Important Safety Information about Tracleer

Tracleer can cause serious side effects including liver damage and birth defects. To help detect these side effects, you must have monthly liver function and, if applicable, pregnancy testing.¹ Because of these risks, you must be enrolled in the Tracleer Access Program (T.A.P.^®) to receive your medication. Please see full Prescribing Information, including BOXED WARNING, and Medication Guide.

Liver damage

Patients on Tracleer need to have a blood test to check their liver function before starting treatment with Tracleer and each month for as long as they continue to take Tracleer. By checking your liver each month, your healthcare provider may be able to detect problems with your liver before they become serious or cause permanent harm. Even with regular liver function testing, complications such as liver cirrhosis and liver damage can still occur.¹

What is a liver function test (LFT)?

The LFT is a simple test that shows the level of liver enzymes, or proteins, in your blood. To get an LFT, a blood sample will be drawn either at a lab or at your healthcare provider's office. This will happen both before you start Tracleer and every month that you continue to take Tracleer.

Why do I have to get an LFT every month while taking Tracleer?

• Tracleer can increase liver enzymes in some patients.¹
• Regular LFTs are important because they will help your healthcare provider keep track of your liver enzymes in order to adjust or stop your treatment if necessary.

Elevated liver enzymes are a sign of possible problems. Regular LFTs alert your healthcare provider to take action.

Tell your healthcare provider if you have had liver problems, including liver problems while taking other medicines. Call your healthcare provider right away if you have any of these symptoms of liver problems while taking Tracleer¹:

• Nausea
• Fever
• Stomach area (abdominal) pain
• Vomiting
• Unusual tiredness
• Yellowing of the skin or the whites of your eyes (jaundice)

Serious birth defects

Tracleer can cause serious birth defects if taken during pregnancy. You must not be pregnant when you start taking Tracleer or during Tracleer treatment. Serious birth defects from Tracleer can happen early in pregnancy. Females who are able to get pregnant must have a negative pregnancy test before starting treatment and each month during Tracleer treatment. Talk with your healthcare provider or gynecologist (a doctor who specializes in female reproduction) to find out about how to prevent pregnancy. Do not have unprotected sex. Tell your healthcare provider right away if you miss a menstrual period or you think you may be pregnant.

What should I know about birth control?

Females who are able to get pregnant must use effective birth control (contraception) while taking Tracleer and for one month after stopping treatment. You must choose and use two reliable forms of birth control at the same time, unless you have a tubal sterilization, Copper T 380A IUD, or LNg 20 IUS—these methods can be used alone.

The chart below lists reliable forms of birth control. However, you and your healthcare team should decide which 2 methods of reliable birth control you should use. Your healthcare provider may recommend that you use a different method of birth control to help lower your risk of problems with your PAH*.

Reliable methods of contraception during treatment with Tracleer
Methods to use alone	Hormone (choose 1 and use with a barrier method)	Barrier (use both OR choose 1 and use with a hormone method)
Intrauterine devices (IUDs) —Copper T 380A IUD —LNg-20 IUS (progesterone IUD) Tubal Sterilization	Estrogen and progesterone —Oral contraceptives —Transdermal patch —Vaginal ring Progesterone only —Injection —Implant	Male condom with spermicide Diaphragm with spermicide OR Cervical cap with spermicide
	A partner's vasectomy still requires 1 additional method of contraception.

Additional Safety Information

Fluid retention and swelling of ankles and legs. Tracleer can cause your body to hold too much water, and you may get swelling of your ankles and legs. Tell your healthcare provider if you have swelling of your ankles and legs that happens either with or without weight gain, or if you have more trouble with your breathing than normal. Your healthcare provider will look for the cause of this.
Lower sperm count. Some men who take Tracleer may have lower sperm counts. This may affect your ability to father a child. Tell your healthcare provider if fertility is important to you.
Low red blood cell levels (anemia). Your healthcare provider will do blood tests to check your red blood cells during treatment with Tracleer.

Do not take Tracleer with glyburide because it may increase your chance of liver injury. Do not take Tracleer with cyclosporine-A because it may increase your chance of side effects.

The most common side effects of Tracleer

The following side effects occur most often in people taking Tracleer: respiratory tract infection, headache, fainting, flushing, low blood pressure, inflamed nose passages (sinusitis), joint pain, and irregular heart beats.¹

Immediately tell your healthcare provider about any side effects you experience while taking Tracleer. You may report side effects to FDA at 1-800-FDA-1088.

Learn about what to expect from Tracleer

*What is Tracleer?
Tracleer is a prescription medicine indicated for patients with certain types of pulmonary arterial hypertension (PAH), which is high blood pressure in the vessels of the lungs, (WHO Group I). Tracleer can improve your ability to exercise as measured by 6-minute walk test and can slow the worsening of your physical condition and symptoms.

• In two different studies, Tracleer improved 6-minute walk distance by 35 and 76 meters. These studies focused on patients with WHO Functional Class III-IV.¹
• Clinical worsening was defined as any one of the following: a need to go to the hospital for PAH, stopping treatment because of worsening of PAH, a need for intravenous (IV) treatment (epoprostenol), or death.^2,3

Studies showing Tracleer is effective included mainly patients with NYHA Functional Class II-IV PAH. In these patients, PAH was caused by: unidentified or hereditary factors (60%); connective tissue disease (21%); being born with a hole in the heart between the left and right sides (18%).

In patients with WHO Functional Class II symptoms, Tracleer slowed the worsening of PAH, however, did not show meaningful improvement in walk distance. If you are a patient with WHO Functional Class II symptoms, your healthcare provider will consider whether the potential benefits of Tracleer outweigh the risk of liver damage, which may prevent future use of Tracleer as your disease progresses.

Tracleer is only:

• prescribed by healthcare providers who are enrolled in T.A.P.
• available to people who understand and agree to enroll in T.A.P.

It is not known if Tracleer is safe and works in children below 12 years of age.

What is the most important information I should know about Tracleer?
Tracleer is only available through the Tracleer Access Program (T.A.P.). Before you begin taking Tracleer, you must read and agree to all of the instructions in T.A.P. Because of potential liver damage and in an effort to make the chance of fetal exposure to Tracleer^® (bosentan) as small as possible, Tracleer may be prescribed only through the Tracleer Access Program (T.A.P.), by calling 1-866-228-3546. Adverse events can also be reported directly via this number.

Liver damage:

• Liver damage may not cause symptoms at first. Only a blood test can show if you have early liver damage. So you must have a blood test to check your liver function before you start Tracleer and each month after that. Your healthcare provider will order these tests. Regular blood tests are important because they will help your healthcare provider adjust or stop your treatment before there is permanent damage.
• Tracleer can cause serious liver damage, including in rare cases liver failure. The contribution of Tracleer in these cases could not be excluded. Even in situations with regular liver testing, rare cases of unexplained liver cirrhosis (scar tissue in the liver) have developed in patients with other medical conditions and taking other medications in addition to Tracleer for over 12 months. Tell your healthcare provider if you have had liver problems, including liver problems while taking other medicines. Call your healthcare provider right away if you have any of these symptoms of liver problems while taking Tracleer: nausea, vomiting, fever, unusual tiredness, stomach area (abdominal) pain, or yellowing of the skin or the whites of your eyes (jaundice).

Serious birth defects:

• Tracleer can cause serious birth defects if taken during pregnancy. You must not be pregnant when you start taking Tracleer or during Tracleer treatment. Serious birth defects from Tracleer can happen early in pregnancy. Females who are able to get pregnant must have a negative pregnancy test before starting treatment and each month during Tracleer treatment.
• Talk with your healthcare provider or gynecologist (a doctor who specializes in female reproduction) to find out about how to prevent pregnancy. Do not have unprotected sex. Tell your healthcare provider right away if you miss a menstrual period or think you may be pregnant.
• Females who are able to get pregnant must use birth control (contraception) during Tracleer treatment. You must choose and use two reliable forms of birth control at the same time, unless you have had a tubal sterilization, or have a Copper T 380A IUD or LNg-20 IUS. These methods can be used alone.
• Talk with your healthcare provider about which 2 methods of reliable birth control you should use. Your healthcare provider may recommend that you use a different method of birth control to help lower your risk of problems with your pulmonary arterial hypertension.

Who should not take Tracleer?
Do not take Tracleer if you:

• Are pregnant, plan to become pregnant, or become pregnant during Tracleer treatment. Tracleer can cause serious birth defects. All females should read the birth defects section of "What is the most important information I should know about Tracleer?"
• Have a blood test that shows possible liver injury.
• Take one of these medicines:

  —	Do not take Tracleer with cyclosporine-A, a medication used for psoriasis and rheumatoid arthritis, and to prevent rejection of heart or kidney transplants. Using cyclosporine-A with Tracleer may increase your chance of side effects.
  —	Do not take Tracleer with glyburide. Glyburide is used to treat diabetes and when used with Tracleer it may increase your chance of liver injury.

• Are allergic to any of the ingredients in Tracleer. If you have a rash, hives or your lips swell after taking Tracleer, it may be a sign of an allergy. You should stop taking your Tracleer and talk to your healthcare provider.

What are the possible side effects of Tracleer?
Tracleer can cause serious side effects, including:

• See "What is the most important information I should know about Tracleer?"
• Fluid retention and swelling of ankles and legs. Tracleer can cause your body to hold too much water, and you may get swelling of your ankles and legs. Tell your healthcare provider if you have swelling of your ankles and legs that happens either with or without weight gain, or if you have more trouble with your breathing than normal. Your healthcare provider will look for the cause of this.
• Lower sperm count. Some men who take Tracleer may have lower sperm counts. This may affect your ability to father a child. Tell your healthcare provider if fertility is a concern for you.
• Low red blood cell levels (anemia). Your healthcare provider will do blood tests to check your red blood cells during treatment with Tracleer.

The most common side effects of Tracleer are: respiratory tract infection, headache, fainting, flushing, low blood pressure, inflamed nose passages (sinusitis), joint pain and irregular heartbeats.

Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Tracleer. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.

Please see full Prescribing Information and Medication Guide.

REFERENCES:

1. TRACLEER^® (bosentan) full Prescribing Information. Actelion Pharmaceuticals US, Inc., February 2011.
2. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346(12):896-903.
3. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet. 2001;358:1119-1123.