Drugs List

Therapeutic Indications

Uses

Type 2 diabetes (NIDDM) not controlled by diet,weight loss & exercise alone

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
- in patients on their maximally tolerated doses of metformin along with other glucose-lowering medicinal products including insulin, when these alone do not provide adequate glycaemic control
- in patients already being treated with the combination of empagliflozin with metformin as separate tablets.

Contraindications

Acute alcohol intoxication
Children under 18 years
Patients over 85 years at initiation
Severe infection
Shock
Within 48 hours of using iodinated contrast media
Alcoholism
Breastfeeding
Decompensated cardiac failure
Dehydration
Diabetic pre-coma
Hepatic impairment
Hypoxia
Metabolic acidosis
Pregnancy
Recent myocardial infarction
Renal impairment - glomerular filtration rate below 60ml/minute at baseline
Respiratory failure

Precautions and Warnings

Acute illness
Elderly
Major surgery
Predisposition to hypotension
Cardiovascular disorder
Hypotension
Hypovolaemia
Renal impairment - glomerular filtration rate 45-60ml/minute
Urinary tract infection

Advise ability to drive/operate machinery may be affected by side effects
Test vit B12 levels if deficiency is suspected or risk factors are present
Monitor renal function prior to initiating treatment
Adjust dose if glomerular filtration rate between 45 and 60ml/minute
Electrolyte & volume depletion may occur - interrupt treatment as necessary
Hospitalised patients: Monitor blood ketones before restart treatment
Monitor blood pressure
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
Monitor renal function if concomitant drugs that impair 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
Interrupt treatment temporarily in complicated urinary tract infections
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 glomerular filtration rate below 45ml/minute
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
Pregnancy confirmed: Discontinue this medication
Discontinue if diabetic ketoacidosis is suspected
Advise patient to avoid excess of alcohol
Dietary restrictions should be maintained
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

Diabetic ketoacidosis
Cases of diabetic ketoacidosis (DKA) have been reported in patient taking inhibitors of sodium-glucose co-transporter 2 (SGLT2), including empagliflozin. The risk of DKA must be considered in the event of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness. Patients should be assessed for DKA immediately if the presence of these symptoms, regardless of blood sugar levels. The 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.
Restarting SGLT2 inhibitor treatment in patients with previous DKA while on SGLT2 inhibitor is not recommended, unless another clear precipitating factor is identified and resolved.

Lactic acidosis
Lactic acidosis (LA) is a rare but serious complication which most often occurs at acute worsening of renal function, cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute worsening of renal function and increases the risk of LA.
Patients and/or care-givers should be informed of the risk of LA. Symptoms of LA include acidotic dyspnoea, abdominal pain, muscle cramps, asthenia, hypothermia and coma. LA is also indicated by decreased blood pH, plasma lactate levels above 5 mmol/L and an increased anion gap and lactate pyruvate ratio.
If LA is suspected, discontinue metformin and hospitalise the patient immediately.
Risk factors for LA include:
Poorly controlled diabetes.
Ketosis.
Prolonged fasting.
Excessive alcohol intake.
Hepatic impairment.
Any condition associated with hypoxia.
Special caution should be exercised in situations where renal function may become impaired, e.g. when starting therapy with a non-steroidal anti-inflammatory drug (NSAID).

Lower limb amputation
Clinical trials suggest there is an increased risk of lower limb amputation in patients treated with another sodium-glucose co-transporter-2 (SGLT2) inhibitor. An increased risk of amputation has not yet been seen in studies of empagliflozin. However, the increased risk of amputation cannot be excluded and caution should be advised in patients receiving empagliflozin.

Fournier's gangrene
Cases of necrotising fasciitis of the perineum 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 perineal 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. Empagliflozin with metformin tablets should be discontinued and prompt treatment, including antibiotics and surgical debridement, should be instituted.

Pregnancy and Lactation

Pregnancy

Empagliflozin with metformin is contraindicated during pregnancy.

There are no data from the use of empagliflozin or in combination with metformin in pregnant women.

Some animal studies show that empagliflozin crosses the placenta during the late gestation to a very limited extent, but do not indicate direct or indirect harmful effects with respect to early embryonic development. However, some studies have shown adverse effects on postnatal development.

Metformin is generally considered to present a low risk when used during pregnancy (Briggs 2015) and a limited amount of information suggests that the use of metformin in pregnant women is not associated with an increased risk of congenital malformations.

Animal studies with the combination of empagliflozin and metformin or with metformin alone have shown reproductive toxicity at higher doses of metformin only.

The manufacturer states that empagliflozin with 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. Maintaining the blood glucose levels during pregnancy as close to normal as possible reduces the risk of malformations of the foetus associated with abnormal levels. Also, insulin, unlike metformin, does not cross the human placenta.

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.

Lactation

Empagliflozin with metformin is contraindicated in breastfeeding.

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

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

LactMed (2018) recommends that an alternative drug to empagliflozin should be used, although unlikely to pass into breast milk in clinically important amounts.

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 (Briggs, 2015) and (Schaefer, 2015).
LactMed recommends that caution be used in mothers with newborn and premature infants, and infants with renal impairment when metformin is taken.

Side Effects

Abdominal pain
Abnormal liver function tests
Angioedema
Balanitis
Decrease in blood pressure
Decrease in glomerular filtration rate
Decreased appetite
Decreased vitamin-B12 absorption
Dehydration
Diarrhoea
Dysuria
Erythema
Fournier's gangrene
Genital infections
Hepatitis
Hypoglycaemia
Hypotension
Hypovolaemia
Increase in haematocrit
Increased urination
Ketoacidosis
Lactic acidosis
Nausea
Nocturia
Orthostatic hypotension
Plasma volume depletion
Pollakiuria
Polyuria
Pruritus
Rash
Rise in blood lipids
Serum creatinine increased
Syncope
Taste disturbances
Thirst
Urinary tract infections
Urticaria
Vaginal candidiasis
Vomiting
Vulvovaginal irritation

Presentation

Oral formulations of empagliflozin with metformin hydrochloride.

Drugs List

Therapeutic Indications

Uses

Type 2 diabetes (NIDDM) not controlled by diet,weight loss & exercise alone

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
- in patients on their maximally tolerated doses of metformin along with other glucose-lowering medicinal products including insulin, when these alone do not provide adequate glycaemic control
- in patients already being treated with the combination of empagliflozin with metformin as separate tablets.

Dosage

Adults

Patients with Renal Impairment

Additional Dosage Information

Contraindications

Acute alcohol intoxication
Children under 18 years
Patients over 85 years at initiation
Severe infection
Shock
Within 48 hours of using iodinated contrast media
Alcoholism
Breastfeeding
Decompensated cardiac failure
Dehydration
Diabetic pre-coma
Hepatic impairment
Hypoxia
Metabolic acidosis
Pregnancy
Recent myocardial infarction
Renal impairment - glomerular filtration rate below 60ml/minute at baseline
Respiratory failure

Precautions and Warnings

Acute illness
Elderly
Major surgery
Predisposition to hypotension
Cardiovascular disorder
Hypotension
Hypovolaemia
Renal impairment - glomerular filtration rate 45-60ml/minute
Urinary tract infection

Advise ability to drive/operate machinery may be affected by side effects
Test vit B12 levels if deficiency is suspected or risk factors are present
Monitor renal function prior to initiating treatment
Adjust dose if glomerular filtration rate between 45 and 60ml/minute
Electrolyte & volume depletion may occur - interrupt treatment as necessary
Hospitalised patients: Monitor blood ketones before restart treatment
Monitor blood pressure
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
Monitor renal function if concomitant drugs that impair 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
Interrupt treatment temporarily in complicated urinary tract infections
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 glomerular filtration rate below 45ml/minute
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
Pregnancy confirmed: Discontinue this medication
Discontinue if diabetic ketoacidosis is suspected
Advise patient to avoid excess of alcohol
Dietary restrictions should be maintained
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

Diabetic ketoacidosis
Cases of diabetic ketoacidosis (DKA) have been reported in patient taking inhibitors of sodium-glucose co-transporter 2 (SGLT2), including empagliflozin. The risk of DKA must be considered in the event of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness. Patients should be assessed for DKA immediately if the presence of these symptoms, regardless of blood sugar levels. The 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.
Restarting SGLT2 inhibitor treatment in patients with previous DKA while on SGLT2 inhibitor is not recommended, unless another clear precipitating factor is identified and resolved.

Lactic acidosis
Lactic acidosis (LA) is a rare but serious complication which most often occurs at acute worsening of renal function, cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute worsening of renal function and increases the risk of LA.
Patients and/or care-givers should be informed of the risk of LA. Symptoms of LA include acidotic dyspnoea, abdominal pain, muscle cramps, asthenia, hypothermia and coma. LA is also indicated by decreased blood pH, plasma lactate levels above 5 mmol/L and an increased anion gap and lactate pyruvate ratio.
If LA is suspected, discontinue metformin and hospitalise the patient immediately.
Risk factors for LA include:
Poorly controlled diabetes.
Ketosis.
Prolonged fasting.
Excessive alcohol intake.
Hepatic impairment.
Any condition associated with hypoxia.
Special caution should be exercised in situations where renal function may become impaired, e.g. when starting therapy with a non-steroidal anti-inflammatory drug (NSAID).

Lower limb amputation
Clinical trials suggest there is an increased risk of lower limb amputation in patients treated with another sodium-glucose co-transporter-2 (SGLT2) inhibitor. An increased risk of amputation has not yet been seen in studies of empagliflozin. However, the increased risk of amputation cannot be excluded and caution should be advised in patients receiving empagliflozin.

Fournier's gangrene
Cases of necrotising fasciitis of the perineum 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 perineal 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. Empagliflozin with metformin tablets should be discontinued and prompt treatment, including antibiotics and surgical debridement, should be instituted.

Pregnancy and Lactation

Pregnancy

Empagliflozin with metformin is contraindicated during pregnancy.

There are no data from the use of empagliflozin or in combination with metformin in pregnant women.

Some animal studies show that empagliflozin crosses the placenta during the late gestation to a very limited extent, but do not indicate direct or indirect harmful effects with respect to early embryonic development. However, some studies have shown adverse effects on postnatal development.

Metformin is generally considered to present a low risk when used during pregnancy (Briggs 2015) and a limited amount of information suggests that the use of metformin in pregnant women is not associated with an increased risk of congenital malformations.

Animal studies with the combination of empagliflozin and metformin or with metformin alone have shown reproductive toxicity at higher doses of metformin only.

The manufacturer states that empagliflozin with 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. Maintaining the blood glucose levels during pregnancy as close to normal as possible reduces the risk of malformations of the foetus associated with abnormal levels. Also, insulin, unlike metformin, does not cross the human placenta.

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.

Lactation

Empagliflozin with metformin is contraindicated in breastfeeding.

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

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

LactMed (2018) recommends that an alternative drug to empagliflozin should be used, although unlikely to pass into breast milk in clinically important amounts.

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 (Briggs, 2015) and (Schaefer, 2015).
LactMed recommends that caution be used in mothers with newborn and premature infants, and infants with renal impairment when metformin is taken.

Counselling

Advise patient to take empagliflozin and metformin tablets after food to reduce gastro-intestinal disturbances.

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

Advise patient of the warning signs of hypoglycaemia, especially when used in combination with insulin or insulin secretagogues.

Advise patient to report symptoms of volume depletion.

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

Advise patient to avoid excessive intake of alcohol.

Advise patient to report symptoms of lactic acidosis such as acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia.

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

Advise patient to report symptoms of low vitamin B12 levels.

Advise patient to temporarily discontinue treatment in case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake) and to contact a healthcare professional for advice.

Advise patient that their ability to drive or operate machinery may be impaired.

Advise patient on the need for adequate foot care.

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
Angioedema
Balanitis
Decrease in blood pressure
Decrease in glomerular filtration rate
Decreased appetite
Decreased vitamin-B12 absorption
Dehydration
Diarrhoea
Dysuria
Erythema
Fournier's gangrene
Genital infections
Hepatitis
Hypoglycaemia
Hypotension
Hypovolaemia
Increase in haematocrit
Increased urination
Ketoacidosis
Lactic acidosis
Nausea
Nocturia
Orthostatic hypotension
Plasma volume depletion
Pollakiuria
Polyuria
Pruritus
Rash
Rise in blood lipids
Serum creatinine increased
Syncope
Taste disturbances
Thirst
Urinary tract infections
Urticaria
Vaginal candidiasis
Vomiting
Vulvovaginal irritation

Effects on Laboratory Tests

Patients will test positive for glucose in their urine due to the mechanism of action.

Interference with 1,5-anhydroglucitol (1,5-AG) assay
Monitoring glycaemic control with 1,5-AG assay is not recommended due to unreliable measurements of 1,5-AG in patients taking SGLT2 inhibitors. Alternative methods to monitor glycaemic control is advised.

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: May 2020.

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: Synjardy film coated tablets. Boehringer Ingelheim Ltd. Revised June 2020.

US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Metformin. Last revised: 31 October 2018.
Empagliflozin. Last revised: 03 December 2018.
Last accessed: 12 February 2020.

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