Adempas

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



2 

 
1. NAME OF THE MEDICINAL PRODUCT 
 
Adempas 0.5 mg film-coated tablets 
Adempas 1 mg film-coated tablets 
Adempas 1.5 mg film-coated tablets 
Adempas 2 mg film-coated tablets 
Adempas 2.5 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Adempas 0.5 mg film-coated tablets 
Each film-coated tablet contains 0.5 mg of riociguat. 
 
Adempas 1 mg film-coated tablets 
Each film-coated tablet contains 1 mg of riociguat. 
 
Adempas 1.5 mg film-coated tablets 
Each film-coated tablet contains 1.5 mg of riociguat. 
 
Adempas 2 mg film-coated tablets 
Each film-coated tablet contains 2 mg of riociguat. 
 
Adempas 2.5 mg film-coated tablets 
Each film-coated tablet contains 2.5 mg of riociguat. 
 
Excipient with known effect 
 
Adempas 0.5 mg film-coated tablets 
Each 0.5 mg film-coated tablet contains 37.8 mg lactose (as monohydrate). 
 
Adempas 1 mg film-coated tablets 
Each 1 mg film-coated tablet contains 37.2 mg lactose (as monohydrate). 
 
Adempas 1.5 mg film-coated tablets 
Each 1.5 mg film-coated tablet contains 36.8 mg lactose (as monohydrate). 
 
Adempas 2 mg film-coated tablets 
Each 2 mg film-coated tablet contains 36.3 mg lactose (as monohydrate). 
 
Adempas 2.5 mg film-coated tablets 
Each 2.5 mg film-coated tablet contains 35.8 mg lactose (as monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet). 
 0.5 mg tablet: white, round, biconvex tablets of 6 mm, marked with the Bayer cross on one side 
and 0.5 and an “R” on the other side.  
 1 mg tablet: pale yellow, round, biconvex tablets of 6 mm, marked with the Bayer cross on one 

side and 1 and an “R” on the other side.  
 1.5 mg tablet: yellow-orange, round, biconvex tablets of 6 mm, marked with the Bayer cross on 

one side and 1.5 and an “R” on the other side.  



3 

 2 mg tablet: pale orange, round, biconvex tablets of 6 mm, marked with the Bayer cross on one 
side and 2 and an “R” on the other side.  

 2.5 mg tablet: red-orange, round, biconvex tablets of 6 mm, marked with the Bayer cross on one 
side and 2.5 and an “R” on the other side.  

 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Chronic thromboembolic pulmonary hypertension (CTEPH) 
 
Adempas is indicated for the treatment of adult patients with WHO Functional Class (FC) II to III with 
 inoperable CTEPH,  
 persistent or recurrent CTEPH after surgical treatment, 
 to improve exercise capacity (see section 5.1).  
 
Pulmonary arterial hypertension (PAH) 
 
Adempas, as monotherapy or in combination with endothelin receptor antagonists, is indicated for the 
treatment of adult patients with pulmonary arterial hypertension (PAH) with WHO Functional Class 
(FC) II to III to improve exercise capacity. 
Efficacy has been shown in a PAH population including aetiologies of idiopathic or heritable PAH or 
PAH associated with connective tissue 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 
CTEPH or PAH. 
 
Posology 
 
Dose titration 
The recommended starting dose is 1 mg three times daily for 2 weeks. Tablets should be taken three 
times daily approximately 6 to 8 hours apart (see section 5.2). 
 
Dose should be increased by 0.5 mg three times daily every two weeks to a maximum of 2.5 mg three 
times daily, if systolic blood pressure is ≥95 mmHg and the patient has no signs or symptoms of 
hypotension. In some PAH patients, an adequate response on the 6-minute walk distance (6MWD) 
may be reached at a dose of 1.5 mg three times a day (see section 5.1). If systolic blood pressure falls 
below 95 mmHg, the dose should be maintained provided the patient does not show any signs or 
symptoms of hypotension. If at any time during the up-titration phase systolic blood pressure 
decreases below 95 mmHg and the patient shows signs or symptoms of hypotension the current dose 
should be decreased by 0.5 mg three times daily. 
 
Maintenance dose 
The established individual dose should be maintained unless signs and symptoms of hypotension 
occur. The maximum total daily dose is 7.5 mg i.e., 2.5 mg 3 times daily. If a dose is missed, treatment 
should be continued with the next dose as planned. 
If not tolerated, dose reduction should be considered at any time. 
 



4 

Food 
Tablets can generally be taken with or without food. For patients prone to hypotension, as a 
precautionary measure, switches between fed and fasted Adempas intake are not recommended 
because of increased peak plasma levels of riociguat in the fasting compared to the fed state (see 
section 5.2). 
 
Treatment discontinuation 
In case treatment has to be interrupted for 3 days or more, treatment should be restarted with 1 mg 
three times daily for 2 weeks, and continued with the dose titration regimen as described above. 
 
Transitioning between phosphodiesterase-5 (PDE5) inhibitors and riociguat 
Sildenafil must be discontinued at least 24 hours prior to administration of riociguat. 
Tadalafil must be discontinued at least 48 hours prior to administration of riociguat. 
Riociguat must be discontinued at least 24 hours prior to administration of a PDE5 inhibitor. 
It is recommended to monitor for signs and symptoms of hypotension after any transition (see 
sections 4.3, 4.5 and 5.1). 
 
Special populations 
 
Individual dose titration at treatment initiation allows adjustment of the dose to the patient´s needs. 
 
Elderly 
In elderly patients (65 years or older) there is a higher risk of hypotension and therefore particular care 
should be exercised during individual dose titration (see section 5.2).  
 
Hepatic impairment 
Patients with severe hepatic impairment (Child Pugh C) have not been studied and therefore use of 
Adempas is contraindicated in these patients (see section 4.3). Patients with moderate hepatic 
impairment (Child Pugh B) showed a higher exposure to this medicinal product (see section 5.2). 
Particular care should be exercised during individual dose titration.  
 
Renal impairment 
Data in patients with severe renal impairment (creatinine clearance <30 mL/min) are limited and there 
are no data for patients on dialysis. Therefore use of Adempas is not recommended in these patients 
(see section 4.4). 
Patients with mild and moderate renal impairment (creatinine clearance <80 - 30 mL/min) showed a 
higher exposure to this medicinal product (see section 5.2). There is a higher risk of hypotension in 
patients with renal impairment, therefore particular care should be exercised during individual dose 
titration. 
 
Patients on stable doses of strong multi pathway CYP / P-glycoprotein (P-gp) and breast cancer 
resistance protein (BCRP) inhibitors  
When initiating Adempas in patients on stable doses of strong multi pathway CYP and P-gp/BCRP 
inhibitors, such as azole antimycotics (e.g. ketoconazole, posaconazole,  itraconazole) or HIV protease 
inhibitors (e.g. ritonavir), consider a starting dose of 0.5 mg, three times a day to mitigate the risk of 
hypotension. Monitor for signs and symptoms of hypotension on initiation and on treatment. 
Consider a dose reduction for patients on Adempas doses higher than or equal to 1.0 mg if the 
patient develops signs or symptoms of hypotension (see sections 4.4 and 4.5). 
 
Paediatric population 
The safety and efficacy of riociguat in children and adolescents below 18 years have not been 
established. No clinical data are available. Non-clinical data show undesirable effects on growing bone 
(see section 5.3). Until more is known about the implications of these findings the use of riociguat in 
children and in growing adolescents should be avoided. 
 



5 

Smokers 
Current smokers should be advised to stop smoking due to a risk of a lower response. Plasma 
concentrations of riociguat in smokers are reduced compared to non-smokers. A dose increase to the 
maximum daily dose of 2.5 mg three times daily may be required in patients who are smoking or start 
smoking during treatment (see sections 4.5 and 5.2). 
A dose decrease may be required in patients who stop smoking. 
 
Method of administration 
 
For oral use. 
 
Crushed tablets 
For patients who are unable to swallow whole tablets, Adempas tablets may be crushed and mixed 
with water or soft foods, such as apple sauce, immediately prior to use and administered orally (see 
section 5.2). 
 
4.3 Contraindications 
 
- Co-administration with PDE5 inhibitors (such as sildenafil, tadalafil, vardenafil) (see 

sections 4.2 and 4.5). 
- Severe hepatic impairment (Child Pugh C). 
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
- Pregnancy (see sections  4.4; 4.5 and 4.6). 
- Co-administration with nitrates or nitric oxide donors (such as amyl nitrite) in any form 

including recreational drugs called ‘poppers’ (see section 4.5). 
- Patients with systolic blood pressure < 95 mm Hg at treatment initiation. 
- Patients with pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-

IIP) (see section 5.1)  
 
4.4 Special warnings and precautions for use 
 
In pulmonary arterial hypertension, studies with riociguat have been mainly performed in forms 
related to idiopathic or heritable PAH and PAH associated with connective tissue disease. The use of 
riociguat in other forms of PAH not studied is not recommended (see section 5.1). 
In chronic thromboembolic pulmonary hypertension, pulmonary endarterectomy is the treatment of 
choice as it is a potentially curative option. According to standard medical practice, expert assessment 
of operability should be done prior to treatment with riociguat. 
 
Pulmonary veno-occlusive disease 
 
Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary 
veno-occlusive disease (PVOD). Therefore, administration of riociguat to such patients is not 
recommended. Should signs of pulmonary oedema occur, the possibility of associated PVOD should 
be considered and treatment with riociguat should be discontinued. 
 
Respiratory tract bleeding 
 
In pulmonary hypertension patients there is increased likelihood for respiratory tract bleeding, 
particularly among patients receiving anticoagulation therapy. A careful monitoring of patients taking 
anticoagulants according to common medical practice is recommended. 
The risk of serious and fatal respiratory tract bleeding may be further increased under treatment with 
riociguat, especially in the presence of risk factors, such as recent episodes of serious haemoptysis 
including those managed by bronchial arterial embolisation. Riociguat should be avoided in patients 
with a history of serious haemoptysis or who have previously undergone bronchial arterial 
embolisation. In case of respiratory tract bleeding, the prescriber should regularly assess the benefit-
risk of treatment continuation. 



6 

Serious bleeding occurred in 2.4% (12/490) of patients taking riociguat compared to 0/214 of placebo 
patients. Serious haemoptysis occurred in 1% (5/490) patients taking riociguat compared to 0/214 
patients taking placebo, including one event with fatal outcome. Serious haemorrhagic events also 
included 2 patients with vaginal haemorrhage, 2 with catheter site haemorrhage, and 1 each with 
subdural haematoma, haematemesis, and intra-abdominal haemorrhage. 
 
Hypotension 
 
Riociguat has vasodilatory properties which may result in lowering of blood pressure. Before 
prescribing riociguat, physicians should carefully consider whether patients with certain underlying 
conditions, could be adversely affected by vasodilatory effects (e.g. patients on antihypertensive 
therapy or with resting hypotension, hypovolaemia, severe left ventricular outflow obstruction or 
autonomic dysfunction). 
Riociguat must not be used in patients with a systolic blood pressure below 95 mmHg (see 
section 4.3). Patients older than 65 years are at increased risk of hypotension. Therefore, caution 
should be exercised when administering riociguat in these patients.  
 
Renal impairment 
 
Data in patients with severe renal impairment (creatinine clearance < 30 mL/min) are limited and there 
are no data for patients on dialysis, therefore riociguat is not recommended in these patients. Patients 
with mild and moderate renal impairment were included in the pivotal studies. There is increased 
riociguat exposure in these patients (see section 5.2). There is a higher risk of hypotension in these 
patients, particular care should be exercised during individual dose titration.  
 
Hepatic impairment 
 
There is no experience in patients with severe hepatic impairment (Child Pugh C); riociguat is 
contraindicated in these patients (see section 4.3). PK data show that higher riociguat exposure was 
observed in patients with moderate hepatic impairment (Child Pugh B) (see section 5.2). Particular 
care should be exercised during individual dose titration.  
 
There is no clinical experience with riociguat in patients with elevated liver aminotransferases 
(> 3 x Upper Limit of Normal (ULN)) or with elevated direct bilirubin (> 2 x ULN) prior to initiation 
of treatment; riociguat is not recommended in these patients. 
 
Pregnancy/contraception 
 
Adempas is contraindicated during pregnancy (see section 4.3). Therefore, female patients at potential 
risk of pregnancy must use an effective method of contraception. Monthly pregnancy tests are 
recommended. 
 
Smokers 
 
Plasma concentrations of riociguat in smokers are reduced compared to non-smokers. Dose adjustment 
may be necessary in patients who start or stop smoking during treatment with riociguat (see 
sections 4.2 and 5.2). 
 
Concomitant use with other medicinal products 
 
 The concomitant use of riociguat with strong multi pathway cytochrome P450 (CYP) and P-

glycoprotein (P-gp) / breast cancer resistance protein (BCRP) inhibitors such as azole 
antimycotics (e.g. ketoconazole, posaconazole, itraconazole) or HIV protease inhibitors (e.g. 
ritonavir) results in a pronounced increase in riociguat exposure (see sections 4.5 and 5.2). 

 



7 

 Assess the benefit-risk for each patient individually before prescribing Adempas in patients on 
stable doses of strong multi pathway CYP and P-gp/BCRP inhibitors. To mitigate the risk of 
hypotension, consider dose reduction and monitoring for signs and symptoms of hypotension 
(see sections 4.2 and 4.5). 

 
 In patients on stable doses of Adempas, the initiation of strong multi pathway CYP and 

P-gp/BCRP inhibitors is not recommended as no dosage recommendation can be given due to 
limited data. Alternative treatments should be considered. 

 
 The concomitant use of riociguat with strong CYP1A1 inhibitors, such as the tyrosine kinase 

inhibitor erlotinib, and strong P-glycoprotein (P-gp) / breast cancer resistance protein (BCRP) 
inhibitors, such as the immuno-suppressive agent cyclosporine A, may increase riociguat 
exposure (see sections 4.5 and 5.2). These medicinal products should be used with caution. 
Blood pressure should be monitored and dose reduction of riociguat be considered. 

 
Adempas contains lactose 
 
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or 
glucose-galactose malabsorption should not take this medicinal product. 
 
Adempas contains sodium 
 
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium 
free”. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Pharmacodynamic interactions 
 
Nitrates 
In a clinical study the highest dose of Adempas (2.5 mg tablets three times daily) potentiated the blood 
pressure lowering effect of sublingual nitroglycerin (0.4 mg) taken 4 and 8 hours after intake. 
Therefore co-administration of Adempas with nitrates or nitric oxide donors (such as amyl nitrite) in 
any form, including recreational drugs called ‘poppers’, is contraindicated (see section 4.3). 
 
PDE5 inhibitors 
Preclinical studies in animal models showed additive systemic blood pressure lowering effect when 
riociguat was combined with either sildenafil or vardenafil. With increased doses, over additive effects 
on systemic blood pressure were observed in some cases. 
In an exploratory interaction study in 7 patients with PAH on stable sildenafil treatment (20 mg three 
times daily) single doses of riociguat (0.5 mg and 1 mg sequentially) showed additive haemodynamic 
effects. Doses above 1 mg riociguat were not investigated in this study. 
A 12 week combination study in 18 patients with PAH on stable sildenafil treatment (20 mg three 
times daily) and riociguat (1.0 mg to 2.5 mg three times daily) compared to sildenafil alone was 
performed. In the long term extension part of this study (non controlled) the concomitant use of 
sildenafil and riociguat resulted in a high rate of discontinuation, predominately due to hypotension. 
There was no evidence of a favourable clinical effect of the combination in the population studied. 
Concomitant use of riociguat with PDE5 inhibitors (such as sildenafil, tadalafil, vardenafil) is 
contraindicated (see sections 4.2 and 4.3). 
RESPITE was a 24-week, uncontrolled study to investigate switching from PDE5 inhibitors to 
riociguat, in 61 adult PAH patients on stable PDE5 inhibitors. All patients were WHO Functional 
Class III and 82% received background therapy with an endothelin receptor antagonist (ERA). For the 
transition from PDE5 inhibitors to riociguat, median treatment-free time for sildenafil was 1 day and 
for tadalafil 3 days. Overall, the safety profile observed in the study was comparable with that 
observed in the pivotal trials, with no serious adverse events reported during the transition period. 
Six patients (10%) experienced at least one clinical worsening event, including 2 deaths unrelated to 



8 

study drug. Changes from baseline suggested beneficial effects in selected patients, e.g. improvement 
in 6MWD (+31m), N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels 
(-347 pg/mL) and WHO FC I/II/III/IV,% (2/52/46/0), cardiac index (+0.3 L/min/m2). 
 
Warfarin/phenprocoumon  
Concomitant treatment of riociguat and warfarin did not alter prothrombin time induced by the 
anticoagulant. The concomitant use of riociguat with other cumarin-derivatives (e.g. phenprocoumon) 
is also not expected to alter prothrombin time. 
Lack of pharmacokinetic interactions between riociguat and the CYP2C9 substrate warfarin was 
demonstrated in vivo. 
 
Acetylsalicylic acid 
Riociguat did not potentiate the bleeding time caused by acetyl-salicylic acid or affect the platelet 
aggregation in humans. 
 
Effects of other substances on riociguat 
 
Riociguat is cleared mainly via cytochrome P450-mediated (CYP1A1, CYP3A4, CYP3A5, CYP2J2) 
oxidative metabolism, direct biliary/faecal excretion of unchanged riociguat and renal excretion of 
unchanged riociguat via glomerular filtration.  
 
Concomitant use with strong multi pathway CYP and P-gp/BCRP inhibitors  
 
Highly active antiretroviral therapy (HAART) 
 
In vitro, abacavir, rilpivirine, efavirenz, ritonavir, cobicistat and elvitegravir inhibited CYP1A1 and 
the metabolism of riociguat in the order listed with abacavir as the strongest inhibitor. Cobicistat, 
ritonavir, atazanavir and darunavir are additionally classified as CYP3A inhibitors. In addition, 
ritonavir showed inhibition of P-gp. 
 
The impact of  HAART (including different combinations of abacavir, atazanavir, cobicistat, 
darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, lamivudine, rilpivirine, ritonavir, and 
tenofovir) on riociguat exposure was investigated in a dedicated study in HIV patients. Concomitant 
administration of HAART combinations led to an increase in riociguat mean AUC of up to about 
160% and to an approximate 20% increase in mean Cmax. The safety profile observed in HIV patients 
taking a single dose of 0.5 mg riociguat together with different combinations of HIV drugs used in 
HAART was generally comparable to other patient populations. 
 
To mitigate the risk of hypotension when Adempas is initiated in patients on stable doses of strong 
multi pathway CYP (especially CYP1A1 and CYP3A4) and P-gp/BCRP inhibitors, e.g. as contained 
in HAART, consider a reduced starting dose. It is recommended to monitor these patients for signs 
and symptoms of hypotension (see sections 4.2 and  4.4). 
 
Antifungals 
 
In vitro, ketoconazole, classified as a strong CYP3A4 and P-glycoprotein (P-gp) inhibitor, has been 
shown to be a multi-pathway CYP and P-gp/breast cancer resistance protein (BCRP) inhibitor for 
riociguat metabolism and excretion (see section 5.2). Concomitant administration of 400 mg once 
daily ketoconazole led to a 150% (range up to 370%) increase in riociguat mean AUC and a 46% 
increase in mean Cmax. Terminal half-life increased from 7.3 to 9.2 hours and total body clearance 
decreased from 6.1 to 2.4 L/h. 
 
To mitigate the risk of hypotension when Adempas is initiated in patients on stable doses of strong 
multi pathway CYP (especially CYP1A1 and CYP3A4) and P-gp/BCRP inhibitors, e.g. ketoconazole, 
posaconazole or itraconazole consider a reduced starting dose. It is recommended to monitor these 
patients for signs and symptoms of hypotension (see sections 4.2 and 4.4). 
 



9 

Concomitant use with other CYP and P-gp/BCRP inhibitors  
 
Medicinal products strongly inhibiting P-gp/BCRP such as the immuno-suppressive cyclosporine A, 
should be used with caution (see sections 4.4 and 5.2). 
 
Inhibitors for the UDP-Glykosyltransferases (UGT) 1A1 and 1A9 may potentially increase the 
exposure of the riociguat metabolite M1, which is pharmacologically active (pharmacological 
activity: 1/10th to 1/3rd of riociguat). For co-administration with these substances follow the 
recommendation on dose titration (see section 4.2). 
 
From the recombinant CYP isoforms investigated in vitro CYP1A1 catalysed formation of riociguat’s 
main metabolite most effectively. The class of tyrosine kinase inhibitors was identified as potent 
inhibitors of CYP1A1, with erlotinib and gefitinib exhibiting the highest inhibitory potency in vitro. 
Therefore, drug-drug interactions by inhibition of CYP1A1 could result in increased riociguat 
exposure, especially in smokers (see section 5.2). Strong CYP1A1 inhibitors should be used with 
caution (see section 4.4). 
 
Concomitant use with medicinal products  increasing gastric pH  
 
Riociguat exhibits a reduced solubility at neutral pH vs. acidic medium. Co-treatment of medicinal 
products increasing the upper gastro intestinal pH may lead to lower oral bioavailability. 
 
Co-administration of the antacid aluminium hydroxide / magnesium hydroxide reduced riociguat mean 
AUC by 34% and mean Cmax by 56% (see section 4.2). Antacids should be taken at least 2 hours 
before, or 1 hour after riociguat. 
 
Concomitant use with CYP3A4 inducers 
 
Bosentan, reported to be a moderate inducer of CYP3A4, led to a decrease of riociguat steady-state 
plasma concentrations in PAH patients by 27% (see sections 4.1 and 5.1). For co-administration with 
bosentan follow the recommendation on dose titration (see section 4.2). 
 
The concomitant use of riociguat with strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, 
phenobarbitone or St. John’s Wort) may also lead to decreased riociguat plasma concentration. For co-
administration with strong CYP3A4 inducers follow the recommendation on dose titration (see section 
4.2). 
 
Smoking 
 
In cigarette smokers riociguat exposure is reduced by 50-60% (see section 5.2). Therefore, patients are 
advised to stop smoking (see section 4.2). 
 
Effects of riociguat on other substances 
 
Riociguat and its main metabolite are strong inhibitors of CYP1A1 in vitro. Therefore, clinically 
relevant drug-drug interactions with co-treatment which are significantly cleared by 
CYP1A1-mediated biotransformation, such as erlotinib or granisetron cannot be ruled out. 
 
Riociguat and its main metabolite are not inhibitors or inducers of major CYP isoforms (including 
CYP 3A4) or transporters (e.g. P-gp/BCRP) in vitro at therapeutic plasma concentrations. 
 
Patients must not get pregnant during Adempas therapy (see section 4.3). Riociguat (2.5 mg three 
times per day) did not have a clinically meaningful effect on the plasma levels of combined oral 
contraceptives containing levonorgestrel and ethinyl estradiol when concomitantly administered to 
healthy female subjects. Based  on this study and as riociguat is not an inducer of any of the relevant 



10 

metabolic enzymes, also no pharmacokinetic interaction is expected with other hormonal 
contraceptives. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential / Contraception  
 
Women of childbearing potential must use effective contraception during treatment with Adempas. 
 
Pregnancy  
 
There are no data from the use of riociguat in pregnant women. Studies in animals have shown 
reproductive toxicity and placental transfer (see section 5.3). Therefore, Adempas is contraindicated 
during pregnancy (see section 4.3). Monthly pregnancy tests are recommended. 
 
Breast-feeding  
 
No data on the use of riociguat in breast-feeding women are available. Data from animals indicate that 
riociguat is excreted into milk. Due to the potential for serious adverse reactions in breast-fed infants 
Adempas should not be used during breast-feeding. A risk to the suckling child cannot be excluded. 
Breast-feeding should be discontinued during treatment with this medicinal product. 
 
Fertility 
 
No specific studies with riociguat in humans have been conducted to evaluate effects on fertility. In a 
reproduction toxicity study in rats, decreased testes weights were seen, but there were no effects on 
fertility (see section 5.3). The relevance of this finding for humans is unknown. 
 
4.7 Effects on ability to drive and use machines 
 
Adempas has moderate influence on the ability to drive and use machines. Dizziness has been reported 
and may affect the ability to drive and use machines (see section 4.8). Patients should be aware of how 
they react to this medicinal product, before driving or using machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The safety of Adempas has been evaluated in phase III studies of 681 patients with CTEPH and PAH 
receiving at least one dose of riociguat (see section 5.1). 
 
Most of the adverse reactions are caused by relaxation of smooth muscle cells in vasculature or the 
gastrointestinal tract. 
 
The most commonly reported adverse reactions, occurring in ≥10% of patients under Adempas 
treatment (up to 2.5 mg three times daily), were headache, dizziness, dyspepsia, peripheral oedema, 
nausea, diarrhoea and vomiting.  
 
Serious haemoptysis and pulmonary haemorrhage, including cases with fatal outcome have been 
observed in patients with CTEPH or PAH treated with Adempas (see section 4.4).  
 
The safety profile of Adempas in patients with CTEPH and PAH appeared to be similar, therefore 
adverse reactions identified from placebo controlled 12 and 16 weeks clinical studies are presented as 
pooled frequency in the table listed below (see table 1). 
 



11 

Tabulated list of adverse reactions 
 
The adverse reactions reported with Adempas are listed in the table below by MedDRA system organ 
class and by frequency. 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) and not known (cannot be estimated from the available data). 
 
Table 1: Adverse reactions reported with Adempas in the phase III studies 

MedDRA 
System Organ Class 

Very common Common Uncommon 

Infections and infestations  Gastroenteritis  
Blood and lymphatic 
system disorders 

 Anaemia (incl. respective 
laboratory parameters) 

 

Nervous system disorders Dizziness, 
Headache 

  

Cardiac disorders  Palpitations  
Vascular disorders  Hypotension  
Respiratory, thoracic and 
mediastinal disorders 

 Haemoptysis, 
Epistaxis, 
Nasal congestion 

Pulmonary 
haemorrhage* 

Gastrointestinal disorders Dyspepsia, 
Diarrhoea, 
Nausea, 
Vomiting 

Gastritis, 
Gastro-oesophageal reflux 
disease, 
Dysphagia, 
Gastrointestinal and 
abdominal pains, 
Constipation,  
Abdominal distension 

 

General disorders and 
administration site 
conditions 

Oedema 
peripheral 

  

* fatal pulmonary haemorrhage was reported in uncontrolled long term extension studies 
 
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 
 
Inadvertent overdosing with total daily doses of 9 to 25 mg riociguat between 2 to 32 days was 
reported. Adverse reactions were similar to those seen at lower doses (see section 4.8). 
 
In case of overdose, standard supportive measures should be adopted as required.  
In case of pronounced hypotension, active cardiovascular support may be required.  
Based on the high plasma protein binding riociguat is not expected to be dialysable. 
 
 



12 

5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antihypertensives (antihypertensives for pulmonary arterial 
hypertension) 
ATC code: C02KX05 
 
Mechanism of action 
 
Riociguat is a stimulator of soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary 
system and the receptor for nitric oxide (NO). When NO binds to sGC, the enzyme catalyses synthesis 
of the signalling molecule cyclic guanosine monophosphate (cGMP). Intra-cellular cGMP plays an 
important role in regulating processes that influence vascular tone, proliferation, fibrosis, and 
inflammation. 
Pulmonary hypertension is associated with endothelial dysfunction, impaired synthesis of NO and 
insufficient stimulation of the NO-sGC-cGMP pathway. 
Riociguat has a dual mode of action. It sensitises sGC to endogenous NO by stabilising the NO-sGC 
binding. Riociguat also directly stimulates sGC independently of NO. 
Riociguat restores the NO-sGC-cGMP pathway and leads to increased generation of cGMP. 
 
Pharmacodynamic effects 
 
Riociguat restores the NO-sGC-cGMP pathway resulting in a significant improvement of pulmonary 
vascular haemodynamics and an increase in exercise ability. 
There is a direct relationship between riociguat plasma concentration and haemodynamic parameters 
such as systemic and pulmonary vascular resistance, systolic blood pressure and cardiac output. 
 
Clinical efficacy and safety 
 
Efficacy in patients with CTEPH 
 
A randomised, double-blind, multi-national, placebo controlled, phase III study (CHEST-1) was 
conducted in 261 adult patients with inoperable chronic thromboembolic pulmonary hypertension 
(CTEPH) (72%) or persistent or recurrent CTEPH after pulmonary endarterectomy (PEA; 28%). 
During the first 8 weeks riociguat was titrated every 2-weeks based on the patient’s systolic blood 
pressure and signs or symptoms of hypotension to the optimal individual dose (range 0.5 mg to 2.5 mg 
three times daily) which was then maintained for a further 8 weeks. The primary endpoint of the study 
was the placebo adjusted change from baseline in 6-minute walk distance (6MWD) at the last visit 
(week 16). 
At the last visit, the increase in 6MWD in patients treated with riociguat was 46 m (95% confidence 
interval (CI): 25 m to 67 m; p<0.0001), compared to placebo. Results were consistent in the main 
sub-groups evaluated (ITT analysis, see table 2). 
 



13 

Table 2: Effects of riociguat on 6MWD in CHEST-1 at last visit  
Entire patient population Riociguat  

(n=173) 
Placebo 
(n=88) 

Baseline (m) 
[SD] 

342 
[82] 

356 
 [75] 

Mean change from baseline (m) 
[SD] 

39 
[79] 

-6 
[84] 

Placebo-adjusted difference (m)  
95% CI, [p-value] 

46 
25 to 67 [<0.0001] 

 
FC III patient population 

 
Riociguat  
(n=107) 

Placebo 
(n=60) 

Baseline (m) 
[SD] 

326 
[81] 

345 
 [73] 

Mean change from baseline (m) 
[SD] 

38 
[75] 

-17 
[95] 

Placebo-adjusted difference (m)  
95% CI  

56 
29 to 83  

FC II patient population 
 

Riociguat  
(n=55) 

Placebo 
(n=25) 

Baseline (m) 
[SD] 

387 
[59] 

386 
 [64] 

Mean change from baseline (m) 
[SD] 

45 
[82] 

20 
[51] 

Placebo-adjusted difference (m)  
95% CI 

25 
-10 to 61 

 
 Inoperable patient population  

 
Riociguat  
(n=121) 

Placebo 
(n=68) 

Baseline (m)  
[SD] 

335 
[83] 

351 
[75] 

Mean change from baseline (m)  
[SD] 

44 
[84] 

-8 
[88] 

Placebo-adjusted difference (m) 
95% CI 

54 
29 to 79 

 Patient population with CTEPH 
post-PEA 

Riociguat  
(n=52) 

Placebo 
(n=20) 

Baseline (m)  
[SD] 

360 
[78] 

374 
[72] 

Mean change from baseline (m) 
[SD] 

27 
[68] 

1.8 
[73] 

Placebo- adjusted difference (m) 
95% CI 

27 
-10 to 63 

 
Improvement in exercise capacity was accompanied by improvement in multiple clinically relevant 
secondary endpoints. These findings were in accordance with improvements in additional 
haemodynamic parameters. 
 



14 

Table 3: Effects of riociguat in CHEST-1 on PVR, NT-proBNP and WHO functional class at last visit 
 

PVR 
Riociguat 
(n=151) 

Placebo 
(n=82) 

Baseline (dyn·s·cm-5) 
[SD] 

790.7 
[431.6] 

779.3 
[400.9] 

Mean change from baseline 
(dyn·s·cm-5) 
[SD] 

-225.7 
 

[247.5] 

23.1 
 

[273.5] 
Placebo-adjusted difference 
(dyn·s·cm-5) 
95% CI, [p-value] 

-246.4 
 

–303.3 to –189.5 [<0.0001] 
NT-proBNP Riociguat  

(n=150) 
Placebo 
(n=73) 

Baseline (ng/L) 
[SD] 

1508.3 
[2337.8] 

1705.8 
[2567.2] 

Mean change from baseline (ng/L) 
[SD] 

-290.7 
[1716.9] 

76.4 
[1446.6] 

Placebo-adjusted difference (ng/L) 
95% CI, [p-value] 

-444.0 
-843.0 to -45.0 [<0.0001] 

Change in WHO Functional Class Riociguat  
(n=173) 

Placebo 
(n=87) 

Improved 57 (32.9%) 13 (14.9%) 
Stable 107 (61.8%) 68 (78.2%) 
Deteriorated 9 (5.2%) 6 (6.9%) 
p-value 0.0026 
PVR= pulmonary vascular resistance 
 
Adverse Events leading to discontinuation occurred at a similar frequency in both treatment groups 
(riociguat individual dose titration (IDT) 1.0-2.5 mg, 2.9%; placebo, 2.3%). 
 
Long-term treatment 
 
An open-label extension study (CHEST-2) included 237 patients who had completed CHEST-1. In 
CHEST-2, all patients received an individualised riociguat dose up to 2.5 mg three times daily. 
The mean change in 6MWD from baseline to week 12 (last observation until week 12) in CHEST-2 
(28 weeks on-study for CHEST-1 + CHEST-2) was 57 m in the former 1.0–2.5 mg riociguat group 
and 43 m in the former placebo group. Improvements in 6MWD persisted at 2 years in CHEST-2. 
Mean change from baseline for the overall population (N=237) was 57 m at 6 months (n=218), 51 m at 
9 months (n=219), 52 m at 12 months (n=209) and 48 m at 24 months (n=193). 
 
The probability of survival at 1 year was 97%, at 2 years 93% and at 3 years 89%. Survival in patients 
of WHO functional class II at baseline at 1, 2 and 3 years was 97%, 94% and 90% respectively, and 
for patients of WHO functional class III at baseline was 97%, 93% and 88% respectively. 
 
Efficacy in patients with PAH 
 
A randomised, double-blind, multi-national, placebo controlled, phase III study (PATENT-1) was 
conducted in 443 adult patients with PAH (riociguat individual dose titration up to 2.5 mg three times 
daily: n=254, placebo: n=126, riociguat “capped” dose titration (CT) up to 1.5 mg (exploratory dose 
arm, no statistical testing performed; n=63)). Patients were either treatment-naïve (50%) or pre-treated 
with ERA (43%) or a prostacyclin analogue (inhaled (iloprost), oral (beraprost) or subcutaneous 
(treprostinil); 7%) and had been diagnosed with idiopathic or heritable PAH (63.4%), PAH associated 
with connective tissue disease (25.1%) and congenital heart disease (7.9%). 
During the first 8 weeks riociguat was titrated every 2-weeks based on the patient’s systolic blood 
pressure and signs or symptoms of hypotension to the optimal individual dose (range 0.5 mg to 2.5 mg 



15 

three times daily), which was then maintained for a further 4 weeks. The primary endpoint of the study 
was placebo-adjusted change from baseline in 6MWD at the last visit (week 12).  
 
At the last visit the increase in 6MWD with riociguat individual dose titration (IDT) was 36 m 
(95% CI: 20 m to 52 m; p0.0001) compared to placebo. Treatment-naïve patients (n=189) improved 
by 38 m, and pre-treated patients (n=191) by 36 m (ITT analysis, see table 4). Further exploratory 
subgroup analysis revealed a treatment effect of 26 m, (95% CI: 5 m to 46 m) in patients pre-treated 
with ERAs (n=167) and a treatment effect of 101 m (95% CI: 27 m to 176 m) in patients pre-treated 
with prostacyclin analogues (n=27). 
 



16 

Table 4: Effects of riociguat on 6MWD in PATENT-1 at last visit  
Entire patient population Riociguat IDT 

(n=254) 
Placebo 
(n=126) 

Riociguat CT 
(n=63) 

Baseline (m)  
[SD] 

361 
[68] 

368 
[75] 

363 
[67] 

Mean change from baseline 
(m) 
[SD] 

30 
 

[66] 

-6 
 

[86] 

31 
 

[79] 
Placebo-adjusted difference 
(m) 
95% CI, [p-value] 
 

36 
 

20 to 52 [<0.0001] 

 

FC III patients Riociguat IDT 
(n=140) 

Placebo 
(n=58) 

Riociguat CT 
(n=39) 

Baseline (m)  
[SD] 

338 
[70] 

347 
[78] 

351 
[68] 

Mean change from baseline 
(m) 
[SD] 

31 
 

[64] 

-27 
 

[98] 

29 
 

[94] 
Placebo-adjusted difference 
(m) 
95% CI 

58 
 

35 to 81 

 

 FC II patients Riociguat IDT 
(n=108) 

Placebo 
(n=60) 

Riociguat CT 
(n=19) 

Baseline (m)  
[SD] 

392 
[51] 

393 
[61] 

378 
[64] 

Mean change from baseline 
(m) 
[SD] 

29 
 

[69] 

19 
 

[63] 

43 
 

[50] 
Placebo-adjusted difference 
(m) 
95% CI 

10 
 

-11 to 31  

 

 Treatment-naïve patient 
population  

Riociguat IDT 
(n=123) 

Placebo 
(n=66) 

Riociguat CT 
(n=32) 

Baseline (m)  
[SD] 

370 
[66] 

360 
[80] 

347 
[72] 

Mean change from baseline 
(m)  
[SD] 

32 
 

[74] 

-6 
 

[88] 

49 
 

[47] 
Placebo-adjusted difference 
(m) 
95% CI 

38 
14 to 62 

 

 Pre-treated patient 
population  

Riociguat IDT 
(n=131) 

Placebo 
(n=60) 

Riociguat CT 
(n=31) 

Baseline (m)  
[SD] 

353 
[69] 

376 
[68] 

380 
[57] 

Mean change from baseline 
(m) 
[SD] 

27 
 

[58] 

-5 
 

[83] 

12 
 

[100] 
Placebo- adjusted difference 
(m) 
95% CI 

36 
 

15 to 56 

 

 
Improvement in exercise capacity was accompanied by consistent improvement in multiple clinically-
relevant secondary endpoints. These findings were in accordance with improvements in additional 
haemodynamic parameters (see table 5). 



17 

 
Table 5: Effects of riociguat in PATENT-1 on PVR and NT-proBNP at last visit 

 
PVR 

Riociguat IDT 
(n=232) 

Placebo 
(n=107) 

Riociguat CT 
(n=58) 

Baseline (dyn·s·cm-5) 
[SD] 

791 
[452.6] 

834.1 
[476.7] 

847.8 
[548.2] 

Mean change from PVR baseline 
(dyn·s·cm-5) 
[SD] 

-223 
 

[260.1] 

-8.9 
 

[316.6] 

-167.8 
 

[320.2] 
Placebo-adjusted difference 
(dyn·s·cm-5)  
95% CI, [p-value] 

-225.7 
 

-281.4 to -170.1[<0.0001] 

 

NT-proBNP Riociguat IDT 
 (n = 228) 

Placebo 
(n = 106) 

Riociguat CT 
(n=54) 

Baseline (ng/L)  
[SD] 

1,026.7 
[1,799.2] 

1,228.1 
[1,774.9] 

1,189.7 
[1,404.7] 

Mean change from baseline (ng/L) 
[SD] 

-197.9 
[1721.3] 

232.4 
[1011.1] 

-471.5 
[913.0] 

Placebo-adjusted difference (ng/L)  
95% CI, [p-value] 

-431.8 
-781.5 to -82.1 [<0.0001] 

 

Change in WHO Functional 
Class 

Riociguat IDT 
(n = 254) 

Placebo 
(n = 125) 

Riociguat CT 
(n=63) 

Improved 53 (20.9%) 18 (14.4%) 15 (23.8%) 
Stable 192 (75.6%) 89 (71.2%) 43 (68.3%) 
Deteriorated 9 (3.6%) 18 (14.4%) 5 (7.9%) 
p-value 0.0033  
 
Riociguat-treated patients experienced a significant delay in time to clinical worsening versus 
placebo-treated patients (p = 0.0046; Stratified log-rank test) (see table 6).  
 
Table 6: Effects of riociguat in PATENT-1 on events of clinical worsening  

Clinical Worsening Events Riociguat IDT 
(n=254) 

Placebo 
(n=126) 

Riociguat CT 
(n=63) 

Patients with any clinical worsening 3 (1.2%) 8 (6.3%) 2 (3.2%) 
 Death 2 (0.8%) 3 (2.4%) 1 (1.6%) 
 Hospitalisations due to PH 1 (0.4%) 4 (3.2%) 0 
 Decrease in 6MWD due to PH 1 (0.4%) 2 (1.6%) 1 (1.6%) 
 Persistent worsening of Functional 

Class due to PH 
0 1 (0.8%) 0 

 Start of new PH treatment 1 (0.4%) 5 (4.0%) 1 (1.6%) 
 
Patients treated with riociguat showed significant improvement in Borg CR 10 dyspnoea score (mean 
change from baseline (SD): riociguat -0.4 (2), placebo 0.1 (2); p = 0.0022). 
 
Adverse Events leading to discontinuation occurred less frequently in both riociguat treatment groups 
than in the placebo group (riociguat IDT 1.0-2.5 mg, 3.1%; riociguat CT 1.6%; placebo, 7.1%). 
 
Long-term treatment 
 
An open-label extension study (PATENT-2) included 396 patients who had completed PATENT-1 at 
the cut-off-date. In PATENT-2, all patients received an individualised riociguat dose up to 2.5 mg 
three times daily. The mean change in 6MWD from baseline to week 12 (last observation until 
week 12) in PATENT-2 (24 weeks on-study for PATENT-1 + PATENT-2) was 52 m in the former 
1.0–2.5 mg riociguat group,45 m in the former placebo group and 52 m in the former 1.0–1.5 mg 
riociguat group. Improvements in 6MWD persisted at 2 years in PATENT-2. Mean change from 



18 

baseline for the overall population (N=396) was 53 m at 6 months (n=366), 52 m at 9 months (n=354), 
50 m at 12 months (n=351) and 46 m at 24 months (n=316). 
 
The probability of survival at 1 year was 97%, at 2 years 93% and at 3 years 88%. Survival in patients 
of WHO functional class II at baseline at 1, 2 and 3 years was 98%, 96% and 93% respectively, and 
for patients of WHO functional class III at baseline was 96%, 91% and 84% respectively. 
 
Patients with pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP)  
 
A randomised, double blind, placebo-controlled phase II study (RISE-IIP) to evaluate the efficacy and 
safety of riociguat in patients with symptomatic pulmonary hypertension associated with idiopathic 
interstitial pneumonias (PH-IIP) was terminated early due to an increased risk of mortality and serious 
adverse events in patients treated with riociguat and a lack of efficacy. More patients taking riociguat 
died (11% vs. 4%) and had serious adverse events (37% vs. 23%) during the main phase. In the long-
term extension, more patients who switched from the placebo group to riociguat (21%) died than those 
who continued in the riociguat group (3%). 
 
Riociguat is therefore contraindicated in patients with pulmonary hypertension associated with 
idiopathic interstitial pneumonias (see section 4.3).  
 
Paediatric population 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Adempas in one or more subsets of the paediatric population in the treatment of pulmonary 
hypertension. 
See section 4.2 for information on paediatric use. 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
The absolute bioavailability of riociguat is high (94%). Riociguat is rapidly absorbed with maximum 
concentrations (Cmax) appearing 1-1.5 hours after tablet intake. Intake with food reduced riociguat 
AUC slightly, Cmax was reduced by 35%. 
 
Bioavailability (AUC and Cmax) is comparable for Adempas administered orally as a crushed tablet 
suspended in apple sauce or in water compared to a whole tablet (see section 4.2). 
 
Distribution 
 
Plasma protein binding in humans is high at approximately 95%, with serum albumin and 
alpha 1-acidic glycoprotein being the main binding components. The volume of distribution is 
moderate with volume of distribution at steady state being approximately 30 L. 
 
Biotransformation 
 
N-demethylation, catalysed by CYP1A1, CYP3A4, CYP3A5 and CYP2J2 is the major 
biotransformation pathway of riociguat leading to its major circulating active metabolite M-1 
(pharmacological activity: 1/10th to 1/3rd of riociguat) which is further metabolised to the 
pharmacologically inactive N-glucuronide. 
CYP1A1 catalyses the formation of riociguat’s main metabolite in liver and lungs and is known to be 
inducible by polycyclic aromatic hydrocarbons, which, for example, are present in cigarette smoke. 
 



19 

Elimination  
 
Total riociguat (parent compound and metabolites) is excreted via both renal (33-45%) and 
biliary/faecal routes (48-59%). Approximately 4-19% of the administered dose was excreted as 
unchanged riociguat via the kidneys. Approximately 9-44% of the administered dose was found as 
unchanged riociguat in faeces. 
Based on in vitro data riociguat and its main metabolite are substrates of the transporter proteins P-gp 
(P-glycoprotein) and BCRP (breast cancer resistance protein). With a systemic clearance of about 
3-6 L/h, riociguat can be classified as a low-clearance drug. Elimination half-life is about 7 hours in 
healthy subjects and about 12 hours in patients. 
 
Linearity 
 
Riociguat pharmacokinetics are linear from 0.5 to 2.5 mg. Inter-individual variability (CV) of 
riociguat exposure (AUC) across all doses is approximately 60%. 
 
Special populations  
 
Gender 
Pharmacokinetic data reveal no relevant differences due to gender in the exposure to riociguat.  
 
Paediatric population 
No studies have been conducted to investigate the pharmacokinetics of riociguat in paediatric patients.  
 
Elderly population 
Elderly patients (65 years or older) exhibited higher plasma concentrations than younger patients, with 
mean AUC values being approximately 40% higher in elderly, mainly due to reduced (apparent) total 
and renal clearance.  
 
Inter-ethnic differences 
Pharmacokinetic data reveal no relevant inter-ethnic differences.  
 
Different weight categories 
Pharmacokinetic data reveal no relevant differences due to weight in the exposure to riociguat.  
 
Hepatic impairment 
In cirrhotic patients (non-smokers) with mild hepatic impairment (classified as Child Pugh A) 
riociguat mean AUC was increased by 35% compared to healthy controls, which is within normal 
intra-individual variability. In cirrhotic patients (non-smokers) with moderate hepatic impairment 
(classified as Child Pugh B), riociguat mean AUC was increased by 51% compared to healthy 
controls. There are no data in patients with severe hepatic impairment (classified as Child Pugh C). 
 
Patients with ALT > 3 x ULN and bilirubin > 2 x ULN were not studied (see section 4.4). 
 
Renal impairment 
Overall, mean dose- and weight- normalised exposure values for riociguat were higher in subjects with 
renal impairment compared to subjects with normal renal function. Corresponding values for the main 
metabolite were higher in subjects with renal impairment compared to healthy subjects. In non-
smoking individuals with mild (creatinine clearance 80-50 mL/min), moderate (creatinine clearance 
<50-30 mL/min) or severe (creatinine clearance <30 mL/min) renal impairment, riociguat plasma 
concentrations (AUC) were increased by 53%, 139% or 54%, respectively.  
Data in patients with creatinine clearance <30 mL/min are limited and there are no data for patients on 
dialysis. 
Due to the high plasma protein binding riociguat is not expected to be dialysable. 
 



20 

5.3 Preclinical safety data 
 
Non-clinical data revealed no specific hazard for humans based on conventional studies of safety 
pharmacology, single dose toxicity, phototoxicity, genotoxicity and carcinogenicity. 
 
Effects observed in repeat-dose toxicity studies were mainly due to the exaggerated pharmacodynamic 
activity of riociguat (haemodynamic and smooth muscle relaxing effects). 
 
In growing, juvenile and adolescent rats, effects on bone formation were seen. In juvenile rats, the 
changes consisted of thickening of trabecular bone and of hyperostosis and remodeling of metaphyseal 
and diaphyseal bone, whereas in adolescent rats an overall increase of bone mass was observed. No 
such effects were observed in adult rats. 
 
In a fertility study in rats, decreased testes weights occurred at systemic exposure of about 7-fold of 
human exposure, whereas no effects on male and female fertility were seen. Moderate passage across 
the placental barrier was observed. Developmental toxicity studies in rats and rabbits have shown 
reproductive toxicity of riociguat. In rats, an increased rate of cardiac malformation was observed as 
well as a reduced gestation rate due to early resorption at maternal systemic exposure of about 7-fold 
of human exposure (2.5 mg three times daily). In rabbits, starting at systemic exposure of about 3-fold 
of human exposure (2.5 mg three times daily) abortion and foetal toxicity were seen. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core:  
 
cellulose microcrystalline 
crospovidone (type B) 
hypromellose 5 cP 
magnesium stearate 
lactose monohydrate 
sodium laurilsulfate 
 
Film-coat:  
 
hydroxypropylcellulose 
hypromellose 3 cP 
propylene glycol (E 1520) 
titanium dioxide (E 171) 
iron oxide yellow (E 172) (in 1 mg, 1.5 mg, 2 mg and 2.5 mg tablets only) 
iron oxide red (E 172)  (in 2 mg and 2.5 mg tablets only) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 



21 

6.5 Nature and contents of container 
 
PP/Aluminium foil blister. 
Pack sizes: 42, 84, 90 or 294 film-coated tablets. 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
Adempas 0.5 mg film-coated tablets 
EU/1/13/907/001 
EU/1/13/907/002 
EU/1/13/907/003 
EU/1/13/907/016 
 
Adempas 1 mg film-coated tablets 
EU/1/13/907/004 
EU/1/13/907/005 
EU/1/13/907/006 
EU/1/13/907/017 
 
Adempas 1.5 mg film-coated tablets 
EU/1/13/907/007 
EU/1/13/907/008 
EU/1/13/907/009 
EU/1/13/907/018 
 
Adempas 2 mg film-coated tablets 
EU/1/13/907/010 
EU/1/13/907/011 
EU/1/13/907/012 
EU/1/13/907/019 
 
Adempas 2.5 mg film-coated tablets 
EU/1/13/907/013 
EU/1/13/907/014 
EU/1/13/907/015 
EU/1/13/907/020 
 
 



22 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 27 March 2014 
Date of latest renewal: 18 January 2019 
 
 
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 



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER 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 
 
 



24 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Bayer AG 
Kaiser-Wilhelm-Allee 
51368 Leverkusen 
Germany 
 
 
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  
 
The requirements for submission of periodic safety update reports 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 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.  

 
 



25 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



26 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 



27 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Adempas 0.5 mg film-coated tablets 
Adempas 1 mg film-coated tablets 
Adempas 1.5 mg film-coated tablets 
Adempas 2 mg film-coated tablets 
Adempas 2.5 mg film-coated tablets 
riociguat 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
Each film-coated tablet contains 0.5 mg, 1 mg, 1.5 mg, 2 mg or 2.5 mg riociguat. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
42 film-coated tablets 
84 film-coated tablets 
90 film-coated tablets 
294 film-coated tablets 
 
 
5. METHOD AND ROUTE 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 
 
 



28 

9. SPECIAL STORAGE CONDITIONS
 
 
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 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
Bayer (logo) 
 
 
12. MARKETING AUTHORISATION NUMBER 
 
Adempas 0.5 mg – pack of 42 film-coated tablets - EU/1/13/907/001 
Adempas 0.5 mg – pack of 84 film-coated tablets - EU/1/13/907/002 
Adempas 0.5 mg – pack of 90 film-coated tablets - EU/1/13/907/003 
Adempas 0.5 mg – pack of 294 film-coated tablets - EU/1/13/907/016 
Adempas 1 mg – pack of 42 film-coated tablets - EU/1/13/907/004 
Adempas 1 mg – pack of 84 film-coated tablets - EU/1/13/907/005 
Adempas 1 mg – pack of 90 film-coated tablets - EU/1/13/907/006 
Adempas 1 mg – pack of 294 film-coated tablets - EU/1/13/907/017 
Adempas 1.5 mg – pack of 42 film-coated tablets - EU/1/13/907/007 
Adempas 1.5 mg – pack of 84 film-coated tablets - EU/1/13/907/008 
Adempas 1.5 mg – pack of 90 film-coated tablets - EU/1/13/907/009 
Adempas 1.5 mg – pack of 294 film-coated tablets - EU/1/13/907/018 
Adempas 2 mg – pack of 42 film-coated tablets - EU/1/13/907/010 
Adempas 2 mg – pack of 84 film-coated tablets - EU/1/13/907/011 
Adempas 2 mg – pack of 90 film-coated tablets - EU/1/13/907/012 
Adempas 2 mg – pack of 294 film-coated tablets - EU/1/13/907/019 
Adempas 2.5 mg – pack of 42 film-coated tablets - EU/1/13/907/013 
Adempas 2.5 mg – pack of 84 film-coated tablets - EU/1/13/907/014 
Adempas 2.5 mg – pack of 90 film-coated tablets - EU/1/13/907/015 
Adempas 2.5 mg – pack of 294 film-coated tablets - EU/1/13/907/020 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 



29 

16. INFORMATION IN BRAILLE 
 
Adempas 0.5 mg, 1 mg, 1.5 mg, 2 mg or 2.5 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 



30 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER - PACKS OF 42, 84, 90, 294 FILM-COATED TABLETS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Adempas 0.5 mg tablets 
Adempas 1 mg tablets 
Adempas 1.5 mg tablets 
Adempas 2 mg tablets 
Adempas 2.5 mg tablets 
riociguat 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer (Logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
MON 
TUE 
WED 
THU 
FRI 
SAT 
SUN 
 

       
 
 



31 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



32 

  
Package Leaflet: Information for the user 

 
Adempas 0.5 mg film-coated tablets 
Adempas 1 mg film-coated tablets 

Adempas 1.5 mg film-coated tablets 
Adempas 2 mg film-coated tablets 

Adempas 2.5 mg film-coated tablets 
 

riociguat 
 

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 Adempas is and what it is used for 
2. What you need to know before you take Adempas 
3. How to take Adempas 
4. Possible side effects 
5. How to store Adempas 
6. Contents of the pack and other information 
 
 
1. What Adempas is and what it is used for 
 
Adempas contains the active substance riociguat. Riociguat is a type of medicine called a guanylate 
cyclase (sGC)-stimulator. It works by widening the pulmonary arteries (the blood vessels that connect 
the heart to the lungs), making it easier for the heart to pump blood through the lungs. Adempas can be 
used to treat adults with certain forms of pulmonary hypertension, a condition in which these blood 
vessels become narrowed, making it harder for the heart to pump blood through them and leading to 
high blood pressure in the vessels. Because the heart must work harder than normal, people with 
pulmonary hypertension feel tired, dizzy and short of breath. By widening the narrowed arteries, 
Adempas leads to an improvement in your ability to carry out physical activity. 
 
Adempas is used in either of two types of pulmonary hypertension: 
 
 chronic thromboembolic pulmonary hypertension (CTEPH). 

In CTEPH, the blood vessels of the lung are blocked or narrowed with blood clots. Adempas 
can be used for patients with CTEPH who cannot be operated on, or after surgery for patients in 
whom increased blood pressure in the lungs remains or returns. 

 certain types of pulmonary arterial hypertension (PAH).  
In PAH, the wall of the blood vessels of the lungs are thickened and the vessels become 
narrowed. Adempas is only prescribed for certain forms of PAH, i.e. idiopathic PAH (the cause 
of PAH is unknown), heritable PAH and PAH caused by connective tissue disease. Your doctor 
will check this. Adempas can be taken alone or together with certain other medicines used to 
treat PAH. 

 
 



33 

2. What you need to know before you take Adempas 
 
Do not take Adempas: 
- if you are taking certain medicines called PDE5 inhibitors (e.g. sildenafil, tadalafil, vardenafil). 

These are medicines used for the treatment of high blood pressure in the arteries of the lungs 
(PAH) or erectile dysfunction. 

- if you have severe liver problems (severe hepatic impairment, Child Pugh C). 
- if you are allergic to riociguat or any of the other ingredients of this medicine (listed in 

section 6). 
- if you are pregnant. 
- if you are taking nitrates or nitric oxide donors (such as amyl nitrite) in any form, medicines 

often used to treat high blood pressure, chest pain or heart disease. This also includes 
recreational drugs called poppers. 

- if you have low blood pressure (systolic blood pressure less than 95 mmHg) before starting 
first treatment with this medicine. 

- if you have increased pressure in your pulmonary circulation associated with scarring of the 
lungs, of unknown cause (idiopathic pulmonary pneumonia).  

If any of these applies to you, talk to your doctor first and do not take Adempas. 
 
Warnings and precautions 
Talk to your doctor or pharmacist before taking Adempas if: 
- you have recently experienced serious bleeding from the lung, or if you have undergone 

treatment to stop coughing up blood (bronchial arterial embolisation). 
- you take blood-thinning medicines (anticoagulants) since this may cause bleeding from the 

lungs. Your doctor will regularly monitor you. 
- you feel short of breath during treatment with this medicine, this can be caused by a build-up 

of fluid in the lungs. Talk to your doctor if this happens. 
- you have any symptoms of low blood pressure (hypotension) such as dizziness, 

lightheadedness, or fainting or if you are taking medicines to lower your blood pressure or 
medicines that cause an increase in urination or if you have problems with your heart or 
circulation. Your doctor may decide to monitor your blood pressure. If you are older than 
65 years, you have an increased risk of developing low blood pressure. 

- you take medicines used to treat fungal infections (e.g. ketoconazole, posaconazole, 
itraconazole) or medicines for the treatment of HIV infection (e.g. abacavir, atazanavir, 
cobicistat, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, lamivudine, rilpivirine, 
ritonavir, and tenofovir). Your doctor will monitor your health status and should consider a 
reduced starting dose for Adempas.  

- your kidneys do not work properly (creatinine clearance < 30 ml/min) or if you are on 
dialysis as the use of this medicine is not recommended. 

- you have moderate liver problems (hepatic impairment, Child Pugh B). 
- you start or stop smoking during treatment with this medicine, because this may influence the 

level of riociguat in your blood. 
 
You will receive Adempas only for special types of pulmonary arterial hypertension (PAH), see 
section 1. There is no experience in the use of Adempas in other types of PAH. Use of Adempas in 
other types of PAH is therefore not recommended. Your doctor will check if Adempas is suitable for 
you. 
 
Children and adolescents 
The use of Adempas in children and adolescents (under 18 years of age) should be avoided because 
efficacy and safety have not been established for this age group. 
 



34 

Other medicines and Adempas 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, in particular, medicines used for: 
- high blood pressure or heart disease (such as nitrates and amyl nitrite) in any form, as you must 

not take those medicines together with Adempas. 
- high blood pressure in the lung vessels (the pulmonary arteries), as you must not take certain 

medicines (sildenafil and tadalafil) together with Adempas. Other medicines for high blood 
pressure in the lung vessels (PAH), such as bosentan and iloprost, can be used with Adempas, 
but you should still tell your doctor. 

- erectile dysfunction (such as sildenafil, tadalafil, vardenafil), as you must not take those 
medicines together with Adempas. 

- fungal infections (such as ketoconazole, posaconazole, itraconazole) or HIV infection (such as 
abacavir, atazanavir, cobicistat, darunavir, dolutegravir, efavirenz, elvitegravir, 
emtricitabine, rilpivirine or ritonavir)  because alternative treatment options may be 
considered. If you already take one of these medicines and start treatment with Adempas, 
your doctor will monitor your health status and should consider a reduced starting dose for 
Adempas. 

- epilepsy (e.g. phenytoin, carbamazepine, phenobarbitone). 
- depression (St. John’s Wort). 
- preventing rejection of transplanted organs (ciclosporin). 
- joint and muscular pain (niflumic acid). 
- cancer (such as erlotinib, gefitinib). 
- stomach disease or heartburn (antacids such as aluminium hydroxide/magnesium hydroxide). 

These antacid medicines should be taken at least two hours before or one hour after taking 
Adempas. 

- nausea, vomiting (feeling or being sick) (such as granisetron). 
 
Smoking 
If you smoke, it is recommended that you stop, as smoking may reduce the effectiveness of these 
tablets. Please tell your doctor if you smoke or if you stop smoking during treatment. 
 
Pregnancy and breast-feeding 
 
Pregnancy 
Do not take Adempas during pregnancy. If there is a chance you could become pregnant, use reliable 
forms of contraception while you are taking these tablets. You are also advised to take monthly 
pregnancy tests. If you are pregnant, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
 
Breast-feeding 
If you are breast-feeding or planning to breast-feed, ask your doctor or pharmacist for advice before 
taking this medicine because it might harm your baby. You should not breast-feed while taking this 
medicine. Your doctor will decide with you if you either should stop breast-feeding or stop treatment 
with Adempas. 
 
Driving and using machines 
Adempas has moderate influence on the ability to drive and use machines. It may cause side effects 
such as dizziness. You should be aware of the side effects of this medicine before driving or using 
machines (see section 4). 
 
Adempas contains lactose 
If you have been told by a doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicine. 
 



35 

Adempas contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium 
free”. 
 
 
3. How to take Adempas 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
Treatment should only be started and monitored by a doctor experienced in the treatment of CTEPH or 
PAH. During the first weeks of treatment your doctor will need to measure your blood pressure at 
regular intervals. Adempas is available in different strengths and by checking your blood pressure 
regularly at the beginning of your treatment, your doctor will ensure that you are taking the 
appropriate dose. 
 
Crushed tablets: 
If you have difficulty swallowing the whole tablet, talk to your doctor about other ways to take 
Adempas. The tablet may be crushed and mixed with water or a soft food, such as apple sauce, 
immediately before you take it. 
 
Dose 
The recommended starting dose is a 1-mg tablet taken 3 times a day for 2 weeks.  
The tablets should be taken 3 times a day, approximately 6 to 8 hours apart. They can generally be 
taken with or without food.  
However, if you are prone to having low blood pressure (hypotension), you should not switch from 
taking Adempas with food to taking Adempas without food because it may affect how you react to this 
medicine.  
 
Your doctor will increase the dose every 2 weeks to a maximum of 2.5 mg 3 times a day (maximum 
daily dose of 7.5 mg) unless you experience any side effects or very low blood pressure. In this case, 
your doctor will prescribe you Adempas at the highest dose you are comfortable on. For some patients 
lower doses three times a day might be sufficient, the optimal dose will be selected by your doctor.  
 
Special considerations for patients with kidney or liver problems 
You should tell your doctor if you have kidney or liver problems. Your dose may need to be adjusted. 
If you have severe liver problems (Child Pugh C), do not take Adempas. 
 
65 years or older 
If you are 65 years or older your doctor will take extra care in adjusting your dose of Adempas, 
because you may be at greater risk of low blood pressure. 
 
Special considerations for patients who smoke 
You should tell your doctor if you start or stop smoking during treatment with this medicine. Your 
dose may be adjusted. 
 
If you take more Adempas than you should 
If you have taken more tablets than you should and experience any side effects (see section 4), please 
contact your doctor. If your blood pressure drops (which can make you feel dizzy) then you may need 
immediate medical attention. 
 
If you forget to take Adempas 
Do not take a double dose to make up for a forgotten dose. If you miss a dose, continue with the next 
dose as planned. 
 



36 

If you stop taking Adempas 
Do not stop taking this medicine without talking to your doctor first, because this medicine prevents 
the progression of the disease. If your treatment has to be stopped for 3 days or more, please tell your 
doctor before restarting your treatment. 
 
If you are transitioning between sildenafil or tadalafil and Adempas 
 If you are stopping sildenafil, you must wait at least 24 hours before you take Adempas.  
 If you are stopping tadalafil, you must wait at least 48 hours before you take Adempas.  
 If you are stopping Adempas to change to another medicine called a PDE5 inihibitor (e.g. 

sildenafil or tadalafil) you must wait at least 24 hours from your last dose of Adempas before you 
take the PDE5 inhibitor. 

 
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. 
 
The most serious side effects are: 
 coughing up blood (haemoptysis) (common side effect, may affect up to 1 in 10 people), 
 acute bleeding from the lungs (pulmonary haemorrhage) may result in coughing up blood, 

cases with fatal outcomes were observed (uncommon side effect, may affect up to 
1 in 100 people). 

If this happens, contact your doctor immediately as you may need urgent medical treatment.  
 
Overall list of possible side effects: 
 
Very common: may affect more than 1 in 10 people 
- headache 
- dizziness 
- indigestion (dyspepsia) 
- swelling of limbs (oedema peripheral) 
- diarrhoea  
- feeling or being sick (nausea and vomiting) 
 
Common: may affect up to 1 in 10 people 
- inflammation of the stomach (gastritis) 
- inflammation in the digestive system (gastroenteritis) 
- reduction of red blood cells (anaemia) seen as pale skin, weakness or breathlessness  
- awareness of an irregular, hard, or rapid heartbeat (palpitation) 
- low blood pressure (hypotension)  
- nose bleed (epistaxis) 
- difficulty breathing through your nose (nasal congestion) 
- pain in the stomach, intestine or abdomen (gastrointestinal and abdominal pain) 
- heartburn (gastro-oesophageal reflux disease) 
- difficulty in swallowing (dysphagia) 
- constipation  
- bloating (abdominal distension) 
 
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. 
 



37 

 
5. How to store Adempas 
 
Keep this medicine out of the sight and reach of children. 
 
This medicine does not require any special storage conditions. 
 
Do not use this medicine after the expiry date which is stated on the blister and carton after “EXP”. 
The expiry date refers to the last day of that month. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Adempas contains 
 
- The active substance is riociguat. 

Adempas 0.5 mg film-coated tablets 
Each film-coated tablet contains 0.5 mg riociguat. 

Adempas 1 mg film-coated tablets 
Each film-coated tablet contains 1 mg riociguat. 

Adempas 1.5 mg film-coated tablets 
Each film-coated tablet contains 1.5 mg riociguat. 

Adempas 2 mg film-coated tablets 
Each film-coated tablet contains 2 mg riociguat. 

Adempas 2.5 mg film-coated tablets 
Each film-coated tablet contains 2.5 mg riociguat. 

 
- The other ingredients are: 

Tablet core: cellulose microcrystalline, crospovidone (type B), hypromellose 5 cP, lactose 
monohydrate, magnesium stearate and sodium laurilsulfate (see end of section 2 for further 
information on lactose). 
Film-coat: hydroxypropylcellulose, hypromellose 3 cP, propylene glycol (E 1520) and titanium 
dioxide (E 171). 
Adempas 1 mg, 1.5 mg tablets also contains iron oxide yellow (E 172). 
Adempas 2 mg and 2.5 mg tablets also contains iron oxide yellow (E172) and iron oxide red 
(E 172). 

 
What Adempas looks like and contents of the pack 
 
Adempas is a film-coated tablet: 
Adempas 0.5 mg film-coated tablets 
 0.5 mg tablet: white, round, biconvex tablets of 6 mm, marked with the Bayer cross on one side 

and 0.5 and an “R” on the other side.  
Adempas 1 mg film-coated tablets 
 1 mg tablet: pale yellow, round, biconvex tablets of 6 mm, marked with the Bayer cross on one 

side and 1 and an “R” on the other side.  
Adempas 1.5 mg film-coated tablets 
 1.5 mg tablet: yellow-orange, round, biconvex tablets of 6 mm, marked with the Bayer cross on 

one side and 1.5 and an “R” on the other side.  
Adempas 2 mg film-coated tablets 
 2 mg tablet: pale orange, round, biconvex tablets of 6 mm, marked with the Bayer cross on one 

side and 2 and an “R” on the other side.  
Adempas 2.5 mg film-coated tablets 



38 

 2.5 mg tablet: red-orange, round, biconvex tablets of 6 mm, marked with the Bayer cross on one 
side and 2.5 and an “R” on the other side.  

 
They are available in packs of:  
 42 tablets: two transparent calendar blisters of 21 tablets each. 
 84 tablets: four transparent calendar blisters of 21 tablets each. 
 90 tablets: five transparent blisters of 18 tablets each. 
 294 tablets: fourteen transparent calendar blisters of 21 tablets each. 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Bayer AG 
51368 Leverkusen 
Germany 
 
Manufacturer 
Bayer AG 
Kaiser-Wilhelm-Allee 
51368 Leverkusen 
Germany 
 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België / Belgique / Belgien 
MSD Belgium BVBA/SPRL 
Tél/Tel:  +32(0)27766211 
dpoc_belux@merck.com 

Lietuva 
UAB Merck Sharp & Dohme 
Tel: + 370 5 2780247 
msd_lietuva@merck.com 
 

България 
Мерк Шарп и Доум България ЕООД 
Teл.: + 359 2 819 37 37 
info-msdbg@merck.com 
 

Luxembourg / Luxemburg 
MSD Belgium BVBA/SPRL 
Tél/Tel: +32(0)27766211 
dpoc_belux@merck.com 
 

Česká republika 
Merck Sharp & Dohme s.r.o. 
Tel.: +420 233 010 111 
dpoc_czechslovak@merck.com 
 

Magyarország 
MSD Pharma Hungary Kft. 
Tel.: + 36 1 888 5300 
hungary_msd@merck.com 
 

Danmark 
MSD Danmark ApS 
Tlf: + 45 4482 4000 
dkmail@merck.com 
 

Malta 
Merck Sharp & Dohme Cyprus Limited 
Tel: 8007 4433 (+356 99917558) 
malta_info@merck.com 
 

Deutschland 
MSD SHARP & DOHME GMBH 
Tel: 0800 673 673 673 (+49 (0) 89 4561 2612) 
email@msd.de 
 

Nederland 
Merck Sharp & Dohme B.V. 
Tel: 0800 9999 000 (+ 31 23 5153153) 
medicalinfo.nl@merck.com 
 

Eesti 
Merck Sharp & Dohme OÜ 
Tel: + 372 6144 200 
msdeesti@merck.com 
 

Norge 
MSD (Norge) AS 
Tlf: + 47 32 20 73 00 
msdnorge@msd.no 
 



39 

Ελλάδα 
MSD Α.Φ.Β.Ε.Ε 
Τηλ: + 30 210 98 97 300 
dpoc_greece@merck.com 
 

Österreich 
Merck Sharp & Dohme Ges.m.b.H. 
Tel: +43 (0) 1 26 044 
msd-medizin@merck.com 
 

España 
Merck Sharp & Dohme de España, S.A. 
Tel: +34 91 321 06 00 
msd_info@merck.com 
 

Polska 
MSD Polska Sp.z o.o. 
Tel.: +48 22 549 51 00 
msdpolska@merck.com 
 

France 
MSD France 
Tél : + 33 (0) 1 80 46 40 40 
 

Portugal 
Merck Sharp & Dohme, Lda 
Tel: + 351 214465700 
inform_pt@merck.com 
 

Hrvatska 
Merck Sharp & Dohme d.o.o. 
Tel: + 385 1 6611 333 
croatia_info@merck.com 
 

România 
Merck Sharp & Dohme Romania S.R.L. 
Tel: + 40 21 529 29 00 
msdromania@merck.com 
 

Ireland 
Merck Sharp & Dohme Ireland (Human Health) 
Limited 
Tel: +353 (0)1 2998700 
medinfo_ireland@merck.com 
 

Slovenija 
Merck Sharp & Dohme, inovativna zdravila d.o.o. 
Tel: + 386 1 5204201 
msd_slovenia@merck.com 
 

Ísland 
Vistor hf. 
Sími: + 354 535 7000 
 

Slovenská republika 
Merck Sharp & Dohme, s. r. o. 
Tel: + 421 2 58282010 
dpoc_czechslovak@merck.com 
 

Italia 
MSD Italia S.r.l. 
Tel: +39 06 361911 
medicalinformation.it@merck.com 
 

Suomi/Finland 
MSD Finland Oy 
Puh/Tel: + 358 (0)9 804650 
info@msd.fi 
 

Κύπρος 
Merck Sharp & Dohme Cyprus Limited 
Τηλ: 800 00 673 (+357 22866700) 
cyprus_info@merck.com 
 

Sverige 
Merck Sharp & Dohme (Sweden) AB 
Tel: + 46 77 5700488 
medicinskinfo@merck.com 
 

Latvija 
SIA Merck Sharp & Dohme Latvija 
Tel: + 371 67364224 
msd_lv@merck.com 
 

United Kingdom 
Merck Sharp & Dohme Limited  
Tel: +44 (0) 1992 467272 
medicalinformationuk@merck.com 
 

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


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