Interactions : אינטראקציות

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).

PDE 5 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 PDE 5 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 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).

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

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 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.

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).
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-Glycosyltransferases (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 metabolic enzymes, also no pharmacokinetic interaction is expected with other hormonal contraceptives.