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Objective: To interrogate the National Veterans Health Administration (VA) database to determine if beta-blocker use at time of initiation of androgen therapy deprivation (ADT) would result in improved oncological outcomes in advanced prostate cancer (PCa).Methods: All men diagnosed with high risk PCa (PSA >20) from 2000-2008 who were on ADT ≥ 6 months were identified. Patients receiving ADT concurrently with primary radiation therapy were excluded. Pharmacy data was interrogated for all beta-blockers, but then focused on the selective beta-1 blocker metoprolol. Cox proportional hazards ratios were calculated for overall survival (OS), PCa specific survival (CSS) and skeletal related events (SREs).Results: In 39,198 patients with high risk PCa on ADT, use of any beta-blocker was not associated with improvement in OS, CSS, or SREs. Further analyses focusing on metoprolol found that 10,224 (31.9%) had used metoprolol while 21,834 had no beta-blocker use. Multivariable analysis with Inverse Propensity Score Weighting, adjusted for factors including PSA, Gleason score, and duration ADT, found that utilization of metoprolol was not associated with improvement in OS (hazard ratio [HR] 0.97, P = .19), CSS (HR 0.94, P = .23) or SREs (HR 0.98, P = .79).Conclusion: In this large cohort, metoprolol use in conjunction with ADT in high risk PCa was not associated with improvement in OS, CSS, or risk of SRE. In contrast to a recent smaller clinical study, our data strongly suggests no cancer specific benefit to beta-blocker use in advanced PCa. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the pharmacokinetics of of a developed metoprolol and a reference standard (Mepressor®). Methods: Metoprolol tartrate-loaded Eudragit® FS microparticles were formulated and compressed into tablets. The tablets were tested for their physicochemical properties according to United States Pharmacopoeia (USP) criteria. In vivo studies of the formulations were carried out in 28 young healthy fasting male volunteers based on a randomized open label 4×4 crossover study design with a washout period of 7 days. Results: In vitro tests showed that the developed and reference standard of metoprolol tablets met compendia (USP) requirements. Zero order release of drug was observed from all the tablets. In vivo data demonstrated that there were significant (p < 0.05) differences in tmax, Cmax, MRT, AUC0-t, and AUC0-&infin; between the reference and test (developed) formulations. However, the 90 % class interval for the mean ratios of the ln-transformed Cmax, AUC0-t and AUC0-α for the reference, T1, T2, and T3 lied in the bioequivalence range (80 to 125 %) indicating bioequivalence between the compared formulations. Conclusion: It can be concluded from this single-dose study that the reference and test (developed) formulations met the predetermined criteria for bioequivalence in young healthy fasting male human subjects as the bioequivalence factor lie in the pre-determined limits for bioequivalence. Thus, the two formulations can be considered bioequivalent. [ABSTRACT FROM AUTHOR]

The article focuses on quality problems involving brand-name drugs and their generic versions and calls for the U.S. Food and Drug Administration (FDA) to deal with such problems through greater transparency. It relates the case of Missouri-based Ethex which is now under court to correct manufacturing and quality-control problems involving its drugs like Metoprolol ER, the generic version of AstraZeneca's brand-name beta-blocker, Toprol XL. According to the author, there are also some brand-name companies that produce generic versions of their own drugs. Ambrose Carrejo of Kaiser Permanente suggests health plans, pharmacy-benefits programs and other companies to do their own research to ensure the quality of products and suppliers.

The article offers information on several medical researches carried out in the U.S. on perioperative medicine. A study on the effect of metoprolol succinate in patients of non-cardiac surgery, conducted by P.J. Devereaux, found that perioperative beta-blockers in high doses increases mortality. Another study shows that preoperative revascularization is not good for patients of vascular surgery. A study also indicates that higher statin dose leads to lower cardiovascular complication rates.

Two beta-blockers are approved for the treatment of heart failure (HF): carvedilol and metoprolol XL Bucindolol, an investigational agent under FDA review for the treatment of HF, is a nonspecific beta-blocker with weak alpha-blocking properties that may or may not possess intrinsic sympathomimetic activity. The largest and most comprehensive clinical trial evaluating the effect of bucindolol on HF outcomes was the Beta-Blocker Evaluation of Survival Trial (BEST). This randomized, placebo-controlled trial was terminated early because of an inability to demonstrate a survival benefit with bucindiol versus placebo. However, subsequent analyses from BEST have demonstrated benefits in discrete subgroups, including a genetically identified subgroup, if approved, bucindiol may become the first genetically targeted medication for the treatment of HF. INSET: Formulary considerations. [ABSTRACT FROM AUTHOR]

Heart failure (HF) guidelines recommend that β blockers be titrated to achieve the target doses shown to be effective in major clinical trials, if tolerated. Little is known, however, regarding the doses of β blockers used in patients with HF in routine clinical practice before, during, and after hospitalization for HF. The Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF) enrolled 5,791 patients admitted with HF in a registry with prespecified 60- to 90-day follow-up at 91 academic and community hospitals throughout the United States. Among 2,373 patients with systolic HF eligible for β blockers at discharge, 1,350 (56.9%) were receiving β-blocker therapy before admission and continued on therapy, and 632 (26.6%) were newly started. The mean total daily dose for β blockers before hospital admission was <1/2 the recommended target dose (carvedilol 21.5 ± 17.8 mg and metoprolol succinate 69.2 ± 51.9 mg), with infrequent up- or down-titration during the HF hospitalization. More than 2/3 of patients had no change in their β-blocker doses in the first 60 to 90 days after hospital discharge. At 60- to 90-day postdischarge follow-up, only 17.5% and 7.9% of patients were being treated with recommended target doses of carvedilol and metoprolol succinate, respectively. In conclusion, these data reveal that the doses of β blockers applied in clinical practice are substantially less that the doses achieved in randomized clinical trials in HF and recommended in national guidelines. In the first 60 to 90 days after hospital discharge, little up-titration in β-blocker dosing occurs. Further efforts are needed to help understand and overcome this β-blocker titration gap. [Copyright &y& Elsevier]

The article focuses on the decision made by the Federal Circuit regarding the In re Metoprolol Succinate Patent Litigation in the U.S. It was found that the decision has expanded its applicability to the generic pharmaceutical companies. The obviousness-type double patenting invalidity defense of the composition of metoprolol succinate is also discussed.

The extent to which subgroup analyses should affect the interpretation and conclusions in a trial report is a contentious matter, and guidelines regarding this issue have been established by the US Food and Drug Administration (FDA) and the EU Committee for Proprietary Medicinal Products (CPMP). ubgroup analyses should be set out in the protocol of clinical trials. The treatment effect itself may vary within a subgroup or covariate. In some cases, interactions are anticipated or are of particular a priori interest; hence a subgroup analysis or a statistical model including interactions is part of the planned analysis. However, subgroup or interaction analyses are often merely exploratory and should be clearly identified as such in the protocol. When exploratory, these analyses should be interpreted cautiously. Market approval of a compound is based on the overall trial results, and, importantly, no drug has so far been approved or not-approved either in the US or in the EU on the basis of subgroup analysis. However, subgroup analysis can influence the approval or can even be required, and therefore it can influence the labelling of the Summary Characteristics of a Product. Two examples in heart failure are given by the Val-HeFT trial comparing valsartan to placebo and the MERIT-HF trial comparing metoprolol to placebo, from which some remarkable regulatory issues arose that were debated by the FDA and CPMP. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

This article focuses on the pharmacodynamics of β-blockers in heart failure. Heart failure is a growing public health problem in the United States, and the approach to the treatment of heart failure has undergone a radical transformation in the past decade. The prevalence of heart failure is currently increasing, largely as a consequence of decreasing mortality from coronary heart disease that allows more patients to progress to heart failure; the aging of the population; and the rising prevalence of diabetes mellitus in older individuals. The concept of heart failure as a disease of progressive left ventricular dysfunction and cardiac pump failure is still an essential clinical model on which are based therapies to relieve symptoms and improve outcomes.

Background: Although prior literature suggests that metoprolol may worsen glucose control compared to carvedilol, whether this has clinical relevance among older adults with diabetes and heart failure (HF) remains an open question., Methods: This was a US retrospective cohort study utilizing data sourced from a 50% national sample of Medicare fee-for-service claims of patients with part D prescription drug coverage (2007-2017). Among patients with diabetes and HF, we identified initiators of metoprolol or carvedilol, which were 1:1 propensity score matched on >90 variables. The primary outcome was initiation of a new oral or injectable antidiabetic medication (proxy for uncontrolled diabetes); secondary outcomes included initiation of insulin and severe hyperglycemic event (composite of emergency room visits or hospitalizations related to hyperglycemia)., Results: Among 24 239 propensity score-matched pairs (mean [SD] age 77.7 [8.0] years; male [39.1%]), there were 8150 (incidence rate per 100 person-years [IR] = 33.5) episodes of antidiabetic medication initiation among metoprolol users (exposure arm) compared to 8576 (IR = 33.4) among carvedilol users (comparator arm) compared to corresponding to an adjusted hazard ratio (aHR) of 0.97 (95% confidence interval [CI]: 0.94, 1.01). Similarly, metoprolol was not associated with a significant increase in the risk of secondary outcomes including insulin initiation: aHR of 0.98 (95% CI: 0.93, 1.04) and severe hyperglycemic events: aHR of 0.98 (95% CI: 0.93, 1.02)., Conclusions: In this large study of older adults with HF and diabetes, initiation of metoprolol compared to carvedilol was not associated with an increase in the risk of clinically relevant hyperglycemia., (© 2021 John Wiley & Sons Ltd.)

Real-world spontaneous adverse event reports and administrative health care data were utilized as one part of a multipronged approach to verify surveillance signals related to generic drug formulations. This study used metoprolol succinate extended release as a historic case example from which to develop an analytic framework. The US Food and Drug Administration Adverse Event Reporting System was utilized for disproportionality analyses and to identify outcomes of interest. Claims data were analyzed for generic uptake, proportion of prescriptions with "dispense as written" orders, time to discontinuation or switching, and relative rates of clinical events. Adverse Event Reporting System data showed that the Medical Dictionary for Regulatory Activities terms for product quality were higher for generic metoprolol cases and that a number of clinical events were increased that could be side effects of high or low variability in drug levels. Compared to amlodipine-benazepril, which also had a first-approved generic at the same time, market share data showed that metoprolol succinate had lower utilization and more prescriptions written as dispense as written. Switching and discontinuation were generally higher for metoprolol users compared to amlodipine-benazepril users. Finally, clinical event rates were generally higher for generic versus brand metoprolol but lower for the same comparison for amlodipine-benazepril users. In the claims-based analyses, the 90-day period immediately after generic entry provided stronger signal capture than using the entire study period. This analytic framework can be implemented to actively monitor new generic formulations for potential bioequivalence failures. Signals from these analyses require confirmation (eg, via pharmacometric analyses) to be informative for regulatory action., (© 2019, The American College of Clinical Pharmacology.)

Background: Shortages of chronic medications are an increasingly common problem, yet little is known about their impact on drug utilization and clinical outcomes. We evaluated the population-level impact of metoprolol extended release shortage that occurred in the United States in 2009 to 2010., Methods and Results: We conducted a population-based, time series analysis of 38 914 patients (mean age, 60 years; 69% men) discharged after hospitalization for myocardial infarction (MI) between January 2006 and November 2012 in a large commercial insurance database. The shortage period was defined as February 2009 to June 2010. Data before September 2008 was defined as preshortage period and data after June 2010 as postshortage period. Outcomes were proportion of patients who filled any long- or short-acting β-blocker within 30 days of discharge, adherence to β-blockers within the first year of therapy among patients who initiated β-blockers, and rates of 1-year rehospitalization for MI or unstable angina. Post-MI statin utilization and adherence were evaluated as control outcomes. During the preshortage period, 70% of patient filled a β-blocker, mean monthly adherence was 76%, and the average monthly rate of rehospitalization was 6.5 events per 100 person-years, as compared with β-blocker use of 62%, average adherence of 70%, and rehospitalization rate of 5.6 events per 100 person-years during the shortage. After accounting for the baseline (preshortage) trends, the shortage was associated with significant monthly reductions in postdischarge β-blocker use (-0.57% of patients [95% CI, -0.90 to -0.24] per month) and an immediate decrease in adherence (-4.58% days covered [95% CI, -6.12 to -3.04]). No negative impact on rates of rehospitalization, post-MI statin utilization, or statin adherence was observed. β-Blocker utilization began to increase after the resolution of the shortage., Conclusions: The nationwide metoprolol extended release shortage in the United States was associated with fewer patients receiving any long- or short-acting β-blocker post-MI and lower adherence to β-blocker therapy for those who did receive it, but did not appear to appreciably affect clinical outcomes at the population level.

Although orthostatic hypotension (OH) is often considered a contraindication to blood pressure (BP) treatment, evidence is lacking. We examined the effect of BP goal or initial medication choice on OH in AASK (African American Study of Kidney Disease and Hypertension), a 2×3 factorial trial. Blacks with chronic kidney disease attributed to hypertension were randomly assigned 1 of 2 BP goals: intensive (mean arterial pressure, ≤92 mm Hg) or standard (mean arterial pressure, 102-107 mm Hg) and 1 of 3 initial medications (ramipril, metoprolol, and amlodipine). Postural changes in systolic BP, diastolic BP, or heart rate (HR) were determined after 2 minutes and 45 seconds of standing. OH was assessed each visit and defined using the consensus definition (drop in systolic BP ≥20 mm Hg or diastolic BP ≥10 mm Hg). Median follow-up was 4 years. Outcomes were congestive heart failure, stroke, nonfatal cardiovascular disease (CVD), fatal CVD, any CVD (composite of preceding events), and all-cause mortality. There were 1094 participants (mean age, 54.5±10.7 years; 38.8% female; OH was assessed at 52 864 visits). Mean seated systolic BP, diastolic BP, and HR were 150.3±23.9 mm Hg, 95.5±14.2 mm Hg, and 72.0±12.6 bpm, respectively. A more intensive BP goal did not alter the distributions of standing BP and was not associated with OH, but metoprolol was associated with systolic OH compared with ramipril (odds ratio, 1.68; 95% CI, 1.15-2.46) and amlodipine (odds ratio, 1.94; 95% CI, 1.09-3.44). Although consensus OH was associated with stroke (HR, 5.01; 95% CI, 1.80-13.92), nonfatal CVD (HR, 2.28; 95% CI, 1.21-4.30), and any CVD event (HR, 2.12; 95% CI, 1.12-3.98), neither BP goal or medication altered this risk. Concerns about causing OH or its CVD consequences should not deter a lower BP goal among adults with chronic kidney disease attributed to hypertension.

Despite the availability of many antihypertensive drug classes, half of patients with hypertension have uncontrolled blood pressure (BP). The authors sought to assess the effect of age on BP response in European American and African American patients with hypertension. Clinic BP from the PEAR2 (Pharmacogenomics Evaluation of Antihypertensive Responses 2) study was used to estimate BP responses from baseline following sequential treatment with metoprolol 100 mg twice daily and chlorthalidone 25 mg daily for 8 to 9 weeks each, with a minimum 4-week washout between treatments. BP responses to both drugs were compared in 159 European Americans and 119 African Americans by age with adjustment for baseline BP and sex. European Americans younger than 50 years responded better to metoprolol than chlorthalidone (diastolic BP: -9.6 ± 8.0 vs -5.9 ± 6.8 mm Hg, adjusted P = .003), whereas patients 50 years and older responded better to chlorthalidone than metoprolol (systolic BP: -18.7 ± 13.8 vs -13.6 ± 14.8 mm Hg, adjusted P = .008). African Americans younger than 50 years responded similarly to both drugs, whereas those 50 years and older responded better to chlorthalidone than metoprolol (-17.0 ± 13.2/-9.6 ± 7.5 vs -7.0 ± 18.6/-6.7 ± 9.3 mm Hg, adjusted P<.0001/.008). Therefore, age should be considered when selecting antihypertensive therapy in European and African American populations with hypertension., (©2017 Wiley Periodicals, Inc.)

The article presents findings on a randomized controlled study which examines the impact of metoprolol for high-risk patients undergoing noncardiac surgery in the U.S. During the trial, high-risk patients over 45 years old were randomly assigned to receive extended-release metoprolol perioperatively. Researchers used several criteria to identity high-risk patients including the one with coronary artery disease, peripheral vascular abnormality and those who are hospitalized for congestive heart failure. Results reveal that patients receiving metoprolol had a lower mortality rate than individuals receiving placebo.

The article cites key research findings from the U.S. in 2007 indicating that the use of the continued-release beta-blocker metoprolol, or Toprol XL, in non-cardiac surgery patients reduced their risk of myocardial infarction but increased their risk of disabling stroke and death. Also cited are the issues' implications for cardiology.

The article announces the market approval issued by the U.S. Food and Drug Administration for metoprolol succinate extended-release/hydrochlorothiazide. The medication is indicated for the clinical management of hypertension. The approval was based on clinical trials which showed the effectiveness of such medication in decreasing sitting diastolic and systolic blood pressure.

The article discusses cases of medication errors in the U.S. A nurse and a pharmacist reminded a prescriber that the intravenous (IV) administration of 50 mg of beta-blocker metoprolol could kill a patient. IV drug dosages are sometimes lower than those for oral forms because IV drugs enter the bloodstream directly. A telephone order to a pharmacy for Omacor was misheard as Amicar. Omacor is use to reduce very high triglyceride levels, while Amicar is use to enhance hemostasis when fibrinolysis contributes to bleeding. Fortunately the patient read the drug information sheet and detected the medication error.

The article reports on the decisions of the U.S. District Court that the two key patents of AstraZeneca PLC angina drug metoprolol succinate are invalid and enforceable. This ruling of the court comes after the pharmaceutical industry has sued several drugmakers for filing Abbreviated New Drug Application for generic versions of the drug. The court considers that the drug are invalid because of double patenting and enforceable due to inequitable conduct.

Objectives: To estimate and compare the risk of emergent bradycardia associated with starting immediate-release (IR) and slow-release (SR) formulations of metoprolol., Design: Retrospective analysis of administrative claims data., Data Source: State of California Medicaid program (Medi-Cal) claims database., Patients: A total of 31,574 adults beginning metoprolol between May 1, 2004, and November 1, 2009, without a pharmacy claim for a β blocker within the previous 6 months of metoprolol initiation; patients with a primary or secondary diagnosis of symptomatic bradycardia, pacemaker, or implantable cardioverter-defibrillator placement before metoprolol initiation were excluded., Measurements and Main Results: The study outcome was the time to first occurrence of emergent bradycardia, measured at an emergency department visit or hospitalization due to diagnosis of symptomatic bradycardia, after metoprolol initiation. We calculated the incidence and compared the risk of emergent bradycardia by using a proportional hazards model that included the metoprolol formulation with adjustment for total daily metoprolol dose and the use of other drugs as time-varying covariates, as well as demographics and comorbidities. Among 31,574 patients starting metoprolol, 18,516 (58.6%) used the IR formulation. The incidence of emergent bradycardia was 19.1/1000 person-years overall but was nearly twice as common in patients using the IR versus the SR formulation (24.1/1000 person-yrs in the IR group versus 12.9/1000 person-yrs in the SR group, unadjusted hazard ratio [HR] 1.81, 95% confidence interval [CI] 1.28-2.56). Adjustment for other drugs also associated with symptomatic bradycardia (cytochrome P450 2D6 inhibitors, class I or III antiarrhythmics, and atrioventricular node-blocking agents), metoprolol dose, and other participant characteristics somewhat attenuated the association (adjusted HR 1.48, 95% CI 1.03-2.13)., Conclusion: The risk of emergent bradycardia associated with metoprolol initiation was higher with the IR formulation than the SR formulation, although the absolute risk was low., (© 2013 Pharmacotherapy Publications, Inc.)