Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use
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). Opsumit is not to be initiated in patients with severe hepatic impairment or elevated aminotransferases (> 3 × ULN) (see sections 4.2 and 4.3), 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. If sustained, unexplained, clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin > 2 × ULN, or by clinical symptoms of liver injury (e.g., 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.

Haemoglobin concentration

Decrease in haemoglobin concentrations has been associated with endothelin receptor antagonists (ERAs) including macitentan (see section 4.8). 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.


Use in women of childbearing potential
Opsumit_PI_EUPI update_January-2023
Opsumit treatment should only be initiated in women of childbearing potential when the absence of pregnancy has been verified, appropriate advice on contraception provided, and reliable contraception is practised (see sections 4.3 and 4.6). 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. The combination of macitentan with strong CYP3A4 inducers (e.g., rifampicin, St. John’s wort, carbamazepine, and phenytoin) should be avoided (see section 4.5).

Concomitant use with strong CYP3A4 inhibitors

Caution should be exercised when macitentan is administered concomitantly with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir) (see section 4.5).

Concomitant use with moderate dual or combined CYP3A4 and CYP2C9 inhibitors 
Caution should be exercised when macitentan is administered concomitantly with moderate dual inhibitors of CYP3A4 and CYP2C9 (e.g., fluconazole and amiodarone) (see section 4.5).

Caution should also be exercised when macitentan is administered concomitantly with both a moderate CYP3A4 inhibitor (e.g., ciprofloxacin, cyclosporine, diltiazem, erythromycin, verapamil) and moderate CYP2C9 inhibitor (e.g., miconazole, piperine) (see section 4.5).

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. There is no experience with the use of macitentan in patients undergoing dialysis, therefore Opsumit is not recommended in this population (see sections 4.2 and 5.2).

Elderly

There is limited clinical experience with macitentan in patients over the age of 75 years, therefore Opsumit should be used with caution in this population (see section 4.2).

Excipients

Opsumit contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Opsumit contains soya bean lecithin If a patient is hypersensitive to soya, Opsumit must not S


 be used (see section 4.3).

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



Opsumit_PI_EUPI update_January-2023


Effects on Driving

4.7 Effects on ability to drive and use machines

Macitentan has minor influence on the ability to drive and use machines. No studies on the effects on the ability to drive and use machines have been performed. However, undesirable effects may occur (e.g headache, hypotension). that may influence the ability to drive and use machines. (see section 4.8).