Adempas Special Precautions





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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 (see Pharmacology: Pharmacodynamics under Actions).
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 oedema 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 benefit-risk of treatment continuation.
Serious bleeding occurred in 2.4% (12/490) of patients taking riociguat compared to 0/214 of placebo patients. Serious haemoptysis occurred in 1% (5/490) patients taking riociguat compared to 0/214 patients taking placebo, including one event with fatal outcome. Serious haemorrhagic events also included 2 patients with vaginal haemorrhage, 2 with catheter site haemorrhage, and 1 each with subdural haematoma, haematemesis, and intra-abdominal haemorrhage.
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 (see Contraindications). 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. Patients with mild and moderate renal impairment were included in the pivotal studies. There is increased riociguat exposure in these patients (see Pharmacology: Pharmacokinetics under Actions). There is a higher risk of hypotension in these patients, particular care should be exercised during individual dose titration.
Hepatic impairment: There is no experience in patients with severe hepatic impairment (Child Pugh C); riociguat is contraindicated in these patients (see Contraindications). PK data show that higher riociguat exposure was observed in patients with moderate hepatic impairment (Child Pugh B) (see Pharmacology: Pharmacokinetics under Actions). Particular care 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 initiation of treatment; riociguat is not recommended in these patients.
Smokers: Plasma concentrations of riociguat in smokers are reduced compared to non-smokers. Dose adjustment may be necessary in patients who start or stop smoking during treatment with riociguat (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Concomitant use with other medicinal products: The concomitant use of riociguat with strong multi pathway cytochrome P450 (CYP) and P-glycoprotein (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 (see Interactions and Pharmacology: Pharmacokinetics under Actions).
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 (see Interactions and Pharmacology: Pharmacokinetics under Actions). These medicinal products should be used with caution. Blood pressure should be monitored and dose reduction of riociguat be considered.
Information about excipients: Each 1 mg, 1.5 mg, 2 mg or 2.5 mg film coated tablet contains 37.2 mg, 36.8 mg, 36.3 mg or 35.8 mg lactose, respectively.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Effects on ability to drive and use machines: Adempas has moderate influence on the ability to drive and use machines. Dizziness has been reported and may affect the ability to drive and use machines (see Adverse Reactions). Patients should be aware of how they react to this medicine, before driving or operating machines.
Use in Pregnancy: Adempas is contraindicated during pregnancy (see Contraindications). Therefore, female patients at potential risk of pregnancy must use an effective method of contraception. Monthly pregnancy tests are recommended.
Use in Children: The safety and efficacy of riociguat in children and adolescents below 18 years have not been established. No clinical data are available. Non-clinical data show an adverse effect on growing bone (see Pharmacology: Toxicology: Preclinical safety data under Actions). Until more is known about the implications of these findings the use of riociguat in children and in growing adolescents should be avoided.
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