Date of approval: May 29, 2007
Revision date: Year Month Day
Miglitol Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Miglitol Tablets
English name: Miglitol Tablets
Hanyu Pinyin: Migeliechun Pian
Ingredients
The main ingredient of this product is Miglitol, whose chemical name is (2R,3R,4R,5S)-2-hydroxymethyl-1-(2-hydroxyethyl)-3,4,5-piperidinetriol.
Its structural formula is
Molecular formula: C8H17NO5
Molecular weight: 207.2
Properties】This product is a film-coated tablet, which appears white to slightly yellow after removing the coating.
Indications】It is used to improve blood glucose control in adult type 2 diabetic patients with diet control and exercise. It can be used in combination with sulfonylureas when monotherapy or sulfonylureas cannot achieve satisfactory glycemic control.
Specification】50mg
Dosage]
The dose of miglitol must be determined by its efficacy and patient tolerance, but should not exceed the maximum recommended dose (100mg, 3 times daily). At the beginning of treatment and at increasing doses, the minimum effective dose is determined by using the 1-hour postprandial glucose as an indicator of the efficacy of miglitol, after which glycosylated hemoglobin is measured approximately once every 3 months.
Miglitol is administered at the beginning of each meal and is titrated as follows.
Initial Dose
The recommended initial dose is 25 mg three times daily. To reduce gastrointestinal adverse effects, some patients have been started on 25 mg once daily and then gradually increased until 3 times daily. After 4-8 weeks of using Miglitol 25mg 3 times daily, the dose should be increased to 50mg 3 times daily.
Maintenance dose.
The recommended maintenance dose is 50 mg 3 times daily. The maintenance period is approximately 3 months, after which glycosylated hemoglobin levels should be measured. If the glycosylated hemoglobin level is not satisfactory at this time, the dose should be increased to 100 mg 3 times daily, the maximum recommended dose. If no further reduction in postprandial glucose or glycosylated hemoglobin levels is seen after taking miglitol (100 mg, 3 times daily), consider reducing the dose. Once an effective tolerated dose has been found, this dose should be maintained.
Maximum Dose.
The maximum recommended dose is 100 mg three times daily. A clinical trial has demonstrated that higher doses of miglitol (200 mg 3 times daily) may increase the control of hyperglycemic symptoms but also increase the incidence of gastrointestinal adverse effects.
Combination with sulfonylureas.
Sulfonylureas can cause hypoglycemia. Although it has been demonstrated in clinical trials that the combination of this product with sulfonylureas does not increase the incidence of hypoglycemia compared to sulfonylureas alone, when this product is used in combination with sulfonylureas, the incidence of hypoglycemia is not increased. However, when this product is used in combination with sulfonylureas, it may cause a further decrease in blood glucose and increase the risk of hypoglycemia, which may be due to the cumulative effect of the two drugs. If hypoglycemia occurs, the dose of this product and sulfonylureas should be adjusted promptly.
Adverse reactions】According to the literature
Gastrointestinal reactions: Gastrointestinal symptoms are the most common adverse reactions to miglitol. In a placebo-controlled trial in the United States, the incidence of abdominal pain, diarrhea, and flatulence was 11.7%, 28.7%, and 41.5%, respectively, in 962 patients taking miglitol (25-100 mg 3 times daily), compared with 4.7%, 10%, and 12%, respectively, in 603 patients in the corresponding placebo group. The incidence of abdominal pain and diarrhea was reduced with continued administration of the drug.
Skin reactions: The incidence of rash was 4.3% with miglitol compared to 2.4% in the corresponding placebo group. The rash was usually transient.
Abnormal laboratory parameters: The incidence of reduced serum iron levels was higher in patients on miglitol (9.2%) than in the placebo group (4.2%). However, the majority of patients had a transient rash and it was not associated with decreased hemoglobin or other hematologic abnormalities.
Postmarketing Experience
The following adverse reactions were reported after the marketed use of miglitol. Because these reactions were spontaneously reported by an indeterminate number of people, it is usually not possible to reliably estimate their frequency or to establish a causal relationship with drug exposure.
Gastrointestinal disorders: intestinal obstruction (including paralytic intestinal obstruction), incomplete intestinal obstruction, gastrointestinal pain, nausea, abdominal distention.
Intestinal pneumatocystosis: There are rare postmarketing reports of intestinal pneumatocystosis associated with the use of alpha-glucosidase inhibitors (including miglitol). Intestinal pneumatocystosis may be accompanied by symptoms of diarrhea, mucus secretion, rectal bleeding, and constipation. Complications may include pneumoperitoneum, intestinal kinking, intestinal obstruction, intussusception, intestinal bleeding, and intestinal perforation. If intestinal pneumatocysts are suspected, discontinue miglitol and undergo appropriate diagnostic imaging.
Contraindications
Contraindicated in the following patients.
Diabetic ketoacidosis.
Inflammatory bowel disease, colonic ulcer, incomplete intestinal obstruction, patients with a tendency to intestinal obstruction.
Patients with chronic intestinal diseases with significant gastrointestinal dysfunction, or with conditions that may further aggravate the appearance of intestinal distension.
Patients who are allergic to the drug or its ingredients.
[Precautions].
General matters.
Hypoglycemia: The mechanism of action of miglitol itself makes it possible that it does not cause postprandial or fasting hypoglycemia when administered alone, whereas sulfonylureas can cause hypoglycemia. Since miglitol can enhance the hypoglycemic efficacy of sulfonylureas, the combination of the two can further aggravate the lowering of blood glucose, and a reduction in the dose of sulfonylureas or insulin should be considered when miglitol is used in combination with these drugs. Since oral glucose, whose absorption is not inhibited by miglitol, is used for the treatment of mild to moderate hypoglycemia, oral glucose is usually used instead of sucrose. Miglitol can inhibit the hydrolysis of sucrose to glucose or fructose, so sucrose should not be used as a drug for rapid correction of hypoglycemia. Severe hypoglycemia needs to be corrected by intravenous glucose drip or glucagon injection.
Poor blood glucose control: When diabetic patients are in stressful conditions such as fever, trauma, infection or surgery, temporary poor blood glucose control will occur, and insulin therapy must be applied temporarily at this moment.
Renal impairment: In patients with renal impairment, the serum concentration of miglitol increases in proportion to the degree of renal impairment and reduced renal function. Long-term clinical trials have not been performed in diabetic patients with severe renal hypoplasia (blood creatinine > 2.0 mg/dl). Therefore, the use of miglitol is not recommended for these patients .
Patient information.
Patients should be provided with the following information.
Miglitol should be taken orally 3 times daily at the beginning of each regular meal. Concurrent dietary control, appropriate exercise, and regular blood glucose/urine testing are important.
Miglitol itself does not cause hypoglycemia, even when taken on an empty stomach. Sulfonylureas and insulin, however, can cause hypoglycemia and even life-threatening hypoglycemia. Since the combination of miglitol with sulfonylureas or insulin will aggravate the decrease in blood sugar, it may increase the risk of hypoglycemia from these drugs. The risk of hypoglycemia, its symptoms, treatment, and trends should be understood by the patient and the patient’s family. Because of the ability of miglitol to inhibit the breakdown of edible sugar, glucose should be kept on hand for the prompt treatment of hypoglycemia caused by the combination of miglitol with sulfonylureas or insulin.
Side effects of miglitol, if any, usually occur within a few weeks of treatment initiation. Clinical symptoms are usually mild to moderate dose-dependent gastrointestinal disturbances such as bloating, loose stools, diarrhea or abdominal discomfort. However, the frequency and intensity of these symptoms often decrease over time. Discontinuation of the drug may provide immediate relief of the above symptoms.
Doctor’s advice.
When starting treatment for type 2 diabetes, it should be emphasized that diet is also the main form of treatment. Calorie restriction and weight reduction are necessary in obese patients. Proper diet alone may be effective in controlling blood glucose and hyperglycemic symptoms. Regular physical activity is equally important, and attention should be paid to the development of cardiovascular risk factors and improvement measures if necessary. Physicians and patients must view miglitol or other medications for diabetes as a means to complement dietary control, not as a substitute for dietary therapy or as an easy way to avoid diet moderation. In addition, poor glycemic control when treated with diet alone may be temporary and require only short-term use of miglitol or other medications for diabetes. Continuation or discontinuation of the use of miglitol or other medications for the treatment of diabetes should be based on a clinical diagnosis through routine clinical and laboratory evaluation.
Laboratory Tests.
The therapeutic effects of miglitol may be monitored by periodic blood glucose testing. Measurement of glycosylated hemoglobin levels is used as a monitoring indicator for long-term control of hyperglycemic symptoms.
Pregnant women and nursing mothers
There is no information on the safety of this product in pregnant women. Since animal tests cannot fully predict human response, it should be used in pregnant women only when needed.
The secretion of this product into human milk is very small, and the total secretion into breast milk is only 0.02% of the mother’s dose of 100 mg, and it is estimated that the nursing infant receives about 0.4% of the mother’s dose. Although the amount of this product secreted into human milk is very low, it is still not recommended for use in nursing women.
The safety and efficacy of this product in children have not been confirmed.
Geriatric use】According to the literature
Of the total number of cases in clinical studies conducted in the United States, 24% of those older than 65 years of age and 3% of those older than 75 years of age were determined to be safe, and the difference in effectiveness and safety was not significant between young people and older adults.
A trial investigating the altered pharmacokinetics of miglitol in older versus younger men (n=8 in each group) found no significant difference between the two groups at a dose of 100 mg 3 times daily for 3 days.
[Drug Interactions] According to the literature
Several studies have found possible interactions between miglitol and glibenclamide. In six healthy subjects given a single dose of glibenclamide 5 mg after six days of either miglitol (first 50 mg three times daily for four days, then 100 mg three times daily for two days) or placebo, the mean peak blood concentration (Cmax) and area under the drug-time curve (AUC value) of glibenclamide were reduced by 17% and 25%, respectively. The study also found that for diabetic patients taking glibenclamide 3.5 mg/day, if 100 mg of miglitol was given three times daily for seven days, the mean AUC of glibenclamide was reduced by 18% in the miglitol combination group, but was not statistically significant compared to the placebo group. A US clinical trial provided further information on the potential interaction of the combination of miglitol and glibenclamide. In this trial, patients were given either miglitol or placebo, and these patients were on 10 mg of glibenclamide twice daily before and after. At 6-month and 1-year follow-up, the mean Cmax of glibenclamide was found to be 16% and 8% lower in patients on the combination of miglitol (100 mg, 3 times daily) than in patients on glibenclamide alone. However, the above differences were not statistically significant. Therefore, although the combination of miglitol and glibenclamide had a trend toward lower AUC and Cmax, none of the above three studies could confirm a definite interaction between the two.
A study of the pharmacokinetic effects of miglitol (100 mg three times daily for 7 days) on metformin (1000 mg single dose) in healthy subjects showed that the AUC and Cmax of metformin were reduced by 12%-13% in the miglitol combination group compared to the placebo group, but the results were not statistically significant.
In a study of healthy subjects it was also found that when miglitol (50 mg or 100 mg three times daily) was combined with digoxin, it decreased digoxin plasma concentrations by 19% and 28%, respectively. However, in diabetic patients taking digoxin, their plasma concentrations were not altered by the combination of miglitol (100 mg three times daily for 14 days).
Other trials in healthy subjects confirmed that miglitol decreased the bioavailability of ranitidine and propranolol by 60% and 40%, respectively, with no significant effect on the pharmacokinetic or pharmacodynamic parameters of warfarin and nifedipine.
Both enterosorbents (e.g., charcoal pellets) and digestive enzyme preparations including carbohydrate-degrading enzymes (e.g., amylin, trypsin) can reduce the effect of miglitol and therefore should not be co-administered.
In 12 healthy male subjects, it was found that the acid preparations did not affect the pharmacokinetic parameters of miglitol.
[Drug Overdose].
Unlike sulfonylureas and insulin, overdose of miglitol does not cause hypoglycemia. However, it may cause temporary gastric distention, diarrhea and abdominal discomfort. Since no other extraintestinal symptoms have been observed with miglitol, it is not expected that an overdose of miglitol may cause serious systemic reactions.
Pharmacology and Toxicology
Pharmacological effects
Miglitol exerts its anti-hyperglycemic effect through reversible inhibition of alpha-glucosidase in the intestinal mucosa. Alpha-glucosidase on the brush border of the small intestinal mucosa hydrolyzes oligosaccharides and disaccharides into glucose and other monosaccharides. In diabetic patients, inhibition of this enzyme delays glucose absorption and reduces postprandial hyperglycemia.
Unlike the mechanism of action of sulfonylureas, miglitol does not stimulate insulin secretion, and when the two are combined, miglitol enhances the glycemic control effect of sulfonylureas. In addition, miglitol can reduce the insulin-producing and weight gain effects of sulfonylureas. The inhibition of lactase by miglitol is small and does not cause lactose intolerance at recommended doses.
Toxicological studies
Genotoxicity
Negative results from the Ames test, in vitro mammalian cell Hprt gene mutation test, in vivo mouse micronucleus test and dominant lethality test for miglitol.
Reproductive toxicity
In a fertility toxicity test in rats, oral administration of 300 mg/kg of miglitol (approximately 8 times the maximum recommended human dose based on body surface area) to Wistar rats had no significant effect on fertility in female and male rats and no significant effect on offspring survival, growth, development and fertility.
No teratogenic effects associated with miglitol administration were seen in embryo-fetal developmental toxicity tests in rats (50, 150 and 450 mg/kg, approximately 1.5, 4 and 12 times the maximum recommended human dose based on body surface area) and rabbits (10, 45 and 200 mg/kg, approximately 0.5, 3 and 10 times the human dose). No significant effects on maternal fertility or fetal development were observed in rats and rabbits given 4 and 3 times the human dose of miglitol (based on body surface area). At the highest administered dose (450 and 200 mg/kg in rats and rabbits, respectively), maternal toxicity and/or fetal toxicity was observed, with a slight but statistically significant decrease in body weight in rat fetuses and a slight decrease in body weight, delayed ossification and increased mortality in rabbit fetuses.
In a perinatal toxicity assay with miglitol in rats, the no adverse effect dose (NOAEL) was 100 mg/kg, which is approximately four times the human dose based on body surface area. At the high dose (300 mg/kg), an increased stillbirth rate was seen, which was not observed at the delivery stage in the high dose (450 mg/kg) of the rat embryo-fetal development toxicity test. Otherwise, no adverse effects on pup survival, development, behavior and fertility were observed in the rat embryo-fetal development and perinatal toxicity tests.
Carcinogenicity
No carcinogenic effects associated with miglitol were observed in mice given up to approximately 500 mg/kg (more than 5 times the human exposure based on AUC) for 21 months of adulteration and in rats given miglitol for 2 years of adulteration (comparable to the maximum human exposure based on AUC).
Pharmacokinetics】According to the literature
Absorption: The absorption of miglitol is saturated at high doses, with complete absorption at a dose of 25 mg and only 50%-70% absorption at a dose of 100 mg. Regardless of the dose, it reaches its highest blood concentration 2-3 hours after dosing. There is no evidence that systemic absorption of miglitol contributes to its therapeutic effect.
Distribution: The protein binding of miglitol is very low (<4.0%) with a volume of distribution of 0.18 L/kg, mainly in the extracellular fluid.
Metabolism: Miglitol is not metabolized in humans or in any of the animals studied. No metabolites were detected in plasma, urine and feces, indicating that the substance has no systemic systemic metabolism and pre-metabolism into the systemic system.
Excretion: Miglitol is excreted from the kidneys in its original form. Thus, >95% of the dose given at 25 mg is recovered in the urine within 24 hours. In contrast, due to incomplete bioavailability, the cumulative recovery from urine is slightly lower if a dose greater than 25 mg is given. The elimination half-life of miglitol is approximately 2 hours.
Special Populations
Patients with renal impairment: Since miglitol is primarily excreted by the kidneys, it accumulates in patients with renal impairment. Patients with creatinine clearance less than 25 ml/min taking 25 mg three times daily have more than twice the blood concentration of miglitol than patients with creatinine clearance greater than 60 ml/min. Because miglitol acts locally, it is not feasible to correct the increased blood levels by adjusting the dose. The safety of dosing in patients with creatinine clearance less than 25 ml/min has not been established.
Patients with hepatic impairment: The pharmacokinetics of miglitol are not altered in patients with cirrhosis compared to healthy subjects. Because miglitol is not metabolized by the liver, the pharmacokinetics of this product have no effect on hepatic function.
Gender: There was little difference in the pharmacokinetics of miglitol between men and women under the same weight conditions.
Race: Several pharmacokinetic studies in Japanese and Caucasian subjects have shown similar results. A study on black and Caucasian healthy subjects suggested that when the pharmacodynamics were compared at the same dose of 50mg, they resulted in similar glucose and insulin effects.
Storage】Sealed and stored below 25℃.
Package】Pharmaceutical PVC rigid tablets/PTP aluminum foil for pharmaceutical packaging, 10 tablets/plate x2 plate/box; 10 tablets/plate x3 plate/box; 10 tablets/plate x4 plate/box; 12 tablets/plate x2 plate/box; 12 tablets/plate x3 plate/box; 12 tablets/plate x4 plate/box.
Effective period】24 months
【Execution standard
【Approval Number】State Drug Certificate H20045403
[Marketing license holder
Company name: Sichuan Vio Pharmaceutical Co.
Registered Address: No. 252, Culture Road, Tianpeng Town, Pengzhou City, Sichuan Province
Manufacturer
Company name: Sichuan Vio Pharmaceutical Co.
Production Address: No. 252, Culture Road, Tianpeng Town, Pengzhou City, Sichuan Province
Postal code：611930
Telephone number: 028-88504086
Fax number: 028-88506655
Web address: www.scweiao.com