Leaflet QTRILMET 1000mg / 2.5mg / 5mg modified release tablets

Qtrilmet 850 mg/2.5 mg/5 mg modified-release tablets

Qtrilmet 1,000 mg/2.5 mg/5 mg modified-release tablets

Qtrilmet 850 mg/2.5 mg/5 mg modified-release tablets

Each tablet contains 850 mg of metformin hydrochloride, saxagliptin hydrochloride equivalent to2.5 mg saxagliptin and dapagliflozin propanediol monohydrate equivalent to 5 mg dapagliflozin.

Qtrilmet 1,000 mg/2.5 mg/5 mg modified-release tablets

Each tablet contains 1,000 mg of metformin hydrochloride, saxagliptin hydrochloride equivalent to2.5 mg saxagliptin and dapagliflozin propanediol monohydrate equivalent to 5 mg dapagliflozin.

Each tablet contains 48 mg of lactose (as anhydrous).

For the full list of excipients, see section 6.1.

Modified-release tablet (tablet).

Qtrilmet 850 mg/2.5 mg/5 mg modified-release tablets

Beige, biconvex, 11 x 21 mm oval tablet, with 3005 debossed on one side.

Qtrilmet 1,000 mg/2.5 mg/5 mg modified-release tablets

Green, biconvex, 11 x 21 mm oval tablet, with 3002 debossed on one side.

Qtrilmet is indicated in adults aged 18 years and older with type 2 diabetes mellitus:

- to improve glycaemic control when metformin with or without sulphonylurea (SU) and eithersaxagliptin or dapagliflozin does not provide adequate glycaemic control.

- when already being treated with metformin and saxagliptin and dapagliflozin.

Each tablet contains a fixed dose of metformin, saxagliptin and dapagliflozin (see section 2). If noadequate strength of Qtrilmet is available, individual mono-components should be used instead of themodified-release combination.

The maximum recommended daily dose of Qtrilmet is metformin 2,000 mg/saxagliptin5 mg/dapagliflozin 10 mg.

For patients inadequately controlled on dual combination with either saxagliptin or dapagliflozin andmetformin

Patients should receive a total daily dose of Qtrilmet equivalent to saxagliptin 5 mg, dapagliflozin10 mg, plus the total daily dose of metformin, or the nearest therapeutically appropriate dose, alreadybeing taken. The dose should be taken as two tablets orally, once daily at the same time of the day,with food.

Switching from separate tablets of metformin, saxagliptin and dapagliflozin

Patients switching from separate tablets of metformin, saxagliptin 5 mg and dapagliflozin 10 mg to

Qtrilmet should receive the same daily dose of metformin, saxagliptin and dapagliflozin already beingtaken or the nearest therapeutically appropriate dose of metformin. The dose should be taken as twotablets orally, once daily at the same time of the day, with food.

Switching from metformin immediate-release to metformin modified-release

In patients switching from metformin immediate-release to metformin modified-release, the dose of

Qtrilmet should provide metformin at the dose already being taken, or the nearest therapeuticallyappropriate dose (see sections 5.1 and 5.2).

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

Because elderly patients (≥ 65 years) are more likely to have decreased renal function, this medicinalproduct should be used with caution as age increases. Monitoring of renal function is necessary to aidin prevention of metformin associated lactic acidosis, particularly in elderly patients (see sections 4.3and 4.4). Risk of volume depletion with this medicinal product should also be taken into account (seesections 4.4 and 5.2). Due to the limited therapeutic experience with this medicinal product in patients75 years and older, initiation of therapy is not recommended in this population.

No dose adjustment is recommended for Qtrilmet in patients with mild renal impairment,

GFR 60-89 mL/min.

A GFR should be assessed before initiation of treatment with metformin containing medicinal productsand at least annually thereafter. In patients at increased risk of further progression of renal impairmentand in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months.

This medicinal product should not be used in patients with moderate to severe renal impairment(patients with GFR < 60 mL/min (see sections 4.4, pct. 4.8, 5.1 and 5.2). This medicinal product iscontraindicated in patients with GFR < 30 mL/min (see sections pct. 4.3, pct. 4.4, pct. 4.8 and 5.2).

This medicinal product must not be used in patients with hepatic impairment (see section 4.3).

The safety and efficacy of this medicinal product in children and adolescents aged 0 to < 18 years havenot yet been established. No data are available.

Qtrilmet dose is taken orally once daily at the same time of the day with food to reduce thegastrointestinal adverse reactions associated with metformin. Each tablet is to be swallowed whole.

Occasionally, the inactive ingredients of this medicine will be eliminated in the faeces as a soft,hydrated mass that may resemble the original tablet.

Qtrilmet is contraindicated in patients with:

- hypersensitivity to the active substances or to any of the excipients listed in section 6.1, historyof a serious hypersensitivity reaction, including anaphylactic reaction, anaphylactic shock, andangioedema, to any dipeptidyl peptidase-4 (DPP-4) inhibitor or to any sodium-glucoseco-transporter 2 (SGLT2) inhibitor (see sections 4.4, pct. 4.8 and 6.1);

- any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis) (see sections4.4 and 4.8);

- diabetic pre-coma (see section 4.4);

- severe renal failure (GFR < 30 mL/min) (see sections 4.2, pct. 4.4 and 5.2);

- acute conditions with the potential to alter renal function such as:

o dehydration,o severe infection,o shock;

- acute or chronic disease which may cause tissue hypoxia such as:o cardiac or respiratory failure,o recent myocardial infarction,o shock;

- hepatic impairment (see sections 4.2 and 5.2);

- acute alcohol intoxication, alcoholism (see section 4.5).

Lactic acidosis

Lactic acidosis, a very rare but serious metabolic complication, most often occurs at acute worsening ofrenal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute worseningof renal function and increases the risk of lactic acidosis.

In case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake), Qtrilmet should betemporarily discontinued and contact with a health care professional is recommended.

Medicinal products that can acutely impair renal function (such as anti-hypertensives, diuretics, and

NSAIDs) should be initiated with caution in metformin-treated patients. Other risk factors for lacticacidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis,prolonged fasting, and any conditions associated with hypoxia, as well as concomitant use of medicinalproducts that may cause lactic acidosis (see sections 4.3 and 4.5).

Patients and/or care-givers should be informed on the risk of lactic acidosis. Lactic acidosis ischaracterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia, and hypothermiafollowed by coma. In case of suspected symptoms, the patient should stop taking Qtrilmet and seekimmediate medical attention. Diagnostic laboratory findings are decreased blood pH (< 7.35),increased plasma lactate levels above 5 mmol/L, and an increased anion gap and lactate/pyruvate ratio.

Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have beenreported in patients treated with SGLT2 inhibitors, including dapagliflozin. In a number of cases, thepresentation of the condition was atypical with only moderately increased blood glucose values, below14 mmol/litres. 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 asnausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusualfatigue, or sleepiness. Patients should be assessed for ketoacidosis immediately if these symptomsoccur, regardless of blood glucose level.

In patients where DKA is suspected or diagnosed, treatment with Qtrilmet should be discontinuedimmediately.

Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acuteserious medical illnesses. Monitoring of ketones is recommended in these patients. Measurement ofblood ketone levels is preferred to urine. Treatment with Qtrilmet may be restarted when the ketonevalues are normal and the patient’s condition has stabilised.

Before initiating Qtrilmet, factors in the patient history that may predispose to ketoacidosis should beconsidered.

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 patientswith a history of pancreatitis), patients with conditions that lead to restricted food intake or severedehydration, patients for whom insulin doses are reduced and patients with increased insulinrequirements due to acute medical illness, surgery, or alcohol abuse. SGLT2 inhibitors should be usedwith caution in these patients.

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

The safety and efficacy in patients with type 1 diabetes have not been established and Qtrilmet shouldnot be used in patients with type 1 diabetes. In type 1 diabetes mellitus studies with dapagliflozin,

DKA was reported with common frequency.

The efficacy of dapagliflozin is dependent on renal function, and efficacy is reduced in patients whohave moderate renal impairment and likely absent in patients with severe renal impairment (seesection 4.2). In subjects with moderate to severe renal impairment (patients with GFR < 60 mL/min), ahigher proportion of subjects treated with dapagliflozin had adverse reactions of increase in creatinine,phosphorus, parathyroid hormone (PTH), and hypotension, compared with placebo. Therefore,

Qtrilmet should not be used in patients with moderate to severe renal impairment (patients with

GFR < 60 mL/min). This medicinal product has not been studied in severe renal impairment(GFR < 30 mL/min) or end-stage renal disease (ESRD).

Metformin is excreted by the kidney, and moderate to severe renal insufficiency increases the risk oflactic acidosis (see section 4.4).

Renal function should be assessed:

- prior to initiation of this medicinal product and regularly thereafter (see sections 4.2, pct. 4.8, 5.1 and5.2);

- prior to initiation of concomitant medicinal products that may reduce renal function andperiodically thereafter (see section 4.5);

- for renal function with GFR levels approaching moderate renal impairment and in elderlypatients, at least 2 to 4 times per year. If renal function falls below GFR < 60 mL/min, treatmentshould be discontinued.

Metformin is contraindicated in patients with GFR of < 30 mL/min and this treatment should betemporarily interrupted in the presence of conditions that alter renal function (see section 4.3).

Decreased renal function in elderly patients is frequent and asymptomatic. Special caution should beexercised in situations where renal function may become impaired, for example when initiatinganti-hypertensive or diuretic therapy or when starting treatment with a NSAID.

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

Due to dapagliflozin’s mechanism of action, Qtrilmet increases diuresis associated with a modestdecrease in blood pressure (see section 5.1), which may be more pronounced in patients with very highblood 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 asacute gastrointestinal illness with nausea, vomiting or diarrhoea).

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

For patients receiving Qtrilmet, 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 oftreatment with this medicinal product is recommended for patients who develop volume depletion untilthe depletion is corrected (see section 4.8).

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

In post-marketing experience of saxagliptin, there have been spontaneously reported adverse reactionsof acute pancreatitis.

Post-marketing cases of necrotising fasciitis of the perineum (also known as Fournier’s gangrene) havebeen reported in female and male patients taking SGLT2 inhibitors (see section 4.8). This is a rare butserious and potentially life-threatening event that requires urgent surgical intervention and antibiotictreatment.

Patients should be advised to seek medical attention if they experience a combination of symptoms ofpain, tenderness, erythema, or swelling in the genital or perineal area, with fever or malaise. Be awarethat either uro-genital infection or perineal abscess may precede necrotising fasciitis. If Fournier’sgangrene is suspected, Qtrilmet should be discontinued and prompt treatment (including antibiotics andsurgical debridement) should be instituted.

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

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

Urinary tract infections

Treatment with SGLT2 inhibitors increases the risk for urinary tract infections (see section 4.8).

Patients with signs and symptoms of urinary tract infections should be evaluated and promptly treated,if indicated.

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

Temporary interruption of treatment should be considered when treating pyelonephritis or urosepsis.

Elderly patients are more likely to have impaired renal function, and may be at a greater risk forvolume depletion. In addition, elderly patients are more likely to be treated with anti-hypertensivemedicinal 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 startingtreatment with Qtrilmet. The same recommendations for monitoring of renal function apply to elderlypatients as to all patients (see sections 4.2, pct. 4.4, pct. 4.8 and 5.1).

In subjects ≥ 65 years of age, a higher proportion of subjects treated with dapagliflozin had adversereactions related to volume depletion and renal impairment or failure compared with placebo (seesection 4.8).

Ulcerative and necrotic skin lesions have been reported in extremities of monkeys in non-clinicaltoxicology studies with saxagliptin (see section 5.3). Skin lesions were not observed at an increasedincidence in saxagliptin clinical trials. Post-marketing reports of rash have been described in the DPP-4inhibitor 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 asblistering, ulceration, or rash, is recommended.

Bullous pemphigoid

Postmarketing cases of bullous pemphigoid requiring hospitalisation have been reported with DPP4inhibitor use, including saxagliptin. In reported cases, patients typically responded to topical orsystemic immunosuppressive treatment and discontinuation of the DPP4 inhibitor. If a patient developsblisters or erosions while receiving saxagliptin and bullous pemphigoid is suspected, this medicinalproduct should be discontinued and referral to a dermatologist should be considered for diagnosis andappropriate treatment (see section 4.8).

Cardiac failure

Experience in NYHA class I-II is limited in dapagliflozin. There is no experience in clinical trials withdapagliflozin 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 thesaxagliptin-treated patients compared to placebo, although a causal relationship has not beenestablished (see section 5.1). Additional analysis did not indicate a differential effect among NYHAclasses.

Caution is warranted if Qtrilmet is used in patients who have known risk factors for hospitalisation forheart failure, such as a history of heart failure or moderate to severe renal impairment. Patients shouldbe 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 (seesection 4.8). Patients experienced relief of symptoms after discontinuation of the medicinal product andsome 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 oftreatment. If a patient presents with severe joint pain, continuation of therapy should be individuallyassessed.

Immunocompromised patients, such as patients who have undergone organ transplantation or patientsdiagnosed with human immunodeficiency syndrome have not been studied in the saxagliptin clinicalprogramme. The efficacy and safety profiles of Qtrilmet in these patients have not been established.

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

Use with insulin or insulin secretagogues known to cause hypoglycaemia

Both saxagliptin and dapagliflozin can individually increase the risk of hypoglycaemia when combinedwith insulin or an insulin secretagogue (sulphonylurea). Hypoglycaemia does not occur in patientsreceiving metformin alone under usual circumstances of use but could occur during concomitant usewith other glucose-lowering agents. Therefore, a lower dose of insulin or insulin secretagogue may berequired to reduce the risk of hypoglycaemia when these agents are used in combination with Qtrilmet(see sections 4.5 and 4.8).

Qtrilmet must be discontinued at the time of surgery with general, spinal or epidural anaesthesia.

Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition andprovided that renal function has been re-evaluated and found to be stable.

Administration of iodinated contrast agents

Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy,resulting in metformin accumulation and increased risk of lactic acidosis. Qtrilmet should bediscontinued prior to, or at the time of, the imaging procedure and not restarted until at least 48 hoursafter, provided that renal function has been re-evaluated and found to be stable (see sections 4.2and 4.5).

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

Due to its mechanism of action, patients taking dapagliflozin will test positive for glucose in theirurine.

Use in patients treated with pioglitazone

While a causal relationship between dapagliflozin and bladder cancer is unlikely (see sections 4.8 and5.3), as a precautionary measure, Qtrilmet is not recommended for use in patients concomitantlytreated with pioglitazone. Available epidemiological data for pioglitazone suggest a small increasedrisk of bladder cancer in diabetic patients treated with pioglitazone.

Use with potent CYP3A4 inducers

Using CYP3A4 inducers like glucocorticoids, beta-2 agonists, diuretics, carbamazepine,dexamethasone, phenobarbital, phenytoin, and rifampicin may reduce the glycaemic lowering effect of

Qtrilmet. Glycaemic control should be assessed, especially at the beginning, when it is usedconcomitantly with a potent CYP3A4/5 inducer (see section 4.5).

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

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

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

Interaction studies have been performed with the individual active substances of Qtrilmet.

Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in the case offasting, malnutrition or hepatic impairment due to the metformin active substance of this medicinalproduct (see section 4.4). Consumption of alcohol and medicinal products containing alcohol should beavoided.

Iodinated contrast agents

Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy,resulting in metformin accumulation and increased risk of lactic acidosis. Qtrilmet must bediscontinued prior to, or at the time of the imaging procedure and not restarted until at least 48 hoursafter, provided that renal function has been re-evaluated and found to be stable (see sections 4.2and 4.4).

Combinations requiring precautions for use

Glucocorticoids (given by systemic and local routes), beta-2 agonists, and diuretics have intrinsichyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoringperformed, especially at the beginning of treatment with such medicinal products, and observed for lossof blood glucose control or hypoglycaemia. If necessary, the dose of the glucose-lowering medicinalproduct should be adjusted during therapy with the other medicinal product and on its discontinuation.

Some medicinal products can adversely affect renal function which may increase the risk of lacticacidosis, e.g. NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors, ACE inhibitors,angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using suchproducts in combination with metformin, close monitoring of renal function is necessary.

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

Use with medicinal products known to cause hypoglycaemia

Saxagliptin and dapagliflozin can individually increase the risk of hypoglycaemia when combined withinsulin or an insulin secretagogue. Hypoglycaemia does not occur in patients receiving metforminalone under usual circumstances of use, but could occur during concomitant use with other glucose-lowering agents. Therefore, a lower dose of insulin or insulin secretagogue may be required to reducethe risk of hypoglycaemia when these agents are used in combination with Qtrilmet (see sections 4.4and 4.8).

Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.

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 uridinediphosphate (UDP) glucuronosyltransferase 1A9 (UGT1A9).

Effect of other medicinal products on metformin, saxagliptin or dapagliflozin

No clinically relevant interaction has been identified.

Saxagliptin

The coadministration of saxagliptin and CYP3A4/5 inducers, other than rifampicin (such ascarbamazepine, dexamethasone, phenobarbital, and phenytoin) has not been studied and may result indecreased 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.

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

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 correspondingvalues for the active metabolite were decreased by 44% and 34%, respectively. These pharmacokineticeffects 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 correspondingvalues for the active metabolite were decreased by 95% and 88%, respectively. These pharmacokineticeffects are not clinically meaningful and do not require dose adjustment.

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

Dapagliflozin

Following coadministration of dapagliflozin with rifampicin (an inducer of uridine 5’-diphospho-glucuronosyl transferase [UGT] and CYP3A4/5), a 22% decrease in dapagliflozin systemicexposure (AUC) was observed, but with no clinically meaningful effect on 24-hour urinary glucoseexcretion. No dose adjustment is recommended. A clinically relevant effect with other inducers (e.g.carbamazepine, phenytoin and phenobarbital) is not expected.

Following coadministration of dapagliflozin with mefenamic acid (an inhibitor of UGT 1A9), a 55%increase in dapagliflozin systemic exposure was seen, but with no clinically meaningful effect on24-hour urinary glucose excretion.

The pharmacokinetics of dapagliflozin were not meaningfully altered by saxagliptin, metformin,pioglitazone, sitagliptin, glimepiride, voglibose, hydrochlorothiazide, bumetanide, valsartan, orsimvastatin.

Effect of metformin, saxagliptin or dapagliflozin on other medicinal products

Organic cation transporters (OCT)

Metformin is a substrate of both transporters OCT1 and OCT2.

Co-administration of metformin with:

- inhibitors of OCT1 (such as verapamil) may reduce efficacy of metformin;

- inducers of OCT1 (such as rifampicin) may increase gastrointestinal absorption and efficacy ofmetformin;

- inhibitors of OCT2 (such as cimetidine, dolutegravir, ranolazine, trimethoprime, vandetanib,isavuconazole) may decrease the renal elimination of metformin and thus lead to an increase inmetformin plasma concentration;

- inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may alter efficacy and renalelimination of metformin.

Caution is therefore advised, especially in patients with renal impairment, when these medicinalproducts are co-administered with metformin, as metformin plasma concentration may increase (seesection 4.4).

Saxagliptin

Saxagliptin did not meaningfully alter the pharmacokinetics of dapagliflozin, 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 oralcontraceptive (ethinylestradiol and norgestimate), diltiazem or ketoconazole.

Dapagliflozin

In interaction studies conducted in healthy subjects, using mainly a single-dose design, dapagliflozindid not alter the pharmacokinetics of saxagliptin, 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 theanticoagulatory effects of warfarin as measured by INR. Combination of a single dose of dapagliflozin20 mg and simvastatin (a CYP3A4 substrate) resulted in a 19% increase in AUC of simvastatin and31% increase in AUC of simvastatin acid. The increase in simvastatin and simvastatin acid exposuresare not considered clinically relevant.

The use of this medicinal product, or its components (metformin hydrochloride, saxagliptin anddapagliflozin) has not been studied in pregnant women. Studies in animals with saxagliptin have shownreproductive toxicity at high doses (see section 5.3). Studies with dapagliflozin in rats have showntoxicity to the developing kidney in the time period corresponding to the second and third trimesters ofhuman pregnancy (see section 5.3). A limited amount of data from the use of metformin in pregnantwomen does not indicate an increased risk of congenital malformations. Animal studies withmetformin do not indicate harmful effects with respect to pregnancy, embryonic or foetal development,parturition or postnatal development (see section 5.3).

Qtrilmet should not be used during pregnancy. If pregnancy is detected, treatment with this medicinalproduct should be discontinued.

When the patient plans to become pregnant, and during pregnancy, it is recommended that diabetes isnot treated with this medicinal product, but insulin be used to maintain blood glucose levels as close tonormal as possible, to reduce the risk of malformations of the foetus associated with abnormal bloodglucose levels.

Metformin is excreted in human milk in small amounts. A risk to the newborns/infants cannot beexcluded. It is unknown whether saxagliptin and dapagliflozin and/or their metabolites are excreted inhuman milk. Animal studies have shown excretion of saxagliptin and/or metabolite in milk. Availablepharmacodynamic/toxicological data in animals have shown excretion of dapagliflozin/metabolites inmilk, as well as pharmacologically-mediated effects in breast-feeding offspring (see section 5.3).

This medicinal product should not be used while breast-feeding.

The effect of this medicinal product, or its components (metformin hydrochloride, saxagliptin anddapagliflozin) on fertility in humans has not been studied. Effects on fertility were observed usingsaxagliptin in male and female rats at high doses producing overt signs of toxicity (see section 5.3). Inmale and female rats, dapagliflozin showed no effects on fertility at any dose tested. For metformin,studies in animals have not shown reproductive toxicity (see section 5.3).

Qtrilmet 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 instudies with saxagliptin. In addition, patients should be alerted to the risk of hypoglycaemia when thismedicinal product is used in combination with other glucose-lowering medicinal products known tocause hypoglycaemia (e.g. insulin and sulphonylureas).

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

The safety profile of the combined use of metformin, saxagliptin and dapagliflozin is comparable to theadverse reactions identified for the respective mono-components.

The safety profile is based on pooled analysis of three placebo controlled phase 3 clinical trials in1,169 patients for up to 52 weeks, of which 492 patients received a combination of saxagliptin 5 mg,dapagliflozin 10 mg, plus metformin (see section 5.1). Additional safety data include clinical trials,post-authorisation safety studies and post-marketing experience with the mono-components. Theadverse reactions associated with Qtrilmet are presented in Table 1. The adverse reactions are listed bysystem organ class (SOC) and frequency. Frequency categories were defined according to verycommon (≥ 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 ( 1/100,000 to < 1/10,000) and not known (cannot be estimated from theavailable data).

Table 1. Compilation of adverse reactions for Qtrilmet

System organ Very CommonA UncommonB Rare Very rare Not knownclass common

Infections and Upper Urinary tract Fungal Necrotisinginfestations respiratory infection#¶ 2, infection# fasciitis oftract vulvo- theinfection¶1 vaginitis, perineumbalanitis and (Fournier'srelated gangrene)genital #,C,7infection# 3,gastro-enteritis¶D

Immune Hypersen- Anaphyl-system sitivity acticdisorders reactions¶ C reactionsincludinganaphylacticshock¶ C

Metabolism Hypo- Dyslipid- Volume Diabetic Lacticand nutrition glycaemiaD#¶ aemia# 4 depletion#, ketoacidosis acidosis§,disorders (when used thirst# #,H,7 Vitamin B12with SU) deficiency§G

Nervous Headache¶,system dizziness¶disorders

Gastro- Gastro- DyspepsiaD ¤ Constipation#intestinal intestinal gastritisD ¤ , dry mouth#,disorders symptoms§ F taste pancreatitis¶ Cdisturbance§

Hepatobiliary Liverdisorders functiondisorders§ ,hepatitis§

Renal and Dysuria#, Nocturia#,urinary polyuria# D, 5 renaldisorders impairment#

Skin and Rash# ¶ 6 Dermatitis¶C, Angio- Erythema§ Bulloussubcutaneous pruritus¶ C, edema¶ C pemphi-tissue urticaria¶ C goidC,7

System organ Very CommonA UncommonB Rare Very rare Not knownclass commondisorders

Musculo- Arthralgia¤,skeletal and back pain#,connective myalgiaD ¤tissuedisorders

Reproductive Erectilesystem and dysfunction¤,breast pruritusdisorders genital#,vulvovaginalpruritus#

General Fatigue¶ D,disorders and oedemaadministratio peripheral¶ Dn siteconditions

Investigations Creatinine Bloodrenal creatinineclearance increased#,decreased# , blood ureahaematocrit increased#,increased# E weightdecreased## Adverse reaction reported for dapagliflozin.¶ Adverse reaction reported for saxagliptin.§ Adverse reaction reported for metformin.¤ Adverse reaction reported for the combined use of saxagliptin and metformin.

A Adverse reactions, except for taste disturbance, reported in ≥ 2% of subjects treated with the combined use ofsaxagliptin + dapagliflozin + metformin in the pooled safety analysis, or if reported in < 2% in the pooledsafety 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 any of the mono-components, and ≥ 1% more thanplacebo, but not in the pooled safety analysis.

E Haematocrit values > 55% were reported in 1.3% of the subjects treated with dapagliflozin 10 mg versus0.4% of placebo subjects.

F Gastrointestinal symptoms (subsumed terms included nausea, vomiting, diarrhoea, abdominal pain, and lossof appetite) occur most frequently during initiation of therapy and resolve spontaneously in most cases.

G Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption whichmay very rarely result in clinically significant vitamin B12 deficiency. Consideration of such etiology isrecommended if a patient presents with megaloblastic anaemia.

H Reported in the dapagliflozin cardiovascular outcomes study in patients with type 2 diabetes. Frequency isbased on annual rate.

1 Upper respiratory tract infection includes the following preferred terms: nasopharyngitis, influenza, upperrespiratory 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 urinarytract infection, pyelonephritis, and prostatitis.

3 Vulvovaginitis, balanitis and related genital infection include the following preferred terms: vulvovaginalmycotic 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 indapagliflozin 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.

In the pooled safety analysis, the overall incidence of hypoglycaemia (all reported events includingthose with central laboratory FPG ≤ 3.9 mmol/L) was 2.0% in subjects treated with dapagliflozin10 mg and saxagliptin 5 mg plus metformin (combination therapy), 0.6% in the saxagliptin plusmetformin 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 orwithout SU, with insulin plus metformin with or without SU, the overall incidence rates forhypoglycaemia in patients without a background treatment of SU, were 12.7% for the combinationcompared to 33.1% for insulin. The overall incidence rates of hypoglycaemia in two 52-week studiescomparing the combination therapy to glimepiride (SU) were: for the 1st study, 4.2% for thecombination therapy versus 27.9% for glimepiride plus metformin versus 2.9% for dapagliflozin plusmetformin; for the 2nd study, 18.5% for the combination therapy versus 43.1% for glimepiride plusmetformin.

In the pooled safety analysis, events related to volume depletion (hypotension, dehydration, andhypovolemia) were reflective of the adverse events with dapagliflozin and were reported in twosubjects (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 plusmetformin group (2 AEs of syncope and 1 of hypotension).

Decreased renal function

Metformin/saxagliptin/dapagliflozin combination: In the pooled safety analysis for Qtrilmet, theincidence of adverse events related to decreased renal function was 2.0% subjects in the saxagliptinplus dapagliflozin plus metformin group, 1.8% subjects in the saxagliptin plus metformin group, and0.6% subjects in the dapagliflozin plus metformin group. Subjects with adverse events of renalimpairment had lower mean eGFR values at baseline of 61.8 mL/min/1.73 m2 compared to93.6 mL/min/1.73 m2 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 24was -1.17 mL/min/1.73 m2 in the saxagliptin plus dapagliflozin plus metformin group, -0.46mL/min/1.73 m2 in saxagliptin plus metformin, and 0.81 mL/min/1.73 m2 in dapagliflozin plusmetformin.

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

Vulvovaginitis, balanitis and related genital infections

The reported adverse reactions of vulvovaginitis, balanitis and related genital infections from pooledsafety analysis were reflective of the safety profile of dapagliflozin. Adverse reactions of genitalinfection were reported in 3.0% in the saxagliptin plus dapagliflozin plus metformin group, 0.9% ofsaxagliptin plus metformin group and 5.9% of subjects in the dapagliflozin plus metformin group. Themajority of the genital infection adverse reactions were reported in females (84% of subjects with agenital infection), were mild or moderate in intensity, of single occurrence, and most patients continuedon therapy.

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 amedian exposure time of 48 months, a total of 6 cases of Fournier’s gangrene were reported, one in thedapagliflozin-treated group and 5 in the placebo group.

In the dapagliflozin cardiovascular outcomes study, with a median exposure time of 48 months, eventsof DKA were reported in 27 patients in the dapagliflozin 10 mg group and 12 patients in the placebogroup. The events occurred evenly distributed over the study period. Of the 27 patients with DKAevents 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 (seesection 4.4).

Urinary tract infections

In the pooled safety analysis, urinary tract infections (UTIs) were balanced across the 3 treatmentgroups: 5.7% in the saxagliptin plus dapagliflozin plus metformin group, 7.4% in the saxagliptin plusmetformin group, and 5.6% in the dapagliflozin plus metformin group. One patient in the saxagliptinplus dapagliflozin plus metformin group experienced an SAE of pyelonephritis and discontinuedtreatment. The majority of the urinary tract infections were reported in females (81% of subjects with

UTI), were mild or moderate in intensity, of single occurrence, and most patients continued on therapy.

Saxagliptin/dapagliflozin combination: Malignant and unspecified neoplasms were reported in3 subjects included in the pooled safety analysis. They included adverse events of gastric neoplasm,pancreatic cancer with hepatic metastases, and invasive ductal breast carcinoma in the saxagliptin plusdapagliflozin plus metformin group. Considering the short latency between first drug exposure andtumour 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 subjectswith 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 animaldata (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 overallincreased tumour risk associated with dapagliflozin. The increased/decreased risk was not statisticallysignificant in any of the organ systems. Considering the lack of tumour findings in non-clinical studiesas well as the short latency between first drug exposure and tumour diagnosis, a causal relationship isconsidered unlikely. The numerical imbalance of breast, bladder, and prostate tumours must beconsidered with caution; it will be further investigated in post-authorisation studies.

Laboratory findings

Decrease in lymphocyte counts

Saxagliptin: Across clinical studies in the saxagliptin programme a small decrease in absolutelymphocyte count was observed, approximately 100 cells/microL relative to placebo. Mean absolutelymphocyte counts remained stable with daily dosing up to 102 weeks in duration. This decrease inmean absolute lymphocyte count was not associated with clinically relevant adverse reactions.

Data from the saxagliptin and dapagliflozin plus metformin treatment arms of the three individualstudies included in the pooled analysis, 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 decreasesfrom baseline in triglycerides (ranging from -3.0% to -10.8%).

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 inpatients 75 years and older.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In the event of an overdose, appropriate supportive treatment should be initiated as dictated by thepatient’s clinical status. Saxagliptin and its major metabolite are removed by haemodialysis (23% ofdose over four hours). The removal of dapagliflozin by haemodialysis has not been studied. Highoverdose or concomitant risks of metformin may lead to lactic acidosis. Lactic acidosis is a medicalemergency and must be treated in a hospital. The most effective method to remove lactate andmetformin is haemodialysis.

Pharmacotherapeutic group: Drugs used in diabetes, combinations of oral blood glucose loweringdrugs, ATC code: A10BD25.

Qtrilmet combines three anti-hyperglycaemic medicinal products with different and complementarymechanisms of action to improve glycaemic control in patients with type 2 diabetes: metforminhydrochloride, a member of the biguanide class, saxagliptin, a DPP-4 inhibitor and dapagliflozin, a

SGLT2 inhibitor.

Metformin is a biguanide with anti-hyperglycaemic effects, lowering both basal and postprandialplasma glucose. It does not stimulate insulin secretion and therefore, does not produce hypoglycaemia.

Metformin may act via three mechanisms; by reduction of hepatic glucose production by inhibitinggluconeogenesis and glycogenolysis, by modestly increasing insulin sensitivity, improving peripheralglucose uptake and utilisation in muscle, and by delaying intestinal glucose absorption. Metforminstimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin increases thetransport capacity of specific types of membrane glucose transporters (GLUT-1 and GLUT-4).

Saxagliptin is a highly potent (Ki: 1.3 nM), selective, reversible and competitive inhibitor of DPP-4, anenzyme responsible for the breakdown of incretin hormones. This results in a glucose-dependentincrease in insulin secretion, thus reducing fasting and post-prandial blood glucose concentrations.

Dapagliflozin is a highly potent (Ki: 0.55 nM), selective and reversible inhibitor of sodium-glucoseco-transporter 2 (SGLT2). Dapagliflozin blocks reabsorption of filtered glucose from the S1 segmentof the renal tubule, effectively lowering blood glucose in a glucose dependent and insulin-independentmanner. Dapagliflozin improves both fasting and post-prandial plasma glucose levels by reducing renalglucose reabsorption leading to urinary glucose excretion. The increased urinary glucose excretion with

SGLT2 inhibition produces an osmotic diuresis, and can result in a reduction in systolic BP.

The safety and efficacy of the fixed-dose combination of metformin/saxagliptin/dapagliflozin wasevaluated in five randomised, double-blind, active/placebo-controlled clinical trials in adult subjectswith type 2 diabetes mellitus. Two add-on therapy trials, which added either dapagliflozin tosaxagliptin plus metformin or saxagliptin to dapagliflozin plus metformin, were conducted for24 weeks followed by a 28-week extension treatment period. In one trial conducted for 24 weeks,saxagliptin and dapagliflozin added to metformin was compared to saxagliptin or dapagliflozin addedto metformin. In one of two supportive studies, therapy with saxagliptin and dapagliflozin wascompared to glimepiride in patients inadequately controlled on metformin. The other study comparedtherapy with saxagliptin and dapagliflozin to insulin glargine in patients inadequately controlled onmetformin with or without a sulphonylurea.

Add-on therapy with dapagliflozin in patients inadequately controlled on saxagliptin plus metformin

A 24-week randomised, double-blind, placebo-controlled study with a 28-week extension comparedthe sequential addition of 10 mg dapagliflozin to 5 mg saxagliptin and metformin to the addition ofplacebo to 5 mg saxagliptin (DPP-4 inhibitor) and metformin in patients with type 2 diabetes mellitusand inadequate glycaemic control (HbA1c ≥ 7% and ≤ 10.5%). Three hundred twenty (320) patientswere randomised equally into either the dapagliflozin added to saxagliptin plus metformin treatmentgroup or placebo plus saxagliptin plus metformin treatment group. The treatment groups wereproportionally well balanced with regard to demographics, subject characteristics, diseasecharacteristics, and medical history. The mean age was 55.1 years and 54.4% of patients were female.

The mean duration of T2DM when entering the study was 7.6 years, mean baseline HbA1c of 8.2%.

All patients had been on a stable dose of metformin (1,500 mg or greater per day) for at least 8 weeksprior to screening visit. 101 patients were on a maximum dose of DPP4 inhibitor for at least 8 weeksbefore the screening visit and then switched to saxagliptin 5 mg for 8 weeks ahead of the study start.

The remaining 219 patients started to take 5 mg saxagliptin 16 weeks ahead of the study start.

The group with dapagliflozin sequentially added to saxagliptin and metformin achieved statisticallysignificant (p-value < 0.0001) greater reductions in HbA1c versus the group with placebo sequentiallyadded to saxagliptin plus metformin group at 24 weeks (see Table 2). The effect in HbA1c observed atweek 24 was sustained at week 52. The adjusted mean changes from baseline in HbA1c for thedapagliflozin and saxagliptin plus metformin and placebo and saxagliptin plus metformin groups were

- 0.74% (95% CI: -0.90, -0.57) and 0.07% (95% CI: -0.13, 0.27), respectively. The difference in theadjusted mean change from baseline to week 52 between the treatment groupswas -0.81% (95% CI: -1.06, -0.55).

Add-on therapy with saxagliptin in patients inadequately controlled on dapagliflozin plus metformin

A 24-week randomised, double-blind, placebo-controlled study conducted on patients with type 2diabetes mellitus and inadequate glycaemic control (HbA1c ≥ 7% and ≤ 10.5%) on metformin anddapagliflozin alone, compared the sequential addition of 5 mg saxagliptin to 10 mg dapagliflozin andmetformin, to the addition of placebo to 10 mg dapagliflozin and metformin. 153 patients wererandomised into the saxagliptin added to dapagliflozin plus metformin treatment group, and 162patients were randomised into the placebo added to dapagliflozin plus metformin treatment group. Thetreatment groups were proportionally well balanced with regard to demographics, subjectcharacteristics, disease characteristics, and medical history. The mean age was 54.6 years and 52.7% ofpatients were female. The mean duration of T2DM when entering the study was 7.7 years, meanbaseline HbA1c of 7.9%. Patients had been on a stable dose of metformin (1,500 mg or greater perday) for at least 8 weeks prior to screening visit and were then treated with metformin anddapagliflozin 10 mg for 10 weeks ahead of the study start.

The group with saxagliptin 5 mg sequentially added to dapagliflozin 10 mg and metformin achievedstatistically significant (p-value < 0.0001) greater reductions in HbA1c versus the group with placebosequentially added to dapagliflozin plus metformin group at 24 weeks (see Table 2). The effect in

HbA1c observed at week 24 was sustained at week 52. At week 52, adjusted mean changes frombaseline in HbA1c in the saxagliptin and dapagliflozin plus metformin and placebo and dapagliflozinplus metformin groups were -0.38% (95% CI: -0.53, -0.22) and 0.05% (95% CI: -0.11, 0.20),respectively. The difference in the adjusted mean change from baseline to week 52 between thetreatment groups was -0.42% [95% CI: -0.64, -0.20].

Table 2. HbA1c change from baseline at week 24 excluding data after rescue for randomisedsubjects - studies MB102129 and CV181168

Sequential add-on clinical trials

Study MB102129 Study CV181168

Dapagliflozin Saxagliptin

Efficacy 10 mg added 5 mg added to Placebo +parameter to saxagliptin Placebo + dapagliflozin dapagliflozin5 mg + saxagliptin 5 mg + 10 mg + 10 mg +metformin metformin metformin metformin(N=160) † (N=160) † (N=153) † (N=162) †

HbA1c (%) at week 24*

Baseline(mean) 8.24 8.16 7.95 7.85

Change frombaseline(adjusted

- 0.82 -0.10 -0.51 -0.16mean‡)(95% CI) (-0.96, 0.69) (-0.24, 0.04) (-0.63, -0.39) (-0.28, -0.04)

Difference in

HbA1c effect

Adjustedmean -0.72 -0.35(95% CI) (-0.91, -0.53) (-0.52, -0.18)p-value < 0.0001 < 0.0001 LRM = Longitudinal repeated measures (using values prior to rescue).† N is the number of randomised and treated patients with baseline and at least 1 post-baseline efficacy measurement.‡ Least squares mean adjusted for baseline value.

Proportion of patients achieving HbA1c < 7% in study MB102129 and study CV181168

The proportion of patients achieving HbA1c < 7.0% at week 24 in the add-on therapy withdapagliflozin 10 mg to saxagliptin 5 mg plus metformin trial was higher in the dapagliflozin 10 mg andsaxagliptin 5 mg plus metformin group 38.0% (95% CI [30.9, 45.1]) compared to the placebo plussaxagliptin 5 mg plus metformin group 12.4% (95% CI [7.0, 17.9]). The effect in HbA1c observed atweek 24 was sustained at week 52. The adjusted percent of subjects with HbA1c < 7.0% at week 52was 29.4% in the dapagliflozin and saxagliptin plus metformin group and 12.6% in the placebo andsaxagliptin plus metformin group. The adjusted percent difference at week 52 between the treatmentgroups was 16.8%.

The proportion of patients achieving HbA1c < 7% at week 24 for add-on therapy with saxagliptin 5 mgto dapagliflozin 10 mg plus metformin trial was higher in the saxagliptin 5 mg and dapagliflozin 10 mgplus metformin group 35.3% (95% CI [28.2, 42.2]) compared to the placebo plus dapagliflozin 10 mgplus metformin group 23.1% (95% CI [16.9, 29.3]). The effect in HbA1c observed at week 24 wassustained at week 52. The adjusted percent of subjects with HbA1c < 7.0% at week 52 was 29.3% inthe saxagliptin and dapagliflozin plus metformin group and 13.1% in the placebo and dapagliflozinplus metformin group. The adjusted percent difference at week 52 between the treatment groups was16.2%.

Therapy with saxagliptin 5 mg and dapagliflozin 10 mg in patients inadequately controlled onmetformin

A total of 534 adult patients with type 2 diabetes mellitus and inadequate glycaemic control onmetformin alone (HbA1c ≥ 8% and ≤ 12%), participated in this 24-week randomised, double-blind,active comparator-controlled superiority trial to compare the combination of saxagliptin 5 mg anddapagliflozin 10 mg added concurrently to metformin, versus saxagliptin 5 mg (DPP-4 inhibitor) ordapagliflozin 10 mg (SGLT2 inhibitor) added to metformin. The treatment groups were proportionallywell balanced with regard to demographics, subject characteristics, disease characteristics, and medicalhistory. The mean age was 53.8 years and 49.8% of patients were female. The mean duration of T2DMwhen entering the study was 7.6 years, mean baseline HbA1c of 8.94% and patients had been on astable dose of metformin (1,500 mg or greater per day) for at least 8 weeks prior to the screening visit.

Patients were randomised to one of three double-blind treatment groups to receive saxagliptin 5 mg anddapagliflozin 10 mg added to metformin, saxagliptin 5 mg and placebo added to metformin, ordapagliflozin 10 mg and placebo added to metformin.

The saxagliptin and dapagliflozin group achieved significantly greater reductions in HbA1c versuseither the saxagliptin group or dapagliflozin group at 24 weeks (see Table 3).

Table 3. HbA1c at week 24 in active-controlled study comparing the combination of saxagliptin5 mg and dapagliflozin 10 mg added concurrently to metformin with either saxagliptin 5 mg ordapagliflozin 10 mg added to metformin

Saxagliptin 5 mg + Saxagliptin Dapagliflozindapagliflozin 10 mg 5 mg 10 mg

Efficacy parameter+ metformin + metformin + metformin

N=179† N=176† N=179†

HbA1c (%) at week 24*

Baseline (mean) 8.93 9.03 8.87

Change from baseline(adjusted mean‡)(95% Confidence interval -1.47 -0.88 -1.20[CI]) (-1.62, -1.31) (-1.03, -0.72) (-1.35, -1.04)

Difference from saxagliptin +metformin (adjusted mean‡) -0.59§(95% CI) (-0.81, -0.37) - -

Difference fromdapagliflozin + metformin(adjusted mean‡) -0.27¶(95% CI) (-0.48, -0.05) - -

* LRM = Longitudinal repeated measures using values prior to rescue.† Randomised and treated patients.‡ Least squares mean adjusted for baseline value.

§ p-value < 0.0001.¶ p-value = 0.0166.

The majority of patients in this study had a baseline HbA1c of > 8% (see Table 4). The combination ofsaxagliptin 5 mg and dapagliflozin 10 mg added to metformin consistently demonstrated greaterreductions in HbA1c irrespective of baseline HbA1c compared with saxagliptin 5 mg or dapagliflozin10 mg alone added to metformin. In a separate pre-specified subgroup analysis, mean reductions frombaseline in HbA1c were generally greater for patients with higher baseline HbA1c values.

Table 4. HbA1c subgroup analysis by baseline HbA1c at week 24 in randomised subjects

Adjusted mean change from baseline by baseline

HbA1c

Treatments < 8.0% ≥ 8% to < 9.0% ≥ 9.0%

Saxagliptin + Dapagliflozin +

Adjusted mean change from

- 0.80 -1.17 -2.03baseline(n=37) (n=56) (n=65)(95% CI) (-1.12, -0.47) (-1.44, -0.90) (-2.27, -1.80)

Saxagliptin + Metformin

Adjusted mean change from -0.69 -0.51 -1.32baseline(n=29) (n=51) (n=63)(95% CI) (-1.06, -0.33) (-0.78, -0.25) (-1.56, -1.09)

Dapagliflozin + Metformin

Adjusted mean change from -0.45 -0.84 -1.87baseline(n=37) (n=52) (n=62)(95% CI) (-0.77, -0.13) (-1.11, -0.57) (-2.11, -1.63)n = number of subjects with non-missing baseline and a week 24 value.

Proportion of patients achieving HbA1c < 7%41.4% (95% CI [34.5, 48.2]) of patients in the saxagliptin 5 mg and dapagliflozin 10 mg combinationgroup achieved HbA1c levels of less than 7% compared to 18.3% (95% CI [13.0, 23.5]) patients in thesaxagliptin 5 mg group and 22.2% (95% CI [16.1, 28.3]) patients in the dapagliflozin 10 mg group atweek 24.

Therapy with saxagliptin 5 mg and dapagliflozin 10 mg in comparison to glimepiride in patientsinadequately controlled on metformin

A 52-week randomised, double-blind, active-controlled, parallel-group study with a blinded 104-weekextension compared once daily saxagliptin 5 mg and dapagliflozin 10 mg plus metformin toglimepiride (a sulphonylurea) up-titrated 1-6 mg plus placebo with metformin in T2DM patients withinadequate glycaemic control (HbA1c ≥ 7.5% and ≤ 10.5%) on metformin alone. Patients onglimepiride/placebo dose were up-titrated starting at 1 mg per day over 12 weeks to optimal glycaemiceffect (FPG < 6.1 mmol/L) or the highest tolerable dose. Thereafter, glimepiride/placebo dose werekept constant, except for down-titration to prevent hypoglycaemia.

At week 52, the adjusted mean change in HbA1c from baseline was -1.35% for the saxagliptin 5 mgand dapagliflozin 10 mg plus metformin group (N=218), compared to -0.98% for the glimepiride plusmetformin group (N=212) (difference -0.37%, 95% CI [-0.57, -0.18], p < 0.001).

Therapy with saxagliptin 5 mg and dapagliflozin 10 mg in comparison to insulin glargine in patientsinadequately controlled on metformin with or without a sulphonylurea

A 24-week randomised, open-label, active-controlled, parallel-group study with a 28-week extensioncompared orally once daily saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without asulphonylurea to titrated subcutaneous insulin glargine plus metformin with or without a sulphonylureain T2DM patients with inadequate glycaemic control (HbA1c ≥ 8.0% and ≤ 12.0%).

At week 24, the adjusted mean change in HbA1c from baseline was -1.67% for the saxagliptin 5 mgand dapagliflozin 10 mg plus metformin with or without SU group (N=319), which was noninferior tothe change of -1.54% in the insulin glargine plus metformin with or without SU group (N=312)(difference -0.13%, 95% CI [-0.30, 0.03]).

Combination therapy with saxagliptin 5 mg and dapagliflozin 10 mg compared to glimepiride in

T2DM patients with inadequate glycaemic control on metformin alone resulted in significant differencein mean body weight change at week 52. The adjusted mean change from baseline was -3.11 kg (95%

CI [-3.65, -2.57]) for the saxagliptin 5 mg and dapagliflozin 10 mg plus metformin group, and 0.95 kg(95% CI [0.38, 1.51]) for the glimepiride plus metformin group. The difference in mean body weightbetween treatment groups was -4.06 kg (95% CI [-4.84, -3.28] p < 0.001) at week 52.

The combination of saxagliptin 5 mg and dapagliflozin 10 mg plus metformin, with or without asulphonylurea group, compared to treatment with insulin glargine and metformin, with or without a

SU, resulted in significant difference in body weight change at week 24. The mean change frombaseline was -1.50 kg (95% CI [-1.89, -1.11]) for the saxagliptin 5 mg and dapagliflozin 10 mg, plusmetformin group, versus 2.14 kg (95% CI [1.75, 2.54]) in the insulin glargine plus metformin group.

The difference in mean body weight between treatment groups was -3.64 kg (95% CI [-4.20, -3.09]p < 0.001).

In the study of concomitant addition of saxagliptin and dapagliflozin, the adjusted mean change frombaseline in body weight at week 24 (excluding data after rescue) was -2.05 kg (95% CI [-2.52, -1.58])in the saxagliptin 5 mg and dapagliflozin 10 mg plus metformin group and -2.39 kg(95% CI [-2.87, -1.91]) in the dapagliflozin 10 mg plus metformin group, while the saxagliptin 5 mgplus metformin group had no change (0.00 kg) (95% CI [-0.48, 0.49]).

In study MB102129 and study CV181168, treatment with Qtrilmet resulted in change from baseline forsystolic blood pressure ranging from -1.3 to -2.2 mmHg and for diastolic blood pressure rangingfrom -0.5 to -1.2 mmHg caused by Qtrilmet’s mild diuretic effect. The modest lowering effects on BPwere consistent over time and a similar number of patients had systolic BP < 130 mmHg or diastolic

BP < 80 mmHg at week 24 across the treatment groups.

In the study comparing concomitant therapy of saxagliptin and dapagliflozin with glimepiride inpatients inadequately controlled on metformin alone, the decrease in systolic blood pressure at week 52in the saxagliptin 5 mg and dapagliflozin 10 mg plus metformin group (-2.6 mmHg 95%

CI [-4.4, -0.8]) was greater than in the glimepiride plus metformin group (1.0 mmHg 95% CI [-0.9,2.9]). The difference in mean SBP between treatment groups was -3.6 mmHg (95% CI [-6.3, -1.0]p = 0.007).

In the pooled safety analysis, cardiovascular (CV) events that were adjudicated and confirmed as CVevents were reported in a total of 1.0% of subjects in the saxagliptin plus dapagliflozin plus metformingroup, 0.6% in the saxagliptin plus metformin group, and 0.9% in the dapagliflozin plus metformingroup.

The prospective randomised (UKPDS) study has established the long-term benefit of intensive bloodglucose control in type 2 diabetes. Analysis of the results for overweight patients treated withmetformin after failure of diet alone showed:

- a significant reduction of the absolute risk of any diabetes-related complication in the metformingroup (29.8 events/1,000 patient-years) versus diet alone (43.3 events/1,000 patient-years),p = 0.0023, and versus the combined sulphonylurea and insulin monotherapy groups (40.1events/1,000 patient-years), p = 0.0034;

- a significant reduction of the absolute risk of any diabetes-related mortality: metformin 7.5events/1,000 patient-years, diet alone 12.7 events/1,000 patient-years, p = 0.017;

- a significant reduction of the absolute risk of overall mortality: metformin 13.5 events/1,000patient-years versus diet alone 20.6 events/1,000 patient-years, (p = 0.011), and versus thecombined sulphonylurea and insulin monotherapy groups 18.9 events/1,000 patient-years(p = 0.021);

- a significant reduction in the absolute risk of myocardial infarction: metformin 11 events/1,000patient-years, diet alone 18 events/1,000 patient-years, (p = 0.01).

Saxagliptin assessment of vascular outcomes recorded in patients with diabetes mellitus - thrombolysisin myocardial infarction (SAVOR) study

SAVOR was a CV outcome trial in 16,492 patients with HbA1c ≥ 6.5% and < 12% (12,959 withestablished CV disease; 3,533 with multiple risk factors only) who were randomised to saxagliptin(n=8,280) or placebo (n=8,212) added to regional standards of care for HbA1c and CV risk factors.

The study population included those ≥ 65 years (n = 8,561) and ≥ 75 years (n = 2,330), with normal ormild renal impairment (n = 13,916) as well as moderate (n = 2,240) or severe (n = 336) renalimpairment.

The primary safety (non-inferiority) and efficacy (superiority) endpoint was a composite endpointconsisting of the time-to-first occurrence of any of the following major adverse CV events (MACE):

CV death, nonfatal myocardial infarction, or nonfatal ischemic stroke.

After a mean follow up of 2 years, the trial met its primary safety endpoint demonstrating saxagliptindoes not increase the cardiovascular risk in patients with type 2 diabetes compared to placebo whenadded to current background therapy.

No benefit was observed for MACE or all-cause mortality.

One component of the secondary composite endpoint, hospitalisation for heart failure, occurred at agreater rate in the saxagliptin group (3.5%) compared with the placebo group (2.8%), with nominalstatistical significance favouring placebo [HR=1.27; (95% CI 1.07, 1.51); P = 0.007]. Clinicallyrelevant factors predictive of increased relative risk with saxagliptin treatment could not be definitivelyidentified. Subjects at higher risk for hospitalisation for heart failure, irrespective of treatmentassignment, could be identified by known risk factors for heart failure, such as baseline history of heartfailure or impaired renal function. However, subjects on saxagliptin with a history of heart failure orimpaired renal function at baseline were not at an increased risk relative to placebo for the primary orsecondary composite endpoints or all-cause mortality.

Another secondary endpoint, all-cause mortality, occurred at a rate of 5.1% in the saxagliptin groupand 4.6% in the placebo group. CV deaths were balanced across the treatment groups. There was anumerical imbalance in non-CV death, with more events on saxagliptin (1.8%) than placebo (1.4%)[HR = 1.27; (95% CI 1.00, 1.62); P = 0.051].

Dapagliflozin

A meta-analysis of cardiovascular events in the clinical program was performed. In the clinicalprogram, 34.4% of subjects had a history of cardiovascular disease (excluding hypertension) atbaseline and 67.9% had hypertension. The hazard ratio comparing dapagliflozin to comparatorwas 0.79 (95% CI: 0.58, 1.07), indicating that in this analysis dapagliflozin is not associatedwith an increase in cardiovascular risk in patients with type 2 diabetes mellitus. Cardiovasculardeath, MI, and stroke were observed with a hazard ratio of 0.77 (95% CI: 0.54, 1.10).

The European Medicines Agency has waived the obligation to submit the results of studies with

Qtrilmet in all subsets of the paediatric population in the treatment of type 2 diabetes (see section 4.2for information on paediatric use).

Bioequivalence has been confirmed between Qtrilmet tablets and the individual components(metformin modified-release, saxagliptin and dapagliflozin) in healthy subjects when administered inthe fed state.

Metformin: Following a single oral dose of metformin extended-release tablet, Cmax is achieved with amedian value of 7 hours and a range of 4 to 8 hours. The extent of metformin absorption (as measuredby AUC) from the metformin extended-release tablet increased by approximately 50% when givenwith food. There was no effect of food on Cmax and Tmax of metformin.

Saxagliptin: Saxagliptin was rapidly absorbed after oral administration in the fasted state, withmaximum plasma concentrations (Cmax) of saxagliptin and its major metabolite attained within 2 and4 hours (Tmax), respectively. The Cmax and AUC values of saxagliptin and its major metaboliteincreased proportionally with the increment in the saxagliptin dose, and this dose-proportionality wasobserved 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 and214 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 than12%.

Dapagliflozin: Dapagliflozin was rapidly and well absorbed after oral administration. Maximumdapagliflozin plasma concentrations (Cmax) were usually attained within 2 hours after administration inthe fasted state. Geometric mean steady-state dapagliflozin Cmax and AUCτ values following once daily10 mg doses of dapagliflozin were 158 ng/mL and 628 ng h/mL, respectively. The absolute oralbioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Food hasrelatively modest effects on the pharmacokinetics of dapagliflozin in healthy subjects. Administrationwith a high-fat meal decreases dapagliflozin Cmax by up to 50% and prolonged Tmax by approximately1 hour, but does not alter AUC as compared with the fasted state. These changes are not considered tobe clinically meaningful.

Metformin: Plasma protein binding is negligible. Metformin partitions into erythrocytes. The bloodpeak is lower than the plasma peak and appears at approximately the same time. The red blood cellsmost likely represent a secondary compartment of distribution. The mean Vd ranged between 63-276 L.

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

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

Metformin: Metformin is excreted unchanged in the urine. No metabolites have been identified inhumans.

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.

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: Dapagliflozin is extensively metabolised, primarily to yielddapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide or othermetabolites do not contribute to the glucose-lowering effects. The formation ofdapagliflozin 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.

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 co-administered medicinalproducts that are metabolised by these enzymes.

Metformin: Renal clearance of metformin is > 400 mL/min, indicating that metformin is eliminated byglomerular filtration and tubular secretion. Following an oral dose, the apparent terminal eliminationhalf-life is approximately 6.5 hours.

Saxagliptin: The mean plasma terminal half-life (t1/2) values for saxagliptin and its major metaboliteare 2.5 hours and 3.1 hours, respectively, and the mean t1/2 value for plasma DPP-4 inhibition was26.9 hours. Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mgdose of 14C-saxagliptin, 24%, 36% and 75% of the dose was excreted in the urine as saxagliptin, itsactive 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 asingle oral dose of dapagliflozin 10 mg to healthy subjects. The mean total systemic clearance ofdapagliflozin administered intravenously was 207 mL/min. Dapagliflozin and related metabolites areprimarily eliminated via urinary excretion with less than 2% as unchanged dapagliflozin.

Metformin: At steady state, the AUC and Cmax are less than dose proportional for metforminextended-release within the range of 500 to 2,000 mg administered once daily.

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

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

Metformin: The available data in subjects with moderate renal insufficiency are scarce and no reliableestimation of the systemic exposure to metformin in this subgroup as compared to subjects with normalrenal function could be made. In patients with decreased renal function, the plasma and blood half-lifeof metformin is prolonged and the renal clearance is decreased, leading to increased levels ofmetformin in plasma, (see sections 4.2, pct. 4.3 and 4.4).

Saxagliptin: After a single dose of saxagliptin in subjects with mild, moderate or severe renalimpairment (or ESRD) classified on the basis of creatinine clearance the mean AUC values ofsaxagliptin were 1.2-, and up to 2.1- and 4.5- fold higher, respectively, than AUC values in subjectswith normal renal function. The AUC values of 5-OH-saxagliptin were also increased. The degree ofrenal 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 2diabetes mellitus and mild, moderate or severe renal impairment (as determined by iohexol plasmaclearance) 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-hoururinary glucose excretion was highly dependent on renal function and 85, 52, 18 and 11 g ofglucose/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 haemodialysis on dapagliflozinexposure is not known.

Metformin hydrochloride: No pharmacokinetic studies of metformin have been conducted in patientswith 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-foldhigher, 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 tohealthy matched control subjects. These differences were not considered to be clinically meaningful. Insubjects with severe hepatic impairment (Child-Pugh class C) mean Cmax and AUC of dapagliflozinwere 40% and 67% higher than matched healthy controls, respectively.

Metformin hydrochloride: Limited data from controlled pharmacokinetic studies of metformin inhealthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life isprolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears thatthe change in metformin pharmacokinetics with aging is primarily accounted for by a change in renalfunction (see sections 4.2 and 4.4).

Saxagliptin: Elderly patients (65-80 years) had about 60% higher saxagliptin AUC than young patients(18-40 years). This is not considered clinically meaningful.

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

Metformin hydrochloride: Metformin pharmacokinetic parameters did not differ significantly betweennormal subjects and patients with type 2 diabetes when analysed according to gender (males=19,females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the anti-hyperglycaemic effect of metformin was comparable in males and females.

Saxagliptin: Females had approximately 25% higher systemic exposure values for saxagliptin. Therewere no clinically relevant differences observed in saxagliptin pharmacokinetics between males andfemales.

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

Metformin hydrochloride: No studies of metformin pharmacokinetic parameters according to race havebeen performed.

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

Dapagliflozin: There were no clinically relevant differences in systemic exposures between White,

Black or Asian races.

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 isconsidered not clinically relevant.

Dapagliflozin: Dapagliflozin exposure was found to decrease with increased weight. Consequently,low-weight patients may have somewhat increased exposure and patients with high-weight somewhatdecreased exposure. However, the differences in exposure were not considered clinically meaningful.

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

Saxagliptin: Saxagliptin produced reversible skin lesions (scabs, ulcerations and necrosis) inextremities (tail, digits, scrotum and/or nose) in cynomolgus monkeys. The no observed 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 skinlesions is not known, and skin lesions have not been observed in humans.

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

Saxagliptin produced gastrointestinal toxicity in dogs, including bloody/mucoid faeces andenteropathy at higher doses with a NOEL 4 and 2 times the human exposure for saxagliptin and themajor metabolite, respectively, at RHD. The effect on offspring body weights were noted untilpostnatal day 92 and 120 in females and males, respectively.

No non-clinical studies have been conducted in metformin/saxagliptin/dapagliflozin combination.

Metformin: Animal studies with metformin do not indicate harmful effects with respect to pregnancy,embryonic or foetal development, parturition or postnatal development.

Saxagliptin: Saxagliptin has effects on fertility in male and female rats at high doses producing overtsigns of toxicity. Saxagliptin was not teratogenic at any doses evaluated in rats or rabbits. At highdoses in rats, saxagliptin caused reduced ossification (a developmental delay) of the foetal pelvis anddecreased foetal body weight (in the presence of maternal toxicity), with a NOEL 303 and 30 times thehuman exposure for saxagliptin and the major metabolite, respectively, at RHD. In rabbits, the effectsof saxagliptin were limited to minor skeletal variations observed only at maternally toxic doses (NOEL158 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 atmaternally toxic doses, with NOEL 488 and 45 times the human exposure for saxagliptin and the majormetabolite, respectively, at RHD. The effect on offspring body weights were noted until postnatal day92 and 120 in females and males, respectively.

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

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

Dapagliflozin dosed to maternal rats from gestation day 6 through postnatal day 21, and pups wereindirectly exposed in utero and throughout lactation. Increased incidence or severity of renal pelvicdilatation was observed in adult offspring of treated dams, although only at the highest dose tested (atmaternal and pup dapagliflozin exposures of 1,415 times and 137 times, respectively, the human valuesat the maximum recommended human dose [MRHD]). Additional developmental toxicity was limitedto dose-related reductions in pup body weights, and observed only at doses ≥ 15 mg/kg/day (pupexposures ≥ 29 times the human values at the MRHD). Maternal toxicity was evident only at thehighest 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 thehuman values at the MRHD.

In additional studies of embryo-foetal development in rabbits, dapagliflozin caused neither maternalnor developmental toxicities at any dose tested; the highest dose tested corresponded to a systemicexposure 1,191 times the MRHD. In rats, dapagliflozin was neither embryolethal nor teratogenic atexposures up to 1,441 times the human values at the MRHD.

Carmellose sodium (E466)

Crospovidone (E1202)

Hypromellose (E464)

Magnesium stearate (E470b)

Cellulose, microcrystalline (E460i)

Silica, dental type (E551)

Qtrilmet 850 mg/2.5 mg/5 mg modified-release tablets

Macrogol (E1521)

Poly(vinyl alcohol) (E1203)

Titanium dioxide (E171)

Talc (E553b)

Iron oxide yellow (E172)

Iron oxide red (E172)

Iron oxide black (E172)

Qtrilmet 1,000 mg/2.5 mg/5 mg modified-release tablets

Macrogol (E1521)

Poly(vinyl alcohol) (E1203)

Titanium dioxide (E171)

Talc (E553b)

Iron oxide black (E172)

Iron oxide yellow (E172)

Not applicable.

PVC/PCTFE/alu blister

Shelf life: 2 years

PA/alu/PVC/alu blister

Shelf life: 30 months

PVC/PCTFE/alu blister

Do not store above 30°C.

PA/alu/PVC/alu blister

This medicinal product does not require any special storage conditions.

PVC/PCTFE/alu blister

Pack size of 14, 28, 56 and 196 modified-release tablets in calendar blisters.

Pack size of 14, 28, 56, 60 and 196 modified-release tablets in blisters.

PA/alu/PVC/alu blister

Pack size of 14, 28, 56, 60 and 196 modified-release tablets in blisters.

Not all pack sizes may be marketed.

No special requirements.

AstraZeneca AB

SE-151 85 Södertälje

Sweden

Qtrilmet 850 mg/2.5 mg/5 mg modified-release tablets

PVC/PCTFE/alu blister

EU/1/19/1401/001 14 modified-release tablets

EU/1/19/1401/002 28 modified-release tablets

EU/1/19/1401/003 56 modified-release tablets

EU/1/19/1401/004 60 modified-release tablets

EU/1/19/1401/005 196 modified-release tablets

EU/1/19/1401/006 14 modified-release tablets (calendar blister)

EU/1/19/1401/007 28 modified-release tablets (calendar blister)

EU/1/19/1401/008 56 modified-release tablets (calendar blister)

EU/1/19/1401/009 196 modified-release tablets (calendar blister)

PA/alu/PVC/alu blister

EU/1/19/1401/010 14 modified-release tablets

EU/1/19/1401/011 28 modified-release tablets

EU/1/19/1401/012 56 modified-release tablets

EU/1/19/1401/013 60 modified-release tablets

EU/1/19/1401/014 196 modified-release tablets

Qtrilmet 1,000 mg/2.5 mg/5 mg modified-release tablets

PVC/PCTFE/alu blister

EU/1/19/1401/015 14 modified-release tablets

EU/1/19/1401/016 28 modified-release tablets

EU/1/19/1401/017 56 modified-release tablets

EU/1/19/1401/018 60 modified-release tablets

EU/1/19/1401/019 196 modified-release tablets

EU/1/19/1401/020 14 modified-release tablets (calendar blister)

EU/1/19/1401/021 28 modified-release tablets (calendar blister)

EU/1/19/1401/022 56 modified-release tablets (calendar blister)

EU/1/19/1401/023 196 modified-release tablets (calendar blister)

PA/alu/PVC/alu blister

EU/1/19/1401/024 14 modified-release tablets

EU/1/19/1401/025 28 modified-release tablets

EU/1/19/1401/026 56 modified-release tablets

EU/1/19/1401/027 60 modified-release tablets

EU/1/19/1401/028 196 modified-release tablets

Date of first authorisation: 11 November 2019

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu