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 dapagliflozin with metformin as separate tablets.

Contraindications

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

Precautions and Warnings

Acute illness
Major surgery
Patients over 65 years
Predisposition to hypotension
Dehydration
History of alcohol abuse
Hypotension
Hypovolaemia
Polycythaemia
Renal impairment - glomerular filtration rate 45-60ml/minute
Urinary tract infection

Correct hypovolaemia prior to administration
Exclude volume depletion before commencing treatment
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 blood pressure
Monitor fluid and electrolyte status
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
Test for raised ketones in patients with symptoms of diabetic ketoacidosis
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
May affect results of some laboratory tests
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
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 alcohol during treatment
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

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 5mmol/L and an increased anion gap and lactate pyruvate ratio.
If lactic acidosis is suspected, discontinue metformin and hospitalise the patient immediately.
Risk factors for lactic acidosis 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).

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 dapagliflozin. However, the increased risk of amputation cannot be excluded and caution should be advised in patients receiving dapagliflozin.

Cases of diabetic ketoacidosis (DKA) 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. 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.

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

Dapagliflozin with metformin is contraindicated in pregnancy.

There are no data from the use of dapagliflozin in pregnant women. Studies in rats have shown toxicity to the developing kidney in the time period corresponding to the second and third trimesters for human pregnancy.

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

Dapagliflozin with metformin is contraindicated in breastfeeding.

It is unknown whether dapagliflozin and/or its metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of dapagliflozin and/or its metabolites in milk, as well as pharmacologically-mediated effects in nursing offspring. A risk to the newborns/infants 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 (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.
The manufacturer 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

Back pain
Constipation
Decreased vitamin-B12 absorption
Dehydration
Dyslipidaemia
Dysuria
Erythema
Fournier's gangrene
Gastro-intestinal symptoms
Genital infections
Hepatitis
Hyperhidrosis
Hypoglycaemia
Hypotension
Hypovolaemia
Increase in blood urea or creatinine
Increase in haematocrit
Ketoacidosis
Lactic acidosis
Liver function disturbances
Nocturia
Polyuria
Pruritus
Pruritus vulvae
Rash
Renal impairment
Taste disturbances
Thirst
Urinary tract infections
Urticaria

Presentation

Tablets containing dapagliflozin and metformin.

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 dapagliflozin with metformin as separate tablets.

Dosage

Adults

Patients with Renal Impairment

Additional Dosage Information

Contraindications

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

Precautions and Warnings

Acute illness
Major surgery
Patients over 65 years
Predisposition to hypotension
Dehydration
History of alcohol abuse
Hypotension
Hypovolaemia
Polycythaemia
Renal impairment - glomerular filtration rate 45-60ml/minute
Urinary tract infection

Correct hypovolaemia prior to administration
Exclude volume depletion before commencing treatment
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 blood pressure
Monitor fluid and electrolyte status
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
Test for raised ketones in patients with symptoms of diabetic ketoacidosis
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
May affect results of some laboratory tests
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
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 alcohol during treatment
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

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 5mmol/L and an increased anion gap and lactate pyruvate ratio.
If lactic acidosis is suspected, discontinue metformin and hospitalise the patient immediately.
Risk factors for lactic acidosis 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).

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 dapagliflozin. However, the increased risk of amputation cannot be excluded and caution should be advised in patients receiving dapagliflozin.

Cases of diabetic ketoacidosis (DKA) 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. 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.

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

Dapagliflozin with metformin is contraindicated in pregnancy.

There are no data from the use of dapagliflozin in pregnant women. Studies in rats have shown toxicity to the developing kidney in the time period corresponding to the second and third trimesters for human pregnancy.

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

Dapagliflozin with metformin is contraindicated in breastfeeding.

It is unknown whether dapagliflozin and/or its metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of dapagliflozin and/or its metabolites in milk, as well as pharmacologically-mediated effects in nursing offspring. A risk to the newborns/infants 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 (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.
The manufacturer 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 to seek medical advice if they occur. The risk factors of DKA should be discussed with the patient.

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

Advise patient to report symptoms of volume depletion.

Advise patient to report symptoms of low vitamin B12 levels.

Advise patient to avoid alcohol.

Advise patient on the need for adequate hydration.

Advise patient on the need for appropriate 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 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

Back pain
Constipation
Decreased vitamin-B12 absorption
Dehydration
Dyslipidaemia
Dysuria
Erythema
Fournier's gangrene
Gastro-intestinal symptoms
Genital infections
Hepatitis
Hyperhidrosis
Hypoglycaemia
Hypotension
Hypovolaemia
Increase in blood urea or creatinine
Increase in haematocrit
Ketoacidosis
Lactic acidosis
Liver function disturbances
Nocturia
Polyuria
Pruritus
Pruritus vulvae
Rash
Renal impairment
Taste disturbances
Thirst
Urinary tract infections
Urticaria

Effects on Laboratory Tests

In diabetic patients taking dapagliflozin, it is advisable not to use the 1,5-anhydroglucitol (1,5 AG) assay to monitor glycaemic control. This is because measurements of 1,5 AG are unreliable in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycaemic control.

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: January 2019

Reference Sources

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd 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: Xigduo 5 mg/850 mg & 5 mg/1,000 mg film coated tablets. AstraZeneca UK Ltd. Revised July 2019.

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

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
Last accessed: 04 January 2019