QTERN 5 MG / 10 MG FILM-COATED TABLETS - summary of medicine characteristics

Qtern 5 mg/10 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains saxagliptin hydrochloride equivalent to 5 mg saxagliptin and dapagliflozin propanediol monohydrate equivalent to 10 mg dapagliflozin.

Excipient with known effect

Each tablet contains 40 mg of lactose (as anhydrous).

Qtern contains less than 1 mmol sodium (23 mg) per dose, i.e. is essentially ‘sodium-free’.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Light brown to brown, biconvex, 0.8 cm round, film-coated tablet, with “5/10 printed on one side, and “1122” printed on the other side, in blue ink.

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).

Special , populations

Renal impairment

Qtern can be used in patients with mild 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 section 4.4, 4.8, 5.1 and 5.2).

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

There is no restriction based solely on age. However, renal function and risk of volume depletion should be taken into account in elderly patients (> 65 years).

Based on very limited experience in patients 75 years and older, initiation of Qtern therapy is not recommended in this population (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.

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.

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.

Monitoring of renal function

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. Qtern should not be initiated in patients with a GFR < 60 mL/min and should be discontinued at GFR persistently below 45 mL/min. Qtern 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, Qtern treatment should be discontinued.

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

Due to dapagliflozin’s mecha­nism of action, Qtern increases diuresis associated with a modest decrease in blood pressure (see section 5.1), which may be more pronounced in patients with very high blood glucose concentrations.

This medicinal product is not recommended for use in patients at risk of volume depletion (e.g. receiving loop diuretics) (see section 4.5) or who are volume depleted, e.g. due to acute illness (such as acute gastrointestinal illness with nausea, vomiting or diarrhoea).

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

For patients receiving Qtern, in case of intercurrent conditions that may lead to volume depletion, 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).

Qtern 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 nonspecific 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 Qtern 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 Qtern, 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 betacell 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 Qtern in patients with type 1 diabetes have not been established and Qtern 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

Qtern 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.

Qtern 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

In the pooled safety data, urinary tract infections were frequently reported 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 at 52 weeks (see section 4.8).

Additionally, urinary tract infections were frequently reported in saxagliptin and dapagliflozin clinical programmes.

Urosepsis and pyelonephritis

There have been post-marketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalisation in patients receiving dapagliflozin and other SGLT2 inhibitors.

Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Patients with signs and symptoms of urinary tract infections should be evaluated and promptly treated, if indicated (see section 4.8).

Elderly

Elderly patients are more likely to have impaired renal function, and may be at a greater risk for volume depletion. In addition, elderly patients are more likely to be treated with anti-hypertensive medicinal products that may cause volume depletion and/or changes in renal function [e.g. angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II type 1 receptor blockers (ARB)].

Therefore, renal function and risk of volume depletion should be taken into account prior to starting treatment with Qtern. 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).

In subjects > 65 years of age, a higher proportion of subjects treated with dapagliflozin had adverse reactions related to volume depletion and renal impairment or failure compared with placebo (see section 4.8). The most commonly reported adverse reaction related to renal function was serum creatinine increases, the majority of which were transient and reversible (see section 4.8).

Therapeutic experience with Qtern in patients 65 years and older is limited, and very limited in patients 75 years and older. Initiation of this medicinal product’s therapy in this population (> 75 years) is not recommended (see sections 4.2, 4.8, and 5.2).

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

Postmarketing cases of bullous pemphigoid requiring hospitalisation have been reported with DPP4 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

Experience in NYHA class I-II is limited in dapagliflozin. There is no experience in clinical trials with dapagliflozin in NYHA class III-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 Qtern 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.

Use in patients treated with pioglitazone

While a causal relationship between dapagliflozin and bladder cancer is unlikely (see sections 4.8 and 5.3), as a precautionary measure, Qtern is not recommended for use in patients concomitantly treated with pioglitazone. Available epidemiological data for pioglitazone suggest a small increased risk of bladder cancer in diabetic patients treated with pioglitazone.

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 Qtern in these patients has not been established.

Elevated haematocrit

Haematocrit increase was observed with dapagliflozin treatment, (see section 4.8); therefore, caution in patients with already elevated haematocrit is warranted.

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 Qtern is used in combination with insulin secretagogue (sulphonylurea), a reduction in the dose of sulphonylurea may be required to minimize the risk of hypoglycaemia (see section 4.8).

Urine laboratory assessments

Due to its mechanism of action, patients taking Qtern 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 Qtern. 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.

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 Qtern is used in combination with insulin secretagogue (sulphonylurea), a reduction in the dose of sulphonylurea may be required to minimize 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 medications 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 breastfeeding.

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 1169 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.

Tabulated list of adverse reactions

The adverse reactions of Qtern are presented in table 1 based on the summarised data from the saxagliptin/da­pagliflozin combination clinical trials pooled safety data. 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 (> 1/1000 to

1/100), rare (1/10,000 to < 1/1000), very rare (< 1/10,000), and not known (cannot be estimated from the available data).

Table 1. Compilation of reported adverse reactions for Qtern

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

6 Rash was reported during the postmarketing 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.

7 See section 4.4

SU = sulphonylurea

Description of selected adverse reactions

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 related to volume depletion (hypotension, dehydration, and hypovolaemia) were reflective of the adverse events with dapagliflozin and 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 f 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 2 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.

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.

Necrotising f 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 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, 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.

Cardiovascular safety

Saxagliptin/da­pagliflozin combination: Cardiovascular (CV) events that were adjudicated and confirmed as CV events were reported in a total of 1.0% of subjects in the saxagliptin plus dapagliflozin plus metformin group, 0.6% in the saxagliptin plus metformin group, and 0.9% in the dapagliflozin plus metformin group.

Malignancies

Saxagliptin/da­pagliflozin combination: Malignant and unspecified neoplasms were reported in 3 subjects included in the pooled safety data. They included adverse events of gastric neoplasm, pancreatic cancer with hepatic metastases, and invasive ductal breast carcinoma in the saxagliptin plus dapagliflozin plus metformin group. Considering the short latency between first drug exposure and tumour diagnosis, a causal relationship to any specific tumour type is considered unlikely.

Dapagliflozin: In the 21-study active- and placebo-controlled pool, the overall proportion of subjects with malignant or unspecified tumours was similar between those treated with dapagliflozin (1.50%) and placebo/comparator (1.50%), and there was no carcinogenicity or mutagenicity signal in animal data (see section 5.3). When considering the cases of tumours occurring in the different organ systems, the relative risk associated with dapagliflozin was above 1 for some tumours (bladder, prostate, breast) and below 1 for others (e.g. blood and lymphatic, ovary, renal tract), not resulting in an overall increased tumour risk associated with dapagliflozin. The increased/decreased risk was not statistically significant in any of the organ systems. Considering the lack of tumour findings in non-clinical studies as well as the short latency between first drug exposure and tumour diagnosis, a causal relationship is considered unlikely. The numerical imbalance of breast, bladder and prostate tumours must be considered with caution; it will be further investigated in post-authorisation studies.

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 1169 subjects treated in the pooled safety data from the 3 clinical trials, 1007 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

Saxagliptin/da­pagliflozin combination: There is no information available on overdose with Qtern. In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient’s clinical status. Saxagliptin and its major metabolite are removed by haemodialysis (23% of dose over four hours). The removal of dapagliflozin by haemodialysis has not been studied.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

5.2 Pharmacokinetic properties

Saxagliptin/da­pagliflozin combination: Overall, the pharmacokinetics of saxagliptin and dapagliflozin were not affected in clinically relevant manner when administered as Qtern compared with independent doses of saxagliptin and dapagliflozin.

The following reflects the pharmacokinetic properties of Qtern unless stated that the presented data are from administration of saxagliptin or dapagliflozin.

Bioequivalence has been confirmed between the Qtern 5 mg/10 mg tablet and the individual saxagliptin 5 mg and dapagliflozin 10 mg tablets after single dose administration in the fasted state in healthy subjects. The pharmacokinetics of dapagliflozin, and saxagliptin and its major metabolite were similar in healthy subjects and in patients with type 2 diabetes.

Administration of Qtern with a high-fat meal decreases dapagliflozin Cmax by up to 35% and prolongs Tmax by approximately 1.5 hours, but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful. There was no food effect observed for saxagliptin. Qtern can be administered with or without food.

Drug interactions:

Saxagliptin/da­pagliflozin combination: No drug interaction studies have been performed with Qtern and other medicinal products. Such studies have been conducted with the individual active substances.

Saxagliptin: In in vitro studies, saxagliptin and its major metabolite neither inhibited CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4, nor induced CYP1A2, 2B6, 2C9, or 3A4.

Dapagliflozin: In in vitro studies, dapagliflozin neither inhibited cytochrome P450 (CYP) 1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, nor induced CYP1A2, CYP2B6 or CYP3A4. Therefore, dapagliflozin is not expected to alter the metabolic clearance of coadministered medicinal products that are metabolised by these enzymes.

Absorption

Saxagliptin: Saxagliptin was rapidly absorbed after oral administration in the fasted state, with maximum plasma concentrations (Cmax) of saxagliptin and its major metabolite attained within 2 and 4 hours (Tmax), respectively. The Cmax and AUC values of saxagliptin and its major metabolite increased proportionally with the increment in the saxagliptin dose, and this dose-proportionality was observed in doses up to 400 mg. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its major metabolite were 78 ng h/mL and 214 ng h/mL, respectively. The corresponding plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively. The intra-subject coefficients of variation for saxagliptin Cmax and AUC were less than 12%.

Dapagliflozin: Dapagliflozin was rapidly and well absorbed after oral administration. Maximum dapagliflozin plasma concentrations (Cmax) were usually attained within 2 hours after administration in the fasted state. Geometric mean steady-state dapagliflozin Cmax and AUCT values following once daily 10 mg doses of dapagliflozin were 158 ng/mL and 628 ng h/mL, respectively. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%.

Distribution

Saxagliptin: The in vitro protein binding of saxagliptin and its major metabolite in human serum is negligible. Thus, changes in blood protein levels in various disease states (e.g. renal or hepatic impairment) are not expected to alter the disposition of saxagliptin. The volume of distribution of saxagliptin was 205 l.

Dapagliflozin: Dapagliflozin is approximately 91% protein bound. Protein binding was not altered in various disease states (e.g. renal or hepatic impairment). The mean steady-state volume of distribution of dapagliflozin was 118 l.

Biotransformation

Saxagliptin: The biotransformation of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major active metabolite of saxagliptin, 5-OH-saxagliptin, is also a selective, reversible, competitive DPP-4 inhibitor, half as potent as saxagliptin.

Dapagliflozin: Dapagliflozin is extensively metabolised, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite.

Dapagliflozin 3-O-glucuronide or other metabolites do not contribute to the glucose-lowering effects. The formation of dapagliflozin 3-O-glucuronide is mediated by UGT1A9, an enzyme present in the liver and kidney, and CYP-mediated metabolism was a minor clearance pathway in humans.

Elimination

Saxagliptin: The mean plasma terminal half-life (t1/2) values for saxagliptin and its major metabolite are 2.5 hours and 3.1 hours respectively, and the mean t1/2 value for plasma DPP-4 inhibition was 26.9 hours. Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of 14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin (~230 mL/min) was greater than the average estimated glomerular filtration rate (~120 mL/min), suggesting some active renal excretion.

Dapagliflozin: The mean plasma terminal half-life (t1/2) for dapagliflozin was 12.9 hours following a single oral dose of dapagliflozin 10 mg to healthy subjects. The mean total systemic clearance of dapagliflozin administered intravenously was 207 mL/min. Dapagliflozin and related metabolites are primarily eliminated via urinary excretion with less than 2% as unchanged dapagliflozin.

Linearity

Saxagliptin: The Cmax and AUC of saxagliptin and its major metabolite increased proportionally to the saxagliptin dose. No appreciable accumulation of either saxagliptin or its major metabolite was observed with repeated once-daily dosing at any dose level. No dose- and time-dependence was observed in the clearance of saxagliptin and its major metabolite over 14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 mg to 400 mg.

Dapagliflozin: Dapagliflozin exposure increased proportional to the increment in dapagliflozin dose over the range of 0.1 to 500 mg and its pharmacokinetics did not change with time upon repeated daily dosing for up to 24 weeks.

Special populations

Renal impairment

Saxagliptin: After a single dose of saxagliptin in subjects with mild, moderate or severe renal impairment (or ESRD) classified on the basis of creatinine clearance the mean AUC values of saxagliptin were 1.2-, and up to 2.1– and 4.5– fold higher, respectively, than AUC values in subjects with normal renal function. The AUC values of 5-OH-saxagliptin were also increased. The degree of renal impairment did not affect the Cmax of saxagliptin or its major metabolite.

Dapagliflozin: At steady-state (20 mg once-daily dapagliflozin for 7 days), subjects with type 2 diabetes mellitus and mild, moderate or severe renal impairment (as determined by iohexol plasma clearance) had mean systemic exposures of dapagliflozin of 32%, 60% and 87% higher, respectively, than those of subjects with type 2 diabetes mellitus and normal renal function. The steady-state 24-hour urinary glucose excretion was highly dependent on renal function and 85, 52, 18 and 11 g of glucose/day was excreted by subjects with type 2 diabetes mellitus and normal renal function or mild, moderate or severe renal impairment, respectively. The impact of hemodialysis on dapagliflozin exposure is not known.

Hepatic impairment

Saxagliptin: In subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment the exposures to saxagliptin were 1.1-, 1.4– and 1.8-fold higher, respectively, and the exposures to BMS-510849 (saxagliptin metabolite) were 22%, 7% and 33% lower, respectively, than those observed in healthy subjects.

Dapagliflozin: In subjects with mild or moderate hepatic impairment (Child-Pugh classes A and B), mean Cmax and AUC of dapagliflozin were up to 12% and 36% higher, respectively, compared to healthy matched control subjects. These differences were not considered to be clinically meaningful. In subjects with severe hepatic impairment (Child-Pugh class C) mean Cmax and AUC of dapagliflozin were 40% and 67% higher than matched healthy controls, respectively.

Elderly

Saxagliptin: Elderly patients (65–80 years) had about 60% higher saxagliptin AUC than young patients (18–40 years). This is not considered clinically meaningful, therefore, no dose adjustment for saxagliptin is recommended on the basis of age alone.

Dapagliflozin: There is no clinically meaningful increase in exposure based on age alone in subjects up to 70 years old. However, an increased exposure due to age-related decrease in renal function can be expected. There are insufficient data to draw conclusions regarding exposure in patients > 70 years old.

Gender

Saxagliptin: Females had approximately 25% higher systemic exposure values for saxagliptin. There were no clinically relevant differences observed in saxagliptin pharmacokinetics between males and females.

Dapagliflozin: The mean dapagliflozin AUCss in females was estimated to be about 22% higher than in males.

Race

Saxagliptin: Race was not identified as a statistically significant covariate on the apparent clearance of saxagliptin and its metabolite.

Dapagliflozin: There were no clinically relevant differences in systemic exposures between White, Black or Asian races.

Body weight

Dapagliflozin: Dapagliflozin exposure was found to decrease with increased weight. Consequently, low-weight patients may have somewhat increased exposure and patients with high-weight somewhat decreased exposure.

However, the differences in exposure were not considered clinically meaningful.

Saxagliptin: Body weight had a small and non-clinically meaningful impact on saxagliptin exposure. Females had approximately 25% higher systemic-exposure values for saxagliptin, this difference is considered not clinically relevant.

5.3 Preclinical safety data

Non-clinical studies of either saxagliptin or dapagliflozin revealed no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity or carcinogenicity.

Saxagliptin produced reversible skin lesions (scabs, ulcerations and necrosis) in extremities (tail, digits, scrotum and/or nose) in cynomolgus monkeys. The no effect level (NOEL) for the lesions is 1 and 2 times the human exposure of saxagliptin and the major metabolite respectively, at the recommended human dose (RHD) of 5 mg/day. The clinical relevance of the skin lesions is not known and skin lesions have not been observed in humans.

Immune related findings of minimal, nonprogressive, lymphoid hyperplasia in spleen, lymph nodes and bone marrow with no adverse sequelae have been reported in all species tested at exposures starting from 7 times the RHD.

Saxagliptin produced gastrointestinal toxicity in dogs, including bloody/mucoid faeces and enteropathy at higher doses with a NOEL 4 and

2 times the human exposure for saxagliptin and the major metabolite, respectively at RHD. The effect on offspring body weights were noted until postnatal day 92 and 120 in females and males, respectively.

Reproductive and developmental toxicity

Saxagliptin has effects on fertility in male and female rats at high doses producing overt signs of toxicity. Saxagliptin was not teratogenic at any doses evaluated in rats or rabbits. At high doses in rats, saxagliptin caused reduced ossification (a developmental delay) of the foetal pelvis and decreased foetal body weight (in the presence of maternal toxicity), with a NOEL 303 and 30 times the human exposure for saxagliptin and the major metabolite, respectively, at RHD. In rabbits, the effects of saxagliptin were limited to minor skeletal variations observed only at maternally toxic doses (NOEL 158 and 224 times the human exposure for saxagliptin and the major metabolite, respectively at RHD). In a pre- and postnatal developmental study in rats, saxagliptin caused decreased pup weight at maternally toxic doses, with NOEL 488 and 45 times the human exposure for saxagliptin and the major metabolite, respectively at RHD. The effect on offspring body weights were noted until postnatal day 92 and 120 in females and males, respectively.

Direct administration of dapagliflozin to weanling juvenile rats and indirect exposure during late pregnancy (corresponding to the second and third trimesters of pregnancy with respect to human renal maturation) and lactation are each associated with increased incidence and/or severity of renal pelvic and tubular dilatations in progeny.

In a juvenile study, when dapagliflozin was dosed directly to young rats from postnatal day 21 until postnatal day 90, renal pelvic and tubular dilatations (with dose-related increases in kidney weight and macroscopic kidney enlargement) were reported at all dose levels; pup exposures at the lowest dose tested were > 15 times the maximum recommended human dose. The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within the approximate 1-month recovery period.

Dapagliflozin dosed to maternal rats from gestation day 6 through postnatal day 21, and pups were indirectly exposed in utero and throughout lactation. Increased incidence or severity of renal pelvic dilatation was observed in adult offspring of treated dams, although only at the highest dose tested (at maternal and pup dapagliflozin exposures of 1415 times and 137 times, respectively, the human values at the maximum recommended human dose [MRHD]). Additional developmental toxicity was limited to dose-related reductions in pup body weights, and observed only at doses > 15 mg/kg/day (pup exposures > 29 times the human values at the MRHD). Maternal toxicity was evident only at the highest dose tested, and limited to transient reductions in body weight and food consumption at dose. The NOAEL for developmental toxicity is associated with a maternal systemic exposure 19 times the human values at the MRHD.

In studies of embryo-foetal development in rabbits, dapagliflozin caused neither maternal nor developmental toxicities at any dose tested; the highest dose tested corresponded to a systemic exposure 1191 times the MRHD. In rats, dapagliflozin was neither embryolethal nor teratogenic at exposures up to 1441 times the human values at the MRHD.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Microcrystalline cellulose (E460i)

Croscarmellose sodium (E468)

Lactose, anhydrous

Magnesium stearate (E470b)

Dental type silica (E551)

Film-coating

Polyvinyl alcohol (E1203)

Macrogol 3350

Titanium dioxide (E171)

Talc (E553b)

Iron oxide yellow (E172)

Iron oxide red (E172)

Printing ink

Shellac

Indigo carmine aluminium lake (E132)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PA/Alu/PVC-Alu blister

Pack sizes of 14, 28, and 98 film-coated tablets in calendar blisters

Pack size of 30 film-coated tablets in blisters

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

AstraZeneca UK Limited, 600 Capability Green, Luton,

LU1 3LU,

UK.