Forxiga 10mg 30 tablets

Forxiga Dapagliflozin Film-coated tablets Each tablet contains 12.30 mg of dapagliflozin propanediol, equivalent to 10 mg of dapagliflozin. Excipients: Tablet core: Microcrystalline cellulose (E460i) Lactose Crospovidone (E1201) Silicon dioxide (E551) Magnesium stearate (E470b) Coating composition: Polyvinyl alcohol (E1203) Titanium dioxide (E171) Macrogol 3350 (E1521) Talc (E553b) Iron yellow oxide (E172) Yellow, biconvex, approximately 1.1 x 0.8 cm on the diagonal, diamond-shaped, film-coated tablets, engraved with "10" on one side and "1428" on the other. See blog: Forxiga — a drug for controlling blood glucose levels Therapeutic indications Type 2 diabetes mellitus Forxiga is indicated in adults for the treatment of inadequately controlled type 2 diabetes mellitus as an adjunct to diet and exercise, as monotherapy when metformin is not suitable due to intolerance, and in combination with other medicinal products for the treatment of type 2 diabetes mellitus. For information on study results with combination therapies, drug effects on glycemic control, cardiovascular and renal events, and studied populations, see "Special warnings and precautions for use", "Interactions with other medicinal products and other forms of interaction", "Pharmacodynamic effects". 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. Dosage and method of administration Dosage Type 2 diabetes mellitus The recommended dose is 10 mg of dapagliflozin once daily. When dapagliflozin is used in combination with insulin or insulin secretagogues, such as sulfonylureas, a lower dose of insulin or its secretagogue may be used to reduce the risk of hypoglycemia (see "Interactions with other medicinal products and other forms of interaction", "Adverse effects"). Heart failure The recommended dose is 10 mg of dapagliflozin once daily. Chronic kidney disease The recommended dose is 10 mg of dapagliflozin once daily. Special populations Renal impairment No dose adjustment is required based on renal function. Due to limited experience, initiating treatment with dapagliflozin is not recommended in patients with an eGFR < 25 mL/min. In patients with type 2 diabetes mellitus, the glucose-lowering efficacy of dapagliflozin decreases when the glomerular filtration rate (GFR) is < 45 mL/min and the effect is unlikely to be present in patients with severe renal impairment. Therefore, if the GFR falls below 45 mL/min, additional glucose-lowering treatment should be considered in patients with type 2 diabetes mellitus if better glycemic control is needed (see "Special warnings and precautions for use", "Adverse effects", "Pharmacodynamic effects", "Pharmacokinetic effects"). Hepatic impairment No dose adjustment is necessary in patients with mild to moderate hepatic impairment. In case of severe hepatic impairment, the initial recommended dose is 5 mg. If well tolerated, the dose can be increased to 10 mg (see "Special warnings and precautions for use", "Pharmacokinetic effects"). Elderly patients (≥ 65 years) There is no recommendation for dose adjustment based on age. Pediatric population The safety and efficacy of dapagliflozin in children aged 0 to < 18 years have not yet been established. Data are not available. Method of administration Forxiga can be taken orally once daily, at any time of the day, with or without food. The tablets should be swallowed whole. Contraindications Hypersensitivity to the active substance or to any of the excipients. Special warnings and precautions for use General Dapagliflozin should not be used in patients with type 1 diabetes mellitus (see "Special warnings and precautions for use" - "Diabetic ketoacidosis"). Renal impairment Due to limited experience, initiating treatment with dapagliflozin is not recommended in patients with an eGFR < 25 mL/min. The glucose-lowering efficacy of dapagliflozin is dependent on renal function and decreases in patients with GFR < 45 mL/min and may not be present in cases of severe renal impairment (see "Dosage and method of administration", "Pharmacodynamic effects", "Pharmacokinetic effects"). In one study in patients with type 2 diabetes mellitus and moderate renal impairment (GFR < 60 mL/min), more patients treated with dapagliflozin developed adverse events compared to placebo - increased creatinine, phosphorus, parathyroid hormone (PTH), and hypotension. Hepatic impairment There is limited clinical trial experience in patients with hepatic impairment. Dapagliflozin exposure increases in patients with severe hepatic impairment (see "Dosage and method of administration", "Pharmacokinetic effects"). Use in patients at increased risk of volume depletion and/or hypotension Due to its mechanism of action, dapagliflozin increases diuresis, which may lead to a slight decrease in blood pressure, as observed in studies (see "Pharmacodynamic effects"). This may be more pronounced in cases of very high blood glucose concentrations. Caution is advised in patients receiving antihypertensive treatment, those with hypotension, or the elderly. In the presence of concomitant conditions that may cause volume depletion (e.g., gastrointestinal illness), intensive monitoring of volume status (e.g., physical examination, blood pressure measurement, laboratory tests including hematocrit and electrolytes) is recommended. Temporary discontinuation of dapagliflozin therapy is recommended in patients experiencing volume depletion until the condition is corrected (see "Adverse effects"). Diabetic ketoacidosis Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have been reported during treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitors, including dapagliflozin. In some cases, the presentation of the condition was atypical with only moderately elevated blood glucose levels below 14 mmol/L (250 mg/dL). The risk of DKA should be considered in the presence of a combination of non-specific symptoms such as nausea, vomiting, anorexia, abdominal pain, increased thirst, difficulty breathing, confusion, unusual fatigue, or somnolence. Patients should be assessed for ketoacidosis immediately upon the onset of such symptoms, regardless of blood glucose level. In patients in whom DKA is suspected or confirmed, treatment with dapagliflozin should be discontinued immediately. Treatment should be discontinued in patients hospitalized for major surgery or acute serious illnesses. Ketone monitoring is recommended in these patients. Blood ketone levels are preferred over urine ketone levels. Dapagliflozin treatment may be resumed when ketone levels are normalized and the patient's condition has stabilized. Before initiating dapagliflozin, factors in the patient's history that may predispose to ketoacidosis should be considered. Patients at higher risk of DKA include those with a low beta-cell reserve (e.g., patients with type 2 diabetes mellitus with low C-peptide or latent autoimmune diabetes in adults (LADA) or patients with a history of pancreatitis) or those with conditions that lead 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 these patients. Resumption of SGLT2 inhibitor treatment in patients who developed diabetic ketoacidosis during SGLT2 inhibitor treatment is not recommended until the actual precipitating factor has been identified and resolved. In studies of type 1 diabetes mellitus where dapagliflozin was used, diabetic ketoacidosis was frequently observed. Dapagliflozin should not be used for the treatment of patients with type 1 diabetes. Urinary tract infections Glucose excretion in the urine may be associated with urinary tract infections; therefore, temporary discontinuation of dapagliflozin may be considered during treatment for pyelonephritis or urosepsis. Elderly patients (≥ 65 years) Elderly patients are at higher risk of volume depletion and are more likely to be treated with diuretics. Elderly patients are more likely to have impaired renal function and/or be taking antihypertensive medicinal products that may cause changes in renal function, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs). Recommendations related to renal function are the same for elderly and other patients (see "Dosage and method of administration", "Special warnings and precautions for use", "Adverse effects", "Pharmacodynamic effects"). Heart failure Experience with dapagliflozin in NYHA class IV is limited. Infiltrative cardiomyopathy Patients with infiltrative cardiomyopathy have not been studied. 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 benefit more from dapagliflozin treatment. Urine laboratory testing Due to its mechanism of action, urine glucose tests will be positive in patients taking Forxiga. Lactose The tablets contain anhydrous lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. Interactions with other medicinal products and other forms of interaction Pharmacodynamic interactions Diuretic medicinal products Dapagliflozin may enhance the diuretic effect of thiazide and loop diuretics and increase the risk of dehydration and hypotension (see "Special warnings and precautions for use"). Insulin and insulin secretagogues Insulin and insulin secretagogues, such as sulfonylureas, cause hypoglycemia. Therefore, when used in combination with dapagliflozin, a lower dose of these agents may be necessary to reduce the risk of hypoglycemia (see "Dosage and method of administration", "Adverse effects"). Pharmacokinetic interactions Dapagliflozin is primarily metabolized by glucuronide conjugation, mediated by UDP-glucuronosyltransferase (UGT1A9). In vitro studies showed that dapagliflozin did not inhibit cytochrome P450 isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, nor did it induce isoforms CYP1A2, CYP2B6, or CYP3A4. Therefore, dapagliflozin is not expected to affect the metabolic clearance of concomitant medicinal products that are metabolized by these enzymes. Effect of other medicinal products on dapagliflozin Interaction studies in healthy volunteers, primarily receiving a single dose of the medicinal product, showed that metformin, pioglitazone, sitagliptin, glimepiride, voglibose, hydrochlorothiazide, bumetanide, valsartan, or simvastatin did not affect the pharmacokinetics of dapagliflozin. After co-administration of dapagliflozin and rifampicin, an inducer of various active transporters and enzymes involved in drug metabolism, a 22% decrease in systemic exposure (AUC) of dapagliflozin was observed, without a clinically significant effect on the amount of glucose excreted by the kidneys. Dose adjustment is not recommended. Clinically significant effects are not expected with co-administration with other inducers (e.g., carbamazepine, phenytoin, phenobarbital). Co-administration of dapagliflozin and mefenamic acid (a UGT1A9 inhibitor) resulted in a 55% increase in systemic exposure of dapagliflozin, without a clinically significant effect on the amount of glucose excreted by the kidneys over 24 hours. Dose adjustment is not recommended. Effect of dapagliflozin on other medicinal products Dapagliflozin may increase the renal excretion of lithium, and blood lithium levels may decrease. Monitoring of serum lithium concentrations is recommended after initiation of dapagliflozin treatment and upon dose adjustment. The patient should be referred to a physician specializing in lithium for monitoring of serum lithium concentrations. In interaction studies in healthy volunteers, primarily receiving a single dose of the medicinal product, dapagliflozin did not affect the pharmacokinetics or anticoagulant effect of metformin, pioglitazone, sitagliptin, glimepiride, hydrochlorothiazide, bumetanide, valsartan, digoxin (a P-gp substrate), or warfarin (S-warfarin, a CYP2C9 substrate), as assessed by the international normalized ratio. Co-administration of a single dose of dapagliflozin 20 mg and simvastatin (a CYP3A4 substrate) resulted in a 19% increase in simvastatin AUC and a 31% increase in simvastatin acid AUC. The increased exposure to simvastatin and simvastatin acid is not considered clinically significant. Overlap with quantitative analysis of 1,5-anhydroglucitol (1,5-AG) Monitoring of glycemic control by quantitative analysis of 1,5-AG is not recommended, as 1,5-AG levels are unreliable for assessing glycemic control in patients taking SGLT2 inhibitors. Alternative methods are preferred for monitoring glycemic control. Pediatric population Interaction studies have only been conducted in adults. Fertility, pregnancy and lactation Pregnancy There are no data on the use of dapagliflozin in pregnant women. Studies in rats showed toxic effects on the kidneys during the period corresponding to the second and third trimesters of human pregnancy. Therefore, the use of dapagliflozin during the second and third trimesters of pregnancy is not recommended. If pregnancy is detected, treatment with dapagliflozin should be discontinued. Breastfeeding It is unknown whether dapagliflozin and/or its metabolites are excreted in breast milk. Animal pharmacokinetic/toxicological data have shown excretion of dapagliflozin/metabolites in milk, as well as pharmacological effects on offspring. The risk to newborns/infants cannot be excluded. Dapagliflozin should not be used during breastfeeding. Fertility The effect of dapagliflozin on human fertility has not been studied. Dapagliflozin did not affect fertility at any of the tested doses in male and female rats. Ability to drive and use machines Forxiga has no significant influence on the ability to drive and use machines. Patients should be warned of the risk of hypoglycemia when dapagliflozin is used in combination with sulfonylureas or insulin. Adverse effects Summary of safety profile Type 2 diabetes mellitus In clinical studies related to type 2 diabetes, over 15,000 patients were treated 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 duration) placebo-controlled studies involving 2360 subjects in the 10 mg dapagliflozin group and 2295 in the placebo group. In the study evaluating cardiovascular outcomes of dapagliflozin in patients with type 2 diabetes mellitus (DECLARE study, see "Pharmacodynamic effects"), 8,574 patients received 10 mg dapagliflozin and 8,569 received placebo, with a median exposure time of 48 months. Total exposure to dapagliflozin was 30,623 patient-years. The most frequently reported adverse reaction in various clinical studies was genital infections. Heart failure In the study evaluating the effect of dapagliflozin on cardiovascular outcomes in patients with heart failure with reduced ejection fraction (DAPA-HF study), 2,368 patients were treated with 10 mg dapagliflozin and 2,368 patients with placebo over a median treatment period of 18 months. The patient population included patients with and without type 2 diabetes mellitus, and patients with eGFR ≥ 30 mL/min/1.73 m². In the study evaluating cardiovascular outcomes with dapagliflozin, DELIVER, conducted in patients with heart failure with left ventricular ejection fraction > 40%, 3,126 patients were treated with 10 mg dapagliflozin, and 3,127 patients received placebo, with a median observation time of 27 months. The patient population included patients with and without type 2 diabetes mellitus, and 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 effect of dapagliflozin on renal outcomes in patients with chronic kidney disease (DAPA-CKD), 2,149 patients were treated with 10 mg dapagliflozin and 2,149 patients with placebo, with a median exposure period of 27 months. The patient population included patients with type 2 diabetes and without diabetes, with eGFR ranging from ≥ 25 to ≤ 75 mL/min/1.73 m² and albuminuria (urine albumin-to-creatinine ratio [UACR] ≥ 200 to ≤ 5000 mg/g). Treatment continued until eGFR fell 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 table below presents adverse reactions reported in placebo-controlled clinical studies and post-marketing experience. None were dose-dependent. The frequency of adverse reactions is presented by frequency and organ system class (SOC). Frequency is presented with the following gradations: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), and frequency not known (cannot be estimated from the available data). Table 1. Adverse reactions in placebo-controlled clinical studies a and post-marketing experience System and organ class | Very common | Common* | Uncommon** | Rare Infections and infestations | | Vulvovaginitis, balanitis and related genital infections b,c | Urinary tract infection b | Fungal infection ** Metabolism and nutrition disorders | Hypoglycemia (when taken with sulfonylurea derivatives or insulin) b | | Volume depletion b,e | Thirst ** | Diabetic ketoacidosis (when used in type 2 diabetes mellitus) b,i,l Nervous system disorders | | Dizziness | | Gastrointestinal disorders | | Constipation ** | Dry mouth ** | Skin and subcutaneous tissue disorders | | Rash k | | Musculoskeletal and connective tissue disorders | | Back pain * | | Renal and urinary disorders | | Dysuria | Polyuria*, f | Nocturia * Reproductive system and breast disorders | | | Vulvovaginal pruritus ** | Genital pruritus ** Investigations | | Increased hematocrit z | Decreased renal clearance of creatinine upon initiation of treatment b | Dyslipidemia th | Increased serum creatinine upon initiation of treatment **, b | Increased blood urea ** | Weight loss ** a - The table presents data on the use of the medicinal product up to 24 weeks (short-term therapy) regardless of the use of additional hypoglycemic medicinal products. b - See the relevant subsection below for additional information. c - Vulvovaginitis, balanitis and related genital infections include, for example, the following predefined terms: vulvovaginal fungal infection, vaginal infection, balanitis, genital fungal infection, vulvovaginal candidiasis, vulvovaginitis, candidal balanitis, genital candidiasis, genital infections, male genital infections, penile infections, vulvitis, bacterial vaginitis, vulvar abscess. d - Urinary tract infection includes the following terms listed by frequency: urinary tract infection, cystitis, urinary tract infection due to Escherichia, genitourinary tract infection, pyelonephritis, trigonitis, kidney infection, and prostatitis. e - Volume depletion includes, for example, the following predefined terms: dehydration, hypovolemia, hypotension. f - Polyuria includes the terms: pollakiuria, polyuria, and increased diuresis. z - The mean change in hematocrit from baseline was 2.30% in the 10 mg dapagliflozin group and 0.33% in the placebo group. Hematocrit values > 55% were reported in 1.3% of subjects treated with 10 mg dapagliflozin and 0.4% in the placebo group. th - In the 10 mg dapagliflozin and placebo groups, the mean percentage changes from baseline were: total cholesterol 2.5% vs 0.0%; LDL cholesterol; 6.0% vs 2.7%; HDL cholesterol 2.9% vs -1.0%; triglycerides –2.7% vs –0.7%. i - See paragraph "Special warnings and precautions for use". k - Adverse events were identified during post-marketing surveillance. Rash primarily includes the following conditions, listed by frequency of occurrence in clinical studies: rash, generalized rash, pruritic rash, macular rash, maculopapular rash, pustular rash, vesicular and erythematous rash. In placebo-controlled clinical studies, the incidence of rash was similar in the active and placebo treatment groups (dapagliflozin, N=5936, control group, N=3403) (1.4% and 1.4% respectively). l - Reported in the cardiovascular outcomes study in patients with type 2 diabetes mellitus (DECLARE). The frequency is based on annual incidence. * ≥ 2% of patients receiving 10 mg dapagliflozin and ≥ 1% and at least 3 subjects more frequent than in the placebo group. ** Described by the investigator as related or possibly related to the investigational treatment in ≥ 0.2% and ≥ 0.1% of subjects and occurring in at least 3 more subjects with 10 mg dapagliflozin compared to placebo. Description of individual adverse reactions Vulvovaginitis, balanitis and related genital infections In the pooled analysis of 13 safety studies, vulvovaginitis, balanitis, and related genital infections were reported in 5.5% and 0.6% of patients receiving 10 mg dapagliflozin and placebo, respectively. Most infections were mild to moderate: standard initial treatment was effective, leading to rare discontinuation of dapagliflozin. These infections were more common in women (8.4% and 1.2% for dapagliflozin and placebo, respectively), and recurrence was more frequent in patients with a history of these infections. In the DECLARE study, the number of patients with serious adverse events in the form of genital infections was small and balanced: 2 patients in the dapagliflozin group and 2 in the placebo group. In the DAPA-HF study, no patient experienced a serious adverse event related to genital infections in the dapagliflozin group, and there was one case in the placebo group. 7 patients (0.3%) had adverse events leading to discontinuation of the medicinal product due to genital infections in the dapagliflozin group, and no cases in the placebo group. In the DELIVER study, one (< 0.1%) patient in each treatment group experienced a serious adverse event of genital infections. In the dapagliflozin group, 3 (0.1%) patients experienced adverse events leading to discontinuation of treatment due to genital infection, while in the placebo group, none. In the DAPA-CKD study, serious adverse events of genital infections occurred in 3 (0.1%) patients in the dapagliflozin group and none in the placebo group. In the dapagliflozin group, 3 (0.1%) patients experienced an adverse event leading to discontinuation of treatment due to genital infections, and no cases in the placebo group. Serious adverse events of genital infections or adverse events leading to discontinuation of treatment due to genital infections did not occur in any patients without diabetes. Hypoglycemia The incidence of hypoglycemia was dependent on the type of background therapy used in clinical studies involving patients with diabetes mellitus. In the dapagliflozin monotherapy study, combined therapy with metformin for up to 102 weeks, the incidence of mild hypoglycemia episodes was similar (< 5%) across treatment groups, including placebo. Severe hypoglycemia episodes were reported infrequently in all studies, with similar incidence in the dapagliflozin and placebo groups. In studies where sulfonylurea and insulin therapy were added, the incidence of hypoglycemia was higher (see "Interactions with other medicinal products and other forms of interaction"). In the study with added glimepiride, minor hypoglycemia episodes were more frequently reported at weeks 24 and 48 in the group using 10 mg dapagliflozin and glimepiride (6.0% and 7.9%) compared to the placebo and glimepiride group (2.1% and 2.1%). In the study with added insulin, major hypoglycemia episodes were reported in 0.5% and 1.0% of subjects treated with 10 mg dapagliflozin and insulin at weeks 24 and 104, and in 0.5% of subjects treated with placebo and insulin. Minor hypoglycemia episodes were reported in 40.3% and 53.1% of the dapagliflozin and insulin group and 34% and 41.6% of the placebo and insulin group at weeks 24 and 104. In the study with added metformin and sulfonylurea, no major hypoglycemia episodes were reported by week 24. Minor hypoglycemia episodes were observed in 12.8% of subjects receiving 10 mg dapagliflozin plus metformin and sulfonylurea, and in 3.7% of subjects receiving placebo plus metformin and sulfonylurea. In the DECLARE study, no increased risk of severe hypoglycemia was observed with dapagliflozin compared to placebo, with 58 (0.7%) patients treated with dapagliflozin and 83 (1.0%) patients treated with placebo. In the DAPA-HF study, major hypoglycemia events were reported in 4 patients (0.2%) in both the dapagliflozin and placebo treatment groups. In the DELIVER study, major hypoglycemia events were reported in 6 (0.2%) patients in the dapagliflozin group and 7 (0.2%) in the placebo group. Major hypoglycemia events were reported only in patients with type 2 diabetes mellitus. In the DAPA-CKD study, major hypoglycemia events were reported in 14 (0.7%) patients in the dapagliflozin group and 28 (1.3%) patients in the placebo group, and were reported only in patients with type 2 diabetes mellitus. Volume depletion In the pooled analysis of 13 safety studies, signs of volume depletion (including reports of dehydration, hypovolemia, or hypotension) were observed in 1.1% and 0.7% of patients receiving 10 mg dapagliflozin and placebo, respectively; serious events were observed in < 0.2% of patients and were comparable between the 10 mg dapagliflozin and placebo groups (see "Special warnings and precautions for use"). In the DECLARE study, the number of patients with events indicative of volume depletion was balanced between treatment groups: 213 (2.5%) and 207 (2.4%) in the dapagliflozin and placebo groups, respectively. Events were generally balanced between treatment groups in subgroups stratified by age, diuretic use, blood pressure, and ACE-I/ARB therapy. In patients with baseline eGFR < 60 mL/min/1.73 m², the number of serious adverse events indicative of volume depletion was 19 in the dapagliflozin group and 13 in the placebo group. In the DAPA-HF study, the number of patients with events indicative of hypovolemia was 170 (7.2%) in the dapagliflozin group and 153 (6.5%) in the placebo group. There were a small number of patients with serious symptoms indicative of hypovolemia in the dapagliflozin group (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 study, the number of patients with serious events with symptoms indicative of volume depletion was 35 (1.1%) in the dapagliflozin group and 31 (1.0%) in the placebo group. In the DAPA-CKD study, the number of patients with events indicative of volume depletion was 120 (5.6%) in the dapagliflozin group and 84 (3.9%) in the placebo group. 16 (0.7%) patients in the dapagliflozin group experienced serious events with symptoms indicative of volume depletion, and 15 (0.7%) patients in the placebo group experienced similar events. Diabetic ketoacidosis in type 2 diabetes mellitus In the DECLARE study, with a median exposure of 48 months, diabetic ketoacidosis events were reported in 27 patients in the 10 mg dapagliflozin group and 12 patients in the placebo group. The distribution of events was consistent throughout the study period. Of the 27 patients with diabetic ketoacidosis in the dapagliflozin group, 22 were on insulin therapy at the time of the event. Factors predisposing to diabetic ketoacidosis in the type 2 diabetes mellitus population were as expected. In the DAPA-HF study, cases of DKA were reported in 3 patients with type 2 diabetes mellitus in the dapagliflozin group and none in the placebo group. In the DELIVER study, DKA events were reported in 2 patients with type 2 diabetes mellitus in the dapagliflozin group and in no patients in the placebo group. In the DAPA-CKD study, DKA events were not reported in any patients in the dapagliflozin group and were reported in 2 patients with type 2 diabetes mellitus in the placebo group. Urinary tract infections In the pooled safety analysis of 13 studies, urinary tract infections were reported more frequently with 10 mg dapagliflozin than with placebo (4.7% vs 3.5%; see "Special warnings and precautions for use"). Most infections were mild to moderate. Standard initial treatment was effective, leading to rare discontinuation of dapagliflozin. These infections were more common in women, and recurrence was more frequent in patients with a history of these infections. In the DECLARE study, serious adverse events of urinary tract infections were less frequent with 10 mg dapagliflozin compared to placebo, with 79 (0.9%) events for dapagliflozin and 109 (1.3%) events for placebo. In the DAPA-HF study, the number of patients with serious adverse events of urinary tract infections was 14 (0.6%) in the dapagliflozin group and 17 (0.7%) in the placebo group. Discontinuation of the investigational medicinal product due to urinary tract infections occurred in 5 (0.2%) patients in each of the dapagliflozin and placebo groups. In the DELIVER study, the number of patients with serious adverse events of urinary tract infections was 41 (1.3%) in the dapagliflozin group and 37 (1.2%) in the placebo group. 13 (0.4%) patients in the dapagliflozin group experienced adverse events leading to discontinuation of treatment due to urinary tract infections, and 9 (0.3%) patients in the placebo group. In the DAPA-CKD study, the number of patients with serious adverse events of urinary tract infections was 29 (1.3%) in the dapagliflozin group and 18 (0.8%) in the placebo group. 8 (0.4%) patients in the dapagliflozin group experienced an adverse event leading to discontinuation of treatment due to urinary tract infections, and 3 (0.1%) patients in the placebo group experienced a similar event. The number of patients without diabetes who experienced serious adverse events of urinary tract infections or adverse events leading to discontinuation of the medicinal product due to urinary tract infections was similar between treatment groups (6 [0.9%] and 4 [0.6%] for serious adverse events, and 1 [0.1%] and 0 for events leading to discontinuation, in the dapagliflozin and placebo groups, respectively). Increased creatinine Adverse reactions related to increased creatinine were grouped (e.g., decreased renal creatinine clearance, renal impairment, increased blood creatinine levels, and decreased glomerular filtration rate). In the pooled safety group of 13 studies, this grouping of reactions was reported in 3.2% and 1.8% of patients treated with 10 mg dapagliflozin and placebo, respectively. In patients with normal renal function or mild impairment (baseline GFR ≥ 60 mL/min/1.73 m²), this group of reactions was reported in 1.3% with 10 mg dapagliflozin and 0.8% with placebo. These reactions were more frequent in patients with baseline GFR ≥ 30 and < 60 mL/min/1.73 m² (18.5% for 10 mg dapagliflozin vs 9.3% for placebo). Subsequent evaluation of patients who experienced renal-related adverse events revealed that most had serum creatinine changes of < 44 µmol/L (≤ 0.5 mg/dL) compared to baseline. Increased creatinine was usually transient with continued treatment and reversible upon discontinuation. In the DECLARE study, which included elderly patients and patients with renal impairment (eGFR < 60 mL/min/1.73 m²), eGFR decreased over time in both treatment groups. The mean eGFR was slightly lower in the dapagliflozin group compared to the placebo group after 1 year, and slightly higher after 4 years. In the DAPA-HF and DELIVER studies, eGFR decreased over time in both the dapagliflozin and placebo groups. In the DAPA-HF study, the initial mean decrease in 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. At month 20, the change in eGFR from baseline was similar between the two treatment groups: -5.3 mL/min/1.73 m² for dapagliflozin and -4.5 mL/min/1.73 m² for placebo. In the DELIVER study, the mean decrease in eGFR per 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. At 24 months, the change in eGFR from baseline was similar between treatment groups: -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 study, eGFR decreased over time in both the dapagliflozin and placebo groups. The initial mean decrease in eGFR (Day 14) was -4.0 mL/min/1.73 m² in the dapagliflozin group and -0.8 mL/min/1.73 m² in the placebo group. At month 28, 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. Overdose In healthy subjects, oral doses up to 500 mg (50 times the maximum recommended human dose) of dapagliflozin showed no toxicity. In these subjects, urinary glucose was dose-dependent (500 mg for at least 5 days), no dehydration, hypotension, or electrolyte imbalance was reported, and no clinically significant effect on the QTc interval was observed. The incidence of hypoglycemia was similar to placebo. In clinical studies in healthy subjects and subjects with type 2 diabetes mellitus, a dose of 100 mg once daily (10 times the maximum recommended human dose) was used for 2 weeks; the incidence of hypoglycemia was slightly higher compared to placebo and was not dose-dependent. The incidence of adverse events, including dehydration and hypotension, was similar to placebo, and no clinically significant changes in laboratory parameters, including serum electrolytes and renal function biomarkers, were observed. In case of overdose, appropriate supportive treatment should be initiated according to the patient's clinical status. The excretion of dapagliflozin by hemodialysis has not been studied. Pharmacological properties Pharmacotherapeutic group: Antidiabetic agents. Sodium-glucose cotransporter 2 (SGLT2) inhibitors. ATC code: A10BK01 Mechanism of action Dapagliflozin is a potent (inhibition constant (Ki: 0.55 nM), selective, reversible inhibitor of SGLT2. Inhibition of SGLT2 by dapagliflozin reduces glucose reabsorption from the glomerular filtrate in the renal proximal tubule and is accompanied by reduced sodium reabsorption, leading to urinary glucose excretion and osmotic diuresis. Consequently, dapagliflozin increases sodium delivery to the distal tubule, which enhances tubuloglomerular feedback and reduces intraglomerular pressure. This, in combination with osmotic diuresis, reduces volume overload, lowers blood pressure, and also reduces preload and afterload, which may have beneficial effects on myocardial remodeling and diastolic function, and preserve renal function. The effects of dapagliflozin on the heart and kidneys are not solely dependent on its glucose-lowering effect and are not limited to patients with diabetes, as shown in the DAPA-HF, DELIVER, and DAPA-CKD studies. Other effects include increased hematocrit and reduced body weight. By inhibiting glucose transport in the kidneys, dapagliflozin reduces its reabsorption in the renal tubules, leading to glucose excretion by the kidneys. Glucose excretion (glucosuric effect) is observed from the first dose of the medicinal product, is maintained for the following 24 hours, and continues throughout the course of therapy. The amount of glucose excreted by the kidneys via this mechanism depends on its concentration in the blood and the glomerular filtration rate (GFR). Therefore, in subjects with normal blood glucose levels, dapagliflozin has a low propensity to cause hypoglycemia. Dapagliflozin does not impair normal endogenous glucose production in response to hypoglycemia. The action of dapagliflozin is not dependent on insulin secretion or sensitivity. Improvement in beta-cell function (HOMA beta-cell test) has been observed in clinical studies of dapagliflozin. SGLT2 is selectively expressed in the kidney. Dapagliflozin does not affect other glucose transporters responsible for glucose transport into peripheral tissues and exhibits 1400 times greater selectivity for SGLT2 than for SGLT1, which is the main transporter responsible for glucose absorption in the intestine. Pharmacodynamic effects Increased urinary glucose excretion was observed in healthy volunteers and patients with type 2 diabetes mellitus after administration of dapagliflozin. In patients with type 2 diabetes mellitus, administration of dapagliflozin 10 mg/day for 12 weeks resulted in approximately 70 g of glucose excreted by the kidneys per day (equivalent to 280 kcal/day). Glucose-lowering excretion was observed in patients with type 2 diabetes mellitus receiving dapagliflozin 10 mg/day for up to 2 years. The urinary glucose excretion with dapagliflozin also causes osmotic diuresis and increases urine volume in patients with type 2 diabetes mellitus. In patients with type 2 diabetes mellitus receiving dapagliflozin 10 mg/day, the increase in urine volume was maintained for 12 weeks and was approximately 375 mL per day. The increase in urine volume was accompanied by a small and transient increase in sodium excretion by the kidneys, which did not cause changes in its concentration in blood serum. Urinary acid secretion also transiently increased (for 3-7 days) and was accompanied by a decrease in urinary acid concentration in serum. By week 24, the decrease in serum urinary acid concentration ranged from -48.3 to -18.3 µmol/L (-0.87 to -0.33 mg/dL). Clinical efficacy and safety Type 2 diabetes mellitus Improvement of glycemic control and reduction of cardiovascular and renal morbidity and mortality are essential components of type 2 diabetes treatment. Fourteen double-blind, randomized, controlled clinical trials involving 4,737 subjects with type 2 diabetes mellitus were conducted to evaluate the glycemic efficacy and safety of Forxiga; 4,273 subjects in these trials were treated with dapagliflozin. Twelve trials had a treatment duration of 24 weeks, 8 trials were extended from 24 to 80 weeks (total trial duration 104 weeks), one trial had a duration of 52 weeks, extended from 52 to 104 weeks (total duration 208 weeks). The mean duration of diabetes was 1.4-16.9 years. Fifty percent (50%) had mild renal impairment and 11% had moderate renal impairment. Thirty-one percent (51%) of subjects were male, 84% were Caucasian, 8% Asian, 4% Black, and 4% belonged to other racial groups. In eighty-one percent (81%) of subjects, the body mass index (BMI) was ≥ 27. In addition, two 12-week, placebo-controlled studies were conducted in patients with inadequately controlled type 2 diabetes mellitus and hypertension. To assess the impact on cardiovascular and renal events, a cardiovascular outcomes study (DECLARE) was conducted comparing 10 mg dapagliflozin to placebo in 17,160 patients with type 2 diabetes mellitus, with or without established cardiovascular disease. 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 Forxiga monotherapy in subjects with inadequately controlled type 2 diabetes mellitus. Dapagliflozin once daily resulted in a statistically significant reduction in HbA1c (p < 0.0001) compared to placebo (Table 2). In the extension period, the HbA1c reduction was maintained for 102 weeks (-0.61% and -0.17% for the adjusted mean change from baseline for 10 mg dapagliflozin and placebo, respectively). Table 2. Results of a 24-week placebo-controlled study of dapagliflozin monotherapy (LOCF a ) Monotherapy | Dapagliflozin 10 mg | Placebo N b | 70 | 75 HbA1c (%) | | Baseline (mean) | 8.01 | 7.79 Change from baseline c | -0.89 | -0.23 Difference from placebo c (95% CI) | -0.66 * (-0.96, -0.36) | Subjects (%) who achieved: HbA1c < 7% | 50.8 § | 31.6 Weight (kg) | | Baseline (mean) | 94.13 | 88.77 Change from baseline c | -3.16 | -2.19 Difference from placebo c (95% CI) | -0.97 (-2.20, 0.25) | a LOCF: Last Observation Carried Forward (until survival of surviving subjects) b All randomized subjects who received at least one dose of the double-blind investigational medicinal product during the short-term double-blind period c Last square implies change from baseline * p-value < 0.0001 versus placebo § Not assessed for statistical significance due to the sequential testing procedure of secondary endpoints Combination therapy In a 52-week, actively controlled, efficacy-matching study (with 52 and 104-week extension periods), Forxiga was evaluated as add-on therapy to metformin compared to glipizide (sulfonylurea) used as add-on therapy to metformin in subjects with inadequate glycemic control (HbA1c > 6.5% and ≤ 10%). The results showed a similar mean reduction in HbA1c from baseline compared to glipizide, demonstrating comparable efficacy to the respective active substance (Table 3). 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 was -0.10% for dapagliflozin and 0.20% for glipizide. At 52, 104, and 208 weeks, a significantly lower proportion of subjects in the dapagliflozin group (3.5%, 4.3%, and 5.0%) experienced at least one episode of hypoglycemia compared to the glipizide group (40.8%, 47.0%, and 50.0%). The proportion of subjects remaining 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, respectively. Table 3. Results at 52 weeks (LOCF a ) in an actively controlled study comparing dapagliflozin and glipizide as add-on to metformin Parameter | Dapagliflozin + Metformin | Glipizide + Metformin N b | 400 | 401 HbA1c (%) | | Baseline (mean) | 7.69 | 7.74 Change from baseline c | -0.52 | -0.52 Difference from dapagliflozin + metformin c (95% CI) | | 0.00 d (-0.11, 0.11) Weight (kg) | | Baseline (mean) | 88.44 | 87.60 Change from baseline c | -3.22 | 1.44 Difference from dapagliflozin + metformin c (95% CI) | | -4.65 * (-5.14, -4.17) a LOCF: Last Observation Carried Forward b Randomized and treated subjects with at least one efficacy parameter measured at baseline and subsequently c Last squares implies change from baseline d Non-inferiority to glipizide + metformin * p-value < 0.0001 Dapagliflozin, when used as an add-on to metformin, glimepiride, metformin and sulfonylurea, sitagliptin (with or without metformin), or insulin, resulted in a statistically significant reduction in HbA1c compared to placebo (p < 0.0001; Tables 4, 5, and 6) by week 24. The observed HbA1c reduction at week 24 was maintained in combination studies (glimepiride and insulin) with data at 48 weeks (glimepiride) and 104 weeks (insulin). At 48 weeks, the mean change from baseline for 10 mg dapagliflozin and placebo when added to sitagliptin (with or without metformin) was -0.30% and 0.38%, respectively. In the add-on to metformin study, HbA1c reduction was maintained for 102 weeks (-0.78% and 0.02% mean change from baseline for 10 mg and placebo, respectively). At 104 weeks with insulin use (with or without oral glucose-lowering medicinal products), the HbA1c reduction was -0.71% and -0.06% from baseline for 10 mg dapagliflozin and placebo, respectively. At 48 and 104 weeks, the insulin dose remained stable in subjects treated with 10 mg dapagliflozin, averaging 76 IU/day. In the placebo group, there was a mean increase of 10.5 IU/day and 18.3 IU/day at 48 and 104 weeks (average dose 84 and 92 IU/day, respectively). The proportion of subjects remaining in the study at 104 weeks was 72.4% for 10 mg dapagliflozin and 54.8% for placebo. Table 4. Results of 24-week placebo-controlled studies where dapagliflozin was used in combination with metformin or sitagliptin (with or without metformin) Add-on combination | Metformin 1 | DPP-4 inhibitor (sitagliptin 2) ± metformin 1 | Dapagliflozin 10 mg | Placebo | Dapagliflozin 10 mg | Placebo N b | 135 | 137 | 223 | 224 HbA1c (%) | | | | Baseline (mean) | 7.92 | 8.11 | 7.90 | 7.97 Change from baseline c | -0.84 | -0.30 | -0.45 | 0.04 Difference from placebo c (95% CI) | -0.54 * (-0.74, -0.34) | | -0.48 * (-0.62, -0.34) | Subjects (%) who achieved HbA1c < 7% | 40.6 ** | 25.9 | | Change from baseline | | | | Weight (kg) | | | | Baseline (mean) | 86.28 | 87.74 | 91.02 | 89.23 Change from baseline c | -2.86 | -0.89 | -2.14 | -0.26 Difference from placebo c (95% CI) | -1.97 * (-2.63, -1.31) | | -1.89 * (-2.37, -1.40) | 1 Metformin ≥ 1500 mg/day 2 Sitagliptin 100 mg/day a LOCF: Last Observation Carried Forward (for subjects surviving until the last observation) b All randomized subjects who received at least one dose of the double-blind investigational medicinal product during the short-term double-blind period c Last squares implies change from baseline * p-value < 0.0001 versus placebo + oral glucose-lowering medicinal product ** p-value < 0.05 versus placebo + oral glucose-lowering medicinal product Table 5. Results of 24-week placebo-controlled studies of dapagliflozin used in combination with sulfonylurea (glimepiride) or with metformin and sulfonylurea Add-on combination | Sulfonylurea (glimepiride 1) | Sulfonylurea + Metformin 2 | Dapagliflozin 10 mg | Placebo | Dapagliflozin 10 mg | Placebo N a | 151 | 145 | 108 | 108 HbA1c (%) b | | | | Baseline (mean) | 8.07 | 8.15 | 8.08 | 8.24 Change from baseline c | -0.82 | -0.13 | -0.86 | -0.17 Difference from placebo c (95% CI) | -0.68 * (-0.86, -0.51) | | -0.69 * (-0.89, -0.49) | Subjects (%) who achieved HbA1c < 7% (LOCF) d | 31.7 * | 13.0 | 31.8 * | 11.1 Weight (kg) (LOCF) d | | | | Baseline (mean) | 80.56 | 80.94 | 88.57 | 90.07 Change from baseline c | -2.26 | -0.72 | -2.65 | -0.58 Difference from placebo c (95% CI) | -1.54 * (-2.17, -0.92) | | -2.07 * (-2.79, -1.35) | 1 Glimepiride 4 mg/day; 2 Metformin (immediate or extended-release formulation) ≥ 1500 mg/day plus maximum tolerated dose of sulfonylurea, which should be at least half of the maximum dose, for at least 8 weeks prior to inclusion a Randomized and treated patients with at least one efficacy parameter measured at baseline and subsequently b Columns 1 and 2, HbA1c analysis using LOCF (see Appendix d); Columns 3 and 4, HbA1c analysis using LRM (see Appendix e) c Last squares implies change from baseline d LOCF: Last Observation Carried Forward (for subjects surviving until the last observation) e LRM: Linear analysis of repeated measurements * p-value < 0.0001 versus placebo + oral glucose-lowering medicinal product Table 6. Results at 24 weeks (LOCF a ) in a placebo-controlled study of dapagliflozin in combination with insulin (with or without oral glucose-lowering medicinal products) Parameter | Dapagliflozin 10 mg + Insulin ± Oral glucose-lowering medicinal products 2 | Placebo + Insulin ± Oral glucose-lowering medicinal products 2 N b | 194 | 193 HbA1c (%) | | Baseline (mean) | 8.58 | 8.46 Change from baseline c | -0.90 | -0.30 Difference from placebo c (95% CI) | -0.60 * (-0.74, -0.45) | Body weight (kg) | | Baseline (mean) | 94.63 | 93.96 Change from baseline c | -1.67 | 0.02 Difference from placebo c (95% CI) | -1.68 * (-2.19, -1.18) | Mean daily dose of insulin (IU) 1 | | Baseline (mean) | 77.96 | 73.96 Change from baseline c | -1.16 | 5.08 Difference from placebo c (95% CI) | -6.23 * (-8.84, -3.63) | Subjects (%) whose mean daily insulin dose was reduced by at least 10% (%) | 19.7 ** | 11.0 a LOCF: Last Observation Carried Forward (until insulin dose increase or on the day of increase as needed) b All randomized subjects who received at least one dose of the double-blind investigational medicinal product during the short-term double-blind period c Last squares implies change from baseline and presence of oral glucose-lowering medicinal product * p-value < 0.0001 versus placebo + insulin ± oral glucose-lowering medicinal product ** p-value < 0.05 versus placebo + insulin ± oral glucose-lowering medicinal product 1 Increase in insulin regimen dose (short-acting, intermediate, and basal insulin) was allowed only in subjects meeting pre-defined FPG criteria. 2 Fifty percent of subjects were on insulin monotherapy at baseline; 50% were on 1 or 2 oral glucose-lowering medicinal products; of the latter group, 80% were on metformin only; 12% were on metformin and sulfonylurea; the remainder were on other oral glucose-lowering medicinal products. In combination with metformin in treatment-naïve patients In two actively controlled 24-week studies, the efficacy and safety of dapagliflozin (5 mg or 10 mg) in combination with metformin were evaluated compared to monotherapy with individual components in 1236 treatment-naïve patients with inadequately controlled type 2 diabetes mellitus (HbA1c ≥ 7.5% and ≤ 12%). The combination of 10 mg dapagliflozin and metformin (2000 mg daily) provided significant improvement in HbA1c compared to individual component use (Table 7), and resulted in greater reduction in fasting plasma glucose (FPG) (compared to individual component use) and body weight reduction (compared to metformin). Table 7. Results of an actively controlled study of combination therapy of dapagliflozin with metformin in treatment-naïve patients at 24 weeks (LOCF a ) Parameter | Dapagliflozin 10 mg + Metformin | Dapagliflozin 10 mg | Metformin N b | 211 | 219 | 208 HbA1c (%) | | | Baseline (mean) | 9.10 | 9.03 | 9.03 Change from baseline c | -1.98 | -1.45 | -1.44 Difference from dapagliflozin c (95%Cl) | | -0.53* (-0.74, -0.32) | -0.54* (-0.75, -0.33) Difference from metformin c (95%Cl) | | | -0.01 (-0.22, -0.20) a. LOCF - Last Observation Carried Forward (for subjects recovered before recovery) b. All randomized patients who received at least one dose of the double-blind investigational medicinal product during the short-term double-blind period. c. Least squares mean arithmetic modified for baseline. * p-value < 0.0001. Combination 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 to dapagliflozin monotherapy and extended-release exenatide monotherapy in subjects with inadequate glycemic control on metformin monotherapy (HbA1c ≥ 8% and ≤ 12%). All treatment groups showed a reduction in HbA1c levels compared to baseline. The group receiving the combination of 10 mg dapagliflozin and extended-release exenatide showed superior reduction in HbA1c from baseline compared to dapagliflozin monotherapy and extended-release exenatide monotherapy (Table 8). Table 8. 28-week study comparing dapagliflozin and extended-release exenatide combination to dapagliflozin monotherapy and extended-release exenatide monotherapy, in combination with metformin (planned treatment patients) Parameter | Dapagliflozin 10 mg once daily + Extended-release exenatide 2 mg once weekly | Dapagliflozin 10 mg once daily + Placebo once weekly | Extended-release exenatide 2 mg once weekly + Placebo once daily N | 228 | 230 | 227 HbA1c (%) | | | Baseline (mean) | 9.29 | 9.25 | 9.26 Change from baseline a | -1.98 | -1.39 | -1.60 Difference in mean change from baseline between combination and active substance monotherapy (95% CI) | -0.59* (-0.84, -0.34) | -0.38** (-0.63, -0.13) Proportion of subjects (%) who achieved HbA1c < 7% | 44.7 | 19.1 | 26.9 Body mass (kg) | | | Baseline (mean) | 92.13 | 90.87 | 89.12 Change from baseline a | -3.55 | -2.22 | -1.56 Difference in mean change from baseline between combination and active substance monotherapy (95% CI) | -1.33* (-2.12, -0.55) | -2.00* (-2.79, -1.20) N=number of patients, CI=confidence interval. a Least squares mean modified for baseline and model of change from baseline values for treatment group using a mixed model for repeated measures (MMRM) with treatment, region, baseline HbA1c group (< 9.0% or ≥ 9.0%), week, and interaction of week by treatment as fixed factors, and baseline as covariate. * p < 0.001, ** p < 0.01. P-values represent modified multiple factor p-values. Data from backup treatment and early discontinuation of investigational medicinal product groups were excluded from the analyses. Fasting plasma glucose level Treatment with 10 mg dapagliflozin, used as monotherapy or as an add-on to metformin, glimepiride, metformin and sulfonylurea, sitagliptin (with or without metformin), or insulin, resulted in a statistically significant reduction in fasting plasma glucose levels (-1.90 to -1.20 mmol/L [-34.2 to -21.7 mg/dL]) compared to placebo (-0.33 to 0.21 mmol/L [-6.0 to 3.8 mg/dL]). This effect was observed from 1 week of treatment and was maintained up to 104 weeks in extended studies. Combination therapy with 10 mg dapagliflozin and extended-release exenatide resulted in a significantly greater reduction in fasting glucose levels at week 28 - 3.66 mmol/L (-65.8 mg/dL), compared to dapagliflozin monotherapy (-2.73 mmol/L [-49.2 mg/dL]) and exenatide monotherapy (-2.54 mmol/L [-45.8 mg/dL]) (p < 0.001). In an exploratory clinical study in patients with diabetes and eGFR ≥ 45 to < 60 mL/min/1.73 m², dapagliflozin treatment showed 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 glucose levels The use of 10 mg dapagliflozin in combination with glimepiride resulted in a statistically significant reduction in 2-hour postprandial glucose levels by week 24, an effect maintained until week 48. Under combination therapy with 10 mg dapagliflozin and extended-release exenatide, a more pronounced reduction in postprandial glucose levels was observed at week 28 compared to monotherapy with either medicinal product. Weight Treatment with 10 mg dapagliflozin, used as an add-on to metformin, glimepiride, metformin and sulfonylurea, sitagliptin (with or without metformin), or insulin, resulted in a statistically significant reduction in weight by week 24 (p < 0.0001, Tables 4 and 5). These effects were maintained in long-term studies. At 48 weeks, the difference in weight between dapagliflozin and sitagliptin (with or without metformin) compared to placebo was -2.2 kg. At 102 weeks, the difference in weight between dapagliflozin and metformin compared to placebo, or dapagliflozin and insulin compared to placebo, was -2.14 and -2.88 kg, respectively. In the actively controlled efficacy-matching study as an add-on to metformin, dapagliflozin resulted in a statistically significant reduction in weight compared to glipizide of -4.65 kg by 52 weeks (p < 0.0001, Table 3), which was maintained at 104 and 208 weeks (-5.06 kg and -4.38 kg, respectively). 10 mg dapagliflozin and extended-release exenatide showed significantly greater reductions in body weight compared to monotherapy with either medicinal product (Table 7). A 24-week study of 182 subjects with diabetes, using dual-energy X-ray absorptiometry (DXA) to assess body composition, revealed reductions in body weight and fat with 10 mg dapagliflozin and metformin compared to placebo, with no reduction in muscle mass and fluid. Treatment with Forxiga and metformin resulted in a reduction of visceral adipose tissue compared to placebo and metformin, as assessed by magnetic resonance imaging. Blood pressure In a pooled analysis of 13 placebo-controlled studies, treatment with 10 mg dapagliflozin by week 24 resulted in a change of -3.7 mm in systolic pressure and -1.8 mm in diastolic pressure compared to baseline, while in the placebo group, these values were -0.05 mm and -0.5 mm, respectively. Treatment with the combination of 10 mg dapagliflozin and extended-release exenatide showed a significantly greater reduction in systolic blood pressure (-4.3 mmHg) at week 28 compared to dapagliflozin monotherapy (-1.8 mmHg, p < 0.05) and extended-release exenatide monotherapy (-1.2 mmHg, p < 0.01). In two 12-week, placebo-controlled studies, 1,062 patients with inadequately controlled type 2 diabetes mellitus and hypertension (despite stable treatment with ACE-I or ARB in 1 study and with ACE-I or ARB plus additional antihypertensive medication in the second study) were treated with 10 mg dapagliflozin or placebo. By week 12, in both studies, the use of 10 mg dapagliflozin and conventional antidiabetic agents resulted in HbA1c improvement and a reduction in placebo-corrected systolic blood pressure by an average of 3.1 and 4.3 mm, respectively. In an exploratory clinical study in patients with diabetes and eGFR ≥ 45 to < 60 mL/min/1.73 m², dapagliflozin treatment showed a reduction in seated systolic blood pressure at week 24: -4.8 mmHg compared to -1.7 mmHg for placebo (p < 0.05). Glycemic control in patients with moderate renal impairment - chronic kidney disease stage 3A (eGFR ≥ 45 to < 60 mL/min/1.73 m²) The efficacy of dapagliflozin was evaluated in an exploratory study in patients with diabetes and eGFR ≥ 45 to < 60 mL/min/1.73 m² with inadequate glycemic control on standard management. Dapagliflozin treatment resulted in reductions in HbA1c and body weight compared to placebo (Table 9). Table 9. Results of a 24-week placebo-controlled study of dapagliflozin in patients with diabetes and eGFR ≥ 45 to < 60 mL/min/1.73 m² | Dapagliflozin a 10 mg | Placebo a | | N b | 159 | 161 HbA1c (%) | | Baseline (mean) | 8.35 | 8.03 Change from baseline b | -0.37 | -0.03 Difference from placebo b (95% CI) | -0.34* (-0.53, -0.15) | Body weight (kg) | | Baseline (mean) | 92.51 | 88.30 Percentage change from baseline c | -3.42 | -2.02 Difference in percentage change from placebo c (95% CI) | -1.43* (-2.15, -0.69) | a 69.4% and 64.0% of patients in the dapagliflozin and placebo groups, respectively, had metformin or metformin hydrochloride as part of usual management. b Least squares mean arithmetic modified for baseline. c Least squares mean arithmetic modified for baseline from the least squares mean. * p<0.001 Patients with baseline HbA1c ≥ 9% In a specific analysis of subjects with baseline HbA1c ≥ 9.0%, monotherapy with 10 mg dapagliflozin and its use in combination with metformin resulted in significant reductions in HbA1c by week 24 (change from baseline: -2.04% and 0.19% for dapagliflozin and placebo, respectively), (change from baseline: -1.32% and 0.53% for dapagliflozin and placebo, respectively). Cardiovascular and renal outcomes The effect of dapagliflozin on cardiovascular events (DECLARE) was an international, multicenter, randomized, double-blind, placebo-controlled clinical trial conducted to compare the effect of dapagliflozin on cardiovascular outcomes to placebo when added to ongoing background therapy. All patients had type 2 diabetes mellitus and at least two additional cardiovascular risk factors (age ≥ 55 years in men or ≥ 60 years in women and one or more of the following: dyslipidemia, hypertension, or current tobacco use) or established cardiovascular disease. Of the 17,160 randomized patients, 6,974 (40.6%) had established cardiovascular disease, and 10,186 (59.4%) did not have established cardiovascular disease. 8,582 patients were randomized to the 10 mg dapagliflozin group and 8,578 to the placebo group, and they were observed for a median of 4.2 years. The mean age of the study population was 63.9 years, 37.4% were female. A total of 22.4% had diabetes for ≤ 5 years, with a median diabetes duration of 11.9 years. The mean HbA1c was 8.3%, and the mean BMI was 32.1 kg/m². At study entry, 10.0% of patients had a history of heart failure. The mean eGFR was 85.2 mL/min/1.73 m², with eGFR < 60 mL/min/1.73 m² in 7.4% of patients and micro- or macroalbuminuria (UACR ≥ 30 to ≤ 300 mg/g or > 300 mg/g, respectively) in 30.3% of patients. The majority of patients (98%) were taking one or more antidiabetic medications at study entry, including metformin (82%), insulin (41%), and sulfonylurea (43%). The primary endpoint was: time to first occurrence of the composite endpoint of cardiovascular death, myocardial infarction, or ischemic stroke (MACE), and time to the composite endpoint of hospitalization for heart failure or death from cardiovascular causes. Secondary endpoints were the renal composite endpoint and all-cause mortality. Major cardiovascular adverse events In terms of reducing the composite endpoint of cardiovascular death, myocardial infarction, and ischemic stroke (one-sided p < 0.001), 10 mg dapagliflozin showed non-inferiority compared to placebo. Heart failure or cardiovascular death. In terms of reducing the composite endpoint of hospitalization for heart failure and death from cardiovascular causes, 10 mg dapagliflozin showed superiority compared to placebo. The difference in treatment efficacy was due to hospitalization for heart failure, while there was no difference in death from cardiovascular causes. The treatment benefit of dapagliflozin compared to placebo was observed in patients with and without established cardiovascular disease, and in patients with and without heart failure at study entry. Results were consistent across all major subgroups (including by age, sex, renal function (eGFR), and region). The reduction in MACE was not superior with dapagliflozin compared to placebo (p=0.172). Renal composite endpoint and all-cause mortality The composite endpoint of nephropathy was not determined by the confirmatory testing procedure. Nephropathy Dapagliflozin reduced the incidence of sustained ≥ 50% eGFR decline, end-stage renal disease, and death from renal or cardiovascular causes. The difference between groups was due to a reduction in renal component events; sustained eGFR decline, end-stage renal disease, and renal death. The relative risk of developing nephropathy (sustained eGFR decline, end-stage renal disease, and renal death) was 0.53 (95% CI 0.43, 0.66) for dapagliflozin compared to placebo. Additionally, dapagliflozin reduced the incidence of new cases of persistent albuminuria (relative risk 0.79 [95% CI 0.72, 0.87]) and more significantly reduced macroalbuminuria (relative risk 1.82 [95% CI 1.51, 2.20]) compared to placebo. Heart failure DAPA-HF study: Heart failure with reduced ejection fraction (LVEF ≤ 40%). Dapagliflozin and prevention of adverse outcomes in heart failure (DAPA-HF) was an international, multicenter, randomized, double-blind, placebo-controlled study in patients with heart failure (New York Heart Association [NYHA] functional class II-IV) with reduced ejection fraction (left ventricular ejection fraction [LVEF] ≤ 40%) to determine the effect of dapagliflozin compared to placebo on cardiovascular death and heart failure events (incidence) when added to standard background therapy. Of 4,744 patients, 2,373 were randomized to the 10 mg dapagliflozin group and 2,371 to the placebo group, with a median treatment duration of 18 months. The mean age of the study population was 66 years, and 77% were male. At baseline, 67.5% of patients were classified as NYHA class II, 31.6% as class III, and 0.9% as class IV, with a mean left ventricular ejection fraction (LVEF) of 32%. 56% of heart failure was ischemic, 36% non-ischemic, and 8% of unknown etiology. In each treatment group, 42% of patients had a history of type 2 diabetes mellitus, and an additional 3% of patients in each group were classified as having type 2 diabetes mellitus based on HbA1c ≥ 6.5% at both enrollment and randomization. Patients were on standard treatment; 94% of patients were treated with ACE-I, ARB, or angiotensin receptor-neprilysin inhibitor (ARNI, 11%), 96% received beta-blockers, 71% received mineralocorticoid receptor antagonists (MRA), 93% received diuretics, and 26% had an implanted device (with defibrillator function). Patients with eGFR ≥ 30 mL/min/1.73 m² at enrollment participated in the study. The mean eGFR was 66 mL/min/1.73 m², with 41% having eGFR < 60 mL/min/1.73 m² and 15% having eGFR < 45 mL/min/1.73 m². Cardiovascular death and worsening heart failure Dapagliflozin was superior to placebo in the primary composite endpoint of cardiovascular death, hospitalization for heart failure, or urgent heart failure visit (HR 0.74 [95% CI 0.65, 0.85], p < 0.0001). The effect was observed early and was maintained throughout the study. Dapagliflozin also reduced the number of hospitalizations for heart failure (first and recurrent) and deaths from cardiovascular causes; there were 567 events in the dapagliflozin group compared to 742 in the placebo group (hazard ratio 0.75 [95% CI 0.65, 0.88]; p=0.0002). The treatment benefit of dapagliflozin 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 incidence with a hazard ratio of 0.75 (95% CI 0.63, 0.90) in patients with type 2 diabetes and 0.73 (95% CI 0.60, 0.88) in patients without diabetes. The treatment effect of dapagliflozin compared to placebo on the primary endpoint was consistent across other major subgroups, including heart failure background therapy, renal function (eGFR), age, sex, and region. Patient-reported outcome - heart failure symptoms The effect of dapagliflozin treatment on heart failure symptoms was assessed using the Kansas City Cardiomyopathy Questionnaire Symptom Summary Score (KCCQ-TSS), which quantifies 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. Dapagliflozin treatment resulted in a statistically significant and clinically meaningful benefit compared to placebo in heart failure symptoms, as measured by the change from baseline to month 8 on the KCCQ-TSS (win ratio 1.18 [95% CI 1.11, 1.26]; p < 0.0001). Both symptom frequency and symptom burden contributed to the results. The effect (benefit) was observed in terms of both improvement in heart failure symptoms and prevention of worsening heart failure symptoms. In the responder analysis, the proportion of patients with a clinically meaningful improvement on the KCCQ-TSS scale from baseline to month 8, defined as ≥ 5 points, was higher in the dapagliflozin treatment group compared to placebo. The proportion of patients with a clinically meaningful worsening, defined as ≥ 5 points, was lower in the dapagliflozin treatment group compared to placebo. The benefit obtained with dapagliflozin was maintained when using more conservative thresholds for clinically meaningful change (Table 10). Table 10. Number and percentage of patients with clinically meaningful improvement and worsening on the KCCQ-TSS scale at month 8 Change from baseline to month 8 | Dapagliflozin 10 mg N a =2086 | Placebo N a =2062 | Improvement n (%) | Improved b n (%) | Improvement ratio c (95% CI) | p-value d | Worsening n (%) | Worsened d n (%) | Worsening ratio e (95% CI) | p-value d ≥ 5 points | 933 (44.7) | 794 (38.5) | 1.14 (1.06, 1.22) | 0.0002 | 537 (25.7) | 693 (33.6) | 0.84 (0.78, 0.89) | <0.0001 ≥ 10 points | 689 (33.0) | 579 (28.1) | 1.13 (1.05, 1.22) | 0.0018 | 395 (18.9) | 506 (24.5) | 0.85 (0.79, 0.92) | <0.0001 ≥ 15 points | 474 (22.7) | 406 (19.7) | 1.10 (1.01, 1.19) | 0.0300 | | | | a Number of patients assessed on the KCCQ-TSS scale or who died before month 8. b Number of patients who showed improvement of at least 5, 10, or 15 points from baseline. Patients who died before the given time point are considered unimproved. c For improvement, an odds ratio >1 indicates benefit for 10 mg dapagliflozin. d Number of patients who showed worsening of at least 5, 10, or 15 points from baseline. Patients who died before the given time point are considered worsened. e For worsening, an odds ratio <1 indicates benefit for 10 mg dapagliflozin. d p-values are nominal. Nephropathy Several cases of the renal composite endpoint (confirmed sustained ≥ 50% eGFR decline, ESKD, or death due to renal failure) were observed; 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% The Dapagliflozin and prevention of adverse outcomes in heart failure (DELIVER) study was an international, multicenter, randomized, double-blind, placebo-controlled study in patients aged ≥ 40 years with heart failure (NYHA class II-IV) and LVEF > 40% and evidence of structural heart disease, to determine the effect of dapagliflozin on the incidence of cardiovascular death and worsening heart failure compared to placebo. Of 6,263 patients, 3,131 were randomized to the 10 mg dapagliflozin group and 3,132 to the placebo group, and were observed for a median of 28 months. The study included 654 (10%) patients with subacute heart failure (defined as hospitalization for heart failure within 30 days of randomization or 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 mean LVEF was 54%, with 34% of patients having LVEF ≤ 49%, 36% having LVEF 50-59%, and 30% having LVEF ≥ 60%. 45% in each treatment group had a history of type 2 diabetes mellitus. Baseline therapy included ACEi/ARB/ARNI (77%), beta-blockers (83%), diuretics (98%), and MRA (43%). The mean eGFR was 61 mL/min/1.73 m², with 49% of patients having eGFR < 60 mL/min/1.73 m², 23% having eGFR < 45 mL/min/1.73 m², and 3% having eGFR < 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). Dapagliflozin was superior to placebo in reducing the total number of heart failure events (defined as first and recurrent hospitalizations for heart failure or urgent heart failure visits) and cardiovascular deaths; there were 815 events in the dapagliflozin group compared to 1057 events in the placebo group (hazard ratio 0.77 [95% CI 0.67, 0.89]; p=0.0003). The treatment benefit of dapagliflozin compared to placebo on the primary endpoint was observed in subgroups of patients with LVEF ≤ 49%, 50-59%, and ≥ 60%. Effects were also consistent across other major subgroups, stratified by e.g., age, sex, NYHA class, NT-proBNP level, subacute status, and type 2 diabetes mellitus status. Patient-reported outcome - heart failure symptoms Dapagliflozin treatment resulted in a statistically significant benefit compared to placebo in heart failure symptoms, as assessed by the change from baseline to 8 months in KCCQ-TSS, (Win Ratio 1.11 [95% CI 1.03, 1.21] p=0.0086). Results showed both symptom frequency and symptom burden. In statistical analysis, the proportion of patients who experienced moderate (≥ 5 points) or large (≥ 14 points) worsening from baseline to 8 months was lower in the dapagliflozin treatment group; 24.1% of patients on dapagliflozin experienced moderate worsening compared to 29.1% of patients on placebo (Odds Ratio 0.78 [95% CI 0.64, 0.95]), and 13.5% of patients on dapagliflozin experienced large worsening compared to 18.4% on placebo (Odds Ratio 0.78 [95% CI 0.55, 0.88]). The proportion of patients with mild to moderate improvement (≥ 13 points) or significant improvement (≥ 17 points) did not differ between treatment groups. Heart failure DAPA-HF and DELIVER studies In the pooled analysis of DAPA-HF and DELIVER, the HR for dapagliflozin compared to placebo for the composite endpoint of cardiovascular death, hospitalization for heart failure, or urgent visit for heart failure was 0.78 (95% CI 0.72, 0.85), p < 0.0001. The treatment effect was consistent across LVEF ranges, with no attenuation of effect by LVEF. In a pre-specified patient-level pooled analysis of the DAPA-HF and DELIVER studies, dapagliflozin reduced the risk of cardiovascular death compared to placebo (HR 0.85 [95% CI 0.75, 0.96], p=0.0115). This result includes the analysis of both studies. Chronic kidney disease The Dapagliflozin and prevention of adverse outcomes on renal and cardiovascular mortality in patients with chronic kidney disease (DAPA-CKD) study was an international, multicenter, randomized, double-blind, placebo-controlled study in patients with chronic kidney disease (CKD) with eGFR from ≥ 25 to ≤ 75 mL/min/1.73 m² and albuminuria (UACR ≥ 200 to ≤ 5000 mg/g). The study evaluated the effect of dapagliflozin compared to placebo as an add-on to standard therapy on the composite endpoint of sustained ≥ 50% decline in eGFR, end-stage renal disease (ESKD) (defined as sustained eGFR < 15 mL/min/1.73 m², chronic treatment with dialysis, or kidney transplant), cardiovascular or renal death. Of 4,304 patients, 2,152 were randomized to 10 mg dapagliflozin and 2,152 to placebo, with a median observation period of 28.5 months. Treatment continued throughout the study if eGFR fell below 25 mL/min/1.73 m² and could be continued if dialysis was required. The mean age of the study population was 61.8 years, and 66.9% were male. At baseline, the mean eGFR was 43.1 mL/min/1.73 m² and the mean UACR was 949.3 mg/g; 44.1% of patients had an eGFR of 30 to 45 mL/min/1.73 m², and 14.5% had an eGFR < 30 mL/min/1.73 m². 67.5% of patients had type 2 diabetes mellitus. Patients were on standard of care (SOC); 97.0% of patients were receiving an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). The study was stopped early for efficacy at the recommendation of the independent Data Monitoring Committee, prior to the planned analysis. Dapagliflozin was superior to placebo in terms of reducing the incidence of the primary composite endpoint of sustained ≥ 50% decline in eGFR, development of end-stage renal disease, cardiovascular or renal death (HR 0.61 [95% CI 0.51, 0.72]; p < 0.0001). Based on Kaplan-Meier curves for time to first occurrence of the primary composite endpoint, the treatment effect was apparent from 4 months and was maintained until the end of the study. All four components of the primary composite endpoint individually contributed to the treatment effect. Dapagliflozin also reduced the incidence of the composite endpoint of sustained ≥ 50% decline in eGFR, development of end-stage renal disease, cardiovascular or renal death, and the composite endpoint of cardiovascular death (HR 0.56 [95% CI 0.45, 0.68], p<0.0001) and hospitalization for heart failure (HR 0.71 [95% CI 0.55, 0.92], p=0.0089). Dapagliflozin treatment improved overall survival in patients with chronic kidney disease and significantly reduced all-cause mortality (HR 0.69 [95% CI 0.53, 0.88], p=0.0035). The treatment benefit of dapagliflozin was similar in patients with chronic kidney disease with and without type 2 diabetes. Dapagliflozin reduced the primary composite endpoint of sustained ≥ 50% decline in eGFR, development of end-stage renal disease, cardiovascular or renal death with a hazard ratio of 0.64 (95% CI 0.52, 0.79) in patients with type 2 diabetes mellitus and 0.50 (95% CI 0.35, 0.72) in patients without diabetes. The superiority of dapagliflozin treatment compared to placebo was also stable across other major subgroups, including by eGFR, age, sex, and region. Pediatric population The European Medicines Agency has waived the requirement to submit study results for dapagliflozin conducted in the pediatric population with type 2 diabetes mellitus (for information on use in the pediatric population, see "Dosage and method of administration"). The European Medicines Agency has waived the obligation to submit study results for dapagliflozin in all pediatric subpopulations related to the prevention of cardiovascular events in patients with chronic heart failure and in the treatment of chronic kidney disease (for information on use in pediatrics, see the "Dosage and method of administration" section). Pharmacokinetic properties Absorption After oral administration, dapagliflozin was rapidly and completely absorbed. The maximum plasma concentration (Cmax) of dapagliflozin was usually reached approximately 2 hours after administration in the fasted state. The geometric mean steady-state Cmax and AUCτ of dapagliflozin after once-daily administration of 10 mg were 158 ng/mL and 628 ng·h/mL, respectively. The absolute bioavailability of dapagliflozin after administration of a 10 mg dose was 78%. Administration with a high-fat meal reduced dapagliflozin Cmax by approximately 50% and prolonged Tmax by 1 hour, without affecting AUC compared to the fasted state. These changes are not clinically significant. Therefore, Forxiga can be taken with or without food. Distribution Dapagliflozin is approximately 91% bound to plasma proteins. This binding is not altered in patients with various diseases (e.g., renal or hepatic impairment). The mean steady-state volume of distribution of dapagliflozin was 1181 L. Biotransformation Dapagliflozin is extensively metabolized, primarily to dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide or other metabolites do not contribute to the glucose-lowering effects. The formation of dapagliflozin 3-O-glucuronide is mediated by UGT1A9, an enzyme present in the liver and kidney, while CYP-mediated metabolism was a minor clearance pathway in humans. Excretion In healthy subjects, the mean elimination half-life (t1/2) of dapagliflozin from plasma was 12.9 hours after a single oral dose of 10 mg. The mean total systemic clearance of intravenously administered dapagliflozin was 207 mL/min. Dapagliflozin and its metabolites are primarily excreted by the kidneys, with only 2% excreted unchanged. After administration of 50 mg of [14C]-dapagliflozin, 96% to 75% of the radioactivity was recovered in urine and 21% in feces. Approximately 15% of the radioactivity recovered in feces was excreted unchanged. Linearity Dapagliflozin exposure increased proportionally with dose from 0.1 to 500 mg, and its pharmacokinetics did not change over time during repeated dosing for up to 24 weeks. Special populations Renal impairment In the steady state (20 mg dapagliflozin once daily for 7 days), systemic exposure to dapagliflozin was 32%, 60%, and 87% higher in patients with type 2 diabetes mellitus and mild, moderate, or severe renal impairment (defined by iohexol clearance), respectively, compared to patients with type 2 diabetes mellitus and normal renal function. In the steady state, the amount of glucose excreted by the kidneys over 24 hours during dapagliflozin administration was dependent on renal function. In patients with type 2 diabetes mellitus and normal renal function, and with mild, moderate, and severe hepatic impairment, 85, 52, 18, and 11 g of glucose were excreted per day, respectively. No difference in dapagliflozin protein binding was observed in healthy volunteers and patients with varying degrees of renal impairment. It is unknown whether hemodialysis affects dapagliflozin exposure. The effect of reduced renal function on systemic exposure was assessed in a population pharmacokinetic model. Similar to previous results, the model predicted higher AUC in patients with chronic kidney disease compared to patients with normal renal function, and did not significantly differ between patients with chronic kidney disease with and without type 2 diabetes mellitus. Hepatic impairment In patients with mild or moderate hepatic impairment (Child-Pugh class A and B), Cmax and AUC of dapagliflozin were 12% and 36% higher, respectively, compared to control subjects. These differences are not clinically significant. In patients with severe hepatic impairment (Child-Pugh class C), the mean values of Cmax and AUC of dapagliflozin were 40% and 67% higher, respectively, compared to healthy volunteers. Elderly patients (≥ 65 years) No clinically significant increase in exposure was observed in patients under 70 years of age. However, exposure may increase with age-related decline in renal function. Data on exposure in patients over 70 years of age are insufficient. Pediatric population Pharmacokinetics in the pediatric population have not been studied. Sex In women, the mean AUC in the steady state was 22% higher than in men. Race No clinically significant differences in systemic exposure were observed between white, black, and Asian races. Body weight Dapagliflozin exposure decreases with increasing body weight. Therefore, patients with low body weight may experience increased exposure, while patients with high body weight may experience decreased dapagliflozin exposure. However, these differences are not clinically significant. Shelf life: 3 years. Storage conditions: Store at a temperature not exceeding 30°C, out of reach of children. Dispensing category: Pharmaceutical product group II, dispensed with prescription form №3. Dosage form: Film-coated tablets, 10 mg. 10 tablets in an Alu/Alu blister, 3 blisters together with the instructions for use in a cardboard box.