Dosage & Administration
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Letairis Prescribing Information
Letairis may cause fetal harm when administered to a pregnant female. Letairis is contraindicated in females who are pregnant. Letairis was consistently shown to have teratogenic effects when administered to animals. 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
Based on data from animal reproduction studies, Letairis may cause fetal harm, including birth defects and fetal death, when administered to a pregnant woman and is contraindicated during pregnancy. There are limited data on Letairis use in pregnant women. Available data from post-marketing reports and published literature over decades of use with endothelin receptor antagonists in the same class as Letairis have not identified an increased risk of major birth defects; however, these data are limited. Methodological limitations of these postmarketing reports and published literature include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and missing data. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal endothelin receptor antagonist use. In animal reproduction studies, Letairis was teratogenic in rats and rabbits at doses which resulted in exposures of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Letairis was teratogenic at oral dosages of ≥15 mg/kg/day (AUC 51.7 h•µg/mL) in rats and ≥7 mg/kg/day (24.7 h•µg/mL) in rabbits; it was not studied at lower dosages. These dosages are of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day (14.8 h•µg/mL) based on AUC. In both species, there were abnormalities of the lower jaw and hard and soft palate, malformation of the heart and great vessels, and failure of formation of the thymus and thyroid.
A preclinical study in rats has shown decreased survival of newborn pups (mid and high dosages) and effects on testicle size and fertility of pups (high dosage) following maternal treatment with ambrisentan from late gestation through weaning. The mid and high dosages were 51 ×, and 170 × (on a mg/m2body surface area basis) the maximum oral human dose of 10 mg and an average adult body weight of 70 kg. These effects were absent at a maternal dosage 17 × the human dose based on mg/m2.
Letairis may cause fetal harm when administered to a pregnant female. Letairis is contraindicated in females who are pregnant. Letairis was consistently shown to have teratogenic effects when administered to animals. 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
Based on data from animal reproduction studies, Letairis may cause fetal harm, including birth defects and fetal death, when administered to a pregnant woman and is contraindicated during pregnancy. There are limited data on Letairis use in pregnant women. Available data from post-marketing reports and published literature over decades of use with endothelin receptor antagonists in the same class as Letairis have not identified an increased risk of major birth defects; however, these data are limited. Methodological limitations of these postmarketing reports and published literature include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and missing data. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal endothelin receptor antagonist use. In animal reproduction studies, Letairis was teratogenic in rats and rabbits at doses which resulted in exposures of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Letairis was teratogenic at oral dosages of ≥15 mg/kg/day (AUC 51.7 h•µg/mL) in rats and ≥7 mg/kg/day (24.7 h•µg/mL) in rabbits; it was not studied at lower dosages. These dosages are of 3.5 and 1.7 times, respectively, the human dose of 10 mg per day (14.8 h•µg/mL) based on AUC. In both species, there were abnormalities of the lower jaw and hard and soft palate, malformation of the heart and great vessels, and failure of formation of the thymus and thyroid.
A preclinical study in rats has shown decreased survival of newborn pups (mid and high dosages) and effects on testicle size and fertility of pups (high dosage) following maternal treatment with ambrisentan from late gestation through weaning. The mid and high dosages were 51 ×, and 170 × (on a mg/m2body surface area basis) the maximum oral human dose of 10 mg and an average adult body weight of 70 kg. These effects were absent at a maternal dosage 17 × the human dose based on mg/m2.
Based on data from animal reproductive toxicity studies, ambrisentan may cause fetal harm, including birth defects and fetal death, when administered to a pregnant patient and is contraindicated during pregnancy
Verify that patients who can become pregnant are not pregnant prior to initiating ambrisentan. The patient should contact their physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected. If the pregnancy test is positive, the physician and patient should discuss the risks to the pregnancy and the fetus.
Patients who can become pregnant who are using ambrisentan should use effective contraception prior to initiation of treatment, during treatment, and for one month after discontinuation of treatment with ambrisentan to prevent pregnancy
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
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- To improve exercise ability and delay clinical worsening.
- In combination with tadalafil to reduce the risks of disease progression and hospitalization for worsening PAH, and to improve exercise ability [see].
14.2 Combination Treatment of PAHIn a randomized, double-blind, active-controlled trial (AMBITION), 605 patients with WHO Functional Class II or III PAH were randomized 2:1:1 to once daily Letairis plus tadalafil or to Letairis or tadalafil alone. Treatment was initiated with Letairis 5 mg and tadalafil 20 mg. If tolerated, tadalafil was increased to 40 mg at 4 weeks and Letairis was increased to 10 mg at 8 weeks.
The primary endpoint was time to first occurrence of (a) death, (b) hospitalization for worsening PAH, (c) >15% decrease from baseline in 6MWD combined with WHO Functional Class III or IV symptoms sustained over 14 days (short term clinical worsening), or (d) reduction in 6MWD sustained over 14 days combined with WHO Functional Class III or IV symptoms sustained over 6 months (inadequate long term clinical response).
Patients had idiopathic PAH (55%), heritable PAH (3%), or PAH associated with connective tissue diseases, congenital heart disease, stable HIV infection, or drugs or toxins (APAH, 43%). Median time from diagnosis to first study drug administration was 25 days. Approximately 32% and 68% of patients were in WHO Functional Class II and III, respectively. The mean patient age was 55.7 years (34% were ≥65 years old). Most patients were white (90%) and female (76%); 45% were North American.
Principal results are shown in Figures 6 and 7.
Figure 6 Time to Primary Endpoint Event (AMBITION)Figure 7 Primary Endpoint Events and First Occurrences of Each Component at Any Time (AMBITION)The treatment effect of Letairis plus tadalafil compared with individual monotherapy on time to first primary endpoint event was consistent across subgroups. (Figure 8).
Figure 8 Primary Endpoint by Subgroups (AMBITION)Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified, if not the groupings. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over interpreted.
Figure 6Figure 7Figure 8Exercise AbilityResults of the 6MWD at 24 weeks for the AMBITION study are shown in Table 5 and Figure 9.
Table 5 6-Minute Walk Distance at Week 24 (meters)Missing values at Week 24 were imputed using Worst Rank scores for patients with an adjudicated clinical failure event of death or hospitalization, and Last Observed Carried Forward otherwise.(AMBITION) Letairis + Tadalafil
(N=302)Letairis Monotherapy
(N=152)Tadalafil Monotherapy
(N=151)Baseline (median) 356 366 352 Change from baseline (median) 43 23 22 Median difference from Letairis + Tadalafil
(95% CI)24
(11, 37)20
(8, 32)P-Value 0.0004 0.0016 Figure 9 Median Change in 6-Minute Walk Distance (meters) in AMBITIONFigure 9
Studies establishing effectiveness included predominantly patients with WHO Functional Class II–III symptoms and etiologies of idiopathic or heritable PAH (60%) or PAH associated with connective tissue diseases (34%).
- Initiate treatment at 5 mg once daily ().
2.1 Adult DosageInitiate treatment at 5 mg once daily, with or without tadalafil 20 mg once daily. At 4-week intervals, either the dose of Letairis or tadalafil can be increased, as needed and tolerated, to Letairis 10 mg or tadalafil 40 mg.
Do not split, crush, or chew tablets.
- May be started with tadalafil ().
2.1 Adult DosageInitiate treatment at 5 mg once daily, with or without tadalafil 20 mg once daily. At 4-week intervals, either the dose of Letairis or tadalafil can be increased, as needed and tolerated, to Letairis 10 mg or tadalafil 40 mg.
Do not split, crush, or chew tablets.
- Titrate at 4-week intervals as needed and tolerated ().
2.1 Adult DosageInitiate treatment at 5 mg once daily, with or without tadalafil 20 mg once daily. At 4-week intervals, either the dose of Letairis or tadalafil can be increased, as needed and tolerated, to Letairis 10 mg or tadalafil 40 mg.
Do not split, crush, or chew tablets.
- Do not split, crush, or chew tablets ().
2.1 Adult DosageInitiate treatment at 5 mg once daily, with or without tadalafil 20 mg once daily. At 4-week intervals, either the dose of Letairis or tadalafil can be increased, as needed and tolerated, to Letairis 10 mg or tadalafil 40 mg.
Do not split, crush, or chew tablets.
5 mg and 10 mg film
- 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.
- Breastfeeding: Choose Letairis or breastfeeding ().
8.2 LactationRisk SummaryIt is not known whether ambrisentan is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions in breastfed infants from Letairis, a decision should be made whether to discontinue breastfeeding or discontinue Letairis, taking into account the importance of the drug to the mother.
- Not recommended in patients with moderate or severe hepatic impairment ().
8.7 Hepatic ImpairmentPre-existing Hepatic ImpairmentThe influence of pre-existing hepatic impairment on the pharmacokinetics of ambrisentan has not been evaluated. Because there is in vitro and in vivo evidence of significant metabolic and biliary contribution to the elimination of ambrisentan, hepatic impairment might be expected to have significant effects on the pharmacokinetics of ambrisentan
[see Clinical Pharmacology (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 TransaminasesOther 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 elevations of liver aminotransferases are >5 × ULN or if elevations are accompanied by bilirubin >2 × ULN, or by signs or symptoms of liver dysfunction and other causes are excluded.