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  • Adempas
    / Bayer


    Active Ingredient
    Riociguat 0.5, 1, 1.5, 2, 2.5 mg

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Film Coated Tablets

    42 X 1 mg

    partial basket chart 28789 9870

    Film Coated Tablets

    42 X 1.5 mg

    partial basket chart 28790 9871

    Film Coated Tablets

    42 X 2 mg

    partial basket chart 28791 9872

    Film Coated Tablets

    84 X 2.5 mg

    partial basket chart 29094 9873

    Related information


    Dosage

    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. 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. 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.
    Food: Tablets can generally be taken with or without food. For patients prone to hypotension, as a precautionary measure, switches between fed and fasted Riociguat intake are not recommended because of increased peak plasma levels of riociguat in the fasting compared to the fed state.
    Treatment discontinuation: In case treatment has to be interrupted for 3 days or more, restart treatment at 1 mg three times daily for 2 weeks, and continue treatment with the dose titration regimen as described above.
    Transitioning between PDE5 inhibitors and riociguat: Discontinue sildenafil at least 24 hours or tadalafil at least 48 hours prior to administering riociguat.
    Discontinue riociguat at least 24 hours prior to administering a PDE5 inhibitor. It is recommended to monitor for signs and symptoms of hypotension after any transition.
    Special populations: Individual dose titration at treatment initiation allows adjustment of the dose to the patient´s needs.
    Paediatric population: The safety and efficacy of riociguat in children and adolescents below 18 years have not been established.
    Elderly population: 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.
    Hepatic impairment: Patients with severe hepatic impairment (Child Pugh C) have not been studied and therefore use of Riociguat is contraindicated in these patients. Patients with moderate hepatic impairment (Child Pugh B) showed a higher exposure to this medicine. 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 Riociguat is not recommended in these patients.
    Smokers: Current smokers should be advised to stop smoking due to a risk of a lower response.


    Indications

    Chronic thromboembolic pulmonary hypertension (CTEPH): Riociguat 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.
    Pulmonary arterial hypertension (PAH): Riociguat, 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.


    Contra-Indications

    Co-administration with  PDE 5 inhibitors (such as sildenafil, tadalafil, vardenafil). Severe hepatic  impairment (Child Pugh C). Hypersensitivity to the active substance or to any of the excipients . Co-administration  with nitrates or nitric oxide donors (such as amyl nitrite) in any form. Patients with systolic blood pressure < 95 mm Hg at treatment initiation.


    Special Precautions

    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 . 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 edema 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 benefitrisk of treatment continuation.
    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. 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.
    Hepatic impairment: There is no experience in patients with severe hepatic impairment (Child Pugh C); riociguat is contraindicated in these patients.
    See prescribing information for full details.


    Side Effects

    Headache, dizziness, dyspepsia, peripheral oedema, nausea, diarrhea, vomiting, haemoptysis and pulmonary haemorrhage.
    See prescribing information for full details.


    Drug interactions

    The concomitant use of riociguat with strong multi pathway cytochrome P450 (CYP) and Pglycoprotein (P-gp) / breast cancer resistance protein (BCRP) inhibitors such as azole antimycotics (e.g. ketoconazole, itraconazole) or HIV protease inhibitors (e.g. ritonavir) is not recommended, due to the pronounced increase in riociguat exposure. 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. These medicinal products should be used with caution. Blood pressure should be monitored and dose reduction of riociguat be considered.
    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 is contraindicated.
    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 prescribing information for full details.


    Pregnancy and Lactation

    Pregnancy: There are no data from the use of riociguat in pregnant women. Women of childbearing potential must use effective contraception during treatment with this drug.
    Lactation: No data on the use of riociguat in breast-feeding women are available.
    See prescribing information for full details.


    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. 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.
    See prescribing information for full details.


    Manufacturer
    Bayer Pharma AG
    Licence holder
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