Metoprolol succinate extended release/hydrochlorothiazide combination tablets

Figures & data

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).

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.

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.

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).

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.

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.

Table 1 Placebo-corrected predicted valuesafor change from baseline in SBP/DBP

TOPROL-XL^® dosage
HCT dosage	0 mg SBP/DBP	25 mg SBP/DBP	50 mg SBP/DBP	100 mg SBP/DBP	200 mg SBP/DBP
0 mg	0/0	−2.0/−1.4	−3.7/−2.6	−6.1/−4.5	−7.0/−6.1
6.25 mg	−3.5/−1.9	−5.5/−3.3	−7.2/−4.5	−9.6/−6.4	−10.5/−8.0b
12.5 mg	−5.9/−3.3	−7.9/−4.7	−9.6/−5.9	−12.0/−7.8	−12.9/−9.3
25 mg	−7.7/−4.3	−9.7/−5.7b	−11.4/−6.9b	−13.8/−8.8	−14.7/−10.4

a Predicted values from a least-squares quadratic regression model.

b These doses were not studied.

Abbreviations: HCT, hydrochlorothiazide; SBP/DBP, systolic blood pressure/diastolic blood pressure.

Table 2 Clinical studies of metoprolol/hydrochlorothiazide combination tablets

Reference	Study design/population	Number of patients	Principal findings
Hildemann et al 2002	Prospective, open-label, 8-week, observational study/hypertensive adults	14,964	Mean BP reduction from baseline to week 8 was 24.5/13.6 mmHg. The reduction in BP was consistent whether or not patients were receiving other antihypertensive drugs, which included ACEIs, aldosterone antagonists, alpha-blockers, other beta-blockers, calcium antagonists, and other diuretics. Tolerability was excellent.
Geisler 1981	Open-label study in patients treated with metoprolol/HCT 100/12.5 mg, 1–2 tablets daily for 6 weeks/hypertensive patients.	12,336	BP was significantly reduced across all age groups in this large patient population. SBP decreased by 29–30 mmHg and DBP by 13–15 mmHg after 6 weeks treatment. The incidence of AEs was low and similar in all age groups.
Goodfellow and Westberg 1981	Post-marketing surveillance for 3 months of hypertensive patients in general practice. Treatment: metoprolol/HCT 100/12.5 mg, 1–2 tablets daily	1,446	After 3 months treatment mean BP was reduced from 181/108 mmHg to 153/91mmHg. Previously untreated patients showed a more marked reduction in BP (33/20 mmHg) than patients previously treated (23/15 mmHg). All age groups showed a similar reduction in SBP and DBP although older patients had a higher BP on entry. The incidence of AEs was similar in all age groups. Treatment was withdrawn in 117 patients due to AEs. The rate of withdrawal was somewhat higher in patients aged over 65 years. Conclusion: The fixed dose combination of HCT and metoprolol constitutes a simple once daily regimen, which is effective, produces few side-effects and is well tolerated by patients of all ages.
LaPalio et al 1992	Prospective, open-label surveillance study. Multicenter outpatient. Patients with mild to moderate hypertension aged 50–75 years. Patients were treated with 100 mg of metoprolol once daily for 4 weeks. If BP was controlled, therapy continued. If not controlled, 25 mg of HCT was added.	21,692 (approx. 6000 on metoprolol /HCT	After 4 weeks of therapy, mean SBP and DBP decreased from 162/95 to 148/87 mmHg (p < 0.001). 58% of the patients had satisfactory BP control. At 4 weeks 28% were requested to add HCT 25 mg to metoprolol 100 mg. At the end of 8 weeks, mean SBP and DBP decreased to 143/84 mmHg. BP response was similar in all age groups. At the termination of the study, 50% of the patients were continued on monotherapy, and 27% were continued on combined therapy. Overall, there was <5% incidence of medical problems, tolerability was good-excellent for 94% of the patients. Conclusion: Metoprolol administered as monotherapy or in combination with HCT was effective in normalizing BP in a majority of elderly hypertensive patients. Both regimens were well tolerated.
Wikstrand et al 1986	Randomized, double-blind parallel group study of patients with untreated essential hypertension. Patients were treated with either metoprolol 100 mg or HCT 25 mg for 4 weeks. Patients with controlled DBP were treated for a further 4 weeks at the same doses. If DBP remained >95 mmHg then HCT 12.5 mg was added to metoprolol and HCT dose was doubled to 50 mg for another 4 weeks.	562 Aged 60–75 years	A significant reduction in BP was recorded on both treatment regimens. Both treatment regimens were well tolerated. The dropout rate due to serious side-effects was similar in the 2 groups, 2% in the metoprolol group and 3% in the HCT group. Conclusion: Beginning treatment with metoprolol 100 mg bd and adding HCT 12.5 mg in patients not responding to metoprolol alone appears to be effective and safe in elderly hypertensive patients.

Abbreviations: ACEI, angiotensin converting enzyme inhibitor; BP, blood pressure; HCT, hydrochlorothiazide; SBP, systolic blood pressure; DBP, diastolic blood pressure; AE adverse event.

Table 3 Clinical outcome trials in support of safety and tolerability with combination treatment

Reference	Study design	Population and number of patients	Principal findings
Dahlof et al 1991	This was a double-blind, multicenter, randomized study to compare antihypertensive treatment with placebo. Initial drug therapy consisted of a once-daily diuretic (25 mg HCT and 2.5 mg of amiloride), a beta-blocker (50 mg of atenolol, 100 mg of metoprolol succinate ER, or 5 mg of pindolol), or matching placebo after a 1- to 6-month washout period. Active treatment drugs could be combined if BP exceeded 160/95 mmHg after 2 months. For the placebo group, antihypertensive therapy could be added if the BP exceeded 230/120 mmHg. The primary outcome was MI, stroke, and other CV death.	Patients had a SBP between 180 and 230 mmHg and a DBP of 90 mmHg or higher, OR a DBP of 105–129 mmHg. 1627 patients aged 70–84 years	Average follow-up time was 25 months. At 12 months, the placebo-corrected changes in BP were greatest when the beta-blocker was combined with a diuretic. Less than 1/3 of the active treatment patients were on monotherapy. Treatment reduced total mortality by 43% (p = 0.0079) and strokes by 47% (p = 0.0081). The rate of all MIs was not reduced over this short duration of follow-up.
Hansson et al 1999	This was a double-blind, multicenter, randomized study to compare older antihypertensive agents with newer agents. 1st group) Conventional treatment group, which consisted of once-daily diuretic, beta-blocker, or both: 50 mg of atenolol, 100 mg metoprolol succinate ER, 5 mg of pindolol, or the combination of 25 mg HCT and 2.5 mg of amiloride, which could be combined with the beta-blocker monotherapy if the target BP of 160/95 was not achieved. 2nd group) To achieve treatment goals, ACEI was supplemented with HCT. 3rd group) The calcium antagonists felodipine or isradipine were augmented with any of the above beta-blockers to achieve the target BP. The primary combined endpoint was fatal stroke, fatal MI, and other fatal CV diseases.	Patients had a SBP of 180 mmHg or higher, DBP was 105 mmHg or higher, or both. Patients with isolated systolic hypertension were also included. A total of 6614 patients aged 70–84 years - 2213 patients received conventional treatment - 2205 received ACEI - 2196 received a calcium antagonists 33,249 patient-years were accumulated	After 24 months, there was no difference in reduction of BP among the 3 treatment groups. After 60.3 months, there was no difference among the 3 groups for the primary endpoint of CV death. Major morbidity events were similar among the groups. The primary endpoint did not differ significantly among the 719 diabetic elderly patients. Combination therapy was used for 46% of patients.

Abbreviations: ACEI, angiotensin converting enzyme inhibitor; BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; HCT, hydrochlorothiazide; ER, extended release; CV, cardiovascular; MI, myocardial infarction.

Figure 5 Potassium values: mean change from baseline to Visit 8 (safety population) (ATTACH Trial).

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DahlofBLindholmLHHanssonLMorbidity and mortality in the Swedish trial in old patients with hypertension (STOP-hypertension)Lancet1991338128151682683

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