Miglitol

Miglitol is an Antidiabetic Agent belonging to pharmacology class of Alpha-Glucosidase Inhibitor.

Miglitol can be used in the treatment of Diabetes mellitus, type 2, treatment.

Miglitol Absorption from GI tract is saturable at high doses. Bioavailability: 50-70% (100 mg); 100% (25 mg). Time to peak plasma concentration: W/in 2-3 hr.It crosses the placenta and enters breast milk (small amounts). Volume of distribution: 0.18 L/kg. Plasma protein binding: <4%. It is not metabolized and get excreted Via urine (95%) as unchanged drug.

Miglitol is available in the form of Tablets.

The molecule is available in India, USA, Japan, Germany.

In contrast to sulfonylureas, miglitol does not enhance insulin secretion; the antihyperglycemic action of miglitol results from a reversible inhibition of membrane-bound intestinal alpha-glucosidases which hydrolyze oligosaccharides and disaccharides to glucose and other monosaccharides in the brush border of the small intestine. In patients with diabetes, this enzyme inhibition results in delayed glucose absorption and lowering of postprandial hyperglycemia.

Miglitol is available in tablets.

Miglitol can be used in the treatment of Diabetes mellitus, type 2, treatment. It is also used to treat Postprandial hyperinsulinemic hypoglycemia after gastric bypass surgery.

Miglitol competitively and reversibly inhibits membrane-bound intestinal α-glucosidases and pancreatic α-amylase resulting in the delayed absorption of glucose and degradation of ingested complex carbohydrates and disaccharides in the small intestine. This action leads to a reduced post-prandial rise in blood glucose, therefore decreasing blood glucose fluctuations.

Miglitol is approved for use in the following clinical indications:

Diabetes mellitus, type 2 (noninsulin-dependent, NIDDM): Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Diabetes mellitus, type 2: Oral: Initial: 25 mg 3 times daily at the start of each meal or may consider 25 mg once daily with gradual titration to 25 mg 3 times daily to minimize GI intolerance. After 4 to 8 weeks dose should be titrated to maintenance dose of 50 mg 3 times daily and continue for ~3 months; if glycosylated hemoglobin is not satisfactory, may further increase to maximum recommended dose: 100 mg 3 times daily. As tolerated, the lowest effective dose should be maintained.

Tablets

25 mg, 50 mg, 100 mg

Tablets

• Dose Adjustment in Kidney impairment patient:

CrCl ≥25 mL/minute: No dosage adjustment necessary. Although miglitol is primarily excreted unchanged, the increased plasma levels in renal impairment are not expected to affect efficacy (clinical response is localized to the GI tract); however, the effects on adverse effects are unknown.

CrCl <25 mL/minute or SCr >2 mg/dL: Use not recommended

• Dose Adjustment in Pediatric Patient:

Diabetes mellitus, type 2: Limited data available: Note: Alpha glucosidase inhibitors could be considered an additional therapeutic option in pediatric patients with type 2 diabetes mellitus who are ≥3 months post diagnosis and if target HbA_1c <7% not attained while on metformin therapy (maximized) in addition to a healthy lifestyle (eg, diet and exercise) with or without insulin. However, due to limited data and adverse effects, use of Miglitol is limited to those who cannot tolerate other therapies; based on mechanism of action, Miglitol will be more effective in those in whom carbohydrates make up a large part of the diet.

Children ≥10 years and Adolescents: Oral: Initial dose: 25 mg 3 times daily with the first bite of each main meal; may also initiate at 25 mg once daily with gradual titration to 25 mg 3 times daily as tolerated; then increase in 25 mg/dose increments in 2- to 4-week intervals as tolerated. Weight-based maximum dose: ≤60 kg: 50 mg/dose, >60 kg: 100 mg/dose. Clinical trials in pediatric patients are lacking; dosing based on expert-reported clinical experience; overall dosing is similar to that used in adult patients

Dumping syndrome (reactive hypoglycemia) after Nissen fundoplication: Limited data available:

Infants ≥4 months and young children who have failed nutritional manipulations: Oral: Initial dose: 12.5 to 25 mg before each bolus feeding of formula containing complex carbohydrates. Increase in 12.5 to 25 mg/dose increments until postprandial serum glucose stable (>60 mg/dL was used in clinical reports). Reported dose range: 12.5 to 100 mg/dose. Dosing based on a few small studies (total n=11). Miglitol was well tolerated in most patients, except for a few patients who experienced flatulence.

Miglitol may be contraindicated in the following conditions:

Hypersensitivity to miglitol or any of component of the formulation; diabetic ketoacidosis; inflammatory bowel disease; colonic ulceration; partial intestinal obstruction or predisposition to intestinal obstruction; chronic intestinal diseases associated with marked disorders of digestion or absorption or with conditions that may deteriorate as a result of increased gas formation in the intestine.

Concerns related to adverse effects:

• GI symptoms: Most common reactions are gastrointestinal related; incidence of abdominal pain and diarrhea tend to diminish considerably with continued treatment.

• Hypoglycemia: Hypoglycemia is unlikely to occur with miglitol monotherapy but may occur with combination therapy (eg, sulfonylurea, insulin). In patients taking miglitol, oral glucose (dextrose) should be used instead of sucrose (cane sugar) in the treatment of mild-to-moderate hypoglycemia since the hydrolysis of sucrose to glucose and fructose is inhibited by miglitol. Correction of severe hypoglycemia may require the use of either glucagon or IV glucose.

Disease-related concerns:

• Renal impairment: Not recommended in severe impairment (serum creatinine >2 mg/dL or CrCl <25 mL/minute).

• Stress-related states: It may be necessary to discontinue miglitol and administer insulin if the patient is exposed to stress (ie, fever, trauma, infection, surgery).

There is no sufficient scientific evidence traceable regarding use and safety of Miglitol in concurrent use with alcohol,

Miglitol is present in breast milk.

The exposure to a breastfeeding infant is ~0.4% of a 100 mg maternal dose.

Pregnancy Category B

The safety of Miglitol in pregnant women has not been established. Developmental toxicology studies have been performed in rats at doses of 50, 150 and 450 mg/kg, corresponding to levels of approximately 1.5, 4, and 12 times the maximum recommended human exposure based on body surface area. In rabbits, doses of 10, 45, and 200 mg/kg corresponding to levels of approximately 0.5, 3, and 10 times the human exposure were examined. These studies revealed no evidence of fetal malformations attributable to miglitol. Doses of miglitol up to 4 and 3 times the human dose (based on body surface area), for rats and rabbits respectively, did not reveal evidence of impaired fertility or harm to the fetus. The highest doses tested in these studies, 450 mg/kg in the rat and 200 mg/kg in the rabbit promoted maternal and/or fetal toxicity. Fetotoxicity was indicated by a slight but significant reduction in fetal weight in the rat study and slight reduction in fetal weight, delayed ossification of the fetal skeleton and increase in the percentage of non-viable fetuses in the rabbit study. In the peri-postnatal study in rats, the NOAEL (No Observed Adverse Effect Level) was 100 mg/kg (corresponding to approximately four times the exposure to humans, based on body surface area). An increase in stillborn progeny was noted at the high dose (300 mg/kg) in the rat peri-postnatal study, but not at the high dose (450 mg/kg) in the delivery segment of the rat developmental toxicity study. Otherwise, there was no adverse effect on survival, growth, development, behavior, or fertility in either the rat developmental toxicity or peri-postnatal studies. There are however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, miglitol should be used during pregnancy only if clearly needed.

The adverse reactions related to Miglitol can be categorized as

Common Adverse effects:

The clinically relevant drug interactions of Miglitol is briefly summarized here:

Concomitant use w/ insulin increases the risk of hypoglycemia. Intestinal adsorbents (e.g. charcoal) and carbohydrate-splitting digestive enzyme supplements (e.g. amylase, pancreatin) may reduce glycemic effects. May significantly reduce the bioavailability of ranitidine and propranolol.

The most common side effects of Miglitol includes: abdominal pain, diarrhea, and flatulence.

Pregnancy Category (FDA): B The safety of Miglitol in pregnant women has not been established. Reproduction studies have been performed in rats at doses up to 480 mg/kg (corresponding to 9 times the exposure in humans, based on drug blood levels) and have revealed no evidence of impaired fertility or harm to the fetus due to Miglitol. In rabbits, reduced maternal body weight gain, probably the result of the pharmacodynamic activity of high doses of Miglitol in the intestines, may have been responsible for a slight increase in the number of embryonic losses. However, rabbits given 160 mg/kg Miglitol (corresponding to 10 times the dose in man, based on body surface area) showed no evidence of embryotoxicity and there was no evidence of teratogenicity at a dose 32 times the dose in man (based on body surface area). There are, however, no adequate and well-controlled studies of Miglitol in pregnant women. Because animal reproduction studies are not always predictive of the human response, this drug should be used during pregnancy only if clearly needed. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies as well as increased neonatal morbidity and mortality, most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.

Animal Data

In animal reproductive studies, pregnant rats and rabbits received Miglitol at doses up to approximately 17 (rat) and 40 (rabbit) times the maximum recommended human oral dose (MRHD) based on body surface area (mg/m2); no teratogenicity was observed. Increases in embryotoxicity (increased postimplantation losses, delayed development, reduced fetal weights, and delayed parturition) occurred in rats that received oral doses approximately 10 or more times the MRHD (mg/m2 basis). No functional or behavioral toxicity was observed in rat offspring. When pregnant rats received Miglitol during late gestation and lactation, delayed postnatal development, attributed to decreased body weight, occurred in rat offspring at oral maternal doses approximately two or more times the MRHD (mg/m2 basis). In rabbits, embryotoxicity occurred at oral doses approximately 40 times the MRHD (mg/m2 basis).

Nursing Mothers

Miglitol has been shown to be excreted in human milk to a very small degree. Total excretion into milk accounted for 0.02% of a 100 mg maternal dose. The estimated exposure to a nursing infant is approximately 0.4% of the maternal dose. Although the levels of miglitol reached in human milk are exceedingly low, it is recommended that Miglitol not be administered to a nursing woman.

Pediatric Use

Safety and effectiveness of Miglitol in pediatric patients have not been established.

Geriatric Use

Of the total number of subjects in clinical studies of Miglitol in the United States, patients valid for safety analyses included 24% over 65, and 3% over 75. No overall differences in safety and effectiveness were observed between these subjects and younger subjects. The pharmacokinetics of miglitol were studied in elderly and young males (n=8 per group). At the dosage of 100 mg 3 times daily for 3 days, no differences between the two groups were found.

Gender

There is no FDA guidance on the use of Miglitol with respect to specific gender populations.

Race

There is no FDA guidance on the use of Miglitol with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Miglitol in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Miglitol in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Miglitol in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Miglitol in patients who are immunocompromised.

Acute Overdose

Unlike sulfonylureas or insulin, an overdose of Miglitol tablets will not result in hypoglycemia. An overdose may result in transient increases in flatulence, diarrhea, and abdominal discomfort. Because of the lack of extra-intestinal effects seen with Miglitol, no serious systemic reactions are expected in the event of an overdose.

Chronic Overdose

There is limited information regarding Chronic Overdose of Miglitol in the drug label.

Pharmacodynamics:

Miglitol reversibly inhibits membrane-bound intestinal α-glucosidase enzymes which hydrolyze oligosaccharides and disaccharides to glucose and other monosaccharides in the small intestinal brush border. It delays carbohydrate breakdown, glucose absorption and reduces postprandial hyperglycemia.

Pharmacokinetics:

Absorption

<2% (as active drug) and approx 35% (as metabolites) are absorbed from the gastrointestinal tract. Time to peak plasma concentration: Approx 1 hour (active drug).

Metabolism: Exclusively metabolised in the gastrointestinal tract mainly by intestinal bacteria and digestive enzymes into at least 13 metabolites, including sulfate, methyl, and glucuronide conjugates as the major metabolites.

Excretion: Via urine (approx 34% as inactive metabolites; <2% as unchanged drug and active metabolites); faeces (approx 51% as unabsorbed drug). Elimination half-life: Approx 2 hours.

1. https://www.uptodate.com/contents/ Miglitol -drug-information?search= Miglitol &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/ Miglitol _2015-1215.pdf
4. https://www.mims.com/india/drug/info/ Miglitol ?type=full&mtype=generic#mechanism-of-action