Kedgeo 5/10 5mg. 10mg Tablet

Type 2 diabetes mellitus

KEDGEO is indicated in adults aged 18 years and older with type 2 diabetes mellitus:

• as monotherapy as an adjunct to diet and exercise to improve glycaemic control
• as add-on combination therapy, with glucose-lowering medicines, including metformin, a thiazolidinedione, a sulfonylurea, a DPP4 inhibitor, or insulin, when these, together with diet and exercise, do not provide adequate glycaemic control
• to reduce the risk of developing new or worsening existing heart failure or cardiovascular death in patients with established cardiovascular (CV) disease or multiple CV risk factors.

Heart failure

KEDGEO is indicated in adults to reduce the risk of worsening heart failure or cardiovascular death, in patients with heart failure (NYHA class II-IV), and with a left ventricular ejection fraction (LVEF) u2264 40 %.

Type 2 diabetes mellitus

Monotherapy and add-on combination therapy

The recommended dose is 10 mg KEDGEO once daily for monotherapy and add-on combination therapy with other glucose-lowering medicines, including metformin, a thiazolidinedione, a sulfonylurea, a DPP4 inhibitor, or insulin.

Use with medicines known to cause hypoglycaemia:

When KEDGEO is used in combination with insulin or an insulin secretagogue, such as a sulfonylurea, a lower dose of insulin or insulin secretagogue may be considered to reduce the risk of hypoglycaemia.

Heart failure

The recommended dose of KEDGEO is 10 mg taken orally once daily at any time of the day regardless of meals. KEDGEO can be used in conjunction with other heart failure therapies.

Special Populations

Renal impairment:

Treatment of diabetes mellitus

No dosage adjustment is required based on renal function. As glycaemic efficacy is dependent on renal function (see sections 4.4 and 4.8), KEDGEO is not recommended to improve glycaemic control in the treatment of diabetes in patients where eGFR is below 45 mL/min/1,73 m2.

Monitoring of renal function is recommended as follows:

• Prior to initiation of KEDGEO and at least annually thereafter.
• Prior to initiation of concomitant medicines that may reduce renal function and periodically thereafter.
• For renal function approaching moderate renal impairment, at least 2 to 4 times per year. If renal function falls below eGFR < 45 mL/min/1,73 m2, KEDGEO treatment should be discontinued (See sections 4.3).

Treatment of heart failure

No dosage adjustment is required based on renal function.

Hepatic impairment:

No dosage adjustment for KEDGEO is necessary for patients with mild or moderate hepatic impairment. KEDGEO is not recommended for patients with severe hepatic impairment as efficacy has not been established. (See section 5.2).

Elderly:

No dosage adjustment for KEDGEO is required based on age. (See section 4.4).

Paediatric population:

Safety and effectiveness of KEDGEO in paediatric and adolescent patients have not been established. No data is available.

• Hypersensitivity to dapaglifozin or to any of the excipients of KEDGEO.
• Moderate and severe renal impairment with GFR < 45 mL/min/1,73 m2, end stage renal failure or patients on dialysis when used for type 2 diabetes mellitus indication.
• Diabetes mellitus Type 1.
• Pregnant women or women who are breast-feeding their infants (See section 4.6).

General:

KEDGEO may cause a decrease in systolic blood pressure and diastolic blood pressure.

KEDGEO should not be used for the treatment of diabetic ketoacidosis.

Metabolic acidosis including ketoacidosis in patients with diabetes mellitus:

There have been reports of ketoacidosis, including diabetic ketoacidosis, in patients with type 2 diabetes mellitus taking KEDGEO. KEDGEO is contraindicated for the treatment of patients with type 1 diabetes mellitus (see section 4.3).

Patients treated with KEDGEO who present with signs and symptoms consistent with ketoacidosis, including nausea, vomiting, abdominal pain, malaise and shortness of breath, should be assessed for ketoacidosis, even if blood glucose levels are below 11 mmol/L (196 mg/dL). If ketoacidosis is suspected, KEDGEO should be discontinued and the patient should be promptly evaluated.

Predisposing factors for ketoacidosis include low beta-cell function reserve resulting from pancreatic disorders, e.g. history of pancreatitis or pancreatic surgery. KEDGEO is not indicated in these patients.

Impairment of renal function/acute kidney injury:

SGLT2 inhibitors such as KEDGEO may cause a decrease in the glomerular filtration rate (GFR), with an increase in serum creatinine and serum urea. Acute kidney injury (AKI) has been reported with the use of SGLT2 inhibitors.

Based on their mode of action, SGLT2 inhibitors may cause glycosuria, osmotic diuresis, fluid and electrolyte loss with a risk of dehydration/hypovolaemia and hypotension, which may precipitate acute kidney injury. Renal function and hydration status should be assessed before treatment is initiated with a SGLT2 inhibitor such as KEDGEO and should be frequently monitored during treatment.

Other factors that may predispose patients to AKI during treatment with SGLT2 inhibitors include reduced oral intake of fluids, congestive cardiac failure, gastrointestinal fluid losses, excessive heat exposure, and concomitant use of medicines such as diuretics, NSAIDS, ACE inhibitors and ARBs. Discontinue treatment with SGLT2 inhibitors in patients with AKI and consider other appropriate treatment options for their diabetes mellitus.

SGLT2 inhibitors such as KEDGEO, are contraindicated in patients with moderate to severe renal impairment and in patients on dialysis (See section 4.3).

There is limited experience with KEDGEO in patients with severe renal impairment (eGFR < 30 mL/min/1,73 m2) or end-stage renal disease (ESRD).

Urinary tract and genital infections:

SGLT2 inhibitors such as KEDGEO 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 and fungal infections appear to be more common in females. Balanoposthitis in males may result in phimosis.

Treatment of diabetes mellitus

KEDGEO is not recommended for use in the treatment of diabetes to improve glycaemic control when eGFR is below 45 mL/min/1,73 m2 as the glycaemic efficacy of dapagliflozin is dependent on renal function. Renal function should be evaluated prior to initiation of KEDGEO and periodically thereafter (See section 4.2).

Use with medicines known to cause hypoglycaemia:

Insulin and insulin secretagogues, such as sulfonylureas, cause 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 KEDGEO (See section 4.8).

Paediatric use:

Safety and efficacy of KEDGEO in paediatric patients has not been established.

Other populations:

Patients with severe renal impairment (eGFR < 30 mL/min/ 1,73 m2) or End Stage Renal Disease or with recent (< 2 months) cardiovascular event or who are breast-feeding or are pregnant, have been excluded from clinical studies.

Lactose:

KEDGEO contains lactose anhydrous. Patients with rare hereditary problems of galactose intolerance, e.g. galactosaemia, the Lapp lactase deficiency, or glucose-galactose malabsorption should not use KEDGEO.

The metabolism of dapagliflozin is primarily mediated by UGT1A9- dependent glucuronide conjugation. The major metabolite, dapagliflozin 3-O-glucuronide, is not an SGLT2 inhibitor.

In in-vitro studies, dapagliflozin and dapagliflozin 3-O-glucuronide neither inhibited CYP 1A2, 2C9, 2C19, 2D6, 3A4, nor induced CYP1A2, 2B6 or 3A4. Dapagliflozin is a weak substrate of the P-glycoprotein (P-gp) active transporter and dapagliflozin 3-O-glucuronide is a substrate for the OAT3 active transporter. Dapagliflozin or dapagliflozin 3-O-glucuronide did not meaningfully inhibit P-gp, OCT2, OAT1, or OAT3 active transporters.

The dependence of dapagliflozin elimination on dapagliflozin 3-O-glucuronide formation in humans also suggests the possibility of interactions mediated by UGT1A9. Ketoconazole is an in vitro inhibitor of dapagliflozin 3-O-glucuronide formation by UGT1A9 (IC50 = 32 u03bcM).

Effects of other medicines on KEDGEO:

In interaction studies conducted in healthy subjects, using mainly single dose design, the pharmacokinetics of KEDGEO were not altered by metformin (a human OCT-1 and hOCT-2 substrate), pioglitazone (a CYP2C8 [major] and CYP3A4 [minor] substrate), sitagliptin (a human OAT-3 substrate and P-glycoprotein substrate), glimepiride (a CYP2C9 substrate), voglibose (an alpha-glucosidase inhibitor), hydrochlorothiazide, bumetanide, valsartan, or simvastatin (a CYP3A4 substrate). Therefore, meaningful interaction of dapagliflozin with other substrates of hOCT-1, hOCT-2, hOAT-3, P-gp, CYP2C8, CYP2C9, CYP3A4, and other alpha-glucosidase inhibitor would not be expected.

A 22 % decrease in dapagliflozin systemic exposure following co-administration with rifampicin was considered not to be large enough to warrant a dose adjustment.

Co-administration of dapagliflozin and bumetanide did not meaningfully change the pharmacodynamic effect of dapagliflozin to increase urinary glucose excretion in healthy subjects.

Effect of KEDGEO on other medicines:

In interaction studies conducted in healthy subjects, using mainly single dose design, KEDGEO did not alter the pharmacokinetics of metformin (an hOCT 1 and hOCT 2 substrate), pioglitazone (a CYP2C8 [major] and CYP3A4 [minor] substrate), sitagliptin (a hOAT 3 substrate and P-glycoprotein substrate), glimepiride (a CYP2C9 substrate), hydrochlorothiazide, bumetanide, valsartan, simvastatin (a CYP3A4 substrate), digoxin (a P-gp substrate) or warfarin (S warfarin, a CYP2C19 substrate, R warfarin or the anticoagulatory effects of warfarin as measured by the prothrombin time [International Normalised Ratio (INR)]). Therefore, dapagliflozin is not a clinically meaningful inhibitor of hOCT-1, hOCT-2, hOAT-3, P-gp transporter pathway, and CYP2C8, CYP2C9, CYP2C19 and CYP3A4 mediated metabolism.

Co-administration of dapagliflozin and bumetanide did not meaningfully alter the steady-state pharmacodynamic responses (urinary sodium excretion, urine volume) to bumetanide in healthy subjects.

Dapagliflozin did not affect the anticoagulant activity of warfarin, as measured by the prothrombin time (International Normalized Ratio [INR]).

Other interactions:

The effects of smoking, diet, herbal products and alcohol use on the pharmacokinetics of KEDGEO have not been studied.

Interference with 1,5-anhydroglucitol (1,5-AG) Assay:

Monitoring glycaemic control with 1,5-AG assay should not be used, as measurements of 1,5-AG are unreliable in assessing glycaemic control in patients taking SGLT2 inhibitors, including KEDGEO. Alternative methods of monitoring glycaemic control should be used.

Pregnancy:

KEDGEO is contraindicated in pregnancy. Maternal exposure to KEDGEO in rat studies was associated with increased incidence and/or severity of renal pelvic and tubular dilatations in progeny. When pregnancy is detected, KEDGEO should be discontinued (See section 4.3).

Breastfeeding:

Mothers on KEDGEO should not breast-feed their infants. Alternatively, mothers breastfeeding their infants must not use KEDGEO. Studies in rats have shown excretion of KEDGEO in milk. Exposure to KEDGEO must be avoided during the first 2 years of life (See section 4.3).

Fertility:

The effect of dapagliflozin on fertility in humans has not been studied.

Patients must bear in mind the possibility of hypoglycaemia and its effects on their motor skills.

a. Summary of the safety profile

More than 28 000 patients with type 2 diabetes and heart failure were randomised, including 15 000 patients treated for type 2 diabetes and more than 2 000 subjects treated for heart failure with KEDGEO, in 22 double-blind, controlled, clinical safety and efficacy studies conducted to evaluate the effects of KEDGEO. KEDGEO 10 mg was evaluated in 13 of these studies.

The incidence of adverse reactions was determined using a pre-specified pool of patients from 13 short-term (mean duration 22 weeks), placebo-controlled studies in type 2 diabetes. Across these 13 studies, 2 360 patients were treated once daily with KEDGEO 10 mg and 2 295 were treated with placebo (either as monotherapy or in combination with other antidiabetic therapies).

Additionally, KEDGEO 5 mg was evaluated in a 12-study, short-term, placebo-controlled pool of type 2 diabetes patients that included 1 145 patients treated with KEDGEO 5 mg (mean exposure = 22 weeks) and 1 393 patients treated with placebo (mean exposure = 21 weeks), either as monotherapy or in combination with other antidiabetic therapies. In the dedicated cardiovascular (CV) outcomes study in patients with type 2 diabetes mellitus (DECLARE), 8 574 patients received KEDGEO 10 mg and 8 569 received placebo for a median exposure time of 48 months. In total, there were 30 623 patient-years of exposure to KEDGEO. In the dapagliflozin cardiovascular outcome study in patients with heart failure with reduced ejection fraction (DAPA-HF), 2 368 patients were treated with dapagliflozin 10 mg and 2 368 patients with placebo for a median exposure time of 18 months. The patient population included patients with type 2 diabetes mellitus and without diabetes, and patients with eGFR u226530 mL/min/m2.

The safety profile of dapagliflozin was overall consistent across the studied indications. DKA was observed only in patients with diabetes mellitus.

The adverse reactions are listed by system organ class and absolute frequency. Frequencies are defined as very common (u2265 1/10), common (u2265 1/100, < 1/10), uncommon (u2265 1/1 000, <1/100) and rare (u2265 1/10 000, < 1/1 000).

b) Tabulated list of adverse reactions

Table 1 Adverse reactions (Regardless of Investigator Assessment of Causality) in Placebo-Controlled Studies a reported in u2265 2 % of patients treated with KEDGEO 10 mg and u2265 1 % more frequently than in patients treated with placebo.

In overdose, side effects may be elicited or exacerbated. Appropriate symptomatic and supportive treatment should be initiated as dictated by the patientu2019s clinical status. The removal of KEDGEO by haemodialysis has not been studied.