Letairis Side Effects

Generic Name: ambrisentan

Please note - some side effects for Letairis may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Letairis - for the Consumer

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 when using Letairis:

Constipation; flushing; headache; nose or throat irritation; stomach pain; stuffy nose.

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

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); irregular heartbeat; shortness of breath; sudden weight gain; swelling (eg, of the arms, legs, hands, feet); 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.

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Letairis Side Effects - for the Professional

Letairis

Clinical Trials Experience

See Warnings and Precautions (5.4) for discussion of hematological changes.

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 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 events that occurred in >3% of the patients receiving Letairis and were more frequent on Letairis than placebo are shown in Table 1.

Table 1 Adverse Events in >3% of PAH Patients Receiving Letairis and More Frequent than Placebo

	Placebo (N=132)	Letairis (N=261)
Adverse event	n (%)	n (%)	Placebo-adjusted (%)
Note: This table includes all adverse events >3% incidence in the combined Letairis treatment group and more frequent than in the placebo group, with a difference of ≥1% between the Letairis and placebo groups.
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
Palpitations	3 (2)	12 (5)	3
Nasopharyngitis	1 (1)	9 (3)	2
Abdominal pain	1 (1)	8 (3)	2
Constipation	2 (2)	10 (4)	2
Dyspnea	4 (3)	11 (4)	1
Headache	18 (14)	38 (15)	1

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

Few notable differences in the incidence of adverse drug 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 pulmonary hypertension during the clinical trials in patients with pulmonary arterial hypertension 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 pulmonary hypertension during the clinical trials in patients with pulmonary arterial hypertension 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: Fluid retention [see Warnings and Precautions (5.2)], heart failure (associated with fluid retention), hypersensitivity (e.g., angioedema, rash), anemia, 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)]. Discontinue Letairis if >5× ULN or if elevations are accompanied by bilirubin >2× ULN, or by signs or symptoms of liver dysfunction and other causes are excluded.

Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

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Side Effects by Body System - for Healthcare Professionals

Hepatic

Hepatic side effects have included dose-dependent liver injury manifested primarily by elevation of serum aminotransferases (ALT or AST), but sometimes accompanied by abnormal liver function (elevated bilirubin). The combination of aminotransferases greater than 3 times the upper limit of normal and total bilirubin 2 times the upper limit of normal is a marker for potentially serious hepatic injury.

Hematologic

Hematologic side effects have included decreases in hemoglobin concentration and hematocrit. Postmarketing reports have included anemia.

Cardiovascular

Cardiovascular side effects have included peripheral edema, palpitations, and flushing. Fluid retention has been reported during postmarketing use of ambrisentan. Additional postmarketing reports have included heart failure (associated with fluid retention).

Respiratory

Respiratory side effects have included dyspnea, nasal congestion, sinusitis, and nasopharyngitis.

Gastrointestinal

Gastrointestinal side effects have included abdominal pain and constipation. Postmarketing experience has included nausea and vomiting.

Nervous system

Nervous system side effects have included headache.

Hypersensitivity

Hypersensitivity side effects have included postmarketing reports of angioedema and rash.

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