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Tekturna HCT (aliskiren/hydrochlorothiazide)
美国食品和药物管理局（FDA）批准了阿利吉仑和氢氯噻嗪组合的复方制剂作为抗高血压的一线用药。
阿利吉仑（Tekturna）是一种肾素抑制剂，是目前唯一的针对肾素的肾素血管紧张素醛固酮系统（RAAS）抑制剂。目前正在进行的一项包括14个试验、35000例患者的大规模心肾预后研究ASPIRE HIGHER表明，阿利吉仑的心肾保护作用可能与降低血压无关，具体作用还在进一步研究中。阿利吉仑于2007年3月在美国批准上市，2007年8月在欧洲上市，2009年7月，在日本也获得批准。阿利吉仑/氢氯噻嗪是第一个含有阿利吉仑的复方制剂，在2008年1月被批准用于高血压的二线治疗。目前阿利吉仑/氢氯噻嗪复方制剂有4种组合：150mg/12.5mg；300mg/25mg；300mg/12.5mg；300mg/25mg。均为片剂。
FDA批准阿利吉仑/氢氯噻嗪用于高血压一线治疗，主要是根据一项为期8周的双盲、随机、安慰剂对照、平行临床试验作出的。研究共入选6200多例患者，其中2762例轻中度原发性高血压患者随机接受不同剂量的阿利吉仑（75～300mg）和氢氯噻嗪(6.25～25mg)联合治疗（均作为初次治疗）。与安慰剂组比较，单用150～300mg阿利吉仑，收缩压/舒张压下降（5～8）/（2～3）mmHg；单用12.5～25mg氢氯噻嗪，下降（6～7）/（2～3）mmHg；而（150～300）mg/（12.5～25）mg阿利吉仑/氢氯噻嗪联合治疗可以使收缩压/舒张压下降（10～14）/（5～7）mmHg。联合用药的效果明显优于单用。研究还评估了联合应用阿利吉仑和氢氯噻嗪作为一线治疗药物的安全性和有效性。阿利吉仑/氢氯噻嗪可以在治疗1周内显效，治疗4周时，可以达到最大疗效。
对于血压值高于目标值20/10mmHg的患者，目前的美国治疗指南主张一开始就使用两种药物，其中一种应为利尿剂。使用多种药物可使这类患者血压很快达标。目前，有高达85％的患者需要联合治疗，阿利吉仑/氢氯噻嗪复方制剂的获批，使医生有机会使用单一的复方制剂对患者实施积极的治疗。
Tekturna HCT (aliskiren/hydrochlorothiazide)
Drug SummaryNovartis Pharmaceuticals Corporation
Tekturna HCT(aliskiren/hydrochlorothiazide)
BOXED WARNING
D/C when pregnancy is detected. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
THERAPEUTIC CLASS
Renin inhibitor/thiazide diuretic
DEA CLASS
RX
ADULT DOSAGE & INDICATIONS
Hypertension
Add-On/Initial Therapy:
Patients whose BP is not adequately controlled w/ aliskiren alone or hydrochlorothiazide (HCTZ) alone may be switched to Tekturna HCT, patients whose BP is controlled w/ HCTZ alone but who experience hypokalemia may be switched to Tekturna HCT, or patients who experience dose-limiting adverse reactions on either component alone may be switched to Tekturna HCT containing a lower dose of that component in combination w/ the other. May be used as initial therapy in patients likely to need multiple drugs to achieve BP goals
Initial: 150mg/12.5mg qd prn to control BP
Titrate: May increase if BP remains uncontrolled after 2-4 weeks
Max: 300mg/25mg qd
Replacement Therapy:
May substitute for individually titrated components
ADMINISTRATION
Oral route
Establish a routine pattern for taking drug w/ regard to meals; high-fat meals decrease absorption substantially.
HOW SUPPLIED
Tab: (Aliskiren/HCTZ) 150mg/12.5mg, 150mg/25mg, 300mg/12.5mg, 300mg/25mg
CONTRAINDICATIONS
Coadministration w/ ARBs or ACE inhibitors in patients w/ diabetes, known anuria, hypersensitivity to sulfonamide-derived drugs (eg, HCTZ) or to any of the components.
WARNINGS/PRECAUTIONS
Not for initial therapy w/ intravascular volume depletion. Symptomatic hypotension may occur in patients w/ marked volume depletion or w/ salt depletion; correct volume/salt depletion prior to administration or begin therapy under close medical supervision. Renal function changes may occur, including acute renal failure; caution in patients whose renal function may depend in part on the activity of the renin-angiotensin-aldosterone system (RAAS) (eg, renal artery stenosis, severe heart failure [HF], post-MI, or volume depletion). Consider withholding or discontinuing therapy if clinically significant decrease in renal function develops. May cause hypo/hyperkalemia; d/c if hypokalemia is accompanied by clinical signs (eg, muscular weakness, paresis, ECG alterations). Aliskiren: Hypersensitivity reactions (eg, anaphylactic reactions) and head/neck angioedema reported; d/c therapy immediately and do not readminister if anaphylactic reactions or angioedema develops. May cause hyperkalemia. HCTZ: May cause hypersensitivity reactions, w/ or w/o bronchial asthma, and exacerbation or activation of systemic lupus erythematosus (SLE). May cause hypokalemia and hyponatremia; hypomagnesemia may result in hypokalemia. Correct hypokalemia and any coexisting hypomagnesemia prior to initiation of thiazides. May cause idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma; d/c as rapidly as possible. May alter glucose tolerance and increase serum cholesterol and TG levels. May cause or exacerbate hyperuricemia and precipitate gout in susceptible patients. May cause hypercalcemia. Minor alterations of fluid and electrolyte balance may precipitate hepatic coma in patients w/ hepatic impairment or progressive liver disease.
ADVERSE REACTIONS
Dizziness, influenza, diarrhea, cough, vertigo, asthenia, arthralgia.
DRUG INTERACTIONS
See Contraindications. Aliskiren: Cyclosporine or itraconazole may increase levels; avoid concomitant use. NSAIDs (eg, selective COX-2 inhibitors) may deteriorate renal function, including possible acute renal failure, and may attenuate antihypertensive effect. Dual blockade of the RAAS is associated w/ increased risk of hypotension, hyperkalemia, and changes in renal function (including acute renal failure); in general, avoid combined use w/ ACE inhibitors or ARBs, particularly in patients w/ CrCl <60mL/min. Reduced furosemide exposure w/ concomitant use. May develop hyperkalemia w/ NSAIDs (eg, selective COX-2 inhibitors), K+ supplements, or K+-sparing diuretics. HCTZ: Dosage adjustment of antidiabetic drugs (oral agents and insulin) may be required. May increase risk of lithium toxicity; monitor serum lithium levels. Observe patients closely to determine if the desired effect of the diuretic is obtained when used concomitantly w/ NSAIDs and COX-2 selective agents. Administer ≥4 hrs before or 4-6 hrs after the administration of ion exchange resins (eg, cholestyramine, colestipol).
PREGNANCY AND LACTATION
Pregnancy: Category D. Use of drugs that act on the renin-angiotensin system during the 2nd and 3rd trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. When pregnancy is detected, d/c therapy as soon as possible. Thiazides cross the placenta and their use is associated w/ risk of fetal or neonatal jaundice, thrombocytopenia, and possible other adverse reactions.
Lactation: Not for use in nursing. Thiazides appear in human milk.
MECHANISM OF ACTION
Aliskiren: Direct renin inhibitor; decreases plasma renin activity and inhibits conversion of angiotensinogen to angiotensin I. HCTZ: Thiazide diuretic; has not been established. Affects renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of Na+ and Cl-, and indirectly reduces plasma volume.
PHARMACOKINETICS
Absorption: Aliskiren: Poor. Bioavailability (2.5%); Tmax=1 hr (median). HCTZ: Absolute bioavailability (70%); Tmax=2.5 hrs (median). Distribution: HCTZ: Plasma protein binding (40-70%, albumin); crosses placenta; found in breast milk. Metabolism: Aliskiren: Via CYP3A4. Elimination: Aliskiren: Urine (25%, unchanged); T1/2=24 hrs. HCTZ: Urine (70%, unchanged); T1/2=10 hrs.
ASSESSMENT
Assess for diabetes, anuria, sulfonamide-derived drug hypersensitivity, history of penicillin allergy, volume/salt depletion, renal artery stenosis, HF, post-MI status, SLE, hepatic/renal impairment, pregnancy/nursing status, and possible drug interactions. Correct electrolyte abnormalities (eg, hypokalemia, hypomagnesemia) prior to initiating therapy.
MONITORING
Monitor for signs/symptoms of idiosyncratic reactions, hypersensitivity reactions, angioedema, airway obstruction, exacerbation/activation of SLE, hyperuricemia, precipitation of gout, and other adverse reactions. Monitor BP, renal function, serum electrolytes, cholesterol, and TG levels.
PATIENT COUNSELING
Inform female patients of childbearing age of the consequences of exposure during pregnancy and of the treatment options for women planning to become pregnant. Advise to report pregnancies to physicians as soon as possible. Inform that lightheadedness may occur, especially during the 1st days of therapy; instruct to contact physician if lightheadedness occurs. Advise to d/c treatment until physician has been consulted if syncope occurs. Caution that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in BP. Advise to d/c therapy and immediately report any signs/symptoms of a severe allergic reaction or angioedema. Advise not to use K+ supplements or salt substitutes containing K+ w/o consulting physician. Instruct to establish a routine pattern for taking the medication w/ regard to meals.
STORAGE
25°C (77°F); excursions permitted to 15-30°C (59-86°F). Protect from moisture. |
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