Opsumit（macitentan，10mg，中文药名为马西替坦片、美西特田片），作为每日一次的疗法，用于治疗肺动脉高压（PAH）。 Actelion公司11月4日宣布，在美国推出Opsumit（macitentan，10mg），该药为每日一次的口服片剂，用于治疗肺动脉高压（PAH），以延缓疾病进展。 Opsumit于2013年10月18日获FDA批准，并于10月25日获得了欧洲药品管理局（EMA）人用医药产品委员会（CHMP）的积极意见。CHMP建议批准Opsumit，作为单药疗法或联合其他药物，用于肺动脉高压（PAH）成人患者（WHO功能分级II-III）的长期治疗。 Opsumit属于一类名为内皮素受体拮抗剂的药物，能够放松肺动脉并降低血压，Opsumit与该类药物中的其他药物一样，具有一个黑框警示，指出该药不可用于孕妇，因为Opsumit可能对胎儿造成伤害。 Opsumit (macitentan) 10mg Opsumit 10mg film-coated tablets 1. Name of the medicinal product  Opsumit 10 mg film-coated tablets. 2. Qualitative and quantitative composition Each film-coated tablet contains 10 mg macitentan. Excipients with known effect: Each film-coated tablet contains approximately 37 mg of lactose (as monohydrate) and approximately 0.06 mg of lecithin (soya) (E322). For the full list of excipients, see section 6.1. 3. Pharmaceutical form Film-coated tablet. 5.5 mm, round, biconvex, white to off-white film-coated tablets, debossed with “10” on one side. 4. Clinical particulars 4.1 Therapeutic indications Opsumit, as monotherapy or in combination, is indicated for the long-term treatment of pulmonary arterial hypertension (PAH) in adult patients of WHO Functional Class (FC) II to III. Efficacy has been shown in a PAH population including idiopathic and heritable PAH, PAH associated with connective tissue disorders, and PAH associated with corrected simple congenital heart 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 PAH. Posology Opsumit is to be taken orally at a dose of 10 mg once daily, with or without food. The film-coated tablets are not breakable and are to be swallowed whole, with water. Opsumit should be taken every day at about the same time. If the patient misses a dose of Opsumit, the patient should be told to take it as soon as possible and then take the next dose at the regularly scheduled time. The patient should be told not to take two doses at the same time if a dose has been missed. Elderly patients No dose adjustment is required in patients over the age of 65 years (see section 5.2). There is limited clinical experience in patients over the age of 75 years. Therefore Opsumit should be used with caution in this population (see section 4.4). Patients with hepatic impairment Based on pharmacokinetic (PK) data, no dose adjustment is required in patients with mild, moderate or severe hepatic impairment (see sections 4.4 and 5.2). However, there is no clinical experience with the use of macitentan in PAH patients with moderate or severe hepatic impairment. Opsumit must not be initiated in patients with severe hepatic impairment, or clinically significant elevated hepatic aminotransferases (greater than 3 times the Upper Limit of Normal (> 3 × ULN); see sections 4.3 and 4.4). Patients with renal impairment Based on PK data, no dose adjustment is required in patients with renal impairment. There is no clinical experience with the use of macitentan in PAH patients with severe renal impairment. The use of Opsumit is not recommended in patients undergoing dialysis (see sections 4.4 and 5.2). Paediatric population The safety and efficacy of macitentan in children have not yet been established. 4.3 Contraindications • Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. • Pregnancy (see section 4.6). • Women of childbearing potential who are not using reliable contraception (see sections 4.4 and 4.6). • Breastfeeding (see section 4.6). • Patients with severe hepatic impairment (with or without cirrhosis) (see section 4.2). • Baseline values of hepatic aminotransferases (aspartate aminotransferases (AST) and/or alanine aminotransferases (ALT) > 3 × ULN) (see sections 4.2 and 4.4). 4.4 Special warnings and precautions for use The benefit/risk balance of macitentan has not been established in patients with WHO class I functional status of pulmonary arterial hypertension. Liver function Elevations of liver aminotransferases (AST, ALT) have been associated with PAH and with endothelin receptor antagonists (ERAs). Opsumit is not to be initiated in patients with severe hepatic impairment or elevated aminotransferases (> 3 × ULN) (see sections 4.2 and 4.3), and is not recommended in patients with moderate hepatic impairment. Liver enzyme tests should be obtained prior to initiation of Opsumit. Patients should be monitored for signs of hepatic injury and monthly monitoring of ALT and AST is recommended. If sustained, unexplained, clinically relevant aminotransferase elevations occur, or if elevations are accompanied by an increase in bilirubin > 2 × ULN, or by clinical symptoms of liver injury (e.g., jaundice), Opsumit treatment should be discontinued. Reinitiation of Opsumit may be considered following the return of hepatic enzyme levels to within the normal range in patients who have not experienced clinical symptoms of liver injury. The advice of a hepatologist is recommended. Haemoglobin concentration As with other ERAs, treatment with macitentan has been associated with a decrease in haemoglobin concentration (see section 4.8). In placebo-controlled studies, macitentan-related decreases in haemoglobin concentration were not progressive, stabilised after the first 4–12 weeks of treatment and remained stable during chronic treatment. Cases of anaemia requiring blood cell transfusion have been reported with macitentan and other ERAs. Initiation of Opsumit is not recommended in patients with severe anaemia. It is recommended that haemoglobin concentrations be measured prior to initiation of treatment and tests repeated during treatment as clinically indicated. Pulmonary veno-occlusive disease Cases of pulmonary oedema have been reported with vasodilators (mainly prostacyclins) when used in patients with pulmonary veno-occlusive disease. Consequently, if signs of pulmonary oedema occur when macitentan is administered in patients with PAH, the possibility of pulmonary veno-occlusive disease should be considered. Use in women of childbearing potential Opsumit treatment should only be initiated in women of childbearing potential when the absence of pregnancy has been verified, appropriate advice on contraception provided, and reliable contraception is practised (see sections 4.3 and 4.6). Women should not become pregnant for 1 month after discontinuation of Opsumit. Monthly pregnancy tests during treatment with Opsumit are recommended to allow the early detection of pregnancy. Concomitant use with strong CYP3A4 inducers In the presence of strong CYP3A4 inducers reduced efficacy of macitentan could occur. The combination of macitentan with strong CYP3A4 inducers (e.g., rifampicin, St. John's wort, carbamazepine, and phenytoin) should be avoided (see section 4.5). Concomitant use with strong CYP3A4 inhibitors Caution should be exercised when macitentan is administered concomitantly with strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir) (see section 4.5). Patients with renal impairment Patients with renal impairment may run a higher risk of experiencing hypotension and anaemia during treatment with macitentan. Therefore, monitoring of blood pressure and haemoglobin should be considered. There is no clinical experience with the use of macitentan in PAH patients with severe renal impairment. Caution is recommended in this population. There is no experience with the use of macitentan in patients undergoing dialysis, therefore Opsumit is not recommended in this population (see sections 4.2 and 5.2). Elderly patients There is limited clinical experience with macitentan in patients over the age of 75 years, therefore Opsumit should be used with caution in this population (see section 4.2). Excipients Opsumit tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Opsumit tablets contain lecithin derived from soya. If a patient is hypersensitive to soya, Opsumit must not be used (see section 4.3). 4.5 Interaction with other medicinal products and other forms of interaction In vitro studies The cytochrome P450 enzymes CYP3A4, CYP2C8, CYP2C9, and CYP2C19 are involved in the metabolism of macitentan and formation of its metabolites (see section 5.2). Macitentan and its active metabolite do not have clinically relevant inhibitory or inducing effects on cytochrome P450 enzymes. Macitentan and its active metabolite are not inhibitors of hepatic or renal uptake transporters at clinically relevant concentrations, including the organic anion transporting polypeptides (OATP1B1 and OATP1B3). Macitentan and its active metabolite are not relevant substrates of OATP1B1 and OATP1B3, but enter the liver by passive diffusion. Macitentan and its active metabolite are not inhibitors of hepatic or renal efflux pumps at clinically relevant concentrations, including the multi-drug resistance protein (P-gp, MDR-1) and multidrug and toxin extrusion transporters (MATE1 and MATE2-K). Macitentan inhibits the breast cancer resistance protein (BCRP) at clinically relevant intestinal concentrations. Macitentan is not a substrate for P-gp/MDR-1. At clinically relevant concentrations, macitentan and its active metabolite do not interact with proteins involved in hepatic bile salt transport, i.e., the bile salt export pump (BSEP) and the sodium-dependent taurocholate co-transporting polypeptide (NTCP). In vivo studies Interaction studies have only been performed in adults. Warfarin: Macitentan given as multiple doses of 10 mg once daily had no effect on exposure to S-warfarin (CYP2C9 substrate) or R-warfarin (CYP3A4 substrate) after a single dose of 25 mg warfarin. The pharmacodynamic effect of warfarin on International Normalized Ratio (INR) was not affected by macitentan. The pharmacokinetics of macitentan and its active metabolite were not affected by warfarin. Sildenafil: At steady-state, the exposure to sildenafil 20 mg t.i.d. was increased by 15% during concomitant administration of macitentan 10 mg once daily. Sildenafil, a CYP3A4 substrate, did not affect the pharmacokinetics of macitentan, while there was a 15% reduction in the exposure to the active metabolite of macitentan. These changes are not considered clinically relevant. In a placebo-controlled trial in patients with PAH, the efficacy and safety of macitentan in combination with sildenafil were demonstrated. Ketoconazole: In the presence of ketoconazole 400 mg once daily, a strong CYP3A4 inhibitor, exposure to macitentan increased approximately 2-fold. The predicted increase was approximately 3-fold in the presence of ketoconazole 200 mg twice daily using physiologically based pharmacokinetic (PBPK) modelling. The uncertainties of such modelling should be considered. Exposure to the active metabolite of macitentan was reduced by 26%. Caution should be exercised when macitentan is administered concomitantly with strong CYP3A4 inhibitors (see section 4.4). Cyclosporine A: Concomitant treatment with cyclosporine A 100 mg b.i.d., a combined CYP3A4 and OATP inhibitor, did not alter the steady-state exposure to macitentan and its active metabolite to a clinically relevant extent. Strong CYP3A4 inducers: Concomitant treatment with rifampicin 600 mg daily, a potent inducer of CYP3A4, reduced the steady-state exposure to macitentan by 79% but did not affect the exposure to the active metabolite. Reduced efficacy of macitentan in the presence of a potent inducer of CYP3A4 such as rifampicin should be considered. The combination of macitentan with strong CYP3A4 inducers should be avoided (see section 4.4). Hormonal contraceptives: Although specific drug-drug interaction studies with hormonal contraceptives have not been conducted, macitentan did not affect the exposure to other CYP3A4 substrates such as sildenafil. Therefore, no reduced efficacy of hormonal contraceptives is expected. 4.6 Fertility, pregnancy, and lactation Pregnancy There are no data on the use of macitentan in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). The potential risk for humans is still unknown. Opsumit is contraindicated during pregnancy and in women of childbearing potential who are not using reliable contraception (see section 4.3). Use in women of childbearing potential Opsumit treatment should only be initiated in women of childbearing potential when the absence of pregnancy has been verified, appropriate advice on contraception provided, and reliable contraception is practised (see sections 4.3 and 4.4). Women should not become pregnant for 1 month after discontinuation of Opsumit. Monthly pregnancy tests during treatment with Opsumit are recommended to allow the early detection of pregnancy. Breastfeeding It is not known whether macitentan is excreted into human breast milk. In rats, macitentan and its metabolites are excreted into milk during lactation (see section 5.3). A risk to the breastfeeding child cannot be excluded. Opsumit is contraindicated during breastfeeding (see section 4.3). Male fertility The development of testicular tubular atrophy in male animals was observed after treatment with macitentan (see section 5.3). The relevance of this finding to humans is unknown, but a deterioration of spermatogenesis cannot be excluded. 4.7 Effects on ability to drive and use machines Macitentan may have a minor influence on the ability to drive and use machines. The clinical status of the patient and the adverse reaction profile of macitentan (such as headache, hypotension) should be kept in mind when considering the patient's ability to drive and use machines. 4.8 Undesirable effects Summary of the safety profile. The most commonly reported adverse drug reactions are nasopharyngitis (14.0%), headache (13.6%) and anaemia (13.2%, see section 4.4). The majority of adverse reactions are mild to moderate in intensity. Tabulated list of adverse reactions The safety of macitentan has been eva luated in a long-term placebo-controlled trial of 742 patients with symptomatic PAH. The mean treatment duration was 103.9 weeks in the macitentan 10 mg group, and 85.3 weeks in the placebo group. Adverse reactions associated with macitentan obtained from this clinical study are tabulated below. 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). System organ class Frequency Adverse reaction Infections and infestations Very Common Nasopharyngitis Very Common Bronchitis Common Pharyngitis Common Influenza Common Urinary tract infection Blood and lymphatic system disorders Very Common Anaemia Nervous system disorders Very Common Headache Vascular disorders Common Hypotension* Description of selected adverse reactions * Hypotension has been associated with the use of ERAs. In a long-term double-blind study in patients with PAH, hypotension was reported for 7.0% and 4.4% of patients on macitentan 10 mg and placebo, respectively. This corresponded to 3.5 events / 100 patient-years on macitentan 10 mg compared to 2.7 events / 100 patient-years on placebo. Oedema/fluid retention has been associated with the use of ERAs and is also a clinical manifestation of right heart failure and underlying PAH disease. In a long-term double-blind study in patients with PAH, the incidence of oedema AEs in the macitentan 10 mg and placebo treatment groups was 11.0 events / 100 patient-years on macitentan 10 mg compared to 12.5 events / 100 patient-years on placebo. Laboratory abnormalities Liver aminotransferases The incidence of aminotransferase elevations (ALT/AST) > 3 × ULN was 3.4% on macitentan 10 mg and 4.5% on placebo in a double-blind study in patients with PAH. Elevations > 5 × ULN occurred in 2.5% of patients on macitentan 10 mg versus 2% of patients on placebo. Haemoglobin In a double-blind study in patients with PAH, macitentan 10 mg was associated with a mean decrease in haemoglobin versus placebo of 1 g/dL. A decrease from baseline in haemoglobin concentration to below 10 g/dL was reported in 8.7% of patients treated with macitentan 10 mg and 3.4% of placebo-treated patients. White blood cells In a double-blind study in patients with PAH, macitentan 10 mg was associated with a decrease in mean leucocyte count from baseline of 0.7 × 109/L versus no change in placebo-treated patients. Platelets In a double-blind study in patients with PAH, macitentan 10 mg was associated with a decrease in mean platelet count of 17 × 109/L, versus a mean decrease of 11 × 109/L in placebo-treated patients. Paediatric population The safety and efficacy of macitentan in children have not yet been established. 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 national reporting system listed below. United Kingdom Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard Ireland IMB Pharmacovigilance Earlsfort Terrace IRL - Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.imb.ie e-mail: imbpharmacovigilance@imb.ie Malta ADR Reporting The Medicines Authority Post-Licensing Directorate 203 Level 3, Rue D'Argens GŻR-1368 Gżira Website: www.medicinesauthority.gov.mt e-mail: postlicensing.medicinesauthority@gov.mt 4.9 Overdose Macitentan has been administered as a single dose of up to 600 mg to healthy subjects. Adverse reactions of headache, nausea, and vomiting were observed. In the event of an overdose, standard supportive measures must be taken, as required. Due to the high degree of protein binding of macitentan, dialysis is unlikely to be effective. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: other anti-hypertensives, ATC code: C02KX04. Mechanism of action Endothelin (ET)-1 and its receptors (ETA and ETB) mediate a variety of effects such as vasoconstriction, fibrosis, proliferation, hypertrophy, and inflammation. In disease conditions such as PAH, the local ET system is upregulated and is involved in vascular hypertrophy and in organ damage. Macitentan is an orally active potent endothelin receptor antagonist, active on both ETA and ETB receptors and approximately 100-fold more selective for ETA as compared to ETB in vitro. Macitentan displays high affinity and sustained occupancy of the ET receptors in human pulmonary arterial smooth muscle cells. This prevents endothelin-mediated activation of second messenger systems that result in vasoconstriction and smooth muscle cell proliferation. Clinical efficacy and safety Efficacy in patients with pulmonary arterial hypertension A multicenter, double-blind, placebo-controlled, parallel-group, event-driven, Phase 3 outcome study (AC-055-302/SERAPHIN) was conducted in 742 patients with symptomatic PAH, who were randomised to three treatment groups (placebo [N = 250], 3 mg [N = 250] or 10 mg [N = 242] of macitentan once daily), to assess the long-term effect on morbidity or mortality. At baseline, the majority of enrolled patients (64%) were treated with a stable dose of specific therapy for PAH, either oral phosphodiesterase inhibitors (61%) and/or inhaled/oral prostanoids (6%). The primary endpoint was the time to first occurrence of a morbidity or mortality event, up to the end of double-blind treatment, defined as death, or atrial septostomy, or lung transplantation, or initiation of intravenous (i.v.) or subcutaneous (s.c.) prostanoids, or other worsening of PAH. Other worsening of PAH was defined as the presence of all of the three following components: a sustained decrease in 6-minute walk distance (6MWD) of at least 15% from baseline; worsening of PAH symptoms (worsening of WHO FC or right heart failure); and need for new treatment for PAH. All events were confirmed by an independent adjudication committee, blinded to treatment allocation. All patients were followed up to end-of-study (EOS) for vital status. EOS was declared when the predefined number of primary endpoint events was reached. In the period between end-of-treatment (EOT) and EOS, patients could receive open-label macitentan 10 mg or alternative PAH therapy. The overall median double-blind treatment duration was 115 weeks (up to a maximum of 188 weeks on macitentan). The mean age of all patients was 46 years (range 12–85 years of age, including 20 patients below 18, 706 patients between 18–74 years, and 16 patients aged 75 and older) with the majority of subjects being Caucasian (55%) and female (77%). Approximately 52%, 46%, and 2% of patients were in WHO FC II, III, and IV, respectively. Idiopathic or heritable PAH was the most common aetiology in the study population (57%), followed by PAH due to connective tissue disorders (31%), PAH associated with corrected simple congenital heart disease (8%), and PAH associated with other aetiologies (drugs and toxins [3%] and HIV [1%]). Outcome endpoints Treatment with macitentan 10 mg resulted in a 45% risk reduction (hazard ratio [HR] 0.55; 97.5% CI: 0.39 to 0.76; logrank p < 0.0001) of the composite morbidity-mortality endpoint up to EOT when compared to placebo [Figure 1 and Table 1]. The treatment effect was established early and was sustained. Efficacy of macitentan 10 mg on the primary endpoint was consistent across subgroups of age, sex, ethnic origin, geographical region, aetiology, by monotherapy or in combination with another PAH therapy and by WHO FC (I/II and III/IV). Figure 1 Kaplan-Meier estimates of the first morbidity-mortality event in SERAPHIN Table 1 Summary of outcome events Endpoints & Statistics Patients with events Treatment Comparison: Macitentan 10 mg vs Placebo Placebo (N = 250) Macitentan 10 mg (N = 242) Absolute Risk Reduction Relative Risk Reduction (97.5% CI) HR a (97.5% CI) Logrank p-value Morbidity-mortality event b   53% 37% 16% 45% (24%; 61%) 0.55 (0.39; 0.76) < 0.0001 Death c n (%) 19 (7.6%) 14 (5.8%) 2% 36% (−42%; 71%) 0.64 (0.29; 1.42) 0.20 Worsening of PAH n (%) 93 (37.2%) 59 (24.4%) 13% 49% (27%, 65%) 0.51 (0.35; 0.73) < 0.0001 i.v./s.c. Prostanoid Initiation n (%) 6 (2.4%) 1 (0.4%) 2% a = based on Cox's Proportional Hazards Model b = % of patients with an event at 36 months = 100 × (1 - KM estimate) c= all cause death up to EOT regardless of prior worsening The number of deaths of all causes up to EOS on macitentan 10 mg was 35 versus 44 on placebo (HR 0.77; 97.5% CI: 0.46 to 1.28). The risk of PAH related death or hospitalisation for PAH up to EOT was reduced by 50% (HR 0.50; 97.5% CI: 0.34 to 0.75; logrank p < 0.0001) in patients receiving macitentan 10 mg (50 events) compared to placebo (84 events). At 36 months, 44.6% of patients on placebo and 29.4% of patients on macitentan 10 mg (Absolute Risk Reduction = 15.2%) had been hospitalised for PAH or died from a PAH-related cause. Symptomatic endpoints Exercise capacity was eva luated as a secondary endpoint. Treatment with macitentan 10 mg at Month 6 resulted in a placebo-corrected mean increase in 6MWD of 22 meters (97.5% CI: 3 to 41; p = 0.0078). eva luation of 6MWD by functional class resulted in a placebo-corrected mean increase from baseline to Month 6 in FC III/IV patients of 37 meters (97.5% CI: 5 to 69) and in FC I/II of 12 meters (97.5% CI: −8 to 33). The increase in 6MWD achieved with macitentan was maintained for the duration of the study. Treatment with macitentan 10 mg at Month 6 led to a 74% higher chance of WHO FC improvement relative to placebo (risk ratio 1.74; 97.5% CI: 1.10 to 2.74; p = 0.0063). Macitentan 10 mg improved quality of life assessed by the SF-36 questionnaire. Haemodynamic endpoints Haemodynamic parameters were assessed in a subset of patients (placebo [N = 67], macitentan 10 mg [N = 57]) after 6 months of treatment. Patients treated with macitentan 10 mg achieved a median reduction of 36.5% (97.5% CI: 21.7 to 49.2%) in pulmonary vascular resistance and an increase of 0.58 L/min/m2 (97.5% CI: 0.28 to 0.93 L/min/m2) in cardiac index compared to placebo. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with macitentan in all subsets of the paediatric population in PAH (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties The pharmacokinetics of macitentan and its active metabolite have mainly been documented in healthy subjects. Exposure to macitentan in patients with PAH was approximately 1.2-fold greater than in healthy subjects. The exposure to the active metabolite in patients, which is approximately 5-fold less potent than macitentan, was approximately 1.3-fold higher than in healthy subjects. The pharmacokinetics of macitentan in PAH patients were not influenced by the severity of the disease. After repeated administration, the pharmacokinetics of macitentan are dose-proportional up to and including 30mg. Absorption Maximum plasma concentrations of macitentan are achieved about 8 hours after administration. Thereafter, plasma concentrations of macitentan and its active metabolite decrease slowly, with an apparent elimination half-life of approximately 16 hours and 48 hours, respectively. In healthy subjects, the exposure to macitentan and its active metabolite is unchanged in the presence of food and, therefore, macitentan may be taken with or without food. Distribution Macitentan and its active metabolite are highly bound to plasma proteins (> 99%), primarily to albumin and to a lesser extent to alpha1-acid glycoprotein. Macitentan and its active metabolite ACT-132577 are well distributed into tissues as indicated by an apparent volume of distribution (Vss/F) of approximately 50 L and 40 L for macitentan and ACT-132577, respectively. Biotransformation Macitentan has four primary metabolic pathways. Oxidative depropylation of the sulfamide yields a pharmacologically active metabolite. This reaction is dependent on the cytochrome P450 system, mainly CYP3A4 (approximately 99%) with minor contributions of CYP2C8, CYP2C9 and CYP2C19. The active metabolite circulates in human plasma and may contribute to the pharmacological effect. Other metabolic pathways yield products without pharmacological activity. Several members of the CYP2C family, namely CYP2C8, CYP2C9 and CYP2C19, as well as CYP3A4, are involved in the formation of these metabolites. Elimination Macitentan is only excreted after extensive metabolism. The major excretion route is via urine, accounting for about 50% of the dose. Special populations There is no clinically relevant effect of age, sex or ethnic origin on the pharmacokinetics of macitentan and its active metabolite. Renal impairment Exposure to macitentan and its active metabolite was increased by 1.3- and 1.6-fold, respectively, in patients with severe renal impairment. This increase is not considered clinically relevant (see sections 4.2 and 4.4). Hepatic impairment Exposure to macitentan was decreased by 21%, 34%, and 6% and, for the active metabolite by 20%, 25%, and 25% in subjects with mild, moderate or severe hepatic impairment, respectively. This decrease is not considered clinically relevant (see sections 4.2 and 4.4). 5.3 Preclinical safety data In dogs, macitentan decreased blood pressure at exposures similar to the therapeutic human exposure. Intimal thickening of coronary arteries was observed at 17-fold the human exposure after 4 to 39 weeks of treatment. Due to the species-specific sensitivity and the safety margin, this finding is considered not relevant for humans. Increased liver weight and hepatocellular hypertrophy were observed in mice, rats and dogs after treatment with macitentan. These changes were largely reversible and considered non-adverse adaptations of the liver to increased metabolic demand. Macitentan induced minimal to slight mucosal hyperplasia and inflammatory infiltration in the submucosa of the nasal cavity in the mouse carcinogenicity study at all doses. No nasal cavity findings were noted in the 3-month mouse toxicity study or in rat and dog studies. Macitentan was not genotoxic in a standard battery of in vitro and in vivo assays. Macitentan was not phototoxic in vivo after single dose at exposures of up to 24-fold the human exposure. Carcinogenicity studies of 2 years' duration did not reveal a carcinogenic potential at exposures 20-fold and 140-fold the human exposure in rats and mice, respectively. Testicular tubular dilatation was observed in chronic toxicity studies with male rats and dogs with safety margins of 11.6 and 5.8, respectively. Tubular dilatation was fully reversible. After 2 years of treatment, testicular tubular atrophy was seen in rats at 4-fold the human exposure. Hypospermatogenesis was observed in the life-long carcinogenicity study in rats and in the repeat-dose toxicity studies in dogs at exposures that provide safety margins of 9.7 in rats and 23 in dogs. The safety margins for fertility were 18 for male and 44 for female rats. No testicular findings were noted in mice after treatment up to 2 years. The effect of macitentan on human male fertility is not known (section 4.6). Macitentan was teratogenic in rabbits and rats at all doses tested. In both species there were cardiovascular and mandibular arch fusion abnormalities Administration of macitentan to female rats from late pregnancy through lactation at maternal exposures 5-fold the human exposure, caused reduced pup survival and impairment of the reproductive capability of the offspring, which was exposed to macitentan during late intrauterine life and via the milk during the suckling period. Treatment of juvenile rats from postnatal Day 4 to Day 114 caused reduced body weight gain leading to secondary effects on development (slight delay of descensus testis, reversible reduction of long-bone length, prolonged estrous cycle). Slightly increased pre- and post-implantation loss, decreased mean number of pups, and decreased testis and epididymis weights, were observed at exposures 7-fold the human exposure. Testicular tubular atrophy, and minimal effects on reproductive variables and sperm morphology were recorded at exposures 3.8-fold the human exposure. 6. Pharmaceutical particulars 6.1 List of excipients Tablet core Lactose monohydrate Microcrystalline cellulose (E460i) Sodium starch glycolate Type A Povidone Magnesium stearate (E572) Polysorbate 80 (E433) Film coat Polyvinyl alcohol (E1203) Titanium dioxide (E171) Talc (E553b) Lecithin, soybean (E322) Xanthan gum (E415) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage Do not store above 30 °C. 6.5 Nature and contents of container White, opaque PVC/PE/PVdC/Aluminium foil blisters in cartons containing 15 or 30 film-coated tablets. White high-density polyethylene bottles with a silica gel desiccant, in cartons containing 30 film-coated tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling No special requirements. 7. Marketing authorisation holder Actelion Registration Ltd Chiswick Tower 13th Floor 389 Chiswick High Road London W4 4AL United Kingdom 8. Marketing authorisation number(s) EU/1/13/893/001 EU/1/13/893/002 EU/1/13/893/003 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 20 December 2013 10. Date of revision of the text May 2014 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://opsumit.com/ 美国上市的Opsumit产品： 欧洲上市的Opsumit产品： 肺动脉高压（PAH）是一种极度严重的疾病，症状包括：呼吸短促、易于疲劳、晕厥、胸痛以及腿部和踝部水肿。此外，患者的肺动脉高压会逐步加重，甚至使寿命缩短。多数肺动脉高压相关的症状源自右心衰竭。 Approved indication: pulmonary arterial hypertension Opsumit (Actelion) andCorrection August 2014 The 3 mg dose has been deleted as only the 10mg dose is available 10mg film-coated tablets Australian Medicines Handbook section 6.6.2 Pulmonary arterial hypertension can cause dyspnoea on exertion and leads to right heart failure. It can be idiopathic and familial or can be associated with connective tissue diseases and congenital heart disease with repaired shunts. The available treatments for pulmonary arterial hypertension include calcium channel blockers, endothelin antagonists, phosphodiesterase 5 inhibitors and prostacyclins. Some patients require combinations of these drugs and some will not respond and will need a lung transplant. Macitentan was developed by modifying the structure of the endothelin receptor antagonist bosentan. It stops endothelin from binding to the endothelin A and B receptors. These receptors are associated with vasoconstriction. Although the maximum plasma concentration is reached eight hours after an oral dose, macitentan has a rapid onset of effect. The drug is metabolised, mainly by cytochrome P450 3A4, to form an active metabolite. Macitentan has a half-life of 16 hours and its active metabolite has a half-life of 48 hours. Most of the metabolites are excreted in the urine. The main trial of macitentan involved 742 patients with an average age of 45.6 years. Most of the patients had idiopathic or heritable pulmonary arterial hypertension or an associated connective tissue disease. They were randomised to start macitentan 3 mg or 10 mg, or a placebo, once daily. Other treatments for pulmonary arterial hypertension could be continued. The primary end point of the study was a composite of clinically worsening pulmonary arterial hypertension, the need for prostanoids, lung transplant or death.1 After a median treatment duration of 115 weeks, one of these events had occurred in 38% of the macitentan 3 mg group, 31.4% of the 10mg group and 46.4% of the placebo group. Another composite end point of death or hospitalisation for pulmonary arterial hypertension was reached by 26% of the 3mg group, 20.7% of the 10 mg group and 33.6% of the placebo group. The advantages of macitentan over placebo in these composite end points were statistically significant.There were also improvements in exercise capacity.1 Adverse events led to treatment discontinuation in 13.6% of the 3 mg group, 10.7% of the 10 mg group and 12.4% of the placebo group. Compared with placebo, patients taking macitentan 10 mg (the dose recommended in Australia) more frequently developed respiratory infections, headache and anaemia.1 The blood count should be measured before and during treatment. As liver function can be affected, macitentan is contraindicated in patients with aminotransferase concentrations greater than three times the upper limit of normal. Monthly monitoring of liver function is recommended. Patients with renal impairment may have an increased risk of hypotension or anaemia. Macitentan is teratogenic. Although exercise tolerance improved with macitentan, the increase was relatively small. At the start of the study the patients could walk an average of 360 metres in six minutes. After six months the patients taking macitentan 10 mg could walk 12.5 metres further.1 As this change may not be a good surrogate for clinical outcomes, it is important that mortality was studied. However, the drug did not have a significant effect on all components of the primary composite outcome. Most of the benefit was due to macitentan 10 mg reducing the proportion of patients with worsening pulmonary arterial hypertension. Deaths from any cause and from pulmonary arterial hypertension were not significantly different from placebo.1