|
|
| Line 1: |
Line 1: |
| __NOTOC__
| | #REDIRECT [[Metoprolol succinate#Clinical Studies]] |
| {{Metoprolol}}
| |
| {{CMG}}
| |
| | |
| In five controlled studies in normal healthy subjects, the same daily doses of TOPROL-XL and immediate-release metoprolol were compared in terms of the extent and duration of [[beta1]]-blockade produced. Both [[formulation]]s were given in a dose range equivalent to 100-400 mg of immediate-release metoprolol per day. In these studies, TOPROL-XL was administered once a day and immediate-release metoprolol was administered once to four times a day. A sixth controlled study compared the [[beta1]]-blocking effects of a 50 mg daily dose of the two [[formulation]]s. In each study, [[beta1]]-blockade was expressed as the percent change from baseline in [[exercise]] [[heart rate]] following standardized submaximal exercise tolerance tests at steady state. TOPROL-XL administered once a day, and immediate-release metoprolol administered once to four times a day, provided comparable total [[beta1]]-blockade over 24 hours (area under the [[beta1]]-blockade versus time curve) in the dose range 100-400 mg. At a dosage of 50 mg once daily, TOPROL-XL produced significantly higher total [[beta1]]-blockade over 24 hours than immediate-release metoprolol. For TOPROL-XL, the percent reduction in exercise [[heart rate]] was relatively stable throughout the entire dosage interval and the level of beta1-blockade increased with increasing doses from 50 to 300 mg daily. The effects at peak/trough (ie, at 24-hours post-dosing) were: 14/9, 16/10, 24/14, 27/22 and 27/20% reduction in exercise [[heart rate]] for doses of 50, 100, 200, 300 and 400 mg TOPROL-XL once a day, respectively. In contrast to TOPROL-XL, immediate-release metoprolol given at a dose of 50-100 mg once a day produced a significantly larger peak effect on [[exercise]] [[tachycardia]], but the effect was not evident at 24 hours. To match the peak to trough ratio obtained with TOPROL-XL over the dosing range of 200 to 400 mg, a t.i.d. to q.i.d. divided dosing regimen was required for immediate-release metoprolol. A controlled cross-over study in [[heart failure]] patients compared the plasma concentrations and [[beta1]]-blocking effects of 50 mg immediate-release metoprolol administered t.i.d., 100 mg and 200 mg TOPROL-XL once daily. A 50 mg dose of immediate-release metoprolol t.i.d. produced a peak plasma level of metoprolol similar to the peak level observed with 200 mg of TOPROL-XL. A 200 mg dose of TOPROL-XL produced a larger effect on suppression of exercise-induced and [[Holter monitor|Holter-monitored]] [[heart rate]] over 24 hours compared to 50 mg t.i.d. of immediate-release metoprolol.
| |
| | |
| In a double-blind study, 1092 patients with mild-to-moderate [[hypertension]] were randomized to once daily TOPROL-XL (25, 100, or 400 mg), PLENDIL® ([[felodipine]] extended-release tablets), the combination, or placebo. After 9 weeks, TOPROL-XL alone decreased sitting [[blood pressure]] by 6-8/4-7 mmHg (placebo-corrected change from baseline) at 24 hours post-dose. The combination of TOPROL-XL with PLENDIL has greater effects on [[blood pressure]].
| |
| | |
| In controlled clinical studies, an immediate-release dosage form of metoprolol was an effective [[antihypertensive agent]] when used alone or as concomitant therapy with [[thiazide]]-type [[diuretic]]s at dosages of 100-450 mg daily. TOPROL-XL, in dosages of 100 to 400 mg once daily, produces similar [[beta1|β1]]-blockade as conventional metoprolol tablets administered two to four times daily. In addition, TOPROL-XL administered at a dose of 50 mg once daily lowered [[blood pressure]] 24-hours post-dosing in [[placebo]]-controlled studies. In controlled, comparative, clinical studies, immediate-release metoprolol appeared comparable as an [[antihypertensive agent]] to [[propranolol]], [[methyldopa]], and [[thiazide]]-type [[diuretic]]s, and affected both supine and standing [[blood pressure]]. Because of variable plasma levels attained with a given dose and lack of a consistent relationship of [[antihypertensive]] activity to drug plasma concentration, selection of proper dosage requires individual titration.
| |
| | |
| ====Angina Pectoris====
| |
| | |
| By blocking [[catecholamine]]-induced increases in [[heart rate]], in velocity and extent of myocardial contraction, and in [[blood pressure]], metoprolol reduces the oxygen requirements of the [[heart]] at any given level of effort, thus making it useful in the long-term management of [[angina pectoris]].
| |
| | |
| In controlled clinical trials, an immediate-release [[formulation]] of metoprolol has been shown to be an effective antianginal agent, reducing the number of [[angina]] attacks and increasing [[exercise]] tolerance. The dosage used in these studies ranged from 100 to 400 mg daily. TOPROL-XL, in dosages of 100 to 400 mg once daily, has been shown to possess [[beta-blockade]] similar to conventional metoprolol tablets administered two to four times daily.
| |
| | |
| ====Heart Failure====
| |
| | |
| MERIT-HF was a double-blind, [[placebo]]-controlled study of TOPROL-XL conducted in 14 countries including the US. It randomized 3991 patients (1990 to TOPROL-XL) with [[ejection fraction]] ≤0.40 and [[NYHA]] Class II-IV [[heart failure]] attributable to [[ischemia]], [[hypertension]], or [[cardiomyopathy]]. The protocol excluded patients with contraindications to [[beta-blocker]] use, those expected to undergo heart surgery, and those within 28 days of [[myocardial infarction]] or [[unstable angina]]. The primary endpoints of the trial were (1) all-cause mortality plus all-cause hospitalization (time to first event) and (2) all-cause mortality. Patients were stabilized on optimal concomitant therapy for [[heart failure]], including [[diuretic]]s, [[ACE inhibitor]]s, [[cardiac glycoside]]s, and [[nitrate]]s. At randomization, 41% of patients were [[NYHA]] Class II; 55% [[NYHA]] Class III; 65% of patients had [[heart failure]] attributed to [[ischemic heart disease]]; 44% had a history of [[hypertension]]; 25% had [[diabetes mellitus]]; 48% had a history of [[myocardial infarction]]. Among patients in the trial, 90% were on [[diuretic]]s, 89% were on [[ACE inhibitor]]s, 64% were on [[digitalis]], 27% were on a lipid-lowering agent, 37% were on an oral [[anticoagulant]], and the mean [[ejection fraction]] was 0.28. The mean duration of follow-up was one year. At the end of the study, the mean daily dose of TOPROL-XL was 159 mg.
| |
| | |
| The trial was terminated early for a statistically significant reduction in all-cause [[mortality]] (34%, nominal p= 0.00009). The risk of all-cause [[mortality]] plus all-cause hospitalization was reduced by 19% (p= 0.00012). The trial also showed improvements in [[heart failure]]-related [[mortality]] and [[heart failure]]-related hospitalizations, and [[NYHA]] functional class.
| |
| | |
| The table below shows the principal results for the overall study population. The figure below illustrates principal results for a wide variety of subgroup comparisons, including US vs. non-US populations (the latter of which was not pre-specified). The combined endpoints of all-cause [[mortality]] plus all-cause hospitalization and of [[mortality]] plus [[heart failure]] hospitalization showed consistent effects in the overall study population and the subgroups, including women and the US population. However, in the US subgroup (n=1071) and women (n=898), overall [[mortality]] and [[cardiovascular]] [[mortality]] appeared less affected. Analyses of female and US patients were carried out because they each represented about 25% of the overall population. Nonetheless, subgroup analyses can be difficult to interpret and it is not known whether these represent true differences or chance effects.<ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = TOPROL XL (METOPROLOL SUCCINATE) TABLET, EXTENDED RELEASE [BRYANT RANCH PREPACK] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=01038198-b4f0-41f3-9a9c-5c84e5a0d3b9 | publisher = | date = | accessdate = }}</ref>
| |
| | |
| {|
| |
| | [[File:Toprol04a.png|600px|thumb]]
| |
| |}
| |
| {|
| |
| | [[File:Toprol04b.png|600px|thumb]]
| |
| |}
| |
| | |
| ==References==
| |
| | |
| {{Reflist}}
| |
| | |
| {{FDA}}
| |
| | |
| [[Category:Antianginals]]
| |
| [[Category:Antiarrhythmic agents]]
| |
| [[Category:Antihypertensive agents]]
| |
| [[Category:Antimigraine drugs]]
| |
| [[Category:Beta blockers]]
| |
| [[Category:Cardiovascular Drugs]]
| |