Tracleer
Tracleer - General Information
Tracleer is a dual endothelin receptor antagonist important in the treatment of pulmonary artery hypertension (PAH). It is licensed in the United States, the European Union and other countries by Actelion Pharmaceuticals for the management of PAH under the trade name Tracleer®. Tracleer is used to treat pulmonary hypertension by blocking the action of endothelin molecules that would otherwise promote narrowing of the blood vessels and lead to high blood pressure.
Pharmacology of Tracleer
Tracleer belongs to a class of drugs known as endothelin receptor antagonists (ERAs). Patients with PAH have elevated levels of endothelin, a potent blood vessel constrictor, in their plasma and lung tissue. Tracleer blocks the binding of endothelin to its receptors, thereby negating endothelin's deleterious effects.
Tracleer for patients
Patients are advised to consult the TRACLEER® Medication Guide on the safe use of TRACLEER®.
The physician should discuss with the patient the importance of monthly monitoring of serum aminotransferases and urine or serum pregnancy testing and of avoidance of pregnancy. The physician should discuss options for effective contraception and measures to prevent pregnancy with their female patients. Input from a gynecologist or similar expert on adequate contraception should be sought as needed.
Medication Guide Tracleer
(tra-KLEER) Tablets (bosentan)
Read this information carefully before you start taking Tracleer tablets. Read the information you get with Tracleer each time you refill your prescription. There may be new information. This information does not take the place of talking with your doctor.
What is the most important information I should know about Tracleer?
· Liver damage.
Tracleer can cause liver damage if liver problems are not found early. Therefore, you must have a blood test to check your liver function before you start Tracleer and each month after that.
· Major birth defects.
Tracleer can cause major birth defects if taken during pregnancy. Therefore, women must not be pregnant when they start taking Tracleer or during Tracleer treatment.
Women who are sexually active must have a negative pregnancy test before beginning treatment. A negative test means you are not pregnant. The test should be during the first five days of a normal menstrual period and at least 11 days after the last unprotected sexual intercourse. Pregnancy tests must be done each month during Tracleer treatment, if you are sexually active.
Women who are able to get pregnant must use effective birth control while taking Tracleer. Birth control pills, shots, implants, or other hormone-based birth control may not be enough when Tracleer is used. Talk with your doctor and, if needed, with a gynecologist (a doctor who specializes in female reproduction) or another doctor who knows about birth control, to find out how to avoid pregnancy. Tell your doctor right away if you miss a period or think you may be pregnant.
What is Tracleer?
Tracleer is a medicine to treat pulmonary arterial hypertension, which is high blood pressure in the lung arteries. You take it by mouth.
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 effectively.
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 major birth defects. All women should read the birth defects section of "What is the most important information I should know about Tracleer?" Severe birth defects from Tracleer happen early in pregnancy. Therefore, you must not be pregnant while taking Tracleer.
· your blood test shows possible liver injury
· you are taking cyclosporine-A (used for psoriasis and rheumatoid arthritis, and to prevent rejection of heart or kidney transplants) or glyburide (used for diabetes)
· you are allergic to any ingredients in Tracleer. The active ingredient is bosentan. Ask your doctor or pharmacist if you need to know the inactive ingredients.
Tell your doctor if you have moderate or severe liver problems. Tracleer may not be right for you.
Tell your doctor about all the medicines you use. They may affect how Tracleer works, or Tracleer may affect how the other medicines work. Be sure to tell your doctor if you take
· ketoconazole (used for fungal infections)
· hormone-based birth control, such as pills, shots, and implants
· cyclosporine A (used for psoriasis and rheumatoid arthritis, and to prevent rejection of heart or kidney transplants)
· tacrolimus (used to prevent rejection liver or kidney transplants)
· glyburide (used for diabetes)
· cholesterol lowering medicines
· warfarin (used to prevent blood clots).
How should I take Tracleer?
Tracleer will be mailed to you by a central pharmacy. Your doctor will give you complete details:
· In most cases, you will take 1 tablet in the morning and 1 in the evening.
· You can take it with or without food.
· Your doctor will tell you how much to take.
· It will be easier to remember to take Tracleer if you do it at the same time each morning and evening. If you have trouble remembering, ask a family member to remind you, or put written notes where you will be sure to see them.
· If you take more than the prescribed dose of Tracleer, call your doctor right away.
· If you miss a dose, take your tablet as soon as you remember. However, do not take 2 doses to make up for a missed dose. Take your next tablet at the regular time.
· Do not stop taking Tracleer unless your doctor tells you to do so. Suddenly stopping your treatment may cause your symptoms to get worse. If you need to stop taking Tracleer, you doctor may tell you to reduce the dose over a few days before stopping completely.
During treatment, your doctor will test your blood for signs of side effects to your liver and red blood cells.
What should I avoid while taking Tracleer?
· Do not get pregnant while taking Tracleer. If you miss a period, call your doctor.
· Breast feeding is not recommended while taking Tracleer. It is not known if Tracleer can pass through your milk and harm the baby.
· Do not use hormone-based birth control (pills, injections, implants) as your only method of birth control. These may not work when used with Tracleer. Ask your doctor about effective birth control choices.
· Do not take cyclosporine-A. This medicine can cause too much Tracleer in your blood and increase your chance of liver damage.
· Do not take glyburide. This medicine can increase your chance of liver damage.
What are the possible side effects of Tracleer?
Tracleer can have serious side effects:
· Liver damage. Tracleer can cause liver damage if it is not found early. Because this side effect may not cause symptoms at first, only a blood test can show that you have early liver damage. Regular blood tests let your doctor change or stop your therapy before there is permanent damage. Therefore, it is very important that you have a liver function blood test before you start treatment and every month after that.
Call your doctor right away if you have any of these symptoms of liver problems: nausea, vomiting, fever, unusual tiredness, abdominal (stomach area) pain, or yellowing of the skin or the whites of your eyes (jaundice).
· Major birth defects. All females should read the birth defects section of "What is the most important information I should know about Tracleer?"
· Low sperm count. Drugs like Tracleer lower sperm count in animals. If this happens in men taking Tracleer, they may lose the ability to father children.
Other possible side effects
The most common side effects of Tracleer are:
· low red blood cell levels (anemia)
· headache
· inflamed throat and irritated nose passages
· flushing (hot flashes)
· ankle and leg swelling
· low blood pressure
· irregular heart beats
· upset stomach
· tiredness
· itching
General advice about prescription medicines
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you have any concerns or questions about Tracleer, ask your doctor or other health care provider. This Medication Guide is only a summary of some important information about Tracleer. Your doctor can give you information about Tracleer that was written for health care professionals. Do not use Tracleer for a condition for which it was not prescribed. Do not share Tracleer with other people.
This Medication Guide has been approved by the US Food and Drug Administration.
November 24, 2004
©2004 Actelion Pharmaceuticals US, Inc.
Tracleer Interactions
Bosentan is metabolized by CYP2C9 and CYP3A4. Inhibition of these isoenzymes may increase the plasma concentration of bosentan. Bosentan is an inducer of CYP3A4 and CYP2C9. Consequently, plasma concentrations of drugs metabolized by these two isoenzymes will be decreased when TRACLEER® is co-administered. Bosentan had no relevant inhibitory effect on any CYP isoenzymes tested (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4). Consequently, TRACLEER® is not expected to increase the plasma concentrations of drugs metabolized by these enzymes.
Hormonal Contraceptives, Including Oral, Injectable, Transdermal, and Implantable Contraceptives: An interaction study demonstrated that co-administration of bosentan and the oral hormonal contraceptive Ortho-Novum® produced average decreases of norethindrone and ethinyl estradiol levels of 14% and 31%, respectively. However, decreases in exposure were as much as 56% and 66%, respectively, in individual subjects. Therefore, hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when TRACLEER® is co-administered. Women should practice additional methods of contraception and not rely on hormonal contraception alone when taking TRACLEER®.
Specific interaction studies have demonstrated the following:
Cyclosporine A: During the first day of concomitant administration, trough concentrations of bosentan were increased by about 30-fold. Steady-state bosentan plasma concentrations were 3- to 4-fold higher than in the absence of cyclosporine A. The concomitant administration of bosentan and cyclosporine A is contraindicated. Co-administration of bosentan decreased the plasma concentrations of cyclosporine A (a CYP3A4 substrate) by approximately 50%.
Tacrolimus: Co-administration of tacrolimus and bosentan has not been studied in man. Co-administration of tacrolimus and bosentan resulted in markedly increased plasma concentrations of bosentan in animals. Caution should be exercised if tacrolimus and bosentan are used together.
Glyburide: An increased risk of elevated liver aminotransferases was observed in patients receiving concomitant therapy with glyburide. Therefore, the concomitant administration of TRACLEER® and glyburide is contraindicated, and alternative hypoglycemic agents should be considered.
Co-administration of bosentan decreased the plasma concentrations of glyburide by approximately 40%. The plasma concentrations of bosentan were also decreased by approximately 30%. Bosentan is also expected to reduce plasma concentrations of other oral hypoglycemic agents that are predominantly metabolized by CYP2C9 or CYP3A4. The possibility of worsened glucose control in patients using these agents should be considered.
Ketoconazole: Co-administration of bosentan 125 mg b.i.d. and ketoconazole, a potent CYP3A4 inhibitor, increased the plasma concentrations of bosentan by approximately 2-fold. No dose adjustment of bosentan is necessary, but increased effects of bosentan should be considered.
Simvastatin and Other Statins: Co-administration of bosentan decreased the plasma concentrations of simvastatin (a CYP3A4 substrate), and its active ß-hydroxy acid metabolite, by approximately 50%. The plasma concentrations of bosentan were not affected. Bosentan is also expected to reduce plasma concentrations of other statins that have significant metabolism by CYP3A4, such as lovastatin and atorvastatin. The possibility of reduced statin efficacy should be considered. Patients using CYP3A4 metabolized statins should have cholesterol levels monitored after TRACLEER® is initiated to see whether the statin dose needs adjustment.
Warfarin: Co-administration of bosentan 500 mg b.i.d. for 6 days decreased the plasma concentrations of both S-warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A4 substrate) by 29 and 38%, respectively. Clinical experience with concomitant administration of bosentan and warfarin in patients with pulmonary arterial hypertension did not show clinically relevant changes in INR or warfarin dose (baseline vs. end of the clinical studies), and the need to change the warfarin dose during the trials due to changes in INR or due to adverse events was similar among bosentan- and placebo-treated patients.
Digoxin, Nimodipine and Losartan: Bosentan has no significant pharmacokinetic interactions with digoxin and nimodipine, and losartan has no significant effect on plasma levels of bosentan.
Tracleer Contraindications
Pregnancy Category X. TRACLEER® is expected to cause fetal harm if administered to pregnant women. Bosentan was teratogenic in rats given oral doses 60 mg/kg/day (twice the maximum recommended human oral dose of 125 mg, b.i.d., on a mg/m2 basis). In an embryo-fetal toxicity study in rats, bosentan showed dose-dependent teratogenic effects, including malformations of the head, mouth, face and large blood vessels. Bosentan increased stillbirths and pup mortality at oral doses of 60 and 300 mg/kg/day (2 and 10 times, respectively, the maximum recommended human dose on a mg/m2 basis). Although birth defects were not observed in rabbits given oral doses of up to 1500 mg/kg/day, plasma concentrations of bosentan in rabbits were lower than those reached in the rat. The similarity of malformations induced by bosentan and those observed in endothelin-1 knockout mice and in animals treated with other endothelin receptor antagonists indicates that teratogenicity is a class effect of these drugs. There are no data on the use of TRACLEER® in pregnant women.
Pregnancy must be excluded before the start of treatment with TRACLEER® and prevented thereafter by use of reliable contraception. Hormonal contraceptives, including oral, injectable, and implantable contraceptives may not be reliable in the presence of TRACLEER® and should not be used as the sole contraceptive method in patients receiving TRACLEER®. Input from a gynecologist or similar expert on adequate contraception should be sought as needed.
TRACLEER® should be started only in patients known not to be pregnant. For female patients of childbearing potential, a prescription for TRACLEER® should not be issued by the prescriber unless the patient assures the prescriber that she is not sexually active or provides negative results from a urine or serum pregnancy test performed during the first 5 days of a normal menstrual period and at least 11 days after the last unprotected act of sexual intercourse.
Follow-up urine or serum pregnancy tests should be obtained monthly in women of childbearing potential taking TRACLEER®. The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, she must notify the physician immediately for pregnancy testing. If the pregnancy test is positive, the physician and patient must discuss the risk to the pregnancy and to the fetus.
Cyclosporine A: Co-administration of cyclosporine A and bosentan resulted in markedly increased plasma concentrations of bosentan. Therefore, concomitant use of TRACLEER® and cyclosporine A is contraindicated.
Glyburide: An increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan. Therefore co-administration of glyburide and TRACLEER® is contraindicated.
Hypersensitivity: TRACLEER® is also contraindicated in patients who are hypersensitive to bosentan or any component of the medication.
Additional information about Tracleer
Tracleer Indication: Used in the treatment of pulmonary arterial hypertension (PAH), to improve exercise ability and to decrease the rate of clinical worsening (in patients with WHO Class III or IV symptoms).
Mechanism Of Action: Endothelin-1 (ET-1) is a neurohormone, the effects of which are mediated by binding to ETA and ETB receptors in the endothelium and vascular smooth muscle. ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension, suggesting a pathogenic role for ET-1 in this disease. Tracleer is a specific and competitive antagonist at endothelin receptor types ETA and ETB. Tracleer has a slightly higher affinity for ETA receptors than for ETB receptors.
Drug Interactions: Anisindione Increases the anticoagulant effect
Atorvastatin Tracleer could decrease atorvastatin effect
Cerivastatin Tracleer could decrease the statin effect
Cyclosporine Cyclosporine increases the effect and toxicity of bosentan
Dicumarol Increase the anticoagulant effect
Ethinyl Estradiol Decreases the effect of contraceptive
Glibenclamide Increased risk of hepatic toxicity
Itraconazole This imidazole increases the effect and toxicity of bosentan
Ketoconazole This imidazole increases the effect and toxicity of bosentan
Lovastatin Tracleer could decrease the statin effect
Medroxyprogesterone Decreases the effect of contraceptive
Mestranol Decreases the effect of contraceptive
Acenocoumarol Increases the anticoagulant effect
Norethindrone Decreases the effect of contraceptive
Simvastatin Tracleer could decrease the statin effect
Voriconazole This imidazole increases the effect and toxicity of bosentan
Warfarin Increases the anticoagulant effect
Food Interactions: Take without regard to meals.
Generic Name: Bosentan
Synonyms: Bosentan hydrate
Drug Category: Antihypertensive Agents
Drug Type: Small Molecule; Approved; Investigational
Other Brand Names containing Bosentan: Tracleer;
Absorption: Absolute bioavailability is approximately 50% and food does not affect absorption.
Toxicity (Overdose): Bosentan has been given as a single dose of up to 2400 mg in normal volunteers, or up to 2000 mg/day for 2 months in patients, without any major clinical consequences. The most common side effect was headache of mild to moderate intensity. In the cyclosporine A interaction study, in which doses of 500 and 1000 mg b.i.d. of bosentan were given concomitantly with cyclosporine A, trough plasma concentrations of bosentan increased 30-fold, resulting in severe headache, nausea, and vomiting, but no serious adverse events. Mild decreases in blood pressure and increases in heart rate were observed. There is no specific experience of overdosage with bosentan beyond the doses described above. Massive overdosage may result in pronounced hypotension requiring active cardiovascular support.
Protein Binding: Greater than 98% to plasma proteins, mainly albumin.
Biotransformation: Bosentan is metabolized in the liver by the cytochrome P450 enzymes CYP2C9 and CYP3A4 (and possibly CYP2C19), producing three metabolites, one of which, Ro 48-5033, is pharmacologically active and may contribute 10 to 20% to the total activity of the parent compound.
Half Life: Terminal elimination half-life is about 5 hours in healthy adult subjects.
Dosage Forms of Tracleer: Tablet Oral
Tablet Oral
Chemical IUPAC Name: 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-pyrimidin-2-ylpyrimidin-4-yl]benzenesulfonamide
Chemical Formula: C27H29N5O6S
Bosentan on Wikipedia: https://en.wikipedia.org/wiki/Bosentan
Organisms Affected: Humans and other mammals