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Product Name
:
GLYCON
Chemical Name
:
Gliclazide
Therapeutic Category
:
Anti-diabetic drugs
Pharmacologic Category
:
Antidiabetic Agent, Sulfonylurea
Pharmaceutical Form
:
Tablets
Composition
:
Gliclazide 80mg
Dosing
 
Dosing: Adult
Type 2 diabetes: Oral: Note: There is no fixed-dosage regimen for the management of diabetes mellitus with gliclazide. Dose must be individualized based on frequent determinations of blood glucose during dose titration and throughout maintenance.
Immediate release tablet: Recommended initial: 80 mg twice daily; titrate based on blood glucose levels. Usual dosage range 80-320 mg/day (maximum dose: 320 mg/day); dosage of ≥160 mg should be divided into 2 equal parts for twice-daily administration

Modified release tablet:
Initial: 30 mg once daily; titrate in 30 mg increments every 2 weeks based on blood glucose levels. Maximum dose: 120 mg once daily
Maturity-onset diabetes: Oral: May consider conversion from insulin to gliclazide therapy in patients receiving <40 units/day insulin. Prior to conversion, discontinue insulin for 48-72 hours with close monitoring (≥3 times/day) of urine for glucose and ketones. Patients with ketonuria and glycosuria 12-24 hours after discontinuing insulin should not be converted to gliclazide therapy and should remain on insulin therapy.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Mild-moderate impairment (Clcr ≥15 mL/minute): Dose reductions may be necessary. There are no dosage adjustments provided in manufacturer's labeling.
Severe impairment: Use is contraindicated.

Dosing: Hepatic Impairment

Mild-moderate impairment: Dose reductions may be necessary. There are no dosage adjustments provided in manufacturer's labeling.
Severe impairment: Use is contraindicated.
Use
 
Management of type 2 diabetes mellitus (noninsulin dependent, NIDDM)
Adverse Reactions
 
>10%: Endocrine & metabolic: Hypoglycemia (11% to 12%; dose dependent)
1% to 10%:
Cardiovascular: Angina, arteritis, cardiac failure, cerebrovascular disorder, coronary artery disorder, hyper-/hypotension, MI, peripheral edema, tachycardia, thrombophlebitis, vasculitis, vein disorder
Central nervous system: Depression, dizziness, headache, insomnia, nervousness, pyrexia
Dermatologic: Dermatitis, erythema, pruritus, rash (including maculopapular, morbilliform), skin disorder, urticaria Endocrine & metabolic: Hyperlipidemia, hypoglycemia, hyponatremia (rare)
Gastrointestinal (often dose dependent): Abdominal pain, constipation, diarrhea, dyspepsia, epigastric fullness, gastritis, gastroenteritis, nausea, vomiting
Genitourinary: Urinary tract infection
Hematologic: Agranulocytosis, anemia, hemolytic anemia, leukopenia, pancytopenia, porphyria, thrombocytopenia
Hepatic: Alkaline phosphatase increased, cholestasis, jaundice, LDH increased, transaminases increased
Neuromuscular & skeletal: Arthralgia,arthritis, arthrosis, back pain, myalgia, neuralgia, paresthesia, shakiness, tendonitis,weakness
Ocular: Conjunctivitis
Otic: Otitis media
Renal: Creatinine increased
Respiratory: Bronchitis, cough, epistaxis, pharyngitis, pneumonia, rhinitis, sinusitis, upper respiratory infection
Miscellaneous: Disulfiram reaction (very low potential), viral infection
<1% (Limited to important or life-threatening): Abnormal lacrimation, albuminuria, allergy, anxiety, appetite increased, arthropathy, asthma, balanitis, bursitis, bullous reactions, cataract, colitis, coma (hypoglycemic), confusion, conjunctival hemorrhage, cystitis, diplopia, dry skin, duodenal ulcer, dyspnea, eczema, esophagitis, fecal incontinence, flatulence, fungal infection, gastroesophageal reflux, glycosuria, gout, hearing decreased, hemorrhoids, hepatitis, hepatomegaly, hyperkeratosis, impotence, infection, leg pain, malaise, mastitis, melena, menstrual disorder, nail disorder, neuropathy, onychomycosis, pain, palpitation, pancreatitis (acute), photosensitivity, porphyria cutanea tarda, prostatic disorder, renal calculus, renal cyst, retinal disorder, salivation, skeletal pain, skin ulceration, thirst, tinnitus, tooth disorder, tracheitis, vaginitis, vision abnormal, vitreous disorder, weight gain, xerophthalmia, xerostomia
Contraindications
 
Hypersensitivity to gliclazide, other sulfonylureas or sulfonamides, or any component of the formulation; type 1 diabetes mellitus (insulin dependent, IDDM); diabetic ketoacidosis with or without coma; severe renal or hepatic impairment; stress conditions (eg, serious infection, trauma, surgery); concurrent use with miconazole (systemic or oromucosal gel); pregnancy; breast-feeding
Warnings / Precautions Drug
 
Concerns related to adverse effects:
• Cardiovascular mortality: U.S. product labeling of sulfonylureas states oral hypoglycemic drugs may be associated with an increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. Data to support this association are limited, and several studies, including a large prospective trial (UKPDS), have not supported an association.
• Hypoglycemia: All sulfonylurea drugs are capable of producing severe hypoglycemia; the incidence of hypoglycemia is least with gliclazide compared to other sulfonylureas (eg, glimepiride or glyburide) (CDA, 2008). Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when ethanol is ingested, or when more than one glucose-lowering drug is used. It is also more likely in elderly patients, malnourished patients and in patients with impaired renal or hepatic function. Hypoglycemic effects (eg, dizziness, weakness) may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
• Sulfonamide allergy: Chemical similarities are present among sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics (except ethacrynic acid). Use in patients with sulfonamide allergy is contraindicated in the product labeling due to the risk of cross-reaction that exists in patients with allergy to any of these compounds, especially when the previous reaction has been severe.

Disease-related concerns:

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency: Patients with G6PD deficiency may be at an increased risk of sulfonylurea-induced hemolytic anemia; however, cases have also been described in patients without G6PD deficiency during postmarketing surveillance. Use with caution and consider a nonsulfonylurea alternative in patients with G6PD deficiency.
• Hepatic impairment: Use with caution in hepatic impairment; dose reductions may be necessary. Use in severe impairment is contraindicated.
• Renal impairment: Use with caution in renal impairment; dose reductions may be necessary. Use in severe impairment is contraindicated.
• Stress-related states: Use during periods of stress (eg, trauma, infection, surgery) is contraindicated. It may be necessary to discontinue therapy and administer insulin if the patient is exposed to stress conditions.

Other warnings/precautions:

• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.
• Secondary failure: Loss of efficacy may be observed following prolonged use as a result of the progression of type 2 diabetes mellitus which results in continued beta cell destruction. In patients who were previously responding to sulfonylurea therapy, consider additional factors which may be contributing to decreased efficacy (eg, inappropriate dose, nonadherence to diet and exercise regimen). If no contributing factors can be identified, consider discontinuing use of the sulfonylurea due to secondary failure of treatment. Additional antidiabetic therapy (eg, insulin) will be required.
Metabolism/Transport Effects
Substrate of CYP2C9 (major), CYP2C19 (minor)
Interactions
 
Alcohol (Ethyl): Sulfonylureas may enhance the adverse/toxic effect of Alcohol (Ethyl). A flushing reaction may occur. Risk C: Monitor therapy
Beta-Blockers: May enhance the hypoglycemic effect of Sulfonylureas. Cardioselective beta-blockers (eg, acebutolol, atenolol, metoprolol, and penbutolol) may be safer than nonselective beta-blockers. All beta-blockers appear to mask tachycardia as an initial symptom of hypoglycemia. Ophthalmic beta-blockers are probably associated with lower risk than systemic agents. Exceptions: Levobunolol; Metipranolol. Risk C: Monitor therapy
Chloramphenicol: May decrease the metabolism of Sulfonylureas. Risk C: Monitor therapy
Cimetidine: May increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy
Corticosteroids (Orally Inhaled): May diminish the hypoglycemic effect of Antidiabetic Agents. In some instances, corticosteroid-mediated HPA axis suppression has led to episodes of acute adrenal crisis, which may manifest as enhanced hypoglycemia, particularly in the setting of insulin or other antidiabetic agent use. Risk C: Monitor therapy
Corticosteroids (Systemic): May diminish the hypoglycemic effect of Antidiabetic Agents. In some instances, corticosteroid-mediated HPA axis suppression has led to episodes of acute adrenal crisis, which may manifest as enhanced hypoglycemia, particularly in the setting of insulin or other antidiabetic agent use. Risk C: Monitor therapy
Cyclic Antidepressants: May enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy
CYP2C9 Inducers (Highly Effective): May increase the metabolism of CYP2C9 Substrates (High risk). Risk C: Monitor therapy
CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates (High risk). Risk C: Monitor therapy
CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates (High risk). Risk D: Consider therapy modification
Fibric Acid Derivatives: May enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy
Fluconazole: May increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy
GLP-1 Agonists: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose reductions when used in combination with GLP-1 agonists. Risk D: Consider therapy modification
Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemic Agents. Risk C: Monitor therapy
Hypoglycemic Agents: May enhance the adverse/toxic effect of other Hypoglycemic Agents. Risk C: Monitor therapy
Luteinizing Hormone-Releasing Hormone Analogs: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Miconazole (Oral): May increase the serum concentration of Gliclazide. Risk X: Avoid combination
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2C9 Substrates (High risk). Risk C: Monitor therapy
Pegvisomant: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy
Quinolone Antibiotics: May enhance the hypoglycemic effect of Sulfonylureas. This appears to be particularly concerning early in the course of combination therapy. Quinolone Antibiotics may diminish the hypoglycemic effect of Sulfonylureas. With longer-term combination, there is a greater risk of hyperglycemia. Risk C: Monitor therapy
Ranitidine: May increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy
Rifampin: May increase the metabolism of Sulfonylureas. Risk C: Monitor therapy
Salicylates: May enhance the hypoglycemic effect of Sulfonylureas. Of concern with regular, higher doses of salicylates, not sporadic, low doses. Risk C: Monitor therapy
Somatropin: May diminish the hypoglycemic effect of Antidiabetic Agents. Risk D: Consider therapy modification
Sulfonamide Derivatives: May enhance the hypoglycemic effect of Sulfonylureas. Exceptions: Sulfacetamide. Risk C: Monitor therapy
Thiazide Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Voriconazole: May increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may cause hypoglycemia and/or rare disulfiram reactions).
Herb/Nutraceutical: Avoid chromium, garlic, gymnema (may cause hypoglycemia).
Pregnancy
 
Pregnancy Implications
Use during pregnancy is contraindicated. Severe hypoglycemia lasting 4-10 days has been noted in infants born to mothers taking a sulfonylurea at the time of delivery. Maternal hyperglycemia can be associated with adverse effects in the fetus, including macrosomia, neonatal hyperglycemia, and hyperbilirubinemia; the risk of congenital malformations is increased when the Hb A1c is above the normal range. Diabetes can also be associated with adverse effects in the mother. Poorly-treated diabetes may cause end-organ damage that may in turn negatively affect obstetric outcomes. Physiologic glucose levels should be maintained prior to and during pregnancy to decrease the risk of adverse events in the mother and the fetus. Insulin is the drug of choice for the control of diabetes mellitus during pregnancy.
Lactation
 
Excretion in breast milk unknown/contraindicated
Breast-Feeding Considerations
Potential for neonatal hypoglycemia in a nursing infant contraindicates use.
Monitoring Parameters
 
Signs and symptoms of hypoglycemia, fasting blood glucose, hemoglobin A1c; renal and hepatic function (baseline [all patients] then periodically thereafter in patients with mild-moderate dysfunction)
Reference Range
Recommendations for glycemic control in adults with diabetes (CDA, 2008):
Hb A1c: ≤7%
Preprandial capillary plasma glucose: 72-126 mg/dL (4-7 mmol/L)
Peak postprandial capillary blood glucose: 90-180 mg/dL (5-10 mmol/L); if target Hb A1c is not met: 90-144 mg/dL (5-8 mmol/L)
Mechanism of Action
 
Stimulates insulin release from the pancreatic beta cells; reduces glucose output from the liver; insulin sensitivity is increased at peripheral target sites. Gliclazide has also been shown to decrease platelet aggregation at therapeutic doses.
Pharmacodynamics / Kinetics
 
Duration of action: Modified release tablet: 24 hours
Absorption: Immediate release formulation: Rapid; Modified release formulation: Slow and complete
Bioavailability: 97%
Protein binding: ~94% to 95%
Metabolism: Hepatic (via CYP2C9 and CYP2C19; Elliot, 2007) to inactive metabolites
Half-life elimination: Immediate release tablet: 10 hours; Modified release tablet: 16 hours (range: 12-20 hours)
Time to peak: Immediate release tablet: 4-6 hours; Modified release tablet: ~6 hours
Excretion: Urine (60% to 70%; <1% as unchanged drug); feces (10% to 20%) as metabolites
 
   
 
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