Date of approval.
Date of revision.
Metoprolol Tartrate Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Metoprolol Tartrate Tablets
English name: Metoprolol Tartrate Tablets
Hanyu Pinyin: Jiushisuan Meituoluo’er Pian
Ingredients
The main ingredient of this product is metoprolol tartrate.
Chemical name: (±)-1-isopropylamino-3-[4-(2-methoxyethyl)phenoxy]-2-propanol L(+)-tartaric acid salt
The chemical structure formula is
Molecular formula: (C15H25NO3)2-C4H6O6
Molecular weight: 684.82
【Properties】.
This product is a white tablet.
Indications】
It is used for the treatment of hypertension, angina pectoris, myocardial infarction, hypertrophic cardiomyopathy, aortic coarctation, cardiac arrhythmia, hyperthyroidism, cardiac neurosis and so on. In recent years, it is also used for the treatment of heart failure, which should be used under the guidance of an experienced physician.
Specification
(1) 25 mg (2) 50 mg
Dosage
Take orally. The dose should be individualized to avoid the occurrence of bradycardia. It should be taken on an empty stomach. Taking the drug with a meal increases the bioavailability of metoprolol by 40%.
Treatment of hypertension: 100 mg to 200 mg daily in 1 to 2 doses.
Acute myocardial infarction: Early use within the first few hours is recommended because immediate use reduces the extent of infarction and short-term (15-day) mortality in patients who have not been thrombolized (this effect occurs as early as 24 hours after dosing). In patients who have been thrombolized, it reduces the rate of reinfarction and reischemia and, if administered within 2 hours, reduces mortality. General Use: Metoprolol can be given intravenously 2.5-5 mg once (within 2 minutes) every 5 minutes for a total of 3 doses of 10-15 mg, followed by oral doses of 25-50 mg every 6-12 hours for 24-48 hours starting 15 minutes, and then oral doses of 50-100 mg twice a day.
Unstable angina: Early use is also advocated, and the dosage can be referred to acute myocardial infarction.
If atrial fibrillation occurs in acute myocardial infarction, metoprolol can be used intravenously if not contraindicated, in the same way as above.
If not contraindicated after myocardial infarction, long-term use should be used, as this has been shown to reduce cardiac mortality, including sudden death. Usually 50 to 100 mg once, twice a day.
In the treatment of hypertension, angina pectoris, arrhythmia, hypertrophic cardiomyopathy, and hyperthyroidism generally 25-50 mg once, 2-3 times a day, or 100 mg twice a day.
Heart Failure: This drug should be used in addition to anti-heart failure treatment with digitalis and/or diuretics. Initially 6.25 mg once, 2-3 times a day, and then increase 6.25-12.5 mg once every few days to a week, 2-3 times a day, depending on the clinical situation, the maximum dose can be 50-100 mg once, twice a day.
The maximum dose should not exceed 300 mg-400 mg a day.
[Adverse reactions].
The incidence of adverse reactions is about 10% and is usually dose-related.
Common (≥ 1/100 to < 1/10).
General side effects: fatigue, headache, dizziness
Circulatory system: chills in extremities, bradycardia, palpitations
Gastrointestinal system: abdominal pain, nausea, vomiting, diarrhea and constipation
Uncommon (≥1/1,000 to < 1/100).
General side effects: chest pain, weight gain
Circulatory: temporary worsening of heart failure
Neurological: sleep disturbances, sensory abnormalities
Respiratory: shortness of breath, bronchial asthma or bronchospasm in those with asthma symptoms
Rare (≥ 1/10,000 to < 1/1,000).
General side effects: excessive sweating, hair loss, altered taste, reversible abnormalities of sexual function
Hematologic: thrombocytopenia
Circulatory system: prolonged atrioventricular conduction time, arrhythmias, edema, syncope
Nervous system: nightmares, depression, memory impairment, confusion, neuroticism, anxiety, hallucinations
Skin: allergic skin reactions, exacerbation of psoriasis, photosensitivity
Liver: elevated transaminases
Ocular: visual impairment, dry eyes and/or eye irritation
Ear: tinnitus
Occasional cases of arthralgia, hepatitis, painful muscle cramps, dry mouth, conjunctivitis-like symptoms, rhinitis and attention impairment, and gangrene in patients with concomitant vascular disease have been reported.
Contraindications]
Cardiogenic shock. Pathological sinus node syndrome. Second and third degree AV block. Patients with unstable, decompensated heart failure (pulmonary edema, hypoperfusion, or hypotension) who are receiving beta agonist orthotropic therapy on a continuous or intermittent basis. Symptomatic bradycardia or hypotension. This product should not be given to patients with suspected acute myocardial infarction with a heart rate <45 beats/min, P-Q interval >0.24 seconds, or systolic blood pressure <100 mmHg. Patients with severe peripheral vascular disease with risk of gangrene. Hypersensitivity to any component of this product or other beta-blockers.
Precautions]
Renal impairment
Renal function has no significant effect on the clearance of this product, so no dose adjustment is necessary in patients with renal impairment.
Hepatic impairment
The dose of metoprolol for patients with cirrhosis is usually the same as for those with normal liver function. Dose reduction should be considered only in cases of very severe impairment of hepatic function (e.g., patients undergoing bypass surgery).
Verapamil should not be given intravenously to patients receiving beta-blocker therapy.
Metoprolol may worsen symptoms of peripheral vascular circulation disorders such as intermittent claudication. Caution must be exercised in cases of severe renal impairment, severe acute illness with metabolic acidosis, and in the combination of digitalis.
It should not be used in patients with underlying or symptomatic cardiac insufficiency in the absence of concomitant therapy. Patients suffering from variant (Prinzmetal’s) angina pectoris may experience an increase in the frequency and extent of anginal episodes due to alpha receptor-mediated coronary vasoconstriction following the use of beta-blockers. Therefore, non-selective β-blockers should not be used in such patients. Selective beta1 receptor blockers must also be used with caution.
In patients with bronchial asthma or other chronic obstructive pulmonary disease, adequate concomitant bronchodilator therapy should be given, and the dose of beta2 agonists may need to be increased.
The effect of metoprolol treatment on glucose metabolism or the risk of masking hypoglycemia is lower than with non-selective beta-blockers.
In rare cases, pre-existing moderate atrioventricular conduction abnormalities may be exacerbated (possibly leading to atrioventricular block).
Treatment with beta-blockers may hinder treatment of allergic reactions, and conventional doses of epinephrine therapy do not always have the desired efficacy. Patients with pheochromocytoma who use this product should consider combining it with an alpha-blocker.
It should be withdrawn as gradually as possible over a period of at least two weeks, with doses being tapered to 25 mg, during which time close monitoring should be performed, particularly in patients with known ischemic heart disease. The risk of coronary events, including sudden cardiac death, may be increased during withdrawal of beta-blockers.
The anesthesiologist should be informed prior to surgery that the patient is taking this product. Discontinuation of beta-blockers is not recommended for patients undergoing surgery.
Effects on driving a car and operating machinery
Vertigo and fatigue may occur during treatment with this product and should be used with caution when concentration is required, such as when driving and operating machinery.
Use with caution in athletes.
Pregnant women and nursing mothers
Beta-blockers (including metoprolol) reduce placental perfusion and may cause fetal growth retardation, bradycardia, intrauterine death, miscarriage and preterm delivery.
Metoprolol is highly concentrated in human milk (approximately three times the maternal plasma concentration). beta-blockers (including metoprolol) can have adverse effects on the newborn and infant, especially bradycardia.
Metoprolol should not be used in pregnant or lactating women unless necessary.
If you are pregnant or are breastfeeding, may become pregnant or are trying to become pregnant, you should consult your doctor before using this product.
[Pediatric Use].
There is limited experience with the use of this product in children.
[Geriatric Use].
The pharmacokinetics in the elderly are not significantly altered compared to those in younger adults; therefore, no dosage adjustment is necessary in elderly patients.
Drug Interactions]
Metoprolol is a substrate for the action of CYP2D6. Drugs that inhibit CYP2D6 can affect the plasma concentration of metoprolol. Drugs that inhibit CYP2D6 such as quinidine, terbinafine, paroxetine, fluoxetine, sertraline, celecoxib, propafenone, and benadryl. For patients taking this product, the dose of this product should be reduced at the start of treatment with the above drugs.
This product should be avoided in combination with the following drugs.
Barbiturates: Barbiturates (pentobarbital has been studied) can increase the metabolism of metoprolol through enzyme induction.
Propafenone: In four patients already using metoprolol, plasma concentrations of metoprolol were increased 2 to 5-fold after administration of propafenone, and two of them experienced side effects related to metoprolol. This interaction was confirmed in 8 healthy volunteers. A possible explanation for this interaction is that propafenone, similar to quinidine, inhibits the metabolism of metoprolol via the cytochrome P450 2D6 pathway. Since propafenone also has beta-blocking effects, its combination with metoprolol is difficult to master.
Verapamil: Verapamil has the potential to cause bradycardia and decreased blood pressure when combined with beta-blockers (has been reported with atenolol, propranolol, and indolol). Verapamil and beta-blockers have additive inhibitory effects on atrioventricular conduction and sinus node function.
Dose adjustment may be required when this product is used in combination with
Amiodarone: One case report showed the possibility of significant sinus bradycardia with concomitant use of amiodarone and metoprolol. The long half-life of amiodarone (approximately 50 days) means that interactions between the two drugs may still occur with metoprolol for a longer period of time after amiodarone therapy has been discontinued.
Class I antiarrhythmic drugs: Class I antiarrhythmic drugs have additive negative inotropic effects with beta-blockers and therefore have the potential to cause serious hemodynamic side effects in patients with impaired left ventricular function. Concomitant use of metoprolol and class I antiarrhythmic drugs should also be avoided in patients with pathologic sinus node syndrome and pathologic AV block. The interaction between propiamine and metoprolol has been clearly documented.
Non-steroidal anti-inflammatory/anti-rheumatic drugs (NSAIDs): NSAID anti-inflammatory analgesics have been found to counteract the antihypertensive effects of beta-blockers. The main drug studied in this regard is indomethacin. β-blockers are likely not to interact with sulforaphane. In a study of diclofenac, no interaction of beta-blockers with diclofenac was found.
Diphenhydramine: In a rapidly hydroxylating metabolizing population, diphenhydramine reduced the clearance of metoprolol to alpha-hydroxymetoprolol via CYP 2D6 conversion metabolism by 2.5-fold. The effect of metoprolol was thus enhanced. Diphenhydramine may inhibit the metabolism of other CYP 2D6 substrates.
Diltiazem: Calcium antagonists and beta-blockers have additive inhibitory effects on atrioventricular conduction and sinus node function. Cases of significant bradycardia have been reported when β-blockers are combined with diltiazem.
Epinephrine: Approximately 10 cases have been reported showing significant hypertension and bradycardia after administration of epinephrine in patients treated with nonselective beta-blockers, including indololol and propranolol. These clinical observations have been confirmed in studies of healthy volunteers. It is possible that epinephrine in local anesthetics may cause such reactions when administered intravascularly. Presumably, the risk of this reaction is lower when cardioselective beta-blockers are used.
Phenylpropanolamine: Phenylpropanolamine 50 mg administered as a single dose elevates diastolic blood pressure to pathological levels in healthy volunteers. Propranolol usually antagonizes this increase in blood pressure caused by phenylpropanolamine. However, in patients treated with high doses of phenylpropanolamine, beta-blockers can paradoxically cause a hypertensive response. Hypertensive reactions have also been reported during treatment with phenylpropanolamine alone.
Quinidine: Quinidine inhibits metabolism of metoprolol in the so-called “fast hydroxylators” (a type that exceeds 90% in Sweden), resulting in significantly higher plasma concentrations and enhanced beta-blocking effects of the latter. Other beta-blockers metabolized via the same enzymatic pathway (cytochrome P450 2D6) may also interact with quinidine in the same way.
Colistin: Beta-blockers have the potential to exacerbate the rebound hypertension that occurs when colistin is abruptly discontinued. To discontinue combination therapy with colistin, beta-blockers should be discontinued several days prior to the discontinuation of colistin.
Rifampin: Rifampin can induce metabolism of metoprolol, resulting in lower blood levels of the latter.
Patients receiving concomitant other beta-blockers (e.g., eye drops) or monoamine oxidase (MAO) inhibitors should be closely monitored. Inhalation anesthesia increases cardiac depression in patients receiving beta-blockers.
The dose of oral hypoglycemic agents should be readjusted in patients receiving beta-blocker therapy. The plasma concentration of metoprolol will increase if combined with cimetidine or hydrazidiazide.
[Drug Overdose].
Toxicity: Metoprolol 7.5 g caused lethal poisoning in adults. A 5-year-old child accidentally took 100 mg without any symptoms after gastric lavage. 450 mg in a 12-year-old child caused moderate poisoning, 1.4 g in adults caused moderate poisoning, 2.5 g in adults caused severe poisoning, and 7.5 g in adults caused very severe poisoning.
Symptoms: Cardiovascular system symptoms are the most significant, but in some cases, especially in children and young patients, central nervous system symptoms and respiratory depression may be the main manifestations. The main symptoms of intoxication include bradycardia, I-III degree AV block, cardiac arrest, decreased blood pressure, poor perfusion of peripheral circulation, cardiac insufficiency, cardiogenic shock, respiratory depression, and asphyxia. Other symptoms include fatigue, confusion, loss of consciousness, frequent fine tremor, spasms, sweating, abnormal sensation, bronchospasm, nausea, vomiting, possible esophageal spasm, hypoglycemia (children are particularly susceptible) or hyperglycemia, hyperkalemia, effects on the kidneys, and transient myasthenia gravis syndrome. The combination of alcohol, anti-hypertensives, quinidine or barbiturates may aggravate the patient’s condition. The first symptoms of drug overdose are seen 20 minutes to 2 hours after taking the drug.
Treatment: If the diagnosis is clear, gastric lavage and activated charcoal are given and the condition is closely monitored for changes. Caution! To reduce the risk of vagal irritation, atropine (0.25-0.5 mg in adults, 10-20 μg/kg in children) should be given intravenously before gastric lavage. When indicated, perform endotracheal intubation and respiratory support therapy. Give appropriate volume replacement therapy, glucose infusion, and monitor ECG. Atropine 1.0 to 2.0 mg intravenously, repeated if necessary (mainly to control vagal symptoms). In patients with depressed myocardial function, dobutamine or dobutamine, and calcium glucuronide (9 mg/ml) 10-20 ml may be administered drip. another alternative is glucagon 50-150 μg/kg IV over 1 minute followed by IV drip, or amrinone. The addition of epinephrine is effective in some patients. in patients with widened QRS waves and arrhythmias, sodium chloride or sodium bicarbonate may be infused. A pacemaker may be required. Resuscitation of patients in cardiac arrest sometimes takes up to several hours. For the treatment of bronchospasm, terbutaline (injection or inhalation) may be used. In addition, symptomatic treatment is carried out.
Pharmacology and toxicology]
Pharmacological effects
Metoprolol is a cardioselective β1-adrenoceptor blocker, but at higher plasma concentrations it also inhibits β2 adrenoceptors present mainly on bronchial and vascular smooth muscle.
Clinical pharmacological studies have shown that metoprolol has the following beta-blocking activities: decreases heart rate and cardiac output at rest and during exercise, decreases systolic blood pressure during exercise, inhibits isoproterenol-induced tachycardia, and reduces reflex upright tachycardia.
Hypertension: The antihypertensive mechanism of beta-blockers has not been elucidated. Possible mechanisms include: reduction of cardiac output by competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuronal sites, reduction of sympathetic action on the periphery by central action, and inhibition of renin activity.
Angina: Metoprolol blocks the catecholamine-induced increase in heart rate, the rate and extent of myocardial contraction, and the increase in blood pressure, and reduces the oxygen demand of the heart during activity, which is beneficial for the long-term control of angina.
Myocardial infarction: The exact mechanism of action of metoprolol in patients with suspected or definite myocardial infarction is not known.
Toxicological studies
Genotoxicity.
Metoprolol Ames test, somatic chromosome test, somatic interphase cell nuclear abnormality test, and dominant lethality test in mice all showed negative results.
Reproductive toxicity.
Embryonic and/or fetal toxicity was seen in rats and rabbits given metoprolol tartrate from doses of 50 mg/kg and 25 mg/kg, respectively, as evidenced by increased pre-laying loss, decreased number of live fetuses, and/or decreased number of surviving neonates in each dose group. Maternal toxicity and intrauterine embryonic growth retardation with correspondingly lower birth weights were observed in the higher dose groups. No teratogenic effects were observed in embryo-fetal developmental toxicity tests in mice, rats and rabbits administered orally, and the NOAELs were 25, 200 and 12.5 mg/kg, respectively, which are approximately 0.3, 4 and 0.5 times the maximum human oral dose of metoprolol tartrate (8 mg/kg/day), respectively, converted to body surface area. In rats given metoprolol tartrate orally, reversible adverse effects on spermatogenesis were seen from a dose of 3.5 mg/kg (0.1 times the human dose in terms of body surface area), but no effects on reproductive function were seen in other tests in male rats. Metoprolol at a dose equivalent to 11 times the maximum daily human dose (450 mg) (converted to body surface area) caused an increase in post-implantation loss and a decrease in surviving neonates in rats. Distribution tests in pregnant mice have shown that metoprolol can be exposed in the embryo.
Carcinogenicity.
No statistically or biologically significant increase in tumor incidence was seen in CD-1 mice administered orally for 21 months and in rats for two years at doses up to 750 mg/kg/day and 800 mg/kg/day, respectively. Histopathological changes associated with administration were an increased incidence of mild focal aggregation of foamy macrophages in the alveoli and a slight increase in bile duct hyperplasia in rats. The incidence of benign lung tumors (small adenomas) was not increased in the high-dose group.
Pharmacokinetics]
The bioavailability of this product is 40-50%. The maximum beta-blocking effect is achieved 1 to 2 hours after dosing. The effect on heart rate remains significant after 12 hours following a single daily oral dose of 100 mg. Metoprolol is metabolized primarily in the liver by CYP2D6, and three major metabolites have been identified, none of which have clinically significant beta-blocking effects. The plasma half-life is 3 to 5 hours. About 5% of metoprolol is excreted by the kidney in its original form, and the rest is metabolized.
Storage
Keep away from light and sealed.
Package】
Aluminum-plastic packaging.
(1) 25mg: 10 tablets per box, 16 tablets per box, 20 tablets per box, 24 tablets per box, 30 tablets per box, 36 tablets per box, 40 tablets per box, 50 tablets per box, 60 tablets per box.
(2) 50mg: 10 tablets per box, 16 tablets per box, 20 tablets per box, 24 tablets per box, 30 tablets per box, 36 tablets per box, 40 tablets per box, 50 tablets per box, 60 tablets per box.
[Expiration date
12 months
Execution Standard
【Approval number】
25mg.
State Drug Authentication H20057288
50mg.
State Drug Quantifier H20057289
Marketing license holder
Name of the marketing license holder: Zhuhai Tongyuan Pharmaceutical Co.
Address of the holder of the marketing license: No. 6, Jinhai East Road, Sanzao, Jinwan District, Zhuhai
Postal Code: 519041
Telephone number: 0756-7623818, 7636858
Fax number: 0756-7623898
Web
Address: www.zhtyyy.com
Manufacturer
Company name: Zhuhai Tongyuan Pharmaceutical Co.
Address: No. 6, Jinhai East Road, Sanzao, Jinwan District, Zhuhai
Postal Code: 519041
Telephone number: 0756-7623818, 7636858
Fax number: 0756-7623898
Web
Address: www.zhtyyy.com