Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

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 section 5.1).
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 section 4.3).
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 section 5.2). 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 section 4.3). PK data show that higher riociguat exposure was observed in patients with moderate hepatic impairment (Child Pugh B) (see section 5.2). 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.

Pregnancy/contraception

Adempas is contraindicated during pregnancy (see section 4.3). Therefore, female patients at potential risk of pregnancy must use an effective method of contraception. Monthly pregnancy tests are recommended.

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 sections 4.2 and 5.2).

Concomitant use with other medicinal products

•     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 (see sections 4.5 and 5.2).

•     Assess the benefit-risk for each patient individually before prescribing Adempas in patients on stable doses of strong multi pathway CYP and P-gp/BCRP inhibitors. To mitigate the risk of hypotension, consider dose reduction and monitoring for signs and symptoms of hypotension (see sections 4.2 and 4.5).

•     In patients on stable doses of Adempas, 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.

• 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 sections 4.5 and 5.2). These medicinal products should be used with caution. Blood pressure should be monitored and dose reduction of riociguat be considered.

Adempas contains lactose
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Adempas contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium free”.


Effects on Driving

4.7    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 section 4.8). Patients should be aware of how they react to this medicinal product, before driving or using machines.