Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Janssen-Cilag International NV, Turnhoutseweg 30, B 2340, Beerse, Belgium
The benefit/risk balance of macitentan has not been established in patients with WHO class I functional status of pulmonary arterial hypertension.
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.
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.
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.
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.
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).
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).
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).
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).
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 (see section 4.3).
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
The cytochrome P450 enzymes CYP3A4, CYP2C8, CYP2C9, and CYP2C19 are involved in the metabolism of macitentan and formation of its metabolites (see section 5.2). 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 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).
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 (see section 4.4).
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 (see section 4.4).
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.
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.
Concomitant treatment with cyclosporine A 100 mg twice daily, a combined CYP3A4 and OATP inhibitor, did not alter the steady-state exposure to macitentan and its active metabolite to a clinically relevant extent.
Macitentan 10 mg once daily did not affect the pharmacokinetics of an oral contraceptive (norethisterone 1 mg and ethinyl estradiol 35 μg).
Macitentan 10 mg once daily did not affect the pharmacokinetics of a BCRP substrate drug (riociguat 1 mg; rosuvastatin 10 mg).
Interaction studies have only been performed in adults.
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 4.4). 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.
There are no data from the use of macitentan in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). 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 (see section 4.3).
It is unknown whether macitentan is excreted in human milk. In rats, macitentan and its metabolites are excreted into milk during lactation (see section 5.3). A risk to the breastfeeding child cannot be excluded. Opsumit is contraindicated during breastfeeding (see section 4.3).
The development of testicular tubular atrophy in male animals was observed after treatment with macitentan (see section 5.3). The relevance of this finding to humans is unknown, but a deterioration of spermatogenesis cannot be excluded.
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).
The most commonly reported adverse reactions are nasopharyngitis (14%), headache (13.6%) and anaemia (13.2%, see section 4.4). The majority of adverse reactions are mild to moderate in intensity.
The safety of macitentan has been evaluated in a long-term placebo-controlled trial of 742 patients with symptomatic PAH. The mean treatment duration was 103.9 weeks in the macitentan 10 mg group, and 85.3 weeks in the placebo group. Adverse reactions associated with macitentan obtained from this clinical study are tabulated below.
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).
Very common: Nasopharyngitis, Bronchitis
Common: Pharyngitis, Influenza, Urinary tract infection
Very common: Anaemia, haemoglobin decrease5
Common: Leukopenia6, Thrombocytopenia7
Common: Aminotransferase elevations4
Uncommon: Hypersensitivity reactions (e.g., angioedema, pruritus, rash)1
Very common: Headache
Common: Hypotension2
Common: Nasal congestion1
Very common: Oedema, fluid retention3
1 Data derived from pooled placebo-controlled studies.
2 Hypotension has been associated with the use of ERAs including macitentan. In a long-term doubleblind study in patients with PAH, hypotension was reported for 7.0% and 4.4% of patients on macitentan 10 mg and placebo, respectively. This corresponded to 3.5 events/100 patient-years on macitentan 10 mg compared to 2.7 events/100 patient-years on placebo.
3 Oedema/fluid retention has been associated with the use of ERAs including macitentan. In a longterm double-blind study in patients with PAH, the incidence of oedema AEs in the macitentan 10 mg and placebo treatment groups was 21.9% and 20.5%, respectively. In a double-blind study in patients with idiopathic pulmonary fibrosis, the incidence of peripheral oedema AEs in the macitentan and placebo treatment groups was 11.8% and 6.8%, respectively. In two double-blind clinical studies in patients with digital ulcers associated with systemic sclerosis, the incidences of peripheral oedema AEs ranged from 13.4% to 16.1% in the macitentan 10 mg groups and from 6.2% to 4.5% in the placebo groups.
The incidence of aminotransferase elevations (ALT/AST) >3 × ULN was 3.4% on macitentan 10 mg and 4.5% on placebo in a double-blind study in patients with PAH. Elevations >5 × ULN occurred in 2.5% of patients on macitentan 10 mg versus 2% of patients on placebo.
In a double-blind study in patients with PAH, macitentan 10 mg was associated with a mean decrease in haemoglobin versus placebo of 1 g/dL. A decrease from baseline in haemoglobin concentration to below 10 g/dL was reported in 8.7% of patients treated with macitentan 10 mg and 3.4% of placebo-treated patients.
In a double-blind study in patients with PAH, macitentan 10 mg was associated with a decrease in mean leucocyte count from baseline of 0.7 × 109/L versus no change in placebo-treated patients.
In a double-blind study in 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.
The safety of macitentan in children and adolescents below 18 years has not yet been established.
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 Appendix V.
Not applicable.
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