Cardiosel

Metoprolol tartrate (Cardiosel) 50 mg Tablet: White, ¹/₄" diameter, round, biconvex tablet, plain on both sides.
Metoprolol tartrate (Cardiosel) 100 mg Tablet: White, ¹¹/₃₂" diameter, round, biconvex tablet, bisected on one side and plain on the other side.
Each tablet contains: Metoprolol tartrate 50 mg or 100 mg.

Pharmacology: Pharmacodynamics: Metoprolol is a beta-adrenergic receptor blocking agent which acts preferentially on beta₁ adrenoceptors, mainly located in cardiac muscle. This preferential effect is not absolute since at higher doses metoprolol also inhibits beta₂ adrenoceptors, mainly located in the bronchial and vascular musculature. Metoprolol has no partial agonist (intrinsic sympathomimetic) activity and membrane-stabilizing activity is detectable only at doses much greater than required for beta blockade.
Metoprolol's beta-blocking activity is manifested by (1) a decrease in heart rate and cardiac output at rest and upon exercise, (2) decrease in systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) decrease in reflex orthostatic tachycardia.
The antihypertensive mechanism of beta-blockers has not been elucidated. Several possible mechanisms have been proposed: (1) competitive antagonism of catecholamines at peripheral (particularly cardiac) adrenergic neuron sites resulting in decreased cardiac output, (2) a central effect leading to decreased sympathetic outflow to the periphery, and (3) suppression of renin activity.
In angina pectoris, metoprolol decreases the frequency and severity of ischemic episodes and increases physical working capacity. These beneficial effects may be due to decreased myocardial oxygen demand as a result of the decreased heart rate and myocardial contractility.
In supraventricular tachycardia, atrial fibrillation, ventricular extrasystoles or other ventricular arrhythmias, metoprolol has a regulating effect on the heart rate. Its anti-arrhythmic effect is due to inhibition of automaticity of pacemaker cells and prolongation of atrioventricular (AV) conduction.
Metoprolol decreased mortality in patients with suspected or confirmed myocardial infarction. This effect is due to a decreased incidence of severe ventricular arrhythmias and limitation of infarct size. Metoprolol has also been shown to decrease the incidence of non-fatal myocardial reinfarction.
Pharmacokinetics: Metoprolol is readily and completely absorbed from the gastrointestinal tract. Peak plasma metoprolol concentrations are achieved 1.5 to 2 hours after dosing. Due to extensive hepatic first-pass metabolism, the bioavailability of a single metoprolol dose is about 50%, increasing to 70% during repeated administration. Ingestion with food may increase the bioavailability of a single oral dose by about 20 to 40%.
Metoprolol is widely distributed, with a volume of distribution of 3.2 to 5.6 L/kg. It crosses the blood-brain barrier and the placenta, and is distributed into breast milk. It is about 10% bound to plasma protein. Metoprolol levels in cerebrospinal fluid are similar to those in plasma in patients with hypertension.
Metoprolol is extensively metabolized in the liver, predominantly by the cytochrome P450 isoenzyme CYP2D6, and undergoes oxidative deamination, O-dealkylation followed by oxidation, and aliphatic hydroxylation. There are marked ethnic differences in the prevalence of poor metabolizers phenotype. About 7% of Caucasians and less than 1% Orientals are poor metabolizers. CYP2D6 poor metabolizers exhibit several-fold higher plasma metoprolol concentrations than extensive metabolizers with normal CYP2D6 activity. However, the CYP2D6 dependent metabolism of metoprolol appears to have little or no effect on its safety or tolerability.
Metoprolol and its inactive metabolites are excreted in urine mainly via glomerular filtration, although tubular secretion and reabsorption may be involved. Metoprolol's average elimination half-life is 3 to 4 hours; it may be 7 to 9 hours in poor metabolizers. About 95% of the dose can be recovered in urine within 72 hours. Less than 5% of an oral metoprolol dose is excreted unchanged in urine.
The excretion of metabolites is decreased in patients with renal impairment. Significant accumulation of metabolites will occur only in patients with creatinine clearance of about 5 mL/min or less, and this accumulation would not influence metoprolol's beta-blocking properties.
Liver cirrhosis may increase the bioavailability of unchanged metoprolol and decrease its total clearance.
Inflammatory disease has no effect on metoprolol's pharmacokinetics. Hyperthyroidism may increase pre-systemic metoprolol clearance.

Hypertension: As monotherapy or in combination with other antihypertensive agents.
Angina pectoris: Long-term prophylaxis.
Cardiac arrhythmias: Disturbances of cardiac rhythm, including supraventricular and ventricular arrhythmias.
Myocardial infarction (MI): Treatment of hemodynamically stable patients with definite or suspected acute MI to reduce cardiovascular mortality.
Adjunct to treatment of thyrotoxicosis.
Prevention of migraine.

General Dosing Recommendations: Patients should regularly and continuously take metoprolol, as directed, with or immediately after meals. If a dose is missed, the patient should take only the next scheduled dose (without doubling it).
Individualize dosage according to patient's clinical response. (See Table.)

Click on icon to see table/diagram/image

Metoprolol overdosage may be expected to produce effects that are mainly extensions of pharmacologic effects, including symptomatic bradycardia, severe hypotension, bronchospasm, acute cardiac failure, impaired conduction, decreased cardiac contractility, heart block, shock, and cardiac arrest.
The first manifestations of overdose occur within 20 minutes to 2 hours after metoprolol ingestion. The effects of massive overdose may persist for several days, despite decreasing plasma levels.
In cases of overdose, patients should be admitted to a hospital and should be managed in an intensive care setting, with continuous monitoring of cardiac function, blood gases, and blood chemistry. Institute emergency supportive measures (e.g., artificial ventilation, cardiac pacing) if appropriate. Patients who have taken small overdose should be closely observed for manifestations of poisoning for at least 4 hours.
In acute metoprolol overdose, immediately empty the stomach by gastric lavage and/or activated charcoal. Initiate supportive and symptomatic treatment. For symptomatic bradycardia, IV atropine may be given; if bradycardia persists, IV isoproterenol hydrochloride may be administered cautiously. A vasopressor (e.g., dopamine, dobutamine, norepinephrine) may be given for severe hypertension; IV glucagon may be useful if hypotension is refractory to vasopressors. A beta-adrenergic agonist (e.g., isoproterenol) and/or a theophylline derivative may be given for bronchospasm. Monitor patients for evidence of cardiac arrhythmias during and after administration of the bronchodilator. Diazepam may be administered to control seizures. For heart failure, a cardiac glycoside, diuretic, and oxygen should be used; IV glucagons may also be useful.

Hypersensitivity to metoprolol or any other beta-blocker or any component of the product.
Severe bronchial asthma or history of severe bronchospasm.
Hypotension.
Metabolic acidosis.
Hypertensive and angina patients with the following conditions: Sinus bradycardia; Heart block greater than first degree; Cardiogenic shock; Overt or decompensated cardiac failure; Sick sinus syndrome; Severe peripheral arterial circulatory disorders; Untreated pheochromocytoma.
Patients with acute myocardial infarction who have the following conditions: Heart rate <45 beats/minute; Second- and third-degree heart block; Significant first degree heart block (P-R interval ≥0.24 sec); Systolic blood pressure <100 mmHg; Moderate to severe cardiac failure.

Ischemic Heart Disease: Exacerbations of angina pectoris, and in some cases, myocardial infarction have occurred after abrupt discontinuation of certain beta-blockers. Gradually reduce dosage over a period of 1 to 2 weeks and carefully monitor the patient when discontinuing chronically administered metoprolol, particularly in patients with ischemic heart disease. Metoprolol should promptly be reinstated, at least temporarily, and initiate other measures appropriate for the management of unstable angina if angina markedly worsens or acute coronary insufficiency develops. Patients should be warned against interruption or discontinuation of therapy without physician's advice. It may be prudent not to discontinue metoprolol abruptly even in patients treated only for hypertension since coronary artery disease is common and may be unrecognized.

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 or exacerbating minimal cardiac failure. Cautiously administer metoprolol in hypertensive and angina patients who have congestive heart failure controlled by digitalis and diuretics. Both digitalis and metoprolol slow AV conduction. Carefully monitor the hemodynamic status of the patient during metoprolol treatment. Discontinue metoprolol if heart failure occurs or persists despite appropriate treatment.
Bronchospastic Diseases: IN GENERAL, PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD NOT RECEIVE BETA-BLOCKERS, INCLUDING METOPROLOL. 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, coadminister a beta₂-stimulating agent, and use the lowest possible metoprolol dose. In these cases it would be prudent initially to give metoprolol in smaller doses thrice a day, instead of larger doses twice a day, to avoid higher plasma levels associated with longer dosing intervals.
Because it is not known to what extent beta₂-stimulating agents may exacerbate myocardial ischemia and the extent of infarction, these agents should not be used prophylactically. Discontinue metoprolol if bronchospasm not related to congestive heart failure occurs. Administer a theophylline derivative or a beta₂-agonist cautiously, depending on the clinical condition of the patient. Both theophylline derivatives and beta₂-agonists may produce serious cardiac arrhythmias.
Hypertension and Angina: In Patients without a History of Cardiac Failure: Cardiac failure may result from prolonged depression of myocardium with beta-blockers over a period of time. Fully digitalize and/or give patient a diuretic at the first sign or symptom of impending cardiac failure (e.g., weight gain, increasing shortness of breath). If cardiac failure continues, discontinue metoprolol, gradually if possible.
Major Surgery: The necessity or desirability of withdrawing beta-blockers, including metoprolol, prior to major surgery is controversial. The impaired ability of the heart to respond to reflex adrenergic stimuli may increase the risks of general anesthesia and surgical procedures.
Like other beta-blockers, metoprolol is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by administration of such agents (e.g., dobutamine or isoproterenol). However, such patients may be subject to protracted severe hypotension. Difficulty in restarting and maintaining the heartbeat has also been observed with beta-blockers.
Diabetes and Hypoglycemia: Use with caution in patients with diabetes mellitus, particularly those who are receiving insulin or oral hypoglycemic agents. Diabetic patients should be warned that beta-blockers, including metoprolol, may mask the tachycardia occurring with hypoglycemia; however, other manifestations of hypoglycemia such as dizziness and sweating may not be significantly affected.
Pheochromocytoma: Metoprolol is contraindicated in patients known to have, or suspected of having, pheochromocytoma. Metoprolol should always 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 (e.g., tachycardia) of hyperthyroidism. Carefully manage patients suspected of developing thyrotoxicosis to avoid abrupt withdrawal of beta blockade, which might precipitate a thyroid storm.
Myocardial Infarction: Bradycardia: Metoprolol decreases sinus heart rate in most patients. This decrease is greatest among patients with high initial heart rates and least among patients with low initial heart rates. Acute myocardial infarction, particularly inferior infarction, may in itself produce significant lowering of the sinus rate. If the sinus rate decreases to <40 beats/min, particularly if associated with evidence of lowered cardiac output, administer atropine 0.25 to 0.5 mg intravenously. Discontinue metoprolol if treatment with atropine is not successful, and consider cautious administration of isoproterenol or installation of a cardiac pacemaker.
AV Block: Metoprolol slows AV conduction and may produce significant first- (P-R interval ≥0.26 sec), second-, or third-degree heart block. Similarly, acute myocardial infarction produces heart block.
Discontinue metoprolol and administer atropine 0.25 to 0.5 mg intravenously if heart block occurs. Consider cautious administration of isoproterenol or installation of a cardiac pacemaker if treatment with atropine is not successful.
Hypotension: Discontinue metoprolol if hypotension (systolic blood pressure ≤90 mmHg) occurs and carefully assess the hemodynamic status of the patient and the extent of myocardial damage. Invasive monitoring of central venous, pulmonary capillary wedge, and arterial pressures may be required. Institute appropriate therapy with fluids, positive inotropic agents, balloon counter pulsation, or other treatment modalities. If hypotension is associated with sinus bradycardia or AV block, treatment should be directed at reversing these.
General: Use with caution in patients with impaired hepatic failure.
Patients should be advised (1) to avoid operating machinery or engaging in other tasks requiring alertness until the patient's response to metoprolol therapy has been determined, (2) to contact the physician if any difficulty in breathing occurs, and (3) to inform the physician/dentist before any type of surgery that he or she is taking metoprolol.
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.
The full oculomucocutaneous syndrome has not been observed with metoprolol; however, part of this syndrome (dry eyes either alone or, occasionally, with skin rashes) has occurred. In most cases, symptoms cleared upon discontinuation of metoprolol. Carefully observe patients for potential ocular effects. If such effects occur, metoprolol should be discontinued.
Use in Children: The safety and efficacy in children have not been established.
Use in the Elderly: There were no age-related differences in safety and efficacy.

Pregnancy: Pregnancy Category C. Although there are no adequate and controlled studies to date in humans, metoprolol has been shown to increase post-implantation loss and to decrease neonatal survival in rats when given at metoprolol tartrate dosages up to 55.5 times the maximum recommended human dosage of 450 mg daily. Metoprolol should be used in pregnancy only if clearly needed.
Lactation: Since metoprolol is distributed into milk, the drug should be used with caution in breastfeeding mothers.

Cardiovascular: Arterial insufficiency (e.g., Raynaud's phenomenon), bradycardia, cold extremities, cardiac arrhythmias, cardiac conduction disorders, chest pain, claudication, congestive heart failure, decreased high-density lipoprotein (HDL), edema, first-degree heart block, gangrene in patients with pre-existing severe peripheral circulatory disorders (rare), hypotension, increased triglycerides, orthostatic hypotension occasionally with syncope, palpitations, peripheral edema, precordial pain, second- or third-degree heart block.
Endocrine/Metabolic: Decreased libido, hypoglycemia, unstable diabetes, weight gain; Increases in the following: alkaline phosphatase, transaminases, lactate dehydrogenase, blood urea nitrogen (BUN), serum creatinine, uric acid.
Gastrointestinal: Abdominal pain, constipation, diarrhea, digestive tract disorders, dry mouth, flatulence, gastric pain, heartburn, hepatitis (rare), hiccups, jaundice (rare), nausea, non-specific hepatic dysfunction (rare), retroperitoneal fibrosis, vomiting, xerostomia.
Musculoskeletal: Arthritis, general weakness, muscle cramps, musculoskeletal pain, polymyalgia-like syndrome, restless legs.
Nervous: Confusion, decreased alertness, depression, dizziness, full headedness, hallucination, headache, impotence, increased dreaming, insomnia, lethargy, mental confusion, nervousness, nightmares, paresthesia, personality disorder, short-term memory loss, sleep disturbances, somnolence, tiredness, vertigo.
Respiratory: Bronchospasm, dyspnea, rhinitis, shortness of breath, wheezing.
Skin: Alopecia, dry skin, hyperhidrosis, photosensitivity (very rare), pruritus, rash, sweating, worsening of psoriasis (very rare).
Special senses: Blurred vision, dry eyes, eye irritation, hearing disorders (e.g., hypoacusis or deafness), tinnitus, visual disturbances.
Others: Peyronie's disease, agranulocytosis, fatigue, increased or decreased antinuclear factor (ANF) levels, lassitude, thrombocytopenia.
Potential Undesirable Effects: Cardiovascular: Intensification of AV block.
Hematologic: Eosinophilia, nonthrombocytopenic purpura, thrombocytopenic purpura.
Hypersensitivity reactions: Erythematous rash, fever combined with aching and sore throat, laryngospasm, respiratory distress.
Nervous: Reversible mental depression progressing to catatonia, acute reversible syndrome characterized by disorientation to time and place, emotional lability, slightly clouded sensorium, decreased performance on neuropyschometrics.

Catecholamine-depleting drugs (e.g., reserpine): Additive effect when given with beta-blockers. Patients given these drugs should be observed for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.
Calcium channel blockers (e.g., verapamil, diltiazem): May potentiate the depressant effects of beta-blockers on blood pressure, heart rate, cardiac contractility and AV conduction. A calcium channel blocker of the verapamil (phenylalkylamine) type should not be given intravenously to patients taking metoprolol due to the risk of cardiac arrest in this situation. Closely monitor patients taking an oral calcium channel blocker of the verapamil type in combination with metoprolol.
Class I Anti-arrhythmic drugs and Amiodarone: Amiodarone, propafenone and other class I anti-arrhythmic agents (e.g., quinidine, disopyramide) may potentiate the effects of beta-blockers on heart rate and AV conduction.
Clonidine: If a patient is treated concurrently with clonidine and metoprolol, and clonidine is to be discontinued, metoprolol should be withdrawn several days before clonidine. This is because the hypertension that can follow withdrawal of clonidine may be increased in patients receiving concurrent beta-blocker treatment.
CYP2D6 inhibitors: Potent inhibitors of CYP2D6 may increase plasma metoprolol concentration. Strong inhibition of CYP2D6 would result in the change of phenotype into poor metabolizer. Thus, use with caution when coadministering potent CYP2D6 inhibitors with metoprolol. Known clinically significant potent inhibitors of CYP2D6 are antidepressants (e.g., fluoxetine, paroxetine, bupropion), antipsychotics (e.g., thioridazine), antiarrhythmics (e.g., quinidine, propafenone), antiretrovirals (e.g., ritonavir), antihistamines (e.g., diphenhydramine), antimalarials (e.g., hydroxychloroquine, quinidine), antifungals (e.g., terbinafine), and medications for stomach ulcers (e.g., cimetidine).
Digitalis glycosides: Concomitant use may result in excessive bradycardia and/or increase in AV conduction time.
General anesthetics: Some inhalation anesthetics may enhance the cardio depressant effect of beta-blockers.
Hepatic enzyme inducers: Enzyme inducing agents (e.g., rifampicin) may reduce plasma concentrations of metoprolol.
Insulin and oral hypoglycemic drugs: Beta-blockers may be associated with increased or prolonged hypoglycemia in diabetic patients who use insulin. Beta-blockers may also antagonize the hypoglycemic effects of sulfonylureas. The risk of either effect is less with a beta₁-selective drug such as metoprolol than with a non-selective beta-blocker. However, diabetic patients receiving metoprolol should be monitored to ensure that diabetes control is maintained.
Lidocaine (xylocaine): Metoprolol may reduce the clearance of lidocaine, leading to increased lidocaine effects.
Nitroglycerin: May enhance metoprolol's hypotensive effect.
Nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., indomethacin): May decrease metoprolol's antihypertensive effect.
Prazosin: The acute postural hypotension that can follow the first dose of prazosin may be increased in patients already taking a beta-blocker.
Sympathomimetics: Metoprolol will antagonize the beta₁ effects of sympathomimetic agents but should have little influence on the bronchodilator effects of beta₂-agonists at normal therapeutic doses.
Alcohol: During concomitant ingestion of alcohol and metoprolol the concentration of blood alcohol may reach higher levels and may decrease more slowly.
Other drugs: Other antihypertensive drugs: Additive effect; care should be taken to avoid hypotension. However, combinations of antihypertensive drugs may often be used with benefit to improve control of hypertension.
As beta-blockers may affect the peripheral circulation, exercise caution when drugs with similar activity (e.g., ergotamine) are given concurrently.
Use with caution when beta-blockers are coadministered with sympathetic ganglion blocking agents, other beta blockers (including eye drops), or monoamine oxidase (MAO) inhibitors.

Store at temperatures not exceeding 30°C.

Beta-Blockers

C07AB02 - metoprolol ; Belongs to the class of selective beta-blocking agents. Used in the treatment of cardiovascular diseases.

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