Bosentan

Talk to your doctor about drinking grapefruit juice while taking this medication.

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom).

Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Symptoms of overdose may include the following:

• headache
• upset stomach
• vomiting
• fast heartbeat
• fainting
• dizziness
• blurred vision

Do not let anyone else take your medication. Ask your doctor any questions you have about refilling your prescription.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have signs of liver problems--nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Call your doctor at once if you have:

• swelling in your legs or ankles, with or without weight gain;
• pale skin, feeling short of breath, rapid or irregular heart rate, trouble concentrating;
• a light-headed feeling, like you might pass out; or
• new lung problems--anxiety, sweating, pale skin, severe shortness of breath, wheezing, gasping for breath, cough with foamy mucus, chest pain, fast or uneven heart rate.

Common side effects may include:

• headache;
• flushing (warmth, redness, or tingly feeling);
• joint pain; or
• stuffy nose, sinus pain, sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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

Tell your doctor about all medicines you use, and those you start or stop using during your treatment with bosentan, especially:

• rifampin;
• tacrolimus;
• warfarin (Coumadin, Jantoven);
• antifungal medication--fluconazole, itraconazole, ketoconazole, voriconazole; or
• "statin" medicine to treat high cholesterol--Crestor, Lipitor, Mevacor, Pravachol, Vytorin, Zocor, and others.

This list is not complete. Other drugs may interact with bosentan, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Bosentan is part of the drug class:

• OTHER ANTIHYPERTENSIVES

Bosentan can cause serious side effects, including:

• Fluid retention and swelling of your ankles and legs. Bosentan 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 bosentan 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 bosentan.

The most common side effects of bosentan are:

• 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 bosentan. 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.

• Store bosentan at 68°F to 77°F (20°C-25°C).
• Keep bosentan and all medicines out of the reach of children.

You should not use bosentan if you are allergic to it, or if you are pregnant or might become pregnant during treatment.

Some medicines can interact with bosentan and should not be used at the same time. Your doctor may need to change your treatment plan if you use any of the following drugs:

• cyclosporine; or

• glyburide.

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

• liver disease;

• fluid retention;

• diabetes;

• an autoimmune disorder such as rheumatoid arthritis or psoriasis; or

• if you have had or will have a heart or kidney transplant.

Do not use bosentan if you are pregnant or think you might be pregnant. This medicine can cause serious birth defects, especially if taken during early pregnancy. Tell your doctor right away if you miss a menstrual period or think you may have become pregnant during treatment.

You will need to have a negative pregnancy test before starting this treatment. You will be re-tested every month during your treatment, and 1 month after you stop taking this medicine.

Even if you are not planning a pregnancy, you are considered able to become pregnant if:

• you have entered puberty (even if you have not yet started having periods);

• you have never had a hysterectomy or had your ovaries removed; or

• you have not gone through menopause (you have never gone 12 months in a row without a menstrual period).

While taking bosentan and for at least 30 days after your last dose, you must use a highly effective form of birth control or two methods together.

• A tubal ligation alone is an effective birth control method.

• An intrauterine device (IUD) alone is also an effective birth control method.

• If you use birth control pills, implants, injections, skin patches, or vaginal rings, you must use a back-up barrier form of birth control, such as a condom or diaphragm or cervical cap. Always use a spermicide gel or insert together with a barrier form of birth control.

• If you use only a barrier method, you must use a second barrier method as a back-up. For example, use a diaphragm or cervical cap in addition to a condom, plus a spermicide gel or insert.

• If your sexual partner has had a vasectomy, you must still use a second method of birth control--either a barrier method or a hormonal form (birth control pills, injections, skin patch, or vaginal ring).

Bosentan comes with patient instructions about acceptable forms of birth control to use while taking this medicine. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions.

If you are the parent or caregiver of a female child taking this medicine, talk to the child's doctor once you notice any signs of puberty (breast development or pubic hair), even if menstrual periods have not yet begun.

Bosentan can decrease sperm count and may affect fertility in men (your ability to have children).

It is not known whether bosentan passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Vasodilator; an endothelin receptor antagonist.1

Contraindications

• Known or suspected pregnancy.1

• Concomitant therapy with cyclosporine or glyburide.1

• Known hypersensitivity to bosentan or any ingredient in the formulation.1

Warnings/Precautions

Warnings

With close monitoring, unexplained hepatic cirrhosis and liver failure reported rarely after prolonged (i.e., >12 months) bosentan therapy.1 11 (See Boxed Warning.)

Manufacturer reinforces importance of strict adherence to monthly monitoring schedule and to dosage adjustment and monitoring guidelines throughout bosentan therapy.1 11 (See Patients with Adverse Hepatic Effects under Dosage and Administration.)

Dose-dependent elevations in AST or ALT of >3 times ULN were observed in 11% of patients receiving bosentan (<2 g daily) in clinical trials; occasionally accompanied by elevations in bilirubin,1 9 indicating potentially serious hepatic injury.1

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.1 Teratogenicity appears to be a class effect of endothelin-receptor antagonists.1 14

Exclude pregnancy (i.e., negative results on a urine or serum pregnancy test performed during the first 5 days of a normal menstrual period and ≥11 days after the last unprotected act of sexual intercourse) prior to initiating bosentan therapy in women of childbearing potential.1 5 6 Perform urine or serum pregnancy tests monthly.1 9 11

Women of childbearing potential must use 2 reliable contraceptive methods (including a nonhormonal method) during and for 1 month following cessation of therapy, unless patient has a Copper T380A or LNg 20 IUD or has undergone tubal sterilization, in which case no other contraceptive method required.1 (See Specific Drugs under Interactions.)

If used during pregnancy or patient becomes pregnant during therapy, apprise of potential fetal hazard.1

Sensitivity Reactions

Angioedema (occurring 8 hours to 21 days after initiating therapy) reported.1

General Precautions

Fluid retention, sometimes requiring intervention (e.g., diuretics, fluid management, hospitalization), reported.1 Peripheral edema a known class effect of endothelin-receptor antagonists and also a consequence of PAH.1 17

If clinically important fluid retention occurs, evaluate further to determine cause; initiate specific treatment or discontinue bosentan if necessary.1

Reduced sperm counts observed in men with PAH receiving usual dosages of bosentan; cannot exclude possibility of adverse effects on spermatogenesis.1

Possible dose-related decreases in hemoglobin and hematocrit.1 9 Monitor hemoglobin 1 and 3 months after initiation of therapy and every 3 months thereafter.1

Consider possibility of associated pulmonary veno-occlusive disease (PVOD) and discontinue bosentan if manifestations of pulmonary edema occur.1

Specific Populations

Category X.1 (See Fetal/Neonatal Morbidity and Mortality and also see Contraindications under Cautions.)

Not known whether bosentan is distributed into milk.1 Discontinue nursing or the drug.1

Safety and efficacy not established in children <12 years of age.9 Evaluated in a limited number of pediatric patients 3–15 years of age; safety, efficacy, and pharmacokinetics of bosentan were similar to those parameters reported in adults.35

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1

Extensively metabolized by liver; hepatic impairment expected to increase exposure to bosentan.1 Use not recommended in patients with preexisting moderate to severe hepatic impairment or AST/ALT >3 times ULN.1 9

Minimal effect of severe renal impairment (Scr 15–30 mL/minute) on bosentan pharmacokinetics.1

Common Adverse Effects

Headache,1 nasopharyngitis,1 flushing,1 abnormal hepatic function,1 lower limb edema,1 hypotension,1 palpitations,1 dyspepsia,1 edema,1 fatigue,1 pruritus,1 rash,1 anemia.1

Bosentan is used to treat the symptoms of pulmonary arterial hypertension. This is the high blood pressure that occurs in the main artery that carries blood from the right side of the heart (the ventricle) to the lungs. When the smaller blood vessels in the lungs become more resistant to blood flow, the right ventricle must work harder to pump enough blood through the lungs. Bosentan works by blocking a hormone (a naturally occurring substance), that is found in the blood and lungs in large quantities of the people with pulmonary arterial hypertension. Bosentan helps by increasing the supply of blood to the lungs and reducing the workload of the heart.

bosentan is available only under a special restricted distribution program called the Tracleer Access Program (T.A.P.).

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 bosentan, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to bosentan 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 bosentan 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 bosentan in the elderly. However, elderly patients are more likely to have age-related heart, liver, or kidney problems, which may require caution in patients receiving bosentan.

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 bosentan, 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 bosentan with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Cyclosporine
• Glyburide

Using bosentan 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.

• Atazanavir
• Axitinib
• Bosutinib
• Cobicistat
• Cobimetinib
• Daclatasvir
• Darunavir
• Deflazacort
• Desogestrel
• Dienogest
• Doxorubicin
• Doxorubicin Hydrochloride Liposome
• Drospirenone
• Elbasvir
• Elvitegravir
• Enzalutamide
• Estradiol
• Ethinyl Estradiol
• Ethynodiol
• Etonogestrel
• Fosamprenavir
• Gestodene
• Grazoprevir
• Levonorgestrel
• Lopinavir
• Mestranol
• Nifedipine
• Norethindrone
• Norgestimate
• Norgestrel
• Olaparib
• Piperaquine
• Ritonavir
• Saquinavir
• Simeprevir
• Tacrolimus
• Tipranavir
• Velpatasvir
• Venetoclax

Using bosentan 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.

• Atorvastatin
• Ketoconazole
• Lovastatin
• Ospemifene
• Rifampin
• Sildenafil
• Simvastatin
• Warfarin

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 bosentan. Make sure you tell your doctor if you have any other medical problems, especially:

• Edema (fluid retention or body swelling) or
• Heart failure or
• Liver disease, mild or
• Lung problems—Use with caution. Bosentan may make these conditions worse.

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

In patients with severe renal impairment (CrCl 15 to 30 mL/minute), concentrations of the 3 metabolites may increase 2-fold, although it is not clinically significant.

May be administered with or without food, once in the morning and once in the evening.

Serum transaminase (AST and ALT) and bilirubin (prior to treatment initiation and monthly thereafter, or more frequently if clinically necessary [every 2 weeks following transaminase elevations and 3 days after reintroducing therapy if withheld due to transaminase elevations]). Hemoglobin and hematocrit (at baseline, at 1 month and 3 months of treatment, and every 3 months thereafter [generally stabilizes after 4 to 12 weeks of treatment]).

Pregnancy test in women of childbearing potential (prior to the initiation of therapy and monthly thereafter, prior to shipment of monthly refill).

Monitor for clinical signs/symptoms of liver injury (eg, abdominal pain, fatigue, fever, jaundice, nausea, vomiting). Monitor for fluid retention.

Bosentan prevents thickening of the blood vessels, especially those in the lungs and heart. Bosentan also lowers blood pressure in your lungs, helping your heart pump blood more efficiently.

Bosentan is used to treat pulmonary arterial hypertension (PAH). It improves your ability to exercise and prevents your condition from getting worse.

Bosentan may also be used for other purposes not listed in this medication guide.