Drugs List

Therapeutic Indications

Uses

Oral combination treatment of type 2 diabetes

Treatment of type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control:
- in patients not adequately controlled on their maximally tolerated dose of metformin alone or metformin plus other glucose-lowering drugs, including insulin.
- in patients already being treated with the combination of canagliflozin with metformin as separate tablets.

Contraindications

Acute alcohol intoxication
Children under 18 years
Severe infection
Shock
Alcoholism
Breastfeeding
Cardiac failure
Dehydration
Diabetic ketoacidosis
Diabetic pre-coma
Hepatic impairment
Hypoxia
Lactic acidosis
Pregnancy
Recent myocardial infarction
Renal impairment - creatinine clearance below 45ml/minute
Respiratory failure

Precautions and Warnings

Acute illness
Major surgery
Patients over 65 years
Predisposition to hypotension
Cardiovascular disorder
History of alcohol abuse
History of pancreatitis
Hypotension
Hypovolaemia
Polycythaemia
Renal impairment

Correct electrolyte disorders before treatment
Advise ability to drive/operate machinery may be affected by side effects
Correct hypovolaemia prior to administration
Test vit B12 levels if deficiency is suspected or risk factors are present
Monitor renal function prior to initiating treatment
Electrolyte & volume depletion may occur - interrupt treatment as necessary
Hospitalised patients: Monitor blood ketones before restart treatment
Monitor for development of lactic acidosis
Monitor renal function 3 to 6 monthly in elderly patients
Monitor renal function 3- 6 monthly if renal function is borderline normal
Monitor renal function annually in patients with normal renal function
Advise patient to report genital/perineal symptoms with fever or malaise
Advise patient to report symptoms of diabetic ketoacidosis immediately
Advise patient to report symptoms of low vitamin B12 levels
Advise patient/carer to report immediately symptoms of lactic acidosis
Discontinue SGLT2 inhibitor if Fournier's gangrene is suspected
Increased risk of genital mycotic infection
Increased risk of urinary tract infection
Test results for urinary glucose will be positive
Withhold until at least 48hrs after general, spinal or epidural anaesthesia
Advise patient to seek advice at first indications of pregnancy
Discontinue if lactic acidosis is suspected
If dehydration occurs, discontinue treatment until patient has recovered
Interrupt therapy if acute serious illness requiring hospitalisation occurs
Interrupt treatment in patients undergoing major surgery
Discontinue if diabetic ketoacidosis is suspected
Discontinue if foot infection, ulcer or gangrene occurs
Advise patient not to take St John's wort concurrently
Advise patient to avoid excess of alcohol
Advise patient on the need for adequate foot hygiene
Advise patient on the need for adequate hydration
Advise patient to report symptoms of volume depletion
Patient to inform DVLA if fitness to drive impaired or hypoglycaemic risk

Lactic acidosis can occur due to metformin accumulation. To reduce the incidence of this occurring, patients should be assessed for risk factors associated with the development of lactic acidosis and monitored regularly. Symptoms of lactic acidosis include acidotic dyspnoea, abdominal pain, hypothermia and coma. A diagnosis of lactic acidosis should be considered in the presence of non-specific symptoms such as muscle cramps, digestive disorders, abdominal pain or severe asthenia. Lactic acidosis is also indicated by decreased blood pH, plasma lactate levels above 5 mmol/L and an increased anion gap and lactate pyruvate ratio. Risk factors for lactic acidosis include: poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic impairment and any condition associated with hypoxia.

Patients who develop laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis occurs treatment must be stopped immediately and other appropriate corrective measures initiated.

Clinical trials suggest there is an increased risk of lower limb amputation (primarily of the toe) in patients treated with canagliflozin. This risk is independent of predisposing factors, however the absolute risk is higher in patients with previous amputations, existing peripheral vascular disease or neuropathy. Patients with these risk factors should be carefully monitored and discontinuation or interruption of treatment can be considered in the event of any significant complication such as lower-extremity skin ulcer, osteomyelitis or gangrene.

Cases of diabetic ketoacidosis (DKA), including rare life-threatening and fatal cases, have been reported in patient taking SGLT2 inhibitors. The signs and symptoms of DKA are rapid weight loss; feeling or being sick; stomach pain; fast and deep breathing; sleepiness; a sweet smell to the breath; a sweet or metallic taste in the mouth; or a different odour to urine or sweat. Patients with moderate to severe renal impairment who require insulin appear to be at a greater risk of developing DKA. Other risk factors for DKA include low beta cell function reserve; conditions leading to restricted food intake or severe dehydration; sudden reduction in insulin; increased insulin requirements due to acute illness; surgery and alcohol abuse.

Cases of necrotising fasciitis of the perineum (Fournier's gangrene) have been reported in patients taking SGLT2 inhibitors. This a rare but serious event that requires urgent intervention and may be preceded by genital infection or penineal abscess. Patients should be advised to report a combination of symptoms of pain, tenderness, erythema, or swelling in the genital or perineal area, accompanied by fever or malaise.

Pregnancy and Lactation

Pregnancy

Canagliflozin with metformin is contraindicated in pregnancy.

At the time of writing there are no data from the use of canagliflozin alone or in combination with metformin during pregnancy. Animal studies have shown reproductive toxicity at high doses. The potential risk for humans is unknown.

Metformin is generally considered to present a low risk when used during pregnancy (Briggs, 2015) and animal data generally do not indicate harmful effects on pregnancy, embryonal or foetal development, parturition or postnatal development. Rare cases of neural tube defects and malformations of the heart and eye have been seen in animals though studies in pregnant women indicate a low risk to the foetus. The manufacturer states that metformin is not recommended for the treatment of diabetes in pregnancy as it does not provide adequate maternal glycaemic control and insulin therapy is preferred.

Detailed guidance on the treatment of diabetes during pregnancy is available from the National Institute for Health and Clinical Excellence (NICE) at https://www.nice.org.uk/guidance/ng3

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Canagliflozin with metformin is contraindicated in breastfeeding.

No animal studies have been conducted on the co-administration of canagliflozin and metformin.

It is unknown whether canagliflozin is excreted in human breast milk. Animal studies have shown excretion of canagliflozin and/or metabolite in milk, therefore a risk to the nursing infant cannot be excluded.

Metformin is known to be excreted in breast milk, and has occasionally been detected in low-levels in the serum of breastfed infants, although studies have found no adverse effects in infants breastfed by women taking metformin. LactMed recommends that caution be used in mothers with newborn and premature infants, and infants with renal impairment. Briggs and Schaefer both agree that metformin appears in breast milk at low concentrations and that it appears to have a low risk of adverse effects on a breastfed infant. Current NICE guidelines (at the time of writing) state that women with pre-existing type 2 diabetes who are breastfeeding can resume or continue to take metformin immediately following birth (NICE Clinical Guideline 3: February 2015). The manufacturer, however, recommends that the use of metformin is not recommended during breastfeeding.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Abdominal pain
Abnormal liver function tests
Anaphylactic reaction
Angioedema
Balanitis
Balanoposthitis
Constipation
Decreased appetite
Decreased vitamin-B12 absorption
Dehydration
Diarrhoea
Dyslipidaemia
Elevated serum potassium
Erythema
Fournier's gangrene
Hepatitis
Hypoglycaemia
Hypotension
Increase in blood urea or creatinine
Increase in haematocrit
Increased risk of fractures
Increased serum inorganic phosphate
Ketoacidosis
Lactic acidosis
Lower limb amputation
Nausea
Orthostatic hypotension
Pollakiuria
Polyuria
Postural dizziness
Pruritus
Rash
Renal failure
Syncope
Taste disturbances
Thirst
Urinary tract infections
Urticaria
Vaginal candidiasis
Vomiting

Presentation

Tablets containing canagliflozin with metformin.

Drugs List

Therapeutic Indications

Uses

Oral combination treatment of type 2 diabetes

Treatment of type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control:
- in patients not adequately controlled on their maximally tolerated dose of metformin alone or metformin plus other glucose-lowering drugs, including insulin.
- in patients already being treated with the combination of canagliflozin with metformin as separate tablets.

Dosage

The dose of glucose-lowering therapy with canagliflozin with metformin should be individualised on the basis of the patient's current regimen, effectiveness, and tolerability, while not exceeding the daily dose of 300mg of canagliflozin and 3g of metformin. If no adequate strength is available, individual monocomponents should be used instead of the fixed combination.

Adults

Patients with Renal Impairment

Contraindications

Acute alcohol intoxication
Children under 18 years
Severe infection
Shock
Alcoholism
Breastfeeding
Cardiac failure
Dehydration
Diabetic ketoacidosis
Diabetic pre-coma
Hepatic impairment
Hypoxia
Lactic acidosis
Pregnancy
Recent myocardial infarction
Renal impairment - creatinine clearance below 45ml/minute
Respiratory failure

Precautions and Warnings

Acute illness
Major surgery
Patients over 65 years
Predisposition to hypotension
Cardiovascular disorder
History of alcohol abuse
History of pancreatitis
Hypotension
Hypovolaemia
Polycythaemia
Renal impairment

Correct electrolyte disorders before treatment
Advise ability to drive/operate machinery may be affected by side effects
Correct hypovolaemia prior to administration
Test vit B12 levels if deficiency is suspected or risk factors are present
Monitor renal function prior to initiating treatment
Electrolyte & volume depletion may occur - interrupt treatment as necessary
Hospitalised patients: Monitor blood ketones before restart treatment
Monitor for development of lactic acidosis
Monitor renal function 3 to 6 monthly in elderly patients
Monitor renal function 3- 6 monthly if renal function is borderline normal
Monitor renal function annually in patients with normal renal function
Advise patient to report genital/perineal symptoms with fever or malaise
Advise patient to report symptoms of diabetic ketoacidosis immediately
Advise patient to report symptoms of low vitamin B12 levels
Advise patient/carer to report immediately symptoms of lactic acidosis
Discontinue SGLT2 inhibitor if Fournier's gangrene is suspected
Increased risk of genital mycotic infection
Increased risk of urinary tract infection
Test results for urinary glucose will be positive
Withhold until at least 48hrs after general, spinal or epidural anaesthesia
Advise patient to seek advice at first indications of pregnancy
Discontinue if lactic acidosis is suspected
If dehydration occurs, discontinue treatment until patient has recovered
Interrupt therapy if acute serious illness requiring hospitalisation occurs
Interrupt treatment in patients undergoing major surgery
Discontinue if diabetic ketoacidosis is suspected
Discontinue if foot infection, ulcer or gangrene occurs
Advise patient not to take St John's wort concurrently
Advise patient to avoid excess of alcohol
Advise patient on the need for adequate foot hygiene
Advise patient on the need for adequate hydration
Advise patient to report symptoms of volume depletion
Patient to inform DVLA if fitness to drive impaired or hypoglycaemic risk

Lactic acidosis can occur due to metformin accumulation. To reduce the incidence of this occurring, patients should be assessed for risk factors associated with the development of lactic acidosis and monitored regularly. Symptoms of lactic acidosis include acidotic dyspnoea, abdominal pain, hypothermia and coma. A diagnosis of lactic acidosis should be considered in the presence of non-specific symptoms such as muscle cramps, digestive disorders, abdominal pain or severe asthenia. Lactic acidosis is also indicated by decreased blood pH, plasma lactate levels above 5 mmol/L and an increased anion gap and lactate pyruvate ratio. Risk factors for lactic acidosis include: poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic impairment and any condition associated with hypoxia.

Patients who develop laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis occurs treatment must be stopped immediately and other appropriate corrective measures initiated.

Clinical trials suggest there is an increased risk of lower limb amputation (primarily of the toe) in patients treated with canagliflozin. This risk is independent of predisposing factors, however the absolute risk is higher in patients with previous amputations, existing peripheral vascular disease or neuropathy. Patients with these risk factors should be carefully monitored and discontinuation or interruption of treatment can be considered in the event of any significant complication such as lower-extremity skin ulcer, osteomyelitis or gangrene.

Cases of diabetic ketoacidosis (DKA), including rare life-threatening and fatal cases, have been reported in patient taking SGLT2 inhibitors. The signs and symptoms of DKA are rapid weight loss; feeling or being sick; stomach pain; fast and deep breathing; sleepiness; a sweet smell to the breath; a sweet or metallic taste in the mouth; or a different odour to urine or sweat. Patients with moderate to severe renal impairment who require insulin appear to be at a greater risk of developing DKA. Other risk factors for DKA include low beta cell function reserve; conditions leading to restricted food intake or severe dehydration; sudden reduction in insulin; increased insulin requirements due to acute illness; surgery and alcohol abuse.

Cases of necrotising fasciitis of the perineum (Fournier's gangrene) have been reported in patients taking SGLT2 inhibitors. This a rare but serious event that requires urgent intervention and may be preceded by genital infection or penineal abscess. Patients should be advised to report a combination of symptoms of pain, tenderness, erythema, or swelling in the genital or perineal area, accompanied by fever or malaise.

Pregnancy and Lactation

Pregnancy

Canagliflozin with metformin is contraindicated in pregnancy.

At the time of writing there are no data from the use of canagliflozin alone or in combination with metformin during pregnancy. Animal studies have shown reproductive toxicity at high doses. The potential risk for humans is unknown.

Metformin is generally considered to present a low risk when used during pregnancy (Briggs, 2015) and animal data generally do not indicate harmful effects on pregnancy, embryonal or foetal development, parturition or postnatal development. Rare cases of neural tube defects and malformations of the heart and eye have been seen in animals though studies in pregnant women indicate a low risk to the foetus. The manufacturer states that metformin is not recommended for the treatment of diabetes in pregnancy as it does not provide adequate maternal glycaemic control and insulin therapy is preferred.

Detailed guidance on the treatment of diabetes during pregnancy is available from the National Institute for Health and Clinical Excellence (NICE) at https://www.nice.org.uk/guidance/ng3

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Canagliflozin with metformin is contraindicated in breastfeeding.

No animal studies have been conducted on the co-administration of canagliflozin and metformin.

It is unknown whether canagliflozin is excreted in human breast milk. Animal studies have shown excretion of canagliflozin and/or metabolite in milk, therefore a risk to the nursing infant cannot be excluded.

Metformin is known to be excreted in breast milk, and has occasionally been detected in low-levels in the serum of breastfed infants, although studies have found no adverse effects in infants breastfed by women taking metformin. LactMed recommends that caution be used in mothers with newborn and premature infants, and infants with renal impairment. Briggs and Schaefer both agree that metformin appears in breast milk at low concentrations and that it appears to have a low risk of adverse effects on a breastfed infant. Current NICE guidelines (at the time of writing) state that women with pre-existing type 2 diabetes who are breastfeeding can resume or continue to take metformin immediately following birth (NICE Clinical Guideline 3: February 2015). The manufacturer, however, recommends that the use of metformin is not recommended during breastfeeding.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Counselling

Advise the patient of the signs and symptoms of diabetic ketoacidosis (DKA) and lactic acidosis. Advise to seek medical advice if they occur. The risk factors of DKA should be discussed with the patient.

Advise patient to avoid excess consumption of alcohol.

Advise patient not to take St. John's wort concurrently.

Patients should be advised to report symptoms of volume depletion.

Advise patient to report symptoms of low vitamin B12 levels.

Advise patient on the need for adequate hydration.

Advise patient on the need for adequate foot hygiene.

Advise patient to report symptoms of pain, tenderness, erythema, or swelling in the genital or perineal area, accompanied by fever or malaise.

Advise female patients to consult their GP if pregnancy is suspected or planned.

Advise patients that their ability to drive or operate machinery may be impaired due to possible side effects.

Advise patient to report to DVLA if there is a risk of hypoglycaemia, or if fitness to drive may be impaired due to diabetes complications. Guidance can be found by accessing Gov.uk website.

Side Effects

Abdominal pain
Abnormal liver function tests
Anaphylactic reaction
Angioedema
Balanitis
Balanoposthitis
Constipation
Decreased appetite
Decreased vitamin-B12 absorption
Dehydration
Diarrhoea
Dyslipidaemia
Elevated serum potassium
Erythema
Fournier's gangrene
Hepatitis
Hypoglycaemia
Hypotension
Increase in blood urea or creatinine
Increase in haematocrit
Increased risk of fractures
Increased serum inorganic phosphate
Ketoacidosis
Lactic acidosis
Lower limb amputation
Nausea
Orthostatic hypotension
Pollakiuria
Polyuria
Postural dizziness
Pruritus
Rash
Renal failure
Syncope
Taste disturbances
Thirst
Urinary tract infections
Urticaria
Vaginal candidiasis
Vomiting

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: September 2018

Reference Sources

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 3rd edition (2015) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition (2015) ed. Briggs, G., Freeman, R. Wolters Kluwer Health, Philadelphia.

Summary of Product Characteristics: Vokanamet 50mg/850mg, 50mg/1000mg film-coated tablets. Napp Pharmaceuticals Limited. Revised May 2020.

Summary of Product Characteristics: Glucophage 500mg and 850mg tablets. Merck Serono. Revised December 2016.

MHRA Drug Safety Update February 2019
Available at:https://www.mhra.gov.uk
Last accessed: 22 February 2019

MHRA Drug Safety Update June 2022
Available at: https://www.mhra.gov.uk
Last accessed: 21 July 2022

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 20 August 2018