英文药名:Edarbi(azilsartan medoxomil tablets) 中文药名:阿齐沙坦酯片 生产厂家:武田制药德国公司
When Edarbi was coadministered with chlortalidone, the frequencies of blood creatinine increased and hypotension were increased from uncommon to common. When Edarbi was coadministered with amlodipine, the frequency of peripheral oedema was increased from uncommon to common, but was lower than amlodipine alone. Investigations Serum creatinine The incidence of elevations in serum creatinine following treatment with Edarbi was similar to placebo in the randomised placebo-controlled monotherapy studies. Coadministration of Edarbi with diuretics, such as chlortalidone, resulted in a greater incidence of creatinine elevations, an observation consistent with that of other angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors. The elevations in serum creatinine during coadminstiration of Edarbi with diuretics were associated with larger blood pressure reductions compared with a single medicinal product. Many of these elevations were transient or nonprogressive while subjects continued to receive treatment. Following discontinuation of treatment, the majority of the elevations that had not resolved during treatment were reversible, with the creatinine levels of most subjects returning to Baseline or near-Baseline values. Uric acid Small mean increases of serum uric acid were observed with Edarbi (10.8 µmol/l) compared with placebo (4.3 µmol/l). Hemoglobin and hematocrit Small decreases in hemoglobin and hematocrit (mean decreases of approximately 3 g/l and 1 volume percent, respectively) were observed in placebo-controlled monotherapy studies. This effect is also seen with other inhibitors of the renin-angiotensin-aldosterone system. Reporting of suspected adverse reactions Reporting suspected adverse reactions is an important way to gather more information to continuously monitor 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 Symptoms Based on pharmacological considerations, the main manifestation of an overdose is likely to be symptomatic hypotension and dizziness. During controlled clinical studies in healthy subjects, once daily doses up to 320 mg of Edarbi were administered for 7 days and were well tolerated. Management If symptomatic hypotension should occur, supportive treatment should be instituted and vital signs monitored. Azilsartan is not removed by dialysis. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Angiotensin II antagonists, plain ATC Code: C09CA09 Mechanism of action and pharmacodynamic effect Azilsartan medoxomil is an orally active prodrug that is rapidly converted to the active moiety, azilsartan, which selectively antagonises the effects of angiotensin II by blocking its binding to the AT1 receptor in multiple tissues (see section 5.2). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Blockade of the AT1 receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increases in plasma renin activity and angiotensin II circulating levels do not overcome the antihypertensive effect of azilsartan. Essential hypertension In seven double blind controlled studies, a total of 5941 patients (3672 given Edarbi, 801 given placebo, and 1468 given active comparator) were evaluated. Overall, 51% of patients were male and 26% were 65 years or older (5% ≥ 75 years); 67% were white and 19% were black. Edarbi was compared with placebo and active comparators in two 6-week randomized, double blind studies. Blood pressure reductions compared with placebo based on 24 hour mean blood pressure by ambulatory blood pressure monitoring (ABPM) and clinic blood pressure measurements at trough are shown in the table below for both studies. Additionally, Edarbi 80 mg resulted in significantly greater reductions in SBP than the highest approved doses of olmesartan medoxomil and valsartan.
Significant difference vs. Placebo at 0.05 level within the framework of the step-wise analysis Significant difference vs. Comparator(s) at 0.05 level within the framework of the step-wise analysis Maximum dose achieved in study 2. Doses were force-titrated at Week 2 from 20 to 40 mg and 40 to 80 mg for Edarbi, and 20 to 40 mg and 160 to 320 mg, respectively, for olmesartan medoxomil and valsartan In these two studies, clinically important and most common adverse events included dizziness, headache and dyslipidemia. For Edarbi, olmesartan medoxomil and valsartan, respectively dizziness was observed at an incidence of 3.0%, 3.3% and 1.8%; headache at 4.8%, 5.5% and 7.6% and dyslipidemia at 3.5%, 2.4% and 1.1%. In active-comparator studies with either valsartan or ramipril, the blood-pressure-lowering effect with Edarbi was sustained during long-term treatment. Edarbi had a lower incidence of cough (1.2%) compared with ramipril (8.2%). The antihypertensive effect of Edarbi occurred within the first 2 weeks of dosing with the full effect achieved by 4 weeks. The blood pressure lowering effect of Edarbi was also maintained throughout the 24-hour dosing interval. The placebo-corrected trough-to-peak ratios for SBP and DBP were approximately 80% or higher. Rebound hypertension was not observed following abrupt cessation of Edarbi therapy after 6 months of treatment. No overall differences in safety and effectiveness were observed between elderly patients and younger patients, but greater sensitivity to blood pressure lowering effects in some elderly individuals cannot be ruled out (see section 4.2). As with other angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors the antihypertensive effect was lower in black patients (usually a low-renin population). Coadministration of Edarbi 40 and 80 mg with a calcium channel blocker (amlodipine) or a thiazide-type diuretic (chlortalidone) resulted in additional blood pressure reductions compared with the other antihypertensive alone. Dose dependent adverse events including dizziness, hypotension and serum creatinine elevations were more frequent with diuretic coadministration compared with Edarbi alone, while hypokalemia was less frequent compared with diuretic alone. Beneficial effects of Edarbi on mortality and cardiovascular morbidity and target organ damage are currently unknown. Effect on cardiac repolarisation A thorough QT/QTc study was conducted to assess the potential of Edarbi to prolong the QT/QTc interval in healthy subjects. There was no evidence of QT/QTc prolongation at a dose of 320 mg of Edarbi. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with Edarbi in one or more subsets of the paediatric population in hypertension (see section 4.2 for information on paediatric use). Additional information Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE inhibitor with an angiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy. These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers. ACE inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy. ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group. 5.2 Pharmacokinetic properties Following oral administration, azilsartan medoxomil is rapidly hydrolyzed to the active moiety azilsartan in the gastrointestinal tract and/or during absorption. Based on in vitro studies, carboxymethylenebutenolidase is involved in the hydrolysis in the intestine and liver. In addition, plasma esterases are involved in the hydrolysis of azilsartan medoxomil to azilsartan. Absorption The estimated absolute oral bioavailability of azilsartan medoxomil based on plasma levels of azilsartan is approximately 60%. After oral administration of azilsartan medoxomil, peak plasma concentrations (Cmax) of azilsartan are reached within 1.5 to 3 hours. Food does not affect the bioavailability of azilsartan (see section 4.2). Distribution The volume of distribution of azilsartan is approximately 16 litres. Azilsartan is highly bound to plasma proteins (> 99%), mainly serum albumin. Protein binding is constant at azilsartan plasma concentrations well above the range achieved with recommended doses. Biotransformation Azilsartan is metabolised to two primary metabolites. The major metabolite in plasma is formed by O-dealkylation, referred to as metabolite M-II, and the minor metabolite is formed by decarboxylation, referred to as metabolite M-I. Systemic exposures to the major and minor metabolites in humans were approximately 50% and less than 1% that of azilsartan, respectively. M-I and M-II do not contribute to the pharmacologic activity of Edarbi. The major enzyme responsible for azilsartan metabolism is CYP2C9. Elimination Following an oral dose of 14C-labelled azilsartan medoxomil, approximately 55% of radioactivity was recovered in feces and approximately 42% in urine, with 15% of the dose excreted in urine as azilsartan. The elimination half-life of azilsartan is approximately 11 hours and renal clearance is approximately 2.3 ml/min. Steady-state levels of azilsartan are achieved within 5 days and no accumulation in plasma occurs with repeated once-daily dosing. Linearity/non-linearity Dose proportionality in exposure was established for azilsartan in the azilsartan medoxomil dose range of 20 mg to 320 mg after single or multiple dosing. Characteristics in specific groups of patients Paediatric population The pharmacokinetics of azilsartan have not been studied in children under 18 years of age. Older people Pharmacokinetics of azilsartan do not differ significantly between young (age range 18-45 years) and elderly (age range 65-85 years) patients. Renal impairment In patients with mild, moderate, and severe renal impairment azilsartan total exposure (AUC) was +30%, +25% and +95% increased. No increase (+5%) was observed in end-stage renal disease patients who were dialysed. However, there is no clinical experience in patients with severe renal impairment or end stage renal disease (see section 4.2). Hemodialysis does not remove azilsartan from the systemic circulation. Hepatic impairment Administration of Edarbi for up to 5 days in subjects with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment resulted in slight increase in azilsartan exposure (AUC increased by 1.3 to 1.6 fold, see section 4.2). Edarbi has not been studied in patients with severe hepatic impairment. Gender Pharmacokinetics of azilsartan do not differ significantly between males and females. No dose adjustment is necessary based on gender. Race Pharmacokinetics of azilsartan do not differ significantly between black and white populations. No dose adjustment is necessary based on race. 5.3 Preclinical safety data In preclinical safety studies, azilsartan medoxomil and M-II, the major human metabolite, were examined for repeated-dose toxicity, reproduction toxicity, mutagenicity and carcinogenicity. In the repeated-dose toxicity studies, doses producing exposure comparable to that in the clinical therapeutic range caused reduced red cell parameters, changes in the kidney and renal haemodynamics, as well as increased serum potassium in normotensive animals. These effects, which were prevented by oral saline supplementation, do not have clinical significance in treatment of hypertension. In rats and dogs, increased plasma renin activity and hypertrophy/hyperplasia of the renal juxtaglomerular cells were observed. These changes, also a class effect of angiotensin converting enzyme inhibitors and other angiotensin II receptor antagonists, do not appear to have clinical significance. Azilsartan and M-II crossed the placenta and were found in the fetuses of pregnant rats and were excreted into the milk of lactating rats. In the reproduction toxicity studies, there were no effects on male or female fertility. There is no evidence of a teratogenic effect, but animal studies indicated some hazardous potential to the postnatal development of the offspring such as lower body weight, a slight delay in physical development (delayed incisor eruption, pinna detachment, eye opening), and higher mortality. Azilsartan and M-II showed no evidence of mutagenicity and relevant clastogenic activity in in vitro studies and no evidence of carcinogenicity in rats and mice. 6. Pharmaceutical particulars 6.1 List of excipients Mannitol (E 421) Fumaric acid (E 297) Sodium hydroxide Hydroxypropylcellulose (E 463) Croscarmellose sodium Cellulose, microcrystalline (E 460) Magnesium stearate (E 572) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage Store in the original package in order to protect from light and moisture. This medicinal product does not require any special temperature storage conditions. 6.5 Nature and contents of container Cartons containing aluminum blisters packs integrated with desiccant. Pack sizes: One blister pack contains either 14 tablets or 15 tablets. 14, 28, 30, 56, 90 or 98 tablets. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling No special requirements. Any unused product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Takeda Pharma A/S Dybendal Alle 10 2630 Taastrup Denmark 8. Marketing authorisation number(s) EU/1/11/734/001 14 tablets EU/1/11/734/002 28 tablets EU/1/11/734/012 30 tablets EU/1/11/734/003 56 tablets EU/1/11/734/013 90 tablets EU/1/11/734/004 98 tablets EU/1/11/734/005 14 tablets EU/1/11/734/006 28 tablets EU/1/11/734/014 30 tablets EU/1/11/734/007 56 tablets EU/1/11/734/015 90 tablets EU/1/11/734/008 98 tablets EU/1/11/734/016 14 tablets EU/1/11/734/009 28 tablets EU/1/11/734/017 30 tablets EU/1/11/734/010 56 tablets EU/1/11/734/018 90 tablets EU/1/11/734/011 98 tablets 9. Date of first authorisation/renewal of the authorisation 7 December 2011 10. Date of revision of the text 9 September 2014 Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu 阿齐沙坦国外上市情况 阿齐沙坦由日本武田公司原研,2012年4月在日本上市,商品名为“Azilva”,规格为20mg和40mg。目前没有在其他国家上市。阿齐沙坦酯为阿齐沙坦的前药,目前在欧美上市,商品名为Edarbi。 阿齐沙坦特点 阿齐沙坦作为新一代双重功能ARBs,不仅拮抗血管紧张素II的1型受体(AT1受体),还可能通过多种机制降低心血管疾病及糖尿病的风险。临床试验证明阿齐沙坦具有较好疗效,且不良反应发生率较低,依从性较好的特点。 阿齐沙坦的前药阿齐沙坦酯(azilsartan medoxomil)已经在美国及欧洲等国家和地区上市销售,通过动态血压监测(ABPM)测定,阿齐沙坦酯与两种常用ARB类处方药奥美沙坦酯(olmesartan medoxomil)(40mg/天)和缬沙坦(valsartan)(320mg/天)最高批准剂量相比,EDARBI(80mg/天)在降低临床收缩压(SBP)和24小时平均SBP方面有显著性统计学优势。 阿齐沙坦作为新一代的血管紧缩素II受体抑制剂,与血管紧张素转化酶抑制剂(ACEI)类降压药物相比,单独或联合用药均具有平稳降压、不会引起干咳的优点,平稳持久降血压作用。尽管已上市多个ARBs,但对于许多患者,仅抑制肾素-醛固酮系统(RAS)活性并不足以控制血压和降低心血管疾病及糖尿病的风险,而阿齐沙坦还能通过部分激活过氧化物酶体增殖物激活受体-γ(PPAR-γ)而对糖尿病患者产生潜在的保护作用,相关临床试验结果表明其临床效果要优于现在临床广泛使用的奥美沙坦酯和缬沙坦。 在一项为期24周的试验中,982例患者随机接受阿齐沙坦酯40mg/d(n=327)、80mg/d(n=329)或缬沙坦320mg/d(n=326)治疗。结果显示,与基线相比,阿齐沙坦酯两种剂量分别使主要的观察终点24h动态血压监控的平均收缩压分别降低了14.9mmHg和15.3mmHg;同样,次要终点临床谷血压测定,两种剂量的阿齐沙坦酯分别使收缩压降低了14.9mmHg和16.9mmHg;降压作用均明显强于320mg/d缬沙坦(分别为:11.3mmHg和11.6mmHg)。 -------------------------------------------------- 产地国家:德国 原产地英文商品名: EDARBI 20mg/tab 98tabs/box 原产地英文药品名: AZILSARTAN MEDOXOMIL 中文参考商品译名: EDARBI 20毫克/片 98片/盒 中文参考药品译名: 阿齐沙坦酯 生产厂家中文参考译名: 武田 生产厂家英文名: TAKEDA -------------------------------------------------- 产地国家:德国 原产地英文商品名: EDARBI 40mg/tab 98tabs/box 原产地英文药品名: AZILSARTAN MEDOXOMIL 中文参考商品译名: EDARBI 40毫克/片 98片/盒 中文参考药品译名: 阿齐沙坦酯 生产厂家中文参考译名: 武田 生产厂家英文名: TAKEDA ---------------------------------------------- 产地国家: 美国 原产地英文商品名: EDARBI 80mg/tab 30tabs/bottle 原产地英文药品名: AZILSARTAN MEDOXOMIL 中文参考商品译名: EDARBI 80毫克/片 30片/瓶 中文参考药品译名: 阿齐沙坦酯 生产厂家中文参考译名: 武田 生产厂家英文名: TAKEDA -------------------------------------------------- 产地国家: 美国 原产地英文商品名: EDARBI 40mg/tab 30tabs/bottle 原产地英文药品名: AZILSARTAN MEDOXOMIL 中文参考商品译名: EDARBI 40毫克/片 30片/瓶 中文参考药品译名: 阿齐沙坦酯 生产厂家中文参考译名: 武田 生产厂家英文名: TAKEDA |