Metformin Hydrochloride

Registered South African indications:

• Type 2 diabetes mellitus
• Risk reduction or delay of the onset of type 2 diabetes mellitus

Contraindications

South African recommendations

Immediate release film-coated tablet

• Hypersensitivity to metformin hydrochloride or to any of the excipients
• Diabetic ketoacidosis and diabetic pre-coma
• Renal failure or renal dysfunction (e.g. serum creatinine levels >135µmol/l in males and >110µmol/l in females)
• Acute conditions with the potential to alter renal function, such as:
  - Dehydration
  - Severe infection
  - Shock
  - Intravascular administration of iodinated contrast agents
• Hepatic insufficiency, acute alcohol intoxication, alcoholism
• Pregnancy
• Lactation

Extended-release tablet

• Hypersensitivity to metformin hydrochloride or any of the other ingredients
• Diabetic ketoacidosis, diabetic pre-coma
• Renal failure or renal dysfunction (creatinine clearance <60ml/min)
• Acute conditions with the potential to alter renal function e.g. dehydration, severe infection, shock, intravascular administration of iodinated contrast media
• Acute or chronic disease which may cause tissue hypoxia such as cardiac or respiratory failure, recent myocardial infarction, shock, pancreatitis
• Hepatic insufficiency
• Acute alcohol intoxication
• Alcoholism (acute or chronic)
• Pregnancy

Recommendations in other jurisdictions

• Hypersensitivity to metformin or to any of the excipients
• Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis)
• Diabetic pre-coma
• Severe renal failure (GFR<30ml/min)
• Acute conditions with the potential to alter renal function such as;
  - Dehydration
  - Severe infection
  - Shock
• Disease which may cause tissue hypoxia (especially acute disease, or worsening of chronic disease) such as;
  - Decompensated heart failure
  - Respiratory failure
  - Recent myocardial infarction
  - Shock
• Hepatic insufficiency
• Acute alcohol intoxication
• Alcoholism

Cautions

• Pregnancy (Recommendations in other jurisdictions)
• Breastfeeding (XR tab) (South African recommendations)
• Breastfeeding (Recommendations in other jurisdictions)
• Renal impairment (CrCl≥60ml/min) (XR tab) (South African recommendations)
• Renal impairment (GFR≥30ml/min) (Recommendations in other jurisdictions)
• Elderly
• Acute worsening of renal function
• Congestive heart failure 
• Children
• Surgery 
• Dehydration
• Cardiorespiratory illness 
• Sepsis

Forms avail. in SA and covered in this monograph: tab (extended-release tab (XR tab)), fct

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Type 2 diabetic mellitus (Additional agent(s) may be required)
- Particularly in those who are overweight, when dietary management and exercise alone do not result in adequate glycaemic control, as monotherapy in initial therapy or in combination with other oral antidiabetic medicines or with insulin

Immediate release
500mg
850mg
1000mg

• Oral (fct): Initial: 500mg, 8hrly OR 850mg, 12hrly OR 1000mg, 12hrly with or after food; Titrate at intervals of 10-15 days on the basis of blood glucose measurements; A slow increase of dose may improve gastrointestinal tolerability; If control is incomplete increase cautiously: Max: 2550mg/24hrs

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Good diabetic control may be achieved within a few days, but it is not unusual for the full effect to be delayed for up to 2 weeks. Once control has been obtained it may be possible to reduce the dosage of metformin

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XR 500mg

Usual therapy

• Oral (tab): Initial: 500mg, dly with the evening meal; Titrate by 500mg at intervals of 10-15 days on the basis of blood glucose measurements; A slow increase of dose may improve gastrointestinal tolerability; Max: 2000mg/24hrs

If glycaemic control is not achieved with 2000mg once daily

• Oral (tab): 1000mg, 12hrly with food

Combination therapy with insulin

• Oral (tab): Initial: 500mg, dly with the evening meal (while insulin dosage is adjusted on the basis of blood glucose measurements); After titration: 1000mg, dly may be considered

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Metformin XR tablets and insulin may be used in combination therapy to achieve better blood glucose control

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XR 750mg

Usual therapy

• Oral (tab): Initial: 750mg, dly in the evening OR equivalent to the daily dose of metformin tablets (prolonged or immediate release) the patient was previously on; Titrate at intervals of 10-15 days on the basis of blood glucose measurements; A slow increase of dose may improve gastrointestinal tolerability; Max: 1500mg, dly with evening meal

If glycaemic control is not achieved with 1500mg once daily

• Oral (tab): 2250mg, dly with evening meal; If glycaemic control is not achieved; Morning dose: 750mg; Evening dose: 1500mg, both with food

Combination therapy with insulin

• Oral (tab): Equivalent to the daily dose of metformin tablets (prolonged or immediate release) the patient was previously on; While insulin dosage is adjusted on the basis of blood glucose measurements; Max: 1500mg, dly with evening meal

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Metformin XR 750mg is intended for patients who are already treated with metformin tablets (prolonged or immediate release)

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XR 1000mg

Maintenance therapy for those currently treated with either 1000mg or 2000mg of metformin hydrochloride

• Oral (tab): 1000mg, dly with the evening meal; Max: 2000mg/24hrs

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Metformin XR 1000mg is intended as maintenance therapy for patients already treated with either 1000mg (2 tablets of metformin XR 500mg) or 2000mg (4 tablets of metformin XR 500mg) of sustained release metformin hydrochloride

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If glycaemic control is not achieved with 2000mg once daily

• Oral (tab): 1000mg, 12hrly with food

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For XR 500mg, XR 750mg & XR 1000mg dosing: If glycaemic control is still not achieved, patients may be switched to standard metformin tablets to a maximum dose of 3000mg daily

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Switching patients already treated with metformin tablets: In patients already treated with metformin tablets, the starting dose of XR tablets should be equivalent to the daily dose of metformin immediate-release tablets. In patients treated with metformin at a dose above 2000mg, switching to XR tablets is not recommended

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Switching patients from other oral antidiabetic medicines: If transfer from another oral antidiabetic medicine is intended, discontinue the other medicines and initiate XR prolonged-release tablets at the doses indicated above

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Risk reduction or delay of the onset of type 2 diabetes mellitus
- In those who are, overweight with prediabetes (impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG), and/or increased HbA1c) and additional risk factors**, in whom lifestyle change has not resulted in adequate glycaemic control

XR tab

• Oral (tab): Initial: 500mg, dly with the evening meal; Titrate at intervals of 10-15 days on the basis of blood glucose measurements; A slow increase of dose may improve gastrointestinal tolerability; Max: 2000mg, dly with the evening meal

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**Identified risk factors include obesity, age, hypertension, cardiovascular disease, family history of diabetes, dyslipidaemia, gestational diabetes, and polycystic ovary syndrome (PCOS)

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Metformin should only be considered where intensive lifestyle modifications for 3-6 months have not resulted in adequate glycaemic control. It is recommended to regularly monitor (every 3-6 months) the glycaemic status (OGTT (oral glucose tolerance test) and/or FPG and/or HbA1C value) as well as the risk factors to evaluate whether treatment needs to be adapted

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Indications and dosages registered in other jurisdictions

Type 2 diabetic mellitus (Additional agent(s) may be required)
- Particularly in those who are overweight, when dietary management and exercise alone do not result in adequate glycaemic control

Monotherapy and combination with other oral antidiabetic agents

Immediate release
500mg
850mg
1000mg

• Oral (fct): Initial: 500mg OR 850mg, 8-12hrly with or after food; Titrate at intervals of 10-15 days on the basis of blood glucose measurements; A slow increase of dose may improve gastrointestinal tolerability; Max: 3000mg/day, in 3 divided doses

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For patients taking high doses of metformin hydrochloride (2-3g daily), two metformin 500mg tablets may be replaced with metformin 1000mg film-coated tablets

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If transfer from another oral antidiabetic agent is intended: discontinue the other agent and initiate metformin at the dose indicated above

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Combination with insulin

Immediate release
500mg
850mg
1000mg

• Oral (fct): 500mg OR 850mg, 8-12hrly with or after food; Adjust insulin on the basis of blood glucose measurements

---

Metformin and insulin may be used in combination therapy to achieve better blood glucose control

---

SR 500mg

Usual therapy

• Oral (tab): Initial: 500mg, dly with the evening meal; Titrate by 500mg at intervals of 10-15 days on the basis of blood glucose measurements; A slow increase of dose may improve gastrointestinal tolerability; Max: 2000mg/24hrs

If glycaemic control is not achieved with 2000mg once daily

• Oral (tab): 1000mg, 12hrly with food

Combination therapy with insulin

• Oral (tab): Initial: 500mg, dly with the evening meal (while insulin dosage is adjusted on the basis of blood glucose measurements); After titration: 1000mg, dly

SR 750mg

Usual therapy

• Oral (tab): Equivalent to the daily dose of metformin tablets (prolonged or immediate release) the patient was previously on; After 10-15 days, it is recommended to check that the dose is adequate on the basis of blood
  glucose measurements; Max: 1500mg, dly with evening meal

Combination therapy with insulin

• Oral (tab): Equivalent to the daily dose of metformin tablets (prolonged or immediate release) the patient was previously on; While insulin dosage is adjusted on the basis of blood glucose measurements; Max: 1500mg, dly with evening meal

---

Metformin SR 750mg is intended for patients who are already treated with metformin tablets (prolonged or immediate release)

---

SR 1000mg

Maintenance therapy for those currently treated with either 1000mg or 2000mg of metformin hydrochloride

• Oral (tab): 1000mg, dly with the evening meal; Max: 2000mg/24hrs

---

Metformin SR 1000mg is intended as a maintenance therapy for patients currently treated with either 1000mg or 2000mg of metformin hydrochloride. On switch, the daily dose of metformin SR should be equivalent to the current daily dose of metformin hydrochloride

---

In patients treated with metformin hydrochloride at a dose above 2000mg daily, switching to metformin SR is not recommended

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If glycaemic control is not achieved with 2000mg once daily

• Oral (tab): 1000mg, 12hrly with food

---

For SR 500mg & SR 1000mg dosing: If glycaemic control is still not achieved, patients may be switched to standard metformin tablets to a maximum dose of 3000mg daily

---

Switching patients already treated with metformin tablets: In patients already treated with metformin tablets, the starting dose of SR tablets should be equivalent to the daily dose of metformin immediate-release tablets. In patients treated with metformin at a dose above 2000mg, switching to SR tablets is not recommended

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Switching patients from other oral antidiabetic medicines: If transfer from another oral antidiabetic medicine is intended, discontinue the other medicines and initiate SR prolonged-release tablets at the doses indicated above. Titration should begin with metformin SR 500mg before switching to metformin SR 1000mg

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Metformin hydrochloride and insulin may be used in combination therapy to achieve better blood glucose control. The usual starting dose of metformin SR is 500mg once daily (see SR 500mg recommendations above) with the evening meal, while insulin dosage is adjusted on the basis of blood glucose measurements. After titration, switch to metformin SR 1000mg should be considered

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The SR tablets should be swallowed whole with a drink of water. They should not be chewed or crushed

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Risk reduction or delay of the onset of type 2 diabetes mellitus
- In those who are overweight with impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG), and/or increased HbA1c who are at high risk for developing overt type 2 diabetes mellitus and still progressing towards type 2 diabetes mellitus despite implementation of intensive lifestyle change for 3-6 months

• Oral (tab): Initial: 500mg, dly with the evening meal; Titrate at intervals of 10-15 days on the basis of blood glucose measurements; A slow increase of dose may improve gastrointestinal tolerability; Max: 2000mg, dly with the evening meal

---

Metformin should only be considered where intensive lifestyle modifications for 3-6 months have not resulted in adequate glycaemic control. It is recommended to regularly monitor (every 3-6 months) the glycaemic status (OGTT and/or FPG and/or HbA1c value) as well as the risk factors to evaluate whether treatment needs to be continued, modified or discontinued

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A decision to re-evaluate therapy is also required if the patient subsequently implements improvements to diet and/or exercise, or if changes to the medical condition will allow increased lifestyle interventions to be possible

Paed. forms avail. in SA and covered in this monograph: fct

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

The diagnosis of type 2 diabetes mellitus must be confirmed before treatment with metformin is initiated

Type 2 diabetic mellitus (Additional agent(s) is required)
- Particularly in those who are overweight, when dietary management and exercise alone do not result in adequate glycaemic control, as monotherapy or in combination with insulin

Immediate release
500mg
850mg
1000mg

Younger than 12 years

• Not established for use

12 years and older

• Oral (fct): Initial: 500mg, dly OR 850mg, dly with or after food; Titrate at intervals of 10-15 days on the basis of blood glucose measurements; A slow increase of dose may improve gastrointestinal tolerability; Max: 2000mg/day, in 2-3 divided doses

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XR tablets should not be used in children

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Indications and dosages registered in other jurisdictions

Type 2 diabetic mellitus (Additional agent(s) may be required)
- Particularly in those who are overweight, when dietary management and exercise alone do not result in adequate glycaemic control as monotherapy or in combination with insulin

Immediate release
500mg
850mg
1000mg

Younger than 10 years

• Not established for use

10 years and older

• Oral (fct): Initial: 500mg, dly OR 850mg, dly with or after food; Titrate at intervals of 10-15 days on the basis of blood glucose measurements; A slow increase of dose may improve gastrointestinal tolerability; Max: 2000mg/day, in 2-3 divided doses

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In the absence of available data, metformin SR should not be used in children

Pregnancy

South African recommendations

• Contraindicated
• The use of metformin during pregnancy is not recommended

Recommendations in other jurisdictions

Immediate release film-coated tablet

• Caution; not recommended
• Uncontrolled diabetes during pregnancy (gestational or permanent) is associated with increased risk of congenital abnormalities and perinatal mortality
• A limited amount of data from the use of metformin in pregnant women does not indicate an increased risk of congenital abnormalities. Animal studies do not indicate harmful effects with respect to pregnancy, embryonic or foetal development, parturition or postnatal development
• When the patient plans to become pregnant and during pregnancy, it is recommended that diabetes is not treated with metformin but insulin be used to maintain blood glucose levels as close to normal as possible to reduce the risk of malformations of the foetus

Slow-release tablet

• Caution
• Uncontrolled hyperglycaemia in the periconceptional phase and during pregnancy is associated with increased risk of congenital abnormalities, pregnancy loss, pregnancy-induced hypertension, preeclampsia, and perinatal mortality
• It is important to maintain blood glucose levels as close to normal as possible throughout pregnancy, to reduce the risk of adverse hyperglycaemia-related outcomes to the mother and her child
• Metformin crosses the placenta with levels that can be as high as maternal concentrations
• A large amount of data on pregnant women (more than 1000 exposed outcomes) from a register-based cohort study and published data (meta-analyses, clinical studies, and registries) indicates no increased risk of congenital abnormalities nor feto/neonatal toxicity after exposure to metformin in the periconceptional phase and/or during pregnancy
• There is limited and inconclusive evidence on the metformin effect on the long-term weight outcome of children exposed in utero
• Metformin does not appear to affect motor and social development up to 4 years of age in children exposed during pregnancy although data on long term outcomes are limited
• If clinically needed, the use of metformin can be considered during pregnancy and in the periconceptional phase as an addition or an alternative to insulin

Breastfeeding

South African recommendations

Immediate release film-coated tablet

• Contraindicated
• Metformin is contraindicated during breastfeeding

Extended-release tablet

• Caution; no information available
• There is no information available concerning the safety of metformin XR during breastfeeding

Recommendations in other jurisdictions

• Caution; not recommended
• Metformin is excreted into human breast milk
• No adverse effects were observed in breastfed newborns/infants. However, as only limited data are available, breastfeeding is not recommended during metformin treatment
• A decision on whether to discontinue breastfeeding should be made, taking into account the benefit of breast-feeding and the potential risk to adverse effect on the child

Fertility

South African recommendations

• There are no data available on the effect of metformin on human fertility

Recommendations in other jurisdictions

• Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons

Renal Impairment

South African recommendations

• CrCl≥60ml/min: Caution; no dose adjustment recommended (XR tab)
• CrCl<60ml/min: Contraindicated (XR tab) 
• Serum creatinine levels>135µmol/l in males & >110µmol/l in females: Contraindicated (fct)

Recommendations in other jurisdictions

• GFR≥30ml/min: Caution; dose adjustment recommended
• GFR<30ml/min: Contraindicated

GFR ml/min	Total maximum daily dose	Additional considerations
60-89	2000mg (XR tab) 3000mg (fct)	Dose reduction may be considered in relation to declining renal function
45-59	2000mg	Factors that may increase the risk of lactic acidosis should be reviewed before considering initiation of metformin The starting dose is at most half of the maximum dose
30-44	1000mg
<30	-	Contraindicated

Hepatic Impairment

• Contraindicated 

Elderly

South African recommendations

• Caution; no dose adjustment recommended 
  Due to the potential for decreased renal function in elderly subjects, the dosage for metformin should be adjusted based on renal function. Regular assessment of renal function is necessary

Recommendations in other jurisdictions

Immediate release film-coated tablet

• Caution; no dose adjustment recommended
  Due to the potential for decreased renal function in elderly subjects, the dosage for metformin should be adjusted based on renal function. Regular assessment of renal function is necessary

Slow-release tablet

• <75 years: Caution; no dose adjustment recommended
  Due to the potential for decreased renal function in elderly subjects, the metformin dosage should be adjusted based on renal function. Regular assessment of renal function is necessary
• ≥75 years: Not recommended for use
  Due to the limited therapeutic efficacy data in the reduction of risk or delay of type 2 diabetes in patients 75 years and older, metformin initiation is not recommended in these patients

Porphyria Information

• Not porphyrinogenic (NP)

Drugs in Sport

• Permitted - No warnings

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

• 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
• Sulphonureas
• Insulin
• Oral antidiabetic agents

• Renal function

Specific cases may require

• Serum B12
• Cardiac function 
• Hepatic function

Lactic acidosis, a very rare, but serious metabolic complication, most often occurs with acute worsening of renal function or cardiorespiratory illness or sepsis.  

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.

Film-coated tablet 500mg

• Austell Metformin (Austell)
• Forminal 500 (Gulf Drug) 

Tablet 500mg 

• Accord Metformin (Accord)
• Arrow Metformin (Arrow)
• Bigsens (Zydus Healthcare)
• Diaformin (Camox)
• Diamin-500 (Unimed Healthcare)
• Diaphage (Cipla)
• Gluconorm 500 (Unicorn Pharmaceuticals)
• Glucophage (Merck) originator
• Indo Metformin (Dezzo)
• Mengen (Novagen)
• Metchek (Medivision)
• Metformin Alkem (Alkem)
• Metformin Ascendis (Dezzo)
• Metformin Biotech (Biotech)
• Metforal (Adcock Ingram)
• Metored (Ranbaxy)
• Metphage (Pharmacare)
• Mylan Metformin (Mylan)
• Romidab (Aurobindo)
• Sandoz Metformin (Sandoz)

Film-coated tablet 850mg

• Austell Metformin (Austell)
• Forminal 850 (Gulf Drug) 

Tablet 850mg 

• Accord Metformin (Accord)
• Arrow Metformin (Arrow)
• Austell Metformin (Austell)
• Bigsens (Zydus)
• Diabetmin Retard (Gulf Drug)
• Diaformin Forte (Camox)
• Diamin-850 (Unimed Healthcare)
• Diaphage (Cipla)
• Gluconorm (Ranbaxy)
• Glucophage (Merck) originator
• Indo Metformin (Dezzo)
• Mengen (Novagen)
• Metchek (Medivision)
• Metformin Alkem (Alkem)
• Metformin Ascendis (Dezzo)
• Metformin Biotech (Biotech)
• Metforal (Adcock Ingram)
• Metored (Ranbaxy)
• Metphage (Pharmacare)
• Mylan Metformin (Mylan)
• Romidab (Aurobindo)
• Sandoz Metformin (Sandoz)

Tablet 1000mg 

• Bigsens (Zydus)
• Diaphage (Cipla)
• Glucophage (Merck) originator
• Mengen (Neovagen)
• Metored (Ranbaxy)
• Mylan Metformin (Mylan)
• Romidab (Aurobindo)

Tablet xr 500mg

• Bigsens XR (Zydus)
• Cadbower XR 500 (Trinity Pharma)
• Carbuce XR 500 (Strides Pharma SA)
• Glucophage XR (Merck) originator
• Glucotrin XR 500 (Trinity Pharma)
• Metformin XR 500 mg Accord (Accord)

Tablet xr 750mg 

• Glucophage XR (Merck) originator (Discontinued: 21/06/19)

Tablet fct 1000mg

• Mylan Metformin  (Mylan)

Tablet xr 1000mg 

• Cadbower XR 1000 (Trinity Pharma)
• Carbuce XR 1000 (Strides Pharma SA)
• Glucophage XR (Merck) originator
• Glucotrin XR 1000 (Trinity Pharma)
• Metformin Teva ER 1000mg (Teva Pharmaceuticals)