Fixed-dose combination therapy with statins: strengths, limitations, and clinical and regulatory considerations

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.