Jardiance 10 mg, 25 mg FC tablets

Type 2 diabetes mellitus (T2DM) Glycaemic control: JARDIANCE is indicated as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus.

Add-on combination therapy: In combination with glucose-lowering medicines, including metformin, a thiazolidinedione, a sulphonylurea, a DPP-4 inhibitor, or insulin, when these together with diet and exercise, do not provide adequate glycaemic control.

Prevention of cardiovascular events: JARDIANCE is indicated in patients with type 2 diabetes mellitus and high cardiovascular risk* to reduce the risk of:

• cardiovascular death due to myocardial infarction
• cardiovascular death or hospitalisation for heart failure.

*e.g. previous myocardial infarction, multi vessel coronary artery disease, previous coronary revitalisation, single vessel coronary disease, at least 50 % narrowing of coronary artery lumen.

Heart failure (HF) JARDIANCE is indicated in adult patients with heart failure (NYHA class II-IV) independent of left ventricular ejection fraction, with or without type 2 diabetes mellitus:

• to reduce the risk of cardiovascular death and hospitalisation for heart failure
• to slow kidney function decline.

Chronic kidney disease (CKD) JARDIANCE is indicated in adult patients with chronic kidney disease to reduce the risk of:

• Kidney disease progression (sustained decline in estimated glomerular filtration rate (eGFR), end-stage kidney disease or renal death) or cardiovascular death
• All-cause hospitalisation.

Assess hydration status and renal function before initiating treatment with JARDIANCE. Do not initiate treatment in patients who are volume-depleted or acidotic (see section 4.4).

Posology Type 2 diabetes mellitus (T2DM) indications: The recommended starting dose of JARDIANCE is 10 mg once daily. In patients tolerating JARDIANCE 10 mg once daily who have an eGFR u2265 30 mL/min/1,73 mu00b2 and requiring additional glycaemic control, the dose may be increased to 25 mg once daily.

Heart failure (HF) indication: The recommended dose of JARDIANCE is 10 mg once daily (see section 5.1 clinical trials).

Chronic kidney disease (CKD) indication: The recommended dose of JARDIANCE is 10 mg once daily (see section 5.1 clinical trials).

JARDIANCE can be taken with or without food.

Special populations Patients with Renal Impairment: Empagliflozin 10 mg can be used regardless of renal function. However, due to limited experience, it is not recommended to initiate treatment with JARDIANCE in patients on dialysis. Glycaemic efficacy of empagliflozin is dependent on renal function and likely absent in patients with severe renal impairment. If eGFR falls below 30 mL/min/1,73 mu00b2 the recommended dose of empagliflozin is limited to 10 mg and additional glucose lowering treatment should be considered if needed (see section 4.4).

Patients with Hepatic Impairment: Dose adjustment may be necessary for patients with severe hepatic impairment.

Elderly Patients: No dosage adjustment is recommended based on age.

Combination therapy: When JARDIANCE is used in combination with a sulphonylurea or with insulin, a lower dose of the sulphonylurea or insulin should be considered to reduce the risk of hypoglycaemia (see sections 4.4 and 4.8).

Paediatric population: Safety and effectiveness of JARDIANCE in children under 18 years of age have not been established.

Method of administration Film-coated tablets for oral administration.

Missed dose If a dose is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day.

• Hypersensitivity to empagliflozin or any of the excipients of JARDIANCE (see section 6.1).
• Type 1 diabetes mellitus.
• Treatment of ketoacidosis.
• Pregnancy and lactation.

General JARDIANCE should not be used in patients with type 1 diabetes.

Ketoacidosis with atypical presentation Cases of ketoacidosis, which may be serious, life threatening or fatal, have been reported in patients with diabetes mellitus treated with JARDIANCE. Such cases require hospitalisation. The presentation of ketoacidosis is frequently atypical with either euglycaemia or with blood glucose values mildly or moderately increased below 11 mmol/L (196 mg/dL). Although ketoacidosis is less likely to occur in patients without diabetes mellitus, cases have 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 fatigue or sleepiness. Patients should be assessed for ketoacidosis immediately if these symptoms occur, regardless of blood glucose level. Treatment with JARDIANCE should be discontinued immediately in such cases and treatment instituted. Treatment, amongst others, may require fluids, carbohydrate and insulin.

The risk of developing ketoacidosis while taking JARDIANCE, is increased in patients with a reduced fluid and food intake, patients on a very low carbohydrate diet, severely dehydrated patients, insulin dose reduction in patients also requiring insulin, patients with a history of ketoacidosis or who are known to have a low beta-cell function reserve, or any pancreatic disease/disorder with or without an insulin deficiency, or patients with alcohol abuse or misusing alcohol.

A progressive increase in blood and urine ketones and a progressive increase in metabolic acidosis may be indicative of the development of ketoacidosis irrespective of blood glucose levels. Blood and urine ketones as well as blood pH should be regularly monitored.

In clinical situations known to predispose to ketoacidosis (e.g. prolonged fasting due to an acute illness or surgery), the treatment with JARDIANCE should be temporarily discontinued. In these situations, consider monitoring of ketones, even if JARDIANCE treatment has been interrupted. Treatment should be interrupted in patients who are hospitalised for acute serious medical illnesses.

The underlying mechanism for SGLT2 inhibition-associated ketoacidosis has not been established. Atypical metabolic acidosis (no ketone bodies) may present in a very similar manner to ketoacidosis.

Haemoconcentration An increase in the haematocrit of patients on treatment with JARDIANCE can be expected.

Hypoglycaemia with concomitant use with insulin and insulin secretagogues The risk of hypoglycaemia is increased when JARDIANCE is used in combination with insulin secretagogues (e.g. sulphonylurea) or insulin (see section 4.8). Therefore, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycaemia when used in combination with JARDIANCE (see section 4.2).

Use in patients with renal impairment Due to limited experience, it is not recommended to initiate treatment with JARDIANCE in patients on dialysis. Glycaemic efficacy of JARDIANCE is dependent on renal function and likely absent in patients with an eGFR<30 mL/min/1,73 mu00b2 (see section 4.2).

Monitoring of renal function Assessment of renal function is recommended prior to JARDIANCE initiation and periodically during treatment, i.e. at least 6-monthly. Consider renal function when used in conjunction with metformin.

Hepatic injury Cases of hepatic injury have been reported.

Use in patients at risk for volume depletion Based on the mode of action of SGLT2 inhibitors, osmotic diuresis accompanying glycosuria may lead to intravascular volume contraction with a decrease in blood pressure. Therefore, caution should be exercised in patients for whom an empagliflozin-induced drop in blood pressure could pose a risk, such as patients with known cardiovascular disease, patients on anti-hypertensive therapy and/or diuretics, and with a history of hypotension, or the elderly especially patients aged 75 years and older. In conditions that may lead to fluid loss (e.g. gastrointestinal illness), careful monitoring of volume status (e.g. physical examination, blood pressure measurements, laboratory tests including haematocrit) and electrolytes is recommended for patients receiving JARDIANCE. Temporary interruption of treatment with JARDIANCE should be considered until the fluid loss is corrected.

Complicated urinary tract infections and genital infections SGLT2 inhibitors such as JARDIANCE have been associated with an increased risk of urinary tract infection and/or genital infection in both males and females caused by bacteria and/or fungi. Genital fungal infections appear to be more common in females. Balanoposthitis in males may result in phimosis.

Urosepsis and Pyelonephritis Patients with a history of chronic or recurrent urinary tract infection (UTI) were more likely to experience UTI. Cases of complicated urinary tract infections including pyelonephritis and urosepsis have been reported in patients treated with JARDIANCE (see section 4.8). Temporary interruption of JARDIANCE should be considered in patients with complicated urinary tract infections.

Necrotising fasciitis of the perineum (Fournieru2019s gangrene) Cases of necrotising fasciitis of the perineum (also known as Fournieru2019s gangrene), a rare, but serious and life threatening necrotising infection, have been reported in female and male patients with diabetes mellitus treated with SGLT2 inhibitors, including empagliflozin. Serious outcomes have included hospitalisation, multiple surgeries, and death. Patients treated with JARDIANCE who present with pain or tenderness, erythema, swelling in the genital or perineal area, fever, malaise should be evaluated for necrotising fasciitis. If suspected, JARDIANCE should be discontinued, and prompt treatment should be instituted (including broad-spectrum antibiotics and surgical debridement if necessary).

Elderly patients Patients aged 75 years and older are at increased risk of volume depletion, therefore, JARDIANCE should be prescribed with caution in these patients (see section 4.8).

Paediatric population JARDIANCE is not recommended for use in children below 18 years due to lack of data on safety and efficacy.

Pharmacodynamic Interactions Diuretics: JARDIANCE may add to the diuretic effect of thiazide and loop diuretics and may increase the risk of dehydration and hypotension.

Effects on laboratory tests: Interference with 1,5-anhydroglucitol (1,5-AG) Assay: Monitoring of glycaemic control cannot be done by urine glucose monitoring or with a 1,5 AG blood assay, as SGLT2 inhibitors interfere with the assay.

Pharmacokinetic Interactions Lithium: Concomitant use of SGLT2 inhibitors, including empagliflozin, with lithium may decrease blood lithium levels through increased renal lithium elimination. Therefore, serum lithium concentration should be monitored more frequently with empagliflozin initiation or following dose changes. Please refer the patient to the lithium prescribing doctor in order to monitor serum concentration of lithium.

In vitro assessment of medicine interactions: JARDIANCE does not inhibit, inactivate, or induce CYP450 isoforms.

In vivo assessment of medicine interactions: No clinically meaningful pharmacokinetic interactions were observed when empagliflozin was co-administered with other commonly used medicinal products. Empagliflozin pharmacokinetics were similar with and without co-administration of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril, simvastatin, in healthy volunteers and with or without co-administration of torasemide and hydrochlorothiazide in patients with T2DM. Increases in overall exposure (AUC) of empagliflozin were seen following co-administration with gemfibrozil (59 %), rifampicin (35 %), or probenecid (53 %). These changes were not considered to be clinically meaningful. Empagliflozin had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, pioglitazone, sitagliptin, linagliptin, warfarin, digoxin, ramipril, simvastatin, hydrochlorothiazide, torasemide and oral contraceptives when co-administered in healthy volunteers.

JARDIANCE is contraindicated in pregnancy and lactation.

Pregnancy Animal studies showed that empagliflozin as contained in JARDIANCE crosses the placenta.

Breastfeeding Mothers should not breastfeed their infants while taking JARDIANCE. Animal studies have shown excretion of empagliflozin as contained in JARDIANCE, in milk of animals. A risk to human new-borns/infants cannot be excluded.

Hypoglycaemia may impair driving and machinery use capabilities. Patients should be aware of symptoms that may herald the onset of hypoglycaemia and act appropriately.

Summary of the safety profile Adverse Reactions in Clinical Trials Type 2 Diabetes Mellitus Indications: A total of 15 582 patients with type 2 diabetes were treated in clinical studies to evaluate the safety of empagliflozin, of which 10 004 patients were treated with empagliflozin, either alone or in combination with metformin, a sulphonylurea, a PPAR u03b3 agonist, DPP-4 inhibitors or insulin. This pool includes the EMPA-REG OUTCOME study involving 7 020 patients at high cardiovascular risk (mean age 63,1 years, 9,3 % patients at least 75 years old, 28,5 % women) treated with JARDIANCE 10 mg/day (N=2 345), JARDIANCE 25 mg/day (N=2 342), or placebo (N=2 333) up to 4,5 years. The overall safety profile of empagliflozin in this study was comparable to the previously known safety profile. In the above-described trials, the frequency of AEs leading to discontinuation was similar by treatment groups for placebo, JARDIANCE 10 mg and JARDIANCE 25 mg. The most frequent adverse drug reaction was hypoglycaemia, which depended on the type of background therapy used in the respective studies (see Table 1).

HF Indication: 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 10 mg empagliflozin or placebo. Approximately half of the patients had type 2 diabetes mellitus. The most frequent adverse drug reaction was volume depletion (empagliflozin 10 mg: 11,4 %; placebo: 9,7 %).

Chronic Kidney Disease Indication: The EMPA-KIDNEY study included patients with chronic kidney disease (N = 6 609) treated with 10 mg empagliflozin or placebo. About 44 % of the patients had type 2 diabetes mellitus. No new adverse reactions were identified in the EMPA-KIDNEY study. The overall safety profile of JARDIANCE was generally consistent across the studied indications.

Tabulated summary of adverse reactions Frequency classes: Very common (u2265 1/10); common (u2265 1/100, <1/10); uncommon (u2265 1/1 000, <1/100); rare (u2265 1/10 000, <1/1 000); very rare (<1/10 000); Not known (cannot be estimated from the available data).

The risk and severity of adverse reactions may be increased (see section 4.8). In the event of an overdose, symptomatic and supportive treatment should be initiated as appropriate to the patientu2019s clinical status. The removal of empagliflozin by haemodialysis has not been studied. Hypoglycaemia should be monitored for, especially when other antidiabetic medication has been co-administered.