SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Glipizide 5 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains glipizide 5 mg

Excipient with known effect:

Each tablet contains 152 mg lactose monohydrate

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablets

White oval biconvex uncoated tablets. Tablets are identified by ‘GP’, a breakline and ‘5’ on one side and ‘G’ on the reverse.

The tablet can be divided into equal doses.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Glipizide is indicated in the control of blood glucose levels in addition to the control of diet for patients with non insulin dependent diabetes mellitus (Type II NIDDM), when hyperglycaemia cannot be controlled by diet alone and advice has been given on weight reduction and exercise.

Stable patients with non insulin dependent diabetes mellitus not controlled by regulation of their diet alone are likely to be controlled by glipizide.

4.2 Posology and method of administration

Tablets for oral administration, ideally taken 30 minutes prior to a meal to ensure the greatest reduction in post prandial hyperglycaemia. There are no fixed dosage recommendations for the control of diabetes mellitus by glipizide. The required dosage is dependent upon patient response. Either regular urinary glucose and periodic blood glucose monitoring or regular blood glucose monitoring should be undertaken to determine and confirm dosage.

Posology

Initial Dose:    One tablet (5 mg) given before breakfast or the midday meal. In milder

cases the patient may begin with half a tablet (2.5 mg)

Maintenance:    Patients are usually established on a daily dosage between 2.5 mg and 20

mg. The maximum recommended dosage is 20 mg. Patients may be effectively controlled on once a day therapy. Total daily dosages above 15mg should however be divided.

Titration:    Any dosage adjustments should be in increments of 2.5 - 5 mg, as

determined by blood glucose response. At least several days should elapse between any titration steps. The maximum recommended single dose is 15mg, any dosage greater than this up to a daily maximum of 20 mg should be divided.

Elderly

Elderly patients are more sensitive to the hypoglycaemic effect of glipizide and other sulfonylurea drugs. The elderly are also particularly susceptible to hypoglycaemia, which may be difficult to recognise.

Initial dose: Half a tablet (2.5 mg) before breakfast or midday meal

In elderly debilitated or malnourished patients and those with impaired renal or hepatic function, the initial and maintenance dosage should be reduced sufficiently, to avoid hypoglycaemic reactions and retain effectiveness.

Paediatric Population

The safety and efficacy of glipizide have not been established in children.

Patients currently receiving insulin

After careful consideration some stable NIDDM patients inappropriately receiving insulin or receiving insulin short term may be safely transferred to glipizide or other sulfonylurea hypoglycaemic agents.

Patients receiving other oral hypoglycaemic drugs

Patients can transfer from other sulfonylurea drugs without a transition period. When transferring from a drug with a longer half-life (e.g. glibenclamide or chlorpropamide) to glipizide the patient should be monitored for up to 2 weeks in case hypoglycaemia develops due to an overlap of effect.

Concomitant use of a biguanide

Patients who do not achieve optimal control with glipizide alone or experience any secondary failure may improve control by the addition of a biguanide. The glipizide dosage should be maintained and the biguanide introduced progressively, beginning with low doses, until control is achieved.

4.3 Contraindications

Hypersensitivity to the active substance, other sulfonylureas or to any of the excipients listed in section 6.1.

Patients with severe renal, hepatic or thyroid impairment, including patients with renal or hepatic disease.

During pregnancy and lactation.

Patients with insulin dependent (juvenile onset type I) diabetes, or diabetic ketoacidosis (with or without coma) or a history of ketoacidotic coma.

Patients treated with miconazole.

4.4 Special warnings and precautions for use

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.

All potential patients, including those previously treated unsuccessfully with other oral sulfonylurea drugs, should undergo a trial period of at least 7 days. During this trial, the absence of ketonuria together with satisfactory control of blood glucose indicates that the patient is responsive to glipizide. Patients who do develop ketonuria or glycosuria, during glipizide therapy should be considered for treatment with insulin.

Primary and secondary failure should be explained, primary failure being when the drug is ineffective when first administered. Over a period of time the effectiveness of glipizide and other sulfonylurea hypoglycaemic drugs may diminish, this is known as secondary failure. If the treatment fails to achieve a satisfactory lowering of blood glucose levels or either an objective or subjective clinical improvement the patient can be considered unresponsive.

Patients should be informed of the potential risks and advantages of glipizide and of alternative modes of therapy. They should also be made aware of the importance of regular exercise, adherence to a proper diet and the need for regular testing of urine and blood glucose levels.

The risks 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.

A patient stabilised on a diabetic therapy may, when exposed to stress, fever, trauma, infection or surgery lose control of blood glucose levels. At such times it may be necessary to replace glipizide therapy with insulin.

All sulfonylurea drugs are capable of producing severe hypoglycaemia. Proper dosage, initial patient selection and instructions are all important in avoiding hypoglycaemic episodes. Renal or hepatic insufficiency may cause elevated glipizide blood levels. Hepatic insufficiency may also diminish gluconeogenic capacity. These both increase the risk of a severe hypoglycaemic reaction. If hypoglycaemia should occur in such patients, it may be prolonged and appropriate management should be instituted.

The elderly, debilitated, malnourished 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 those taking beta blockers.

Hypoglycaemia is also likely when food calorie intake is deficient, after severe or prolonged exercise, when alcohol is taken or if more than one glucose lowering drug is used.

Blood and urine glucose should be monitored periodically. Measurement of glycosylated haemoglobin may be useful.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5    Interaction with other medicinal products and other forms of interaction

Treatment with miconazole is contra-indicated in patients taking glipizide due to increase in hypoglycaemic effect, possibly leading to symptoms of hypoglycaemia or even coma (see section 4.3).

The hypoglycaemic action of sulfonylurea drugs may be potentiated by non-steroidal anti-inflammatory drugs, ACE inhibitors, salicylates, monoamine oxidase inhibitors, beta blockers and drugs that are highly protein bound, e.g. sulfonamides, chloramphenicol, probenecid, coumarins and fibrates. Fluconazole may increase the half-life and voriconazole the plasma levels of glipizide and therefore cause hypoglycaemia. Cimetidine may be associated with a reduction in post-prandial blood glucose in patients treated with glipizide. When such drugs are administered, the patient should be observed closely for signs of hypoglycaemia and when they are withdrawn, the patient should be observed for signs of any loss of control.

Thiazides and other diuretics, corticosteroids, phenothiazines at high doses, thyroid products, oestrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, progestogens, calcium channel blocking drugs, and isoniazid tend to produce hyperglycaemia and may lead to loss of control. The use of danazol is not advised during treatment with glipizide. If it cannot be avoided the patient should regularly monitor blood glucose and urine and dosage adjustment of glipizide, during and after discontinuation of danazol treatment, may be necessary.

Also alcohol has been found to increase the hypoglycaemic effect of glipizide, which can lease to hypoglycaemic coma.

4.6    Fertility, pregnancy and lactation

Pregnancy

Glipizide is contraindicated during pregnancy. Diabetes during pregnancy should be controlled with insulin. Abnormal blood glucose levels are associated with a higher incidence of congenital abnormalities, during early pregnancy and with increased perinatal morbidity and mortality in later pregnancy.

Prolonged severe hypoglycaemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery.

Studies in the rat indicate that glipizide is foetotoxic. Tests in the rat and rabbit have failed to find any teratogenic effects.

Breast-feeding

No data are available on secretion into breast milk; therefore glipizide is contraindicated in lactation.

4.7 Effects on ability to drive and use machines

Clinical experience suggests that glipizide is unlikely to affect the patient’s ability to drive or use machinery. Transient dizziness, drowsiness and headache have been reported. Also the ability of the patient to concentrate may be affected if control of diabetes is unsatisfactory, particularly in the event of hypoglycaemia. Patients should be aware of the symptoms of hypoglycaemia and be careful about driving and using machines, especially when optimum stabilisation has not been achieved, for example during the change-over from other medications or during irregular use.

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 sulfonylureas, some side effects associated with hypersensitivity may be severe and deaths have been reported in some instances.

The reported adverse reactions, which may possibly be associated with glipizide, are listed below by system organ class and frequency group. Frequencies are defined as very common (>1/10), common (>1/100 to 1</10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).

Blood and lymphatic system disorders

Not known:    Leucopenia, agranulocytosis, thrombocytopenia,    haemolytic    anaemia,

pancytopenia. Aplastic anaemia has been reported with other sulfonylureas.

Metabolism and nutrition disorders Common:    Hypoglycaemia.

Not known:    Hyponatraemia, disulfiram-like reactions have been reported    with other

sulfonylureas.

Psychiatric disorders

Not known:    Confusional state#.

Nervous system disorders

Uncommon:    Dizziness#, somnolence#, tremor#.

Not known:    Headache#.

Eye disorders

Uncommon:    Vision blurred#.

Not known:    Diplopia#, visual impairment#, visual acuity reduced#.

Gastrointestinal disorders

Common:    Nausea*, diarrhoea*, abdominal pain upper* and abdominal pain.

Uncommon:    Vomiting.

Not known:    Constipation*.

Hepatobiliary disorders

Uncommon:    Jaundice cholestatic"⁰

Not known:    Hepatic function abnormal,    hepatitis,

Skin and subcutaneous tissue disorders Uncommon:    Eczema*

Not known:    Dermatitis allergic*, erythema*, rash morbilliform*, rash maculopapular*,

urticaria* pruritus*, photosensitivity reaction.

Congenital, familial and genetic disorders Not known:    Porphyria non-acute

General disorders and administration site conditions Not known:    Malaise#

Investigations

Not known:    Aspartate aminotransferase    increased*, blood lactate dehydrogenase

increased*, blood alkaline phosphatase increased*, blood urea increased*, blood creatinine increased*.

*    They are usually transient and do not require discontinuance of therapy, however, they may also be symptoms of hypoglycaemia.

$ They appear to be dose related and usually disappear on division or reduction of dosage.

% Discontinue treatment if cholestatic jaundice occurs.

*    They frequently disappear with continued therapy. However if they persist, glipizide should be discontinued.

*    The relationship of these abnormalities to glipizide is uncertain. These have rarely been associated with clinical symptoms.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme (www.mhra.gov.uk/yellowcard).

4.9 Overdose

Overdose of sulfonylurea drugs, including glipizide can produce hypoglycaemia. Mild hypoglycaemia, without loss of consciousness or neurological findings should be treated with oral glucose, adjustment of drug dosage and/or meal patterns. The patient should be closely monitored.

Severe hypoglycaemia accompanied with coma, seizure or other neurological impairment occurs rarely but should be regarded as an emergency requiring immediate hospitalisation.

Hypoglycaemic coma requires a rapid intravenous injection of 50% glucose solution followed by infusion of 10% glucose solution, at a rate that will maintain glucose

levels above 5.6 mmol/l. Patients should be monitored for a minimum of 48 hours because hypoglycaemia may recur after apparent recovery.

As glipizide is extensively protein bound, dialysis is unlikely to be of benefit.

Clearance would be prolonged in a patient with liver disease.

Paediatric population

Children who have accidentally ingested Glipizide should be admitted to hospital for monitoring, as there is a potential for late onset hypoglycaemia.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes, blood glucose lowering drugs excl. insulin’s, sulfonylureas, ATC code: A10BB07

Glipizide is a sulfonylurea drug which when taken orally is effective at reducing blood glucose levels in patients with non insulin dependent diabetes mellitus. Glipizide reduces glycosuria and improves symptoms such as polyurea, polydipsia and pruritus.

In experimental animals, glipizide was found to stimulate insulin release by beta cells in the islets of Langerhans. In Man, stimulation of insulin secretion by glipizide in response to a meal is undoubtedly of major importance. Fasting insulin levels are not elevated even with long term therapy. Post prandial insulin response continues to be enhanced after at least 6 months therapy. The insulinotropic response to a meal occurs within 30 minutes after an oral dose of glipizide in diabetic patients, but the elevated insulin levels do not persist beyond the meal.

Evidence also indicates that extrapancreatic effects including potentiation of insulin effect is significant in the activity of glipizide.

5.2 Pharmacokinetic properties

The control of blood glucose levels persists for up to 24 hours after a single dose of glipizide. This is despite the fact that plasma levels will have declined to a fraction of the peak level by that time.

Once daily administration of up to 15 mg has been shown to be a safe and effective maintenance therapy.

Although some patients may fail to respond initially or gradually lose response to sulfonylurea drugs. Some patients may respond to glipizide when they have not responded to other sulfonylurea drugs or their response has declined.

Gastrointestinal absorption is uniform, rapid and almost complete, in man. Peak plasma levels occur 1 - 3 hours after a single dose. The elimination half-life is between 2 - 4 hours, in normal volunteers, by oral or intravenous route.

First pass metabolism is not significant as oral and intravenous administration results in similar metabolism and excretion. Glipizide does not accumulate in plasma, following repeated oral administration.

Total absorption and disposition of an oral dose was unaffected by food in normal volunteers, but in patients absorption was delayed by about 40 minutes. Thus glipizide is more effective when administered 30 minutes prior to rather than with a meal. Studies in volunteers, who received either oral or intravenous glipizide found 98 - 99% protein binding, one hour after administration.

The apparent volume of distribution of glipizide after intravenous administration was 11 litres, indicative of localisation within the extracellular fluid compartment. In mice, no glipizide or metabolites were detectable autoradiographically in the brain or spinal cord of males or females, nor in the foetuses of pregnant females. In another study, however, very small amounts of radioactivity were detected in the foetuses of rats given labelled drug.

Glipizide is extensively metabolised in the liver. The primary metabolites are inactive hydroxylation products and polar conjugates, excreted mainly in the urine. Less than 10% unchanged glipizide is found in urine.

5.3 Preclinical safety data

Studies indicate that the acute oral toxicity was low in all species studied. LD₅₀ values were greater than 4 g/kg. Chronic studies in rats and mice have failed to show any evidence of carcinogenicity related to glipizide. Neither bacterial nor in-vivo mutagenicity testing detected any evidence of mutagenicity.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Glipizide 5 mg Tablets contain the following excipients: Lactose monohydrate Maize starch

Maize starch, pregelatinised Stearic acid

6.2. Incompatibilities

Not applicable.

6.3 Shelf life

3 years when stored in PVC/PVDC/Aluminium foil blister strips and high density polyethylene containers fitted with polypropylene tamper evident caps.

2 years when stored in Polypropylene containers with polyethylene caps (Securitainers)

6.4    Special precautions for storage

Store below 25 °C and keep in the original package in order to protect from light.

6.5    Nature and contents of container

Glipizide 5 mg Tablets are available either in cartoned blister packs, high density polyethylene containers or in polypropylene containers with polyethylene caps.

Either 10 or 14 tablets are packed in PVC/PVDC/Aluminium foil blister strips. The blister strips are then packed in cardboard cartons to produce packs containing 20, 28, 30, 50, 56, 60 or 100 tablets.

High density polyethylene containers fitted with polypropylene tamper evident caps are available in pack sizes of 20, 30, 50, 60, 100, 250 and 500 tablets.

Polypropylene Containers with Polyethylene caps (Securitainers) are available in pack sizes of 20, 30, 50, 60, 100, 250 and 500 tablets.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Generics [UK] Ltd t/a Mylan

Station Close

Potters Bar

Herts

EN6 1TL

8.    MARKETING AUTHORIZATION NUMBER(S)

PL 04569/0308.

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

26/06/2006

10 DATE OF REVISION OF THE TEXT

15/05/2015