日本第一三共公司研发的新型复方抗高血压药物Tribenzor获FDA批准用于治疗联合2种常用抗高血压药疗效不佳的难治性患者，Tribenzor由氨氯地平、奥美沙坦酯、氢氯噻嗪组成，能有效降低患者血压，但不作为一线用药。
日前，美国FDA批准，在应用血管紧张素受体阻滞剂、钙通道阻滞剂和利尿剂中任意2种药物仍无法充分控制患者血压的情况下，可考虑使用三联药物Tribenzor。
Tribenzor是日本第一三共公司研发的新型复方抗高血压药物，含氨氯地平、奥美沙坦酯、氢氯噻嗪。Tribenzor被FDA批准用于那些应用抗高血压药物的其他组合不能使高血压得到很好控制的患者。但不宜用作一线抗高血压药。
一项研究试验结果证明了Tribenzor的有效性，该试验共纳入2,492例高血压患者(平均基线血压为168.5/100.9mmHg)。在患者接受了氨氯地平/氢氯噻嗪(10/25 mg)，奥美沙坦/氢氯噻嗪(40/25 mg)和奥美沙坦/氨氯地平(40/10mg)这3种双药组合疗法中的其中一种后，医生开始改用Tribenzor(40/10/25mg)对患者进行抗高血压治疗。在接受了为期8周的Tribenzor治疗后，患者的平均血压进一步降低(分别为8.1/5.4mmHg、7.6/5.4 mmHg和8.4/4.5 mmHg，对每一种双药组合治疗而言，P值均<0.0001)。
Tribenzor最常见不良反应包括头晕、外周水肿、头痛、乏力、鼻咽炎、肌肉痉挛、恶心、上呼吸道感染、腹泻、尿道感染和关节肿胀。
高血压是一种常见的多发性疾病，有效平稳控制血压是目前治疗高血压的主要目标。但在目前接受抗高血压治疗的患者中，大约有56%的患者在血压控制方面并未达到现行推荐目标。此外，有超过66%的高血压患者需要联用2种或2种以上的抗高血压药物方能达到期望的血压控制目标。
Tribenzor是一种新型的3三联混合型药物，每日只需服药1次，有望简化血压难以控制患者的给药方案，减少药丸负荷，并可以减少整张处方的费用。为难治性高血压患者提供一种更方便有效的治疗方法，一天一次用药能避免患者忘服漏服药物，避免出现血压波动现象.
Tribenzor禁用于无尿或对其他磺胺类药物过敏的患者。对肾素-血管紧张素业已激活的患者[如那些血容量耗竭和(或)盐耗竭的患者]而言，其一旦开始接受Tribenzor治疗后便有可能发生症状性低血压。当患者(尤其是那些存在严重阻塞性冠状动脉疾病的患者)开始接受钙通道阻滞剂治疗或增加给药剂量时，其可能会出现心绞痛发作频率增高、持续时间延长，或病情严重程度加重，其发生急性心肌梗死的几率也会增高。应该避免对那些存在严重肾功能损害的患者使用Tribenzor。
INDICATIONS:
BENICAR, AZOR, and TRIBENZOR are 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 the class to which these drugs principally belong. There are no controlled trials demonstrating risk reduction with BENICAR, AZOR, or TRIBENZOR.

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 one drug to achieve blood pressure goals.
BENICAR HCT is indicated for the treatment of hypertension. BENICAR HCT is not indicated for initial therapy.
BENICAR, BENICAR HCT, AZOR, and TRIBENZOR can be used alone or with other antihypertensive agents.
AZOR is indicated as initial therapy in patients likely to need multiple antihypertensive agents to achieve their blood pressure goals.
Initial therapy with AZOR is not recommended in patients ≥75 years of age or in hepatically impaired patients.
TRIBENZOR is not indicated for the initial therapy of hypertension.
Important Safety Information for BENICAR®, BENICAR HCT®, AZOR®, and TRIBENZOR®
WARNING: FETAL TOXICITY
•When pregnancy is detected, discontinue BENICAR, BENICAR HCT, AZOR, or TRIBENZOR as soon as possible
•Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. See WARNINGS AND PRECAUTIONS: Fetal Toxicity
Please see the following Important Safety Information for BENICAR:
Morbidity in Infants
Children <1 year of age must not receive BENICAR for hypertension. Drugs that act directly on the renin-angiotensin-aldosterone system (RAAS) can have effects on the development of immature kidneys.
Please see the following Important Safety Information for BENICAR, BENICAR HCT, AZOR, and TRIBENZOR:
Contraindication
Do not co-administer aliskiren with BENICAR, BENICAR HCT, AZOR, or TRIBENZOR in patients with diabetes.
Fetal Toxicity
Pregnancy 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 BENICAR, BENICAR HCT, AZOR, or TRIBENZOR as soon as possible.
Hypotension in Volume- or Salt-Depleted Patients
In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (eg, those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with BENICAR, BENICAR HCT, AZOR, or TRIBENZOR. Treatment should start under close medical supervision.
Impaired Renal Function
In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of olmesartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected.
Sprue-like Enteropathy
Severe, chronic diarrhea with substantial weight loss has been reported in patients taking olmesartan months to years after drug initiation. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider discontinuation of BENICAR, BENICAR HCT, AZOR, or TRIBENZOR in cases where no other etiology is identified.
Non-Steroidal Anti-Inflammatory Agents
In patients who are elderly, volume-depleted (including those on diuretics), or with compromised renal function, co-administration of olmesartan medoxomil and NSAIDs, including COX-2 inhibitors, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in these patients. The antihypertensive effect of olmesartan medoxomil may be attenuated by NSAIDs, including COX-2 inhibitors.
Dual Blockade of the Renin-Angiotensin System (RAS)
Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on BENICAR, BENICAR HCT, AZOR, or TRIBENZOR and other agents that affect the RAS.
Avoid use of aliskiren with BENICAR, BENICAR HCT, AZOR, or TRIBENZOR in patients with renal impairment (GFR <60 mL/min).
Concurrent Use with Colesevelam Hydrochloride
Concurrent administration of bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of olmesartan. Consider administering olmesartan at least 4 hours before the colesevelam hydrochloride dose.
Nursing Mothers
Avoid use while nursing; discontinue either nursing or the drug.
Due to the hydrochlorothiazide component, BENICAR HCT and TRIBENZOR have the following Important Safety Information:
Contraindications
BENICAR HCT and TRIBENZOR are contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.
Impaired Renal Function
BENICAR HCT is not recommended in patients with severe renal impairment. Avoid use of TRIBENZOR in patients with severely impaired renal function (creatinine clearance ≤30 mL/min). If progressive renal impairment becomes evident, consider withholding or discontinuing TRIBENZOR.
Thiazides may precipitate azotemia in patients with renal disease. Cumulative effects of the drug may develop in patients with impaired renal function.
Hepatic Impairment
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. Avoid use of TRIBENZOR in patients with severely impaired hepatic function.
Electrolyte and Metabolic Imbalances
Due to the hydrochlorothiazide component, observe patients for clinical signs of fluid or electrolyte imbalance.
Hypersensitivity Reaction
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.
Systemic Lupus Erythematosus
Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.
Acute Myopia and Secondary Angle-Closure Glaucoma
Thiazides 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. Discontinue hydrochlorothiazide as rapidly as possible in these patients. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
Lithium Interaction
Lithium generally should not be given with thiazides.
Fetal/Neonatal Morbidity and Mortality
Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.
Due to the amlodipine component, AZOR and TRIBENZOR have the following Important Safety Information:
Vasodilation
Although vasodilation attributable to amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration. Patients with severe aortic stenosis may be at particular risk.
Increased Angina and/or Myocardial Infarction
Patients, particularly those with severe obstructive coronary artery disease, may develop increased frequency, duration, or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase.
Hepatic Impairment
Since amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t1/2) is 56 hours in patients with severely impaired hepatic function, caution should be exercised when administering AZOR to patients with severe hepatic impairment. Initial therapy with AZOR is not recommended in hepatically impaired patients. Avoid use of TRIBENZOR in patients with severely impaired hepatic function.
Effect of Amlodipine on Simvastatin
Due to increased exposure to simvastatin, if simvastatin is co-administered with amlodipine, do not exceed doses of greater than 20 mg daily of simvastatin.
Geriatric Use
Elderly patients have decreased clearance of amlodipine. Initial therapy with AZOR is not recommended in patients ≥75 years old.
Adverse Reactions
BENICAR/BENICAR HCT
The withdrawal rates due to adverse reactions were similar with BENICAR and BENICAR HCT to placebo: BENICAR (2.4% vs 2.7%); BENICAR HCT (2.0% vs 2.0%).
The incidence of adverse reactions with BENICAR and BENICAR HCT was similar to placebo.
– The only adverse reaction that occurred in >1% of patients treated with BENICAR and more frequently than placebo was dizziness (3% vs 1%)
– Adverse reactions reported in >2% of patients taking BENICAR HCT and more frequently than placebo included nausea (3% vs 0%), hyperuricemia (4% vs 2%), dizziness (9% vs 2%), and upper respiratory tract infection (7% vs 0%)
AZOR
The only adverse reaction that occurred in greater than or equal to 3% of patients treated with AZOR and more frequently than placebo was edema. The placebo-subtracted incidence was 5.7% (5/20 mg), 6.2% (5/40 mg), 13.3% (10/20 mg), and 11.2% (10/40 mg). The edema incidence for placebo was 12.3%.
Adverse reactions seen at lower rates but at about the same or greater incidence as in patients receiving placebo included hypotension, orthostatic hypotension, rash, pruritus, palpitation, urinary frequency, and nocturia.
In individual clinical trials of amlodipine and olmesartan medoxomil, other commonly reported adverse reactions included headache, dizziness, and flushing.
TRIBENZOR
The most frequently reported adverse reaction was dizziness (5.8 to 8.9%). The other most frequent adverse reactions occurring in greater than or equal to 2% of patients treated with TRIBENZOR were peripheral edema (7.7%), headache (6.4%), fatigue (4.2%), nasopharyngitis (3.5%), muscle spasms (3.1%), nausea (3.0%), upper respiratory tract infection (2.8%), diarrhea (2.6%), urinary tract infection (2.4%), and joint swelling (2.1%).
Laboratory Tests
There was a greater decrease in hemoglobin and hematocrit with AZOR compared to either component alone.
Dosage and Administration
No initial dosage adjustments are recommended with BENICAR in elderly or in moderate to marked renal impairment (creatinine clearance <40 mL/min)/hepatic dysfunction.
– In patients with possible depletion of intravascular volume (eg, patients on diuretics, particularly with impaired renal function), BENICAR should be initiated under close medical supervision and consideration given to use of a lower starting dose
BENICAR HCT is not indicated for initial therapy. Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range.
Initial therapy with AZOR is not recommended in patients ≥75 years old or in hepatically impaired patients.
TRIBENZOR is not indicated for initial therapy. Avoid use of TRIBENZOR in patients with severely impaired hepatic function and in patients with severely impaired renal function (creatinine clearance ≤30 mL/min).
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