Ambrisentan
FDA Drug Information • Also known as: Ambrisentan, Letairis
- Brand Names
- Ambrisentan, Letairis
- Drug Class
- Endothelin Receptor Antagonist [EPC]
- Route
- ORAL
- Dosage Form
- TABLET, FILM COATED
- Product Type
- HUMAN PRESCRIPTION DRUG
⚠ Boxed Warning (Black Box)
WARNING: EMBRYO-FETAL TOXICITY Do not administer ambrisentan to a pregnant female because it may cause fetal harm. Ambrisentan is very likely to produce serious birth defects if used by pregnant females, as this effect has been seen consistently when it is administered to animals [see Contraindications (4.1) , Warnings and Precautions (5.1) , and Use in Specific Populations (8.1) ] . Exclude pregnancy before the initiation of treatment with ambrisentan. Females of reproductive potential must use acceptable methods of contraception during treatment with ambrisentan and for one month after treatment. Obtain monthly pregnancy tests during treatment and 1 month after discontinuation of treatment [see Dosage and Administration (2.2) and Use in Specific Populations (8.3) ] . Because of the risk of embryo-fetal toxicity, females can only receive ambrisentan through a restricted program called the Ambrisentan REMS program [see Warnings and Precautions (5.2) ] . WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. Do not administer ambrisentan to a pregnant female because it may cause fetal harm ( 4.1 , 5.1 , 8.1 ). Females of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and 1 month after stopping treatment. Prevent pregnancy during treatment and for one month after stopping treatment by using acceptable methods of contraception ( 2.2 , 8.3 ). For all female patients, ambrisentan is available only through a restricted program called the Ambrisentan Risk Evaluation and Mitigation Strategy (REMS) ( 5.2 ).
Description
11 DESCRIPTION Ambrisentan is an endothelin receptor antagonist that is selective for the endothelin type-A (ET A ) receptor. The chemical name of ambrisentan is (+)-(2 S )-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid. It has a molecular formula of C 22 H 22 N 2 O 4 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. Ambrisentan tablets are 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, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Ambrisentan tablets, 5 mg tablets also contain FD&C Blue #2. Each square shaped, light pink ambrisentan tablet contains 5 mg of ambrisentan. Each oval shaped, dark pink ambrisentan tablet contains 10 mg of ambrisentan. Ambrisentan tablets are unscored. figure1
What Is Ambrisentan Used For?
1 INDICATIONS AND USAGE Ambrisentan tablets are indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1): 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 Clinical Studies (14.2) ]. 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%). Ambrisentan is an endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1): 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. Studies establishing effectiveness included trials predominantly in patients with WHO Functional Class II-III symptoms and etiologies of idiopathic or heritable PAH (60%) or PAH associated with connective tissue diseases (34%) ( 1 ).
Dosage and Administration
2 DOSAGE AND ADMINISTRATION Initiate treatment at 5 mg once daily ( 2.1 ). May be started with tadalafil ( 2.1 ). Titrate at 4-week intervals as needed and tolerated ( 2.1 ). Do not split, crush, or chew tablets ( 2.1 ). 2.1. Adult Dosage Initiate treatment at 5 mg once daily, with or without tadalafil 20 mg once daily. At 4-week intervals, either the dose of ambrisentan or tadalafil can be increased, as needed and tolerated, to ambrisentan tablets, 10 mg or tadalafil 40 mg. Do not split, crush, or chew tablets. 2.2. Pregnancy Testing in Females of Reproductive Potential Initiate treatment with ambrisentan in females of reproductive potential only after a negative pregnancy test. Obtain monthly pregnancy tests during treatment [see Use in Specific Populations (8.3) ] .
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS Clinically significant adverse reactions that appear in other sections of the labeling include: Embryo-fetal Toxicity [see Warnings and Precautions (5.1) , Use in Specific Populations (8.1) ] Fluid Retention [see Warnings and Precautions (5.3) ] Pulmonary Edema with PVOD [see Warnings and Precautions (5.4) ] Decreased Sperm Count [see Warnings and Precautions (5.5) ] Hematologic Changes [see Warnings and Precautions (5.6) ] Most common adverse reactions (>3% compared to placebo) are peripheral edema, nasal congestion, sinusitis, and flushing ( 6.1 ). When used in combination with tadalafil, most common adverse reactions (>5% compared with either Monotherapy) are peripheral edema, headache, nasal congestion, cough, anemia, dyspepsia, and bronchitis ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Sigmapharm Laboratories, LLC, Pharmacovigilance at 1-855-332-0731 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1. 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 ambrisentan are presented from two 12-week, placebo-controlled studies (ARIES-1 and ARIES-2) in patients with pulmonary arterial hypertension (PAH), and one randomized, double-blind, active-controlled trial in 605 patients with PAH (AMBITION) comparing ambrisentan plus tadalafil to ambrisentan or tadalafil alone. The exposure to ambrisentan in these studies ranged from 1 day to 4 years (N=357 for at least 6 months and N=279 for at least 1 year). In ARIES-1 and ARIES-2, a total of 261 patients received ambrisentan 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 ambrisentan than receiving placebo are shown in Table 1. Table 1 Adverse Reactions with Placebo-Adjusted Rates >3% in ARIES-1 and ARIES-2 Placebo (N = 132) Ambrisentan (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 ambrisentan (14%; 29/205) or placebo (13%; 13/104), and was greater in elderly patients (≥65 years) receiving ambrisentan (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 ambrisentan (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 ambrisentan (5%; 13/261 patients). During 12-week controlled clinical trials, the incidence of aminotransferase elevations >3 x upper limit of normal (ULN) were 0% on ambrisentan and 2.3% on placebo. In practice, cases of hepatic injury should be carefully evaluated for cause. Combination Use with Tadalafil The mean exposure to ambrisentan + tadalafil in the AMBITION study was 78.7 weeks. The adverse reactions that occurred in >5% more patients receiving ambrisentan + tadalafil than receiving ambrisentan or tadalafil monotherapy in AMBITION are shown in Table 2. Table 2 Adverse Reactions Reported More Commonly (>5%) on Ambrisentan + Tadalafil than on Ambrisentan or Tadalafil Monotherapy (ITT) in AMBITION Adverse Reactions Ambrisentan + Tadalafil Combination Therapy (N=302) n (%) Ambrisentan...
Drug Interactions
7 DRUG INTERACTIONS Multiple dose coadministration 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 coadministered with cyclosporine [see Clinical Pharmacology (12.3) ] . Cyclosporine increases ambrisentan exposure; limit ambrisentan dose to 5 mg once daily ( 7 ).
Contraindications
4 CONTRAINDICATIONS Pregnancy ( 4.1 ) Idiopathic Pulmonary Fibrosis ( 4.2 ) 4.1. Pregnancy Ambrisentan may cause fetal harm when administered to a pregnant female. Ambrisentan is contraindicated in females who are pregnant. Ambrisentan 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 [see Warnings and Precautions (5.1 , 5.2 ) and Use in Specific Populations (8.1) ] . 4.2. Idiopathic Pulmonary Fibrosis Ambrisentan is contraindicated in patients with Idiopathic Pulmonary Fibrosis (IPF), including IPF patients with pulmonary hypertension (WHO Group 3) [see Clinical Studies (14.4) ] .
Overdosage
10 OVERDOSAGE There is no experience with overdosage of ambrisentan. The highest single dose of ambrisentan 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.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING Ambrisentan film-coated tablets are supplied as follows: Tablet Strength Package Configuration NDC No. Description of Tablet; Debossed on Tablet; Size 5 mg 30 count bottle 42794-051-08 Square shaped; light pink; “∑” on one side and “51” on the other side; 6.6 mm Square 10 count bottle 42794-051-22 10 mg 30 count bottle 42794-052-08 Oval shaped; dark pink; “∑” on one side and “52” on the other side; 9.8 mm x 4.9 mm Oval 10 count bottle 42794-052-22 Store at 25° C (77° F); excursions permitted to 15–30° C (59–86° F) [see USP controlled room temperature] . Store ambrisentan tablets in its original packaging.
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.