WARNINGS
Potential Liver Injury (see BOX WARNING)
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 PAH patients on 125 mg b.i.d. and 14% of 70 PAH patients on 250 mg b.i.d. Eight-fold increases were seen in 2% of PAH patients on 125 mg b.i.d. and 7% of PAH patients on 250 mg b.i.d. 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.1
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 to date have been reversible after treatment interruption or cessation. These aminotransferase elevations may reverse spontaneously while continuing treatment with TRACLEER®.
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 (see DOSAGE AND ADMINISTRATION). 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® in these circumstances.
PRE-EXISTING LIVER IMPAIRMENT
Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly. TRACLEER® should generally be avoided in patients with moderate or severe liver impairment (see Clinical Pharmacology and DOSAGE AND ADMINISTRATION). In addition, TRACLEER® should generally be avoided in patients with elevated aminotransferases (> 3 × ULN) because monitoring liver injury in these patients may be more difficult (see BOX WARNING).
PRECAUTIONS
HEMATOLOGIC CHANGES
Treatment with TRACLEER® caused a dose-related decrease in hemoglobin and hematocrit. Hemoglobin levels should be monitored after 1 and 3 months of treatment and then every 3 months. 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 < 11 g/dl) were observed in 6% of bosentan-treated patients and 3% of placebo-treated patients. In patients with pulmonary arterial hypertension treated with doses of 125 and 250 mg b.i.d., 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 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.
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.
FLUID RETENTION
In a placebo-controlled trial of patients with severe chronic heart failure, there was an increased incidence of hospitalization for CHF associated with weight gain and increased leg edema during the first 4-8 weeks of treatment with TRACLEER®. In addition, there have been numerous post-marketing 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 (see CLINICAL STUDIES ; Congestive Heart Failure).
INFORMATION 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.
DRUG INTERACTIONS
Bosentan is metabolized by CYP2C9 and CYP3A4. Inhibition of these isoenzymes may increase the plasma concentration of bosentan (see ketoconazole). 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, and Implantable Contraceptives: Specific interaction studies have not been performed to evaluate the effect of co-administration of bosentan and hormonal contraceptives, including oral, injectable or implantable contraceptives. Since many of these drugs are metabolized by CYP3A4, there is a possibility of failure of contraception when TRACLEER® is co-administered. Women should 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 (see CONTRAINDICATIONS). 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 (see CONTRAINDICATIONS).
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 (beta)-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 been shown to have no pharmacokinetic interactions with digoxin and nimodipine, and losartan has no effect on plasma levels of bosentan.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
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 b.i.d., 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.
IMPAIRMENT OF FERTILITY/TESTICULAR FUNCTION
Many endothelin receptor antagonists have profound effects on the histology and function of the testes in animals. These drugs have been shown to induce atrophy of the seminiferous tubules of the testes and to reduce sperm counts and male fertility in rats when administered for longer than 10 weeks. Where studied, testicular tubular atrophy and decreases in male fertility observed with endothelin receptor antagonists appear irreversible.
In fertility studies in which male and female rats were treated 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, no effects on sperm count, sperm motility, mating performance or fertility were observed. 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).
There are no data on the effects of bosentan or other endothelin receptor antagonists on testicular function in man. Pregnancy, Teratogenic Effects: Category X (See CONTRAINDICATIONS).
NURSING MOTHERS
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, breastfeeding while taking TRACLEER® is not recommended.
PEDIATRIC USE
Safety and efficacy in pediatric patients have not been established (see DOSAGE AND ADMINISTRATION).
USE IN ELDERLY PATIENTS
Clinical experience with TRACLEER® in subjects aged 65 or older has not included a sufficient number of such subjects to identify a difference in response between elderly and younger patients (see DOSAGE AND ADMINISTRATION).
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