Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Bayer AG, 51368, Leverkusen, Germany
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 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.
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.
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.
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.
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.
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.
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).
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, 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.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium free”.
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 section 4.3).
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 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 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).
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.
Riociguat did not potentiate the bleeding time caused by acetyl-salicylic acid or affect the platelet aggregation in humans.
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, abacavir, rilpivirine, efavirenz, ritonavir, cobicistat and elvitegravir inhibited CYP1A1 and the metabolism of riociguat in the order listed with abacavir as the strongest inhibitor. Cobicistat, ritonavir, atazanavir and darunavir are additionally classified as CYP3A inhibitors. In addition, ritonavir showed inhibition of P-gp.
The impact of HAART (including different combinations of abacavir, atazanavir, cobicistat, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, lamivudine, rilpivirine, ritonavir, and tenofovir) on riociguat exposure was investigated in a dedicated study in HIV patients. Concomitant administration of HAART combinations led to an increase in riociguat mean AUC of up to about 160% and to an approximate 20% 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.
To mitigate the risk of hypotension when Adempas is initiated in patients on stable doses of strong multi pathway CYP (especially CYP1A1 and CYP3A4) and P-gp/BCRP inhibitors, e.g. as contained in HAART, consider a reduced starting dose. It is recommended to monitor these patients for signs and symptoms of hypotension (see sections 4.2 and 4.4).
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 section 5.2). 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.
To mitigate the risk of hypotension when Adempas is initiated in patients on stable doses of strong multi pathway CYP (especially CYP1A1 and CYP3A4) and P-gp/BCRP inhibitors, e.g. ketoconazole, posaconazole or itraconazole consider a reduced starting dose. It is recommended to monitor these patients for signs and symptoms of hypotension (see sections 4.2 and 4.4).
Medicinal products strongly inhibiting P-gp/BCRP such as the immuno-suppressive cyclosporine A, should be used with caution (see sections 4.4 and 5.2).
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: 1/10 th to ⅓ rd of riociguat). For co-administration with these substances follow the recommendation on dose titration (see section 4.2).
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 (see section 4.4).
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.
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).
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).
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 Adempas therapy (see section 4.3). Riociguat (2.5 mg 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.
Women of childbearing potential must use effective contraception during treatment with Adempas.
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, Adempas is contraindicated during pregnancy (see section 4.3). Monthly pregnancy tests are recommended.
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 Adempas 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.
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.
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.
The safety of Adempas has been evaluated in phase III studies of 681 patients with CTEPH and PAH receiving at least one dose of riociguat (see section 5.1).
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 Adempas treatment (up to 2.5 mg three 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 Adempas (see section 4.4).
The safety profile of Adempas 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).
The adverse reactions reported with Adempas 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 Adempas in the phase III studies:
Common: Gastroenteritis
Common: Anaemia (incl. respective laboratory parameters)
Very common: Dizziness, Headache
Common: Palpitations
Common: Hypotension
Common: Haemoptysis, Epistaxis, Nasal congestion
Uncommon: Pulmonary haemorrhage*
Very common: Dyspepsia, Diarrhoea, Nausea, Vomiting
Common: Gastritis, Gastro-oesophageal reflux disease, Dysphagia, Gastrointestinal and abdominal pains, Constipation, Abdominal distension
Very common: Oedema peripheral
* fatal pulmonary haemorrhage was reported in uncontrolled long term extension studies
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 national reporting system listed in Appendix V.
Not applicable.
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