Glibenclamide 5mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Glibenclamide 5 mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 5 mg of glibenclamide For the full list of excipients, see 6.1.
3 PHARMACEUTICAL FORM
Tablet.
White, oval, biconvex tablets engraved ‘5’ breakline and ‘3104’ on one side, plain on the reverse.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Glibenclamide tablets are indicated for the treatment of maturity onset diabetes as an oral hypoglycaemic agent. It may therefore be used in the management of non-insulin dependent diabetes mellitus in patients who have responded poorly to dietary measures alone.
4.2 Posology and method of administration
For oral administration.
Adults: Previously untreated diabetes mellitus:
Treatment should be started with 5 mg daily, taken during or immediately following breakfast or the first main meal of the day. Where control is satisfactory, one tablet is continued as the maintenance dose. If control of diabetic symptoms remains inadequate, the daily dose may be increased not more frequently than weekly in steps of 2.5 mg (usual) or 5 mg (maximum) dose to a maximum dose not exceeding 15 mg daily. This is normally given as a single dose during or immediately after breakfast or the first main meal of the day. However, care should be taken to apportion the diet with daily activity schedule and the final dosage schedule for each individual patient.
Elderly: In debilitated or aged patients, who may be more liable to hypoglycaemia, treatment should be initiated with one 2.5 mg glibenclamide tablet daily. See Special Warnings and Precautions for Use.
Adults: Changing from other oral sulphonylurea hypoglycaemic agents:
These changes may be made without any formal break in treatment. Where the patient is already well controlled, glibenclamide treatment should commence with one 5 mg dose daily, adjusted weekly in increments not exceeding 5 mg to a maximum of 15 mg daily -see above. Where control has not been adequate on previous therapy, glibenclamide treatment may be started on the approximately equivalent dose provided this does not exceed 10 mg daily. It may then be raised at weekly intervals to a maximum dose of 15 mg daily.
5 mg of glibenclamide is approximately equivalent to:
Acetohexamide 500 mg
Tolazamide 250 mg
Chlorpropamide 250 mg
Adults: Changing from biguanides such as metformin:
The biguanide should be withdrawn and glibenclamide treatment should be started at a dose of 2.5mg tablet daily. To achieve control the dose of glibenclamide should be adjusted at weekly intervals in increments of 2.5 mg daily but not exceeding the maximum dose of 15 mg daily.
Adults: Combination therapy with biguanides:
Where control of diabetic symptoms has not been achieved with a single oral hypoglycaemic agent such as glibenclamide at the maximum dosage of 15 mg daily, control may often be achieved by adding a biguanide derivative to the regime.
Adults: Changing from insulin regime:
A few patients with very low daily insulin requirements may remain controlled if transferred to glibenclamide and should be treated as new patients. Tablets should always be taken with or immediately after the first main meal of the day and the insulin dose should be reduced further with each increased dose level of glibenclamide.
Children:
Juvenile-onset diabetes mellitus is normally insulin-dependent, and consequently glibenclamide is not suitable for use in children.
4.3 Contraindications
Glibenclamide should not be used in patients who are hypersensitive to Glibenclamide or to any of the excipients , patients known to have sensitivity to other sulphonylureas and related drugs. In patients who are suffering from or with a history of diabetic ketoacidosis or diabetic coma or pre-coma or in patients with serious impairment of function in the kidneys, liver or adrenal glands, or in juvenile or insulin dependent diabetes mellitus and in elderly (> 70 years).
It should also not be used in circumstances of severe infection, unusual stress, trauma, surgical procedures or other severe conditions e.g. patients undergoing surgery, in pregnant patients, or for whom insulin treatment and dietary measures are essential.
This drug should not be used when the drug is unlikely to control the hyperglycaemia. This drug should not be used in patients with porphyria and in case of pregnancy.
4.4 Special warnings and precautions for use
Hypoglycaemia: all sulphonylurea drugs are capable of producing moderate or severe hypoglycaemia, particularly in the following conditions:
• In patients controlled by diet alone.
• In cases of overdose.
• When calorie or glucose intake is insufficient
• In patients with irregular mealtimes and/or missed meals
• During excessive exercise
• In debilitated patients as these patients are more likely to suffer from hypoglycaemia
• In patients with mild to moderate renal impairment. However, in long-term clinical trials patients with renal insufficiency have been treated satisfactorily using glibenclamide at reduced doses with careful patient monitoring.
• In patients with adrenal or pituitary insufficiency
In order to reduce the risk of hypoglycaemia it is therefore recommended:
• To initiate treatment for non-insulin dependent diabetics by diet alone, if this is possible.
• To adjust the dose of glibenclamide according to the blood glucose response and to the 24 hour urinary glucose during the first days of treatment
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Treatment with sulphonylureas has been associated with occasional disturbances of liver function and cholestatic jaundice. If clinical jaundice or hepatitis occurs, glibenclamide should be discontinued.
Treatment of patients with G6PD- deficiency with sulfonylurea agents can lead to haemolytic anaemia. Since Glibenclamide belongs to the class of sulfonylurea agents , caution should be used in patients with G6PD- deficiency and non- sulfonylurea alternative should be considered.
4.5 Interaction with other medicinal products and other forms of interaction
Concomitant use of glibenclamide with the following medicine should be avoided:
Bosentan: There is the potential for an increased risk of hepatotoxicity when glibenclamide is given with bosentan and therefore concomitant use should be avoided.
The following medicines affect the use of glibenclamide:
Analgesics and anti-inflammatory agents: Large doses of salicylates and possibly other NSAIDs may lower blood glucose levels and the glibenclamide dose may need to be reduced. Azapropazone and phenylbutazone may enhance the hypoglycaemic effect of glibenclamide.
Antibacterials: Isoniazid may increase blood sugar levels, so the dose of sulphonylurea may need to be adjusted. Chloramphenicol, ciprofloxacin, co-trimoxazole, sulphonamides and tetracyclines may enhance the hypoglycaemic effect of glibenclamide.Concomitant use with rifamycins may reduce the hypoglycaemic effect of sulphonylureas.
Sulfinpyrazone can inhibit the metabolism of sulphonylureas, potentiating the hypoglycaemic effect of glibenclamide.
Cytotoxic drugs: Crisantaspase may induce hyperglycaemia and the dose of glibenclamide may need to be adjusted.
Alcohol: May enhance the hypoglycaemic effect of glibenclamide.
Anticoagulants: Anticoagulants and disopyramide may enhance the hypoglycaemic effect of glibenclamide.
Antidepressants: MAOIs may enhance the hypoglycaemic effect of glibenclamide
Antifungals: Miconazole increases plasma concentrations of sulphonylureas. There is the potential for fluconazole to increase the plasma concentration of glibenclamide.
Anti-gout agents: Enhanced hypoglycaemic effect with allopurinol, sulphinpyrazone and probenecid.
Antihypertensives: ACE inhibitors, such as captopril and enalapril, may enhance the hypoglycaemic effect of glibenclamide. Beta blockers may reduce the hypoglycaemic effects of sulphonylureas and mask the symptoms of hypoglycaemia. Concomitant use with diazoxide may reduce the hypoglycaemic effect of sulphonylureas.
Antimalarials: Possible increase in hypoglycaemia with quinine and quinidine.
Antipsychotics: Chlorpromazine in daily doses of 100mg or more can reduce the hypoglycaemic effect of sulphonylureas.
Antiulcer drugs: Cimetidine and ranitidine may enhance the hypoglycaemic effect of glibenclamide.
Diuretics: Loop and thiazide diuretics may reduce the hypoglycaemic effect of glibenclamide.
Lipid-lowering drugs: Clofibrate group drugs may improve glucose tolerance and have an additive effect.
Lithium: May occasionally impair glucose tolerance.
Sex hormones, hormone antagonists and steroids: Testosterone and anabolic steroids may enhance the hypoglycaemic effect of glibenclamide. Octreotide may cause hypoglycaemia or hyperglycaemia. Concomitant use with oestrogens, progesterones, oral contraceptives, and corticosteroids may reduce the hypoglycaemic effect of sulphonylureas.
Thyroid hormones: May reduce the hypoglycaemic action of glibenclamide.
Glibenclamide affects the use of the following medicines:
Anti-coagulant : Anti-coagulant effects of warfarin and other coumarins may be changed by Glibenclamide.
Immunosuppressants: There is the potential for glibenclamide to raise plasma levels of cyclosporin, which would necessitate a dose reduction of cyclosporin.
Cyclophosphamide may depress blood sugar levels enhancing the hypoglycaemic effect of glibenclamide.
Other drugs which interact with glibenclamide causing an increased blood sugarlowering effect include bezafibrate, coumarin derivatives, fenfluramine, fluoxetine, guanethidine, quinolone antibacterials.
Glucagon, laxative abuse, high doses of nicotinic acid, phenothiazine derivatives, phenytoin, sympathomimetic agents also reduce the hypoglycaemic action of glibenclamide
Clonidine has been reported to both enhance and reduce the hypoglycaemic action of glibenclamide.
Concurrent therapy with clonidine or guanethidine may mask the warning signs of a hypoglycaemic attack.
4.6 Fertility, pregnancy and lactation
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.
4.7 Effects on ability to drive and use machines
None known (unless there is a risk of hypoglycaemia).
4.8 Undesirable effects
Like other oral hypoglycaemic agents, glibenclamide is well tolerated in normal use. Untoward effects are usually mild and rarely require treatment to be discontinued.
The following convention has been utilised for the classification of undesirable effects: - Very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1,000), very rare (<1/10,000).
At initiation of therapy, transient visual disturbances may occur.
Immune system disorders Hypersensitivity reactions:
Rare: Leucopenia, thrombocytopenia
Very rare: Agranulocytosis, pancytopenia, aplastic and haemolytic anaemia
Unknown: Rash, urticaria, erythema multiforme, erythema nodosum, bullous eruptions, pruritus, exfoliative dermatitis, photosensitivity, cholestatic jaundice, neutropenia, fever and Stevens-Johnson syndrome.
Hypersensitivity reactions affecting the skin usually occur within the first six weeks of treatment with a sulphonylurea. Cross sensitivity to sulphonamides or their derivatives may occur.
Metabolism and nutrition disorders
Unknown: Hypoglycaemia (see section 4.4). Syndrome of inappropriate secretion of antidiuretic hormone, characterised by water retention and hyponatraemia.
Gastrointestinal disorders
Unknown: Nausea, heartburn, anorexia, and diarrhoea. This type of adverse reaction can be avoided if glibenclamide is taken during a meal. Vomiting, metallic taste, increased appetite and weight gain.
As with all other oral hypoglycaemic agents, an over-response to treatment may occur, especially in relation to unexpected heavy exercise or lack of consideration to the patient’s diet. These hypoglycaemic attacks are not usually prolonged and should be managed as for overdosage.
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 at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Conscious patients with early signs of hypoglycaemia - faintness, nausea, cold-sweats and/or palpitation - may be treated with glucose water of 3-4 lumps of sugar (sucrose) with water. This treatment may be repeated as necessary and, if symptoms continue to recur, at intervals may be supplemented with half a pint of milk after successful management of the current recurrence of symptoms.
Comatose patients should receive glucose administered as a continuous intravenous infusion, because a bolus injection may lead to a more severe and prolonged rebound hypoglycaemia. An alternative approach is to administer 1 mg of glucagon as a subcutaneous or intramuscular injection. The objective of both treatments is to achieve rapid recovery of consciousness, when further ‘feeding’ should be instituted, as above.
Symptoms: hypoglycaemia.
Treatment:
• Patient should be transferred to hospital
• Activated charcoal to be administered
• Hypoglycaemia should be treated with urgency by appropriate means
• Vital signs should be monitored and appropriate supportive measures used, including the treatment of cerebral oedema should this occur
Observation should continue for several days in case hypoglycaemia is prolonged or recurs.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC Code: Al 0B B01 (sulfonamides, urea derivatives)
The pharmacodynamic effect of glibenclamide is to lower blood glucose levels. Mechanisms proposed for this effect include:
Stimulation of insulin release from pancreatic beta-cells Increasing insulin-releasing response to beta-cells Formation of new alpha and beta-cells
Increasing insulin binding and receptor density in peripheral tissues.
Plasma glucose levels affect the insulin-releasing response to glibenclamide, (a high glucose level increases the response). The minimum active concentration for effect is considered to be 30-50 nanograms/ml glibenclamide.
Investigations of the relationship between insulin, glucose levels and glibenclamide in the hypoglycaemic effect continue.
5.2 Pharmacokinetic properties
Orally administered glibenclamide is rapidly absorbed and substantially metabolised. 50% of the administered dose is excreted in the urine and 50% in the bile.
The major (hydroxylated) metabolite in man has no significant hypoglycaemic activity.
After absorption, the plasma half-life of the drug follows a 2-compartment model.
1st phase: 2. 1 hours 2nd phase: 8-10 hours.
The second phase has been reported to affect insulin levels for longer, owing to the existence of a “deep compartment”.
97% binds to serum protein.
5.3 Preclinical safety data
Preclinical information has not been included because the safety profile of glibenclamide has been established after many years of clinical use. Please refer to section 4.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose anhydrous Croscarmellose sodium Magnesium Stearate (E572)
6.2 Incompatibilities
Not applicable
6.3 Shelf life
36 months.
6.4 Special precautions for storage
Do not store above 25°C.
6.5 Nature and contents of container
250 pm PVC/40 gsm PVdC with 20 pm hard tempered aluminium foil strips in packs of 7, 10, 14, 21, 28, 30, 56, 60, 84, 90, 100, 110, 112, 120, 150, 160 and 168 tablets.
HDPE or polypropylene containers with caps or child resistant closures in packs of 100, 250, 500 and 1000 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Not applicable.
7 MARKETING AUTHORISATION HOLDER
TEVA UK Limited
Brampton Road, Hampden Park
Eastbourne, East Sussex, BN22 9AG
8 MARKETING AUTHORISATION NUMBER
PL 00289/0048
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
17/09/1998 / 22/12/2003
10 DATE OF REVISION OF THE TEXT
11/05/2015