Miglitol

MIGLITOL- miglitol tablet, coated
Proficient Rx LP

For Oral Use

DESCRIPTION

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-(2a,3ß,4a, 5ß)]-. It is a white to pale-yellow powder with a molecular weight of 207.2. Miglitol is soluble in water and has a pK a of 5.9. Its empirical formula is C 8 H 17 NO 5 and its chemical structure is as follows: abcdea2-1f08-4f44-bac7-e6a43bc5a32f

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.

CLINICAL PHARMACOLOGY

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

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.

Distribution

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.

Metabolism

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.

Excretion

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

Renal Impairment

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.

Hepatic impairment

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.

Gender

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

Race

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 STUDIES

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 Error! Hyperlink reference not valid.).

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.

Table 1 Results of Monotherapy Study with Miglitol Tablets

HbA1c (%) 1-hour Postprandial Glucose (mg/dL)
Study Treatment Mean Change from Baseline * Treatment Effect Mean Change from Baseline Treatment Effect 2
*
Mean baseline ranged from 7.54 to 8.72% in these studies.
The result of subtracting the placebo group average.
p≤ 0.05
§
Although results for the 200 mg 3 times daily are presented for completeness, the maximum recommended dosage of Miglitol tablets is 100 mg 3 times daily.

1

Placebo

+0.71

+24

(U.S.)

Miglitol tablets 50 mg 3 times daily

+0.13

-0.58

-39

-63 3

2

Placebo

+0.47

+15

(U.S.)

Miglitol tablets 50 mg 3 times daily

-0.22

-0.69 3

-52

-67 3

Miglitol tablets 100 mg 3 times daily

-0.28

-0.75 3

-59

-74 3

3

Placebo

+0.18

+2

(non-U.S.)

Miglitol tablets 25 mg 3 times daily

-0.08

-0.26

-33

-35 3

Miglitol tablets 50 mg 3 times daily

-0.22

-0.40

-45

-47 3

Miglitol tablets 100 mg 3 times daily

-0.63

-0.81 3

-62

-64 3

Miglitol tablets 200 mg 3 times daily §

-0.84

-1.02 3

-85

-87 3

4

Placebo

+0.01

+8

(non-U.S.)

Miglitol tablets 50 mg 3 times daily

-0.35

-0.36 3

-20

-28 3

Miglitol tablets 100 mg 3 times daily

-0.57

-0.58 3

-25

-33 3

5

Placebo

+0.32

+17

(non-U.S.)

Miglitol tablets 100 mg 3 times daily

-0.43

-0.75 3

-38

-55 3

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