Tracleer Information
Tracleer (Bosentan) . Dosage And Administration
Tracleer (Bosentan) treatment should be initiated at a dose of 62.5 mg twice daily for 4 weeks and then increased to the maintenance dose of 125 mg twice daily. Doses above 125 mg twice daily did not appear to confer additional benefit sufficient to offset the increased risk of liver injury.
Tablets should be administered morning and evening with or without food.
The table below summarizes the dosage adjustment and monitoring recommendations for patients who develop aminotransferase elevations >3 × ULN during therapy with Tracleer (Bosentan) . If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 × ULN, treatment with Tracleer (Bosentan) should be stopped. There is no experience with the re-introduction of Tracleer (Bosentan) in these circumstances.
If Tracleer (Bosentan) is re-introduced it should be at the starting dose; aminotransferase levels should be checked within 3 days and thereafter according to the recommendations above.
Tracleer (Bosentan) . Dosage Forms And Strengths
Tracleer (Bosentan) is available as 62.5 mg and 125 mg film-coated, unscored tablets for oral administration.
62.5 mg tablets: film-coated, round, biconvex, orange-white tablets, embossed with identification marking "62,5"
125 mg tablets: film-coated, oval, biconvex, orange-white tablets, embossed with identification marking "125"
Tracleer (Bosentan) . Contraindications
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Use of Tracleer (Bosentan) is contraindicated in females who are or may become pregnant. While there are no adequate and well controlled studies in pregnant females, animal studies show that Tracleer (Bosentan) is likely to cause major birth defects when administered during pregnancy. In animal studies, bosentan caused teratogenic effects including malformations of the head, mouth, face, and large blood vessels. Therefore, pregnancy must be excluded before the start of treatment with Tracleer (Bosentan) . Throughout treatment and for one month after stopping Tracleer (Bosentan) , females of child bearing potential must use two reliable methods of contraception unless the patient has a tubal sterilization or Copper T 380A IUD or LNg 20 IUS inserted, in which case no other contraception is needed. Monthly pregnancy tests should also be obtained. If this drug is used during pregnancy or if a patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. .
Tracleer (Bosentan) Warnings And Precautions
Elevations in ALT or AST by more than 3 × ULN were observed in 11% of bosentan-treated patients (N = 658) compared to 2% of placebo-treated patients (N = 280). Three-fold increases were seen in 12% of 95 pulmonary arterial hypertension (PAH) patients on 125 mg twice daily and 14% of 70 PAH patients on 250 mg twice daily. Eight-fold increases were seen in 2% of PAH patients on 125 mg twice daily and 7% of PAH patients on 250 mg twice daily. Bilirubin increases to ≥3 × ULN were associated with aminotransferase increases in 2 of 658 (0.3%) of patients treated with bosentan. The combination of hepatocellular injury (increases in aminotransferases of > 3 × ULN) and increases in total bilirubin (≥ 3 × ULN) is a marker for potential serious liver injury.
Elevations of AST and/or ALT associated with bosentan are dose-dependent, occur both early and late in treatment, usually progress slowly, are typically asymptomatic, and usually have been reversible after treatment interruption or cessation. Aminotransferase elevations also may reverse spontaneously while continuing treatment with Tracleer (Bosentan) .
Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly. If elevated aminotransferase levels are seen, changes in monitoring and treatment must be initiated. If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 × ULN, treatment should be stopped. There is no experience with the re-introduction of Tracleer (Bosentan) in these circumstances .
Peripheral edema is a known clinical consequence of PAH and worsening PAH and is also a known effect of other endothelin receptor antagonists. In PAH clinical trials with Tracleer (Bosentan) , combined adverse events of fluid retention or edema were reported in 1.7 percent (placebo-corrected) of patients .
In addition, there have been numerous post-marketing reports of fluid retention in patients with pulmonary hypertension occurring within weeks after starting Tracleer (Bosentan) . Patients required intervention with a diuretic, fluid management, or hospitalization for decompensating heart failure.
If clinically significant fluid retention develops, with or without associated weight gain, further evaluation should be undertaken to determine the cause, such as Tracleer (Bosentan) or underlying heart failure, and the possible need for treatment or discontinuation of Tracleer (Bosentan) therapy.
Treatment with Tracleer (Bosentan) can cause a dose-related decrease in hemoglobin and hematocrit. It is recommended that hemoglobin concentrations be checked after 1 and 3 months, and every 3 months thereafter. If a marked decrease in hemoglobin concentration occurs, further evaluation should be undertaken to determine the cause and need for specific treatment.
The overall mean decrease in hemoglobin concentration for bosentan-treated patients was 0.9 g/dL (change to end of treatment). Most of this decrease of hemoglobin concentration was detected during the first few weeks of bosentan treatment and hemoglobin levels stabilized by 4–12 weeks of bosentan treatment. In placebo-controlled studies of all uses of bosentan, marked decreases in hemoglobin (> 15% decrease from baseline resulting in values
A decrease in hemoglobin concentration by at least 1 g/dL was observed in 57% of bosentan-treated patients as compared to 29% of placebo-treated patients. In 80% of those patients whose hemoglobin decreased by at least 1 g/dL, the decrease occurred during the first 6 weeks of bosentan treatment.
During the course of treatment the hemoglobin concentration remained within normal limits in 68% of bosentan-treated patients compared to 76% of placebo patients. The explanation for the change in hemoglobin is not known, but it does not appear to be hemorrhage or hemolysis.
Because of the risks of liver injury and birth defects, Tracleer (Bosentan) is available only through a special restricted distribution program called the Tracleer (Bosentan) Access Program (T.A.P.). Only prescribers and pharmacies registered with T.A.P. may prescribe and distribute Tracleer (Bosentan) . In addition, Tracleer (Bosentan) may be dispensed only to patients who are enrolled in and meet all conditions of T.A.P. Information about Tracleer (Bosentan) and T.A.P. can be obtained by calling 1-866-228-3546.
To enroll in T.A.P., prescribers must complete the T.A.P. Tracleer (Bosentan) Enrollment and Renewal Form (see T.A.P. Tracleer (Bosentan) Enrollment and Renewal Form for full prescribing physician agreement) indicating agreement to:
Throughout treatment and for one month after stopping Tracleer (Bosentan) , females of childbearing potential must use two reliable methods of contraception unless the patient has a tubal sterilization or Copper T 380A IUD or LNg 20 IUS inserted, in which case no other contraception is needed. Hormonal contraceptives, including oral, injectable, transdermal, and implantable contraceptives should not be used as the sole means of contraception because these may not be effective in patients receiving Tracleer (Bosentan) .
Tracleer (Bosentan) . Adverse Reactions
The following important adverse reactions are described elsewhere in the labeling:
Safety data on bosentan were obtained from 13 clinical studies (9 placebo-controlled and 4 open-label) in 870 patients with pulmonary arterial hypertension and other diseases. Doses up to 8 times the currently recommended clinical dose (125 mg twice daily) were administered for a variety of durations. The exposure to bosentan in these trials ranged from 1 day to 4.1 years (N=94 for 1 year; N=61 for 1.5 years and N=39 for more than 2 years). Exposure of pulmonary arterial hypertension patients (N=328) to bosentan ranged from 1 day to 1.7 years (N=174 more than 6 months and N=28 more than 12 months).
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Treatment discontinuations due to adverse events other than those related to pulmonary hypertension during the clinical trials in patients with pulmonary arterial hypertension were more frequent on bosentan (6%; 15/258 patients) than on placebo (3%; 5/172 patients). In this database the only cause of discontinuations > 1% and occurring more often on bosentan was abnormal liver function.
The adverse drug events that occurred in ≥3% of the bosentan-treated patients and were more common on bosentan in placebo-controlled trials in pulmonary arterial hypertension at doses of 125 or 250 mg twice daily are shown in Table 2:
There have been several post-marketing reports of angioedema associated with the use of bosentan. The onset of the reported cases occurred within a range of 8 hours to 21 days after starting therapy. Some patients were treated with an antihistamine and their signs of angioedema resolved without discontinuing Tracleer (Bosentan) .
The following additional adverse reactions have been reported during the post approval use of Tracleer (Bosentan) . Because these adverse reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Tracleer (Bosentan) exposure:
Tracleer (Bosentan) . Drug Interactions
Bosentan is metabolized by CYP2C9 and CYP3A. Inhibition of these enzymes may increase the plasma concentration of bosentan (see ). Concomitant administration of both a CYP2C9 inhibitor (such as fluconazole or amiodarone) and a strong CYP3A inhibitor (e.g., ketoconazole, itraconazole) or a moderate CYP3A inhibitor (e.g., amprenavir, erythromycin, fluconazole, diltiazem) with bosentan will likely lead to large increases in plasma concentrations of bosentan. Co-administration of such combinations of a CYP2C9 inhibitor plus a strong or moderate CYP3A inhibitor with Tracleer (Bosentan) is not recommended.
Bosentan is an inducer of CYP3A and CYP2C9. Consequently plasma concentrations of drugs metabolized by these two isozymes will be decreased when Tracleer (Bosentan) is co-administered. Bosentan had no relevant inhibitory effect on any CYP isozyme in vitro (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A). Consequently, Tracleer (Bosentan) is not expected to increase the plasma concentrations of drugs metabolized by these enzymes.
Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when Tracleer (Bosentan) is co-administered. Females should practice additional methods of contraception and not rely on hormonal contraception alone when taking Tracleer (Bosentan) .
An interaction study demonstrated that co-administration of bosentan and a combination oral hormonal contraceptive 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.
The concomitant administration of bosentan and cyclosporine A is contraindicated .
During the first day of concomitant administration, trough concentrations of bosentan were increased by about 30-fold. The mechanism of this interaction is most likely inhibition of transport protein-mediated uptake of bosentan into hepatocytes by cyclosporine. Steady-state bosentan plasma concentrations were 3- to 4-fold higher than in the absence of cyclosporine A. Co-administration of bosentan decreased the plasma concentrations of cyclosporine A (a CYP3A substrate) by approximately 50%.
An increased risk of elevated liver aminotransferases was observed in patients receiving concomitant therapy with glyburide. Therefore, the concomitant administration of Tracleer (Bosentan) 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 CYP3A. The possibility of worsened glucose control in patients using these agents should be considered.
In vitro
In normal volunteers, co-administration of Tracleer (Bosentan) 125 mg twice daily and lopinavir/ritonavir 400/100 mg twice daily increased the trough concentrations of bosentan on Days 4 and 10 approximately 48-fold and 5-fold, respectively, compared with those measured after Tracleer (Bosentan) administered alone. Therefore, adjust the dose of Tracleer (Bosentan) when initiating lopinavir/ritonavir .
Co-administration of Tracleer (Bosentan) 125 mg twice daily had no substantial impact on the pharmacokinetics of lopinavir/ritonavir 400/100 mg twice daily.
Tracleer (Bosentan) . Use In Specific Populations
Pregnancy Category X: Teratogenic Effects
Use of Tracleer (Bosentan) is contraindicated in females who are or may become pregnant. While there are no adequate and well controlled studies in pregnant females, animal studies show that Tracleer (Bosentan) is likely to cause major birth defects when administered during pregnancy. Bosentan caused teratogenic effects in animals including malformations of the head, mouth, face, and large blood vessels. If this drug is used during pregnancy or if a patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Females of childbearing potential should have a negative pregnancy test before starting treatment with Tracleer (Bosentan) . The prescriber should not dispense a prescription for Tracleer (Bosentan) without documenting a negative 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 females of childbearing potential taking Tracleer (Bosentan) . The patient should contact her physician immediately for pregnancy testing if onset of menses is delayed or pregnancy is suspected. If the pregnancy test is positive, the physician and patient must discuss the risks to her, the pregnancy, and the fetus.
Drug interaction studies show that Tracleer (Bosentan) reduces serum levels of the estrogen and progestin in oral contraceptives. Based on these findings, hormonal contraceptives (including oral, injectable, transdermal, and implantable contraceptives) may be less effective for preventing pregnancy in patients using Tracleer (Bosentan) and should not be used as a patient's only contraceptive method Females of childbearing potential using Tracleer (Bosentan) must use two reliable forms of contraception unless she has a tubal sterilization or has a Copper T 380A IUD or LNg 20 IUS. In these cases, no additional contraception is needed. Contraception should be continued until one month after completing Tracleer (Bosentan) therapy. Females of childbearing potential using Tracleer (Bosentan) should seek contraception counseling from a gynecologist or other expert as needed.
Bosentan was teratogenic in rats given oral doses two times the maximum recommended human dose [MRHD] (on a mg/ m 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 2 and 10 times the MRHD (on a mg/m basis). Although birth defects were not observed in rabbits given oral doses of up to the equivalent of 10.5 g/day in a 70 kg person, 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
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Tracleer (Bosentan) . Overdosage
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 twice daily 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.
In the postmarketing period, there was one reported overdose of 10,000 mg of bosentan taken by an adolescent male patient. He had symptoms of nausea, vomiting, hypotension, dizziness, sweating, and blurred vision. He recovered within 24 hours with blood pressure support.
Bosentan is unlikely to be effectively removed by dialysis due to the high molecular weight and extensive plasma protein binding.
Tracleer (Bosentan) . Description
Bosentan is an endothelin receptor antagonist, belonging to a class of highly substituted pyrimidine derivatives, with no chiral centers. It is designated chemically as 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2´]-bipyrimidin-4-yl]- benzenesulfonamide monohydrate and has the following structural formula:
Bosentan has a molecular weight of 569.64 and a molecular formula of CHNOS•HO. Bosentan is a white to yellowish powder. It is poorly soluble in water (1.0 mg/100 mL) and in aqueous solutions at low pH (0.1 mg/100 mL at pH 1.1 and 4.0; 0.2 mg/100 mL at pH 5.0). Solubility increases at higher pH values (43 mg/100 mL at pH 7.5). In the solid state, bosentan is very stable, is not hygroscopic and is not light sensitive.
Tracleer (Bosentan) is available as 62.5 mg and 125 mg film-coated tablets for oral administration, and contains the following excipients: corn starch, pregelatinized starch, sodium starch glycolate, povidone, glyceryl behenate, magnesium stearate, hydroxypropylmethylcellulose, triacetin, talc, titanium dioxide, iron oxide yellow, iron oxide red, and ethylcellulose. Each Tracleer (Bosentan) 62.5 mg tablet contains 64.541 mg of bosentan, equivalent to 62.5 mg of anhydrous bosentan. Each Tracleer (Bosentan) 125 mg tablet contains 129.082 mg of bosentan, equivalent to 125 mg of anhydrous bosentan.
Tracleer (Bosentan) . Clinical Studies
Tracleer (Bosentan) . How Supplied/storage And Handling
62.5 mg film-coated, round, biconvex, orange-white tablets, embossed with identification marking "62,5", packaged in a white high-density polyethylene bottle and a white polypropylene child-resistant cap.
NDC 66215-101-06: Bottle containing 60 tablets.
125 mg film-coated, oval, biconvex, orange-white tablets, embossed with identification marking "125", packaged in a white high-density polyethylene bottle and a white polypropylene child-resistant cap.
NDC 66215-102-06: Bottle containing 60 tablets.
Tracleer (Bosentan)
Tracleer (Bosentan) . Patient Counseling Information
Advise patients to consult the Medication Guide on the safe use of Tracleer (Bosentan)
The physician should discuss with the patient the importance of monthly monitoring of serum aminotransferases.
Patients should be advised that Tracleer (Bosentan) is likely to cause birth defects based on animal studies. Tracleer (Bosentan) treatment should only be initiated in females of childbearing potential following a negative pregnancy test. Females of childbearing potential must have monthly pregnancy tests and need to use two different forms of contraception while taking Tracleer (Bosentan) and for one month after discontinuing Tracleer (Bosentan) . Females who have a tubal ligation or a Copper T 380A IUD or LNg 20 IUS can use these contraceptive methods alone. Patients should be instructed to immediately contact their physician if they suspect they may be pregnant and should seek contraceptive advice from a gynecologist or similar expert as needed.
The physician should discuss with the patient possible drug interactions with Tracleer (Bosentan) , and which medications should not be taken with Tracleer (Bosentan) . The physician should discuss the importance of disclosing all concomitant or new medications.
Tracleer (Bosentan)
Tracleer (Bosentan) Principal Display Panel - . Mg Bottle Carton
Tracleer (Bosentan) Principal Display Panel - Mg Bottle Carton
