4.1. Therapeutic indications

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).

Bosentan 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).

4.2. Posology and method of administration

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.

Posology

Pulmonary arterial hypertension

Treatment should only be initiated and monitored by a physician experienced in the treatment of PAH. A Patient Alert Card providing important safety information that patients need to be aware of before and during treatment with Bosentan is included in the pack.

Adults

In adult patients, Bosentan Milpharm 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 Bosentan Milpharm 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 bosentan 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 bosentan 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 bosentan may respond favourably after an additional 4 to 8 weeks of treatment.

In the case of late clinical deterioration despite treatment with bosentan (i.e., after several months of treatment), the treatment should be re-assessed. Some patients not responding well to 125 mg twice daily of bosentan 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 bosentan 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 bosentan 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.

A Patient Alert Card providing important safety information that patients need to be aware of before and during treatment with Bosentan is included in the pack.

Adults

Bosentan 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 Bosentan 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-evaluated 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 Bosentan in young children with this disease.

Special populations

Hepatic impairment

Bosentan 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.

4.3. Contraindications

• 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 aminotransferase, i.e., aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT), greater than 3x 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 child-bearing potential who are not using reliable methods of contraception (see sections 4.4, 4.5 and 4.6)

4.4. Special warnings and precautions for use

The efficacy of bosentan 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 pulmonary arterial hypertension.

Bosentan Milpharm should only be initiated if the systemic systolic blood pressure is higher than 85 mmHg.

Bosentan Milpharm 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. Rare cases of autoimmune hepatitis with a latency of few months to years have been reported. 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 Bosentan Milpharm. 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 Bosentan Milpharm, possibly at a reduced dose, or to stop Bosentan Milpharm 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 Bosentan Milpharm 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 Bosentan Milpharm according to the conditions described below should be considered..

> 8 × ULN

Treatment must be stopped and re-introduction of Bosentan Milpharm is not to be considered.

In the event of associated clinical symptoms of liver injury or autoimmune hepatitis, 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 Bosentan Milpharm is not to be considered.

Re-introduction of treatment

Re-introduction of treatment with Bosentan Milpharm should only be considered if the potential benefits of treatment with Bosentan Milpharm 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 child-bearing potential

As bosentan 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:

• Bosentan Milpharm treatment must not be initiated in women of Child-bearing 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 Bosentan Milpharm

• 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 Bosentan Milpharm 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 Bosentan Milpharm 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 Bosentan Milpharm.

Pulmonary arterial hypertension associated with HIV infection

There is limited clinical study experience with the use of bosentan 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 bosentan is initiated in patients who require ritonavir-boosted protease inhibitors, the patient's tolerability of bosentan 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 Bosentan Milpharm and cyclosporine A is contraindicated (see sections 4.3 and 4.5).

Concomitant use of Bosentan Milpharm 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 Bosentan Milpharm should be avoided (see section 4.5).

Bosentan Milpharm contains Sodium:

Bosentan Milpharm contains less than 1 mmol (23 mg) of sodium per tablet, that is to say it is essentially 'sodium-free.'

4.5. Interaction with other medicinal products and other forms of interaction

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 Bosentan Milpharm 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 Bosentan Milpharm 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:

Concomitant 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 Bosentan Milpharm is not recommended.

Cyclosporine A: co-administration of Bosentan Milpharm 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 Bosentan Milpharm has not been studied in man but co-administration of tacrolimus or sirolimus and Bosentan Milpharm may result in increased plasma concentrations of bosentan in analogy to co-administration with cyclosporine A. Concomitant Bosentan Milpharm may reduce the plasma concentrations of tacrolimus and sirolimus. Therefore, concomitant use of Bosentan Milpharm and tacrolimus or sirolimus is not advisable. Patients in need of the combination should be closely monitored for adverse events related to Bosentan Milpharm 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 aminotransferases was observed in patients receiving concomitant therapy. Both glibenclamide and bosentan inhibit the bile salt export pump, which could explain the elevated aminotransferases. This combination should not be used. No drug-drug interaction data are available with the other sulfonylureas.

Rifampicin: co-administration in 9 healthy subjects for 7 days of bosentan 125 mg twice daily with rifampicin, a potent inducer of CYP2C9 and CYP3A4, decreased the plasma concentrations of bosentan by 58%, and this decrease could achieve almost 90% in an individual case. As a result, a significantly reduced effect of bosentan is expected when it is co-administered with rifampicin. Concomitant use of rifampicin and bosentan is not recommended. Data on other CYP3A4 inducers, e.g., carbamazepine, phenobarbital, phenytoin and St. John's wort are lacking, but their concomitant administration is expected to lead to reduced systemic exposure to bosentan. A clinically significant reduction of efficacy cannot be excluded.

Lopinavir+ritonavir (and other ritonavir-boosted protease inhibitors): co-administration of bosentan 125 mg twice daily and lopinavir+ritonavir 400+100 mg twice daily for 9.5 days in healthy volunteers resulted in initial trough plasma concentrations of bosentan that were approximately 48-fold higher than those measured after bosentan administered alone. On day 9, plasma concentrations of bosentan were approximately 5-fold higher than with bosentan administered alone. Inhibition by ritonavir of transport protein-mediated uptake into hepatocytes and of CYP3A4, thereby reducing the clearance of bosentan, most likely causes this interaction. When administered concomitantly with lopinavir+ritonavir, or other ritonavir-boosted protease inhibitors, the patient's tolerability of bosentan should be monitored.

After co-administration of bosentan for 9.5 days, the plasma exposures to lopinavir and ritonavir decreased to a clinically non-significant extent (by approximately 14% and 17%, respectively). However, full induction by bosentan might not have been reached and a further decrease of protease inhibitors cannot be excluded. Appropriate monitoring of the HIV therapy is recommended. Similar effects would be expected with other ritonavir-boosted protease inhibitors (see section 4.4).

Other antiretroviral agents: no specific recommendation can be made with regard to other available antiretroviral agents due to the lack of data. Due to the marked hepatotoxicity of nevirapine, which could add to bosentan liver toxicity, this combination is not recommended.

Hormonal contraceptives: co-administration of bosentan 125 mg twice daily for 7 days with a single dose of oral contraceptive containing norethisterone 1 mg + ethinyl estradiol 35 mcg decreased the AUC of norethisterone and ethinyl estradiol by 14% and 31%, respectively. However, decreases in exposure were as much as 56% and 66%, respectively, in individual subjects. Therefore, hormone-based contraceptives alone, regardless of the route of administration (i.e., oral, injectable, transdermal or implantable forms), are not considered as reliable methods of contraception (see sections 4.4 and 4.6).

Warfarin: co-administration of bosentan 500 mg twice daily 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 with warfarin in patients with pulmonary arterial hypertension did not result in clinically relevant changes in International Normalized Ratio (INR) or warfarin dose (baseline versus end of the clinical studies).

In addition, the frequency of changes in warfarin dose during the studies due to changes in INR or due to adverse events was similar among bosentan- and placebo-treated patients. No dose adjustment is needed for warfarin and similar oral anticoagulant agents when bosentan is initiated, but intensified monitoring of INR is recommended, especially during bosentan initiation and the up-titration period.

Simvastatin: co-administration of bosentan 125 mg twice daily for 5 days decreased the plasma concentrations of simvastatin (a CYP3A4 substrate) and its active β-hydroxy acid metabolite by 34% and 46%, respectively. The plasma concentrations of bosentan were not affected by concomitant simvastatin. Monitoring of cholesterol levels and subsequent dosage adjustment should be considered.

Ketoconazole: co-administration for 6 days of bosentan 62.5 mg twice daily with ketoconazole, a potent CYP3A4 inhibitor, increased the plasma concentrations of bosentan approximately 2-fold. No dose adjustment of Bosentan Milpharm is considered necessary. Although not demonstrated through in vivo studies, similar increases in bosentan plasma concentrations are expected with the other potent CYP3A4 inhibitors (such as itraconazole or ritonavir). However, when combined with a CYP3A4 inhibitor, patients who are poor metabolisers of CYP2C9 are at risk of increases in bosentan plasma concentrations that may be of higher magnitude, thus leading to potential harmful adverse events.

Epoprostenol: limited data obtained from a study (AC-052-356 [BREATHE-3]) in which 10 paediatric patients received the combination of bosentan and epoprostenol indicate that after both single- and multiple-dose administration, the Cmax and AUC values of bosentan were similar in patients with or without continuous infusion of epoprostenol (see section 5.1).

Sildenafil: co-administration of bosentan 125 mg twice daily (steady state) with sildenafil 80 mg three times a day (at steady state) concomitantly administered during 6 days in healthy volunteers resulted in a 63% decrease in the sildenafil AUC and a 50% increase in the bosentan AUC. Caution is recommended in the case of co-administration.

Tadalafil: Bosentan (125 mg twice daily) reduced tadalafil (40 mg once per day) systemic exposure by 42 % and Cmax by 27 % following multiple dose co-administration. Tadalafil did not affect the exposure (AUC and Cmax) of bosentan or its metabolites.

Digoxin: co-administration for 7 days of bosentan 500 mg twice daily with digoxin decreased the AUC, Cmax and Cmin of digoxin by 12%, 9% and 23%, respectively. The mechanism for this interaction may be induction of P-glycoprotein. This interaction is unlikely to be of clinical relevance.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Pregnancy

Studies in animals have shown reproductive toxicity (teratogenicity, embryotoxicity; see section 5.3). There are no reliable data on the use of bosentan in pregnant women. The potential risk for humans is still unknown. Bosentan Milpharm is contraindicated in pregnancy (see section 4.3).

Women of child-bearing potential

Before the initiation of Bosentan Milpharm 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, Bosentan Milpharm may render hormonal contraceptives ineffective (see section 4.5). Therefore, women of child-bearing potential must not use hormonal contraceptives (including oral, injectable, transdermal or implantable forms) as the sole method of contraception but must 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 Bosentan Milpharm treatment, and also bearing in mind the risk that pulmonary hypertension severely deteriorates with pregnancy, monthly pregnancy tests during treatment with Bosentan Milpharm are recommended to allow early detection of pregnancy.

Breast-feeding

Data from a case report describe the presence of bosentan in human milk in a low concentration. There is insufficient information about the effects of bosentan on the breastfed infant. A risk to the breastfed infant cannot be excluded. Breast-feeding is not recommended during treatment with Bosentan Milpharm.

Fertility

Animal studies showed testicular effects (see section 5.3). In a clinical study investigating the effects of bosentan on testicular function in male PAH patients, six of the 24 subjects (25%) had a decreased sperm concentration of at least 50% from baseline at 6 months of treatment with bosentan. Based on these findings and preclinical data, it cannot be excluded that bosentan may have a detrimental effect on spermatogenesis in men. In male children, a long-term impact on fertility after treatment with bosentan cannot be excluded.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

In 20 placebo-controlled studies, conducted in a variety of therapeutic indications, a total of 2,486 patients were treated with bosentan at daily doses ranging from 100 mg to 2000 mg and 1,838 patients were treated with placebo. The mean treatment duration was 45 weeks. Adverse reactions were defined as events occurring in at least 1% of patients on bosentan and at a frequency at least 0.5% more than on placebo. The most frequent adverse reactions are headache (11.5%), oedema/fluid retention (13.2%), abnormal liver function test (10.9%) and anaemia/haemoglobin decrease (9.9%).

Treatment with bosentan has been associated with dose-dependent elevations in liver aminotransferases and decreases in haemoglobin concentration (see section 4.4, Special warnings and precautions for use).

Adverse reactions observed in 20 placebo-controlled studies and post-marketing experience with bosentan are ranked according to frequency using the following convention: very common (≥ 1/10); common (≥1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. No clinically relevant differences in adverse reactions were observed between the overall dataset and the approved indications.

System organ class

Frequency

Adverse reaction

Blood and lymphatic system disorders

Common

Anaemia, haemoglobin decrease, (see section 4.4)

Not known

Anaemia or haemoglobin decreases requiring red blood cell transfusion1

Uncommon

Thrombocytopenia1, Neutropenia, leukopenia1

Immune system disorders

Common

Hypersensitivity reactions (including dermatitis, pruritus and rash)2

Rare

Anaphylaxis and/or angioedema1

Nervous system disorders

Very common

Headache3,

Common

Syncope1, 4

Eye disorders

Not known

Blurred vision

Cardiac disorders

Common

Palpitations1, 4

Vascular disorders

Common

Flushing

Hypotension1, 4

Respiratory, thoracic and mediastinal disorders

Common

Nasal congestion1

Gastrointestinal disorders

Common

Gastro-oesophageal reflux disease, Diarrhoea

Hepatobiliary disorders

Very common

Abnormal liver function test, (see section 4.4)

Uncommon

Aminotransferase elevations associated with hepatitis (including possible exacerbation of underlying hepatitis) and/or jaundice1 (see section 4.4)

Rare

Liver cirrhosis, liver failure1

Autoimmune hepatitis

Skin and subcutaneous disorders

Common

Erythema

General disorders and administration site conditions

Very common

Oedema, fluid retention5

1 Data derived from post-marketing experience, frequencies based on statistical modelling of placebo-controlled clinical trial data.

2 Hypersensitivity reactions were reported in 9.9% of patients on bosentan and 9.1% of patients on placebo.

3 Headache was reported in 11.5% of patients on bosentan and 9.8% of patients on placebo.

4 These types of reactions can also be related to the underlying disease.

5 Oedema or fluid retention was reported in 13.2% of patients on bosentan and 10.9% of patients on placebo.

In the post-marketing period rare cases of unexplained hepatic cirrhosis were reported after prolonged therapy with bosentan in patients with multiple co-morbidities and therapies with medicinal products. There have also been rare reports of liver failure and autoimmune hepatitis with a latency of few months to years. These cases reinforce the importance of strict adherence to the monthly schedule for monitoring of liver function for the duration of treatment with bosentan (see section 4.4).

Paediatric population

Uncontrolled clinical studies in paediatric patients:

The safety profile in the first paediatric uncontrolled study performed with the film-coated tablet (BREATHE-3: n = 19, median age 10 years [range 3–15 years], open-label bosentan 2 mg/kg twice daily; treatment duration 12 weeks) was similar to that observed in the pivotal trials in adult patients with PAH. In BREATHE-3, the most frequent adverse reactions were flushing (21%), headache, and abnormal liver function test (each 16%). A pooled analysis of uncontrolled paediatric studies conducted in PAH with the bosentan 32 mg dispersible tablet formulation (FUTURE ½, FUTURE 3/Extension) included a total of 100 children treated with bosentan 2 mg/kg twice daily (n = 33), 2 mg/kg three times daily (n = 31), or 4 mg/kg twice daily (n = 36). At enrolment, six patients were between 3 months and 1 year old, 15 children were between 1 and less than 2 years old, and 79 were between 2 and 12 years old. The median treatment duration was 71.8 weeks (range 0.4–258 weeks).

The safety profile in this pooled analysis of uncontrolled paediatric studies was similar to that observed in the pivotal trials in adult patients with PAH except for infections, which were more frequently reported than in adults (69.0% vs 41.3%). This difference in infection frequency may in part be due to the longer median treatment exposure in the paediatric set (median 71.8 weeks) compared with the adult set (median 17.4 weeks). The most frequent adverse events were upper respiratory tract infections (25%), pulmonary (arterial) hypertension (20%), nasopharyngitis (17%), pyrexia (15%), vomiting (13%), bronchitis (10%), abdominal pain (10%), and diarrhoea (10%). There was no relevant difference in adverse event frequencies between patients above and below the age of 2 years; however, this is based on only 21 children less than 2 years, including 6 patients between 3 months to 1 year of age. Adverse events of liver abnormalities and anaemia/haemoglobin decrease occurred in 9% and 5% of patients, respectively.

In a randomised placebo-controlled study, conducted in PPHN patients (FUTURE-4), a total of 13 neonates were treated with the bosentan dispersible tablet formulation at a dose of 2 mg/kg twice daily (8 patients were on placebo). The median bosentan and placebo treatment duration was, respectively, 4.5 days (range 0.5–10.0 days) and 4.0 days (range 2.5-6.5 days). The most frequent adverse events in the bosentan- and the placebo-treated patients were, respectively, anaemia or haemoglobin decrease (7 and 2 patients), generalised oedema (3 and 0 patients), and vomiting (2 and 0 patients).

Laboratory abnormalities

Liver test abnormalities

In the clinical programme, dose-dependent elevations in liver aminotransferases generally occurred within the first 26 weeks of treatment, usually developed gradually, and were mainly asymptomatic. In the post-marketing period rare cases of liver cirrhosis and liver failure have been reported.

The mechanism of this adverse effect is unclear. These elevations in aminotransferases may reverse spontaneously while continuing treatment with the maintenance dose of Bosentan Milpharm or after dose reduction, but interruption or cessation may be necessary (see section 4.4).

In the 20 integrated placebo-controlled studies, elevations in liver aminotransferases ≥ 3 x ULN were observed in 11.2% of the bosentan-treated patients as compared to 2.4% of the placebo-treated patients. Elevations to ≥ 8 × ULN were seen in 3.6% of the bosentan-treated patients and 0.4% of the placebo-treated patients. Elevations in aminotransferases were associated with elevated bilirubin (≥ 2 × ULN) without evidence of biliary obstruction in 0.2% (5 patients) on bosentan and 0.3% (6 patients) on placebo.

In the pooled analysis of 100 PAH children from uncontrolled paediatric studies FUTURE½ and FUTURE 3/Extension, elevations in liver aminotransferases ≥ 3 × ULN were observed in 2% of patients.

In the FUTURE-4 study including 13 neonates with PPHN treated with bosentan 2 mg/kg twice daily for less than 10 days (range 0.5–10.0 days), there were no cases of liver aminotransferases ≥ 3 × ULN during treatment, but one case of hepatitis occurred 3 days after the end of bosentan treatment.

Haemoglobin

In the adult placebo-controlled studies, a decrease in haemoglobin concentration to below 10 g/dL from baseline was reported in 8.0% of bosentan-treated patients and 3.9% of placebo-treated patients (see section 4.4).

In the pooled analysis of 100 PAH children from uncontrolled paediatric studies FUTURE½ and FUTURE 3/Extension, a decrease in haemoglobin concentration from baseline to below 10 g/dL was reported in 10.0% of patients. There was no decrease to below 8 g/dL.

In the FUTURE-4 study, 6 out of 13 bosentan-treated neonates with PPHN experienced a decrease in haemoglobin from within the reference range at baseline to below the lower limit of normal during the treatment.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.

4.9. Overdose

Bosentan has been administered as a single dose of up to 2400 mg to healthy subjects and up to 2000 mg/day for 2 months in patients with a disease other than pulmonary hypertension. The most common adverse reaction was headache of mild to moderate intensity.

Massive overdose may result in pronounced hypotension requiring active cardiovascular support. In the post-marketing period there was one reported overdose of 10,000 mg of bosentan taken by an adolescent male patient. He had symptoms of nausea, vomiting, hypotension, dizziness, sweating and blurred vision. He recovered completely within 24 hours with blood pressure support. Note: bosentan is not removed through dialysis.