Dapagliflozin 5 Mg/10 Mg Tablets

DAPAGLIFLOZIN GLENMARK is indicated in adults aged 18 years and older with type 2 diabetes mellitus to improve glycaemic control as:

• Monotherapy: As an adjunct to diet and exercise to improve glycaemic control in adult patients with type 2 diabetes mellitus.
• Add-on combination therapy: In combination 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.

Posology:

Monotherapy and add-on combination therapy

The recommended dose is 10 mg DAPAGLIFLOZIN GLENMARK 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. When DAPAGLIFLOZIN GLENMARK 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.

Special populations:

Renal impairment: No dosage adjustment for DAPAGLIFLOZIN GLENMARK is indicated for mild renal impairment. The efficacy of DAPAGLIFLOZIN GLENMARK is dependent on renal function. DAPAGLIFLOZIN GLENMARK should not be used in patients with moderate to severe renal impairment (defined as eGFR < 60 mL/min/1,73 m2 by MDRD or CrCl < 60 mL/min by Cockcroft-Gault) (see Sections 4.3, 4.4 and 4.8). Monitoring of renal function is recommended as follows:

• Prior to initiation of DAPAGLIFLOZIN GLENMARK 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 CrCl < 60 mL/min or eGFR < 60 mL/min/1,73 m2, DAPAGLIFLOZIN GLENMARK treatment should be discontinued.

Hepatic impairment: No dosage adjustment for DAPAGLIFLOZIN GLENMARK is necessary for patients with mild or moderate hepatic impairment. DAPAGLIFLOZIN GLENMARK is not recommended for patients with severe hepatic impairment as efficacy has not been established (see Section 5.2).

Patients at risk for volume depletion: For patients at risk for volume depletion due to co-existing conditions or concomitant medicines, such as loop diuretics, a 5 mg starting dose of DAPAGLIFLOZIN GLENMARK may be appropriate (see Sections 4.4 and 4.8).

Elderly: No dosage adjustment for DAPAGLIFLOZIN GLENMARK is required based on age (see Section 4.4).

Paediatric population: Safety and effectiveness of DAPAGLIFLOZIN GLENMARK in paediatric and adolescent patients have not been established.

Method of administration: DAPAGLIFLOZIN GLENMARK is for oral use and can be taken without regard to meals. Do not crush, split, or chew the tablets.

• Hypersensitivity to dapagliflozin or to any of the excipients.
• Moderate and severe renal impairment with GFR < 60 mL/min, end stage renal failure or patients on dialysis.
• Diabetes Mellitus Type 1
• Pregnant women or women who are breast-feeding their infants (see Section 4.6).

General: DAPAGLIFLOZIN GLENMARK may cause a decrease in systolic blood pressure and diastolic blood pressure. DAPAGLIFLOZIN GLENMARK should not be used for the treatment of diabetic ketoacidosis.

Metabolic acidosis including ketoacidosis: There have been post-marketing reports of ketoacidosis, including diabetic ketoacidosis, in patients with type 1 and type 2 diabetes mellitus taking dapagliflozin, as contained in DAPAGLIFLOZIN GLENMARK. DAPAGLIFLOZIN GLENMARK is contraindicated for the treatment of patients with type 1 diabetes mellitus (see Section 4.3). Patients treated with DAPAGLIFLOZIN GLENMARK 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, DAPAGLIFLOZIN GLENMARK 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. DAPAGLIFLOZIN GLENMARK is not indicated in these patients.

Acute kidney injury: DAPAGLIFLOZIN GLENMARK causes intravascular volume contraction and can cause acute kidney injury. Use in patients with renal impairment: The efficacy of DAPAGLIFLOZIN GLENMARK is dependent on renal function. Therefore, renal function should be monitored prior to initiation of DAPAGLIFLOZIN GLENMARK and periodically thereafter (see Section 4.2). DAPAGLIFLOZIN GLENMARK is contraindicated in patients with moderate and severe renal impairment with GFR < 60 mL/min, end stage renal failure or on dialysis (see Section 4.3).

Use in patients at risk for volume depletion: The diuretic effect of DAPAGLIFLOZIN GLENMARK is a potential concern for volume depleted patients. There is limited experience in clinical trials in patients at increased risk for volume depletion. For patients at risk for volume depletion due to co-existing conditions or concomitant medicines, such as loop diuretics, a 5 mg starting dose of DAPAGLIFLOZIN GLENMARK may be appropriate. DAPAGLIFLOZIN GLENMARK should be permanently discontinued in patients who develop volume depletion (see Section 4.8).

Urinary tract infections: Urinary tract infections were more frequently reported for dapagliflozin, as contained in DAPAGLIFLOZIN GLENMARK compared to control in a placebo-pooled analysis up to 24 weeks. Urinary glucose excretion may be associated with an increased risk of urinary tract infection; therefore, temporary interruption of DAPAGLIFLOZIN GLENMARK should be considered when treating pyelonephritis or urosepsis (see Section 4.8). Treatment with DAPAGLIFLOZIN GLENMARK increases the risk for urinary tract infections. There have been post-marketing reports of serious urinary tract infections, including pyelonephritis, requiring hospitalisation in patients receiving DAPAGLIFLOZIN GLENMARK and other SGLT2 inhibitors. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated.

Necrotising fasciitis of the perineum (Fournieru2019s Gangrene): Reports of necrotising fasciitis of the perineum (Fournieru2019s Gangrene), a rare but serious and life-threatening necrotising infection required urgent surgical intervention, have been identified in post-marketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including dapagliflozin, as contained in DAPAGLIFLOZIN GLENMARK. Cases have been reported in both females and males. Serious outcomes have included hospitalisation, multiple surgeries and death. Patients treated with DAPAGLIFLOZIN GLENMARK presenting with pain or tenderness, erythema or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotising fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue DAPAGLIFLOZIN GLENMARK, closely monitor blood glucose levels, and provide appropriate alternate therapy for glycaemic control.

Genital mycotic infections: DAPAGLIFLOZIN GLENMARK increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections.

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 DAPAGLIFLOZIN GLENMARK (see Section 4.8).

Paediatric use: Safety and efficacy of DAPAGLIFLOZIN GLENMARK in paediatric patients have not been established.

Other populations: In general, 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 heart failure New York Heart Association class IV or who are breast-feeding or are pregnant, have been excluded from clinical studies.

Excipients: DAPAGLIFLOZIN GLENMARK contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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 vitro studies, dapagliflozin and dapagliflozin 3-O-glucuronide neither inhibited CYP1A2, 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 DAPAGLIFLOZIN GLENMARK: In studies conducted in healthy subjects, the pharmacokinetics of dapagliflozin 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). A 22 % decrease in dapagliflozin systemic exposure following co-administration with rifampicin was considered not to be large enough to warrant a dose adjustment.

Effect of DAPAGLIFLOZIN GLENMARK on other medicines: In studies conducted in healthy subjects, dapagliflozin 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)].

Other interactions: The effects of smoking, diet, herbal products and alcohol use on the pharmacokinetics of DAPAGLIFLOZIN GLENMARK 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 DAPAGLIFLOZIN GLENMARK. Use alternate methods to monitor glycaemic control.

Positive Urine Glucose Test: Monitoring glycaemic control with urine glucose tests is not recommended in patients taking SGLT2 Inhibitors, including DAPAGLIFLOZIN GLENMARK, as SGLT2 Inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Use alternative methods to monitor glycaemic control.

Pregnancy: DAPAGLIFLOZIN GLENMARK is contraindicated in pregnancy. Maternal exposure to DAPAGLIFLOZIN GLENMARK in rat studies was associated with increased incidence and/or severity of renal pelvic and tubular dilatations in progeny. When pregnancy is detected, DAPAGLIFLOZIN GLENMARK should be discontinued (see Section 4.3).

Breastfeeding: Mothers on DAPAGLIFLOZIN GLENMARK should not breast-feed their infants. DAPAGLIFLOZIN GLENMARK must not be used by a nursing woman. Studies in rats have shown excretion of dapagliflozin in milk. Exposure to DAPAGLIFLOZIN GLENMARK must be avoided during the first 2 years of life (see Section 4.3).

No studies on the effects on the ability to drive and use machines have been performed. Patients must bear in mind the possibility of hypoglycaemia and its effects on their motor skills.

Tabulated summary of adverse reactions

a The table shows up to 24-week (short-term) data regardless of glycaemic rescue.

b See corresponding subsection below for additional information.

c Genital infection includes the preferred terms: Vulvovaginitis, balanitis and related genital infections includes, e.g. the predefined preferred terms: vulvovaginal mycotic infection, vaginal infection, balanitis, genital infection fungal, vulvovaginal candidiasis, vulvovaginitis, balanitis candida, genital candidiasis, genital infection, genital infection male, penile infection, vulvitis, vaginitis bacterial, vulval abscess, balanoposthitis, genitourinary tract infection, penile abscess, posthitis.

d Polyuria includes the preferred terms: pollakiuria, polyuria, increased urine output, osmotic diuresis.

f Mean percent change from baseline for dapagliflozin 10 mg versus placebo, respectively, was: total cholesterol 1,4 % versus -0,4 %; HDL cholesterol 5,5 % versus 3,8 %; LDL cholesterol 2,7 % versus -1,9 %; triglycerides -5,4 % versus -0,7 %.

g Mean changes from baseline in haematocrit were 2,30 % for dapagliflozin 10 mg versus -0,33 % for placebo. Haematocrit values > 55 % were reported in 1,3 % of the subjects treated with dapagliflozin 10 mg versus 0,4 % of placebo subjects.

*Reported in u2265 2 % of subjects and u2265 1 % more and at least 3 more subjects treated with dapagliflozin 10 mg compared to placebo.

**Reported by the investigator as possibly related, probably related or related to study treatment and reported in u2265 0,2 % of subjects and u2265 0,1 % more and at least 3 more subjects treated with dapagliflozin 10 mg compared to placebo.

Additional adverse reactions in u2265 5 % of patients treated with dapagliflozin 10 mg, u2265 1 % more than patients in placebo/comparator, and reported in at least 3 more patients treated with dapagliflozin 10 mg and regardless of relationship to dapagliflozin reported by investigator, are described below by treatment regimen.

• Add-on to metformin studies: headache (5,3 % dapagliflozin 10 mg and 3,1 % placebo).
• Add-on to thiazolidinedione study: nasopharyngitis (7,9 % dapagliflozin 10 mg and 3,6 % placebo), diarrhoea (6,4 % dapagliflozin 10 mg and 4,3 % placebo).

In a study of patients with moderate renal impairment, a higher frequency of bone fractures was observed in groups treated with DAPAGLIFLOZIN GLENMARK dapagliflozin (8,2 %) compared with placebo (0 %) (see Section 4.3).

Description of selected adverse reactions

Volume depletion: Events related to volume depletion (including reports of dehydration, hypovolaemia or hypotension) were reported in 0,7 %, 0,6 % and 0,4 % of patients who received dapagliflozin 10 mg, dapagliflozin 5 mg and placebo, respectively, in the short-term, placebo-pooled analysis. Serious events occurred in u2264 0,2 % of patients in the 14 clinical studies and were balanced between dapagliflozin 10 mg, dapagliflozin 5 mg and comparator (see Section 4.4).

In the following subgroups, the proportion of patients with events related to volume depletion for dapagliflozin 10 mg, dapagliflozin 5 mg and placebo were: In patients who received loop diuretics: 2 patients (6,5 %), 0 patients, and 1 patient (1,8 %), respectively. In patients u2265 65 years of age: 2 patients (1,0 %), 1 patient (0,5 %) and 1 patient (0,4 %), respectively.

Genital infections: Events of genital infections were reported in 4,8 % and 0,9 % of patients who received dapagliflozin 10 mg and placebo, respectively, in the short-term, placebo-pooled analysis. Infections were more frequently reported in females (6,9 % dapagliflozin 10 mg vs. 1,5% placebo) than in males (2,7 % dapagliflozin 10 mg vs. 0,3 % placebo). Overall, treatment with dapagliflozin 5 mg was similar to dapagliflozin 10 mg treatment.

Urinary tract infections: Events of urinary tract infections were reported in 4,3 % and 3,7 % of patients who received dapagliflozin 10 mg and placebo, respectively, in the short-term, placebo-pooled analysis. Infections were more frequently reported in females (7,7 % dapagliflozin 10 mg vs. 6.6 % placebo) than in males (0,8 % dapagliflozin 10 mg vs. 1 % placebo) (see Section 4.4).

Hypoglycaemia: The frequency of hypoglycaemia depended on the type of background therapy used in each study. Studies with add-on sulfonylurea and add-on insulin therapies had higher rates of hypoglycaemia (see Section 4.4). In an add-on to glimepiride study up to 24 weeks, episodes of hypoglycaemia were reported in 10 (6,6 %) patients in the dapagliflozin 10 mg plus glimepiride group and 3 (2,1 %) patients in the placebo plus glimepiride group. In an add-on to insulin study up to 24 weeks, episodes of hypoglycaemia were reported in 79 (40,3 %) patients in the dapagliflozin 10 mg plus insulin group and in 67 (34 %) patients in placebo plus insulin group. Patients in this study could also be treated with a maximum of 2 oral anti-diabetes medications (OADs) including metformin.

Decrease on blood pressure: In the pool of 13 placebo-controlled studies, a decrease in blood pressure was observed in patients treated with dapagliflozin 10 mg (mean seated systolic blood pressure change from baseline at Week 24 of -3,7 mmHg and mean seated diastolic blood pressure change of -1,8 mmHg for dapagliflozin 10 mg vs. -0,5 mmHg systolic and -0,5 mmHg diastolic blood pressure change for placebo group). Postural blood pressure measurement revealed orthostatic hypotension in 13,1 % of patients treated with dapagliflozin 10 mg vs. 11,3 % of patients treated with placebo over the 24-week treatment period. In addition, in 2 studies with patients with type 2 diabetes and hypertension, postural blood pressure measurement revealed orthostatic hypotension in 3,2 % of dapagliflozin 10 mg-treated patients versus 1,7 % of placebo-treated patients across the 2 studies over the 12-week treatment period.

Laboratory findings: Haematocrit: A moderate increase in haematocrit occurs and may be an indication of volume depletion. Serum inorganic phosphorus: Increases from baseline in mean serum phosphorus levels were reported at Week 24 in dapagliflozin 10 mg treated patients compared with placebo (mean increases of 0,0549 mmol/L vs. 0,0097 mmol/L, respectively). Similar results were seen at Week 50. Higher proportions of patients with marketed laboratory abnormalities of hyperphosphatemia (u2265 1,81 mmol/L if age 17-65 or u2265 1,65 mmol/L if u2265 age 66) were reported in dapagliflozin 10 mg group vs. placebo at Week 24 (1,7 % vs. 0,7 %, respectively) and during the short-term plus long-term phase (2,6 % vs. 1,5 %, respectively). The clinical relevance of these finding is unknown.

Skin and subcutaneous tissue disorders: Rash, rash generalised, rash pruritic, rash macular, rash maculo-papular, rash pustular, rash vesicular, rash erythematous, ketoacidosis, acute kidney injury, necrotising fasciitis of the perineum (Fournieru2019s Gangrene), genital mycotic infections, urosepsis and pyelonephritis.

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