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Metoprolol Tartrate and and Hydrochlorothiazide Tablets

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING


1. DESCRIPTION

Metoprolol tartrate and hydrochlorothiazide tablets, USP have the antihypertensive effect of metoprolol tartrate, a selective beta1-adrenoreceptor blocking agent, and the antihypertensive and diuretic actions of hydrochlorothiazide.

Metoprolol tartrate, USP is a selective beta1-adrenoreceptor blocking agent, available as 25 mg, 50 mg and 100 mg tablets for oral administration. Metoprolol tartrate is (±)-1-(isopropylamino)-3-[p-2-methoxyethyl)phenoxy]-2-propanol (2:1) dextro-tartrate salt. Its structural formula is:

(C15H25NO3)2•C4H6O6 M.W. 684.82

Metoprolol tartrate is a white, practically odorless, crystalline powder. It is very soluble in water; freely soluble in methylene chloride, in chloroform, and in alcohol; slightly soluble in acetone; and insoluble in ether.

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:

Hydrochlorothiazide USP is a white, or practically white, practically odorless, crystalline powder. It is freely soluble in sodium hydroxide solution, in n-butylamine, and in dimethylformamide; sparingly soluble in methanol; slightly soluble in water; and insoluble in ether, in chloroform, and in dilute mineral acids. Its molecular weight is 297.73.

Metoprolol tartrate and hydrochlorothiazide, USP is available as tablets for oral administration. The 50 mg/25 mg tablets contain 50 mg of metoprolol tartrate USP and 25 mg of hydrochlorothiazide USP; the 100 mg/25 mg tablets contain 100 mg of metoprolol tartrate USP and 25 mg of hydrochlorothiazide USP; and the 100 mg/50 mg tablets contain 100 mg of metoprolol tartrate USP and 50 mg of hydrochlorothiazide USP.

Inactive Ingredients: Anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, FD&C Yellow No. 6 Aluminum Lake, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch and sodium lauryl sulfate.

2. INDICATIONS AND USAGE

Metoprolol tartrate and hydrochlorothiazide tablets are indicated for the management of hypertension.

This fixed-combination drug is not indicated for initial therapy of hypertension. If the fixed combination represents the dose titrated to the individual patient's needs, therapy with the fixed combination may be more convenient than with the separate components.

3. DOSAGE AND ADMINISTRATION

Dosage should be determined by individual titration (see INDICATIONS AND USAGE).

Hydrochlorothiazide is usually given at a dosage of 12.5 mg to 50 mg per day. The usual initial dosage of metoprolol tartrate tablets is 100 mg daily in single or divided doses. Dosage may be increased gradually until optimum blood pressure control is achieved. The effective dosage range is 100 mg to 450 mg per day. While once daily dosing is effective and can maintain a reduction in blood pressure throughout the day, lower doses (especially 100 mg) may not maintain a full effect at the end of the 24-hour period, and larger or more frequent daily doses may be required. This can be evaluated by measuring blood pressure near the end of the dosing interval to determine whether satisfactory control is being maintained throughout the day. Beta1 selectivity diminishes as dosage of metoprolol tartrate tablets is increased.

The following dosage schedule may be used to administer from 100 mg to 200 mg of metoprolol tartrate per day and from 25 mg to 50 mg of hydrochlorothiazide per day:

Dosing regimens that exceed 50 mg of hydrochlorothiazide per day are not recommended. When necessary, another antihypertensive agent may be added gradually, beginning with 50% of the usual recommended starting dose to avoid an excessive fall in blood pressure.

4. CONTRAINDICATIONS

Metoprolol

Metoprolol tartrate tablets are contraindicated in sinus bradycardia, heart block greater than first degree, cardiogenic shock, and overt cardiac failure (see WARNINGS).

Hypersensitivity to metoprolol tartrate and related derivatives, or to any of the excipients; hypersensitivity to other beta blockers (cross sensitivity between beta blockers can occur).

Sick-sinus syndrome.

Severe peripheral arterial circulatory disorders.

Hydrochlorothiazide

Hydrochlorothiazide is contraindicated in patients with anuria or hypersensitivity to this or other sulfonamide-derived drugs (see WARNINGS).

5. MECHANISM OF ACTION

Metoprolol

Metoprolol tartrate is a beta-adrenergic receptor blocking agent. In vitro and in vivo animal studies have shown that it has a preferential effect on beta1 adrenoreceptors, chiefly located in cardiac muscle. This preferential effect is not absolute, however, and at higher doses, metoprolol tartrate also inhibits beta2 adrenoreceptors, chiefly located in the bronchial and vascular musculature.

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.

Hydrochlorothiazide

The mechanism of the antihypertensive effect of thiazides is unknown. Hydrochlorothiazide does not usually affect normal blood pressure.

Hydrochlorothiazide affects the distal renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage all thiazides are approximately equal in their diuretic efficacy.

Hydrochlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category C

There are no adequate and well controlled studies of metoprolol tartrate and hydrochlorothiazide tablets in pregnant women. Metoprolol tartrate and hydrochlorothiazide tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Thiazides cross the placental barrier and appear in cord blood, and there is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

6.2 Nursing Mothers

Metoprolol is excreted in breast milk in a very small quantity. An infant consuming one liter of breast milk daily would receive a dose of metoprolol of less than 1 mg. Thiazides are also excreted in breast milk. If the use of metoprolol tartrate and hydrochlorothiazide tablets is deemed essential, the patient should stop nursing.

6.3 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

6.4 Geriatric Use

Clinical studies of metoprolol tartrate and hydrochlorothiazide tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Hydrochlorothiazide is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see WARNINGS). In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy.

7. WARNINGS AND PRECAUTIONS

WARNINGS

7.1 Metoprolol

Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure, and beta blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. In hypertensive and angina patients who have congestive heart failure controlled by digitalis and diuretics, metoprolol should be administered cautiously. Both digitalis and metoprolol slow AV conduction.

In Patients Without a History of Cardiac Failure: Continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or given a diuretic. The response should be observed closely. If cardiac failure continues, despite adequate digitalization and diuretic therapy, metoprolol should be withdrawn.


Ischemic Heart Disease:

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 metoprolol, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of 1−2 weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, metoprolol succinate administration should be reinstated promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Patients should be warned against interruption or discontinuation of therapy without the physician’s advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue metoprolol therapy abruptly even in patients treated only for hypertension.


Bronchospastic Diseases: PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Because of its relative beta1-selectivity, however, metoprolol may be used with caution in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Since beta1-selectivity is not absolute, a beta2-stimulating agent should be administered concomitantly, and the lowest possible dose of metoprolol should be used. In these circumstances it would be prudent initially to administer metoprolol in smaller doses three times daily, instead of larger doses two times daily, to avoid the higher plasma levels associated with the longer dosing interval. (see DOSAGE AND ADMINISTRATION).

Major Surgery: The necessity or desirability of withdrawing beta-blocking therapy prior to major surgery is controversial; the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

Metoprolol, like other beta-blockers, is a competitive inhibitor of betareceptor agonists, and its effects can be reversed by administration of such agents, eg, dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Difficulty in restarting and maintaining the heart beat has also been reported with beta blockers.

Diabetes and Hypoglycemia: Metoprolol should be used with caution in diabetic patients if a beta-blocking agent is required. Beta-blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected. Selective beta blockers do not potentiate insulin-induced hypoglycemia and, unlike nonselective beta blockers, do not delay recovery of blood glucose to normal levels.

Pheochromocytoma: If Lopressor is used in the setting of pheochromocytoma, it should be given in combination with an alpha blocker, and only after the alpha blocker has been initiated.

Administration of beta blockers alone in the setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure due to the attenuation of beta-mediated vasodilatation in skeletal muscle.

Thyrotoxicosis: Beta-adrenergic blockade may mask certain clinical signs (eg, tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-blockade, which might precipitate a thyroid storm.

7.2 Hydrochlorothiazide

Use with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Thiazides may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs with ganglionic or peripheral adrenergic blocking drugs.

Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.

The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.

Acute Myopia and Secondary Angle-Closure Glaucoma: Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

PRECAUTIONS

General

7.3 Metoprolol

Metoprolol should be used with caution in patients with impaired hepatic function.

7.4 Hydrochlorothiazide

All patients receiving diuretic therapy should be observed for evidence of fluid or electrolyte imbalance: namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present or after prolonged therapy.

Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Hypokalemia may be avoided or treated by use of potassium sparing diuretics or potassium supplements such as foods with a high potassium content.

Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis.

Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt, except in rare instances when the hyponatremia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice.

Hyperuricemia may occur or acute gout may be precipitated in certain patients receiving thiazides. In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest during thiazide therapy.

The antihypertensive effects of the drug may be enhanced in the post-sympathectomy patient.

If progressive renal impairment becomes evident, consider withholding or discontinuing diuretic therapy.

Calcium excretion is decreased by thiazides. Pathological changes in the parathyroid gland with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. The common complications of hyperparathyroidism, such as renal lithiasis, bone resorption, and peptic ulceration, have not been seen.

Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

Information for Patients

Patients should be advised to take Lopressor HCT regularly and continuously, as directed, with or immediately following meals. If a dose should be missed, the patient should take only the next scheduled dose (without doubling it). Patients should not discontinue Lopressor HCT without consulting the physician.

Patients should be advised (1) to avoid operating automobiles and machinery or engaging in other tasks requiring alertness until the patient’s response to therapy with Lopressor HCT has been determined; (2) to contact the physician if any difficulty in breathing occurs; (3) to inform the physician or dentist before any type of surgery that he or she is taking Lopressor HCT.

Laboratory Tests

Lopressor: Clinical laboratory findings may include elevated levels of serum transaminase, alkaline phosphatase, and lactate dehydrogenase.

Hydrochlorothiazide: Initial and periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids.

8. ADVERSE REACTIONS

The following adverse reactions were reported in controlled clinical studies of the combination of metoprolol tartrate tablets and hydrochlorothiazide.

Body as a Whole: Fatigue or lethargy and flu syndrome have each been reported in about 10 in 100 patients.

Nervous System: Dizziness or vertigo, drowsiness or somnolence, and headache have each occurred in about 10 in 100 patients.

Nightmare has occurred in 1 in 100 patients.

Cardiovascular: Bradycardia has occurred in about 6 in 100 patients. Decreased exercise tolerance and dyspnea have each occurred in about 1 of 100 patients.

Digestive: Diarrhea, digestive disorder, dry mouth, nausea or vomiting, and constipation have each occurred in about 1 in 100 patients.

Metabolic and Nutritional: Hypokalemia has occurred in fewer than 10 in 100 patients. Edema, gout, and anorexia have each occurred in 1 in 100 patients.

Special Senses: Blurred vision, tinnitus, and earache have each been reported in 1 in 100 patients.

Skin: Sweating and purpura have each occurred in 1 in 100 patients.

Urogenital: Impotence has occurred in 1 in 100 patients.

Musculoskeletal: Muscle pain has occurred in 1 in 100 patients.

Potential Adverse Reactions

A variety of adverse reactions not listed above have been reported with other beta-adrenergic blocking agents and should be considered potential adverse reactions to Lopressor.

Central Nervous System: Reversible mental depression progressing to catatonia; visual disturbances; hallucinations; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics.

Cardiovascular: Intensification of AV block (see CONTRAINDICATIONS).

Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.

Hypersensitive Reactions: Fever combined with aching and sore throat, laryngospasm, and respiratory distress.

Postmarketing Experience

The following adverse reactions have been reported during postapproval use of Lopressor: confusional state, an increase in blood triglycerides and a decrease in High Density Lipoprotein (HDL). Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency.

9. OVERDOSAGE

Acute Toxicity

Several cases of overdosage with metoprolol have been reported, some leading to death. No deaths have been reported with hydrochlorothiazide. Oral LD50 (mg/kg): mice, 1,158 (metoprolol); rats, 3,090 (metoprolol), 2,750 (hydrochlorothiazide).

Signs and Symptoms

Metoprolol

Potential signs and symptoms associated with overdosage with metoprolol are bradycardia, hypotension, bronchospasm, and cardiac failure.

Hydrochlorothiazide

The most prominent feature of poisoning is acute loss of fluid and electrolytes.

Cardiovascular: Tachycardia, hypotension, shock.

Neuromuscular: Weakness, confusion, dizziness, cramps of the calf muscles, paresthesia, fatigue, impairment of consciousness.

Digestive: Nausea, vomiting, thirst.

Renal: Polyuria, oliguria, or anuria (due to hemoconcentration).

Laboratory Findings: Hypokalemia, hyponatremia, hypochloremia, alkalosis; increased BUN (especially in patients with renal insufficiency).

Combined Poisoning: Signs and symptoms may be aggravated or modified by concomitant intake of antihypertensive medication, barbiturates, curare, digitalis (hypokalemia), corticosteroids, narcotics, or alcohol.

Treatment

There is no specific antidote.

On the basis of the pharmacologic actions of metoprolol tartrate tablets and hydrochlorothiazide, the following general measures should be employed:

Elimination of the Drug

Inducement of vomiting, gastric lavage, and activated charcoal.

Bradycardia: Atropine should be administered. If there is no response to vagal blockade, isoproterenol should be administered cautiously.

Hypotension: The patient's legs should be elevated and lost fluid and electrolytes (potassium, sodium) should be replaced. A vasopressor should be administered, e.g., levarterenol or dopamine.

Bronchospasm: A beta2-stimulating agent and/or a theophylline derivative should be administered.

Cardiac Failure: A digitalis glycoside and diuretic should be administered. In shock resulting from inadequate cardiac contractility, administration of dobutamine, isoproterenol, or glucagon may be considered.

Surveillance: Fluid and electrolyte balance (especially serum potassium) and renal function should be monitored until conditions become normal.

10. DRUG INTERACTIONS

Metoprolol

Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients treated with metoprolol plus a catecholamine depletor should therefore be closely observed for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.

Both digitalis glycosides and beta blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

Risk of Anaphylactic Reaction

While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.

General Anesthetics

Some inhalation anesthetics may enhance the cardiodepressant effect of beta blockers (see WARNINGS: Metoprolol: Major Surgery).

CYP2D6 Inhibitors

Potent inhibitors of the CYP2D6 enzyme may increase the plasma concentration of metoprolol. Strong inhibition of CYP2D6 would mimic the pharmacokinetics of CYP2D6 poor metabolizer. Caution should therefore be exercised when administering potent CYP2D6 inhibitors with metoprolol. Known clinically significant potent inhibitors of CYP2D6 are antidepressants such as fluoxetine, paroxetine or bupropion, antipsychotics such as thioridazine, antiarrhythmics such as quinidine or propafenone, antiretrovirals such as ritonavir, antihistamines such as diphenhydramine, antimalarials such as hydroxychloroquine or quinidine, antifungals such as terbinafine and medications for stomach ulcers such as cimetidine.

Clonidine

If a patient is treated with clonidine and metoprolol concurrently, and clonidine treatment is to be discontinued, metoprolol should be stopped several days before clonidine is withdrawn. Rebound hypertension that can follow withdrawal of clonidine may be increased in patients receiving concurrent beta blocker treatment.

Hydrochlorothiazide

Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).

Hypokalemia may develop during concomitant use of steroids or ACTH.

Insulin requirements in diabetic patients may be increased, decreased, or unchanged.

Thiazides may decrease arterial responsiveness to norepinephrine, but not enough to preclude effectiveness of the pressor agent for therapeutic use.

Thiazides may increase the responsiveness to tubocurarine.

Lithium renal clearance is reduced by thiazides, increasing the risk of lithium toxicity.

There have been rare reports in the literature of hemolytic anemia occurring with the concomitant use of hydrochlorothiazide and methyldopa.

Concurrent administration of some nonsteroidal anti-inflammatory agents may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics.

Cholestyramine and Colestipol Resins

Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.

Drug/Laboratory Test Interactions

Hydrochlorothiazide

Thiazides may decrease serum levels of protein bound iodine without signs of thyroid disturbance. Thiazides should be discontinued before tests for parathyroid function are made. (See PRECAUTIONS: General: Hydrochlorothiazide: Calcium excretion.)

11. PHARMACOKINETICS

Metoprolol

In man, absorption of metoprolol is rapid and complete. Plasma levels following oral administration, however, approximate 50% of levels following intravenous administration, indicating about 50% first-pass metabolism.

Plasma levels achieved are highly variable after oral administration. Only a small fraction of the drug (about 12%) is bound to human serum albumin. 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 clinical significance. 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. Consequently, no reduction in dosage is usually needed in patients with chronic renal failure.

Significant beta-blocking effect (as measured by reduction of exercise heart rate) occurs within 1 hour after oral administration, and its duration is dose-related. For example, a 50% reduction of the maximum registered effect after single oral doses of 20, 50, and 100 mg occurred at 3.3, 5.0, and 6.4 hours, respectively, in normal subjects. After repeated oral doses of 100 mg twice daily, a significant reduction in exercise systolic blood pressure was evident at 12 hours.

Equivalent maximal beta-blocking effect is achieved with oral and intravenous doses in the ratio of approximately 2.5:1.

There is a linear relationship between the log of plasma levels and reduction of exercise heart rate. However, antihypertensive activity does not appear to be related to plasma levels. Because of variable plasma levels attained with a given dose and lack of a consistent relationship of antihypertensive activity to dose, selection of proper dosage requires individual titration.

In several studies of patients with acute myocardial infarction, intravenous followed by oral administration of metoprolol caused a reduction in heart rate, systolic blood pressure, and cardiac output. Stroke volume, diastolic blood pressure, and pulmonary artery end diastolic pressure remained unchanged.

In patients with angina pectoris, plasma concentration measured at 1 hour is linearly related to the oral dose within the range of 50 to 400 mg. Exercise heart rate and systolic blood pressure are reduced in relation to the logarithm of the oral dose of metoprolol. The increase in exercise capacity and the reduction in left ventricular ischemia are also significantly related to the logarithm of the oral dose.

In elderly subjects with clinically normal renal and hepatic function, there are no significant differences in metoprolol pharmacokinetics compared to young subjects.

Hydrochlorothiazide

Hydrochlorothiazide is rapidly absorbed, as indicated by peak plasma concentrations 1 to 2.5 hours after oral administration. Plasma levels of the drug are proportional to dose; the concentration in whole blood is 1.6 to 1.8 times higher than in plasma. Thiazides are eliminated rapidly by the kidney. After oral administration of 25 mg to 100 mg doses, 72% to 97% of the dose is excreted in the urine, indicating dose independent absorption. Hydrochlorothiazide is eliminated from plasma in a biphasic fashion with a terminal half-life of 10 to 17 hours. Plasma protein binding is 67.9%. Plasma clearance is 15.9 to 30 L/hr; volume of distribution is 3.6 to 7.8 L/kg.

Gastrointestinal absorption of hydrochlorothiazide is enhanced when administered with food. Absorption is decreased in patients with congestive heart failure, and the pharmacokinetics are considerably different in these patients.

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: LOPRESSOR HCT, by NOVARTIS.

b) Generic drugs: Metoprolol tartrate and hydrochlorothiazide, by MYLAN.

2) How Supplied:

Metoprolol Tartrate and Hydrochlorothiazide Tablets, USP (by MYLAN) are available containing 50 mg/25 mg, 100 mg/25 mg and 100 mg/50 mg of metoprolol tartrate, USP and hydrochlorothiazide, USP.

The 50 mg/25 mg tablets are peach, round, scored tablets debossed with M above the score and 424 below the score on one side of the tablet and blank on the other side. They are available as follows:

NDC 0378-0424-93, bottles of 30 tablets

NDC 0378-0424-01, bottles of 100 tablets

NDC 0378-0424-05, bottles of 500 tablets

The 100 mg/25 mg tablets are peach, oval, scored tablets debossed with M to the left of the score and 434 to the right of the score on one side of the tablet and blank on the other side. They are available as follows:

NDC 0378-0434-93, bottles of 30 tablets

NDC 0378-0434-01, bottles of 100 tablets

NDC 0378-0434-05, bottles of 500 tablets

The 100 mg/50 mg tablets are peach, capsule-shaped, scored tablets debossed with M to the left of the score and 445 to the right of the score on one side of the tablet and blank on the other side. They are available as follows:

NDC 0378-0445-93, bottles of 30 tablets

NDC 0378-0445-01, bottles of 100 tablets

NDC 0378-0445-05, bottles of 500 tablets

3) Storage:

Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]

Protect from moisture.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Rx only

Rev 03/11