Metoprolol succinate and hydrochlorothiazide

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Metoprolol succinate and hydrochlorothiazide
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]

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Black Box Warning

Ischemic Heart Disease
See full prescribing information for complete Boxed Warning.
  • Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred. When discontinuing chronically administered DUTOPROL, particularly in patients with ischemic heart disease, gradually reduce the dosage over a period of 1–2 weeks and monitor the patient. If angina markedly worsens or acute coronary ischemia develops, promptly reinstate DUTOPROL, and take measures appropriate for the management of unstable angina. Warn patients not to interrupt therapy without the physician’s advice. Because coronary artery disease is common and may be unrecognized, avoid abruptly discontinuing DUTOPROL in patients treated only for hypertension.

Overview

Metoprolol succinate and hydrochlorothiazide is a combination of beta1-selective adrenoceptor blocking agent and a diuretic that is FDA approved for the {{{indicationType}}} of hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include .

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Condition1
  • Dosing Information
  • Dosage
Condition2
  • Dosing Information
  • Dosage
Condition3
  • Dosing Information
  • Dosage
Condition4
  • Dosing Information
  • Dosage

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Condition1
  • Developed by:
  • Class of Recommendation:
  • Strength of Evidence:
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding Off-Label Guideline-Supported Use of Metoprolol succinate and hydrochlorothiazide in adult patients.

Non–Guideline-Supported Use

Condition1
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding Off-Label Non–Guideline-Supported Use of Metoprolol succinate and hydrochlorothiazide in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Condition1
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding FDA-Labeled Use of Metoprolol succinate and hydrochlorothiazide in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

Condition1
  • Developed by:
  • Class of Recommendation:
  • Strength of Evidence:
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding Off-Label Guideline-Supported Use of Metoprolol succinate and hydrochlorothiazide in pediatric patients.

Non–Guideline-Supported Use

Condition1
  • Dosing Information
  • Dosage
Condition2

There is limited information regarding Off-Label Non–Guideline-Supported Use of Metoprolol succinate and hydrochlorothiazide in pediatric patients.

Contraindications

  • Condition1

Warnings

Ischemic Heart Disease
See full prescribing information for complete Boxed Warning.
  • Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred. When discontinuing chronically administered DUTOPROL, particularly in patients with ischemic heart disease, gradually reduce the dosage over a period of 1–2 weeks and monitor the patient. If angina markedly worsens or acute coronary ischemia develops, promptly reinstate DUTOPROL, and take measures appropriate for the management of unstable angina. Warn patients not to interrupt therapy without the physician’s advice. Because coronary artery disease is common and may be unrecognized, avoid abruptly discontinuing DUTOPROL in patients treated only for hypertension.
  • Description

Precautions

  • Description

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Clinical Trial Experience of Metoprolol succinate and hydrochlorothiazide in the drug label.

Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Metoprolol succinate and hydrochlorothiazide in the drug label.

Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous

Drug Interactions

  • Drug
  • Description

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

  • Pregnancy Category


Pregnancy Category (AUS):

  • Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Metoprolol succinate and hydrochlorothiazide in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Metoprolol succinate and hydrochlorothiazide during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Metoprolol succinate and hydrochlorothiazide with respect to nursing mothers.

Pediatric Use

There is no FDA guidance on the use of Metoprolol succinate and hydrochlorothiazide with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Metoprolol succinate and hydrochlorothiazide with respect to geriatric patients.

Gender

There is no FDA guidance on the use of Metoprolol succinate and hydrochlorothiazide with respect to specific gender populations.

Race

There is no FDA guidance on the use of Metoprolol succinate and hydrochlorothiazide with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Metoprolol succinate and hydrochlorothiazide in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Metoprolol succinate and hydrochlorothiazide in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Metoprolol succinate and hydrochlorothiazide in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Metoprolol succinate and hydrochlorothiazide in patients who are immunocompromised.

Administration and Monitoring

Administration

  • Oral
  • Intravenous

Monitoring

There is limited information regarding Monitoring of Metoprolol succinate and hydrochlorothiazide in the drug label.

  • Description

IV Compatibility

There is limited information regarding IV Compatibility of Metoprolol succinate and hydrochlorothiazide in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

  • Description

Management

  • Description

Chronic Overdose

There is limited information regarding Chronic Overdose of Metoprolol succinate and hydrochlorothiazide in the drug label.

Pharmacology

There is limited information regarding Metoprolol succinate and hydrochlorothiazide Pharmacology in the drug label.

Mechanism of Action

  • Metoprolol and hydrochlorothiazide have been used individually and in combination for the treatment of hypertension. The antihypertensive effects of these agents are additive.
  • Metoprolol is a beta1-selective (cardioselective) adrenergic receptor-blocking agent. This preferential effect is not absolute, however, and at higher plasma concentrations, metoprolol also inhibits beta2-adrenoreceptors, chiefly located in the bronchial and vascular musculature. Metoprolol has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is detectable only at plasma concentrations much greater than required for beta—blockade. Animal and human experiments indicate that metoprolol slows the sinus rate and decreases AV nodal conduction.
  • Clinical pharmacology studies have confirmed the beta—blocking activity of metoprolol in man, as shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2) reduction of systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) reduction of reflex orthostatic tachycardia.
  • The relative beta1-selectivity of metoprolol has been confirmed by the following: (1) In normal subjects, metoprolol is unable to reverse the beta2-mediated vasodilating effects of epinephrine. This contrasts with the effect of nonselective beta-blockers, which completely reverse the vasodilating effects of epinephrine. (2) In asthmatic patients, metoprolol reduces FEV1 and FVC significantly less than a nonselective beta-blocker, propranolol, at equivalent beta1-receptor blocking doses.
  • The relationship between plasma metoprolol levels and reduction in exercise heart rate is independent of the pharmaceutical formulation. Using an Emax model, the maximum effect is a 30% reduction in exercise heart rate, which is attributed to beta1-blockade. Beta1-blocking effects in the range of 30–80% of the maximal effect (approximately 8–23% reduction in exercise heart rate) correspond to metoprolol plasma concentrations from 30-540 nmol/L. The relative beta1-selectivity of metoprolol diminishes and blockade of beta2-adrenoceptors increases at higher plasma concentrations above 300 nmol/L.
  • Although beta-adrenergic receptor blockade is useful in the treatment of angina, hypertension, and heart failure there are situations in which sympathetic stimulation is vital. In patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. In the presence of AV block, beta-blockade may prevent the necessary facilitating effect of sympathetic activity on conduction. Beta2-adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm and may also interfere with exogenous bronchodilators in such patients.
  • Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equimolar amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium.
  • After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.

Structure

  • DUTOPROL® (metoprolol succinate extended release/hydrochlorothiazide) combines a beta1-selective (cardioselective) adrenoceptor blocking agent and a diuretic, hydrochlorothiazide.
  • Metoprolol succinate is chemically described as (±)1-(isopropylamino)-3-[p-(2-methoxyethyl) phenoxy]-2-propanol succinate (2:1) (salt). Its structural formula is:
This image is provided by the National Library of Medicine.
  • Metoprolol succinate is a white crystalline powder with a molecular weight of 652.8. It is freely soluble in water; soluble in methanol; sparingly soluble in ethanol; slightly soluble in dichloromethane and 2-propanol; practically insoluble in ethyl-acetate, acetone, diethylether and heptane.
  • Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C7H8ClN3O4S2 and its structural formula is:
This image is provided by the National Library of Medicine.
  • Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight of 297.74, which is slightly soluble in water, but freely soluble in sodium hydroxide solution.
  • DUTOPROL is available for oral administration in 3 tablet strengths of metoprolol succinate extended release and hydrochlorothiazide.
  • DUTOPROL 25/12.5 contains 23.75 mg of metoprolol succinate extended release equivalent to 25 mg of metoprolol tartrate and 12.5 mg of hydrochlorothiazide. DUTOPROL 50/12.5 contains 47.5 mg of metoprolol succinate extended release equivalent to 50 mg of metoprolol tartrate and 12.5 mg of hydrochlorothiazide. DUTOPROL 100/12.5 contains 95 mg of metoprolol succinate extended release equivalent to 100 mg of metoprolol tartrate and 12.5 mg of hydrochlorothiazide. The inactive ingredients of the tablets are silicon dioxide, ethylcellulose, hydroxypropyl cellulose, cornstarch, microcrystalline cellulose, polyvinyl pyrrolidone, sodium stearyl fumarate, hydroxypropyl methylcellulose, polyethylene glycol 6000, titanium dioxide, iron oxide (yellow), iron oxide (red) and paraffin.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Metoprolol succinate and hydrochlorothiazide in the drug label.

Pharmacokinetics

  • Metoprolol succinate extended release/hydrochlorothiazide
  • After single oral doses of DUTOPROL tablets, the peak plasma concentrations (Cmax) of metoprolol and hydrochlorothiazide are observed within 10-12 hours and 2.0 hours of dose intake, respectively.
  • The rate and extent of absorption of metoprolol/ hydrochlorothiazide are similar in the fasting state and after a high-fat meal when given as DUTOPROL tablets. (See DOSAGE AND ADMINISTRATION.)
  • Single dose pharmacokinetics of metoprolol/hydrochlorothiazide given as DUTOPROL tablets is similar to that of each drug given individually as TOPROL-XL and a formulation of hydrochlorothiazide created for the clinical trial.
  • Metoprolol
  • In man, absorption of metoprolol is rapid and complete. Plasma levels following oral administration of immediate release metoprolol tablets, however, approximate 50% of levels following intravenous administration, indicating about 50% first-pass metabolism. Metoprolol crosses the blood brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous plasma concentration.
  • Plasma levels achieved are highly variable after oral administration of immediate release metoprolol. Only a small fraction of the drug (about 12%) is bound to human serum albumin. Metoprolol is a racemic mixture of R- and S- enantiomers, and is primarily metabolized by CYP2D6. When administered orally, it exhibits stereoselective metabolism that is dependent on oxidation phenotype. Elimination is mainly by biotransformation in the liver, and the plasma half-life ranges from approximately 3 to 7 hours. Less than 5% of an oral dose of metoprolol is recovered unchanged in the urine; the rest is excreted by the kidneys as metabolites that appear to have no beta blocking activity. Following intravenous administration of metoprolol, the urinary recovery of unchanged drug is approximately 10%. The systemic availability and half-life of metoprolol in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. (See DOSAGE AND ADMINISTRATION.)
  • Metoprolol is metabolized predominantly by CYP2D6, an enzyme that is absent in about 8% of Caucasians (poor metabolizers) and about 2% of most other populations. CYP2D6 can be inhibited by a number of drugs. Concomitant use of inhibiting drugs in poor metabolizers will increase blood levels of metoprolol several-fold, decreasing metoprolol's cardioselectivity. (See PRECAUTIONS, Drug Interactions, Metoprolol.)
  • Metoprolol succinate extended release
  • The metoprolol component of DUTOPROL is bioequivalent to TOPROL-XL. In comparison to immediate release metoprolol, the plasma metoprolol levels following administration of TOPROL-XL are characterized by lower peaks, longer time to peak and significantly lower peak to trough variation. The peak plasma levels following once-daily administration of TOPROL-XL average one-fourth to one-half the peak plasma levels obtained following a corresponding dose of immediate release metoprolol, administered once daily or in divided doses. At steady state the average bioavailability of metoprolol following administration of TOPROL-XL, across the dosage range of 50 to 400 mg once daily, was 77% relative to the corresponding single or divided doses of immediate release metoprolol. Nevertheless, over the 24-hour dosing interval, ß1-blockade is similar and dose-related (see CLINICAL PHARMACOLOGY). The bioavailability of metoprolol shows a dose-related, although not directly proportional, increase with dose and is not significantly affected by food following TOPROL-XL administration.
  • Hydrochlorothiazide
  • Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract with a bioavailability of about 60-80%.
  • Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.
  • Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. At least 61% of the oral dose is eliminated unchanged within 24 hours.
  • When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. In a study of patients with impaired renal function (mean creatinine clearance of 19 mL/min), the half-life of hydrochlorothiazide elimination was lengthened to 21 hours (See DOSAGE AND ADMINISTRATION). The bioavailability of hydrochlorothiazide is not significantly affected by food following DUTOPROL administration.
  • Hypertension
  • The mechanism of the antihypertensive effects of beta-blocking agents has not been elucidated. However, several possible mechanisms have been proposed: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output; (2) a central effect leading to reduced sympathetic outflow to the periphery; and (3) suppression of renin activity.
  • The mechanism of the antihypertensive effect of thiazide is unknown.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Metoprolol succinate and hydrochlorothiazide in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Metoprolol succinate and hydrochlorothiazide in the drug label.

How Supplied

Storage

There is limited information regarding Metoprolol succinate and hydrochlorothiazide Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Metoprolol succinate and hydrochlorothiazide in the drug label.

Precautions with Alcohol

  • Alcohol-Metoprolol succinate and hydrochlorothiazide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

Look-Alike Drug Names

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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