Hennekens Charles H
Department of Clinical Science and Medical Education and Center of Excellence, Charles E. Schmidt College of Biomedical Science, Florida Atlantic University, Boca Raton, Florida 33434, USA.
Am J Cardiovasc Drugs. 2008;8(3):155-60. doi: 10.2165/00129784-200808030-00002.
The obvious strengths of fixed-dose drug combinations include the potential advantages of increased compliance, convenience, and cost savings. In contrast, potential disadvantages include reduced flexibility in dosing, exposure of some patients to therapies they do not require, and possible increased risks of adverse effects without added benefits. With respect to fixed-dose drug combinations of HMG-CoA reductase inhibitors (statins), the totality of evidence is far less for the non-statin component leading to possible over utilization of two drugs when single-agent efficacy will suffice to maximize the benefit and minimize the risks. The current US FDA policy for fixed-dose drug combinations was established in 1971. The policy states that "two or more drugs may be combined in a single dosage form when each component makes a contribution to the claimed effects and the dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy as defined in the labeling for the drug." The FDA was concerned with several disadvantages associated with fixed-dose combination drugs, including the lack of flexibility in titration, exposure of patients to unnecessary drugs when one component alone would be effective, as well as the increased possibility of adverse reactions without increased efficacy. The FDA has considered novel fixed-dose combination drugs to be composed of component drugs at least one of which has not been previously approved, labeled for an indication that is new to at least one or more of the component drugs, or where no significant evidence exist to support concurrent use of the components in a patient population. Based on the current FDA regulatory approval process for fixed-dose drug combinations with statins, it was possible to gain regulatory approval with intermediate endpoints such as lipids for example niacin/lovastatin and ezetimibe/simvastatin and BP/lipids, for example, amlodipine/atorvastatin. Based on the more stringent criteria of additive benefits on clinical endpoints of myocardial infarction, stroke, and cardiovascular disease death, it was possible to gain regulatory approval for aspirin/pravastatin. In summary, the approvals of several fixed-dose drug combinations with statins have both strengths and limitations. The availability to the healthcare provider of many individual statins with varying potency on lipids as well as several fixed-dose drug combinations reinforces the fact that the final decision should be made on astute and individual clinical judgements based on randomized clinical trial data, guidelines and FDA approvals with evidence to do more good than harm to the patient.
固定剂量复方药物的明显优势包括提高依从性、便利性和节省成本等潜在益处。相比之下，潜在劣势包括给药灵活性降低、一些患者接受了他们不需要的治疗，以及在没有额外益处的情况下不良反应风险可能增加。对于HMG-CoA还原酶抑制剂（他汀类药物）的固定剂量复方药物而言，当单药疗效足以实现利益最大化和风险最小化时，非他汀类成分导致两种药物可能过度使用的证据要少得多。美国食品药品监督管理局（FDA）目前关于固定剂量复方药物的政策制定于1971年。该政策规定：“当每种成分对所宣称的疗效都有贡献，且每种成分的剂量（数量、频率、持续时间）使该复方制剂对标签中定义的需要这种联合治疗的大量患者群体安全有效时，两种或更多药物可制成单一剂型。”FDA关注与固定剂量复方药物相关的几个劣势，包括滴定缺乏灵活性、当单一成分有效时患者接触不必要的药物，以及不良反应可能性增加而疗效未提高。FDA认为新型固定剂量复方药物由至少一种以前未获批准的成分药物组成，或其标签用于至少一种或多种成分药物的新适应症，或在患者群体中没有显著证据支持成分药物联合使用。基于目前FDA对含他汀类药物的固定剂量复方药物的监管审批程序，有可能凭借中间终点指标（如血脂，例如烟酸/洛伐他汀和依折麦布/辛伐他汀）以及血压/血脂（例如氨氯地平/阿托伐他汀）获得监管批准。基于对心肌梗死、中风和心血管疾病死亡等临床终点更严格的相加获益标准，有可能获得阿司匹林/普伐他汀的监管批准。总之，几种含他汀类药物的固定剂量复方药物的批准既有优势也有局限性。医疗保健提供者可获得多种对血脂有不同效力的单一他汀类药物以及几种固定剂量复方药物，这强化了一个事实，即最终决策应基于敏锐的个体临床判断，依据随机临床试验数据、指南以及FDA批准，确保对患者的益处大于危害。
