Qtrilmet - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

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

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

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Each tablet contains 850 mg of metformin hydrochloride, saxagliptin hydrochloride equivalent to 2.5 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 e

• 2.5 mg saxagliptin and dapagliflozin propanediol monohydrate equivalent to 5 mg dapagliflozin.

Excipient with known effect

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

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Modified-release tablet (tablet).

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

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

Qtrilmet 1,000 mg/2.5 mg/5 mg moi

4.1 Therapeutic indicationsQtrilmet is i

ted in adults aged 18 years and older with type 2 diabetes mellitus:

ove glycaemic control when metformin with or without sulphonylurea (SU) and either gliptin or dapagliflozin does not provide adequate glycaemic control.

when already being treated with metformin and saxagliptin and dapagliflozin.

4.2 Posology and method of administration

Posology

Each tablet contains a fixed dose of metformin, saxagliptin and dapagliflozin (see section 2). If no adequate strength of Qtrilmet is available, individual mono-components should be used instead of the modified-release combination.

The maximum recommended daily dose of Qtrilmet is metformin 2,000 mg/saxa­gliptin

• 5 mg/dapagliflozin 10 mg.

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

Patients should receive a total daily dose of Qtrilmet equivalent to saxagliptin 5 mg, dapagliflozin 10 mg, plus the total daily dose of metformin, or the nearest therapeutically appropriate dose, already being 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 be taken or the nearest therapeutically appropriate dose of metformin. The dose should be taken as two tablets 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 therapeutically appropriate dose (see sections 5.1 and 5.2).

Missed doses

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

Special populations

Elderly

Because elderly patients (> 65 years) are more likely to have decreased renal function, this medicinal product should be used with caution as age increases. Monitoring of renal function is necessary to aid in prevention of metformin associated lactic acidosis, particularly in elderly patients (see sections 4.3 and 4.4). Risk of volume depletion w         edicinal product should also be taken into account (see

sections 4.4 and 5.2). Due to the limi      rapeutic experience with this medicinal product in patients

s not recommended in this population.

ded for Qtrilmet in patients with mild renal impairment,

sed before initiation of treatment with metformin containing medicinal products

thereafter. In patients at increased risk of further progression of renal impairment , 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, 4.8, 5.1 and 5.2). This medicinal product is contraindicated in patients with GFR < 30 mL/min (see sections 4.3, 4.4, 4.8 and 5.2).

Hepatic impairment

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

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

Qtrilmet dose is taken orally once daily at the same time of the day with food to reduce the gastrointestinal 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.

4.3 Contraindications

Qtrilmet is contraindicated in patients with:

• – hypersensitivity to the active substances or to any of the excipients listed in section 6.1, 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);

• – any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis) (see section

• 4.4 and 4.8);

  
  

• – diabetic pre-coma (see section 4.4);

• – severe renal failure (GFR < 30 mL/min) (see sections 4.2, 4.4 and 5.2);

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

dehydration, severe infection, shock;

acute or chronic disease which may cause tissue hypoxia such as:

cardiac or respiratory failure, recent myocardial infarction, shock;

• – hepatic impairment (see sections 4.2 and 5.2);

• – acute alcohol intoxication, alcoholism (see section 4.5).

4.4 Special warnings and precautions for use

Lactic acidosis lic complication, most often occurs at acute worsening of psis. Metformin accumulation occurs at acute worsening c acidosis.

arrhoea or vomiting, fever or reduced fluid intake), Qtrilmet should be tact 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 lactic acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting, and any conditions associated with hypoxia, as well as concomitant use of medicinal products 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 is characterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia, and hypothermia followed by coma. In case of suspected symptoms, the patient should stop taking Qtrilmet and seek immediate 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.

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

Renal function should be assessed:

• –     prior to initiation of this medicinal product and regularly 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 (see section 4.5);

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

Metformin is contraindicated in patients with GFR of < 30 mL/min and this treatment should be temporarily 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 be exercised in situations where renal function may become impaired, for example when initiating anti-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 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 Qtrilmet, in case of intercurrent conditionmay 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 of DPP-4 inhibitors has been ass

should be informed of the chara pain. If pancreatitis is suspected confirmed, it should not be resta pancreatitis.

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

itis 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, Qtrilmet should be discontinued and prompt treatment (including antibiotics and surgical debridement) should be instituted.

Hypersensitivity reactions

of bullous pemphigoid requiring hospitalisation have been reported with DPP4 ing 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 Qtrilmet is used in patients who have known risk factors for hospitalisation for heart failure, such as a history of heart failure or moderate to severe renal impairment. Patients should be advised of the characteristic symptoms of heart failure, and to immediately report such symptoms.

Arthralgia

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

Immunocompromised patients

Immunocompromised patients, such as patients who have undergone organ transplan      or patients

diagnosed with human immunodeficiency syndrome have not been studied in the saxtin clinical programme. The efficacy and safety profiles of Qtrilmet in these patients have not been established.

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 counselnts on routine preventative foot care.

Use with insulin or insulin secretagogues known to causi

Both saxagliptin and dapagliflozin can individually increase the risk of hypoglycaemia when combined with insulin or an insulin secretagogue (sulphonylurea). Hypoglycaemia does not occur in patients receiving metformin alone 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 reduce the risk of hy          ia when these agents are used in combination with Qtrilmet

(see sections 4.5 and 4.8).

Surgery

Qtrilmet must be discontinuethe 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 and provided that renal function has been re-evaluated and found to be stable.

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

Elevated haematocrit

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

Urine laboratory assessments

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

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, Qtrilmet 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.

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

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.

Lactose

The tablets contain lactose. Patients with rare hereditary p deficiency, or glucose-galactose malabsorption should not

Sodium content

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

Pharmacodynamic interaction;

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

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 be discontinued prior to, or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable (see sections 4.2 and 4.4).

Combinations requiring precautions for use

Glucocorticoids (given by systemic and local routes), beta-2 agonists, and diuretics have intrinsic hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring performed, especially at the beginning of treatment with such medicinal products, and observed for loss of blood glucose control or hypoglycaemia. If necessary, the dose of the glucose-lowering medicinal product 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 lactic acidosis, 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 such products in combination with metformin, close monitoring of renal function is necessary.

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

Saxagliptin and dapagliflozin can individually increase the risk of hypoglycaemia when combi

insulin or an insulin secretagogue. Hypoglycaemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur during concomitant use with otlucose-lowering agents. Therefore, a lower dose of insulin or insulin secretagogue may be requto reduce the risk of hypoglycaemia when these agents are used in combination with Qtril and 4.8).

Pharmacokinetic interactions

Metformin

Metformin is excreted unchanged in the urine. No metabolites

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 uridine diphosphate (UDP) glucuronosyltran­sferase 1A9 (UGT1A9).

Effect of other medicinal products on

gliptin and CYP3A4/5 inducers, other than rifampicin (such as carbamazepine, dex     asone, phenobarbital, and phenytoin) has not been studied and may result in

decreased plasma c   entration of saxagliptin and increased concentration of its major metabolite.

Glycaemic      l should be carefully assessed when saxagliptin is used concomitantly with a potent

CYP3A4/5     er.

t administration of saxagliptin with the potent CYP3A4/5 inducer rifampicin reduced Cmax and      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).

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.

In studies conducted in healthy subjects, neither the pharmacokinetics of saxagliptin nor its major metabolite 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 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 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 on 24-hour urinary glucose excretion.

The pharmacokinetics of dapagliflozin were not meaningfully altered by saxa pioglitazone, sitagliptin, glimepiride, voglibose, hydrochlorothi­azide, bumetani simvastatin.

Effect of metformin, saxagliptin or dapagliflozin on other medicinal products

Metformin

Organic cation transporters (OCT)

Metformin is a substrate of both transporters OCT1 and OC

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 of

metformin;

• – inhibitors of OCT2 (such as cimetidine, dolutegravir, ranolazine, trimethoprime, vandetanib,

  nal elimination of metformin and thus lead to an increase in

  
  

isavuconazole) may decrease the metformin plasma concentration; inhibitors of both OCT1 and OCT elimination of metformin.

Caution is therefore advised,cially in patients with renal impairment, when these medicinal products are co-administered with metformin, as metformin plasma concentration may increase (see section 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 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 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 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.

4.6 Fertility, pregnancy and lactation

Pregnancy

The use of this medicinal product, or its components (metformin hydrochloride, saxagliptin and dapagliflozin) has not been studied 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). A limited amount of data from the use of metformin in pregnant women does not indicate an increased risk of congenital malformations. Animal studies with metformin 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 medici product should be discontinued.

When the patient plans to become pregnant, and during pregnancy, it is recommended that diabetes is not treated with this medicinal product, but insulin be used to maintain blood glucose levels as close to normal as possible, to reduce the risk of malformations of the foetus associated with abnormal blood glucose levels.

Breast-feeding

Metformin is excreted in human milk in small amounts. A risk to excluded. It is unknown whether saxagliptin and dapagliflozi human milk. Animal studies have shown excretion of saxaglipti pharmacodynamic/to­xicological data in animals have shocretion of dapagliflozin/me­tabolites in milk, as well as pharmacologically-mediated effects in breast-feeding offspring (see section 5.3).

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

Fertility

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

reproductive toxicity (see section 5.3).

egligible influence on the ability to drive and use machines.

or using machines, it should be taken into account that dizziness has been reported in ith saxagliptin. In addition, patients should be alerted to the risk of hypoglycaemia when this l product is used in combination with other glucose-lowering medicinal products known to

4.8 Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions associated with Qtrilmet are upper respiratory tract infections (very common), hypoglycaemia when used with SU (very common), gastrointestinal symptoms (very common) and urinary tract infections (common). Diabetic ketoacidosis may occur rarely 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 the adverse reactions identified for the respective mono-components.

Tabulated list of adverse reactions

The safety profile is based on pooled analysis of three placebo controlled phase 3 clinical trials in 1,169 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. The adverse reactions associated with Qtrilmet are presented in Table 1. The adverse reactions are listed by system organ class (SOC) and frequency. Frequency categories were defined according to very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), very rare (> 1/100,000 to < 1/10,000) and not known (cannot be estimated from the available data).

Table 1. Compilation of adverse reactions for Qtrilmet

System organ class	Very common	Common A	Uncommon B	Rare	Very rare	Not known
Infections and infestations	Upper respiratory tract infection111	Urinary tract infection#12, vulvovaginitis, balanitis and related genital infection#3, gastroenteritis^	Fungal infection#	X r	Necrotising fasciitis of the perineum (Fournier's gan­grene) #,C,7
Immune system disorders		i	Hypersensitivity reactions1 C	Anaphylactic reactions including anaphylactic shock1 C
Metabolism and nutrition disorders	Hypo-. X glycaemiaD#1 (when used with SU)	Dyslipid- • #4 aemia	Volume depletion#, thirst#	Diabetic ketoacidosis #,H,7	Lactic acidosis§, Vitamin B12 deficiency§G
Nervous system disorders	r	Headache1, dizziness1
Gastrointestinal disorders	Gastrointestinal symptoms§F	DyspepsiaD ° gastritisD ° taste disturbance§	Constipation# , dry mouth#, pancreatitis1 C
Hepatobiliary disorders					Liver function disorders§, hepatitis§
Renal and urinary disorders		Dysuria#, polyuria# D,5	Nocturia#, renal impairment#
Skin and subcutaneous tissue		Rash#16	DermatitislC, pruritus1 C, urticaria1 C	Angio-edema1 C	Erythema§	Bullous pemphi-goidC,7

System organ class	Very common	Common A	Uncommon B	Rare	Very rare	Not known
disorders
Musculoskeletal and connective tissue disorders		Arthralgia0, back pain#, myalgiaD0
Reproductive system and breast disorders			Erectile dysfunction0, pruritus genital#, vulvovaginal pruritus#
General disorders and administratio n site conditions		Fatigue1D, oedema peripheral1D			♦
Investigations		Creatinine renal clearance decreased#, haematocrit increased# E	Blood creatinine increased#, blood urea increased#, weight decreased# {

# Adverse reaction reported for dapagliflozin.

• 1 Adverse reaction reported for saxagliptin.

• § Adverse reaction reported for metformin.

Q 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 of saxagliptin + dapagliflozin + metformin 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 any of the mono-components, and > 1% more than placebo, but not in the pooled safety 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  Gastrointestinal symptoms (subsumed terms included nausea, vomiting, diarrhoea, abdominal pain, and loss

of 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 which may very rarely result in clinically significant vitamin B12 deficiency. Consideration of such etiology is recommended if a patient presents with megaloblastic anaemia.

H 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.

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 dapagliflozin 10 mg and saxagliptin 5 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 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 comb

compared to 33.1% for insulin. The overall incidence rates of hypoglycaemia in two 52-comparing the combination therapy to glimepiride (SU) were: for the 1ststudy, 4.2% combination therapy versus 27.9% for glimepiride plus metformin versus 2.9% for dliflozin plus metformin; for the 2ndstudy, 18.5% for the combination therapy versus 43.1% for glimepiride plus metformin.

Volume depletion

In the pooled safety analysis, events related to volume depletion (hypotension, dehydration, and hypovolemia) 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).

Metformin/saxa­gliptin/dapagli­flozin combination: In the pooled safety analysis for Qtrilmet, the

incidence of adverse events related plus dapagliflozin plus metformin 0.6% subjects in the dapagliflozin

impairment had lower mean

93.6 mL/min/1­.73 m2in the      ll population. The majority of events were considered non-serious,

mild or moderate in intensity     resolved. The change in mean eGFR from baseline at week 24

was –1.17 mL/min/1­.73 m2in the saxagliptin plus dapagliflozin plus metformin group, –0.46 mL/min/1­.73 m2in saxagliptin plus metformin, and 0.81 mL/min/1­.73 m2in dapagliflozin plus metformin.

n: Adverse reactions related to increased creatinine have been reported for dapagliflozin as ponent. The increases in creatinine were generally transient during continuous treatment or er discontinuation of treatment.

Vulvovaginitis, balanitis and related genital infections

The reported adverse reactions of vulvovaginitis, balanitis and related genital infections from pooled safety analysis were reflective of the safety profile of dapagliflozin. Adverse reactions 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 reactions 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 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

In the pooled safety analysis, urinary tract infections (UTIs) were balance

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 treatment. The majority of the urinary tract infections were re UTI), were mild or moderate in intensity, of single occurrence

Malignancies

Laboratory findings

Decrease in lymphocyte counts

Saxagliptin: Across clinical studies in the saxagliptin programme 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

Data from the saxagliptin and dapagliflozin plus metformin treatment arms of the three individual studies 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 decreases from baseline in triglycerides (ranging from –3.0% to –10.8%).

Special populations

Elderly

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal pro allows continued monitoring of the benefit/risk balance of the medicinal professionals are asked to report any suspected adverse reactions via the listed in Appendix V.

4.9 Overdose

In the event of an overdose, appropriate supportive treatm patient’s clinical status. Saxagliptin and its major metabol

dose over four hours). The removal of dapagliflozin by haemodialysis has not been studied. High overdose or concomitant risks of metformin may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in a hospital. The most effective method to remove lactate and metformin is haemodialysis.

5.1 Pharmacody­namic pro

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

Mechanism of acti

Qtrilmet combines three anti-hyperglycaemic medicinal products with different and complementary mechanisms of action to improve glycaemic control in patients with type 2 diabetes: metformin hydrochloride, 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 postprandial plasma 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 inhibiting gluconeogenesis and glycogenolysis, by modestly increasing insulin sensitivity, improving peripheral glucose uptake and utilisation in muscle, and by delaying intestinal glucose absorption. Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin increases the transport 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, an enzyme responsible for the breakdown of incretin hormones. This results in a glucose-dependent increase 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-glucose co-transporter 2 (SGLT2). Dapagliflozin blocks reabsorption of filtered glucose from the S1 segment of the renal tubule, effectively lowering blood glucose in a glucose dependent and insulin-independent manner. Dapagliflozin improves both fasting and post-prandial plasma glucose levels by reducing renal glucose 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.

Clinical efficacy and safety

The safety and efficacy of the fixed-dose combination of metformin/saxa­gliptin/dapagli­flozin evaluated in five randomised, double-blind, active/placebo-controlled clinical trials in with type 2 diabetes mellitus. Two add-on therapy trials, which added either dapagliflo saxagliptin plus metformin or saxagliptin to dapagliflozin plus metformin, were condu

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 2 diabetes mellitus and inadequate glycaemic control (HbA1c > 7% and < 10.5%) on metformin and dapagliflozin alone, compared the sequential addition of 5 mg saxagliptin to 10 mg dapagliflozin and metformin, to the addition of placebo to 10 mg dapagliflozin and metformin. 153 patients were randomised into the saxagliptin added to dapagliflozin plus metformin treatment group, and 162 patients were randomised into the placebo added to dapagliflozin plus metformin treatment group. The treatment groups were proportionally well balanced with regard to demographics, subject characteristics, disease characteristics, and medical history. The mean age was 54.6 years and 52.7% of patients were female. The mean duration of T2DM when entering the study was 7.7 years, mean baseline HbA1c of 7.9%. Patients had been on a stable dose of metformin (1,500 mg or greater per day) for at least 8 weeks prior to screening visit and were then treated with metformin and dapagliflozin 10 mg for 10 weeks ahead of the study start.

The group with saxagliptin 5 mg sequentially added to dapagliflozin 10 mg and metformin achieved statistically significant (p-value < 0.0001) greater reductions in HbA1c versus the group with placebo sequentially 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 from baseline in HbA1c in the saxagliptin and dapagliflozin plus metformin and placebo and dapagliflo plus 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 the treatment groups was –0.42% [95% CI: –0.64, –0.20].

Table 2. HbA1c change from baseline at week 24 excluding data after rescue for randomised subjects – studies MB102129 and CV181168

Sequential add-on clinical trials

• * LRM = Longitudinal repeated measures (using values prior to rescue).

t 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 with dapagliflozin 10 mg to saxagliptin 5 mg plus metformin trial was higher in the dapagliflozin 10 mg and saxagliptin 5 mg plus metformin group 38.0% (95% CI [30.9, 45.1]) compared to the placebo plus saxagliptin 5 mg plus metformin group 12.4% (95% CI [7.0, 17.9]). The effect in HbA1c observed at week 24 was sustained at week 52. The adjusted percent of subjects with HbA1c < 7.0% at week 52 was 29.4% in the dapagliflozin and saxagliptin plus metformin group and 12.6% in the placebo and saxagliptin plus metformin group. The adjusted percent difference at week 52 between the treatment groups was 16.8%.

The proportion of patients achieving HbA1c < 7% at week 24 for add-on therapy with saxagliptin 5 mg to dapagliflozin 10 mg plus metformin trial was higher in the saxagliptin 5 mg and dapagliflozin 10 mg plus metformin group 35.3% (95% CI [28.2, 42.2]) compared to the placebo plus dapagliflozin 10 mg plus metformin group 23.1% (95% CI [16.9, 29.3]). The effect in HbA1c observed at week 24 was sustained at week 52. The adjusted percent of subjects with HbA1c < 7.0% at week 52 was 29.3% in the saxagliptin and dapagliflozin plus metformin group and 13.1% in the placebo and dapagliflozin plus metformin group. The adjusted percent difference at week 52 between the treatment groups was 16.2%.

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

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

Table 3. HbA1c at week 24 in active-contr     study comparing the combination of saxagliptin

5 mg and dapagliflozin 10 mg added concurrently to metformin with either saxagliptin 5 mg or dapagliflozin 10 mg added to metformin

Efficacy parameter	Saxagliptin 5 mg + dapagliflozin 10 mg + metformin N=179 t	Saxagliptin 5 mg + metformin N=176 t	Dapagliflozin 10 mg + metformin N=179 t
HbAlc (%) at week 24
Baseline (mean)	8.93	9.03	8.87
Change from baseline (adjusted meant) (95% Confidence interval [CI])	–1.47 (-1.62, –1.31)	–0.88 (-1.03, –0.72)	–1.20 (-1.35, –1.04)
Difference from saxagliptin + metformin (adjusted meant) (95% CI)	–0.59§ (-0.81, –0.37)	-	-
Difference from dapagliflozin + metformin (adjusted meant) (95% CI)	–0.2711 (-0.48, –0.05)	-	-

LRM = Longitudinal repeated measures using values prior to rescue.

t Randomised and treated patients.

t Least squares mean adjusted for baseline value.

§ p-value < 0.0001.

1 p-value = 0.0166.

The majority of patients in this study had a baseline HbA1c of > 8% (see Table 4). The combination of saxagliptin 5 mg and dapagliflozin 10 mg added to metformin consistently demonstrated greater reductions in HbA1c irrespective of baseline HbA1c compared with saxagliptin 5 mg or dapagliflozin 10 mg alone added to metformin. In a separate pre-specified subgroup analysis, mean reductions from baseline 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 HbAlc
Treatments	< 8.0%	> 8% to < 9.0%	> 9.0%	.(2>
Saxagliptin + Dapagliflozin + Metformin Adjusted mean change from baseline (95% CI)	–0.80 (n=37) (-1.12, –0.47)	–1.17 (n=56) (-1.44, –0.90)	(n=65) (-2.27, –1.80)
Saxagliptin + Metformin Adjusted mean change from baseline (95% CI)	–0.69 (n=29) (-1.06, –0.33)	■0L^ (n=51) (-0.78, –0.25)	–1.32 (n=63) (-1.56, –1.09)
Dapagliflozin + Metformin Adjusted mean change from baseline (95% CI)	–0.45 (n=37) (-0.77, –0.13)	■0.84 (n=52) ►    (-1.11, –0.57)	–1.87 (n=62) (-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 combination group achieved HbA1c levels of less than 7% compared to 18.3% (95% CI [13.0, 23.5]) patients in the saxagliptin 5 mg group and 22.2% (95% CI [16.1, 28.3]) patients in the dapagliflozin 10 mg group at week 24.

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

A 52-week randomised, double-blind, active-controlled, parallel-group study with a blinded 104-week extension compared once daily saxagliptin 5 mg and dapagliflozin 10 mg plus metformin to glimepiride (a sulphonylurea) up-titrated 1–6 mg plus placebo with metformin in T2DM patients with inadequate glycaemic control (HbAlc >7.5% and < 10.5%) on metformin alone. Patients on glimepiride/placebo dose were up-titrated starting at 1 mg per day over 12 weeks to optimal glycaemic effect (FPG < 6.1 mmol/L) or the highest tolerable dose. Thereafter, glimepiride/placebo dose were kept 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 mg and dapagliflozin 10 mg plus metformin group (N=218), compared to –0.98% for the glimepiride plus metformin 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 patients inadequately controlled on metformin with or without a sulphonylurea

A 24-week randomised, open-label, active-controlled, parallel-group study with a 28-week extension compared orally once daily saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without a sulphonylurea to titrated subcutaneous insulin glargine plus metformin with or without a sulphonylurea in T2DM patients with inadequate glycaemic control (HbAlc > 8.0% and < 12.0%).

At week 24, the adjusted mean change in HbA1c from baseline was –1.67% for the saxagliptin 5 mg and dapagliflozin 10 mg plus metformin with or without SU group (N=319), which was noninferior to the 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]).

Body weight

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 dif

in mean body weight change at week 52. The adjusted mean change from baseline was –3. CI [-3.65, –2.57]) for the saxagliptin 5 mg and dapagliflozin 10 mg plus metformin group, (95% CI [0.38, 1.51]) for the glimepiride plus metformin group. The difference in mean b between 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 a sulphonylurea 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 from baseline was –1.50 kg (95% CI [-1.89, –1.11]) for the saxagliptin 5 mg and dapagliflozin 10 mg, plus metformin 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 from baseline 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

g plus metformin group, while the saxagliptin 5 mg 5% CI [-0.48, 0.49]).

Blood pressure

In study MB102129 and study CV181168, treatment with Qtrilmet resulted in change from baseline for systolic blood pressure ranging from –1.3 to –2.2 mmHg and for diastolic blood pressure ranging from –0.5 to –1.2 mmHg caused by Qtrilmet’s mild diuretic effect. The modest lowering effects on BP were 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 in patients inadequately controlled on metformin alone, the decrease in systolic blood pressure at week 52 iptin 5 mg and dapagliflozin 10 mg plus metformin group (-2.6 mmHg 95%

.8]) was greater than in the glimepiride plus metformin group (1.0 mmHg 95% CI [-0.9, e difference in mean SBP between treatment groups was –3.6 mmHg (95% CI [-6.3, –1.0]

Cardiovascular safety

In the pooled safety analysis, 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.

Metformin

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

• – a significant reduction of the absolute risk of any diabetes-related complication in the metformin

group (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 (40.1 events/1,000 pa­tient-years), p = 0.0034;

• – a significant reduction of the absolute risk of any diabetes-related mortality: metformin 7.5

events/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/1,000

5.2 Pharmacokinetic properties

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

Absorption

Metformin: Following a single oral dose of metformin extended-release tablet, C

median value of 7 hours and a range of 4 to 8 hours. The extent o by AUC) from the metformin extended-release tablet increase with food. There was no effect of food on Cmax and Tmax of

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%.

rapidly and well absorbed after oral administration. Maximum rations (Cmax) were usually attained within 2 hours after administration in etric mean steady-state dapagliflozin Cmax and AUCt values following once daily iflozin were 158 ng/mL and 628 ng h/mL, respectively. The absolute oral

pagliflozin following the administration of a 10 mg dose is 78%. Food has effects on the pharmacokinetics of dapagliflozin in healthy subjects. Administration

-fat meal decreases dapagliflozin Cmax by up to 50% and prolonged Tmax by approximately does not alter AUC as compared with the fasted state. These changes are not considered to

be clinically meaningful.

Distribution

Metformin: Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most 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 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

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

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 yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozi metabolites do not contribute to the glucose-lowering effects. The formation dapagliflozin 3-O-glucuronide is mediated by UGT1A9, an enzyme present CYP-mediated metabolism was a minor clearance pathway in humans.

Linearity

Metformin: At steady state, the AUC and Cmax are less than dose proportional for metformin extended-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 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

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

Saxagliptin: After a single dose of saxagliptin in subjects with mild, moderate or severe impairment (or ESRD) classified on the basis of creatinine clearance the mean AUC saxagliptin were 1.2-, and up to 2.1– and 4.5– fold higher, respectively, than AU with normal renal function. The AUC values of 5-OH-saxagliptin were 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.     mpact of haemodialysis on dapagliflozin

exposure is not known.

Hepatic impairment

Metformin hydrochloride: No pharmacokinetic studies of metformin have been conducted in patients with 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.

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

Elderly

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

Metformin hydrochloride: Metformin pharmacokinetic parameters did not differ significantly between normal 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. 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

Metformin hydrochloride: No studies of metformin pharmacokinetic para been performed.

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 Black or Asian races.

Body weight

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.

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.

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

Saxagliptin: Saxagliptin produced reversible skin lesions (scabs, ulcerations and necrosis) in extremities (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 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.

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

Reproductive and developmental toxicity

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 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 ti human exposure for saxagliptin and the major metabolite, respectively, at RHD. In rabbits, th of saxagliptin were limited to minor skeletal variations observed only at maternally toxic d 158 and 224 times the human exposure for saxagliptin and the major metabolite, respec

RHD). In a pre- and postnatal developmental study in rats, saxagliptin caused decrea maternally toxic doses, with NOEL 488 and 45 times the human exposure for s metabolite, respectively, at RHD. The effect on offspring body weights were n 92 and 120 in females and males, respectively.

Dapagliflozin: Direct administration of dapagliflozin to weanling juvenile rats and indirect exposure during late pregnancy (corresponding to the second and third trimes human renal maturation) and lactation are each associated with i 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.

station day 6 through postnatal day 21, and pups were ut lactation. Increased incidence or severity of renal pelvic ring of treated dams, although only at the highest dose tested (at

maternal and pup dapagliflozin exposures of 1,415 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 tim     human values at the MRHD). Maternal toxicity was evident only at the

highest dose tesimited to transient reductions in body weight and food consumption at dose. The NOAEL foelopmental toxicity is associated with a maternal systemic exposure 19 times the human values at the MRHD.

l studies of embryo-foetal development in rabbits, dapagliflozin caused neither maternal mental toxicities at any dose tested; the highest dose tested corresponded to a systemic

exposure 1,191 times the MRHD. In rats, dapagliflozin was neither embryolethal nor teratogenic at exposures up to 1,441 times the human values at the MRHD.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Tablet core

Carmellose sodium (E466)

6.2 Incompatibilities

6.3 Shelf life

6.4 Special precautions for storage

6.5 Nature and contents of container

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.

6.6 Special precautions for disposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER

AstraZeneca AB

SE-151 85 Sodertalje

Sweden

8. MARKETING AUTHORISATION NUMBER(S)

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 (

EU/1/19/1401/­009 196 modifi­ed-release tablets

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

EU/1/19/1401/­014 196 modifi­ed-releas

Qtrilmet 1,000 mg/2.5 mg/5 mg

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

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 11 November 2019