Metformin Hydrochloride Tablets 0.25g

Metformin Hydrochloride Tablets are used for patients with type II diabetes mellitus who are not satisfied with simple dietary control, especially those who are obese and accompanied by hyperinsulinemia. Using this medicine not only has the effect of lowering blood sugar, but may also have the effects of reducing body weight and hyperinsulinemia.

【Drug Name】

Generic Name: Metformin Hydrochloride Tablets

English Name: Metformin Hydrochloride Tablets

【Ingredients】The main ingredient of this product is metformin hydrochloride.

Chemical Name: 1,1 - Dimethylbiguanide hydrochloride.

Molecular formula: C₄H₁₁N₅ · H C 1

Molecular weight: 165.63

【Appearance】 A film coated tablet, which appears white after removing the coating.

【Indications】This product is the first choice for type 2 diabetes in cases where blood glucose control through diet and physical exercise alone is ineffective. For adults, this product can be used for monotherapy or in combination with sulfonylurea drugs or insulin.
For children and adolescents aged 10 and above, this product can be used for monotherapy or in combination with insulin.
【Specification】0.25 g

【Usage and Dosage】To reduce the occurrence of gastrointestinal complications and to control the patient's blood sugar with the minimum dose of the drug, the medication should be started at a low dose and gradually increased.

During the initiation of treatment and the dosage adjustment period (see the recommended dosing schedule), measuring fasting blood glucose can be used to determine the treatment response of this product and to identify the minimum effective dose for the patient. Thereafter, glycated hemoglobin should be measured every three months. Whether used alone or in combination, the treatment goal is to use the lowest effective dose to reduce fasting blood glucose and glycated hemoglobin levels to normal or near - normal levels.

Recommended Dosing Schedule

Normal renal function (eGFR ≥ 90 mL/min/1.73 m²): Monotherapy and combination with sulfonylureas

Oral administration. For adults and children, the initial dose is 0.25 g each time, 2 - 3 times a day. After 10 - 15 days, the dose is gradually increased according to the efficacy. The maximum recommended dose is 2 g per day. Taking the medicine with meals can reduce gastrointestinal reactions.

Combination with Sulfonylurea Drugs

For patients who show no response after taking the maximum recommended dose of this product for several weeks, consideration should be given to gradually adding sulfonylurea oral hypoglycemic drugs while maintaining the maximum dose treatment, unless the patient already has primary or secondary failure to sulfonylurea drugs. Currently, there are only clinical and pharmacokinetic data on the interaction between metformin and glibenclamide (Glyburide).

When this product is taken in combination with sulfonylurea drugs, satisfactory blood glucose control can be achieved by adjusting the doses of the two drugs. During combination treatment with this product, the risk of hypoglycemia associated with sulfonylurea drugs persists and may even increase. Appropriate preventive measures should be taken.

If a patient's blood glucose cannot be satisfactorily controlled after 1 to 3 months of treatment with the maximum dose of this product in combination with the maximum dose of oral sulfonylurea drugs, consideration should be given to changing the treatment method. This includes combination treatment of this product with insulin or insulin monotherapy.

Use in combination with insulin

When starting to add this product, the insulin dose can be maintained. For patients on insulin therapy, the initial dose of this product should be 0.5 g, once a day. If the patient's response is insufficient, increase the dose by 0.5 g after one week, and then it can be increased by 0.5 g every week until satisfactory blood glucose control is achieved. The recommended maximum daily dose is 2 g. When the fasting blood glucose of patients using this product in combination with insulin drops below 120 ng/dL, it is recommended to reduce the insulin dose by 10% - 25%. Individualized adjustments should be continued according to the blood glucose - lowering response or follow the doctor's advice.

Dose adjustment for adults with impaired renal function

No dose adjustment is required when eGFR≥60 nL/min/1.73m². Reduce the dose when eGFR is 45 - 59 mL/min/1.73m², and it is contraindicated when eGFR < 45 mL/min/1.73m².

【Adverse reactions】

According to literature reports:
During the initial treatment, the most common adverse reactions include nausea, vomiting, diarrhea, abdominal pain, and loss of appetite. Most patients can usually relieve these symptoms on their own. The following adverse reactions may occur when taking metformin hydrochloride tablets.
The definitions of adverse reaction occurrence frequencies are 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%); very rare (<0.01%). In each frequency group, the adverse reactions are arranged in descending order of severity.

Metabolic and nutritional disorders:

Very rare:

Lactic acidosis (see 【Precautions】)

Long - term use of metformin may reduce the absorption of vitamin B12. When patients present with megaloblastic anemia, this cause should be considered.

Nervous system abnormalities:

Common:

Taste disorders

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 relieve them spontaneously. Gradually increasing the dose can improve gastrointestinal tolerance.

Hepatobiliary function abnormalities:

Very rare:

There are reports of individual cases of abnormal liver function tests or hepatitis that returned to normal after stopping the use of metformin.

Skin and subcutaneous tissue abnormalities:

Very rare:

Skin reactions such as erythema, itching, urticaria, etc.

Other possible adverse reactions include: bloating, fatigue, indigestion, abdominal discomfort, headache, abnormal stools, constipation, flatulence, hypoglycemia, myalgia, dizziness, nail abnormalities, rash, increased sweating, chest discomfort, chills, flu - like symptoms, flushing, palpitations, weight loss, etc.

In children:
In the published data, post-marketing data, and a one-year clinical controlled study conducted in a limited number of children aged 10 - 16 years, the adverse events and their severity are similar to those in adults.

【Contraindications:】

Severe renal failure (eGFR < 45 mL/min/1.73 m²).

Acute conditions that may affect renal function, such as dehydration, severe infections, shock.

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.

Severe infections and trauma, major surgeries, clinical hypotension, and hypoxia.

Known hypersensitivity to metformin hydrochloride and any components of this product.

Any acute metabolic acidosis, including lactic acidosis, diabetic ketoacidosis.

Prodromal stage of diabetic coma.

Liver dysfunction, acute alcoholism, alcohol tolerance.

Uncorrected vitamin B12 or folic acid deficiency.

【Precautions】

Warning

Lactic Acidosis:
Lactic acidosis is a very rare but severe metabolic complication that can be induced by the accumulation of metformin in the body. It is commonly seen in patients with acute deterioration of renal function, those with cardiopulmonary diseases, or patients with sepsis.
Patients who experience dehydration (severe diarrhea or vomiting, fever, or reduced fluid intake) should temporarily stop taking metformin and inform their doctor.
Among patients taking metformin, caution should be exercised when using drugs that can cause acute renal impairment [including antihypertensive drugs, diuretics, and non - steroidal anti - inflammatory drugs (NSAIDs)]. Risk factors for lactic acidosis also include excessive alcohol consumption, liver dysfunction, poor diabetes control, ketosis, long-term fasting, any disease that may cause hypoxia, and concurrent use of drugs 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, which may progress to coma. Once any suspicious symptoms occur, the patient should immediately stop taking metformin and inform the doctor in a timely manner. Abnormal laboratory findings include a decrease in pH value (<7.35), a plasma lactic acid level higher than 5 mmol/L, an increase in the anion gap, and an increase in the lactate/pyruvate ratio.

General Precautions

Lactic acidosis is an emergency that must be treated in a hospital. Patients with lactic acidosis who are taking this product should immediately stop the drug and undergo timely examinations to support the diagnosis.
Renal Function:
Chronic kidney disease is a common complication of diabetes. Once diabetes is diagnosed, renal function should be routinely examined. Metformin is excreted through the kidneys. As the degree of renal function impairment increases, the risk of metformin accumulation and lactic acidosis also increases. Renal function should be examined at least once a year before starting treatment and during treatment.
This product is contraindicated in patients with an eGFR < 45 mL/min/1.73 m². Patients with acute conditions affecting renal function, such as dehydration, severe infection, or shock, should temporarily stop using this product. (See [Contraindications])

Cardiac function:
Patients with heart failure are at a higher risk of hypoxia and renal insufficiency. Patients with stable chronic heart failure can take metformin under the condition of regular examination of cardiac and renal functions.
Metformin is contraindicated in patients with acute and unstable heart failure (see [Contraindications]).

Use of iodinated contrast media:
Intravascular injection of iodinated contrast media may lead to contrast-induced nephropathy, which may cause metformin accumulation and increase the risk of lactic acidosis. Therefore, patients scheduled for such examinations must stop taking metformin before or during the examination.
The drug can be resumed only after the examination is completed for at least 48 hours and only if the renal function is stable upon re-examination.

Surgery:
Metformin must be stopped during surgery under general, spinal, or epidural anesthesia. Treatment can be restarted at least 48 hours after surgery or when the patient resumes eating and the renal function is evaluated as stable.
Other Precautions:
All patients should continue to have a reasonable intake of carbohydrates. Obese patients should continue a calorie-restricted diet. Routine laboratory tests should be carried out regularly to monitor diabetes.
Vitamin B12 level - Some patients (those with insufficient intake or absorption of vitamin B12 and calcium) may be more prone to a decrease in vitamin B12 level. It is beneficial for such patients to measure the serum vitamin B12 level every 2 - 3 years.
Hypoglycemia - Patients treated with this drug alone do not normally experience hypoglycemia. However, when used in combination with insulin or other hypoglycemic drugs (such as sulfonylureas or meglitinides), hypoglycemia should be watched for. Elderly, frail or malnourished patients, as well as those with adrenal and pituitary hypofunction and alcohol intoxication are more prone to hypoglycemia.
Children - Type 2 diabetes should be diagnosed before starting metformin treatment. According to literature reports, a 1-year-long clinical - controlled study has not found that metformin has an impact on children's growth and puberty, but there is no long - term data in this regard. Therefore, children receiving metformin treatment, especially pre-pubertal children, should be carefully followed up to determine the impact of metformin on these parameters.
Children aged 10-12
According to literature reports, a clinical-controlled study carried out among children and adolescents only included 15 children aged 10-12. Although there is no difference in the efficacy and safety data of metformin in these children compared with those in older children and adolescents, metformin should still be prescribed with particular caution for children aged 10-12.

【Use in Pregnant and Lactating Women】

Pregnant
For patients who are planning to become pregnant or are already pregnant, metformin is not recommended, but insulin can be used to maintain blood glucose levels as close to the normal level as possible, thus reducing the risk of fetal malformations.

Lactating Women

For lactating women, metformin can be excreted through breast milk. Breast - feeding is not recommended during metformin treatment.
【Use in Children】
This product can be used in children and adolescents aged 10 years and above, as a single - drug treatment or in combination with insulin. See 【Usage and Dosage】.

This product is not recommended for children under 10 years old.
【Use in the Elderly】
Since elderly patients may have decreased 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 normally experience hypoglycemia, so metformin has no effect on the ability to drive and operate machinery. However, when used in combination with insulin or other hypoglycemic drugs (such as sulfonylureas), hypoglycemia should be vigilant.
【Drug Interactions】

No change in the pharmacokinetic parameters of metformin was found when metformin and glibenclamide were used in a single - dose combination.

When metformin is used in combination with furosemide (Lasix), the AUC of metformin increases, but there is no change in renal clearance; at the same time, the C_max and AUC of furosemide both decrease, the terminal half - life is shortened, and there is no change in renal clearance.

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. Therefore, it is recommended to closely monitor and adjust the dose of this product and/or the interacting drugs.

When metformin is used in combination with cimetidine, the plasma and whole-blood AUC of metformin increase. However, when the two drugs are used alone, no change in the elimination half-life of metformin is seen. The pharmacokinetics of cimetidine is not changed.

When taking certain drugs that can cause blood glucose to rise, such as thiazide drugs or other diuretics, glucocorticoids, phenothiazines, thyroid preparations, estrogen, oral contraceptives, phenytoin, nicotinic acid, sympathomimetic drugs, calcium-channel blockers and isoniazid, blood glucose should be closely monitored. And after these drugs are discontinued, attention should be paid to the occurrence of hypoglycemia.

Metformin does not bind to plasma proteins. Therefore, compared with sulfonylurea drugs, drugs that are highly bound to proteins, such as salicylates, sulfanilamide, chloramphenicol, probenecid, etc., are less likely to interact. The latter mainly binds to serum proteins.

Except for chlorpropamide, when patients change from other oral hypoglycemic drugs to this product for treatment, a conversion period is usually not required. For patients taking chlorpropamide, close attention should be paid in the first two weeks of changing to this product, because chlorpropamide has a long-lasting effect in the body and is prone to overdose and hypoglycemia.

In healthy people, when nifedipine and metformin are used in a single-dose combination, the plasma peak concentration and the area under the plasma concentration-time curve of metformin increase by 20% and 9% respectively, and the excretion in urine increases, and there is no effect on T_max and half - life.

Metformin has an increasing tendency of the anticoagulant effect of warfarin.

When resin-type drugs are used in combination with this product, the absorption of metformin can be reduced.
【Overdose】

According to literature reports, even when the metformin dosage reaches 85g, hypoglycemia does not occur. However, in this case, lactic acidosis will occur. Under the condition of good hemodynamics, metformin can be dialyzed and cleared at a rate of 170 mL/min. Therefore, for patients suspected of metformin overdose, hemodialysis can clear the accumulated drug.

【Pharmacology and Toxicology】

Pharmacological Actions

Metformin can reduce hepatic glucose production, inhibit the intestinal absorption of glucose, and increase the uptake and utilization of glucose in peripheral tissues. It can enhance insulin sensitivity by increasing the uptake and utilization of peripheral glucose.

Toxicological Studies

Genetic Toxicity

The results of the Ames test, mouse lymphocyte gene mutation test, human lymphocyte chromosome aberration test, and mouse micronucleus test for this product were all negative.

Reproductive Toxicity

Male rats and female rabbits were given metformin hydrochloride at a dose of up to 600 mg/kg/day (equivalent to 3 times the maximum recommended daily dose for humans based on body surface area conversion), and no effect on fertility was observed. When 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 recommended daily dose for humans based on body surface area conversion, respectively), there was no teratogenic effect. The results of studies in lactating rats showed that metformin hydrochloride can be secreted into breast milk and reach the same level as in plasma.

Carcinogenicity

In a 104 - week carcinogenicity study, rats were given metformin at 900 mg/kg/day, and in a 91 - week study, mice were given metformin at 1500 mg/kg/day (these doses are equivalent to 4 times the maximum recommended daily dose of 2000 mg of metformin based on body surface area calculation). No evidence of carcinogenic effects of metformin was found in male and female mice. Metformin also did not show carcinogenic effects in male rats. However, in female rats at a dose of 900 mg/kg/day, there was an increase in benign stromal uterine polyps.

【Pharmacokinetics】

According to foreign literature reports:

Absorption

After oral administration of metformin hydrochloride, the blood drug concentration reaches its peak value (Cmax) at approximately 2.5 hours (Tmax). In the healthy population, the absolute bioavailability of orally administered metformin hydrochloride tablets is approximately 50 - 60%.

Eating reduces the degree of drug absorption and slightly delays its absorption rate. Take metformin hydrochloride tablets orally after a meal, the peak blood drug concentration is observed to decrease by 40%, and the area under the concentration-time curve (AUC) decreases by 25%.

Distribution

Metformin hardly binds to plasma proteins. Metformin partially enters red blood cells. The peak value of the whole-blood concentration of metformin is lower than that of the plasma concentration, but the appearance time is approximately the same. Red blood cells may be the second distribution compartment of metformin, with an average volume of distribution (Vd) of approximately 1.12 L/kg.

Metabolize

Metformin is excreted in the urine in its original form. No relevant metabolites were detected in the human body.

Excretion

The renal clearance rate of metformin is > 400 mL/min, indicating that glomerular filtration and tubular secretion are the excretion pathways of metformin. After oral administration, the terminal plasma elimination half-life of metformin is approximately 3.6 hours. In case of renal insufficiency, the renal elimination half-life decreases as the creatinine clearance rate decreases. Therefore, the elimination half-life of metformin is prolonged, leading to an increase metformin concentration in the blood .

Characteristics in Special Populations

Renal Insufficiency

Currently, there is limited data on the treatment of patients with moderate renal insufficiency, and there is no reliable estimate of the systemic exposure of metformin in these populations compared with patients with normal renal function. Therefore, the clinical efficacy/tolerance should be considered to adjust the dose.

Children

According to foreign literature reports:
Single-dose study: Single oral administration of 0.5 g of metformin hydrochloride tablets to pediatric patients showed similar pharmacokinetic characteristics to healthy adults.
Multiple-dose study: The data are only from one study. Pediatric patients took 0.5 g of metformin hydrochloride tablets twice a day for 7 days. The peak blood drug concentration and systemic exposure (AUC0 0-t ) were approximately 33% and 40% lower, respectively, compared with adult diabetic patients taking the same dose for 14 days. Since the drug dose is titrated according to the individual's blood glucose level, the clinical relevance is limited.

【Storage】Store in a tightly closed container.
【Package】 Packed in oral solid medical used high - density polyethylene bottles. 100 tablets per bottle, 1 bottle per box; 48 tablets per bottle, 1 bottle per box. Packed in oral solid medical PVC hard sheets and PTP aluminum foil blisters. 12 tablets per plate, 2 plates per box.
【Expiry Date】36 months
【Implementation Standard】Drug Registration Standard of the National Medical Products Administration YBH07482022
【Approval Number】Guoyao Zhunzi H12020797