|
|||
|
DRUGS & SUPPLEMENTS
|
Active ingredient: Metoprolol Fumarate
What are the side effects you encounter while taking this medicine? |
Metoprolol Fumarate uses
- Description
- Clinical pharmacology
- Indications and usage
- Contraindications
- Warnings
- Hydrochlorothiazide
- Precautions
- Adverse reactions
- Overdosage
- Dosage and administration
- How supplied
DESCRIPTION
Metoprolol Fumarate (metoprolol succinate extended release/hydrochlorothiazide) combines a beta1-selective (cardioselective) adrenoceptor blocking agent and a diuretic, hydrochlorothiazide.
Metoprolol Fumarate succinate is chemically described as (±)1-(isopropylamino)-3-[p-(2-methoxyethyl) phenoxy]-2-propanol succinate (2:1) (salt). Its structural formula is:
Metoprolol Fumarate 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:
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.
Metoprolol Fumarate is available for oral administration in 3 tablet strengths of Metoprolol Fumarate succinate extended release and hydrochlorothiazide.
Metoprolol Fumarate 25/12.5 contains 23.75 mg of Metoprolol Fumarate succinate extended release equivalent to 25 mg of Metoprolol Fumarate tartrate and 12.5 mg of hydrochlorothiazide. Metoprolol Fumarate 50/12.5 contains 47.5 mg of Metoprolol Fumarate succinate extended release equivalent to 50 mg of Metoprolol Fumarate tartrate and 12.5 mg of hydrochlorothiazide. Metoprolol Fumarate 100/12.5 contains 95 mg of Metoprolol Fumarate succinate extended release equivalent to 100 mg of Metoprolol Fumarate 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.
structural formula structural formula 2
CLINICAL PHARMACOLOGY
General
Metoprolol Fumarate and hydrochlorothiazide have been used individually and in combination for the treatment of hypertension. The antihypertensive effects of these agents are additive.
Metoprolol Fumarate is a beta1-selective adrenergic receptor-blocking agent. This preferential effect is not absolute, however, and at higher plasma concentrations, Metoprolol Fumarate also inhibits beta2-adrenoreceptors, chiefly located in the bronchial and vascular musculature. Metoprolol Fumarate 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 Fumarate slows the sinus rate and decreases AV nodal conduction.
Clinical pharmacology studies have confirmed the beta-blocking activity of Metoprolol Fumarate 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 Fumarate has been confirmed by the following: (1) In normal subjects, Metoprolol Fumarate 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 Fumarate reduces FEV1 and FVC significantly less than a nonselective beta-blocker, propranolol, at equivalent beta1-receptor blocking doses.
The relationship between plasma Metoprolol Fumarate 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 Fumarate plasma concentrations from 30-540 nmol/L. The relative beta1-selectivity of Metoprolol Fumarate 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.
Pharmacokinetics
Metoprolol Fumarate succinate extended release/hydrochlorothiazide
After single oral doses of Metoprolol Fumarate tablets, the peak plasma concentrations of Metoprolol Fumarate 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 Metoprolol Fumarate tablets.
Single dose pharmacokinetics of metoprolol/hydrochlorothiazide given as Metoprolol Fumarate tablets is similar to that of each drug given individually as TOPROL-XL and a formulation of hydrochlorothiazide created for the clinical trial.
Metoprolol Fumarate
In man, absorption of Metoprolol Fumarate is rapid and complete. Plasma levels following oral administration of immediate release Metoprolol Fumarate tablets, however, approximate 50% of levels following intravenous administration, indicating about 50% first-pass metabolism. Metoprolol Fumarate 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 Fumarate. Only a small fraction of the drug (about 12%) is bound to human serum albumin. Metoprolol Fumarate 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 Fumarate 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 Fumarate, the urinary recovery of unchanged drug is approximately 10%. The systemic availability and half-life of Metoprolol Fumarate in patients with renal failure do not differ to a clinically significant degree from those in normal subjects.
Metoprolol Fumarate 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 Fumarate several-fold, decreasing metoprolol's cardioselectivity.
Metoprolol Fumarate succinate extended release
The Metoprolol Fumarate component of Metoprolol Fumarate is bioequivalent to TOPROL-XL. In comparison to immediate release Metoprolol Fumarate, the plasma Metoprolol Fumarate 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 Fumarate, administered once daily or in divided doses. At steady state the average bioavailability of Metoprolol Fumarate 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 Fumarate. Nevertheless, over the 24-hour dosing interval, ß1-blockade is similar and dose-related. The bioavailability of Metoprolol Fumarate 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. The bioavailability of hydrochlorothiazide is not significantly affected by food following Metoprolol Fumarate administration.
Hypertension
The mechanism of the antihypertensive effects of beta-blocking agents has not been elucidated. However, several possible mechanisms have been proposed: 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.
Clinical Trials
Metoprolol Fumarate succinate extended release and hydrochlorothiazide
A randomized, double-blind, placebo-controlled, 8-week, unbalanced factorial study (N=1571) evaluated the antihypertensive effects of various doses of Metoprolol Fumarate succinate extended release (25, 50, 100 and 200 mg) and hydrochlorothiazide (6.25, 12.5 and 25 mg), and 9 of their combinations. The trial established that Metoprolol Fumarate succinate extended release and hydrochlorothiazide both contribute to the antihypertensive effect, change from baseline to week 8 in sitting diastolic (p= 0.0015) and systolic (p=0.0006) blood pressure). The predicted values for the drugs effects are shown in Table 1.
Blood pressure declines were apparent within 2 weeks and were maintained throughout the 8-week study. The blood pressure lowering 24 hours post dosing retained approximately 96% of the peak (6 hours post dosing) effect. The antihypertensive effect was similar regardless of age or gender, and the response to the Metoprolol Fumarate succinate extended release and hydrochlorothiazide combination appears similar in black and non-black patients.
| Metoprolol Fumarate succinate extended release Dosage | |||||
|---|---|---|---|---|---|
| HCT Dosage | 0 mg SBP/DBP | 25 mg SBP/DBP | 50 mg SBP/DBP | 100 mg SBP/DBP | 200 mg SBP/DBP |
| 0 mg | 0/0 | -2.0/-1.4 | -3.7/-2.6 | -6.1/-4.5 | -7.0/-6.1 |
| 6.25 mg | -3.5/-1.9 | -5.5/-3.3 | -7.2/-4.5 | -9.6/-6.4 | -10.5/-8.0 |
| 12.5 mg | -5.9/-3.3 | -7.9/-4.7 | -9.6/-5.9 | -12.0/-7.8 | -12.9/-9.3 |
| 25 mg | -7.7/-4.3 | -9.7/-5.7 | -11.4/-6.9 | -13.8/-8.8 | -14.7/-10.4 |
There are no trials of the Metoprolol Fumarate combination tablet demonstrating reductions in cardiovascular risk in patients with hypertension, but both the Metoprolol Fumarate and hydrochlorothiazide components have demonstrated such benefits.
INDICATIONS AND USAGE
Hypertension
Metoprolol Fumarate is a combination tablet of Metoprolol Fumarate succinate, a beta adrenoceptor blocking agent and hydrochlorothiazide, a diuretic. Metoprolol Fumarate is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarction. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including Metoprolol Fumarate and hydrochlorothiazide.
Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (eg, on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.
Metoprolol Fumarate may be administered with other antihypertensive agents.
CONTRAINDICATIONS
Metoprolol Fumarate succinate extended release/hydrochlorothiazide is contraindicated in patients in cardiogenic shock, overt cardiac failure, second or third degree AV block, marked sinus bradycardia, anuria, and hypersensitivity to either component of this product or to other sulfonamide-derived drugs.
WARNINGS
Metoprolol Fumarate succinate extended release
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 Fumarate, 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 Metoprolol Fumarate, 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 Metoprolol Fumarate in patients treated only for hypertension.
Bronchospastic Disease: PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Because of its relative beta1 cardio-selectivity, however, Metoprolol Fumarate succinate extended release/hydrochlorothiazide may be used in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment. Because beta1-selectivity is not absolute, use the lowest possible dose of Metoprolol Fumarate. Bronchodilators, including beta2-agonists, should be readily available or administered concomitantly.
Pheochromocytoma: If Metoprolol Fumarate 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.
Major Surgery: Avoid initiation of high-dose regimen of extended- release Metoprolol Fumarate in patients undergoing non-cardiac surgery, since such use in patients with cardiovascular risk factors has been associated with bradycardia, hypotension, stroke and death.
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery, however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
Diabetes and Hypoglycemia: Beta-blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected..
Thyrotoxicosis: Beta-adrenergic blockade may mask certain clinical signs of hyperthyroidism, such as tachycardia. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-blockade, which might precipitate a thyroid storm.
Peripheral Vascular Disease: Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.
Calcium Channel Blockers: Because of significant inotropic and chronotropic effects in patients treated with beta-blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be exercised in patients treated with these agents concomitantly.
Hydrochlorothiazide
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.
Renal Disease: Thiazides should be used 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..
Hepatic Disease: Thiazide diuretics 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..
Hypersensitivity Reaction: Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.
Systemic Lupus Erythematosus: Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.
Lithium Interaction: Lithium generally should not be given with thiazides.
PRECAUTIONS
General
Metoprolol Fumarate succinate extended release/hydrochlorothiazide
The precautions for the use of Metoprolol Fumarate succinate extended release/hydrochlorothiazide are the same as for the individual agents.
Metoprolol Fumarate should be used with caution in patients with impaired hepatic function. In patients with pheochromocytoma, an alpha-blocking agent should be initiated prior to the use of any beta-blocking agent.
Metoprolol Fumarate succinate extended release
Worsening cardiac failure may occur during up-titration of beta blockers. If such symptoms occur, diuretics should be increased and the dose of beta-blocking agent should not be advanced until clinical stability is restored. It may be necessary to lower the dose of Metoprolol Fumarate or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of Metoprolol Fumarate.
Hydrochlorothiazide
Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.
All patients receiving thiazide therapy should be observed for clinical signs 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 (eg, 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 thiazide therapy.
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.
Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.
Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.
Anaphylactic Reactions
While taking beta-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge and may be unresponsive to the usual doses of epinephrine used to treat an allergic reaction.
Information for Patients
Advise patients to take Metoprolol Fumarate regularly and continuously, as directed. If a dose is missed, the patient should take only the next scheduled dose. Patients should not interrupt or discontinue Metoprolol Fumarate without consulting the physician.
Advise patients (1) to avoid operating automobiles and machinery or engaging in other tasks requiring alertness until the patient’s response to therapy with Metoprolol Fumarate 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 Metoprolol Fumarate.
Drug Interactions
Metoprolol Fumarate
Catecholamine-depleting drugs inhibitors) may have an additive effect when given with beta-blocking agents. Observe patients treated with Metoprolol Fumarate plus a catecholamine depletor for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.
Drugs that inhibit CYP2D6 such as quinidine, fluoxetine, paroxetine, and propafenone are likely to increase Metoprolol Fumarate concentration. In healthy subjects with CYP2D6 extensive metabolizer phenotype, coadministration of quinidine 100 mg and immediate release Metoprolol Fumarate 200 mg tripled the concentration of S-metoprolol and doubled the Metoprolol Fumarate elimination half-life. In four patients with cardiovascular disease, coadministration of propafenone 150 mg t.i.d. with immediate-release Metoprolol Fumarate 50 mg t.i.d. resulted in two- to five-fold increases in the steady-state concentration of Metoprolol Fumarate. These increases in plasma concentration would decrease the cardioselectivity of Metoprolol Fumarate.
Digitalis glycosides, clonidine, diltiazem and verapamil slow atrioventricular conduction and decrease heart rate. Concomitant use with beta blockers can increase the risk of bradycardia.
If clonidine and a beta blocker, such as Metoprolol Fumarate are coadministered, withdraw the beta-blocker several days before the gradual withdrawal of clonidine because beta-blockers may exacerbate the rebound hypertension that can follow the withdrawal of clonidine. If replacing clonidine by beta-blocker therapy, delay the introduction of beta-blockers for several days after clonidine administration has stopped.
Hydrochlorothiazide
When administered concurrently the following drugs may interact with thiazide diuretics:
Alcohol, barbiturates, or narcotics – Potentiation of orthostatic hypotension may occur.
Antidiabetic drugs (oral agents and insulin) – Dosage adjustment of the antidiabetic drug may be required.
Other antihypertensive drugs – Additive effect or potentiation.
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 percent, respectively.
Corticosteroids, ACTH – Intensified electrolyte depletion, particularly hypokalemia.
Pressor amines (eg, norepinephrine) – Possible decreased response to pressor amines but not sufficient to preclude their use.
Skeletal muscle relaxants, nondepolarizing (eg, tubocurarine) – Possible increased responsiveness to the muscle relaxant.
Lithium – Generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with Metoprolol Fumarate.
Non-steroidal Anti-inflammatory Drugs – In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium sparing and thiazide diuretics. Therefore, when Metoprolol Fumarate and non-steroidal anti- inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Metoprolol/Hydrochlorothiazide
Carcinogenicity and mutagenicity studies have not been conducted with combinations of Metoprolol Fumarate and hydrochlorothiazide.
A combination of Metoprolol Fumarate tartrate and hydrochlorothiazide produced no adverse effects on the fertility and reproductive performance of male and female rats at doses of up to 200/50 mg/kg/day [about 10 and 20 times the maximum recommended human dose of Metoprolol Fumarate and hydrochlorothiazide, respectively, on a mg/m2 basis].
Metoprolol Fumarate
Long-term studies in animals have been conducted to evaluate the carcinogenic potential of Metoprolol Fumarate tartrate. In 2-year studies in rats at oral dosage levels of up to 800 mg/kg/day (41 times, on a mg/m2 basis, the daily dose of 200 mg for a 60-kg patient), there was no increase in the development of spontaneously occurring benign or malignant neoplasms of any type. The only histologic changes that appeared to be drug related were an increased incidence of generally mild focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary hyperplasia. In a 21-month study in Swiss albino mice at three oral dosage levels of up to 750 mg/kg/day (about 18 times, on a mg/m2 basis, the daily dose of 200 mg for a 60-kg patient), benign lung tumors (small adenomas) occurred more frequently in female mice receiving the highest dose than in untreated control animals. There was no increase in malignant or total (benign plus malignant) lung tumors, nor in the overall incidence of tumors or malignant tumors. This 21-month study was repeated in CD-1 mice, and no statistically or biologically significant differences were observed between treated and control mice of either sex for any type of tumor.
All genotoxicity tests performed on Metoprolol Fumarate tartrate (a dominant lethal study in mice, chromosomal studies in somatic cells, a Salmonella/mammalian-microsome mutagenicity test, and a nucleus anomaly test in somatic interphase nuclei) and Metoprolol Fumarate succinate (a Salmonella/mammalian-microsome mutagenicity test) were negative.
No evidence of impaired fertility due to Metoprolol Fumarate tartrate was observed in a study performed in rats at doses up to 22 times, on a mg/m2 basis, the daily dose of 200 mg in a 60 kg patient.
Hydrochlorothiazide
Two-year feeding studies in mice and rats uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice at doses of up to 600 mg/kg/day or in male and female rats at doses of up to 100 mg/kg/day (about 40 times the MRHD). However, there was equivocal evidence of hepatocarcinogenicity in male mice.
Hydrochlorothiazide was not genotoxic in the Ames bacterial mutagenicity test or the in vitro Chinese Hamster Ovary (CHO) test for chromosomal aberrations. Nor was it genotoxic in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) test, the Mouse Lymphoma Cell (mutagenicity) assay and the Aspergillus nidulans non-disjunction assay.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg/day (about 20 and 1.6 times the MRHD, on a mg/m2 basis), respectively, prior to mating and throughout gestation.
Pregnancy
Pregnancy Category C
Metoprolol/Hydrochlorothiazide
Oral administration of Metoprolol Fumarate tartrate/hydrochlorothiazide combinations to pregnant rats during organogenesis at doses up to 200/50 mg/kg/day or to pregnant rabbits at doses up to 25/6.25 mg/kg/day (about 2.5 and 5 times the MRHD for Metoprolol Fumarate and hydrochlorothiazide, respectively) produced no teratogenic effects. A 200/50 mg/kg/day Metoprolol Fumarate tartrate/hydrochlorothiazide combination administered to rats from mid-late gestation through lactation produced increased post-implantation loss and decreased neonatal survival.
Metoprolol Fumarate
Metoprolol Fumarate tartrate has been shown to increased post-implantation loss and decreased neonatal survival in rats at doses up to 22 times, on a mg/m2 basis, the daily dose of 200 mg in a 60-kg patient. Distribution studies in mice confirm exposure of the fetus when Metoprolol Fumarate tartrate is administered to the pregnant animal. These studies have revealed no evidence of impaired fertility or teratoenicity. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, use this drug during pregnancy only if clearly needed.
Hydrochlorothiazide
Hydrochlorothiazide administered to pregnant mice and rats during organogenesis at doses up to 3000 and 1000 mg/kg/day, respectively, produced no harm to the fetus. Thiazides cross the placental barrier and appear in the cord blood. The use of thiazides in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult.
Nursing Mothers
Metoprolol Fumarate is excreted in breast milk in very small quantities. An infant consuming 1 liter of breast milk daily would receive a dose of less than 1 mg of the drug. Thiazides appear in human milk. Consider possible infant exposure when Metoprolol Fumarate is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Of the 849 subjects randomized to treatment with both Metoprolol Fumarate succinate extended release and hydrochlorothiazide in a factorial clinical study, 129 (15%) were 65 and over, while 16 (2%) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. In addition, patients 70 to 84 years of age were studied in two clinical outcome trials (n=3025), which included a treatment regimen of a thiazide diuretic or beta blocker (metoprolol succinate extended release, atenolol or pindolol) or their combination have 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.
ADVERSE REACTIONS
Metoprolol Fumarate succinate extended release/hydrochlorothiazide
The Metoprolol Fumarate succinate extended release and hydrochlorothiazide combination was evaluated for safety in 891 patients treated for hypertension in clinical trials. In a placebo-controlled trial, 843 patients were treated with various combinations of Metoprolol Fumarate succinate and hydrochlorothiazide (doses of 6.25 to 25 mg). Overall, the incidence of adverse experiences reported with the combination was comparable to placebo. Adverse events, whether or not attributed to treatment, occurring in greater than 1% of patients treated with Metoprolol Fumarate and at a rate equal to or greater than with placebo were: nasopharyngitis (3.4% vs 1.3%), fatigue (2.6% vs 0.7%), dizziness (2.6% vs 2.6%), back pain (1.7% vs 1.3%), and nausea (1.4% vs 0.7%). Adverse experiences were usually mild and transient in nature and infrequently required discontinuation of therapy (2.7% vs 2.6% with placebo).
Metoprolol Fumarate
Most adverse effects have been mild and transient. The following adverse reactions have been reported for immediate release Metoprolol Fumarate tartrate.
Central Nervous System: Tiredness and dizziness have occurred in about 10 of 100 patients. Depression has been reported in about 5 of 100 patients. Mental confusion and short-term memory loss have been reported. Headache, somnolence, nightmares, and insomnia have also been reported.
Cardiovascular: Shortness of breath and bradycardia have occurred in approximately 3 of 100 patients. Cold extremities; arterial insufficiency, usually of the Raynaud type; palpitations; congestive heart failure; peripheral edema; syncope; chest pain; and hypotension have been reported in about 1 of 100 patients.
Respiratory: Wheezing (bronchospasm) and dyspnea have been reported in about 1 of 100 patients.
Gastrointestinal: Diarrhea has occurred in about 5 of 100 patients. Nausea, dry mouth, gastric pain, constipation, flatulence, digestive tract disorders, and heartburn have been reported in about 1 of 100 patients.
Hypersensitive Reactions: Pruritus or rash have occurred in about 5 of 100 patients. Worsening of psoriasis has also been reported.
Miscellaneous: Peyronie’s disease has been reported in fewer than 1 of 100,000 patients. Musculoskeletal pain, blurred vision, decreased libido, and tinnitus have also been reported.
There have been rare reports of reversible alopecia, agranulocytosis, and dry eyes. Discontinuation of the drug should be considered if any such reaction is not otherwise explicable. The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with Metoprolol Fumarate.
Potential Adverse Reactions
In addition, there are a variety of adverse reactions not listed above, which have been reported with other beta-adrenergic blocking agents and should be considered potential adverse reactions to Metoprolol Fumarate.
Central Nervous System: Reversible mental depression progressing to catatonia; 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.
Hematologic: Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.
Hypersensitive Reactions: Fever combined with aching and sore throat, laryngospasm, and respiratory distress.
Post-Marketing Experience
In addition, the following adverse reactions have been reported with Metoprolol Fumarate succinate in worldwide post-marketing use, regardless of causality:
Cardiovascular: 2nd and 3rd degree heart block.
Gastrointestinal: hepatitis, vomiting.
Hematologic: thrombocytopenia.
Musculoskeletal: arthralgia.
Nervous System/Psychiatric: anxiety/nervousness, hallucinations, paresthesia.
Reproductive, male: impotence.
Skin: increased sweating, photosensitivity, urticaria.
Special Sense Organs: taste disturbances.
Hydrochlorothiazide
Other adverse experiences that have been reported with hydrochlorothiazide, without regard to causality, are listed below:
Body As A Whole: weakness; Cardiovascular: hypotension including orthostatic hypotension ; Digestive: pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, anorexia; Hematologic: aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia; Hypersensitivity: anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, fever, urticaria, rash, purpura; Metabolic: electrolyte imbalance, glycosuria; Musculoskeletal: muscle spasm; Nervous System/Psychiatric: Vertigo, paresthesias, dizziness, headache, restlessness; Renal: renal failure, renal dysfunction, interstitial nephritis; Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia; Special Senses: transient blurred vision, xanthopsia; Urogenital: impotence.
LABORATORY TEST FINDINGS
In controlled clinical trials, clinically important changes in standard laboratory parameters were infrequently associated with the administration of Metoprolol Fumarate. The laboratory test findings with Metoprolol Fumarate or hydrochlorothiazide or their combination may include:
Creatinine, Blood Urea Nitrogen-Minor increases in blood urea nitrogen (BUN).
Serum Electrolytes-Declines in serum potassium, sodium, chloride, magnesium. Increases in serum calcium and uric acid..
Glucose-Increase in serum or blood glucose.
Lipids-Increase in serum total cholesterol, triglycerides. Decreases in high density lipoprotein (HDL).
Liver Function Tests-Increases in liver enzymes and/or serum bilirubin.
OVERDOSAGE
Metoprolol Fumarate and Hydrochlorothiazide
The most frequently observed signs expected with overdosage of a beta-blocker are bradycardia and hypotension. Lethargy is also common, and with severe overdoses, delirium, coma, convulsions, and respiratory arrest have been reported to occur. Congestive heart failure, bronchospasm, and hypoglycemia may occur, particularly in patients with underlying conditions. With thiazide diuretics, acute intoxication is rare. The most prominent feature of overdose is acute loss of fluid and electrolytes. Signs and symptoms include cardiovascular (tachycardia, hypotension, shock), neuromuscular (weakness, confusion, dizziness, cramps of the calf muscles, paresthesia, fatigue, impairment of consciousness), gastrointestinal (nausea, vomiting, thirst) renal (polyuria, oliguria, or anuria [due to hemoconcentration]), and laboratory findings (hypokalemia, hyponatremia, hypochloremia, alkalosis, increased BUN [especially in patients with renal insufficiency]).
If overdosage of Metoprolol Fumarate and hydrochlorothiazide is suspected, the patient should be observed closely. Treatment is symptomatic and supportive; there is no specific antidote. Limited data suggest Metoprolol Fumarate is not dialyzable; similarly, there is no indication that hydrochlorothiazide is dialyzable. Suggested general measures include induction of emesis and/or gastric lavage, administration of activated charcoal, respiratory support, correction of fluid and electrolyte imbalance, and treatment of convulsions. Based on the expected pharmacologic actions and recommendations for other beta blockers and hydrochlorothiazide, the following measures should be considered when clinically warranted.
Bradycardia: Administer IV atropine. If the response is inadequate, isoproterenol or another agent with positive chronotropic properties may be given cautiously. Under some circumstances, transvenous pacemaker insertion may be necessary.
Hypotension, Shock: The patient’s legs should be elevated. IV fluids should be administered and lost electrolytes (potassium, sodium) replaced. Intravenous glucagon may be useful. Vasopressors should be considered.
Heart Block (second or third degree): Patients should be carefully monitored and treated with isoproterenol infusion or transvenous cardiac pacemaker insertion, as appropriate.
Congestive Heart Failure: Initiate conventional therapy (ie, digitalis, diuretics, vasodilating agents, inotropic agents).
Bronchospasm: Administer a bronchodilator such as isoproterenol and/or aminophylline.
Hypoglycemia: Administer IV glucose.
Surveillance: Fluid and electrolyte balance (especially serum potassium) and renal function should be monitored until normalized.
DOSAGE AND ADMINISTRATION
Dosing must be individualized considering baseline and target blood pressure as well as experience with individual agents.
The side effects of Metoprolol Fumarate succinate extended release are a mixture of dose-dependent phenomena (primarily bradycardia and fatigue); those of hydrochlorothiazide are a mixture of dose-dependent (primarily hypokalemia) and dose independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of Metoprolol Fumarate succinate extended release and hydrochlorothiazide will be associated with both sets of dose independent side effects. To minimize the known dose-related tolerability and safety-related effects of the individual agents, consideration should be given to initiating treatment at less than their maximum doses.
Metoprolol Fumarate may be administered with other antihypertensive agents.
Metoprolol Fumarate may be administered with or without food.
Metoprolol Fumarate is administered once daily.
Hydrochlorothiazide is effective in doses of 12.5 mg to 50 mg once daily.
Patients usually do not require doses in excess of 50 mg hydrochlorothiazide daily when used concomitantly with other antihypertensive agents.
The usual initial dose of Metoprolol Fumarate succinate extended release is 25 to 100 mg daily in a single dose.
Metoprolol Fumarate succinate extended release doses greater than 400 mg have not been studied.
Replacement Therapy
Metoprolol Fumarate may be substituted for treatment with individual components.
Dose Titration by Clinical Effect
Use the dose necessary based on patient response once the need for combination product is established. Response rates are greater at higher doses.
Patients with insufficient blood pressure effects with Metoprolol Fumarate succinate extended release or hydrochlorothiazide alone may be switched to Metoprolol Fumarate.
The lowest Metoprolol Fumarate tablet available is 25/12.5 mg. A 50/6.25 mg dose can be achieved by splitting the 100/12.5 mg tablet. Subsequently titration may be carried out every 2 weeks up to a maximum of 200/25 mg.
Patients with Renal Impairment
The usual regimens of therapy with Metoprolol Fumarate may be followed as long as the patient’s creatinine clearance is > 30 mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so Metoprolol Fumarate is not recommended.
Patients with Hepatic Impairment
The usual regimens of therapy with Metoprolol Fumarate may be followed in patients with mild hepatic impairment. In patients with moderate hepatic impairment, consideration should be given to initiation of Metoprolol Fumarate with lower doses of hydrochlorothiazide.
HOW SUPPLIED
Metoprolol Fumarate 25/12.5
Yellow, circular, biconvex, film-coated tablet engraved with “A” above “IH” on one side, are supplied in bottles of 30.
Metoprolol Fumarate 50/12.5 (NDC 0310-1095-30)
Light orange, circular, biconvex, film-coated tablet engraved with “A” above “IK” on one side, are supplied in bottles of 30.
Metoprolol Fumarate 100/12.5 (NDC 0310-1097-30)
Yellow, circular, biconvex, film-coated tablet engraved with “A” above “IL” on one side and scored on the other side, are supplied in bottles of 30.
Storage:
Store at 25°C (77°F). Excursions permitted to 15-30°C (59–86°F).
All trademarks are the property of the AstraZeneca group of companies
©AstraZeneca 2011
AstraZeneca Pharmaceuticals LP Wilmington, DE 19850
Rev. 12/11
NDC 0310-1087-30
30 tablets
Metoprolol Fumarate
(metoprolol SUCCINATE extended
release/hydrochlorothiazide)
25*/12.5 mg tablets
Mfd. for: AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
By: AstraZeneca AB
S-151 85 Södertälje, Sweden
Product of Sweden
Rx only
AstraZeneca
NDC 0310-1095-30
30 tablets
Metoprolol Fumarate
(metoprolol SUCCINATE extended
release/hydrochlorothiazide)
50*/12.5 mg tablets
Mfd. for: AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
By: AstraZeneca AB
S-151 85 Södertälje, Sweden
Product of Sweden
Rx only
AstraZeneca
NDC 0310-1097-30
30 tablets
Metoprolol Fumarate
(metoprolol SUCCINATE extended
release/hydrochlorothiazide)
100*/12.5 mg tablets
Mfd. for: AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
By: AstraZeneca AB
S-151 85 Södertälje, Sweden
Product of Sweden
Rx only
AstraZeneca
Metoprolol Fumarate available forms, composition, doses:
Indications and Usages:
ATC codes:
ICD-10 codes:
Metoprolol Fumarate destination | category:
Drugs with same active ingredients (Pharmaceutical companies):
References
- Dailymed."METOPROLOL FUMARATE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
- "metoprolol". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
- "metoprolol". http://www.drugbank.ca/drugs/DB0026... (accessed August 28, 2018).
Frequently asked Questions
Can i drive or operate heavy machine after consuming Metoprolol Fumarate?Depending on the reaction of the Metoprolol Fumarate after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Metoprolol Fumarate not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.
Is Metoprolol Fumarate addictive or habit forming?Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
Review
sdrugs.com conducted a study on Metoprolol Fumarate, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Metoprolol Fumarate consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.Visitor reports
Visitor reported useful
No survey data has been collected yetVisitor reported side effects
No survey data has been collected yetVisitor reported price estimates
No survey data has been collected yetVisitor reported frequency of use
No survey data has been collected yetVisitor reported doses
No survey data has been collected yetVisitor reported time for results
No survey data has been collected yetVisitor reported administration
No survey data has been collected yetVisitor reported age
No survey data has been collected yetVisitor reviews
There are no reviews yet. Be the first to write one! |
The information was verified by Dr. Rachana Salvi, MD Pharmacology