Metformin sustained-release tablets, also known as metformin hydrochloride sustained-release tablets, are Western medicine names. They are hypoglycemic drugs. They are used for patients with type 2 diabetes who cannot be well controlled by diet and exercise alone. This product can be used alone or in combination with sulfonylureas or insulin.
Element
The main ingredient of this product is metformin hydrochloride.
Characteristics
Metformin hydrochloride sustained-release tablets: This product is white to off-white tablets or film-coated tablets, which appear white to off-white after removing the coating.
Metformin hydrochloride sustained-release tablets (II): This product is a film-coated tablet, which appears white after removing the coating.
Metformin hydrochloride sustained-release tablets (III): This product is a white coated tablet, which appears white after removing the coating.
Indications
This product is used for patients with type 2 diabetes who cannot be well controlled by diet and exercise alone. This product can be used alone or in combination with sulfonylureas or insulin.
Specification
Metformin hydrochloride sustained-release tablets: 0.5g.
Metformin hydrochloride sustained-release tablets (II): 0.5g.
Metformin hydrochloride sustained-release tablets (III): (1) 0.5 g; (2) 1.0 g.
Dosage
Metformin hydrochloride extended-release tablets, metformin hydrochloride extended-release tablets (II):
1. Oral administration, during or after meals. The initial dosage is usually 500 mg once a day, taken at dinner.
2. Adjust the dosage according to blood sugar and urine sugar. The maximum daily dose should not exceed 2000 mg.
3. If taking 2000 mg once a day does not achieve satisfactory therapeutic effect, it can be changed to taking 1000 mg twice a day.
4. This product should be swallowed whole and not chewed.
Metformin hydrochloride sustained-release tablets (III):
1. The tablet must be swallowed whole and must not be crushed or chewed before taking.
(1) There is no fixed dose for the treatment of hyperglycemia with this product in type 2 diabetes. The dose should be adjusted individually based on efficacy and tolerance without exceeding the maximum recommended daily dose of 2500 mg.
(2) This product is usually taken as a single dose with dinner. In order to reduce the occurrence of gastrointestinal complications and to use the minimum dose of the drug to adequately control the patient’s blood sugar, the drug should be taken from a small dose and gradually increased.
(3) At the beginning of treatment and during the dosage adjustment period (see recommended medication plan), fasting blood glucose can be used to determine the therapeutic response of this product and determine the patient’s minimum effective dose. Thereafter, glycated hemoglobin should be measured every three months. Whether used alone or in combination with sulfonylureas or insulin, the goal of treatment is to use the lowest effective dose to reduce fasting blood glucose and glycated hemoglobin levels to normal or near normal levels.
2. Recommended medication plan: Adults with normal renal function (eGFR ≥ 90 mL/min/1.73 m2): Usually the starting dose of this product is 500 mg once a day, taken with a glass of water at dinner. According to clinical needs, 1000 mg can also be taken once a day. The dose is increased by 500 mg per week to a maximum dose of 2500 mg, once a day, taken with dinner. The results of a trial in which patients treated with metformin hydrochloride tablets were switched to metformin hydrochloride extended-release tablets suggested that patients treated with metformin hydrochloride tablets can be safely switched to metformin hydrochloride extended-release tablets once a day at the same dose, up to 2500 mg once a day. After the switch, blood sugar should be closely monitored and the dose adjusted accordingly.
3. Switching from other hypoglycemic treatments: Except for chlorpropamide, patients usually do not need a conversion period when switching from other oral hypoglycemic drugs to this product. Patients taking chlorpropamide should pay close attention during the first 2 weeks of switching to this product, because chlorpropamide stays in the body for a long time, which can easily lead to overdose of the drug and hypoglycemia.
4. Combined use with sulfonylureas: If the patient still does not respond after taking the maximum recommended dose of this product for four weeks, it should be considered to gradually add sulfonylurea oral hypoglycemic drugs while maintaining the maximum dose of treatment, unless the patient has already failed to respond to sulfonylureas. Currently, there are only clinical and pharmacokinetic data on the interaction between metformin and glibenclamide (glyburide). Taking this product in combination with sulfonylureas can achieve satisfactory blood sugar control by adjusting the doses of the two drugs. The risk of hypoglycemia caused by sulfonylureas persists and even increases when combined with this product, and appropriate prevention should be carried out. (See the packaging instructions of the selected sulfonylurea drug). If the patient still cannot satisfactorily control blood sugar after 1 to 3 months of combined treatment with the maximum dose of this product and the maximum dose of oral sulfonylurea drugs, consider changing the treatment method, including combined treatment with this product and insulin or insulin alone.
5. Used in combination with insulin in adults: When starting to add this product, the insulin dose can be maintained. The starting dose of this product for patients treated with insulin should be 500 mg once a day. If the patient’s response is insufficient, increase 500 mg after 1 week, and then increase 500 mg per week until satisfactory blood sugar control is achieved. The recommended maximum daily dose is 2500 mg. When the fasting blood sugar of patients using this product in combination with insulin drops below 120 mg/dL, it is recommended to reduce the insulin dose by 10%-25%. Individualized adjustments should continue to be made based on the response to lower blood sugar or follow the doctor’s advice.
6. Recommended use in patients with renal impairment: Before administering this product, the patient’s renal function should be assessed and then regularly assessed. No dose adjustment is required for eGFR ≥ 60 mL/min/1.73 m2 , and the dose should be reduced for eGFR 45-59 mL/min/1.73 m2 . This product is not suitable for patients with a glomerular filtration rate below 45 mL/min/1.73 m2 .
7. Temporary discontinuation of medication for patients undergoing iodinated contrast imaging: Patients with an eGFR between 45-60 mL/min/l.73 m2 should stop taking this drug before or during iodinated contrast imaging. Patients with a history of liver damage, alcoholism, or heart failure should stop taking this drug before arterial perfusion iodine contrast imaging. Reassess eGFR 48 hours after the end of the contrast imaging, and the medication can be restarted after renal function recovers.
Clinical Application and Guidelines
1. Wu Jin, Zhu Lisheng, Yu Li, Wang Shengfeng, Hu Shibing, and Chen Jun conducted a study on the efficacy of glargine insulin combined with metformin sustained-release tablets in the treatment of type 2 diabetes and concluded that the combination of glargine insulin and metformin can not only control blood sugar, but also reduce bleeding tendency, with good compliance, and is worthy of clinical promotion and application. (Journal of Clinical Rational Drug Use, 2019, 12(04): 72-73.)
2. Hao Kaihua conducted a clinical study on the combined use of metformin hydrochloride sustained-release tablets and repaglinide in the treatment of obese type 2 diabetes and concluded that metformin hydrochloride sustained-release tablets combined with repaglinide can significantly reduce the blood sugar level and body mass index of obese type 2 diabetes patients, and is worthy of clinical promotion and application. (World Latest Medical Information Abstracts, 2018, 18 (A0): 141+208.)
3. Shan Haizhou conducted a clinical observation study on the effect of metformin hydrochloride sustained-release tablets in the treatment of elderly type 2 diabetes and concluded that the use of metformin sustained-release tablets in the treatment of elderly type 2 diabetes can not only effectively control blood sugar, but also has high safety and can be promoted in clinical practice. (Strait Pharmacy, 2018, 30 (05): 124-126.)
Adverse Reactions
Metformin hydrochloride extended-release tablets:
1. Occasionally, nausea, vomiting, diarrhea, abdominal pain, metallic taste in the mouth, etc.
2. Occasionally, there may be symptoms such as fatigue, tiredness, weight loss, dizziness, and rash.
3. Although the incidence of lactic acidosis is very low, it should be noted. The clinical manifestations are vomiting, abdominal pain, hyperventilation, impaired consciousness, and increased lactic acid concentration in the blood that cannot be explained by uremia, ketoacidosis or salicylic acid poisoning.
4. It can reduce the intestinal absorption of vitamin B12 , reduce hemoglobin, produce megaloblastic anemia, and may also cause malabsorption.
Metformin hydrochloride sustained-release tablets (Ⅱ):
Some patients may experience gastrointestinal discomfort after taking this product orally, such as nausea, vomiting, diarrhea, abdominal pain, constipation, bloating, indigestion, heartburn, as well as dizziness, headache, flu-like symptoms, abnormal taste, muscle pain, hypotension, palpitations, flushing, chills, chest discomfort, rash, weakness, tiredness, etc.
Metformin hydrochloride sustained-release tablets (III):
1. According to foreign literature reports: During the initial treatment, the most common adverse reactions are nausea, vomiting, diarrhea, abdominal pain and loss of appetite, which can usually be relieved by most patients.
2. The following adverse reactions may occur when taking metformin hydrochloride extended-release tablets. The frequency of adverse reactions is defined as follows: very common (≥10%); common (1%-10%, including 1%), occasional (0.1%-1%, including 0.1%), rare (0.01%-0.1%, including 0.01%), and very rare (<0.01%). In each frequency group, adverse reactions are arranged in descending order of severity.
(1) Metabolic and nutritional disorders: Very rare: lactic acidosis (see [Precautions]), long-term use of metformin may reduce the absorption of vitamin B12. This cause should be considered if the patient develops megaloblastic anemia.
(2) Nervous system abnormalities: Common: taste disorders.
(3) Gastrointestinal abnormalities: Very common: Gastrointestinal abnormalities such as nausea, vomiting, diarrhea, abdominal pain and loss of appetite. These adverse reactions mostly occur at the beginning of treatment and most patients can usually resolve on their own. Slowly increasing the dose can improve gastrointestinal tolerance.
(4) Abnormal liver and gallbladder function: Very rare: There are reports of individual cases of abnormal liver function tests or hepatitis that returned to normal after stopping metformin.
(5) Skin and subcutaneous tissue abnormalities: Very rare: skin reactions such as erythema, itching, urticaria.
3. Other possible adverse reactions include: bloating, fatigue, indigestion, abdominal discomfort and headache, abnormal stool, constipation, abdominal distension, hypoglycemia, myalgia, dizziness, abnormal nails, rash, increased sweating, chest discomfort, chills, flu symptoms, hot flashes, palpitations, weight loss, accidental injury, infection, rhinitis, etc.
4. Adverse reactions reported with post-marketing metformin treatment include cholestasis, hepatocellular and mixed hepatocellular injury.
Taboo
Metformin hydrochloride extended-release tablets, metformin hydrochloride extended-release tablets (II):
This product is contraindicated in patients with type 2 diabetes accompanied by ketoacidosis, liver and kidney dysfunction, heart failure, acute myocardial infarction, severe infection and trauma, major surgery, clinical hypotension and hypoxia, a history of lactic acidosis, and those who are allergic to this product.
Metformin hydrochloride sustained-release tablets (III):
1. Severe renal failure (eGFR<45mL/min/1.73m2 ) .
2. Acute conditions that may affect renal function, such as dehydration, severe infection, and shock.
3. Diseases that can cause tissue hypoxia (especially acute diseases or exacerbation of chronic diseases), such as decompensated heart failure, respiratory failure, recent myocardial infarction and shock.
4. Severe infection and trauma, major surgical operations, clinical symptoms such as hypotension and hypoxia, etc.
5. Known allergy to metformin hydrochloride and any ingredients in this product.
6. Any acute metabolic acidosis, including lactic acidosis and diabetic ketoacidosis.
7. Prodromal stage of diabetic coma.
8. Patients with liver dysfunction, acute alcohol poisoning, alcoholism, and uncorrected vitamin B12 and folic acid deficiency .
Precautions
Metformin hydrochloride extended-release tablets, metformin hydrochloride extended-release tablets (II):
1. In patients using metformin hydrochloride, lactic acidosis may occur due to the accumulation of metformin hydrochloride. This is a rare and serious metabolic complication, which can be life-threatening if it occurs. Patients taking this product should undergo renal function monitoring and administer the drug at the lowest effective dose, thereby significantly reducing the risk of lactic acidosis.
2. This product is not allowed to be chewed orally. It should be swallowed whole and taken during or after meals.
3. Blood sugar, glycosylated hemoglobin, urine sugar and urine ketone bodies should be monitored regularly.
4. When this product is used in combination with sulfonylurea drugs, it may cause hypoglycemia and the patient’s blood sugar level should be monitored.
5. The combined use of this product with insulin will enhance the hypoglycemic effect, so the dosage should be adjusted.
6. When patients need to undergo radiological studies using intravenous iodinated contrast agents, they should temporarily stop taking this product because this may cause acute changes in renal function.
7. Some patients were found to have lower than normal vitamin B12 levels without clinical symptoms . This may be due to metformin interfering with the absorption of vitamin B12 , which may lead to anemia. Although the possibility is small, it is still recommended to monitor blood counts and patients should check blood parameters at least once a year.
8. When this product is taken together with ethanol, the effect of metformin hydrochloride on lactic acid metabolism will be enhanced, which can easily lead to lactic acidosis. Therefore, alcohol consumption should be avoided as much as possible when taking this product.
9. If allergic reactions such as rash occur, stop using this product.
Metformin hydrochloride sustained-release tablets (III):
1. Lactic acidosis:
(1) There have been reports of metformin-related lactic acidosis after marketing, including fatal cases. These patients have insidious onset and are only accompanied by non-specific symptoms such as discomfort, myalgia, abdominal pain, respiratory distress, and drowsiness. In severe cases, hypotension and refractory bradyarrhythmias may occur. Metformin-related lactic acidosis is characterized by elevated blood lactate levels (>5mmol/L), decreased blood pH (ketonuria or ketonemia), anion gap acidosis (without ketonuria or ketonemia), and increased lactate/pyruvate ratio. Plasma metformin concentrations are usually >5µg/mL. Metformin can reduce the liver’s uptake of lactate, thereby increasing the lactate content in the blood and increasing the risk of lactic acidosis, especially in high-risk patients.
(2) If metformin-related lactic acidosis is suspected, general supportive treatment should be started immediately and the use of this product should be stopped immediately. For patients who take this product and are diagnosed or strongly suspected of lactic acidosis, it is recommended to immediately undergo hemodialysis to correct acidosis and eliminate accumulated metformin (metformin hydrochloride can be dialyzed at a clearance rate of 170 mL/min when the hemodynamic condition is good). After such treatment, symptoms will usually be relieved and cured quickly.
(3) Patients and their families should be educated on the symptoms of lactic acidosis and instructed to stop taking this product immediately and seek medical attention if symptoms occur.
(4) For each known and potential risk factor for metformin-related lactic acidosis, the following methods are recommended to reduce risk and manage it: Renal impairment – Post-marketing metformin-related lactic acidosis cases mainly occurred in patients with significant renal impairment. Because metformin is mainly excreted by the kidneys, severe renal impairment increases the risk of metformin accumulation and its related lactic acidosis. Clinical recommendations are based on the patient’s renal function, see [Dosage and Administration]: Before starting treatment, test the estimated glomerular filtration rate (eGFR). Patients with eGFR below 45mL/min/l.73m2 should not take the drug, and those with eGFR 45-59mL/min/1.73m2 should reduce the dose . All patients taking this product should have their eGFR tested at least annually, and patients who may be at risk of renal impairment (such as the elderly) should have their renal function assessed more frequently. Drug Interactions—Concomitant use of certain medications may increase the risk of metformin-associated lactic acidosis, such as those that impair renal function, cause significant hemodynamic changes, interfere with acid-base balance, or increase metformin accumulation. Consider closer monitoring. Age 65 and older—Patient age is associated with an increased risk of metformin-associated lactic acidosis, as elderly patients are more likely to have liver, kidney, and heart impairment than younger patients. Elderly patients should be closely evaluated for renal function. Radiographic studies using contrast agents—Intravenous administration of iodinated contrast agents to patients treated with metformin can lead to acute changes in renal function and the development of lactic acidosis. Patients with an eGFR between 45 and 60 mL/min/1.73 m2 should stop taking this drug before or during iodinated contrast imaging, and patients with a history of liver damage, alcohol abuse, or heart failure should stop taking this drug before arterial infusion of iodinated contrast. Reassess eGFR 48 hours after contrast imaging, and the drug can be restarted when renal function recovers. Surgery – Food and fluid restrictions during surgery or other procedures may increase the risk of hypovolemia, hypotension, and renal impairment. This product should be temporarily discontinued when the patient is restricted from eating or drinking. Tissue hypoxia – Several cases of metformin-related lactic acidosis have occurred in patients with acute congestive heart failure (particularly with hypoperfusion and hypoxemia) after marketing. Cardiovascular failure (shock), acute myocardial infarction, sepsis, or other conditions characterized by hypoxia are associated with lactic acidosis and can also lead to prerenal azotemia. This product should be discontinued immediately in the above situations. Excessive alcohol consumption – Alcohol is known to affect the effect of metformin on lactate metabolism. Therefore, patients treated with this product should be warned to avoid sudden or prolonged excessive alcohol consumption. Hepatic impairment – Some patients with hepatic impairment have developed metformin-related lactic acidosis, which may be due to decreased lactate clearance, resulting in elevated lactate levels in the blood. Therefore, patients with clinical or laboratory diagnosed liver disease should avoid using this product.
2. Vitamin B12 level : In a 29-week clinical trial of metformin tablets, it was observed that about 7% of patients with normal blood vitamin B12 levels had their vitamin B12 levels drop below the normal range after taking the drug , but there were no clinical symptoms. This decrease in vitamin B12 levels may be due to metformin interfering with the absorption of vitamin B12 by the vitamin B12 -intrinsic factor complex , but anemia is rare in patients with this condition, and it is quickly relieved after discontinuation of metformin or vitamin B12 supplementation . It is recommended that patients taking this product undergo annual examinations of hematological parameters (such as hemoglobin/hematocrit and red blood cell indexes), and any obvious abnormalities in parameters should be carefully traced and treated accordingly. Although megaloblastic anemia rarely occurs in rapid-release metformin treatment, vitamin B12 deficiency should be excluded if suspected . Some individuals (who have insufficient intake or absorption of vitamin B12 or calcium) seem to be more likely to have vitamin B12 levels below normal, and such patients may benefit from routine blood vitamin B levels every 2-3 years.
3. Hypoglycemia: Patients who receive this product alone will not experience hypoglycemia under normal circumstances, but hypoglycemia may occur when eating too little, not replenishing enough calories after heavy exercise, using it in combination with other hypoglycemic drugs (such as sulfonylureas or insulin), drinking alcohol, etc. Elderly, frail or malnourished patients, as well as patients with reduced adrenal and pituitary function and alcohol poisoning are more likely to experience hypoglycemia. Hypoglycemia in elderly patients and patients taking beta-adrenal blockers is difficult to identify.
Pregnant and lactating women
Metformin hydrochloride extended-release tablets, metformin hydrochloride extended-release tablets (II):
At present, there are no adequate and strictly controlled clinical studies on pregnant women, and the efficacy and safety of this product in pregnant women are still unclear, so pregnant women are prohibited from taking this product. Metformin can be excreted through breast milk, so this product is prohibited for breastfeeding women.
Metformin hydrochloride sustained-release tablets (III):
1. Pregnant women: Metformin is not recommended for patients who are planning to become pregnant or are already pregnant. However, insulin can be used to maintain blood sugar levels as close to normal as possible, thereby reducing the risk of fetal malformations.
2. Lactating women: Metformin can be excreted through breast milk. Breastfeeding is not recommended during metformin treatment.
Children’s medication
Metformin hydrochloride extended-release tablets, metformin hydrochloride extended-release tablets (II):
The clinical safety and effectiveness of this product in children have not been confirmed.
Metformin hydrochloride sustained-release tablets (III):
The safety and efficacy of this product in children (under 17 years old) have not been established and its use is not recommended.
Medication for the elderly
Metformin hydrochloride extended-release tablets, metformin hydrochloride extended-release tablets (II):
Elderly patients will experience physiological decline in renal function as they age, so attention should be paid to the choice of dosage and regular renal function checks. Elderly patients should not usually receive the maximum dose of this product. Elderly patients over 80 years old should not use this product unless their creatinine clearance shows that their renal function has not decreased.
Metformin hydrochloride sustained-release tablets (III):
Since elderly patients may have impaired renal function, renal function should be checked regularly and the dose of metformin should be adjusted according to renal function.
Drug interactions
Metformin hydrochloride extended-release tablets, metformin hydrochloride extended-release tablets (II):
1. Glibenclamide: When metformin is used in combination with glibenclamide, the pharmacokinetics of metformin will not be affected, but the AUC and C max of glibenclamide will be reduced.
2. Furosemide: When a single dose of metformin is used in combination with furosemide, the pharmacokinetic parameters of both drugs change. The C max and AUC values of metformin increased by 22% and 15%, respectively, while the renal clearance did not change significantly. The AUC and C max values of furosemide decreased by 12% and 31%, respectively, and the half-life was shortened by 32%, but the renal clearance did not change significantly. There is no interaction data for the long-term combination of the two drugs.
3. Nifedipine: When a single dose of metformin is used in combination with nifedipine, the C max and AUC of metformin increase by 20% and 90% respectively, and the excretion through urine increases, while the T max and half-life are not affected. Metformin has little effect on the pharmacokinetic parameters of nifedipine.
4. Cationic drugs such as digoxin, morphine, amiloride, propranolol, quinidine, quinine, ranitidine, triamterene or vancomycin. In theory, cationic drugs are cleared through the renal tubules and may interact with metformin by competing for the renal tubular transport system. Therefore, blood sugar levels should be carefully monitored and dosage adjusted.
5. Others: When this product is used in combination with drugs that can cause hyperglycemia, such as corticosteroids, thyroxine, estrogen, oral contraceptives, nicotinic acid, calcium channel blockers, phenobarbital, etc., blood sugar control may be disturbed. Blood sugar levels should be closely monitored. When the above drugs are discontinued, hypoglycemia should also be closely monitored.
Metformin hydrochloride sustained-release tablets (III):
1. The combined use of metformin and glibenclamide as a single dose did not change the pharmacokinetic parameters of metformin. The AUC and C max of the pharmacokinetic curve of glibenclamide decreased, but there was no fixed trend, which is of little clinical significance.
2. When metformin is used in combination with furosemide (Lasix), the AUC and C max of metformin increase, but the renal clearance does not change. At the same time, the C max and AUC of furosemide decrease, the terminal half-life shortens, and the renal clearance does not change.
3. Cationic drugs excreted through the renal tubules (such as amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim and vancomycin) may theoretically compete with metformin for the renal tubular transport system and interact with it, which may increase the risk of lactic acidosis. Therefore, it is recommended to closely monitor and adjust the dose of this product and/or interacting drugs.
4. When metformin is used in combination with cimetidine, the plasma and whole blood AUC of metformin increases, and there is no change in the elimination half-life of metformin. There is no change in the pharmacokinetics of cimetidine.
5. If you are taking certain drugs that may cause blood sugar to rise at the same time, such as thiazides or other diuretics, glucocorticoids, phenothiazines, thyroid preparations, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers and isoniazid, you should monitor your blood sugar closely. After these drugs are stopped, pay close attention to the occurrence of hypoglycemia.
6. Metformin does not bind to plasma proteins. Therefore, drugs that are highly bound to proteins, such as salicylates, sulfonamides, chloramphenicol, and probenecid, are less likely to interact with sulfonylureas, which mainly bind to serum proteins.
7. Except for chlorpropamide, patients usually do not need a conversion period when switching from other oral hypoglycemic drugs to this product. Patients taking chlorpropamide should pay close attention in the first 2 weeks of switching to this product, because chlorpropamide has a long retention in the body, which can easily lead to overdose of the drug and hypoglycemia.
8. When healthy subjects took a single dose of nifedipine and metformin together, the C max and AUC of metformin increased by 20% and 9%, respectively, and the excretion in urine increased, but the T max and half-life were not affected.
9. Metformin has the tendency to increase the anticoagulant effect of warfarin.
10. The combined use of resin drugs and this product can reduce the absorption of metformin.
11. Studies in healthy subjects have shown that metformin and propranolol, and metformin and ibuprofen, do not affect each other’s pharmacokinetics when administered as a single dose.
12. Topiramate or other carbonic anhydrase inhibitors (such as zonisamide, acetazolamide, dichlorphenamide) can cause a decrease in plasma bicarbonate, reduce non-anion gap and metabolic acidosis. The combined use of these drugs with this product will increase the risk of lactic acidosis, and these patients should be monitored more closely.
13. Alcohol is known to affect the effect of metformin on lactic acid metabolism. Therefore, patients receiving this product should be warned to avoid excessive drinking.
Overdose
Metformin hydrochloride extended-release tablets, metformin hydrochloride extended-release tablets (II):
Lactic acidosis may occur when taking an overdose of this product. The onset of lactic acidosis is usually difficult to monitor, and it is only accompanied by some non-specific symptoms, such as discomfort, muscle aches, drowsiness, respiratory distress, etc. It may also be accompanied by hypothermia, hypotension, hypotension, bradycardia, etc. Dialysis is an effective way to remove accumulated metformin.
Metformin hydrochloride sustained-release tablets (III):
Even if hypoglycemia does not occur when taking up to 85 g of metformin, lactic acidosis will occur in this case. Under good hemodynamic conditions, metformin can be dialyzed at a rate of 170 mL/min. Therefore, hemodialysis can be used to remove the accumulated drug in patients with suspected metformin overdose.
Pharmacological Action
Metformin hydrochloride extended-release tablets, metformin hydrochloride extended-release tablets (II):
Metformin hydrochloride is a hypoglycemic drug that improves blood sugar tolerance in patients with type 2 diabetes and reduces basal and postprandial blood sugar. The mechanism of action of metformin hydrochloride is different from that of other types of oral anti-glycemic drugs. It can reduce the production of glycogen, reduce intestinal absorption of sugar, and increase insulin sensitivity by increasing peripheral sugar uptake and utilization. Unlike sulfonylurea drugs, metformin hydrochloride will not cause hypoglycemia in patients with type 2 diabetes or patients with normal blood sugar (except in special circumstances – see precautions). After treatment with metformin hydrochloride, insulin secretion remains unchanged, while fasting insulin levels and daily plasma insulin levels are reduced.
Metformin hydrochloride sustained-release tablets (III):
Metformin can reduce hepatic glucose production, inhibit intestinal absorption of glucose, and increase the uptake and utilization of glucose by peripheral tissues. It can improve insulin sensitivity by increasing peripheral glucose uptake and utilization.
Toxicological effects
1. Genetic toxicity: The results of Ames test, mouse lymphocyte gene mutation test, human lymphocyte chromosome aberration test and mouse micronucleus test were all negative.
2. Reproductive toxicity: Male and female rats were given metformin hydrochloride at a dose of up to 600 mg/kg/day (equivalent to 3 times the maximum daily dose recommended by human clinical practice based on body surface area), and no effect on fertility was observed. Rats and rabbits were given metformin hydrochloride at a dose of up to 600 mg/kg/day (equivalent to 2 times and 6 times the maximum daily dose recommended by human clinical practice based on body surface area, respectively), and no teratogenic effect was observed. The results of studies on lactating rats showed that metformin hydrochloride can be secreted into breast milk and can reach the level in plasma.
3. Carcinogenicity: Rats were given metformin hydrochloride 900 mg/kg/day for 104 weeks and mice were given metformin hydrochloride 1500 mg/kg/day for 91 weeks (both equivalent to 4 times the maximum daily dose recommended by human clinical practice based on body surface area conversion), and no carcinogenic effect was observed in the animals. However, in female rats given 900 mg/kg/day, there was an increase in the occurrence of benign stromal uterine polyps.
Pharmacokinetics
1. Absorption: Metformin sustained-release tablets are absorbed from the gastrointestinal tract after oral administration, and the average time for the peak blood concentration is 7 hours. When taken with food, the absorption of metformin can be increased by about 50%, but its C max and T max have no effect. High-fat diet and low-fat diet have similar effects on the pharmacokinetic parameters of metformin sustained-release tablets. When taking metformin sustained-release tablets multiple times, metformin will not accumulate in plasma.
2. Distribution: The binding rate of metformin to plasma proteins is negligible, while the binding rate of sulfonylurea drugs to plasma proteins is higher than 90%. Metformin can enter red blood cells, which is most likely related to its duration of action.
When metformin extended-release tablets are taken at usual clinical doses, steady-state blood concentrations are reached within 24-48 hours and are usually less than 1 μg/ml.
3. Metabolism and excretion: Metformin is excreted in urine in its original form, without being metabolized by the liver or excreted by bile. The renal clearance rate is about 3.5 times the creatinine clearance rate, indicating that excretion through the renal tubules is the main route of metformin elimination. After oral administration, about 90% of the absorbed drug is eliminated through the kidney within 24 hours, and the plasma elimination half-life is about 6.2 hours. In the blood, the elimination half-life of metformin hydrochloride sustained-release tablets is about 17.6 hours.
4. Pharmacokinetics in special populations:
(1) Patients with type 2 diabetes: When patients still have normal renal function, the pharmacokinetic parameters of patients after single or multiple doses of metformin are not statistically different from those of normal subjects.
(2) Patients with renal insufficiency: In patients with decreased renal function (measured by creatinine clearance), the plasma half-life of metformin is prolonged and the clearance from the kidneys is reduced in direct proportion to the decrease in creatinine clearance.
(3) Effect of age: The plasma clearance of metformin decreases, the half-life prolongs, and the C max increases in the elderly.
(4) Children: Currently, there is no data on the pharmacokinetic studies of metformin hydrochloride extended-release tablets in children.
(5) Gender: There were no statistically significant differences in the pharmacokinetic parameters of metformin in patients with type 2 diabetes.
(6) Racial factors: There are no studies on the pharmacokinetic parameters of metformin related to racial factors. In a controlled clinical study of metformin tablets in patients with type 2 diabetes, metformin hydrochloride extended-release tablets had similar anti-hyperglycemic effects in whites (249 cases), blacks (51 cases), and Hispanics (24 cases).
Metformin hydrochloride sustained-release tablets (III):
1. Absorption and bioavailability: Compared with immediate-release metformin tablets, metformin sustained-release tablets release drugs more slowly in plasma and prolong the drug effect. Multiple oral doses of 2000 mg of this product once a day (after dinner) and 1000 mg of metformin hydrochloride tablets twice a day (after breakfast and dinner) show that the median time to peak of this product is about 6 hours (range 3-10 hours) under steady-state conditions, the mean (± standard deviation) of the area under the drug-time curve (AUC 0-24h ) is 26811 (± 7055) ng·hr/mL, and the mean (± standard deviation) of the maximum blood drug concentration (C max ) is 2894 (± 797) ng/mL. Calculated by AUC, the two preparations of 2000 mg of this product once a day (after dinner) and 1000 mg of metformin hydrochloride tablets twice a day (after breakfast and dinner) are bioequivalent. The efficacy of taking two 500 mg tablets of this product and one 1000 mg tablet at dinner is equivalent. After taking 1000mg, 1500mg, 2000mg and 2500mg of this product for 24 hours, the increase in metformin concentration is dose-related. When taking 2000mg of this product after dinner, 1000mg after breakfast and dinner, and 2500mg after dinner, the pharmacokinetic AUC of metformin is linearly correlated with the dose. When this product is taken with food, the absorption of metformin calculated by AUC increases by about 60%, C max increases by about 30%, and T max is prolonged compared with fasting (6.1 hours vs 4.0 hours).
2. Drug distribution: No drug distribution study has been conducted for this product. Studies on immediate-release metformin tablets have shown that compared to the 90% protein binding rate of sulfonylurea drugs, metformin rarely binds to plasma proteins. Metformin can be distributed in red blood cells, most likely according to a certain time function. After taking immediate-release metformin hydrochloride tablets according to conventional clinical dosage and usage, steady-state blood drug concentration is reached in 24-48 hours and is generally <1μg/mL. Controlled clinical trials of immediate-release metformin tablets have shown that even at the highest dose, the maximum blood concentration of metformin will not exceed 5μg/mL.
3. Metabolism: Metabolism studies have not been conducted on this product. Studies on single-dose intravenous administration have shown that metformin is excreted unchanged in the urine, that is, it is not metabolized by the liver (no metabolites have been detected in the human body) and is not excreted through bile.
4. Excretion: Take 2500 mg of this product orally once a day. After 24 hours, 40.9% of metformin is excreted through urine, and the renal clearance rate is 542±310 mL/min. After repeated administration, there is almost no accumulation of metformin in plasma, and most of the drug is cleared by the kidneys after 24 hours. The half-life t 1/2 of this product is 5.4 hours. The renal clearance rate of metformin hydrochloride is about 3.5 times the creatinine clearance rate, which shows that renal tubular secretion is the main route of metformin clearance. After oral administration of metformin, about 90% of the absorbed drug is cleared through the kidneys within 24 hours, and the plasma clearance half-life of the drug is 6.2 hours. The clearance half-life of the drug in the blood is about 17.6 hours, suggesting that red blood cell aggregates may be where metformin is distributed.
5. Special groups:
(1) Elderly: Compared with healthy young subjects, the total plasma clearance of metformin in elderly patients is decreased, the half-life is prolonged, and the C max is increased. The pharmacokinetics of metformin change with the patient’s age mainly because the patient’s renal function changes with age.
(2) Children: There is currently no pharmacokinetic data for pediatric patients.
(3) Gender: The pharmacokinetic results in males and females were consistent.
(4) Renal damage: The half-life of metformin in plasma and blood of patients with impaired renal function will be prolonged, and the renal clearance rate will be reduced.
(5) Hepatic impairment: There are currently no studies on the pharmacokinetics of metformin in patients with hepatic impairment.
(6) Race: There are currently no racial pharmacokinetic studies on metformin.
Storage method
Seal tightly and store in a cool (not exceeding 20°C) dry place.
Validity
24 months
Implementation Standards
Metformin hydrochloride sustained-release tablets: National Food and Drug Administration National Drug Standard WS 1 -(X-035)-2013Z.
Metformin hydrochloride sustained-release tablets (II): National Food and Drug Administration National Drug Standard WS 1- (X-075)-2012Z.
Metformin hydrochloride sustained-release tablets (III): National drug standard of the State Food and Drug Administration YBH03042019.