OPSUMIT

Treatment should only be initiated and monitored by a physician experienced in the treatment of PAH. Posology Paediatric population (aged ≥2 years to less than 18 years) The recommended daily dose of Opsumit is based on body weight (Table 1).

Opsumit should be taken every day at about the same time. 5 mg* *Opsumit is also available as a 10 mg film-coated tablet. 5 mg dispersible tablets. 2). Please refer to the Opsumit film-coated tablets Summary of Product Characteristics.

If the patient misses a dose of Opsumit, administer it as soon as possible and then take the next dose at the regularly scheduled time. The patient should not take two doses at the same time if a dose has been missed. 2). 2). However, there is no clinical experience with the use of macitentan in PAH patients with moderate or severe hepatic impairment.

4). Renal impairment Based on PK data, no dose adjustment is required in patients with renal impairment. There is no clinical experience with the use of macitentan in PAH patients with severe renal impairment. 2). Paediatric population Dosing and efficacy of macitentan in children below 2 years of age have not been established.

2 but no recommendation on a posology can be made. Method of administration Opsumit should be taken orally once a day with or without food. Opsumit dispersible tablets must be dispersed in room temperature liquids and are to be taken as an oral suspension only.

The oral suspension must be prepared and administered using a small glass. Care should be taken to ensure the entire dose of medicine has been taken. If not administered within 2 hours of preparation, the medicine should be discarded and a new dose of medicine should be prepared.

6). Administration by a glass The prescribed daily dose of dispersible tablets should be placed in a small glass containing a small volume (from 10 mL (approximately 2 teaspoonfuls) up to maximum 100 mL) of room temperature drinking water to form a white cloudy liquid.

The liquid can be gently stirred with a spoon for 1 to 2 minutes. Administer the medicine to the patient right away. A little more water (minimum 5 mL (approximately 1 teaspoonful) should be added to the glass and stirred with the same spoon to re-suspend any remaining medicine.

The entire contents of the glass should be administered to the patient to make sure all the medicine has been taken. In case of difficulties in using only water for administration, alternative suitable soft foods or beverages may be used, as detailed below.

Administration by a small glass for mixing with soft foods or beverages The prescribed daily dose of dispersible tablets should be placed in a small glass containing 5 mL (1 teaspoonful) of room temperature drinking water to form a white cloudy liquid.

The liquid can be gently stirred with a spoon for 1 to 2 minutes. Mix it further with a small amount of apple sauce or yogurt to facilitate immediate consumption. To ensure that all the medicine has been taken, a little more water (minimum 5 mL) should be added to the glass and stirred with the same spoon to re- suspend any remaining medicine.

The entire contents of the glass should be administered to the patient to make sure all the medicine has been taken. Alternatively, the tablets can be dispersed in 5 mL (1 teaspoonful) of room temperature orange juice, apple juice, or skimmed milk and be administered to the patient right away.

The glass must be rinsed with a minimum of 5 mL of the chosen liquid to make sure the whole dose is taken. The administration of the oral suspension via enteral tubes has not been tested

Summary of the safety profile. 4). Tabulated list of adverse reactions The safety of macitentan has been evaluated in a long-term placebo-controlled trial of 742 adult and adolescent patients with symptomatic PAH (SERAPHIN study). 3 weeks in the placebo group.

Adverse reactions associated with macitentan obtained from this clinical study are tabulated below. Post-marketing adverse reactions are also included. Frequencies are defined as: 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).

, angioedema, pruritus, rash)1 Nervous system disorders Very common Headache Vascular disorders Common Hypotension2, flushing Respiratory, thoracic and mediastinal disorders Common Nasal congestion1 Hepatobiliary disorders Common Aminotransferase elevations4 Reproductive system and breast disorders Common Increased uterine bleeding8 General disorders and administration site conditions Very common Oedema, fluid retention3 1 Data derived from pooled placebo-controlled studies.

8 Includes PTs of heavy menstrual bleeding, abnormal uterine bleeding, intermenstrual bleeding, uterine/vaginal haemorrhage, polymennorhoea and menstruation irregular. Frequency based on exposure in females. Description of selected adverse reactions 2 Hypotension has been associated with the use of ERAs including macitentan.

4% of patients on macitentan 10 mg and placebo, respectively. 7 events / 100 patient-years on placebo. 3 Oedema/fluid retention has been associated with the use of ERAs including macitentan. 5%, respectively. 8%, respectively. 5% in the placebo groups.

5% on placebo in SERAPHIN, a double-blind study in adult patients with PAH. 5% of patients on macitentan 10 mg versus 2% of patients on placebo. 5 Haemoglobin In SERAPHIN, a double-blind study in adult patients with PAH, macitentan 10 mg was associated with a mean decrease in haemoglobin versus placebo of 1 g/dL.

4% of placebo-treated patients. 7 × 109/L versus no change in placebo-treated patients. 7 Platelets In SERAPHIN, a double-blind study in adult patients with PAH, macitentan 10 mg was associated with a decrease in mean platelet count of 17 × 109/L, versus a mean decrease of 11 × 109/L in placebo-treated patients.

Long-term safety Of the 742 patients who participated in the pivotal SERAPHIN double-blind study, 550 patients entered a long-term open-label (OL) extension study. 9 years showed a safety profile that was consistent as described above during the SERAPHIN double-blind phase.

Paediatric population (aged ≥ 2 years to less than 18 years) The safety of macitentan was evaluated in TOMORROW, a Phase 3 study in paediatric patients with PAH. A total of 72 patients aged ≥ 2 years to less than 18 years were randomised and received Opsumit.

9 years). 4 weeks) in the Opsumit arm. Overall, the safety profile in this paediatric population was consistent with that observed in the adult population. 1%). Paediatric population (aged ≥ 1 month to less than 2 years) An additional 11 patients, aged ≥ 1 month to less than 2 years old were enroled to receive Opsumit without randomisation, 9 patients from the open-label arm of the TOMORROW study and 2 Japanese patients from the PAH3001 study.

9 weeks). At enrolment, the ages […]

The benefit/risk balance of macitentan has not been established in patients with WHO class I functional status of pulmonary arterial hypertension. Liver function Elevations of liver aminotransferases (AST, ALT) have been associated with PAH and with endothelin receptor antagonists (ERAs).

3) and is not recommended in patients with moderate hepatic impairment. Liver enzyme tests should be obtained prior to initiation of Opsumit. Patients should be monitored for signs of hepatic injury and monthly monitoring of ALT and AST is recommended.

, jaundice), Opsumit treatment should be discontinued. Reinitiation of Opsumit may be considered following the return of hepatic enzyme levels to within the normal range in patients who have not experienced clinical symptoms of liver injury.

The advice of a hepatologist is recommended. 8). In placebo-controlled studies, macitentan-related decreases in haemoglobin concentration were not progressive, stabilised after the first 4–12 weeks of treatment and remained stable during chronic treatment.

Cases of anaemia requiring blood cell transfusion have been reported with macitentan and other ERAs. Initiation of Opsumit is not recommended in patients with severe anaemia. It is recommended that haemoglobin concentrations be measured prior to initiation of treatment and tests repeated during treatment as clinically indicated.

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, if signs of pulmonary oedema occur when macitentan is administered in patients with PAH, the possibility of pulmonary veno-occlusive disease should be considered.

6). Women should not become pregnant for 1 month after discontinuation of Opsumit. Monthly pregnancy tests during treatment with Opsumit are recommended to allow the early detection of pregnancy. Concomitant use with strong CYP3A4 inducers In the presence of strong CYP3A4 inducers reduced efficacy of macitentan could occur.

, rifampicin, St. 5). 5). 5). 5). Renal impairment Patients with renal impairment may run a higher risk of experiencing hypotension and anaemia during treatment with macitentan. Therefore, monitoring of blood pressure and haemoglobin should be considered.

There is no clinical experience with the use of macitentan in PAH patients with severe renal impairment. Caution is recommended in this population. 2). Excipients with known effects Opsumit dispersible tablets contain isomalt. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Other excipients This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

1. 6). 6). 6). 2). 4).