Glufast

Glufast

Manufacturer:

Eisai

Distributor:

DKSH
Full Prescribing Info
Contents
Mitiglinide calcium hydrate.
Description
Mitiglinide calcium hydrate (10 mg) per tablet.
Nonproprietary name: Mitiglinide Calcium Hydrate (JAN).
Chemical name: (+)-Monocalcium bis [(2S,3a,7a-cis)-α-benzylhexahydro-γ-oxo-2-isoindolinebutyrate] dihydrate.
Molecular formula: C38H48CaN2O6·2H2O.
Molecular weight: 704.91.
Mitiglinide calcium hydrate is a white powder. It is freely soluble in methanol or ethanol (99.5), slightly soluble in water, and very slightly soluble in acetonitrile.
Action
Pharmacology:Pharmacodynamics: Blood glucose elevation suppression activity: Twenty Type 2 diabetes mellitus patients underwent single-dose study using the double-blind crossover method. Administration of 10 mg of this drug promoted additional secretion of insulin at an early stage after meals, and suppressed the increase in blood glucose level. (See Figures 1 and 2.)

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When mitiglinide calcium hydrate was administered orally to streptozotocin-induced diabetes mellitus model rats, because of its rapid-acting insulin secretion promoting activity, an increase in blood glucose after oral loading of liquid meal was suppressed, and post-loading plasma glucose area under the concentration-time curve value dropped (in vivo).
Mechanism of action: By bonding with pancreatic beta-cells' sulfonylurea receptors, mitiglinide calcium hydrate promotes the secretion of insulin by inhibiting the ATP-sensitive K+ channel (KATP channel) current (in vitro).
Pharmacokinetics: Plasma concentration: When a single dose of 5, 10 and 20 mg of mitiglinide was administered orally to healthy adult males immediately before meals, maximum plasma concentration (Cmax) was reached 0.23-0.28 hours after administration, and the half-life (t½) was approximately 1.2 hours. (See Table 1 and Figure 3.)

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On the other hand, when 5 mg of mitiglinide was administered orally after meals to healthy adult males, compared with immediately before meals, a reduction in maximum plasma concentration (Cmax) and a delay in the time to reach maximum plasma concentration (Tmax) were observed. (See Table 2.)

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When a single dose of 10 mg of mitiglinide was administered orally to adults with normal renal function, patients with decreased renal function, and patients with chronic renal failure (mean creatinine clearance values on the day before administration of this drug were 113.75, 37.01 and 3.431 mL/min, respectively) immediately before meals, along with a reduction in creatinine clearance, the half-life (t½) was prolonged. However, no significant correlation was seen between creatinine clearance and other major parameters (Cmax, AUC0-inf and CL tot/F). (See Table 3 and Figure 4.)

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Click on icon to see table/diagram/image

When a single dose of mitiglinide at 10 mg was administered concomitantly with voglibose (an α-glucosidase inhibitor) immediately before meal in patients with Type 2 diabetes mellitus whose blood glucose control by voglibose alone was inadequate, maximum plasma concentration (Cmax) of 1395.8 ng/mL was reached 0.28 hours after administration, and the half-life (t½) was 1.29 hours. Thus, no significant changes were observed in pharmacokinetic profiles compared with mitiglinide administration alone.
Metabolism and excretion: When a single dose of 5, 10 and 20 mg of mitiglinide was administered orally to healthy adult males immediately before meals, approximately 54-74% of the dose was excreted in the urine within 24 hours, a majority in the form of glucuronide conjugate metabolites. Mitiglinide accounted for less than 1%.
When a single dose of the 11 mg solution of 14C-labeled mitiglinide calcium hydrate was administered orally to non-Japanese healthy adult males immediately before meals, radioactivity in the plasma 0.5 hours and 4 hours after administration was primarily mitiglinide-derived, and the amount of mitiglinide's glucuronide conjugate that existed was approximately 1/3 to 1/6 the amount of mitiglinide. There were even fewer hydroxyl metabolites. Approximately 93% of the radioactivity was excreted in the urine, and approximately 6% in the feces.
In vitro studies have confirmed that mitiglinide calcium hydrate is metabolized in the liver and kidneys in humans, while glucuronide conjugates are mainly produced by the drug metabolic enzymes UGT1A9 and 1A3, and hydroxymetabolites, mainly by CYP2C9.
Clinical Studies: Monotherapy: Placebo-controlled double-blind phase II study: In 190 patients with Type 2 diabetes mellitus who are unable to obtain sufficient blood glucose control with diet therapy alone (44.4% had no history of drug therapy for diabetes mellitus; mean HbA1c value at the start of administration: 8.03%), a dose of 5, 10 and 20 mg of this drug was administered TID orally immediately before meals for 12 weeks. The patients in the 10-mg group showed a significant decrease in HbA1c eight weeks after administration. At the time of the final evaluation, the HbA1c variation was, compared with +0.49% in the placebo group, -0.22%, -0.35%, and -0.38% in the 5-, 10- and 20-mg group, respectively, showing significant reductions over the placebo in all dose groups (p<0.025, Shirley-Williams test). Frequencies of hypoglycemic symptoms, moreover, were 6.7%, 2.2%, and 6.3%, respectively, in the drug groups compared with 6.5% in the placebo group.
Placebo-controlled double-blind phase III study: In 314 patients with Type 2 diabetes mellitus who are unable to obtain sufficient blood glucose control with diet therapy alone (79.4% had no history of drug therapy for diabetes mellitus; mean HbA1c value at the start of administration: 7.47%), a dose of 10 mg of this drug was administered TID orally immediately before meals for 12 weeks. At the time of the final evaluation, the HbA1c variation was compared with +0.21% in the placebo group, -0.44% in the 10-mg group, showing a significant difference (p<0.001, t-test). Frequency of hypoglycemic symptoms, moreover, was 2.0% in the 10-mg group compared with 2.9% in the placebo group.
Long-term study: In the long-term administration study, with a dose of 10 mg, 218 out of 351 patients showed their HbA1c decreased, and stable blood glucose control was successfully maintained thereafter. Thirty-seven patients showed improvements in HbA1c with increased dose to 20 mg sixteen weeks after the start of administration because of failing to obtain effects with a dose of 10 mg.
Concomitant treatment with α-glucosidase inhibitors: Double-blind phase II/III study: In 385 patients with Type 2 diabetes mellitus whose blood glucose control was inadequate (mean HbA1c at the start of concomitant treatment: 7.10%) by the treatment regimen with diet and voglibose monotherapy (a single dose: 0.2 mg), voglibose at a dose of 0.2 mg and mitiglinide at a dose of 5 or 10 mg were orally administered 3 times daily immediately before meals for 12 weeks. The changes in HbA1c at the time of the final evaluation showed a significant decrease: -0.64% in the 10 mg mitiglinide treatment group and -0.44% in the 5 mg mitiglinide treatment group whereas the change was -0.02% in the voglibose monotherapy group (p<0.001, ANOVA for all groups).
Frequencies of hypoglycemic symptoms were 6.9% in the 10 mg mitiglinide treatment group and 3.3% in the 5 mg mitiglinide treatment group whereas the frequency was 1.1% in the voglibose monotherapy group.
Long-term concomitant treatment study: In 161 patients with Type 2 diabetes mellitus receiving long-term administration of mitiglinide concomitantly with voglibose, stable improvement in HbA1c was observed.
Indications/Uses
GLUFAST is indicated for improvement in postprandial plasma glucose transition in patients with type 2 diabetes mellitus who experience inadequate response to any of the following treatments: Dietary treatment and exercise therapy alone; Use of α-glucosidase inhibitors, in addition to diet and physical exercise.
Dosage/Direction for Use
The recommended usual dose of GLUFAST for adults is 10 mg three times daily just before meals. The dose should be increased/decreased according to symptoms.
Precautions: Administering GLUFAST orally after meals results in decreased efficacy due to diminished absorption. To lower the blood glucose level after the meals effectively, GLUFAST should be administered just before meals (within 5 min). However, because of its rapid action after administration, when administered 30 min prior to meals, blood insulin levels increase 15 min before meal and could result in hypoglycemia at the start of meals.
Overdosage
Specific clinical picture of mitiglinide calcium hydrate according to the overdose is unknown. Thus, appropriate symptomatic therapy should be provided as necessary in case of overdose. There is no specific antidote.
Contraindications
GLUFAST is contraindicated in the following patients: Patient with severe ketosis, diabetic coma or pre-coma, or Type 1 diabetes mellitus. [It is essential to treat hyperglycemia immediately with administration of intravenous fluid or insulin.]
Patient with severe infections, before or after surgery, or with serious trauma. [It is desirable to control blood glucose with the injection of insulin. Therefore, this drug should not be administered to these patients.]
Patient with a history of hypersensitivity to any of the ingredients of this product.
Women who are pregnant or may possibly be pregnant. (See Use in Pregnancy & Lactation.)
Special Precautions
GLUFAST should only be administered to patients who have been positively diagnosed with diabetes mellitus. Special attention should be paid to verify the diagnosis since, other than diabetes, some diseases (impaired glucose tolerance, urine sugar positive, etc.) show diabetes-like symptoms, such as renal diabetes, senile glycometabolic disorder and abnormal thyroid function.
In patients on the basic regimen for treatment of diabetes mellitus only with dietary treatment and exercise therapy alone or those on the regimen with α-glucosidase inhibitors in addition to diet and physical exercise, GLUFAST should be prescribed only when fasting blood glucose level ≥126 mg/dL or postprandial blood glucose level or ≥200 mg/dL within 1- or 2-hour period.
Careful Administration: GLUFAST should be administered with care in the following patients: Patients with hepatic dysfunction [Since GLUFAST is metabolized mainly in the liver, it may worsen hepatic dysfunction in those patients as well as result in hypoglycemia].
Patients with renal dysfunction. [Prolongation of elimination half-life for mitiglinide in plasma was observed in patients with chronic renal failure which may result in secondary hypoglycemia (See Pharmacology: Pharmacokinetics under Actions).]
Patients with the following conditions: Patients with ischemic heart disease [Myocardial infarction has been reported. See Adverse Reactions].
Patients with pituitary or adrenal insufficiency. [GLUFAST may cause hypoglycemia.]
Patients with gastroenteropathy such as diarrhoea and vomiting. [GLUFAST may cause hypoglycemia.]
Malnutrition, starvation, insufficient intake of foods, or debility. [GLUFAST may cause hypoglycemia.]
Strenuous physical exercise. [GLUFAST may cause hypoglycemia.]
Excessive ingestion of alcohol. [GLUFAST may cause hypoglycemia.]
Elderly. [Compromised physiological functions is generally observed in elderly people. See Use in the Elderly as follows.]
Important Precautions: Since GLUFAST may cause hypoglycemia, due care should be exercised for patients engaged in work at high elevations (risk of falling) or patients operating machinery or motor vehicles. When hypoglycemia symptoms are observed, patients should be treated appropriately with sucrose, glucose, or soft drinks containing adequate amounts of glucose. If hypoglycemia occurs on the concomitant use of α-glucosidase inhibitors, glucose should be administered instead of sucrose, since α-glucosidase inhibitors delay the digestion and absorption of disaccharides. In addition, the risks and management of hypoglycemia symptoms should be carefully explained to patients.
During maintenance of GLUFAST treatment, blood glucose level and condition should be monitored periodically. If satisfactory effect is not achieved after two to three months' treatment with GLUFAST, alternative treatments should be considered.
Sometimes during treatment, drug administration may be unnecessary, lowered doses may be required, or the effectiveness may be completely or partially impaired by patient's poor regimen management compliance or complications of infectious diseases. Therefore, the necessity of continuous treatment, the dose, the selection of appropriate drug, should always be determined considering patients' dietary habits, blood glucose level and infections.
GLUFAST has rapid onset of insulin secretagogue activity. The site of this action is the same as sulfonylurea-type agents, therefore since the additive/synergistic clinical effects and safety of interactions with sulfonylurea-type agents have not been confirmed, GLUFAST should not be used in combination with sulfonylurea-type agents. [See Pharmacology and Pharmacodynamics under Actions.]
Effectiveness and safety has not been confirmed for concomitant use of GLUFAST with insulin sensitizer (pioglitazone hydrochloride) or biguanides (metformin etc.).
Use in Children: The safety of GLUFAST in pediatric patients has not been established. [GLUFAST has not been administered to pediatric patients.]
Use in the Elderly: As physiological functions are generally compromised in the elderly, administration should be carefully performed taking into consideration blood glucose level or initiating treatment at a lower dose (5 mg each time).
Use In Pregnancy & Lactation
GLUFAST should not be administered to women who are pregnant or possibly pregnant. [In the rat study, GLUFAST is confirmed to pass through the placenta. In addition, one dam rat died during perinatal period, and the causality of hypoglycemia induced by pharmacological effect of GLUFAST could not be excluded.]
Nursing mothers administered GLUFAST should avoid lactation. [GLUFAST is confirmed to be excreted in the breast milk in the rat study.]
Adverse Reactions
Adverse reactions were reported in 245 patients (21.5%) of total 1142 patients. The common adverse events were hypoglycemic symptoms (5.8%: See Pharmacology: Clinical Studies under Actions), gastrointestinal disorders such as abdominal distension (1.7%), constipation (1.2%) and diarrhea (1.1%), and headache (1.0%). The laboratory abnormalities were observed in 245 patients (21.5%) of total 1137 patients. The common events were increased pyruvic acid (6.4%), increased γ-GTP (4.1%), increased lactic acid (2.9%), increased ALT (GPT) (2.8%) and increased free fatty acid (2.1%). (At the time of the latest approval of indication.)
Clinically significant adverse reactions: Myocardial infarction (0.1%): Occurrence of myocardial infarction has been reported. Therefore, adequate heart monitoring should be performed and if any abnormalities are observed, administration should be discontinued and appropriate treatment administered.
Hypoglycemia: Hypoglycemic symptoms (dizziness, hunger pangs, tremor, feeling of weakness, cold sweat, loss of consciousness, etc.) may occur. If hypoglycemic symptoms are observed, patients should be treated appropriately with sucrose, glucose or soft drinks containing sufficient amounts of glucose. If hypoglycemia occurs with the concomitant use of α-glucosidase inhibitors, glucose should be administered instead of sucrose, since α-glucosidase inhibitors delay the digestion and absorption of disaccharides. In such cases, administration should be carefully performed while considering decrease of dose to 5 mg at a time.
Hepatic dysfunction: Hepatic dysfunction associated with marked increases in AST (GOT), ALT (GPT) or γ-GTP may occur. In such cases, perform adequate monitoring and if any abnormalities are observed, treatment should be discontinued and appropriate treatment administered.
Other adverse reactions: See Table 4.

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Drug Interactions
GLUFAST is mainly metabolized by glucuronidation with UGT1A9 and 1A3. [See Pharmacology: Pharmacokinetics under Actions.] (See Table 5.)

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Caution For Usage
Precautions concerning Use: When GLUFAST is supplied in PTP package, it should be removed from the PTP sheet for administration. [It was reported that, when PTP sheet was accidentally swallowed by a patient, the hard and acute angle of the PTP pierced the esophageal mucosa resulting in an esophageal opening, which led to serious complications such as mediastinitis.]
Storage
Store at room temperature not exceeding 30°C.
MIMS Class
ATC Classification
A10BX08 - mitiglinide ; Belongs to the class of other blood glucose lowering drugs excluding insulins. Used in the treatment of diabetes.
Presentation/Packing
Tab 10 mg (white, plain, scored) x 3 x 10's.
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