Miglitol

There are no safety and efficacy studies in humans. Insulin therapy is recommended during pregnancy.

Miglitol is excreted in human breast milk in small amounts. Drug exposure to the infant is expected although in small amounts. Miglitol is not recommended for nursing mothers.

Tell your doctor if you are breastfeeding or plan to breastfeed.

Miglitol has been detected in human breast milk. Because of the possibility for adverse reactions in nursing infants from miglitol, it is recommended that miglitol not be administered to nursing women.

If you take too much miglitol, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If miglitol is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

You should not use miglitol if you have inflammatory bowel disease (ulcerative colitis, Crohn's), a blockage in your intestines, a chronic intestinal disorder that affects digestion, or a stomach disorder that causes excess gas. Do not take miglitol if you are in a state of diabetic ketoacidosis.

Antidiabetic agent; an α-glucosidase inhibitor.1 6 16 38

In the U.S.

• Glyset

Available Dosage Forms:

• Tablet

Therapeutic Class: Antidiabetic

Pharmacologic Class: Alpha-Glucosidase Inhibitor

Miglitol is used to treat high blood sugar levels that are caused by type 2 diabetes. Normally, after you eat, your pancreas releases insulin to help your body store excess sugar for later use. This process occurs during normal digestion of food. In type 2 diabetes, your body does not work properly to store the excess sugar and the sugar remains in your bloodstream. Having high blood sugar can lead to serious health problems in the future. Proper diet is the first step in managing type 2 diabetes but often medicines are needed to help your body. Miglitol is a medicine that slows the digestion of sugars so your body has time to store extra sugar. Sometimes another medicine called sulfonylurea can be used in combination with miglitol to help your body store more sugar.

miglitol is available only with your doctor's prescription.

Miglitol Tablets, an oral alpha-glucosidase inhibitor for use in the management of non-insulin-dependent diabetes mellitus (NIDDM). Miglitol is a desoxynojirimycin derivative, and is chemically known as 3,4,5-piperidinetriol, 1-(2-hydroxyethyl) -2-(hydroxymethyl)-, [2R-(2α,3β,4α, 5β)]-. It is a white to pale-yellow powder with a molecular weight of 207.2. Miglitol is soluble in water and has a pKa of 5.9. Its empirical formula is C8H17NO5 and its chemical structure is as follows:

Miglitol tablets are available as 25 mg, 50 mg, and 100 mg tablets for oral use. The inactive ingredients are corn starch, microcrystalline cellulose, magnesium stearate, hypromelloses, polyethylene glycols, titanium dioxide, and polysorbate 80.

Miglitol is a desoxynojirimycin derivative that delays the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals. As a consequence of plasma glucose reduction, Miglitol tablets reduce levels of glycosylated hemoglobin in patients with Type II (non-insulin-dependent) diabetes mellitus. Systemic nonenzymatic protein glycosylation, as reflected by levels of glycosylated hemoglobin, is a function of average blood glucose concentration over time.

Mechanism of Action

In contrast to sulfonylureas, Miglitol tablets do not enhance insulin secretion. The antihyperglycemic action of Miglitol results from a reversible inhibition of membrane-bound intestinal α-glucoside hydrolase enzymes. Membrane-bound intestinal α-glucosidases hydrolyze oligosaccharides and disaccharides to glucose and other monosaccharides in the brush border of the small intestine. In diabetic patients, this enzyme inhibition results in delayed glucose absorption and lowering of postprandial hyperglycemia.

Because its mechanism of action is different, the effect of Miglitol tablets to enhance glycemic control is additive to that of sulfonylureas when used in combination. In addition, Miglitol tablets diminish the insulinotropic and weight-increasing effects of sulfonylureas.

Miglitol has minor inhibitory activity against lactase and consequently, at the recommended doses, would not be expected to induce lactose intolerance.

Pharmacokinetics

Absorption of Miglitol is saturable at high doses: a dose of 25 mg is completely absorbed, whereas a dose of 100 mg is 50% to 70% absorbed. For all doses, peak concentrations are reached in 2 to 3 hours. There is no evidence that systemic absorption of Miglitol contributes to its therapeutic effect.

The protein binding of Miglitol is negligible (<4.0%). Miglitol has a volume of distribution of 0.18 L/kg, consistent with distribution primarily into the extracellular fluid.

Miglitol is not metabolized in humans or in any animal species studied. No metabolites have been detected in plasma, urine, or feces, indicating a lack of either systemic or pre-systemic metabolism.

Miglitol is eliminated by renal excretion as unchanged drug. Following a 25 mg dose, over 95% of the dose is recovered in the urine within 24 hours. At higher doses, the cumulative recovery of drug from urine is somewhat lower due to the incomplete bioavailability. The elimination half-life of Miglitol from plasma is approximately 2 hours.

Special Populations

Because Miglitol is excreted primarily by the kidneys, accumulation of Miglitol is expected in patients with renal impairment. Patients with creatinine clearance <25 mL/min taking 25 mg 3 times daily, exhibited a greater than two-fold increase in Miglitol plasma levels as compared to subjects with creatinine clearance >60 mL/min. Dosage adjustment to correct the increased plasma concentrations is not feasible because Miglitol acts locally. Little information is available on the safety of Miglitol in patients with creatinine clearance <25 mL/min. Therefore, treatment of these patients with Miglitol is not recommended.

Miglitol pharmacokinetics were not altered in cirrhotic patients relative to healthy control subjects. Since Miglitol is not metabolized, no influence of hepatic function on the kinetics of Miglitol is expected.

No significant difference in the pharmacokinetics of Miglitol was observed between elderly men and women when body weight was considered.

Several pharmacokinetic studies were conducted in Japanese volunteers, with results similar to those observed in Caucasians. A study comparing the pharmacodynamic response to a single 50 mg dose in Black and Caucasian healthy volunteers indicated similar glucose and insulin responses in both populations.

Clinical Experience in Non-Insulin-Dependent Diabetes Mellitus (NIDDM) Patients on Dietary Treatment Only

Miglitol tablets were evaluated in two U.S. and three non-U.S. controlled, fixed-dose, monotherapy studies, in which 735 patients treated with Miglitol tablets were evaluated for efficacy analyses (see Table 1).

In Study 1, a 1-year study in which Miglitol tablets were evaluated as monotherapy and also as combination therapy, there was a statistically significantly smaller increase in mean glycosylated hemoglobin (HbA1c) over time in the Miglitol 50 mg 3 times daily monotherapy arm compared to placebo. Significant reductions in mean fasting and postprandial plasma glucose levels and in mean postprandial insulin levels were observed in patients treated with Miglitol tablets compared with the placebo group.

In Study 2, a 14-week study, there was a significant decrease in HbA1c in patients receiving Miglitol tablets 50 mg 3 times daily or 100 mg 3 times daily compared to placebo. In addition, there were significant reductions in postprandial plasma glucose and postprandial serum insulin levels compared to placebo.

Study 3 was a 6-month dose-ranging trial evaluating Miglitol tablets at doses from 25 mg 3 times daily, to 200 mg 3 times daily. Miglitol tablets produced a greater reduction in HbA1c than placebo at all doses, although the effect was statistically significant at the 100 mg 3 times daily and 200 mg 3 times daily. In addition, all doses of Miglitol tablets produced significant reductions in postprandial plasma glucose and postprandial insulin levels compared to placebo.

Studies 4 and 5 were 6-month studies evaluating Miglitol tablets at 50 and 100 mg 3 times daily, and 100 mg 3 times daily, respectively. As compared to placebo, Miglitol tablets produced reductions in HbA1c, as well as a significant reduction in postprandial plasma glucose in both studies at the doses employed.

Clinical Experience in NIDDM Patients Receiving Sulfonylureas

Miglitol tablets were studied as adjunctive therapy to a background of maximal or near-maximal sulfonylurea (SFU) treatment in three large, double-blind, randomized studies (two U.S. and one non-U.S.) in which 471 patients treated with Miglitol tablets were evaluated for efficacy (see Table 2).

Study 6 included patients under treatment with maximal doses of SFU at entry. At the end of this 14-week study, the mean treatment effects on glycosylated hemoglobin (HbA1c) were -0.82% and -0.74% for patients receiving Miglitol tablets 50 mg 3 times daily plus SFU, and Miglitol tablets 100 mg 3 times daily plus SFU, respectively.

Study 7 was a 1-year study in which Miglitol tablets at 25, 50 or 100 mg 3 times daily was added to a maximal dose of glyburide (10 mg twice daily). At the end of this study, the mean treatment effects on HbA1c of Miglitol tablets when added to maximum glyburide therapy were -0.30%, -0.62%, and -0.73% with the 25, 50 and 100 mg 3 times daily dosages of Miglitol tablets, respectively.

In Study 8, the addition of Miglitol tablets 100 mg 3 times daily to a background of treatment with glyburide produced an additional mean treatment effect on HbA1c of -0.66%.

Dose-Response

Results from controlled, fixed-dose studies of Miglitol tablets as monotherapy or as combination treatment with a sulfonylurea were combined to derive a pooled estimate of the difference from placebo in the mean change from baseline in glycosylated hemoglobin (HbA1c) and postprandial plasma glucose as shown in Figures 1 and 2:

Because of its mechanism of action, the primary pharmacologic effect of Miglitol is manifested as a reduction in postprandial plasma glucose, as shown previously in all of the major clinical trials. Miglitol tablets were statistically significantly different from placebo at all doses in each of the individual studies with respect to effect on mean one-hour postprandial plasma glucose, and there is a dose response from 25 to 100 mg 3 times daily for this efficacy parameter.

Miglitol tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

There is no fixed dosage regimen for the management of diabetes mellitus with Miglitol tablets or any other pharmacologic agent. Dosage of Miglitol tablets must be individualized on the basis of both effectiveness and tolerance while not exceeding the maximum recommended dosage of 100 mg 3 times daily. Miglitol tablets should be taken three times daily at the start of each main meal. Miglitol tablets should be started at 25 mg, and the dosage gradually increased both to reduce gastrointestinal adverse effects and to permit identification of the minimum dose required for adequate glycemic control of the patient.

During treatment initiation and dose titration, one-hour postprandial plasma glucose may be used to determine the therapeutic response to Miglitol tablets and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately 3 months. The therapeutic goal should be to decrease both postprandial plasma glucose and glycosylated hemoglobin levels to normal or near normal by using the lowest effective dose of Miglitol tablets, either as monotherapy or in combination with a sulfonylurea.

Initial Dosage

The recommended starting dosage of Miglitol tablets is 25 mg, given orally three times daily at the start of each main meal. However, some patients may benefit by starting at 25 mg once daily to minimize gastrointestinal adverse effects, and gradually increasing the frequency of administration to 3 times daily.

Maintenance Dosage

The usual maintenance dose of Miglitol tablets is 50 mg taken 3 times daily, although some patients may benefit from increasing the dose to 100 mg 3 times daily. To allow adaptation to potential gastrointestinal adverse effects, it is recommended that Miglitol tablets therapy be initiated at a dosage of 25 mg 3 times daily, then gradually titrated upward to allow adaptation. After 4 to 8 weeks of the 25 mg 3 times daily regimen, the dosage should be increased to 50 mg 3 times daily for approximately three months, following which a glycosylated hemoglobin level should be measured to assess therapeutic response. If at that time, the glycosylated hemoglobin level is not satisfactory, the dosage may be further increased to 100 mg 3 times daily, the maximum recommended dosage. Pooled data from controlled studies suggest a dose-response for both HbA1c and one-hour postprandial plasma glucose throughout the recommended dosage range. However, no single study has examined the effect on glycemic control of titrating patients' doses upwards within the same study. If no further reduction in postprandial glucose or glycosylated hemoglobin levels is observed with titration to 100 mg 3 times daily, consideration should be given to lowering the dose. Once an effective and tolerated dosage is established, it should be maintained.

Maximum Dosage

The maximum recommended dosage of Miglitol tablets is 100 mg 3 times daily. In one clinical trial, 200 mg 3 times daily gave additional improved glycemic control but increased the incidence of the gastrointestinal symptoms described above.

Patients Receiving Sulfonylureas

Sulfonylurea agents may cause hypoglycemia. There was no increased incidence of hypoglycemia in patients who took Miglitol tablets in combination with sulfonylurea agents compared to the incidence of hypoglycemia in patients receiving sulfonylureas alone in any clinical trial. However, Miglitol tablets given in combination with a sulfonylurea will cause a further lowering of blood glucose and may increase the risk of hypoglycemia due to the additive effects of the two agents. If hypoglycemia occurs, appropriate adjustments in the dosage of these agents should be made (see PRECAUTIONS).

• Antidiabetic Agent, Alpha-Glucosidase Inhibitor

Because miglitol is excreted primarily by the kidneys, accumulation is expected. However, dosage adjustment to correct the increased plasma concentrations is not feasible because miglitol acts locally.

No dosage adjustment necessary.

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).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Applies to miglitol: oral tablet

General

The most commonly reported adverse reactions include gastrointestinal symptoms; they tend to diminish in frequency and intensity with time.

Gastrointestinal

Very common (10% or more): Flatulence (41.5%), diarrhea (28.7%), abdominal pain (11.7%)
Postmarketing reports: Pneumatosis cystoides intestinalis (may present with symptoms of diarrhea, mucus discharge, rectal bleeding, and constipation), ileus (including paralytic ileus), subileus, gastrointestinal pain, nausea, abdominal distention.[Ref]

The severity of gastrointestinal symptoms may be decreased by dosage reduction and avoiding high gas-producing foods and sucrose. Some studies have demonstrated a decrease in the severity of gastrointestinal effects over time with continued administration.[Ref]

Dermatologic

Common (1% to 10%): Skin rash[Ref]

Hematologic

Common (1% to 10%): Low serum iron[Ref]

Some side effects of miglitol may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.