BOSENTAN CIPLA

Posology Pulmonary arterial hypertension Treatment should only be initiated and monitored by a physician experienced in the treatment of pulmonary arterial hypertension. 5 mg twice daily for 4 weeks and then increased to the maintenance dose of 125 mg twice daily.

4). 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. 2). Dose of bosentan 2 mg/kg are not possible with these medicinal products in children with a body weight below 31 kg.

For such patients a bosentan tablet with lower strength is needed. , 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. , 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.

1). Discontinuation of treatment There is limited experience with abrupt discontinuation of bosentan in patients with pulmonary arterial hypertension. 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.

5 mg twice daily for 4 weeks and then increased to the maintenance dose of 125 mg twice daily. 4). 1). The patient's response to treatment and need for continued therapy should be re- evaluated on a regular basis. 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. 2). 2). Renal impairment No dose adjustment is required in patients with renal impairment. 2). Elderly No dose adjustment is required in patients over the age of 65 years.

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.

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.

5% more than on placebo. 9%). 4). 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. 4) Hepatobiliary disorders Rare Liver cirrhosis, liver failure1 Skin and subcutaneous Common Erythema disorders 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.

1% of patients on placebo. 8% of patients on placebo. 4 These types of reactions can also be related to the underlying disease. 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. 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 1/2, 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. 4–258 weeks). 3%). 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). 5 days).

The most frequent adverse events in the bosentan and the placebo-treated patients […]

The efficacy of bosentan has not been established in patients with severe pulmonary arterial hypertension. 2). The benefit/risk balance of bosentan has not been established in patients with WHO class I functional status of pulmonary arterial hypertension.

Bosentan should only be initiated if the systemic systolic blood pressure is higher than 85 mmHg. Bosentan has not been shown to have a beneficial effect on the healing of existing digital ulcers. , aspartate and alanine aminotransferases (AST and/or ALT), associated with bosentan are dose dependent.

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. 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.

In addition, liver aminotransferase levels must be measured 2 weeks after any dose increase. 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 Cipla 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 Cipla according to the conditions described below should be considered.

> 8 × ULN Treatment must be stopped and re-introduction of Bosentan Cipla is not to be considered. , 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 Cipla is not to be considered.

Re-introduction of treatment Re-introduction of treatment with Bosentan Cipla should only be considered if the potential benefits of treatment with Bosentan Cipla outweigh the potential risks and when liver aminotransferase levels are within pre-treatment values.

The advice of a hepatologist is recommended. 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. 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.

8). Women of child-bearing potential As Bosentan Cipla 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 Cipla 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 Cipla.

5 and

6)