Wirkstoffe & Arzneimittelsicherheit

Gegenanzeigen · Adempas

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 · Abschnitt 4.3 · PDF-Seite 6

HOS-129020 · Präparat HOS-096659

- 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). - Concomitant use with other soluble guanylate cyclase stimulators. - Treatment initiation for o children aged 6 to < 12 years with systolic blood pressure < 90 mmHg, o patients ≥ 12 years with systolic blood pressure < 95 mmHg. - Patients with pulmonary hypertension associated with idiopathic interstitial pneumonias (PH- IIP) (see section 5.1).

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): tadalafil (HOS-086316) nitric oxide (HOS-088773) sildenafil (HOS-086162) amyl nitrite (HOS-088775) vardenafil (HOS-086163)

Gegenanzeigen · Adempas

Adempas 0.15 mg/mL granules for oral suspension · Abschnitt 4.3 · PDF-Seite 29

HOS-129069 · Präparat HOS-096659

- 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). - Concomitant use with other soluble guanylate cyclase stimulators. - Treatment initiation for o children aged 6 to < 12 years with systolic blood pressure < 90 mmHg, o patients ≥ 12 to < 18 years with systolic blood pressure < 95 mmHg. - Patients with pulmonary hypertension associated with idiopathic interstitial pneumonias (PH- IIP) (see section 5.1).

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): tadalafil (HOS-086316) nitric oxide (HOS-088773) sildenafil (HOS-086162) amyl nitrite (HOS-088775) vardenafil (HOS-086163)

Wechselwirkungen · Adempas

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 · Abschnitt 4.5 · PDF-Seite 7

HOS-129026 · Präparat HOS-096659

Interaction studies have been performed only in adults. Therefore, the absolute extent of interactions in the paediatric population is not known. The interaction data obtained in adults and the warnings in section 4.4 should be taken into account for the paediatric population.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Adempas

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 · Abschnitt 4.5 · PDF-Seite 7–8

HOS-129027 · Präparat HOS-096659

7 Pharmacodynamic interactions

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Adempas

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 · Abschnitt 4.5 · PDF-Seite 8

HOS-129028 · Präparat HOS-096659

Nitrates In a clinical study the highest dose of riociguat (2.5 mg tablets 3 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 riociguat with nitrates or nitric oxide donors (such as amyl nitrite) in any form, including recreational drugs called ‘poppers’, is contraindicated (see section 4.3).

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): nitric oxide (HOS-088773) nitroglycerin (HOS-108517) amyl nitrite (HOS-088775)

Wechselwirkungen · Adempas

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 · Abschnitt 4.5 · PDF-Seite 8

HOS-129030 · Präparat HOS-096659

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 3 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 3 times daily) and riociguat (1.0 mg to 2.5 mg 3 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 reactions reported during the transition period. Six patients (10%) experienced at least one clinical worsening event, including 2 deaths unrelated to study drug. Changes from baseline suggested beneficial effects in selected patients, e.g. improvement in 6MWD (+31 m), N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels (-347 pg/mL), percent distribution of WHO FC I/II/III/IV (2% / 52% / 46% / 0%), and cardiac index (+0.3 L/min/m2).

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): tadalafil (HOS-086316) sildenafil (HOS-086162) vardenafil (HOS-086163)

Wechselwirkungen · Adempas

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 · Abschnitt 4.5 · PDF-Seite 8

HOS-129031 · Präparat HOS-096659

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

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Adempas

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 · Abschnitt 4.5 · PDF-Seite 8

HOS-129032 · Präparat HOS-096659

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.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): phenprocoumon (HOS-091031) prothrombin (HOS-085093) warfarin (HOS-085950)

Wechselwirkungen · Adempas

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 · Abschnitt 4.5 · PDF-Seite 8

HOS-129034 · Präparat HOS-096659

Acetylsalicylic acid Riociguat did not potentiate the bleeding time caused by acetyl-salicylic acid or affect the platelet aggregation in humans.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): salicylic acid (HOS-088803)

Wechselwirkungen · Adempas

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 · Abschnitt 4.5 · PDF-Seite 8

HOS-129035 · Präparat HOS-096659

Effects of other substances on riociguat

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Adempas

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 · Abschnitt 4.5 · PDF-Seite 8

HOS-129036 · Präparat HOS-096659

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.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Adempas

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 · Abschnitt 4.5 · PDF-Seite 8–9

HOS-129037 · Präparat HOS-096659

8 Concomitant use with strong multi pathway CYP and P-gp/BCRP inhibitors The concomitant use of riociguat with 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) results in a pronounced increase in riociguat exposure: Concomitant administration of HAART combinations led to an increase in riociguat mean AUC of up to about 160% and to an approximate 30% 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. 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. Assess the benefit-risk for each patient individually before prescribing riociguat in patients on stable doses of strong multi pathway CYP and P-gp/BCRP inhibitors. To mitigate the risk of hypotension when riociguat is initiated in patients on stable doses of strong multi pathway CYP (especially CYP1A1 and CYP3A4) and P-gp/BCRP inhibitors, consider a reduced starting dose. It is recommended to monitor these patients for signs and symptoms of hypotension (see sections 4.2 ). 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 to limited data. Alternative treatments should be considered.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): protease (HOS-085623) ketoconazole (HOS-084513) itraconazole (HOS-084516) ritonavir (HOS-084521) posaconazole (HOS-085622)

Wechselwirkungen · Adempas

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 · Abschnitt 4.5 · PDF-Seite 9

HOS-129038 · Präparat HOS-096659

Concomitant use with CYP1A1, UGT1A1 and UGT1A9 inhibitors 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. 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).

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): gefitinib (HOS-121309) erlotinib (HOS-113527) tyrosine (HOS-108875)

Wechselwirkungen · Adempas

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 · Abschnitt 4.5 · PDF-Seite 9

HOS-129041 · Präparat HOS-096659

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 section 5.2).

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): cyclosporine (HOS-084512)

Wechselwirkungen · Adempas

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 · Abschnitt 4.5 · PDF-Seite 9

HOS-129042 · Präparat HOS-096659

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.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): lead (HOS-085592)

Wechselwirkungen · Adempas

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 · Abschnitt 4.5 · PDF-Seite 9

HOS-129043 · Präparat HOS-096659

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.

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): magnesium hydroxide (HOS-088789)

Wechselwirkungen · Adempas

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 · Abschnitt 4.5 · PDF-Seite 9

HOS-129045 · Präparat HOS-096659

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).

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): bosentan (HOS-086291)

Wechselwirkungen · Adempas

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 · Abschnitt 4.5 · PDF-Seite 9

HOS-129046 · Präparat HOS-096659

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).

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

RxNorm-Namen im Text (wörtliche Treffer, Rolle nicht bewertet): carbamazepine (HOS-085618) lead (HOS-085592) phenytoin (HOS-084531)

Wechselwirkungen · Adempas

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 · Abschnitt 4.5 · PDF-Seite 9–10

HOS-129047 · Präparat HOS-096659

9 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).

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.

Wechselwirkungen · Adempas

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 · Abschnitt 4.5 · PDF-Seite 10

HOS-129048 · Präparat HOS-096659

Effects of riociguat on other substances

Originalpassage; keine automatisch abgeleitete Schwere, Häufigkeit oder Kausalität. Auch verneinte Befunde und nicht untersuchte Kombinationen bleiben sichtbar.