Metoprolol succinate extended release/hydrochlorothiazide combination tablets

Abstract

Lowering elevated blood pressure (BP) with drug therapy reduces the risk for catastrophic fatal and nonfatal cardiovascular events such as stroke and myocardial infarction. Given the heterogeneity of hypertension as a disease, the marked variability in an individual patient's BP response, and low response rates with monotherapy, expert groups such as the Joint National Committee (JNC) emphasize the value of combination antihypertensive regimens, noting that combinations, usually of different classes, have additive antihypertensive effects. Metoprolol succinate extended-release tablet is a beta-1 (cardio-selective) adrenoceptor-blocking agent formulated to provide controlled and predictable release of metoprolol. Hydrochlorothiazide (HCT) is a well-established diuretic and antihypertensive agent, which promotes natruresis by acting on the distal renal tubule. The pharmacokinetics, efficacy, and safety/tolerability of the antihypertensive combination tablet, metoprolol extended release hydrochlorothiazide, essentially reflect the well-described independent characteristics of each of the component agents. Not only is the combination product more effective than monotherapy with the individual components but the combination product allows a low-dose multidrug regimen as an alternative to high-dose monotherapy, thereby, minimizing the likelihood of dose-related side-effects.

Figure 1

Mean metoprolol plasma concentration versus time curve after administration of the fixed combination tablet and the free combination of metoprolol succinate ER (1 × 95 mg) and HCT (1 × 12.5 mg) in a fasting (n = 48) and fed state (fixed; n = 48, free; n = 47): Study D4026C00005.

Figure 2

Mean HCT plasma concentration versus time curve after administration of the fixed combination tablet and the free combination of metoprolol succinate ER (1 × 95 mg) and HCT (1 × 12.5 mg) in a fasting (n = 48) and fed state (fixed; n = 48, free; n = 47): Study D4026C00005.

Figure 3

Dose response surface from polynomial regression of changes from baseline to week 8/LOCF in trough sitting diastolic blood pressure (intent-to-treat population) (ATTACH Trial). Note: Pyramids represent the treatment group mean values. Upward pyramids are above the surface, and downward pyramids are below the surface. Lines connect the pyramids with the corresponding fitted value on the regression surface. Regression equation: DBP: y = −5.34392 −0.06023*Toprol-XL −0.34772*HCT + 0.00015*Toprol-XL² + 0.00703*HCT². Reprinted with permission from Papademetriou V, Hainer JW, Sugg J, et al, and ATTACH Study Group. 2006. Factorial antihypertensive study of an extended-release metoprolol and hydrochlorothiazide combination. Am J Hypertens, 19:1217–25. Copyright © 2006 American Journal of Hypertension, Ltd.

Figure 4

Dose response surface from polynomial regression of changes from baseline to Week 8/LOCF in trough sitting diastolic blood pressure (intent-to-treat population) (ATTACH Trial). Note: Pyramids represent the treatment group mean values. Upward pyramids are above the surface, and downward pyramids are below the surface. Lines connect the pyramids with the corresponding fitted value on the regression surface. Regression equation: SBP: y = −4.20691 −0.08645*Toprol-XL −0.63844*HCT + 0.00026*Toprol-XL² + 0.01324*HCT². Reprinted with permission from Papademetriou V, Hainer JW, Sugg J, et al, and ATTACH Study Group. 2006. Factorial antihypertensive study of an extended-release metoprolol and hydrochlorothiazide combination. Am J Hypertens, 19:1217–25. Copyright © 2006 American Journal of Hypertension, Ltd.

Figure 5

Potassium values: mean change from baseline to Visit 8 (safety population) (ATTACH Trial).