Inglyflo 10 mg & 25 mg FC tablets

INGLYFLO film - coated tablets are indicated as an adjunct to diet and exercise to improve glycaemic control in adults (aged 18 years and older) with type 2 diabetes mellitus. Prevention of cardiovascular events: INGLYFLO is indicated in patients with type 2 diabetes mellitus and high cardiovascular risk* to reduce the risk of:

• cardiovascular death due to myocardial infarction

*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. INGLYFLO tablets are not recommended for use in combination with other antidiabetic medicines and for treatment of chronic kidney disease and heart failure. However, it is recommended to use another suitable medicine containing empagliflozin for the same.

Posology

Assess hydration status and renal function before initiating treatment with INGLYFLO. Do not initiate treatment if the estimated glomerular filtration rate (eGFR) is < 60 mL/min/1,73 mu00b2 (or creatinine clearance < 60 mL/min) and/or in patients who are volume depleted or acidotic (see section 4.4). The recommended starting dose of INGLYFLO is 10 mg once daily. In patients tolerating INGLYFLO 10 once daily and requiring additional glycaemic control, the dose may be increased to 25 mg once daily.

Special populations

Patients with renal insufficiency

No dose adjustment is required for patients with mild renal insufficiency (e.g., eGFR u2265 60 to < 90 mL/min/1,73 mu00b2). INGLYFLO is not recommended for use in patients with moderate to severe renal impairment (defined as eGFR < 60 mL/min/1,73 mu00b2 by modification of diet in renal disease or creatinine clearance < 60 mL/min by Cockroft - Gault) (see sections 4.3 and 4.4).

Patients with hepatic insufficiency

Dose adjustment may be necessary for patients with severe hepatic impairment.

Elderly patients

No dosage adjustment is recommended based on age if the creatinine clearance is u2265 60 mL/min. Therapeutic experience in patients aged 85 years and older is limited. Initiation of INGLYFLO therapy in this population is not recommended (see section 4.4).

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.

Paediatric population

Safety and effectiveness of INGLYFLO in children under 18 years of age have not been established.

Method of administration

For oral use. INGLYFLO can be taken with or without food.

• Hypersensitivity to empagliflozin or any of the excipients listed in section 6.1.
• Treatment of Type 1 diabetes mellitus.
• Treatment of ketoacidosis (see section 4.4).
• Moderate and severe renal impairment (creatinine clearance < 60 mL/min), end-stage renal disease or dialysis (see section 4.4).
• Pregnancy and lactation (see section 4.6).

Diabetic ketoacidosis

Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have been reported in patients treated with sodium-glucose co-transporter-2 (SGLT2) inhibitors, including empagliflozin. In a number of cases, the presentation of the condition was atypical with only moderately increased blood glucose values, below 14 mmol/L (250 mg/100 mL). It is not known if DKA is more likely to occur with higher doses of empagliflozin.

The risk of diabetic 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. In patients where diabetic ketoacidosis (DKA) is suspected or diagnosed, treatment with empagliflozin should be discontinued immediately. Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses. Monitoring of ketones is recommended in these patients. Measurement of blood ketone levels is preferred to urine.

Treatment with empagliflozin may be restarted when the ketone values are normal, and the condition of the patient has stabilised. Before initiating empagliflozin, factors in the patient history that may predispose to ketoacidosis should be considered. Patients who may be at higher risk of DKA include patients with a low beta cell function reserve (e.g., type 2 diabetes patients with low C-peptide or latent autoimmune diabetes in adults [LADA] or patients with a history of pancreatitis), patients with conditions that lead to restricted food intake or severe dehydration, patients for whom insulin doses are reduced and patients with increased insulin requirements due to acute medical illness, surgery or alcohol abuse. SGLT2 inhibitors should be used with caution in these patients.

Restarting SGLT2 inhibitor treatment in patients with previous DKA while on SGLT-2 inhibitor treatment is not recommended, unless another clear precipitating factor is identified and resolved. INGLYFLO should not be used for treatment of patients with type 1 diabetes. Data from a clinical trial program in patients with type 1 diabetes showed increased DKA with a frequent occurrence in patients treated with empagliflozin 10 mg and 25 mg as an adjunct to insulin compared to placebo.

Renal impairment

INGLYFLO should not be initiated in patients with an eGFR below 60 mL/min/1,73 mu00b2 or CrCl < 60 mL/min. In patients tolerating empagliflozin whose eGFR is persistently below 60 mL/min/1,73 mu00b2 or CrCl < 60 mL/min, the dose of empagliflozin should be adjusted to or maintained at 10 mg once daily. Empagliflozin should be discontinued when eGFR is persistently below 45 mL/min/1,73 mu00b2 or CrCl persistently below 45 mL/min. Empagliflozin should not be used in patients with end-stage renal disease (ESRD) or in patients on dialysis as it is not expected to be effective in these patients (see sections 4.2 and 5.2).

Monitoring of renal function

Due to the mechanism of action, the glycaemic efficacy of empagliflozin is dependent on renal function. Therefore, assessment of renal function is recommended as follows:

• Prior to INGLYFLO initiation and periodically during treatment, i.e. at least yearly (see sections 4.2, 5.1 and 5.2).
• Prior to initiation of any concomitant medicine that may have a negative impact on renal function.

Hepatic injury

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

Elevated haematocrit

Increase in haematocrit values were observed with empagliflozin treatment (see section 4.8).

Risk for volume depletion

Based on the mode of action of SGLT-2 inhibitors, osmotic diuresis accompanying therapeutic glucosuria may lead to a modest decrease in blood pressure (see section 5.1). 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 with a history of hypotension or patients aged 75 years and older. In case of conditions that may lead to fluid loss (e.g., gastrointestinal illness), careful monitoring of volume status (e.g., physical examination, blood pressure measurements, laboratory tests including haematocrit) and electrolytes is recommended for patients receiving empagliflozin. Temporary interruption of treatment with empagliflozin should be considered until the fluid loss is corrected.

Elderly patients

The effect of empagliflozin on urinary glucose excretion is associated with osmotic diuresis, which could affect the hydration status. Patients aged 75 years and older may be at an increased risk of volume depletion. A higher number of these patients treated with empagliflozin had adverse reactions related to volume depletion as compared to placebo (see section 4.8). Therefore, special attention should be given to their volume intake in case of co-administered medicines which may lead to volume depletion (e.g., diuretics, ACE inhibitors). Therapeutic experience in patients aged 85 years and older is limited. Initiation of empagliflozin therapy in this population is not recommended (see section 4.2).

Complicated urinary tract infections and genital infections

SGLT2 inhibitors such as INGLYFLO 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. Temporary interruption of INGLYFLO should be considered in patients with complicated urinary tract infections.

Urinary tract infections

In a pool of placebo-controlled double-blind trials of 18 to 24 weeks duration, the overall frequency of urinary tract infection reported as adverse event was similar in patients treated with empagliflozin 25 mg and placebo and higher in patients treated with empagliflozin 10 mg (see section 4.8). Patients with a history of chronic or recurrent urinary tract infection (UTI) were more likely to experience UTI.

Post-marketing cases of complicated urinary tract infections including pyelonephritis and urosepsis have been reported in patients treated with empagliflozin. Temporary interruption of empagliflozin should be considered in patients with complicated urinary tract infections.

Necrotising fasciitis of the perineum (Fournier's gangrene)

Post-marketing cases of necrotising fasciitis of the perineum, (also known as Fournier's gangrene), have been reported in female and male patients taking SGLT2 inhibitors. This is a rare but serious and potentially life-threatening event that requires urgent surgical intervention and antibiotic treatment. Patients should be advised to seek medical attention if they experience a combination of symptoms of pain, tenderness, erythema, or swelling in the genital or perineal area, with fever or malaise. Be aware that either urogenital infection or perineal abscess may precede necrotising fasciitis. If Fournier's gangrene is suspected, INGLYFLO should be discontinued, and prompt treatment (including antibiotics and surgical debridement) should be instituted.

Infiltrative disease or Takotsubo cardiomyopathy

Patients with infiltrative disease or with Takotsubo cardiomyopathy have not been specifically studied. Therefore, efficacy in these patients has not been established.

Lower limb amputations

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

Cardiac failure

Experience in New York Heart Association (NYHA) class I - II is limited, and there is no experience in clinical studies with empagliflozin in NYHA class III - IV. In the EMPA-REG OUTCOME study, 10.1 % of the patients were reported with cardiac failure at baseline. The reduction of cardiovascular death in these patients was consistent with the overall study population.

Urine laboratory assessments

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

Interference with 1,5 - anhydroglucitol (1,5 - AG) assay

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

Lactose

INGLYFLO tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take INGLYFLO.

Sodium

INGLYFLO contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially u2018sodium-freeu2019.

Pharmacodynamic interactions

Diuretics

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

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.

Effects of other medicines on empagliflozin

In vitro data suggest that the primary route of metabolism of empagliflozin in humans is glucuronidation 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.

Women of childbearing potential / Contraception in males and females

No available data.

Pregnancy

There are no data from the use of empagliflozin in pregnant women. Animal studies show that empagliflozin crosses the placenta during late gestation to a very limited extent but do not indicate direct or indirect harmful effects with respect to early embryonic development. However, animal studies have shown adverse effects on postnatal development. INGLYFLO is contraindicated during pregnancy (see section 4.3).

Breastfeeding

No data in humans are available on excretion of empagliflozin into milk. Available toxicological data in animals have shown excretion of empagliflozin in milk. A risk to the new-born/infant cannot be excluded. INGLYFLO is contraindicated during breastfeeding (see section 4.3).

Fertility

No studies on the effect on human fertility have been conducted for INGLYFLO. Animal studies do not indicate direct or indirect harmful effects with respect to fertility.

INGLYFLO has minor influence on the ability to drive a vehicle and use machines.

a) Summary of safety profile

The most frequent undesirable effect was hypoglycaemia.

b) Tabulated summary of adverse reactions

a See sub-sections below for additional information.

b 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 % versus 10,5 %.

c 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 values returned towards baseline values after a follow-up period of 30 days after treatment discontinuation.

* See section 4.4.

Description of selected adverse reactions

Major hypoglycaemia (events requiring assistance) No increase in major hypoglycaemia was observed with empagliflozin compared to placebo as monotherapy.

Vaginal moniliasis, vulvovaginitis, balanitis and other genital infection Vaginal moniliasis, vulvovaginitis, balanitis and other genital infections were reported more frequently 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 treated with empagliflozin compared to placebo, and the difference in frequency was less pronounced in males. The genital tract infections were mild or moderate in intensity.

Increased urination Increased urination (including the predefined terms pollakiuria, polyuria, and nocturia) was observed at higher frequencies in patients treated with empagliflozin (empagliflozin 10 mg: 3,5 %, empagliflozin 25 mg: 3,3 %) compared to placebo (1,4 %). Increased urination was mostly mild or moderate in intensity. The frequency of reported nocturia was similar for placebo and empagliflozin (< 1 %).

Urinary tract infection The overall frequency of urinary tract infection reported as adverse event was similar in patients treated 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 in patients 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 compared to placebo; there was no difference in males.

Volume depletion 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 of volume 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 %).

Blood creatinine increased/glomerular filtration rate decreased The overall frequency of patients with increased blood creatinine and decreased glomerular filtration rate were similar between empagliflozin and placebo (blood creatinine increased: empagliflozin 10 mg 0,6 %, empagliflozin 25 mg 0,1 %, placebo 0,5 %; glomerular filtration rate decreased: empagliflozin 10 mg 0,1 %, empagliflozin 25 mg 0 %, placebo 0,3 %). Initial increases in creatinine and initial decreases in estimated glomerular filtration rates in patients treated with empagliflozin were generally transient during continuous treatment or reversible after discontinuation of medicine treatment. Consistently, in the EMPA-REG OUTCOME study, patients treated with empagliflozin experienced an initial fall in eGFR (mean: 3 mL/min/1,73 mu00b2). Thereafter, eGFR was maintained during continued treatment. Mean eGFR returned to baseline after treatment discontinuation suggesting acute haemodynamic changes may play a role in these renal function changes.

Serum lipids increased 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 % versus 10.5 %.

Haematocrit increased 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 values returned towards baseline values after a follow-up period of 30 days after treatment discontinuation.

Symptoms

The risk and severity of side effects may be increased. Empagliflozin, as in INGLYFLO, increased urine glucose excretion leading to an increase in urine volume. The observed increase in urine volume was not dose-dependent and is not clinically meaningful. There is no experience with doses above 800 mg in humans.

Therapy

In the event of an overdose, treatment should be initiated as appropriate to the patient's clinical status. The removal of empagliflozin, as in INGLYFLO, by haemodialysis has not been studied. Hypoglycaemia should be monitored for, especially when other antidiabetic medication has been co-administered.