Forxiga
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FORXIGA (FORXIGA®)
Composition:
Active substance: dapagliflozin;
One film-coated tablet contains 6.15 mg or 12.30 mg of dapagliflozin propandiol monohydrate equivalent to 5 mg or 10 mg of dapagliflozin;
Excipients: microcrystalline cellulose, anhydrous lactose, crospovidone, silicon dioxide, magnesium stearate, Opadry II Yellow.
Pharmaceutical form.
Film-coated tablets.
Main physicochemical properties:
5 mg tablets: yellow, round, biconvex film-coated tablets, engraved with "5" on one side and "1427" on the other side;
10 mg tablets: yellow, biconvex, rhomboid-shaped film-coated tablets, engraved with "10" on one side and "1428" on the other side.
Pharmacotherapeutic group.
Antidiabetic agents, sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors). ATC code A10BK01.
Pharmacological Properties.
Pharmacodynamics.
Mechanism of action
Dapagliflozin is a highly potent (Ki: 0.55 nM), selective, and reversible inhibitor of sodium-glucose cotransporter 2 (SGLT2).
Inhibition of SGLT2 by dapagliflozin reduces glucose reabsorption from the glomerular filtrate in the proximal renal tubules, along with reduced sodium reabsorption, resulting in urinary glucose excretion and osmotic diuresis. Thus, dapagliflozin increases sodium delivery to the distal tubules, enhancing tubuloglomerular feedback and reducing intraglomerular pressure. Together with osmotic diuresis, this leads to reduced volume overload, lowered arterial blood pressure, and reduced preload and afterload, which may have beneficial effects on myocardial remodeling and diastolic function, as well as preservation of kidney function. The benefits of dapagliflozin on the heart and kidneys are not solely dependent on glucose-lowering effects and are not limited to patients with diabetes mellitus, as demonstrated by the DAPA-HF, DELIVER, and DAPA-CKD trials. Other effects include increased hematocrit and reduced body weight.
Dapagliflozin improves fasting and postprandial plasma glucose levels by reducing renal glucose reabsorption, leading to urinary glucose excretion. This glucose excretion (glucuretic effect) is observed after the first dose, persists throughout the 24-hour dosing interval, and is maintained during treatment. The amount of glucose excreted by the kidneys via this mechanism depends on blood glucose concentration and glomerular filtration rate (GFR). Thus, in patients with normal blood glucose levels, dapagliflozin has a low potential to cause hypoglycemia. Dapagliflozin does not impair normal endogenous glucose production in response to hypoglycemia. Dapagliflozin acts independently of insulin secretion and action. In clinical studies, improvement in beta-cell function (HOMA beta-cell function) was observed when assessed using the homeostasis model.
SGLT2 is selectively expressed in the kidneys. Dapagliflozin does not inhibit other glucose transporters important for glucose transport into peripheral tissues and is more than 1400 times more selective for SGLT2 than for SGLT1, the primary intestinal glucose transporter responsible for glucose absorption.
Pharmacodynamic effects
In healthy study participants and patients with type 2 diabetes, administration of dapagliflozin resulted in increased urinary glucose excretion. Approximately 70 g of glucose per day (equivalent to 280 kcal/day) was excreted in urine when dapagliflozin 10 mg once daily was administered to patients with type 2 diabetes for 12 weeks. In patients with type 2 diabetes receiving dapagliflozin 10 mg/day for up to 2 years, evidence of sustained glucose excretion was observed.
This urinary glucose excretion with dapagliflozin also leads to osmotic diuresis and increased urine volume in patients with type 2 diabetes. The increase in urine volume in patients with type 2 diabetes reaches approximately 375 mL/day. The increased urine volume was associated with a slight and transient increase in urinary sodium excretion, without changes in serum sodium concentration.
Urinary excretion of uric acid was also transiently increased (over 3–7 days) and was accompanied by a sustained reduction in serum uric acid concentration. At week 24, the reduction in serum uric acid concentration ranged from –48.3 to –18.3 µmol/L (from –0.87 to –0.33 mg/dL).
Clinical efficacy and safety
Type 2 diabetes
Improvement of glycemic control and reduction of cardiovascular and renal morbidity and mortality are integral components of type 2 diabetes management.
Fourteen double-blind, randomized, controlled clinical trials involving 7056 adult patients with type 2 diabetes were conducted to evaluate the glycemic efficacy and safety of the medicinal product Forxiga; 4737 patients in these trials received dapagliflozin treatment. In twelve studies, the treatment period was 24 weeks; in eight long-term extensions, it ranged from 24 to 80 weeks (total study duration up to 104 weeks); in one study, the treatment period was 28 weeks; and in another study, treatment duration was 52 weeks with long-term extensions of 52 and 104 weeks (total study duration of 208 weeks). The mean duration of diabetes among participants ranged from 1.4 to 16.9 years. Mild renal impairment was present in 50% of participants, and moderate renal impairment in 11%. 51% of participants were male, 84% were of Caucasian race, 8% of Mongoloid race, 4% of Negroid race, and 4% of other racial groups. 81% of participants had a body mass index (BMI) ≥ 27. Additionally, two 12-week placebo-controlled trials were conducted in patients with inadequately controlled type 2 diabetes and arterial hypertension.
A cardiovascular outcomes trial (DECLARE) with dapagliflozin 10 mg versus placebo was conducted in 17,160 patients with type 2 diabetes with or without established cardiovascular disease to evaluate its impact on cardiovascular and renal events.
Glycemic control
Monotherapy
A double-blind, placebo-controlled 24-week study (with an additional extension period) was conducted to evaluate the safety and efficacy of monotherapy with Forxiga in patients with inadequately controlled type 2 diabetes. Once-daily administration of dapagliflozin resulted in a statistically significant (p < 0.0001) reduction in glycated hemoglobin (HbA1c) compared to placebo (Table 1).
During the extension period, the reduction in HbA1c was maintained up to week 102 (adjusted mean change from baseline: –0.61% and –0.17% for dapagliflozin 10 mg and placebo, respectively).
Table 1. Results at 24 weeks (ITT-LOCF) from the placebo-controlled study of dapagliflozin as monotherapy
| Monotherapy |
||
| Dapagliflozin 10 mg |
Placebo |
|
| Nb |
70 |
75 |
| HbA1c (%) Baseline (mean) |
8.01 |
7.79 |
| Change from baseline |
|
|
| Difference vs placebo (95% CI) |
(–0.96; –0.36) |
|
| Patients (%) achieving: HbA1c (%) ˂ 7% Adjusted for baseline |
50.8§ |
31.6 |
| Body weight (kg) |
||
| Baseline (mean) |
94.13 |
88.77 |
| Change from baseline |
|
|
| Difference vs placebo (95% CI) |
(–2.20; 0.25) |
|
a Last observation carried forward (prior to treatment of treated patients).
b All randomized patients who received at least one dose of the study drug during the short-term double-blind period of the study.
c Least squares mean adjusted for baseline value.
* p-value < 0.0001 versus placebo.
§ Not tested for statistical significance due to the sequential testing procedure for secondary endpoints.
Additional Combination Therapy
In a 52-week active-controlled non-inferiority study (with 52- and 104-week extension periods), the effect of Forxiga was evaluated when added to metformin compared to glipizide added to metformin in patients with inadequate glycaemic control (HbA1c > 6.5% and ≤ 10%). Results showed a similar mean reduction in HbA1c from baseline at 52 weeks compared to glipizide, demonstrating non-inferior efficacy of the study drug. At 104 weeks, the adjusted mean change in HbA1c from baseline was –0.32% for dapagliflozin and –0.14% for glipizide. At 208 weeks, the adjusted mean change in HbA1c from baseline was –0.10% for dapagliflozin and 0.20% for glipizide. At 52, 104, and 208 weeks, significantly fewer patients in the dapagliflozin treatment group (3.5%, 4.3%, and 5.0%, respectively) experienced at least one episode of hypoglycaemia compared to the glipizide group (40.8%, 47.0%, and 50.0%, respectively). The proportion of patients continuing in the study at 104 and 208 weeks was 56.2% and 39.7% in the dapagliflozin group and 50.0% and 34.6% in the glipizide group.
Dapagliflozin as add-on to metformin, glimepiride, metformin and sulphonylurea, sitagliptin (with or without metformin), or insulin resulted in a statistically significant reduction in HbA1c at 24 weeks compared to placebo (p < 0.0001).
The HbA1c reduction observed at 24 weeks was maintained in add-on combination therapy studies (with glimepiride and insulin) up to 48 weeks (glimepiride) and up to 104 weeks (insulin). At 48 weeks, when added to sitagliptin (with or without metformin), the adjusted mean change from baseline for dapagliflozin 10 mg and placebo was –0.30% and 0.38%, respectively. In the metformin add-on study, HbA1c reduction was maintained at 102 weeks (adjusted mean change from baseline of –0.78% and 0.02% for the 10 mg dose and placebo, respectively). At 104 weeks with insulin (with or without additional oral glucose-lowering medicinal products), the adjusted mean change from baseline in HbA1c reduction was –0.71% and –0.06% for dapagliflozin 10 mg and placebo, respectively. At 48 and 104 weeks, insulin dose remained stable compared to baseline in patients receiving dapagliflozin 10 mg, averaging 76 IU/day. In the placebo group, the mean increase in insulin dose was 10.5 IU/day and 18.3 IU/day from baseline (average dose was 84 and 92 IU/day) at 48 and 104 weeks, respectively. The proportion of patients continuing in the study at 104 weeks was 72.4% in the dapagliflozin 10 mg treatment group and 54.8% in the placebo group.
Use of combination with metformin in treatment-naïve patients
Overall, 1236 treatment-naïve patients with inadequately controlled type 2 diabetes (HbA1c ≥ 7.5% and ≤ 12%) participated in two 24-week active-controlled studies to evaluate the efficacy and safety of dapagliflozin (5 mg or 10 mg) in combination with metformin compared to monotherapy with single-component medicinal products.
Treatment with dapagliflozin 10 mg in combination with metformin (up to 2000 mg per day) provided significant improvement in HbA1c compared to treatment with single-component medicinal products (Table 2) and resulted in greater reductions in fasting plasma glucose (FPG) (compared to single-component medicinal product therapy) and body weight (compared to metformin).
Table 2. Results at Week 24 (LOCFa) in the active-controlled study of combination therapy with dapagliflozin and metformin in treatment-naïve patients
| Dapagliflozin 10 mg + Metformin |
Dapagliflozin 10 mg |
Metformin |
|
| Parameter |
|||
| Nb |
211b |
219b |
208b |
| HbA1c (%) Baseline (mean) Change from baselinec Difference vs dapagliflozinc (95% CI) (95% CI) |
9.10
|
9.03
|
9.03
|
a LOCF – last observation carried forward.
b All randomized patients who received at least one dose of the double-blind study medication during the short-term double-blind period.
c Least squares mean adjusted for baseline value.
* p-value < 0.0001.
Combination therapy with extended-release exenatide
In a 28-week, double-blind, active-controlled study, the combination of dapagliflozin and extended-release exenatide (GLP-1 receptor agonist) was compared with treatment with dapagliflozin alone and extended-release exenatide alone in patients with inadequately controlled diabetes on metformin monotherapy (HbA1c ≥ 8% and ≤12%). HbA1c levels decreased from baseline in all treatment groups. Combination therapy with dapagliflozin 10 mg and extended-release exenatide resulted in a significantly greater reduction in HbA1c from baseline compared to treatment with either dapagliflozin or extended-release exenatide alone (Table 3).
Table 3. Results from one 28-week study of dapagliflozin and extended-release exenatide compared to dapagliflozin alone and extended-release exenatide alone, each in combination with metformin (intent-to-treat population according to assigned treatment)
| Parameter |
Dapagliflozin 10 mg once daily + Exenatide extended-release 2 mg once weekly |
Dapagliflozin 10 mg once daily + Placebo once weekly |
Exenatide extended-release 2 mg once weekly + Placebo once daily |
| N |
228 |
230 |
227 |
| HbA1c (%) Baseline (mean) Change from baselinea |
9.29
|
9.25
|
9.26
|
| Mean difference in change from baseline between combination and individual medicines (95% CI) |
(–0.84; –0.34) |
(–0.63; –0.13) |
|
| Patients (%) achieving HbA1c < 7% |
44.7 |
19.1 |
26.9 |
| Body weight (kg) Baseline (mean) Change from baselinea |
92.13 |
90.87
|
89.12
|
| Mean difference in change from baseline between combination and individual medicines (95% CI) |
(–2.12; –0.55) |
(–2.79; –1.20) |
1 r/d = once daily. 1 r/t = once weekly. N = number of patients. CI = confidence interval.
a Least squares mean adjusted for baseline value and treatment group difference in change from baseline at week 28 modeled using a mixed model for repeated measurements, including treatment, region, baseline HbA1c (< 9.0% or ≥ 9.0%), week, and treatment-by-week interaction as fixed effects, and baseline value as covariate.
* p < 0.001.
** p < 0.01.
p-values – all adjusted p-values for multiplicity.
Analyses exclude measurements after rescue therapy and after premature discontinuation of investigational medicinal product.
Fasting plasma glucose levels
Treatment with dapagliflozin 10 mg as monotherapy or as add-on to metformin, glimepiride, metformin and sulphonylurea, sitagliptin (with or without metformin), or insulin resulted in statistically significant reductions in FPG (from –1.90 to –1.20 mmol/L [from –34.2 to –21.7 mg/dL]) compared to placebo (from –0.33 to 0.21 mmol/L [from –6.0 to 3.8 mg/dL]). This effect was observed at week 1 of treatment and was maintained in studies with duration up to week 104.
Combination therapy with dapagliflozin 10 mg and extended-release exenatide led to a significantly greater reduction in FPG at week 28: –3.66 mmol/L (–65.8 mg/dL), compared to dapagliflozin alone (–2.73 mmol/L [–49.2 mg/dL], p < 0.001) and exenatide extended-release alone (–2.54 mmol/L [–45.8 mg/dL], p < 0.001).
In a dedicated study in patients with diabetes and eGFR from ≥ 45 to < 60 mL/min/1.73 m², treatment with dapagliflozin demonstrated a reduction in FPG at week 24: –1.19 mmol/L (–21.46 mg/dL) compared to –0.27 mmol/L (–4.87 mg/dL) for placebo (p = 0.001).
Postprandial plasma glucose levels
Treatment with dapagliflozin 10 mg added to glimepiride therapy resulted in statistically significant reductions in plasma glucose levels 2 hours after meals at week 24, with these effects maintained through week 48.
Treatment with dapagliflozin 10 mg as add-on to sitagliptin (with or without metformin) resulted in reduced 2-hour post-meal glucose levels at week 24, which were sustained through week 48.
Combination therapy with dapagliflozin 10 mg and extended-release exenatide resulted in significant reductions in 2-hour postprandial glucose levels at week 28 compared to each individual agent alone.
Body weight
Dapagliflozin 10 mg as add-on to metformin, glimepiride, metformin and sulphonylurea, sitagliptin (with or without metformin), or insulin resulted in statistically significant reductions in body weight at week 24 (p < 0.0001). These effects were maintained in long-term studies. At week 48, the difference from placebo with dapagliflozin added to sitagliptin (with or without metformin) was –2.22 kg. At week 102, the difference from placebo with dapagliflozin added to metformin or insulin was –2.14 kg and –2.88 kg, respectively.
In an active-controlled non-inferiority study, dapagliflozin as add-on to metformin resulted in a statistically significant reduction in body weight compared to glipizide: –4.65 kg at week 52 (p < 0.0001), which was maintained at weeks 104 and 208 (–5.06 kg and –4.38 kg, respectively).
The combination of dapagliflozin 10 mg and extended-release exenatide demonstrated significantly greater reduction in body weight compared to either agent alone (Table 3).
Results from a 24-week study in 182 patients with diabetes, using dual-energy X-ray absorptiometry to assess body composition, showed greater reductions in total body weight and fat mass than in lean body mass or fluid loss in patients receiving dapagliflozin 10 mg with metformin compared to placebo with metformin. Treatment with Forxiga and metformin numerically reduced visceral adipose tissue compared to placebo and metformin, as assessed in a substudy using magnetic resonance imaging.
Arterial blood pressure
Based on data from a pre-specified pooled analysis of 13 placebo-controlled studies, treatment with dapagliflozin 10 mg resulted in a change from baseline in systolic blood pressure of –3.7 mm Hg and diastolic blood pressure of –1.8 mm Hg, compared to –0.5 mm Hg for systolic and –0.5 mm Hg for diastolic blood pressure in the placebo group at week 24. A similar reduction was observed throughout the treatment period up to 104 weeks.
Combination therapy with dapagliflozin 10 mg and extended-release exenatide led to a significant reduction in systolic blood pressure at week 28 (–4.3 mm Hg) compared to dapagliflozin alone (–1.8 mm Hg, p < 0.05) and extended-release exenatide alone (–1.2 mm Hg, p < 0.01).
In two 12-week placebo-controlled studies involving a total of 1062 patients with inadequately controlled type 2 diabetes and hypertension (despite ongoing treatment with an angiotensin-converting enzyme inhibitor (ACE inhibitor) or angiotensin II receptor type 1 blocker (ARB) in one study, and ACE inhibitor or ARB plus one additional antihypertensive agent in the other study), patients received dapagliflozin 10 mg or placebo. By week 12, in both studies dapagliflozin 10 mg in combination with standard antidiabetic therapy improved HbA1c levels and reduced (placebo-corrected) systolic blood pressure by an average of 3.1 and 4.3 mm Hg, respectively.
In a dedicated study in diabetic patients with eGFR from ≥45 to <60 mL/min/1.73 m², treatment with dapagliflozin demonstrated a reduction in systolic blood pressure at week 24: –4.8 mm Hg compared to placebo –1.7 mm Hg (p < 0.05).
Glycemic control in patients with moderate renal impairment (chronic kidney disease stage 3A CKD) (estimated glomerular filtration rate (eGFR) from ≥ 45 to < 60 mL/min/1.73 m²)
The efficacy of dapagliflozin was also evaluated separately in a dedicated study involving patients with diabetes and eGFR ≥ 45 mL/min/1.73 m² to < 60 mL/min/1.73 m² who had inadequate glycemic control on standard therapy. Treatment with dapagliflozin led to reductions in HbA1c and body weight compared to placebo (Table 4).
Table 4. Results of a placebo-controlled study of dapagliflozin in patients with diabetes and eGFR from ≥45 to <60 mL/min/1.73 m² at week 24
| Dapagliflozin 10 mg |
Placebo |
|
| N |
159 |
161 |
| HbA1c (%) Baseline (mean) Change from baselineb Difference vs placebob (95% CI) |
8.35 -0.37 -0.34* (-0.53; -0.15) |
8.03 -0.03 |
| Body weight (kg) Baseline (mean) Percent change from baselinec Percent difference vs placeboc (95% CI) |
92.51 -3.42 -1.43* (-2.15; -0.69) |
88.30 -2.02 |
and metformin or metformin hydrochloride were part of standard therapy in 69.4% and 64.0% of patients in the dapagliflozin and placebo groups, respectively.
b Least squares mean adjusted for baseline value.
c Least squares mean change from baseline adjusted for baseline value.
* p<0.001
Patients with baseline HbA1c ≥ 9%
In a pre-specified analysis of patients with baseline HbA1c ≥ 9.0%, monotherapy with dapagliflozin 10 mg (adjusted mean change from baseline: –2.04% and 0.19% with dapagliflozin 10 mg and placebo, respectively) and dapagliflozin added to metformin therapy (adjusted mean change from baseline: –1.32% and –0.53% with dapagliflozin and placebo, respectively) resulted in statistically significant reductions in HbA1c levels at week 24.
Cardiovascular and renal outcomes
Dapagliflozin Effect on Cardiovascular Events (DECLARE) is an international, multicenter, randomized, double-blind, placebo-controlled clinical trial conducted to determine the effect of dapagliflozin compared to placebo on cardiovascular outcomes when added to standard background therapy. All patients had type 2 diabetes and at least two additional cardiovascular risk factors (age ≥ 55 years for men or ≥ 60 years for women and one or more of the following conditions: dyslipidemia, hypertension, or current tobacco use) or established cardiovascular disease.
Among 17,160 randomized patients, 6,974 (40.6%) had established cardiovascular disease and 10,186 (59.4%) did not. 8,582 patients were randomized to dapagliflozin 10 mg and 8,578 to placebo, with a median follow-up of 4.2 years.
The mean age of the study population was 63.9 years, and 37.4% were women. Overall, 22.4% had diabetes for ≤ 5 years, and the mean duration of diabetes was 11.9 years. Mean HbA1c was 8.3%, and mean body mass index was 32.1 kg/m².
At baseline, 10.0% of patients had a history of heart failure. Mean eGFR was 85.2 mL/min/1.73 m², 7.4% of patients had eGFR < 60 mL/min/1.73 m², and 30.3% had micro- or macroalbuminuria (urine albumin-to-creatinine ratio [UACR] ≥ 30 to ≤ 300 mg/g or > 300 mg/g, respectively).
The majority of patients (98%) were using one or more antidiabetic medications at baseline, including metformin (82%), insulin (41%), and sulfonylureas (43%).
The primary composite endpoints were time to first occurrence of cardiovascular death, myocardial infarction, or ischemic stroke (major adverse cardiovascular events [MACE]), and time to first occurrence of hospitalization for heart failure or cardiovascular death. Secondary endpoints included a renal composite endpoint and death from any cause.
Major adverse cardiovascular events
Dapagliflozin 10 mg demonstrated non-inferiority to placebo (non-inferiority versus placebo) for the outcomes of cardiovascular death, myocardial infarction, or ischemic stroke (one-sided p < 0.001).
Heart failure or cardiovascular death
Dapagliflozin 10 mg demonstrated superiority over placebo (superiority versus placebo) in preventing hospitalization for heart failure or cardiovascular death. The treatment effect difference was driven by hospitalization for heart failure, with no difference in cardiovascular death.
The benefit of dapagliflozin treatment compared to placebo was observed in patients both with and without established cardiovascular disease, both with and without heart failure at baseline, and was consistent across various subgroups, including age, sex, renal function (eGFR), and region.
Superiority of dapagliflozin over placebo was not demonstrated for MACE (p = 0.172). The renal composite endpoint and death from any cause were not tested as part of the confirmatory testing procedure.
Nephropathy
Dapagliflozin reduced the incidence of the composite endpoint: sustained confirmed eGFR decline, end-stage kidney disease (ESKD), death due to renal or cardiovascular disease. The difference between groups was driven by reductions in renal components: sustained eGFR decline, end-stage kidney disease, and death due to renal disease.
The hazard ratio for time to nephropathy (sustained eGFR decline, ESKD, and death due to renal disease) was 0.53 (95% CI 0.43; 0.66) for dapagliflozin compared to placebo.
Additionally, dapagliflozin reduced new episodes of sustained albuminuria (hazard ratio 0.79 [95% CI 0.72; 0.87]) and led to greater regression of macroalbuminuria (hazard ratio 1.82 [95% CI 1.51; 2.20]) compared to placebo.
Heart failure
DAPA-HF study: heart failure with reduced ejection fraction (LVEF ≤ 40%)
The Dapagliflozin and the Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial is an international, multicenter, randomized, double-blind, placebo-controlled study conducted in patients with heart failure (New York Heart Association [NYHA] functional class II–IV) and reduced ejection fraction (left ventricular ejection fraction [LVEF] ≤ 40%). The objective of this study was to determine the effect of dapagliflozin compared to placebo, when added to standard therapy, on the incidence of cardiovascular death and worsening heart failure.
Of 4,744 patients, 2,373 were randomized to dapagliflozin 10 mg and 2,371 to placebo, with a median follow-up of 18 months. The mean age of the study population was 66 years, and 77% were men.
At baseline, 67.5% of patients were classified as NYHA class II, 31.6% as class III, and 0.9% as class IV. Mean LVEF was 32%. 56% of heart failure cases were ischemic, 36% non-ischemic, and 8% of unknown etiology. In each treatment group, 42% of patients had a history of type 2 diabetes, and 3% in each group were classified as having type 2 diabetes based on HbA1c ≥ 6.5% at both enrollment and randomization. Patients received standard therapy: 94% received ACE inhibitors, ARBs, or angiotensin receptor-neprilysin inhibitors (ARNI, 11%), 96% beta-blockers, 71% mineralocorticoid receptor antagonists (MRA), 93% diuretics, and 26% had an implanted device (with defibrillator function).
Patients with eGFR ≥ 30 mL/min/1.73 m² at baseline were included in the study. Mean eGFR was 66 mL/min/1.73 m², 41% of patients had eGFR < 60 mL/min/1.73 m², and 15% had eGFR < 45 mL/min/1.73 m².
Cardiovascular death and worsening heart failure
Dapagliflozin was superior to placebo in preventing the primary composite endpoint of cardiovascular death, hospitalization for heart failure, or emergency department visit for heart failure (HR [hazard ratio] 0.74 [95% CI 0.65; 0.85], p < 0.0001). The treatment effect was observed early and was maintained throughout the study period (Figure 1).
Figure 1. Time to first occurrence of cardiovascular death, hospitalization for heart failure, or emergency department visit for heart failure
Emergency department visit for heart failure was defined as an urgent, unplanned physician visit, e.g., in an emergency department, requiring treatment for worsening heart failure (excluding simple increases in oral diuretic dose).
Number at risk represents the number of patients at risk at the beginning of each time interval.
All three components of the primary composite endpoint contributed individually to the treatment effect (Figure 2). A small number of emergency department visits for heart failure were recorded.
Figure 2. Treatment effects on the primary composite endpoint, its components, and all-cause mortality
An emergency department visit for heart failure was defined as an urgent, unplanned evaluation by a physician, for example, in an emergency department, and the need for treatment due to worsening heart failure (excluding simple dose increases of oral diuretics).
The number of first events for individual components represents the actual count of first events for each component and does not sum to the total number of events in the composite endpoint.
Event rates are presented as the number of participants with events per 100 patient-years of follow-up.
p-values for individual components and all-cause mortality are nominal.
Treatment with dapagliflozin also reduced the total number of hospitalizations for heart failure (first and recurrent) and cardiovascular death; 567 events were recorded in the dapagliflozin group compared to 742 events in the placebo group (rate ratio 0.75 [95% CI 0.65; 0.88]; p = 0.0002).
The benefit of dapagliflozin treatment was observed in patients with heart failure both with and without type 2 diabetes. Dapagliflozin reduced the primary composite endpoint of cardiovascular death and worsening heart failure, with a rate ratio of 0.75 (95% CI 0.63; 0.90) in patients with diabetes and 0.73 (95% CI 0.60; 0.88) in patients without diabetes.
The benefit of dapagliflozin treatment compared to placebo on the primary endpoint was also observed in other key subgroups, including subgroups based on concomitant heart failure therapy, kidney function (eGFR), age, sex, and region.
Patient-reported outcomes — heart failure symptoms
The effect of dapagliflozin on heart failure symptoms was assessed using the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS), which measures the frequency and severity of heart failure symptoms, including fatigue, peripheral edema, dyspnea, and orthopnea. Scores range from 0 to 100, with higher scores indicating better health status.
Treatment with dapagliflozin showed statistically and clinically significant benefit compared to placebo in heart failure symptoms, as measured by the change from baseline at month 8 in KCCQ-TSS (odds ratio 1.18 [95% CI 1.11; 1.26]; p < 0.0001). The results accounted for both frequency and severity of symptoms. The benefit was observed both in improvement of heart failure symptoms and in prevention of worsening heart failure symptoms.
In responder analyses, the proportion of patients with clinically meaningful improvement in KCCQ-TSS at 8 months from baseline, defined as an increase of 5 points or more, was higher in the dapagliflozin group compared to the placebo group. The number of patients with clinically meaningful worsening, defined as a decrease of 5 points or more, was lower in the dapagliflozin group compared to the placebo group. The benefits observed with dapagliflozin were maintained when using more conservative thresholds for larger clinically meaningful changes (Table 5).
Table 5. Number and percentage of patients with clinically meaningful improvement and worsening at 8 months in KCCQ-TSS
| Change from baseline at 8 months |
Dapagliflozin |
Placebo |
||
| Improvement |
n (%) |
n (%) |
Relative riskc |
p-valuef |
| ≥ 5 points |
933 (44.7) |
794 (38.5) |
1.14 |
0.0002 |
| ≥ 10 points |
689 (33.0) |
579 (28.1) |
1.13 |
0.0018 |
| ≥ 15 points |
474 (22.7) |
406 (19.7) |
1.10 |
0.0300 |
| Worsening |
n (%) |
n (%) |
Relative riske (95% CI) |
p-valuef |
| ≥ 5 points |
537 (25.7) |
693 (33.6) |
0.84 |
<0.0001 |
| ≥ 10 points |
395 (18.9) |
506 (24.5) |
0.85 |
<0.0001 |
a Number of patients who were censored due to CV death or death prior to completion of 8 months.
b Number of patients who experienced an improvement of at least 5, 10, or 15 points from baseline. Patients who died prior to the specified time are considered not to have experienced improvement.
c For improvement, hazard ratios > 1 favor dapagliflozin 10 mg.
d Number of patients who experienced a worsening of at least 5 or 10 points from baseline. Patients who died prior to the specified time are considered to have experienced worsening.
e For worsening, hazard ratios < 1 favor dapagliflozin 10 mg.
f Nominal p-values.
Renal Impairment
There were few events of the renal composite endpoint (confirmed sustained reduction in eGFR ≥ 50%, ESRD, or death due to renal disease); the incidence was 1.2% in the dapagliflozin group and 1.6% in the placebo group.
DELIVER Study: Heart Failure with Left Ventricular Ejection Fraction > 40%
DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients with PREserved Ejection Fraction Heart Failure) was an international, multicenter, randomized, double-blind, placebo-controlled trial involving patients aged ≥ 40 years with heart failure (NYHA class II–IV) and LVEF > 40% with evidence of structural heart disease, designed to evaluate the effect of dapagliflozin on the incidence of cardiovascular death and worsening of heart failure compared to placebo.
A total of 6,263 participants were randomized: 3,131 patients received dapagliflozin 10 mg and 3,132 received placebo. The median duration of follow-up was 28 months. Among study participants, 654 (10%) had acute heart failure (defined as randomized during hospitalization for heart failure or within 30 days after discharge). The mean age of the study population was 72 years, and 56% were male.
At baseline, 75% of patients were classified as NYHA class II, 24% as class III, and 0.3% as class IV. The median LVEF was 54%. In 34% of patients, LVEF was ≤ 49%, in 36% it was 50–59%, and in 30% it was ≥ 60%. In each treatment group, 45% of patients had a history of type 2 diabetes. Background therapy included angiotensin-converting enzyme inhibitors (ACEi)/angiotensin II receptor blockers (ARB)/angiotensin receptor-neprilysin inhibitors (ARNI) (77%), beta-blockers (83%), diuretics (98%), and mineralocorticoid receptor antagonists (MRA) (43%).
The mean eGFR was 61 mL/min/1.73 m². In 49% of patients, eGFR was < 60 mL/min/1.73 m², in 23% it was < 45 mL/min/1.73 m², and in 3% it was < 30 mL/min/1.73 m².
Dapagliflozin was superior to placebo in reducing the incidence of the primary composite endpoint of cardiovascular death, hospitalization for heart failure, or urgent heart failure visit (HR 0.82 [95% CI 0.73, 0.92]; p = 0.0008) (Figure 3).
Figure 3. Time to first occurrence of the primary composite endpoint of cardiovascular death, hospitalization for heart failure, or urgent heart failure visit
An urgent heart failure visit was defined as an unplanned, urgent physician visit, for example, in an emergency department, requiring treatment for acute worsening of heart failure (excluding an increase in dose of oral diuretics).
At-risk patients are the number of patients at risk at the beginning of the time period.
Figure 4 shows the contribution of the three components of the primary composite endpoint to the treatment effect.
Figure 4. Treatment effect for the primary composite endpoint and its components
An urgent heart failure visit was defined as an unplanned, urgent physician visit, for example, in an emergency department, requiring treatment for acute worsening of heart failure (excluding an increase in dose of oral diuretics).
The number of first events for individual components represents the actual number of first events for each component and does not sum to the number of events in the composite endpoint.
Event rate is the number of patients with the event per 100 patient-years of follow-up.
Data on cardiovascular death, presented here as a component of the primary endpoint, were also analyzed with formal control of type I error as a secondary endpoint.
Dapagliflozin was superior to placebo in reducing the total number of events related to heart failure (defined as first and recurrent hospitalizations for heart failure or urgent heart failure visits) and cardiovascular death. In the dapagliflozin group, 815 such events occurred, compared to 1,057 in the placebo group (hazard ratio 0.77 [95% CI 0.67, 0.89]; p = 0.0003).
The benefit of dapagliflozin treatment on the primary endpoint compared to placebo was observed in subgroups of patients with LVEF ≤ 49%, 50–59%, and ≥ 60%. Effects in other key subgroups, categorized by, for example, age, sex, NYHA class, NT-proBNP level, presence or absence of acute status, and presence or absence of type 2 diabetes, were also consistent.
Patient-reported outcomes – Heart Failure Symptoms
Compared to placebo, treatment with dapagliflozin provided statistically significant benefit in heart failure symptoms, as measured by change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) at 8 months (odds ratio 1.11 [95% CI 1.03, 1.21]; p = 0.0086). The result was influenced by both frequency and severity of symptoms.
In responder analyses, the proportion of patients who experienced moderate (≥ 5 points) or large (≥ 14 points) worsening in KCCQ-TSS score from baseline at 8 months was lower in the dapagliflozin treatment group; moderate worsening occurred in 24.1% of patients receiving dapagliflozin and 29.1% of patients receiving placebo (odds ratio 0.78 [95% CI 0.64, 0.95]). Large worsening occurred in 13.5% of patients in the dapagliflozin group and 18.4% in the placebo group (odds ratio 0.70 [95% CI 0.55, 0.88]). Proportions of patients with small or moderate improvement (≥ 13 points) or large improvement (≥ 17 points) did not differ between treatment groups.
Heart Failure in DAPA-HF and DELIVER Trials
Based on a combined analysis of the DAPA-HF and DELIVER trials, dapagliflozin compared to placebo resulted in a HR of 0.78 (95% CI 0.72, 0.85) for the composite endpoint of cardiovascular death, hospitalization for heart failure, or urgent heart failure visit, p < 0.0001. The treatment effect was consistent across the entire LVEF range without attenuation of effect according to LVEF.
According to results from a pre-specified combined analysis of DAPA-HF and DELIVER, dapagliflozin, compared to placebo, reduced the risk of cardiovascular death (HR 0.85 [95% CI 0.75, 0.96], p = 0.0115). Both trials contributed to the assessment of efficacy.
Chronic Kidney Disease
The Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial was an international, multicenter, randomized, double-blind, placebo-controlled study involving patients with chronic kidney disease (CKD) with eGFR from ≥ 25 to ≤ 75 mL/min/1.73 m² and albuminuria (UACR from ≥ 200 to ≤ 5000 mg/g), designed to evaluate the effect of dapagliflozin compared to placebo added to standard of care on the incidence of a composite renal endpoint — sustained reduction in eGFR of ≥ 50%, end-stage renal disease (ESRD) (defined as sustained eGFR < 15 mL/min/1.73 m², chronic dialysis treatment, or kidney transplantation), or death due to cardiovascular or renal disease.
Of the 4,304 participants, 2,152 patients were randomized to receive 10 mg dapagliflozin and 2,152 to placebo; the median follow-up was 28.5 months. Treatment continued even if eGFR fell below 25 mL/min/1.73 m² during the study and could continue if dialysis became necessary.
The mean age of the study population was 61.8 years, and 66.9% of participants were male. At baseline, the mean eGFR was 43.1 mL/min/1.73 m², and the median UACR was 949.3 mg/g. In 44.1% of patients, eGFR was between 30 and < 45 mL/min/1.73 m², and in 14.5%, eGFR was < 30 mL/min/1.73 m². Type 2 diabetes was present in 67.5% of patients. Patients received standard therapy; 97.0% received treatment with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB).
The trial was stopped early for efficacy based on a recommendation from the independent data monitoring committee prior to the planned analysis. Dapagliflozin was superior to placebo in preventing the primary composite endpoint — sustained reduction in eGFR of ≥ 50%, development of ESRD, or death due to renal or cardiovascular disease. According to the Kaplan-Meier curve for time to first occurrence of the primary composite endpoint, the treatment effect was evident from 4 months and persisted throughout the study (Figure 5).
Figure 5. Time to first occurrence of the primary composite endpoint — sustained reduction in eGFR of ≥ 50%, development of end-stage renal disease, or death due to renal or cardiovascular disease
At-risk patients are the number of patients at risk at the beginning of the study period.
All four components of the primary composite endpoint contributed individually to the treatment effect. Dapagliflozin also reduced the risk of the renal composite endpoint — sustained reduction in eGFR of ≥ 50%, ESRD, or death due to renal disease — and the composite endpoint of cardiovascular death and hospitalization for heart failure. Treatment with dapagliflozin improved overall survival in patients with chronic kidney disease, with a significant reduction in all-cause mortality (Figure 6).
Figure 6. Treatment effects on primary and secondary composite endpoints, their individual components, and all-cause mortality
The number of first events for individual components represents the actual number of first events for each component and does not sum to the number of events in the composite endpoint.
Event rate is presented as the number of participants with events per 100 patient-years of follow-up.
Hazard ratio estimates are not provided for subgroups with fewer than 15 total events in both groups.
The benefits of dapagliflozin treatment in patients with chronic kidney disease and type 2 diabetes were consistent with those in patients without type 2 diabetes. Dapagliflozin reduced the primary composite endpoint — sustained reduction in eGFR of ≥ 50%, development of ESRD, or death due to renal or cardiovascular disease — with HR 0.64 (95% CI 0.52; 0.79) in patients with type 2 diabetes and 0.50 (95% CI 0.35; 0.72) in patients without type 2 diabetes.
The benefits of dapagliflozin over placebo for the primary endpoint were also consistent across other key subgroups, including subgroups by eGFR, age, sex, and region.
Children
Type 2 Diabetes
In a clinical trial involving patients aged 10–24 years with type 2 diabetes, 39 patients were randomized to dapagliflozin 10 mg as add-on therapy to metformin, insulin, or a combination of metformin and insulin, and 33 patients to placebo. At randomization, 74% of patients were under 18 years of age.
The adjusted mean change from baseline in HbA1c in the dapagliflozin group relative to placebo at week 24 was –0.75% (95% CI –1.65; 0.15). In the age group < 18 years, the adjusted mean change in HbA1c in the dapagliflozin group relative to placebo was –0.59% (95% CI –1.66; 0.48). In the age group ≥ 18 years, the adjusted mean change in HbA1c from baseline was –1.52% in the dapagliflozin group (n = 9) and 0.17% in the placebo group (n = 6). Efficacy and safety were similar to those observed in the adult population receiving dapagliflozin. Safety and tolerability were further confirmed during a 28-week treatment extension study.
Heart Failure and Chronic Kidney Disease
The European Medicines Agency has deferred the obligation to submit the results of studies with dapagliflozin in one or more subsets of pediatric patients for the prevention of cardiovascular complications in patients with chronic heart failure and for the treatment of chronic kidney disease (see section "Children" for use in pediatric patients).
Pharmacokinetics.
Absorption
Dapagliflozin was rapidly and well absorbed after oral administration. Maximum plasma concentrations (Cmax) of dapagliflozin were generally reached within 2 hours after dosing in the fasting state. The geometric mean values of Cmax and AUCτ of dapagliflozin at steady state after administration of dapagliflozin 10 mg once daily were 158 ng/mL and 628 ng·h/mL, respectively. The absolute bioavailability of dapagliflozin after oral administration of the 10 mg dose is 78%. Administration with a high-fat meal reduced Cmax of dapagliflozin by 50% and prolonged Tmax by approximately 1 hour, but did not affect AUC compared to administration in the fasting state. These changes are not considered clinically significant. Therefore, the medicinal product Forxiga can be administered independently of food intake.
Distribution
Dapagliflozin is approximately 91% bound to plasma proteins. Protein binding of the drug was not altered by various disease states (e.g., renal or hepatic impairment). The mean volume of distribution of dapagliflozin at steady state was 118 L.
Metabolism
Dapagliflozin is extensively metabolized, primarily to dapagliflozin 3-O-glucuronide, an inactive metabolite. Dapagliflozin 3-O-glucuronide or other metabolites do not contribute to glucose-lowering effects. Formation of dapagliflozin 3-O-glucuronide is mediated by UGT1A9, an enzyme in the liver and kidneys, and CYP-mediated metabolism did not play a significant role in clearance in humans.
Elimination
The mean terminal half-life (t1/2) of dapagliflozin in plasma was 12.9 hours in healthy study participants after a single oral dose of 10 mg dapagliflozin. The mean total systemic clearance of dapagliflozin after intravenous administration was 207 mL/min.
Dapagliflozin and related metabolites are primarily eliminated via urinary excretion, with less than 2% of dapagliflozin excreted unchanged. After administration of a 50 mg dose of [14C]-dapagliflozin, 96% of the dose was recovered: 75% in urine and 21% in feces. Approximately 15% of the dose was excreted unchanged in feces.
Linearity
The effect of dapagliflozin increased proportionally with increasing doses of dapagliflozin in the range of 0.1 to 500 mg, and its pharmacokinetics did not change over time with repeated daily dosing for up to 24 weeks.
Special Patient Populations
Renal Impairment
Mean systemic exposure to dapagliflozin at steady state (20 mg dapagliflozin once daily for 7 days) in patients with type 2 diabetes and mild, moderate, or severe renal impairment (defined by plasma clearance of iohexol) was 32%, 60%, and 87% higher, respectively, compared to patients with type 2 diabetes and normal renal function. Daily urinary glucose excretion at steady-state drug concentrations was highly dependent on renal function and was 85, 52, 18, and 11 g/day in patients with type 2 diabetes and normal renal function or mild, moderate, or severe renal impairment, respectively. The effect of hemodialysis on dapagliflozin exposure is unknown.
The effect of reduced renal function on systemic exposure was evaluated using a population pharmacokinetic model. Based on prior findings, AUC values predicted by the model were higher in patients with chronic kidney disease compared to those with normal renal function and did not differ significantly between patients with chronic kidney disease with or without type 2 diabetes.
Hepatic Impairment
In patients with mild or moderate hepatic impairment (Child-Pugh class A and class B), mean Cmax and AUC values of dapagliflozin were 12% and 36% higher, respectively, compared to healthy control subjects. These differences are not considered clinically significant. In patients with severe hepatic impairment (Child-Pugh class C), mean Cmax and AUC values of dapagliflozin were 40% and 67% higher, respectively, compared to healthy control subjects.
Geriatric Patients (≥ 65 years)
In patients under 70 years of age, no clinically significant increase in drug exposure based solely on age was observed. However, increased drug exposure may be expected due to age-related decline in renal function. Insufficient data are available to draw conclusions about exposure in patients over 70 years of age.
Children
The pharmacokinetics and pharmacodynamics (glucosuria) in children with type 2 diabetes aged 10–17 years were similar to those observed in adults with type 2 diabetes.
Sex
The mean AUCss of dapagliflozin in women is estimated to be approximately 22% higher than in men.
Race
No clinically significant differences in systemic drug exposure were observed between Caucasian, African, or Asian populations.
Body Weight
Dapagliflozin exposure decreased with increasing body weight. Therefore, patients with low body weight may have slightly increased drug exposure, and patients with high body weight may have slightly reduced drug exposure. However, differences in exposure were not considered clinically significant.
Clinical characteristics.
Indications.
Type 2 diabetes mellitus
Forxiga is indicated in adults and children aged 10 years and older for the treatment of inadequately controlled type 2 diabetes mellitus as an adjunct to diet and exercise:
- as monotherapy when use of metformin is considered inappropriate due to intolerance to the medicinal product;
- in combination with other medicinal products for the treatment of type 2 diabetes mellitus.
For study results on combination therapies, effects on glycaemic control, cardiovascular and renal outcomes, and population studies, see sections "Special warnings and precautions for use", "Interaction with other medicinal products and other forms of interaction", and "Pharmacodynamics".
Heart failure
Forxiga is indicated in adults for the treatment of symptomatic chronic heart failure.
Chronic kidney disease
Forxiga is indicated in adults for the treatment of chronic kidney disease.
Contraindications.
Hypersensitivity to the active substance or to any of the excipients.
Interaction with other medicinal products and other forms of interaction.
Pharmacodynamic interactions
Diuretics
The use of dapagliflozin may enhance the diuretic effect of thiazide and loop diuretics and may also increase the risk of dehydration and hypotension (see section "Special warnings and precautions for use").
Insulin and insulin secretagogues
Insulin and insulin secretagogues, such as sulfonylurea medicinal products, may cause hypoglycaemia. Therefore, when used in combination with dapagliflozin in patients with type 2 diabetes mellitus, it may be appropriate to use lower doses of insulin or insulin secretagogues to reduce the risk of hypoglycaemia (see sections "Dosage and administration" and "Undesirable effects").
Pharmacokinetic interactions
Dapagliflozin is primarily metabolized via glucuronidation mediated by UDP-glucuronosyltransferase 1A9 (UGT1A9).
In vitro studies have shown that dapagliflozin does not inhibit the cytochrome P450 (CYP) isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4, and does not induce CYP1A2, CYP2B6, or CYP3A4. Therefore, dapagliflozin is not expected to alter the metabolic clearance of concomitantly administered medicinal products metabolized by these enzymes.
Effect of other medicinal products on dapagliflozin
Drug interaction studies conducted in healthy volunteers, primarily using single doses, indicate 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 drug-metabolizing transporters and enzymes), a 22% reduction in systemic exposure (AUC) of dapagliflozin was observed, but without clinically significant effect on daily urinary glucose excretion. Dose adjustment is not recommended. Clinically significant effects with other inducers (e.g., carbamazepine, phenytoin, phenobarbital) are not expected.
Following co-administration of dapagliflozin with mefenamic acid (an inhibitor of UGT1A9), a 55% increase in systemic exposure of dapagliflozin was observed, but without clinically significant effect on daily urinary glucose excretion. Dose adjustment is not recommended.
Effect of dapagliflozin on other medicinal products
Dapagliflozin may increase renal elimination of lithium, and lithium blood levels may decrease. After initiating dapagliflozin or changing its dose, serum lithium concentrations should be monitored more frequently. Patients should be referred to the physician who prescribed lithium to monitor serum lithium concentrations.
In drug interaction studies conducted in healthy volunteers primarily using single doses, dapagliflozin did not alter the pharmacokinetics of metformin, pioglitazone, sitagliptin, glimepiride, hydrochlorothiazide, bumetanide, valsartan, digoxin (a P-gp substrate), or warfarin (S-warfarin, a CYP2C19 substrate), or the anticoagulant effects of warfarin as assessed by the international normalized ratio (INR). Co-administration of a single 20 mg dose of dapagliflozin with simvastatin (a CYP3A4 substrate) resulted in a 19% increase in AUC of simvastatin and a 31% increase in AUC of simvastatin acid. The increased exposure to simvastatin and simvastatin acid is not considered clinically significant.
Effect on 1,5-anhydroglucitol (1,5-AG) assay results
Monitoring glycaemic control using the 1,5-AG assay is not recommended, as 1,5-AG levels are unreliable for assessing glycaemic control in patients taking SGLT2 inhibitors. Alternative methods are recommended for monitoring glycaemic control.
Paediatric population
Interaction studies have been conducted only in adult patients.
Special precautions
General warnings
Dapagliflozin should not be used in patients with type 1 diabetes mellitus (see below "Diabetic ketoacidosis").
Renal impairment
Due to limited experience, initiation of dapagliflozin treatment is not recommended in patients with eGFR < 25 mL/min.
The glucose-lowering efficacy of dapagliflozin is dependent on renal function and decreases in patients with eGFR < 45 mL/min, and is likely absent in patients with severe renal impairment (see sections "Dosage and administration", "Pharmacodynamics", and "Pharmacokinetics").
In one study involving patients with type 2 diabetes and moderate renal impairment (eGFR < 60 mL/min), adverse reactions such as increased creatinine levels, increased phosphate levels, increased parathyroid hormone (PTH) levels, and arterial hypotension were observed more frequently in patients receiving dapagliflozin than in those receiving placebo.
Hepatic impairment
Experience with the use of the medicinal product in clinical studies involving patients with hepatic impairment is limited. Exposure to dapagliflozin is increased in patients with severe hepatic impairment (see sections "Dosage and administration" and "Pharmacokinetics").
Use in patients at risk of intravascular volume depletion and/or arterial hypotension
Due to its mechanism of action, dapagliflozin increases diuresis, which may lead to a modest reduction in blood pressure, as observed in clinical studies (see section "Pharmacodynamics"). This effect may be more pronounced in patients with very high blood glucose levels.
Caution should be exercised in patients for whom a drop in blood pressure caused by dapagliflozin may pose a risk, for example, patients with a history of arterial hypotension, patients taking antihypertensive medicinal products, or elderly patients.
In cases of concomitant conditions that may lead to intravascular volume depletion (e.g., gastrointestinal disorders), careful monitoring of the degree of intravascular volume depletion (e.g., physical examination, blood pressure measurement, laboratory tests including hematocrit levels) and electrolyte levels is recommended. Patients who develop intravascular volume depletion should temporarily discontinue treatment with dapagliflozin until volume depletion is corrected (see section "Adverse reactions").
Diabetic ketoacidosis
Cases of rare but serious diabetic ketoacidosis (DKA), including life-threatening and fatal events, have been reported in patients treated with sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors), including dapagliflozin. In several cases, the condition presented atypically, with only moderate increases in blood glucose levels not exceeding 14 mmol/L (250 mg/dL).
If a patient presents with non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, dyspnea, confusion, increased fatigue, or somnolence, the risk of developing diabetic ketoacidosis should be considered. In the presence of such symptoms, regardless of blood glucose levels, the patient should be immediately evaluated for ketoacidosis.
Treatment with dapagliflozin should be immediately discontinued in patients with suspected or diagnosed DKA.
Treatment should be suspended in patients hospitalized for major surgical procedures or serious acute illnesses. In such patients, monitoring of ketone levels is recommended. Measurement of blood ketone levels is preferred over urine ketone testing. Treatment with dapagliflozin may be resumed after ketone levels normalize and the patient's condition stabilizes.
Prior to initiating treatment with dapagliflozin, risk factors in the patient's history that may predispose to ketoacidosis should be considered.
Patients at increased risk of DKA include those with low beta-cell functional reserve (e.g., patients with type 2 diabetes with low C-peptide levels or latent autoimmune diabetes in adults (LADA), or patients with a history of pancreatitis), patients with conditions leading to restricted food intake or severe dehydration, patients on reduced insulin doses, and patients with increased insulin requirements due to acute illness, surgery, or alcohol abuse. SGLT2 inhibitors should be used with caution in such patients.
Data from clinical trials of dapagliflozin in patients with type 1 diabetes indicate that DKA occurs with high frequency. Dapagliflozin should not be used for the treatment of patients with type 1 diabetes mellitus.
Necrotizing fasciitis of the perineum (Fournier's gangrene)
Cases of necrotizing fasciitis of the perineum (also known as Fournier's gangrene) have been reported in women and men receiving SGLT2 inhibitors during the post-marketing period (see section "Adverse reactions"). This is a rare but serious and potentially life-threatening condition requiring urgent surgical intervention and antibiotic therapy.
Patients should be advised to seek medical attention if they develop a combination of symptoms such as pain, tenderness, erythema, or swelling in the genital or perineal area, accompanied by fever or malaise.
It should be noted that necrotizing fasciitis may be preceded by genitourinary infection or perianal abscess. If Fournier's gangrene is suspected, treatment with the medicinal product Forxiga must be discontinued immediately, and appropriate treatment initiated (including antibiotics and surgical debridement of necrotic tissue).
Urinary tract infections
Glucose excretion in urine may be associated with an increased risk of urinary tract infections; therefore, temporary discontinuation of dapagliflozin may be appropriate during treatment of pyelonephritis or urosepsis.
Elderly patients (≥ 65 years)
Elderly patients have a higher risk of developing intravascular volume depletion and are more frequently treated with diuretics.
Elderly patients more frequently have impaired renal function and/or are treated with antihypertensive medicinal products that may affect renal function, such as angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor blockers (ARBs).
The same recommendations regarding renal function apply to elderly patients as to all patients (see sections "Dosage and administration", "Special precautions", "Adverse reactions", and "Pharmacodynamics").
Heart failure
Experience with the use of dapagliflozin in clinical trials in patients with NYHA class IV heart failure is limited.
Infiltrative cardiomyopathy
Studies in patients with infiltrative cardiomyopathy have not been conducted.
Chronic kidney disease
There is no experience with the use of dapagliflozin for the treatment of chronic kidney disease in patients without diabetes who do not have albuminuria. Patients with albuminuria may derive greater benefit from treatment with dapagliflozin.
Elevated hematocrit levels
An increase in hematocrit levels has been observed during treatment with dapagliflozin (see section "Adverse reactions"). Patients with marked increases in hematocrit levels require monitoring and evaluation for underlying hematological disorders.
Lower limb amputations
In long-term ongoing clinical trials with other SGLT2 inhibitors in patients with type 2 diabetes, an increased number of lower limb amputations (primarily toe amputations) was observed. It is unknown whether this is a class effect. It is important to advise patients with diabetes on standard preventive foot care, as recommended for all diabetic patients.
Interpretation of urine laboratory tests
Patients receiving the medicinal product Forxiga will have positive urine glucose test results due to the mechanism of action of the drug.
Lactose
The tablets contain lactose. This medicinal product should not be used in patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption.
Use during pregnancy or breastfeeding
Pregnancy
There are no data on the use of dapagliflozin in pregnant women. Animal studies in rats revealed a toxic effect of the drug on kidney development during a period corresponding to the second and third trimesters of human pregnancy. Therefore, dapagliflozin is not recommended during the second and third trimesters of pregnancy.
If pregnancy is confirmed, treatment with dapagliflozin should be discontinued.
Breastfeeding
It is unknown whether dapagliflozin and/or its metabolites are excreted in human breast milk. Available data from pharmacological/toxicological studies have demonstrated excretion of dapagliflozin/metabolites into milk and pharmacologically mediated effects in offspring during lactation. Risk to the newborn/infant cannot be excluded. Dapagliflozin should not be used during breastfeeding.
Fertility
The effect of dapagliflozin on human fertility has not been studied. In male and female animals, dapagliflozin did not affect fertility at any dose tested.
Effect on ability to drive and use machines
The medicinal product Forxiga has no effect or negligible effect on the ability to drive vehicles or operate machinery. Patients should be warned of the risk of hypoglycemia when dapagliflozin is used in combination with sulfonylureas or insulin.
Method of Administration and Dosage
Dosage
Type 2 Diabetes Mellitus
The recommended dose of dapagliflozin is 10 mg once daily.
When dapagliflozin is used in combination with insulin or insulin secretagogues such as sulfonylureas, consideration should be given to using lower doses of insulin or insulin secretagogues to reduce the risk of hypoglycemia (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Side Effects").
Heart Failure
The recommended dose of dapagliflozin is 10 mg once daily.
Chronic Kidney Disease
The recommended dose of dapagliflozin is 10 mg once daily.
Special Patient Populations
Patients with Renal Impairment
Dose adjustment based on renal function is not required.
Due to limited experience, initiation of dapagliflozin treatment is not recommended in patients with eGFR < 25 mL/min.
In patients with type 2 diabetes mellitus, the glucose-lowering efficacy of dapagliflozin decreases when glomerular filtration rate (eGFR) is < 45 mL/min and is likely absent in patients with severe renal impairment. Therefore, if eGFR is below 45 mL/min, additional hypoglycemic therapy should be considered for patients with type 2 diabetes who require further glycemic control (see sections "Special Precautions", "Side Effects", "Pharmacodynamics", and "Pharmacokinetics").
Patients with Hepatic Impairment
No dose adjustment is required for patients with mild or moderate hepatic impairment. For patients with severe hepatic impairment, a starting dose of 5 mg is recommended. If the medicinal product is well tolerated, the dose may be increased to 10 mg (see sections "Special Precautions" and "Pharmacokinetics").
Elderly Patients (≥ 65 years)
Dose adjustment based on age is not required.
Method of Administration
The medicinal product Forxiga should be taken orally once daily at any time of the day, regardless of meals. Tablets should be swallowed whole.
Children
For the treatment of type 2 diabetes mellitus in children aged 10 years and older, dose adjustment of the medicinal product is not required (see sections "Pharmacodynamics" and "Pharmacokinetics"). There are no data on the use of the medicinal product in children under 10 years of age.
The safety and efficacy of dapagliflozin for the treatment of heart failure or chronic kidney disease in pediatric patients aged < 18 years have not yet been established. Data are lacking.
Overdose
Dapagliflozin did not demonstrate any signs of toxicity in healthy study participants following single oral doses up to 500 mg (50 times higher than the maximum recommended human dose). Glucosuria was observed in these participants over a dose-dependent period of time (at least 5 days for the 500 mg dose), without cases of dehydration, hypotension, or electrolyte imbalance, and without clinically significant effect on the QTc interval. The incidence of hypoglycemia was similar to that in the placebo group. In clinical studies using doses up to 100 mg once daily (10 times the maximum recommended human dose) administered for 2 weeks to healthy participants and patients with type 2 diabetes, the incidence of hypoglycemia was slightly higher than in the placebo group but was not dose-dependent. The incidence of adverse reactions, including dehydration or hypotension, was similar to that in the placebo group; clinically significant dose-dependent changes in laboratory parameters, including serum electrolyte levels and renal function biomarkers, were not observed.
In case of overdose, appropriate supportive treatment should be initiated based on the patient's clinical condition. Elimination of dapagliflozin by hemodialysis has not been studied.
Adverse Reactions
Summary of Safety Profile
Type 2 Diabetes Mellitus
In clinical studies of type 2 diabetes, more than 15,000 patients received treatment with dapagliflozin.
The primary assessment of safety and tolerability was conducted in a pre-specified pooled analysis of 13 short-term (up to 24 weeks) placebo-controlled trials involving 2360 patients receiving dapagliflozin 10 mg and 2295 patients receiving placebo.
In the clinical trial evaluating the cardiovascular effects of dapagliflozin in patients with type 2 diabetes (DECLARE study, see section "Pharmacodynamics"), 8574 patients received dapagliflozin 10 mg and 8569 received placebo, with a mean exposure duration of 48 months. In total, there were 30,623 patient-years of exposure to dapagliflozin.
The most commonly reported adverse reaction during clinical trials was genital infections.
Heart Failure
In the study evaluating the cardiovascular effects of dapagliflozin in patients with heart failure and reduced ejection fraction (DAPA-HF study), 2368 patients received 10 mg dapagliflozin and 2368 received placebo, with a median follow-up of 18 months. The patient population included individuals with and without type 2 diabetes, as well as patients with eGFR ≥ 30 mL/min/1.73 m². In the study evaluating the cardiovascular effects of dapagliflozin in patients with heart failure and left ventricular ejection fraction > 40% (DELIVER), 3126 study participants received dapagliflozin 10 mg and 3127 received placebo. The mean duration of treatment was 27 months. The study population included patients with and without type 2 diabetes, as well as patients with eGFR ≥ 25 mL/min/1.73 m².
The overall safety profile of dapagliflozin in patients with heart failure was consistent with the known safety profile of dapagliflozin.
Chronic Kidney Disease
In the study evaluating the effects of dapagliflozin on the kidneys in patients with chronic kidney disease (DAPA-CKD study), 2149 patients received 10 mg dapagliflozin and 2149 received placebo, with a median follow-up of 27 months. The study population included patients with and without type 2 diabetes, with eGFR from ≥ 25 to ≤ 75 mL/min/1.73 m² and albuminuria (urine albumin-to-creatinine ratio [UACR] ≥ 200 and ≤ 5000 mg/g). Treatment was continued if eGFR decreased below 25 mL/min/1.73 m².
The overall safety profile of dapagliflozin in patients with chronic kidney disease was consistent with the known safety profile of dapagliflozin.
List of Adverse Reactions
The adverse reactions listed below were identified in placebo-controlled clinical trials. None of these reactions were found to be dose-dependent. Adverse reactions are classified by frequency and by organ system. Frequency categories were defined according to the following criteria: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).
Table 6. Adverse Reactions in Placebo-Controlled Studies and Post-Marketing Experience
| System organ |
Very common |
Common* |
Uncommon** |
Rare |
Very rare |
| Infections and infestations |
Vulvovaginitis, balanitis and associated genital infections*,b,c Urinary tract infection*,b,d |
Fungal infection** |
Necrotizing fasciitis of the perineum (Fournier's gangrene)b, j |
||
| Metabolism and nutrition disorders |
Hypoglycemia (when used in combination with SU or insulin)b |
Reduction in extracellular fluid volumeb,є Thirst** |
Diabetic ketoacidosis (during use in type 2 diabetes)b,j,i |
||
| Nervous system disorders |
Dizziness |
||||
| Gastrointestinal disorders |
Constipation** Dry mouth** |
||||
| Skin and subcutaneous tissue disorders |
Rashz |
Angioedema |
|||
| Musculoskeletal and connective tissue disorders |
Back pain* |
||||
| Renal and urinary disorders |
Dysuria Polyuria*,e |
Nocturia** |
Tubulointerstitial nephritis |
||
| Reproductive system and breast disorders |
Itching in the vulvar and vaginal area** Itching in the genital area** |
||||
| Investigations |
Increased hematocrit Decreased creatinine renal clearance during initial treatmentb Dyslipidemiaє |
Increased blood creatinine levels during initial treatmentb Elevated blood urea levels** Decreased body weight** |
a The data in the Table are from a period of up to 24 weeks (short-term data), regardless of rescue medication for increased or decreased blood glucose levels.
b Additional information can be found in the corresponding sections below.
c Genital infections including vulvovaginitis, balanitis and related genital infections include the following pre-specified preferred terms: vulvovaginal fungal infection, vaginal infection, balanitis, genital fungal infection, vulvovaginal candidiasis, vulvovaginitis, candidal balanitis, genital candidiasis, genital infection, male genital infection, penile infection, vulvitis, bacterial vaginitis, vulvar abscess.
d Urinary tract infections include the following preferred terms, listed in order of frequency: urinary tract infection, cystitis, Escherichia urinary tract infection, urogenital infection, pyelonephritis, trigonitis, urethritis, kidney infection, prostatitis.
e Volume depletion includes the following pre-specified preferred terms: dehydration, hypovolemia, hypotension.
f Polyuria includes the following preferred terms: pollakiuria, polyuria, increased urine output.
g The mean change from baseline in hematocrit was 2.30 % with dapagliflozin 10 mg compared to –0.33 % with placebo. Hematocrit values > 55 % were observed in 1.3 % of patients receiving dapagliflozin 10 mg compared to 0.4 % of patients receiving placebo.
h The mean percent change from baseline with dapagliflozin 10 mg compared to placebo was: total cholesterol 2.5 % vs. 0.0 %; high-density lipoprotein cholesterol (HDL-C) 6.0 % vs. 2.7 %; low-density lipoprotein cholesterol (LDL-C) 2.9 % vs. –1.0 %; triglycerides –2.7 % vs. –0.7 %.
i See section "Special warnings and precautions for use".
j The adverse reaction was identified during post-marketing surveillance. The following preferred terms related to rash, listed in order of frequency in clinical trials, are: rash, generalized rash, rash with pruritus, macular rash, maculopapular rash, pustular rash, vesicular rash, erythematous rash. In active- and placebo-controlled clinical trials (dapagliflozin, N = 5936; all controls, N = 3403), the incidence of rash was similar with dapagliflozin (1.4 %) and all control medications (1.4 %).
k This was reported in a cardiovascular outcomes trial in patients with type 2 diabetes (DECLARE). The frequency is based on an annualized rate.
* Observed in ≥ 2 % of patients and ≥ 1 % more and at least 3 cases more frequent in patients receiving dapagliflozin 10 mg compared to placebo.
** Investigator-assessed as possibly or definitely related to study treatment and observed in ≥ 0.2 % of patients and ≥ 0.1 % more and at least 3 cases more frequent in patients receiving dapagliflozin 10 mg compared to placebo.
Description of selected adverse reactions
Vulvovaginitis, balanitis and related genital infections
In 13 pooled safety studies, vulvovaginitis, balanitis and related genital infections occurred in 5.5 % and 0.6 % of subjects receiving dapagliflozin 10 mg and placebo, respectively. Most infections were mild to moderate in severity, responded to initial courses of standard therapy, and rarely led to discontinuation of dapagliflozin. These infections occurred more frequently in women (8.4 % and 1.2 % with dapagliflozin and placebo, respectively), and the likelihood of recurrent infection was higher in patients with a history of such problems.
In the DECLARE clinical trial, the number of patients with serious adverse reactions of genital infections was low and balanced: 2 patients in each dapagliflozin and placebo group.
In the DAPA-HF trial, no patient reported serious adverse effects due to genital infections in the dapagliflozin group, while one such case was observed in the placebo group. In the dapagliflozin group, 7 (0.3 %) patients had adverse reactions leading to discontinuation due to genital infections, and none in the placebo group. In the DELIVER trial, one serious adverse event due to genital infection was recorded in each treatment group (< 0.1 %). In the dapagliflozin group, adverse events leading to discontinuation due to genital infections occurred in 3 patients (0.1 %). In the placebo group, no such patient was reported.
In the DAPA-CKD trial, serious adverse reactions due to genital infections were reported in 3 (0.1 %) patients in the dapagliflozin group, and none in the placebo group. In the dapagliflozin group, three (0.1 %) patients experienced adverse reactions leading to discontinuation due to genital infections, and no such adverse reactions were reported in the placebo group. No serious adverse events or events leading to discontinuation due to genital infections were reported in any patient without diabetes.
Cases of phimosis/acquired phimosis associated with genital infections have been reported, and in some cases circumcision was required.
Necrotizing fasciitis of the perineum (Fournier's gangrene)
Cases of Fournier's gangrene have been reported in the post-marketing period in patients taking SGLT2 inhibitors, including dapagliflozin (see section "Special warnings and precautions for use").
In the DECLARE trial assessing cardiovascular outcomes in 17,160 patients with type 2 diabetes and a median exposure of 48 months, a total of 6 cases of Fournier's gangrene were recorded: one in the dapagliflozin treatment group and five in the placebo group.
Hypoglycemia
The frequency of hypoglycemia depended on the type of background therapy used in the clinical trials of diabetes.
In trials of dapagliflozin as monotherapy, as add-on to metformin, or as add-on to sitagliptin (with or without metformin), the frequency of minor hypoglycemic episodes was similar (< 5 %) across treatment groups, including placebo, over treatment periods of up to 102 weeks. In all trials, major hypoglycemic episodes were infrequent and occurred at comparable frequencies in the dapagliflozin and placebo treatment groups. In trials combining with sulfonylureas and insulin, the frequency of hypoglycemia was higher (see section "Interaction with other medicinal products and other forms of interaction").
In the trial combining with glimepiride, minor hypoglycemic episodes were more frequent at weeks 24 and 48 in the dapagliflozin 10 mg plus glimepiride group (6.0 % and 7.9 %, respectively) compared to the placebo plus glimepiride group (2.1 % and 2.1 %, respectively).
In the trial combining with insulin, episodes of severe hypoglycemia were reported in 0.5 % and 1.0 % of patients receiving dapagliflozin 10 mg and insulin at weeks 24 and 104, respectively, and in 0.5 % of patients receiving placebo and insulin at weeks 24 and 104. At weeks 24 and 104, minor hypoglycemic episodes occurred in 40.3 % and 53.1 % of patients receiving dapagliflozin 10 mg and insulin, and in 34.0 % and 41.6 % of patients receiving placebo and insulin.
In the trial combining with metformin and a sulfonylurea, up to 24 weeks, no episodes of severe hypoglycemia were observed. Minor hypoglycemic episodes occurred in 12.8 % of patients receiving dapagliflozin 10 mg with metformin and a sulfonylurea, and in 3.7 % of patients receiving placebo with metformin and a sulfonylurea.
In the DECLARE clinical trial, no increased risk of severe hypoglycemia was observed with dapagliflozin therapy compared to placebo. Episodes of severe hypoglycemia were reported in 58 (0.7 %) patients receiving dapagliflozin and 83 (1.0 %) patients receiving placebo.
In the DAPA-HF trial, events of severe hypoglycemia were reported in 4 (0.2 %) patients in both the dapagliflozin and placebo groups. In the DELIVER trial, events of severe hypoglycemia were recorded in 6 (0.2 %) patients in the dapagliflozin group and in 7 (0.2 %) patients in the placebo group, but occurred only in patients with type 2 diabetes.
In the DAPA-CKD trial, episodes of severe hypoglycemia were reported in 14 (0.7 %) patients in the dapagliflozin group and in 28 (1.3 %) patients in the placebo group, and occurred only in patients with type 2 diabetes.
Volume depletion
In 13 pooled safety studies, reactions indicating volume depletion (including reports of dehydration, hypovolemia, and hypotension) occurred in 1.1 % and 0.7 % of patients receiving dapagliflozin 10 mg and placebo, respectively; serious adverse reactions occurred in < 0.2 % of patients and were equally distributed between the dapagliflozin 10 mg and placebo treatment groups (see section "Special warnings and precautions for use").
In the DECLARE clinical trial, the number of patients with events indicating volume depletion was equally distributed between treatment groups: 213 (2.5 %) and 207 (2.4 %) in the dapagliflozin and placebo groups, respectively. Serious adverse reactions occurred in 81 (0.9 %) and 70 (0.8 %) in the dapagliflozin and placebo groups, respectively. Events were generally equally distributed between treatment groups across subgroups by age, diuretic use, blood pressure, and use of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs). In patients with baseline estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m², 19 serious adverse reactions indicating volume depletion were observed in the dapagliflozin group and 13 in the placebo group.
In the DAPA-HF trial, the number of patients with events indicating volume depletion was 170 (7.2 %) in the dapagliflozin group and 153 (6.5 %) in the placebo group. Fewer patients in the dapagliflozin group had serious symptoms indicating volume depletion (23 [1.0 %]) compared to the placebo group (38 [1.6 %]). Results were similar regardless of baseline diabetes status and baseline eGFR. In the DELIVER trial, the number of patients with serious symptoms of hypovolemia was 35 (1.1 %) in the dapagliflozin group and 31 (1.0 %) in the placebo group.
In the DAPA-CKD trial, the number of patients with events indicating volume depletion was 120 (5.6 %) in the dapagliflozin group and 84 (3.9 %) in the placebo group. In the dapagliflozin group, 16 (0.7 %) patients had serious symptoms indicating volume depletion compared to 15 (0.7 %) patients in the placebo group.
Diabetic ketoacidosis in type 2 diabetes
In the DECLARE clinical trial, with a median exposure of 48 months, episodes of DKA occurred in 27 patients in the dapagliflozin 10 mg group and 12 patients in the placebo group. Observed episodes were evenly distributed over the study period. Among the 27 patients with DKA episodes in the dapagliflozin group, 22 were receiving concomitant insulin therapy during the episode. Precipitating factors for DKA were as expected in the type 2 diabetes population (see section "Special warnings and precautions for use").
In the DAPA-HF trial, DKA cases were recorded in 3 patients with type 2 diabetes in the dapagliflozin group and none in the placebo group. In the DELIVER trial, DKA cases were recorded in 2 patients with type 2 diabetes in the dapagliflozin group and none in the placebo group.
In the DAPA-CKD trial, no episodes of DKA were reported in the dapagliflozin group, while DKA episodes were recorded in 2 patients with type 2 diabetes in the placebo group.
Urinary tract infections
In 13 pooled safety studies, urinary tract infections occurred more frequently in patients receiving dapagliflozin 10 mg compared to those receiving placebo (4.7 % vs. 3.5 %, respectively; see section "Special warnings and precautions for use"). Most infections were mild to moderate in severity, responded to initial courses of standard therapy, and rarely led to premature discontinuation of dapagliflozin. These infections occurred more frequently in women, and the likelihood of recurrent infection was higher in patients with a history of such problems.
In the DECLARE clinical trial, serious episodes of urinary tract infections were less frequent with dapagliflozin 10 mg than with placebo: 79 (0.9 %) episodes vs. 109 (1.3 %) episodes, respectively.
In the DAPA-HF trial, the number of patients with serious adverse reactions due to urinary tract infections was 14 (0.6 %) in the dapagliflozin group and 17 (0.7 %) in the placebo group. Five (0.2 %) patients discontinued the study due to urinary tract infections in both the dapagliflozin and placebo groups. In the DELIVER trial, the number of patients with serious adverse events due to urinary tract infections was 41 (1.3 %) in the dapagliflozin group and 37 (1.2 %) in the placebo group. These adverse events led to discontinuation of treatment in 13 patients (0.4 %) in the dapagliflozin group and 9 patients (0.3 %) in the placebo group.
In the DAPA-CKD trial, the number of patients with serious adverse events due to urinary tract infections was 29 (1.3 %) in the dapagliflozin group and 18 (0.8 %) in the placebo group. Adverse reactions leading to discontinuation due to urinary tract infections occurred in 8 (0.4 %) patients in the dapagliflozin group and 3 (0.1 %) patients in the placebo group. The number of patients without diabetes who reported serious adverse events due to urinary tract infections or adverse events leading to discontinuation due to urinary tract infections was similar between treatment groups (6 [0.9 %] vs. 4 [0.6 %] for serious adverse events and 1 [0.1 %] vs. 0 for discontinuation events in the dapagliflozin and placebo groups, respectively).
Increase in creatinine levels
Adverse drug reactions related to increased creatinine levels were grouped (e.g., decreased creatinine renal clearance, renal function impairment, increased blood creatinine, decreased glomerular filtration rate). In 13 pooled safety studies, grouped adverse reactions occurred in 3.2 % and 1.8 % of patients receiving dapagliflozin 10 mg and placebo, respectively. In patients with normal renal function or mild renal impairment (baseline eGFR ≥ 60 mL/min/1.73 m²), these reactions occurred in 1.3 % and 0.8 % of patients receiving dapagliflozin 10 mg and placebo, respectively. These reactions occurred more frequently in patients with baseline eGFR ≥ 30 and < 60 mL/min/1.73 m² (18.5 % with dapagliflozin 10 mg and 9.3 % with placebo).
Further monitoring of patients who experienced renal adverse events showed that most had changes in serum creatinine levels of ≤ 44 µmol/L (≤ 0.5 mg/dL) compared to baseline. Creatinine levels usually increased temporarily during prolonged treatment and returned to normal after discontinuation of therapy.
In the DECLARE clinical trial, particularly in elderly patients and patients with renal impairment (eGFR less than 60 mL/min/1.73 m²), eGFR decreased over time in both treatment groups. After 1 year, mean eGFR was slightly lower, and after 4 years, mean eGFR was slightly higher in the dapagliflozin group compared to the placebo group.
In the DAPA-HF and DELIVER trials, eGFR decreased over time in both the dapagliflozin and placebo groups. In the DAPA-HF trial, the initial decrease in mean eGFR was –4.3 mL/min/1.73 m² in the dapagliflozin group and –1.1 mL/min/1.73 m² in the placebo group. After 20 months, changes in eGFR (compared to baseline) were comparable between study groups: –5.3 mL/min/1.73 m² with dapagliflozin and –4.5 mL/min/1.73 m² with placebo. In the DELIVER trial, the decrease in mean eGFR at 1 month was –3.7 mL/min/1.73 m² in the dapagliflozin group and –0.4 mL/min/1.73 m² in the placebo group. After 24 months, changes in eGFR (compared to baseline) were comparable: –4.2 mL/min/1.73 m² in the dapagliflozin group and –3.2 mL/min/1.73 m² in the placebo group.
In the DAPA-CKD trial, eGFR decreased over time in both the dapagliflozin and placebo groups. The initial decrease (day 14) in mean eGFR was –4.0 mL/min/1.73 m² in the dapagliflozin group and –0.8 mL/min/1.73 m² in the placebo group. After 28 months, the change in eGFR from baseline was –7.4 mL/min/1.73 m² in the dapagliflozin group and –8.6 mL/min/1.73 m² in the placebo group.
Children
The safety profile of dapagliflozin observed in a clinical trial involving children aged 10 years and older with type 2 diabetes (see section "Pharmacokinetics") was similar to that observed in trials involving adults.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.
Shelf life.
3 years.
Storage conditions.
Store in a place inaccessible to children at a temperature not exceeding 25 °C.
Packaging.
10 tablets in a blister, 3 blisters in a cardboard box.
Prescription status.
Prescription only.
Manufacturer.
AstraZeneca UK Limited/AstraZeneca UK Limited.
Manufacturer's address.
Silk Road Business Park, Macclesfield, SK10 2NA, United Kingdom/Silk Road Business Park, Macclesfield, SK10 2NA, United Kingdom.