Opsumit

/ Janssen

Treatment should only be initiated and monitored by a physician experienced in the treatment of PAH.
Posology: The recommended dose is 10 mg orally once daily.
Elderly: No dose adjustment is required in patients over the age of 65 years. There is limited clinical experience in patients over the age of 75 years.
Therefore Opsumit should be used with caution in this population.
Hepatic impairment: Based on pharmacokinetic (PK) data, no dose adjustment is required in patients with mild, moderate or severe hepatic impairment. However, there is no clinical experience with the use of macitentan in PAH patients with moderate or severe hepatic impairment.
Opsumit must not be initiated in patients with severe hepatic impairment, or clinically significant elevated hepatic aminotransferases (greater than 3 times the Upper Limit of Normal (> 3 × ULN)).
Patients with 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. The use of Opsumit is not recommended in patients undergoing dialysis.
Paediatric population: The safety and efficacy of macitentan in children and adolescents below 18 years have not yet been established. No data are available.
Method of administration: The film-coated tablets are not breakable and are to be swallowed whole, with water. They may be taken with or without food.
Opsumit should be taken every day at about the same time. If a patient misses a dose of Opsumit, the patient should be told to take it as soon as possible and then take the next dose at the regulary scheduled time. The patient should be told not to take two doses at the same time if a dose has been missed.

Macitentan is endothelin receptor antagonist (ERA) indicated for the treatment of pulmonary arterial hypertension (PAH, who GROUP I) to delay disease progression. Disease progression included: death, initiation of intravenous (IV) or subcutaneous prostanoids, or clinical worsening of PAH (decreased 6-minute walk distance, worsened pah symptoms and need for additional PAH treatment). The drug also reduced hospitalization for PAH.

Hypersensitivity to the active substance. soya or to any of the excipients. Pregnancy. Women of childbearing potential who are not using reliable contraception. Breastfeeding. Patients with severe hepatic impairment (with or without cirrhosis). Baseline values of hepatic aminotransferases (aspartate aminotransferases (AST) and/or alanine aminotransferases (ALT) > 3 × ULN).

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

The most commonly reported adverse reactions are nasopharyngitis (14.0%),
headache (13.6%) and anaemia (13.2%, see section 4.4). The majority of adverse reactions are mild to moderate in intensity.
See prescribing information for full details.

In vitro studies: The cytochrome P450 enzymes CYP3A4, CYP2C8, CYP2C9, and CYP2C19 are involved in the metabolism of macitentan and formation of its metabolites. Macitentan and its active metabolite do not have clinically relevant inhibitory or inducing effects on cytochrome P450 enzymes.
Macitentan and its active metabolite are not inhibitors of hepatic or renal uptake transporters at clinically relevant concentrations, including the organic anion transporting polypeptides (OATP1B1 and OATP1B3). Macitentan and its active metabolite are not relevant substrates of OATP1B1 and OATP1B3, but enter the liver by passive diffusion.
Macitentan and its active metabolite are not inhibitors of hepatic or renal efflux pumps at clinically relevant concentrations, including the multi-drug resistance protein (P-gp, MDR-1) and multidrug and toxin extrusion transporters (MATE1 and MATE2-K). Macitentan inhibits the breast cancer resistance protein (BCRP) at clinically relevant intestinal concentrations.
Macitentan is not a substrate for P-gp/MDR-1.
At clinically relevant concentrations, macitentan and its active metabolite do not interact with proteins involved in hepatic bile salt transport, i.e., the bile salt export pump (BSEP) and the sodium-dependent taurocholate co-transporting polypeptide (NTCP).
In vivo studies: Strong CYP3A4 inducers: Concomitant treatment with rifampicin 600 mg daily, a potent inducer of CYP3A4, reduced the steady-state exposure to macitentan by 79% but did not affect the exposure to the active metabolite. Reduced efficacy of macitentan in the presence of a potent inducer of CYP3A4 such as rifampicin should be considered. The combination of macitentan with strong CYP3A4 inducers should be avoided.
Ketoconazole: In the presence of ketoconazole 400 mg once daily, a strong CYP3A4 inhibitor, exposure to macitentan increased approximately 2-fold. The predicted increase was approximately 3-fold in the presence of ketoconazole 200 mg twice daily using physiologically based pharmacokinetic (PBPK) modelling. The uncertainties of such modelling should be considered. Exposure to the active metabolite of macitentan was reduced by 26%. Caution should be exercised when macitentan is administered concomitantly with strong CYP3A4 inhibitors.
Warfarin: Macitentan given as multiple doses of 10 mg once daily had no effect on exposure to S-warfarin (CYP2C9 substrate) or R-warfarin (CYP3A4 substrate) after a single dose of 25 mg warfarin. The pharmacodynamic effect of warfarin on International Normalised Ratio (INR) was not affected by macitentan. The pharmacokinetics of macitentan and its active metabolite were not affected by warfarin.
Sildenafil: At steady-state, the exposure to sildenafil 20 mg three times a day was increased by 15% during concomitant administration of macitentan 10 mg once daily.
Sildenafil, a CYP3A4 substrate, did not affect the pharmacokinetics of macitentan, while there was a 15% reduction in the exposure to the active metabolite of macitentan. These changes are not considered clinically relevant. In a placebo-controlled trial in patients with PAH, the efficacy and safety of macitentan in combination with sildenafil were demonstrated.
Cyclosporine A: Concomitant treatment with cyclosporine A 100 mg b.i.d., a combined CYP3A4 and OATP inhibitor, did not alter the steady-state exposure to macitentan and its active metabolite to a clinically relevant extent.
Hormonal contraceptives: Macitentan 10 mg once daily did not affect the pharmacokinetics of an oral contraceptive (norethisterone 1 mg and ethinyl estradiol 35 μg).
Paediatric population: Interaction studies have only been performed in adults

Pregnancy: There are no data from the use of macitentan in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is still unknown. Opsumit is contraindicated during pregnancy and in women of childbearing potential who are not using reliable contraception.
Lactation: It is unknown whether macitentan is excreted in human milk. A risk
to the breastfeeding child cannot be excluded. Opsumit is contraindicated during breastfeeding.
See prescribing information for full details.                        

Macitentan has been administered as a single dose of up to 600 mg to healthy subjects.
Adverse reactions of headache, nausea, and vomiting were observed. In the event of an overdose, standard supportive measures must be taken, as required. Due to the high degree of protein binding of macitentan, dialysis is unlikely to be effective.

Shelf life: 3 years.
Storage: Do not store above 30 °C.