4.1. Therapeutic indications

Chronic thromboembolic pulmonary hypertension (CTEPH)

Adempas 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 (see section 5.1).

Pulmonary arterial hypertension (PAH)

Adults

Adempas, 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 (see section 5.1).

Paediatrics

Adempas is indicated for the treatment of PAH in paediatric patients aged 6 to less than 18 years with WHO Functional Class (FC) II to III in combination with endothelin receptor antagonists (see section 5.1).

4.2. Posology and method of administration

Treatment should only be initiated and monitored by a physician experienced in the treatment of CTEPH or PAH.

Posology

Starting dose

The recommended starting dose is 1 mg 3 times daily for 2 weeks. Tablets should be taken 3 times daily approximately 6 to 8 hours apart (see section 5.2).

Titration

Adult patients

Dose should be increased in 2-week intervals by 0.5 mg 3 times daily to a maximum of 2.5 mg 3 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 3 times a day (see section 5.1). 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 3 times daily.

Paediatric PAH patients aged 6 to < 18 years with body weight ≥ 50 kg Adempas is available for paediatric use as a tablet for those with body weight ≥ 50 kg.

Titration of riociguat dose is to be performed based on the patient's systolic blood pressure and general tolerability at the discretion of the treating physician/healthcare provider. If the patient has no signs or symptoms of hypotension and systolic blood pressure is ≥ 90 mmHg for the 6 to < 12 year age group or ≥ 95 mmHg for the 12 to < 18 year age group, the dose should be increased in 2-week intervals by 0.5 mg 3 times daily to a maximum daily dose of 3 times 2.5 mg.

If systolic blood pressure falls below these specified levels the dosage should be maintained as long as 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 the specified levels, and the patient shows signs or symptoms of hypotension the current dose should be decreased by 0.5 mg 3 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) for adults and paediatric patients with body weight of at least 50 kg.

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.

Paediatric PAH patients weighing less than 50 kg

Adempas is available as granules for oral suspension to treat paediatric PAH patients at least 6 years of age and weighing less than 50 kg – see Summary of Product Characteristics for Adempas granules for oral suspension for further direction. Patients may switch between tablets and oral suspension during therapy due to body weight changes.

Treatment discontinuation

In case treatment has to be interrupted for 3 days or more, treatment should be restarted with 1 mg 3 times daily for 2 weeks, and continued with the dose titration regimen as described above.

Transitioning between phosphodiesterase-5 (PDE5) inhibitors and riociguat

Sildenafil must be discontinued in adults and children at least 24 hours prior to administration of riociguat.

Tadalafil must be discontinued at least 48 hours in adults and 72 hours in children prior to administration of riociguat.

Riociguat must be discontinued in adults and children at least 24 hours prior to administration of a PDE5 inhibitor.

It is recommended to monitor for signs and symptoms of hypotension after any transition (see sections 4.3, 4.5 and 5.1).

Special populations

Individual dose titration at treatment initiation allows adjustment of the dose to the patient´s needs.

Elderly

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 (see section 5.2).

Hepatic impairment

Patients with severe hepatic impairment (Child Pugh C) have not been studied and therefore use of riociguat is contraindicated in these patients (see section 4.3). Patients with moderate hepatic impairment (Child Pugh B) showed a higher exposure to this medicinal product (see section 5.2). Particular care should be exercised during individual dose titration.

No clinical data are available in children and adolescents less than 18 years of age with hepatic impairment.

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 (see section 4.4).

Patients with mild and moderate renal impairment (creatinine clearance < 80 - 30 mL/min) showed a higher exposure to this medicinal product (see section 5.2). There is a higher risk of hypotension in patients with renal impairment, therefore particular care should be exercised during individual dose titration.

No clinical data are available in children and adolescents less than 18 years of age with renal impairment.

Patients on stable doses of strong multi pathway CYP / P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitors

Coadministration of riociguat 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) increases exposure to riociguat (see section 4.5). When initiating riociguat in patients on stable doses of strong multi pathway CYP and P-gp/BCRP inhibitors, consider a starting dose of 0.5 mg 3 times a day to mitigate the risk of hypotension. Monitor for signs and symptoms of hypotension on initiation and on treatment. Consider a dose reduction for patients on riociguat doses higher than or equal to 1.0 mg if the patient develops signs or symptoms of hypotension (see section 4.5).

No clinical data are available in children and adolescents less than 18 years of age receiving concomitant systemic treatment with strong CYP/P-gp and BCRP inhibitors.

Paediatric population

The safety and efficacy of riociguat have not been established in the following paediatric populations:

• Children aged < 6 years (see section 4.1), because of safety concerns. Non clinical data show undesirable effects on growing bone (see section 5.3).

• Children with PAH aged 6 to < 12 years with systolic blood pressure < 90 mmHg at treatment initiation (see section 4.3)

• Children and adolescents with PAH aged 12 to < 18 years with systolic blood pressure <95 mmHg at treatment initiation (see section 4.3)

• Children and adolescents with CTEPH aged < 18 years old (see section 4.1).

No clinical trial data are available. Therefore, the use of riociguat is not recommended in these populations.

Smokers

Current smokers should be advised to stop smoking due to a risk of a lower response. Plasma concentrations of riociguat in smokers are reduced compared to non-smokers. A dose increase to the maximum daily dose of 2.5 mg 3 times daily may be required in patients who are smoking or start smoking during treatment (see sections 4.5 and 5.2).

A dose decrease may be required in patients who stop smoking.

Method of administration

For oral use.

Food

Riociguat 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 (see section 5.2).

Crushed tablets

For patients who are unable to swallow whole tablets, Adempas tablets may be crushed and mixed with water or soft foods immediately prior to use and administered orally (see section 5.2).

4.3. Contraindications

- Co-administration with PDE5 inhibitors (such as sildenafil, tadalafil, vardenafil) (see sections 4.2 and 4.5).

- Severe hepatic impairment (Child Pugh C).

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Pregnancy (see sections 4.4; 4.5 and 4.6).

- Co-administration with nitrates or nitric oxide donors (such as amyl nitrite) in any form including recreational drugs called 'poppers' (see section 4.5).

- Concomitant use with other soluble guanylate cyclase stimulators.

- Treatment initiation for

• children aged 6 to < 12 years with systolic blood pressure < 90 mmHg

• patients ≥ 12 years with systolic blood pressure < 95 mmHg.

- Patients with pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP) (see section 5.1).

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 adult 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 adult 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

Riociguat 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).

Excipients with known effect

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 medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium free”.

4.5. Interaction with other medicinal products and other forms of interaction

Interaction studies have been performed only in adults. Therefore, the absolute extent of interactions in the paediatric population is not known. The interaction data obtained in adults and the warnings in section 4.4 should be taken into account for the paediatric population.

Pharmacodynamic interactions

Nitrates

In a clinical study the highest dose of riociguat (2.5 mg tablets 3 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 riociguat with nitrates or nitric oxide donors (such as amyl nitrite) in any form, including recreational drugs called 'poppers', is contraindicated (see section 4.3).

PDE5 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 3 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 3 times daily) and riociguat (1.0 mg to 2.5 mg 3 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 PDE5 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 reactions 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 (+31 m), N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels (-347 pg/mL), percent distribution of WHO FC I/II/III/IV (2% / 52% / 46% / 0%), and 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

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: 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. 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.

Assess the benefit-risk for each patient individually before prescribing riociguat in patients on stable doses of strong multi pathway CYP and P-gp/BCRP inhibitors.

To mitigate the risk of hypotension when riociguat is initiated in patients on stable doses of strong multi pathway CYP (especially CYP1A1 and CYP3A4) and P-gp/BCRP inhibitors, consider a reduced starting dose. It is recommended to monitor these patients for signs and symptoms of hypotension (see sections 4.2 ).

In patients on stable doses of riociguat, 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.

Concomitant use with CYP1A1, UGT1A1 and UGT1A9 inhibitors

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.

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). For co-administration with these substances follow the recommendation on dose titration (see section 4.2).

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 section 5.2).

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 riociguat therapy (see section 4.3). Riociguat (2.5 mg 3 times daily) 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 volunteers. 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.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential / Contraception

Women and female adolescents of childbearing potential must use effective contraception during treatment with riociguat.

Pregnancy

There are no data from the use of riociguat in pregnant women. Studies in animals have shown reproductive toxicity and placental transfer (see section 5.3). Therefore, riociguat is contraindicated during pregnancy (see section 4.3). Monthly pregnancy tests are recommended.

Breast-feeding

No data on the use of riociguat in breast-feeding women are available. Data from animals indicate that riociguat is excreted into milk. Due to the potential for serious adverse reactions in breast-fed infants riociguat should not be used during breast-feeding. A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued during treatment with this medicinal product.

Fertility

No specific studies with riociguat in humans have been conducted to evaluate effects on fertility. In a reproduction toxicity study in rats, decreased testes weights were seen, but there were no effects on fertility (see section 5.3). The relevance of this finding for humans is unknown.

4.7. Effects on ability to drive and use machines

Riociguat has moderate influence on the ability to cycle, 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 cycling, driving or using machines.

4.8. Undesirable effects

Summary of the safety profile

The safety of riociguat in adults has been evaluated in phase III studies of 650 patients with CTEPH and PAH receiving at least one dose of riociguat (see section 5.1). With longer observation in uncontrolled long term extension studies the safety profile was similar to that observed in the placebo controlled phase III trials.

Most of the adverse reactions are caused by relaxation of smooth muscle cells in vasculature or the gastrointestinal tract.

The most commonly reported adverse reactions, occurring in ≥ 10% of patients under riociguat treatment (up to 2.5 mg 3 times daily), were headache, dizziness, dyspepsia, peripheral oedema, nausea, diarrhoea and vomiting.

Serious haemoptysis and pulmonary haemorrhage, including cases with fatal outcome have been observed in patients with CTEPH or PAH treated with riociguat (see section 4.4).

The safety profile of riociguat in patients with CTEPH and PAH appeared to be similar, therefore adverse reactions identified from placebo controlled 12 and 16 weeks clinical studies are presented as pooled frequency in the table listed below (see table 1).

Tabulated list of adverse reactions

The adverse reactions reported with riociguat are listed in the table below by MedDRA system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).

Table 1: Adverse reactions reported with riociguat in adult patients in phase III studies (pooled CHEST-1 and PATENT-1 data)

MedDRA

System Organ Class

Very common

Common

Uncommon

Infections and infestations

Gastroenteritis

Blood and lymphatic system disorders

Anaemia (incl. respective laboratory parameters)

Nervous system disorders

Dizziness,

Headache

Cardiac disorders

Palpitations

Vascular disorders

Hypotension

Respiratory, thoracic and mediastinal disorders

Haemoptysis,

Epistaxis,

Nasal congestion

Pulmonary haemorrhage*

Gastrointestinal disorders

Dyspepsia,

Diarrhoea,

Nausea,

Vomiting

Gastritis,

Gastro-oesophageal reflux disease,

Dysphagia,

Gastrointestinal and abdominal pains,

Constipation,

Abdominal distension

General disorders and administration site conditions

Oedema peripheral

* fatal pulmonary haemorrhage was reported in uncontrolled long term extension studies

Paediatric patients

The safety of riociguat has been investigated in 24 paediatric patients aged 6 to less than 18 years over 24 weeks in an open-label uncontrolled trial (PATENT-CHILD) consisting of an individual dose titration phase starting with 1 mg (body weight adjusted) for 8 weeks and a maintenance phase for up to 16 weeks (see section 4.2), followed by an optional long-term extension phase. Most common adverse reactions including the long-term extension phase were hypotension and headache occurring in 4/24, and 2/24 patients, respectively.

Overall, the safety data is consistent with the safety profile observed in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In adults, 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 (see section 4.8).

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.