Glibenese

1. Name Of The Medicinal Product

GLIBENESE™ TABLETS 5mg.

2. Qualitative And Quantitative Composition

Each tablet contains 5mg glipizide as the active ingredient.

3. Pharmaceutical Form

Tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

Glipizide is indicated as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus.

4.2 Posology And Method Of Administration

Route of administration: Oral.

There is no fixed dosage regimen for the management of diabetes mellitus with Glibenese or any other hypoglycaemic agent. In addition to the usual monitoring of urinary glucose, the patient's blood glucose must also be monitored periodically to determine the minimum effective dose for the patient, to detect primary failure: i.e. inadequate lowering of blood glucose at the maximum recommended dose of medication, and to detect secondary failure, i.e. loss of adequate blood-glucose-lowering response after an initial period of effectiveness. Glycosylated haemoglobin levels may also be of value in monitoring the patient's response to therapy.

Short term administration of Glibenese may be sufficient during periods of transient loss of control in patients usually controlled well on diet.

In general, Glibenese should be given approximately 30 minutes before a meal to achieve the greatest reduction in post-prandial hyperglycaemia.

Initial dose: The recommended starting dose is 5mg, given before breakfast or the midday meal. Elderly patients and other patients at risk for hypoglycaemia may be started on 2.5mg (see Use in Elderly and in High Risk Patients).

Titration: Dosage adjustments should ordinarily be in increments of 2.5 or 5mg, as determined by blood glucose response. At least several days should elapse between titration steps. The maximum recommended single dose is 15mg. Doses above 15mg should ordinarily be divided.

Maintenance: Some patients may be effectively controlled on a once-a-day regimen. Total daily dosage above 15mg should ordinarily be divided. Patients can usually be stabilized on a dosage ranging from 2.5 to 20mg daily. The maximum recommended daily dosage is 20mg.

Use in elderly and in high risk patients: Elderly diabetics are more sensitive to the hypoglycaemic effects of sulphonylurea drugs and should therefore be prescribed a low starting dose of 2.5mg daily. The elderly are also particularly susceptible to the effects of hypoglycaemia. Hypoglycaemia may be difficult to recognise in the elderly.

To decrease the risk of hypoglycaemia in patients at risk including elderly, debilitated or malnourished patients, patients with irregular calorie intake and patients with an impaired renal or hepatic function, the initial maintenance dosing should be conservative to avoid hypoglycaemic reactions (see 'Initial Dose' and Section 4.4 'Special warnings and special precautions for use').

Use in children: Safety and effectiveness in children have not been established.

Patients receiving insulin: As with other sulphonylurea-class hypoglycaemics, many stable non-insulin-dependent diabetic patients receiving insulin may be safely placed on Glibenese. When transferring patients from insulin to Glibenese, the following general guidelines should be considered:

For patients whose daily insulin requirement is 20 units or less, insulin may be discontinued and Glibenese therapy begun at usual dosages. Several days should elapse between Glibenese titration steps.

For patients whose daily insulin requirement is greater than 20 units, the insulin dose should be reduced by 50% and Glibenese therapy initiated at usual dosages. Subsequent reductions in insulin dosage should depend on individual patient response. Several days should elapse between Glibenese titration steps.

During the insulin withdrawal period, the patient should self-monitor glucose levels . Patients should be instructed to contact the prescriber immediately if these tests are abnormal. In some cases, especially when the patient has been receiving greater than 40 units of insulin daily, it may be advisable to consider hospitalisation during the transition period.

Patients receiving other oral hypoglycaemic agents: As with other sulphonylurea class hypoglycaemics, no transition period is necessary when transferring patients to Glibenese. Patients should be observed carefully (1-2 weeks) for hypoglycaemia when being transferred from longer half-life sulphonylureas (e.g. chlorpropamide) to Glibenese due to potential overlapping of drug effect.

Combination Use: When adding other blood-glucose-lowering agents to glipizide for combination therapy, the agent should be initiated at the lowest recommended dose and patients should be observed carefully for hypoglycaemia. Refer to the product information supplied with the oral agent for additional information.

When adding glipizide to other blood-glucose-lowering agents, glipizide can be initiated at 5mg. Those patients who may be more sensitive to hypoglycaemic drugs may be started at a lower dose. Titration should be based on clinical judgement.

4.3 Contraindications

Glipizide is contra-indicated in patients with:

1. Hypersensitivity to glipizide or any excipients in the tablets.

2. Type 1 diabetes, diabetic ketoacidosis, diabetic coma.

3. Severe renal, hepatic or thyroid impairment; co-existent renal and hepatic disease.

4. Pregnancy and lactation.

5. Patients treated with miconazole (see 4.5 Interactions)

4.4 Special Warnings And Precautions For Use

G6PD-deficiency: Since glipizide belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD-deficiency. Treatment of patients with G6PD-deficiency with sulfonylurea agents can lead to haemolytic anaemia and a non-sulfonylurea alternative should be considered

Hypoglycaemia: All sulphonylurea drugs including glipizide are capable of producing severe hypoglycaemia which may result in coma, and may require hospitalization. Patients experiencing severe hypoglycaemia should be managed with appropriate glucose therapy and be monitored for a minimum of 24 to 48 hours. Proper patient selection, dosage and instructions are important to avoid hypoglycaemic episodes. Regular, timely carbohydrate intake is important to avoid hypoglycaemic events occurring when a meal is delayed or insufficient food is eaten or carbohydrate intake is unbalanced. Renal or hepatic insufficiency may affect the disposition of glipizide and the latter may also diminish gluconeogenic capacity, both of which increase the risk of serious hypoglycaemic reactions. Elderly, debilitated or malnourished patients and those with adrenal or pituitary insufficiency are particularly susceptible to the hypoglycaemic action of glucose-lowering drugs. Hypoglycaemia may be difficult to recognise in the elderly and in people who are taking beta-adrenergic blocking drugs. Hypoglycaemia is more likely to occur when calorific intake is deficient, after severe or prolonged exercise, when alcohol is ingested or when more than one glucose-lowering drug is used.

Loss of control of blood glucose: When a patient stabilised on any diabetic regimen is exposed to stress such as fever, trauma, infection or surgery, a loss of control may occur. At such times, it may be necessary to discontinue glipizide and administer insulin.

The effectiveness of any oral hypoglycaemic drug, including glipizide, in lowering blood glucose to a desired level decreases in many patients over a period of time. This may be due to progression of the severity of the diabetes or to diminished responsiveness to the drug. This phenomenon is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual patient when first given. Adequate adjustment of dose and adherence to diet should be assessed before classifying a patient as a secondary failure.

Renal and hepatic disease: The pharmacokinetics and/or pharmacodynamics of glipizide may be affected in patients with impaired renal or hepatic function. If hypoglycaemia should occur in such patients, it may be prolonged and appropriate management should be instituted.

Information for patients: Patients should be informed of the potential risks and advantages of glipizide and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise programme and of regular testing of blood glucose.

The risk of hypoglycaemia, its symptoms and treatment and conditions that predispose to its development should be explained to patients and responsible family members. Primary and secondary failure should also be explained.

Laboratory tests: Blood glucose should be monitored periodically. Measurement of glycosylated haemoglobin should be performed and goals assessed by the current standard of care.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The following products are likely to increase the hypoglycaemic effect:

Miconazole: Increase in hypoglycaemic effect, possibly leading to symptoms of hypoglycaemia or even coma.

Fluconazole: There have been reports of hypoglycaemia following the co-administration of glipizide and fluconazole, possibly the result of an increased half-life of glipizide.

Voriconazole – Although not studied, voriconazole may increase the plasma levels of sulfonylureas, (e.g. tolbutamide, glipizide and glyburide) and therefore cause hypoglycemia. Careful monitoring of blood glucose is recommended during co-administration.

Nonsteroidal anti-inflammatory agents (NSAIDS) (e.g. phenylbutazone): increase in hypoglycaemic effect of sulphonylureas (displacement of sulphonylurea binding to plasma proteins and /or decrease in sulphonylurea elimination).

Salicylates (acetylsalicylic acid): Increase in hypoglycaemic effect by high doses of acetylsalicylic acid (hypoglycaemic action of the acetylsalicylic acid).

Alcohol: Increase in hypoglycaemic reaction which can lead to hypoglyaemic coma.

Beta-blockers: All beta-blockers mask some of the symptoms of hypoglycaemia, e.g., palpitations and tachycardia. Most noncardioselective beta-blockers increase the incidence and severity of hypoglycaemia.

Angiotensin converting enzyme inhibitors: The use of angiotensin converting enzyme inhibitors may lead to an increased hypoglycaemic effect in diabetic patients treated with sulphonylureas, including glipizide. Therefore, a reduction in glipizide dosage may be required.

H₂Receptor Antagonists: The use of H₂ receptor antagonists may potentiate the hypoglycaemic effects of sulphonylureas, including glipizide.

The hypoglycaemic action of sulphonylureas in general may also be potentiated by monoamine oxidase inhibitors and drugs that are highly protein bound, such as sulphonamides, chloramphenicol, probenecid and coumarins.

When such drugs are administered to (or withdrawn from) a patient receiving glipizide, the patient should be observed closely for hypoglycaemia (or loss of control).

In vitro binding studies with human serum proteins indicate that glipizide binds to different sites on albumin than does tolbutamide and does not interact with salicylate or dicoumarol. However, caution must be exercised in extrapolating these findings to the clinical situation in the use of glipizide with these drugs.

The following products could lead to hyperglycaemia:

Danazol: diabetogenic effect of danazol.

If it cannot be avoided, warn the patient and step up self-monitoring of blood glucose and urine Possibly adjust the dosage of antidiabetic agent during treatment with danazol and after its discontinuation

Phenothiazines (e.g. chlorpromazine) at high doses (> 100mg per day of chlorpromazine): elevation in blood glucose (reduction in insulin release).

Corticosteroids elevation in blood glucose.

Sympathomimetics (e.g., ritodrine, salbutamol, terbutaline): elevation in blood glucose due to beta-2-adrenoceptor stimulation.

Other drugs that may produce hyperglycaemia and lead to a loss of control include the thiazides and other diuretics, thyroid products, oestrogens, progestogens, oral contraceptives, phenytoin, nicotinic acid, calcium channel blocking drugs and isoniazid.

When such drugs are withdrawn from (or administered to) a patient receiving glipizide, the patient should be observed closely for hypoglycaemia (or loss of control).

4.6 Pregnancy And Lactation

Use in pregnancy: Glipizide is contra-indicated during pregnancy. Diabetes in pregnancy should be treated with insulin and not sulphonylureas. Recent evidence suggests that hyperglycaemia in pregnancy is associated with a higher incidence of congenital abnormalities.

Lactation: Although it is not known whether glipizide is excreted in human milk, some sulphonylurea drugs are known to be excreted in human milk. Therefore glipizide is contra-indicated during lactation.

4.7 Effects On Ability To Drive And Use Machines

The effect of glipizide on the ability to drive or operate machinery has not been studied, however, there is no evidence to suggest that glipizide may affect these abilities. Patients should be aware of the symptoms of hypoglycaemia and be careful about driving and the use of machinery.

4.8 Undesirable Effects

The majority of side-effects have been dose related, transient, and have responded to dose reduction or withdrawal of the medication. However, clinical experience thus far has shown that, as with other sulphonylureas some side-effects associated with hypersensitivity may be severe and deaths have been reported in some instances.

Side effects listed in this section marked with * are usually transient and do not require discontinuance of therapy; however, they may also be symptoms of hypoglycaemia.

Blood and Lymphatic System Disorders: leucopenia, thrombocytopenia, haemolytic anaemia and pancytopenia have been reported. Aplastic anaemia and agranulocytosis have been reported with other sulphonylureas.

Metabolism and Nutritional Disorders: Hypoglycaemia (see 'Special warnings and precautions for use' section 4.4 and 'Overdose' section 4.9). Hyponatraemia has been reported. Disulfiram-like reactions have been reported with other sulphonylureas.

Psychiatric Disorders: Confusion*

Nervous System Disorders: Dizziness*, drowsiness, headache* and tremor*

Eye Disorders: Visual disturbances such as blurred vision*, diplopia* and abnormal vision* including visual impairment* and decreased vision* have each been reported in patients treated with glipizide.

Gastrointestinal Disorders: Nausea, diarrhoea, constipation and gastralgia. They appear to be dose related and usually disappear on division or reduction of dosage. Abdominal pain and vomiting.

Hepatobiliary disorders: Cholestatic jaundice, impaired hepatic function and hepatitis have been reported. Discontinue treatment if jaundice occurs. Hepatic porphyria and porphyria cutanea tarda have been reported.

Skin and Subcutaneous Tissue Disorders: Allergic skin reactions including erythema, morbilliform or maculopapular reactions, urticaria, pruritus and eczema have been reported. They frequently disappear with continued therapy. However, if they persist, the drug should be discontinued. As with other sulphonylureas, photosensitivity reactions have been reported.

General Disorders and Administration Site Conditions: Malaise*.

Laboratory Investigations: Occasional mild to moderate elevations of AST (SGOT), LDH, alkaline phosphatase, BUN and creatinine were noted. The relationship of these abnormalities to glipizide is uncertain and they have rarely been associated with clinical symptoms.

4.9 Overdose

There is no well documented experience with glipizide overdosage.

Overdosage of sulphonylureas including glipizide can produce hypoglycaemia. Mild hypoglycaemic symptoms without loss of consciousness or neurological findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycaemic reactions with coma, seizure or other neurological impairment occur infrequently but constitute medical emergencies requiring immediate hospitalisation. If hypoglycaemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 5.6mmol/1 (100mg/dl).

Patients should be closely monitored for a minimum of 48 hours and depending on the status of the patient at this time the physician should decide whether further monitoring is required. Clearance of glipizide from plasma would be prolonged in persons with liver disease. Because of the extensive protein binding of glipizide, dialysis is unlikely to be of benefit.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Glipizide is an oral blood glucose lowering drug of the sulphonylurea class.

The primary mode of action of glipizide is the stimulation of insulin secretion from the beta-cells of pancreatic islet tissue. Stimulation of insulin secretion by glipizide in response to a meal is of major importance. Fasting insulin levels are not elevated even on long-term glipizide administration but the post-prandial insulin response continues to be enhanced after at least 6 months of treatment. The insulinotropic response to a meal occurs within 30 minutes after an oral dose of glipizide in diabetic patients but elevated insulin levels do not persist beyond the time of the meal challenge. There is also increasing evidence that extrapancreatic effects involving potentiation of insulin action form a significant component of the activity of glipizide.

Blood sugar control persists for up to 24 hours after a single dose of glipizide, even though plasma levels have declined to a small fraction of peak levels by that time. See 'Pharmacokinetic properties' (section 5.2).

Some patients fail to respond initially, or gradually lose their responsiveness to sulphonylurea drugs, including glipizide. Alternatively, glipizide may be effective in some patients who have not responded or have ceased to respond to other sulphonylureas.

5.2 Pharmacokinetic Properties

Gastrointestinal absorption of glipizide in man is uniform, rapid and essentially complete. Peak plasma concentrations occur 1-3 hours after a single oral dose. The half-life of elimination ranges from 2-4 hours in normal subjects, whether given intravenously or orally. The metabolic and excretory patterns are similar with the two routes of administration, indicating that first-pass metabolism is not significant. glipizide does not accumulate in plasma on repeated oral administration. Total absorption and disposition of an oral dose was unaffected by food in normal volunteers but absorption was delayed by about 40 minutes. Thus, glipizide was more effective when administered about 30 minutes before, rather than with a test meal in diabetic patients. Protein binding was studied in serum from volunteers who received either oral or intravenous glipizide and found to be 98%-99% one hour after either route of administration. The apparent volume of distribution of glipizide after intravenous administration was 11 litres, indicative of localisation within the extracellular fluid compartment.

The metabolism of glipizide is extensive and occurs mainly in the liver. The primary metabolites are inactive hydroxylation products and polar conjugates and are excreted mainly in the urine. Less than 10% unchanged glipizide is found in the urine.

5.3 Preclinical Safety Data

Acute toxicity studies showed no specific susceptibility. The acute oral toxicity of glipizide was extremely low in all species tested (LD₅₀ greater than 4 g/kg). Chronic toxicity tests in rats and dogs at doses up to 8.0 mg/kg did not show any evidence of toxic effects.

A 20-month study in rats and an 18-month study in mice at doses up to 75 times the maximum human dose revealed no evidence of drug related carcinogenicity. Bacterial and in vivo mutagenicity tests were uniformly negative. Studies in rats of both sexes at doses up to 75 times the human dose showed no effects on fertility.

6. Pharmaceutical Particulars

6.1 List Of Excipients

The tablets contain the following ingredients: lactose, maize starch, microcrystalline cellulose and stearic acid.

6.2 Incompatibilities

None known.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Store below 25ºC.

6.5 Nature And Contents Of Container

Original packs of 56 tablets per carton. Blister pack formed from 250 μm white opaque PVC, coated 40g/m² PVdC and backed with 20μm hard tempered aluminium foil, coated with 5-6g/m² sealing lacquer.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Pfizer Limited

Ramsgate Road

Sandwich

CT13 9NJ

United Kingdom.

8. Marketing Authorisation Number(S)

PL 00057/0113R.

9. Date Of First Authorisation/Renewal Of The Authorisation

2 September 1997.

10. Date Of Revision Of The Text

June 2008

11. Legal Category

POM

Ref: GL_8_0