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  • Tracleer
    / Janssen


    Active Ingredient
    Bosentan 62.5 mg, 125 mg

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Film Coated Tablets

    60 X 62.5 mg

    partial basket chart 57712 20612

    Film Coated Tablets

    60 X 125 mg

    partial basket chart 57711 20534

    Dosage

    Pulmonary arterial hypertension: Treatment should only be initiated and monitored by a physician experienced in the treatment of pulmonary arterial hypertension. In adult patients, Tracleer 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.
    In the case of clinical deterioration (e.g., decrease in 6-minute walk test distance by at least 10% compared with pre-treatment measurement) despite Tracleer treatment for at least 8 weeks (target dose for at least 4 weeks), alternative therapies should be considered. However, some patients who show no response after 8 weeks of treatment with Tracleer may respond favourably after an additional 4 to 8 weeks of treatment.
    In the case of late clinical deterioration despite treatment with Tracleer (i.e., after several months of treatment), the treatment should be re-assessed. Some patients not responding well to 125 mg twice daily of Tracleer may slightly improve their exercise capacity when the dose is increased to 250 mg twice daily. A careful benefit/risk assessment should be made, taking into consideration that the liver toxicity is dose dependent.
    Discontinuation of treatment: There is limited experience with abrupt discontinuation of Tracleer. No evidence for acute rebound has been observed. However, to avoid the possible occurrence of harmful clinical deterioration due to potential rebound effect, gradual dose reduction (halving the dose for 3 to 7 days) should be considered. Intensified monitoring is recommended during the discontinuation period. If the decision to withdraw Tracleer is taken, it should be done gradually  while an alternative therapy is introduced.
    Systemic sclerosis with ongoing digital ulcer disease: Treatment should only be initiated and monitored by a physician experienced in the treatment of systemic sclerosis. Tracleer 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. Controlled clinical study experience in this indication is limited to 6 months.
    The patient’s response to treatment and need for continued therapy should be re-evaluated on a regular basis. A careful benefit / risk assessment should be made, taking into consideration the liver toxicity of bosentan. There are no data on the safety and efficacy in patients under the age of 18 years. Pharmacokinetic data are not available for Tracleer in young children with this disease.
    Special populations: 
    Dosage in hepatic impairment:  No dose adjustment is needed in patients with mild hepatic impairment (i.e., Child-Pugh class A). Tracleer is contraindicated in patients with moderate to severe liver dysfunction.
    Dosage in renal impairmentNo dose adjustment is required in patients with renal impairment. No dose adjustment is required in patients undergoing dialysis.
    Dosage in elderly patients: No dose adjustment is required in patients over the age of 65 years.
    For full details see prescribing information.


    Indications

    Primary pulmonary arterial hypertension or secondary to scleroderma or other connective tissue disease. To reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease.


    Contra-Indications

    Hypersensitivity to the active substance or to any of the excipients
    Moderate to severe hepatic impairment i.e. Child-Pugh Class B or C
    Baseline values of liver aminotransferases, i.e., aspartate aminotransferases (AST) and/or alanine aminotransferases (ALT), greater than 3 times the upper limit of normal.
    Concomitant use of cyclosporine A.
    Pregnancy.
    Women of childbearing potential who are not using reliable methods of contraception.
    For full details see prescribing information.


    Special Precautions

    The efficacy of Tracleer has not been established in patients with severe pulmonary arterial hypertension. Transfer to a therapy that is recommended at the severe stage of the disease (e.g., epoprostenol) should be considered if the clinical condition deteriorates. The benefit/risk balance of bosentan has not been established in patients with WHO class I functional status of pulmonary arterial hypertension. Tracleer should only be initiated if the systemic systolic blood pressure is higher than 85 mmHg. Tracleer has not been shown to have a beneficial effect on the healing of existing digital ulcers.
    Liver function: Elevations in liver aminotransferases, i.e., aspartate and alanine aminotransferases (AST and/or ALT), associated with bosentan are dose dependent. Liver enzyme changes typically occur within the first 26 weeks of treatment but may also occur late in treatment. These increases may be partly due to competitive inhibition of the elimination of bile salts from hepatocytes but other mechanisms, which have not been clearly established, are probably also involved in the occurrence of liver dysfunction. The accumulation of bosentan in hepatocytes leading to cytolysis with potentially severe damage of the liver, or an immunological mechanism, is not excluded. Liver dysfunction risk may also be increased when medicinal products that are inhibitors of the bile salt export pump, e.g., rifampicin, glibenclamide and cyclosporine A, are co-administered with bosentan, but limited data are available.
    Haemoglobin concentration: Treatment with bosentan has been associated with dose-related decreases in haemoglobin concentration. In placebo-controlled studies, bosentan-related decreases in haemoglobin concentration were not progressive, and stabilised after the first 4–12 weeks of treatment. It is recommended that haemoglobin concentrations be checked prior to initiation of treatment, every month during the first 4 months, and quarterly thereafter. If a clinically relevant decrease in haemoglobin concentration occurs, further evaluation and investigation should be undertaken to determine the cause and need for specific treatment. In the postmarketing period, cases of anaemia requiring red blood cell transfusion have been reported.
    Women of child-bearing potential: Tracleer treatment must not be initiated in women of child-bearing potential unless they practice reliable contraception and the result of the pre-treatment pregnancy test is negative. Before the initiation of Tracleer treatment in women of child-bearing potential, the absence of pregnancy should be checked, appropriate advice on reliable methods of contraception provided, and reliable contraception initiated. Patients and prescribers must be aware that, due to potential pharmacokinetic interactions, Tracleer may render hormonal contraceptives ineffective. Therefore, women of child-bearing potential must not use hormonal contraceptives (including oral, injectable, transdermal, and implantable forms) as the sole method of contraception but should use an additional or an alternative reliable method of contraception. If there is any doubt about what contraceptive advice should be given to the individual patient, consultation with a gynaecologist is recommended. Because of possible hormonal contraception failure during Tracleer treatment and also bearing in mind the risk that pulmonary hypertension severely deteriorates with pregnancy, monthly pregnancy tests during treatment with Tracleer are recommended to allow early detection of pregnancy.
    For full details see prescribing information.


    Side Effects

    Bosentan causes 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 small number of cases. Because these changes are a marker for potential serious liver injury, serum aminotransferase levels must be measured prior to initiation of treatment and then monthly. To date, in a setting of close monitoring, elevations have been reversible, within a few days to 9 weeks, either spontaneously or after dose reduction or discontinuation, and without sequelae. Elevations in aminotransferases require close attention. Tracleer should generally be avoided in patients with elevated aminotransferases (> 3 x ULN) at baseline because monitoring liver injury may be more difficult.If liver aminotransferases 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 x ULN, treatment should be stopped. There is no experience with the re-introduction in these circimstances.
    For fill details see prescribing information.


    Drug interactions

    Bosentan is metabolized by CYP2C9 and CYP3A4. Inhibition of these
    Isoenzymes may increase the plasma concentration of bosentan. Concomitant administration of both a CYP2C9 inhibitor (such as fluconazole or amiodarone) and a CYP3A4 inhibitor (such as ketoconazole, itraconazole, or ritonavir) with bosentan will likely lead to large increases in plasma concentrations of bosentan. Co-administration of such combinations of a potent CYP2C9 inhibitor plus a CYP3A4 inhibitor with TRACLEER™ is not recommended.
    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 . Coadministration 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 CYP2C9 and CYP3A4 inhibitors and inducers, hormonal contraceptives, including oral, injectable and implantable. Cyclosporine A, glyburide, ketoconazole, simvastatin and other statins.
    For full details see prescribing information.


    Pregnancy and Lactation

    Use in Women of Child-bearing Potential: Treatment should only be initiated in women of child-bearing potential following a negative pregnancy test and only in those who practice adequate contraception that does not rely solely upon hormonal contraceptives, including oral, injectable or implantable contraceptives. Input from a gynecologist or similar expert on adequate contraception should be sought as needed. Urine or serum pregnancy tests should be obtained monthly in women of childbearing potential taking TRACLEER™.
    For full details see prescribing information.


    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 overdose with bosentan beyond the doses described above. Massive overdose may result in pronounced hypotension requiring active cardiovascular support.


    Manufacturer
    Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
    Licence holder
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