Tracleer

Bosentan comes as a tablet to take by mouth. It is usually taken with or without food twice a day in the morning and evening. To help you remember to take bosentan, take it at around the same times every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take bosentan exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Your doctor will probably start you on a low dose of bosentan and increase your dose after 4 weeks.

Bosentan controls the symptoms of PAH but does not cure it. It may take 1 to 2 months or longer before you feel the full benefit of bosentan. Continue to take bosentan even if you feel well. Do not stop taking bosentan without talking to your doctor. If you suddenly stop taking bosentan, your symptoms may get worse. Your doctor may decrease your dose gradually.

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

Dosage Forms & Strengths

tablet

• 62.5 mg
• 125 mg

tablet, for oral suspension

• 32 mg

Pulmonary Arterial Hypertension (PAH)

Indicated to improve exercise ability and decrease worsening of PAH; effectiveness shown in NYHA II-IV, idiopathic or heritable PAH, connective tissue diseases that result in PAH, and PAH associated with congenital heart disease with left-to-right shunts

<40 kg: Maintain dose at 62.5 mg PO q12hr

>40 kg: 62.5 mg PO q12hr for 4 weeks and then increased to maintenance dosage 125 mg PO q12hr

Discontinuation of treatment: Consider a reduction in dosage to 62.5 mg PO q12hr for 3-7 days

See Administration

Dosage Modifications

Elevated ALT/AST levels

• Discontinue if elevated ALT/AST levels are accompanied with clinical symptoms of hepatotoxicity (eg, nausea, vomiting, fever, abdominal pain, jaundice, unusual lethargy, fatigue) or bilirubin ≥2X ULN; reintroduction studies have not been established
• Confirm test, if confirmed, reduce/hold dose as described below
• >12 years and >40 kg: Reduce dose to 62.5 mg PO q12hr or interrupt treatment and monitor liver tests at least q2weeks; if levels return to pretreatment values, continue or reintroduce treatment at 62.5mg PO q12hr; reassess levels within 3 days
• >5 and <8X ULN
  • Interrupt treatment and monitor AST/ALT at least q2weeks
  • >12 years and >40 kg: If levels return to pretreatment values, consider reintroducing dose to 62.5 mg PO q12hr; reassess levels within 3 days
• >8X ULN
  • Stop treatment; reintroduction should not be considered

Liver impairment

• Mild: No dose adjustment required
• Moderate or severe: Avoid use
• AST/ALT >3X ULN: Avoid use

Coadministration with ritonavir

• Have been receiving ritonavir for at least 10 days: Initiate bosentan at the recommended starting dose qDay or every other day based on tolerability
• Have been receiving bosentan: Discontinue bosentan <36 hr prior to initiating ritonavir; resume bosentan at recommended initial dose qDay or every other day after at least 10 days of ritonavir treatment

Idiopathic Pulmonary Fibrosis (Orphan)

Orphan indication sponsor

• Actelion Pharmaceuticals Ltd; Gewerbestrasse 16, CH-4123; Switzerland

Systemic Sclerosis (Orphan)

Reduction of the number (treatment) of new digital ulcers in patients with systemic sclerosis

Orphan indication sponsor

• Actelion Pharmaceuticals Ltd; Gewerbestrasse 16, CH-4123; Switzerland

Dosage Strengths & Forms

tablet, film-coated

• 62.5mg
• 125 mg

tablet, for oral suspension

• 32 mg

Pulmonary Arterial Hypertension (PAH)

Indicated in children and adolescents aged ≥3 years with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR)

See Administration

<3 years: Safety and efficacy not established

3 to ≥12 years

• ≥4-8 kg: Maintain dose at 16 mg PO q12hr
• >8-16 kg: Maintain dose at 32 mg PO q12hr
• >16-24 kg: Maintain dose at 48 mg PO q12hr
• >24-40 kg: Maintain dose at 64 mg PO q12hr

>12 years

• <40 kg: Maintain dose at 62.5mg PO q12hr
• >40 kg: 62.5mg PO q12hr initially for 4 weeks, then increase to maintenance dose 125 mg PO q12hr

Dosage Modifications

Discontinue if elevated ALT/AST levels are accompanied with clinical symptoms of hepatotoxicity (eg, nausea, vomiting, fever, abdominal pain, jaundice, unusual lethargy, fatigue) or bilirubin ≥2X ULN; reintroduction should not be considered

Elevated ALT/AST levels

• Confirm test, if confirmed
• >3 and <5X ULN
  • >12 years and >40 kg: Reduce dose to 62.5 mg PO q12hr or interrupt treatment and monitor liver tests at least q2weeks; if levels return to pretreatment values, continue or reintroduce treatment at 62.5mg PO q12hr; reassess levels within 3 days
  • ≥3-12 years and <40 kg: Interrupt treatment; if levels return to pretreatment values, consider reintroduction of initial dose; reassess levels within 3 days
• >5 and <8X ULN
  • Interrupt treatment and monitor AST/ALT at least q2weeks
  • >12 years and >40 kg: If levels return to pretreatment values, consider reintroducing dose to 62.5 mg PO q12hr; reassess levels within 3 days
  • ≥3-12 years and <40 kg: If levels return to pretreatment values, consider reintroduction of initial dose; reassess levels within 3 days
• >8X ULN
  • Stop treatment; reintroduction should not be considered

Coadministration with ritonavir

• Have been receiving ritonavir for at least 10 days: Initiate bosentan at the recommended starting dose qDay or every other day based on tolerability
• Have been receiving bosentan: Discontinue bosentan <36hr prior to initiation of ritonavir treatment; resume bosentan at recommended initial dose qDay or every other day after at least 10 days of ritonavir treatment

This medication can cause birth defects in an unborn baby. Do not use if you are pregnant. Tell your doctor right away if you become pregnant during treatment. Use an effective barrier form of birth control (such as a condom or diaphragm with spermicide gel or inserts). Hormonal forms of contraception (such as birth control pills, injections, implants, skin patches, and vaginal rings) may not be effective enough to prevent pregnancy during your treatment.

Your doctor may have you take a pregnancy test before you start using this medicine, to make sure you are not pregnant. You may also be re-tested each month during your treatment.

Do not use this medication if you are allergic to bosentan, or if you are also taking cyclosporine (Sandimmune, Neoral, Gengraf), glyburide (Micronase, DiaBeta, Glynase Pres Tab), or HIV/AIDS medication that contains lopinavir or ritonavir (Kaletra, Norvir).

Bosentan can cause severe liver problems. Symptoms include nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes). Call your doctor at once if you have any of these symptoms. Your liver function will need to be tested before you start taking bosentan, and again each month during your treatment.

Do not stop taking bosentan without first talking to your doctor. You may need to use less and less before you stop the medication completely.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Tracleer and other medicines may affect how each other works and cause side effects. Especially tell your healthcare provider if you take:

• hormone-based birth control, such as pills, shots, patches, and implants. These birth control methods may not work as well when taken with Tracleer.
• simvastatin or other "-statin" medicines used to lower cholesterol
• rifampin used for tuberculosis
• tacrolimus used to prevent rejection of liver or kidney transplant
• ketoconazole, fluconazole, itraconazole, or voriconazole used for fungal infections
• warfarin sodium used to prevent blood clots
• ritonavir used to treat HIV

There may be more than one brand name medicine. Ask your healthcare provider if you are not sure if your medicine is one that is listed above.

Grapefruit and grapefruit juice may interact with Tracleer and lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor.

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

Vasodilator; an endothelin receptor antagonist.1

Pulmonary Arterial Hypertension (PAH)

Management of PAH (WHO group 1 pulmonary hypertension) to improve exercise capacity and slow clinical worsening.1 2 3 6 Efficacy established principally in patients with NYHA/WHO functional class II–IV PAH (idiopathic, heritable, or associated with connective tissue diseases or congenital systemic-to-pulmonary shunts).1

Endothelin-receptor antagonists (e.g., ambrisentan, bosentan, macitentan) are recommended as one of several treatment options for initial management of PAH in patients with NYHA/WHO functional class II, III, or IV symptoms who are not candidates for calcium-channel blocker therapy or in whom such therapy has failed.27 38 52 Individualize choice of PAH therapy; consider factors such as disease severity, route of administration, potential adverse effects and costs of treatment, clinician experience, and patient preference.27 38 52

When considering use in patients with mild (NYHA/WHO class II) PAH, determine whether benefits are sufficient to outweigh risk of hepatotoxicity; liver injury could preclude future use of the drug.1

In patients with inadequate response to initial monotherapy, may consider combination therapy with a prostanoid, phosphodiesterase (PDE) type 5 inhibitor, or soluble guanylate cyclase stimulator (added sequentially).52 By targeting different pathophysiologic pathways of the disease, combination therapy may provide additive and/or synergistic benefits.25 27 29 38 52

Has been designated an orphan drug by FDA for treatment of PAH.12

CHF

Not effective in treatment of CHF with left ventricular dysfunction†.1

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly and to check for unwanted effects.

It is also important that your doctor does a blood test to check your liver function before you start bosentan and each month after that.

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.

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.

Liver problems may occur while you are using this medicine. Stop using this medicine and check with your doctor right away if you are having more than one of these symptoms: dark urine, fever with or without chills, light colored stools, loss of appetite, nausea and vomiting, skin rash, stomach pain, unusual tiredness, or yellow eyes or skin.

Bosentan 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.

This medicine may cause fluid retention (edema) in some patients. 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.

Pulmonary edema may occur while using this medicine. Stop using this medicine and check with your doctor right away if you have chest pain; difficult, fast, noisy breathing, sometimes with wheezing; blue lips and fingernails; pale skin; increased sweating; coughing that sometimes produces a pink frothy sputum; or shortness of breath.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

• If you have an allergy to bosentan or any other part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have liver disease.
• If you are taking any of these drugs: Cyclosporine or glyburide.
• If you are breast-feeding or plan to breast-feed.

This is not a list of all drugs or health problems that interact with Tracleer.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Tracleer® (tra-KLEER)
(bosentan)
Tablets

Read the Medication Guide that comes with Tracleer before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about Tracleer?

Tracleer is only available through the Tracleer REMS Program. Before you begin taking Tracleer, you must read and agree to all of the instructions in the Tracleer REMS Program.

Tracleer can cause serious side effects including:

Liver damage.

• Liver damage may not cause symptoms at first. Only a blood test can show if you have early liver damage. You must have your blood tested 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.
• 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
  • 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 with Tracleer each month during treatment with Tracleer and 1 month after stopping treatment with Tracleer.
  • Talk to your healthcare provider about your menstrual cycle. Your healthcare provider will decide when to do a pregnancy test and will order a pregnancy test for you depending on your menstrual cycle.
    • Females who are able to get pregnant are females who:
      • have entered puberty, even if they have not started their menstrual period, and
      • have a uterus, and
      • have not gone through menopause. Menopause means that you have not had a menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed.
    • Females who are not able to get pregnant are females who:
      • have not yet entered puberty, or
      • do not have a uterus, or
      • have gone through menopause. Menopause means that you have not had a menstrual period for at least 12 months for natural reasons, or that you have had your ovaries removed or
      • are infertile for other medical reasons and this infertility is permanent and cannot be reversed.
• Females who are able to get pregnant must use two acceptable forms of birth control during treatment with Tracleer, and for one month after stopping Tracleer because the medicine may still be in the body.
  • If you have had a tubal sterilization or have an IUD (intrauterine device), these methods can be used alone and no other form of birth control is needed.
  • Talk with your healthcare provider or gynecologist (a doctor who specializes in female reproduction) to find out about options for acceptable birth control that you may use to prevent pregnancy during treatment with Tracleer.
  • If you decide that you want to change the form of birth control that you use, talk with your healthcare provider or gynecologist to be sure that you choose another acceptable form of birth control.
  See the chart below for Acceptable Birth Control Options during treatment with Tracleer.
  • Do not have unprotected sex. Talk to your healthcare provider or pharmacist right away if you have unprotected sex or if you think your birth control has failed. Your healthcare provider may talk with you about using emergency birth control.
  • Tell your healthcare provider right away if you miss a menstrual period or think you may be pregnant.
  If you are the parent or caregiver of a female child who started taking Tracleer before reaching puberty, you should check your child regularly to see if she is developing signs of puberty. Tell your healthcare provider right away if you notice that she is developing breast buds or any pubic hair. Your healthcare provider should decide if your child has reached puberty. Your child may reach puberty before having her first menstrual period.

See "What are the possible side effects of Tracleer?" for more information about side effects.

What is Tracleer?

Tracleer is a prescription medicine used to treat people with certain types of pulmonary arterial hypertension (PAH), which is high blood pressure in the vessels of the lungs.

Tracleer can improve your ability to exercise and can slow the worsening of your physical condition and symptoms. Tracleer lowers high blood pressure in your lungs and lets your heart pump blood more efficiently.

Tracleer is only:

Prescribed by healthcare providers who are enrolled in the Tracleer REMS Program.

Available to people who understand and agree to enroll in the Tracleer REMS Program.

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

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?"
• take any of these medicines:
  • cyclosporine A used to treat psoriasis and rheumatoid arthritis, and to prevent rejection of heart, liver, and kidney transplants
  • glyburide used to treat diabetes
• are allergic to bosentan or any of the ingredients in Tracleer. See the end of this Medication Guide for a complete list of the ingredients in Tracleer. If you have a rash, hives or your lips swell after taking Tracleer, it may be a sign of allergy. You should stop taking your Tracleer and talk to your healthcare provider.

What should I tell my healthcare provider before taking Tracleer?

Tracleer may not be right for you. Tell your healthcare provider about all your medical conditions, including if you:

• have liver problems.
• are breast-feeding or plan to breast feed. It is not known if Tracleer passes into your milk. You and your healthcare provider should decide if you will take Tracleer or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Tracleer and other medicines may affect how each other works and cause side effects. Especially tell your healthcare provider if you take:

• hormone-based birth control, such as pills, shots, patches, and implants. These birth control methods may not work as well when taken with Tracleer.
• simvastatin or other "-statin" medicines used to lower cholesterol
• rifampin used for tuberculosis
• tacrolimus used to prevent rejection of liver or kidney transplant
• ketoconazole, fluconazole, itraconazole, or voriconazole used for fungal infections
• warfarin sodium used to prevent blood clots
• ritonavir used to treat HIV

There may be more than one brand name medicine. Ask your healthcare provider if you are not sure if your medicine is one that is listed above.

Know the medicines you take. Keep a list of them and show it to your healthcare provider or pharmacist when you get a new medicine.

How should I take Tracleer?

Your healthcare provider will give you detailed information about the Tracleer REMS Program.

• Tracleer will be mailed to you by a specialty pharmacy. You will only receive a 30-day supply of Tracleer at one time.
• Take Tracleer exactly as prescribed.
• Your healthcare provider will tell you how much Tracleer to take and when to take it.
• In most cases, you will take 1 tablet in the morning and 1 in the evening.
• You can take Tracleer with or without food.
• If you take more than the prescribed dose of Tracleer, call your healthcare provider right away.
• If you miss a dose of Tracleer, take your tablet as soon as you remember. Do not take 2 doses at the same time. If it is almost time for your next dose, skip the missed dose. Just take the next dose at your regular time.
• Do not stop taking Tracleer unless your healthcare provider tells you to. Suddenly stopping your treatment may cause your symptoms to get worse. If you need to stop taking Tracleer, speak with your healthcare provider about the right way to stop.

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 your 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 include:

• respiratory tract infection
• headache
• fainting
• flushing
• low blood pressure
• inflamed nose passages (sinusitis)
• joint pain
• irregular heart beats

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.

How should I store Tracleer?

• Store Tracleer at room temperature between 68°F to 77°F (20°C to 25°C).

Keep Tracleer and all medicines out of the reach of children.

General information about Tracleer

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Tracleer for a condition for which it was not prescribed. Do not give Tracleer to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about Tracleer. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Tracleer that is written for health professionals. For more information, go to www.Tracleer.com or call 1-866-228-3546.

What are the ingredients in Tracleer?

Active ingredient: bosentan

Inactive ingredients: corn starch, pregelatinized starch, sodium starch glycolate, povidone, glyceryl behenate, magnesium stearate, hydroxypropylmethylcellulose, triacetin, talc, titanium dioxide, iron oxide yellow, iron oxide red, ethylcellulose.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured for:
Actelion Pharmaceuticals US, Inc.
South San Francisco, CA 94080, USA

ACT20160901
Revised: October 2016

PRINCIPAL DISPLAY PANEL - 62.5 mg Tablet Bottle Carton

NDC 66215-101-06

Tracleer®
BOSENTAN
62.5 mg

Rx only
ACTELION

60 tablets

PRINCIPAL DISPLAY PANEL - 125 mg Tablet Bottle Carton

NDC 66215-102-06

Tracleer®
BOSENTAN
125 mg

Rx only
ACTELION

60 tablets