Opsumit

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
  



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1. NAME OF THE MEDICINAL PRODUCT 
 
Opsumit 10 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 10 mg macitentan. 
 
Excipients with known effect  
Each film-coated tablet contains approximately 37 mg of lactose (as monohydrate) and approximately 
0.06 mg of soya bean lecithin (E322). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet). 
 
5.5 mm, round, biconvex, white to off-white film-coated tablets, debossed with “10” on both sides. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Opsumit, as monotherapy or in combination, is indicated for the long-term treatment of pulmonary 
arterial hypertension (PAH) in adult patients of WHO Functional Class (FC) II to III. 
 
Efficacy has been shown in a PAH population including idiopathic and heritable PAH, PAH 
associated with connective tissue disorders, and PAH associated with corrected simple congenital 
heart disease (see section 5.1). 
 
4.2 Posology and method of administration 
 
Treatment should only be initiated and monitored by a physician experienced in the treatment of PAH. 
 
Posology 
 
The recommended dose is 10 mg once daily. 
 
Special populations 
 
Elderly 
 
No dose adjustment is required in patients over the age of 65 years (see section 5.2). There is limited 
clinical experience in patients over the age of 75 years. Therefore, Opsumit should be used with 
caution in this population (see section 4.4). 
 
Hepatic impairment 
 
Based on pharmacokinetic (PK) data, no dose adjustment is required in patients with mild, moderate 
or severe hepatic impairment (see sections 4.4 and 5.2). However, there is no clinical experience with 
the use of macitentan in PAH patients with moderate or severe hepatic impairment. Opsumit must not 



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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); see sections 4.3 and 
4.4).  
 
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. The use 
of Opsumit is not recommended in patients undergoing dialysis (see sections 4.4 and 5.2). 
 
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 the 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 regularly 
scheduled time. The patient should be told not to take two doses at the same time if a dose has been 
missed. 
 
4.3 Contraindications 
 
• Hypersensitivity to the active substance, soya or to any of the excipients listed in section 6.1. 
• Pregnancy (see section 4.6). 
• Women of childbearing potential who are not using reliable contraception (see sections 4.4 and 

4.6). 
• Breastfeeding (see section 4.6). 
• Patients with severe hepatic impairment (with or without cirrhosis) (see section 4.2). 
• Baseline values of hepatic aminotransferases (aspartate aminotransferases (AST) and/or alanine 

aminotransferases (ALT) > 3 × ULN) (see sections 4.2 and 4.4). 
 
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. 



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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 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). 
 
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. 
 



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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’. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
In vitro studies 
 
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). 
 
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 (see section 4.4). 
 
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 (see section 4.4). 
 
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. 
 



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Cyclosporine A: 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. 
 
Hormonal contraceptives: Macitentan 10 mg once daily did not affect the pharmacokinetics of an oral 
contraceptive (norethisterone 1 mg and ethinyl estradiol 35 µg). 
 
Breast cancer resistance protein (BCRP) substrate drugs: Macitentan 10 mg once daily did not affect 
the pharmacokinetics of a BCRP substrate drug (riociguat 1 mg; rosuvastatin 10 mg). 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, pregnancy, and lactation 
 
Use in women of childbearing potential/Contraception in males and females 
 
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. 
 
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). 
 
Breastfeeding 
 
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). 
 
Male fertility 
 
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. 
 
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).  
 
4.8 Undesirable effects 
 
Summary of the safety profile. 
 
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. 
 



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Tabulated list of adverse reactions 
 
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).  
 

System organ class Frequency Adverse reaction 

Infections and infestations Very common Nasopharyngitis 

 Very common Bronchitis 

 Common Pharyngitis 

 Common Influenza 

 Common Urinary tract infection 

Blood and lymphatic system 
disorders 

Very common Anaemia, haemoglobin 
decrease5 

 Common Leukopenia6 

 Common Thrombocytopenia7 

Hepatobiliary disorders Common Aminotransferase elevations4  

Immune system disorders Uncommon Hypersensitivity reactions (e.g., 
angioedema, pruritus, rash)1 

Nervous system disorders Very common Headache 

Vascular disorders Common Hypotension2 

Respiratory, thoracic and 
mediastinal disorders 

Common Nasal congestion1 

General disorders and 
administration site conditions 

Very common Oedema, fluid retention3 

1 Data derived from pooled placebo-controlled studies. 
 
Description of selected adverse reactions 
 
2 Hypotension has been associated with the use of ERAs including macitentan. In a long-term double-
blind 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 long-
term 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 



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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. 
 
Laboratory abnormalities 
 
4 Liver aminotransferases 
 
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. 
 
5 Haemoglobin 
 
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. 
 
6 White blood cells 
 
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.  
 
7 Platelets 
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. 
 
Paediatric population 
 
The safety of macitentan in children and adolescents below 18 years has not yet been established. 
 
Reporting of suspected adverse reactions 
 
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. 
 
4.9 Overdose 
 
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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: anti-hypertensives, anti-hypertensives for pulmonary arterial 
hypertension. ATC code: C02KX04. 
 
Mechanism of action 
 
Endothelin (ET)-1 and its receptors (ETA and ETB) mediate a variety of effects such as 
vasoconstriction, fibrosis, proliferation, hypertrophy, and inflammation. In disease conditions such as 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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PAH, the local ET system is upregulated and is involved in vascular hypertrophy and in organ 
damage. 
 
Macitentan is an orally active potent endothelin receptor antagonist, active on both ETA and ETB 
receptors and approximately 100-fold more selective for ETA as compared to ETB in vitro. Macitentan 
displays high affinity and sustained occupancy of the ET receptors in human pulmonary arterial 
smooth muscle cells. This prevents endothelin-mediated activation of second messenger systems that 
result in vasoconstriction and smooth muscle cell proliferation. 
 
Clinical efficacy and safety 
 
Efficacy in patients with pulmonary arterial hypertension 
 
A multicenter, double-blind, placebo-controlled, parallel-group, event-driven, Phase 3 outcome study 
(AC-055-302/SERAPHIN) was conducted in 742 patients with symptomatic PAH, who were 
randomised to three treatment groups (placebo [N = 250], 3 mg [N = 250] or 10 mg [N = 242] of 
macitentan once daily), to assess the long-term effect on morbidity or mortality. 
 
At baseline, the majority of enrolled patients (64%) were treated with a stable dose of specific therapy 
for PAH, either oral phosphodiesterase inhibitors (61%) and/or inhaled/oral prostanoids (6%). 
 
The primary endpoint was the time to first occurrence of a morbidity or mortality event, up to the end 
of double-blind treatment, defined as death, or atrial septostomy, or lung transplantation, or initiation 
of intravenous (i.v.) or subcutaneous (s.c.) prostanoids, or other worsening of PAH. Other worsening 
of PAH was defined as the presence of all of the three following components: a sustained decrease in 
6-minute walk distance (6MWD) of at least 15% from baseline; worsening of PAH symptoms 
(worsening of WHO FC or right heart failure); and need for new treatment for PAH. All events were 
confirmed by an independent adjudication committee, blinded to treatment allocation. 
 
All patients were followed up to end-of-study (EOS) for vital status. EOS was declared when the 
predefined number of primary endpoint events was reached. In the period between end-of-treatment 
(EOT) and EOS, patients could receive open-label macitentan 10 mg or alternative PAH therapy. The 
overall median double-blind treatment duration was 115 weeks (up to a maximum of 188 weeks on 
macitentan). 
 
The mean age of all patients was 46 years (range 12–85 years of age, including 20 patients below 18, 
706 patients between 18–74 years, and 16 patients aged 75 and older) with the majority of subjects 
being Caucasian (55%) and female (77%). Approximately 52%, 46%, and 2% of patients were in 
WHO FC II, III, and IV, respectively. 
 
Idiopathic or heritable PAH was the most common aetiology in the study population (57%), followed 
by PAH due to connective tissue disorders (31%), PAH associated with corrected simple congenital 
heart disease (8%), and PAH associated with other aetiologies (medicinal products and toxins [3%] 
and HIV [1%]). 
 
Outcome endpoints 
 
Treatment with macitentan 10 mg resulted in a 45% risk reduction (hazard ratio [HR] 0.55; 97.5% CI: 
0.39 to 0.76; logrank p < 0.0001) of the composite morbidity-mortality endpoint up to EOT when 
compared to placebo [Figure 1 and Table 1]. The treatment effect was established early and was 
sustained. 
 
Efficacy of macitentan 10 mg on the primary endpoint was consistent across subgroups of age, sex, 
ethnic origin, geographical region, aetiology, by monotherapy or in combination with another PAH 
therapy and by WHO FC (I/II and III/IV). 
  



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Figure 1 Kaplan-Meier estimates of the first morbidity-mortality event in SERAPHIN 

 
 
Table 1 Summary of outcome events 

Endpoints 
& statistics 

Patients with events Treatment comparison:  
macitentan 10 mg vs placebo 

Placebo 

(N = 250) 

Macitentan 
10 mg  

(N = 242) 

Absolute 
risk 

reduction 

Relative risk 
reduction 

(97.5% CI) 
HR a 

(97.5% CI) 
Logrank 
p-value 

Morbidity-
mortality 
event b 

 
53% 37% 16% 45% (24%; 61%)  

0.55 
(0.39; 0.76) < 0.0001 

Death c 

n (%) 
19 (7.6%) 14 (5.8%) 2% 36% (−42%; 71%) 

0.64 
(0.29; 1.42) 0.20 

Worsening 
of PAH   
n (%) 

93 (37.2%) 59 (24.4%) 13% 
49% 

(27%; 65%) 
 

0.51 
(0.35; 0.73) < 0.0001 i.v./s.c. prostanoid 

initiation  
n (%) 

6 (2.4%) 1 (0.4%) 2% 

a = based on Cox’s Proportional Hazards Model 
b = % of patients with an event at 36 months = 100 × (1 - KM estimate) 
c= all cause death up to EOT regardless of prior worsening 

 
The number of deaths of all causes up to EOS on macitentan 10 mg was 35 versus 44 on placebo (HR 
0.77; 97.5% CI: 0.46 to 1.28). 
 
The risk of PAH-related death or hospitalisation for PAH up to EOT was reduced by 50% (HR 0.50; 
97.5% CI: 0.34 to 0.75; logrank p < 0.0001) in patients receiving macitentan 10 mg (50 events) 
compared to placebo (84 events). At 36 months, 44.6% of patients on placebo and 29.4% of patients 



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on macitentan 10 mg (Absolute Risk Reduction = 15.2%) had been hospitalised for PAH or died from 
a PAH-related cause. 
 
Symptomatic endpoints 
 
Exercise capacity was evaluated as a secondary endpoint. Treatment with macitentan 10 mg at 
Month 6 resulted in a placebo-corrected mean increase in 6MWD of 22 meters (97.5% CI: 3 to 41; 
p = 0.0078). Evaluation of 6MWD by functional class resulted in a placebo-corrected mean increase 
from baseline to Month 6 in FC III/IV patients of 37 meters (97.5% CI: 5 to 69) and in FC I/II of 12 
meters (97.5% CI: −8 to 33). The increase in 6MWD achieved with macitentan was maintained for the 
duration of the study. 
 
Treatment with macitentan 10 mg at Month 6 led to a 74% higher chance of WHO FC improvement 
relative to placebo (risk ratio 1.74; 97.5% CI: 1.10 to 2.74; p = 0.0063).  
 
Macitentan 10 mg improved quality of life assessed by the SF-36 questionnaire.  
 
Haemodynamic endpoints 
 
Haemodynamic parameters were assessed in a subset of patients (placebo [N = 67], macitentan 10 mg 
[N = 57]) after 6 months of treatment. Patients treated with macitentan 10 mg achieved a median 
reduction of 36.5% (97.5% CI: 21.7 to 49.2%) in pulmonary vascular resistance and an increase of 
0.58 L/min/m2 (97.5% CI: 0.28 to 0.93 L/min/m2) in cardiac index compared to placebo.   
 
Paediatric population 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
macitentan in all subsets of the paediatric population for PAH (see section 4.2 for information on 
paediatric use). 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of macitentan and its active metabolite have mainly been documented in 
healthy subjects. Exposure to macitentan in patients with PAH was approximately 1.2-fold greater 
than in healthy subjects. The exposure to the active metabolite in patients, which is approximately 
5-fold less potent than macitentan, was approximately 1.3-fold higher than in healthy subjects. The 
pharmacokinetics of macitentan in PAH patients were not influenced by the severity of the disease. 
 
After repeated administration, the pharmacokinetics of macitentan are dose-proportional up to and 
including 30 mg. 
 
Absorption 
 
Maximum plasma concentrations of macitentan are achieved about 8 hours after administration. 
Thereafter, plasma concentrations of macitentan and its active metabolite decrease slowly, with an 
apparent elimination half-life of approximately 16 hours and 48 hours, respectively. 
 
In healthy subjects, the exposure to macitentan and its active metabolite is unchanged in the presence 
of food and, therefore, macitentan may be taken with or without food. 
 
Distribution 
 
Macitentan and its active metabolite are highly bound to plasma proteins (> 99%), primarily to 
albumin and to a lesser extent to alpha1-acid glycoprotein. Macitentan and its active metabolite 
ACT-132577 are well distributed into tissues as indicated by an apparent volume of distribution 
(Vss/F) of approximately 50 L and 40 L for macitentan and ACT-132577, respectively. 
 



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Biotransformation  
 
Macitentan has four primary metabolic pathways. Oxidative depropylation of the sulfamide yields a 
pharmacologically active metabolite. This reaction is dependent on the cytochrome P450 system, 
mainly CYP3A4 (approximately 99%) with minor contributions of CYP2C8, CYP2C9 and CYP2C19. 
The active metabolite circulates in human plasma and may contribute to the pharmacological effect. 
Other metabolic pathways yield products without pharmacological activity. Several members of the 
CYP2C family, namely CYP2C8, CYP2C9 and CYP2C19, as well as CYP3A4, are involved in the 
formation of these metabolites. 
 
Elimination 
 
Macitentan is only excreted after extensive metabolism. The major excretion route is via urine, 
accounting for about 50% of the dose. 
 
Special populations 
 
There is no clinically relevant effect of age, sex or ethnic origin on the pharmacokinetics of macitentan 
and its active metabolite. 
 
Renal impairment 
 
Exposure to macitentan and its active metabolite was increased by 1.3- and 1.6-fold, respectively, in 
patients with severe renal impairment. This increase is not considered clinically relevant (see sections 
4.2 and 4.4). 
 
Hepatic impairment 
 
Exposure to macitentan was decreased by 21%, 34%, and 6% and, for the active metabolite by 20%, 
25%, and 25% in subjects with mild, moderate or severe hepatic impairment, respectively. This 
decrease is not considered clinically relevant (see sections 4.2 and 4.4). 
 
5.3 Preclinical safety data 
 
In dogs, macitentan decreased blood pressure at exposures similar to the therapeutic human exposure. 
Intimal thickening of coronary arteries was observed at 17-fold the human exposure after 4 to 39 
weeks of treatment. Due to the species-specific sensitivity and the safety margin, this finding is 
considered not relevant for humans. 
 
Increased liver weight and hepatocellular hypertrophy were observed in mice, rats and dogs after 
treatment with macitentan. These changes were largely reversible and considered non-adverse 
adaptations of the liver to increased metabolic demand. 
 
Macitentan induced minimal to slight mucosal hyperplasia and inflammatory infiltration in the 
submucosa of the nasal cavity in the mouse carcinogenicity study at all doses. No nasal cavity findings 
were noted in the 3-month mouse toxicity study or in rat and dog studies. 
 
Macitentan was not genotoxic in a standard battery of in vitro and in vivo assays. Macitentan was not 
phototoxic in vivo after single dose at exposures of up to 24-fold the human exposure.  
Carcinogenicity studies of 2 years’ duration did not reveal a carcinogenic potential at exposures 
18-fold and 116-fold the human exposure in rats and mice, respectively. 
 
Testicular tubular dilatation was observed in chronic toxicity studies with male rats and dogs with 
safety margins of 11.6 and 5.8, respectively. Tubular dilatation was fully reversible. After 2 years of 
treatment, testicular tubular atrophy was seen in rats at 4-fold the human exposure. 
Hypospermatogenesis was observed in the life-long carcinogenicity study in rats and in the repeat-
dose toxicity studies in dogs at exposures that provide safety margins of 9.7 in rats and 23 in dogs. The 



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safety margins for fertility were 18 for male and 44 for female rats. No testicular findings were noted 
in mice after treatment up to 2 years. The effect of macitentan on human male fertility is not known 
(see section 4.6). 
 
Macitentan was teratogenic in rabbits and rats at all doses tested. In both species there were 
cardiovascular and mandibular arch fusion abnormalities. 
 
Administration of macitentan to female rats from late pregnancy through lactation at maternal 
exposures 5-fold the human exposure, caused reduced pup survival and impairment of the 
reproductive capability of the offspring, which was exposed to macitentan during late intrauterine life 
and via the milk during the suckling period. 
 
Treatment of juvenile rats from postnatal Day 4 to Day 114 caused reduced body weight gain leading 
to secondary effects on development (slight delay of descensus testis, reversible reduction of 
long-bone length, prolonged estrous cycle). Slightly increased pre- and post-implantation loss, 
decreased mean number of pups, and decreased testis and epididymis weights, were observed at 
exposures 7-fold the human exposure. Testicular tubular atrophy, and minimal effects on reproductive 
variables and sperm morphology were recorded at exposures 3.8-fold the human exposure. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Lactose monohydrate 
Microcrystalline cellulose (E460i) 
Sodium starch glycolate Type A 
Povidone K-30 
Magnesium stearate (E572) 
Polysorbate 80 (E433) 
 
Film coating 
Poly(vinyl-alcohol) (E1203) 
Titanium dioxide (E171) 
Talc (E553b) 
Soya bean lecithin (E322) 
Xanthan gum (E415) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
5 years. 
 
6.4 Special precautions for storage 
 
Do not store above 30°C. 
 
6.5 Nature and contents of container 
 
White, opaque PVC/PE/PVdC/Aluminium blisters in cartons containing 15 or 30 film-coated tablets. 
 
White high-density polyethylene (HDPE) bottles with child-resistant closure and a silica gel desiccant. 
Cartons containing 1 bottle of 30 film-coated tablets. 



14 

 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Janssen-Cilag International NV 
Turnhoutseweg 30 
B 2340 Beerse 
Belgium 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/893/001 
 
EU/1/13/893/002 
 
EU/1/13/893/003 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 20 December 2013 
Date of latest renewal: 23 August 2018 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
  

http://www.ema.europa.eu/


15 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 



16 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Actelion Manufacturing GmbH 
Emil-Barell-Strasse 7 
79639 Grenzach-Wyhlen 
Germany 
 
Janssen Pharmaceutica NV 
Turnhoutseweg 30 
B-2340 Beerse 
Belgium 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The  requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance 
activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the 
marketing authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
• Additional risk minimisation measures 
 
The MAH shall agree the details of the Prescriber kit and a controlled distribution system with 
the National Competent Authority and implement it prior to launch in that Member State. The 
MAH shall ensure that prior to prescribing all healthcare professionals who intend to prescribe 
and/or dispense Opsumit are provided with a Prescriber Kit containing the following: 
 
 



17 

• The Summary of Product Characteristics for Opsumit; 
• Prescribing checklists; 
• Healthcare Professional brochure containing information about Opsumit; 
• Patient reminder cards. 

 
The Prescribing Checklist should remind prescribers of the contraindications, warnings and 
precautions as well as the following key elements: 

• To provide patients with appropriate information regarding the safe use of the 
product; 

• To ensure females of childbearing potential are not pregnant and are on reliable 
contraception prior to starting Opsumit; 

• To provide patients with the patient card; 
• The need for baseline and monthly pregnancy tests and monitoring of haemoglobin 

levels and liver function. 
 
The Healthcare Professionals brochure should contain the following key elements: 

• That patients should be capable of complying with the requirements for the safe 
use of Opsumit; 

• The risk of anaemia, hepatotoxicity and teratogenicity and the need for reliable 
contraception; 

• The need for baseline and: 
• monthly pregnancy tests; 
• regular monitoring of haemoglobin levels; 
• regular monitoring of liver function; 

• The importance of telling patients to report immediately any possible pregnancy 
that occurs during Opsumit use. 

 
The Patient Reminder Card for patients prescribed Opsumit should include the following key 
elements: 

• That Opsumit is teratogenic in animals; 
• That pregnant women must not take Opsumit; 
• That women of childbearing potential must use reliable contraception; 
• The need for monthly pregnancy tests; 
• The need for regular blood tests because Opsumit causes a decrease in 

haemoglobin;  
• The need for regular monitoring of liver function because Opsumit has hepatotoxic 

potential. 
  



18 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



20 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON for BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Opsumit 10 mg film-coated tablets 
 
macitentan 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 10 mg macitentan 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains lactose and soya bean lecithin (E322). See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
15 film-coated tablets 
 
30 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C 
 
 



21 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Janssen-Cilag International NV 
Turnhoutseweg 30 
B 2340 Beerse 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/893/001 
 
EU/1/13/893/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Opsumit 10 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
 
  



22 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Opsumit 10 mg tablets 
 
macitentan 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Janssen-Cilag Int 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER, DONATION AND PRODUCT CODES 
 
Lot 
 
 
5. OTHER 
 
 
  



23 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
OUTER CARTON/BOTTLE 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Opsumit 10 mg film-coated tablets 
 
macitentan 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 10 mg macitentan 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains lactose and soya bean lecithin (E322). See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C 
 
 



24 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Janssen-Cilag International NV 
Turnhoutseweg 30 
B 2340 Beerse 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/13/893/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Opsumit 10 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
 



25 

Patient Card 
 
Page 1 (front) Page 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 

Page 3 (inside left) Page 4 (inside centre) 
 
 
 
 
 
 

 

 
 
 
 
 
 
 

 
Page 5 (inside right)     Page 6 (back) 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

Pregnancy 
Opsumit may harm the development of the foetus. Therefore you must 
not take Opsumit if you are pregnant and you must also not become 
pregnant while taking Opsumit. Moreover, if you are suffering from 
pulmonary arterial hypertension, the occurrence of a pregnancy can 
severely deteriorate the symptoms of your disease.  
 
Contraception 
You need to use a reliable form of birth control (contraception) while 
you are taking Opsumit. Be sure to discuss any questions you may have 
with your doctor.  
 

 
You should have a pregnancy test before initiation of Opsumit and every 
month during treatment even if you think that you are not pregnant. 
 
Like other medicines of this class, Opsumit can induce anaemia (a 
reduced number of red blood cells) and can have effects on the liver. 
Your doctor will take blood test before you start treatment with Opsumit 
and during treatment to test: 
 
• whether you have anaemia (a reduced number of red blood 

cells) 
 

• whether your liver is working properly 
 

 
Signs that your liver may not be working properly include: 
• nausea (urge to vomit) 
• vomiting 
• fever (high temperature) 
• pain in your stomach (abdomen) 
• jaundice (yellowing of your skin or the whites of your eyes) 
• dark-coloured urine 
• itching of your skin 
• lethargy or fatigue (unusual tiredness or exhaustion) 
• flu-like syndrome (joint and muscle pain with fever) 

 
If you notice any of these signs, tell your doctor immediately. 
 

The recommended dose of Opsumit is one 10 mg tablet, once a day. 
Swallow the whole tablet, with a glass of water, do not chew or break 
the tablet. You can take Opsumit with or without food. 
 
If you forget to take Opsumit, take a dose as soon as you remember, 
then continue to take your tablets at the usual times. Do not take a 
double dose to make up for a forgotten tablet. 
 
For more information on Opsumit, please read carefully the patient 
information leaflet. 
If you have any question about your treatment, ask your doctor or 
pharmacist. 
 

©2013 Actelion Pharmaceuticals Ltd 
Opsumit is a registered trademark of Actelion Pharmaceuticals Ltd 

 

For the treatment of pulmonary arterial hypertension 
 

This card contains important safety information you need to be aware of 
when receiving treatment with Opsumit. Carry this card with you at all 
times and show it to any doctor involved in your medical care. 

 
 

Opsumit® 10 mg 
macitentan 

film-coated tablets                             
 
 
 
 
       EN 

It is important that you report immediately to your prescribing 
doctor pregnancy or any side effects that may occur during 
treatment with Opsumit. 
 
Treatment centre: ____________________________________ 
 
Name of prescribing doctor: ___________________________ 
 
Phone number of prescribing doctor: _____________________ 
 
 
 



26 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
  



27 

Package leaflet: information for the user 
 

Opsumit 10 mg film-coated tablets 
macitentan 

 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.  
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Opsumit is and what it is used for 
2. What you need to know before you take Opsumit 
3. How to take Opsumit 
4. Possible side effects 
5. How to store Opsumit 
6. Contents of the pack and other information 
 
 
1. What Opsumit is and what it is used for 
 
Opsumit contains the active substance macitentan, which belongs to the class of medicines called 
“endothelin receptor antagonists”. 
 
Opsumit is used for the long-term treatment of pulmonary arterial hypertension (PAH) in adults; it can 
be used on its own or with other medicines for PAH. PAH is high blood pressure in the blood vessels 
that carry blood from the heart to the lungs (the pulmonary arteries). In people with PAH, these 
arteries get narrower, so the heart has to work harder to pump blood through them. This causes people 
to feel tired, dizzy, and short of breath. 
 
Opsumit widens the pulmonary arteries, making it easier for the heart to pump blood through them. 
This lowers the blood pressure, relieves the symptoms and improves the course of the disease. 
 
 
2. What you need to know before you take Opsumit 
 
Do not take Opsumit 
• if you are allergic to macitentan, soya or any of the other ingredients of this medicine (listed in 

section 6). 
• if you are pregnant, if you are planning to become pregnant, or if you could become pregnant 

because you are not using reliable birth control (contraception). See section ‘Pregnancy and 
breastfeeding’. 

• if you are breastfeeding. See section ‘Pregnancy and breastfeeding’. 
• if you have liver disease or if you have very high levels of liver enzymes in your blood. Talk to 

your doctor, who will decide whether this medicine is suitable for you. 
 
If any of these apply to you, please tell your doctor. 
 
Warnings and precautions  
 
Talk to your doctor or pharmacist before taking Opsumit. 



28 

 
You will need blood tests, as indicated by your doctor: 
Your doctor will take blood test before you start treatment with Opsumit and during treatment to test: 
• whether you have anaemia (a reduced number of red blood cells) 
• whether your liver is working properly 
 
If you have anaemia (a reduced number of red blood cells), you may have the following signs: 
• dizziness  
• fatigue/malaise/weakness 
• fast heart rate, palpitations 
• pallor 

 
If you notice any of these signs, tell your doctor. 
 
Signs that your liver may not be working properly include: 
• feeling sick (nausea) 
• vomiting 
• fever  
• pain in your stomach (abdomen) 
• yellowing of your skin or the whites of your eyes (jaundice) 
• dark-coloured urine 
• itching of your skin 
• unusual tiredness or exhaustion (lethargy or fatigue) 
• flu-like syndrome (joint and muscle pain with fever) 
 
If you notice any of these signs, tell your doctor immediately. 
 
If you have kidney problems, talk to your doctor before using Opsumit. Macitentan may lead to more 
reduction of blood pressure and decrease in haemoglobin in patients with kidney problems. 
 
In patients with pulmonary veno-occlusive disease (obstruction of the lung veins), the use of 
medicines for treatment of PAH, including Opsumit, may lead to pulmonary oedema. If you have 
signs of pulmonary oedema when using Opsumit, such as a sudden, important increase in 
breathlessness and low oxygen, tell your doctor immediately. Your doctor may perform additional 
tests, and will determine what treatment regimen is most suitable for you. 
 
Children and adolescents 
Do not give this medicine to children and adolescents below 18 years because Opsumit has not been 
tested in children. 
 
Elderly 
There is limited experience with Opsumit in patients older than 75 years. Opsumit should be used with 
caution in this age group. 
 
Other medicines and Opsumit 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicine. 
Opsumit can affect other medicines. 
 
If you take Opsumit together with other medicines including those listed below, the effects of Opsumit 
or the other medicines might be altered. Please talk to your doctor or pharmacist if you are taking any 
of the following medicines: 
 
• rifampicin, clarithromycin, telithromycin (antibiotics used to treat infections), 
• phenytoin (a medicine used to treat seizures), 
• carbamazepine (used to treat depression and epilepsy), 
• St. John’s Wort (an herbal preparation used to treat depression), 



29 

• ritonavir, saquinavir (used to treat HIV infections), 
• nefazodone (used to treat depression), 
• ketoconazole (except shampoo), itraconazole, voriconazole (medicines used against fungal 

infections) 
 
Pregnancy and breastfeeding 
If you are pregnant or breastfeeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before taking this medicine. 
 
Opsumit may harm unborn babies conceived before, during or soon after treatment. 
 
• If it is possible you could become pregnant, use a reliable form of birth control (contraception) 

while you are taking Opsumit. Talk to your doctor about this. 
• Do not take Opsumit if you are pregnant or planning to become pregnant. 
• If you become pregnant or think that you may be pregnant while you are taking Opsumit, or 

shortly after stopping Opsumit (up to 1 month), see your doctor immediately. 
 
If you are a woman who could become pregnant, your doctor will ask you to take a pregnancy test 
before you start taking Opsumit and regularly (once a month) while you are taking Opsumit. 
 
It is not known if Opsumit is transferred to breast milk. Do not breastfeed while you are taking 
Opsumit. Talk to your doctor about this. 
 
Driving and using machines 
Opsumit can cause side effects such as headaches and hypotension (listed in section 4), and the 
symptoms of your condition can also make you less fit to drive. 
 
Opsumit contains lactose, lecithin from soya and sodium 
Opsumit contains a sugar called lactose. If you have been told by your doctor that you have an 
intolerance to some sugars, contact your doctor before taking this medicine. 
 
Opsumit contains lecithin derived from soya. If you are allergic to soya, do not use this medicine (see 
section 2 ‘Do not take Opsumit’). 
 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 
‘sodium-free’. 
 
 
3. How to take Opsumit 
 
Opsumit should only be prescribed by a doctor experienced in the treatment of pulmonary arterial 
hypertension. 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure. 
 
The recommended dose of Opsumit is one 10 mg tablet, once a day. Swallow the whole tablet, with a 
glass of water, do not chew or break the tablet. You can take Opsumit with or without food. It is best 
to take the tablet at the same time each day. 
 
If you take more Opsumit than you should 
If you have taken more tablets than you have been told to take, you may experience headache, nausea, 
or vomiting. Ask your doctor for advice. 
 
If you forget to take Opsumit 
If you forget to take Opsumit, take a dose as soon as you remember, then continue to take your tablets 
at the usual times. Do not take a double dose to make up for a forgotten tablet. 



30 

 
If you stop taking Opsumit 
Opsumit is a treatment that you will need to keep on taking to control your PAH. Do not stop taking 
Opsumit unless you have agreed this with your doctor.  
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Uncommon side effects (may affect up to 1 in 100 people) 
• Allergic reactions (swelling around the eyes, face, lips, tongue or throat, itching and/or rash) 
If you notice any of these signs, tell your doctor immediately. 
 
Very common side effects (may affect more than 1 in 10 people) 
• Anaemia (low number of red blood cells) or reduced haemoglobin 
• Headache 
• Bronchitis (inflammation of the airways) 
• Nasopharyngitis (inflammation of the throat and nasal passages) 
• Oedema (swelling), especially of the ankles and feet 
 
Common side effects (may affect up to 1 in 10 people) 
• Pharyngitis (inflammation of the throat) 
• Influenza (flu) 
• Urinary tract infection (bladder infection) 
• Hypotension (low blood pressure) 
• Nasal congestion (blocked nose)  
• Elevated liver tests 
• Leukopenia (decreased white blood cell counts) 
• Thrombocytopenia (decreased blood platelet counts) 

 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Opsumit 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use Opsumit after the expiry date which is stated on the carton, bottle and blister after “EXP”. 
The expiry date refers to the last day of that month. 
 
Do not store above 30°C. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer require. These measures will help to protect the environment. 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


31 

6. Contents of the pack and other information 
 
What Opsumit contains  

- The active substance is macitentan. Each tablet contains 10 mg macitentan. 
 

- The other ingredients are lactose monohydrate (see section 2 “Opsumit contains lactose, 
lecithin from soya and sodium”), microcrystalline cellulose (E460i), povidone, sodium starch 
glycolate Type A (see section 2 “Opsumit contains lactose, lecithin from soya and sodium”), 
magnesium stearate (E572), polysorbate 80 (E433), polyvinyl alcohol (E1203), titanium 
dioxide (E171), talc (E553b), soya bean lecithin (E322) (see section 2 “Opsumit contains 
lactose, lecithin from soya and sodium”) and xanthan gum (E415). 

 
What Opsumit looks like and contents of the pack 
Opsumit 10 mg tablets are white to off-white, biconvex, round, film-coated tablets with “10” on both 
sides. 
 
Opsumit is supplied as 10 mg film-coated tablets in blister packs of 15 or 30 tablets, or in bottles of 30 
tablets. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Janssen-Cilag International NV 
Turnhoutseweg 30 
B 2340 Beerse 
Belgium 
 
Manufacturer 
Actelion Manufacturing GmbH 
Emil-Barell-Strasse 7 
79639 Grenzach-Wyhlen 
Germany 
 
Janssen Pharmaceutica NV 
Turnhoutseweg 30 
B-2340 Beerse 
Belgium 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 

België/Belgique/Belgien 
Actelion, a division of Janssen-Cilag International 
NV 
Tél/Tel: +32 14 64 94 11 
janssen@jacbe.jnj.com 
 

Lietuva 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +370 5 278 68 88 
lt@its.jnj.com 
 

България 
Actelion, a division of Janssen-Cilag International 
NV 
Тел.: +359 2 489 94 00 
jjsafety@its.jnj.com 
 

Luxembourg/Luxemburg 
Actelion, a division of Janssen-Cilag International 
NV 
Tél/Tel: +32 14 64 94 11 
janssen@jacbe.jnj.com 
 



32 

Česká republika 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +420 227 012 227 
 

Magyarország 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +36 1 884 2858 
janssenhu@its.jnj.com 
 

Danmark 
Actelion, a division of Janssen-Cilag International 
NV 
Tlf: +45 4594 8282 
jacdk@its.jnj.com 
 

Malta 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +356 2397 6000 
 

Deutschland 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +49 2137 955 955 
jancil@its.jnj.com 
 

Nederland 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +31 76 711 1111 
janssen@jacnl.jnj.com 
 

Eesti 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +372 617 7410 
ee@its.jnj.com 
 

Norge 
Actelion, a division of Janssen-Cilag International 
NV 
Tlf: +47 24 12 65 00 
jacno@its.jnj.com 
 

Ελλάδα 
Actelion, a division of Janssen-Cilag International 
NV 
Τηλ: +30 210 675 25 00  
 

Österreich 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +43 1 505 4527 
 

España 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +34 91 722 81 00  
contacto@its.jnj.com 
 

Polska 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +48 22 237 60 00 
 

France 
Actelion, a division of Janssen-Cilag International 
NV 
Tél: 0 800 25 50 75 / +33 1 55 00 40 03 
medisource@its.jnj.com 
 

Portugal 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +351 214 368 600 
 

Hrvatska 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +385 1 6610 700 
jjsafety@JNJCR.JNJ.com 
 

România 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +40 21 207 1800 
 

Ireland 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +353 1 800 709 122 
 

Slovenija 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +386 1 401 18 00 
Janssen_safety_slo@its.jnj.com 
 



33 

Ísland 
Actelion, a division of Janssen-Cilag International 
NV 
Sími: +354 535 7000 
janssen@vistor.is 
 

Slovenská republika 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +421 232 408 400 
 

Italia 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: 800.688.777 / +39 02 2510 1 
janssenita@its.jnj.com 
 

Suomi/Finland 
Actelion, a division of Janssen-Cilag International 
NV 
Puh/Tel: +358 207 531 300 
jacfi@its.jnj.com 
 

Κύπρος 
Actelion, a division of Janssen-Cilag International 
NV 
Τηλ: +30 210 675 25 00 
 

Sverige 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: ++46 8 626 50 00 
jacse@its.jnj.com 
 

Latvija 
Actelion, a division of Janssen-Cilag International 
NV 
Tel: +371 678 93561 
lv@its.jnj.com 
 

United Kingdom 
Janssen-Cilag Ltd. 
Tel: +44 1 494 567 444 
 

 
This leaflet was last revised in 
 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET