Metformin Hydrochloride/ Glibenclamide

Registered South African indications: 

• Type 2 diabetes mellitus

Contraindications 

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Hypersensitivity to other sulphonylureas and sulphonamides
• Breastfeeding
• Renal impairment (CrCl<60ml/min) (See additional prescribing points)
• Chronic hepatic disease
• Porphyria
• Type 1 diabetes (insulin-dependent diabetes)
• Ketosis or ketoacidosis
• Diabetic precoma
• Acute or chronic disease which may cause severe tissue hypoxia such as
  - Cardiac or respiratory failure
  - Recent myocardial infarction
  - Shock
• Major surgery (See additional prescribing points)
• Acute alcohol intoxication
• Alcoholism
• Pancreatitis
• Coadministration with miconazole

Cautions

• Pregnancy
• Renal  impairment (CrCl≥60ml/min)
  - Initiating coadministration with antihypertensive or diuretic
  - Initiating coadministration with a nonsteroidal anti-inflammatory drug (NSAID)
• Hepatic impairment
• Elderly
• Risk factors associated with lactic acidosis 
  - Diabetic patients with significant renal failure
  - Poorly controlled diabetes
  - Ketosis
  - Prolonged fasting
  - Prolonged fasting
  - Excessive alcohol intake
  - Hepatocellular failure
  - Any condition associated with hypoxia
• Risk factors associated with hypoglycaemia
  - Unjustified administration, namely when diabetes can be controlled by diet alone
  - Accidental excessive intake, particularly in the elderly
  - Insufficient carbohydrate intake especially if combined with physical exercise
  - Hepatic or renal impairment
  - Elderly
  - Malnourishment
  - Alteration in general condition 
  - Adrenal, thyroid or pituitary insufficiency
  - Potentiation of the hypoglycaemic effect by coadministration agents or by alcohol consumption, especially when combined with fasting
• Oral hypoglycaemics (See additional prescribing points)
• Congenital galactosemia
• Glucose and galactose malabsorption syndrome
• Lactase deficiency
• May impair ability to drive and operate machinery 

Forms avail. in SA and covered in this monograph: tab

Type 2 diabetes mellitus
- Initial therapy, as an adjunct to diet and exercise, to improve glycaemic control in patients whose glycaemia cannot be satisfactorily managed with diet and exercise alone

Metformin Hydrochloride/ Glibenclamide
 250/1.25 (mg)

• Oral (tab): Initial: 1 tab, dly

Initiation of therapy: 500/5 (mg) must not be used as initial therapy due to an increased risk of hypoglycaemia

- Second-line therapy when diet and exercise, and initial treatment with a sulphonylurea or metformin do not result in adequate glycaemic control 

In patients inadequately controlled by monotherapy

Metformin Hydrochloride/ Glibenclamide
500/2.5 (mg)

• Oral (tab): Initial: 1 tab, dly

The initial dose must not exceed the daily doses of sulphonylurea or metformin already being taken

In substitution from combination-therapy with metformin and a sulphonylurea

Metformin Hydrochloride/ Glibenclamide
500/2.5 (mg)
500/5 (mg)

•  Oral (tab): Initial: 1-2 tab, dly to be adjusted according to the previous dose of each component; Titrate at intervals of 1-2 weeks; Max: 4 tab (500/5 (mg))/24hrs

The recommended initial dose must not exceed the daily dose of glibenclamide (or equivalent dose of another sulphonylurea) and metformin hydrochloride  already being taken

Titration: A gradual increase in the dosage may aid gastrointestinal tolerance and prevent the onset of hypoglycaemia. The dosage can be adjusted every 1-2 weeks, depending on the results

The dosage must be adjusted to each individual case. It is recommended to initiate the treatment with a low dose, which can then be gradually increased according to results obtained

The tablets must be administered just before a meal, in one or two daily intakes in the morning and evening. Any intake must be followed by a meal with a sufficiently high carbohydrate content to prevent the onset of hypoglycaemic episodes

Not established for use in children

Pregnancy

• Caution; not recommended
• Metformin hydrochloride/ glibenclamide must not be used for the treatment of diabetes during pregnancy. It is imperative that insulin be used to achieve adequate blood glucose control. It is recommended that the patient be transferred from oral antidiabetic therapy to insulin as soon as she plans to become pregnant or if pregnancy is exposed to metformin hydrochloride/ glibenclamide

Breastfeeding 

• Contraindicated 

Fertility

• No information available

Renal Impairment

• CrCl≥60ml/min: Caution; no dose adjustment recommended 
• CrCl<60ml/min: Contraindicated 

Hepatic Impairment

• Mild (Child-Pugh class A): Caution; no dose adjustment recommended 
  Closely monitor hepatic function. The use of conservative initial and maintenance doses should be considered
• Moderate to severe (Child-Pugh class B and C): Caution; not recommended 
  Use is contraindicated if renal impairment co-exists 
• Chronic hepatic disease: Contraindicated 

Elderly

• Caution; no dose adjustment recommended 
  Initiate at lower end of dosing range: Oral (tab): Initial: 1 tab (250/1.25 (mg)), dly
  The dose should then be adjusted according to results obtained and depending on renal function parameters

Porphyria Information

• Possibly porphyrinogenic (PSP) 

Drugs in Sport

• Permitted - No warnings 

Gastrointestinal Disorders 

• Nausea and vomiting
• Diarrhoea
• Abdominal pain 
• Loss of appetite

Hepatobiliary Disorders 

• Hepatic porphyria crisis
• Hepatic function test abnormalities
• Hepatitis 

Genitourinary Disorders

• Elevated serum urea 
• Elevated serum creatinine

Endocrine and Metabolic Disorders 

• Hypoglycaemia
• Lactic acidosis 
• Decreased vitamin B₁₂ absorption 
• Decreased vitamin B₁₂ serum levels
• Hyponatraemia
• Disulfiram-like reaction (with alcohol intake)

Skin and Subcutaneous Tissue Disorders 

• Porphyria cutanea
• Pruritus
• Urticaria
  - Urticaria evolving in shock
• Maculopapular rash
• Cutaneous or visceral allergic angiitis
• Erythema multiforme
• Exfoliative dermatitis
• Photosensitization
• Cross-reactivity to sulphonamide(s) and their derivatives 

Immune, Blood and Lymphatic System Disorders 

• Leucopenia
• Thrombocytopenia
• Agranulocytosis
• Haemolytic anaemia
• Megaloblastic anaemia
• Bone marrow aplasia 
• Pancytopenia

Sensory Disorders 

• Taste disturbance
• Transient visual disturbances

Metformin Hydrochloride/ Glibenclamide

• Glucocorticosteroids
• Beta-2-agonists
• Chlorpromazine
• Diuretics
• Angiotensin-converting enzyme (ACE) inhibitors

Other interactions

• Alcohol
• Alcohol-containing agents

Metformin Hydrochloride

• Diuretics
• Loop diuretics

Other interactions

• Iodinated contrast agents (See additional prescribing points)

Glibenclamide

• Miconazole (systemic route, oromucosal gel)
• Phenylbutazone
• Fluconazole
• Bosentan
• Antibacterial sulphonamides
• Fluoroquinolones 
• Warfarin
• Monoamine oxidase inhibitors (MAOIs)
• Chloramphenicol
• Lipid-lowering agents
• Fenofibrate
• Pentoxifylline
• Disopyramide
• Clofibrate
• Cyclophosphamide
• Salicylate
• Propranolol
• Beta-blockers
• Clonidine
• Reserpine
• Guanethidine
• Sympathomimetics 
• Desmopressin

• Blood glucose  
• Renal function
• Full blood count
• Hepatic function
• Serum vitamin B₁₂ 

Specific cases may require

• Folate levels
• HbA1c

Major surgery

• Treatment must be discontinued 48 hours before elective major surgery and should not be resumed earlier than 48 hours afterwards and only after renal function has been reevaluated and found to be normal
• All patients should continue their diet with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet
• The usual laboratory tests for diabetes monitoring should be performed regularly

Renal disease or impairment contraindication

• Renal disease or impairment (CrCl<60ml/min) may also result from conditions such as shock, dehydration, severe infection, intravascular administration of iodinated contrast agents

Coadministration with iodinated contrast agents

• As the intravascular administration of iodinated contrast materials in radiologic studies can lead to renal failure, treatment should be discontinued prior to, or at the time of the test, depending on the renal function, and not reinstituted until 48 hours afterwards and only after renal function has been re-evaluated and found to be normal

Oral hypoglycaemics

• The administration of oral hypoglycaemics may be associated with an increased risk of cardiovascular mortality as compared to treatment with diet alone or diet with insulin although controversy exists concerning interpretation of these findings

Metformin hydrochloride and glibenclamide are two antihyperglycaemic agents with complementary mechanisms of action. Metformin hydrochloride is a biguanide oral anti-hyperglycaemic agent. It improves glucose tolerance, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilisation. Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin also increases the transport capacity of all types of membrane glucose transporters. Glibenclamide is a second-generation sulphonylurea which appears to lower blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent on functioning beta cells in the pancreatic islets. The mechanism of action by which glibenclamide lowers blood glucose during long term administration has not been clearly established.

COMBINATION PREPARATIONS

Metformin Hydrochloride/ Glibenclamide

Film-coated tablet 250mg/1.25mg

• Glucovance 250mg/1.25mg (Merck) originator (Discontinued: 17/05/2019)

Tablet 500mg/2.5mg

• Glucovance 500mg/2.5mg (Merck) originator

Tablet 500mg/5mg

• Glucovance 500mg/5mg (Merck) originator