Empagliflozin with metformin oral
- Drugs List
- Therapeutic Indications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
Oral formulations of empagliflozin with metformin hydrochloride.
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.
The recommended dose is one tablet twice daily. The dosage should be individualised on the basis of the patient's current regimen, effectiveness, and tolerability using the recommended daily dose of 10mg or 25mg of empagliflozin while not exceeding the recommended daily dose of metformin.
All doses should be taken with a meal.
If no adequate strength of empagliflozin with metformin tablets is available, individual monocomponents should be used instead of the fixed dose combination.
For patients inadequately controlled on maximal tolerated dose of metformin monotherapy or metformin in combination with other glucose-lowering products including insulin
The initial dose should provide 5mg empagliflozin twice daily plus a similar dose of metformin already being taken.
In patients tolerating a total daily dose of 10mg empagliflozin and who need tighter glycaemic control, the dose can be increased to a total daily dose of 25mg empagliflozin.
For patients switching from separate tablets of empagliflozin and metformin
Patients switching from separate tablets of empagliflozin and metformin should receive the same daily dose of empagliflozin and metformin already being taken or the nearest therapeutically appropriate dose of metformin.
Patients with Renal Impairment
Glomerular Filtration Rate (GFR) of 60 to 89ml/minute
Metformin: Maximum daily dose is 3g. Dose reduction may be considered in relation to declining renal function. Empagliflozin: Maximum daily dose is 25mg.
GFR of 45 to 59ml/minute
Metformin: Maximum daily dose is 2g. The starting dose is at most half of the maximum dose. Empagliflozin: Empagliflozin should not be initiated. The dose should be adjusted to or maintained at a maximum daily dose of 10mg.
GFR of 30 to 44ml/minute
Combination is not recommended.
Metformin: Maximum daily dose is 1g. The starting dose is at most half of the maximum dose. Empagliflozin: Empagliflozin is not recommended.
Additional Dosage Information
When used as add-on therapy with insulin or other antidiabetic agents which can cause hypoglycaemia, a lower dose of insulin or other antidiabetic agents may be considered to reduce risk of hypoglycaemia.
If a dose is missed, it should be taken as soon as possible, providing that a double dose is not administered at the same time.
Acute alcohol intoxication
Children under 18 years
Patients over 85 years at initiation
Within 48 hours of using iodinated contrast media
Decompensated cardiac failure
Recent myocardial infarction
Renal impairment - glomerular filtration rate below 60ml/minute at baseline
Precautions and Warnings
Predisposition to hypotension
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
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 (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.
Excessive alcohol intake.
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.
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
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.
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.
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.
Abnormal liver function tests
Decrease in blood pressure
Decrease in glomerular filtration rate
Decreased vitamin-B12 absorption
Increase in haematocrit
Plasma volume depletion
Rise in blood lipids
Serum creatinine increased
Urinary tract infections
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.
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 ).
Last Full Review Date: May 2020.
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
Already a member? Log in
Medscape UK | Univadis prescription drug monographs & interactions are based on FDB Multilex Content
FDB Disclaimer : FDB Multilex is intended for the use of healthcare professionals and is provided on the basis that the healthcare professionals will retain FULL and SOLE responsibility for deciding what treatment to prescribe or dispense for any particular patient or circumstance.