部份中文复代文处方资料（仅供参考） 通用名 缬沙坦氢氯噻嗪片 英文名 Valsartan and Hydrochlorothiazide Tablets 汉语拼音 XieShaTanQingLvSaiQinPian 主要成分 每片含缬沙坦80mg，氢氯噻嗪12.5mg。 性状 复代文为复方制剂，淡桔红色薄膜衣片，除去包衣后显白色。 适应症 复代文用于治疗单一药物不能充分控制血压的轻-中度原发性高血压。 用量用法 口服，一次1片，一日1次。 药理毒理 1、缬沙坦：血管紧张素I在血管紧张素转化酶（ACE）作用下形成血管紧张素II（AngII）。AngII是肾素-血管紧张素-醛固酮系统（RAAS）的重要活性成分，与各种组织细胞膜上的特异受体结合发挥广泛的生理作用，包括直接或间接参与血压调节； 2、血管紧张素II是一种强的缩血管物质，可发挥直接的升压效应，还可促进钠的重吸收，刺激醛固酮分泌。缬沙坦是一种口服有效的特异性的血管紧张素（Ang）II受体拮抗剂，它选择性地作用于AT1受体亚型，与AT1受体的亲和力比AT2受体的亲和力强20000倍； 3、AT1受体亚型介导血管紧张素II的生理反应，AT2受体亚型与心血管作用无关，缬沙坦对AT1受体没有部分激动剂的活性。缬沙坦不抑制ACE（又名激肽酶II），此酶使血管紧张素I转化为血管紧张素II且降解缓激肽； 4、缬沙坦对ACE没有抑制作用，不引起缓激肽和P物质的潴留，故不易引起咳嗽。比较缬沙坦与ACE抑制剂的临床试验证实，缬沙坦组干咳的发生率（2.6%）显著低于ACE抑制剂组（7.9%，P<0.05）； 5、在一项对曾接受ACE抑制剂治疗后发生干咳症状的患者进行的临床试验发现，缬沙坦组、利尿剂组、ACEI组分别有19.5%，19.0%，68.5%患者出现咳嗽（P<0.05）。在对照临床试验中，用缬沙坦和氢氯噻嗪联合治疗的病人咳嗽的发生率为2.9%； 6、缬沙坦对其他已知的在心血管调节中起重要作用的激素受体或离子通道无影响。缬沙坦降低升高的血压，不影响心率。对大多数患者，单剂口服2小时内产生降压效果，4-6小时达作用高峰，降压效果维持至服药后24小时以上； 7、在长期治疗中，治疗2-4周后达大降压疗效，并得以维持。与氢氯噻嗪联合应用显著地增强缬沙坦的降压作用。突然终止缬沙坦治疗，不引起高血压"反跳"或其他副作用。缬沙坦不影响高血压患者的空腹总胆固醇、甘油三酯、血糖或尿酸水平； 8、氢氯噻嗪：噻嗪类利尿剂的主要作用部位是在远曲小管近端。研究表明，在肾皮质存在着高亲和力的受体，其为噻嗪类利尿剂的主要结合部位和作用部位，抑制远曲小管近端的氯化钠转运； 9、噻嗪类的作用方式为抑制钠和氯离子的共转运。竞争氯离子作用部位能影响电解质的重吸收，这将直接增加钠和氯的排泄，并间接减少血浆容积，继而增加血浆肾素活性，醛固酮分泌和钾排泄，使血清钾降低。因为肾素-醛固酮系统是血管紧张素II依赖性的，联合使用血管紧张素II受体拮抗剂可减少与噻嗪类相关的钾丢失。 不良反应 在共包括1570名病人的两项对照临床试验中，730名病人接受缬沙坦与氢氯噻嗪的联合应用，报道的不良事件如下： 1、中枢神经系统常见(>5%)：头痛(10.8%：安慰剂17.2%)、眩晕。偶见(5～0.1%)：乏力、抑郁； 2、上呼吸道偶见(5～0.1%)：咳嗽、鼻炎、鼻窦炎、咽炎、上呼吸道感染、鼻出血； 3、胃肠道偶见(5～0.1%)：恶心、腹泻、消化不良、腹痛； 4、下尿道偶见(5～0.1%)：尿频，尿道感染； 5、肌肉骨骼系统偶见(5～0.1%)：手臂或腿疼痛、关节炎、肌痛、扭伤和拉伤、肌肉痉挛； 6、其它，偶见(5～0.1%)：无力、胸痛、虚弱、病毒感染、视觉障碍、结膜炎； 7、产品进入市场后，曾出现一些罕见的报道，包括：血管性水肿、皮疹瘙痒及其他过敏反应如血清病、血管炎等； 8、实验室检查：在使用同产品治疗的病人中，5.8%的病人可观察到血清钾降低超过20%，接受安慰剂的病人为3.3%。下面的不良事件与单独应用缬沙坦有关，而与本品无关。罕见情况下，缬沙坦引起血红蛋白和红细胞压积降低。临床对照试验发现，缬沙坦治疗组血红蛋白和红细胞压积明显降低(>20%)的分别占0.8%和0.4%。安慰剂组占0.1%。临床对照试验发现，缬沙坦组、ACEI组中性粒细胞减少的发生率分别为1.9%、1.6%。缬沙坦组血清肌酐、血钾、总胆素显著升高者分别为0.8%、4.4%、6%，ACEI组分别为1.6%、6.4%、12.9%。偶见肝功能指标升高。对原发性高血压患者接受缬沙坦治疗来说，不需要特别监测实验室指标； 9、缬沙坦：临床试验中报道的其他不良反应事件有： （1）偶见（5～0.1%）：关节痛、胃肠炎、神经痛。 仅见一例血管神经性水肿报道。未证明与缬沙坦治疗存在因果关系； （2）氢氯噻嗪：在接受单一噻嗪类利尿剂（包括氢氯噻嗪）治疗的患者中，报道的不良反应如下，多数病人应用的剂量高于本品中的剂量：电解质和代谢紊乱（参见【注意事项】）常见（>5%）：低钾血症。偶见（5～0.1%）：低钠血症，低镁血症和高尿酸血症。罕见（<0.1%）：高钙血症，血糖升高，糖尿和糖尿病恶化。极罕见：低氯性碱中毒； （3）皮肤偶见（5～0.1%）：荨麻疹和其它类型皮疹。罕见（<0.1%）：光敏感症。极罕见：坏死性血管炎，急性中毒性表皮松解症，红斑狼疮样反应，皮肤红斑狼疮复发； （4）胃肠道偶见（5～0.1%）：食欲不振，轻度恶心和呕吐。罕见（<0.1%）：腹部症状，便秘，腹泻，胃肠道症状。极罕见：胰腺炎； （5）肝脏罕见（<0.1%）：肝内胆汁郁积或黄疸； （6）心血管系统偶见（5～0.1%）：体位性低血压、酒精、麻醉或镇静剂可使其加重。罕见(<0.1%)：心律失常； （7）中枢神经系统罕见（<0.1%）：头痛、眩晕或光-头痛、睡眠紊乱、抑郁、感觉异常； （8）感觉器官：视觉障碍，尤其是在治疗的前几周； （9）血液罕见（<0.1%）：血小板减少症，偶伴紫癜。极罕见：白细胞减少，粒细胞减少，骨髓抑制，溶血性贫血； （10）其它，偶见（5～0.1%）：阳痿。极罕见：过敏反应，包括肺炎和肺水肿的呼吸道症状。 注意事项 1、血清电解质变化：与保钾利尿剂、补钾制剂、含钾的盐替代物或其它可以增加钾水平(如肝素)的药物合用需要小心。因而应当定期监测血钾水平。噻嗪类利尿剂与低钠血症和低氯性碱中毒有关。噻嗪类药物可通过增加肾脏镁的排泄而引起低镁血症； 2、钠和/或血容量不足：极少数情况下，在严重缺钠和/或血容量不足患者（如大剂量应用利尿剂），开始给予本药治疗时可能出现症状性低血压。在开始应用本药治疗前，应纠正低钠和/或血容量不足。如果发生低血压，应该让患者仰卧，必要时可以给予生理盐水。血压稳定后可以恢复治疗； 3、肾动脉狭窄：在单侧或双侧肾动脉狭窄或孤立肾狭窄的病人中，没有使用本药的经验； 4、肾功能不全：对于肌酐清除率≥（greaterthanorequalto）30mL/分的病人不需要调整剂量； 5、肝功能不全：对于非胆汁郁积的轻度至中度肝功能不全的病人应小心使用本药。但是，由于缬沙坦每日80mg的剂量并未超过限度，以及氢氯噻嗪的药代动力学在肝功能不全时受到的影响并不显著，因此对上述病人不需要调整剂量； 6、系统性红斑狼疮：噻嗪类利尿剂能引发或加重系统性红斑狼疮； 7、其它代谢紊乱：噻嗪类利尿剂可影响葡萄糖耐量和增加血清胆固醇，甘油三酯和尿酸水平； 8、对驾驶和操纵机器能力的影响：与其它抗高血压药一样，服药患者在驾驶和操纵机器时应小心； 9、与青年志愿者相比，一些老年人（>65岁）的缬沙坦浓度稍增高，但无临床意义。与年轻人相比，老年人氢氯噻嗪的稳态浓度高且系统清除率显著降低。因而接受氢氯噻嗪治疗的老年病人需要密切监测。 禁忌 以下患者禁用：对本药中的任一成分或磺胺衍生物过敏；妊娠（见妊娠和哺乳）；严重的肝脏衰竭，胆汁性肝硬化或胆汁郁积；严重的肾脏衰竭（肌酐清除率<30mL/分）或无尿；难治性低钾血症、低钠血症或高钙血症和症状性高尿酸血症(痛风或尿酸结石病史)。 药物相互作用 慎与以下药物合用：可增加钾水平的药物、非甾体抗炎药、皮质激素、促肾上腺皮质激素、两性霉素B、甘珀酸、青霉素G或水杨酸衍生物、心脏 糖苷类、箭毒类肌肉松弛剂、别嘌呤醇、金刚烷胺、二氮嗪、细胞毒药物、抗胆碱能药物、甲基多巴、维生素D或钙盐、环孢素。消胆胺和考来替泊减少噻嗪类利尿 剂的吸收。与抗糖尿病药物合用时，需调整这些药物的剂量。 老年用药 与青年志愿者相比，一些老年人（>65岁）的缬沙坦浓度稍增高，但无临床意义。与年轻人相比，老年人氢氯噻嗪的稳态浓度高且系统清除率显著降低。因而接受氢氯噻嗪治疗的老年病人需要密切检测。 贮藏 防潮，30℃以下保存。 有效期 36个月 生产企业 瑞士诺华制药有限公司 注：本品由瑞士、德国、英国等欧洲国家均有上市，采购以咨询为准 Co-Diovan 320mg/12.5mg 1. NAME OF THE MEDICINAL PRODUCT Co-Diovan 320 mg/12.5 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each film-coated tablet contains 320 mg of valsartan and 12.5 mg of hydrochlorothiazide. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablets. Pink, ovaloid shaped, beveled edge tablet, imprinted with NVR on one side and HIL on the other side. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Treatment of essential hypertension in adults. Co-Diovan fixed-dose combination is indicated in patients whose blood pressure is not adequately controlled on valsartan or hydrochlorothiazide monotherapy. 4.2 Posology and method of administration Posology The recommended dose of Co-Diovan is one film-coated tablet once daily. Dose titration with the individual components is recommended. In each case, up-titration of individual components to the next dose should be followed in order to reduce the risk of hypotension and other adverse events. When clinically appropriate direct change from monotherapy to the fixed combination may be considered in patients whose blood pressure is not adequately controlled on valsartan or hydrochlorothiazide monotherapy, provided the recommended dose titration sequence for the individual components is followed. The clinical response to Co-Diovan should be evaluated after initiating therapy and if blood pressure remains uncontrolled, the dose may be increased by increasing either one of the components to a maximum dose of Co-Diovan 320 mg/25 mg. The antihypertensive effect is substantially present within 2 weeks. In most patients, maximal effects are observed within 4 weeks. However, in some patients 4-8 weeks treatment may be required. This should be taken into account during dose titration. Method of administration Co-Diovan can be taken with or without food and should be administered with water. Special populations Patients with Renal impairment No dose adjustment is required for patients with mild to moderate renal impairment (Glomerular Filtration Rate (GFR) ≥ 30 ml/min). Due to the hydrochlorothiazide component, Co-Diovan is contraindicated in patients with severe renal impairment (GFR < 30 mL/min) and anuria (see sections 4.3, 4.4 and 5.2). Patients with Hepatic impairment In patients with mild to moderate hepatic impairment without cholestasis the dose of valsartan should not exceed 80 mg (see section 4.4). No adjustment of the hydrochlorothiazide dose is required for patients with mild to moderate hepatic impairment. Due to the valsartan component, Co-Diovan is contraindicated in patients with severe hepatic impairment or with biliary cirrhosis and cholestasis (see sections 4.3, 4.4 and 5.2). Older people No dose adjustment is required in elderly patients. Paediatric patients Co-Diovan is not recommended for use in children below the age of 18 years due to a lack of data on safety and efficacy. 4.3 Contraindications − Hypersensitivity tothe active substance(s), other sulfonamide-derived medicinal products or to any of the excipients listed in section 6.1. − Second and third trimester of pregnancy (section 4.4 and 4.6). − Severe hepatic impairment, biliary cirrhosis and cholestasis. − Severe renal impairment (creatinine clearance < 30 ml/min), anuria. − Refractory hypokalaemia, hyponatraemia, hypercalcaemia, and symptomatic hyperuricaemia. − Concomitant use of Co-Diovan with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m2) (see sections 4.5 and 5.1). 4.4 Special warnings and precautions for use Serum electrolyte changes Valsartan Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other agents that may increase potassium levels (heparin, etc.) is not recommended. Monitoring of potassium should be undertaken as appropriate. Hydrochlorothiazide Hypokalaemia has been reported under treatment with thiazide diuretics, including hydrochlorothiazide. Frequent monitoring of serum potassium is recommended. Treatment with thiazide diuretics, including hydrochlorothiazide, has been associated with hyponatraemia and hypochloraemic alkalosis. Thiazides, including hydrochlorothiazide, increase the urinary excretion of magnesium, which may result in hypomagnesaemia. Calcium excretion is decreased by thiazide diuretics. This may result in hypercalcaemia. As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals. Sodium and/or volume-depleted patients Patients receiving thiazide diuretics, including hydrochlorothiazide, should be observed for clinical signs of fluid or electrolyte imbalance. In severely sodium-depleted and/or volume-depleted patients, such as those receiving high doses of diuretics, symptomatic hypotension may occur in rare cases after initiation of therapy with Co-Diovan. Sodium and/or volume depletion should be corrected before starting treatment with Co-Diovan. Patients with severe chronic heart failure or other conditions with stimulation of the renin-angiotensin-aldosterone-system In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors has been associated with oliguria and/or progressive azotaemia, and in rare cases with acute renal failure and/or death. Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function. The use of Co-Diovan in patients with severe chronic heart failure has not been established. Hence it cannot be excluded that because of the inhibition of the renin-angiotensin-aldosterone system the application of Co-Diovan as well may be associated with impairment of the renal function. Co-Diovan should not be used in these patients. Renal artery stenosis Co-Diovan should not be used to treat hypertension in patients with unilateral or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, since blood urea and serum creatinine may increase in such patients. Primary hyperaldosteronism Patients with primary hyperaldosteronism should not be treated with Co-Diovan as their renin-angiotensin system is not activated. Aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy As with all other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or hypertrophic obstructive cardiomyopathy (HOCM). Renal impairment No dosage adjustment is required for patients with renal impairment with a creatinine clearance ≥30 ml/min (see section 4.2). Periodic monitoring of serum potassium, creatinine and uric acid levels is recommended when Co-Diovan is used in patients with renal impairment. Kidney transplantation There is currently no experience on the safe use of Co-Diovan in patients who have recently undergone kidney transplantation. Hepatic impairment In patients with mild to moderate hepatic impairment without cholestasis, Co-Diovan should be used with caution (see sections 4.2 and 5.2). Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. History of angioedema Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue has been reported in patients treated with valsartan; some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Co-Diovan should be immediately discontinued in patients who develop angioedema, and Co-Diovan should not be re-administered (see section 4.8). Systemic lupus erythematosus Thiazide diuretics, including hydrochlorothiazide, have been reported to exacerbate or activate systemic lupus erythematosus. Other metabolic disturbances Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and raise serum levels of cholesterol, triglycerides and uric acid. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required. Thiazides may reduce urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia may be evidence of underlying hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function. Photosensitivity Cases of photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA. Pregnancy Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRAs therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6). General Caution should be exercised in patients who have shown prior hypersensitivity to other angiotensin II receptor antagonists. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergy and asthma. Acute Angle-Closure Glaucoma Hydrochlorothiazide, a sulfonamide, has been associated with an idiosyncratic reaction resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to week of a drug initiation. Untreated acute-angle closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatment may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle closure glaucoma may include a history of sulfonamide or penicillin allergy. Dual Blockade of the Renin-Angiotensin-Aldosterone System (RAAS) There is evidence that the concomitant use of ACE inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia, and decreased renal function (including acute renal failure). Dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1). If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy. 4.5 Interaction with other medicinal products and other forms of interaction Interactions related to both valsartan and hydrochlorothiazide Concomitant use not recommended Lithium Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors, angiotensin II receptor antagonists or thiazides, including hydrochlorothiazide. Since renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity may presumably be increased further with Co-Diovan. If the combination proves necessary, a careful monitoring of serum lithium levels is recommended. Concomitant use requiring caution Other antihypertensive agents Co-Diovan may increase the effects of other agents with antihypertensive properties (e.g. guanethidine, methyldopa, vasodilators, ACEI, ARBs, beta blockers, calcium channel blockers and DRIs). Pressor amines (e.g. noradrenaline, adrenaline) Possible decreased response to pressor amines. The clinical significance of this effect is uncertain and not sufficient to preclude their use. Non-steroidal anti-inflammatory medicines (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid (>3 g/day), and non-selective NSAIDs NSAIDS can attenuate the antihypertensive effect of both angiotensin II antagonists and hydrochlorothiazide when administered simultaneously. Furthermore, concomitant use of Co-Diovan and NSAIDs may lead to worsening of renal function and an increase in serum potassium. Therefore, monitoring of renal function at the beginning of the treatment is recommended, as well as adequate hydration of the patient. Interactions related to valsartan Dual blockade of the Renin-Angiotensin-Aldosterone System (RAAS) with ARBs, ACEIs, or aliskiren Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1). Concomitant use not recommended Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and other substances that may increase potassium levels If a medicinal product that affects potassium levels is considered necessary in combination with valsartan, monitoring of potassium plasma levels is advised. Transporters In vitro data indicates that valsartan is a substrate of the hepatic uptake transporter OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical relevance of this finding is unknown. Co-administration of inhibitors of the uptake transporter (eg. rifampin, ciclosporin) or efflux transporter (eg. ritonavir) may increase the systemic exposure to valsartan. Exercise appropriate care when initiating or ending concomitant treatment with such drugs. No interaction In drug interaction studies with valsartan, no interactions of clinical significance have been found with valsartan or any of the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide. Digoxin and indomethacin could interact with the hydrochlorothiazide component of Co-Diovan (see interactions related to hydrochlorothiazide). Interactions related to hydrochlorothiazide Concomitant use requiring caution Medicinal products affecting serum potassium level The hypokalaemic effect of hydrochlorothiazide may be increased by concomitant administration of kaliuretic diuretics, corticosteroids, laxatives, ACTH, amphotericin, carbenoxolone, penicillin G, salicylic acid and derivatives. If these medicinal products are to be prescribed with the hydrochlorothiazide-valsartan combination, monitoring of potassium plasma levels is advised (see section 4.4). Medicinal products that could induce torsades de pointes Due to the risk of hypokalaemia, hydrochlorothiazide should be administered with caution when associated with medicinal products that could induce torsades de pointes, in particular Class Ia and Class III antiarrhythmics and some antipsychotics. Medicinal products affecting serum sodium level The hyponatraemic effect of diuretics may be intensified by concomitant administration of drugs such as antidepressants, antipsychotics, antiepileptics, etc. Caution is advised in long-term administration of these drugs. Digitalis glycosides Thiazide-induced hypokalaemia or hypomagnesaemia may occur as undesirable effects favouring the onset of digitalis-induced cardiac arrhythmias (see section 4.4). Calcium salts and vitamin D Administration of thiazide diuretics, including hydrochlorothiazide, with vitamin D or with calcium salts may potentiate the rise in serum calcium. Concomitant use of thiazide type diuretics with calcium salts may cause hypercalcaemia in patients pre-disposed for hypercalcaemia (e.g. hyperparathyroidism, malignancy or vitamin-D-mediated conditions) by increasing tubular calcium reabsorption. Antidiabetic agents (oral agents and insulin) Thiazides may alter glucose tolerance. Dose adjustment of the antidiabetic medicinal product may be necessary. Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothiazide. Beta blockers and diazoxide Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta blockers may increase the risk of hyperglycaemia. Thiazide diuretics, including hydrochlorothiazide, may enhance the hyperglycaemic effect of diazoxide. Medicinal products used in the treatment of gout (probenecid, sulfinpyrazone and allopurinol) Dose adjustment of uricosuric medications may be necessary as hydrochlorothiazide may raise the level of serum uric acid. Increase of dosage of probenecid or sulfinpyrazone may be necessary. Co-administration of thiazide diuretics, including hydrochlorothiazide, may increase the incidence of hypersensitivity reactions to allopurinol. Anticholinergic agents and other medicinal products affecting gastric motility The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g. atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate. Conversely, it is anticipated that prokinetic drugs such as cisapride may decrease the bioavailability of thiazide-type diuretics. Amantadine Thiazides, including hydrochlorothiazide, may increase the risk of adverse effects caused by amantadine. Ion exchange resins Absorption of thiazide diuretics, including hydrochlorothiazide, is decreased by cholestyramine or colestipol. This could result in sub-therapeutic effects of thiazide diuretics. However, staggering the dosage of hydrochlorothiazide and resin such that hydrochlorothiazide is administered at least 4 h before or 4-6 h after the administration of resins would potentially minimise the interaction. Cytotoxic agents Thiazides, including hydrochlorothiazide, may reduce renal excretion of cytotoxic agents (e.g. cyclophosamide, methotrexate) and potentiate their myelosuppressive effects. Non-depolarising skeletal muscle relaxants (e.g. tubocurarine) Thiazides, including hydrochlorothiazide, potentiate the action of skeletal muscle relaxants such as curare derivatives. Ciclosporin Concomitant treatment with ciclosporin may increase the risk of hyperuricaemia and gout-type complications. Alcohol, barbiturates or narcotics Concomitant administration of thiazide diuretics with substances that also have a blood pressure lowering effect (e.g. by reducing sympathetic central nervous system activity or direct vasodilatation activity) may potentiate orthostatic hypotension. Methyldopa There have been isolated reports of haemolytic anaemia in patients receiving concomitant treatment with methyldopa and hydrochlorothiazide. Iodine contrast media In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses of the iodine product. Patients should be rehydrated before the administration. 4.6 Fertility, pregnancy and lactation Pregnancy Valsartan The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during first trimester of pregnancy (see section 4.4).The use of AIIRAs is contra-indicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4). Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II Receptor Inhibitors (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRAs therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately and, if appropriate, alternative therapy should be started. AIIRAs therapy exposure during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see also section 5.3). Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see also section 4.3 and 4.4). Hydrochlorothiazide There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia. Breast-feeding No information is available regarding the use of valsartan during breastfeeding. Hydrochlorothiazide is excreted in human milk. Therefore the use of Co-Diovan during breast feeding is not recommended. Alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant. 4.7 Effects on ability to drive and use machines No studies on the effect of Co-Diovan on the ability to drive and use machines have been performed. When driving vehicles or operating machines it should be taken into account that occasionally dizziness or weariness may occur. 4.8 Undesirable effects Adverse drug reactions reported in clinical trials and laboratory findings occurring more frequently with valsartan plus hydrochlorothiazide versus placebo and individual postmarketing reports are presented below according to system organ class. Adverse drug reactions known to occur with each component given individually but which have not been seen in clinical trials may occur during treatment with valsartan/hydrochlorothiazide. Adverse drug reactions Adverse drug reactions are ranked by frequency, the most frequent first, using the following convention: 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); not known (frequency cannot be estimated from the available data). Within each frequency grouping, adverse drug reactions are ranked in order of decreasing seriousness. Table 1. Frequency of adverse reactions with valsartan/hydrochlorothiazide Metabolism and nutrition disorders Uncommon  Dehydration Nervous system disorders Very rare  Dizziness Uncommon  Paraesthesia Not known  Syncope Eye disorders Uncommon  Vision blurred Ear and labyrinth disorders Uncommon  Tinnitus Vascular disorders Uncommon  Hypotension Respiratory, thoracic and mediastinal disorders Uncommon  Cough  Not known  Non cardiogenic pulmonary oedema Gastrointestinal disorders Very rare  Diarrhoea Musculoskeletal and connective tissue disorders Uncommon  Myalgia Very rare  Arthralgia Renal and urinary disorders Not known  Impaired renal function General disorders and administration site conditions Uncommon  Fatigue Investigations Not known  Serum uric acid increased, Serum bilirubin and Serum creatinine increased, Hypokalaemia, Hyponatraemia, Elevation of Blood Urea Nitrogen, Neutropenia Additional information on the individual components Adverse reactions previously reported with one of the individual components may be potential undesirable effects with Co-Diovan as well, even if not observed in clinical trials or during postmarketing period. Table 2. Frequency of adverse reactions with valsartan Blood and lymphatic system disorders Not known  Decrease in haemoglobin, decrease in haematocrit, thrombocytopenia Immune system disorders Not known  Other hypersensitivity/allergic reactions including serum sickness Metabolism and nutrition disorders Not known  Increase of serum potassium, hyponatraemia Ear and labyrinth disorders Uncommon  Vertigo Vascular disorders Not known  Vasculitis Gastrointestinal disorders Uncommon  Abdominal pain Hepatobiliary disorders Not known  Elevation of liver function values Skin and subcutaneous tissue disorders Not known  Angioedema, rash, dermatitis bullous, pruritus Renal and urinary disorders  Not known  Renal failure Table 3: Frequency of adverse reactions with hydrochlorothiazide Hydrochlorothiazide has been extensively prescribed for many years, frequently in higher doses than those administered with Co-Diovan. The following adverse reactions have been reported in patients treated with monotherapy of thiazide diuretics, including hydrochlorothiazide: Blood and lymphatic system disorders Rare  Thrombocytopenia sometimes with purpura Very rare  Agranulocytosis, leucopenia, haemolytic anaemia, bone marrow failure Not known  Aplastic anemia Immune system disorders Very rare  Hypersensitivity reactions Metabolism and nutrition disorders Very common  Hypokalaemia, blood lipids increased (mainly at higher doses) Common  Hyponatraemia, hypomagnesaemia, hyperuricaemia Rare  Hypercalcaemia, hyperglycaemia, glycosuria and worsening of diabetic metabolic state Very rare  Hypochloraemic alkalosis Psychiatric disorders Rare  Depression, sleep disturbances Nervous system disorders Rare  Headache, dizziness, paraesthesia Eye disorders Rare  Visual impairment Not known  Acute angle-closure glaucoma Cardiac disorders Rare  Cardiac arrhythmias Vascular disorders Common  Postural hypotension Respiratory, thoracic and mediastinal disorders Very rare  Respiratory distress including pneumonitis and pulmonary oedema  Gastrointestinal disorders Common  Loss of appetite, mild nausea and vomiting Rare  Constipation, gastrointestinal discomfort, diarrhoea Very rare  Pancreatitis Hepatobiliary disorders Rare  Intrahepatic cholestasis or jaundice Renal and urinary disorders Not known  Renal dysfunction, acute renal failure Skin and subcutaneous tissue disorders Common  Urticaria and other forms of rash Rare  Photosensitisation Very rare  Necrotising vasculitis and toxic epidermal necrolysis, cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus Not known  Erythema multiforme General disorders and administration site conditions Not known  Pyrexia, asthenia Musculoskeletal and connective tissue disorders Not known  Muscle spasm Reproductive system and breast disorders Common    Impotence 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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie. 4.9 Overdose Symptoms Overdose with valsartan may result in marked hypotension, which could lead to depressed level of consciousness, circulatory collapse and/or shock. In addition, the following signs and symptoms may occur due to an overdose of the hydrochlorothiazide component: nausea, somnolence, hypovolaemia, and electrolyte disturbances associated with cardiac arrhythmias and muscle spasms. Treatment The therapeutic measures depend on the time of ingestion and the type and severity of the symptoms, stabilisation of the circulatory condition being of prime importance. If hypotension occurs, the patient should be placed in the supine position and salt and volume supplementation should be given rapidly. Valsartan cannot be eliminated by means of haemodialysis because of its strong plasma binding behaviour whereas clearance of hydrochlorothiazide will be achieved by dialysis. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties  Pharmacotherapeutic group: Angiotensin II antagonists and diuretics, valsartan and diuretics; ATC code: C09D A03. Valsartan/hydrochlorothiazide In a double-blind, randomised, active-controlled trial in patients not adequately controlled on valsartan 320 mg, significantly greater mean systolic/diastolic BP reductions were observed with both the combination of valsartan/hydrochlorothiazide 320/25 mg (15.4/10.4 mmHg) and valsartan/hydrochlorothiazide 320/12.5 mg (13.6/9.7 mmHg) compared to valsartan 320 mg (6.1/5.8 mmHg). The difference in systolic BP reduction between the 320/25 mg and 320/12.5 mg doses also reached statistical significance. In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 320/25 mg (75%) and 320/12.5 mg (69%) compared to valsartan 320 mg (53%). In a double-blind, randomised, placebo-controlled, factorial design trial comparing various dose combinations of valsartan/hydrochlorothiazide to their respective components, significantly greater mean systolic/diastolic BP reductions were observed with the combination of valsartan/hydrochlorothiazide 320/12.5 mg (21.7/15.0 mmHg) and 320/25 mg (24.7/16.6 mmHg) compared to placebo (7.0/5.9 mmHg) and the respective monotherapies, i.e. hydrochlorothiazide 12.5 mg (11.1/9.0 mmHg), hydrochlorothiazide 25 mg (14.5/10.8 mmHg) and valsartan 320 mg (13.7/11.3 mmHg). In addition, a significantly greater percentage of patients responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 320/25 mg (85%) and 320/12.5 mg (83%) compared to placebo (45%) and the respective monotherapies, i.e. hydrochlorothiazide 12.5 mg (60%), hydrochlorothiazide 25 mg (66%), and valsartan 320 mg (69%). Dose-dependent decreases in serum potassium occurred in controlled clinical studies with valsartan + hydrochlorothiazide. Reduction in serum potassium occurred more frequently in patients given 25 mg hydrochlorothiazide than in those given 12.5 mg hydrochlorothiazide. In controlled clinical trials with valsartan/hydrochlorothiazide the potassium lowering effect of hydrochlorothiazide was attenuated by the potassium-sparing effect of valsartan. Beneficial effects of valsartan in combination with hydrochlorothiazide on cardiovascular mortality and morbidity are currently unknown. Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity. Valsartan Valsartan is an orally active and specific angiotensin II (Ang II) receptor antagonist. It acts selectively on the AT1 receptor subtype, which is responsible for the known actions of angiotensin II. The increased plasma levels of Ang II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor, which appears to counterbalance the effect of the AT1 receptor. Valsartan does not exhibit any partial agonist activity at the AT1 receptor and has much (about 20,000-fold) greater affinity for the AT1 receptor than for the AT2 receptor. Valsartan is not known to bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. Valsartan does not inhibit ACE, also known as kininase II, which converts Ang I to Ang II and degrades bradykinin. Since there is no effect on ACE and no potentiation of bradykinin or substance P, angiotensin II antagonists are unlikely to be associated with coughing. In clinical trials where valsartan was compared with an ACE inhibitor, the incidence of dry cough was significantly (P <0.05) lower in patients treated with valsartan than in those treated with an ACE inhibitor (2.6% versus 7.9% respectively). In a clinical trial of patients with a history of dry cough during ACE inhibitor therapy, 19.5% of trial subjects receiving valsartan and 19.0% of those receiving a thiazide diuretic experienced cough compared to 68.5% of those treated with an ACE inhibitor (P <0.05). Administration of valsartan to patients with hypertension results in reduction of blood pressure without affecting pulse rate. In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs within 2 hours, and the peak reduction of blood pressure is achieved within 4–6 hours. The antihypertensive effect persists over 24 hours after dosing. During repeated dosing, the maximum reduction in blood pressure with any dose is generally attained within 2–4 weeks and is sustained during long-term therapy. Combined with hydrochlorothiazide, a significant additional reduction in blood pressure is achieved. Abrupt withdrawal of valsartan has not been associated with rebound hypertension or other adverse clinical events. In hypertensive patients with type 2 diabetes and microalbuminuria, valsartan has been shown to reduce the urinary excretion of albumin. The MARVAL (Micro Albuminuria Reduction with Valsartan) study assessed the reduction in urinary albumin excretion (UAE) with valsartan (80-160 mg/od) versus amlodipine (5-10 mg/od), in 332 type 2 diabetic patients (mean age: 58 years; 265 men) with microalbuminuria (valsartan: 58 µg/min; amlodipine: 55.4 µg/min), normal or high blood pressure and with preserved renal function (blood creatinine <120 µmol/l). At 24 weeks, UAE was reduced (p <0.001) by 42% (–24.2 µg/min; 95% CI: –40.4 to –19.1) with valsartan and approximately 3% (–1.7 µg/min; 95% CI: –5.6 to 14.9) with amlodipine despite similar rates of blood pressure reduction in both groups. The Diovan Reduction of Proteinuria (DROP) study further examined the efficacy of valsartan in reducing UAE in 391 hypertensive patients (BP=150/88 mmHg) with type 2 diabetes, albuminuria (mean=102 µg/min; 20-700 µg/min) and preserved renal function (mean serum creatinine = 80 µmol/l). Patients were randomised to one of 3 doses of valsartan (160, 320 and 640 mg/od) and treated for 30 weeks. The purpose of the study was to determine the optimal dose of valsartan for reducing UAE in hypertensive patients with type 2 diabetes. At 30 weeks, the percentage change in UAE was significantly reduced by 36% from baseline with valsartan 160 mg (95%CI: 22 to 47%), and by 44% with valsartan 320 mg (95%CI: 31 to 54%). It was concluded that 160-320 mg of valsartan produced clinically relevant reductions in UAE in hypertensive patients with type 2 diabetes. Other: dual blockade of the renin-angiotensin-aldosterone system (RAAS) 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. Hydrochlorothiazide The site of action of thiazide diuretics is primarily in the renal distal convoluted tubule. It has been shown that there is a high-affinity receptor in the renal cortex as the primary binding site for the thiazide diuretic action and inhibition of NaCl transport in the distal convoluted tubule. The mode of action of thiazides is through inhibition of the Na+Cl- symporter perhaps by competing for the Cl- site, thereby affecting electrolyte reabsorption mechanisms:directly increasing sodium and chloride excretion to an approximately equal extent, and indirectly by this diuretic action reducing plasma volume, with consequent increases in plasma renin activity, aldosterone secretion and urinary potassium loss, and a decrease in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so with co-administration of valsartan the reduction in serum potassium is less pronounced as observed under monotherapy with hydrochlorothiazide. 5.2 Pharmacokinetic properties Valsartan/hydrochlorothiazide The systemic availability of hydrochlorothiazide is reduced by about 30% when co-administered with valsartan. The kinetics of valsartan are not markedly affected by the co-administration of hydrochlorothiazide. This observed interaction has no impact on the combined use of valsartan and hydrochlorothiazide, since controlled clinical trials have shown a clear anti-hypertensive effect, greater than that obtained with either active substance given alone, or placebo. Valsartan Absorption Following oral administration of valsartan alone, peak plasma concentrations of valsartan are reached in 2–4 hours. Mean absolute bioavailability is 23%. Food decreases exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (Cmax) by about 50%, although from about 8 h post dosing plasma valsartan concentrations are similar for the fed and fasted groups. This reduction in AUC is not, however, accompanied by a clinically significant reduction in the therapeutic effect, and valsartan can therefore be given either with or without food. Distribution The steady-state volume of distribution of valsartan after intravenous administration is about 17 litres, indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (94–97%), mainly serum albumin. Biotransformation Valsartan is not biotransformed to a high extent as only about 20% of dose is recovered as metabolites. A hydroxy metabolite has been identified in plasma at low concentrations (less than 10% of the valsartan AUC). This metabolite is pharmacologically inactive. Elimination Valsartan shows multiexponential decay kinetics (t½α <1 h and t½ß about 9 h). Valsartan is primarily eliminated in faeces (about 83% of dose) and urine (about 13% of dose), mainly as unchanged drug. Following intravenous administration, plasma clearance of valsartan is about 2 l/h and its renal clearance is 0.62 l/h (about 30% of total clearance). The half-life of valsartan is 6 hours. Hydrochlorothiazide Absorption The absorption of hydrochlorothiazide, after an oral dose, is rapid (tmax about 2 h). The increase in mean AUC is linear and dose proportional in the therapeutic range. The effect of food on hydrochlorothiazide absorption, if any, has little clinical significance. Absolute bioavailability of hydrochlorothiazide is 70% after oral administration. Distribution The apparent volume of distribution is 4–8 l/kg. Circulating hydrochlorothiazide is bound to serum proteins (40–70%), mainly serum albumin. Hydrochlorothiazide also accumulates in erythrocytes at approximately 3 times the level in plasma. Elimination Hydrochlorotiazide is eliminated predominantly as unchanged drug. Hydrochlorothiazide is eliminated from plasma with a half-life averaging 6 to 15 hours in the terminal elimination phase. There is no change in the kinetics of hydrochlorothiazide on repeated dosing, and accumulation is minimal when dosed once daily. There is more than 95% of the absorbed dose being excreted as unchanged compound in the urine. The renal clearance is composed of passive filtration and active secretion into the renal tubule. Special populations Older people A somewhat higher systemic exposure to valsartan was observed in some elderly subjects than in young subjects; however, this has not been shown to have any clinical significance. Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers. Renal impairment At the recommended dose of Co-Diovan no dose adjustment is required for patients with a Glomerular Filtration Rate (GFR) of 30–70 ml/min. In patients with severe renal impairment (GFR <30 ml/min) and patients undergoing dialysis no data are available for Co-Diovan. Valsartan is highly bound to plasma protein and is not to be removed by dialysis, whereas clearance of hydrochlorothiazide will be achieved by dialysis. In the presence of renal impairment, mean peak plasma levels and AUC values of hydrochlorothiazide are increased and the urinary excretion rate is reduced. In patients with mild to moderate renal impairment, a 3-fold increase in hydrochlorothiazide AUC has been observed. In patients with severe renal impairment an 8-fold increase in AUC has been observed. Hydrochlorothiazide is contraindicated in patients with severe renal impairment (see section 4.3). Hepatic impairment In a pharmacokinetics trial in patients with mild (n=6) to moderate (n=5) hepatic dysfunction, exposure to valsartan was increased approximately 2-fold compared with healthy volunteers (see sections 4.2 and 4.4). There is no data available on the use of valsartan in patients with severe hepatic dysfunction (see section 4.3). Hepatic disease does not significantly affect the pharmacokinetics of hydrochlorothiazide. 5.3 Preclinical safety data The potential toxicity of the valsartan - hydrochlorothiazide combination after oral administration was investigated in rats and marmosets in studies lasting up to six months. No findings emerged that would exclude the use of therapeutic doses in man. The changes produced by the combination in the chronic toxicity studies are most likely to have been caused by the valsartan component. The toxicological target organ was the kidney, the reaction being more marked in the marmoset than the rat. The combination led to kidney damage (nephropathy with tubular basophilia, rises in plasma urea, plasma creatinine and serum potassium, increases in urine volume and urinary electrolytes from 30 mg/kg/day valsartan + 9 mg/kg/day hydrochlorothiazide in rats and 10 + 3 mg/kg/d in marmosets), probably by way of altered renal haemodynamics. These doses in rat, respectively, represent 0.9 and 3.5-times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m2 basis. These doses in marmoset, respectively, represent 0.3 and 1.2-times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m2 basis. (Calculations assume an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient.) High doses of the valsartan - hydrochlorothiazide combination caused falls in red blood cell indices (red cell count, haemoglobin, haematocrit, from 100 + 31 mg/kg/d in rats and 30 + 9 mg/kg/d in marmosets). These doses in rat, respectively, represent 3.0 and 12 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m2 basis. These doses in marmoset, respectively, represent 0.9 and 3.5 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m2 basis. (Calculations assume an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient). In marmosets, damage was observed in the gastric mucosa (from 30 + 9 mg/kg/d). The combination also led in the kidney to hyperplasia of the afferent aterioles (at 600 + 188 mg/kg/d in rats and from 30 + 9 mg/kg/d in marmosets). These doses in marmoset, respectively, represent 0.9 and 3.5 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m2 basis. These doses in rat, respectively, represent 18 and 73 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m2 basis. (Calculations assume an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient). The above mentioned effects appear to be due to the pharmacological effects of high valsartan doses (blockade of angiotensin II-induced inhibition of renin release, with stimulation of the renin-producing cells) and also occur with ACE inhibitors. These findings appear to have no relevance to the use of therapeutic doses of valsartan in humans. The valsartan - hydrochlorothiazide combination was not tested for mutagenicity, chromosomal breakage or carcinogenicity, since there is no evidence of interaction between the two substances. However, these tests were performed separately with valsartan and hydrochlorothiazide, and produced no evidence of mutagenicity, chromosomal breakage or carcinogenicity. In rats, maternally toxic doses of valsartan (600 mg/kg/day) during the last days of gestation and lactation led to lower survival, lower weight gain and delayed development (pinna detachment and ear-canal opening) in the offspring (see section 4.6). These doses in rats (600 mg/kg/day) are approximately 18 times the maximum recommended human dose on a mg/m2 basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient). Similar findings were seen with valsartan/hydrochlorothiazide in rats and rabbitsIn embryo-fetal development (Segment II) studies with valsartan/hydrochlorothiazide in rat and rabbit, there was no evidence of teratogenicity; however, fetotoxicity associated with maternal toxicity was observed. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipient(s) Tablet core Microcrystalline cellulose Silica, colloidal anhydrous Crospovidone Magnesium stearate. Coating Hypromellose Macrogol 8000 Talc Titanium dioxide (E171) Black iron oxide (E172) Red iron oxide (E172) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. 6.4 Special precautions for storage Do not store above 30° C. Store in the original package in order to protect from moisture. 6.5 Nature and contents of container PVC/ PVDC/Alu blisters. 7, 14, 28 as calendar pack, 56, 98 as calendar pack, 280 film-coated tablets PVC/PVDC/Alu perforated unit dose blisters 56x1, 98x1, 280x1 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 Novartis Pharmaceuticals UK Ltd. Frimley Business Park Frimley Camberley Surrey GU16 7SR United Kingdom 8. MARKETING AUTHORISATION NUMBER(S) PA13/91/4 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 1st February 2008 Date of last renewal: 29 May 2010 10. DATE OF REVISION OF THE TEXT 19th August 2015 诺华公司8月3日宣布，FDA已批准缬沙坦(valsartan，Diovan)一项新的适应证－－用于降低心脏病发作后高危患者（左心室衰竭或左心室功能紊乱）的心血管死亡率。FDA同时还扩大了其心力衰竭适应证的适用范围，不再仅限于ACE抑制剂不耐受患者。 此项适应证的批准是基于一项迄今为止最大、持续时间最长的针对有心脏病发作史患者的临床研究之一：VALIANT研究的结果。此项临床研究比较了本品、ACE抑制剂卡托普利及两者合用对心脏病发作后高危患者的影响，共募集14703例患者。结果证明本品可提高这些患者存活率和降低心脏病再发作和因心力衰竭而住院等心血管事件的发生率。各治疗组的总死亡率无差异。此项研究结果发表在《新英格兰医学杂志》上，并在2003年11月举行的美国心脏病协会学术讲座上宣读。 诺华公司押宝缬沙坦，在高血压和心脏病领域发起了多个世界级的空前规模的临床研究，共涉及超过5.5万患者。近期结束的临床研究包括针对高血压患者的VALUE、针对心脏病发作后患者的VALIANT和针对心力衰竭患者的Val-HeFT。进行中的临床研究包括测试本品延缓或预防糖耐量受损人群2型糖尿病和（或）心血管事件潜力的NAVIGATOR和测试本品对心脏病炎症性标志C反应蛋白影响的Val-MARC。