Brand Names:

• Letairis

Dosage Forms:

• Tablet

Warnings:

WARNING: POTENTIAL LIVER INJURY

Ambrisentan can cause elevation of liver aminotransferases (ALT and AST) to at least 3 times the upper limit of normal (ULN). Ambrisentan treatment was associated with aminotransferase elevations greater than 3 times the ULN in 0.8% of patients in 12-week trials and 2.8% of patients including long-term open-label trials out to one year. Once case of aminotransferase elevations greater than 3 times the ULN has been accompanied by bilirubin elevations greater than 2 times the ULN. Because these changes are a marker for potentially serious liver injury, serum aminotransferase levels (and bilirubin if aminotransferase levels are elevated) must be measured prior to initiation of treatment and then monthly.

In the post-marketing period with another endothelin receptor antagonist (ERA), bosentan, rare cases of unexplained hepatic cirrhosis were reported after prolonged (greater than 12 months) therapy. In at least one case with bosentan, a late presentation (after more than 20 months of treatment) included pronounced elevations in aminotransferases and bilirubin levels accompanied by non-specific symptoms, all of which resolved slowly over time after discontinuation of the suspect drug. This case reinforces the importance of strict adherence to the monthly monitoring schedule for the duration of treatment.

Elevations in aminotransferases require close attention. Ambrisentan should generally be avoided in patients with elevated aminotransferases (greater than 3 times the ULN) at baseline because monitoring liver injury may be more difficult. If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such a nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin greater than 2 times the ULN, treatment should be stopped. There is no experience with the re-introduction of ambrisentan in these circumstances.

CONTRAINDICATION: PREGNANCY

Ambrisentan 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. Pregnancy must therefore be excluded before the initiation of treatment with ambrisentan and prevented thereafter by the use of at least two reliable methods of contraception unless the patient has had a tubal sterilization or Copper T 380A IUD or LNg 20 IUD inserted, in which case no other contraception is needed. Obtain monthly pregnancy tests.

Because of the risks of liver injury and birth defects, ambrisentan is available only through a special 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. In addition, ambrisentan may be dispensed only to patients who are enrolled in and meet all conditions of LEAP .

Elevations of liver aminotransferases (ALT, AST) have been reported with ambrisentan and serious liver injury has been reported with related drugs. Monitor liver aminotransferases monthly and discontinue ambrisentan if greater than 5 times the upper limit of normal (ULN) or if elevations are accompanied by bilirubin greater than 2 times ULN or by signs or symptoms of liver dysfunction. Ambrisentan may cause fetal harm if taken during pregnancy. Must exclude pregnancy before the start of treatment and two reliable methods of contraception must be used to prevent pregnancy. Ambrisentan is only available through a restricted distribution program called the LETAIRIS(TM) Education and Access Program (LEAP), by calling 1-866-664-LEAP (5327). Only prescribers and pharmacies registered with LEAP may prescribe and distribute LETAIRIS(TM). In addition, LETAIRIS(TM) may be dispensed only to patients who are enrolled in and meet all conditions of LEAP .

Classifications:

Therapeutic—

Antihypertensive

Pharmacologic—

Endothelin Receptor Antagonist

Uses of This Medicine:

Ambrisentan is used to treat the 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 .

Before Using This Medicine:

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.

Children—

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 .

Older adults—

Appropriate studies performed to date have not demonstrated geriatrics-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.

Other 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. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Other interactions—

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 or
• Edema (swelling in hands, lower legs, or feet) or
• Liver disease, mild—Use with caution. May worsen these conditions .

• Liver disease, moderate or severe—Should not use in patients with this condition .

Proper Use of This Medicine:

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 up 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 This Medicine:

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly. 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, an IUD, 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, 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. 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 with 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, 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 .

Side Effects of This Medicine:

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 face, arms, hands, lower legs, or feet

rapid weight gain

tingling of hands or feet

unusual weight gain or loss

Less common

Cough

difficult or labored breathing

fast, irregular, pounding, or racing heartbeat or pulse

fever

headache

muscle aches

pain or tenderness around eyes and cheekbones

shortness of breath or troubled breathing

sore throat

stuffy or runny nose

tightness of chest or wheezing

unusual tiredness or weakness

wheezing

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 from a lying or sitting position suddenly

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

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