Dapagliflozin 5 Mg/10 Mg/200 mg/350 mg Film-Coated Tablets

[PRODUCT NAME] 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 sulphonyl urea, a DPP4 inhibitor, or insulin, when these, together with diet and exercise, do not provide adequate glycaemic control.
• Heart failure: [PRODUCT NAME] 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 %.
• Chronic kidney disease: [PRODUCT NAME] is indicated for the treatment of chronic kidney disease.

Posology

Monotherapy and add-on combination therapy: The recommended dose is 10 mg [PRODUCT NAME] once daily for monotherapy and add-on combination therapy with other glucose-lowering medicines, including metformin, a thiazolidinedione, a sulphonyl urea, a DPP4 inhibitor, or insulin. When [PRODUCT NAME] is used in combination with insulin or an insulin secretagogue, such as a sulphonyl urea, a lower dose of insulin or insulin secretagogue may be considered to reduce the risk of hypoglycaemia.

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

Chronic kidney disease: The recommended dose of [PRODUCT NAME] is 10 mg taken orally once daily at any time of the day regardless of meals. In the DAPA-CKD study, dapagliflozin was administered in conjunction with other chronic kidney disease related therapies (see section 5.1).

Special populations

Renal impairment: No dosage adjustment for [PRODUCT NAME] is indicated for mild renal impairment. The efficacy of [PRODUCT NAME] is dependent on renal function. [PRODUCT NAME] should not be used in patients with moderate to severe renal impairment (defined as eGFR, <45 ml/min/1.73 mu00b2) (See sections 4.3, 4.4 and 4.8). Monitoring of renal function is recommended as follows:

• Prior to initiation of [PRODUCT NAME] 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 mu00b2, [PRODUCT NAME] treatment should be discontinued (see section 4.3).

Hepatic impairment: No dosage adjustment for [PRODUCT NAME] is necessary for patients with mild to moderate hepatic impairment. [PRODUCT NAME] 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 medications, such as loop diuretics, a 5 mg starting dose of [PRODUCT NAME] may be appropriate. (See sections 4.3 and 4.8)

Elderly: No dosage adjustment for [PRODUCT NAME] is required based on age. (See section 4.3)

Paediatric and adolescent: Safety and efficacy of [PRODUCT NAME] in pediatric and adolescent patients has not been established.

Method of administration: For oral use

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Moderate and severe renal impairment with GFR < 60 ml/min, end stage renal failure or patients on dialysis.
• Diabetes mellitus type 1
• Pregnant and breastfeeding women. (See section 4.6)
• Patients with history of pancreatitis or pancreatic surgery (see 4.4 Special warnings and precautions for use).

General: [PRODUCT NAME] may cause a decrease in systolic blood pressure and diastolic blood pressure. [PRODUCT NAME] 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 [PRODUCT NAME]. [PRODUCT NAME] is contraindicated for the treatment of patients with Type 1 diabetes mellitus (see section 4.3). Patients treated with [PRODUCT NAME] 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, [PRODUCT NAME] should be discontinued and the patient should be promptly evaluated. Predisposing factors for ketoacidosis include beta-cell function reserve resulting from pancreatic disorders e.g. history of pancreatitis or pancreatic surgery. [PRODUCT NAME] is not indicated in these patients.

Impairment of renal function/acute kidney injury: SGLT2 inhibitors such as [PRODUCT NAME] 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 SGLT2 inhibitor such as [PRODUCT NAME] 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 heart 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 [PRODUCT NAME] are contraindicated in patients with moderate to severe renal impairment and in patients on dialysis (see section 4.3). There is limited experience with [PRODUCT NAME] in patients with severe renal impairment (eGFR < 30 mL/min/1.73mu00b2) or end stage renal disease (ESRD).

Urinary tract and genital infections: SGLT2 inhibitors such as [PRODUCT NAME] 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: [PRODUCT NAME] is not recommended for use in the treatment of diabetes to improve glycaemic control when eGFR is below 45 mL/min/1.73mu00b2 as the glycaemic efficacy of dapagliflozin is dependent on renal function. Renal function should be evaluated prior to initiation of [PRODUCT NAME] 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 [PRODUCT NAME] (see section 4.8).

Paediatric use: Safety and efficacy of [PRODUCT NAME] in paediatric patients has not been established.

Other populations: Patients with severe renal impairment (eGFR < 30 mL/min/1.73 mu00b2) or End Stage Renal Disease or with recent (< 2 months) cardiovascular event or who are breastfeeding or are pregnant, have been included from clinical studies.

Hepatic impairment: There is limited experience in clinical studies in patients with hepatic impairment. Dapagliflozin exposure is increased in patients with severe hepatic impairment (see sections 4.2 and 5.2).

Use in patients at risk for volume depletion and/or hypotension: Due to its mechanism of action, dapagliflozin increases diuresis which may lead to the modest decrease in blood pressure observed in clinical studies (see section 5.1). It may be more pronounced in patients with very high blood glucose concentrations. Caution should be exercised in patients for whom a dapagliflozin-induced drop in blood pressure could pose a risk, such as patients on anti-hypertensive therapy with a history of hypotension or elderly patients. In case of intercurrent conditions that may lead to volume depletion (e.g. gastrointestinal illness), careful monitoring of volume status (e.g. physical examination, blood pressure measurements, laboratory tests including haematocrit and electrolytes) is recommended. Temporary interruption of treatment with dapagliflozin is recommended for patients who develop volume depletion until the depletion is corrected (see section 4.8).

Elderly (u2265 65 years): Elderly patients may be at a greater risk for volume depletion and are more likely to be treated with diuretics. Elderly patients are more likely to have impaired renal function, and/or to be treated with anti-hypertensive medicinal products that may cause changes in renal function such as angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II type 1 receptor blockers (ARB). The same recommendations for renal function apply to elderly patients as to all patients (see sections 4.2, 4.4, 4.8 and 5.1).

Cardiac failure: Experience with dapagliflozin in NYHA class IV is limited.

Lower limb amputations: An increase in cases of lower limb amputation (primarily of the toe) has been observed in long-term, clinical studies in type 2 diabetes mellitus with SGLT2 inhibitors. It is unknown whether this constitutes a class effect. It is important to counsel patients with diabetes on routine preventative foot care.

Urine laboratory assessments: Due to its mechanism of action, patients taking [PRODUCT NAME] will test positive for glucose in their urine.

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

Pharmacodynamic interactions

Diuretics: Dapagliflozin 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, 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 in patients with type 2 diabetes mellitus (see sections 4.2 and 4.8).

Pharmacokinetic interactions: The metabolism of dapagliflozin is primarily via glucuronide conjugation mediated by UDP glucuronosyl transferase1A9 (UGT1A9). In vitro studies, dapagliflozin neither inhibited cytochrome P450 (CYP) 1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, nor induced CYP1A2, CYP2B6 or CYP3A4. Therefore, dapagliflozin is not expected to alter the metabolic clearance of co-administered medicines that are metabolised by these enzymes.

Effect of other medicines on dapagliflozin: Interaction studies conducted in healthy subjects, using mainly a single-dose design, suggest that the pharmacokinetics of dapagliflozin are not altered by metformin, pioglitazone, sitagliptin, glimepiride, voglibose, hydrochlorothiazide, bumetanide, valsartan, or simvastatin. Following co administration of dapagliflozin with rifampicin (an inducer of various active transporters and drug-metabolising enzymes) a 22% decrease in dapagliflozin systemic exposure (AUC) was observed, but with no clinically meaningful effect on 24-hour urinary glucose excretion. No dose adjustment is recommended. A clinically relevant effect with other inducers (e.g. carbamazepine, phenytoin, Phenobarbital) is not expected. Following co administration of dapagliflozin with mefenamic acid (an inhibitor of UGT1A9), a 55% increase in dapagliflozin systemic exposure was seen, but with no clinically meaningful effect on 24-hour urinary glucose excretion. No dose adjustment is recommended.

Effect of dapagliflozin on other medicines: In interaction studies conducted in healthy subjects, using mainly a single-dose design, dapagliflozin did not alter the pharmacokinetics of metformin, pioglitazone, sitagliptin, glimepiride, hydrochlorothiazide, bumetanide, valsartan, digoxin(a P-gp substrate) or warfarin (S-warfarin, a CYP2C9 substrate), or the anti coagulatory effects of warfarin as measured by INR. Combination of a single dose of dapagliflozin 20 mg and simvastatin (a CYP3A4 substrate) resulted in a 19% increase in AUC of simvastatin and 31% increase in AUC of simvastatin acid. The increase in simvastatin and simvastatin acid exposures are not considered clinically relevant.

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.

Pregnancy: [PRODUCT NAME] is contraindicated during pregnancy (see section 4.3)

Breastfeeding: [PRODUCT NAME] is contraindicated during lactation (see section 4.3).

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

[PRODUCT NAME] has no or negligible influence on the ability to drive and use machines. Patients should be alerted to the risk of hypoglycaemia when dapagliflozin is used in combination with a sulphonylurea or insulin and possible dizziness.

Summary of the safety profile: The most commonly reported adverse drug reactions, during controlled clinical trials with dapagliflozin were genital infections.

Tabulated summary of adverse reactions:

System organ class

• Frequent: Infections and infestations: Vulvovaginitis, balanitis and related genital infections. Urinary tract infections including pyelonephritis, cystitis
• Less frequent: Fungal infection, Necrotising fasciitis of the perineum (Fournieru2019s gangrene)
• Frequency unknown: Metabolism and nutrition disorders: Hypoglycaemia (when used with SU or insulin), Volume depletion, Dehydration, hypovolaemia, hypotension, Thirst, Diabetic ketoacidosis (when used in type 2 diabetes mellitus)
• Nervous system disorders: Dizziness
• Gastrointestinal disorders: Constipation, dry mouth
• Skin and subcutaneous tissue disorders: Rash, Angioedema, hyperhidrosis
• Musculoskeletal and connective tissue disorders: Back pain
• Renal and urinary disorders: Glucosuria, Dysuria, Polyuria, Nocturia
• Reproductive system and breast disorders: Vulvovaginal pruritis, Pruritis genital
• Investigations: Haematocrit increased, Creatinine renal clearance decreased during initial treatment, Dyslipidaemia, Blood creatinine increased during initial treatment, Blood urea increased, Weight decreased

a) 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, balanitiscandida, genital candidiasis, genital infection, genital infection male, penile infection, vulvitis, vaginitis bacterial, vulval abscess.

b) Urinary tract infection includes the following preferred terms, listed in order of frequency reported: urinary tract infection, cystitis, Escherichia urinary tract infection, genitourinary tract infection, pyelonephritis, trigonitis, urethritis, kidney infection and prostatitis.

c) Volume depletion includes, e.g. the predefined preferred terms: dehydration, hypovolaemia, and hypotension.

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

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