Tuerizin 10 & 25 10 mg, 25 mg Tablet

TUERIZIN film-coated tablets are 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 dipeptidyl peptidase 4 (DPP4) inhibitor, or insulin, when these together with diet and exercise do not provide adequate glycaemic control. Prevention of cardiovascular events: TUERIZIN 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.

Posology Assess hydration status and renal function before initiating treatment with TUERIZIN. Do not initiate treatment if the estimated glomerular filtration rate (eGFR) < 30 mL/min/1,73 m2 (or creatinine clearance < 30 mL/min) and/or in patients who are volume depleted or acidotic (see sections 4.3 and 4.4). The recommended starting dose of TUERIZIN is 10 mg once daily. In patients tolerating TUERIZIN 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 eGFR u2265 30 mL/min/1,73 m2. TUERIZIN is not recommended for use in patients with severe renal impairment (defined as eGFR < 30 mL/min/1,73 m2 by modification of diet in renal disease or creatinine clearance < 30 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 30 mL/min. Therapeutic experience in patients aged 85 years and older is limited. Initiation of TUERIZIN therapy in this population is not recommended (see section 4.4). Combination therapy: When TUERIZIN 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 section 4.8). 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 TUERIZIN in children under 18 years of age have not been established. Method of administration TUERIZIN can be taken with or without food.

• Hypersensitivity to empagliflozin or any of the excipients listed in section 6.1.
• Treatment of type I diabetes mellitus.
• Treatment of ketoacidosis.
• Severe renal impairment (creatinine clearance < 30 mL/min), end-stage renal disease or dialysis.
• Pregnancy and lactation.

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.

Urine laboratory assessments Due to its mechanism of action, patients taking TUERIZIN will test positive for glucose in their urine. TUERIZIN 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 treated with empagliflozin, as in TUERIZIN. 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). 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 TUERIZIN 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 TUERIZIN, 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 TUERIZIN should be temporarily discontinued. 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 TUERIZIN can be expected.

Hypoglycaemia with concomitant use with insulin and insulin secretagogues The risk of hypoglycaemia is increased when TUERIZIN 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 TUERIZIN (see section 4.4).

Use in patients with renal impairment The efficacy of TUERIZIN is dependent on renal function. Therefore, assessment of renal function is recommended prior to TUERIZIN 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 therapeutic 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 TUERIZIN. Temporary interruption of treatment with TUERIZIN should be considered until the fluid loss is corrected.

Urinary tract infections and genital infections The overall frequency of urinary tract infection, and/or genital infection, reported as an adverse event was higher than placebo in patients treated with TUERIZIN especially mycotic infections in females. Genital infections occurred more frequently in females than in males. 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 TUERIZIN (see section 4.8). Temporary interruption of TUERIZIN should be considered in patients with complicated urinary tract infections.

Necrotising fasciitis of the perineum (Fournieru2019s gangrene) Post-marketing 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 TUERIZIN who present with pain or tenderness, erythema, swelling in the genital or perineal area, fever, malaise should be evaluated for necrotising fasciitis. If suspected, TUERIZIN 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, TUERIZIN should be prescribed with caution in these patients (see section 4.8). Therapeutic experience in patients aged 85 years and older is limited. Initiation of TUERIZIN therapy in this population is not recommended.

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

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

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). Insulin and insulin secretagogues 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 of hypoglycaemia when used in combination with empagliflozin (see sections 4.2 and 4.8).

Pharmacokinetic interactions 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. Empagliflozin is a substrate of P-glycoprotein (P-gp) and breast cancer 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 in area under the concentration-time curve (AUC). These changes were not considered to be clinically meaningful. The effect of UGT induction (e.g. induction by rifampicin or phenytoin) on empagliflozin has not been studied. Co-treatment with known inducers of UGT enzymes is not recommended due to a potential risk of decreased efficacy. If an inducer of these UGT enzymes must be co-administered, monitoring of glycaemic control to assess response to TUERIZIN 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 to be clinically meaningful. Empagliflozin 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 empagliflozin. 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, digoxin, diuretics, oral contraceptives and hydrochlorothiazide in patients with type 2 diabetes mellitus.

Effects of empagliflozin on other medicines Based on in vitro studies, empagliflozin does not inhibit, inactivate, or induce CYP450 isoforms. Empagliflozin does not inhibit UGT1A1, UGT1A3, UGT1A8, UGT1A9 or UGT2B7. Medicine-medicine interactions involving the major CYP450 and UGT isoforms with empagliflozin and concomitantly administered substrates of these enzymes are therefore considered unlikely. Empagliflozin does not inhibit P-gp at therapeutic doses. Based on in vitro studies, empagliflozin is considered 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 and 14 % increase in Cmax of digoxin. These changes were not considered to be clinically meaningful. Empagliflozin does not inhibit human uptake transporters such as OAT3, OATP1B1, and OATP1B3 in vitro at clinically relevant plasma concentrations and, as such, medicine-medicine interactions with substrates of these uptake transporters are considered unlikely.

Pregnancy TUERIZIN is contraindicated in pregnancy (see section 4.3). Animal studies showed that empagliflozin, as contained in TUERIZIN, crosses the placenta.

Breastfeeding TUERIZIN is contraindicated in lactation (see section 4.3). Mothers should not breastfeed their infants while taking TUERIZIN. Animal studies have shown excretion empagliflozin as contained in TUERIZIN, in milk of animals. A risk to human newborns/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.

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

System Organ Class Frequent Less frequent Not known Infections and infestations vaginal moniliasis, vulvovaginitis, balanitis and other genital infection (including pyelonephritis and necrotising fasciitis of the perineum (Fournieru2019s gangrene) urosepsis), urinary tract infection Metabolism and nutrition disorders hypoglycaemia (when used with sulphonylurea or insulin), weight loss, increased serum lipids diabetic ketoacidosis Skin and subcutaneous tissue disorders pruritus (generalised), rash urticaria angioedema Vascular disorders volume depletion (hypotension and dehydration) Gastro-intestinal disorders thirst Renal and urinary disorders increased urination, glycosuria dysuria, ketonuria Investigations increased serum lipids increased blood creatinine, decreased glomerular filtration rate, increased haematocrit.

Description of selected adverse reactions 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 to placebo. The effect of empagliflozin, as in TUERIZIN, on urinary glucose excretion is associated with osmotic diuresis, which could affect hydration status of patients aged 75 years and older or those otherwise at risk. In patients u2265 75 years of age the frequency of volume depletion events was similar for empagliflozin 10 mg compared to placebo, but it increased with empagliflozin 25 mg. 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, as in TUERIZIN, and placebo. In placebo controlled, double-blind studies up to 76 weeks, initial transient increases in creatinine and initial decreases in estimated glomerular filtration rates have been observed. These changes were generally reversible during continuous treatment or after medicine discontinuation.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of TUERIZIN is important. It allows continued monitoring of the benefit/risk balance of TUERIZIN. Health care providers are asked to report any suspected adverse reactions via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

The risk and severity of undesirable effects 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 TUERIZIN by haemodialysis has not been studied. Hypoglycaemia should be monitored for, especially when other antidiabetic medication has been co-administered.