Adempas

Adempas Drug Interactions

riociguat

Manufacturer:

Bayer

Distributor:

Zuellig
/
Four Star
Full Prescribing Info
Drug Interactions
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 Contraindications).
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 Dosage & Administration and Contraindications).
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).
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.
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 Pharmacology: Pharmacokinetics under Actions). 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.
Therefore concomitant use with strong multi-pathway CYP and P-gp/BCRP inhibitors, such as azole antimycotics (e.g. ketoconazole, itraconazole) or HIV protease inhibitors (e.g. ritonavir) is not recommended (see Precautions).
Drugs strongly inhibiting P-gp/BCRP such as the immuno-suppressive cyclosporine A, should be used with caution (see Precautions and Pharmacology: Pharmacokinetics under Actions).
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).
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 Pharmacology: Pharmacokinetics under Actions). Strong CYP1A1 inhibitors should be used with caution (see Precautions).
Riociguat exhibits a reduced solubility at neutral pH vs. acidic medium. Co-medication of drugs 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 Dosage & Administration). Antacids should be taken at least 2 hours before, or 1 hour after riociguat.
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 Indications/Uses and Pharmacology: Pharmacodynamics under Actions).
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.
Smoking: In cigarette smokers riociguat exposure is reduced by 50-60% (see Pharmacology: Pharmacokinetics under Actions). Therefore, patients are advised to stop smoking (see Dosage & Administration).
Effects of riociguat on other substances: 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 Contraindications). Riociguat (2.5mg 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.
Riociguat and its main metabolite are strong inhibitors of CYP1A1 in vitro. Therefore, clinically relevant drug-drug interactions with co-medications which are significantly cleared by CYP1A1-mediated biotransformation, such as erlotinib or granisetron cannot be ruled out.
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