ADEMPAS 1.5mg tablets medication leaflet

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

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.

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.

Film-coated tablet (tablet).

- 0.5 mg tablet: white, round, biconvex tablets of 6 mm, marked with the Bayer cross on one sideand 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 oneside 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 onone side and 1.5 and an “R” on the other side.

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

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 thetreatment 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).

Paediatrics

Adempas is indicated for the treatment of PAH in paediatric patients aged less than 18 years of ageand body weight ≥ 50 kg with WHO Functional Class (FC) II to III in combination with endothelinreceptor antagonists (see section 5.1).

Treatment should only be initiated and monitored by a physician experienced in the treatment of

CTEPH or PAH.

The recommended starting dose is 1 mg 3 times daily for 2 weeks. Tablets should be taken 3 timesdaily approximately 6 to 8 hours apart (see section 5.2).

Titration

Adult patients

Dose should be increased by 0.5 mg 3 times daily every two weeks to a maximum of 2.5 mg 3 timesdaily, if systolic blood pressure is ≥95 mmHg and the patient has no signs or symptoms ofhypotension. In some PAH patients, an adequate response on the 6-minute walk distance (6MWD)may be reached at a dose of 1.5 mg 3 times a day (see section 5.1). If systolic blood pressure fallsbelow 95 mmHg, the dose should be maintained provided the patient does not show any signs orsymptoms of hypotension. If at any time during the up-titration phase systolic blood pressuredecreases below 95 mmHg and the patient shows signs or symptoms of hypotension the current doseshould be decreased by 0.5 mg 3 times daily.

Paediatric patients of 6 years of age or older

Adempas is available for pediatric use as a tablet for those with body weight ≥ 50 kg.

Titration of riociguat dose is to be performed based on the patient’s systolic blood pressure andgeneral tolerability at the discretion of the treating physician/healthcare provider. If systolic bloodpressure is ≥ 90 mmHg for the 6 to < 12 years age group or ≥ 95 mmHg for the 12 to < 18 years agegroup and the patient has no signs or symptoms of hypotension, the dosage should be increased by0.5 mg every 2 weeks to a maximum dose of 2.5 mg 3 times daily.

If systolic blood pressure falls below these specified levels the dosage should be maintained providedthe patient does not show any signs or symptoms of hypotension. If at any time during the up-titrationphase systolic blood pressure decreases below the specified levels, or the patient shows signs andsymptoms of hypotension the current dose should be decreased by 0.5 mg 3 times daily.

(See below for further information on other indications and other age groups)

The established individual dose should be maintained unless signs and symptoms of hypotensionoccur.

The maximum total daily dose is 7.5 mg (i.e., 2.5 mg 3 times daily) for adults and paediatric patientswith body weight of at least 50 kg.

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.

In case treatment has to be interrupted for 3 days or more, treatment should be restarted with 1 mg3 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 in adults and children at least 24 hours prior to administration ofriociguat.

Tadalafil must be discontinued at least 48 hours in adults and 72 hours in children prior toadministration of riociguat.

Riociguat must be discontinued in adults and children 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 (seesections pct. 4.3, 4.5 and 5.1).

Individual dose titration at treatment initiation allows adjustment of the dose to the patient´s needs.

In elderly patients (65 years or older) there is a higher risk of hypotension and therefore particular careshould be exercised during individual dose titration (see section 5.2).

Patients with severe hepatic impairment (Child Pugh C) have not been studied and therefore use ofriociguat is contraindicated in these patients (see section 4.3). Patients with moderate hepaticimpairment (Child Pugh B) showed a higher exposure to this medicinal product (see section 5.2).

Particular care should be exercised during individual dose titration.

No clinical data are available in children with hepatic impairment.

Data in patients with severe renal impairment (creatinine clearance <30 mL/min) are limited and thereare no data for patients on dialysis. Therefore, use of riociguat is not recommended in these patients(see section 4.4).

Patients with mild and moderate renal impairment (creatinine clearance <80 - 30 mL/min) showed ahigher exposure to this medicinal product (see section 5.2). There is a higher risk of hypotension inpatients with renal impairment, therefore particular care should be exercised during individual dosetitration.

No clinical data are available in children with renal impairment.

Patients on stable doses of strong multi pathway CYP/P-glycoprotein (P-gp) and breast cancerresistance protein (BCRP) inhibitors

Coadministration of riociguat with strong multi pathway CYP and P-gp/BCRP inhibitors such as azoleantimycotics (e.g. ketoconazole, itraconazole) or HIV protease inhibitors (e.g. ritonavir) increasesexposure to riociguat (see section 4.5). When initiating riociguat in patients on stable doses of strongmulti pathway CYP and P-gp/BCRP inhibitors, consider a starting dose of 0.5 mg 3 times a day tomitigate the risk of hypotension. Monitor for signs and symptoms of hypotension on initiation and ontreatment. Consider a dose reduction for patients on riociguat doses higher than or equal to 1.0 mg ifthe patient develops signs or symptoms of hypotension (see sections 4.4 and 4.5).

No clinical data is available in children receiving concomitant systemic treatment with strong CYP/P-gp and BCRP inhibitors.

The safety and efficacy of riociguat have not been established in the following pediatric populations:

- Children aged < 6 years (see section 4.1), because of safety concerns. Non clinical data showundesirable effects on growing bone (see section 5.3).

- Children with PAH aged 6 to < 12 years with systolic blood pressure < 90 mmHg at treatmentinitiation (see section 4.3)

- Children and adolescents with PAH aged 12 to < 18 years with systolic bloodpressure <95 mmHg at treatment initiation (see section 4.3)

- Children and adolescents with CTEPH aged < 18 years old (see section 4.1).

No clinical trial data are available. Therefore, the use of riociguat is not recommended in thesepopulations.

Smokers

Current smokers should be advised to stop smoking due to a risk of a lower response. Plasmaconcentrations of riociguat in smokers are reduced compared to non-smokers. A dose increase to themaximum daily dose of 2.5 mg 3 times daily may be required in patients who are smoking or startsmoking during treatment (see sections 4.5 and 5.2).

A dose decrease may be required in patients who stop smoking.

For oral use.

Tablets can generally be taken with or without food. For patients prone to hypotension, as aprecautionary measure, switches between fed and fasted riociguat intake are not recommendedbecause of increased peak plasma levels of riociguat in the fasting compared to the fed state (seesection 5.2).

Crushed tablets

For patients who are unable to swallow whole tablets, Adempas tablets may be crushed and mixedwith water or soft foods, such as apple sauce, immediately prior to use and administered orally (seesection 5.2).

- Co-administration with PDE5 inhibitors (such as sildenafil, tadalafil, vardenafil) (seesections 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 formincluding recreational drugs called ‘poppers’ (see section 4.5).

- Concomitant use with other soluble guanylate cyclase stimulators.

- Treatment initiation for

* children aged 6 to < 12 years with systolic blood pressure < 90 mmHg,

* patients ≥ 12 years with systolic blood pressure < 95 mmHg.

- Patients with pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-

IIP) (see section 5.1)

In pulmonary arterial hypertension, studies with riociguat have been mainly performed in formsrelated to idiopathic or heritable PAH and PAH associated with connective tissue disease. The use ofriociguat in other forms of PAH not studied is not recommended (see section 5.1).

In chronic thromboembolic pulmonary hypertension, pulmonary endarterectomy is the treatment ofchoice as it is a potentially curative option. According to standard medical practice, expert assessmentof operability should be done prior to treatment with riociguat.

Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonaryveno-occlusive disease (PVOD). Therefore, administration of riociguat to such patients is notrecommended. Should signs of pulmonary oedema occur, the possibility of associated PVOD shouldbe 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 takinganticoagulants according to common medical practice is recommended.

The risk of serious and fatal respiratory tract bleeding may be further increased under treatment withriociguat, especially in the presence of risk factors, such as recent episodes of serious haemoptysisincluding those managed by bronchial arterial embolisation. Riociguat should be avoided in patientswith a history of serious haemoptysis or who have previously undergone bronchial arterialembolisation. In case of respiratory tract bleeding, the prescriber should regularly assess the benefit-risk of treatment continuation.

Serious bleeding occurred in 2.4% (12/490) of patients taking riociguat compared to 0/214 of placebopatients. Serious haemoptysis occurred in 1% (5/490) patients taking riociguat compared to 0/214patients taking placebo, including one event with fatal outcome. Serious haemorrhagic events alsoincluded 2 patients with vaginal haemorrhage, 2 with catheter site haemorrhage, and 1 each withsubdural haematoma, haematemesis, and intra-abdominal haemorrhage.

Riociguat has vasodilatory properties which may result in lowering of blood pressure. Beforeprescribing riociguat, physicians should carefully consider whether patients with certain underlyingconditions, could be adversely affected by vasodilatory effects (e.g. patients on antihypertensivetherapy or with resting hypotension, hypovolaemia, severe left ventricular outflow obstruction orautonomic dysfunction).

Riociguat must not be used in patients with a systolic blood pressure below 95 mmHg (seesection 4.3). Patients older than 65 years are at increased risk of hypotension. Therefore, cautionshould be exercised when administering riociguat in these patients.

Data in adult patients with severe renal impairment (creatinine clearance < 30 mL/min) are limited andthere 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 isincreased riociguat exposure in these patients (see section 5.2). There is a higher risk of hypotension inthese patients, particular care should be exercised during individual dose titration.

There is no experience in adult patients with severe hepatic impairment (Child Pugh C); riociguat iscontraindicated in these patients (see section 4.3). PK data show that higher riociguat exposure wasobserved in patients with moderate hepatic impairment (Child Pugh B) (see section 5.2). Particularcare 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 initiationof treatment; riociguat is not recommended in these patients.

Pregnancy/contraception

Riociguat is contraindicated during pregnancy (see section 4.3). Therefore, female patients at potentialrisk of pregnancy must use an effective method of contraception. Monthly pregnancy tests arerecommended.

Smokers

Plasma concentrations of riociguat in smokers are reduced compared to non-smokers. Dose adjustmentmay be necessary in patients who start or stop smoking during treatment with riociguat (seesections 4.2 and 5.2).

* The concomitant use of riociguat with strong multi pathway CYP and P-gp/BCRP inhibitorssuch as azole antimycotics (e.g. ketoconazole, posaconazole, itraconazole) or HIV proteaseinhibitors (e.g. ritonavir) results in a pronounced increase in riociguat exposure (see sections 4.5and 5.2).

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

* In patients on stable doses of riociguat, the initiation of strong multi pathway CYP and

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

* The concomitant use of riociguat with strong CYP1A1 inhibitors, such as the tyrosine kinaseinhibitor erlotinib, and strong P-glycoprotein (P-gp)/breast cancer resistance protein (BCRP)inhibitors, such as the immuno-suppressive agent cyclosporine A, may increase riociguatexposure (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 orglucose-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 “sodiumfree”.

Interaction studies have only been performed in adults. The absolute extent of interactions in thepaediatric population is not known. The interaction data obtained in adults and the warnings in section4.4 should be taken into account for the paediatric population.

Nitrates

In a clinical study the highest dose of riociguat (2.5 mg tablets 3 times daily) potentiated the bloodpressure lowering effect of sublingual nitroglycerin (0.4 mg) taken 4 and 8 hours after intake.

Therefore, co-administration of riociguat with nitrates or nitric oxide donors (such as amyl nitrite) inany 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 whenriociguat was combined with either sildenafil or vardenafil. With increased doses, over additive effectson systemic blood pressure were observed in some cases.

In an exploratory interaction study in 7 patients with PAH on stable sildenafil treatment (20 mg3 times daily) single doses of riociguat (0.5 mg and 1 mg sequentially) showed additivehaemodynamic 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 3 timesdaily) and riociguat (1.0 mg to 2.5 mg 3 times daily) compared to sildenafil alone was performed. Inthe long-term extension part of this study (non-controlled) the concomitant use of sildenafil andriociguat resulted in a high rate of discontinuation, predominately due to hypotension. There was noevidence of a favourable clinical effect of the combination in the population studied.

Concomitant use of riociguat with PDE5 inhibitors (such as sildenafil, tadalafil, vardenafil) iscontraindicated (see sections 4.2 and 4.3).

RESPITE was a 24-week, uncontrolled study to investigate switching from PDE5 inhibitors toriociguat, 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 thetransition from PDE5 inhibitors to riociguat, median treatment-free time for sildenafil was 1 day andfor tadalafil 3 days. Overall, the safety profile observed in the study was comparable with thatobserved 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 tostudy drug. Changes from baseline suggested beneficial effects in selected patients, e.g. improvementin 6MWD (+31 m), 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).

Soluble Guanylate Cyclase Stimulators

Concomitant use of riociguat with other soluble guanylate cyclase stimulators is contraindicated (seesection 4.3).

Warfarin/phenprocoumon

Concomitant treatment of riociguat and warfarin did not alter prothrombin time induced by theanticoagulant. 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 wasdemonstrated in vivo.

Acetylsalicylic acid

Riociguat did not potentiate the bleeding time caused by acetyl-salicylic acid or affect the plateletaggregation 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 ofunchanged 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 andthe 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, andtenofovir) on riociguat exposure was investigated in a dedicated study in HIV patients. Concomitantadministration of HAART combinations led to an increase in riociguat mean AUC of up to about160% and to an approximate 30% increase in mean Cmax. The safety profile observed in HIV patientstaking 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 riociguat is initiated in patients on stable doses of strongmulti pathway CYP (especially CYP1A1 and CYP3A4) and P-gp/BCRP inhibitors, e.g. as containedin HAART, consider a reduced starting dose. It is recommended to monitor these patients for signsand 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 beenshown to be a multi-pathway CYP and P-gp/breast cancer resistance protein (BCRP) inhibitor forriociguat metabolism and excretion (see section 5.2). Concomitant administration of 400 mg oncedaily 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 clearancedecreased from 6.1 to 2.4 L/h.

To mitigate the risk of hypotension when riociguat is initiated in patients on stable doses of strongmulti 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 thesepatients for signs and symptoms of hypotension (see sections 4.2 and 4.4).

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 theexposure 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 ondose titration (see section 4.2).

From the recombinant CYP isoforms investigated in vitro CYP1A1 catalysed formation of riociguat’smain metabolite most effectively. The class of tyrosine kinase inhibitors was identified as potentinhibitors 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 riociguatexposure, especially in smokers (see section 5.2). Strong CYP1A1 inhibitors should be used withcaution (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 medicinalproducts 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 hoursbefore, 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-stateplasma concentrations in PAH patients by 27% (see sections 4.1 and 5.1). For co-administration withbosentan 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 (seesection 4.2).

Smoking

In cigarette smokers riociguat exposure is reduced by 50-60% (see section 5.2). Therefore, patients areadvised 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, clinicallyrelevant 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 riociguat therapy (see section 4.3). Riociguat (2.5 mg 3 times perday) did not have a clinically meaningful effect on the plasma levels of combined oral contraceptivescontaining levonorgestrel and ethinyl estradiol when concomitantly administered to healthy femalesubjects. Based on this study and as riociguat is not an inducer of any of the relevant metabolicenzymes, also no pharmacokinetic interaction is expected with other hormonal contraceptives.

Women and female adolescents of childbearing potential must use effective contraception duringtreatment with riociguat.

There are no data from the use of riociguat in pregnant women. Studies in animals have shownreproductive toxicity and placental transfer (see section 5.3). Therefore, riociguat is contraindicatedduring pregnancy (see section 4.3). Monthly pregnancy tests are recommended.

No data on the use of riociguat in breast-feeding women are available. Data from animals indicate thatriociguat is excreted into milk. Due to the potential for serious adverse reactions in breast-fed infantsriociguat 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.

No specific studies with riociguat in humans have been conducted to evaluate effects on fertility. In areproduction toxicity study in rats, decreased testes weights were seen, but there were no effects onfertility (see section 5.3). The relevance of this finding for humans is unknown.

Riociguat has moderate influence on the ability to cycle, drive and use machines. Dizziness has beenreported and may affect the ability to drive and use machines (see section 4.8). Patients should beaware of how they react to this medicinal product, before cycling, driving or using machines.

The safety of riociguat in adults has been evaluated in phase III studies of 650 patients with CTEPHand PAH receiving at least one dose of riociguat (see section 5.1). With longer observation inuncontrolled long-term extension studies the safety profile was similar to that observed in the placebocontrolled phase III trials.

Most of the adverse reactions are caused by relaxation of smooth muscle cells in vasculature or thegastrointestinal tract.

The most commonly reported adverse reactions, occurring in ≥ 10% of patients under riociguattreatment (up to 2.5 mg 3 times daily), were headache, dizziness, dyspepsia, peripheral oedema,nausea, diarrhoea and vomiting.

Serious haemoptysis and pulmonary haemorrhage, including cases with fatal outcome have beenobserved in patients with CTEPH or PAH treated with riociguat (see section 4.4).

The safety profile of Adempas in patients with CTEPH and PAH appeared to be similar, thereforeadverse reactions identified from placebo controlled 12 and 16 weeks clinical studies are presented aspooled frequency in the table listed below (see table 1).

The adverse reactions reported with Adempas are listed in the table below by MedDRA system organclass 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 adult patients in phase III studies (pooled

CHEST 1 and PATENT 1 data)

MedDRA Very common Common Uncommon

System Organ Class

Infections and infestations Gastroenteritis

Blood and lymphatic Anaemia (incl. respectivesystem disorders laboratory parameters)

Nervous system disorders Dizziness,

Cardiac disorders Palpitations

Vascular disorders Hypotension

Respiratory, thoracic and Haemoptysis, Pulmonarymediastinal disorders Epistaxis, haemorrhage*

Nasal congestion

Gastrointestinal disorders Dyspepsia, Gastritis,

Diarrhoea, Gastro-oesophageal reflux

Nausea, disease,

Vomiting Dysphagia,

Gastrointestinal andabdominal pains,

Constipation,

Abdominal distension

General disorders and Oedemaadministration site peripheralconditions

* fatal pulmonary haemorrhage was reported in uncontrolled long-term extension studies

The safety of riociguat has been investigated in 24 paediatric patients aged 6 to less than 18 years over24 weeks in a open-label uncontrolled trial (PATENT-CHILD) consisting of an individual dosetitration phase starting with 1 mg (body weight adjusted) for 8 weeks and a maintenance phase for upto 16 weeks (see section 4.2), followed by an optional long-term extension phase. Most commonadverse reactions including the long-term extension phase were hypotension and headache occurringin 4/24, and 2/24 patients, respectively.

Overall, the safety data is consistent with the safety profile observed in adults.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In adults, inadvertent overdosing with total daily doses of 9 to 25 mg riociguat between 2 to 32 dayswas 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.

Pharmacotherapeutic group: Antihypertensives (antihypertensives for pulmonary arterialhypertension)

ATC code: C02KX05

Riociguat is a stimulator of soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonarysystem and the receptor for nitric oxide (NO). When NO binds to sGC, the enzyme catalyses synthesisof the signalling molecule cyclic guanosine monophosphate (cGMP). Intra-cellular cGMP plays animportant role in regulating processes that influence vascular tone, proliferation, fibrosis, andinflammation.

Pulmonary hypertension is associated with endothelial dysfunction, impaired synthesis of NO andinsufficient stimulation of the NO-sGC-cGMP pathway.

Riociguat has a dual mode of action. It sensitises sGC to endogenous NO by stabilising the NO-sGCbinding. Riociguat also directly stimulates sGC independently of NO.

Riociguat restores the NO-sGC-cGMP pathway and leads to increased generation of cGMP.

Riociguat restores the NO-sGC-cGMP pathway resulting in a significant improvement of pulmonaryvascular haemodynamics and an increase in exercise ability.

There is a direct relationship between riociguat plasma concentration and haemodynamic parameterssuch as systemic and pulmonary vascular resistance, systolic blood pressure and cardiac output.

Efficacy in adult patients with CTEPH

A randomised, double-blind, multi-national, placebo controlled, phase III study (CHEST-1) wasconducted 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 bloodpressure and signs or symptoms of hypotension to the optimal individual dose (range 0.5 mg to 2.5 mg3 times daily) which was then maintained for a further 8 weeks. The primary endpoint of the studywas 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% confidenceinterval (CI): 25 m to 67 m; p<0.0001), compared to placebo. Results were consistent in the mainsub-groups evaluated (ITT analysis, see table 2).

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

Entire patient population Riociguat Placebo(n=173) (n=88)

Baseline (m) 342 356[SD] [82] [75]

Mean change from baseline (m) 39 -6[SD] [79] [84]

Placebo-adjusted difference (m) 4695% CI, [p-value] 25 to 67 [<0.0001]

FC III patient population Riociguat Placebo(n=107) (n=60)

Baseline (m) 326 345[SD] [81] [73]

Mean change from baseline (m) 38 -17[SD] [75] [95]

Placebo-adjusted difference (m) 5695% CI 29 to 83

FC II patient population Riociguat Placebo(n=55) (n=25)

Baseline (m) 387 386[SD] [59] [64]

Mean change from baseline (m) 45 20[SD] [82] [51]

Placebo-adjusted difference (m) 2595% CI -10 to 61

Inoperable patient population Riociguat Placebo(n=121) (n=68)

Baseline (m) 335 351[SD] [83] [75]

Mean change from baseline (m) 44 -8[SD] [84] [88]

Placebo-adjusted difference (m) 5495% CI 29 to 79

Patient population with CTEPH Riociguat Placebopost-PEA (n=52) (n=20)

Baseline (m) 360 374[SD] [78] [72]

Mean change from baseline (m) 27 1.8[SD] [68] [73]

Placebo- adjusted difference (m) 2795% CI -10 to 63

Improvement in exercise capacity was accompanied by improvement in multiple clinically relevantsecondary endpoints. These findings were in accordance with improvements in additionalhaemodynamic parameters.

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

Riociguat Placebo

PVR (n=151) (n=82)

Baseline (dyn·s·cm-5) 790.7 779.3[SD] [431.6] [400.9]

Mean change from baseline -225.7 23.1(dyn·s·cm-5)[SD] [247.5] [273.5]

Placebo-adjusted difference -246.4(dyn·s·cm-5)95% CI, [p-value] -303.3 to -189.5 [<0.0001]

NT-proBNP Riociguat Placebo(n=150) (n=73)

Baseline (ng/L) 1508.3 1705.8[SD] [2337.8] [2567.2]

Mean change from baseline (ng/L) -290.7 76.4[SD] [1716.9] [1446.6]

Placebo-adjusted difference (ng/L) -444.095% CI, [p-value] -843.0 to -45.0 [<0.0001]

Change in WHO Functional Class Riociguat Placebo(n=173) (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 of CTEPH

An open-label extension study (CHEST-2) included 237 adult patients who had completed CHEST-1.

At the end of the study, mean (SD) treatment duration in the total group was 1285 (709) days andmedian duration was 1174 days (ranging from15 to 3512 days). In total, 221 patients (93.2%) had atreatment duration of approximately 1 year (at least 48 weeks), 205 patients (86.5%) of approximately2 years (at least 96 weeks) and 142 patients (59.9%) of approximately 3 years (at least 144 weeks).

Treatment exposure was 834 person years in total.

The safety profile in CHEST-2 was similar to that observed in pivotal trials. After treatment withriociguat, the mean 6MWD improved in the overall population by 53 m at 12 months (n=208), 48 m at24 months (n=182), and 49 m at 36 months (n=117) compared to baseline. Improvements in 6MWDpersisted until the end of the study.

Table 4 shows the proportion of patients* with changes in WHO functional class during riociguattreatment compared to baseline.

Table 4: CHEST-2: Changes in WHO Functional Class

Changes in WHO Functional Class(n (%) of patients)

Treatment duration in Improved Stable Worsened

CHEST-21 year (n=217) 100 (46%) 109 (50%) 6 (3%)2 years (n=193) 76 (39%) 111 (58%) 5 (3%)3 years (n=128) 48 (38%) 65 (51%) 14 (11%)

*Patients participated in the study until the drug was approved and commerciallyavailable in their countries.

The probability of survival was 97% after 1 year, 93% after to 2 years and 89% after 3 years ofriociguat treatment.

Efficacy in adult patients with PAH

A randomised, double-blind, multi-national, placebo controlled, phase III study (PATENT-1) wasconducted in 443 adult patients with PAH (riociguat individual dose titration up to 2.5 mg 3 timesdaily: n=254, placebo: n=126, riociguat “capped” dose titration (CT) up to 1.5 mg (exploratory dosearm, no statistical testing performed; n=63)). Patients were either treatment-naïve (50%) or pre-treatedwith 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 associatedwith 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 bloodpressure and signs or symptoms of hypotension to the optimal individual dose (range 0.5 mg to 2.5 mg3 times daily), which was then maintained for a further 4 weeks. The primary endpoint of the studywas 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) improvedby 38 m, and pre-treated patients (n=191) by 36 m (ITT analysis, see table 5). Further exploratorysubgroup analysis revealed a treatment effect of 26 m, (95% CI: 5 m to 46 m) in patients pre-treatedwith ERAs (n=167) and a treatment effect of 101 m (95% CI: 27 m to 176 m) in patients pre-treatedwith prostacyclin analogues (n=27).

Table 5: Effects of riociguat on 6MWD in PATENT-1 at last visit

Entire patient population Riociguat IDT Placebo Riociguat CT(n=254) (n=126) (n=63)

Baseline (m) 361 368 363[SD] [68] [75] [67]

Mean change from baseline 30 -6 31(m)[SD] [66] [86] [79]

Placebo-adjusted difference 36(m)95% CI, [p-value] 20 to 52 [<0.0001]

FC III patients Riociguat IDT Placebo Riociguat CT(n=140) (n=58) (n=39)

Baseline (m) 338 347 351[SD] [70] [78] [68]

Mean change from baseline 31 -27 29(m)[SD] [64] [98] [94]

Placebo-adjusted difference 58(m)95% CI 35 to 81

FC II patients Riociguat IDT Placebo Riociguat CT(n=108) (n=60) (n=19)

Baseline (m) 392 393 378[SD] [51] [61] [64]

Mean change from baseline 29 19 43(m)[SD] [69] [63] [50]

Placebo-adjusted difference 10(m)95% CI -11 to 31

Treatment-naïve patient Riociguat IDT Placebo Riociguat CTpopulation (n=123) (n=66) (n=32)

Baseline (m) 370 360 347[SD] [66] [80] [72]

Mean change from baseline 32 -6 49(m)[SD] [74] [88] [47]

Placebo-adjusted difference 38(m) 14 to 6295% CI

Pre-treated patient Riociguat IDT Placebo Riociguat CTpopulation (n=131) (n=60) (n=31)

Baseline (m) 353 376 380[SD] [69] [68] [57]

Mean change from baseline 27 -5 12(m)[SD] [58] [83] [100]

Placebo- adjusted difference 36(m)95% CI 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 additionalhaemodynamic parameters (see table 6).

Table 6: Effects of riociguat in PATENT-1 on PVR and NT-proBNP at last visit

Riociguat IDT Placebo Riociguat CT

PVR (n=232) (n=107) (n=58)

Baseline (dyn·s·cm-5) 791 834.1 847.8[SD] [452.6] [476.7] [548.2]

Mean change from PVR baseline -223 -8.9 -167.8(dyn·s·cm-5)[SD] [260.1] [316.6] [320.2]

Placebo-adjusted difference -225.7(dyn·s·cm-5)95% CI, [p-value] -281.4 to -170.1[<0.0001]

NT-proBNP Riociguat IDT Placebo Riociguat CT(n = 228) (n = 106) (n=54)

Baseline (ng/L) 1,026.7 1,228.1 1,189.7[SD] [1,799.2] [1,774.9] [1,404.7]

Mean change from baseline (ng/L) -197.9 232.4 -471.5[SD] [1721.3] [1011.1] [913.0]

Placebo-adjusted difference (ng/L) -431.895% CI, [p-value] -781.5 to -82.1 [<0.0001]

Change in WHO Functional Riociguat IDT Placebo Riociguat CT

Class (n = 254) (n = 125) (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 versusplacebo-treated patients (p = 0.0046; Stratified log-rank test) (see table 7).

Table 7: Effects of riociguat in PATENT-1 on events of clinical worsening

Clinical Worsening Events Riociguat IDT Placebo Riociguat CT(n=254) (n=126) (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 0 1 (0.8%) 0

Class due to PH

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 (meanchange 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 groupsthan in the placebo group (riociguat IDT 1.0-2.5 mg, 3.1%; riociguat CT 1.6%; placebo, 7.1%).

Long-term treatment of PAH

An open label extension study (PATENT-2) included 396 adult patients who had completed

PATENT-1.

In PATENT-2, mean (SD) treatment duration in the total group (not including exposure in

PATENT-1) was 1375 (772) days and median duration was 1331 days (ranging from 1 to 3565 days).

In total, treatment exposure was approximately 1 year (at least 48 weeks) for 90%, 2 years (at least96 weeks) for 85%, and 3 years (at least 144 weeks) for 70% of patients. Treatment exposure was1491 person years in total.

The safety profile in PATENT-2 was similar to that observed in pivotal trials. After treatment withriociguat, the mean 6MWD improved in the overall population by 50 m at 12 months (n=347), 46 m at24 months (n=311) and 46 m at 36 months (n=238) compared to baseline. Improvements in 6MWDpersisted until the end of the study.

Table 8 shows the proportion of patients* with changes in WHO functional class during riociguattreatment compared to baseline.

Table 8: PATENT-2: Changes in WHO Functional Class

Changes in WHO Functional Class(n(%) of patients)

Treatment duration in PATENT- Improved Stable Worsened1 year (n=358) 116 (32%) 222 (62%) 20 (6%)2 years (n=321) 106 (33%) 189 (59%) 26 (8%)3 years (n=257) 88 (34%) 147 (57%) 22 (9%)

*Patients participated in the study until the study drug was approved and commerciallyavailable in their countries.

The probability of survival was 97% after 1 year, 93% after 2 years and 88% after 3 years of riociguattreatment.

Efficacy in paediatric patients with PAH

PATENT-CHILD

The safety and tolerability of riociguat 3 times daily for 24 weeks was evaluated in an open-labeluncontrolled study in 24 paediatric patients with PAH aged 6 to less than 18 years (median 9.5 years).

Only patients who were receiving stable doses of ERA (n=15, 62.5%) or ERA + prostacyclinanalogue (PCA) (n=9, 37.5%) were enrolled, and they continued their PAH treatment during the study.

The main exploratory efficacy endpoint of the study was exercise capacity (6MWD).

The aetiologies of PAH were idiopathic (n=18, 75.0%), persistent congenital PAH despite shuntclosure (n=4, 16.7%), heritable (n=1, 4.2%), and pulmonary hypertension associated withdevelopmental abnormalities (n=1, 4.2%). Two distinct age groups were included (≥ 6 to < 12 years[n=6] and > 12 to < 18 years [n=18]).

At baseline, the majority of patients were WHO functional class II (n=18, 75%) one patient (4.2%)was WHO functional class I and five patients (20.8%) were WHO functional class III. The mean6MWD at baseline was 442.12 m.

The 24-week treatment period was completed by 21 patients while 3 patients withdrew from the studydue to adverse events.

For patients with assessments at baseline and at week 24:

* mean change in 6MWD from baseline +23.01 m (SD 68.8) (n=19)

* WHO functional class remained stable compared to baseline (n=21).

* median change in NT-proBNP was -12.05 pg/mL, n=14

Two patients were hospitalized for right heart failure

Long-term data were generated from 21 patients who completed the first 24 weeks of treatment in

PATENT-CHILD. All patients continued to receive riociguat in combination with either ERA or ERA+ PCAs. The mean overall duration of exposure to riociguat treatment was 109.79 ± 80.38 weeks (upto 311.9 weeks), with 37.5% (n=9) of patients treated for at least 104 weeks and 8.3% (n=2) for atleast 208 weeks.

During the long-term extension (LTE) phase improvements or stabilization in 6MWD weremaintained for patients on treatment with observed mean changes from baseline (before start oftreatment [PATENT-CHILD]) of +5.86 m at month 6, -3.43 m at month 12; +28.98 m at month 18 and

- 11.80 m at month 24.

A majority of patients remained stable regarding WHO functional class II between baseline andmonth 24. Clinical worsening was observed in 8 (33.3%) subjects in total including the main phase.

Hospitalization for right heart failure was reported in 5 (20.8%) subjects. No deaths occurred duringthe observation period.

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 andsafety of riociguat in adult patients with symptomatic pulmonary hypertension associated withidiopathic interstitial pneumonias (PH-IIP) was terminated early due to an increased risk of mortalityand serious adverse events in patients treated with riociguat and a lack of efficacy. More patientstaking riociguat died (11% vs. 4%) and had serious adverse events (37% vs. 23%) during the mainphase. 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 withidiopathic interstitial pneumonias (see section 4.3).

The absolute bioavailability of riociguat is high (94%). Riociguat is rapidly absorbed with maximumconcentrations (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 riociguat administered orally as a crushed tabletsuspended in apple sauce or in water compared to a whole tablet (see section 4.2).

Children received riociguat tablet with or without food intake. Population PK modeling has shown thatriociguat is readily absorbed in children as in adults, after oral administration.

Plasma protein binding in adults is high at approximately 95%, with serum albumin and alpha 1-acidicglycoprotein being the main binding components. The volume of distribution is moderate with volumeof distribution at steady state being approximately 30 L.

No data on riociguat plasma protein binding specific to children is available. Vss estimated viapopulation PK modeling in children (age range 6 to <18 years) following oral administration ofriociguat is 26 L on average.

N-demethylation, catalysed by CYP1A1, CYP3A4, CYP3A5 and CYP2J2 is the majorbiotransformation 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 thepharmacologically inactive N-glucuronide.

CYP1A1 catalyses the formation of riociguat’s main metabolite in liver and lungs and is known to beinducible by polycyclic aromatic hydrocarbons, which, for example, are present in cigarette smoke.

No metabolism data specific to children is available.

Total riociguat (parent compound and metabolites) is excreted via both renal (33-45%) andbiliary/faecal routes (48-59%). Approximately 4-19% of the administered dose was excreted asunchanged riociguat via the kidneys. Approximately 9-44% of the administered dose was found asunchanged 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 about3-6 L/h, riociguat can be classified as a low-clearance drug. Elimination half-life is about 7 hours inhealthy subjects and about 12 hours in patients.

No mass balance study and metabolism data specific to children are available. Clearence estimated viapopulation PK modeling in children (age range 06 to < 18 years) following oral administration ofriociguat is on average of 2.48 L/h. The geometric mean values for half-lives (t1/2) estimated viapopulation PK modeling was 8.24 h.

Riociguat pharmacokinetics are linear from 0.5 to 2.5 mg. Inter-individual variability (CV) ofriociguat exposure (AUC) across all doses is approximately 60%.

The PK profile is similar in children as in adults.

Pharmacokinetic data reveal no relevant differences due to gender in the exposure to riociguat.

Elderly patients (65 years or older) exhibited higher plasma concentrations than younger patients, withmean AUC values being approximately 40% higher in elderly, mainly due to reduced (apparent) totaland renal clearance.

Inter-ethnic differences

In adults pharmacokinetic data reveal no relevant inter-ethnic differences.

Different weight categories

In adults pharmacokinetic data reveal no relevant differences due to weight in the exposure toriociguat.

In cirrhotic adult 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 normalintra-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 healthycontrols. There are no data in patients with severe hepatic impairment (classified as Child Pugh C).

No clinical data is available in children with hepatic impairment.

Patients with ALT > 3 x ULN and bilirubin > 2 x ULN were not studied (see section 4.4).

Overall, mean dose- and weight- normalised exposure values for riociguat were higher in subjects withrenal impairment compared to subjects with normal renal function. Corresponding values for the mainmetabolite 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 plasmaconcentrations (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 ondialysis.

Due to the high plasma protein binding riociguat is not expected to be dialysable.

No clinical data is available in children with renal impairment.

Non-clinical data revealed no specific hazard for humans based on conventional studies of safetypharmacology, single dose toxicity, phototoxicity, genotoxicity and carcinogenicity.

Effects observed in repeat-dose toxicity studies were mainly due to the exaggerated pharmacodynamicactivity of riociguat (haemodynamic and smooth muscle relaxing effects).

In growing, juvenile and adolescent rats, effects on bone formation were seen. In juvenile rats, thechanges consisted of thickening of trabecular bone and of hyperostosis and remodeling of metaphysealand diaphyseal bone, whereas in adolescent rats an overall increase of bone mass was observed atdoses 10 times the unbound AUC in the pediatric population. The clinical relevance of this finding isnot known. No such effects were observed in juvenile rats at doses ≤ 2 times the unbound AUC in thepediatric population, or in adult rats. No new target organs were identified.

In a fertility study in rats, decreased testes weights occurred at systemic exposure of about 7-fold ofhuman exposure, whereas no effects on male and female fertility were seen. Moderate passage acrossthe placental barrier was observed. Developmental toxicity studies in rats and rabbits have shownreproductive toxicity of riociguat. In rats, an increased rate of cardiac malformation was observed aswell as a reduced gestation rate due to early resorption at maternal systemic exposure of about 8-foldof human exposure (2.5 mg 3 times daily). In rabbits, starting at systemic exposure of about 4-fold ofhuman exposure (2.5 mg 3 times daily) abortion and foetal toxicity were seen.

cellulose microcrystallinecrospovidone (type B)hypromellose 5 cPmagnesium stearatelactose monohydratesodium laurilsulfate

Film-coat:

hydroxypropylcellulosehypromellose 3 cPpropylene 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)

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

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Germany

Adempas 0.5 mg film-coated tablets

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Date of first authorisation: 27 March 2014

Date of latest renewal: 18 January 2019

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