SYNJARDY 12.5mg / 1000mg tablets medication leaflet

Synjardy 5 mg/850 mg film-coated tablets

Synjardy 5 mg/1,000 mg film-coated tablets

Synjardy 12.5 mg/850 mg film-coated tablets

Synjardy 12.5 mg/1,000 mg film-coated tablets

Synjardy 5 mg/850 mg film-coated tablets

Each tablet contains 5 mg empagliflozin and 850 mg metformin hydrochloride.

Synjardy 5 mg/1,000 mg film-coated tablets

Each tablet contains 5 mg empagliflozin and 1,000 mg metformin hydrochloride.

Synjardy 12.5 mg/850 mg film-coated tablets

Each tablet contains 12.5 mg empagliflozin and 850 mg metformin hydrochloride.

Synjardy 12.5 mg/1,000 mg film-coated tablets

Each tablet contains 12.5 mg empagliflozin and 1,000 mg metformin hydrochloride.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Synjardy 5 mg/850 mg film-coated tablets

Yellowish white, oval, biconvex film coated tablets debossed with “S5” and the Boehringer Ingelheimlogo on one side and “850” on the other side (tablet length: 19.2 mm, tablet width: 9.4 mm).

Synjardy 5 mg/1,000 mg film-coated tablets

Brownish yellow, oval, biconvex film coated tablets debossed with “S5” and the Boehringer

Ingelheim logo on one side and “1000” on the other side (tablet length: 21.1 mm, tablet width:

9.7 mm).

Synjardy 12.5 mg/850 mg film-coated tablets

Pinkish white, oval, biconvex film coated tablets debossed with “S12” and the Boehringer Ingelheimlogo on one side and “850” on the other side (tablet length: 19.2 mm, tablet width: 9.4 mm).

Synjardy 12.5 mg/1,000 mg film-coated tablets

Dark brownish purple, oval, biconvex film coated tablets debossed with “S12” and the Boehringer

Ingelheim logo on one side and “1000” on the other side (tablet length: 21.1 mm, tablet width:

9.7 mm).

Synjardy is indicated in adults and children aged 10 years and above for the treatment of type 2diabetes mellitus as an adjunct to diet and exercise:

* in patients insufficiently controlled on their maximally tolerated dose of metformin alone

* in combination with other medicinal products for the treatment of diabetes, in patientsinsufficiently controlled with metformin and these medicinal products

* in patients already being treated with the combination of empagliflozin and metformin asseparate tablets.

For study results with respect to combinations, effects on glycaemic control and cardiovascular events,and the population studied, see sections 4.4, 4.5 and 5.1.

Adults with normal renal function (eGFR ≥90 ml/min/1.73 m2)

The recommended dose is one tablet twice daily. The dosage should be individualised on the basis ofthe patient’s current regimen, effectiveness, and tolerability using the recommended daily dose of10 mg or 25 mg of empagliflozin, while not exceeding the maximum recommended daily dose ofmetformin.

For patients insufficiently controlled on metformin (either alone or in combination with othermedicinal products for the treatment of diabetes)

In patients insufficiently controlled on metformin alone or in combination with other medicinalproducts for the treatment of diabetes, the recommended starting dose of Synjardy should provideempagliflozin 5 mg twice daily (10 mg daily dose) and the dose of metformin similar to the dosealready being taken. In patients tolerating a total daily dose of empagliflozin 10 mg and who needtighter glycaemic control, the dose can be increased to a total daily dose of empagliflozin 25 mg.

When Synjardy is used in combination with a sulphonylurea and/or insulin, a lower dose ofsulphonylurea and/or insulin may be required to reduce the risk of hypoglycemia (see sections 4.5 and4.8).

For patients switching from separate tablets of empagliflozin and metformin

Patients switching from separate tablets of empagliflozin (10 mg or 25 mg total daily dose) andmetformin to Synjardy should receive the same daily dose of empagliflozin and metformin alreadybeing taken or the nearest therapeutically appropriate dose of metformin (for available strengths seesection 2).

If a dose is missed, it should be taken as soon as the patient remembers; however, a double doseshould not be taken on the same time. In that case, the missed dose should be skipped.

The glycaemic efficacy of empagliflozin is dependent on renal function. For cardiovascular riskreduction as add on to standard of care, a dose of 10 mg empagliflozin daily should be used in patientswith an eGFR below 60 ml/min/1.73 m2 (see Table 1). Because the glycaemic lowering efficacy ofempagliflozin is reduced in patients with moderate renal impairment and likely absent in patients withsevere renal impairment, if further glycaemic control is needed, the addition of other anti-hyperglycaemic agents should be considered.

For dose adjustment recommendations according to eGFR or CrCL refer to Table 1.

A eGFR should be assessed before initiation of treatment with metformin containing products and atleast annually thereafter. In patients at increased risk of further progression of renal impairment and inthe elderly, renal function should be assessed more frequently, e.g. every 3-6 months.

If no adequate strength of Synjardy is available, individual monocomponents should be used instead ofthe fixed dose combination.

For dosing recommendations in the paediatric population see subsection paediatric patients below.

Table 1: Posology for renally impaired adult patientsaeGFR Metformin Empagliflozin[ml/min/1.73m²] or CrCL[ml/min]≥60 Maximum daily dose is 3000 mg. Initiate with 10 mg.

Dose reduction may be considered in In patients tolerating 10 mg andrelation to declining renal function. requiring additional glycaemiccontrol, the dose can be increased to25 mg.

45 to <60 Maximum daily dose is 2000 mg. Initiate with 10 mg.b

The starting dose is at most half of the Continue with 10 mg in patientsmaximum dose. already taking empagliflozin.

30 to <45 Maximum daily dose is 1000 mg. Initiate with 10 mg. b

The starting dose is at most half of the Continue with 10 mg in patientsmaximum dose. already taking empagliflozin.b<30 Metformin is contraindicated. Empagliflozin is not recommended.a See sections 4.4, pct. 4.8, 5.1 and 5.2b patients with type 2 diabetes mellitus and established cardiovascular disease

This medicinal product must not be used in patients with hepatic impairment (see sections pct. 4.3, pct. 4.4 and5.2).

Due to the mechanism of action, decreased renal function will result in reduced glycaemic efficacy ofempagliflozin. Because metformin is excreted by the kidney and elderly patients are more likely tohave decreased renal function, Synjardy should be used with caution in these patients. Monitoring ofrenal function is necessary to aid in prevention of metformin-associated lactic acidosis, particularly inelderly patients (see sections 4.3 and 4.4). In patients 75 years and older, an increased risk for volumedepletion should be taken into account (see sections 4.4 and 4.8).

The dosage should be individualised on the basis of the patient’s current regimen, effectiveness, andtolerability.

If empagliflozin is added in patients already receiving metformin, the metformin dose should remainthe same as the patient is already taking. The recommended empagliflozin starting dose is 5 mg twicedaily (10 mg total daily doses). In patients tolerating empagliflozin 5 mg twice daily and requiringadditional glycaemic control, the dose can be increased to 12.5 mg twice daily (25 mg total dailydose).

If patients switching from separate tablets of empagliflozin and metformin to Synjardy the same dailydose of empagliflozin and metformin should remain as already being taken or the nearesttherapeutically appropriate dose of metformin.

The maximum recommended daily dose of Synjardy is 25 mg of empagliflozin and 2000 mg ofmetformin (see general information above in section 4.2).

No data are available for children with eGFR <60 ml/min/1.73 m² and children below 10 years of age.

Synjardy should be taken twice daily with meals to reduce the gastrointestinal adverse reactionsassociated with metformin. The tablets should be swallowed whole with water. All patients shouldcontinue their diet with an adequate distribution of carbohydrate intake during the day. Overweightpatients should continue their energy restricted diet.

* Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

* Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis) (see section4.4).

* Diabetic pre-coma.

* Severe renal failure (eGFR <30 ml/min/1.73 m2) (see sections 4.2 and 4.4).

* Acute conditions with the potential to alter renal function such as: dehydration, severe infection,shock (see sections 4.4 and 4.8).

* Disease which may cause tissue hypoxia (especially acute disease, or worsening of chronicdisease) such as: decompensated heart failure, respiratory failure, recent myocardial infarction,shock (see section 4.4).

* Hepatic impairment, acute alcohol intoxication, alcoholism (see sections 4.2 and 4.5).

Empagliflozin should not be used in patients with type 1 diabetes mellitus (see “Diabetic ketoacidosis”in section 4.4)

Lactic acidosis

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

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

Medicinal products that can acutely impair renal function (such as antihypertensives, 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 of the risk of lactic acidosis. Lactic acidosis ischaracterised by acidotic dyspnea, abdominal pain, muscle cramps, asthenia and hypothermia followedby coma. In case of suspected symptoms, the patient should stop taking metformin and seekimmediate medical attention. Diagnostic laboratory findings are decreased blood pH (<7.35),increased plasma lactate levels (>5 mmol/l) and an increased anion gap and lactate/pyruvate ratio.

Patients with known or suspected mitochondrial diseases

In patients with known mitochondrial diseases such as Mitochondrial Encephalopathy with Lactic

Acidosis, and Stroke-like episodes (MELAS) syndrome and Maternal inherited diabetes and deafness(MIDD), metformin is not recommended due to the risk of lactic acidosis exacerbation and neurologiccomplications which may lead to worsening of the disease.

In case of signs and symptoms suggestive of MELAS syndrome or MIDD after the intake ofmetformin, treatment with metformin should be withdrawn immediately and prompt diagnosticevaluation should be performed.

Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have beenreported in patients treated with SGLT2 inhibitors, including empagliflozin. In a number of cases, thepresentation of the condition was atypical with only moderately increased blood glucose values, below14 mmol/l (250 mg/dl). It is not known if DKA is more likely to occur with higher doses ofempagliflozin.

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 empagliflozin should bediscontinued immediately.

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 empagliflozin may be restarted when theketone values are normal and the patient’s condition has stabilised.

Before initiating empagliflozin, factors in the patient history that may predispose to ketoacidosisshould be considered.

Prolonged diabetic ketoacidosis and prolonged glucosuria have been observed with empagliflozin.

Diabetic ketoacidosis may last longer after discontinuation of empagliflozin than expected from theplasma half-life (see section 5.2). Empagliflozin-independent factors, such as insulin deficiency, mightbe involved in prolonged periods of diabetic ketoacidosis.

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) orpatients with a history of pancreatitis), patients with conditions that lead to restricted food intake orsevere dehydration, 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.

Synjardy should not be used in patients with type 1 diabetes. Data from a clinical trial program inpatients with type 1 diabetes showed increased DKA occurrence with common frequency in patientstreated with empagliflozin 10 mg and 25 mg as an adjunct to insulin compared to placebo.

Administration of iodinated contrast agent

Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy,resulting in metformin accumulation and an increased risk of lactic acidosis. Metformin 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 4.2 and4.5).

Due to the mechanism of action, decreased renal function will result in reduced glycaemic efficacy ofempagliflozin. Empagliflozin/metformin is contraindicated in patients with eGFR<30 ml/min/1.73 m2and should be temporarily discontinued in the presence of conditions that alter renal function (seesection 4.3).

Assessment of renal function is recommended as follows:

- Prior to empagliflozin/metformin initiation and periodically during treatment, i.e. at least yearly (seesection 4.2).

- Prior to initiation of any concomitant medicinal product that may have a negative impact on renalfunction.

Cardiac function

Patients with heart failure are more at risk of hypoxia and renal insufficiency. In patients with stablechronic heart failure, Synjardy may be used with a regular monitoring of cardiac and renal function.

For patients with acute and unstable heart failure, Synjardy is contraindicated due to the metformincomponent (see section 4.3).

Metformin must be discontinued at the time of surgery under general, spinal or epidural anaesthesia.

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

Based on the mode of action of SGLT2 inhibitors, osmotic diuresis accompanying therapeuticglucosuria may lead to a modest decrease in blood pressure (see section 5.1). Therefore, cautionshould be exercised in patients for whom a empagliflozin-induced drop in blood pressure could pose arisk, such as patients with known cardiovascular disease, patients on anti-hypertensive therapy with ahistory of hypotension or patients aged 75 years and older.

In case of conditions that may lead to fluid loss (e.g. gastrointestinal illness), careful monitoring ofvolume status (e.g. physical examination, blood pressure measurements, laboratory tests includinghaematocrit) and electrolytes is recommended for patients receiving Synjardy. Temporary interruptionof treatment with Synjardy should be considered until the fluid loss is corrected.

The effect of empagliflozin on urinary glucose excretion is associated with osmotic diuresis, whichcould affect the hydration status. Patients aged 75 years and older may be at an increased risk ofvolume depletion. Therefore, special attention should be given to their volume intake in case of co-administered medicinal products which may lead to volume depletion (e.g. diuretics, ACE inhibitors).

Urinary tract infections

Post marketing cases of complicated urinary tract infections including pyelonephritis and urosepsishave been reported in patients treated with empagliflozin (see section 4.8). Temporary interruption oftreatment should be considered in patients with complicated urinary tract infections.

Cases of necrotising fasciitis of the perineum, (also known as Fournier’s gangrene), have beenreported in female and male patients taking SGLT2 inhibitors, including empagliflozin. This is a rarebut serious and potentially life-threatening event that requires urgent surgical intervention andantibiotic treatment.

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, Synjardy should be discontinued and prompt treatment (including antibioticsand surgical debridement) should be instituted.

An increase in cases of lower limb amputation (primarily of the toe) has been observed in long-termclinical studies with another SGLT2 inhibitor. It is unknown whether this constitutes a class effect.

Like for all diabetic patients it is important to counsel patients on routine preventative foot-care.

Cases of hepatic injury have been reported with empagliflozin in clinical trials. A causal relationshipbetween empagliflozin and hepatic injury has not been established.

Haematocrit increase was observed with empagliflozin treatment (see section 4.8). Patients withpronounced elevations in haematocrit should be monitored and investigated for underlyinghaematological disease.

There is experience with empagliflozin for the treatment of diabetes in patients with chronic kidneydisease (eGFR ≥30 mL/min/1.73 m2) both with and without albuminuria. Patients with albuminuriamay benefit more from treatment with empagliflozin.

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

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.

Vitamin B12

Metformin may reduce vitamin B12 levels. The risk of low vitamin B12 levels increases withincreasing metformin dose, treatment duration, and/or in patients with risk factors known to causevitamin B12 deficiency. In case of suspicion of vitamin B12 deficiency (such as anaemia orneuropathy), vitamin B12 serum levels should be monitored. Periodic vitamin B12 monitoring couldbe necessary in patients with risk factors for vitamin B12 deficiency. Metformin therapy should becontinued for as long as it is tolerated and not contra-indicated and appropriate corrective treatment forvitamin B12 deficiency provided in line with current clinical guidelines.

In the DINAMO trial (see section 5.1), the overall safety profile in children and adolescents wassimilar with the known safety profile seen in adult patients and there were no relevant differencesbetween placebo and empagliflozin regarding growth assessments or concerning the sexual maturationafter 26 weeks of treatment.

No effect of metformin on growth and puberty has been detected during controlled clinical studies ofone-year duration but no long-term data on these specific points are available. Therefore, a carefulfollow-up of the effect of metformin on these parameters in metformin-treated children, especiallyprepubescent children, is recommended.

Children aged between 10 and 12

In metformin studies, only 15 patients aged between 10 and 12 years were included in the controlledclinical studies conducted in children and adolescents.

The DINAMO trial included 157 patients and 91% were on metformin as background therapy, 25 ofthese patients were between 10 and 12 years old.

Although efficacy and safety of metformin in these children did not differ from efficacy and safety inolder children and adolescents, particular caution is recommended when prescribing to children agedbetween 10 and 12 years.

Co-administration of multiple doses of empagliflozin and metformin does not meaningfully alter thepharmacokinetics of either empagliflozin or metformin in healthy subjects.

No interaction studies have been performed for Synjardy. The following statements reflect theinformation available on the individual active substances.

Empagliflozin

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

Insulin and insulin secretagogues, such as sulphonylureas, may increase the risk of hypoglycaemia.

Therefore, a lower dose of insulin or an insulin secretagogue may be required to reduce the risk ofhypoglycaemia when used in combination with empagliflozin (see sections 4.2 and 4.8).

In vitro data suggest that the primary route of metabolism of empagliflozin in humans isglucuronidation by uridine 5'-diphosphoglucuronosyltransferases UGT1A3, UGT1A8, UGT1A9, and

UGT2B7. Empagliflozin is a substrate of the human uptake transporters OAT3, OATP1B1, and

OATP1B3, but not OAT1 and OCT2. Empagliflozin is a substrate of P-glycoprotein (P-gp) and breastcancer resistance protein (BCRP).

Co-administration of empagliflozin with probenecid, an inhibitor of UGT enzymes and OAT3,resulted in a 26% increase in peak empagliflozin plasma concentrations (Cmax) and a 53% increase inarea under the concentration-time curve (AUC). These changes were not considered to be clinicallymeaningful.

The effect of UGT induction (e.g. induction by rifampicin or phenytoin) on empagliflozin has not beenstudied. Co-treatment with known inducers of UGT enzymes is not recommended due to a potentialrisk of decreased efficacy. If an inducer of these UGT enzymes must be co-administered, monitoringof glycaemic control to assess response to Synjardy is appropriate.

An interaction study with gemfibrozil, an in vitro inhibitor of OAT3 and OATP1B1/1B3 transporters,showed that empagliflozin Cmax increased by 15% and AUC increased by 59% followingco-administration. These changes were not considered to be clinically meaningful.

Inhibition of OATP1B1/1B3 transporters by co-administration with rifampicin resulted in a 75%increase in Cmax and a 35% increase in AUC of empagliflozin. These changes were not considered tobe clinically meaningful.

Empagliflozin exposure was similar with and without co-administration with verapamil, a P-gpinhibitor, indicating that inhibition of P-gp does not have any clinically relevant effect onempagliflozin.

Interaction studies suggest that the pharmacokinetics of empagliflozin were not influenced byco-administration with metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin,verapamil, ramipril, simvastatin, torasemide and hydrochlorothiazide.

Empagliflozin may increase renal lithium excretion and the blood lithium levels may be decreased.

Serum concentration of lithium should be monitored more frequently after empagliflozin initiation anddose changes. Please refer the patient to the lithium prescribing doctor in order to monitor serumconcentration of lithium.

Based on in vitro studies, empagliflozin does not inhibit, inactivate, or induce CYP450 isoforms.

Empagliflozin does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. Drug-druginteractions involving the major CYP450 and UGT isoforms with empagliflozin and concomitantlyadministered substrates of these enzymes are therefore considered unlikely.

Empagliflozin does not inhibit P-gp at therapeutic doses. Based on in vitro studies, empagliflozin isconsidered unlikely to cause interactions with active substances that are P-gp substrates.

Co-administration of digoxin, a P-gp substrate, with empagliflozin resulted in a 6% increase in AUCand 14% increase in Cmax of digoxin. These changes were not considered to be clinically meaningful.

Empagliflozin does not inhibit human uptake transporters such as OAT3, OATP1B1, and OATP1B3in vitro at clinically relevant plasma concentrations and, as such, drug-drug interactions withsubstrates of these uptake transporters are considered unlikely.

Interaction studies conducted in healthy volunteers suggest that empagliflozin had no clinicallyrelevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin,linagliptin, simvastatin, warfarin, ramipril, digoxin, diuretics and oral contraceptives.

Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases offasting, malnutrition or hepatic impairment.

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 drugs are co-administered with metformin, as metformin plasma concentration may increase. If needed, doseadjustment of metformin may be considered as OCT inhibitors/inducers may alter the efficacy ofmetformin (see sections 4.2 and 4.4).

Iodinated contrast agents

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

Combination requiring precautions for use

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.

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. If necessary, thedose of the anti hyperglycaemic medicinal product should be adjusted during therapy with the othermedicinal product and on its discontinuation.

Insulin and insulin secretagogues, such as sulphonylureas, may increase the risk of hypoglycaemia.

Therefore, a lower dose of insulin or an insulin secretagogue may be required to reduce the risk ofhypoglycaemia when used in combination with metformin (see sections 4.2 and 4.8).

Interaction studies have only been performed in adults.

There are no data from the use of this medicinal product or empagliflozin in pregnant women. Animalstudies show that empagliflozin crosses the placenta during late gestation to a very limited extent butdo not indicate direct or indirect harmful effects with respect to early embryonic development.

However, animal studies have shown adverse effects on postnatal development. A limited amount ofdata suggests that the use of metformin in pregnant women is not associated with an increased risk ofcongenital malformations. Animal studies with the combination of empagliflozin and metformin orwith metformin alone have shown reproductive toxicity at higher doses of metformin only (see section5.3).

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 into human milk. No effects have been shown in breastfed newborns/infants oftreated women. No data in humans are available on excretion of empagliflozin into milk. Availableanimal data have shown excretion of empagliflozin and metformin in milk. A risk to thenewborns/infants cannot be excluded.

This medicinal product should not be used during breast feeding.

No studies on the effect on human fertility have been conducted for this medicinal product orempagliflozin. Animal studies with empagliflozin and metformin do not indicate direct or indirectharmful effects with respect to fertility (see section 5.3).

Synjardy has minor influence on the ability to drive and use machines. Patients should be advised totake precautions to avoid hypoglycaemia while driving and using machines, in particular when

Synjardy is used in combination with a sulphonylurea and/or insulin.

The most commonly reported adverse reactions in clinical trials were hypoglycaemia in combinationwith insulin and/or sulphonylurea and gastrointestinal symptoms (nausea, vomiting, diarrhoea,abdominal pain and loss of appetite). No additional adverse reactions were identified in clinical trialswith empagliflozin as add-on to metformin compared to the side effects of the single components.

The adverse reactions are listed by absolute frequency. Frequencies are defined as 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), orvery rare (<1/10,000), and not known (cannot be estimated from the available data).

Table 2: Tabulated list of adverse reactions (MedDRA) from placebo-controlled studies and frompost-marketing experience

System organ Very common Common Uncommon Rare Very rareclass

Infections and Vaginal moniliasis, Necrotisinginfestations vulvovaginitis, fasciitis ofbalanitis and other thegenital infection1, 2 perineum

Urinary tract (Fournier´sinfection (including gangrene) apyelonephritis andurosepsis)1, 2

Metabolism and Hypoglycaemia Thirst2 Diabetic Lactic acidosis3nutrition (when used Vitamin B12 ketoacidosisdisorders with decrease/deficiency3,a asulphonylureaor insulin)1

Nervous system Taste disturbance3disorders

Vascular Volumedisorders depletion1, 2,d

Gastrointestinal Gastrointestinal Constipationdisorders symptoms3, 4

Hepatobiliary Liver functiondisorders testsabnormalities3

Hepatitis3

Skin and Pruritus Urticaria Erythema3subcutaneous (generalised)2, 3 Angioedematissue disorders Rash

Renal and Increased urination1, 2 Dysuria2 Tubulointerstitialurinary nephritisdisorders

Investigations Serum lipids Bloodincreased2, b creatinineincreased/

Glomerularfiltrationratedecreased1

Haematocritincreased2, c1 See subsections below for additional information2 Identified adverse reactions of empagliflozin monotherapy3 Identified adverse reactions of metformin monotherapy4 Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite occur mostfrequently during initiation of therapy and resolve spontaneously in most cases.a See section 4.4b Mean percent increases from baseline for empagliflozin 10 mg and 25 mg versus placebo, respectively, weretotal cholesterol 5.0% and 5.2% versus 3.7%; HDL-cholesterol 4.6% and 2.7% versus -0.5%; LDL-cholesterol9.1% and 8.7% versus 7.8%; triglycerides 5.4% and 10.8% versus 12.1%.c Mean changes from baseline in haematocrit were 3.6% and 4.0% for empagliflozin 10 mg and 25 mg,respectively, compared to 0% for placebo. In the EMPA-REG Outcome study, haematocrit values returnedtowards baseline values after a follow-up period of 30 days after treatment stop.d Pooled data of empagliflozin trials in patients with heart failure (where half of the patients had type 2 diabetesmellitus) showed a higher frequency of volume depletion (“very common”: 11.4% for empagliflozin versus9.7% for placebo).

The frequency of hypoglycaemia depended on the background therapy in the respective studies andwas similar for empagliflozin and placebo as add-on to metformin, as add-on to linagliptin andmetformin, for the combination of empagliflozin with metformin in drug-naïve patients compared tothose treated with empagliflozin and metformin as individual components, and as adjunct to standardcare therapy. An increased frequency was noted when empagliflozin given as add-on to metformin anda sulfonylurea (empagliflozin 10 mg: 16.1%, empagliflozin 25 mg: 11.5% and placebo: 8.4%), or asadd-on to metformin and insulin (empagliflozin 10 mg: 31.3%, empagliflozin 25 mg: 36.2% andplacebo: 34.7%).

The overall frequency of patients with major hypoglycaemic events was low (<1%) and similar forempagliflozin and placebo as add-on to metformin, and for the combination of empagliflozin withmetformin in drug-naïve patients compared to those treated with empagliflozin and metformin asindividual components, and as adjunct to standard care therapy. Major hypoglycaemic events occurredin 0.5%, 0% and 0.5% of patients treated with empagliflozin 10 mg, empagliflozin 25 mg and placebowhen added on to metformin and insulin, respectively. No patient had a major hypoglycaemic event inthe combination with metformin and a sulphonylurea and as add-on to linagliptin and metformin.

The overall frequency of urinary tract infection adverse events was higher in metformin-treatedpatients who received empagliflozin 10 mg (8.8%) compared to empagliflozin 25 mg (6.6%) orplacebo (7.8%). Similar to placebo, urinary tract infection was reported more frequently forempagliflozin in patients with a history of chronic or recurrent urinary tract infections. The intensity ofurinary tract infections (i.e. mild/moderate/severe) was similar to placebo. Urinary tract infectionevents were reported more frequently for empagliflozin 10 mg compared with placebo in femalepatients, but not for empagliflozin 25 mg. The frequencies of urinary tract infections were low formale patients and were balanced across treatment groups.

Vaginal moniliasis, vulvovaginitis, balanitis and other genital infections were reported morefrequently in metformin-treated patients who received empagliflozin 10 mg (4.0%) and empagliflozin25 mg (3.9%) compared to placebo (1.3%), and were reported more frequently for empagliflozincompared to placebo in female patients. The difference in frequency was less pronounced in malepatients. Genital tract infections were mild and moderate in intensity, none was severe in intensity.

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

As expected from the mechanism of action, increased urination (as assessed by PT search includingpollakiuria, polyuria, nocturia) was observed at higher frequencies in metformin-treated patients whoreceived empagliflozin 10 mg (3.0%) and empagliflozin 25 mg (2.9%) compared to placebo (1.4%) asadd-on to metformin therapy. Increased urination was mostly mild or moderate in intensity. Thefrequency of reported nocturia was comparable between placebo and empagliflozin (<1%).

The overall frequency of volume depletion (including the predefined terms blood pressure(ambulatory) decreased, blood pressure systolic decreased, dehydration, hypotension, hypovolaemia,orthostatic hypotension, and syncope) in metformin-treated patients who received empagliflozin waslow: 0.6% for empagliflozin 10 mg, 0.3% for empagliflozin 25 mg and 0.1% for placebo. The effect ofempagliflozin on urinary glucose excretion is associated with osmotic diuresis, which could affecthydration status of patients age 75 years and older. In patients ≥75 years of age volume depletionevents have been reported in a single patient treated with empagliflozin 25 mg as add-on to metformintherapy.

The overall frequency of patients with increased blood creatinine and decreased glomerular filtrationrate were similar between empagliflozin and placebo as add-on to metformin (blood creatinineincreased: empagliflozin 10 mg 0.5%, empagliflozin 25 mg 0.1%, placebo 0.4%; glomerular filtrationrate decreased: empagliflozin 10 mg 0.1%, empagliflozin 25 mg 0%, placebo 0.2%).

Initial increases in creatinine and initial decreases in estimated glomerular filtration rates in patientstreated with empagliflozin as add-on to metformin therapy were generally transient during continuoustreatment or reversible after drug discontinuation of treatment.

Consistently, in the EMPA-REG OUTCOME study, patients treated with empagliflozin experiencedan initial fall in eGFR (mean: 3 ml/min/1.73 m2). Thereafter, eGFR was maintained during continuedtreatment. Mean eGFR returned to baseline after treatment discontinuation suggesting acutehaemodynamic changes may play a role in these renal function changes.

In the DINAMO trial 157 children aged 10 years and above with type 2 diabetes were treated, inwhich 52 patients received empagliflozin, 52 linagliptin and 53 placebo (see section 5.1). During theplacebo-controlled phase, the most frequent adverse drug reaction was hypoglycaemia (empagliflozin10 mg and 25 mg, pooled: 23.1%, placebo: 9.4%). None of these events was severe or requiredassistance.

Overall, the safety profile in children was similar to the safety profile in adults with type 2 diabetesmellitus.

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.

Empagliflozin

In controlled clinical studies single doses of up to 800 mg empagliflozin (equivalent to 32-times thehighest recommended daily dose) in healthy volunteers and multiple daily doses of up to 100 mgempagliflozin (equivalent to 4-times the highest recommended daily dose) in patients with type 2diabetes did not show any toxicity. Empagliflozin increased urine glucose excretion leading to anincrease in urine volume. The observed increase in urine volume was not dose-dependent and is notclinically meaningful. There is no experience with doses above 800 mg in humans.

Hypoglycaemia has not been seen with metformin doses of up to 85 g, although lactic acidosis hasoccurred in such circumstances. High overdose of metformin or concomitant risks may lead to lacticacidosis. Lactic acidosis is a medical emergency and must be treated in hospital (see sections 4.4 and4.5).

In the event of an overdose, treatment should be initiated as appropriate to the patient‘s clinical status.

The most effective method to remove lactate and metformin is haemodialysis. The removal ofempagliflozin by haemodialysis has not been studied.

Pharmacotherapeutic group: Drugs used in diabetes, combinations of oral blood glucose loweringdrugs, ATC code: A10BD20

Synjardy combines two antihyperglycaemic medicinal products with complementary mechanisms ofaction to improve glycaemic control in patients with type 2 diabetes: empagliflozin, an inhibitor ofsodium-glucose co-transporter 2 (SGLT2), and metformin hydrochloride, a member of the biguanideclass.

Empagliflozin

Empagliflozin is a reversible, highly potent (IC50 of 1.3 nmol) and selective competitive inhibitor of

SGLT2. Empagliflozin does not inhibit other glucose transporters important for glucose transport intoperipheral tissues and is 5000-times more selective for SGLT2 versus SGLT1, the major transporterresponsible for glucose absorption in the gut. SGLT2 is highly expressed in the kidney, whereasexpression in other tissues is absent or very low. It is responsible, as the predominant transporter, forthe reabsorption of glucose from the glomerular filtrate back into the circulation. In patients with type2 diabetes and hyperglycaemia a higher amount of glucose is filtered and reabsorbed.

Empagliflozin improves glycaemic control in patients with type 2 diabetes by reducing renal glucosereabsorption. The amount of glucose removed by the kidney through this glucuretic mechanism isdependent on blood glucose concentration and GFR. Inhibition of SGLT2 in patients with type 2diabetes and hyperglycaemia leads to excess glucose excretion in the urine. In addition, initiation ofempagliflozin increases excretion of sodium resulting in osmotic diuresis and reduced intravascularvolume.

In patients with type 2 diabetes, urinary glucose excretion increased immediately following the firstdose of empagliflozin and is continuous over the 24 hour dosing interval. Increased urinary glucoseexcretion was maintained at the end of the 4-week treatment period, averaging approximately 78 g/daywith empagliflozin 25 mg. Increased urinary glucose excretion resulted in an immediate reduction inplasma glucose levels in patients with type 2 diabetes.

Empagliflozin improves both fasting and post-prandial plasma glucose levels. The mechanism ofaction of empagliflozin is independent of beta cell function and insulin pathway and this contributes toa low risk of hypoglycaemia. Improvement of surrogate markers of beta cell function including

Homeostasis Model Assessment-β (HOMA-β) was noted. In addition, urinary glucose excretiontriggers calorie loss, associated with body fat loss and body weight reduction. The glucosuria observedwith empagliflozin is accompanied by mild diuresis which may contribute to sustained and moderatereduction of blood pressure. The glucosuria, natriuresis and osmotic diuresis observed withempagliflozin may contribute to the improvement in cardiovascular outcomes.

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

Metformin may act via 3 mechanisms:

* reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis,

* in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilization,

* and delay of intestinal glucose absorption.

Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metforminincreases the transport capacity of all types of membrane glucose transporters (GLUTs) known to date.

In humans, independently of its action on glycaemia, metformin has favourable effects on lipidmetabolism. This has been shown at therapeutic doses in controlled, medium-term or long-termclinical studies: metformin reduces total cholesterol, LDL cholesterol and triglyceride levels.

Both improvement of glycaemic control and reduction of cardiovascular morbidity and mortality arean integral part of the treatment of type 2 diabetes.

Glycaemic efficacy and cardiovascular outcomes have been assessed in a total of 10,366 patients withtype 2 diabetes who were treated in 9 double-blind, placebo or active-controlled clinical studies of atleast 24 weeks duration, of which 2950 patients received empagliflozin 10 mg and 3701 receivedempagliflozin 25 mg as add-on to metformin therapy. Of these, 266 or 264 patients were treated withempagliflozin 10 mg or 25 mg as add-on to metformin plus insulin, respectively.

Treatment with empagliflozin in combination with metformin with or without other antidiabeticmedicinal products (pioglitazone, sulfonylurea, DPP-4 inhibitors, and insulin) led to clinically relevantimprovements in HbA1c, fasting plasma glucose (FPG), body weight, systolic and diastolic bloodpressure. Administration of empagliflozin 25 mg resulted in a higher proportion of patients achieving

HbA1c goal of less than 7% and fewer patients needing glycaemic rescue compared to empagliflozin10 mg and placebo. In patients age 75 years and older, numerically lower reductions in HbA1c wereobserved with empagliflozin treatment. Higher baseline HbA1c was associated with a greaterreduction in HbA1c. In addition, empagliflozin as adjunct to standard care therapy reducedcardiovascular mortality in patients with type 2 diabetes and established cardiovascular disease.

Empagliflozin as add-on to metformin, metformin and a sulphonylurea, or pioglitazone and metforminresulted in statistically significant (p<0.0001) reductions in HbA1c and body weight compared toplacebo (Table 3). In addition it resulted in a clinically meaningful reduction in FPG, systolic anddiastolic blood pressure compared to placebo.

In the double-blind placebo-controlled extension of these studies, reduction of HbA1c, body weightand blood pressure were sustained up to Week 76.

Table 3: Efficacy results of 24 week placebo-controlled studies

Add-on to metformin therapya

Empagliflozin

Placebo10 mg 25 mg

N 207 217 213

HbA1c (%)

Baseline (mean) 7.90 7.94 7.86

Change from baseline1 -0.13 -0.70 -0.77

Difference from placebo1

- 0.57* (-0.72, -0.42) -0.64* (-0.79, -0.48)(97.5% CI)

N 184 199 191

Patients (%) achieving

HbA1c <7% with baseline 12.5 37.7 38.7

HbA1c ≥7%2

N 207 217 213

Body Weight (kg)

Baseline (mean) 79.73 81.59 82.21

Change from baseline1 -0.45 -2.08 -2.46

Difference from placebo1

- 1.63* (-2.17, -1.08) -2.01* (-2.56, -1.46)(97.5% CI)

N 207 217 213

SBP (mmHg)2

Baseline (mean) 128.6 129.6 130.0

Change from baseline1 -0.4 -4.5 -5.2

Difference from placebo1

- 4.1* (-6.2, -2.1) -4.8* (-6.9, -2.7)(95% CI)

Add-on to metformin and a sulphonylurea therapya

Empagliflozin

Placebo10 mg 25 mg

N 225 225 216

HbA1c (%)

Baseline (mean) 8.15 8.07 8.10

Change from baseline1 -0.17 -0.82 -0.77

Difference from placebo1

- 0.64* (-0.79, -0.49) -0.59* (-0.74, -0.44)(97.5% CI)

N 216 209 202

Patients (%) achieving

HbA1c <7% with baseline 9.3 26.3 32.2

HbA1c ≥7%2

N 225 225 216

Body Weight (kg)

Baseline (mean) 76.23 77.08 77.50

Change from baseline1 -0.39 -2.16 -2.39

Difference from placebo1

- 1.76* (-2.25, -1.28) -1.99* (-2.48, -1.50)(97.5% CI)

N 225 225 216

SBP (mmHg)2

Baseline (mean) 128.8 128.7 129.3

Change from baseline1 -1.4 -4.1 -3.5

Difference from placebo1

- 2.7 (-4.6, -0.8) -2.1 (-4.0, -0.2)(95% CI)

Add-on to pioglitazone + metformin therapyb

Empagliflozin

Placebo10 mg 25 mg

N 124 125 127

HbA1c (%)

Baseline (mean) 8.15 8.07 8.10

Change from baseline1 -0.11 -0.55 -0.70

Difference from placebo1

- 0.45* (-0.69, -0.21) -0.60* (-0.83, -0.36)(97.5% CI)

N 118 116 123

Patients (%) achieving

HbA1c <7% with baseline 8.5 22.4 28.5

HbA1c ≥7%2

N 124 125 127

Body Weight (kg)

Baseline (mean) 79.45 79.44 80.98

Change from baseline1 0.40 -1.74 -1.59

Difference from placebo1

- 2.14* (-2.93, -1.35) -2.00* (-2.78, -1.21)(97.5% CI)

N 124 125 127

SBP (mmHg)2, 3

Baseline (mean) 125.5 126.3 126.3

Change from baseline1 0.8 -3.5 -3.3

Difference from placebo1

- 4.2** (-6.94, -1.53) -4.1** (-6.76, -1.37)(95% CI)a Full analysis set (FAS) using last observation carried forward (LOCF) prior to glycaemic rescuetherapybSubgroup analysis for patients on additional background of metformin (FAS, LOCF)1 Mean adjusted for baseline value2 Not evaluated for statistical significance as a part of the sequential confirmatory testing procedure3 LOCF, values after antihypertensive rescue censored

* p-value <0.0001

** p-value <0.01

Empagliflozin in combination with metformin in drug-naïve patients

A factorial design study of 24 weeks duration was conducted to evaluate the efficacy and safety ofempagliflozin in drug-naïve patients. Treatment with empagliflozin in combination with metformin(5 mg and 500 mg; 5 mg and 1000 mg; 12.5 mg and 500 mg, and 12.5 mg and 1000 mg given twicedaily) provided statistically significant improvements in HbA1c (Table 4) and led to greater reductionsin FPG (compared to the individual components) and body weight (compared to metformin).

Table 4: Efficacy results at 24 week comparing empagliflozin in combination with metformin to theindividual componentsa

Empagliflozin 10 mgb Empagliflozin 25 mgb Metforminc+ Met + Met No + Met + Met No 1000 20001000 mgc 2000 mgc Met 1000 mgc 2000 mgc Met mg mg

N 161 167 169 165 169 163 167 162

HbA1c (%)

Baseline 8.68 8.65 8.62 8.84 8.66 8.86 8.69 8.55(mean)

Change from -1.98 -2.07 -1.35 -1.93 -2.08 -1.36 -1.18 -1.75baseline1

Comparison -0.63* -0.72* -0.57* -0.72*vs. empa (-0.86, (-0.96, (-0.81, (-0.95,(95% CI)1 -0.40) -0.49) -0.34) -0.48)

Comparison -0.79* -0.33* -0.75* -0.33*vs. met (95% (-1.03, (-0.56, (-0.98 (-0.56,

CI)1 -0.56) -0.09) -0.51) -0.10)

Met = metformin; empa = empagliflozin1 mean adjusted for baseline valuea Analyses were performed on the full analysis set (FAS) using an observed cases (OC) approachb Given in two equally divided doses per day when given together with metforminc Given in two equally divided doses per day

*p≤0.0062 for HbA1c

In patients inadequately controlled with metformin and linagliptin 5 mg, treatment with bothempagliflozin 10 mg or 25 mg resulted in statistically significant (p<0.0001) reductions in HbA1c andbody weight compared to placebo (Table 5). In addition it resulted in clinically meaningful reductionsin FPG, systolic and diastolic blood pressure compared to placebo.

Table 5: Efficacy results of a 24 week placebo-controlled study in patients inadequately controlledwith metformin and linagliptin 5 mg

Add-on to metformin and linagliptin 5 mg

Placebo5 Empagliflozin610 mg 25 mg

N 106 109 110

HbA1c (%)3

Baseline (mean) 7.96 7.97 7.97

Change from baseline1 0.14 -0.65 -0.56

Difference from placebo

- 0.79* (-1.02, -0.55) -0.70* (-0.93, -0.46)(95% CI)

N 100 100 107

Patients (%) achieving

HbA1c <7% with baseline 17.0 37.0 32.7

HbA1c ≥7%2

N 106 109 110

Body Weight (kg)3

Baseline (mean) 82.3 88.4 84.4

Change from baseline1 -0.3 -3.1 -2.5

Difference from placebo

- 2.8* (-3.5, -2.1) -2.2* (-2.9, -1.5)(95% CI)

N 106 109 110

SBP (mmHg)4

Baseline (mean) 130.1 130.4 131.0

Change from baseline1 -1.7 -3.0 -4.3

Difference from placebo -1.3 (-4.2, 1.7) -2.6 (-5.5, 0.4)(95% CI)1 Mean adjusted for baseline value2 Not evaluated for statistical significance; not part of sequential testing procedure for the secondaryendpoints3 MMRM model on FAS (OC) included baseline HbA1c, baseline eGFR (MDRD), geographicalregion, visit, treatment, and treatment by visit interaction. For weight, baseline weight was included.4 MMRM model included baseline SBP and baseline HbA1c as linear covariate(s), and baseline eGFR,geographical region, treatment, visit, and visit by treatment interaction as fixed effects.5 Patients randomized to the placebo group were receiving the placebo plus linagliptin 5 mg withbackground metformin6 Patients randomized to the empagliflozin 10 mg or 25 mg groups were receiving empagliflozin10 mg or 25 mg and linagliptin 5 mg with background metformin

* p-value <0.0001

In a prespecified subgroup of patients with baseline HbA1c greater or equal than 8.5% the reductionfrom baseline in HbA1c was -1.3% with empagliflozin 10 mg or 25 mg at 24 weeks (p<0.0001)compared to placebo.

In a study comparing the efficacy and safety of empagliflozin 25 mg versus glimepiride (up to 4 mgper day) in patients with inadequate glycaemic control on metformin alone, treatment withempagliflozin daily resulted in superior reduction in HbA1c (Table 6), and a clinically meaningfulreduction in FPG, compared to glimepiride. Empagliflozin daily resulted in a statistically significantreduction in body weight, systolic and diastolic blood pressure and a statistically significantly lowerproportion of patients with hypoglycaemic events compared to glimepiride (2.5% for empagliflozin,24.2% for glimepiride, p<0.0001).

Table 6: Efficacy results at 104 week in an active controlled study comparing empagliflozin toglimepiride as add on to metformina

Empagliflozin 25 mg Glimepirideb

N 765 780

HbA1c (%)

Baseline (mean) 7.92 7.92

Change from baseline1 -0.66 -0.55

Difference from glimepiride1 (97.5% CI) -0.11* (-0.20, -0.01)

N 690 715

Patients (%) achieving HbA1c <7% with2 33.6 30.9baseline HbA1c ≥7%

N 765 780

Body Weight (kg)

Baseline (mean) 82.52 83.03

Change from baseline1 -3.12 1.34

Difference from glimepiride1 (97.5% CI) -4.46** (-4.87, -4.05)

N 765 780

SBP (mmHg)3

Baseline (mean) 133.4 133.5

Change from baseline1 -3.1 2.5

Difference from glimepiride1 (97.5% CI) -5.6** (-7.0,-4.2)a Full analysis set (FAS) using last observation carried forward (LOCF) prior to glycaemic rescuetherapyb Up to 4 mg glimepiride1 Mean adjusted for baseline value2 Not evaluated for statistical significance as a part of the sequential confirmatory testing procedure3 LOCF, values after antihypertensive rescue censored

* p-value <0.0001 for non-inferiority, and p-value = 0.0153 for superiority

** p-value <0.0001

The efficacy and safety of empagliflozin as add-on to multiple daily insulin with concomitantmetformin therapy was evaluated in a double-blind, placebo-controlled trial of 52 weeks duration.

During the initial 18 weeks and the last 12 weeks, the insulin dose was kept stable, but was adjusted toachieve pre-prandial glucose levels <100 mg/dl [5.5 mmol/l], and post-prandial glucose levels<140 mg/dl [7.8 mmol/l] between Weeks 19 and 40.

At Week 18, empagliflozin provided statistically significant improvement in HbA1c compared withplacebo (Table 7).

At Week 52, treatment with empagliflozin resulted in a statistically significant decrease in HbA1c andinsulin sparing compared with placebo and a reduction in body weight.

Table 7: Efficacy results at 18 and 52 weeks in a placebo-controlled study of empagliflozin as add-onto multiple daily doses of insulin with concomitant metformin therapyempagliflozin

Placebo10 mg 25 mg

N 135 128 137

HbA1c (%) at week 18a

Baseline (mean) 8.29 8.42 8.29

Change from baseline1 -0.58 -0.99 -1.03

Difference from placebo1

- 0.41* (-0.61, -0.21) -0.45* (-0.65, -0.25)(97.5% CI)

N 86 84 87

HbA1c (%) at week 52b

Baseline (mean) 8.26 8.43 8.38

Change from baseline1 -0.86 -1.23 -1.31

Difference from placebo1

- 0.37** (-0.67, -0.08) -0.45* (-0.74, -0.16)(97.5% CI)

N 84 84 87

Patients (%) achieving

HbA1c <7% with27.4 41.7 48.3baseline HbA1c ≥7% atweek 52b, 2

N 86 83 86

Insulin dose (IU/day)at week 52b, 3

Baseline (mean) 91.01 91.77 90.22

Change from baseline1 12.84 0.22 -2.25

Difference from placebo1

- 12.61** (-21.43, -3.80) -15.09** (-23.79, -6.40)(97.5% CI)

N 86 84 87

Body Weight (kg)at week 52b

Baseline (mean) 97.78 98.86 94.93

Change from baseline1 0.42 -2.47 -1.94

Difference from placebo1

- 2.89* (-4.29, -1.49) -2.37* (-3.75, -0.98)(97.5% CI)a Subgroup analysis for patients on additional background of metformin (FAS, LOCF)b Subgroup analysis for patients on additional background of metformin (PPS-Completers, LOCF)1 Mean adjusted for baseline value2 not evaluated for statistical significance as a part of the sequential confirmatory testing procedure3 Week 19-40: treat-to-target regimen for insulin dose adjustment to achieve pre-defined glucose targetlevels (pre-prandial <100 mg/dl (5.5 mmol/l), post-prandial <140 mg/dl (7.8 mmol/l)

* p-value ≤0.0005

** p-value <0.005

Empagliflozin as add on to basal insulin

The efficacy and safety of empagliflozin as add on to basal insulin with concomitant metformintherapy was evaluated in a double-blind, placebo-controlled trial of 78 weeks duration. During theinitial 18 weeks the insulin dose was kept stable, but was adjusted to achieve a FPG <110 mg/dl in thefollowing 60 weeks.

At week 18, empagliflozin provided statistically significant improvement in HbA1c. A greaterproportion of patients treated with empagliflozin and with a baseline HbA1c ≥7.0% achieved a target

HbA1c of <7% compared to placebo (Table 8).

At 78 weeks, the decrease in HbA1c and insulin sparing effect of empagliflozin was maintained.

Furthermore, empagliflozin resulted in a reduction in FPG, body weight and blood pressure.

Table 8: Efficacy results at 18 and 78 weeks in a placebo-controlled study of empagliflozin as add onto basal insulin with metformina

Empagliflozin Empagliflozin

Placebo10 mg 25 mg

N 96 107 99

HbA1c (%) at week 18

Baseline (mean) 8.02 8.21 8.35

Change from baseline1 -0.09 -0.62 -0.72

Difference from placebo1

- 0.54* (-0.77, -0.30) -0.63* (-0.88, -0.39)(97.5% CI)

N 89 105 94

HbA1c (%) at week 78

Baseline (mean) 8.03 8.24 8.29

Change from baseline1 -0.08 -0.42 -0.71

Difference from placebo1

- 0.34** (-0.64, -0.05) -0.63* (-0.93, -0.33)(97.5% CI)

N 89 105 94

Basal insulin dose (IU/day)at week 78

Baseline (mean) 49.61 47.25 49.37

Change from baseline1 4.14 -2.07 -0.28

Difference from placebo1

- 6.21** (-11.81, -0.61) -4.42 (-10.18, 1.34)(97.5% CI)a Subgroup analysis of full analysis set (FAS) for patients on additional background of metformin -

Completers using last observation carried forward (LOCF) prior to glycaemic rescue therapy1 mean adjusted for baseline value

* p-value <0.0001

** p-value ≤0.025

Empagliflozin and linagliptin as add-on therapy to metformin

In a double-blind trial in patients with inadequate glycemic control, 24-weeks treatment with bothdoses of empagliflozin plus linagliptin as add-on to metformin therapy provided statisticallysignificant (p<0.0001) reductions in HbA1c (change from baseline of -1.08% for empagliflozin 10 mgplus linagliptin 5 mg, -1.19% for empagliflozin 25 mg plus linagliptin 5 mg, -0.70% for linagliptin5 mg). Compared to linagliptin 5 mg, both doses of empagliflozin plus linagliptin 5 mg providedstatistically significant reductions in FPG and blood pressure. Both doses provided similar statisticallysignificant reductions in body weight, expressed as kg and percentage change. A greater proportion ofpatients with a baseline HbA1c ≥7.0% and treated with empagliflozin plus linagliptin achieved a target

HbA1c of <7% compared to linagliptin 5 mg. Clinically meaningful reductions in HbA1c weremaintained for 52 weeks.

Empagliflozin twice daily versus once daily as add on to metformin therapy

The efficacy and safety of empagliflozin twice daily versus once daily (daily dose of 10 mg and25 mg) as add-on therapy in patients with in sufficient glycemic control on metformin monotherapywas evaluated in a double blind placebo-controlled study of 16 weeks duration. All treatments withempagliflozin resulted in significant reductions in HbA1c from baseline (total mean 7.8%) after 16weeks of treatment compared with placebo. Empagliflozin twice daily dose regimens on a backgroundof metformin led to comparable reductions in HbA1c versus once daily dose regimens with atreatment difference in HbA1c reductions from baseline to week 16 of -0.02% (95% CI -0.16, 0.13)for empagliflozin 5 mg twice daily versus 10 mg once daily, and -0.11% (95% CI -0.26, 0.03) forempagliflozin 12.5 mg twice daily versus 25 mg once daily.

The double-blind, placebo-controlled EMPA-REG OUTCOME study compared pooled doses ofempagliflozin 10 mg and 25 mg with placebo as adjunct to standard care therapy in patients withtype 2 diabetes and established cardiovascular disease. A total of 7020 patients were treated(empagliflozin 10 mg: 2345, empagliflozin 25 mg: 2342, placebo: 2333) and followed for a median of3.1 years. The mean age was 63 years, the mean HbA1c was 8.1%, and 71.5% were male. At baseline,74% of patients were being treated with metformin, 48% with insulin, and 43% with a sulfonylurea.

About half of the patients (52.2%) had an eGFR of 60-90 ml/min/1.73 m2, 17.8% of45-60 ml/min/1.73 m2 and 7.7% of 30-45 ml/min/1.73 m2.

At week 12, an adjusted mean (SE) improvement in HbA1c when compared to baseline of 0.11%(0.02) in the placebo group, 0.65% (0.02) and 0.71% (0.02) in the empagliflozin 10 and 25 mg groupswas observed. After the first 12 weeks glycaemic control was optimized independent of investigativetreatment. Therefore the effect was attenuated at week 94, with an adjusted mean (SE) improvement in

HbA1c of 0.08% (0.02) in the placebo group, 0.50% (0.02) and 0.55% (0.02) in the empagliflozin10 and 25 mg groups.

Empagliflozin was superior in preventing the primary combined endpoint of cardiovascular death,non-fatal myocardial infarction, or non-fatal stroke, as compared with placebo. The treatment effectwas driven by a significant reduction in cardiovascular death with no significant change in non-fatalmyocardial infarction, or non-fatal stroke. The reduction of cardiovascular death was comparable forempagliflozin 10 mg and 25 mg (see Figure 1) and confirmed by an improved overall survival (Table9). The effect of empagliflozin on the primary combined endpoint of CV death, non-fatal MI, or non-fatal stroke was largely independent of glycaemic control or renal function (eGFR) and generallyconsistent across eGFR categories down to an eGFR of 30 ml/min/1.73 m2 in the EMPA-REG

OUTCOME study.

The efficacy for preventing cardiovascular mortality has not been conclusively established in patientsusing empagliflozin concomitantly with DPP-4 inhibitors or in Black patients because therepresentation of these groups in the EMPA-REG OUTCOME study was limited.

Table 9: Treatment effect for the primary composite endpoint, its components and mortalitya

Placebo Empagliflozinb

N 2333 4687

Time to first event of CV death, non-fatal282 (12.1) 490 (10.5)

MI, or non-fatal stroke N (%)

Hazard ratio vs. placebo (95.02% CI)* 0.86 (0.74, 0.99)p−value for superiority 0.0382

CV Death N (%) 137 (5.9) 172 (3.7)

Hazard ratio vs. placebo (95% CI) 0.62 (0.49, 0.77)p-value <0.0001

Non-fatal MI N (%) 121 (5.2) 213 (4.5)

Hazard ratio vs. placebo (95% CI) 0.87 (0.70, 1.09)p−value 0.2189

Non-fatal stroke N (%) 60 (2.6) 150 (3.2)

Hazard ratio vs. placebo (95% CI) 1.24 (0.92, 1.67)p−value 0.1638

All-cause mortality N (%) 194 (8.3) 269 (5.7)

Hazard ratio vs. placebo (95% CI) 0.68 (0.57, 0.82)p-value <0.0001

Non-CV mortality N (%) 57 (2.4) 97 (2.1)

Hazard ratio vs. placebo (95% CI) 0.84 (0.60, 1.16)

CV = cardiovascular, MI = myocardial infarctiona Treated set (TS), i.e. patients who had received at least one dose of study drugb Pooled doses of empagliflozin 10 mg and 25 mg

* Since data from the trial were included in an interim analysis, a two-sided 95.02% confidenceinterval applied which corresponds to a p-value of less than 0.0498 for significance.

Figure 1 Time to occurrence of cardiovascular death in the EMPA-REG OUTCOME study

In the EMPA-REG OUTCOME study, empagliflozin reduced the risk of heart failure requiringhospitalization compared with placebo (empagliflozin 2.7 %; placebo 4.1 %; HR 0.65, 95 % CI 0.50,0.85).

In the EMPA-REG OUTCOME study, for time to first nephropathy event, the HR was 0.61 (95 % CI0.53, 0.70) for empagliflozin (12.7 %) vs placebo (18.8 %).

In addition, empagliflozin showed a higher (HR 1.82, 95 % CI 1.40, 2.37) occurrence of sustainednormo- or micro-albuminuria (49.7 %) in patients with baseline macro-albuminuria compared withplacebo (28.8 %).

2 hour post-prandial glucose

Treatment with empagliflozin as add-on to metformin or metformin plus sulfonylurea resulted inclinically meaningful improvement of 2-hour post-prandial glucose (meal tolerance test) at 24 weeks(add-on to metformin, placebo: +5.9 mg/dl, empagliflozin 10 mg: -46.0 mg/dl, empagliflozin25 mg: -44.6 mg/dl; add-on to metformin plus sulphonylurea, placebo: -2.3 mg/dl, empagliflozin10 mg: -35.7 mg/dl, empagliflozin 25 mg: -36.6 mg/dl).

Patients with baseline HbA1c ≥9%

In a pre-specified analysis of subjects with baseline HbA1c ≥9.0%, treatment with empagliflozin10 mg or 25 mg as add-on to metformin resulted in statistically significant reductions in HbA1c at

Week 24 (adjusted mean change from baseline of -1.49% for empagliflozin 25 mg, -1.40% forempagliflozin 10 mg, and -0.44% for placebo).

In a pre-specified pooled analysis of 4 placebo controlled studies, treatment with empagliflozin (68%of all patients were on metformin background) resulted in body weight reduction compared to placeboat week 24 (-2.04 kg for empagliflozin 10 mg, -2.26 kg for empagliflozin 25 mg and -0.24 kg forplacebo) that was maintained up to week 52 (-1.96 kg for empagliflozin 10 mg, -2.25 kg forempagliflozin 25 mg and -0.16 kg for placebo).

The efficacy and safety of empagliflozin was evaluated in a double-blind, placebo controlled study of12 weeks duration in patients with type 2 diabetes and high blood pressure on different antidiabeticand up to 2 antihypertensive therapies. Treatment with empagliflozin once daily resulted instatistically significant improvement in HbA1c, and 24 hour mean systolic and diastolic blood pressureas determined by ambulatory blood pressure monitoring (Table 10). Treatment with empagliflozinprovided reductions in seated SBP and DBP.

Table 10: Efficacy results at 12 week in a placebo-controlled study of empagliflozin in patients withtype 2 diabetes and uncontrolled blood pressureaempagliflozin

Placebo10 mg 25 mg

N 271 276 276

HbA1c (%) at week 121

Baseline (mean) 7.90 7.87 7.92

Change from baseline2 0.03 -0.59 -0.62

Difference from placebo12 -0.62* (-0.72, -0.52) -0.65* (-0.75, -0.55)(95% CI)24 hour SBP at week 123

Baseline (mean) 131.72 131.34 131.18

Change from baseline4 0.48 -2.95 -3.68

Difference from placebo4

- 3.44* (-4.78, -2.09) -4.16* (-5.50, -2.83)(95% CI)24 hour DBP at week 123

Baseline (mean) 75.16 75.13 74.64

Change from baseline5 0.32 -1.04 -1.40

Difference from placebo5

- 1.36** (-2.15, -0.56) -1.72* (-2.51, -0.93)(95% CI)a Full analysis set (FAS)1 LOCF, values after taking antidiabetic rescue therapy censored2 Mean adjusted for baseline HbA1c, baseline eGFR, geographical region and number ofantihypertensive medicinal products3 LOCF, values after taking antidiabetic rescue therapy or changing antihypertensive rescue therapycensored4 Mean adjusted for baseline SBP, baseline HbA1c, baseline eGFR, geographical region and numberof antihypertensive medicinal products5 Mean adjusted for baseline DBP, baseline HbA1c, baseline eGFR, geographical region and numberof antihypertensive medicinal products

* p-value <0.0001

** p-value <0.001

In a pre-specified pooled analysis of 4 placebo-controlled studies, treatment with empagliflozin (68%of all patients were on metformin background) resulted in a reduction in systolic blood pressure(empagliflozin 10 mg: -3.9 mmHg, empagliflozin 25 mg: -4.3 mmHg) compared with placebo(-0.5 mmHg), and in diastolic blood pressure (empagliflozin 10 mg: -1.8 mmHg, empagliflozin25 mg: -2.0 mmHg) compared with placebo (-0.5 mmHg), at week 24, that were maintained up toweek 52.

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

* a significant reduction of the absolute risk of any diabetes-related mortality: metformin7.5 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: metformin13.5 events/1,000 patient-years versus diet alone 20.6 events/1,000 patient-years, (p=0.011), andversus the combined sulphonylurea and insulin monotherapy groups18.9 events/1,000 patient-years (p=0.021),

* a significant reduction in the absolute risk of myocardial infarction: metformin11 events/1,000 patient-years, diet alone 18 events/1,000 patient-years, (p=0.01).

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

Synjardy in all subsets of the paediatric population from birth to less than 10 years of age in type 2diabetes (see section 4.2 for information on paediatric use).

The clinical efficacy and safety of empagliflozin (10 mg with a possible dose-increase to 25 mg) andlinagliptin (5 mg) once daily has been studied in children and adolescents from 10 to 17 years of agewith type 2 diabetes mellitus in a placebo-controlled study (DINAMO) over 26 weeks, with a safetyextension period up to 52 weeks. Background therapies as adjunct to diet and exercise includedmetformin (51%), a combination of metformin and insulin (40.1%), insulin (3.2%), or none (5.7%).

The adjusted mean changes in HbA1c at week 26 between empagliflozin (N=52) and placebo (N=53)of -0.84% was clinically meaningful and statistically significant (95% CI -1.50, -0.19; p=0.0116). Inaddition, treatment with empagliflozin versus placebo resulted in a clinically meaningful adjustedmean change in FPG of -35.2 mg/dl (95% CI -58.6, -11.7) [-1.95 mmol/l (-3.25, -0.65)]. These were -0.76% (95%CI -1.45%, -0.08%) for HbA1c and -38.28 mg/dL (95% CI: −60.47 to −16.10) for FPG inthe metformin subgroup (N=48 empagliflozin, N=47 placebo).

Synjardy

The results of bioequivalence studies in healthy subjects demonstrated that Synjardy(empagliflozin/metformin hydrochloride) 5 mg/850 mg, 5 mg/1,000 mg, 12.5 mg/850 mg, and12.5 mg/1,000 mg combination tablets are bioequivalent to co-administration of corresponding dosesof empagliflozin and metformin as individual tablets.

Administration of empagliflozin/metformin 12.5 mg/1,000 mg under fed conditions resulted in 9%decrease in AUC and a 28% decrease in Cmax for empagliflozin, when compared to fasted conditions.

For metformin, AUC decreased by 12% and Cmax decreased by 26% compared to fasting conditions.

The observed effect of food on empagliflozin and metformin is not considered to be clinicallyrelevant. However, as metformin is recommended to be given with meals, Synjardy is also proposed tobe given with food.

The following statements reflect the pharmacokinetic properties of the individual active substances of

Synjardy.

Empagliflozin

The pharmacokinetics of empagliflozin have been extensively characterised in healthy volunteers andpatients with type 2 diabetes. After oral administration, empagliflozin was rapidly absorbed with peakplasma concentrations occurring at a median tmax of 1.5 hours post-dose. Thereafter, plasmaconcentrations declined in a biphasic manner with a rapid distribution phase and a relatively slowterminal phase. The steady state mean plasma AUC and Cmax were 1870 nmol.h/l and 259 nmol/l withempagliflozin 10 mg and 4740 nmol.h/l and 687 nmol/l with empagliflozin 25 mg once daily.

Systemic exposure of empagliflozin increased in a dose-proportional manner. The single-dose andsteady-state pharmacokinetic parameters of empagliflozin were similar suggesting linearpharmacokinetics with respect to time. There were no clinically relevant differences in empagliflozinpharmacokinetics between healthy volunteers and patients with type 2 diabetes.

The pharmacokinetics of 5 mg empagliflozin twice daily and 10 mg empagliflozin once daily werecompared in healthy subjects. Overall exposure (AUCss) of empagliflozin over a 24-hour period withempagliflozin 5 mg administered twice daily was similar to empagliflozin 10 mg administered oncedaily. As expected, empagliflozin 5 mg administered twice daily compared with 10 mg empagliflozinonce daily resulted in lower Cmax and higher trough plasma empagliflozin concentrations (Cmin).

Administration of empagliflozin 25 mg after intake of a high-fat and high calorie meal resulted inslightly lower exposure; AUC decreased by approximately 16% and Cmax by approximately 37%compared to fasted condition. The observed effect of food on empagliflozin pharmacokinetics was notconsidered clinically relevant and empagliflozin may be administered with or without food. Similarresults were obtained when Synjardy (empagliflozin/metformin) combination tablets wereadministered with high-fat and high calorie meal.

The apparent steady-state volume of distribution was estimated to be 73.8 l based on the populationpharmacokinetic analysis. Following administration of an oral [14C]-empagliflozin solution to healthyvolunteers, the red blood cell partitioning was approximately 37% and plasma protein binding was86%.

No major metabolites of empagliflozin were detected in human plasma, as defined by at least 10% oftotal drug-related material, and the most abundant metabolites were three glucuronide conjugates (2-,3-, and 6-O-glucuronide). In vitro studies suggested that the primary route of metabolism ofempagliflozin in humans is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases

UGT2B7, UGT1A3, UGT1A8, and UGT1A9.

Based on the population pharmacokinetic analysis, the apparent terminal elimination half-life ofempagliflozin was estimated to be 12.4 hours and apparent oral clearance was 10.6 l/hour. Theinter-subject and residual variabilities for empagliflozin oral clearance were 39.1% and 35.8%,respectively. With once-daily dosing, steady-state plasma concentrations of empagliflozin werereached by the fifth dose. Consistent with the half-life, up to 22% accumulation, with respect toplasma AUC, was observed at steady-state. Following administration of an oral [14C]-empagliflozinsolution to healthy volunteers, approximately 96% of the drug-related radioactivity was eliminated infaeces (41%) or urine (54%). The majority of drug-related radioactivity recovered in faeces wasunchanged parent drug and approximately half of drug-related radioactivity excreted in urine wasunchanged parent drug.

In patients with mild, moderate or severe renal impairment (creatinine clearance <30 - <90 ml/min)and patients with kidney failure/end stage renal disease (ESRD), AUC of empagliflozin increased byapproximately 18%, 20%, 66%, and 48%, respectively compared to subjects with normal renalfunction. Peak plasma levels of empagliflozin were similar in subjects with moderate renal impairmentand kidney failure/ESRD compared to patients with normal renal function. Peak plasma levels ofempagliflozin were roughly 20% higher in subjects with mild and severe renal impairment ascompared to subjects with normal renal function. The population pharmacokinetic analysis showedthat the apparent oral clearance of empagliflozin decreased with a decrease in creatinine clearanceleading to an increase in drug exposure.

In subjects with mild, moderate, and severe hepatic impairment according to the Child-Pughclassification, AUC of empagliflozin increased approximately by 23%, 47%, and 75% and Cmax byapproximately 4%, 23%, and 48%, respectively, compared to subjects with normal hepatic function.

Body mass index had no clinically relevant effect on the pharmacokinetics of empagliflozin based onthe population pharmacokinetic analysis. In this analysis, AUC was estimated to be 5.82%, 10.4%, and17.3% lower in subjects with BMI of 30, 35, and 45 kg/m2, respectively, compared to subjects with abody mass index of 25 kg/m2.

Gender had no clinically relevant effect on the pharmacokinetics of empagliflozin based on thepopulation pharmacokinetic analysis.

In the population pharmacokinetic analysis, AUC was estimated to be 13.5% higher in Asians with abody mass index of 25 kg/m2 compared to non-Asians with a body mass index of 25 kg/m2.

Age did not have a clinically meaningful impact on the pharmacokinetics of empagliflozin based onthe population pharmacokinetic analysis.

A paediatric Phase 1 study examined the pharmacokinetics and pharmacodynamics of empagliflozin(5 mg, 10 mg and 25 mg) in children and adolescents ≥10 to <18 years of age with type 2 diabetesmellitus. The observed pharmacokinetic and pharmacodynamic responses were consistent with thosefound in adult subjects.

A paediatric Phase 3 study examined the pharmacokinetics and pharmacodynamics (HbA1c changefrom baseline) of empagliflozin 10 mg with a possible dose-increase to 25 mg in children andadolescents 10 to 17 years of age with type 2 diabetes mellitus. The observed exposure-responserelationship was overall comparable in adults and children and adolescents. Oral administration ofempagliflozin resulted in an exposure within the range observed in adult patients.

The observed geometric mean trough concentrations and geometric mean concentrations at 1.5 hourspost-administration at steady state were 26.6 nmol/l and 308 nmol/l with empagliflozin 10 mg oncedaily and 67.0 nmol/l and 525 nmol/l with empagliflozin 25 mg once daily.

After an oral dose of metformin, tmax is reached in 2.5 hours. Absolute bioavailability of a 500 mg or850 mg metformin hydrochloride tablet is approximately 50-60% in healthy subjects. After an oraldose, the non-absorbed fraction recovered in faeces was 20-30%. After oral administration, metforminabsorption is saturable and incomplete. It is assumed that the pharmacokinetics of metforminabsorption are non-linear. At the recommended metformin doses and dosing schedules, steady-stateplasma concentrations are reached within 24 to 48 hours and are generally less than 1 microgram/ml.

In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 5 microgram/ml,even at maximum doses.

Food decreases the extent and slightly delays the absorption of metformin. Following administrationof a dose of 850 mg metformin hydrochloride, a 40% lower plasma peak concentration, a 25%decrease in AUC and a 35 minute prolongation of the time to peak plasma concentration wereobserved. The clinical relevance of these decreases is unknown.

Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lowerthan the plasma peak and appears at approximately the same time. The red blood cells most likelyrepresent a secondary compartment of distribution. The mean volume of distribution (Vd) rangedbetween 63 - 276 l.

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

Renal clearance of metformin is >400 ml/min, indicating that metformin is eliminated by glomerularfiltration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life isapproximately 6.5 hours.

When renal function is impaired, renal clearance is decreased in proportion to that of creatinine andthus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.

Single dose study: after single doses of metformin hydrochloride 500 mg, paediatric patients haveshown a similar pharmacokinetic profile to that observed in healthy adults.

Multiple-dose study: After repeated doses of 500 mg twice daily for 7 days in paediatric patients thepeak plasma concentration (Cmax) and systemic exposure (AUC0-t) were approximately 33% and 40%lower, respectively, compared to diabetic adults who received repeated doses of 500 mg twice dailyfor 14 days. As the dose is individually titrated based on glycaemic control, this is of limited clinicalrelevance.

Empagliflozin and metformin

General toxicity studies in rats of up to 13 weeks were performed with the combination ofempagliflozin and metformin and did not reveal any additional target organs when compared toempagliflozin or metformin alone. Some responses were increased by the combination treatment, suchas effects on renal physiology, electrolyte balance and acid/base state. However, only hypochloremiawas considered adverse at exposures of approximately 9- and 3-times the clinical AUC exposure ofthe maximum recommended dose of empagliflozin and metformin, respectively.

An embryofetal development study in pregnant rats did not indicate a teratogenic effect attributed tothe co-administration of empagliflozin and metformin at exposures of approximately 14-times theclinical AUC exposure of empagliflozin associated with the highest dose, and 4-times the clinical

AUC exposure of metformin associated with the 2000 mg dose.

Empagliflozin

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, genotoxicity, fertility and early embryonic development.

In long term toxicity studies in rodents and dogs, signs of toxicity were observed at exposures greaterthan or equal to 10-times the clinical dose of empagliflozin. Most toxicity was consistent withsecondary pharmacology related to urinary glucose loss and electrolyte imbalances includingdecreased body weight and body fat, increased food consumption, diarrhoea, dehydration, decreasedserum glucose and increases in other serum parameters reflective of increased protein metabolism andgluconeogenesis, urinary changes such as polyuria and glucosuria, and microscopic changes includingmineralisation in kidney and some soft and vascular tissues. Microscopic evidence of the effects ofexaggerated pharmacology on the kidney observed in some species included tubular dilatation, andtubular and pelvic mineralisation at approximately 4-times the clinical AUC exposure of empagliflozinassociated with the 25 mg dose.

Empagliflozin is not genotoxic.

In a 2-year carcinogenicity study, empagliflozin did not increase the incidence of tumours in femalerats up to the highest dose of 700 mg/kg/day, which corresponds to approximately 72-times themaximal clinical AUC exposure to empagliflozin. In male rats, treatment-related benign vascularproliferative lesions (haemangiomas) of the mesenteric lymph node were observed at the highest dose,but not at 300 mg/kg/day, which corresponds to approximately 26-times the maximal clinical exposureto empagliflozin. Interstitial cell tumours in the testes were observed with a higher incidence in rats at300 mg/kg/day and above, but not at 100 mg/kg/day which corresponds to approximately 18-times themaximal clinical exposure to empagliflozin. Both tumours are common in rats and are unlikely to berelevant to humans.

Empagliflozin did not increase the incidence of tumours in female mice at doses up to1,000 mg/kg/day, which corresponds to approximately 62-times the maximal clinical exposure toempagliflozin. Empagliflozin induced renal tumours in male mice at 1,000 mg/kg/day, but not at300 mg/kg/day, which corresponds to approximately 11-times the maximal clinical exposure toempagliflozin. The mode of action for these tumours is dependent on the natural predisposition of themale mouse to renal pathology and a metabolic pathway not reflective of humans. The male mouserenal tumours are considered not relevant to humans.

At exposures sufficiently in excess of exposure in humans after therapeutic doses, empagliflozin hadno adverse effects on fertility or early embryonic development. Empagliflozin administered during theperiod of organogenesis was not teratogenic. Only at maternally toxic doses, empagliflozin alsocaused bent limb bones in the rat and increased embryofetal loss in the rabbit.

In pre- and postnatal toxicity studies in rats, reduced weight gain of offspring was observed atmaternal exposures approximately 4-times the maximal clinical exposure to empagliflozin. No sucheffect was seen at systemic exposure equal to the maximal clinical exposure to empagliflozin. Therelevance of this finding to humans is unclear.

In a juvenile toxicity study in the rat, when empagliflozin was administered from postnatal day 21until postnatal day 90, non-adverse, minimal to mild renal tubular and pelvic dilation in juvenile ratswas seen only at 100 mg/kg/day, which approximates 11-times the maximum clinical dose of 25 mg.

These findings were absent after a 13 weeks drug-free recovery period.

Preclinical data for metformin reveal no special hazard for humans based on conventional studies ofsafety pharmacology, repeated dose toxicity, genotoxicity, or carcinogenic potential or reproductivetoxicity. At dose levels of 500 mg/kg/day administered to Wistar Hannover rats, associated with7-times the maximum recommended human dose (MRHD) of metformin, teratogenicity of metforminwas observed, mostly evident as an increase in the number of skeletal malformations.

Synjardy 5 mg/850 mg film-coated tablets and Synjardy 5 mg/1,000 mg film-coated tablets

Maize starch

Copovidone (K-value nominally 28)

Colloidal anhydrous silica

Magnesium stearate

Hypromellose

Macrogol 400

Titanium dioxide (E171)

Talc

Iron oxide yellow (E172)

Synjardy 12.5 mg/850 mg film-coated tablets and Synjardy 12.5 mg/1,000 mg film-coated tablets

Maize starch

Copovidone (K-value nominally 28)

Colloidal anhydrous silica

Magnesium stearate

Hypromellose

Macrogol 400

Titanium dioxide (E171)

Talc

Iron oxide black (E172)

Iron oxide red (E172)

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

PVC/PVDC/aluminium perforated unit dose blisters.

Pack sizes of 10 x 1, 14 x 1, 30 x 1, 56 x 1, 60 x 1, 90 x 1 and 100 x 1 film-coated tablets andmultipacks containing 120 (2 packs of 60 x 1), 180 (2 packs of 90 x 1) and 200 (2 packs of 100 x 1)film-coated tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Boehringer Ingelheim International GmbH

Binger Str. 17355216 Ingelheim am Rhein

Germany

Synjardy 5 mg/850 mg film-coated tablets

EU/1/15/1003/001

EU/1/15/1003/002

EU/1/15/1003/003

EU/1/15/1003/004

EU/1/15/1003/005

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Synjardy 5 mg/1,000 mg film-coated tablets

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Synjardy 12.5 mg/850 mg film-coated tablets

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Synjardy 12.5 mg/1,000 mg film-coated tablets

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Date of first authorisation: 27 May 2015

Date of latest renewal: 01 April 2020

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

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