. You may need to use less and less before you stop the medication completely.

    Store at room temperature away from moisture and heat. Keep this medicine in its original container.

    See also: Letairis dosage (in more detail)

    What happens if I miss a dose?

    Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

    What happens if I overdose?

    Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

    Overdose symptoms may include feeling like you might pass out.

    What should I avoid while using ambrisentan?

    Follow your doctor’s instructions about any restrictions on food, beverages, or activity.

    Ambrisentan side effects

    Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

    Call your doctor at once if you have a serious side effect such as:

    • anxiety, sweating, pale skin, severe shortness of breath, wheezing, gasping for breath, cough with foamy mucus, chest pain, fast or uneven heart rate;

    • swelling of the feet, ankles, or legs;
    • pounding heartbeats or fluttering in your chest; or
    • nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

    Less serious side effects may include:

    • headache;

    • stomach pain, vomiting, constipation;
    • stuffy nose, sinus pain, sore throat; or
    • warmth, redness, or tingly feeling under your skin.

    This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    See also: Letairis side effects (in more detail)

    What other drugs will affect ambrisentan?

    Before you take ambrisentan, tell your doctor if you are using cyclosporine (Sandimmune, Neoral, Gengraf).

    This list is not complete and other drugs may interact with ambrisentan. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

    Next Page → Side Effects

    More Letairis resources

    • Side Effects
    • Recommended Dosage
    • Pregnancy Warnings
    • Drug Images
    • Drug Interactions
    • Support Group
    • 3 Reviews - Add your own review/rating
    • Letairis Prescribing Information (FDA)
    • Letairis Monograph (AHFS DI)
    • Letairis Advanced Consumer (Micromedex) – Includes Dosage Information
    • Letairis Consumer Overview
    • Letairis MedFacts Consumer Leaflet (Wolters Kluwer)
    • Ambrisentan Professional Patient Advice (Wolters Kluwer)

    Compare Letairis with other medications

    • Pulmonary Arterial Hypertension

    Where can I get more information?

    • Your doctor or pharmacist can provide more information about ambrisentan.

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