Enter drug's generic or brand name below. Results will appear here. Note: all drug related information obtained on this page is provided by RX List.
Using the RX LIST database:
(1) Enter the drug name in the search box below and hit ENTER
(2) The rx list web site will open here with the drug search completed. Next, scroll down the page to locate the link to the drug you are searching for and then click on the link.
WARNING
RISKS OF HEPATOTOXICITY and EMBRYO-FETAL TOXICITY
Because of the risks of hepatotoxicity and birth defects, Tracleer is available only through a restricted program called the Tracleer REMS Program. The Tracleer REMS Program is a component of the Tracleer Risk Evaluation and Mitigation Strategy (REMS). Under the Tracleer REMS, prescribers , patients , and pharmacies must enroll in the program [see WARNINGS AND PRECAUTIONS].
In clinical studies, Tracleer caused at least 3-fold upper limit of normal (ULN) elevation of liver aminotransferases (ALT and AST) in about 11% of patients, accompanied by elevated bilirubin in a s mall number of cases. Because these changes are a marker for potential serious hepatotoxicity, serum aminotransferase levels must be measured prior to initiation of treatment and then monthly [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]. In the postmarketing period, in the setting of close monitoring, rare cases of unexplained hepatic cirrhos is were reported after prolonged (> 12 months ) therapy with Tracleer in patients with multiple comorbidities and drug therapies . There have also been reports of liver failure. The contribution of Tracleer in these cases could not be excluded.
In at least one case, the initial presentation (after > 20 months of treatment) included pronounced elevations in aminotransferases and bilirubin levels accompanied by non-specific symptoms, all of which resolved slowly over time after discontinuation of Tracleer. This case reinforces the importance of strict adherence to the monthly monitoring schedule for the duration of treatment and the treatment algorithm, which includes stopping Tracleer with a rise of aminotransferases accompanied by signs or symptoms of liver dysfunction [see DOSAGE AND ADMINISTRATION].
Elevations in aminotransferases require close attention [see DOSAGE AND ADMINISTRATION]. Tracleer should generally be avoided in patients with elevated aminotransferases (> 3 × ULN) at baseline because monitoring for hepatotoxicity may be more difficult. If liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥ 2 × ULN, treatment with Tracleer should be s topped. There is no experience with the reintroduction of Tracleer in these circumstances.
Tracleer is likely to cause major birth defects if used by pregnant females based on animal data [see WARNINGS AND PRECAUTIONS, Use In Specific Populations]. Therefore, pregnancy must be excluded before the s tart of treatment with Tracleer. Throughout treatment and for one month after stopping Tracleer, females of reproductive potential must use two reliable methods of contraception unless the patient has an intrauterine device (IUD) or tubal sterilization, in which case no other contraception is needed. Hormonal contraceptives, including oral, injectable, trans dermal, and implantable contraceptives should not be used as the sole means of contraception because these may not be effective in patients receiving Tracleer [see DRUG INTERACTIONS]. Obtain monthly pregnancy tests.
Tracleer is the proprietary name for bosentan, an endothelin receptor antagonist that belongs 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 C27H29N5O6S·H2O. 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 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 62.5 mg tablet contains 64.54 mg of bosentan monohydrate, equivalent to 62.5 mg of anhydrous bosentan. Each Tracleer 125 mg tablet contains 129.08 mg of bosentan monohydrate, equivalent to 125 mg of anhydrous bosentan.
Tracleer is also available as a 32 mg tablet for oral suspension and contains the following excipients: cellulose microcrystalline, calcium hydrogen phosphate anhydrous, croscarmellose sodium, silica colloidal anhydrous, tartaric acid, tutti frutti flavor, aspartame (E951), acesulfame potassium, and magnesium stearate. Each dispersible tablet contains 1.87 mg of phenylalanine. Each dispersible tablet contains 33.045 mg of bosentan monohydrate, equivalent to 32 mg anhydrous bosentan.
The following important adverse reactions are described elsewhere in the labeling:
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.
Safety data on TRACLEER were obtained from 13 clinical studies (9 placebo-controlled and 4 open-label) in 870 adult patients with PAH 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 TRACLEER 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 PAH patients (n=328) to TRACLEER ranged from 1 day to 1.7 years (n=174 more than 6 months and n=28 more than 12 months).
Treatment discontinuations due to adverse events other than those related to pulmonary hypertension during the clinical trials in adult patients with PAH were more frequent on TRACLEER (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 TRACLEER was abnormal liver function.
The adverse drug events that occurred in ≥3% of the TRACLEER-treated patients and were more common on TRACLEER in placebo-controlled trials in PAH at doses of 125 or 250 mg twice daily are shown in Table 3:
Table 3: Adverse events* Occurring in ≥3% of Patients Treated with TRACLEER 125-250 mg Twice Daily and More Common on TRACLEER in Placebo-Controlled Studies in Pulmonary Arterial Hypertension
| Adverse Event |
TRACLEER |
Placebo n=172 |
||
|
No. |
% |
No. |
% |
|
|
Respiratory Tract Infection** |
56 |
22% |
30 |
17% |
|
Headache |
39 |
15% |
25 |
14% |
|
Edema |
28 |
11% |
16 |
9% |
|
Chest Pain |
13 |
5% |
8 |
5% |
|
Syncope |
12 |
5% |
7 |
4% |
|
Flushing |
10 |
4% |
5 |
3% |
|
Hypotension |
10 |
4% |
3 |
2% |
|
Sinusitis |
9 |
4% |
4 |
2% |
|
Arthralgia |
9 |
4% |
3 |
2% |
|
Serum Aminotransferases, abnormal |
9 |
4% |
3 |
2% |
|
Palpitations |
9 |
4% |
3 |
2% |
|
Anemia |
8 |
3% |
- |
- |
|
* Note: only AEs with onset from start of treatment to 1 calendar day after end of treatment are included. All reported events (at least 3%) are included except those too general to be informative, and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population. |
||||
TRACLEER was evaluated for safety in 119 pediatric patients in uncontrolled studies. The safety profile was similar to that observed in adult patients with PAH.
An open-label, single-arm, multicenter, safety study evaluated the effect on testicular function of TRACLEER 62.5 mg twice daily for 4 weeks, followed by 125 mg twice daily for 5 months. Twenty-five male patients with WHO functional class III and IV PAH and normal baseline sperm count were enrolled. Twenty-three completed the study and 2 discontinued due to adverse events not related to testicular function. There was a decline in sperm count of at least 50% in 25% of the patients after 3 or 6 months of treatment with TRACLEER. Sperm count remained within the normal range in all 22 patients with data after 6 months and no changes in sperm morphology, sperm motility, or hormone levels were observed. One patient developed marked oligospermia at 3 months and the sperm count remained low with 2 follow-up measurements over the subsequent 6 weeks. TRACLEER was discontinued and after 2 months the sperm count had returned to baseline levels. Based on these findings and preclinical data from endothelin receptor antagonists, it cannot be excluded that endothelin receptor antagonists such as TRACLEER have an adverse effect on spermatogenesis.
Treatment with TRACLEER 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 adult TRACLEER-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 TRACLEER treatment and hemoglobin levels stabilized by 4–12 weeks of TRACLEER treatment. In placebo-controlled studies of all uses of TRACLEER, marked decreases in hemoglobin (>15% decrease from baseline resulting in values <11 g/dL) were observed in 6% of TRACLEER-treated patients and 3% of placebo-treated patients. In patients with PAH treated with doses of 125 and 250 mg twice daily, marked decreases in hemoglobin occurred in 3% compared to 1% in placebo-treated patients.
A decrease in hemoglobin concentration by at least 1 g/dL was observed in 57% of TRACLEER- 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 TRACLEER treatment.
During the course of treatment, the hemoglobin concentration remained within normal limits in 68% of TRACLEER-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.
In a pooled analysis of pediatric patients (N=100) with PAH treated with TRACLEER, a decrease in hemoglobin levels to <10 g/dL from baseline was reported in 11% of patients. There was no decrease to <8 g/dL.
There have been several postmarketing reports of angioedema associated with the use of TRACLEER. 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.
The following additional adverse reactions have been reported during the post approval use of TRACLEER. 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 exposure:
Bosentan is metabolized by CYP2C9 and CYP3A. Inhibition of these enzymes may increase the plasma concentration of bosentan [see Pharmacokinetics (12.3)]. 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 TRACLEER 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 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 is co-administered. Bosentan had no relevant inhibitory effect on any CYP isozyme in vitro (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A). Consequently, TRACLEER is not expected to increase the plasma concentrations of drugs metabolized by these enzymes.
Figure 1: CYP3A induction-mediated effect of bosentan on other drugs
 |
Figure 2: Effect of other drugs on bosentan
 |
Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when TRACLEER is co-administered. Females should practice additional methods of contraception and not rely on hormonal contraception alone when taking TRACLEER [see Use in Specific Populations (8.3)].
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.
Included as part of the PRECAUTIONS section.
ALT or AST >3×ULN were observed in 11% of TRACLEER-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 TRACLEER. In a pooled analysis of four pediatric studies conducted in PAH (n =100), elevations in liver aminotransferases ≥3×ULN were observed in 2% of patients. The combination of hepatocellular injury (increases in aminotransferases of >3×ULN) and increases in total bilirubin (≥2×ULN) is a marker for potential serious hepatotoxicity.
Elevations of AST or ALT associated with TRACLEER 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.
Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly and therapy adjusted accordingly [see Dosage and Administration (2.1, 2.4)]. Discontinue TRACLEER if liver aminotransferase elevations are accompanied by clinical symptoms of hepatotoxicity (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin ≥2×ULN.
Avoid initiation of TRACLEER in patients with elevated aminotransferases (>3×ULN) prior to drug initiation because monitoring hepatotoxicity in these patients may be more difficult [see Boxed Warning, Dosage and Administration (2.6), Use in Specific Populations (8.6)].
In WHO Functional Class II patients, consider whether the benefits of TRACLEER are sufficient to offset the risk of hepatotoxicity, which may preclude future use as their disease progresses.
Based on data from animal reproduction studies, TRACLEER may cause fetal harm when administered to a pregnant female and is contraindicated in females who are pregnant. Advise females of reproductive potential of the potential risk to a fetus. Obtain a pregnancy test prior to TRACLEER treatment, monthly during treatment and for one month after stopping treatment. Advise females of reproductive potential to use two reliable forms of contraception during treatment with TRACLEER and for at least one month after the last dose [see Dosage and Administration (2), Use in Specific Populations (8.1, 8.3)].
TRACLEER is only available for females through a restricted program under REMS [see Warnings and Precautions (5.3)].
Because of the risks of hepatotoxicity and birth defects, TRACLEER is available only through a restricted program called the Bosentan REMS Program. As a component of the Bosentan REMS, prescribers, patients, and pharmacies must enroll in the program [see Boxed Warning, Warnings and Precautions (5.1, 5.2), Contraindications (4.1)].
Required components of the Bosentan REMS are:
Further information about TRACLEER and the Bosentan REMS Program is available at www.BosentanREMSProgram.com or 1-866-359-2612.
Peripheral edema is a known clinical consequence of PAH and worsening PAH and is also a known effect of TRACLEER and other endothelin receptor antagonists. In PAH clinical trials with TRACLEER, combined adverse events of fluid retention or edema were reported in 1.7% (placebo-corrected) of patients.
In addition, there have been numerous postmarketing reports of fluid retention in patients with pulmonary hypertension occurring within weeks after starting TRACLEER. 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 or underlying heart failure, and the possible need for treatment or discontinuation of TRACLEER [see Adverse Reactions (6.1), Clinical Studies (14.2)].
If signs of pulmonary edema occur, consider the possibility of associated pulmonary veno- occlusive disease and consider whether TRACLEER should be discontinued.
Decreased sperm counts have been observed in patients receiving TRACLEER. Preclinical data also suggest that TRACLEER, similar to other endothelin receptor antagonists, may have an adverse effect on spermatogenesis [see Adverse Reactions (6.1), Nonclinical Toxicology (13.1)].
Treatment with TRACLEER can cause a dose-related decrease in hemoglobin and hematocrit. There have been postmarketing reports of decreases in hemoglobin concentration and hematocrit that have resulted in anemia requiring transfusion. 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 [see Adverse Reactions (6.1)].
Two years of dietary administration of bosentan to mice produced an increased incidence of hepatocellular adenomas and carcinomas in males at doses as low as 450 mg/kg/day (about 8 times the maximum recommended human dose [MRHD] of 125 mg twice daily, on a mg/m2 basis). In the same study, doses greater than 2000 mg/kg/day (about 32 times the MRHD) were associated with an increased incidence of colon adenomas in both males and females. In rats, dietary administration of bosentan for two years was associated with an increased incidence of brain astrocytomas in males at doses as low as 500 mg/kg/day (about 16 times the MRHD). In a comprehensive battery of in vitro tests (the microbial mutagenesis assay, the unscheduled DNA synthesis assay, the V-79 mammalian cell mutagenesis assay, and human lymphocyte assay) and an in vivo mouse micronucleus assay, there was no evidence for any mutagenic or clastogenic activity of bosentan.
The development of testicular tubular atrophy and impaired fertility has been linked with the chronic administration of certain endothelin receptor antagonists in rodents.
Treatment with bosentan at oral doses of up to 1500 mg/kg/day (50 times the MRHD on a mg/m2 basis) or intravenous doses up to 40 mg/kg/day had no effects on sperm count, sperm motility, mating performance or fertility in male and female rats. An increased incidence of testicular tubular atrophy was observed in rats given bosentan orally at doses as low as 125 mg/kg/ day (about 4 times the MRHD and the lowest doses tested) for two years but not at doses as high as 1500 mg/kg/day (about 50 times the MRHD) for 6 months. Effects on sperm count and motility were evaluated only in the much shorter duration fertility studies in which males had been exposed to the drug for 4-6 weeks. An increased incidence of tubular atrophy was not observed in mice treated for 2 years at doses up to 4500 mg/kg/day (about 75 times the MRHD) or in dogs treated up to 12 months at doses up to 500 mg/kg/day (about 50 times the MRHD).
Advise the patient that TRACLEER is only available through a restricted access program called the Bosentan REMS Program.
As a component of the Bosentan REMS, prescribers must review the contents of the TRACLEER Medication Guide with the patient before initiating TRACLEER.
Instruct patients that the risks associated with TRACLEER include:
Hepatotoxicity
Discuss with the patient the requirement to measure serum aminotransferases monthly.
Embryo-fetal toxicity
Educate and counsel female patients of reproductive potential about the need to use reliable methods of contraception during treatment with TRACLEER and for one month after treatment discontinuation. Females of reproductive potential must have monthly pregnancy tests and must use two different forms of contraception while taking TRACLEER and for one month after discontinuing TRACLEER [see Use in Specific Populations (8.1)].
Females who have intrauterine devices (IUD) or tubal sterilization can use these contraceptive methods alone. Patients should be instructed to immediately contact their physician if they suspect they may be pregnant. Patients should seek additional contraceptive advice from a gynecologist or similar expert as needed.
Educate and counsel females of reproductive potential on the use of emergency contraception in the event of unprotected sex or contraceptive failure.
Advise pre-pubertal females to report any changes in their reproductive status immediately to her prescriber.
Advise patients to contact their gynecologist or healthcare provider if they want to change the form of birth control which is used to ensure that another acceptable form of birth control is selected.
Advise the patient that TRACLEER is available only from certified pharmacies that are enrolled in the Bosentan REMS Program.
Patients must sign the Bosentan REMS Program Patient Enrollment Form to confirm that they understand the risks of TRACLEER.
Lactation
Advise women not to breastfeed during treatment with TRACLEER [see Use in Specific Populations (8.2)].
Infertility
Advise males of reproductive potential that TRACLEER may impair fertility [see Warnings and Precautions (5.6), Adverse Reactions (6.1), Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].
Phenylketonurics
TRACLEER dispersible tablets contain phenylalanine, a component of aspartame. Each dispersible tablet contains 1.87 mg of phenylalanine.
Instruct patients that the risks associated with TRACLEER also include the following:
Advise patients that TRACLEER dispersible tablets should not be split into quarters.
Manufactured for:
Actelion Pharmaceuticals US, Inc.
Titusville, NJ 08560, USA
For patent information: www.janssenpatents.com
©Johnson & Johnson and its affiliates 2001 - 2019
JN202xxxxx
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 TRACLEER 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.
Use of TRACLEER is contraindicated in females who are or may become pregnant. To prevent pregnancy, females of reproductive potential must use two reliable forms of contraception during treatment and for one month after stopping TRACLEER [see Boxed Warning, Warnings and Precautions (5.2), Drug Interactions (7.2), Use in Specific Populations (8.1)].
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 [see Cytochrome P450 Drug Interactions (7.1)].
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 [see Cytochrome P450 Drug Interactions (7.1)].
TRACLEER is contraindicated in patients who are hypersensitive to bosentan or any component of the product. Observed reactions include Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), anaphylaxis, rash, and angioedema [see Adverse Reactions (6.2), Description (11)].
Bosentan is a specific and competitive antagonist at endothelin receptor types ETA and ETB. Bosentan has a slightly higher affinity for ETA receptors than for ETB receptors. The clinical impact of dual endothelin blockage is unknown.
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 PAH, suggesting a pathogenic role for ET-1 in this disease.
After oral administration, maximum plasma concentrations of bosentan are attained within 3– 5 hours and the terminal elimination half-life is about 5 hours in healthy adult subjects. The exposure to bosentan after intravenous and oral administration is about twice as high in adult patients with PAH as it is in healthy adult subjects.
In a relative bioavailability study in healthy adults, the peak plasma concentration and area under the plasma concentration-time curve for bosentan are on an average 14% and 11%, respectively, lower following administration of the oral dispersible tablet compared to the film-coated tablet.
The absolute bioavailability of bosentan in normal volunteers is about 50% and is unaffected by food.
Bosentan is highly bound (>98%) to plasma proteins, mainly albumin. Bosentan does not penetrate into erythrocytes. The volume of distribution is about 18 L.
Metabolism
Bosentan has three metabolites, one of which is pharmacologically active and may contribute 10%–20% of the effect of bosentan. Bosentan is an inducer of CYP2C9 and CYP3A and possibly also of CYP2C19. Upon multiple oral dosing, plasma concentrations in healthy adults decrease gradually to 50-65% of those seen after single dose administration, probably the effect of auto-induction of the metabolizing liver enzymes. Steady-state is reached within 3-5 days.
Excretion
Bosentan is eliminated by biliary excretion following metabolism in the liver. Less than 3% of an administered oral dose is recovered in urine. Total clearance after a single intravenous dose is about 4 L/h in patients with PAH.
Pediatrics
The average plasma exposure to bosentan at steady state (AUCss) in pediatric patients with PAH aged 3 to 15 years treated with 31.25, 62.5 or 125 mg (approximately 2 mg/kg) film-coated tablet twice daily is 37% lower than that observed in adult patients with PAH receiving 125 mg film- coated tablet twice daily. Following administration of 4 mg/kg twice daily doses of dispersible tablet in patients with PAH aged 2 to 11 years, the average systemic exposure to bosentan at steady state is similar to that observed with 2 mg/kg. The average exposure to bosentan in these pediatric patients was approximately half the exposure in adult patients treated with 125 mg film- coated tablets twice daily.
The exposure to bosentan at 2 mg/kg three times daily dosing of dispersible tablet is similar to that of 2 mg/kg twice daily dosing in patients with PAH aged 3 months to 12 years.
Based on these findings, exposure to bosentan reaches a plateau at lower doses in pediatric patients than in adults, and doses higher than 2 mg/kg twice daily do not increase the exposure to bosentan in pediatric patients.
Hepatic Impairment
In vitro and in vivo evidence showing extensive hepatic metabolism of bosentan suggests that liver impairment could significantly increase exposure to bosentan. In a study comparing 8 patients with mild liver impairment (Child-Pugh Class A) to 8 controls, the single- and multiple-dose pharmacokinetics of bosentan were not altered in patients with mild hepatic impairment.
In another small (N=8) pharmacokinetic study, the steady-state AUC of bosentan was on average
4.7 times higher and the active metabolite Ro 48-5033 was 12.4 times higher in 5 patients with moderately impaired liver function (Child-Pugh Class B) and PAH associated with portal hypertension than in 3 patients with normal liver function and PAH of other etiologies.
The pharmacokinetics of TRACLEER have not been evaluated in patients with severe liver impairment (Child-Pugh Class C) [see Dosage and Administration (2.2), Warnings and Precautions (5.1), Use in Specific Populations (8.6)].
Renal Impairment
In patients with severe renal impairment (creatinine clearance 15–30 mL/min), plasma concentrations of bosentan were essentially unchanged and plasma concentrations of the three metabolites were increased about 2-fold compared to subjects with normal renal function. These differences do not appear to be clinically important.
Ketoconazole
Co-administration of bosentan 125 mg twice daily and ketoconazole, a potent CYP3A inhibitor, increased the plasma concentrations of bosentan by approximately 100% in normal volunteers.
No dose adjustment of TRACLEER is necessary, but increased effects of TRACLEER should be considered.
Warfarin
Co-administration of bosentan 500 mg twice daily for 6 days in normal volunteers decreased the plasma concentrations of both S-warfarin (a CYP2C9 substrate) and R-warfarin (a CYP3A substrate) by 29 and 38%, respectively. Clinical experience with concomitant administration of TRACLEER and warfarin in patients with PAH 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 TRACLEER- 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.
Sildenafil
In normal volunteers, co-administration of multiple doses of 125 mg twice daily bosentan and 80 mg three times daily sildenafil resulted in a reduction of sildenafil plasma concentrations by 63% and increased bosentan plasma concentrations by 50%. The changes in plasma concentrations were not considered clinically relevant and dose adjustments are not necessary. This recommendation holds true when sildenafil is used for the treatment of PAH or erectile dysfunction.
Tadalafil
Bosentan (125 mg twice daily) reduced tadalafil (40 mg once per day) systemic exposure (AUC) by 42% and Cmax by 27% following multiple dose co-administration. Tadalafil did not affect the exposure (AUC and Cmax) of bosentan or its metabolites.
Figure 3: CYP Induction-mediated effect of bosentan on other drugs
 |
Figure 4: Effects of other drugs on bosentan
 |
MEDICATION GUIDE
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 Bosentan REMS Program. Before you begin taking TRACLEER, you must read and agree to all of the instructions in the Bosentan REMS Program.
TRACLEER can cause serious side effects including:
Liver damage.
Serious birth defects.
See the chart below for Acceptable Birth Control Options during treatment with TRACLEER.
 |
TRACLEER 32 mg dispersible tablets contain Aspartame.
Phenylketonurics: Contains Phenylalanine 1.87 mg per 32 mg dispersible tablet.
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 Bosentan REMS Program. Available to people who understand and agree to enroll in the Bosentan REMS Program.
Who should not take TRACLEER? Do not take TRACLEER if you:
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:
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:
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 Bosentan REMS Program.
 |
What are the possible side effects of TRACLEER?
TRACLEER can cause serious side effects, including:
The most common side effects of TRACLEER include:
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?
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 call 1-800- 526-7736, or go to www.TRACLEER.com.
What are the ingredients in TRACLEER?
Active ingredient: bosentan
Inactive ingredients in 62.5 mg and 125 mg film-coated tablets: corn starch, ethylcellulose, glyceryl behenate, hydroxypropylmethylcellulose, iron oxide red, iron oxide yellow, magnesium stearate, povidone, pregelatinized starch, sodium starch glycolate, talc, titanium dioxide, and triacetin.
Inactive ingredients in 32 mg dispersible tablets: acesulfame potassium, aspartame (E951), calcium hydrogen, cellulose microcrystalline, croscarmellose sodium, magnesium stearate, phosphate anhydrous, silica colloidal anhydrous, tartaric acid, and tutti frutti flavor.
Manufactured for:
Actelion Pharmaceuticals US, Inc.
Titusville, NJ 08560, USA
For patent information: www.janssenpatents.com
© Johnson & Johnson and its affiliates 2001 - 2019
JN202xxxxx
