Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use

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.

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
ALT/AST levels              Treatment and monitoring recommendations
> 3 and ≤ 5 × ULN           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.
> 5 and ≤ 8 × ULN           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.
> 8 × ULN                   Treatment must be stopped and re-introduction of Tracleer is not to be considered.
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.

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 evaluation 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 should be done 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).

Effects on Driving

4.7 Effects on ability to drive and use machines

No specific studies have been conducted to assess the direct effect of Tracleer on the ability to drive and use machines. However, Tracleer may induce hypotension, with symptoms of dizziness, blurred vision or syncope that could affect the ability to drive or use machines.