诺华公司近期宣布，美国是全球首个国家批准Tekturna（aliskiren）上市。Tekturna是10多年来首个新一类高血压治疗药物。据估计，世界范围内有近10亿人患有高血压，其中70%的患者的血压尚未得到控制。 Tekturna作为新一类药物―直接肾素抑制剂的首个药品，获得美国食品药品监督管理局FDA的上市批准。Tekturna每天只需口服一次，以引发高血压产生过程的酶 ― 肾素作为靶向目标。高血压是引发心血管疾病的关键因素，也是全球第一大致死病因。 FDA批准Tekturna既可以用于高血压的单药治疗，也可以和其他高血压药物联合使用。预计三月份，Tekturna以150毫克和300毫克片剂规格在美国药房里有售。 "肾素血管紧张素系统的作用引发多种高血压并发症，”哈佛医学院医学教授，Brigham & Women's医院心脏病学家Marc A. Pfeffer博士说，“通过从肾素生成的源头抑制该重要系统，像Tekturna这一类的直接肾素抑制剂为高血压治疗提供了一个令人兴奋的全新治疗选择。” 在涉及6400多名患者的广泛的临床试验中，Tekturna显示了24小时强效降压的效果。而且，与其他广泛使用的高血压治疗药物联用时，Tekturna也显示了额外的疗效。 在临床试验中，Tekturna批准的剂量显示了良好的耐受性。 “许多患者要求使用两种或者两种以上的药物来控制血压。作为一种全新的治疗方法，Tekturna将帮助这些患者管理疾病，” 诺华制药全球药品开发总裁James Shannon博士说，“Tekturna体现了我们致力于开发创新产品以帮助数以百万计高血压患者的承诺。” 诺华将开展一个大型的临床终点试验项目，以评估Tekturna和直接肾素抑制的远期疗效。 2006年9月，Tekturna的上市申请递交至欧盟药品审评管理局。美国之外，该药的商品名是Rasilez.Tekturna是诺华与Speedel公司合作开发的药品。 美国食品和药物管理局６日批准瑞士诺华公司研制的治疗高血压新药ｔｅｋｔｕｒｎａ上市，这是药管局批准的第一种肾素抑制剂类高血压治疗药物。 据介绍，ｔｅｋｔｕｒｎａ是一种新分子实体，通过抑制与血压调节有关的肾素发挥作用。它能够在血压调节过程刚开始时就发挥作用，而目前其他高血压治疗药物都是在血压调节过程的后期才能起作用。 药管局说，ｔｅｋｔｕｒｎａ在降血压方面的安全性和有效性已经在６项临床实验中得到了验证，其降血压效果可持续长达１年。如果与利尿降压药氢氯噻嗪联合使用，降压效果更为明显。 服用ｔｅｋｔｕｒｎａ最常见的副作用是出现腹泻。药管局警告说，孕期妇女禁用此药，为可能会伤害胎儿甚至造成死胎。 2009年7月21日，诺华公司宣布，对于采用单一降压药降压效果不理想者，美国食品药品管理局(FDA)已批准Tekturna HCT作为其初始治疗药。Tekturna HCT是由直接肾素抑制剂Tekturna(阿利吉仑)与利尿剂氢氯噻嗪(HCTZ)配伍制成的复方片剂，最初于2008年1月在美国获准作为高血压的二线治疗药。 FDA批准Tekturna HCT作为高血压初始治疗药是基于逾2700例患者的临床试验数据。研究结果证实，Tekturna与HCTZ联合治疗获得的血压降幅大于其中任何一种单药治疗。 在临床试验中，Tekturna HCT的降压效果大多数在1w内显效，通常在治疗大约4w后，降压效果达峰值。 Tekturna HCT有如下4种配伍规格(含阿利吉仑与氢氯噻嗪的复方片剂)上市：150mg/12.5mg，150mg/25mg，300mg/12.5mg以及300mg/25mg。 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use TEKTURNA HCT safely and effectively. See full prescribing information for TEKTURNA HCT. TEKTURNA® HCT (aliskiren and hydrochlorothiazide) tablets, for oral use Initial U.S. Approval: 2008 WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning. When pregnancy is detected, discontinue Tekturna HCT as soon as possible. (5.1) Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. (5.1) RECENT MAJOR CHANGES Contraindications (4)                   3/2015 Warnings and Precautions (5.1, 5.2, 5.5, 5.8)                   3/2015 INDICATIONS AND USAGE Tekturna HCT is a combination of aliskiren, a renin inhibitor, and hydrochlorothiazide (HCTZ), a thiazide diuretic, indicated for the treatment of hypertension, to lower blood pressure: In patients not adequately controlled with monotherapy. (1) As initial therapy in patients likely to need multiple drugs to achieve their blood pressure goals. (1) Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarction. DOSAGE AND ADMINISTRATION Initiate with 150/12.5mg daily. Titrate as needed up to a maximum of 300/25 mg (2.2) Order of increasing mean effect: 150/12.5 mg, 150/25 mg or 300/12.5 mg, and 300/25 mg (2.1) Replacement therapy: May be substituted for titrated components (2.4) DOSAGE FORMS AND STRENGTHS Tablets (mg aliskiren/mg HCTZ): 150/12.5, 150/25, 300/12.5, 300/25 (3) CONTRAINDICATIONS Do not use with angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs) in patients with diabetes. (4) Anuria (4) Hypersensitivity to sulfonamide derived drugs or to any of the components. (4) WARNINGS AND PRECAUTIONS Avoid concomitant use with ARBs or ACEIs particularly in patients with renal impairment [creatinine clearance (CrCl) <60 mL/min]. (5.2, 5.4) Anaphylactic Reactions and Angioedema. (5.3) Hypotension: Correct imbalances in volume and/or salt-depleted patients. (5.4) Impaired Renal Function: Monitor serum creatinine periodically. (5.5) Hyperkalemia: Monitor potassium levels periodically. (5.8) Acute Myopia and Secondary Angle Closure Glaucoma. (5.10) ADVERSE REACTIONS The most common adverse reactions (incidence ≥1.5% and more common than with placebo) are: dizziness and diarrhea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Cyclosporine or Itraconazole: Avoid concomitant use. (5.9, 7, 12.3) Nonsteriodal Anti-inflammatory Drugs (NSAIDs): Increased risk of renal impairment and loss of antihypertensive effect. (7) Antidiabetic Drugs: Dosage adjustment of antidiabetic may be required. (7) Cholestyramine and Colestipol: Reduced absorption of thiazides. (7) Lithium: Increased risk of lithium toxicity when used with diuretics. (7) USE IN SPECIFIC POPULATIONS Nursing Mothers: Nursing or drug should be discontinued. (8.3) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 12/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1  INDICATIONS AND USAGE Tekturna HCT is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including hydrochlorothiazide (HCTZ). There are no controlled trials demonstrating risk reduction with Tekturna HCT. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality have also been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (e.g., patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. Add-On Therapy A patient whose blood pressure is not adequately controlled with aliskiren alone or HCTZ alone may be switched to combination therapy with Tekturna HCT. A patient whose blood pressure is controlled with HCTZ alone but who experiences hypokalemia may be switched to combination therapy with Tekturna HCT. A patient who experiences dose-limiting adverse reactions on either component alone may be switched to Tekturna HCT containing a lower dose of that component in combination with the other to achieve similar blood pressure reductions. Replacement Therapy Tekturna HCT may be substituted for the titrated components. Initial Therapy Tekturna HCT may be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals. The choice of Tekturna HCT as initial therapy should be based on an assessment of potential benefits and risks. Patients with Stage 2 hypertension are at a relatively high risk for cardiovascular events (such as strokes, heart attacks, and heart failure), kidney failure, and vision problems, so prompt treatment is clinically relevant. The decision to use a combination as initial therapy should be individualized and should be shaped by considerations such as baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with a combination compared to monotherapy. Individual blood pressure goals may vary based upon the patient’s risk. Data from the high-dose multifactorial study [see Clinical Studies (14)] provide estimates of the probability of reaching a target blood pressure with Tekturna HCT compared to aliskiren or HCTZ monotherapy. Figures 1-4 provide estimates of the likelihood of achieving systolic or diastolic blood pressure control with Tekturna HCT 300/25 mg, based upon baseline systolic or diastolic blood pressure. The curve of each treatment group was estimated by logistic regression modeling. The estimated likelihood at the right tail of each curve is less reliable because of small numbers of subjects with high baseline blood pressures. Figure 1: Probability of Achieving Systolic Blood Pressure (SBP) Less Than 140 mmHg Figure 2: Probability of Achieving Systolic Blood Pressure (SBP) Less Than 130 mmHg Figure 3: Probability of Achieving Diastolic Blood Pressure (DBP) Less Than 90 mmHg Figure 4: Probability of Achieving Diastolic Blood Pressure (DBP) Less Than 80 mmHg At all levels of baseline blood pressure, the probability of achieving any given diastolic or systolic goal is greater with the combination than for either monotherapy. For example, the mean baseline msSBP/msDBP for patients participating in this multifactorial study was 154/99 mmHg. A patient with a baseline blood pressure of 154/99 mmHg has about a 62% chance of achieving a goal of less than 140 mmHg (systolic) and 61% chance of achieving less than 90 mmHg (diastolic) on aliskiren alone, and the chance of achieving these goals on HCTZ alone is about 54% (systolic) and 49% (diastolic). The chance of achieving these goals on Tekturna HCT rises to about 77% (systolic) and 74% (diastolic). The chance of achieving these goals on placebo is about 34% (systolic) and 37% (diastolic) [see Dosage and Administration (2) and Clinical Studies (14)]. 2  DOSAGE AND ADMINISTRATION 2.1 Dose Selection The recommended once-daily doses of Tekturna HCT in order of increasing mean effect are 150/12.5 mg, 150/25 mg or 300/12.5 mg, and 300/25 mg. 2.2 Dose TitrationThe antihypertensive effect of Tekturna HCT is largely manifested within 1 week, with maximal effects generally seen at around 4 weeks. If blood pressure remains uncontrolled after 2 to 4 weeks of therapy, the dose may be titrated up to a maximum of aliskiren 300 mg/HCTZ 25 mg. 2.3 Add-On Therapy A patient whose blood pressure is not adequately controlled with aliskiren alone or hydrochlorothiazide alone may be switched to combination therapy with Tekturna HCT. The usual recommended starting dose is 150/12.5 mg once daily as needed to control blood pressure. The dose may be titrated up to a maximum of aliskiren 300 mg/hydrochlorothiazide 25 mg once daily. 2.4 Replacement TherapyTekturna HCT may be substituted for the individually titrated components. 2.5 Initial TherapyThe usual recommended starting dose is 150/12.5 mg once daily as needed to control blood pressure. The dose may be titrated up to a maximum of aliskiren 300 mg/HCTZ 25 mg once daily. Tekturna HCT is not recommended for use as initial therapy in patients with intravascular volume depletion [see Warnings and Precautions (5.4)]. 2.6 Relationship to MealsPatients should establish a routine pattern for taking Tekturna HCT with regard to meals. High-fat meals decrease absorption substantially [see Clinical Pharmacology (12.3)]. 3  DOSAGE FORMS AND STRENGTHS 150 mg/12.5 mg tablets: white, biconvex ovaloid, film-coated tablets imprinted with NVR/LCI 150 mg/25 mg tablets: pale yellow, biconvex ovaloid, film-coated tablets imprinted with NVR/CLL 300 mg/12.5 mg tablets: violet white, biconvex ovaloid, film-coated tablets imprinted with NVR/CVI 300 mg/25 mg tablets: light yellow, biconvex ovaloid, film-coated tablets imprinted with NVR/CVV 4  CONTRAINDICATIONS Do not use aliskiren with ARBs or ACEIs in patients with diabetes [see Warnings and Precautions (5.2) and Clinical Studies (14.4)]. Tekturna HCT is contraindicated in patients with known anuria or hypersensitivity to sulfonamide derived drugs like HCTZ or to any of the components [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)]. Hypersensitivity reactions may range from urticaria to anaphylaxis.  5 WARNINGS AND PRECAUTIONS 5.1 Fetal ToxicityPregnancy Category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Tekturna HCT as soon as possible [see Use in Specific Populations (8.1)]. Thiazides cross the placenta, and use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice, thrombocytopenia, and possible other adverse reactions that have occurred in adults. 5.2 Renal Impairment/Hyperkalemia/Hypotension when Tekturna HCT is Given in Combination with ARBs or ACEIsTekturna HCT is contraindicated in patients with diabetes who are receiving ARBs or ACEIs because of the increased risk of renal impairment, hyperkalemia, and hypotension. In general, avoid combined use of aliskiren with ACE inhibitors or ARBs, particularly in patients with creatinine clearance (CrCl) less than 60 mL/min [see Contraindications (4), Drug Interactions (7) and Clinical Studies (14.3)]. 5.3 Anaphylactic Reactions and Head and Neck AngioedemaAliskiren Hypersensitivity reactions such as anaphylactic reactions and angioedema of the face, extremities, lips, tongue, glottis and/or larynx have been reported in patients treated with Tekturna and has necessitated hospitalization and intubation. This may occur at any time during treatment and has occurred in patients with and without a history of angioedema with ACEIs or angiotensin receptor antagonists. Anaphylactic reactions have been reported from postmarketing experience with unknown frequency. If angioedema involves the throat, tongue, glottis or larynx, or if the patient has a history of upper respiratory surgery, airway obstruction may occur and be fatal. Patients who experience these effects, even without respiratory distress, require prolonged observation and appropriate monitoring measures since treatment with antihistamines and corticosteroids may not be sufficient to prevent respiratory involvement. Prompt administration of subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and measures to ensure a patent airway may be necessary. Discontinue Tekturna HCT immediately in patients who develop anaphylactic reactions or angioedema, and do not readminister [see Contraindications (4)]. 5.4 HypotensionSymptomatic hypotension may occur after initiation of treatment with Tekturna HCT in patients with marked volume depletion, patients with salt depletion, or with combined use of aliskiren and other agents acting on the renin-angiotensin-aldosterone system (RAAS). The volume or salt depletion should be corrected prior to administration of Tekturna HCT, or the treatment should start under close medical supervision. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. 5.5 Impaired Renal FunctionMonitor renal function periodically in patients treated with Tekturna HCT. Changes in renal function, including acute renal failure, can be caused by drugs that affect the RAAS and by diuretics. Patients whose renal function may depend in part on the activity of the RAAS (e.g., patients with renal artery stenosis, severe heart failure, post-myocardial infarction or volume depletion) or patients receiving ARB, ACEI or nonsteroidal anti-inflammatory drug (NSAID) , including selective Cyclooxygenase-2 inhibitors (COX-2 inhibitors), therapy may be at particular risk of developing acute renal failure on Tekturna HCT [see Warnings and Precautions (5.2), Drug Interactions (7), and Clinical Studies (14.4)]. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Tekturna HCT. 5.6 Hypersensitivity ReactionsHydrochlorothiazide (HCTZ) Hypersensitivity reactions to HCTZ may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history. 5.7  Systemic Lupus ErythematosusHydrochlorothiazide (HCTZ) Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus. 5.8  Serum Electrolyte AbnormalitiesTekturna HCT In the short-term controlled trials of various doses of Tekturna HCT, in patients with hypertension not concomitantly treated with an ARB or ACEI, the incidence of hypertensive patients who developed hypokalemia (serum potassium less than 3.5 mEq/L) was 2.2%; the incidence of hyperkalemia (serum potassium greater than 5.5 mEq/L) was 0.8%. No patients discontinued due to increase or decrease of serum potassium. Aliskiren Monitor serum potassium periodically in patients receiving aliskiren. Drugs that affect the RAAS can cause hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes, combination use with ARBs or ACEIs [see Contraindications (4), Warnings and Precautions (5.2), and Clinical Studies (14.4)], NSAIDs, including selective Cyclooxygenase-2 inhibitors (COX-2 inhibitors) ,or potassium supplements or potassium-sparing diuretics. Hydrochlorothiazide (HCTZ) HCTZ can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. If hypokalemia is accompanied by clinical signs (e.g., muscular weakness, paresis, or ECG alterations), Tekturna HCT should be discontinued. Correction of hypokalemia and any coexisting hypomagnesemia is recommended prior to the initiation of thiazides. 5.9 Cyclosporine or ItraconazoleAliskiren When aliskiren was given with cyclosporine or itraconazole, the blood concentrations of aliskiren were significantly increased. Avoid concomitant use of aliskiren with cyclosporine or itraconazole [see Drug Interactions (7)]. 5.10 Acute Myopia and Secondary Angle-Closure GlaucomaHCTZ, a sulfonamide, can cause 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 weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue HCTZ as rapidly as possible. Prompt medical or surgical treatments 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. 5.11  Metabolic DisturbancesHydrochlorothiazide (HCTZ) HCTZ may alter glucose tolerance and raise serum levels of cholesterol and triglycerides. HCTZ may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients. HCTZ decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels in patients with hypercalcemia receiving Tekturna HCT. 6  ADVERSE REACTIONS 6.1  Clinical Studies ExperienceThe following serious adverse reactions are discussed in greater detail in other sections of the label: Fetal Toxicity [see Warnings and Precautions (5.1)]. Anaphylactic Reactions and Head and Neck Angioedema [see Warnings and Precautions (5.3)]. Hypotension [see Warnings and Precautions (5.4)]. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. Tekturna HCT Tekturna HCT has been evaluated for safety in more than 2,700 patients, including over 700 treated for 6 months and 190 for over 1 year. In placebo-controlled clinical trials, discontinuation of therapy due to a clinical adverse event (including uncontrolled hypertension) occurred in 2.7% of patients treated with Tekturna HCT versus 3.6% of patients given placebo. Adverse events in placebo-controlled trials that occurred in at least 1% of patients treated with Tekturna HCT and at a higher incidence than placebo included dizziness (2.3% versus 1%), influenza (2.3% versus 1.6%), diarrhea (1.6% versus 0.5%), cough (1.3% versus 0.5%), vertigo (1.2% versus 0.5%), asthenia (1.2% versus 0%), and arthralgia (1% versus 0.5%). Aliskiren Aliskiren has been evaluated for safety in 6,460 patients, including 1,740 treated for longer than 6 months, and 1,250 for longer than 1 year. In placebo-controlled clinical trials, discontinuation of therapy due to a clinical adverse event, including uncontrolled hypertension occurred in 2.2% of patients treated with aliskiren, versus 3.5% of patients given placebo. These data do not include information from the ALTITUDE study which evaluated the use of aliskiren in combination with ARBs or ACEIs [see Contraindications (4), Warnings and Precautions (5.2), and Clinical Studies (14.4)]. Two cases of angioedema with respiratory symptoms were reported with aliskiren use in the clinical studies. Two other cases of periorbital edema without respiratory symptoms were reported as possible angioedema and resulted in discontinuation. The rate of these angioedema cases in the completed studies was 0.06%. In addition, 26 other cases of edema involving the face, hands, or whole body were reported with aliskiren use, including 4 leading to discontinuation. In the placebo-controlled studies, however, the incidence of edema involving the face, hands, or whole body was 0.4% with aliskiren compared with 0.5% with placebo. In a long-term active-controlled study with aliskiren and HCTZ arms, the incidence of edema involving the face, hands, or whole body was 0.4% in both treatment arms. Aliskiren produces dose-related gastrointestinal (GI) adverse reactions. Diarrhea was reported by 2.3% of patients at 300 mg, compared to 1.2% in placebo patients. In women and the elderly (age 65 years and older) increases in diarrhea rates were evident starting at a dose of 150 mg daily, with rates for these subgroups at 150 mg comparable to those seen at 300 mg for men or younger patients (all rates about 2% to 2.3%). Other GI symptoms included abdominal pain, dyspepsia, and gastroesophageal reflux, although increased rates for abdominal pain and dyspepsia were distinguished from placebo only at 600 mg daily. Diarrhea and other GI symptoms were typically mild and rarely led to discontinuation. Aliskiren was associated with a slight increase in cough in the placebo-controlled studies (1.1% for any aliskiren use versus 0.6% for placebo). In active-controlled trials with ACE inhibitor (ramipril, lisinopril) arms, the rates of cough for the aliskiren arms were about one-third to one-half the rates in the ACE inhibitor arms. Other adverse reactions with increased rates for aliskiren compared to placebo included rash (1% versus 0.3%) and renal stones (0.2% versus 0%). Single episodes of tonic-clonic seizures with loss of consciousness were reported in 2 patients treated with aliskiren in the clinical trials. One patient had predisposing causes for seizures and had a negative electroencephalogram (EEG) and cerebral imaging following the seizures; for the other patient, EEG and imaging results were not reported. Aliskiren was discontinued and there was no rechallenge in either case. No clinically meaningful changes in vital signs or in ECG (including QTc interval) were observed in patients treated with aliskiren. Hydrochlorothiazide (HCTZ) Other adverse reactions that have been reported with HCTZ, without regard to causality, are listed below: Body As A Whole: weakness Digestive: pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation Hematologic: aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia; Hypersensitivity: purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions Metabolic: hyperglycemia, glycosuria, hyperuricemia Musculoskeletal: muscle spasm Nervous System/Psychiatric: restlessness Renal: renal failure, renal dysfunction, interstitial nephritis Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis Special Senses: transient blurred vision, xanthopsia Clinical Laboratory Test Abnormalities In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of Tekturna HCT in patients with hypertension not concomitantly treated with an ARB or ACEI. Blood Urea Nitrogen (BUN)/Creatinine: In patients with hypertension not concomitantly treated with an ARB or ACEI, elevations (greater than 50% increase) in BUN and creatinine occurred in 11.8% and 0.9%, respectively, of patients taking Tekturna HCT, and 7% and 1.1%, respectively, of patients given placebo in short-term controlled clinical trials. No patients were discontinued due to an increase in either BUN or creatinine. Hemoglobin and Hematocrit: A greater than 20% decrease in hemoglobin and hematocrit were observed in <0.1% and 0.1%, respectively, of patients treated with Tekturna HCT, compared with 0% in placebo-treated patients. No patients were discontinued due to anemia. Liver Function Tests: Occasional elevations (greater than 150%) in ALT (SGPT) were observed in 1.2% of patients treated with Tekturna HCT, compared with 0% in placebo-treated patients. No patients were discontinued due to abnormal liver function tests. 6.2  Post-Marketing ExperienceThe following adverse reactions have been reported in aliskiren or hydrochlorothiazide post-marketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. Aliskiren Hypersensitivity: anaphylactic reactions and angioedema requiring airway management and hospitalization, urticaria, peripheral edema, hepatic enzyme increase with clinical symptoms of hepatic dysfunction, severe cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, pruritus, erythema, nausea, vomiting Hydrochlorothiazide Acute renal failure, renal disorder, aplastic anemia, erythema mutliforme, pyrexia, muscle spasm, asthenia, acute angle-closure glaucoma, bone marrow failure, worsening of diabetes control, hypokalemia, blood lipids increased, hyponatremia, hypomagnesemia, hypercalcemia, hyperchloremic alkalosis, impotence, visual impairment Pathological changes in the parathyroid gland of patients with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. If hypercalcemia occurs, further diagnostic evaluation is necessary. 7  DRUG INTERACTIONS No drug interaction studies have been conducted with Tekturna HCT and other drugs, although studies with the individual aliskiren and HCTZ components are described below. Aliskiren Cyclosporine: Avoid coadministration of cyclosporine with aliskiren [see Warnings and Precautions (5.9) and Clinical Pharmacology (12.3)]. Itraconazole: Avoid coadministration of itraconazole with aliskiren [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.3)]. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) including selective Cyclooxygenase-2 inhibitors (COX-2 inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors with agents that affect the RAAS, including aliskiren, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving aliskiren and NSAID therapy. The antihypertensive effect of aliskiren may be attenuated by NSAIDs. Dual Blockade of the Renin-Angiotensin-Aldosterone System (RAAS): The concomitant use of aliskiren with other agents acting on the RAAS such as ACEIs or ARBs is associated with an increased risk of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two drugs that inhibit the renin-angiotensin system do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of aliskiren with ACE inhibitors or ARBs, particularly in patients with CrCl less than 60 mL/min. Monitor blood pressure, renal function, and electrolytes in patients on aliskiren and other agents that affect the RAAS [see Warnings and Precautions (5.4, 5.5, 5.8)]. The concomitant use of aliskiren with an ARB or an ACEI in diabetic patients is contraindicated [see Contraindications (4)]. Furosemide: Oral coadministration of aliskiren and furosemide reduced exposure to furosemide. Monitor diuretic effects when furosemide is coadministered with aliskiren. Hydrochlorothiazide (HCTZ) When administered concurrently, the following drugs may interact with thiazide diuretics. Antidiabetic drugs (oral agents and insulin): Dosage adjustment of the antidiabetic drug may be required. Lithium: Diuretic agents increase the risk of lithium toxicity. Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists. Monitoring of serum lithium levels is recommended during concomitant use. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and COX-2 selective agents: When Tekturna HCT and NSAIDs are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. Ion-exchange Resins: Staggering the dosage of HCTZ and ion exchange resins (e.g., cholestyramine, colestipol) such that HCTZ is administered at least 4 hours before or 4 to 6 hours after the administration of resins would potentially minimize the interaction [see Clinical Pharmacology (12.3)]. 8  USE IN SPECIFIC POPULATIONS 8.1  PregnancyPregnancy Category D [see Warnings and Precautions (5.1)] Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Tekturna HCT as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimesters of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Tekturna HCT, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Tekturna HCT for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations (8.4)]. Thiazides cross the placenta, and use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice, thrombocytopenia, and possible other adverse reactions that have occurred in adults. Reproductive toxicity studies of aliskiren hemifumarate did not reveal any evidence of teratogenicity at oral doses up to 600 mg aliskiren/kg/day (20 times the maximum recommended human dose [MRHD] of 300 mg/day on a mg/m2 basis) in pregnant rats or up to 100 mg aliskiren/kg/day (7 times the MRHD on a mg/m2 basis) in pregnant rabbits. Fetal birth weight was adversely affected in rabbits at 50 mg/kg/day (3.2 times the MRHD on a mg/m2 basis). Aliskiren was present in placenta, amniotic fluid, and fetuses of pregnant rabbits. When pregnant mice and rats were given HCTZ at doses up to 3000 and 1000 mg/kg/day, respectively (about 600 and 400 times the MRHD) during their respective periods of major organogenesis, there was no evidence of fetal harm. Hydrochlorothiazide (HCTZ) Thiazides can cross the placenta, and concentrations reached in the umbilical vein approach those in the maternal plasma. HCTZ, like other diuretics, can cause placental hypoperfusion. It accumulates in the amniotic fluid, with reported concentrations up to 19 times higher than in umbilical vein plasma. Use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice or thrombocytopenia. Since they do not prevent or alter the course of EPH (Edema, Proteinuria, Hypertension) gestosis (pre eclampsia), these drugs should not be used to treat hypertension in pregnant women. The use of HCTZ for other indications (e.g., heart disease) in pregnancy should be avoided. 8.3 Nursing MothersIt is not known whether aliskiren is excreted in human milk, but aliskiren was secreted in the milk of lactating rats. Thiazides appear in human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4  Pediatric UseSafety and effectiveness in pediatric patients have not been established. Preclinical studies indicate a potential for substantial increase in exposure to aliskiren in pediatric patients [see Nonclinical Toxicology (13.2)]. Neonates with a history of in utero exposure to Tekturna HCT: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. 8.5 Geriatric UseIn the short-term controlled clinical trials of Tekturna HCT, 325 (19.6%) patients treated with Tekturna HCT were 65 years and older and 53 (3.2%) were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6  Renal ImpairmentSafety and effectiveness of Tekturna HCT in patients with severe renal impairment [creatinine clearance (CrCl) less than 30 mL/min] have not been established [see Warnings and Precautions (5.6), Clinical Pharmacology (12.3) and Clinical Studies (14)]. No dose adjustment is required in patients with mild (CrCl 60 to 90 mL/min) or moderate (CrCl 30 to 60 mL/min) renal impairment. 8.7  Hepatic ImpairmentAliskiren No dose adjustment is necessary for patients with mild-to-severe liver disease [see Clinical Pharmacology (12.3)]. Hydrochlorothiazide (HCTZ) Minor alterations of fluid and electrolyte balance may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease. 10  OVERDOSAGE Aliskiren Limited data are available related to overdosage in humans. The most likely manifestation of overdosage would be hypotension. If symptomatic hypotension should occur, supportive treatment should be initiated. Aliskiren is poorly dialyzed. Therefore, hemodialysis is not adequate to treat aliskiren overexposure [see Clinical Pharmacology (12.3)]. Hydrochlorothiazide (HCTZ) The most common signs and symptoms of overdose observed in humans are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. The degree to which HCTZ is removed by hemodialysis has not been established. The oral LD50 of HCTZ is greater than 10 g/kg in both mice and rats. 11  DESCRIPTION Tekturna HCT is a fixed combination of aliskiren hemifumarate, an orally active, nonpeptide, direct renin inhibitor, and HCTZ, a thiazide diuretic that is provided as tablets for oral administration. Aliskiren Aliskiren hemifumarate is chemically described as (2S,4S,5S,7S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamide hemifumarate and its structural formula is: Molecular formula: C30H53N3O6 • 0.5 C4H4O4 Aliskiren hemifumarate is a white to slightly yellowish crystalline powder with a molecular weight of 609.8 (free base- 551.8). It is soluble in phosphate buffer, n-octanol, and highly soluble in water. Hydrochlorothiazide (HCTZ) Hydrochlorothiazide USP is a white, or practically white, practically odorless, crystalline powder. It is slightly soluble in water; freely soluble in sodium hydroxide solution, in n-butylamine, and in dimethylformamide; sparingly soluble in methanol; and insoluble in ether, in chloroform, and in dilute mineral acids. Hydrochlorothiazide is chemically described as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Hydrochlorothiazide is a thiazide diuretic. Its empirical formula is C7H8ClN3O4S2, its molecular weight is 297.73, and its structural formula is: Tekturna HCT tablets are formulated for oral administration to contain aliskiren and hydrochlorothiazide, USP 150/12.5 mg, 150/25 mg, 300/12.5 mg, and 300/25 mg. The inactive ingredients for all strengths of the tablets are colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, iron oxide colorants, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, talc, titanium dioxide, and wheat starch. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of ActionAliskiren Renin is secreted by the kidney in response to decreases in blood volume and renal perfusion. Renin cleaves angiotensinogen to form the inactive decapeptide angiotensin I (Ang I). Ang I is converted to the active octapeptide angiotensin II (Ang II) by angiotensin-converting enzyme (ACE) and non-ACE pathways. Ang II is a powerful vasoconstrictor and leads to the release of catecholamines from the adrenal medulla and prejunctional nerve endings. It also promotes aldosterone secretion and sodium reabsorption. Together, these effects increase blood pressure. Ang II also inhibits renin release, thus providing a negative feedback to the system. This cycle, from renin through angiotensin to aldosterone and its associated negative feedback loop, is known as the renin-angiotensin-aldosterone system (RAAS). Aliskiren is a direct renin inhibitor, decreasing plasma renin activity (PRA) and inhibiting the conversion of angiotensinogen to Ang I. Whether aliskiren affects other RAAS components, e.g., ACE or non-ACE pathways, is not known. All agents that inhibit the RAAS, including renin inhibitors, suppress the negative feedback loop, leading to a compensatory rise in plasma renin concentration. When this rise occurs during treatment with ACE inhibitors and ARBs, the result is increased levels of PRA. During treatment with aliskiren, however, the effect of increased renin levels is blocked, so that PRA, Ang I and Ang II are all reduced, whether aliskiren is used as monotherapy or in combination with other antihypertensive agents. Hydrochlorothiazide (HCTZ) HCTZ is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of HCTZ reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so coadministration of agents that block the production or function of angiotensin II tends to reverse the potassium loss associated with these diuretics. The mechanism of action of the antihypertensive effect of thiazides is unknown. 12.2  PharmacodynamicsTekturna HCT In placebo-controlled clinical trials, PRA was decreased with aliskiren monotherapy (ranging from 54% to 65%) and increased with hydrochlorothiazide monotherapy (ranging from 4% to 72%). Treatment with Tekturna HCT resulted in PRA reductions ranging from approximately 46% to 63% in various doses despite the increase in PRA with hydrochlorothiazide treatment. The clinical implications of the differences in effect on PRA are not known. Aliskiren PRA reductions in clinical trials ranged from approximately 50% to 80%, were not dose-related and did not correlate with blood pressure reductions. The clinical implications of the differences in effect on PRA are not known. Hydrochlorothiazide (HCTZ) After oral administration of HCTZ, diuresis begins within 2 hours, peaks in about 4 hours, and lasts about 6 to 12 hours. Drug Interactions Hydrochlorothiazide (HCTZ) Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur. Skeletal muscle relaxants: Possible increased responsiveness to muscle relaxants such as curare derivatives. Digitalis glycosides: Thiazide-induced hypokalemia or hypomagnesemia may predispose the patient to digoxin toxicity. 12.3 PharmacokineticsAbsorption and Distribution Tekturna HCT Following oral administration of Tekturna HCT combination tablets, the median peak plasma concentration time is within 1 hour for aliskiren and 2.5 hours for HCTZ. When taken with food, mean AUC and Cmax of aliskiren are decreased by 60% and 82%, respectively; mean AUC and Cmax of HCTZ increased by 13% and 10%, respectively. As a result, patients should establish a routine pattern for taking Tekturna HCT with regard to meals. Aliskiren Aliskiren is poorly absorbed (bioavailability about 2.5%). Following oral administration, peak plasma concentrations of aliskiren are reached within 1 to 3 hours. When taken with a high fat meal, mean AUC and Cmax of aliskiren are decreased by 71% and 85% respectively. In the clinical trials of aliskiren, it was administered without requiring a fixed relation of administration to meals. Hydrochlorothiazide (HCTZ) The estimated absolute bioavailability of HCTZ after oral administration is about 70%. Peak plasma HCTZ concentrations (Cmax) are reached within 2 to 5 hours after oral administration. There is no clinically significant effect of food on the bioavailability of HCTZ. HCTZ binds to albumin (40% to 70%) and distributes into erythrocytes. Following oral administration, plasma HCTZ concentrations decline bi-exponentially, with a mean distribution half-life of about 2 hours and an elimination half-life of about 10 hours. Metabolism and Elimination Aliskiren The effective half-life for aliskiren is 24 hours. Steady state blood levels are reached in about 7 to 8 days. About one-fourth of the absorbed dose appears in the urine as parent drug. How much of the absorbed dose is metabolized is unknown. Based on the in vitro studies, the major enzyme responsible for aliskiren metabolism appears to be CYP3A4. Aliskiren does not inhibit the CYP450 isoenzymes (CYP 1A2, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A) or induce CYP3A4. Transporters: Pgp (MDR1/Mdr1a/1b) was found to be the major efflux system involved in intestinal absorption and biliary excretion of aliskiren in preclinical studies. The potential for drug interactions at the Pgp site will likely depend on the degree of inhibition of this transporter. Hydrochlorothiazide (HCTZ) About 70% of an orally administered dose of HCTZ is eliminated in the urine as unchanged drug. Drug Interactions: Aliskiren The effect of coadministered drugs on the pharmacokinetics of aliskiren and vice versa, were studied in several single and multiple dose studies. Pharmacokinetic measures indicating the magnitude of these interactions are presented in Figure 5 (impact of coadministered drugs on aliskiren) and Figure 6 (impact on coadministered drugs). Figure 5: The Impact of Coadministered Drugs on the Pharmacokinetics of Aliskiren *Ketoconazole: A 400 mg once daily dose was not studied, but would be expected to increase aliskiren blood levels further. **Ramipril, valsartan, irbesartan: In general, avoid combined use of aliskiren with ACE inhibitors or ARBs, particularly in patients with CrCl less than 60 mL/min [see Drug Interactions (7)]. Warfarin: There was no clinically significant effect of a single dose of warfarin 25 mg on the pharmacokinetics of aliskiren. Figure 6: The Impact of Aliskiren on the Pharmacokinetics of Coadministered Drugs Furosemide: Patients receiving furosemide may find its effects diminished after starting aliskiren. In patients with heart failure, co-administration of aliskiren (300 mg/day) reduced plasma AUC and Cmax of oral furosemide (60 mg/day) by 17% and 27%, respectively, and reduced 24 hour urinary furosemide excretion by 29%. This change in exposure did not result in statistically significant difference in total urine volume and urinary sodium excretion over 24 hours. However, a transient decrease in urinary sodium excretion and urine volume effects up to 12 hours were observed when furosemide was co-administered with aliskiren 300 mg/day. Ramipril, valsartan: In general, avoid combined use of aliskiren with ACE inhibitors or ARBs, particularly in patients with CrCl less than 60 mL/min [see Drug Interactions (7)]. Hydrochlorothiazide (HCTZ) Drugs that alter gastrointestinal 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, pro-kinetic drugs may decrease the bioavailability of thiazide diuretics. Cholestyramine: In a dedicated drug interaction study, administration of cholestyramine 2 hours before HCTZ resulted in a 70% reduction in exposure to HCTZ. Further, administration of HCTZ 2 hours before cholestyramine, resulted in 35% reduction in exposure to HCTZ. Antineoplastic agents (e.g., cyclophosphamide, methotrexate): Concomitant use of thiazide diuretics may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects. Special Populations Pediatric Patients The pharmacokinetics of aliskiren have not been investigated in patients less than 18 years of age. Geriatric Patients Aliskiren The pharmacokinetics of aliskiren were studied in the elderly (65 years and older). Exposure (measured by AUC) is increased in elderly patients. Hydrochlorothiazide (HCTZ) A limited amount of data suggest that the systemic clearance of HCTZ is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers. Race Too few non-Caucasians have been studied with Tekturna HCT to assess pharmacokinetic differences among races. The pharmacokinetic differences among blacks, Caucasians, and Japanese are minimal with aliskiren therapy. Renal Impairment Aliskiren The pharmacokinetics of aliskiren were evaluated in patients with varying degrees of renal impairment. Rate and extent of exposure (AUC and Cmax) of aliskiren in subjects with renal impairment did not show a consistent correlation with the severity of renal impairment [see Use in Specific Populations (8.6)]. The pharmacokinetics of aliskiren following administration of a single oral dose of 300 mg was evaluated in patients with End Stage Renal Disease (ESRD) undergoing hemodialysis. When compared to matched healthy subjects, changes in the rate and extent of aliskiren exposure (Cmax and AUC) in ESRD patients undergoing hemodialysis were not clinically significant. Timing of hemodialysis did not significantly alter the pharmacokinetics of aliskiren in ESRD patients. Therefore, no dose adjustment is warranted in ESRD patients receiving hemodialysis. Hydrochlorothiazide (HCTZ) In a study in individuals with impaired renal function, the mean elimination half-life of HCTZ was doubled in individuals with mild/moderate renal impairment (30 < CrCl < 90 mL/min) and tripled in severe renal impairment (CrCl less than or equal to 30 mL/min), compared to individuals with normal renal function (CrCl greater than 90 mL/min) [see Use in Specific Populations (8.6)]. Hepatic Impairment Aliskiren The pharmacokinetics of aliskiren were not significantly affected in patients with mild-to-severe liver disease [see Use in Specific Populations (8.7)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityTekturna HCT No carcinogenicity, mutagenicity or fertility studies have been conducted with Tekturna HCT. However, these studies have been conducted for aliskiren as well as HCTZ alone. Aliskiren Carcinogenic potential was assessed in a 2-year rat study and a 6-month transgenic (rasH2) mouse study with aliskiren hemifumarate at oral doses of up to 1500 mg aliskiren/kg/day. Although there were no statistically significant increases in tumor incidence associated with exposure to aliskiren, mucosal epithelial hyperplasia (with or without erosion/ulceration) was observed in the lower gastrointestinal tract at doses of 750 or more mg/kg/day in both species, with a colonic adenoma identified in 1 rat and a cecal adenocarcinoma identified in another, rare tumors in the strain of rat studied. On a systemic exposure (AUC0-24hr) basis, 1500 mg/kg/day in the rat was about 4 times and in the mouse about 1.5 times the MRHD (300 mg aliskiren/day). Mucosal hyperplasia in the cecum or colon of rats was also observed at doses of 250 mg/kg/day (the lowest tested dose) as well as at higher doses in 4- and 13-week studies. Aliskiren hemifumarate was devoid of genotoxic potential in the Ames reverse mutation assay with S. typhimurium and E. coli, the in vitro Chinese hamster ovary cell chromosomal aberration assay, the in vitro Chinese hamster V79 cell gene mutation test and the in vivo mouse bone marrow micronucleus assay. Fertility of male and female rats was unaffected at doses of up to 250 mg aliskiren/kg/day (8 times the MRHD of 300 mg Tekturna/60 kg on a mg/m2 basis). Hydrochlorothiazide (HCTZ) Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of HCTZ in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice. HCTZ was not genotoxic in vitro in the Ames mutagenicity assay of S. typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of HCTZ from 43 to 1300 mcg/mL, and in the Aspergillums Nidulans nondisjunction assay at an unspecified concentration. HCTZ was not teratogenic and had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout gestation. These doses of HCTZ in mice and rats represent 19 and 1.5 times, respectively, the MRHD on a mg/m2 basis. (Calculations assume an oral dose of 25 mg/day and a 60-kg patient.) 13.2 Animal Toxicology and/or PharmacologyReproductive Toxicology Studies [See Use in Specific Populations (8.1).] Juvenile Animal Studies Juvenile toxicity studies indicated increased systemic exposure to aliskiren 85- to 385-fold in 14 day and 8 day old rats respectively, compared with adult rats. The mdr1 gene expression in juvenile rats was also significantly lower when compared to adult rats. The increased aliskiren exposure in juvenile rats appears to be mainly attributed to lack of maturation of P-gp. The overexposure in juvenile rats was associated with high mortality [see Use in Specific Populations (8.4)]. 14 CLINICAL STUDIES 14.1 Tekturna HCTIn all clinical trials including over 6,200 patients, more than 2,700 patients were exposed to combinations of aliskiren and HCTZ. The safety and efficacy of Tekturna HCT were evaluated in patients with mild-to-moderate hypertension in an 8-week, randomized, double-blind, placebo-controlled, parallel-group, 15-arm factorial trial (n=2762). Patients were randomized to receive various combinations of aliskiren (75 mg to 300 mg) plus HCTZ (6.25 mg to 25 mg) once daily (without titrating up from monotherapy) and followed for blood pressure response. The combination of aliskiren and HCTZ resulted in additive placebo-adjusted decreases in systolic and diastolic blood pressure at trough of 10-14/5-7 mmHg at doses of 150-300 mg/12.5-25 mg, compared to 5-8/2-3 mmHg for aliskiren 150 mg to 300 mg and 6-7/2-3 mmHg for HCTZ 12.5 mg to 25 mg, alone. Blood pressure reductions with the combinations were greater than the reductions with the monotherapies as shown in Table 1. Table 1: Placebo-Subtracted Reductions in Seated Trough Cuff Blood Pressure in Combination with Hydrochlorothiazide (HCTZ) Hydrochlorothiazide, mg 0 6.25 12.5 25 Aliskiren, mg Placebo Mean Change Placebo-subtracted Placebo-subtracted Placebo-subtracted Placebo-subtracted 0 7.5/6.9 -- 3.5/2.1 6.4/3.2 6.8/2.4 75 -- 1.9/1.8 6.8/3.8 8.2/4.2 9.8/4.5 150 -- 4.8/2 7.8/3.4 10.1/5 12/5.7 300 -- 8.3/3.3 -- 12.3/7 13.7/7.3 The safety and efficacy of Tekturna HCT as initial therapy was evaluated in this trial. All patients randomized to the combination groups received the combination treatment of Tekturna HCT at assigned doses as initial therapy without titration from monotherapy. The figures [see Indications and Usage (1)] display the probability that a patient will achieve systolic or diastolic blood pressure goal with Tekturna HCT 300/25 mg, based upon their baseline systolic or diastolic blood pressure. At all levels of baseline blood pressure, the probability of achieving any given diastolic or systolic goal is greater with the combination than for either monotherapy. The antihypertensive effect of Tekturna HCT was largely manifested within 1 week. The maximum antihypertensive effect was generally attained after about 4 weeks of therapy. One active-controlled trial investigated the addition of 300 mg aliskiren in obese hypertensive patients who did not respond adequately to HCTZ 25 mg, and showed incremental decreases of systolic and diastolic blood pressure of approximately 7/4 mmHg. In long-term follow-up studies (without placebo control) the effect of the combination of aliskiren and HCTZ was maintained for over 1 year. The antihypertensive effect was independent of age and gender. There were too few non-Caucasians to assess differences in blood pressure effects by race. 14.2 Aliskiren MonotherapyThe antihypertensive effects of aliskiren have been demonstrated in 6 randomized, double-blind, placebo-controlled, 8-week clinical trials in patients with mild-to-moderate hypertension. The placebo response and placebo-subtracted changes from baseline in seated trough cuff blood pressure are shown in Table 2. Table 2: Reductions in Seated Trough Cuff Blood Pressure in the Placebo-Controlled Studies of Aliskiren Monotherapy Aliskiren Daily Dose, mg 75 150 300 600 Study Placebo Mean Change Placebo-subtracted Placebo-subtracted Placebo-subtracted Placebo-subtracted 1 2.9/3.3 5.7/4* 5.9/4.5* 11.2/7.5* -- 2 5.3/6.3 -- 6.1/2.9* 10.5/5.4* 10.4/5.2* 3 10/8.6 2.2/1.7 2.1/1.7 5.1/3.7* -- 4 7.5/6.9 1.9/1.8 4.8/2* 8.3/3.3* -- 5 3.8/4.9 -- 9.3/5.4* 10.9/6.2* 12.1/7.6* 6 4.6/4.1 -- -- 8.4/4.9† -- p value less than 0.05 versus placebo by ANCOVA with Dunnett’s procedure for multiple comparisons. †p value less than 0.05 versus placebo by ANCOVA for the pairwise comparison. The studies included approximately 2,730 patients given doses of 75 mg to 600 mg of aliskiren and 1,231 patients given placebo. As shown in Table 2, there is some increase in response with administered dose in all studies, with reasonable effects seen at 150 mg to 300 mg, and no clear further increase at 600 mg. A substantial proportion (85% to 90%) of the blood pressure lowering effect was observed within 2 weeks of treatment. Studies with ambulatory blood pressure monitoring showed reasonable control throughout the interdosing interval, e.g., the ratios of mean daytime to mean nighttime ambulatory BP ranged from 0.6 to 0.9. Patients in the placebo-controlled trials continued open-label aliskiren for up to 1 year. A persistent blood pressure lowering effect was demonstrated by a randomized withdrawal study (patients randomized to continued drug or placebo), which showed a statistically significant difference between patients kept on aliskiren and those randomized to placebo. With cessation of treatment, blood pressure gradually returned toward baseline levels over a period of several weeks. There was no evidence of rebound hypertension after abrupt cessation of therapy. The effectiveness of aliskiren was demonstrated across all demographic subgroups, although black patients tended to have smaller reductions in blood pressure than Caucasians and Asians, as has been seen with ACE inhibitors and ARBs. 14.3 Aliskiren in Combination with Other AntihypertensivesValsartan Aliskiren 150 mg and 300 mg and valsartan 160 mg and 320 mg were studied alone and in combination in an 8-week, 1,797-patient, randomized, double-blind, placebo-controlled, parallel-group, 4-arm, dose-escalation study. The dosages of aliskiren and valsartan were started at 150 mg and 160 mg, respectively, and increased at 4 weeks to 300 mg and 320 mg, respectively. Seated trough cuff blood pressure was measured at baseline, 4, and 8 weeks. Blood pressure reductions with the combinations were greater than the reductions with the monotherapies as shown in Table 3. In general, avoid use of aliskiren in combination with other drugs that affect the RAAS [see Contraindications (4), Warnings and Precautions (5), and Drug Interactions (7)]. Table 3: Placebo-Subtracted Reductions in Seated Trough Cuff Blood Pressure of Aliskiren in Combination with Valsartan Valsartan, mg Aliskiren, mg Placebo Mean Change 0 160 320 0 4.6/4.1* -- 5.6/3.9 8.2/5.6 150 -- 5.4/2.7 10.0/5.7 -- 300 -- 8.4/4.9 -- 12.6/8.1 The placebo change is 5.2/4.8 for Week 4 endpoint which was used for the dose groups containing aliskiren 150 mg or valsartan 160 mg. Amlodipine Aliskiren 150 mg and 300 mg and amlodipine besylate 5 mg and 10 mg were studied alone and in combination in an 8-week, 1,685-patient, randomized, double-blind, placebo-controlled, multifactorial study. Treatment with aliskiren and amlodipine resulted overall in significantly greater reductions in diastolic and systolic blood pressure compared to the respective monotherapy components as shown in Table 4. Table 4: Placebo-Subtracted Reductions in Seated Trough Cuff Blood Pressure in Combination with Amlodipine  Aliskiren, mg Placebo mean change Amlodipine, mg 0 5 10 0 5.4/6.8 -- 5.6/9.0 8.5/14.3 150 -- 2.6/3.9 8.6/13.9 10.8/17.1 300 -- 4.9/8.6 9.6/15.0 11.1/16.4 ACEIs Aliskiren has not been studied when added to maximal doses of ACEIs to determine whether aliskiren produces additional blood pressure reduction. There are no trials of the Tekturna HCT combination tablet demonstrating reductions in cardiovascular risk in patients with hypertension, but the HCTZ component has demonstrated such benefits. 14.4 Aliskiren in Patients with Diabetes Treated with an ARB or ACEI (ALTITUDE study)Patients with diabetes with renal disease (defined either by the presence of albuminuria or reduced GFR) were randomized to aliskiren 300 mg daily (n=4296) or placebo (n=4310). All patients were receiving background therapy with an ARB or ACEI. The primary efficacy outcome was the time to the first event of the primary composite endpoint consisting of cardiovascular death, resuscitated sudden death, nonfatal myocardial infarction, nonfatal stroke, unplanned hospitalization for heart failure, onset of end stage renal disease, renal death, and doubling of serum creatinine concentration from baseline sustained for at least 1 month. After a median follow up of about 32 months, the trial was terminated early for lack of efficacy. Higher risk of renal impairment, hypotension and hyperkalemia was observed in aliskiren compared to placebo treated patients, as shown in Table 5. Table 5: Incidence of Selected Adverse Events During the Treatment Phase in ALTITUDE Aliskiren N=4272 Placebo N=4285 Serious Adverse Events* (%) Adverse Events (%) Serious Adverse Events* (%) Adverse Events (%) Renal impairment † 5.7 14.5 4.3 12.4 Hypotension †† 2.3 19.9 1.9 16.3 Hyperkalemia ††† 1.0 38.9 0.5 28.8 renal failure, renal failure acute, renal failure chronic, renal impairment  dizziness, dizziness postural, hypotension, orthostatic hypotension, presyncope, syncope Given the variable baseline potassium levels of patients with renal insufficiency on dual RAAS therapy, the reporting of adverse event of hyperkalemia was at the discretion of the investigator.  A Serious Adverse Event (SAE) is defined as: an event which is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, requires inpatient hospitalization or prolongation of existing hospitalization, or is medically significant (i.e., defined as an event that jeopardizes the patient or may require medical or surgical intervention to prevent one of the outcomes previously listed). The risk of stroke (3.4% aliskiren versus 2.7% placebo) and death (8.4% aliskiren versus 8.0% placebo) were also numerically higher in aliskiren-treated patients. 16 HOW SUPPLIED/STORAGE AND HANDLING Tekturna HCT is supplied as biconvex, ovaloid film-coated tablets All strengths are packaged in bottles and unit-dose blister packages (10 strips of 10 tablets) as described below. Table 6: Tekturna HCT Tablets Supply  Tablet Color Imprint Imprint NDC 0078- XXXX-XX Aliskiren/HCTZ Side 1 Side 2 Bottle of 30 Bottle of 90 Blister Packages of 100 150 mg/12.5 mg White NVR LCI 0521-15 0521-34 0521-35 150 mg/25 mg Pale Yellow NVR CLL 0522-15 0522-34 0522-35 300 mg/12.5 mg Violet White NVR CVI 0523-15 0523-34 0523-35 300 mg/25 mg Light Yellow NVR CVV 0524-15 0524-34 0524-35 Storage Store at 25ºC (77ºF); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF) [See USP Controlled Room Temperature]. Protect from moisture. Dispense in original container. 17  PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Pregnancy Inform female patients of childbearing age about the consequences of exposure to Tekturna HCT during pregnancy. Discuss treatment options with women planning to become pregnant. Advise patients to report pregnancies to their physicians as soon as possible. Symptomatic Hypotension Inform patients that lightheadedness can occur, especially during the first days of Tekturna HCT therapy, and that it should be reported to the prescribing physician. Advise patients that if syncope occurs, Tekturna HCT should be discontinued until the physician has been consulted. Caution patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope. Anaphylactic Reactions and Angioedema Advise patients to immediately report any signs or symptoms suggesting a severe allergic reaction (difficulty breathing or swallowing, tightness of the chest, hives, general rash, swelling, itching, dizziness, vomiting, or abdominal pain) or angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have consulted with the prescribing physician. Angioedema, including laryngeal edema, may occur at any time during treatment with Tekturna HCT. Potassium Supplements Advise patients receiving Tekturna HCT not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician. Relationship to Meals Instruct patients to establish a routine pattern for taking Tekturna HCT with regard to meals. High-fat meals decrease absorption substantially. ----------------------------------------------------------------- 产地国家：美国 原产地英文商品名: TEKTURNA HCT(300/12.5)mg/tab 30tabs/bottle 原产地英文药品名: ALISKIREN HEMIFUMARATE/HYDROCHLOROTHIAZIDE 中文参考商品译名: TEKTURNA HCT(300/12.5)毫克/片 30片/瓶 中文参考药品译名: 富马酸阿利吉仑/氢氯噻嗪 生产厂家中文参考译名: 诺华 生产厂家英文名: NOVARTIS ----------------------------------------------------------------- 产地国家：美国 原产地英文商品名: TEKTURNA HCT(300/25)mg/tab 30tabs/bottle 原产地英文药品名: ALISKIREN HEMIFUMARATE/HYDROCHLOROTHIAZIDE 中文参考商品译名: TEKTURNA HCT(300/25)毫克/片 30片/瓶 中文参考药品译名: 富马酸阿利吉仑/氢氯噻嗪 生产厂家中文参考译名: 诺华 生产厂家英文名: NOVARTIS ----------------------------------------------------------------- 产地国家：美国 原产地英文商品名: TEKTURNA HCT(150/25)mg/tab 30tabs/bottle 原产地英文药品名: ALISKIREN HEMIFUMARATE/HYDROCHLOROTHIAZIDE 中文参考商品译名: TEKTURNA HCT(150/25)毫克/片 30片/瓶 中文参考药品译名: 富马酸阿利吉仑/氢氯噻嗪 生产厂家中文参考译名: 诺华 生产厂家英文名: NOVARTIS ----------------------------------------------------------------- 产地国家：美国 原产地英文商品名: TEKTURNA HCT(150/12.5)mg/tab 30tabs/bottle 原产地英文药品名: ALISKIREN HEMIFUMARATE/HYDROCHLOROTHIAZIDE 中文参考商品译名: TEKTURNA HCT(150/12.5)毫克/片 30片/瓶 中文参考药品译名: 富马酸阿利吉仑/氢氯噻嗪 生产厂家中文参考译名: 诺华 生产厂家英文名: NOVARTIS