Approval date: May 21, 2007
Revision date: November 26, 2010
Modification date: 09/03/2016
Modification date: 09/09/2016
Modification date: 09/01/2018
Modification Date: 03/04/2018
Modification Date: 08/20/2019
Modified on.
Metformin Hydrochloride Extended Release Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
[Drug Name].
Generic name: Metformin hydrochloride extended-release tablets
Trade name: Name
English name: Metformin Hydrochloride Sustained-release Tablets
Hanyu Pinyin: YansuanErjiashuangguaHuanshiPian
【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 white or off-white tablet.
Indications】This product is used for adults with type 2 diabetes whose blood glucose control by diet and physical exercise alone is ineffective, and can be used as monotherapy or in combination with sulfonylureas or insulin.
Specification】0.5g
Dosage]
It must be swallowed whole, not crushed or chewed after taking.
In order to reduce the occurrence of gastrointestinal complications, and to use the smallest dose of the drug so that the patient’s blood sugar is sufficiently controlled, the dose should be taken from a small dose and gradually increased.
During treatment initiation and dose adjustment (see recommended dosing schedule), measurement of fasting blood glucose can be used to determine the response to treatment with this drug and 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 with sulfonylureas and insulin, is to reduce fasting glucose and glycated hemoglobin levels to normal or near normal using the lowest effective dose.
Recommended dosing schedule
Adults with normal renal function (eGFR ≥ 90mL/min/1.73m2)
Monotherapy and combination therapy with other oral hypoglycemic agents
The usual starting dose of metformin hydrochloride extended-release tablets is 500 mg once/day with dinner, increasing by 500 mg weekly to a maximum dose of 2000 mg once/day with dinner. If blood glucose is not satisfactorily controlled with up to 2000 mg once/day, consider switching to 1000 mg twice/day with meals. If larger amounts of metformin are also needed, the maximum dose of 2550 mg/day of metformin hydrochloride tablets should be used in divided doses.
Results of a trial of conversion to metformin hydrochloride extended-release tablets in patients treated with metformin hydrochloride tablets suggest that patients treated with metformin hydrochloride tablets can be safely converted to metformin hydrochloride extended-release tablets 1 time/day at the same dose, up to 2000 mg once/day. Monitor blood glucose closely after conversion and adjust the dose accordingly.
Switching therapy from other glucose-lowering treatments
With the exception of chlorosulfonylurea, patients switching from other oral hypoglycemic agents to this product usually do not require a conversion period. Patients taking chlorosulfonylurea should be closely monitored during the first 2 weeks of switching to this product because the long retention time of chlorosulfonylurea in the body can lead to drug overdose and hypoglycemia.
Combined use 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 the maximum dose of therapy, unless the patient already has primary or secondary failure to sulfonylureas. Clinical and pharmacokinetic data on the interaction between metformin and glibenclamide (euglycemia) are only 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 or even increases with combination therapy with this product and should be appropriately prevented. (See the instructions for the selected sulfonylurea)
If a patient does 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 treatment, including combination of this product with insulin therapy or insulin alone.
Combined use with insulin in adults
The dose of insulin can be maintained when adding this product at the beginning. The starting dose of this product for insulin-treated patients should be 500 mg once/day. If the patient does not respond adequately, increase the dose by 500 mg after 1 week, and thereafter by 500 mg weekly until satisfactory glycemic control is achieved. The recommended maximum daily dose is 2000 mg. When the fasting blood glucose of a patient using this product in combination with insulin falls below 120 mg/dL, it is recommended to reduce the insulin dose by 10% to 25%. Individualized adjustments should continue to be made or as prescribed by the physician based on the response to the lowering of blood glucose.
Dose adjustment for patients with impaired renal function
No dose adjustment is required for eGFR ≥ 60mL/min/1.73m2, dose reduction for eGFR 45-59mL/min/1.73m2, and discontinuation for eGFR<45mL/min/1.73m2.
[Adverse reactions] According to foreign literature.
During 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 Extended Release 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 administration of metformin may decrease vitamin B12 absorption. This cause should be considered if the patient develops megaloblastic anemia.
Neurological 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.
Isolated cases of abnormal liver function tests or hepatitis have been reported to return to normal after discontinuation of metformin.
Skin and subcutaneous tissue abnormalities.
Very rare.
Skin reactions, such as erythema, pruritus, and urticaria.
Other possible adverse reactions include: gastric distension, weakness, dyspepsia, 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.
Contraindicated]
Severe renal failure (eGFR<45mL/min/1.73m2).
Acute conditions that may affect renal function, e.g., dehydration, severe infection, shock.
Diseases that can cause tissue hypoxia (especially acute diseases or worsening of chronic diseases), such as decompensated heart failure, respiratory failure, recent episodes of myocardial infarction and shock.
severe infections and traumatic injuries, major surgical procedures, clinical hypotension and hypoxia, etc.
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, alcohol abuse.
Vitamin B12, folic acid deficiency is not corrected
[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, commonly in patients with acute deterioration of renal function, suffering from 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 alert to 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 illness that may cause hypoxia, as well as concomitant use of medications that may cause lactic acidosis.
Patients and/or caregivers should be informed of the risk of lactic acidosis. Lactic acidosis is characterized by acidotic dyspnea, abdominal pain, muscle cramps, weakness 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.
Lactic acidosis is an emergency that must be treated in the hospital. Patients with lactic acidosis on this product should be immediately discontinued and promptly tested to support the diagnosis.
General Precautions
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<45mL/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 of hypoxia and renal insufficiency. Patients with stable chronic heart failure may take metformin with regular checks of cardiac and renal function.
Metformin is contraindicated in patients with acute and unstable heart failure (see [Contraindications]).
Use of Iodinated Contrast Agents
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 for such examinations must stop taking metformin before or at the time of the examination and resume the medication at least 48 hours after completion of the examination and only if renal function is stable on reexamination.
Surgical Procedures
Metformin must be discontinued during 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 dietary intake of carbohydrates. Calorie-restricted diets should be continued in overweight patients.
Routine laboratory tests should be performed regularly to monitor diabetes.
Vitamin B12 levels – Some patients (those with inadequate intake or absorption of vitamin B12 and calcium) may be more susceptible to decreased 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 hypoglycemia when used in combination with insulin or other glucose-lowering drugs (e.g., sulfonylureas or glinides).
Hypoglycemia is more likely to occur in elderly, debilitated or malnourished patients, as well as in patients with hypoadrenal and pituitary function and alcoholism.
Pregnant women and nursing mothers
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, thus reducing the risk of fetal malformations.
Lactating women
Metformin can be excreted through breast milk. Breastfeeding is not recommended during metformin treatment.
[Pediatric Use].
The safety and efficacy of this product in children (under 17 years of age) have not been established and its use is not recommended at this time.
Geriatric use]
Since elderly patients may have reduced renal function, renal function should be checked regularly and the dose of metformin should be adjusted according to renal function.
Effect on the ability to drive and operate machinery
Patients treated with metformin alone do not develop hypoglycemia under normal circumstances, so metformin has no effect on the ability to drive and operate machinery. However, the combination with insulin or other hypoglycemic drugs (such as sulfonylureas or glinides) should be used with caution for hypoglycemia.
[Drug Interactions].
1. No alteration in pharmacokinetic parameters of metformin was found with single dose combination of metformin and glibenclamide.
2. When metformin was combined with furosemide (tachyphylaxis), the AUC of metformin increased, but renal clearance was unchanged; meanwhile, the Cmax and AUC of furosemide decreased, the terminal half-life was shortened, and renal clearance was unchanged.
3. Cationic drugs that are excreted via the renal tubules (e.g., aminoclopramide, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, aminoglutethimide, methoxypyrimethamine, and vancomycin) may theoretically compete with metformin for renal tubular transport systems and interact, so close monitoring and dose adjustment of this product and/or interacting drugs is recommended.
4. The plasma and whole blood AUC of metformin increased when metformin was combined with cimetidine, but no change in the clearance half-life of metformin was seen when the two drugs were combined alone. No change in the pharmacokinetics of cimetidine was observed.
5. Monitor blood glucose closely if certain drugs that can cause elevated blood glucose are taken concomitantly, such as thiazides or other diuretics, glucocorticoids, phenothiazines, thyroid preparations, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid, 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, aminoglutethimide, chloramphenicol, and propofol, are less likely to interact with sulfonylureas than with serum proteins, which are mainly bound to serum proteins.
7. Patients switching from other oral hypoglycemic agents to treatment with this product, except for chlorosulfonylurea, usually do not require a conversion period. Patients taking chlorosulfonylurea should be closely monitored during the first 2 weeks of switching to this product because chlorosulfonylurea has a long retention period in the body, which can lead to drug overdose and hypoglycemia.
8. The single dose combination of nifedipine and metformin in healthy individuals showed an increase in peak plasma concentration and area under the plasma concentration time curve of metformin by 20% and 9%, respectively, and an increase in urinary excretion, with no effect on Tmax and half-life.
9. Metformin has increased the anticoagulant tendency of warfarin.
10. Resin drugs combined with this product can reduce the absorption of metformin.
[Drug overdose].
Even if metformin dose up to 85g did not occur hypoglycemia, but in this case lactic acidosis will occur. In good hemodynamic conditions metformin can be cleared by dialysis at a rate of 170mL/min. Therefore, in patients suspected of metformin overdose, hemodialysis can remove the accumulated drug.
Pharmacology and Toxicology
Pharmacological effects
Metformin can reduce hepatic gluconeogenesis, inhibit intestinal absorption of glucose, and increase glucose uptake and utilization by peripheral tissues, which can 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 effect on fertility was observed in male and female rats given metformin hydrochloride at doses up to 600 mg/kg/day (equivalent to three times the maximum recommended daily human clinical dose based on 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). The results of studies in lactating rats showed that metformin hydrochloride can be secreted into breast milk and can reach levels in plasma.
Carcinogenicity
No evidence of carcinogenic effects of metformin was found in male and female mice given metformin 900 mg/kg/day for 104 weeks and in mice given metformin 1500 mg/kg/day for 91 weeks in carcinogenicity studies (these doses are equivalent to 4 times the maximum recommended clinical daily dose of metformin of 2000 mg based on body surface area). Metformin was also not found to be carcinogenic in male rats, but there was an increase in the occurrence of benign mesometrial polyps in female rats at 900 mg/kg/day.
[Pharmacokinetics].
According to foreign literature.
Absorption.
Compared with metformin immediate-release tablets, the absorption time of metformin is significantly longer, and the blood concentration reaches its peak (Cmax) after 7 hours (Tmax) (Tmax of metformin immediate-release tablets is 2.5 hours). When steady state is reached, similar to metformin immediate-release tablets, the Cmax and AUC of metformin extended-release tablets are not proportional to the oral dose. The AUC of a single oral dose of metformin extended-release tablets 2000 mg was similar to the AUC of metformin immediate-release tablets 1000 mg bid.
The interindividual variation in Cmax and AUC of metformin extended-release tablets was similar to that of metformin immediate-release tablets.
Oral administration of metformin extended-release tablets in the fasted state resulted in a 30% reduction in AUC (Cmax and Tmax were not affected).
The degree of absorption of metformin extended-release tablets is not affected by food composition.
Metformin accumulation was not observed after multiple oral doses of metformin extended-release tablets 2000 mg.
Distribution.
Metformin is barely bound to plasma proteins. Metformin partially enters the red blood cells. Peak metformin whole blood concentrations were lower than peak plasma concentrations, but occurred at approximately the same time. Erythrocytes may be the second distribution compartment for metformin, with a mean volume of distribution (Vd) ranging from 63-276 L.
Metabolism.
Metformin is excreted from the urine primarily as a prototype. No relevant metabolites have been detected in humans.
Excretion.
The renal clearance of metformin >400mL/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 6.5 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 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.
Storage】Seal and store.
Package】High density polyethylene bottle for oral solid medication. 27 tablets/bottle/box; 30 tablets/bottle/box; 36 tablets/bottle/box; 40 tablets/bottle/box; 45 tablets/bottle/box; 50 tablets/bottle/box; 60 tablets/bottle/box.
【Validity】18 months
【Execution standard
【Approval Number】State Drug Administration H20051542
[Marketing license holder
Company name: Shandong Phoenix Pharmaceutical Co.
Registered Address: No. 198, Jin Er Road, Lijin County, Dongying City, Shandong Province
Manufacturer
Company Name: Shandong Fenghuang Pharmaceutical Co.
Address: No. 198, Jin’er Road, Lijin County, Dongying City, Shandong Province
Postal code: 257400
Telephone number: 0546-5629811
Fax number: 0546-5629722
Website: http://www.lihuayi.com