Pharmacodynamic properties:

• Pharmacotherapeutic group
  Drugs used in diabetes, other blood glucose lowering drugs, and excl. insulin
• Mechanism of action
  Empagliflozin is a reversible, highly potent (IC50 of 1.3 nmol) and selective competitive inhibitor of sodium-glucose co-transporter 2 (SGLT2). Empagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is 5000 times more selective for SGLT2 versus SGLT1, the major transporter responsible for glucose absorption in the gut. SGLT2 is highly expressed in the kidney, whereas expression in other tissues is absent or very low. It is responsible, as the predominant transporter, for the reabsorption of glucose from the glomerular filtrate back into the circulation. In patients with type 2 diabetes and Hyperglycemia a higher amount of glucose is filtered and reabsorbed.
  Empagliflozin improves Glycaemic control in patients with type 2 diabetes by reducing renal glucose reabsorption. The amount of glucose removed by the kidney through this Glucuretic mechanism is dependent on blood glucose concentration and GFR. Inhibition of SGLT2 in patients with type 2 diabetes and Hyperglycaemia leads to excess glucose excretion in the urine. In addition, initiation of Empagliflozin increases excretion of sodium resulting in osmotic diuresis and reduced intravascular volume.
  In patients with type 2 diabetes, urinary glucose excretion increased immediately following the first dose of Empagliflozin and is continuous over the 24 hour dosing interval. Increased urinary glucose excretion was maintained at the end of the 4-week treatment period, averaging approximately 78 g/day. Increased urinary glucose excretion resulted in an immediate reduction in plasma glucose levels in patients with type 2 diabetes.
  Empagliflozin improves both fasting and post-prandial plasma glucose levels. The mechanism of action of Empagliflozin is independent of beta cell function and insulin pathway and this contributes to a low risk of Hypoglycemia. Improvement of surrogate markers of beta cell function including Homeostasis Model Assessment-β (HOMA-β) was noted. In addition, urinary glucose excretion triggers calorie loss, associated with body fat loss and body weight reduction. The Glucosuria observed with Empagliflozin is accompanied by diuresis which may contribute to sustained and moderate reduction of blood pressure. The Glucosuria, Natriuresis and Osmotic Diuresis observed with Empagliflozin may contribute to the improvement in cardiovascular outcomes.

Pharmacokinetic Properties

• Absorption
  The pharmacokinetics of Empagliflozin has been extensively characterized in healthy volunteers and patients with type 2 diabetes. After oral administration, Empagliflozin was rapidly absorbed with peak plasma concentrations occurring at a median tmax of 1.5 hours post-dose. Thereafter, plasma concentrations declined in a biphasic manner with a rapid distribution phase and a relatively slow terminal phase. The steady state mean plasma AUC and Cmax were 1870 nmol.h/l and 259 nmol/l with Empagliflozin 10 mg and 4740 nmol.h/l and 687 nmol/l with Empagliflozin 25 mg once daily. Systemic exposure of Empagliflozin increased in a dose-proportional manner. The single-dose and steady-state pharmacokinetic parameters of Empagliflozin were similar suggesting linear pharmacokinetics with respect to time. There were no clinically relevant differences in Empagliflozin pharmacokinetics 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 in slightly 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 not considered clinically relevant and Empagliflozin may be administered with or without food.
• Distribution
  The apparent steady-state volume of distribution was estimated to be 73.8 l based on the population pharmacokinetic analysis. Following administration of an oral. Empagliflozin solution to healthy volunteers, the red blood cell partitioning was approximately 37% and plasma protein binding was 86%.
• Biotransformation
  No major metabolites of Empagliflozin were detected in human plasma and the 4 most abundant metabolites were three Glucuronide conjugates (2-, 3-, and 6-O Glucuronide). Systemic exposure of each metabolite was less than 10% of total drug-related material. In vitro studies suggested that the primary route of metabolism of Empagliflozin in humans is Glucuronidation by the Uridine 5'-Diphospho-GlucuronosylTransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9.
• Elimination
  Based on the population pharmacokinetic analysis, the apparent terminal elimination half-life of Empagliflozin was estimated to be 12.4 hours and apparent oral clearance was 10.6 l/hour. The inter-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 were reached by the fifth dose. Consistent with the half-life, up to 22% accumulation, with respect to plasma AUC, was observed at steady-state. Following administration of an oral .Empagliflozin solution to healthy volunteers, approximately 96% of the drug-related radioactivity was eliminated in faeces (41%) or urine (54%). The majority of drug-related radioactivity recovered in faeces was unchanged parent drug and approximately half of drug related radioactivity excreted in urine was unchanged parent drug.

Pharmacodynamic interactions

• Diuretics
  Glucoemp may add to the diuretic effect of Thiazide and Loop Diuretics and may increase the risk of Dehydration and Hypotension.
• Insulin and Insulin Secretagogues
  Insulin and Insulin Secretagogues, such as Sulphonylureas, may increase the risk of Hypoglycemia. Therefore, a lower dose of insulin or an insulin Secretagogue may be required to reduce the risk of Hypoglycemia when used in combination with Glucoemp.

Pharmacokinetic interactions

• Effects of other medicinal products on Glucoemp
  In vitro data suggest that the primary route of metabolism of Glucoemp in humans is Glucuronidation by Uridine 5'-Diphosphoglucuronosyl Transferases 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 breast cancer resistance protein (BCRP).
• Co-administration of Glucoemp with Probenecid, an inhibitor of UGT enzymes and OAT3, resulted in a 26% increase in peak Empagliflozin plasma concentrations (Cmax) and a 53% increase in area under the concentration-time curve (AUC). These changes were not considered to be clinically meaningful.
• The effect of UGT induction on Glucoemp has not been studied.
• Co-treatment with known inducers of UGT enzymes should be avoided due to a potential risk of decreased efficacy.
• An interaction study with Gemfibrozil, an in vitro inhibitor of OAT3 and OATP1B1/1B3 transporters, showed that Glucoemp 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 Glucoemp. These changes were not considered to be clinically meaningful.
• Glucoemp exposure was similar with and without co-administration with verapamil, a P-gp inhibitor, indicating that inhibition of P-gp does not have any clinically relevant effect on Glucoemp.
• Interaction studies suggest that the pharmacokinetics of Glucoemp were not influenced by co-administration with Metformin, Glimepiride, Pioglitazone, Sitagliptin, Linagliptin, warfarin, Verapamil, Ramipril, Simvastatin, Torasemide and Hydrochlorothiazide.
• Effects of Glucoemp on other medicinal products
  Based on in vitro studies, Glucoemp does not inhibit, inactivate, or induce CYP450 isoforms. Glucoemp does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9, or UGT2B7. Drug-drug interactions involving the major CYP450 and UGT isoforms with Glucoemp and concomitantly administered substrates of these enzymes are therefore considered unlikely. Glucoemp does not inhibit P-gp at therapeutic doses. Based on in vitro studies, Glucoemp is considered unlikely to cause interactions with active substances that are P-gp substrates. Co-administration of digoxin, a P-gp substrate, with Glucoemp resulted in a 6% increase in AUC and 14% increase in Cmax of digoxin. These changes were not considered to be clinically meaningful.

• As monotherapy when Metformin is considered inappropriate due to intolerance
• In addition to other medicinal products for the treatment of diabetes.

• The recommended starting dose is 10 mg Glucoemp once daily for monotherapy and add-on combination therapy with other medicinal products for the treatment of diabetes. In patients tolerating Glucoemp 10 mg once daily who have an eGFR ≥60 ml/min/1.73 m2 and need tighter Glycaemic control, the dose can be increased to 25 mg once daily. The maximum daily dose is 25 mg.
• When Glucoemp is used in combination with a Sulphonylurea or with insulin, a lower dose of the Sulphonylurea or insulin may be considered to reduce the risk of Hypoglycemia.

• Diabetic Ketoacidosis
  Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have been reported in patients treated with SGLT2 inhibitors, including Glucoemp. In a number of cases, the presentation of the condition was atypical with only moderately increased blood glucose values, below14 mmol/l (250 mg/dl). It is not known if DKA is more likely to occur with higher doses of Glucoemp.
  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 DKA is suspected or diagnosed, treatment with Glucoemp should be discontinued immediately.
  Before initiating Glucoemp, factors in the patient history that may predispose to ketoacidosis should be considered. Restarting SGLT2 inhibitor treatment in patients with previous DKA while on SGLT-2 inhibitor treatment is not recommended.
• Renal impairment
  Glucoemp should not be initiated in patients with an eGFR below 60 ml/min/1.73 m2 or CrCl < 60 ml/min. In patients tolerating Empagliflozin whose eGFR is persistently below 60 ml/min/1.73 m2 or CrCl < 60 ml/min, the dose of Glucoemp should be adjusted to or maintained at 10 mg once daily. Glucoemp should be discontinued when eGFR is persistently below 45 ml/min/1.73 m2 or CrCl persistently below 45 ml/min. Glucoemp should not be used in patients with ESRD or in patients on dialysis as it is not expected to be effective in these patients.
• Monitoring of renal function
  Due to the mechanism of action, the Glycaemic efficacy of Glucoemp is dependent on renal function.
• Hepatic injury
  Cases of hepatic injury have been reported with Glucoemp in clinical trials. A causal relationship between Glucoemp and hepatic injury has not been established.
• Elevated Haematocrit
  Haematocrit increase was observed with Glucoemp treatment.
• 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. 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 Glucoemp. Temporary interruption of treatment with Glucoemp should be considered until the fluid loss is corrected.
• Elderly
  The effect of Glucoemp 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 Glucoemp had adverse reactions related to volume depletion as compared to placebo .Therefore, special attention should be given to their volume intake in case of co-administered medicinal products which may lead to volume depletion (e.g. Diuretics, ACE-inhibitors). Therapeutic experience in patients aged 85 years and older is limited. Initiation of Glucoemp therapy in this population is not recommended.
• 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 Glucoemp 25 mg and placebo and higher in patients treated with Glucoemp 10 mg .Post-marketing cases of complicated urinary tract infections including pyelonephritis and Urosepsis have been reported in patients treated with Glucoemp. Temporary interruption of Glucoemp should be considered in patients with complicated urinary tract infections.
• 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
  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 Glucoemp will test positive for glucose in their urine.
• Pregnancy
  There are no data from the use of Glucoemp 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. As a precautionary measure, it is preferable to avoid the use of Glucoemp during pregnancy.
• Breast-feeding
  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 newborns/infants cannot be excluded. Glucoemp should not be used during breast-feeding.
• Fertility
  No studies on the effect on human fertility have been conducted for Empagliflozin. Animal studies do not indicate direct or indirect harmful effects with respect to fertility