Dapagliflozin 10 Mg/5 mg Film-Coated Tablets

Type 2 diabetes mellitus

Dapagliflozin Adco 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

Dapagliflozin Adco 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 %.

Posology

Type 2 diabetes mellitus

Monotherapy and add-on combination therapy

The recommended dose is 10 mg Dapagliflozin Adco 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. The recommended starting doses of Dapagliflozin Adco and metformin when used as initial combination therapy are 10 mg Dapagliflozin Adco plus 500 mg metformin once daily. Patients with inadequate glycaemic control on this starting dose should have their metformin dose increased according to approved metformin product information.

Use with medicines known to cause hypoglycaemia

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

Heart failure

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

Special Populations

Renal impairment: No dosage adjustment is required based on renal function. In patients with diabetes mellitus, the glucose lowering efficacy of dapagliflozin is reduced in patients with eGFR < 45 mL/min/1,73 m2 (see section 4.4). Therefore, if eGFR falls below 45 mL/min/1,73 m2, additional glucose lowering treatment should be considered in patients with type 2 diabetes mellitus if further glycaemic control is needed. Treatment with dapagliflozin should be continued for management of renal and cardiovascular comorbidities. Monitoring of renal function is recommended as follows:

• Prior to initiation of Dapagliflozin Adco and at least annually, thereafter.
• Prior to initiation of concomitant medicines that may reduce renal function and periodically thereafter.

Hepatic impairment: No dosage adjustment for Dapagliflozin Adco is necessary for patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. Dapagliflozin Adco is not recommended for patients with severe hepatic impairment as efficacy has not been established (see section 5.2).

Elderly: No dosage adjustment for Dapagliflozin Adco is required based on age (see section 4.4).

Paediatric population: Safety and effectiveness of Dapagliflozin Adco in paediatric and adolescent patients have not been established. No data is available.

Method of administration

For oral administration.

• Hypersensitivity to dapagliflozin or to any of the excipients of Dapagliflozin Adco as listed in section 6.1.
• Diabetes mellitus Type 1.
• Pregnant women or women who are breastfeeding their infants (see section 4.6).
• Patients with a history of pancreatitis or pancreatic surgery (see section 4.4).

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

Renal impairment: There is limited experience with Dapagliflozin Adco in patients with severe renal impairment (eGFR < 25 mL/min/1,73 m2) or end-stage renal disease (ESRD). Dapagliflozin Adco is not recommended for the treatment of type 2 diabetes mellitus to improve glycaemic control when eGFR is persistently below 45 mL/min/1,73 m2 as the glycaemic efficacy of dapagliflozin is dependent on renal function (see section 4.2). However, treatment with Dapagliflozin Adco should be continued for the management of renal and cardiovascular comorbidities and additional glucose lowering treatment should be considered if further glycaemic control is needed. The renal function should be monitored as follows:

• prior to initiation of Dapagliflozin Adco and at least yearly thereafter.
• prior to initiation of concomitant medicines that may reduce renal function and periodically thereafter.
• for renal function approaching eGFR 45 mL/min/1,73 m2, at least 2 to 4 times per year.

If the renal function falls persistently below eGFR u02c2 45 mL/min/1,73 m2, treatment with Dapagliflozin Adco should be discontinued (see section 4.3).

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, as contained in Dapagliflozin Adco, increases diuresis which may lead to the modest decrease in blood pressure observed in clinical studies. 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 Adco is recommended for patients who develop volume depletion until the depletion is corrected (see section 4.8).

Diabetic ketoacidosis: Cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases have been reported in patients treated with sodium-glucose co-transporter 2 inhibitors, including dapagliflozin. Sodium-glucose co-transporter 2 (SGLT2) inhibitors, such as Dapagliflozin Adco should be used with caution in patients with increased risk of Diabetic ketoacidosis (DKA). Patients who may be at higher risk of DKA include patients with a low beta-cell function reserve (e.g., type 2 diabetes patients with low C-peptide or latent autoimmune diabetes in adults (LADA) or patients with a history of pancreatitis), patients with conditions that lead to restricted food intake or severe dehydration, patients for whom insulin doses are reduced and patients with increased insulin requirements due to acute medical illness, surgery or alcohol abuse. SGLT2 inhibitors should be used with caution in these patients. Restarting SGLT2 inhibitor treatment in patients experiencing a DKA while on SGLT2 inhibitor treatment is not recommended, unless another clear precipitating factor is identified and resolved. 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. If ketoacidosis is suspected, Dapagliflozin Adco should be discontinued and the patient should be promptly evaluated. Before initiating Dapagliflozin Adco, factors in the patient history that may predispose to ketoacidosis should be considered. Treatment should be interrupted in patients who are hospitalised for major surgical procedures or acute serious medical illnesses. Monitoring of ketones is recommended in these patients. Measurement of blood ketone levels is preferred to urine. Treatment with Dapagliflozin Adco may be restarted when the ketone values are normal, and the patientu2019s condition has stabilised. Dapagliflozin Adco is contraindicated for the treatment of patients with type 1 diabetes mellitus (see section 4.3).

Necrotising fasciitis of the perineum (Fournieru2019s gangrene): Post-marketing cases of necrotising fasciitis of the perineum (also known as Fournieru2019s gangrene) have been reported in female and male patients taking SGLT2 inhibitors (see section 4.8). This is a serious and potentially life-threatening event that requires urgent surgical intervention and antibiotic treatment. Patients should be advised to seek medical attention if they experience a combination of symptoms of pain, tenderness, erythema, or swelling in the genital or perineal area, with fever or malaise. Be aware that either uro-genital infection or perineal abscess may precede necrotising fasciitis. If Fournieru2019s gangrene is suspected, Dapagliflozin Adco should be discontinued and prompt treatment (including antibiotics and surgical debridement) should be instituted.

Urinary tract infections: Urinary glucose excretion may be associated with an increased risk of urinary tract infection; therefore, temporary interruption of Dapagliflozin Adco should be considered when treating pyelonephritis or urosepsis.

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 antihypertensive medicines 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 and 4.8).

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

Chronic kidney disease: There is no experience with Dapagliflozin Adco for the treatment of chronic kidney disease in patients without diabetes who do not have albuminuria. Dapagliflozin Adco has not been studied for the treatment of chronic kidney disease in patients with polycystic kidney disease, glomerulonephritis with flares (lupus nephritis or ANCA-associated vasculitis), ongoing or recent requirements of cytotoxic, immunosuppressive or other immunomodulating renal therapy, or in patients who received an organ transplant.

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 Dapagliflozin Adco will test positive for glucose in their urine.

Paediatric population: Safety and efficacy of Dapagliflozin Adco in paediatric patients has not been established.

Pharmacodynamic interactions

Diuretics

Dapagliflozin Adco 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 Adco 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 glucuronosyltransferase 1A9 (UGT1A9). In 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 Adco 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 anticoagulatory 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. Dapagliflozin may increase renal lithium excretion and the blood lithium levels may be decreased. Serum concentration of lithium should be monitored more frequently after dapagliflozin initiation and dose changes. Please refer the patient to the doctor who prescribed lithium in order to monitor serum concentration of lithium.

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 Dapagliflozin Adco. Use of alternative methods to monitor glycaemic control is advised.

Pregnancy

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

Breastfeeding

Mothers on Dapagliflozin Adco should not breastfeed their infants. Dapagliflozin Adco must not be used by a nursing woman. Studies in rats have shown excretion of dapagliflozin in milk. Exposure to Dapagliflozin Adco 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.

Dapagliflozin Adco has little or negligible influence on the ability to drive and use machines. Patients should be alerted to the risk of hypoglycaemia (and its effects on their motor skills) when Dapagliflozin Adco is used in combination with a sulphonylurea or insulin.

a. Summary of the safety profile

Type 2 diabetes mellitus

The most frequently reported adverse reactions were genital infections.

Heart failure

The overall safety profile of dapagliflozin in patients with heart failure was consistent with the known safety profile of dapagliflozin.

b. Tabulated list of adverse reactions

Infections and infestations

Frequent: Vulvovaginitis, balanitis and related genital infections b,c, Urinary tract infection b,d, including pyelonephritis, cystitis.

Less frequent: Fungal infection, Necrotising fasciitis of the perineum (Fournier's gangrene) b,g

Metabolism and nutrition disorders

Frequent: Hypoglycaemia (when used with SU or insulin) b

Less frequent: Volume depletion b,e, Thirst, Diabetic ketoacidosis (when used in type 2 diabetes mellitus) b,g

Nervous system disorders

Frequent: Dizziness

Gastrointestinal disorders

Less frequent: Constipation, Dry mouth

Skin and subcutaneous tissue disorders

Frequent: Rash h

Less frequent: Angioedema, Hyperhidrosis

Musculoskeletal and connective tissue disorders

Frequent: Back pain

Renal and urinary disorders

Frequent: Dysuria, Polyuria f, glucosuria

Less frequent: Nocturia, tubulointerstitial nephritis

Reproductive system and breast disorders

Less frequent: Vulvovaginal pruritus, Pruritus genital

Investigations

Frequent: Haematocrit increased, Creatinine renal clearance decreased during initial treatment b, Dyslipidaemia

Less frequent: Blood creatinine increased during initial treatment b, Blood urea increased, Weight decreased

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

b See corresponding subsection below for additional information.

c 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 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.

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

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

g See section 4.4

h Rash includes the following preferred terms, listed in order of frequency in clinical studies: rash, rash generalised, rash pruritic, rash macular, rash maculo-papular, rash pustular, rash vesicular, and rash erythematous.

c. Description of selected adverse reactions

Vulvovaginitis, balanitis and related genital infections

Vulvovaginitis, balanitis and related genital infections were reported in patients treated with dapagliflozin. Most infections were mild to moderate, and subjects responded to an initial course of standard treatment and less frequently resulted in discontinuation from dapagliflozin treatment. These infections were more frequent in females, and subjects with a prior history were more likely to have a recurrent infection. Serious adverse events of genital infections or adverse events leading to discontinuation due to genital infections were not reported for any patients without diabetes.

Necrotising fasciitis of the perineum (Fournieru2019s gangrene)

Cases of Fournieru2019s gangrene have been reported post-marketing in patients taking SGLT2 inhibitors, including dapagliflozin (see section 4.4).

Hypoglycaemia

The frequency of hypoglycaemia is depended on the type of background therapy used in the clinical studies in diabetes mellitus. For dapagliflozin in monotherapy, as add-on to metformin or as add-on to sitagliptin (with or without metformin), the frequency of minor episodes of hypoglycaemia was similar between all treatment groups. Across all studies, major events of hypoglycaemia were less frequent and comparable between the groups treated with dapagliflozin or placebo. Studies with add-on sulphonylurea and add-on insulin therapies had higher rates of hypoglycaemia (see section 4.5).

Urinary tract infections

Most infections were mild to moderate, and subjects responded to an initial course of standard treatment and less frequently resulted in discontinuation from dapagliflozin treatment. These infections were more frequent in females, and subjects with a prior history were more likely to have a recurrent infection.

Increased creatinine

Adverse reactions related to increased creatinine (e.g., decreased renal creatinine clearance, renal impairment, increased blood creatinine and decreased glomerular filtration rate) was reported. These reactions were more common in patients with baseline e GFR u2265 30 and < 60 mL/min/1,73 m2. Further evaluation of patients who had renal-related adverse events showed that most had serum creatinine changes of u2264 0,5 mg/dL from baseline. The increases in creatinine were generally transient during continuous treatment or reversible after discontinuation of treatment.

Laboratory findings

Serum inorganic phosphorous

Increases from baseline in mean serum phosphorus levels were reported in patients treated with dapagliflozin 10 mg compared to placebo (mean increases of 0,0419 mmol/L vs. 0,0128 mmol/L respectively). The clinical relevance is unknown.

Haematocrit

A moderate increase in haematocrit occurs and may be an indication of volume depletion.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

In 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.