Seibule

Seibule is 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 Seibule Tablets or any other pharmacologic agent. Dosage of Seibule must be individualized on the basis of both effectiveness and tolerance while not exceeding the maximum recommended dosage of 100 mg 3 times daily. Seibule should be taken three times daily at the start of each main meal. Seibule 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 Seibule 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 Seibule, either as monotherapy or in combination with a sulfonylurea.

Initial Dosage

The recommended starting dosage of Seibule 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 Seibule 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 Seibule 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 Seibule 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 Seibule in combination with sulfonylurea agents compared to the incidence of hypoglycemia in patients receiving sulfonylureas alone in any clinical trial. However, Seibule 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).

Seibule Tablets are contraindicated in patients with:

• Diabetic ketoacidosis
• Inflammatory bowel disease, colonic ulceration, or partial intestinal obstruction, and in patients predisposed 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
• Hypersensitivity to the drug or any of its components.

WARNINGS

No information provided..

PRECAUTIONS

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Seibule or any other anti-diabetic drug.

General

Hypoglycemia

Because of its mechanism of action, Seibule, when administered alone, should not cause hypoglycemia in the fasted or postprandial state. Sulfonylureas and insulin can cause hypoglycemia. Because Seibule Tablets given in combination with a sulfonylurea or insulin will cause a further lowering of blood glucose, it may increase the hypoglycemic potential of the sulfonylurea or insulin. Consider reducing the dose of sulfonylureas or insulin when Seibule is used in combination with these medications.

Oral glucose (dextrose), whose absorption is not delayed by Seibule, should be used instead of sucrose (cane sugar) in the treatment of mild-to-moderate hypoglycemia. Sucrose, whose hydrolysis to glucose and fructose is inhibited by Seibule, is unsuitable for the rapid correction of hypoglycemia. Severe hypoglycemia may require the use of either intravenous glucose infusion or glucagon injection.

Loss Of Control Of Blood Glucose

When diabetic patients are exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of control of blood glucose may occur. At such times, temporary insulin therapy may be necessary.

Renal Impairment

Plasma concentrations of Seibule in renally impaired volunteers were proportionally increased relative to the degree of renal dysfunction. Long-term clinical trials in diabetic patients with significant renal dysfunction (serum creatinine >2.0 mg/dL) have not been conducted. Therefore, treatment of these patients with Seibule is not recommended.

Laboratory Tests

Therapeutic response to Seibule may be monitored by periodic blood glucose tests. Measurement of glycosylated hemoglobin levels is recommended for the monitoring of long-term glycemic control.

Carcinogenesis, Mutagenesis, And Impairment Of Fertility

Miglitol was administered to mice by the dietary route at doses as high as approximately 500 mg/kg body weight (corresponding to greater than 5 times the exposure in humans based on AUC) for 21 months. In a two-year rat study, miglitol was administered in the diet at exposures comparable to the maximum human exposures based on AUC. There was no evidence of carcinogenicity resulting from dietary treatment with miglitol.

In vitro, miglitol was found to be nonmutagenic in the bacterial mutagenesis (Ames) assay and the eukaryotic forward mutation assay (CHO/HGPRT). Miglitol did not have any clastogenic effects in vivo in the mouse micronucleus test. There were no heritable mutations detected in dominant lethal assay.

A combined male and female fertility study conducted in Wistar rats treated orally with miglitol at dose levels of 300 mg/kg body weight (approximately 8 times the maximum human exposure based on body surface area) produced no untoward effect on reproductive performance or capability to reproduce. Survival, growth, development, and fertility of the offspring were not compromised.

Pregnancy

Teratogenic Effects

The safety of Seibule 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 peripostnatal 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.

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 Seibule not be administered to a nursing woman.

Pediatric Use

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

Geriatric Use

Of the total number of subjects in clinical studies of Seibule 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.

Gastrointestinal

Gastrointestinal symptoms are the most common reactions to Seibule Tablets. In U.S. placebocontrolled trials, the incidences of abdominal pain, diarrhea, and flatulence were 11.7%, 28.7%, and 41.5% respectively in 962 patients treated with Seibule 25 100 mg 3 times daily, whereas the corresponding incidences were 4.7%, 10.0%, and 12.0% in 603 placebo-treated patients. The incidence of diarrhea and abdominal pain tended to diminish with continued treatment.

Dermatologic

Skin rash was reported in 4.3% of patients treated with Seibule compared to 2.4% of placebo-treated patients. Rashes were generally transient and most were assessed as unrelated to Seibule by physician investigators.

Abnormal Laboratory Findings

Low serum iron occurred more often in patients treated with Seibule (9.2%) than in placebo-treated patients (4.2%) but did not persist in the majority of cases and was not associated with reductions in hemoglobin or changes in other hematologic indices.

Postmarketing Experience

The following adverse reactions have been reported during post-approval use of Seibule. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal Disorders: ileus (including paralytic ileus), subileus, gastrointestinal pain, nausea, abdominal distention.

Pneumatosis Cystoides Intestinalis

There have been rare postmarketing reports of pneumatosis cystoides intestinalis associated with the use of alpha-glucosidase inhibitors, including Seibule. Pneumatosis cystoides intestinalis may present with symptoms of diarrhea, mucus discharge, rectal bleeding, and constipation.

Complications may include pneumoperitoneum, volvulus, intestinal obstruction, intussusception, intestinal hemorrhage, and intestinal perforation. If pneumatosis cystoides intestinalis is suspected, discontinue Seibule and perform the appropriate diagnostic imaging.

Unlike sulfonylureas or insulin, an overdose of Seibule 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 Seibule, no serious systemic reactions are expected in the event of an overdose.

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% – 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.