(GLICLAZIDE 80mg TABLET)
Gliclazide results from the addition to the sulphonylurea
grouping of an N-containing heterocyclic ring with an endocyclic bond.
It is 1-(3-azabicyclo(3,3,0)oct-3-yl)-3-p-tolylsulphonylurea.
It is a white crystalline substance which is poorly soluble in water.
Sulphonylurea hypoglycaemic agent.
Gliclazide stimulates insulin secretion from
functional pancreatic β-cells and increases the sensitivity of the β-cells to a glucose stimulus.
(Some residual β-cells function is therefore necessary.) Gliclazide restores the
diminished first-phase of insulin secretion noted in non-insulin dependent diabetes mellitus.
Any long-term hypoglycaemic activity of
gliclazide can be attributed to an ability to maintain its effect on insulin secretion.
Extrapancreatic effects may also be involved in the long-term efficacy of gliclazide.
Extrapancreatic effects demonstrated for gliclazide include improvement in insulin
mediated glucose utilisation and potentiation of postreceptor insulin sensitive pathways.
At normal therapeutic doses in man,
gliclazide reduces platelet adhesiveness and aggregation.
Absorption. Gliclazide is absorbed in
the gastrointestinal tract reaching peak serum concentrations within 4 to 6 hours.
Single dose studies have demonstrated that maximal falls in blood glucose levels
(23% of an 80mg dose; 30% of a 160mg dose) occur approximately five hours after drug administration;
nine hours after a dose of 160mg, a reduction of 20% was still in evidence.
The half-life of gliclazide is approximately 12 hours.
Distribution. Gliclazide is distributed
to the extracellular fluid. In animals, high concentrations of the drug were found in the liver,
kidneys, skin, lungs, skeletal muscle, intestinal and cardiac tissue. Penetration of gliclazide
into the CNS was negligible. It crosses the placental barrier and penetrates the foetus.
The apparent volume of distribution of gliclazide
(20 to 40% expressed as a percentage of body weight) is low and probably reflects the high degree
of protein binding. Al a plasma concentration of approximately 8 microgram/ml, 94.2% of the drug was protein bound and 5.8% was free.
Metabolism and excretion. There is little information
available in relation to metabolism of the drug. Employing thin layer chromatography and
gas-liquid chromatography, at least 8 metabolites (3 major) have been identified.
Some of these were glucuronic acid conjugates. Only one of the metabolites has been identified
(p-toluene sulphonamide). The liver is the probable site of metabolism.
Approximately 70% of the administered dose appears
to be excreted in the urine and 11% in the faeces. The urinary excretion of the drug is slow and
the maximum rates do not occur until 1 to 10 hours after initial administration.
The metabolic products are detectable in the urine 120 hours after oral administration.
Elimination through the faeces is usually completed within 144 hours of oral administration.
Diabetes mellitus of the maturity onset type which cannot be controlled by diet alone.
Gliclazide should not be used in diabetes
complicated by acidosis, ketosis or coma, or in patients with a history of repeated episodes of ketoacidosis or coma.
Juvenile onset diabetes and unstable
or brittle diabetes. As sulphonylurea hypoglycaemic agents are not effective in juvenile onset,
unstable or brittle diabetes, gliclazide should not be used in these conditions.
Severe renal and liver disease. Gliclazide
is contraindicated in severe hepatic or renal insufficiency. Caution should be exercised
and dosage reduction may be required when using gliclazide in patients with impaired renal or hepatic function.
Hypersensitivity. Gliclazide should not
be used in patients with known sensitivity to sulphonylureas.
Use in Pregnancy
Risk Category: C
It is important to achieve strict
normoglycaemia during pregnancy. Oral hypoglycaemic agents should be replaced by insulin.
The sulphonylureas may enter the foetal
circulation and cause neonatal hypoglycaemia. In animal studies, embryotoxicity and/or birth defects have been demonstrated.
Use in Lactation
Gliclazide should not be used during lactation.
Acute complications such as severe trauma,
fever, infection or surgery. These acute complications provoke additional metabolic stress
which accentuate the predisposition to hypoglycaemia and ketosis. Patients presenting with
such conditions may require insulin to maintain control. It is not appropriate to increase the dosage of gliclazide.
Hypoglycaemia. Close observation and
careful initiation and adjustment d dosage are mandatory in patients who are elderly and debilitated,
malnourished, semistarved or simply neglecting dietary restrictions. In such patients,
severe hypoglycaemia may occur and may require corrective therapy over a period of several days.
Certain conditions such as alcoholism, insulinoma, adrenal thyroid and pituitary
insufficiency increase the sensitivity to sulphonylureas and may dispose to hypoglycaemia.
Monitoring of diabetic state. As with other antidiabetic therapies,
patients must be under close medical supervision. Patients treated with gliclazide must
be monitored regularly to ensure optimal control of the diabetic state and, where necessary,
for the adjustment of dosage. Particular care must be taken during the initial period of stabilisation.
Dietary restrictions. Treatment with gliclazide
does not obviate the necessity for maintaining standard dietary regulations.
Patient awareness. Comprehensive instructions
must be given to the patient about the nature of the disease and what must be done to detect and prevent complications.