GLIPIZIDE 5 MG TABLETS

Active substance: GLIPIZIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Glipizide 5 mg Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 5 mg glipizide as the active ingredient.
For a full list of excipients see section 6.1

3

PHARMACEUTICAL FORM
Tablet.
White to off-white round convex tablet with 'W' logo and a deep breakline.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Glipizide is an orally active hypoglycaemic sulphonylurea and has been shown
to be effective in the treatment of diabetes mellitus Type II whose
hyperglycaemia cannot be controlled by diet alone. In certain patients
receiving insulin, the concurrent use of Glipizide Tablets allows a reduction in
the daily dose of insulin.
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 Glipizide 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 Glipizide may be sufficient during periods of
transient loss of control in patients usually controlled well on diet.
In general, Glipizide should be given approximately 30 minutes before a meal
to achieve the greatest reduction in post-prandial hyperglycaemia.
Concomitant food intake may delay absorption and administration: therapeutic
effects are usually seen within 30 minutes and peak at about 60 minutes.
Glipizide is rapidly metabolised and excreted mainly in the urine and therefore
it is unlikely that delayed hypoglycaemic episodes will occur.
When administered in divided daily doses Glipizide can be considered as
having a physiological action as its peak effect coincides with post-prandial
peak blood-sugar levels.
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 taken in 2 divided doses before meals.
Multiple divided doses (2 or 3 daily) are recommended for patients who
experience particularly high post-prandial blood glucose peaks.
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 the 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-insulindependent diabetic patients receiving insulin may be safely placed on
Glipizide. When transferring patients from insulin to Glipizide, the following
general guidelines should be considered:
For patients whose daily insulin requirement is 20 units or less, insulin may be
discontinued and Glipizide therapy begun at usual dosages. Several days
should elapse between Glipizide titration steps.
For patients whose daily insulin requirement is greater than 20 units, the
insulin dose should be reduced by 50% and Glipizide therapy initiated at usual
dosages. Subsequent reductions in insulin dosage should depend on individual
patient response. Several days should elapse between Glipizide 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 Glipizide. Patients should be observed
carefully (1-2 weeks) for hypoglycaemia when being transferred from longer
half-life sulphonylureas (e.g. chlorpropamide) to Glipizide 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.
A biguanide may be added to the treatment if control is not achieved with
Glipizide Tablets. The dosage of Glipizide should be maintained and the
biguanide added using low doses initially and increasing the dosage of the
biguanide progressively until adequate control is achieved or restored.

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
General
G6PD-deficiency:
Since glipizide belongs to the class of sulfonylurea agents, caution should be
used in patients with G6PD-deficiency. Treatment of patients with G6PDdeficiency with sulfonylurea agents can lead to haemolytic anaemia and a nonsulfonylurea 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 betaadrenergic 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.
Non-steroidal 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 non-cardioselective 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.
H2 Receptor 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

Fertility, Pregnancy and lactation
Use in pregnancy
Glipizide Tablets are contraindicated 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
Patients should be informed that their concentration may be affected if their
diabetes is not satisfactorily controlled, especially at the beginning of
treatment, and 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 special 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.
Gastro-intestinal 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 Disorders
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
Gastro-intestinal 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 firstpass 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
extra cellular 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
Microcrystalline cellulose, maize starch, sorbitol,
hydroxypropylmethylcellulose, sodium starch glycolate, and magnesium
stearate

6.2

Incompatibilities
No major incompatibilities are known.

6.3

Shelf life
36 months

6.4

Special precautions for storage
Store below 25°C. Protect from light and moisture.

6.5

Nature and contents of container
Glipizide Tablets are packed in either blister packaging constructed of 250μm
PVC blister strips and 20μm aluminium foil, or polyethylene containers with
tamper-evident polyethylene caps. Pack sizes of 28, 30, 56, 60 are proposed
for marketing.

6.6

Special precautions for disposal
For oral use only

7

MARKETING AUTHORISATION HOLDER
Teva UK Limited
Brampton Road
Hampden Park
Eastbourne
East Sussex
BN22 9AG
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 00289/1618

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
8 October 1997

10

DATE OF REVISION OF THE TEXT
13/10/2011

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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