The purpose of this guidance is to assist sponsors in the clinical development of fixed-combination drug products for the treatment of hypertension. This guidance focuses on development of two-drug combinations of previously approved drugs, although the general approach is readily applicable to three or more drugs in combination. This guidance does not address combinations that include unapproved drug products.
Hypertension is the most common chronic cardiovascular condition dealt with by primary care physicians and other health care practitioners. Hypertension increases the risk of stroke, coronary artery disease, heart failure, atrial fibrillation, and peripheral vascular disease. Effective control of blood pressure has been shown to reduce the rate of these adverse outcomes.
In general, most patients will require more than one drug product to achieve adequate blood pressure control. In the past, the usual approach was to give patients the drug products sequentially, that is, titrate the first drug product to its full dose, then add a second drug product and titrate to its full dose, etc. More recently, physicians commonly initiate treatments with less than full doses of two drug products, with the goal of avoiding side effects but gaining most of the effect of each drug product and gaining an overall effect greater than the single drug products would have at their maximum doses. The American Society of Hypertension and the International Society of Hypertension have jointly recommended initiating treatment with two drug products if a patient’s untreated blood pressure is at least 20/10 millimeters of mercury (mmHg) above the target blood pressure.
In considering fixed-combination drug products, FDA recognizes the interest both in (1) developing combinations of less than full doses of drug products with distinct mechanisms of action (e.g., a diuretic combined with an angiotensin-converting enzyme inhibitor, an angiotensin-receptor blocker, or a beta blocker) that could be used as initial therapy; and (2) providing a range of combinations that allow dose titration to attain adequate blood pressure control.