Glimepiride/ Metformin

Registered South African indications:

• Non-insulin-dependent diabetes mellitus (Type 2) as an adjunct to diet and exercise
  - Patients, who are well controlled and stabilised on the individual components in the same ratio as contained in this combination
  - In cases where the monotherapy with glimepiride or metformin did not result in adequate glycaemic control
  - Replacement of combination therapy of glimepiride and metformin

Contraindications

• Known hypersensitivity to glimepiride, metformin hydrochloride, sulphonylureas, sulfonamides, biguanides, or any of the excipients
• Insulin-dependent (Type 1) diabetes mellitus (e.g. diabetics with a history of ketonaemia), diabetic ketonaemia, diabetic coma or precoma, and acute or chronic metabolic acidosis
• Hepatic or renal dysfunction
• Pancreatitis
• Safety in pregnancy and lactation has not been established
• History of or states associated with lactic acidosis, such as shock or pulmonary insufficiency
• Cardiac failure and recent myocardial infarction
• Conditions associated with hypoxia
• Hepatic insufficiency, acute alcohol intoxication, or alcoholism
• Patients being administered iodinated contrast material intravenously due to the risk of acute alteration of renal function
• Severe infection, before and after surgery, and serious trauma
• Malnourished, fasting or debilitated patients, or patients with pituitary or adrenal insufficiency
• Porphyria
• Children, as safety and efficacy have not been established

Cautions

Caution in the following patient group

• Elderly
• Not advised in conditions that may cause dehydration or in patients with serious infections or trauma

Increased risk of cardiovascular mortality

• The administration of glimepiride/ metformin may be associated with increased cardiovascular mortality compared to treatment with diet alone or diet with insulin
• Results from the University Group Diabetes Program (UGDP), a large multicentre trial, have shown that the sulphonylurea antidiabetic agent tolbutamide may be associated with increased cardiovascular mortality in patients with Type 2 diabetes mellitus
• Although other studies have not consistently reached the same conclusion and some suggest that controlling hyperglycaemia with oral sulphonylureas may reduce cardiovascular mortality, the UGDP study provides sufficient evidence for caution, especially in patients at high risk for myocardial ischaemia (coronary artery disease, angina pectoris, congestive heart failure)
• Patients should be informed of the potential risks and benefits of sulphonylurea antidiabetic agents, as well as alternative treatment options

Lactic acidosis

• Lactic acidosis is a rare but serious condition (high mortality in the absence of prompt treatment) that can occur due to metformin accumulation during treatment with glimepiride/metformin, especially in diabetic patients with significant renal failure
• Other risk factors include poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency, and any condition associated with hypoxia
• Lactic acidosis is characterised by symptoms such as acidotic dyspnoea, abdominal pain, hypothermia, and can lead to coma
• If lactic acidosis is suspected (e.g., decreased blood pH, plasma lactate >5mmol/L and an increased anion gap and lactate / pyruvate ratio), glimepiride/metformin should be discontinued, and the patient should be hospitalised immediately

Renal function

• As glimepiride/metformin is excreted by the kidneys, serum creatinine levels should be determined before starting treatment and monitored regularly
• Special caution is needed for elderly patients, where decreased renal function can be frequent and asymptomatic, and in situations where renal function may become impaired (e.g., initiation of antihypertensive therapy, diuretics, or NSAIDs)

Administration of iodinated contrast agent

• The intravascular administration of iodinated contrast materials in radiological studies can cause renal failure
• Glimepiride/metformin should be discontinued before or at the time of the test and only restarted 48 hours afterwards, once renal function has been re-evaluated and confirmed as normal

Surgery

• Glimepiride/metformin should be discontinued 48 hours before elective surgery with general anaesthesia and should not be resumed until 48 hours afterwards

Factors that predispose a patient to the development of hypoglycaemia

• Unwillingness or incapacity of the patient to co-operate, particularly in older patients
• Malnutrition, irregular mealtimes, or skipped meals
• Imbalance between physical exertion and carbohydrate intake
• Poor nutrition or dietary changes
• Consumption of alcohol, especially with skipped meals
• Impaired renal function
• Severe impairment of liver function
• Certain endocrine disorders affecting carbohydrate metabolism
• Concurrent administration of certain other medicines

Hypoglycaemia

• Patients and their families must be educated about the symptoms of hypoglycaemia and its treatment
• Hypoglycaemia can typically be treated with carbohydrates like sugar lumps or sweetened juices
• Despite being easily treated, hypoglycaemia may recur with oral antidiabetic agents
• Severe or persistent hypoglycaemia requires immediate treatment and may need hospitalization
• Symptoms of hypoglycaemia may be milder or absent if it develops gradually or in specific populations
• Blood glucose control may deteriorate under stressors such as trauma, surgery, or infections
• A temporary change to insulin therapy may be necessary under such circumstances

Prolonged use

• Patients on long-term treatment should have annual vitamin B12 level estimations

Effects on ability to drive and use machines

• Patients should be advised to drive or operate machinery with caution
• Alertness and reactions may be impaired due to hypo- or hyperglycaemia, especially when beginning or altering treatment

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

Non-insulin-dependent diabetes mellitus (Type 2) as an adjunct to diet and exercise
- Patients, who are well controlled and stabilised on the individual components in the same ratio as contained in this combination
- In cases where the monotherapy with glimepiride or metformin did not result in adequate glycaemic control
- Replacement of combination therapy of glimepiride and metformin

Glimepiride/ Metformin
2/ 500 (mg)

• Oral (fct): 1 tab, once or twice dly before or with meals

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Treatment with glimepiride/ metformin must be initiated and monitored by a doctor

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The dosage of glimepiride/metformin should be individualised based on the patient’s blood glucose levels. It is recommended to initiate the lowest effective dose and increase the dose depending on the patient’s blood glucose levels

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Adequate monitoring of glucose levels in blood and urine must be performed regularly. When switching from combination therapy of glimepiride plus metformin as separate tablets, glimepiride/metformin should be administered on the basis of dosage currently being taken

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Stabilisation of diabetic patients with glimepiride/ metformin and insulin should be carried out in hospital

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To achieve optimal control of blood glucose, adherence to correct diet, regular physical exercise, and reduction of body weight are necessary along with regular ingestion of glimepiride/ metformin
Careful monitoring is necessary during the initial weeks of treatment because of increased risk of hypoglycaemia. Clinical signs of insufficiently lowered blood glucose may require dose adjustment

Not established for use in children (see contraindications)

Pregnancy

• Contraindicated

Breastfeeding

• Contraindicated

Renal Impairment

• Contraindicated

Hepatic Impairment

• Contraindicated

Elderly

• Caution; no dose adjustment recommended

Porphyria Information

• Not yet classified (NC)

Drugs in Sport

• Permitted - No warnings

Combination products may have additional pharmacological effects not accounted for by the action of the individual ingredients

Glimepiride
Central Nervous System Disorder

• Headache
• Sleep disorders
• Restlessness
• Aggression
• Impaired alertness and reactions
• Depression
• Confusion
• Speech disorders
• Aphasia
• Tremor
• Paresis
• Sensory disturbances
• Dizziness
• Delirium
• Cerebral convulsion
• Somnolence
• Coma
• Lassitude
• Anxiety

Cardiovascular Disorder

• Bradycardia
• Tachycardia
• Hypertension
• Palpitations
• Angina pectoris
• Cardiac arrhythmias

Respiratory Disorder

• Shallow breathing

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Abdominal distension
• Abdominal discomfort
• Abdominal pain
• Sensation of fullness in epigastrium
• Metallic taste
• Dry mouth

Hepatobiliary Disorders

• Cholestasis
• Jaundice
• Hepatitis
• Hepatic failure
• Increased hepatic enzymes

Genitourinary Disorders

• Polyuria

Endocrine and Metabolic Disorders

• Hypoglycaemia
• Ravenous hunger
• Anorexia
• Weight gain
• Intense thirst

Skin and Subcutaneous Tissue Disorders

• Pruritus
• Rash
• Urticaria
• Photosensitivity
• Steven-Johnson syndrome
• Erythema multiforme
• Exfoliative dermatitis
• Erythema nodosum
• Dry skin
• Sweating 
• Clammy skin

Immune, Blood and Lymphatic System Disorders

• Thrombocytopenia
• Leukopenia
• Granulocytopenia
• Agranulocytosis
• Erythropenia
• Haemolytic anaemia 
• Pancytopenia
• Thrombocytopenic purpura
• Leukocytoclastic vasculitis
• Hypersensitivity reactions 
• Cross-allergenicity with sulfonylureas, sulfonamides or related substances

Sensory Disorders

• Visual disturbances

Metformin
Central Nervous System Disorders

• Taste disturbance

Gastrointestinal Disorders

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

Hepatobiliary Disorders

• Abnormal hepatic function tests
• Hepatitis 

Genitourinary Disorders 

• Ketoacidocis
• Ketonuria

Endocrine and Metabolic Disorders

• Lactic acidosis 
• Decreased vitamin B12 absorption 

Skin and Subcutaneous Tissue Disorders 

• Erythema
• Pruritus
• Urticaria

Immune, Blood and Lymphatic System Disorders 

• Megaloblastic anaemia

Combination products may have additional pharmacological effects not accounted for by the action of the individual ingredients

Glimepiride

• CYP2C9 inducers
• CYP2C9 inhibitors
• Histamine antagonists
• Beta blockers
• Clonidine 
• Reserpine 
• Guanethidine
• Alcohol
• Warfarin
• Colesevelam  
• Oestrogens
• Progestogens
• Saluretics
• Thiazide diuretics
• Thyroid stimulating agents
• Glucocorticoids
• Phenothiazine derivatives
• Chlorpromazine
• Adrenaline
• Sympathicomimetics
• Nicotinic acid 
• Nicotinic acid derivatives
• Laxatives
• Phenytoin
• Diazoxide
• Glucagon
• Barbiturates
• Rifampicin
• Acetazolamide
• Phenylbutazone
• Azapropazone
• Oxyfenbutazone
• Insulin 
• Oral antidiabetic products
• Salicylates 
• Anabolic steroids
• Male sex hormones
• Chloramphenicol
• Long acting sulfonamides
• Tetracyclines
• Quinolone antibiotics 
• Clarithromycin
• Fenfluramine
• Disopyramide
• Fibrates
• Angiotensin coverting enzyme inhibitors
• Fluoxetine
• Monoamine oxidase inhibitors
• Allopurinol
• Probenecid 
• Sulfinpyrazone
• Sympatholytics
• Cyclophosphamide
• Trophosphamide
• Iphosphamides
• Miconazole
• Fluconazole
• Pentoxifylline 
• Tritoqualine

Metformin

• Alcohol 
• Iodinated contrast agents 
• Non-steroidal anti-inflammatory drugs
• Angiotensin converting enzyme inhibitors 
• Angiotensin II receptor antagonists 
• Diuretics 
• Glucocorticoids 
• Sympathomimetics 
• Organic cation transporters inhibitors 
• Organic cation transporters inducers 
• Warfarin 
• Sulphonurea 
• Insulin
• Oral antidiabetic agents

• Renal function
• Hepatic function
• Full blood count

Specific cases may require

• Serum B12 
• Cardiac function

Glimepiride
Glimepiride stimulates the release of insulin from functioning pancreatic beta cells and increases the sensitivity of peripheral tissues to insulin. On the pancreatic cell surface, glimepiride binds to ATP-sensitive potassium channel receptors reducing potassium conductance and causing depolarization of the membrane. This depolarization stimulates calcium ions to move intracellularly and the increased intracellular calcium ion concentration induces the secretion of insulin. 

Metformin
Metformin is a biguanide which decreases basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia. Metformin reduces hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis and it increases insulin sensitivity, improving peripheral glucose uptake and utilisation and it delays intestinal glucose absorption. Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase and increases the transport capacity of all types of membrane glucose transporters known to date.

COMBINATION PREPARATIONS

Glimepiride/ Metformin

Tablet 2mg/500mg

• Amaryl Combi (Sanofi) originator