Approval Date: 07/03/2007
Revision Date: October 01, 2010
Revision Date: 06/25/2013
Revision Date: 01/12/2015
Revision Date: 03/21/2016
Revision Date.
Description of Metformin Hydrochloride Tablets
Please read the instruction manual carefully and use under the guidance of your physician
[Drug Name].
Generic Name: Metformin Hydrochloride Tablets
English Name: Metformin Hydrochloride Tablets
Hanyu Pinyin: Yansuan Erjiashuanggua Pian
[Composition].
The main ingredient of this product is Metformin Hydrochloride.
Chemical name: 1,1-dimethylbiguanide hydrochloride.
Chemical structure formula.
Molecular Formula: C4H11N5-HCl
Molecular weight: 165.63
[Properties
This product is a film-coated tablet, which appears white after removing the coating.
[Indication
This product is preferred for type 2 diabetes mellitus, especially in overweight patients, where simple dietary control and physical exercise have failed to control blood glucose.
In adults, it can be used as monotherapy or in combination with a sulfonylurea or insulin.
For children and adolescents 10 years of age and older, this product can be used as monotherapy or in combination with insulin.
[Specification
0.25 g
[Dosage].
To reduce the incidence of gastrointestinal complications and to keep the patient’s blood glucose sufficiently controlled using the smallest dose, the dose should be started at a small dose and gradually increased.
During treatment initiation and dose adjustment (see recommended dosing schedule), determination of fasting glucose can be used to determine the therapeutic response to this product as well as to determine the minimum effective dose for the patient. Thereafter, glycated hemoglobin should be measured every three months. The goal of treatment, either alone or in combination, is to reduce fasting glucose and glycosylated hemoglobin levels to normal or near normal using the lowest effective dose.
Recommended Dosing Schedule
Normal renal function (eGFR ≥ 90 mL/min/1.73m2).
Monotherapy and combination therapy with sulfonylureas or insulin
Oral, starting at 0.25 g twice to three times a day for adults and children, and gradually increasing after 10-15 days depending on efficacy, with a maximum recommended dose of 2 g per day. take with meals to reduce gastrointestinal reactions.
Co-administration with sulfonylureas
Patients who do not respond after several weeks on the maximum recommended dose of this product should be considered for gradual addition of a sulfonylurea oral hypoglycemic agent while maintaining maximum dose therapy, unless the patient already has primary or secondary failure to sulfonylureas. Only clinical and pharmacokinetic data on the interaction between metformin and glibenclamide (euglycemia) are available.
Combined administration of this product with a sulfonylurea can achieve satisfactory glycemic control by adjusting the dose of both drugs. The risk of hypoglycemia with sulfonylureas persists and even increases with combination therapy with this drug and should be appropriately prevented.
If patients do not have satisfactory glycemic control after 1 to 3 months of treatment with the maximum dose of this product in combination with the maximum dose of oral sulfonylurea, consider a change in therapy, including this product in combination with insulin therapy or insulin alone.
Dose adjustment for adults with impaired renal function
eGFR ≥ 60 mL/min/1.73m2 no dose adjustment required, eGFR 45-59 mL/min/1.73m2 dose reduction, eGFR& lt;45 mL/min/1.73m2is disabled.
[Adverse Reactions
As reported in foreign literature.
At initial treatment, the most common adverse reactions include nausea, vomiting, diarrhea, abdominal pain, and loss of appetite, which usually resolve on their own in most patients. The following adverse reactions may occur while taking metformin hydrochloride tablets.
The frequency of adverse reactions is defined as follows: very common (≥10%); common (1% to 10% with 1%),occasional (0.1% to 1% with 0.1%), rare (0.01% to 0.1% with 0.01%), very rare (< 0.01%). Within each frequency group, adverse reactions were listed in decreasing order of severity.
Metabolic and nutritional disorders.
Very rare.
– lactic acidosis (see [Precautions])
– Long-term metformin administration may decrease vitamin B12 absorption. This cause should be considered if the patient develops megaloblastic anemia.
Nervous system abnormalities.
Common.
– Taste disorders
Gastrointestinal abnormalities.
Very common.
– Gastrointestinal abnormalities such as nausea, vomiting, diarrhea, abdominal pain, and loss of appetite. Most of these adverse reactions occur at the start of treatment and usually resolve on their own in most patients. Slowly increasing the dose may improve gastrointestinal tolerability.
Abnormal hepatobiliary function.
Very rare.
– Individual cases with abnormal liver function tests or hepatitis have been reported to return to normal after discontinuation of metformin.
Dermal and subcutaneous tissue abnormalities.
Very rare.
– Skin reactions, such as erythema, pruritus, hives.
Other possible adverse reactions include: bloating, fatigue, indigestion, abdominal discomfort and headache, abnormal stools, constipation, bloating, hypoglycemia, myalgia, dizziness, lightheadedness, abnormal nails, rash, increased sweating, chest discomfort, chills, flu symptoms, hot flashes, palpitations Weight loss, etc.
Children
Adverse events and their severity were similar to those in adults in published data, post-marketing data, and a limited number of controlled clinical studies conducted over a one-year period in children aged 10-16 years.
[Contraindication
– Severe renal failure (eGFR<45 mL/min/1.73m2).
– Acute conditions that may affect renal function, e.g., dehydration, severe infection, shock.
– Conditions that can cause tissue hypoxia (especially acute conditions or worsening of chronic conditions), such as decompensated heart failure, respiratory failure, recent onset myocardial infarction and shock.
– severe infections and trauma, major surgical procedures, clinically significant hypotension and hypoxia.
– Known hypersensitivity to metformin hydrochloride and any of the components of this product.
– Any acute metabolic acidosis, including lactic acidosis, diabetic ketoacidosis.
– Diabetic coma prodromal phase.
– hepatic insufficiency, acute alcoholism, alcoholism.
– uncorrected vitamin B12, folic acid deficiency
[Caution
Warning
Lactic acidosis.
Lactic acidosis is a very rare but serious metabolic complication that can be induced by accumulation of metformin in the body and is commonly seen in patients with acute deterioration of renal function, cardiopulmonary disease, or sepsis.
Patients who develop dehydration (severe diarrhea or vomiting, fever, or decreased fluid intake) should temporarily discontinue metformin and inform their physician.
In patients taking metformin, be wary of the use of medications that can cause acute impairment of renal function [including antihypertensives, diuretics, and nonsteroidal anti-inflammatory drugs (NSAIDs)]. Risk factors for lactic acidosis also include excessive alcohol consumption, hepatic insufficiency, poorly controlled diabetes mellitus, ketosis, prolonged fasting, and any disease that may cause hypoxia, as well as concomitant use of medications that may cause lactic acidosis.
The patient and/or caregiver should be informed of the risk of lactic acidosis. Lactic acidosis is characterized by acidotic dyspnea, abdominal pain, muscle cramps, debilitation, and decreased body temperature leading to coma. At the first sign of suspicion, patients should discontinue metformin and promptly inform their physician. Laboratory test abnormalities include decreased pH (<7.35), plasma lactate levels above 5 mmol/L and anion gap, and elevated lactate/pyruvate ratio.
General considerations
Lactic acidosis is an acute condition that must be treated in the hospital. Patients with lactic acidosis taking this product should be discontinued immediately and promptly tested to support the diagnosis.
Renal function:
Chronic kidney disease is a common complication of diabetes mellitus, and once diabetes mellitus is diagnosed, renal function should be routinely checked. Metformin is excreted through the kidneys, and as the degree of impaired renal function increases, the risk of metformin accumulation and the development of lactic acidosis increases. Renal function should be checked before starting treatment and at least annually after treatment.
This product is contraindicated in patients with eGFR<45 mL/min/1.73m2. This product should be temporarily discontinued in patients presenting with acute conditions affecting renal function such as dehydration, severe infection or shock. (See [Contraindications])
Cardiac function:
Patients with heart failure are at higher risk for hypoxia and renal insufficiency. Patients with stable chronic heart failure can take metformin with regular checks of cardiac and renal function.
Metformin is contraindicated in patients with acute and unstable heart failure (see [Contraindications]).
Iodinated contrast agent use:
Intravascular injection of iodinated contrast media may lead to contrast nephropathy, which may cause metformin accumulation and an increased risk of lactic acidosis. Therefore, patients who are scheduled to have this type of test must stop taking metformin before or at the time of the test and resume the drug at least 48 hours after the test is completed and only if renal function is stable on reexamination.
Surgery:
Metformin must be discontinued when undergoing surgery with conventional, spinal, or epidural anesthesia. Treatment should not be restarted until at least 48 hours after surgery or after resumption of feeding and renal function has been assessed as stable.
Other Precautions:
All patients should continue to rationalize their carbohydrate dietary intake. Overweight patients should continue a calorie-restricted diet.
Routine laboratory tests should be performed regularly to monitor diabetes.
Vitamin B12 levels – Some patients (those who do not consume or absorb enough vitamin B12 and calcium) may be more susceptible to lower vitamin B12 levels. It is beneficial for such patients to have their serum vitamin B12 levels measured every 2-3 years.
Hypoglycemia – Patients receiving this product alone do not normally develop hypoglycemia, but should be alerted to use in combination with insulin or other glucose-lowering agents (e.g., sulfonylureas or glinides) for Hypoglycemia. Older, frail, or malnourished patients, as well as patients with hypoadrenal and pituitary function and alcoholism, are more likely to develop hypoglycemia.
Children – A diagnosis of type 2 diabetes should be confirmed before starting metformin therapy. According to the foreign literature, a 1-year controlled clinical study has not found an effect of metformin on growth and puberty in children, but no long-term data are available in this regard. Therefore, children treated with metformin, especially prepubertal children, should be carefully followed to determine the effect of metformin on these parameters.
Children 10-12 years of age – According to the foreign literature, a controlled clinical study in children and adolescents included only 15 children 10-12 years of age. Although the efficacy and safety data for metformin in these children did not differ from those in older children and adolescents, special caution should be exercised when prescribing metformin for children 10-12 years of age.
[For pregnant and lactating women
Pregnant women
Metformin is not recommended for patients who are planning to become pregnant or are already pregnant, but insulin can be used to maintain blood glucose levels as close to normal as possible, thereby reducing the risk of fetal malformations.
Lactating women
Metformin can be excreted through breast milk. Breastfeeding is not recommended during metformin therapy.
[Pediatric Dosage
This product may be used in children and adolescents 10 years of age and older as monotherapy or in combination with insulin. See [Dosage].
This product is not recommended for use in children under 10 years of age.
[Geriatric Use
Because elderly patients may experience decreased renal function, renal function should be checked periodically and the dose of metformin should be adjusted based on renal function.
[Effect on ability to drive and operate machinery
Patients treated with metformin alone do not normally develop hypoglycemia, so metformin has no effect on the ability to drive or operate machinery. However, the combination with insulin or other glucose-lowering agents (e.g., sulfonylureas) should be used with caution for hypoglycemia.
[Drug Interactions
1. No changes in pharmacokinetic parameters of metformin were observed with single-dose combinations of metformin and glibenclamide.
2. In combination with furosemide (tachyphylaxis), the AUC of metformin increased but renal clearance was unchanged; meanwhile, Cmax and AUC of furosemide decreased, terminal half-life was shortened, and renal clearance was unchanged.
3. Cationic drugs that are secreted via the renal tubules (eg, aminoclopramide, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, aminoglutethimide, meperidine, and vancomycin) may theoretically compete with metformin for the renal tubular transport system and interact with each other. Therefore, close monitoring and dose adjustment of this product and/or interacting drugs is recommended.
4. The plasma and whole blood AUC of metformin increased in combination with cimetidine, but no alteration in the clearance half-life of metformin was seen when the two drugs were combined alone. No changes in the pharmacokinetics of cimetidine were seen.
5. Monitor blood glucose closely if certain drugs that can cause elevated blood glucose, such as thiazides or other diuretics, glucocorticoids, phenothiazines, thyroid preparations, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid, are taken concomitantly. Monitor blood glucose closely when these drugs are discontinued, and pay close attention to the occurrence of hypoglycemia after these drugs are discontinued.
6. Metformin does not bind to plasma proteins. Therefore drugs that are highly protein bound, such as salicylates, aminosulfamate, chloramphenicol, and probenecid, are less likely to interact than sulfonylureas, which are primarily bound to serum proteins.
7. With the exception of chlorosulfapresure, a conversion period is usually not required when patients switch from other oral hypoglycemic agents to treatment with this product. Patients taking chlorosulfopropurea should be closely monitored during the first 2 weeks of switching to this product because chlorosulfopropurea has a long retention period in the body, which can lead to drug overdose and hypoglycemia.
8. In healthy individuals on a single-dose combination of nifedipine and metformin, the peak plasma concentration and area under the plasma concentration time curve of metformin increased by 20% and 9%, respectively, and urinary excretion increased, with no effect on Tmax or half-life.
9. Metformin has a tendency to increase the anticoagulant properties of warfarin.
10. Resinous drugs in combination with this product may reduce metformin absorption.
[Drug overdose
It has been reported in the foreign literature that lactic acidosis can occur in this setting even though metformin doses up to 85 g have not been hypoglycemic. In good hemodynamic conditions metformin can be cleared by dialysis at a rate of 170 mL/min. Therefore, in patients with suspected metformin overdose, hemodialysis can remove the accumulated drug.
[Pharmacology and Toxicology
Pharmacological effects
Metformin decreases hepatic gluconeogenesis, inhibits intestinal absorption of glucose, and increases glucose uptake and utilization by peripheral tissues, which may improve insulin sensitivity by increasing peripheral glucose uptake and utilization.
Toxicological studies
Genotoxicity
The results of Ames test, mouse lymphocyte gene mutation test, human lymphocyte chromosome aberration test and mouse micronucleus test were all negative.
Reproductive toxicity
No effects on fertility were seen in male and female rats given metformin hydrochloride at doses up to 600 mg/kg/day (equivalent to 3 times the maximum clinically recommended daily dose in humans, converted to body surface area). No teratogenic effects were observed in rats and rabbits given metformin hydrochloride at doses up to 600 mg/kg/day (2 and 6 times the maximum recommended daily dose for humans based on body surface area). Results in lactating rats showed that metformin hydrochloride can be secreted into breast milk and can reach levels in plasma.
Carcinogenicity
In a carcinogenicity study in rats given metformin 900 mg/kg/day for 104 weeks and in mice given metformin 1500 mg/kg/day for 91 weeks (these doses are equivalent to 4 times the maximum recommended clinical daily dose of metformin of 2000 mg on a body surface area basis ), no evidence of carcinogenic effects of metformin was found in either male or female mice. Metformin was also not found to be carcinogenic in male rats, but there was an increase in the development of benign interstitial uterine polyps in female rats at 900 mg/kg/day.
[Pharmacokinetics
Absorption
Following oral administration of metformin hydrochloride, blood levels peak after approximately 2.5 hours (Tmax) (Cmax). In a healthy population, the absolute bioavailability of oral metformin hydrochloride tablets is approximately 50-60%.
Eating reduces the extent and slightly slows the rate of absorption of the drug. A 40% reduction in peak blood concentrations and a 25% reduction in the area under the concentration curve (AUC) were observed with oral metformin hydrochloride tablets after eating.
Distribution
Metformin is barely bound to plasma proteins. Metformin partially enters the red blood cells. Peak metformin whole blood concentrations are lower than peak plasma concentrations, but occur at approximately the same time. Erythrocytes may be the second distribution compartment for metformin, with a mean volume of distribution (Vd) of approximately 1.12 L/kg.
Metabolism
Metformin is excreted from the urine as a prototype. No relevant metabolites have been detected in humans.
Excretion
The renal clearance of metformin>400 mL/min suggests that glomerular filtration and renal tubular secretion are the routes of metformin excretion. After oral administration, the terminal plasma clearance half-life of metformin is approximately 3.6 hours. In renal insufficiency, renal clearance decreases with creatinine clearance, so the clearance half-life of metformin is prolonged, resulting in an increase in plasma metformin concentration.
Characteristics in special populations
Renal insufficiency
There are few data on treatment in patients with moderate renal insufficiency and there are no reliable estimates of systemic exposure to metformin in these populations compared with patients with normal renal function. Therefore, clinical efficacy/tolerability should be considered for dose adjustment.
Children
According to foreign literature.
Single-dose study: pediatric patients receiving a single oral dose of metformin hydrochloride tablets 0.5 g showed a pharmacokinetic profile similar to that of healthy adults.
Multiple-dose study: data from only one study. Pediatric patients taking metformin hydrochloride tablets 0.5 g orally twice a day for 7 days had approximately 33% and 40% lower peak blood levels and systemic exposure (AUC0-t), respectively, compared with adult diabetic patients taking the same dose for 14 days of treatment. The clinical relevance is limited because the drug dose is titrated according to the individual’s blood glucose level.
[Storage].
Seal and store.
[Package
Aluminum-plastic package, 12 tablets/plate x 2.
[Expiration Date
18 months.
[Execution Standard
[Approval Number
国药准字H11020127
[Manufacturer
Company Name: Beijing Sihuan Pharmaceutical Co.
Address: No.13, Guangyuan West Street, Zhangjiawan Town, Tongzhou District, Beijing
Zip Code: 101113
Fax Number: 010-61563510
Tel: 010-61563510
Web Address: www.sihuanpharm.com