Letairis

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

Clinically significant adverse reactions that appear in other sections of the labeling include:

• Embryo-fetal Toxicity [see WARNINGS AND PRECAUTIONS, Use In Specific Populations]
• Fluid Retention [see WARNINGS AND PRECAUTIONS]
• Pulmonary Edema with PVOD [see WARNINGS AND PRECAUTIONS]
• Decreased Sperm Count [see WARNINGS AND PRECAUTIONS]
• Hematologic Changes [see WARNINGS AND PRECAUTIONS]

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 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 Letairis plus tadalafil to Letairis or tadalafil alone. The exposure to Letairis 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 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% in ARIES-1 and ARIES-2

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 x 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.

The mean exposure to Letairis + tadalafil in the AMBITION study was 78.7 weeks. The adverse reactions that occurred in > 5% more patients receiving Letairis + tadalafil than receiving Letairis or tadalafil monotherapy in AMBITION are shown in Table 2.

Table 2 : Adverse Reactions Reported More Commonly ( > 5%) on Letairis + Tadalafil thanon Letairis or Tadalafil Monotherapy (ITT) in AMBITION

Peripheral edema was more frequent on combination therapy; however, there was no notable difference observed in the incidence of peripheral edema in elderly patients ( ≥ 65 years) versus younger patients ( < 65 years) on combination therapy (44% vs. 45%) or Letairis monotherapy (37% vs. 39%) in AMBITION.

Treatment discontinuations due to adverse events while on randomized treatment were similar across treatment groups: 16% for Letairis + tadalafil, 14% for Letairis alone, and 13% for tadalafil alone.

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 x ULN were treated with Letairis. Prior elevations were predominantly moderate, with 64% of the ALT elevations < 5 x ULN, but 9 patients had elevations > 8 x 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 x 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 post-approval 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 requiring transfusion [see WARNINGS AND PRECAUTIONS] heart failure (associated with fluid retention), symptomatic hypotension, and hypersensitivity (e.g., angioedema, rash).

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].

Black Box Warnings

Pregnancy Contraindication

• Likely to produce serious birth defects if used by pregnant women; this effect has been seen consistently when administered to animals
• Exclude pregnancy before the initiating treatment; obtain monthly pregnancy tests during treatment and 1 month after discontinuing treatment
• Females of reproductive potential must use acceptable methods of contraception during treatment and for 1 month after treatment
• Acceptable methods of contraception include: 1 highly effective form of contraception (IUD, contraceptive implant (including progesterone implant), or tubal sterilization), or a combination of methods (hormone method with a barrier method, or 2 barrier methods)
• If a partner’s vasectomy is the chosen method of contraception, a hormone or barrier method must be used along with this method

Restricted Distribution Program

• Because of risk of birth defects, available only through restricted distribution program called the LETAIRIS Education and Access Program (LEAP), by calling 1-866-664-LEAP (5327); only prescribers and pharmacies registered with LEAP may prescribe and distribute ambrisentan
• May be dispensed only to patients enrolled in and meet all conditions of LEAP

Contraindications

Hypersensitivity

Idiopathic pulmonary fibrosis (IPF) including patients with pulmonary hypertension (WHO Group 3)

Pregnancy; see Black Box Warnings

Cautions

Available only through a special restricted distribution program (see Black Box Warnings)

Caution with hepatic impairment; may be associated with rare cases of hepatic cirrhosis with prolonged use; not recommended in patients with moderate-to-severe hepatic impairment

Discontinue in patients with elevated aminotransferases >5x ULN, or if elevations are accompanied by bilirubin >2X ULN, or signs/symptoms of liver dysfunction

Reports of decreased hemoglobin concentrations from baseline that persisted for up to 4 yr of treatment

Coadministration with cyclosporine or CYP3A4 or CYP2C19 inhibitors

Peripheral edema is known class effect of endothelin receptor antagonists, and also a clinical consequence of pulmonary arterial hypertension (PAH) and worsening PAH; fluid retention in patients with pulmonary hypertension, occurring within weeks of initiating therapy reported; if clinically significant fluid retention develops, with or without associated weight gain, further evaluate to determine cause, such as ambrisentan or underlying heart failure, possible need for specific treatment or discontinuation of therapy

Risk of fluid retention and peripheral edema; more common in combination with tadalafil, than with ambrisentan or tadalafil alone

Adverse effect on spermatogenesis for endotheling receptor antagonists reported

Development of acute pulmonary edema during therapy initiation may be associated with pulmonary veno-occlusive disease

Breastfeeding is not recommended while taking Letairis. It is not known if Letairis can pass through your milk and harm your baby.

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 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 (unless you have had a tubal ligation or are using a copper IUD).

You should not use this medication if you have idiopathic pulmonary fibrosis (IPF).

Ambrisentan is available only from a certified pharmacy under a special program.

You should not use this medication if you are allergic to ambrisentan, or if you have idiopathic pulmonary fibrosis (IPF).

To make sure ambrisentan is safe for you, tell your doctor if you have:

• anemia (low red blood cell counts);

• liver disease; or

• if you are pregnant or plan to become pregnant while taking ambrisentan.

This medicine can harm an unborn baby or cause birth defects. Do not use if you are pregnant, and tell your doctor right away if you become 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 must use two forms of birth control to prevent pregnancy during your treatment, and for at least 1 month after your last dose. If you have had a tubal ligation or use a copper IUD (intrauterine device) or progesterone implant, you will not need to use a second form of birth control.

Recommended combinations of birth control forms include:

• one 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); or

• 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).

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

Ambrisentan is usually taken once daily. Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Ambrisentan can be taken with or without food. Take the medicine at the same time each day.

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

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

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

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

Ambrisentan is used to treat symptoms of pulmonary arterial 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. .

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

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 is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Eliglustat
• Simeprevir

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
• Heart failure or
• Liver disease, mild—Use with caution. May make these conditions worse.

• Idiopathic pulmonary fibrosis (IPF), including IPF patients with pulmonary hypertension—Should not be used in patients with this condition.

• Liver disease, moderate or severe—Use is not recommended in patients with this condition.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache.
• Flushing.
• Stuffy nose.
• Cough.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

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)].

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.

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.

N-terminal pro-B-type natriuretic peptide (NT-proBNP)

In AMBITION [see Clinical Studies (14.2)], the decrease in NT-proBNP in patients on Letairis plus tadalafil was observed early (Week 4) and was sustained, with a reduction of 63% on Letairis plus tadalafil, 50% on Letairis alone, and 41% on tadalafil alone at Week 24.

Pharmacokinetics

The pharmacokinetics of ambrisentan (S-ambrisentan) in healthy subjects is 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 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)]. In vitro studies found ambrisentan to have little to no inhibition of human hepatic transporters. Ambrisentan demonstrated weak dose-dependent inhibition of OATP1B1, OATP1B3, and NTCP (IC50 of 47 µM, 45 µM, and approximately 100 µM, respectively) and no transporter-specific inhibition of BSEP, BRCP, P-gp, or MRP2. 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 coadministration 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

Letairis (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.

Letairis is used to treat pulmonary arterial hypertension (PAH). It improves your ability to exercise and prevents your condition from getting worse. Ambrisentan is sometimes used with a medicine called tadalafil (Adcirca).

Letairis is available only from a certified pharmacy under a special program. You must be registered in the program and sign agreements to use birth control and undergo pregnancy and blood testing.