Blood Pressure
Conditions
Keywords
pharmacokinetics, pharmacodynamics, pharmacogenetics
Brief summary
Recently, the quality of generic metoprolol extended-release (ER) products has been called into question with reports of inconsistent effects when switching from the brand name product to a generic formulation. Problems with how the body processes these drugs could have serious and widespread consequences given the high frequency of metoprolol ER use in the management of various cardiovascular disorders, including high blood pressure, coronary heart disease, heart failure, and cardiac arrhythmias. Investigators hypothesize that both product- and subject-specific factors lead to variability in the way the body breaks down the drug (pharmacokinetics) and clinical response to generic versus name brand metoprolol ER formulations. Investigators will study the brand name and generic metoprolol ER formulations in subjects with high blood pressure to compare the pharmacokinetics and cardiovascular responses among equivalent labeled doses of each product (brand name and two approved generics). The study objective is to provide information on how the body breaks down generic and brand name metoprolol ER products (pharmacokinetics) and how the body responds to generic and brand name metoprolol ER products (pharmacodynamics) to better understand if generic metoprolol ER products are as good as the brand name product.
Detailed description
As a participant in this study the following will happen. A study nurse will draw 3 teaspoonfuls (15 ml) of blood. Two teaspoons (10ml) will be drawn for basic blood work and one teaspoon (5ml) will be drawn for genotyping. The study physician will perform a physical exam and discuss all medical history. The study will be randomized to one of two groups like flipping a coin. * Study Sequence A- start with brand name metoprolol ER, switch to Generic B metoprolol, switch back to brand name metoprolol ER, then switch to Generic A metoprolol * Study Sequence B- start with brand name metoprolol ER, switch to Generic A metoprolol, switch back to brand name metoprolol ER, then switch to Generic B metoprolol. Each study sequence will consist of treatment with brand name metoprolol ER for 2 periods, treatment with Generic A metoprolol ER for one period, and treatment with Generic B metoprolol ER for one period. The generic drug periods will be in a different order for each study group. During the times the switch will take place the following tests will be performed: 24-hour pharmacokinetic parameter assessment, 24-hour heart rate monitoring, 24-hour blood pressure monitoring, 24-hour holter monitoring, exercise treadmill to induce heart rate, and a 24-hour gastric potential hydrogen (pH) monitoring via a wireless capsule.
Interventions
DRUGbrand name metoprolol ER
This medication will be taken for 7 to 28 days
DRUGGeneric A
This medication will be taken for 7 days
DRUGGeneric B
This medication will be taken for 7 days
Sponsors
Food and Drug Administration (FDA)
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
* Subjects will be targeted for enrollment based on current treatment of their hypertension with a beta-blocker or known tolerability to a beta-blocker based on their previous participation in the Pharmacogenomic Evaluation of Antihypertensive Responses studies (PEAR-1 and PEAR-2). If necessary to meet enrollment targets, additional patients will be recruited from the existing patient population in the University of Florida Health Family Medicine clinic or through other means.
Exclusion criteria
* Documented secondary forms of hypertension * Known cardiovascular disease (including history of angina pectoris, myocardial infarction, coronary revascularization procedure, heart failure, or presence of a cardiac pacemaker) * Known cerebrovascular disease (including stroke and TIA) * Known peripheral vascular disease * Diabetes mellitus (Type 1 or 2) (defined as a diabetes diagnosis in the medical record or fasting blood glucose greater than or equal to 126 mg per dl or nonfasting blood glucose greater than or equal to 200 mg per dl on screening laboratories) * Systolic blood pressure (SBP) greater than180 mm Hg on screening visit * Heart rate less than 55 bpm on screening visit (in the absence of treatment with a beta-blocker) * Renal insufficiency (serum creatinine greater than 1.5 in men or greater than 1.4 in women on screening laboratories) * Liver enzymes (ALT and or AST) greater than 3 times the upper limit of normal on screening laboratories. * Known Raynaud's phenomenon * Known asthma or chronic obstructive pulmonary disease * Pregnancy or lactation * Gastric bezoar * Swallowing disorders * Strictures * Fistulas * GI obstruction * Severe dysphagia * Crohn's disease * Diverticulitis * Any implantable electromedical device * Use of non-dihydropyridine calcium channel blockers (diltiazem or verapamil) * Use of digoxin to avoid additive effects on heart rate
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration Versus Time Curve (AUC) | 0.0, 0.30, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 16.0, 20.0, 24.0 hours post dose | The AUC of Brand name metoprolol ER will be compared against each generic for determination of bioequivalence. The mean and standard deviation (SD) values of AUC are entered separately for the 50mg, 100mg and 150mg doses. Results are reported for brand name metoprolol ER, Generic B and Generic A. |
| Peak Plasma Concentration (Cmax) of Metoprolol Succinate | 0.0, 0.30, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 16.0, 20.0, 24.0 hours post dose | The Peak Plasma Concentration (Cmax) of Brand name metoprolol ER will be compared against each generic for determination of bioequivalence. The mean and SD values of Cmax are entered separately for the 50mg, 100mg and 150mg doses. Results are reported for brand name metoprolol ER, Generic B and Generic A. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Heart Rate Variability (HRV) Response to Brand Name Metoprolol ER Versus Each Generic Formulation of Metoprolol Succinate. | Heart rate variability (Low-to-High Frequency Ratio) over each quartile of 6 hours in the 24-hr period | 24-h digital heart rate monitor analyses were obtained after Phase 1 (brand name metoprolol ER ), Phase 2 (Generic B or Generic A), and Phase 4 (Generic A or Generic B). Data were analyzed by quartiles. One 5-minute epoch from each hour of each quartile was selected based on absence of a significant number of ectopic beats and artifact from which spectral measures were calculated: high-frequency variability (measure of parasympathetic activity), low-frequency variability (measure of sympathetic activity). The ratio of low-to-high frequency variability was calculated for each quartile. The averages of values obtained for each hour of each quartile constituted the final quartile measures that were used for analysis. The low to high frequency ratio obtained for each quartile represents the balance between sympathetic and parasympathetic nervous system activity and was the primary variable for heart rate variability analysis. |
| Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | Average value over each quartile of 6 hours in the 24-hr period | 24-hr ambulatory blood pressure (BP) recordings taken 4 times per hour (every 15 minutes) between 6AM and 11PM and 2 times per hour (every 30 minutes) 11PM and 6AM were obtained after Phase 1 (Brand name metoprolol ER), Phase 2 (Generic B or Generic A), and Phase 4 (Generic A or Generic B). |
| Heart Rate (HR) Response Compared Between Brand Name Metoprolol ER and Each Generic (Generic B, Generic A) Formulation of Metoprolol Succinate | Average value over each quartile of 6 hours in the 24-hr period | 24-h ambulatory heart rate recordings taken 4 times per hour (every 15 minutes) between 6AM and 11PM and 2 times per hour (every 30 minutes) 11PM and 6AM were obtained after Phase 1 (brand name metoprolol ER), Phase 2 (Generic B or Generic A), and Phase 4 (Generic A or Generic B) |
Countries
United States
Participant flow
Pre-assignment details
61 participants were consented with 10 participants as screen fails, 2 declining to further participate, and 1 unable to fit standard monitoring equipment.
Participants by arm
| Arm | Count |
|---|---|
| Sequence A: Brand Name Metoprolol ER and Generic B This group will start with the brand name metoprolol ER for 7 to 28 days, and then switch to Generic B metoprolol for 7 days.
Brand name metoprolol ER: This medication will be taken for 7 to 28 days
Generic B metoprolol: This medication will be taken for 7 days
Generic A metoprolol: This medication will be taken for 7 days | 18 |
| Sequence B: Brand Name Metoprolol ER and Generic A This group will start with the brand name metoprolol ER for 7 to 28 days, and then switch to Generic A metoprolol for 7 days.
Brand name metoprolol ER: This medication will be taken for 7 to 28 days
Generic A metoprolol: This medication will be taken for 7 days
Generic B metoprolol: This medication will be taken for 7 days | 18 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Phase 1 Brand Name Metoprolol ER | Lost to Follow-up | 1 | 1 |
| Phase 1 Brand Name Metoprolol ER | Physician Decision | 1 | 0 |
| Phase 1 Brand Name Metoprolol ER | Withdrawal by Subject | 2 | 3 |
| Phase 2 1st Generic Administered | Physician Decision | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Sequence B: Brand Name Metoprolol ER and Generic A | Sequence A: Brand Name Metoprolol ER and Generic B |
|---|---|---|---|
| Age, Continuous | 53 years STANDARD_DEVIATION 12 | 51 years STANDARD_DEVIATION 12 | 55 years STANDARD_DEVIATION 11 |
| BMI | 30 kg/m^2 STANDARD_DEVIATION 5 | 31 kg/m^2 STANDARD_DEVIATION 5 | 30 kg/m^2 STANDARD_DEVIATION 4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 32 Participants | 16 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Height | 171 cm STANDARD_DEVIATION 11 | 172 cm STANDARD_DEVIATION 12 | 169 cm STANDARD_DEVIATION 10 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 7 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 23 Participants | 10 Participants | 13 Participants |
| Region of Enrollment United States | 36 Participants | 18 Participants | 18 Participants |
| Sex: Female, Male Female | 17 Participants | 8 Participants | 9 Participants |
| Sex: Female, Male Male | 19 Participants | 10 Participants | 9 Participants |
| Weight | 89 kg STANDARD_DEVIATION 20 | 93 kg STANDARD_DEVIATION 23 | 85 kg STANDARD_DEVIATION 15 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 48 | 0 / 38 | 0 / 40 |
| other Total, other adverse events | 33 / 48 | 21 / 38 | 16 / 40 |
| serious Total, serious adverse events | 1 / 48 | 0 / 38 | 0 / 40 |
Outcome results
Primary
Area Under the Plasma Concentration Versus Time Curve (AUC)
The AUC of Brand name metoprolol ER will be compared against each generic for determination of bioequivalence. The mean and standard deviation (SD) values of AUC are entered separately for the 50mg, 100mg and 150mg doses. Results are reported for brand name metoprolol ER, Generic B and Generic A.
Time frame: 0.0, 0.30, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 16.0, 20.0, 24.0 hours post dose
Population: This is a 2-way crossover analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Brand Name Metoprolol ER | Area Under the Plasma Concentration Versus Time Curve (AUC) | 100mg | 1584.4 ng.hr/ml | Standard Deviation 671.1 |
| Brand Name Metoprolol ER | Area Under the Plasma Concentration Versus Time Curve (AUC) | 50mg | 645.5 ng.hr/ml | Standard Deviation 461.4 |
| Brand Name Metoprolol ER | Area Under the Plasma Concentration Versus Time Curve (AUC) | 150mg | 12176.1 ng.hr/ml | Standard Deviation 7686.6 |
| Generic B | Area Under the Plasma Concentration Versus Time Curve (AUC) | 100mg | 1446.8 ng.hr/ml | Standard Deviation 604.3 |
| Generic B | Area Under the Plasma Concentration Versus Time Curve (AUC) | 50mg | 633.0 ng.hr/ml | Standard Deviation 523.2 |
| Generic B | Area Under the Plasma Concentration Versus Time Curve (AUC) | 150mg | 12790.2 ng.hr/ml | Standard Deviation 0 |
| Generic A | Area Under the Plasma Concentration Versus Time Curve (AUC) | 50mg | 654.0 ng.hr/ml | Standard Deviation 446 |
| Generic A | Area Under the Plasma Concentration Versus Time Curve (AUC) | 150mg | 9926.6 ng.hr/ml | Standard Deviation 4383.9 |
| Generic A | Area Under the Plasma Concentration Versus Time Curve (AUC) | 100mg | 1492.3 ng.hr/ml | Standard Deviation 393.3 |
p-value: 0.395% CI: [-41.1, 131.2]t-test, 2 sided
90% CI: [0.76, 0.95]
p-value: 0.895% CI: [-60, 74.3]t-test, 2 sided
90% CI: [0.86, 1.01]
Primary
Peak Plasma Concentration (Cmax) of Metoprolol Succinate
The Peak Plasma Concentration (Cmax) of Brand name metoprolol ER will be compared against each generic for determination of bioequivalence. The mean and SD values of Cmax are entered separately for the 50mg, 100mg and 150mg doses. Results are reported for brand name metoprolol ER, Generic B and Generic A.
Time frame: 0.0, 0.30, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12.0, 16.0, 20.0, 24.0 hours post dose
Population: A two-way cross over study in which patients are administered brand name metoprolol ER and Generic B or Generic A
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Brand Name Metoprolol ER | Peak Plasma Concentration (Cmax) of Metoprolol Succinate | 150mg | 653.3 ng/mL | Standard Deviation 399.8 |
| Brand Name Metoprolol ER | Peak Plasma Concentration (Cmax) of Metoprolol Succinate | 50mg | 36.6 ng/mL | Standard Deviation 24 |
| Brand Name Metoprolol ER | Peak Plasma Concentration (Cmax) of Metoprolol Succinate | 100mg | 87.8 ng/mL | Standard Deviation 33.3 |
| Generic B | Peak Plasma Concentration (Cmax) of Metoprolol Succinate | 150mg | 613.8 ng/mL | Standard Deviation 87.1 |
| Generic B | Peak Plasma Concentration (Cmax) of Metoprolol Succinate | 50mg | 35.0 ng/mL | Standard Deviation 26.9 |
| Generic B | Peak Plasma Concentration (Cmax) of Metoprolol Succinate | 100mg | 76.5 ng/mL | Standard Deviation 31.3 |
| Generic A | Peak Plasma Concentration (Cmax) of Metoprolol Succinate | 150mg | 477.0 ng/mL | Standard Deviation 193.7 |
| Generic A | Peak Plasma Concentration (Cmax) of Metoprolol Succinate | 50mg | 39.9 ng/mL | Standard Deviation 22.9 |
| Generic A | Peak Plasma Concentration (Cmax) of Metoprolol Succinate | 100mg | 83.0 ng/mL | Standard Deviation 20.9 |
p-value: 0.295% CI: [-1.5, 6.6]t-test, 2 sided
90% CI: [0.79, 0.95]
p-value: 0.395% CI: [-7.3, 2.3]t-test, 2 sided
90% CI: [1.02, 1.23]
Secondary
Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A)
24-hr ambulatory blood pressure (BP) recordings taken 4 times per hour (every 15 minutes) between 6AM and 11PM and 2 times per hour (every 30 minutes) 11PM and 6AM were obtained after Phase 1 (Brand name metoprolol ER), Phase 2 (Generic B or Generic A), and Phase 4 (Generic A or Generic B).
Time frame: Average value over each quartile of 6 hours in the 24-hr period
Population: The analysis aimed to compare mean BP values in Hg mm between the brand name and each of the generic (Generic B or Generic A) formulation of metoprolol succinate. Patients were included in the analysis if they took brand name metoprolol ER and at least one generic.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Brand Name Metoprolol ER | Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | Systolic Blood Pressure: quartile 1 | 132.8 mm Hg | Standard Deviation 14.1 |
| Brand Name Metoprolol ER | Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | Systolic Blood Pressure: quartile 2 | 134.1 mm Hg | Standard Deviation 16 |
| Brand Name Metoprolol ER | Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | Systolic Blood Pressure: quartile 3 | 124.1 mm Hg | Standard Deviation 17.2 |
| Brand Name Metoprolol ER | Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | Systolic Blood Pressure: quartile 4 | 129.3 mm Hg | Standard Deviation 16.6 |
| Brand Name Metoprolol ER | Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | Diastolic Blood Pressure: quartile 1 | 80.8 mm Hg | Standard Deviation 10.5 |
| Brand Name Metoprolol ER | Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | Diastolic Blood Pressure: quartile 2 | 80.8 mm Hg | Standard Deviation 11.6 |
| Brand Name Metoprolol ER | Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | Diastolic Blood Pressure: quartile 3 | 75.4 mm Hg | Standard Deviation 13.2 |
| Brand Name Metoprolol ER | Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | Diastolic Blood Pressure: quartile 4 | 79.2 mm Hg | Standard Deviation 10.4 |
| Generic B | Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | Systolic Blood Pressure: quartile 3 | 121.0 mm Hg | Standard Deviation 16.3 |
| Generic B | Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | Diastolic Blood Pressure: quartile 3 | 73.2 mm Hg | Standard Deviation 11.4 |
| Generic B | Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | Systolic Blood Pressure: quartile 4 | 127.7 mm Hg | Standard Deviation 17 |
| Generic B | Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | Diastolic Blood Pressure: quartile 1 | 79.3 mm Hg | Standard Deviation 10.2 |
| Generic B | Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | Diastolic Blood Pressure: quartile 2 | 80.3 mm Hg | Standard Deviation 11.4 |
| Generic B | Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | Systolic Blood Pressure: quartile 1 | 129.6 mm Hg | Standard Deviation 15 |
| Generic B | Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | Systolic Blood Pressure: quartile 2 | 131.3 mm Hg | Standard Deviation 16.1 |
| Generic B | Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | Diastolic Blood Pressure: quartile 4 | 80.0 mm Hg | Standard Deviation 13.3 |
| Generic A | Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | Systolic Blood Pressure: quartile 3 | 123.1 mm Hg | Standard Deviation 15.6 |
| Generic A | Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | Systolic Blood Pressure: quartile 2 | 131.0 mm Hg | Standard Deviation 16.4 |
| Generic A | Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | Systolic Blood Pressure: quartile 1 | 129.1 mm Hg | Standard Deviation 15.1 |
| Generic A | Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | Systolic Blood Pressure: quartile 4 | 128.0 mm Hg | Standard Deviation 15.8 |
| Generic A | Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | Diastolic Blood Pressure: quartile 3 | 74.4 mm Hg | Standard Deviation 10.4 |
| Generic A | Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | Diastolic Blood Pressure: quartile 2 | 78.5 mm Hg | Standard Deviation 11.7 |
| Generic A | Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | Diastolic Blood Pressure: quartile 1 | 78.3 mm Hg | Standard Deviation 11.1 |
| Generic A | Blood Pressure Values (Systolic and Diastolic) Compared Between Brand Name Metoprolol ER and Each Generic Metoprolol Formulation (Generic B, Generic A) | Diastolic Blood Pressure: quartile 4 | 78.1 mm Hg | Standard Deviation 9.6 |
p-value: 0.203Mixed Models Analysis
p-value: 0.671Mixed Models Analysis
p-value: 0.2Mixed Models Analysis
p-value: 0.068Mixed Models Analysis
Secondary
Heart Rate (HR) Response Compared Between Brand Name Metoprolol ER and Each Generic (Generic B, Generic A) Formulation of Metoprolol Succinate
24-h ambulatory heart rate recordings taken 4 times per hour (every 15 minutes) between 6AM and 11PM and 2 times per hour (every 30 minutes) 11PM and 6AM were obtained after Phase 1 (brand name metoprolol ER), Phase 2 (Generic B or Generic A), and Phase 4 (Generic A or Generic B)
Time frame: Average value over each quartile of 6 hours in the 24-hr period
Population: The analysis aimed to compare 24-hr HR between the brand name and each generic (generic B or generic A) formulation of metoprolol succinate. Mean and SD values for HR entered for each medication by quartile
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Brand Name Metoprolol ER | Heart Rate (HR) Response Compared Between Brand Name Metoprolol ER and Each Generic (Generic B, Generic A) Formulation of Metoprolol Succinate | HR (beats per minute) Quartile one | 65.1 bpm | Standard Deviation 11.5 |
| Brand Name Metoprolol ER | Heart Rate (HR) Response Compared Between Brand Name Metoprolol ER and Each Generic (Generic B, Generic A) Formulation of Metoprolol Succinate | HR (beats per minute) Quartile two | 65.3 bpm | Standard Deviation 11.5 |
| Brand Name Metoprolol ER | Heart Rate (HR) Response Compared Between Brand Name Metoprolol ER and Each Generic (Generic B, Generic A) Formulation of Metoprolol Succinate | HR (beats per minute) Quartile three | 61.3 bpm | Standard Deviation 9.9 |
| Brand Name Metoprolol ER | Heart Rate (HR) Response Compared Between Brand Name Metoprolol ER and Each Generic (Generic B, Generic A) Formulation of Metoprolol Succinate | HR (beats per minute) Quartile four | 61.4 bpm | Standard Deviation 12.9 |
| Generic B | Heart Rate (HR) Response Compared Between Brand Name Metoprolol ER and Each Generic (Generic B, Generic A) Formulation of Metoprolol Succinate | HR (beats per minute) Quartile four | 62.5 bpm | Standard Deviation 11.6 |
| Generic B | Heart Rate (HR) Response Compared Between Brand Name Metoprolol ER and Each Generic (Generic B, Generic A) Formulation of Metoprolol Succinate | HR (beats per minute) Quartile one | 65.4 bpm | Standard Deviation 11.5 |
| Generic B | Heart Rate (HR) Response Compared Between Brand Name Metoprolol ER and Each Generic (Generic B, Generic A) Formulation of Metoprolol Succinate | HR (beats per minute) Quartile three | 62.8 bpm | Standard Deviation 10.1 |
| Generic B | Heart Rate (HR) Response Compared Between Brand Name Metoprolol ER and Each Generic (Generic B, Generic A) Formulation of Metoprolol Succinate | HR (beats per minute) Quartile two | 65.9 bpm | Standard Deviation 10.5 |
| Generic A | Heart Rate (HR) Response Compared Between Brand Name Metoprolol ER and Each Generic (Generic B, Generic A) Formulation of Metoprolol Succinate | HR (beats per minute) Quartile four | 62.5 bpm | Standard Deviation 11.3 |
| Generic A | Heart Rate (HR) Response Compared Between Brand Name Metoprolol ER and Each Generic (Generic B, Generic A) Formulation of Metoprolol Succinate | HR (beats per minute) Quartile two | 66.9 bpm | Standard Deviation 11.5 |
| Generic A | Heart Rate (HR) Response Compared Between Brand Name Metoprolol ER and Each Generic (Generic B, Generic A) Formulation of Metoprolol Succinate | HR (beats per minute) Quartile three | 63.4 bpm | Standard Deviation 10.6 |
| Generic A | Heart Rate (HR) Response Compared Between Brand Name Metoprolol ER and Each Generic (Generic B, Generic A) Formulation of Metoprolol Succinate | HR (beats per minute) Quartile one | 66.1 bpm | Standard Deviation 11.3 |
p-value: 0.333Mixed Models Analysis
p-value: 0.368Mixed Models Analysis
Secondary
The Heart Rate Variability (HRV) Response to Brand Name Metoprolol ER Versus Each Generic Formulation of Metoprolol Succinate.
24-h digital heart rate monitor analyses were obtained after Phase 1 (brand name metoprolol ER ), Phase 2 (Generic B or Generic A), and Phase 4 (Generic A or Generic B). Data were analyzed by quartiles. One 5-minute epoch from each hour of each quartile was selected based on absence of a significant number of ectopic beats and artifact from which spectral measures were calculated: high-frequency variability (measure of parasympathetic activity), low-frequency variability (measure of sympathetic activity). The ratio of low-to-high frequency variability was calculated for each quartile. The averages of values obtained for each hour of each quartile constituted the final quartile measures that were used for analysis. The low to high frequency ratio obtained for each quartile represents the balance between sympathetic and parasympathetic nervous system activity and was the primary variable for heart rate variability analysis.
Time frame: Heart rate variability (Low-to-High Frequency Ratio) over each quartile of 6 hours in the 24-hr period
Population: The analysis aimed to compare HRV (Low-to-High Frequency Ratio) for patients who took Brand name metoprolol ER and a generic formulation (Generic B or Generic A). Low to High Frequency Ratio values are entered for each quartile for Brand name metoprolol ER, Generic B and Generic A
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Brand Name Metoprolol ER | The Heart Rate Variability (HRV) Response to Brand Name Metoprolol ER Versus Each Generic Formulation of Metoprolol Succinate. | Low to High Frequency Ratio: Quartile1 | 2.08 no units | Standard Deviation 2.43 |
| Brand Name Metoprolol ER | The Heart Rate Variability (HRV) Response to Brand Name Metoprolol ER Versus Each Generic Formulation of Metoprolol Succinate. | Low to High Frequency Ratio: Quartile 2 | 2.06 no units | Standard Deviation 1.74 |
| Brand Name Metoprolol ER | The Heart Rate Variability (HRV) Response to Brand Name Metoprolol ER Versus Each Generic Formulation of Metoprolol Succinate. | Low to High Frequency Ratio: Quartile 3 | 2.06 no units | Standard Deviation 1.57 |
| Brand Name Metoprolol ER | The Heart Rate Variability (HRV) Response to Brand Name Metoprolol ER Versus Each Generic Formulation of Metoprolol Succinate. | Low to High Frequency Ratio: Quartile 4 | 1.95 no units | Standard Deviation 1.18 |
| Generic B | The Heart Rate Variability (HRV) Response to Brand Name Metoprolol ER Versus Each Generic Formulation of Metoprolol Succinate. | Low to High Frequency Ratio: Quartile 4 | 2.22 no units | Standard Deviation 1.79 |
| Generic B | The Heart Rate Variability (HRV) Response to Brand Name Metoprolol ER Versus Each Generic Formulation of Metoprolol Succinate. | Low to High Frequency Ratio: Quartile1 | 1.67 no units | Standard Deviation 1.21 |
| Generic B | The Heart Rate Variability (HRV) Response to Brand Name Metoprolol ER Versus Each Generic Formulation of Metoprolol Succinate. | Low to High Frequency Ratio: Quartile 3 | 1.92 no units | Standard Deviation 1.21 |
| Generic B | The Heart Rate Variability (HRV) Response to Brand Name Metoprolol ER Versus Each Generic Formulation of Metoprolol Succinate. | Low to High Frequency Ratio: Quartile 2 | 1.64 no units | Standard Deviation 1.05 |
| Generic A | The Heart Rate Variability (HRV) Response to Brand Name Metoprolol ER Versus Each Generic Formulation of Metoprolol Succinate. | Low to High Frequency Ratio: Quartile 4 | 2.34 no units | Standard Deviation 1.73 |
| Generic A | The Heart Rate Variability (HRV) Response to Brand Name Metoprolol ER Versus Each Generic Formulation of Metoprolol Succinate. | Low to High Frequency Ratio: Quartile 2 | 1.95 no units | Standard Deviation 1.5 |
| Generic A | The Heart Rate Variability (HRV) Response to Brand Name Metoprolol ER Versus Each Generic Formulation of Metoprolol Succinate. | Low to High Frequency Ratio: Quartile 3 | 2.08 no units | Standard Deviation 0.99 |
| Generic A | The Heart Rate Variability (HRV) Response to Brand Name Metoprolol ER Versus Each Generic Formulation of Metoprolol Succinate. | Low to High Frequency Ratio: Quartile1 | 1.79 no units | Standard Deviation 1.06 |
p-value: 0.0168Mixed Models Analysis
p-value: 0.0858Mixed Models Analysis