This medicinal product is used as an adjunct to appropriate dietary measures for the treatment of non-insulin dependent diabetes, when blood glucose levels cannot be controlled adequately by diet alone.

Posology
For use in adults only
As for all hypoglycemic agents, the dose should be adjusted to each individual case.
In the event of a transient glycemic imbalance, a short period of treatment with the medicinal product maybe sufficient in patients who are usually adequately stabilized by diet.
Subjects aged under 65 years
Initial dose:
The recommended initial dose is 1/2 tablet daily, administered before breakfast.
Doseincrements:
Dose adjustment usually takes place in increments of 1/2 a tablet, based on glycemic response, in divided doses before the 2 or 3 main meals. Each dose increment should be separated by at least several days.
Maintenancetreatment:
Themaximum dosage is 3 tablets daily, divided into 2 or 3 doses before themain meals.
Subjects at risk
Elderly patients aged 65 years and over:
The initial dose and the maintenance doses should be cautiously adjusted to reduce the risk of hypoglycemia. Treatment should be initiated with the smallest available dose and gradually increased if necessary (see Section 4.4).

Other patients at risk:
• In patients who are malnourished or show a considerable deterioration in their general condition, or with irregular calorie intake, and in patients with kidney or liver failure, treatment should be initiated at the lowest dose, and the dose increments scrupulously followed, so as to avoid hypoglycemic reactions (see Section 4.4).
Patients receiving other oral hypoglycemic agents:
• As for all sulfonylureas, this medicinal product may follow on from another antidiabetic treatment without a transition period. When changing over from a sulfonylurea with a longer half-life (such as chlorpropamide) to this medicinal product, patients should be carefully monitored for several weeks in order to avoid the onset of hypoglycemia, due to the possible overlap of therapeutic effects.
Method of administration
Oral use.

Thismedicinal product is contraindicated in the following situations: Known hypersensitivity to glibenclamide or to any of the excipients • Patients known to have sensitivity to other sulphonylureas and related drugs • Juvenile onset diabetes • Diabetic ketoacidosis. • Severe infection, stress, trauma, surgical procedures or other severe conditions where the drug is unlikely to control the hyperglycaemia. • Severe impairment of renal function. • Hepatic impairment. • Diabetic coma and pre-coma. • Porphyria • Pregnancy • Elderly (> 70 years).

Specialwarnings
This medicinal product contains lactose. It is not recommended for use in patients with galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome (rare hereditary diseases).
Cases of acute hemolysis have been reported in patients with G6PD deficiency receiving glibenclamide. Prescription is therefore not recommended in these patients, and use of an alternative treatment is strongly recommended if available. If there is no alternative, the decision must take into account the risk of hemolysis and the potential expected benefit of treatment on a case-by-case basis. If prescription of this medicinal product is necessary, monitoring for the possible onset of hemolysis should be performed.
Hypoglycemia: hypoglycemia may occur with sulfonylureas. The risk appears to be increased with glibenclamide. Some cases of hypoglycemia can be severe and prolonged, therefore requiring hospitalization to bring blood sugar levels back to normal over several days.
In addition, clinical signs of adrenergic counter-regulation may be observed, such as sweating, clammyskin, anxiety, tachycardia, hypertension, palpitations, angina pectoris and cardiac arrhythmias.
The clinical picture of a severe hypoglycemic attack may resemble that of a stroke.
Symptoms generally subside after intake of carbohydrates (sugar) or when hypoglycemia has been corrected.
Careful selection of patients, the dosages used, together with adequate patient information are necessary in order to avoid episodes of hypoglycemia.
Risk factors for hypoglycemia:
• patient refusal or inability to cooperate (particularly elderly patients);
• malnutrition, deterioration in general condition, irregular carbohydrate intake, insufficient calorie intake. This treatment should only be prescribed if the patient is likely to take regular

meals (especiallybreakfast).
• imbalance between physical exercise and carbohydrate intake;
• kidney and liver failure: Glibenclamide pharmacokinetics and/or pharmacodynamics may be altered in patients with kidney or liver failure. If hypoglycemia occurs in these patients, as it is likely to be severe and prolonged, appropriatemanagement should be initiated.
• non-compensated endocrine disorders affecting carbohydrate metabolism or counter- regulation of hypoglycemia: adrenal insufficiencyor hypopituitarism;
• elderly patients: Age 65 years and over has been identified as a risk factor for hypoglycemia in patients treated with sulfonylureas. Hypoglycemiamay be difficult to recognize in the elderly.
• ingestion of alcohol;
• drug combinations liable to enhance the hypoglycemic effect of glibenclamide (see Section 4.5): Hypoglycemia may be difficult to recognize in patients on beta-blocking agents. Hypoglycemia is more likely to occur during administration of a combination of hypoglycemic agents.
In these situations, the initial dose and the maintenance doses should be cautiously adjusted to reduce the risk of hypoglycemia (see Section 4.2).
Glycemic imbalance: glycemic control in a patient receiving antidiabetic treatment may be compromised in the event of fever, trauma, infection or surgical procedures. In this case, it may be necessary to discontinue treatment and administer insulin.
The efficacy of all oral hypoglycemic agents, including glibenclamide, in reducing blood glucose to the desired level, decreases in the long term for certain patients, which may be due to increasing severity of diabetes, or a decline in response to treatment. This is known as secondary failure and should be distinguished from primary failure in which case the medicinal product proves ineffective when prescribed as first-line treatment for a given patient. Adequate dose adjustment and dietary measures should be considered before a patient’s treatment is classed as a secondary failure.
Laboratory tests: blood and urine glucose should be monitored periodically. Measurement of glycosylated hemoglobin levels maybe helpful.
Glibenclamide and cardiovascular mortality: Epidemiological studies suggest that glibenclamide use is associated with an increased risk of cardiovascular mortality compared to treatment with metformin or gliclazide. This risk was observed in particular in patients with coronary heart disease.
Patientinformation:
The risks, symptoms and treatment of hypoglycemia together with the predisposing conditions, should be explained to patients and their families. Primary and secondary treatment failure should also be explained (see "Glycemic imbalance" above).
Patients should be informed of the potential risks and benefits of this treatment and other types of treatment. They should be made aware of the importance of following their diet and a regular exercise program, and of regularlymonitoring of urine and/or blood glucose levels.

Contraindicated combinations
1) The following medicinal product may enhance the hypoglycemic effect:
+ Miconazole (systemic use, oral gel): increase in the hypoglycemic effect with possible onset of hypoglycemic symptoms, or even coma.
Inadvisable combinations
1)The followingmedicinal products may enhance the hypoglycemic effect:
+ Phenylbutazone:
All forms of phenylbutazone, including topical forms: increase in the hypoglycemic effect of sulfonylureas due to a reduction in their hepatic metabolism. Preferably use another anti-inflammatory drug less likely to interact, or warn the patient and advise increased self-monitoring of blood glucose levels: if necessary, adjust the dose during and after treatment with the anti-inflammatory drug.

+ Alcohol: Antabuse effect (heat, flushing, vomiting, tachycardia). Increase in the hypoglycemic effect (inhibition of compensatory reactions), whichmay facilitate the onset of hypoglycemic coma.
Patients should not consume alcoholic beverages or medicinal products containing alcohol. 2)The followingmedicinal product may increase blood glucose levels:
+ Danazol: diabetogenic effect of danazol.
If the combination cannot be avoided, warn the patient and advise increased self-monitoring of blood and urine glucose levels. If necessary, adjust the dose of the antidiabetic drug during and after treatmentwith danazol.
Combinations requiring precautions for use
1)The followingmedicinal productsmay enhance the hypoglycemic effect:
+ Beta blockers (except for esmolol): all beta blockers can mask certain symptoms of hypoglycemia: palpitations and tachycardia. Most non-cardioselective beta blockers increase the incidence and severityof hypoglycemia.
Warn the patient and advise increased self-monitoring of blood glucose levels, particularly at the start of treatment.
+ Fluconazole: Increase in the half-life of the sulfonylurea with possible onset of hypoglycemic symptoms.
Warn the patient, advise increased self-monitoring of blood glucose levels, and, if necessary, adjust the sulfonylurea dose during treatment with fluconazole.
+ ACE inhibitors: The use of ACE inhibitors may lead to an increase in the hypoglycemic effect in diabetic patients treated with sulfonylureas.
Hypoglycemic attack appears to be exceptional. It is thought that improved glucose tolerance could result in reduced insulin requirements.
Advise increased self-monitoring of blood glucose levels.
+ Clarithromycin, erythromycin: risk of hypoglycemia due to increased absorption and plasma concentrations of the antidiabetic drug.
Warn the patient, advise increased self-monitoring of blood glucose levels, and if necessary, adjust sulfonylurea dose during treatment with clarithromycin (or erythromycin).
2)The followingmedicinal products may increase blood glucose levels:
+ Chlorpromazine (neuroleptics): at high doses (over 100 mg chlorpromazine daily), elevated blood glucose levels (decreased insulin release).
Warn the patient and advise increased self-monitoring of blood glucose levels. If necessary, adjust the dose of the antidiabetic drug during and after treatment with the neuroleptic.
+ Glucocorticosteroids (except hydrocortisone as replacement therapy)
(Systemic and topical use: intra-articular, cutaneous and enema) and tetracosactide: Elevated blood glucose levels, sometimes with ketoacidosis (reduced carbohydrate tolerance due to corticosteroid therapy).
Warn the patient and advise increased self-monitoring of blood glucose levels, particularly at the start of treatment. If necessary, adjust the dose of the antidiabetic drug during and after treatment with corticosteroids.
+ Beta-2-adrenergic agonists (ritodrine, salbutamol, terbutaline): (IV use)
Elevation of blood glucose due to beta-2 stimulants. Increase monitoring of blood and urine parameters. Possibly switch to insulin.
3)Otherinteractions:

+ Bosentan:
Risk of decreased efficacy of glibenclamide as a result of reduced plasma concentrations, due to the inducer effect of bosentan. Furthermore, cases of hepatotoxicity have been reported with this combination.
Monitoring of blood glucose levels, treatment adjustment where necessary, and monitoring of liver function tests.
+ Somatostatin analogs:
Risk of hypoglycemia or hyperglycemia: reduction or increase in sulfonylurea requirements, for instance, decreased endogenous glucagon secretion.
Advise increased self-monitoring of blood glucose levels and, if necessary, adjust sulfonylurea dose during treatment with octreotide or lanreotide.
+ Colesevelam:
Concomitant administration of colesevelam and glibenclamide led to a 32% and 47% reduction in glibenclamideAUC0-inf andCmax, respectively.
No interaction was observed when colesevelam was administered four hours after glibenclamide. Therefore, glibenclamide should be taken at least 4 hours before colesevelam.

Pregnancy
Glibenclamide is contraindicated in pregnancy.
Lactation
It has not been established whether glibenclamide is transferred to human milk. However, some sulphonylureas are excreted in breast milk. Because the potential for hypoglycaemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the benefit of breast-feeding to the infant and the benefit of the drug to the mother
if Daonil is discontinued and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.
Fertility
Notapplicable.

Patients should be made aware of the symptoms of hypoglycemia and should exercise caution when driving or usingmachines.

Adverse effect frequencies are defined using the following convention: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1 000, <1/100), rare (≥1/10 000, <1/1 000), very rare (<1/10 000), frequencynot known (cannot be estimated from the available data).
Metabolismand nutritiondisorders
• Very common: hypoglycemia (see Sections 4.4 and 4.9). Cases of hypoglycemia may be prolonged and severe, and are not always easy to correct.
• Frequencynot known: isolated cases of hyponatremia.
Skin and subcutaneous tissue disorders
• Common:mucocutaneous rash.
• Frequency not known: pruritus, maculopapular rash, bullous reactions, erythema polymorphe, exfoliative dermatitis, a few cases of photosensitivity have been reported.
Immune systemdisorders
• Frequencynot known: hypersensitivity reactions, allergic or pseudo-allergic reactions.
• Frequency not known: isolated cases of urticaria-type reactions that may progress to life-threatening reactions with bronchospasm, dyspnea, hypotension or even shock.
Gastrointestinal disorders
• Common: nausea, diarrhea.
• Uncommon: epigastric discomfort.
Hepatobiliary disorders
• Frequency not known: hepatic disorders: elevated liver enzymes have been observed with the possible onset of cytolytic or cholestatic hepatitis requiring discontinuation of treatment. These disordersmayprogress to life-threatening liver failure.
Blood and lymphatic systemdisorders
Hematological disorders generally reversible on treatment discontinuation:
• Frequency not known: hypereosinophilia, leukopenia, moderate or severe thrombocytopenia, possibly manifesting as purpura, agranulocytosis, hemolytic anemia, aplastic anemia and pancytopenia.
Investigations
• Common: like all sulfonylureas, glibenclamidemay cause weight gain.
• Frequencynot known:mild tomoderate occasional elevations of uremia and creatinine.
Eyedisorders
• Frequency not known: transient visual disturbances, such as blurred vision or accommodation disorders, particularly at the start of treatment, with or without changes in blood glucose levels.
Generaldisorders
• Frequencynot known: antabuse effect if alcohol is consumed duringmeals.
Clinical symptoms of porphyria (hepatic or cutaneous) in patients with porphyria (see Section 4.3).
• Frequency not known: in exceptional cases, potentially life-threatening cutaneous or visceral allergic vasculitis.
To report any side effect(s):
• Saudi Arabia:
- The National Pharmacovigilance and Drug Safety Centre (NPC)
o Fax: +966-11-205-7662
o Call NPC at +966-11-2038222, Exts: 2317-2356-2340.
o reporting hotline : 19999

o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc
• Sanofi- Pharmacovigilance: KSA_Pharmacovigilance@sanofi.com

Sulfonylurea overdosemay cause hypoglycemia.
Moderate symptoms of hypoglycemia, not involving loss of consciousness or neurological signs, must imperatively be corrected by carbohydrate intake, dose adjustment and/or changes in eating habits. Closemonitoringmust be continued until the physician is certain the patient is no longer in danger.
Severe hypoglycemic reactions, with coma, seizures or other neurological disorders are possible and constitute a medical emergency requiring immediate treatment as soon as the cause is diagnosed or suspected, before immediate hospitalization of the patient.
If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of a concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more diluted (10%) glucose solution at a rate that makes it possible to maintain blood glucose above 100 mg/dl. Patients should be closely monitored for at least 48 hours and, based on the patient's condition at that time, the physician should decide whether additionalmonitoring is necessary.
Glucagon must not be used as it may cause recurrent hypoglycemia due to secondary insulin hypersecretion.
Plasma clearance of glibenclamide may be prolonged in patients with liver disease. Dialysis is not beneficial to patients as glibenclamide is extensively bound to plasma proteins.

Pharmacotherapeutic group: BLOOD GLUCOSE LOWERING DRUGS EXCLUDING INSULINS - SULFONYLUREAS, ATC code: A10BB01 (A: Alimentary tract andmetabolism).
Glibenclamide, a second-generation sulfonylurea with a short half-life, appears to cause an acute reduction in blood glucose levels by stimulating insulin release by the pancreas; this effect is dependent on the presence of active beta cells in the pancreatic islets.
Stimulation of insulin secretion by glibenclamide in response to a meal is of major importance. Administration of glibenclamide in diabetic patients enhances postprandial insulinotropic response. Enhancement of postprandial insulin and C-peptide secretion responses continues after at least 6months of treatment.

Glibenclamide is extensively absorbed (92%) following oral administration. Peak plasma concentrations are reached in 2 to 6 hours. Food intake does not alter the rate or level of absorption.
Glibenclamide extensively binds to plasma albumin (99%), which can explain certain drug interactions. Glibenclamide is completely metabolized by the liver into 3 inactive metabolites eliminated via the
biliary route (60%) and via the renal route (40%); complete elimination is achieved in 45 to 72 hours. The elimination half-life is 4 to 11 hours.
Hepatocellular insufficiency reduces glibenclamide metabolism and thus considerably slows elimination.
Biliary excretion of the metabolites increases in the event of kidney failure, in proportion to the severity of the renal disorder.
Renal failure does not affect elimination as long as creatinine clearance remains above 30 ml/min.

Notapplicable.

Lactose monohydrate, maize starch, pregelatinized maize starch, talc, magnesium stearate, colloidal anhydrous silica.

Notapplicable.

2 years.

Do not Store above 25°C.

Blisters (PVC/Aluminum).

Notapplicable.