JARDIANCE 25mg tablets medication leaflet

Each tablet contains 10 mg empagliflozin.

Each tablet contains lactose monohydrate equivalent to 154.3 mg lactose anhydrous.

Each tablet contains 25 mg empagliflozin.

Each tablet contains lactose monohydrate equivalent to 107.4 mg lactose anhydrous.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Round, pale yellow, biconvex, bevel-edged film-coated tablet debossed with “S10” on one side andthe Boehringer Ingelheim logo on the other (tablet diameter: 9.1 mm).

Oval, pale yellow, biconvex film-coated tablet debossed with “S25” on one side and the Boehringer

Ingelheim logo on the other (tablet length: 11.1 mm, tablet width: 5.6 mm).

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

- as monotherapy when metformin is considered inappropriate due to intolerance

- in addition to other medicinal products for the treatment of diabetes

For study results with respect to combination of therapies, effects on glycaemic control, cardiovascularand renal events, and the populations studied, see sections 4.4, 4.5 and 5.1.

Jardiance is indicated in adults for the treatment of symptomatic chronic heart failure.

Jardiance is indicated in adults for the treatment of chronic kidney disease.

The recommended starting dose is 10 mg empagliflozin once daily for monotherapy and add-oncombination therapy with other medicinal products for the treatment of diabetes. In patients toleratingempagliflozin 10 mg once daily who have an eGFR ≥60 ml/min/1.73 m2 and need tighter glycaemiccontrol, the dose can be increased to 25 mg once daily. The maximum daily dose is 25 mg (see belowand section 4.4).

The recommended dose is 10 mg empagliflozin once daily.

The recommended dose is 10 mg empagliflozin once daily.

When empagliflozin is used in combination with a sulphonylurea or with insulin, a lower dose of thesulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia (see sections 4.5 and4.8).

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 day.

Due to limited experience, it is not recommended to initiate treatment with empagliflozin in patientswith an eGFR <20 ml/min/1.73 m2.

In patients with an eGFR <60 ml/min/1.73 m2 the daily dose of empagliflozin is 10 mg.

In patients with type 2 diabetes mellitus, the glucose lowering efficacy of empagliflozin is reduced inpatients with an eGFR <45 ml/min/1.73 m2 and likely absent in patients with an eGFR<30 ml/min/1.73 m2. Therefore, if eGFR falls below 45 ml/min/1.73 m2, additional glucose loweringtreatment should be considered if needed (see sections 4.4, pct. 4.8, 5.1 and 5.2).

No dose adjustment is required for patients with hepatic impairment. Empagliflozin exposure isincreased in patients with severe hepatic impairment. Therapeutic experience in patients with severehepatic impairment is limited and therefore not recommended for use in this population (see section5.2).

No dose adjustment is recommended based on age. In patients 75 years and older, an increased risk forvolume depletion should be taken into account (see sections 4.4 and 4.8).

The recommended starting dose is 10 mg empagliflozin once daily. In patients toleratingempagliflozin 10 mg once daily and requiring additional glycaemic control, the dose can be increasedto 25 mg once daily (see sections 5.1 and 5.2). No data are available for children with eGFR <60ml/min/1.73 m² and children below 10 years of age.

The safety and efficacy of empagliflozin for the treatment of heart failure or for the treatment ofchronic kidney disease in children under 18 years of age have not been established. No data areavailable.

The tablets can be taken with or without food, swallowed whole with water.

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

Empagliflozin should not be used in patients with type 1 diabetes mellitus (see “Ketoacidosis” insection 4.4).

Cases of ketoacidosis, including life-threatening and fatal cases, have been reported in patients withdiabetes mellitus 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 ketoacidosis is more likely to occur with higher doses ofempagliflozin. Although ketoacidosis is less likely to occur in patients without diabetes mellitus, caseshave also been reported in these patients.

The risk of ketoacidosis must be considered in the event of non-specific symptoms such as nausea,vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigueor sleepiness. Patients should be assessed for ketoacidosis immediately if these symptoms occur,regardless of blood glucose level.

In patients where ketoacidosis 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 ketoacidosis and prolonged glucosuria have been observed withempagliflozin. Ketoacidosis may last longer after discontinuation of empagliflozin than expected fromthe plasma half-life (see section 5.2). Empagliflozin-independent factors, such as insulin deficiency,might be involved in prolonged periods of ketoacidosis.

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

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

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

Due to limited experience, it is not recommended to initiate treatment with empagliflozin in patientswith an eGFR <20 ml/min/1.73 m2.

In patients with an eGFR <60 ml/min/1.73 m2 the daily dose of empagliflozin is 10 mg (see section4.2).

The glucose lowering efficacy of empagliflozin is dependent on renal function, and is reduced inpatients with an eGFR <45 ml/min/1.73 m2 and is likely absent in patients with an eGFR<30 ml/min/1.73 m2 (see section 4.2, 5.1 and 5.2).

Assessment of renal function is recommended as follows:

- Prior to empagliflozin initiation and periodically during treatment, i.e. at least yearly (seesections 4.2, pct. 4.8, 5.1 and 5.2).

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

Based on the mode of action of SGLT2 inhibitors, osmotic diuresis accompanying glucosuria maylead to a modest decrease in blood pressure (see section 5.1). Therefore, caution should be exercised inpatients for whom an empagliflozin-induced drop in blood pressure could pose a risk, such as patientswith known cardiovascular disease, patients on anti-hypertensive therapy with a history ofhypotension 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 empagliflozin. Temporaryinterruption of treatment with empagliflozin 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. A higher number of these patients treated with empagliflozin had adverse reactionsrelated to volume depletion as compared to placebo (see section 4.8). Therefore, special attentionshould be given to their volume intake in case of co-administered medicinal products which may leadto volume depletion (e.g. diuretics, ACE inhibitors).

Cases of complicated urinary tract infections including pyelonephritis and urosepsis have beenreported in patients treated with empagliflozin (see section 4.8). Temporary interruption ofempagliflozin 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, Jardiance 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.

Patients with albuminuria may benefit more from treatment with empagliflozin.

Patients with infiltrative disease or with Takotsubo cardiomyopathy have not been specifically studied.

Therefore, efficacy in these patients has not been established.

Due to its mechanism of action, patients taking Jardiance 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.

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

Each tablet contains less than 1 mmol sodium (23 mg), that is to say essentially ‘sodium free’.

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 Jardiance 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% following co-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 by co-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 AUC and14% 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.

Interaction studies have only been performed in adults.

There are no data from the use of empagliflozin in pregnant women. Animal studies show thatempagliflozin crosses the placenta during late gestation to a very limited extent but do not indicatedirect or indirect harmful effects with respect to early embryonic development. However, animalstudies have shown adverse effects on postnatal development (see section 5.3). As a precautionarymeasure, it is preferable to avoid the use of Jardiance during pregnancy.

No data in humans are available on excretion of empagliflozin into milk. Available toxicological datain animals have shown excretion of empagliflozin in milk. A risk to the newborns/infants cannot beexcluded. Jardiance should not be used during breast-feeding.

No studies on the effect on human fertility have been conducted for Jardiance. Animal studies do notindicate direct or indirect harmful effects with respect to fertility (see section 5.3).

Jardiance 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

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

A total of 15 582 patients with type 2 diabetes were included in clinical studies to evaluate the safetyof empagliflozin, of which 10 004 patients received empagliflozin, either alone or in combination withmetformin, a sulphonylurea, pioglitazone, DPP-4 inhibitors, or insulin.

In 6 placebo-controlled trials of 18 to 24 weeks duration, 3 534 patients were included of which 1 183were treated with placebo and 2 351 with empagliflozin. The overall incidence of adverse events inpatients treated with empagliflozin was similar to placebo. The most frequently reported adversereaction was hypoglycaemia when used with sulphonylurea or insulin (see description of selectedadverse reactions).

The EMPEROR studies included patients with heart failure and either reduced ejection fraction(N=3 726) or preserved ejection fraction (N=5 985) treated with empagliflozin 10 mg or placebo.

Approximately half of the patients had type 2 diabetes mellitus. The most frequent adverse reaction ofthe pooled EMPEROR-Reduced and EMPEROR-Preserved studies was volume depletion(empagliflozin 10 mg: 11.4%. placebo: 9.7%).

The EMPA-KIDNEY study included patients with chronic kidney disease (N = 6 609) treated with10 mg empagliflozin or placebo. About 44% of the patients had type 2 diabetes mellitus. The mostfrequent adverse events in the EMPA-KIDNEY study were gout (empagliflozin 7.0% vs placebo8.0%), and acute kidney injury (empagliflozin 2.8% vs placebo 3.5%) which were more frequentlyreported in patients on placebo.

The overall safety profile of empagliflozin was generally consistent across the studied indications.

Adverse reactions classified by system organ class and MedDRA preferred terms reported in patientswho received empagliflozin in placebo-controlled studies are presented in the table below (Table 1).

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 1: Tabulated list of adverse reactions (MedDRA) from reported placebo-controlledstudies and from post-marketing experience

System organ Very common Common Uncommon Rare Very Rareclass

Infections and Vaginal Necrotisinginfestations moniliasis, fasciitis of thevulvovaginitis, perineumbalanitis and (Fournier´sother genital gangrene)*infectiona

Urinary tractinfection(includingpyelonephritisand urosepsis)a

Metabolism and Hypoglycaemia Thirst Ketoacidosis*nutrition (when useddisorders withsulphonylureaor insulin)a

Gastrointestinal Constipationdisorders

Skin and Pruritus Urticariasubcutaneous (generalised) Angioedematissue disorders Rash

Vascular Volumedisorders depletiona

Renal and Increased Dysuria Tubulo-urinary urinationa interstitialdisorders nephritis

Investigations Serum lipids Blood creatinineincreaseda increased/

Glomerularfiltration ratedecreaseda

Haematocritincreasedaa see subsections below for additional information

* see section 4.4

The frequency of hypoglycaemia depended on the background therapy in the respective studies andwas similar for empagliflozin and placebo as monotherapy, add-on to metformin, add-on topioglitazone with or without metformin, as add-on to linagliptin and metformin, and as adjunct tostandard care therapy and for the combination of empagliflozin with metformin in drug-naïve patientscompared to those treated with empagliflozin and metformin as individual components. An increasedfrequency was noted when given as add-on to metformin and a sulphonylurea (empagliflozin 10 mg:

16.1%, empagliflozin 25 mg: 11.5%, placebo: 8.4%), add-on to basal insulin with or withoutmetformin and with or without a sulphonylurea (empagliflozin 10 mg: 19.5%, empagliflozin 25 mg:

28.4%, placebo: 20.6% during initial 18 weeks treatment when insulin could not be adjusted;empagliflozin 10 mg and 25 mg: 36.1%, placebo 35.3% over the 78-week trial), and add-on to MDIinsulin with or without metformin (empagliflozin 10 mg: 39.8%, empagliflozin 25 mg: 41.3%,placebo: 37.2% during initial 18 weeks treatment when insulin could not be adjusted; empagliflozin10 mg: 51.1%, empagliflozin 25 mg: 57.7%, placebo: 58% over the 52-week trial).

In the EMPEROR heart failure studies, similar frequency of hypoglycaemia was noted when used add-on to sulphonylurea or insulin (empagliflozin 10 mg: 6.5%, placebo: 6.7%).

No increase in major hypoglycaemia was observed with empagliflozin compared to placebo asmonotherapy, add-on to metformin, add-on to metformin and a sulphonylurea, add-on to pioglitazonewith or without metformin, add-on to linagliptin and metformin, as adjunct to standard care therapyand for the combination of empagliflozin with metformin in drug-naïve patients compared to thosetreated with empagliflozin and metformin as individual components. An increased frequency wasnoted when given as add-on to basal insulin with or without metformin and with or without asulphonylurea (empagliflozin 10 mg: 0%, empagliflozin 25 mg: 1.3%, placebo: 0% during initial18 weeks treatment when insulin could not be adjusted; empagliflozin 10 mg: 0%, empagliflozin25 mg: 1.3%, placebo 0% over the 78-week trial), and add-on to MDI insulin with or withoutmetformin (empagliflozin 10 mg: 0.5%, empagliflozin 25 mg: 0.5%, placebo: 0.5% during initial18 weeks treatment when insulin could not be adjusted; empagliflozin 10 mg: 1.6%, empagliflozin25 mg: 0.5%, placebo: 1.6% over the 52-week trial).

In the EMPEROR heart failure studies, major hypoglycaemia was observed at similar frequencies inpatients with diabetes mellitus when treated with empagliflozin and placebo as add-on tosulphonylurea or insulin (empagliflozin 10 mg: 2.2%, placebo: 1.9%).

Vaginal moniliasis, vulvovaginitis, balanitis and other genital infections were reported morefrequently in patients treated with empagliflozin (empagliflozin 10 mg: 4.0%, empagliflozin 25 mg:

3.9%) compared to placebo (1.0%). These infections were reported more frequently in females treatedwith empagliflozin compared to placebo, and the difference in frequency was less pronounced inmales. The genital tract infections were mild or moderate in intensity.

In the EMPEROR heart failure studies, the frequency of these infections was more pronounced inpatients with diabetes mellitus (empagliflozin 10 mg: 2.3%; placebo: 0.8%) than in patients withoutdiabetes mellitus (empagliflozin 10 mg: 1.7%; placebo: 0.7%) when treated with empagliflozincompared to placebo.

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

Increased urination (including the predefined terms pollakiuria, polyuria, and nocturia) was observedat higher frequencies in patients treated with empagliflozin (empagliflozin 10 mg: 3.5%, empagliflozin25 mg: 3.3%) compared to placebo (1.4%). Increased urination was mostly mild or moderate inintensity. The frequency of reported nocturia was similar for placebo and empagliflozin (<1%).

In the EMPEROR heart failure studies, increased urination was observed at similar frequencies inpatients treated with empagliflozin and placebo (empagliflozin 10 mg: 0.9%, placebo 0.5%).

The overall frequency of urinary tract infection reported as adverse event was similar in patientstreated with empagliflozin 25 mg and placebo (7.0% and 7.2%) and higher in empagliflozin 10 mg(8.8%). Similar to placebo, urinary tract infection was reported more frequently for empagliflozin inpatients with a history of chronic or recurrent urinary tract infections. The intensity (mild, moderate,severe) of urinary tract infection was similar in patients treated with empagliflozin and placebo.

Urinary tract infection was reported more frequently in females treated with empagliflozin comparedto placebo; there was no difference in males.

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) was similar in patients treated with empagliflozin(empagliflozin 10 mg: 0.6%, empagliflozin 25 mg: 0.4%) and placebo (0.3%). The frequency ofvolume depletion events was increased in patients 75 years and older treated with empagliflozin 10 mg(2.3%) or empagliflozin 25 mg (4.3%) compared to placebo (2.1%).

The overall frequency of patients with increased blood creatinine and decreased glomerular filtrationrate were similar between empagliflozin and placebo (blood creatinine increased: empagliflozin 10 mg0.6%, empagliflozin 25 mg 0.1%, placebo 0.5%; glomerular filtration rate decreased: empagliflozin10 mg 0.1%, empagliflozin 25 mg 0%, placebo 0.3%).

Initial increases in creatinine and initial decreases in estimated glomerular filtration rates in patientstreated with empagliflozin were generally transient during continuous treatment or reversible afterdrug 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. This phenomenon is alsoobserved in the EMPEROR heart failure studies and the EMPA-KIDNEY study.

Mean percent increases from baseline for empagliflozin 10 mg and 25 mg versus placebo,respectively, were total cholesterol 4.9% and 5.7% versus 3.5%; HDL-cholesterol 3.3% and 3.6%versus 0.4 %; LDL-cholesterol 9.5% and 10.0% versus 7.5%; triglycerides 9.2% and 9.9% versus10.5%.

Mean changes from baseline in haematocrit were 3.4% and 3.6% for empagliflozin 10 mg and 25 mg,respectively, compared to 0.1% for placebo. In the EMPA-REG Outcome study, haematocrit valuesreturned towards baseline values after a follow-up period of 30 days after treatment stop.

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 the placebo-controlled phase, the most frequent adverse drug reaction was hypoglycaemia withhigher overall rates for patients in the empagliflozin pooled group compared with placebo(empagliflozin 10 mg and 25 mg, pooled: 23.1%, placebo: 9.4%). None of these events was severe orrequired assistance.

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.

In controlled clinical studies single doses of up to 800 mg empagliflozin in healthy volunteers andmultiple daily doses of up to 100 mg empagliflozin in patients with type 2 diabetes did not show anytoxicity. Empagliflozin increased urine glucose excretion leading to an increase in urine volume. Theobserved increase in urine volume was not dose-dependent and is not clinically meaningful. There isno experience with doses above 800 mg in humans.

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

The removal of empagliflozin by haemodialysis has not been studied.

Pharmacotherapeutic group: Drugs used in diabetes, Sodium-glucose co-transporter 2 (SGLT2)inhibitors, ATC code: A10BK03

Empagliflozin is a reversible, highly potent (IC50 of 1.3 nmol) and selective competitive inhibitor ofsodium-glucose co-transporter 2 (SGLT2). Empagliflozin does not inhibit other glucose transportersimportant for glucose transport into peripheral tissues and is 5 000 times more selective for SGLT2versus SGLT1, the major transporter responsible for glucose absorption in the gut. SGLT2 is highlyexpressed in the kidney, whereas expression in other tissues is absent or very low. It is responsible, asthe predominant transporter, for the reabsorption of glucose from the glomerular filtrate back into thecirculation. In patients with type 2 diabetes and hyperglycaemia a higher amount of glucose is filteredand 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 approximately78 g/day. Increased urinary glucose excretion resulted in an immediate reduction in plasma glucoselevels 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 diuresis which may contribute to sustained and moderatereduction of blood pressure.

Empagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distaltubule. This may influence several physiological functions including, but not restricted to: increasingtubuloglomerular feedback and reducing intraglomerular pressure, lowering both pre- and afterload ofthe heart, downregulating of sympathetic activity and reducing left ventricular wall stress as evidencedby lower NT-proBNP values which may have beneficial effects on cardiac remodeling, fillingpressures and diastolic function as well as preserving kidney structure and function. Other effects suchas an increase in haematocrit, a reduction in body weight and blood pressure may further contribute tothe beneficial cardiac and renal effects.

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 14 663 patients withtype 2 diabetes who were treated in 12 double-blind, placebo- and active-controlled clinical studies, ofwhich 9 295 received empagliflozin (empagliflozin 10 mg: 4 165 patients; empagliflozin 25 mg: 5 130patients). Five studies had treatment durations of 24 weeks; extensions of those and other studies hadpatients exposed to empagliflozin for up to 102 weeks.

Treatment with empagliflozin as monotherapy and in combination with metformin, pioglitazone, asulphonylurea, DPP-4 inhibitors, and insulin lead to clinically relevant improvements in HbA1c,fasting plasma glucose (FPG), body weight, and systolic and diastolic blood pressure. Administrationof empagliflozin 25 mg resulted in a higher proportion of patients achieving HbA1c goal of less than7% and fewer patients needing glycaemic rescue compared to empagliflozin 10 mg and placebo.

Higher baseline HbA1c was associated with a greater reduction in HbA1c. In addition, empagliflozinas adjunct to standard care therapy reduced cardiovascular mortality in patients with type 2 diabetesand established cardiovascular disease.

The efficacy and safety of empagliflozin as monotherapy was evaluated in a double-blind,placebo- and active-controlled study of 24 weeks duration in treatment-naïve patients. Treatment withempagliflozin resulted in a statistically significant (p<0.0001) reduction in HbA1c compared toplacebo (Table 2) and a clinically meaningful decrease in FPG.

In a pre-specified analysis of patients (N=201) with a baseline HbA1c ≥8.5%, treatment resulted in areduction in HbA1c from baseline of -1.44% for empagliflozin 10 mg, -1.43% for empagliflozin25 mg, -1.04% for sitagliptin, and an increase of 0.01% for placebo.

In the double-blind placebo-controlled extension of this study, reductions of HbA1c, body weight andblood pressure were sustained up to Week 76.

Table 2: Efficacy results of a 24 week placebo-controlled study of empagliflozin as monotherapya

Jardiance Sitagliptin

Placebo10 mg 25 mg 100 mg

N 228 224 224 223

HbA1c (%)

Baseline (mean) 7.91 7.87 7.86 7.85

Change from baseline1 0.08 -0.66 -0.78 -0.66

Difference from placebo1 -0.74* -0.85* -0.73(97.5% CI) (-0.90, -0.57) (-1.01, -0.69) (-0.88, -0.59)3

N 208 204 202 200

Patients (%) achieving

HbA1c <7% with 12.0 35.3 43.6 37.5baseline HbA1c ≥7%2

N 228 224 224 223

Body Weight (kg)

Baseline (mean) 78.23 78.35 77.80 79.31

Change from baseline1 -0.33 -2.26 -2.48 0.18

Difference from placebo1 -1.93* -2.15* 0.52(97.5% CI) (-2.48, -1.38) (-2.70,-1.60) (-0.04, 1.00)3

N 228 224 224 223

SBP (mmHg)4

Baseline (mean) 130.4 133.0 129.9 132.5

Change from baseline1 -0.3 -2.9 -3.7 0.5

Difference from placebo1 -3.4* (-6.0,

- 2.6* (-5.2, -0.0) 0.8 (-1.4, 3.1)3(97.5% CI) -0.9)a Full analysis set (FAS) using last observation carried forward (LOCF) prior to glycaemic rescuetherapy1 Mean adjusted for baseline value2 Not evaluated for statistical significance as a result of the sequential confirmatory testing procedure3 95% CI4 LOCF, values after antihypertensive rescue censored

*p-value <0.0001

Empagliflozin as add-on to metformin, metformin and a sulphonylurea, or pioglitazone with orwithout metformin resulted in statistically significant (p<0.0001) reductions in HbA1c and bodyweight compared to placebo (Table 3). In addition it resulted in a clinically meaningful reduction in

FPG, systolic and diastolic 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 studiesa

Add-on to metformin therapy

Jardiance

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 therapy

Jardiance

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 therapy

Jardiance

Placebo10 mg 25 mg

N 165 165 168

HbA1c (%)

Baseline (mean) 8.16 8.07 8.06

Change from baseline1 -0.11 -0.59 -0.72

Difference from placebo1

- 0.48* (-0.69, -0.27) -0.61* (-0.82, -0.40)(97.5% CI)

N 155 151 160

Patients (%) achieving

HbA1c <7% with baseline 7.7 24 30

HbA1c ≥7%2

N 165 165 168

Body Weight (kg)

Baseline (mean) 78.1 77.97 78.93

Change from baseline1 0.34 -1.62 -1.47

Difference from placebo1

- 1.95* (-2.64, -1.27) -1.81* (-2.49, -1.13)(97.5% CI)

N 165 165 168

SBP (mmHg)3

Baseline (mean) 125.7 126.5 126

Change from baseline1 0.7 -3.1 -4.0

Difference from placebo1

- 3.9 (-6.23, -1.50) -4.7 (-7.08, -2.37)(95% CI)a Full analysis set (FAS) using last observation carried forward (LOCF) prior to glycaemic rescuetherapy1 Mean adjusted for baseline value2 Not evaluated for statistical significance as a result of the sequential confirmatory testing procedure3 LOCF, values after antihypertensive rescue censored

* p-value <0.0001

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 1 000 mg; 12.5 mg and 500 mg, and 12.5 mg and 1 000 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 1 000 2 0001 000 mgc 2 000 mgc Met 1 000 mgc 2 000 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 randomised to the placebo group were receiving the placebo plus linagliptin 5 mg withbackground metformin6 Patients randomised 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 pre-specified 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% with33.6 30.9baseline HbA1c ≥7%2

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)2

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 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 or withoutconcomitant metformin therapy was evaluated in a double-blind, placebo-controlled trial of 52 weeksduration. During the initial 18 weeks and the last 12 weeks, the insulin dose was kept stable, but wasadjusted to achieve pre-prandial glucose levels <100 mg/dl [5.5 mmol/l], and post-prandial glucoselevels <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 FPG and body weight.

Table 7: Efficacy results at 18 and 52 weeks in a placebo-controlled study of empagliflozin as addon to multiple daily doses of insulin with or without metformin

Jardiance

Placebo10 mg 25 mg

N 188 186 189

HbA1c (%) at week 18

Baseline (mean) 8.33 8.39 8.29

Change from baseline1 -0.50 -0.94 -1.02

Difference from placebo1

- 0.44* (-0.61, -0.27) -0.52* (-0.69, -0.35)(97.5% CI)

N 115 119 118

HbA1c (%) at week 522

Baseline (mean) 8.25 8.40 8.37

Change from baseline1 -0.81 -1.18 -1.27

Difference from placebo1

- 0.38*** (-0.62, -0.13) -0.46* (-0.70, -0.22)(97.5% CI)

N 113 118 118

Patients (%) achieving

HbA1c <7% with26.5 39.8 45.8baseline HbA1c ≥7% atweek 52

N 115 118 117

Insulin dose (IU/day)at week 522

Baseline (mean) 89.94 88.57 90.38

Change from baseline1 10.16 1.33 -1.06

Difference from placebo1

- 8.83# (-15.69, -1.97) -11.22** (-18.09, -4.36)(97.5% CI)

N 115 119 118

Body Weight (kg)at week 522

Baseline (mean) 96.34 96.47 95.37

Change from baseline1 0.44 -1.95 -2.04

Difference from placebo1

- 2.39* (-3.54, -1.24) -2.48* (-3.63, -1.33)(97.5% CI)1 Mean adjusted for baseline value2 Week 19-40: treat-to-target regimen for insulin dose adjustment to achieve predefined glucose targetlevels (pre-prandial <100 mg/dl (5.5 mmol/l), post-prandial <140 mg/dl (7.8 mmol/l)

* p-value <0.0001

** p-value = 0.0003

*** p-value = 0.0005# p-value = 0.0040

The efficacy and safety of empagliflozin as add-on to basal insulin with or without metformin and/or asulphonylurea was evaluated in a double-blind, placebo-controlled trial of 78 weeks duration. Duringthe initial 18 weeks the insulin dose was kept stable, but was adjusted to achieve a FPG <110 mg/dl inthe following 60 weeks.

At week 18, empagliflozin provided statistically significant improvement in HbA1c (Table 8).

At 78 weeks, empagliflozin resulted in a statistically significant decrease in HbA1c and insulin sparingcompared to placebo. Furthermore, empagliflozin resulted in a reduction in FPG, body weight, andblood pressure.

Table 8: Efficacy results at 18 and 78 weeks in a placebo-controlled study of empagliflozin as add-onto basal insulin with or without metformin or a sulphonylureaa

Empagliflozin Empagliflozin

Placebo10 mg 25 mg

N 125 132 117

HbA1c (%) at week 18

Baseline (mean) 8.10 8.26 8.34

Change from baseline1 -0.01 -0.57 -0.71

Difference from placebo1

- 0.56* (-0.78, -0.33) -0.70* (-0.93, -0.47)(97.5% CI)

N 112 127 110

HbA1c (%) at week 78

Baseline (mean) 8.09 8.27 8.29

Change from baseline1 -0.02 -0.48 -0.64

Difference from placebo1

- 0.46* (-0.73, -0.19) -0.62* (-0.90, -0.34)(97.5% CI)

N 112 127 110

Basal insulin dose (IU/day) atweek 78

Baseline (mean) 47.84 45.13 48.43

Change from baseline1 5.45 -1.21 -0.47

Difference from placebo1

- 6.66** (-11.56, -1.77) -5.92** (-11.00, -0.85)(97.5% CI)a Full analysis set (FAS) - Completers using last observation carried forward (LOCF) prior toglycaemic rescue therapy1 mean adjusted for baseline value

* p-value <0.0001

** p-value <0.025

The efficacy and safety of empagliflozin as add-on to antidiabetic therapy was evaluated in patientswith renal impairment in a double-blind, placebo-controlled study for 52 weeks. Treatment withempagliflozin led to a statistically significant reduction of HbA1c (Table 9) and clinically meaningfulimprovement in FPG compared to placebo at Week 24. The improvement in HbA1c, body weight, andblood pressure was sustained up to 52 weeks.

Table 9: Results at 24 week in a placebo-controlled study of empagliflozin in renally impaired type 2diabetes patientsa

Empagliflozin Empagliflozin Empagliflozin

Placebo Placebo10 mg 25 mg 25 mgeGFR ≥30 toeGFR ≥60 to <90 ml/min/1.73 m²<60 ml/min/1.73 m²

N 95 98 97 187 187

HbA1c (%)

Baseline (mean) 8.09 8.02 7.96 8.04 8.03

Change from1 0.06 -0.46 -0.63 0.05 -0.37baseline

Difference from -0.52* -0.68* -0.42*placebo1 (95% CI) (-0.72, -0.32) (-0.88, -0.49) (-0.56, -0.28)

N 89 94 91 178 175

Patients (%)achieving HbA1c6.7 17.0 24.2 7.9 12.0<7% with baseline

HbA1c ≥7%2

N 95 98 97 187 187

Body Weight (kg)2

Baseline (mean) 86.00 92.05 88.06 82.49 83.22

Change from1 -0.33 -1.76 -2.33 -0.08 -0.98baseline

Difference from -1.43 -2.00 -0.91placebo1 (95% CI) (-2.09, -0.77) (-2.66, -1.34) (-1.41, -0.41)

N 95 98 97 187 187

SBP (mmHg)2

Baseline (mean) 134.69 137.37 133.68 136.38 136.64

Change from1 0.65 -2.92 -4.47 0.40 -3.88baseline

Difference from -3.57 -5.12 -4.28placebo1 (95% CI) (-6.86, -0.29) (-8.41, -1.82) (-6.88, -1.68)a Full analysis set (FAS) using last observation carried forward (LOCF) prior to glycaemic rescuetherapy1 Mean adjusted for baseline value2 Not evaluated for statistical significance as a result of the sequential confirmatory testing procedure

* p<0.0001

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 7 020 patients were treated(empagliflozin 10 mg: 2 345, empagliflozin 25 mg: 2 342, placebo: 2 333) and followed for a medianof 3.1 years. The mean age was 63 years, the mean HbA1c was 8.1%, and 71.5% were male. Atbaseline, 74% of patients were being treated with metformin, 48% with insulin, and 43% with asulphonylurea. 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 (Figure 1) and confirmed by an improved overall survival (Table 10).

The effect of empagliflozin on the primary combined endpoint of CV death, non-fatal MI, or non-fatalstroke was largely independent of glycaemic control or renal function (eGFR) and generally consistentacross eGFR categories down to an eGFR of 30 ml/min/1.73 m2 in the EMPA-REG OUTCOMEstudy.

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

Placebo Empagliflozinb

N 2 333 4 687

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

Heart failure requiring hospitalisation

In the EMPA-REG OUTCOME study, empagliflozin reduced the risk of heart failure requiringhospitalisation 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 %).

In four placebo-controlled studies, treatment with empagliflozin as monotherapy or add-on therapy tometformin, pioglitazone, or metformin plus a sulphonylurea resulted in mean changes from baseline in

FPG of -20.5 mg/dl [-1.14 mmol/l] for empagliflozin 10 mg and -23.2 mg/dl [-1.29 mmol/l] forempagliflozin 25 mg compared to placebo (7.4 mg/dl [0.41 mmol/l]). This effect was observed after24 weeks and maintained for 76 weeks.

Treatment with empagliflozin as add-on to metformin or metformin and a sulphonylurea resulted in aclinically meaningful reduction 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 and a sulphonylurea: placebo -2.3 mg/dl, empagliflozin10 mg: -35.7 mg/dl, empagliflozin 25 mg: -36.6 mg/dl).

Patients with high baseline HbA1c >10%

In a pre-specified pooled analysis of three phase 3 studies, treatment with open-label empagliflozin25 mg in patients with severe hyperglycaemia (N=184, mean baseline HbA1c 11.15%) resulted in aclinically meaningful reduction in HbA1c from baseline of 3.27% at week 24; no placebo orempagliflozin 10 mg arms were included in these studies.

In a pre-specified pooled analysis of 4 placebo-controlled studies, treatment with empagliflozinresulted in body weight reduction (-0.24 kg for placebo, -2.04 kg for empagliflozin 10 mgand -2.26 kg for empagliflozin 25 mg) at week 24 that was maintained up to week 52 (-0.16 kg forplacebo, -1.96 kg for empagliflozin 10 mg and -2.25 kg for empagliflozin 25 mg).

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 11). Treatment with empagliflozinprovided reductions in seated SBP and DBP.

Table 11: Efficacy results at 12 week in a placebo-controlled study of empagliflozin in patients withtype 2 diabetes and uncontrolled blood pressurea

Jardiance

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 placebo2

- 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 empagliflozinresulted in a reduction in systolic blood pressure (empagliflozin 10 mg: -3.9 mmHg; empagliflozin25 mg: -4.3 mmHg) compared with placebo (-0.5 mmHg) and in diastolic blood pressure(empagliflozin 10 mg: -1.8 mmHg; empagliflozin 25 mg: -2.0 mmHg) compared with placebo(-0.5 mmHg) at week 24 that were maintained up to week 52.

A randomised, double-blind, placebo-controlled study (EMPEROR-Reduced) was conducted in 3 730patients with chronic heart failure (New York Heart Association [NYHA] II-IV) and reduced ejectionfraction (LVEF ≤40%) to evaluate the efficacy and safety of empagliflozin 10 mg once daily asadjunct to standard of care heart failure therapy. The primary endpoint was the time to adjudicatedfirst event of either cardiovascular (CV) death or hospitalisation for heart failure (HHF). Occurrenceof adjudicated HHF (first and recurrent) and eGFR (CKD-EPI)cr slope of change from baseline wereincluded in the confirmatory testing. Heart Failure therapy at baseline included ACEinhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitor (88.3%), betablockers (94.7%), mineralocorticoid receptor antagonists (71.3%) and diuretics (95.0%).

A total of 1 863 patients were randomised to empagliflozin 10 mg (placebo: 1 867) and followed for amedian of 15.7 months. The study population consisted of 76.1% men and 23.9% women with a meanage of 66.8 years (range: 25-94 years), 26.8% were 75 years of age or older. 70.5% of the studypopulation were White, 18.0% Asian and 6.9% Black/African American. At randomisation, 75.1% ofpatients were NYHA class II, 24.4% were class III and 0.5% were class IV. The mean LVEF was27.5%. At baseline, the mean eGFR was 62.0 ml/min/1.73 m2 and the median urinary albumin tocreatinine ratio (UACR) was 22 mg/g. About half of the patients (51.7%) had an eGFR of≥60 ml/min/1.73 m2, 24.1% of 45 to <60 ml/min/1.73 m2, 18.6% of 30 to <45 ml/min/1.73 m2 and5.3% 20 to <30 ml/min/1.73 m2.

Empagliflozin was superior in reducing the risk of the primary composite endpoint of cardiovasculardeath or hospitalisation for heart failure compared with placebo. Additionally, empagliflozinsignificantly reduced the risk of occurrence of HHF (first and recurrent), and significantly reduced therate of eGFR decline (Table 12; Figure 2).

Table 12: Treatment effect for the primary composite endpoint, its components and the two keysecondary endpoints included in the pre-specified confirmatory testing

Placebo Empagliflozin 10 mg

N 1 867 1 863

Time to first event of CV death or HHF, N462 (24.7) 361 (19.4)(%)

Hazard ratio vs. placebo (95% CI)* 0.75 (0.65, 0.86)p−value for superiority <0.0001

CV Death, N (%) 202 (10.8) 187 (10.0)

Hazard ratio vs. placebo (95% CI) 0.92 (0.75, 1.12)

HHF (first occurrence), N (%) 342 (18.3) 246 (13.2)

Hazard ratio vs. placebo (95% CI) 0.69 (0.59, 0.81)

HHF (first and recurrent), N of events 553 388

Hazard ratio vs. placebo (95% CI)* 0.70 (0.58, 0.85)p−value 0.0003eGFR (CKD-EPI)cr slope**, Rate of

- 2.28 -0.55decline (ml/min/1.73m2/year)

Treatment difference vs. placebo (95% CI) 1.73 (1.10, 2.37)p-value < 0.0001

CV = cardiovascular, HHF = hospitalisation for heart failure, eGFR = Estimated glomerular filtrationrate, CKD EPI = Chronic kidney disease epidemiology collaboration equation

* CV death and HHF events were adjudicated by an independent clinical event committee andanalysed based on the randomised set.

**eGFR slope was analysed based on the treated set. Intercept is -0.95 ml/min/1.73 m2 for placebo and

- 3.02 ml/min/1.73 m2 for empagliflozin. The intercept represents the acute effect on eGFR while theslope represents the long-term effect.

Figure 2 Time to first event of adjudicated CV death or HHF

The results of the primary composite endpoint were generally consistent with a hazard ratio (HR)below 1 across the pre-specified subgroups, including patients with heart failure, with or without type2 diabetes mellitus and with or without renal impairment (down to an eGFR of 20 ml/min/1.73 m2).

A randomised, double-blind, placebo-controlled study (EMPEROR-Preserved) was conducted in5 988 patients with chronic heart failure (NYHA II-IV) and preserved ejection fraction (LVEF >40%)to evaluate the efficacy and safety of empagliflozin 10 mg once daily as adjunct to standard of caretherapy. The primary endpoint was the time to adjudicated first event of either cardiovascular (CV)death or hospitalisation for heart failure (HHF). Occurrence of adjudicated HHF (first and recurrent),and eGFR (CKD-EPI)cr slope of change from baseline were included in the confirmatory testing.

Baseline therapy included ACE inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitor (80.7%), beta blockers (86.3%), mineralocorticoid receptor antagonists (37.5%)and diuretics (86.2%).

A total of 2 997 patients were randomised to empagliflozin 10 mg (placebo: 2 991) and followed for amedian of 26.2 months. The study population consisted of 55.3% men and 44.7% women with a meanage of 71.9 years (range: 22-100 years), 43.0% were 75 years of age or older. 75.9% of the studypopulation were White, 13.8% Asian and 4.3% Black/African American. At randomisation, 81.5% ofpatients were NYHA class II, 18.1% were class III and 0.3% were class IV. The EMPEROR-

Preserved study population included patients with a LVEF <50% (33.1%), with a LVEF 50 to <60%(34.4%) and a LVEF ≥60% (32.5%). At baseline, the mean eGFR was 60.6 ml/min/1.73 m2 and themedian urinary albumin to creatinine ratio (UACR) was 21 mg/g. About half of the patients (50.1%)had an eGFR of ≥60 ml/min/1.73 m2, 26.1% of 45 to <60 ml/min/1.73 m2, 18.6% of 30 to <45ml/min/1.73 m2 and 4.9% 20 to <30 ml/min/1.73 m2.

Empagliflozin was superior in reducing the risk of the primary composite endpoint of cardiovasculardeath or hospitalisation for heart failure compared with placebo. Additionally, empagliflozinsignificantly reduced the risk of occurrence of HHF (first and recurrent), and significantly reduced therate of eGFR decline (Table 13; Figure 3).

Table 13: Treatment effect for the primary composite endpoint, its components and the two keysecondary endpoints included in the pre-specified confirmatory testing

Placebo Empagliflozin 10 mg

N 2 991 2 997

Time to first event of CV death or HHF, N511 (17.1) 415 (13.8)(%)

Hazard ratio vs. placebo (95% CI)* 0.79 (0.69, 0.90)p−value for superiority 0.0003

CV Death, N (%) 244 (8.2) 219 (7.3)

Hazard ratio vs. placebo (95% CI) 0.91 (0.76, 1.09)

HHF (first occurrence), N (%) 352 (11.8) 259 (8.6)

Hazard ratio vs. placebo (95% CI) 0.71 (0.60, 0.83)

HHF (first and recurrent), N of events 541 407

Hazard ratio vs. placebo (95% CI)* 0.73 (0.61, 0.88)p−value 0.0009eGFR (CKD-EPI)cr slope**, Rate of

- 2.62 -1.25decline (ml/min/1.73m2/year)

Treatment difference vs. placebo (95% CI) 1.36 (1.06, 1.66)p-value < 0.0001

CV = cardiovascular, HHF = hospitalisation for heart failure, eGFR = Estimated glomerular filtrationrate, CKD EPI = Chronic kidney disease epidemiology collaboration equation

* CV death and HHF events were adjudicated by an independent clinical event committee andanalysed based on the randomised set.

**eGFR slope was analysed based on the treated set. Intercept is -0.18 ml/min/1.73 m2 for placebo and

- 3.02 ml/min/1.73 m2 for empagliflozin. The intercept represents the acute effect on eGFR while theslope represents the long-term effect.

Figure 3 Time to first event of adjudicated CV death or HHF

The results of the primary composite endpoint were consistent across each of the pre-specifiedsubgroups categorized by e.g., LVEF, diabetes status or renal function (down to an eGFR of20 ml/min/1.73 m2).

A randomised, double-blind, placebo-controlled study of empagliflozin 10 mg once daily (EMPA-

KIDNEY) was conducted in 6 609 patients with chronic kidney disease (eGFR ≥20 -<45 ml/min/1.73 m2; or eGFR ≥45 - <90 ml/min/1.73 m2 with urinary albumin to creatinine ratio(UACR) ≥200 mg/g) to assess cardio-renal outcomes as adjunct to standard of care therapy. Theprimary endpoint was the time to first occurrence of kidney disease progression (sustained ≥40%eGFR decline from randomisation, sustained eGFR <10 ml/min/1.73 m², end-stage kidney disease, orrenal death) or CV death. First occurrence of hospitalisation for heart failure or CV death, all-causehospitalisation (first and recurrent), and all-cause mortality were included in the confirmatory testing.

Baseline therapy included an appropriate use of a RAS-inhibitor (85.2% ACE inhibitor or angiotensinreceptor blocker).

A total of 3 304 patients were randomised to empagliflozin 10 mg (placebo: 3 305) and followed for amedian of 24.3 months. The study population consisted of 66.8% men and 33.2% women with a meanage of 63.3 years (range: 18-94 years), 23.0% were 75 years of age or older. 58.4% of the studypopulation were White, 36.2% Asian and 4.0% Black/African American.

At baseline, the mean eGFR was 37.3 ml/min/1.73 m2, 21.2% patients had an eGFR of≥45 ml/min/1.73 m2, 44.3% of 30 to <45 ml/min/1.73 m2 and 34.5% <30 ml/min/1.73 m2 including254 patients with an eGFR <20 ml/min /1.73 m2. The median UACR was 329 mg/g, 20.1% patientshad an UACR <30 mg/g, 28.2% had an UACR 30 to ≤300 mg/g and 51.7% had an UACR >300 mg/g;41.1% of patients had an UACR <200 mg/g. Primary causes of CKD were diabeticnephropathy/diabetic kidney disease (31%), glomerular disease (25%), hypertensive/renovasculardisease (22%) and other/unknown (22%).

Empagliflozin was superior in reducing the risk of the primary composite endpoint of kidney diseaseprogression or CV death compared with placebo (see Table 14). Additionally, empagliflozinsignificantly reduced the risk of all-cause hospitalisation (first and recurrent).

Table 14: Treatment effect for the primary composite and key secondary endpoints included in the pre-specified confirmatory testing and its components

Placebo Empagliflozin 10 mg

N 3 305 3 304

Time to first occurrence of kidney diseaseprogression (sustained ≥40% eGFRdecline from randomisation, sustained558 (16.9) 432 (13.1)eGFR <10 ml/min/1.73 m2, end-stagekidney disease* (ESKD), or renal death)or CV death, N (%)

Hazard ratio vs. placebo (99.83% CI) 0.72 (0.59, 0.89)p−value for superiority <0.0001

Sustained ≥40% eGFR decline from 474 (14.3) 359 (10.9)randomisation, N (%)

Hazard ratio vs. placebo (95% CI) 0.70 (0.61, 0.81)p-value <0.0001

ESKD* or sustained eGFR 221 (6.7) 157 (4.8)<10 ml/min/1.73 m2, N (%)

Hazard ratio vs. placebo (95% CI) 0.69 (0.56, 0.84)p-value 0.0003

Renal death, N (%)** 4 (0.1) 4 (0.1)

Hazard ratio vs. placebo (95% CI)p-value

CV Death, N (%) 69 (2.1) 59 (1.8)

Hazard ratio vs. placebo (95% CI) 0.84 (0.60, 1.19)p-value 0.3366

ESKD or CV Death, N (%)# 217 (6.6) 163 (4.9)

Hazard ratio vs. placebo (95% CI) 0.73 (0.59, 0.89)p-value 0.0023

Occurrence of all-cause hospitalisation 1 895 1 611(first and recurrent), N of events

Hazard ratio vs. placebo (99.03% CI) 0.86 (0.75, 0.98)p-value 0.0025

CV = cardiovascular, HHF = hospitalisation for heart failure, eGFR = Estimated glomerular filtrationrate

* End-stage kidney disease (ESKD) is defined as the initiation of maintenance dialysis or receipt of akidney transplant.

** There were too few events of renal death to compute a reliable hazard ratio.# Predefined as one of the two stopping criteria in the pre-planned interim analysis.

Figure 4 Time to first event of kidney disease progression or adjudicated CV death, estimatedcumulative incidence function

The results of the primary composite endpoint were generally consistent across the pre-specifiedsubgroups, including eGFR categories, underlying cause of renal disease, diabetes status, orbackground use of RAS inhibitors. Treatment benefits were more clearly evident in patients withhigher levels of albuminuria.

During treatment, eGFR decline over time was slower in the empagliflozin group compared to theplacebo group (Figure 5). Empagliflozin slowed the annual rate of eGFR decline compared to placeboby 1.37 ml/min/1.73 m2/year (95% CI 1.16, 1.59), based on a pre-specified analysis of all eGFRmeasurements taken from the 2-month visit to the final follow-up visit. Patients treated withempagliflozin experienced an initial drop in eGFR which returned towards baseline after treatmentdiscontinuation as demonstrated in several of the empagliflozin studies, supporting thathaemodynamic changes play a role in the acute effects of empagliflozin on eGFR.

Figure 5 Change in eGFR over time*

*eGFR (CKD-EPI) (ml/min/1.73 m2) MMRM results over time - randomised set.

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 change 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)].

Heart failure and chronic kidney disease

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

Jardiance in all subsets of the paediatric population in heart failure and in the treatment of chronickidney disease (see section 4.2 for information on paediatric use).

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 1 870 nmol.h/l and 259 nmol/l withempagliflozin 10 mg and 4 740 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.

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.

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 and the most abundantmetabolites were three glucuronide conjugates (2-, 3-, and 6-O glucuronide). Systemic exposure ofeach metabolite was less than 10% of total drug-related material. In vitro studies suggested that theprimary route of metabolism of empagliflozin in humans is glucuronidation by the uridine5'-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 (eGFR <30 - <90 ml/min/1.73 m2) andpatients with kidney failure/end stage kidney disease (ESKD), 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/ESKD 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 eGFR leading to anincrease 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.

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 at 300mg/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.

Lactose monohydrate

Microcrystalline cellulose

Hydroxypropylcellulose

Croscarmellose sodium

Colloidal anhydrous silica

Magnesium stearate

Hypromellose

Titanium dioxide (E171)

Talc

Macrogol (400)

Iron oxide yellow (E172)

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

PVC/aluminium perforated unit dose blisters.

Pack sizes of 7 x 1, 10 x 1, 14 x 1, 28 x 1, 30 x 1, 60 x 1, 70 x 1, 90 x 1, and 100 x 1 film-coatedtablets.

Not all pack sizes may be marketed.

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

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Germany

EU/1/14/930/010

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Date of first authorisation: 22 May 2014

Date of latest renewal: 14 February 2019

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

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