Riociguat是由德国拜耳先灵制药公司研发的一种口服有效的治疗肺高压（pulmonary hypertension，PH）的药物 2014年4月1日，肺动脉高压药物Adempas（riociguat）获欧盟委员会（EC）批准，作为单药疗法或联合内皮素受体拮抗剂。 用于2种类型的肺动脉高压： a）用于肺动脉高压（PAH）成人患者； b）用于不能手术或手术后持续性、复发性慢性阻塞性肺动脉高压（CTEPH）成人患者。在欧盟，Adempas是首个也是唯一一种获批用于CTEPH的治疗药物。此前，欧盟已授予Adempas孤儿药地位。 Adempas的获批，是基于2项随机、双盲、安慰剂对照、全球性III期研究CHEST-1和PATENT-1、以及CHEST-2和PATENT-2目前获得的的长期数据。这些研究分别调查了口服riociguat治疗CTEPH和PAH的有效性和安全性。2项III期研究CHEST-1和PATENT-1均达到了研究的主要终点，此外riociguat在横跨多个相关次要终点均表现出持续改善，同时耐受性良好。 此前，Adempas已于2013年10月获FDA批准用于CTEPH和PAH的治疗。在加拿大，Adempas分别于2013年9月和2014年3月获批用于CTEPH和PAH的治疗。在瑞士和日本，Adempas分别于2013年11月和2014年1月获批用于CTEPH的治疗。 PAH和CTEPH是2种罕见的、危及生命的肺动脉高压，其特点是肺动脉压力明显增加。 关于Adempas（riociguat）： Riociguat是拜耳开发的首个新一类可溶性鸟苷酸环化酶(sGC)激动剂，能够直接刺激sGC，增强其对低水平一氧化氮（NO）的敏感度，该药开发用于治疗2种肺动脉高压——慢性血栓栓塞性肺动脉高压(CTEPH)和肺动脉高压(PAH)，改善患者的运动能力，riociguat将以品牌名Adempas。 附：德国上市包装ADEMPAS Filmtabletten - Filmtabletten - BAYER VITAL GMBH 42粒x 0.5mg，1mg，1.5mg，2mg，2.5mg：（所有剂量42粒价格一样）  84粒x 0.5mg，1mg，1.5mg，2mg，2.5mg：（所有剂量84粒价格一样） Adempas 2.5 mg film-coated tablets 1. Name of the medicinal product Adempas 0.5 mg film-coated tablets Adempas 1 mg film-coated tablets Adempas 1.5 mg film-coated tablets Adempas 2 mg film-coated tablets Adempas 2.5 mg film-coated tablets 2. Qualitative and quantitative composition Each Adempas 0.5 mg film-coated tablet contains 0.5 mg of riociguat. Each Adempas 1 mg film-coated tablet contains 1 mg of riociguat. Each Adempas 1.5 mg film-coated tablet contains 1.5 mg of riociguat. Each Adempas 2 mg film-coated tablet contains 2 mg of riociguat. Each Adempas 2.5 mg film-coated tablet contains 2.5 mg of riociguat. Excipients with known effect: Each 0.5 mg film-coated tablet contains 37.8 mg lactose (as monohydrate), see section 4.4. Each 1 mg film-coated tablet contains 37.2 mg lactose (as monohydrate), see section 4.4. Each 1.5 mg film-coated tablet contains 36.8 mg lactose (as monohydrate), see section 4.4. Each 2 mg film-coated tablet contains 36.3 mg lactose (as monohydrate), see section 4.4. Each 2.5 mg film-coated tablet contains 35.8 mg lactose (as monohydrate), see section 4.4. For the full list of excipients, see section 6.1. 3. Pharmaceutical form Film-coated tablet. Adempas 0.5 mg film-coated tablets: White, round, biconvex tablets of 6 mm, marked with the Bayer cross on one side and 0.5 and an “R” on the other side. Adempas 1 mg film-coated tablets: Pale yellow, round, biconvex tablets of 6 mm, marked with the Bayer cross on one side and 1 and an “R” on the other side. Adempas 1.5 mg film-coated tablets: Yellow-orange, round, biconvex tablets of 6 mm, marked with the Bayer cross on one side and 1.5 and an “R” on the other side. Adempas 2 mg film-coated tablets: Pale orange, round, biconvex tablets of 6 mm, marked with the Bayer cross on one side and 2 and an “R” on the other side. Adempas 2.5 mg film-coated tablets: Red-orange, round, biconvex tablets of 6 mm, marked with the Bayer cross on one side and 2.5 and an “R” on the other side. 4. Clinical particulars 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) 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. Efficacy has been shown in a PAH population including aetiologies of idiopathic or heritable PAH or PAH associated with connective tissue disease (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 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 (see section 5.2). 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 (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 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 Adempas intake are not recommended because of increased peak plasma levels of riociguat in the fasting compared to the fed state (see section 5.2). 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. 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. No clinical data are available. Non-clinical data show an adverse effect on growing bone (see section 5.3). Until more is known about the implications of these findings the use of riociguat in children and in growing adolescents should be avoided (see section 4.4). 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 (see section 5.2). Hepatic impairment Patients with severe hepatic impairment (Child Pugh C) have not been studied and therefore use of Adempas is contraindicated in these patients (see section 4.3). Patients with moderate hepatic impairment (Child Pugh B) showed a higher exposure to this medicine (see section 5.2). 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 Adempas is not recommended in these patients (see section 4.4). Patients with moderate renal impairment (creatinine clearance <50 - 30 mL/min) showed a higher exposure to this medicine (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. 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 three times daily may be required in patients who are smoking or start smoking during treatment (see section 4.5 and 5.2). A dose decrease may be required in patients who stop smoking. Method of administration For oral use. Crushed tablets For patients who are unable to swallow whole tablets, Adempas tablets may be crushed and mixed with water or soft foods such as applesauce immediately prior to use and administered orally (see section 5.2). 4.3 Contraindications - Co-administration with PDE 5 inhibitors (such as sildenafil, tadalafil, vardenafil) (see section 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 section 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). - Patients with systolic blood pressure < 95 mm Hg at treatment initiation. 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. 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 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 section 4.5 and 5.2). • 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 section 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. Paediatric population 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 section 5.3). Until more is known about the implications of these findings the use of riociguat in children and in growing adolescents should be avoided. Information about excipients Each 0.5 mg film coated tablet contains 37.8 mg lactose. Each 1 mg film coated tablet contains 37.2 mg lactose. Each 1.5 mg film coated tablet contains 36.8 mg lactose. Each 2 mg film coated tablet contains 36.3 mg lactose. Each 2.5 mg film coated tablet contains 35.8 mg lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. 4.5 Interaction with other medicinal products and other forms of interaction 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, including recreational drugs called 'poppers', is contraindicated (see section 4.3). 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 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, CYP2C8, CYP2J2) oxidative metabolism, direct biliary/faecal excretion of unchanged riociguat and renal excretion of unchanged riociguat via glomerular filtration. 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. Therefore concomitant use 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) is not recommended (see section 4.4). Drugs 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: 1/10th to 1/3rd of riociguat). 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-medication of drugs 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). 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. 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 not inhibitors or inducers of major CYP isoforms (including CYP 3A4) or transporters (e.g. P-gp/BCRP) in vitro at therapeutic plasma concentrations. Riociguat and its main metabolite are strong inhibitors of CYP1A1 in vitro. Therefore, clinically relevant drug-drug interactions with co-medications which are significantly cleared by CYP1A1-mediated biotransformation, such as erlotinib or granisetron cannot be ruled out. 4.6 Fertility, pregnancy and lactation 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, Adempas is contraindicated during pregnancy (see section 4.3). Monthly pregnancy tests are recommended. Women of childbearing potential Women of childbearing potential must use effective contraception during treatment with Adempas. Breast-feeding No data on the use of riociguat in breast-feeding women are available. Data from animals indicate that riociguat is secreted into milk. Due to the potential for serious adverse reactions in nursing 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 medicine. 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 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 medicine, before driving or operating machines. 4.8 Undesirable effects Summary of the safety profile 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). Tabulated list of adverse reactions 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) and uncommon (≥ 1/1,000 to < 1/100). Table 1: Adverse reactions reported with Adempas in the phase III studies MedDRA System Organ Class Very common Common Uncommon Infections and infestations   Gastroenteritis   Blood and the 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 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 at: www.mhra.gov.uk/yellowcard. 4.9 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 (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. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antihypertensives for pulmonary arterial hypertension, ATC code: C02KX05 Mechanism of action Riociguat is a stimulator of soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO). When NO binds to sGC, the enzyme catalyses synthesis of the signalling molecule cyclic guanosine monophosphate (cGMP). Intra-cellular cGMP plays an important role in regulating processes that influence vascular tone, proliferation, fibrosis, and inflammation. Pulmonary hypertension is associated with endothelial dysfunction, impaired synthesis of NO and insufficient stimulation of the NO-sGC-cGMP pathway. Riociguat has a dual mode of action. It sensitises sGC to endogenous NO by stabilising the NO-sGC binding. Riociguat also directly stimulates sGC independently of NO. Riociguat restores the NO-sGC-cGMP pathway and leads to increased generation of cGMP. Pharmacodynamic effects Riociguat restores the NO-sGC-cGMP pathway resulting in a significant improvement of pulmonary vascular haemodynamics and an increase in exercise ability. There is a direct relationship between riociguat plasma concentration and haemodynamic parameters such as systemic and pulmonary vascular resistance, systolic blood pressure and cardiac output. Clinical efficacy and safety Efficacy in patients with CTEPH A randomised, double-blind, multi-national, placebo controlled, phase III study (CHEST-1) was conducted in 261 adult patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) (72%) or persistent or recurrent CTEPH after pulmonary endarterectomy (PEA; 28%). During the first 8 weeks riociguat was titrated every 2-weeks based on the patient's systolic blood pressure and signs or symptoms of hypotension to the optimal individual dose (range 0.5 mg to 2.5 mg three times daily) which was then maintained for a further 8 weeks. The primary endpoint of the study was the placebo adjusted change from baseline in 6-minute walk distance (6MWD) at the last visit (week 16). At the last visit, the increase in 6MWD in patients treated with riociguat was 46 m (95% confidence interval (CI): 25 m to 67 m; p<0.0001), compared to placebo. Results were consistent in the main sub-groups evaluated (ITT analysis, see table 2). Table 2: Effects of riociguat on 6MWD in CHEST-1 at last visit Entire patient population Riociguat (n=173) Placebo (n=88) Baseline (m) [SD] 342 [82] 356 [75] Mean change from baseline (m) [SD] 39 [79] -6 [84] Placebo-adjusted difference (m) 95% CI, [p-value] 46 25 to 67 [<0.0001] FC III patient population Riociguat (n=107) Placebo (n=60) Baseline (m) [SD] 326 [81] 345 [73] Mean change from baseline (m) [SD] 38 [75] -17 [95] Placebo-adjusted difference (m) 95% CI 56 29 to 83 FC II patient population Riociguat (n=55) Placebo (n=25) Baseline (m) [SD] 387 [59] 386 [64] Mean change from baseline (m) [SD] 45 [82] 20 [51] Placebo-adjusted difference (m) 95% CI 25 -10 to 61 Inoperable patient population Riociguat (n=121) Placebo (n=68) Baseline (m) [SD] 335 [83] 351 [75] Mean change from baseline (m) [SD] 44 [84] -8 [88] Placebo-adjusted difference (m) 95% CI 54 29 to 79 Patient population with CTEPH post-PEA Riociguat (n=52) Placebo (n=20) Baseline (m) [SD] 360 [78] 374 [72] Mean change from baseline (m) [SD] 27 [68] 1.8 [73] Placebo- adjusted difference (m) 95% CI 27 -10 to 63 Improvement in exercise capacity was accompanied by improvement in multiple clinically relevant secondary endpoints. These findings were in accordance with improvements in additional haemodynamic parameters. Table 3: Effects of riociguat in CHEST-1 on PVR, NT-proBNP and WHO functional class at last visit PVR Riociguat (n=151) Placebo (n=82) Baseline (dyn·s·cm-5) [SD] 790.7 [431.6] 779.3 [400.9] Mean change from baseline (dyn·s·cm-5) [SD] -225.7   [247.5] 23.1   [273.5] Placebo-adjusted difference (dyn·s·cm-5) 95% CI, [p-value] -246.4   –303.3 to –189.5 [<0.0001] NT-proBNP Riociguat (n=150) Placebo (n=73) Baseline (ng/L) [SD] 1508.3 [2337.8] 1705.8 [2567.2] Mean change from baseline (ng/L) [SD] -290.7 [1716.9] 76.4 [1446.6] Placebo-adjusted difference (ng/L) 95% CI, [p-value] -444.0 -843.0 to -45.0 [<0.0001] Change in WHO Functional Class Riociguat (n=173) Placebo (n=87) Improved 57 (32.9%) 13 (14.9%) Stable 107 (61.8%) 68 (78.2%) Deteriorated 9 (5.2%) 6 (6.9%) p-value 0.0026 PVR= pulmonary vascular resistance NT-proBNP =N-terminal prohormone of brain natriuretic peptide Adverse Events leading to discontinuation occurred at a similar frequency in both treatment groups (riociguat individual dose titration (IDT) 1.0-2.5 mg, 2.9%; placebo, 2.3%). Long-term treatment An open-label extension study (CHEST-2) included 237 patients who had completed CHEST-1. In CHEST-2, all patients received an individualised riociguat dose up to 2.5 mg three times daily. The mean change from baseline to week 12 (last observation until week 12) in CHEST-2 (28 weeks on-study for CHEST-1 + CHEST-2) was 63 m in the former 1.0–2.5 mg riociguat group and 35 m in the former placebo group. The probability of survival at 1 year was 97%, at 2 years 94% and at 3 years 88%. Survival in patients of WHO functional class II at baseline at 1, 2 and 3 years was 97%, 94% and 88% respectively, and for patients of WHO functional class III at baseline was 97%, 94% and 87% respectively. Efficacy in patients with PAH A randomised, double-blind, multi-national, placebo controlled, phase III study (PATENT-1) was conducted in 443 adult patients with PAH (riociguat individual dose titration up to 2.5 mg three times daily: n=254, placebo: n=126, riociguat “capped” dose titration (CT) up to 1.5 mg (exploratory dose arm, no statistical testing performed; n=63)). Patients were either treatment-naïve (50%) or pre-treated with an endothelin receptor antagonist (ERA; 43%) or a prostacyclin analogue (inhaled (iloprost), oral (beraprost) or subcutaneous (treprostinil); 7%) and had been diagnosed with idiopathic or heritable PAH (63.4%), PAH associated with connective tissue disease (25.1%) and congenital heart disease (7.9%). During the first 8 weeks riociguat was titrated every 2-weeks based on the patient's systolic blood pressure and signs or symptoms of hypotension to the optimal individual dose (range 0.5 mg to 2.5 mg three times daily), which was then maintained for a further 4 weeks. The primary endpoint of the study was placebo-adjusted change from baseline in 6MWD at the last visit (week 12). At the last visit the increase in 6MWD with riociguat individual dose titration (IDT) was 36 m (95% CI: 20 m to 52 m; p<0.0001) compared to placebo. Treatment-naïve patients (n=189) improved by 38 m, and pre-treated patients (n=191) by 36 m (ITT analysis, see table 4). Further exploratory subgroup analysis revealed a treatment effect of 26 m, (95% CI: 5 m to 46 m) in patients pre-treated with ERAs (n=167) and a treatment effect of 101 m (95% CI: 27 m to 176 m) in patients pre-treated with prostacyclin analogues (n=27). Table 4: Effects of riociguat on 6MWD in PATENT-1 at last visit Entire patient population Riociguat IDT (n=254) Placebo (n=126) Riociguat CT (n=63) Baseline (m) [SD] 361 [68] 368 [75] 363 [67] Mean change from baseline (m) [SD] 30 [66] -6 [86] 31 [79] Placebo-adjusted difference (m) 95% CI, [p-value] 36 20 to 52 [<0.0001]   FC III patients Riociguat IDT (n=140) Placebo (n=58) Riociguat CT (n=39) Baseline (m) [SD] 338 [70] 347 [78] 351 [68] Mean change from baseline (m) [SD] 31 [64] -27 [98] 29 [94] Placebo-adjusted difference (m) 95% CI 58 35 to 81   FC II patients Riociguat IDT (n=108) Placebo (n=60) Riociguat CT (n=19) Baseline (m) [SD] 392 [51] 393 [61] 378 [64] Mean change from baseline (m) [SD] 29 [69] 19 [63] 43 [50] Placebo-adjusted difference (m) 95% CI 10 -11 to 31   Treatment-naïve patient population Riociguat IDT (n=123) Placebo (n=66) Riociguat CT (n=32) Baseline (m) [SD] 370 [66] 360 [80] 347 [72] Mean change from baseline (m) [SD] 32 [74] -6 [88] 49 [47] Placebo-adjusted difference (m) 95% CI 38 14 to 62   Pre-treated patient population Riociguat IDT (n=131) Placebo (n=60) Riociguat CT (n=31) Baseline (m) [SD] 353 [69] 376 [68] 380 [57] Mean change from baseline (m) [SD] 27 [58] -5 [83] 12 [100] Placebo- adjusted difference (m) 95% CI 36 15 to 56 Improvement in exercise capacity was accompanied by consistent improvement in multiple clinically-relevant secondary endpoints. These findings were in accordance with improvements in additional haemodynamic parameters (see table 5). Table 5: Effects of riociguat in PATENT-1 on PVR and NT-proBNP at last visit PVR Riociguat IDT (n=232) Placebo (n=107) Riociguat CT (n=58) Baseline (dyn·s·cm-5) [SD] 791 [452.6] 834.1 [476.7] 847.8 [548.2] Mean change from PVR baseline (dyn·s·cm-5) [SD] -223   [260.1] -8.9   [316.6] -167.8   [320.2] Placebo-adjusted difference (dyn·s·cm-5) 95% CI, [p-value] -225.7   -281.4 to -170.1[<0.0001]   NT-proBNP Riociguat IDT (n = 228) Placebo (n = 106) Riociguat CT (n=54) Baseline (ng/L) [SD] 1026.7 [1799.2] 1228.1 [1774.9] 1189.7 [1404.7] Mean change from baseline (ng/L) [SD] -197.9   [1721.3] 232.4   [1011.1] -471.5   [913.0] Placebo-adjusted difference (ng/L) 95% CI, [p-value] -431.8   -781.5 to -82.1 [<0.0001]   Change in WHO Functional Class Riociguat IDT (n = 254) Placebo (n = 125) Riociguat CT (n=63) Improved 53 (20.9%) 18 (14.4%) 15 (23.8%) Stable 192 (75.6%) 89 (71.2%) 43 (68.3%) Deteriorated 9 (3.6%) 18 (14.4%) 5 (7.9%) p-value 0.0033   Riociguat-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p = 0.0046; Stratified log-rank test) (see table 6). Table 6: Effects of riociguat in PATENT-1 on events of clinical worsening Clinical Worsening Events Riociguat IDT (n=254) Placebo (n=126) Riociguat CT (n=63) Patients with any clinical worsening 3 (1.2%) 8 (6.3%) 2 (3.2%) Death 2 (0.8%) 3 (2.4%) 1 (1.6%) Hospitalisations due to PH 1 (0.4%) 4 (3.2%) 0 Decrease in 6MWD due to PH 1 (0.4%) 2 (1.6%) 1 (1.6%) Persistent worsening of Functional Class due to PH 0 1 (0.8%) 0 Start of new PH treatment 1 (0.4%) 5 (4.0%) 1 (1.6%) Patients treated with riociguat showed significant improvement in Borg CR 10 dyspnoea score (mean change from baseline (SD): riociguat -0.4 (2), placebo 0.1 (2); p = 0.0022). Adverse Events leading to discontinuation occurred less frequently in both riociguat treatment groups than in the placebo group (riociguat IDT 1.0-2.5 mg, 3.1%; riociguat CT 1.6%; placebo, 7.1%). Long-term treatment An open-label extension study (PATENT-2) included 363 patients who had completed PATENT-1 at the cut-off-date. In PATENT-2, all patients received an individualised riociguat dose up to 2.5 mg three times daily. The mean change from baseline to week 12 (last observation until week 12) in PATENT-2 (24 weeks on-study for PATENT-1 + PATENT-2) was 53 m in the former 1.0–2.5 mg riociguat group, 42 m in the former placebo group and 54 m in the former 1.0–1.5 mg riociguat group. The probability of survival at 1 year was 97%, at 2 years 93% and at 3 years 91%. Survival in patients of WHO functional class II at baseline at 1, 2 and 3 years was 98%, 96% and 96% respectively, and for patients of WHO functional class III at baseline was 96%, 91% and 87% respectively. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with Adempas in one or more subsets of the paediatric population in the treatment of pulmonary hypertension. See section 4.2 for information on paediatric use. 5.2 Pharmacokinetic properties Absorption The absolute bioavailability of riociguat is high (94%). Riociguat is rapidly absorbed with maximum concentrations (Cmax) appearing 1-1.5 hours after tablet intake. Intake with food reduced riociguat AUC slightly, Cmax was reduced by 35%. Bioavailability (AUC and Cmax) is comparable for Adempas administered orally as a crushed tablet suspended in applesauce or in water compared to a whole tablet (see section 4.2). Distribution Plasma protein binding in humans is high at approximately 95%, with serum albumin and alpha 1-acidic glycoprotein being the main binding components. The volume of distribution is moderate with volume of distribution at steady state being approximately 30 L. Metabolism N-demethylation, catalysed by CYP1A1, CYP3A4, CYP2C8 and CYP2J2 is the major biotransformation pathway of riociguat leading to its major circulating active metabolite M-1 (pharmacological activity: 1/10th to 1/3rd of riociguat) which is further metabolised to the pharmacologically inactive N-glucuronide. CYP1A1 catalyses the formation of riociguat's main metabolite in liver and lungs and is known to be inducible by polycyclic aromatic hydrocarbons, which, for example, are present in cigarette smoke. Elimination Total riociguat (parent compound and metabolites) is excreted via both renal (33-45%) and biliary/faecal routes (48-59%). Approximately 4-19% of the administered dose was excreted as unchanged riociguat via the kidneys. Approximately 9-44% of the administered dose was found as unchanged riociguat in faeces. Based on in vitro data riociguat and its main metabolite are substrates of the transporter proteins P-gp (P-glycoprotein) and BCRP (breast cancer resistance protein). With a systemic clearance of about 3-6 L/h, riociguat can be classified as a low-clearance drug. Elimination half-life is about 7 hours in healthy subjects and about 12 hours in patients. Linearity Riociguat pharmacokinetics are linear from 0.5 to 2.5 mg. Inter-individual variability (CV) of riociguat exposure (AUC) across all doses is approximately 60%. Special populations Gender Pharmacokinetic data reveal no relevant differences due to gender in the exposure to riociguat. Paediatric population No studies have been conducted to investigate the pharmacokinetics of riociguat in paediatric patients. Elderly population Elderly patients (65 years or older) exhibited higher plasma concentrations than younger patients, with mean AUC values being approximately 40% higher in elderly, mainly due to reduced (apparent) total and renal clearance. Inter-ethnic differences Pharmacokinetic data reveal no relevant inter-ethnic differences. Different weight categories Pharmacokinetic data reveal no relevant differences due to weight in the exposure to riociguat. Hepatic impairment In cirrhotic patients (non-smokers) with mild hepatic impairment (classified as Child Pugh A) riociguat mean AUC was increased by 35% compared to healthy controls, which is within normal intra-individual variability. In cirrhotic patients (non-smokers) with moderate hepatic impairment (classified as Child Pugh B), riociguat mean AUC was increased by 51% compared to healthy controls. There are no data in patients with severe hepatic impairment (classified as Child Pugh C). Patients with ALT > 3 x ULN and bilirubin > 2 x ULN were not studied (see section 4.4). Renal impairment Overall, mean dose- and weight- normalised exposure values for riociguat were higher in subjects with renal impairment compared to subjects with normal renal function. Corresponding values for the main metabolite were higher in subjects with renal impairment compared to healthy subjects. In non-smoking individuals with mild (creatinine clearance 80-50 mL/min), moderate (creatinine clearance <50-30 mL/min) or severe (creatinine clearance <30 mL/min) renal impairment, riociguat plasma concentrations (AUC) were increased by 53%, 139% or 54%, respectively. Data in patients with creatinine clearance <30 mL/min are limited and there are no data for patients on dialysis. Due to the high plasma protein binding riociguat is not expected to be dialysable. 5.3 Preclinical safety data Non-clinical data revealed no specific hazard for humans based on conventional studies of safety pharmacology, single dose toxicity, phototoxicity, genotoxicity and carcinogenicity. Effects observed in repeat-dose toxicity studies were mainly due to the exaggerated pharmacodynamic activity of riociguat (haemodynamic and smooth muscle relaxing effects). In growing, juvenile and adolescent rats, effects on bone formation were seen. In juvenile rats, the changes consisted of thickening of trabecular bone and of hyperostosis and remodeling of metaphyseal and diaphyseal bone, whereas in adolescent rats an overall increase of bone mass was observed. No such effects were observed in adult rats. In a fertility study in rats, decreased testes weights occurred at systemic exposure of about 7-fold of human exposure, whereas no effects on male and female fertility were seen. Moderate passage across the placental barrier was observed. Developmental toxicity studies in rats and rabbits have shown reproductive toxicity of riociguat. In rats, an increased rate of cardiac malformation was observed as well as a reduced gestation rate due to early resorption at maternal systemic exposure of about 7-fold of human exposure (2.5 mg three times daily). In rabbits, starting at systemic exposure of about 3-fold of human exposure (2.5 mg three times daily) abortion and foetal toxicity were seen. 6. Pharmaceutical particulars 6.1 List of excipients Tablet core: cellulose microcrystalline crospovidone hypromellose magnesium stearate lactose monohydrate sodium laurilsulfate Film-coat: hydroxypropylcellulose hypromellose propylene glycol titanium dioxide (E 171) ferric oxide red (E172) (Adempas 2 mg and 2.5 mg film-coated tablets) ferric oxde yellow (E172) (Adempas 1 mg, 1.5 mg, 2 mg and 2.5 mg film-coated tablets) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container PP/Aluminium foil blister. Pack sizes: 42, 84, 90 or 294 film-coated tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Bayer Pharma AG 13342 Berlin Germany 8. Marketing authorisation number(s) Adempas 0.5 mg film-coated tablets:  EU/1/13/907/001, 002, 003, 016 Adempas 1 mg film-coated tablets:  EU/1/13/907/004, 005, 006, 017 Adempas 1.5 mg film-coated tablets:  EU/1/13/907/007, 008, 009, 018 Adempas 2 mg film-coated tablets:  EU/1/13/907/010, 011, 012, 019 Adempas 2.5 mg film-coated tablets:  EU/1/13/907/013, 014, 015, 020 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 27 March 2014 10. Date of revision of the text 07/2015 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 附： Adempas 0.5 mg film-coated tablets（https://www.medicines.org.uk/emc/medicine/28739） Adempas 1 mg film-coated tablets（https://www.medicines.org.uk/emc/medicine/28740） Adempas 1.5 mg film-coated tablets（https://www.medicines.org.uk/emc/medicine/28741） Adempas 2 mg film-coated tablets（https://www.medicines.org.uk/emc/medicine/28738） 美国FDA批准拜耳Adempas（riociguat）用于治疗肺动脉高压 10月8日，美国食品药品管理局FDA批准Adempas（通用名：Riociguat）用于治疗成人两种形式的肺动脉高压。肺动脉高压由肺部动脉异常高血压引起。该病症使右侧心脏工作起来比正常情况更艰难。在其各种疾病形式中，肺动脉高压是一种慢性、进展性并使人衰弱的疾病，常常会导致死亡或需要肺移植。 Adempas属于一类叫做可溶性鸟苷酸环化酶激活剂的药物，这类药物有助于动脉松弛，从而使血流增加，血压降低。这款药物旨在治疗术后慢性血栓栓塞性肺动脉高压（CTEPH）患者或无法接受手术的患者，以改善他们的运动能力。Adempas也用于治疗不明原因引起的、遗传性的或与结缔组织病有关的肺动脉高压（PAH）患者，以改善患者的运动能力并推迟他们疾病的临床恶化进度。 Riociguat的化学结构： Adempas是可溶性鸟苷酸环化酶激活剂中首款获批用于治疗肺动脉高压的药物，也是首款证明对CTEPH患者有效的药物。”FDA药物评价与研究中心心血管与肾病药物产品部门主任、医学博士与理学博士Norman Stockbridge说。FDA是在优先审评计划下完成Adempas审评的，优先审评可以为治疗上能提供重要进展的药物提供一个加快的6个月的审评。 Adempas治疗CTEPH的安全性和有效性基于一项由261名受试者参与的临床试验，试验中受试者被随机配给Adempas，用药剂量逐渐增加到2.5mg，每天用药三次，或配给安慰剂每天使用三次。这项研究的目的是检测受试者6分钟之内所能行走距离的变化。经过16周的治疗后，Adempas用药患者6分钟行走距离平均增加46米，远超过安慰剂治疗患者。 用来评价Adempas治疗PAH安全性和有效性的临床试验由443名受试者参与，患者被随机配给1.5mg或2.5mg剂量的Adempas或者安慰剂，每天用药三次。经过16周治疗后，Adempas用药患者6分钟行走距离平均提高36米，远超过安慰剂治疗患者。 Adempas药品标签中带有一项黑框警告，提示患者与卫生保健专业人员这款药物不能用于孕妇，因为它会伤害胎儿的发育。女性患者只能通过Adempas风险评估与降低（REMS）计划来获取这款药物。所有女性患者必须加入这个计划，遵守怀孕测试要求，并得到需要进行避孕的劝告。限制药品分销的REMS计划要求开处方者加入该项计划并获得认证。同时，药店必须通过认证并只能将这款药物分发给按REMS要求有资格使用的患者。 Adempas治疗患者常见的副作用包括头痛、头晕、消化不良、组织肿胀(外围性水肿)、恶心、腹泻和呕吐。Adempas由位于新泽西州韦恩的拜耳医药保健制药公司上市销售。