4.1. Therapeutic indications

Qtern, fixed dose combination of saxagliptin and dapagliflozin, is indicated in adults aged 18 years and older with type 2 diabetes mellitus:

• to improve glycaemic control when metformin and/or sulphonylurea (SU) and one of the monocomponents of Qtern do not provide adequate glycaemic control,

• when already being treated with the free combination of dapagliflozin and saxagliptin.

(See sections 4.2, 4.4, 4.5 and 5.1 for available data on combinations studied).

4.2. Posology and method of administration

Posology

The recommended dose is one 5 mg saxagliptin/10 mg dapagliflozin tablet once daily (see sections 4.5 and 4.8).

Missed dose

If a dose is missed and it is ≥ 12 hours until the next dose, the dose should be taken. If a dose is missed and it is < 12 hours until the next dose, the missed dose should be skipped and the next dose taken at the usual time.

Special populations

Renal impairment

Qtern should not be initiated in patients with a glomerular filtration rate (GFR) < 60 mL/min and should be discontinued at GFR persistently below 45 mL/min. It should also not be used in patients with end-stage renal disease (ESRD) (see sections 4.4, 4.8, 5.1 and 5.2).

No dose adjustment is recommended based on renal function.

Hepatic impairment

This medicinal product can be used in patients with mild or moderate hepatic impairment. Patients with moderate hepatic impairment should be evaluated prior to initiation and during treatment.

It is not recommended for use in patients with severe hepatic impairment (see section 4.4).

Elderly (≥ 65 years)

No dose adjustment is recommended based on age. Renal function and risk of volume depletion should be taken into account (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of this medicinal product in children and adolescents aged 0 to < 18 years have not yet been established. No data are available.

Method of administration

Qtern is taken orally once daily. It may be taken at any time of day with or without food. Tablet is to be swallowed whole.

4.3. Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or history of a serious hypersensitivity reaction, including anaphylactic reaction, anaphylactic shock, and angioedema, to any dipeptidyl peptidase-4 (DPP-4) inhibitor or to any sodium-glucose co-transporter 2 (SGLT2) inhibitor (see sections 4.4, 4.8 and 6.1).

4.4. Special warnings and precautions for use

Acute pancreatitis

Use of DPP-4 inhibitors has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptoms of acute pancreatitis; persistent, severe abdominal pain. If pancreatitis is suspected, this medicinal product should be discontinued; if acute pancreatitis is confirmed, it should not be restarted. Caution should be exercised in patients with a history of pancreatitis.

In post-marketing experience of saxagliptin, there have been spontaneously reported adverse reactions of acute pancreatitis (see section 4.8).

Renal impairment

The glycaemic efficacy of dapagliflozin is dependent on renal function, and efficacy is reduced in patients who have moderate renal impairment and likely absent in patients with severe renal impairment (see section 4.2). In subjects with moderate renal impairment (GFR < 60 mL/min), a higher proportion of subjects treated with dapagliflozin had adverse reactions of increase in creatinine, phosphorus, parathyroid hormone (PTH) and hypotension, compared with placebo. This medicinal product should not be initiated in patients with a GFR < 60 mL/min and should be discontinued at GFR persistently below 45 mL/min. The saxagliptin/dapagliflozin fixed dose combination has not been studied in severe renal impairment (GFR < 30 mL/min) or end-stage renal disease (ESRD).

Monitoring of renal function is recommended as follows:

• Prior to initiation of this medicinal product and at least yearly, thereafter (see sections 4.2, 4.8, 5.1 and 5.2).

• Prior to initiation of concomitant medicinal products that may reduce renal function and periodically thereafter.

• For renal function approaching moderate renal impairment, at least 2 to 4 times per year. If renal function persistently falls below GFR < 45 mL/min, treatment with this medicinal product should be discontinued.

Use in patients at risk for volume depletion and/or hypotension

Due to dapagliflozin's mechanism of action, this medicinal product increases diuresis which may lead to the modest decrease in blood pressure observed in clinical studies (see section 5.1). It may be more pronounced in patients with very high blood glucose concentrations.

Caution should be exercised in patients for whom a dapagliflozin-induced drop in blood pressure could pose a risk, such as patients on anti-hypertensive therapy with a history of hypotension or elderly patients.

In case of intercurrent conditions that may lead to volume depletion (e.g. gastrointestinal illness), careful monitoring of volume status (e.g. physical examination, blood pressure measurements, laboratory tests including haematocrit and electrolytes) is recommended. Temporary interruption of treatment with this medicinal product is recommended for patients who develop volume depletion until the depletion is corrected (see section 4.8).

Use in patients with hepatic impairment

There is limited experience in clinical trials in patients with hepatic impairment. Dapagliflozin and saxagliptin exposure is increased in patients with severe hepatic impairment (see sections 4.2 and 5.2).

The saxagliptin/dapagliflozin fixed dose combination can be used in patients with mild or moderate hepatic impairment. Patients with moderate hepatic impairment should be evaluated prior to initiation and during treatment. This medicinal product is not recommended for use in patients with severe hepatic impairment (see section 4.2).

Diabetic ketoacidosis

Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have been reported in patients treated with SGLT2 inhibitors, including dapagliflozin. In a number of cases, the presentation of the condition was atypical with only moderately increased blood glucose values, below 14 mmol/litres (250 mg/dL). It is not known if DKA is more likely to occur with higher doses of dapagliflozin.

The risk of diabetic ketoacidosis 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 ketoacidosis immediately if these symptoms occur, regardless of blood glucose level.

In patients where DKA is suspected or diagnosed, treatment with this medicinal product should be discontinued immediately.

Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses. Monitoring of ketones is recommended in these patients. Measurement of blood ketone levels is preferred to urine. Treatment with dapagliflozin may be restarted when the ketone values are normal and the patient's condition has stabilised.

Before initiating treatment with this medicinal product, factors in the patient history that may predispose to ketoacidosis should be considered.

Patients who may be at higher risk of DKA include patients with a low beta-cell function reserve (e.g. type 2 diabetes patients with low C-peptide or latent autoimmune diabetes in adults (LADA) or patients with a history of pancreatitis), patients with conditions that lead to restricted food intake or severe dehydration, patients for whom insulin doses are reduced and patients with increased insulin requirements due to acute medical illness, surgery or alcohol abuse. SGLT2 inhibitors should be used with caution in these patients.

Restarting SGLT2 inhibitor treatment in patients with previous DKA while on SGLT2 inhibitor treatment is not recommended, unless another clear precipitating factor is identified and resolved.

The safety and efficacy of the saxagliptin/dapagliflozin fixed dose combination in patients with type 1 diabetes have not been established and it should not be used for treatment of patients with type 1 diabetes. In type 1 diabetes mellitus studies with dapagliflozin, DKA was reported with common frequency.

Necrotising fasciitis of the perineum (Fournier's gangrene)

Post-marketing cases of necrotising fasciitis of the perineum (also known as Fournier's gangrene) have been reported in female and male patients taking SGLT2 inhibitors (see section 4.8). This is a rare but serious and potentially life-threatening event that requires urgent surgical intervention and antibiotic treatment.

Patients should be advised to seek medical attention if they experience a combination of symptoms of pain, tenderness, erythema, or swelling in the genital or perineal area, with fever or malaise. Be aware that either uro-genital infection or perineal abscess may precede necrotising fasciitis. If Fournier's gangrene is suspected, Qtern should be discontinued and prompt treatment (including antibiotics and surgical debridement) should be instituted.

Hypersensitivity reactions

This medicinal product must not be used in patients who have had any serious hypersensitivity reaction to a DPP-4 inhibitor or a SGLT2 inhibitor (see section 4.3).

During post-marketing experience with saxagliptin, including spontaneous reports and clinical trials, the following adverse reactions have been reported with the use of saxagliptin: serious hypersensitivity reactions, including anaphylactic reaction, anaphylactic shock, and angioedema.

This medicinal product should be discontinued if a serious hypersensitivity reaction is suspected. The event should be assessed and alternative treatment for diabetes should be instituted (see section 4.8).

Urinary tract infections

Urinary glucose excretion may be associated with an increased risk of urinary tract infection; therefore, temporary interruption of this medicinal product should be considered when treating pyelonephritis or urosepsis

Elderly (≥ 65 years)

Elderly patients may be at a greater risk for volume depletion and are more likely to be treated with diuretics.

Elderly patients are more likely to have impaired renal function, and/or to be treated with anti-hypertensive medicinal products that may cause changes in renal function such as angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II type 1 receptor blockers (ARB). The same recommendations for monitoring of renal function apply to elderly patients as to all patients (see sections 4.2, 4.4, 4.8, and 5.1).

Therapeutic experience with this medicinal product in patients 65 years and older is limited, and very limited in patients 75 years and older.

Skin disorders

Ulcerative and necrotic skin lesions have been reported in extremities of monkeys in non clinical toxicology studies with saxagliptin (see section 5.3). Skin lesions were not observed at an increased incidence in saxagliptin clinical trials. Post-marketing reports of rash have been described in the DPP-4 inhibitor class. Rash is also noted as an adverse reaction for this medicinal product (see section 4.8).

Therefore, in keeping with routine care of the diabetic patient, monitoring for skin disorders, such as blistering, ulceration or rash, is recommended.

Bullous pemphigoid

Post-marketing cases of bullous pemphigoid requiring hospitalisation have been reported with DPP-4 inhibitor use, including saxagliptin. In reported cases, patients typically responded to topical or systemic immunosuppressive treatment and discontinuation of the DPP4 inhibitor. If a patient develops blisters or erosions while receiving saxagliptin and bullous pemphigoid is suspected, this medicinal product should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment (see section 4.8).

Cardiac failure

There is no experience in clinical trials with dapagliflozin in NYHA class IV. Experience in NYHA class III-IV is limited with saxagliptin.

In the SAVOR trial, a small increase in the rate for hospitalisation for heart failure was observed in the saxagliptin-treated patients compared to placebo, although a causal relationship has not been established (see section 5.1). Additional analysis did not indicate a differential effect among NYHA classes.

Caution is warranted if the saxagliptin/dapagliflozin fixed dose combination is used in patients who have known risk factors for hospitalisation for heart failure, such as a history of heart failure or moderate to severe renal impairment. Patients should be advised of the characteristic symptoms of heart failure, and to immediately report such symptoms.

Arthralgia

Joint pain, which may be severe, has been reported in post-marketing reports for DPP-4 inhibitors (see section 4.8). Patients experienced relief of symptoms after discontinuation of the medicinal product and some experienced recurrence of symptoms with reintroduction of the same or another DPP-4 inhibitor. Onset of symptoms following initiation of therapy may be rapid or may occur after longer periods of treatment. If a patient presents with severe joint pain, continuation of therapy should be individually assessed.

Immunocompromised patients

Immunocompromised patients, such as patients who have undergone organ transplantation or patients diagnosed with human immunodeficiency syndrome have not been studied in the saxagliptin clinical programme. The efficacy and safety profile of the saxagliptin/dapagliflozin fixed dose combination in these patients has not been established.

Increased haematocrit

Increased haematocrit has been observed with dapagliflozin treatment (see section 4.8). Patients with pronounced elevations in haematocrit should be monitored and investigated for underlying haematological disease.

Lower limb amputations

An increase in cases of lower limb amputation (primarily of the toe) has been observed in ongoing long-term, clinical studies with another SGLT2 inhibitor. It is unknown whether this constitutes a class effect. Like for all diabetic patients it is important to counsel patients on routine preventative foot care.

Use with medicinal products known to cause hypoglycaemia

Both saxagliptin and dapagliflozin can individually increase the risk of hypoglycaemia when combined with an insulin secretagogue. If this medicinal product is used in combination with insulin secretagogue (sulphonylurea), a reduction in the dose of sulphonylurea may be required to minimise the risk of hypoglycaemia (see section 4.8).

Urine laboratory assessments

Due to the mechanism of action of dapagliflozin, patients taking this medicinal product will test positive for glucose in their urine.

Use with potent CYP3A4 inducers

Using CYP3A4 inducers like carbamazepine, dexamethasone, phenobarbital, phenytoin, and rifampicin may reduce the glycaemic lowering effect of this medicinal product. Glycaemic control should be assessed when it is used concomitantly with a potent CYP3A4/5 inducer (see section 4.5).

Lactose

The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

Diuretics

Dapagliflozin may add to the diuretic effect of thiazide and loop diuretics and may increase the risk of dehydration and hypotension (see section 4.4).

Use with medicinal products known to cause hypoglycaemia

If this medicinal product is used in combination with insulin secretagogue (sulphonylurea), a reduction in the dose of sulphonylurea may be required to minimise the risk of hypoglycaemia (see section 4.4).

Pharmacokinetic interactions

Saxagliptin: The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5).

Dapagliflozin: The metabolism of dapagliflozin is primarily via glucuronide conjugation mediated by UDP glucuronosyltransferase 1A9 (UGT1A9).

Interactions with other oral anti-diabetic or cardiovascular medicinal products

Saxagliptin: Saxagliptin did not meaningfully alter the pharmacokinetics of dapagliflozin, metformin, glibenclamide, pioglitazone, digoxin, diltiazem or simvastatin. These medicinal products did not alter the pharmacokinetics of saxagliptin or its major active metabolite.

Dapagliflozin: Dapagliflozin did not meaningfully alter the pharmacokinetics of saxagliptin, metformin, pioglitazone, sitagliptin, glimepiride, voglibose, hydrochlorothiazide, bumetanide, valsartan, or simvastatin. These medicinal products did not alter the pharmacokinetics of dapagliflozin.

Effect of other medicinal products on saxagliptin or dapagliflozin

Saxagliptin: Concomitant administration of saxagliptin with the moderate inhibitor of CYP3A4/5 diltiazem, increased the Cmax and AUC of saxagliptin by 63% and 2.1-fold, respectively, and the corresponding values for the active metabolite were decreased by 44% and 34%, respectively. These pharmacokinetic effects are not clinically meaningful and do not require dose adjustment.

Concomitant administration of saxagliptin with the potent inhibitor of CYP3A4/5 ketoconazole, increased the Cmax and AUC of saxagliptin by 62% and 2.5-fold, respectively, and the corresponding values for the active metabolite were decreased by 95% and 88%, respectively. These pharmacokinetic effects are not clinically meaningful and do not require dose adjustment.

Concomitant administration of saxagliptin with the potent CYP3A4/5 inducer rifampicin reduced Cmax and AUC of saxagliptin by 53% and 76%, respectively. The exposure of the active metabolite and the plasma DPP-4 activity inhibition over a dose interval were not influenced by rifampicin (see section 4.4).

The coadministration of saxagliptin and CYP3A4/5 inducers, other than rifampicin (such as carbamazepine, dexamethasone, phenobarbital and phenytoin) has not been studied and may result in decreased plasma concentration of saxagliptin and increased concentration of its major metabolite.

Glycaemic control should be carefully assessed when saxagliptin is used concomitantly with a potent CYP3A4/5 inducer.

In studies conducted in healthy subjects, neither the pharmacokinetics of saxagliptin nor its major metabolite were meaningfully altered by metformin, glibenclamide, pioglitazone, digoxin, simvastatin, omeprazole, antacids or famotidine.

Dapagliflozin: Following coadministration of dapagliflozin with rifampicin (an inducer of various active transporters and drug-metabolising enzymes) a 22% decrease in dapagliflozin systemic exposure (AUC) was observed, but with no clinically meaningful effect on 24-hour urinary glucose excretion. No dose adjustment is recommended. A clinically relevant effect with other inducers (e.g. carbamazepine, phenytoin, phenobarbital) is not expected.

Following coadministration of dapagliflozin with mefenamic acid (an inhibitor of UGT1A9), a 55% increase in dapagliflozin systemic exposure was seen, but with no clinically meaningful effect on 24-hour urinary glucose excretion.

Effect of saxagliptin or dapagliflozin on other medicinal products

Saxagliptin: Saxagliptin did not meaningfully alter the pharmacokinetics of metformin, glibenclamide (a CYP2C9 substrate), pioglitazone [a CYP2C8 (major) and CYP3A4 (minor) substrate], digoxin (a P-gp substrate), simvastatin (a CYP3A4 substrate), the active components of a combined oral contraceptive (ethinylestradiol and norgestimate), diltiazem or ketoconazole.

Dapagliflozin: In interaction studies conducted in healthy subjects, using mainly a single-dose design, dapagliflozin did not alter the pharmacokinetics of metformin, pioglitazone [a CYP2C8 (major) and CYP3A4 (minor) substrate], sitagliptin, glimepiride (a CYP2C9 substrate), hydrochlorothiazide, bumetanide, valsartan, digoxin (a P-gp substrate) or warfarin (S-warfarin, a CYP2C9 substrate), or the anticoagulatory effects of warfarin as measured by INR. Combination of a single dose of dapagliflozin 20 mg and simvastatin (a CYP3A4 substrate) resulted in a 19% increase in AUC of simvastatin and 31% increase in AUC of simvastatin acid. The increase in simvastatin and simvastatin acid exposures are not considered clinically relevant.

Interference with 1,5-anhydroglucitol (1,5-AG) assay

Monitoring glycaemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycaemic control in patients taking SGLT2 inhibitors. Use of alternative methods to monitor glycaemic control is advised.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of saxagliptin and dapagliflozin in pregnant women. Studies in animals with saxagliptin have shown reproductive toxicity at high doses (see section 5.3). Studies with dapagliflozin in rats have shown toxicity to the developing kidney in the time period corresponding to the second and third trimesters of human pregnancy (see section 5.3). Therefore, Qtern should not be used during pregnancy. If pregnancy is detected, treatment with Qtern should be discontinued.

Breast-feeding

It is unknown whether saxagliptin and dapagliflozin and/or its metabolites are excreted in human milk.

Animal studies have shown excretion of saxagliptin and/or metabolite in milk. Available pharmacodynamic/toxicological data in animals have shown excretion of dapagliflozin/metabolites in milk, as well as pharmacologically-mediated effects in breast-feeding offspring (see section 5.3). A risk to the newborns/infants cannot be excluded. Qtern should not be used while breast-feeding.

Fertility

The effect of saxagliptin and dapagliflozin on fertility in humans has not been studied. In male and female rats, dapagliflozin showed no effects on fertility at any dose tested. Effects on fertility were observed using saxagliptin in male and female rats at high doses producing overt signs of toxicity (see section 5.3).

4.7. Effects on ability to drive and use machines

Qtern has no or negligible influence on the ability to drive and use machines. When driving or using machines, it should be taken into account that dizziness has been reported in studies with combined use of saxagliptin and dapagliflozin. In addition, patients should be alerted to the risk of hypoglycaemia if used in combination with other antidiabetic medicinal products known to cause hypoglycaemia (e.g. sulphonylureas).

4.8. Undesirable effects

Summary of the safety profile of saxagliptin plus dapagliflozin

The combination of saxagliptin 5 mg and dapagliflozin 10 mg in 1 169 adults with type 2 diabetes mellitus (T2DM) and inadequate glycaemic control on metformin has been evaluated in three phase 3, randomised, double-blind, active/placebo-control, parallel group, multi-centre clinical trials for up to 52 weeks (see section 5.1). The pooled safety analysis comprised 3 treatment groups: saxagliptin plus dapagliflozin plus metformin (492 subjects), saxagliptin plus metformin (336 subjects), and dapagliflozin plus metformin (341 subjects). The safety profile of the combined use of saxagliptin plus dapagliflozin plus metformin was comparable to the adverse reactions identified for the respective mono-components.

The most frequently reported adverse reactions associated with Qtern are upper respiratory tract infections (very common), hypoglycaemia when used with SU (very common), and urinary tract infections (common). Diabetic ketoacidosis may occur rarely (see section 4.4).

Tabulated list of adverse reactions

The adverse reactions are presented in table 1. The safety profile is based on the summarised data from the saxagliptin/dapagliflozin combination clinical trials pooled safety data, and also clinical trials, post-authorisation safety studies and post-marketing experience with the mono-components. The adverse reactions are listed by system organ class (SOC) and frequency. Frequency categories were defined according to very common (≥ 1/10), common (≥ 1/ 100 to < 1/ 10), uncommon (≥ 1/1 000 to < 1/100), rare (1/10 000 to < 1/1 000), very rare (< 1/10 000), and not known (cannot be estimated from the available data).

Table 1. Compilation of reported adverse reactions

System organ class

Very common

CommonA

UncommonB

Rare

Very Rare

Not Known

Infections and infestations

Upper respiratory tract infection1

Urinary tract infection2, vulvovaginitis, balanitis and related genital infection3, gastroenteritisD

Fungal infection

Necrotising fasciitis of the perineum (Fournier's gangrene)C,F,7

Immune system disorders

Hypersensitivity reactionsC

Anaphylactic reactions including anaphylactic shockC

Metabolism and nutrition disorders

HypoglycaemiaD

(when used with SU)

Dyslipidaemia4

Volume depletionF, thirst

Diabetic KetoacidosisF,G,7

Nervous system disorders

Headache, dizziness

Gastro-intestinal disorders

Abdominal painC, diarrhoea, dyspepsiaD, gastritisD, nauseaC, vomitingD

Constipation, dry mouth, pancreatitisC

Skin and subcutaneous tissue disorders

Rash5

DermatitisC, pruritusC, urticariaC

AngioedemaC

Bullous pemphigoid C,7

Musculo-skeletal and connective tissue disorders

Arthralgia, back pain, myalgiaD

Renal and urinary disorders

Dysuria, polyuriaD,6

Nocturia

Reproductive system and breast disorders

Erectile dysfunction, pruritus genital, vulvovaginal pruritus

General disorders and administration site conditions

FatigueD, oedema peripheralD

Investigations

Creatinine renal clearance decreased during initial treatmentF, haematocrit increasedE

Blood creatinine increased during initial treatmentF, blood urea increased, weight decreased

A Adverse reactions reported in ≥ 2 % of subjects treated with the combined use of saxagliptin + dapagliflozin in the pooled safety analysis, or if reported in < 2% in the pooled safety analysis, they were based on the individual mono-components data.

B Frequencies of all uncommon adverse reactions were based on the individual mono-components data.

C Adverse reaction originates from saxagliptin or dapagliflozin post-marketing surveillance data.

D Adverse reactions were reported in ≥ 2 % of subjects with either mono-component and ≥ 1 % more than placebo, but not in the pooled analysis.

E Haematocrit values > 55 % were reported in 1.3 % of the subjects treated with dapagliflozin 10 mg versus 0.4 % of placebo subjects.

F Frequency is based on events in the dapagliflozin clinical programme.

G Reported in the dapagliflozin cardiovascular outcomes study in patients with type 2 diabetes (DECLARE). Frequency is based on annual rate.

1 Upper respiratory tract infection includes the following preferred terms: nasopharyngitis, influenza, upper respiratory tract infection, pharyngitis, rhinitis, sinusitis, pharyngitis bacterial, tonsillitis, acute tonsillitis, laryngitis, viral pharyngitis, and viral upper respiratory tract infection.

2 Urinary tract infection includes the following preferred terms: urinary tract infection, Escherichia urinary tract infection, pyelonephritis, and prostatitis.

3 Vulvovaginitis, balanitis and related genital infection include the following preferred terms: vulvovaginal mycotic infection, balanoposthitis, genital infection fungal, vaginal infection, and vulvovaginitis.

4 Dyslipidaemia includes the following preferred terms: dyslipidaemia, hyperlipidaemia, hypercholesterolaemia, and hypertriglyceridaemia.

5 Rash was reported during the post-marketing use of saxagliptin and dapagliflozin. Preferred terms reported in dapagliflozin clinical trials included in order of frequency: rash, rash generalised, rash pruritic, rash macular, rash maculo-papular, rash pustular, rash vesicular, and rash erythematous.

6 Polyuria includes the following preferred terms: polyuria, and pollakiuria.

7 See section 4.4

SU = sulphonylurea

Description of selected adverse reactions

Vulvovaginitis, balanitis and related genital infections

Saxagliptin/dapagliflozin combination: The reported adverse events of vulvovaginitis, balanitis and related genital infections from pooled safety analysis were reflective of the safety profile of dapagliflozin. Adverse events of genital infection were reported in 3.0 % in the saxagliptin plus dapagliflozin plus metformin group, 0.9 % of saxagliptin plus metformin group and 5.9 % of subjects in the dapagliflozin plus metformin group. The majority of the genital infection adverse events were reported in females (84 % of subjects with a genital infection), were mild or moderate in intensity, of single occurrence, and most patients continued on therapy.

Cases of phimosis/acquired phimosis have been reported with dapagliflozin concurrent with genital infections and in some cases, circumcision was required.

Hypoglycaemia

In the pooled safety analysis, the overall incidence of hypoglycaemia (all reported events including those with central laboratory FPG ≤ 3.9 mmol/L) was 2.0% in subjects treated with saxagliptin 5 mg plus dapagliflozin 10 mg plus metformin (combination therapy), 0.6% in the saxagliptin plus metformin group, and 2.3% in the dapagliflozin plus metformin group.

In a 24-week study comparing the combination of saxagliptin and dapagliflozin plus metformin with or without SU, with insulin plus metformin with or without SU, the overall incidence rates for hypoglycaemia in patients without a background treatment of SU, were 12.7% for the combination compared to 33.1% for insulin. The overall incidence rates of hypoglycaemia in two 52-week studies comparing the combination therapy to glimepiride (SU) were: for the 1st study, 4.2% for the combination therapy versus 27.9% for glimepiride plus metformin versus 2.9% for dapagliflozin plus metformin; for the 2nd study, 18.5% for the combination therapy versus 43.1% for glimepiride plus metformin.

Volume depletion

Saxagliptin/dapagliflozin combination: Events suggestive of volume depletion (hypotension, dehydration, and hypovolaemia) were reported in two subjects (0.4%) in the saxagliptin plus dapagliflozin plus metformin group (serious adverse event [SAE] of syncope and an AE of urine output decreased), and 3 subjects (0.9%) in the dapagliflozin plus metformin group (2 AEs of syncope and 1 of hypotension).

Events related to decreased renal function

Saxagliptin/dapagliflozin combination: In the pooled safety analysis, the incidence of adverse events related to decreased renal function was 2.0% subjects in the saxagliptin plus dapagliflozin plus metformin group, 1.8% subjects in the saxagliptin plus metformin group, and 0.6% subjects in the dapagliflozin plus metformin group. Subjects with adverse events of renal impairment had lower mean eGFR values at baseline of 61.8 mL/min/1.73m2 compared to 93.6 mL/min/1.73m2 in the overall population. The majority of events were considered non-serious, mild or moderate in intensity, and resolved. The change in mean eGFR from baseline at week 24 was -1.17 mL/min/1.73m2 in the saxagliptin plus dapagliflozin plus metformin group, -0.46 mL/min/1.73 m2 in saxagliptin plus metformin, and 0.81 mL/min/1.73m2 in dapagliflozin plus metformin.

Dapagliflozin: Adverse reactions related to increased creatinine have been reported for dapagliflozin as a mono-component. The increases in creatinine were generally transient during continuous treatment or reversible after discontinuation of treatment.

Necrotising fasciitis of the perineum (Fournier's gangrene)

Cases of Fournier's gangrene have been reported post-marketing in patients taking SGLT2 inhibitors, including dapagliflozin (see section 4.4).

In the dapagliflozin cardiovascular outcomes study (DECLARE) with 17 160 type 2 diabetes mellitus patients and a median exposure time of 48 months, a total of 6 cases of Fournier's gangrene were reported, one in the dapagliflozin-treated group and 5 in the placebo group.

Diabetic ketoacidosis

In the dapagliflozin cardiovascular outcomes study (DECLARE), with a median exposure time of 48 months, events of DKA were reported in 27 patients in the dapagliflozin 10 mg group and 12 patients in the placebo group. The events occurred evenly distributed over the study period. Of the 27 patients with DKA events in the dapagliflozin group, 22 had concomitant insulin treatment at the time of the event. Precipitating factors for DKA were as expected in a type 2 diabetes mellitus population (see section 4.4).

Urinary tract infections

Saxagliptin/dapagliflozin combination: In the pooled safety analysis, urinary tract infections (UTIs) were balanced across the 3 treatment groups: 5.7% in the saxagliptin plus dapagliflozin plus metformin group, 7.4% in the saxagliptin plus metformin group and 5.6% in the dapagliflozin plus metformin group. One patient in the saxagliptin plus dapagliflozin plus metformin group experienced an SAE of pyelonephritis and discontinued treatment. The majority of the urinary tract infection adverse events were reported in females (81% of subjects with UTI), were mild or moderate in intensity, of single occurrence, and most patients continued on therapy.

Laboratory findings

Decrease in lymphocyte counts

Saxagliptin: In a pool of 5 placebo-controlled studies, a small decrease in absolute lymphocyte count was observed, approximately 100 cells/microl relative to placebo. Mean absolute lymphocyte counts remained stable with daily dosing up to 102 weeks in duration. This decrease in mean absolute lymphocyte count was not associated with clinically relevant adverse reactions.

Lipids

Saxagliptin/dapagliflozin combination: Data from the saxagliptin plus dapagliflozin plus metformin treatment arms of 3 phase 3 trials, demonstrated trends of mean percent increases from baseline (rounded to the nearest tenth) in total cholesterol (Total C), (ranging from 0.4% to 3.8%), LDL-C (ranging from 2.1% to 6.9%) and HDL-C (ranging 2.3% to 5.2%) along with mean percent decreases from baseline in triglycerides (ranging from -3.0% to -10.8%).

Special populations

Elderly

Saxagliptin/dapagliflozin combination: Of the 1 169 subjects treated in the pooled safety data from the 3 clinical trials, 1 007 subjects (86.1%) were aged < 65 years, 162 subjects (13.9%) were aged ≥ 65 years, and 9 subjects (0.8%) were aged ≥ 75 years. Generally, the most common adverse events reported in ≥ 65 years old were similar to < 65 years old. Therapeutic experience in patients 65 years and older is limited, and very limited in patients 75 years and older.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme: Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no information available on overdose with the saxagliptin/dapagliflozin fixed dose combination. In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient's clinical status.

Saxagliptin

Saxagliptin had no clinically meaningful effect on QTc interval or heart rate at oral doses up to 400 mg daily for 2 weeks (80 times the recommended dose). Saxagliptin and its major metabolite are removed by haemodialysis (23% of dose over four hours).

Dapagliflozin

Dapagliflozin did not show any toxicity in healthy subjects at single oral doses up to 500 mg (50 times the maximum recommended human dose). These subjects had detectable glucose in the urine for a dose-related period of time (at least 5 days for the 500 mg dose), with no reports of dehydration, hypotension or electrolyte imbalance, and with no clinically meaningful effect on QTc interval. The incidence of hypoglycaemia was similar to placebo. In clinical studies where once-daily doses of up to 100 mg (10 times the maximum recommended human dose) were administered for 2 weeks in healthy subjects and type 2 diabetes subjects, the incidence of hypoglycaemia was slightly higher than placebo and was not dose-related. Rates of adverse events including dehydration or hypotension were similar to placebo, and there were no clinically meaningful dose-related changes in laboratory parameters, including serum electrolytes and biomarkers of renal function. The removal of dapagliflozin by haemodialysis has not been studied.