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The following important adverse reactions are described elsewhere in the labeling:
- Hepatotoxicity [see BOXED WARNING, WARNINGS AND PRECAUTIONS]
- Fluid retention [see WARNINGS AND PRECAUTIONS]
Clinical Studies Experience
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 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 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 pulmonary arterial hypertension 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 patients with pulmonary arterial hypertension 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 pulmonary arterial hypertension at doses of 125 or 250 mg twice daily are shown in Table 2:
Table 2: 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
n = 258
n = 172
|Respiratory Tract Infection||56||22%||30||17%|
|Serum Aminotransferases, abnormal||9||4%||3||2%|
|*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. Combined data from Study 351, BREATHE-1 and EARLY|
Decreased Sperm Counts
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.
Decreases in Hemoglobin and Hematocrit
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 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.
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 postapproval 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:
Unexplained hepatic cirrhosis [see BOXED WARNING]
Liver failure [see BOXED WARNING]
Hypersensitivity [see CONTRAINDICATIONS]
Anemia requiring transfusion
Neutropenia and leukopenia
Read the Tracleer (bosentan) Side Effects Center for a complete guide to possible side effects
Cytochrome P450 Summary
Bosentan is metabolized by CYP2C9 and CYP3A. Inhibition of these enzymes may increase the plasma concentration of bosentan (see ketoconazole). 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. Coadministration 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 coadministered. 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.
Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when Tracleer is coadministered. Females should practice additional methods of contraception and not rely on hormonal contraception alone when taking Tracleer [see BOXED WARNING, CONTRAINDICATIONS].
An interaction study demonstrated that coadministration 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 Tracleer and cyclosporine A is contraindicated [see CONTRAINDICATIONS
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. Coadministration 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 and glyburide is contraindicated, and alternative hypoglycemic agents should be considered [see CONTRAINDICATIONS].
Coadministration of bosentan decreased the plasma concentrations of glyburide by approximately 40%. The plasma concentrations of bosentan were also decreased by approximately 30%. Tracleer 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.
Lopinavir/Ritonavir or Other Ritonavir-containing HIV Regimens
In vitro data indicate that bosentan is a substrate of the Organic Anion Transport Protein (OATP), CYP3A and CYP2C9. Ritonavir inhibits OATP and inhibits and induces CYP3A. However, the impact of ritonavir on the pharmacokinetics of bosentan may largely result from its effect on OATP.
In normal volunteers, coadministration of Tracleer 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 administered alone. Therefore, adjust the dose of Tracleer when initiating lopinavir/ritonavir [see DOSAGE AND ADMINISTRATION].
Coadministration of bosentan 125 mg twice daily had no substantial impact on the pharmacokinetics of lopinavir/ritonavir 400/100 mg twice daily.
Simvastatin and Other Statins
Coadministration of bosentan decreased the plasma concentrations of simvastatin (a CYP3A substrate), and its active β-hydroxy acid metabolite, by approximately 50%. The plasma concentrations of bosentan were not affected. Tracleer is also expected to reduce plasma concentrations of other statins that are significantly metabolized by CYP3A, such as lovastatin and atorvastatin. The possibility of reduced statin efficacy should be considered. Patients using CYP3A-metabolized statins should have cholesterol levels monitored after Tracleer is initiated to see whether the statin dose needs adjustment.
Coadministration of bosentan and rifampin in normal volunteers resulted in a mean 6fold increase in bosentan trough levels after the first concomitant dose (likely due to inhibition of OATP by rifampin), but about a 60% decrease in bosentan levels at steady-state. The effect of Tracleer on rifampin levels has not been assessed. When consideration of the potential benefits, and known and unknown risks leads to concomitant use, measure serum aminotransferases weekly for the first 4 weeks before reverting to normal monitoring.
Coadministration of tacrolimus and Tracleer has not been studied in humans. Coadministration of tacrolimus and bosentan resulted in markedly increased plasma concentrations of bosentan in animals. Caution should be exercised if tacrolimus and Tracleer are used together.
Coadministration of bosentan 125 mg twice daily and ketoconazole, a potent CYP3A inhibitor, increased the plasma concentrations of bosentan by approximately 2-fold in normal volunteers. No dose adjustment of Tracleer is necessary, but increased effects of Tracleer should be considered.
Coadministration 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 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 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.
In normal volunteers, coadministration 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 pulmonary arterial hypertension or erectile dysfunction.
In a small, randomized, double-blind, placebo-controlled study, 34 patients treated with bosentan 125 mg twice daily for at least 16 weeks tolerated the addition of inhaled iloprost (up to 5 mcg 6 to 9 times per day during waking hours). The mean daily inhaled dose was 27 mcg and the mean number of inhalations per day was 5.6.
Read the Tracleer Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 7/12/2013
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