Tracleer 62.5 mg film-coated tablets
Tracleer 125 mg film-coated tablets
Tracleer 62.5 mg film-coated tablets
Each film-coated tablet contains 62.5 mg bosentan (as monohydrate).
Tracleer 125 mg film-coated tablets
Each film-coated tablet contains 125 mg bosentan (as monohydrate).
For the full list of excipients, see section 6.1.
Film-coated tablet (tablets):
Tracleer 62.5 mg film-coated tablets
Orange-white, round, biconvex, film-coated tablets, embossed with “62,5” on one side.
Tracleer 125 mg film-coated tablets
Orange-white, oval, biconvex, film-coated tablets, embossed with “125” on one side.
Treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and symptoms in patients with WHO functional class III. Efficacy has been shown in:
• Primary (idiopathic and heritable) pulmonary arterial hypertension
• Pulmonary arterial hypertension secondary to scleroderma without significant interstitial pulmonary disease
• Pulmonary arterial hypertension associated with congenital systemic-to-pulmonary shunts and Eisenmenger's physiology
Some improvements have also been shown in patients with pulmonary arterial hypertension WHO functional class II (see section 5.1).
Tracleer is also indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease (see section 5.1).
Method of administration
Tablets are to be taken orally morning and evening, with or without food. The film-coated tablets are to be swallowed with water.
Patients should be advised not to swallow the desiccant found in the white high-density polyethylene bottles.
Posology
Pulmonary arterial hypertension
Treatment should only be initiated and monitored by a physician experienced in the treatment of PAH.
Adults
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. The same recommendations apply to re-introduction of Tracleer after treatment interruption (see section 4.4).
Paediatric population
Paediatric pharmacokinetic data have shown that bosentan plasma concentrations in children with PAH aged from 1 year to 15 years were on average lower than in adult patients and were not increased by increasing the dose of Tracleer above 2 mg/kg body weight or by increasing the dosing frequency from twice daily to three times daily (see section 5.2). Increasing the dose or the dosing frequency will likely not result in additional clinical benefit.
Based on these pharmacokinetic results, when used in children with PAH aged 1 year and older, the recommended starting and maintenance dose is 2 mg/kg morning and evening.
In neonates with persistent pulmonary hypertension of the newborn (PPHN), the benefit of bosentan has not been shown in the standard-of-care treatment. No recommendation on a posology can be made (see sections 5.1 and 5.2).
Management in the event of clinical deterioration of PAH
In the event 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 event 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 (see sections 4.4 and 5.1).
Discontinuation of treatment
There is limited experience with abrupt discontinuation of Tracleer in patients with PAH. 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.
Adults
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. The same recommendations apply to re-introduction of Tracleer after treatment interruption (see section 4.4).
Controlled clinical study experience in this indication is limited to 6 months (see section 5.1).
The patient's response to treatment and need for continued therapy should be re-eva luated on a regular basis. A careful benefit/risk assessment should be made, taking into consideration the liver toxicity of bosentan (see sections 4.4 and 4.8).
Paediatric population
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
Hepatic impairment
Tracleer is contraindicated in patients with moderate to severe liver dysfunction (see sections 4.3, 4.4 and 5.2). No dose adjustment is needed in patients with mild hepatic impairment (i.e., Child-Pugh class A) (see section 5.2).
Renal impairment
No dose adjustment is required in patients with renal impairment. No dose adjustment is required in patients undergoing dialysis (see section 5.2).
Elderly
No dose adjustment is required in patients over the age of 65 years.
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
• Moderate to severe hepatic impairment, i.e., Child-Pugh class B or C (see section 5.2)
• Baseline values of liver aminotransferases, i.e., aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT), greater than 3 × the upper limit of normal (ULN; see section 4.4)
• Concomitant use of cyclosporine A (see section 4.5)
• Pregnancy (see sections 4.4 and 4.6)
• Women of childbearing potential who are not using reliable methods of contraception (see sections 4.4, 4.5 and 4.6)
The efficacy of Tracleer has not been established in patients with severe PAH. 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 (see section 4.2).
The benefit/risk balance of bosentan has not been established in patients with WHO class I functional status of PAH.
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 (see section 4.8). 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, are 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 (see sections 4.3 and 4.5), are co-administered with bosentan, but limited data are available.
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Liver aminotransferase levels must be measured prior to initiation of treatment and subsequently at monthly intervals for the duration of treatment with Tracleer. In addition, liver aminotransferase levels must be measured 2 weeks after any dose increase.
Recommendations in the event of ALT/AST elevations
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ALT/AST levels
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Treatment and monitoring recommendations
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> 3 and ≤ 5 × ULN
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The result should be confirmed by a second liver test; if confirmed, a decision should be made on an individual basis to continue Tracleer, possibly at a reduced dose, or to stop Tracleer administration (see section 4.2). Monitoring of aminotransferase levels should be continued at least every 2 weeks. If the aminotransferase levels return to pre-treatment values continuing or re-introducing Tracleer according to the conditions described below should be considered.
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> 5 and ≤ 8 × ULN
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The result should be confirmed by a second liver test; if confirmed, treatment should be stopped and aminotransferase levels monitored at least every 2 weeks. If the aminotransferase levels return to pre-treatment values re-introducing Tracleer according to the conditions described below should be considered.
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> 8 × ULN
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Treatment must be stopped and re-introduction of Tracleer is not to be considered.
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In the event of associated clinical symptoms of liver injury, i.e., nausea, vomiting, fever, abdominal pain, jaundice, unusual lethargy or fatigue, flu-like syndrome (arthralgia, myalgia, fever), treatment must be stopped and re-introduction of Tracleer is not to be considered.
Re-introduction of treatment
Re-introduction of treatment with Tracleer should only be considered if the potential benefits of treatment with Tracleer outweigh the potential risks and when liver aminotransferase levels are within pre-treatment values. The advice of a hepatologist is recommended. Re-introduction must follow the guidelines detailed in section 4.2. Aminotransferase levels must then be checked within 3 days after re-introduction, then again after a further 2 weeks, and thereafter according to the recommendations above.
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ULN = upper limit of normal
Haemoglobin concentration
Treatment with bosentan has been associated with dose-related decreases in haemoglobin concentration (see section 4.8). 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 eva luation and investigation should be undertaken to determine the cause and need for specific treatment. In the post-marketing period, cases of anaemia requiring red blood cell transfusion have been reported (see section 4.8).
Women of childbearing potential
As Tracleer may render hormonal contraceptives ineffective, and taking into account the risk that pulmonary hypertension deteriorates with pregnancy as well as the teratogenic effects observed in animals:
• Tracleer treatment must not be initiated in women of childbearing potential unless they practise reliable contraception and the result of the pre-treatment pregnancy test is negative
• Hormonal contraceptives cannot be the sole method of contraception during treatment with Tracleer
• Monthly pregnancy tests are recommended during treatment to allow early detection of pregnancy
For further information see sections 4.5 and 4.6.
Pulmonary veno-occlusive disease
Cases of pulmonary oedema have been reported with vasodilators (mainly prostacyclins) when used in patients with pulmonary veno-occlusive disease. Consequently, should signs of pulmonary oedema occur when Tracleer is administered in patients with PAH, the possibility of associated veno-occlusive disease should be considered. In the post-marketing period there have been rare reports of pulmonary oedema in patients treated with Tracleer who had a suspected diagnosis of pulmonary veno-occlusive disease.
Pulmonary arterial hypertension patients with concomitant left ventricular failure
No specific study has been performed in patients with pulmonary hypertension and concomitant left ventricular dysfunction. However, 1,611 patients (804 bosentan- and 807 placebo-treated patients) with severe chronic heart failure (CHF) were treated for a mean duration of 1.5 years in a placebo-controlled study (study AC-052-301/302 [ENABLE 1 & 2]). In this study there was an increased incidence of hospitalisation due to CHF during the first 4–8 weeks of treatment with bosentan, which could have been the result of fluid retention. In this study, fluid retention was manifested by early weight gain, decreased haemoglobin concentration and increased incidence of leg oedema. At the end of this study, there was no difference in overall hospitalisations for heart failure nor in mortality between bosentan- and placebo-treated patients. Consequently, it is recommended that patients be monitored for signs of fluid retention (e.g., weight gain), especially if they concomitantly suffer from severe systolic dysfunction. Should this occur, starting treatment with diuretics is recommended, or the dose of existing diuretics should be increased. Treatment with diuretics should be considered in patients with evidence of fluid retention before the start of treatment with Tracleer.
Pulmonary arterial hypertension associated with HIV infection
There is limited clinical study experience with the use of Tracleer in patients with PAH associated with HIV infection, treated with antiretroviral medicinal products (see section 5.1). An interaction study between bosentan and lopinavir+ritonavir in healthy subjects showed increased plasma concentrations of bosentan, with the maximum level during the first 4 days of treatment (see section 4.5). When treatment with Tracleer is initiated in patients who require ritonavir-boosted protease inhibitors, the patient's tolerability of Tracleer should be closely monitored with special attention, at the beginning of the initiation phase, to the risk of hypotension and to liver function tests. An increased long-term risk of hepatic toxicity and haematological adverse events cannot be excluded when bosentan is used in combination with antiretroviral medicinal products. Due to the potential for interactions related to the inducing effect of bosentan on CYP450 (see section 4.5), which could affect the efficacy of antiretroviral therapy, these patients should also be monitored carefully regarding their HIV infection.
Pulmonary hypertension secondary to chronic obstructive pulmonary disease (COPD)
Safety and tolerability of bosentan was investigated in an exploratory, uncontrolled 12-week study in 11 patients with pulmonary hypertension secondary to severe COPD (stage III of GOLD classification). An increase in minute ventilation and a decrease in oxygen saturation were observed, and the most frequent adverse event was dyspnoea, which resolved with discontinuation of bosentan.
Concomitant use with other medicinal products
Concomitant use of Tracleer and cyclosporine A is contraindicated (see sections 4.3 and 4.5).
Concomitant use of Tracleer with glibenclamide, fluconazole and rifampicin is not recommended. For further details please refer to section 4.5.
Concomitant administration of both a CYP3A4 inhibitor and a CYP2C9 inhibitor with Tracleer should be avoided (see section 4.5).
Bosentan is an inducer of the cytochrome P450 (CYP) isoenzymes CYP2C9 and CYP3A4. In vitro data also suggest an induction of CYP2C19. Consequently, plasma concentrations of substances metabolised by these isoenzymes will be decreased when Tracleer is co-administered. The possibility of altered efficacy of medicinal products metabolised by these isoenzymes should be considered. The dosage of these products may need to be adjusted after initiation, dose change or discontinuation of concomitant Tracleer treatment.
Bosentan is metabolised by CYP2C9 and CYP3A4. Inhibition of these isoenzymes may increase the plasma concentration of bosentan (see ketoconazole). The influence of CYP2C9 inhibitors on bosentan concentration has not been studied. The combination should be used with caution.
Fluconazole and other inhibitors of both CYP2C9 and CYP3A4: Co-administration with fluconazole, which inhibits mainly CYP2C9, but to some extent also CYP3A4, could lead to large increases in plasma concentrations of bosentan. The combination is not recommended. For the same reason, concomitant administration of both a potent CYP3A4 inhibitor (such as ketoconazole, itraconazole or ritonavir) and a CYP2C9 inhibitor (such as voriconazole) with Tracleer is not recommended.
Cyclosporine A: Co-administration of Tracleer and cyclosporine A (a calcineurin inhibitor) is contraindicated (see section 4.3). When co-administered, initial trough concentrations of bosentan were approximately 30-fold higher than those measured after bosentan alone. At steady state, bosentan plasma concentrations were 3- to 4-fold higher than with bosentan alone. The mechanism of this interaction is most likely inhibition of transport protein-mediated uptake of bosentan into hepatocytes by cyclosporine. The blood concentrations of cyclosporine A (a CYP3A4 substrate) decreased by approximately 50%. This is most likely due to induction of CYP3A4 by bosentan.
Tacrolimus, sirolimus: Co-administration of tacrolimus or sirolimus and Tracleer has not been studied in man but co-administration of tacrolimus or sirolimus and Tracleer may result in increased plasma concentrations of bosentan in analogy to co-administration with cyclosporine A. Concomitant Tracleer may reduce the plasma concentrations of tacrolimus and sirolimus. Therefore, concomitant use of Tracleer and tacrolimus or sirolimus is not advisable. Patients in need of the combination should be closely monitored for adverse events related to Tracleer and for tacrolimus and sirolimus blood concentrations.
Glibenclamide: Co-administration of bosentan 125 mg twice daily for 5 days decreased the plasma concentrations of glibenclamide (a CYP3A4 substrate) by 40%, with potential significant decrease of the hypoglycaemic effect. The plasma concentrations of bosentan were also decreased by 29%. In addition, an increased incidence of elevated aminotransfer
