appropriate, as an alternative to an existing GLP-1 agonist
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
CAUTIONARY AND ADVISORY LABELS 10
Lixisenatide 50 microgram per 1 ml Lyxumia 10micrograms/0.2ml
solution for injection 3ml pre-filled pen | 1 pre-filled disposable
injection P £31.67 DT = £31.67
Lixisenatide 100 microgram per 1 ml Lyxumia 20micrograms/0.2ml
solution for injection 3ml pre-filled pen | 2 pre-filled disposable
injection P £57.93 DT = £57.93
Combinations available: Insulin glargine with lixisenatide,
l DRUG ACTION Semaglutide binds to, and activates, the
GLP-1 (glucagon-like peptide-1) receptor to increase
insulin secretion, suppress glucagon secretion, and slow
Type 2 diabetes mellitus [monotherapy (if metformin
inappropriate) or in combination with other antidiabetic
▶ Adult: Initially 0.25 mg once weekly for 4 weeks, then
increased to 0.5 mg once weekly for at least 4 weeks,
then increased if necessary to 1 mg once weekly, for
information on use with other antidiabetic drugs—
DOSE ADJUSTMENTS DUE TO INTERACTIONS
▶ Manufacturer advises dose of concomitant insulin or
sulfonylurea may need to be reduced.
l CONTRA-INDICATIONS Diabetic ketoacidosis . severe
congestive heart failure (no information available)
l CAUTIONS Diabetic retinopathy (in patients treated with
insulin). history of pancreatitis
l INTERACTIONS → Appendix 1: semaglutide
sulfonylurea). nausea . vomiting . weight decreased
SIDE-EFFECTS, FURTHER INFORMATION Discontinue if
symptoms of acute pancreatitis occur, such as persistent,
l CONCEPTION AND CONTRACEPTION Manufacturer advises
women of childbearing potential should use effective
contraception during and for at least two months after
l PREGNANCY Manufacturer advises avoid—toxicity in
l BREAST FEEDING Manufacturer advises avoid—present in
l HEPATIC IMPAIRMENT Manufacturer advises caution
(limited information in severe impairment).
l RENAL IMPAIRMENT Manufacturer advises avoid in endstage renal disease.
l HANDLING AND STORAGE Manufacturer advises store in a
refrigerator (2–8°C)—after first use can also be stored
below 30°C; keep cap on pen to protect from light.
l PATIENT AND CARER ADVICE Manufacturer advises
patients and their carers should be told how to recognise
signs and symptoms of acute pancreatitis and advised to
seek immediate medical attention if symptoms develop.
Missed doses Manufacturer advises if a dose is more than
5 days late, the missed dose should not be taken and the
next dose should be administered at the normal time.
l NATIONAL FUNDING/ACCESS DECISIONS
Scottish Medicines Consortium (SMC) decisions
The Scottish Medicines Consortium has advised (January
2019) that semaglutide (Ozempic ®) is accepted for
restricted use within NHS Scotland for the treatment of
adults with insufficiently controlled type 2 diabetes
mellitus in addition to other oral antidiabetic medicines,
or as an add-on to basal insulin, as an alternative
glucagon-like peptide-1 receptor agonist option.
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
▶ Ozempic (Novo Nordisk Ltd) A
Semaglutide 1.34 mg per 1 ml Ozempic 1mg/0.74ml solution for
injection 3ml pre-filled pen | 1 pre-filled disposable injection P £73.25
BLOOD GLUCOSE LOWERING DRUGS ›
l DRUG ACTION Nateglinide stimulates insulin secretion.
Type 2 diabetes mellitus in combination with metformin
when metformin alone inadequate
▶ Adult: Initially 60 mg 3 times a day (max. per dose
180 mg), adjusted according to response, to be taken
within 30 minutes before main meals
l CONTRA-INDICATIONS Ketoacidosis
l CAUTIONS Debilitated patients . elderly . malnourished
CAUTIONS, FURTHER INFORMATION Substitute insulin
during intercurrent illness (such as myocardial infarction,
coma, infection, and trauma) and during surgery (omit
nateglinide on morning of surgery and recommence when
eating and drinking normally).
l INTERACTIONS → Appendix 1: nateglinide
▶ Common or very common Diarrhoea . gastrointestinal
discomfort. hypoglycaemia . nausea
▶ Rare or very rare Skin reactions
l PREGNANCY Avoid—toxicity in animal studies.
l BREAST FEEDING Avoid—present in milk in animal studies.
l HEPATIC IMPAIRMENT Manufacturer advises caution in
moderate impairment; avoid in severe impairment (no
Driving and skilled tasks Drivers need to be particularly
careful to avoid hypoglycaemia and should be warned of
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
▶ Starlix (Novartis Pharmaceuticals UK Ltd)
Nateglinide 60 mg Starlix 60mg tablets | 84 tablet P £26.12 DT
Nateglinide 120 mg Starlix 120mg tablets | 84 tablet P £29.76
Nateglinide 180 mg Starlix 180mg tablets | 84 tablet P £29.76
l DRUG ACTION Repaglinide stimulates insulin secretion.
Type 2 diabetes mellitus (as monotherapy or in
combination with metformin when metformin alone
▶ Adult 18–74 years: Initially 500 micrograms (max. per
dose 4 mg), adjusted according to response, dose to be
taken within 30 minutes before main meals and
adjusted at intervals of 1–2 weeks; maximum 16 mg
▶ Adult 75 years and over: Not recommended
Type 2 diabetes mellitus (as monotherapy or in
combination with metformin when metformin alone
inadequate), if transferring from another oral
▶ Adult 18–74 years: Initially 1 mg (max. per dose 4 mg),
adjusted according to response, dose to be taken within
30 minutes before main meals and adjusted at intervals
of 1–2 weeks; maximum 16 mg per day
▶ Adult 75 years and over: Not recommended
l CONTRA-INDICATIONS Ketoacidosis
l CAUTIONS Debilitated patients . malnourished patients
CAUTIONS, FURTHER INFORMATION Substitute insulin
during intercurrent illness (such as myocardial infarction,
coma, infection, and trauma) and during surgery.
l INTERACTIONS → Appendix 1: repaglinide
▶ Common or very common Abdominal pain . diarrhoea . hypoglycaemia
▶ Frequency not known Acute coronary syndrome . hypoglycaemic coma . nausea . skin reactions
l BREAST FEEDING Avoid—present in milk in animal studies.
l HEPATIC IMPAIRMENT Manufacturer advises avoid in
severe impairment (risk of increased exposure).
l RENAL IMPAIRMENT Use with caution.
Driving and skilled tasks Drivers need to be particularly
careful to avoid hypoglycaemia and should be warned of
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
▶ Repaglinide (Non-proprietary)
Repaglinide 1 mg Repaglinide 1mg tablets | 30 tablet P £3.33–
£3.47 | 90 tablet P £10.42 DT = £10.42
Repaglinide 2 mg Repaglinide 2mg tablets | 90 tablet P £10.00
▶ Enyglid (Consilient Health Ltd)
Repaglinide 500 microgram Enyglid 0.5mg tablets | 30 tablet P £3.33 | 90 tablet P £9.99 DT = £9.01
Repaglinide 1 mg Enyglid 1mg tablets | 30 tablet P £3.33 | 90 tablet P £9.99 DT = £10.42
Repaglinide 2 mg Enyglid 2mg tablets | 90 tablet P £9.99 DT =
Repaglinide 500 microgram Prandin 0.5mg tablets | 30 tablet P £3.92
Repaglinide 1 mg Prandin 1mg tablets | 30 tablet P £3.92
Repaglinide 2 mg Prandin 2mg tablets | 90 tablet P £11.76 DT =
BLOOD GLUCOSE LOWERING DRUGS › SODIUM
GLUCOSE CO-TRANSPORTER 2 INHIBITORS
tubule to reduce glucose reabsorption and increase urinary
Type 2 diabetes mellitus as monotherapy (if metformin
inappropriate)| Type 2 diabetes mellitus in combination
with insulin or other antidiabetic drugs (if existing
treatment fails to achieve adequate glycaemic control)
▶ Adult: 100 mg once daily; increased if tolerated to
300 mg once daily if required, dose to be taken
DOSE ADJUSTMENTS DUE TO INTERACTIONS
▶ Manufacturer advises increase dose if tolerated to
300 mg once daily with concurrent use of rifampicin.
▶ Dose of concomitant insulin or drugs that stimulate
insulin secretion may need to be reduced.
MHRA/CHM ADVICE (UPDATED APRIL 2016): RISK OF DIABETIC
KETOACIDOSIS WITH SODIUM-GLUCOSE CO-TRANSPORTER 2
(SGLT2) INHIBITORS (CANAGLIFLOZIN, DAPAGLIFLOZIN OR
A review by the European Medicines Agency has
concluded that serious, life-threatening, and fatal cases
of diabetic ketoacidosis (DKA) have been reported rarely
in patients taking an SGLT2 inhibitor. In several cases,
the presentation of DKA was atypical with patients
having only moderately elevated blood glucose levels,
and some of them occurred during off-label use.
To minimise the risk of such effects when treating
patients with a SGLT2 inhibitor, the European Medicines
Agency has issued the following advice:
. inform patients of the signs and symptoms of DKA,
(including rapid weight loss, nausea or vomiting,
abdominal 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), and
advise them to seek immediate medical advice if they
. test for raised ketones in patients with signs and
symptoms of DKA, even if plasma glucose levels are
. use canagliflozin with caution in patients with risk
factors for DKA, (including a low beta cell reserve,
conditions leading to restricted food intake or severe
dehydration, sudden reduction in insulin, increased
insulin requirements due to acute illness, surgery or
alcohol abuse), and discuss these risk factors with
. discontinue treatment if DKA is suspected or
702 Diabetes mellitus and hypoglycaemia BNF 78
. do not restart treatment with any SGLT2 inhibitor in
patients who experienced DKA during use, unless
another cause for DKA was identified and resolved
. interrupt SGLT2 inhibitor treatment in patients who
are hospitalised for major surgery or acute serious
illnesses; treatment may be restarted once the
patient’s condition has stabilised
MHRA/CHM ADVICE (UPDATED MARCH 2017): INCREASED RISK OF
LOWER-LIMB AMPUTATION (MAINLY TOES)
Canagliflozin may increase the risk of lower-limb
amputation (mainly toes) in patients with type 2
diabetes. Preventive foot care is important for all
patients with diabetes. The MHRA has issued the
following advice while clinical trials are ongoing:
. consider stopping canagliflozin if a patient develops a
significant lower limb complication (e.g. skin ulcer,
. carefully monitor patients who have risk factors for
amputation (e.g. previous amputations, existing
peripheral vascular disease, or neuropathy)
. monitor all patients for signs and symptoms of water
or salt loss; ensure patients stay sufficiently hydrated
to prevent volume depletion in line with the
manufacturer’s recommendations
. advise patients to stay well hydrated, carry out routine
preventive foot care, and seek medical advice promptly
if they develop skin ulceration, discolouration, or new
. start treatment for foot problems (e.g. ulceration,
infection, or new pain or tenderness) as early as
. continue to follow standard treatment guidelines for
routine preventive foot care for people with diabetes.
MHRA/CHM ADVICE: SGLT2 INHIBITORS: REPORTS OF FOURNIER’S
GANGRENE (NECROTISING FASCIITIS OF THE GENITALIA OR
Fournier’s gangrene, a rare but serious and potentially
life-threatening infection, has been associated with the
use of sodium-glucose co-transporter 2 (SGLT2)
inhibitors. If Fournier’s gangrene is suspected, stop the
SGLT2 inhibitor and urgently start treatment (including
antibiotics and surgical debridement).
Patients should be advised to seek urgent medical
attention if they experience severe pain, tenderness,
erythema, or swelling in the genital or perineal area,
accompanied by fever or malaise—urogenital infection
or perineal abscess may precede necrotising fasciitis.
l CONTRA-INDICATIONS Ketoacidosis
▶ Volume depletion Correct hypovolaemia before starting
l INTERACTIONS → Appendix 1: canagliflozin
▶ Frequency not known Fournier’s gangrene (discontinue
and initiate treatment promptly)
SIDE-EFFECTS, FURTHER INFORMATION Consider
interrupting treatment if volume depletion occurs.
l PREGNANCY Avoid—toxicity in animal studies.
l BREAST FEEDING Avoid—present in milk in animal studies.
l HEPATIC IMPAIRMENT Manufacturer advises avoid in
severe impairment—no information available.
l RENAL IMPAIRMENT Avoid initiation if eGFR less than
Dose adjustments Reduce dose to 100 mg once daily if
eGFR falls persistently below 60 mL/minute/1.73 m2 and
existing canagliflozin treatment tolerated.
Monitoring Monitor renal function at least twice a year in
l MONITORING REQUIREMENTS Determine renal function
before treatment and at least annually thereafter, and
before initiation of concomitant drugs that reduce renal
function and periodically thereafter.
l PATIENT AND CARER ADVICE Patients should be advised to
report symptoms of volume depletion including postural
hypotension and dizziness. Patients should be informed of
the signs and symptoms of diabetic ketoacidosis, see
l NATIONAL FUNDING/ACCESS DECISIONS
▶ Canagliflozin, dapagliflozin and empagliflozin as
monotherapies for treating type 2 diabetes (May 2016)
Canagliflozin (Invokana ®) as monotherapy is
recommended as an option for treating type 2 diabetes in
adults for whom metformin is contra-indicated or not
tolerated and when diet and exercise alone do not provide
sulfonylurea or pioglitazone is not appropriate.
Patients currently receiving canagliflozin whose disease
does not meet the above criteria should be able to
continue treatment until they and their NHS clinician
consider it appropriate to stop.
www.nice.org.uk/guidance/ta390
▶ Canagliflozin in combination therapy for treating type 2
diabetes (June 2014) NICE TA315
Canagliflozin (Invokana ®) in a dual therapy regimen in
combination with metformin is recommended for the
treatment of type 2 diabetes, only if a sulfonylurea is
contra-indicated or not tolerated, or the patient has a
significant risk of hypoglycaemia.
Canagliflozin in a triple therapy regimen is an option for
the treatment of type 2 diabetes in combination with
metformin and a sulfonylurea, or metformin and a
Canagliflozin in combination with insulin (alone or with
other antidiabetic drugs) is an option for the treatment of
Patients currently receiving canagliflozin in a dual or
triple therapy regimen that is not recommended according
to the above criteria should have the option to continue
treatment until they and their NHS clinician consider it
www.nice.org.uk/guidance/ta315
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
▶ Invokana (Napp Pharmaceuticals Ltd)
Canagliflozin (as Canagliflozin hemihydrate) 100 mg Invokana
100mg tablets | 30 tablet P £39.20 DT = £39.20
Canagliflozin (as Canagliflozin hemihydrate) 300 mg Invokana
300mg tablets | 30 tablet P £39.20 DT = £39.20
Canagliflozin with metformin 01-Mar-2019
The properties listed below are those particular to the
combination only. For the properties of the components
please consider, canagliflozin p. 702, metformin
Type 2 diabetes mellitus not controlled by metformin
alone or by metformin in combination with insulin or
▶ Adult: 1 tablet twice daily, dose based on patient’s
current metformin dose, daily dose of metformin
DOSE ADJUSTMENTS DUE TO INTERACTIONS
▶ Dose of concomitant insulin or drugs that stimulate
insulin secretion may need to be reduced.
l INTERACTIONS → Appendix 1: canagliflozin . metformin
l RENAL IMPAIRMENT Avoid if eGFR less than
l NATIONAL FUNDING/ACCESS DECISIONS
Scottish Medicines Consortium (SMC) decisions
The Scottish Medicines Consortium has advised (January
2015) that canagliflozin with metformin (Vokanamet ®) is
accepted for restricted use within NHS Scotland in patients
with type 2 diabetes mellitus for whom a combination of
canagliflozin and metformin is an appropriate choice of
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
CAUTIONARY AND ADVISORY LABELS 21
▶ Vokanamet (Napp Pharmaceuticals Ltd)
Canagliflozin (as Canagliflozin hemihydrate) 50 mg, Metformin
hydrochloride 850 mg Vokanamet 50mg/850mg tablets | 60 tablet P £39.20 DT = £39.20
Canagliflozin (as Canagliflozin hemihydrate) 50 mg, Metformin
hydrochloride 1 gram Vokanamet 50mg/1000mg tablets | 60 tablet P £39.20 DT = £39.20
tubule to reduce glucose reabsorption and increase urinary
Type 2 diabetes mellitus [as monotherapy if metformin
inappropriate]| Type 2 diabetes mellitus [in combination
with insulin or other antidiabetic drugs]
▶ Adult 18–74 years: 10 mg once daily
▶ Adult 75 years and over: Initiation not recommended
Type 1 diabetes mellitus [as an adjunct to insulin in
patients with a BMI greater than or equal to 27 kg/m2
when insulin alone fails to achieve adequate glycaemic
▶ Adult 18–74 years: 5 mg once daily
▶ Adult 75 years and over: Initiation not recommended
DOSE ADJUSTMENTS DUE TO INTERACTIONS
▶ Dose of concomitant insulin or drugs that stimulate
insulin secretion may need to be reduced (risk of
hypoglycaemia)—consult product literature.
MHRA/CHM ADVICE (UPDATED APRIL 2016): RISK OF DIABETIC
KETOACIDOSIS WITH SODIUM-GLUCOSE CO-TRANSPORTER 2
(SGLT2) INHIBITORS (CANAGLIFLOZIN, DAPAGLIFLOZIN OR
A review by the European Medicines Agency has
concluded that serious, life-threatening, and fatal cases
of diabetic ketoacidosis (DKA) have been reported rarely
in patients taking an SGLT2 inhibitor. In several cases,
the presentation of DKA was atypical with patients
having only moderately elevated blood glucose levels,
and some of them occurred during off-label use.
To minimise the risk of such effects when treating
patients with a SGLT2 inhibitor, the European Medicines
Agency has issued the following advice:
. inform patients of the signs and symptoms of DKA,
(including rapid weight loss, nausea or vomiting,
abdominal 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), and
advise them to seek immediate medical advice if they
. test for raised ketones in patients with signs and
symptoms of DKA, even if plasma glucose levels are
. use dapagliflozin with caution in patients with risk
factors for DKA, (including a low beta cell reserve,
conditions leading to restricted food intake or severe
dehydration, sudden reduction in insulin, increased
insulin requirements due to acute illness, surgery or
alcohol abuse), and discuss these risk factors with
. discontinue treatment if DKA is suspected or
. do not restart treatment with any SGLT2 inhibitor in
patients who experienced DKA during use, unless
another cause for DKA was identified and resolved
. interrupt SGLT2 inhibitor treatment in patients who
are hospitalised for major surgery or acute serious
illnesses; treatment may be restarted once the
patient’s condition has stabilised
MHRA/CHM ADVICE: SGLT2 INHIBITORS: REPORTS OF FOURNIER’S
GANGRENE (NECROTISING FASCIITIS OF THE GENITALIA OR
Fournier’s gangrene, a rare but serious and potentially
life-threatening infection, has been associated with the
use of sodium-glucose co-transporter 2 (SGLT2)
inhibitors. If Fournier’s gangrene is suspected, stop the
SGLT2 inhibitor and urgently start treatment (including
antibiotics and surgical debridement).
Patients should be advised to seek urgent medical
attention if they experience severe pain, tenderness,
erythema, or swelling in the genital or perineal area,
accompanied by fever or malaise—urogenital infection
or perineal abscess may precede necrotising fasciitis.
▶ When used for type 1 diabetes mellitus high risk of diabetic
ketoacidosis (consult product literature)
▶ Volume depletion Correct hypovolaemia before starting
l INTERACTIONS → Appendix 1: dapagliflozin
704 Diabetes mellitus and hypoglycaemia BNF 78
insulin or sulfonylurea). increased risk of infection .rash . urinary disorders
▶ Frequency not known Fournier’s gangrene (discontinue
and initiate treatment promptly)
SIDE-EFFECTS, FURTHER INFORMATION Interrupt treatment
l PREGNANCY Avoid—toxicity in animal studies.
l BREAST FEEDING Avoid—present in milk in animal studies.
l HEPATIC IMPAIRMENT Manufacturer advises caution in
severe impairment (risk of increased exposure, limited
▶ When used for Type 2 diabetes mellitus Manufacturer
advises initially 5 mg daily in severe impairment, increased
l RENAL IMPAIRMENT Manufacturer advises avoid initiation
if eGFR less than 60 mL/minute/1.73 m2 (reduced efficacy).
Manufacturer advises avoid if eGFR persistently less than
45 mL/minute/1.73 m2 (reduced efficacy). If eGFR less than
60 mL/minute/1.73 m2 manufacturer advises monitor renal
function at least 2–4 times per year.
▶ Manufacturer advises monitor renal function before
treatment, and at least annually thereafter.
▶ When used for Type 1 diabetes mellitus Manufacturer advises
patients should monitor ketone levels before starting and
during treatment (blood ketone levels are preferred to
urine)—consult product literature.
l PATIENT AND CARER ADVICE Patients should be informed
of the signs and symptoms of diabetic ketoacidosis, see
l NATIONAL FUNDING/ACCESS DECISIONS
▶ Dapagliflozin in combination therapy for treating type 2
diabetes (updated November 2016) NICE TA288
Dapagliflozin (Forxiga ®) in a dual therapy regimen in
combination with metformin is recommended for the
treatment of type 2 diabetes, only if the patient is at
significant risk of hypoglycaemia or its consequences, or if
a sulfonylurea is contra-indicated or not tolerated.
Dapagliflozin in combination with insulin (alone or with
other antidiabetic drugs) is an option for the treatment of
Patients currently receiving dapagliflozin in a dual
therapy regimen that is not recommended according to the
above criteria should have the option to continue
treatment until they and their clinician consider it
www.nice.org.uk/guidance/ta288
▶ Canagliflozin, dapagliflozin and empagliflozin as
monotherapies for treating type 2 diabetes (May 2016)
Dapagliflozin (Forxiga ®) as monotherapy is recommended
as an option for treating type 2 diabetes in adults for
whom metformin is contra-indicated or not tolerated, only
if a dipeptidyl peptidase-4 (DPP-4) inhibitor would
otherwise be prescribed, and a sulfonylurea or
pioglitazone is not appropriate.
Patients currently receiving dapagliflozin whose disease
does not meet the above criteria should be able to
continue treatment until they and their NHS clinician
consider it appropriate to stop.
www.nice.org.uk/guidance/ta390
▶ Dapagliflozin in triple therapy for treating type 2 diabetes
Dapagliflozin (Forxiga ®) in a triple therapy regimen is
recommended as an option for treating type 2 diabetes in
adults, only in combination with metformin and a
Patients currently receiving dapagliflozin in other triple
therapy regimens, whose treatment was started within the
NHS before this guidance was published should have the
option to continue treatment, without change to their
funding arrangements, until they and their NHS clinician
consider it appropriate to stop.
www.nice.org.uk/guidance/ta418
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
▶ Forxiga (AstraZeneca UK Ltd)
Dapagliflozin (as Dapagliflozin propanediol monohydrate)
5 mg Forxiga 5mg tablets | 28 tablet P £36.59 DT = £36.59
Dapagliflozin (as Dapagliflozin propanediol monohydrate)
10 mg Forxiga 10mg tablets | 28 tablet P £36.59 DT = £36.59
Combinations available: Saxagliptin with dapagliflozin, p. 696
Dapagliflozin with metformin 01-Mar-2019
The properties listed below are those particular to the
combination only. For the properties of the components
please consider, dapagliflozin p. 704, metformin
Type 2 diabetes mellitus not controlled by metformin
alone or by metformin in combination with insulin or
▶ Adult 18–74 years: 1 tablet twice daily, based on
patient’s current metformin dose
▶ Adult 75 years and over: Initiation not recommended
l INTERACTIONS → Appendix 1: dapagliflozin . metformin
l HEPATIC IMPAIRMENT Manufacturer advises avoid
(increased risk of lactic acidosis).
l NATIONAL FUNDING/ACCESS DECISIONS
Scottish Medicines Consortium (SMC) decisions
The Scottish Medicines Consortium has advised (August
2014) that dapagliflozin plus metformin (Xigduo ®) is
accepted for restricted use within NHS Scotland in patients
for whom a combination of dapagliflozin and metformin is
an appropriate choice of therapy i.e when metformin alone
does not provide adequate glycaemic control and a
sulfonylurea is inappropriate, or in combination with
insulin, when insulin and metformin does not provide
adequate control, or in combination with a sulphonylurea,
when a sulfonylurea and metformin does not provide
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
CAUTIONARY AND ADVISORY LABELS 21
Dapagliflozin (as Dapagliflozin propanediol monohydrate) 5 mg,
Metformin hydrochloride 850 mg Xigduo 5mg/850mg tablets | 56 tablet P £36.59 DT = £36.59
Dapagliflozin (as Dapagliflozin propanediol monohydrate) 5 mg,
Metformin hydrochloride 1 gram Xigduo 5mg/1000mg tablets | 56 tablet P £36.59 DT = £36.59
tubule to reduce glucose reabsorption and increase urinary
Type 2 diabetes mellitus as monotherapy (if metformin
inappropriate)| Type 2 diabetes mellitus in combination
with insulin or other antidiabetic drugs (if existing
treatment fails to achieve adequate glycaemic control)
▶ Adult 18–84 years: 10 mg once daily, increased to 25 mg
once daily if necessary and if tolerated
▶ Adult 85 years and over: Initiation not recommended
DOSE ADJUSTMENTS DUE TO INTERACTIONS
▶ Dose of concomitant insulin or drugs that stimulate
insulin secretion may need to be reduced.
MHRA/CHM ADVICE (UPDATED APRIL 2016): RISK OF DIABETIC
KETOACIDOSIS WITH SODIUM-GLUCOSE CO-TRANSPORTER 2
(SGLT2) INHIBITORS (CANAGLIFLOZIN, DAPAGLIFLOZIN OR
A review by the European Medicines Agency has
concluded that serious, life-threatening, and fatal cases
of diabetic ketoacidosis (DKA) have been reported rarely
in patients taking an SGLT2 inhibitor. In several cases,
the presentation of DKA was atypical with patients
having only moderately elevated blood glucose levels,
and some of them occurred during off-label use.
To minimise the risk of such effects when treating
patients with a SGLT2 inhibitor, the European Medicines
Agency has issued the following advice:
. inform patients of the signs and symptoms of DKA,
(including rapid weight loss, nausea or vomiting,
abdominal 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), and
advise them to seek immediate medical advice if they
. test for raised ketones in patients with signs and
symptoms of DKA, even if plasma glucose levels are
. use empagliflozin with caution in patients with risk
factors for DKA, (including a low beta cell reserve,
conditions leading to restricted food intake or severe
dehydration, sudden reduction in insulin, increased
insulin requirements due to acute illness, surgery or
alcohol abuse), and discuss these risk factors with
. discontinue treatment if DKA is suspected or
. do not restart treatment with any SGLT2 inhibitor in
patients who experienced DKA during use, unless
another cause for DKA was identified and resolved
. interrupt SGLT2 inhibitor treatment in patients who
are hospitalised for major surgery or acute serious
illnesses; treatment may be restarted once the
patient’s condition has stabilised
MHRA/CHM ADVICE: SGLT2 INHIBITORS: REPORTS OF FOURNIER’S
GANGRENE (NECROTISING FASCIITIS OF THE GENITALIA OR
Fournier’s gangrene, a rare but serious and potentially
life-threatening infection, has been associated with the
use of sodium-glucose co-transporter 2 (SGLT2)
inhibitors. If Fournier’s gangrene is suspected, stop the
SGLT2 inhibitor and urgently start treatment (including
antibiotics and surgical debridement).
Patients should be advised to seek urgent medical
attention if they experience severe pain, tenderness,
erythema, or swelling in the genital or perineal area,
accompanied by fever or malaise—urogenital infection
or perineal abscess may precede necrotising fasciitis.
l CONTRA-INDICATIONS Diabetic ketoacidosis
l CAUTIONS Cardiovascular disease (increased risk of
volume depletion). complicated urinary tract infections—
consider temporarily interrupting treatment. concomitant
antihypertensive therapy (increased risk of volume
depletion). elderly patients aged over 75 years (increased
risk of volume depletion). heart failure . history of
hypotension (increased risk of volume depletion). patients
at increased risk of volume depletion . predisposition to
fluid disturbances e.g. gastro-intestinal illness,
concomitant use of diuretics (increased risk of volume
▶ Volume depletion Correct hypovolaemia before starting
treatment. Consider interrupting treatment if volume
l INTERACTIONS → Appendix 1: empagliflozin
▶ Common or very common Balanoposthitis . hypoglycaemia
(in combination with insulin or sulfonylurea). increased
risk of infection . pruritus generalised .thirst. urinary
▶ Rare or very rare Diabetic ketoacidosis (discontinue
▶ Frequency not known Fournier’s gangrene (discontinue
and initiate treatment promptly)
l PREGNANCY Manufacturer advises avoid—toxicity in
l BREAST FEEDING Manufacturer advises avoid—present in
l HEPATIC IMPAIRMENT Manufacturer advises avoid in
severe impairment—no information available.
l RENAL IMPAIRMENT Avoid initiation if eGFR below
. Avoid if eGFR is persistently below
Dose adjustments Reduce dose to 10 mg once daily if eGFR
falls persistently below 60 mL/minute/1.73 m2
l MONITORING REQUIREMENTS Determine renal function
before treatment and before initiation of concomitant
drugs that may reduce renal function, then at least
l PATIENT AND CARER ADVICE Patients should be informed
of the signs and symptoms of diabetic ketoacidosis, see
l NATIONAL FUNDING/ACCESS DECISIONS
▶ Canagliflozin, dapagliflozin and empagliflozin as
monotherapies for treating type 2 diabetes (May 2016)
Empagliflozin (Jardiance ®) as monotherapy is
recommended as an option for treating type 2 diabetes in
adults for whom metformin is contra-indicated or not
tolerated and when diet and exercise alone do not provide
sulfonylurea or pioglitazone is not appropriate.
Patients currently receiving empagliflozin whose disease
does not meet the above criteria should be able to
continue treatment until they and their NHS clinician
consider it appropriate to stop.
www.nice.org.uk/guidance/ta390
706 Diabetes mellitus and hypoglycaemia BNF 78
▶ Empagliflozin in combination therapy for treating type 2
diabetes (March 2015) NICE TA336
Empagliflozin (Jardiance ®) in a dual therapy regimen in
combination with metformin is an option for the
treatment of type 2 diabetes, only if:
. a sulfonylurea is contra-indicated or not tolerated, or
. the patient is at significant risk of hypoglycaemia or its
Empagliflozin in a triple therapy regimen is an option for
the treatment of type 2 diabetes in combination with:
. metformin and a sulfonylurea, or
. metformin and a thiazolidinedione.
Empagliflozin in combination with insulin with or without
other antidiabetic drugs is an option for the treatment of
Patients currently receiving empagliflozin whose disease
does not meet the above criteria should have the option to
continue treatment until they and their NHS clinician
consider it appropriate to stop.
www.nice.org.uk/guidance/ta336
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
▶ Jardiance (Boehringer Ingelheim Ltd) A
Empagliflozin 10 mg Jardiance 10mg tablets | 28 tablet P £36.59 DT = £36.59
Empagliflozin 25 mg Jardiance 25mg tablets | 28 tablet P £36.59 DT = £36.59
Empagliflozin with metformin 01-Mar-2019
The properties listed below are those particular to the
combination only. For the properties of the components
please consider, empagliflozin p. 706, metformin
Type 2 diabetes mellitus not controlled by metformin
alone or by metformin in combination with other
▶ Adult 18–84 years: 5/850–5/1000 mg twice daily, based
on patient’s current metformin dose, increased if
necessary to 12.5/850–12.5/1000 mg twice daily
▶ Adult 85 years and over: Initiation not recommended
DOSE ADJUSTMENTS DUE TO INTERACTIONS
▶ Dose of concomitant insulin or drugs that stimulate
insulin secretion may need to be reduced.
DOSE EQUIVALENCE AND CONVERSION
▶ The proportions are expressed in the form "x"/"y"
where "x" and "y" are the strengths in milligrams of
empagliflozin and metformin respectively.
l INTERACTIONS → Appendix 1: empagliflozin . metformin
l NATIONAL FUNDING/ACCESS DECISIONS
Scottish Medicines Consortium (SMC) decisions
The Scottish Medicines Consortium has advised (October
2015) that empagliflozin with metformin (Synjardy ®) is
accepted for restricted use within NHS Scotland in patients
for whom a fixed dose combination of empagliflozin and
metformin is an appropriate choice of therapy, or when
use of a sulfonylurea is considered inappropriate.
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
CAUTIONARY AND ADVISORY LABELS 21
▶ Synjardy (Boehringer Ingelheim Ltd) A
Empagliflozin 12.5 mg, Metformin hydrochloride
850 mg Synjardy 12.5mg/850mg tablets | 56 tablet P £36.59 DT
Empagliflozin 5 mg, Metformin hydrochloride 850 mg Synjardy
5mg/850mg tablets | 56 tablet P £36.59 DT = £36.59
Empagliflozin 12.5 mg, Metformin hydrochloride 1 gram Synjardy
12.5mg/1000mg tablets | 56 tablet P £36.59 DT = £36.59
Empagliflozin 5 mg, Metformin hydrochloride 1 gram Synjardy
5mg/1000mg tablets | 56 tablet P £36.59 DT = £36.59
tubule to reduce glucose reabsorption and increase urinary
Type 2 diabetes mellitus as monotherapy (if metformin
inappropriate)| Type 2 diabetes mellitus in combination
with insulin or other antidiabetic drugs (if existing
treatment fails to achieve adequate glycaemic control)
▶ Adult: 5 mg once daily; increased to 15 mg once daily if
necessary and if tolerated, dose to be taken in the
DOSE ADJUSTMENTS DUE TO INTERACTIONS
▶ Manufacturer advises dose of concomitant insulin or
drugs that stimulate insulin secretion may need to be
MHRA/CHM ADVICE (UPDATED APRIL 2016): RISK OF DIABETIC
KETOACIDOSIS WITH SODIUM-GLUCOSE CO-TRANSPORTER 2
A review by the European Medicines Agency has
concluded that serious, life-threatening, and fatal cases
of diabetic ketoacidosis (DKA) have been reported rarely
in patients taking an SGLT2 inhibitor. In several cases,
the presentation of DKA was atypical with patients
having only moderately elevated blood glucose levels,
and some of them occurred during off-label use.
To minimise the risk of such effects when treating
patients with a SGLT2 inhibitor, the European Medicines
Agency has issued the following advice:
. inform patients of the signs and symptoms of DKA,
(including rapid weight loss, nausea or vomiting,
abdominal 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), and
advise them to seek immediate medical advice if they
. test for raised ketones in patients with signs and
symptoms of DKA, even if plasma glucose levels are
. use empagliflozin with caution in patients with risk
factors for DKA, (including a low beta cell reserve,
conditions leading to restricted food intake or severe
dehydration, sudden reduction in insulin, increased
insulin requirements due to acute illness, surgery or
alcohol abuse), and discuss these risk factors with
. discontinue treatment if DKA is suspected or
. do not restart treatment with any SGLT2 inhibitor in
patients who experienced DKA during use, unless
another cause for DKA was identified and resolved
. interrupt SGLT2 inhibitor treatment in patients who
are hospitalised for major surgery or acute serious
illnesses; treatment may be restarted once the
patient’s condition has stabilised
MHRA/CHM ADVICE: SGLT2 INHIBITORS: REPORTS OF FOURNIER’S
GANGRENE (NECROTISING FASCIITIS OF THE GENITALIA OR
Fournier’s gangrene, a rare but serious and potentially
life-threatening infection, has been associated with the
use of sodium-glucose co-transporter 2 (SGLT2)
inhibitors. If Fournier’s gangrene is suspected, stop the
SGLT2 inhibitor and urgently start treatment (including
antibiotics and surgical debridement).
Patients should be advised to seek urgent medical
attention if they experience severe pain, tenderness,
erythema, or swelling in the genital or perineal area,
accompanied by fever or malaise—urogenital infection
or perineal abscess may precede necrotising fasciitis.
l CONTRA-INDICATIONS Diabetic ketoacidosis
▶ Volume depletion Manufacturer advises correct
hypovolaemia before starting treatment—consider
interrupting treatment if volume depletion occurs.
l INTERACTIONS → Appendix 1: ertugliflozin
▶ Common or very common Hypoglycaemia (in combination
with insulin or sulfonylurea). hypovolaemia . increased
risk of infection . polydipsia .thirst. urinary disorders . vulvovaginal pruritus
▶ Rare or very rare Diabetic ketoacidosis (discontinue
▶ Frequency not known Fournier’s gangrene (discontinue
and initiate treatment promptly). lower limb amputations . phimosis
SIDE-EFFECTS, FURTHER INFORMATION Consider
interrupting treatment if volume depletion occurs.
l PREGNANCY Manufacturer advises avoid—toxicity in
l BREAST FEEDING Manufacturer advises avoid—present in
l HEPATIC IMPAIRMENT Manufacturer advises avoid in
severe impairment (no information available).
l RENAL IMPAIRMENT Manufacturer advises avoid initiation
if eGFR less than 60 mL/minute/1.73 m2
advises frequent monitoring of renal function required if
eGFR less than 60 mL/minute/1.73 m2
advises avoid if eGFR is persistently less than
▶ Manufacturer advises to determine renal function before
treatment and periodically thereafter.
▶ Manufacturer advises monitor volume status and
electrolytes during treatment in patients at risk of volume
l PATIENT AND CARER ADVICE Manufacturer advises that
patients should be informed of the signs and symptoms of
diabetic ketoacidosis, see MHRA advice.
l NATIONAL FUNDING/ACCESS DECISIONS
▶ Ertugliflozin as monotherapy or with metformin for treating
type 2 diabetes (March 2019) NICE TA572
Ertugliflozin (Steglatro ®) as monotherapy is recommended
as an option for treating type 2 diabetes in adults for
whom metformin is contra-indicated or not tolerated and
when diet and exercise alone do not provide adequate
. a dipeptidyl peptidase-4 (DPP-4) inhibitor would
. a sulfonylurea or pioglitazone is not appropriate.
Ertugliflozin (Steglatro ®) in a dual-therapy regimen in
combination with metformin is recommended as an option
for treating type 2 diabetes, only if:
. a sulfonylurea is contra-indicated or not tolerated, or
. the person is at significant risk of hypoglycaemia or its
Patients whose treatment was started within the NHS
before this guidance was published should have the option
to continue treatment, without change to their funding
arrangements, until they and their NHS clinician consider
www.nice.org.uk/guidance/ta572
Scottish Medicines Consortium (SMC) decisions
The Scottish Medicines Consortium has advised (January
2019) that ertugliflozin (Steglatro ®) is accepted for
restricted use within NHS Scotland for the treatment of
type 2 diabetes as monotherapy, in patients who would
otherwise receive a dipeptidyl peptidase-4 inhibitor and in
whom a sulphonylurea or pioglitazone is not appropriate,
l MEDICINAL FORMS There can be variation in the licensing of
different medicines containing the same drug.
▶ Steglatro (Merck Sharp & Dohme Ltd) A
Ertugliflozin (as Ertugliflozin L-pyroglutamic acid) 5 mg Steglatro
5mg tablets | 28 tablet P £29.40
Ertugliflozin (as Ertugliflozin L-pyroglutamic acid)
15 mg Steglatro 15mg tablets | 28 tablet P £29.40
BLOOD GLUCOSE LOWERING DRUGS ›
l DRUG ACTION The sulfonylureas act mainly by augmenting
insulin secretion and consequently are effective only when
some residual pancreatic beta-cell activity is present;
during long-term administration they also have an
l CONTRA-INDICATIONS Presence of ketoacidosis
l CAUTIONS Can encourage weight gain (should be
prescribed only if poor control and symptoms persist
despite adequate attempts at dieting). elderly .G6PD
▶ Common or very common Abdominal pain . diarrhoea . hypoglycaemia . nausea
▶ Uncommon Hepatic disorders . vomiting
▶ Frequency not known Allergic dermatitis (usually in the
first 6–8 weeks of therapy). constipation . visual
l HEPATIC IMPAIRMENT Jaundice may occur.
Dose adjustments Sulfonylureas should be avoided or a
reduced dose should be used in severe hepatic impairment,
because there is an increased risk of hypoglycaemia.
l RENAL IMPAIRMENT Sulfonylureas should be used with
care in those with mild to moderate renal impairment,
because of the hazard of hypoglycaemia. Care is required
to use the lowest dose that adequately controls blood
glucose. Avoid where possible in severe renal impairment.
l PATIENT AND CARER ADVICE The risk of hypoglycaemia
associated with sulfonylureas should be discussed with the
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