Drugs List

Therapeutic Indications

Uses

Oral combination treatment of type 2 diabetes

Treatment of adults with type 2 diabetes mellitus:
To improve glycaemic control when metformin and/or sulfonylurea with saxagliptin or dapagliflozin do not provide adequate glycaemic control.
When already being treated with saxagliptin and dapagliflozin as separate tablets.

Contraindications

Children under 18 years
Patients over 75 years at initiation
Breastfeeding
Galactosaemia
Pregnancy
Renal impairment - glomerular filtration rate below 60ml/minute at baseline
Severe hepatic impairment

Precautions and Warnings

Immunosuppressed transplant recipients
Major surgery
Patients over 65 years
Predisposition to hypotension
Cardiovascular disorder
Dehydration
Glucose-galactose malabsorption syndrome
History of cardiac failure
History of pancreatitis
Hypotension
Hypovolaemia
Immunodeficiency syndromes
Lactose intolerance
Moderate hepatic impairment
Polycythaemia
Renal impairment - glomerular filtration rate 45-60ml/minute
Urinary tract infection

Advise patient dizziness may affect ability to drive or operate machinery
Correct hypovolaemia prior to administration
Exclude volume depletion before commencing treatment
Contains lactose
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 fluid and electrolyte status
Monitor renal function 2-4 times a year in renal impairment
Monitor renal function annually in patients with normal renal function
Monitor renal function if concomitant drugs that impair renal function
Monitor skin changes
Advise patient to report genital/perineal symptoms with fever or malaise
Advise patient to report new or worsening signs of cardiac failure
Advise patient to report symptoms of diabetic ketoacidosis immediately
Advise patient to seek medical advice if joint aches or pain occur
Advise patients to report symptoms of acute pancreatitis immediately
Discontinue if pemphigus-type reactions develop
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
Advise patient to seek advice at first indications of pregnancy
Discontinue if glomerular filtration rate below 45ml/minute
Discontinue if pancreatitis occurs
Discontinue if severe hypersensitivity reactions occur
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 not to take St John's wort concurrently
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 sodium-glucose co-transporter 2 (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.
Restarting treatment in patients with previous DKA while on SGLT2 inhibitor is not recommended, unless another precipitating factor has been identified and resolved.

Clinical trials suggest there is an increased risk of lower limb amputation in patients treated with canagliflozin. 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 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.

Cases of bullous pemphigoid requiring hospitalisation have been reported with saxagliptin use. If bullous pemphigoid is suspected or development of blisters or erosions occur, discontinue treatment and referral to a dermatologist should be considered.

Pregnancy and Lactation

Pregnancy

Saxagliptin with dapagliflozin is contraindicated in pregnancy.
The manufacturer does not recommend the use of this product during pregnancy.
No data is available regarding the use of saxagliptin during pregnancy. Reproductive toxicity at high doses has been demonstrated in animal studies. The potential risk for humans is unknown.
No data is available 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.
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

Saxagliptin with dapagliflozin is contraindicated in breastfeeding.
The manufacturer states that the product should not be used during breastfeeding.
It is unknown whether saxagliptin is excreted in human breast milk. Animal studies have shown excretion of saxagliptin and/or metabolite in milk, and therefore, a risk to the nursing infant cannot be excluded.
It is unknown whether dapagliflozin and/or its metabolites are excreted in human milk. Available pharmacodynamic/toxicological data from animal studies 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.

Side Effects

Abdominal pain
Anaphylactic shock
Angioedema
Arthralgia
Back pain
Balanitis
Bullous pemphigoid
Constipation
Dehydration
Dermatitis
Diarrhoea
Dizziness
Dry mouth
Dyslipidaemia
Dyspepsia
Dysuria
Erectile dysfunction
Fatigue
Fournier's gangrene
Fungal infection
Gastritis
Gastro-enteritis
Genital infections
Genital pruritus
Headache
Hyperhidrosis
Hypersensitivity reactions
Hypertriglyceridaemia
Hypoglycaemia
Hypotension
Hypovolaemia
Increase in blood urea or creatinine
Increase in haematocrit
Increased serum inorganic phosphate
Ketoacidosis
Myalgia
Nasopharyngitis
Nausea
Nocturia
Pancreatitis
Peripheral oedema
Plasma volume depletion
Polyuria
Pruritus
Rash
Renal impairment
Sinusitis
Thirst
Upper respiratory tract infection
Urinary tract infections
Urticaria
Vomiting
Vulvovaginal infections
Vulvovaginal irritation
Vulvovaginal itching
Weight loss

Presentation

Tablets containing saxagliptin and dapagliflozin.

Drugs List

Therapeutic Indications

Uses

Oral combination treatment of type 2 diabetes

Treatment of adults with type 2 diabetes mellitus:
To improve glycaemic control when metformin and/or sulfonylurea with saxagliptin or dapagliflozin do not provide adequate glycaemic control.
When already being treated with saxagliptin and dapagliflozin as separate tablets.

Dosage

Adults

Additional Dosage Information

Contraindications

Children under 18 years
Patients over 75 years at initiation
Breastfeeding
Galactosaemia
Pregnancy
Renal impairment - glomerular filtration rate below 60ml/minute at baseline
Severe hepatic impairment

Precautions and Warnings

Immunosuppressed transplant recipients
Major surgery
Patients over 65 years
Predisposition to hypotension
Cardiovascular disorder
Dehydration
Glucose-galactose malabsorption syndrome
History of cardiac failure
History of pancreatitis
Hypotension
Hypovolaemia
Immunodeficiency syndromes
Lactose intolerance
Moderate hepatic impairment
Polycythaemia
Renal impairment - glomerular filtration rate 45-60ml/minute
Urinary tract infection

Advise patient dizziness may affect ability to drive or operate machinery
Correct hypovolaemia prior to administration
Exclude volume depletion before commencing treatment
Contains lactose
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 fluid and electrolyte status
Monitor renal function 2-4 times a year in renal impairment
Monitor renal function annually in patients with normal renal function
Monitor renal function if concomitant drugs that impair renal function
Monitor skin changes
Advise patient to report genital/perineal symptoms with fever or malaise
Advise patient to report new or worsening signs of cardiac failure
Advise patient to report symptoms of diabetic ketoacidosis immediately
Advise patient to seek medical advice if joint aches or pain occur
Advise patients to report symptoms of acute pancreatitis immediately
Discontinue if pemphigus-type reactions develop
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
Advise patient to seek advice at first indications of pregnancy
Discontinue if glomerular filtration rate below 45ml/minute
Discontinue if pancreatitis occurs
Discontinue if severe hypersensitivity reactions occur
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 not to take St John's wort concurrently
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 sodium-glucose co-transporter 2 (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.
Restarting treatment in patients with previous DKA while on SGLT2 inhibitor is not recommended, unless another precipitating factor has been identified and resolved.

Clinical trials suggest there is an increased risk of lower limb amputation in patients treated with canagliflozin. 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 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.

Cases of bullous pemphigoid requiring hospitalisation have been reported with saxagliptin use. If bullous pemphigoid is suspected or development of blisters or erosions occur, discontinue treatment and referral to a dermatologist should be considered.

Pregnancy and Lactation

Pregnancy

Saxagliptin with dapagliflozin is contraindicated in pregnancy.
The manufacturer does not recommend the use of this product during pregnancy.
No data is available regarding the use of saxagliptin during pregnancy. Reproductive toxicity at high doses has been demonstrated in animal studies. The potential risk for humans is unknown.
No data is available 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.
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

Saxagliptin with dapagliflozin is contraindicated in breastfeeding.
The manufacturer states that the product should not be used during breastfeeding.
It is unknown whether saxagliptin is excreted in human breast milk. Animal studies have shown excretion of saxagliptin and/or metabolite in milk, and therefore, a risk to the nursing infant cannot be excluded.
It is unknown whether dapagliflozin and/or its metabolites are excreted in human milk. Available pharmacodynamic/toxicological data from animal studies 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.

Counselling

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

Advise patients that they should not self-medicate with St John's Wort during treatment as the hypoglycaemic effect of saxagliptin may be reduced.

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 patient to report symptoms of volume depletion.

Advise patient to report new or worsening signs of cardiac failure.

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

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

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
Anaphylactic shock
Angioedema
Arthralgia
Back pain
Balanitis
Bullous pemphigoid
Constipation
Dehydration
Dermatitis
Diarrhoea
Dizziness
Dry mouth
Dyslipidaemia
Dyspepsia
Dysuria
Erectile dysfunction
Fatigue
Fournier's gangrene
Fungal infection
Gastritis
Gastro-enteritis
Genital infections
Genital pruritus
Headache
Hyperhidrosis
Hypersensitivity reactions
Hypertriglyceridaemia
Hypoglycaemia
Hypotension
Hypovolaemia
Increase in blood urea or creatinine
Increase in haematocrit
Increased serum inorganic phosphate
Ketoacidosis
Myalgia
Nasopharyngitis
Nausea
Nocturia
Pancreatitis
Peripheral oedema
Plasma volume depletion
Polyuria
Pruritus
Rash
Renal impairment
Sinusitis
Thirst
Upper respiratory tract infection
Urinary tract infections
Urticaria
Vomiting
Vulvovaginal infections
Vulvovaginal irritation
Vulvovaginal itching
Weight loss

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 (dapagliflozin). 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: June 2019

Reference Sources

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: Qtern 5 mg/10 mg film-coated tablets. AstraZeneca UK Ltd. Revised March 2020.

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 12 June 2019