Forciga, 10 mg 30 pcs.

Pharmacotherapeutic group: hypoglycemic agent for oral use – type 2 sodium-dependent glucose transporter inhibitor

ATX code: A10BK01

Pharmacological properties

Mechanism of action

Dapagliflozin is a potent (inhibition constant (Ki) 0.55 nM), selective reversible inhibitor of sodium-glucose co-transporter type 2 (SGLT2).

Inhibition of SGLT2 by dapagliflozin causes reduction of glucose reabsorption from glomerular filtrate in proximal renal tubules with concomitant reduction of sodium reabsorption, leading to renal glucose excretion and osmotic diuresis. Thus, dapagliflozin increases sodium delivery to the distal tubules, which enhances tubule-glove feedback and decreases intraclavian pressure. This, combined with osmotic diuresis, results in decreased volume overload, decreased blood pressure, and decreased preload and postload, which may have beneficial effects on cardiac remodeling and preserving renal function. Other effects include increased hematocrit and decreased body weight.

The beneficial effects of dapagliflozin on the cardiovascular system and the kidneys are not only due to a decrease in blood glucose concentrations and are not only observed in patients with diabetes. In addition to osmotic diuresis and the associated hemodynamic action resulting from SGLT2 inhibition, secondary effects on myocardial metabolism, ion channels, fibrosis, adipokines and uric acid may be potential mechanisms that provide beneficial effects of dapagliflozin on the cardiovascular system and kidneys.

Dapagliflozin reduces fasting and postprandial plasma glucose concentrations and glycated hemoglobin concentrations by reducing glucose reabsorption in the renal tubules, promoting glucose excretion by the kidneys. Glucose excretion (glucosuric effect) is observed after the first dose of the drug, lasts for the next 24 hours and lasts during the whole therapy. The amount of glucose excreted by the kidneys through this mechanism depends on blood glucose concentration and glomerular filtration rate (GFR). Thus, in patients with normal blood glucose concentration and/or low GFR, against the background of dapagliflozin administration, there is a low propensity to develop hypoglycemia, because the amount of filtered glucose is small and can be reabsorbed by the SGLT1 vector and the unblocked SGLT2 vector. Dapagliflozin does not disrupt normal endogenous glucose production in response to hypoglycemia. The action of dapagliflozin is independent of insulin secretion and insulin sensitivity. In clinical trials, dapagliflozin has improved beta-cell function (HOMA, homeostasis model assessment). SGLT2 is selectively expressed in the kidneys. Dapagliflozin has no effect on other glucose transporters that transport glucose to peripheral tissues and is more than 1,400 times more selective for SGLT2 than for SGLT1, the main transporter in the gut responsible for glucose absorption.

Pharmacodynamics

After dapagliflozin administration in healthy volunteers and patients with type 2 diabetes mellitus (DM2), an increase in the amount of glucose excreted by the kidneys was observed. When dapagliflozin was administered at a dose of 10 mg/day for 12 weeks in patients with T2DM, approximately 70 g of glucose per day was excreted by the kidneys (corresponding to 280 kcal/day). In patients with DM2 who took dapagliflozin at a dose of 10 mg/day for a long time (up to 2 years), glucose excretion was maintained throughout the course of therapy.

Kidney excretion of glucose with dapagliflozin also leads to osmotic diuresis and increased urine volume. The increase in urine volume in patients with DM2 taking dapagliflozin at a dose of 10 mg/day persisted for 12 weeks and was approximately 375 mL/day. The increase in urine volume was accompanied by a small and transient increase in renal sodium excretion, which did not lead to changes in serum sodium concentration.

Clinical efficacy of DM2

The analysis of 13 placebo-controlled studies demonstrated a 3.7 mm Hg reduction in systolic blood pressure (SBP). systolic blood pressure (BP) and diastolic blood pressure (DBP) by 1.8 mm Hg at 24 weeks of dapagliflozin therapy at a dose of 10 mg/day compared with a decrease in BP and BP by 0.5 mm Hg in the placebo group. A similar reduction in blood pressure was observed over 104 weeks of treatment.

The combination therapy of dapagliflozin 10 mg and prolonged-acting exenatide resulted in a significantly greater reduction in BP at 28 weeks of therapy (by 4.3 mm Hg) compared to the reduction in BP with dapagliflozin therapy (by 1.8 mm Hg) and with prolonged-acting exenatide therapy (by 1.2 mm Hg).

. When dapagliflozin was used at a dose of 10 mg/day in patients with DM2 with inadequate glycemic control and arterial hypertension receiving angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, including in combination with another hypotensive drug, there was a 3.1% decrease in the glycated hemoglobin index and a 4.3 mm Hg decrease in BP. Hg after 12 weeks of therapy compared to placebo.

The effect of dapagliflozin compared with placebo on cardiovascular and renal outcomes when added to current baseline therapy was established in the DECLARE clinical trial conducted in 17160 patients with DM2 and two or more additional cardiovascular risk factors (age ≥55 years in men or ≥60 years in women and one or more of the following: dyslipidemia, hypertension, or tobacco smoking) or with diagnosed cardiovascular disease.

Dapagliflozin 10 mg demonstrated superiority compared with placebo in preventing the primary combined end point, which included hospitalization for heart failure or cardiovascular death (hazard ratio (HR) 0.83 [95% confidence interval (CI) 0.73, 0.95]; p=0.005). The difference in the effect of therapy was due to hospitalization for heart failure (OR 0.73 [95% CI 0.61, 0.88]), with no difference in cardiovascular death (OR 0.98 [95% CI 0.82 to 1.17]).

The benefit of dapagliflozin therapy compared with placebo was observed in patients with and without diagnosed cardiovascular disease, with or without baseline heart failure, and was comparable in key subgroups including age, sex, renal function (rCF), and region.

Dapagliflozin reduced the incidence of combined point events, which included a confirmed sustained decrease in rSKF, end-stage renal failure, death due to renal complications, or cardiovascular death. The difference between the groups was due to a decrease in the number of events of the combined renal outcome endpoint components, which included a sustained decrease in rSKF, end-stage renal failure, and death due to renal complications.

The hazard ratio of time to nephropathy (sustained decrease in rSKF, end-stage renal failure, or death due to renal complications) was 0.53 (95% CI 0.43, 0.66) for dapagliflozin compared with placebo.

Dapagliflozin also reduced the risk of new cases of persistent albuminuria (OR 0.79 [95% CI 0.72, 0.87]) and resulted in greater regression of macroalbuminuria (OR 1.82 [95% CI 1.51, 2.20]) compared with placebo.

Chronic Heart Failure

. The DAPA-HF study involving 4,744 patients with chronic heart failure (New York Heart Association [NYHA] functional class II-IV) with reduced ejection fraction (left ventricular ejection fraction [LVEF] ≤ 40%) was conducted to determine whether dapagliflozin reduced the risk of cardiovascular death and hospitalization for heart failure.

Dapagliflozin reduced the incidence of the primary combined end point, which included cardiovascular death, hospitalization for heart failure, or emergency admission for worsening heart failure (OR 0.74 [95% CI 0.65, 0.85]; p< 0.0001). All three components of the primary combined endpoint individually contributed to the treatment effect (cardiovascular death: OR 0.82 [95% CI 0.69, 0.98], hospitalization for heart failure: OR 0.70 [95% CI 0.59, 0.83], emergency care seeking due to worsening heart failure: OR 0.43 [95% CI 0.20, 0.90]). There were several urgent requests for care due to worsening of the course of heart failure. Dapagliflozin also reduced the incidence of cardiovascular death or hospitalization for heart failure (OR 0.75 [95% CI 0.65, 0.85], p< 0.0001).

Dapagliflozin also reduced the total number of hospitalizations for heart failure (first and recurrent) and cardiovascular death; there were 567 cases in the dapagliflozin group compared with 742 cases in the placebo group (odds ratio 0.75 [95% CI 0.65, 0.88]; p=0.0002).

The incidence of death from any cause was lower in the dapagliflozin therapy group compared with placebo (OR 0.83 [95% CI 0.71, 0.97]).

The results for the primary combined endpoint were comparable in patients with and without heart failure with and without DM2 and in other key subgroups, including heart failure severity, renal function (rCF), age, gender, and region.

Dapagliflozin therapy resulted in a statistically significant and clinically meaningful advantage over placebo for heart failure symptoms, as assessed by change after 8 months from baseline in the Kansas Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) (probability of advantage 1.18 [95% CI 1.11, 1.26]; p< 0.0001). Symptom frequency and symptom severity contributed to the outcome obtained on therapy efficacy. A benefit was observed in both improvement of heart failure symptoms and prevention of worsening of heart failure symptoms.

Chronic kidney disease

. The effect of dapagliflozin on renal outcomes and cardiovascular mortality in patients with chronic kidney disease was established in the DAPA-CKD study, in which dapagliflozin was compared with placebo when added to standard basic therapy in patients with chronic kidney disease with rCF ≥ 25 to ≤ 75 ml/min/1.73 m² and albuminuria (urinary albumin/creatinine ratio (urinary A/Cp) ≥200 and ≤5,000 mg/g).

Dapagliflozin was superior to placebo in reducing the incidence of the primary combined endpoint, which included a sustained ≥50% decrease in rCF, achievement of end-stage renal failure, cardiovascular death, or death due to renal complications (OR 0.61 [95% CI 0.51, 0.72]; p< 0.0001).

All four components of the primary combined endpoint individually contributed to the treatment effect. Dapagliflozin also reduced the incidence of the combined endpoint, which included a sustained ≥50% decrease in rCF, end-stage renal failure, or death due to renal complications (OR 0.56 [95% CI 0.45, 0.68], p< 0.0001), the combined end point including cardiovascular death and hospitalization for heart failure (OR 0.71 [95% CI 0.55, 0.92], p=0.0089), and death from any cause (OR 0.69 [95% CI 0.53, 0.88], p=0.0035).

The benefit of dapagliflozin therapy compared with placebo for the primary combined endpoint was comparable in patients with chronic kidney disease with or without DM2 and in other key subgroups, including urinary pSCF and A/Cp values, age, gender, and region.

Pharmacokinetics

Absorption

After oral administration, dapagliflozin is rapidly and completely absorbed in the gastrointestinal tract and may be taken either with or without meals. Maximum plasma concentration of dapagliflozin (Cmax) is usually reached within 2 hours after an empty stomach. Cmax and AUC values (area under the concentration-time curve) increase in proportion to the dose of dapagliflozin. Absolute bioavailability of dapagliflozin at an oral dose of 10 mg is 78%. Food intake had a moderate effect on the pharmacokinetics of dapagliflozin in healthy volunteers. High-fat meal decreased Cmax of dapagliflozin by 50%, prolonged Tmax (time to reach maximum plasma concentration) by approximately 1 hour, but had no effect on AUC compared to fasting meal. These changes are not clinically significant.

Distribution

Dapagliflozin is approximately 91% protein-bound. In patients with various diseases, such as renal or liver dysfunction, this figure did not change.

Metabolism

Dapagliflozin is a C-linked glucoside whose aglycon is bound to glucose by a carbon-carbon bond, which makes it resistant to glucosidases. Mean plasma elimination half-life (T1/2) in healthy volunteers was 12.9 hours after a single oral dapagliflozin dose of 10 mg. Dapagliflozin is metabolized to form mainly the inactive metabolite dapagliflozin-3-O-glucuronide.

After oral administration of 50 mg of ¹⁴C-dapagliflozin, 61% of the dose taken is metabolized to dapagliflozin-3-O-glucuronide, which accounts for 42% of total plasma radioactivity (by AUC0-12 h). The unchanged drug accounts for 39% of total plasma radioactivity. The shares of the remaining metabolites individually do not exceed 5% of total plasma radioactivity. Dapagliflozin-3-O-glucuronide and other metabolites have no pharmacological effect. Dapagliflozin-3-O-glucuronide is formed under the action of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) enzyme, which is present in the liver and kidneys, cytochrome CYP isoenzymes are involved in metabolism to a lesser extent.

Elimation

Dapagliflozin and its metabolites are excreted primarily by the kidneys, and only less than 2% are excreted unchanged. After administration of 50 mg of ¹⁴C-dapagliflozin, 96% radioactivity was detected – 75% in urine and 21% in feces. Approximately 15% of the radioactivity detected in the feces was from unchanged dapagliflozin.

Pharmacokinetics in special patient groups

Patients with impaired renal function

At equilibrium (mean AUC), systemic exposure of dapagliflozin was 32%, 60%, and 87% higher in patients with DM2 and mild, moderate, or severe renal impairment (determined by yohexol clearance) than in patients with DM2 and normal renal function, respectively. The amount of glucose excreted by the kidneys during the day when dapagliflozin was taken in equilibrium depended on the state of renal function. Patients with DM2 and normal renal function and with mild, moderate, or severe renal dysfunction excreted 85, 52, 18, and 11 g of glucose per day, respectively. No differences were found in the binding of dapagliflozin to proteins in healthy volunteers and in patients with renal impairment of varying degrees of severity. It is unknown whether hemodialysis has an effect on dapagliflozin exposure. The effect of reduced renal function on systemic drug exposure was evaluated using a population-based pharmacokinetic model. The model predicted AUC was higher in patients with chronic kidney disease compared with patients with normal renal function and did not differ significantly in patients with chronic kidney disease with or without DM2, consistent with previous findings.

Patients with impaired hepatic function

In patients with mild to moderate hepatic impairment, the mean Cmax and AUC values of dapagliflozin were 12% and 36% higher, respectively, compared with healthy volunteers. These differences are not clinically significant, therefore no dose adjustment of dapagliflozin in mild to moderate hepatic insufficiency is required (see section “Dosage and administration”). In patients with severe hepatic impairment (Child-Pugh class C) mean values of Cmax and AUC of dapagliflozin were 40% and 67% higher, respectively, compared to healthy volunteers.

Elderly patients (≥65 years)

There was no clinically significant increase in exposure in patients under 70 years of age (unless factors other than age are considered). However, increased exposure can be expected due to decreased renal function associated with age. Exposure data in patients over 70 years of age are insufficient. Gender

In women, the average AUC at equilibrium is 22% higher than in men.

Race

There were no clinically significant differences in systemic exposure among Caucasoid, Negroid and Mongoloid races.

Body weight

Lower values of exposure were noted with increased body weight. Therefore, some increased exposure may be noted in patients with low body weight, and some decreased exposure to dapagliflozin in patients with increased body weight. However, these differences are not clinically significant.

Indications

Type 2 diabetes mellitus in adult patients in addition to diet and exercise to improve glycemic control as:

Type 2 diabetes mellitus in adult patients with established cardiovascular disease or two or more cardiovascular risk factors* to reduce the risk of hospitalization for heart failure.

* Age ≥55 years in men or ≥60 years in women and presence of at least one risk factor: dyslipidemia, arterial hypertension, smoking.

Chronic heart failure (NYHA functional class II-IV) with reduced ejection fraction in adult patients to reduce the risk of cardiovascular death and hospitalization for heart failure.

Chronic kidney disease in adult patients at risk of progression to reduce the risk of sustained reduction in rCF, onset of end-stage chronic renal failure, cardiovascular death and hospitalization for heart failure.

Active ingredient

How to take, the dosage

Overly, regardless of meals, without chewing.

Before starting therapy with Forsiga, the state of water-salt metabolism should be assessed and, if necessary, the circulating blood volume (CBV) should be replenished.

Interaction

Special Instructions

Application in patients with impaired renal function

Renal function should be evaluated before starting therapy with Forsiga and further if clinically indicated.

The trials of efficacy and safety of the drug Forsiga did not include patients with rCF less than 25 ml/min/1.73 m2. The use of the drug Forsiga is contraindicated in patients on hemodialysis.

The use of the drug Forcega to improve glycemic control in adult patients with type 2 diabetes mellitus with a pSFR less than 45 ml/min/1.73 m2 is not recommended due to possible ineffectiveness of the drug in this population due to the mechanism of pharmacological action of dapagliflozin.

The use of Forsiga is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or in patients who require or have recently received immunosuppressive therapy for renal failure. Dapagliflozin is not expected to be effective in these patient groups.

In one study in patients with mild-to-moderate renal impairment DM2 (pSF < 60 mL/min/1.73 m2), adverse reactions in the form of increased parathyroid hormone concentrations and arterial hypotension were seen in a higher proportion of patients in the dapagliflozin group than in the placebo group.

Application in patients with hepatic impairment

Limited data on the use of the drug in patients with hepatic impairment have been obtained in clinical studies. Exposure to dapagliflozin is increased in patients with severe hepatic impairment (see sections “Dosage and administration”, “Caution” and “Pharmacokinetics”).

CPU Decrease

The drug Forciga may cause decreased CPR, which may sometimes manifest as symptomatic arterial hypotension or acute transient changes in creatinine concentration. During post-registration use of SGLT2 inhibitors, including Forsiga, cases of acute kidney damage were observed in patients with DM2, some of which required hospitalization and dialysis. In patients with impaired renal function (rCF less than 60 ml/min/1.73 m2), elderly patients or patients taking “loop” diuretics an increased risk of decreased BOD or arterial hypotension may be noted. Before starting therapy with Forciga in patients with one or more of these characteristics, it is necessary to assess the CPR and renal function. After initiation of therapy, patients should be monitored for possible signs and symptoms of arterial hypotension and renal function should be monitored.

Application in patients at risk of arterial hypotension

. According to the mechanism of action, dapagliflozin increases diuresis, which may lead to a slight decrease in blood pressure noted in clinical studies (see section “Pharmacodynamics”). Diuretic effect may be more pronounced in patients with very high blood glucose concentrations.

Waution should be exercised in patients for whom dapagliflozin-induced reduction of blood pressure may be a risk, e.g., in patients receiving hypotensive therapy, with a history of hypotension or in elderly patients.

Ketoacidosis in patients with diabetes

. There have been reports of cases of ketoacidosis, including diabetic ketoacidosis, in patients with type 1 and type 2 diabetes taking Forciga and other SGLT2 inhibitors. The drug Forsiga is not indicated for the treatment of patients with type 1 diabetes mellitus.

Patients taking Forsiga with signs and symptoms suggestive of ketoacidosis, including nausea, vomiting, abdominal pain, malaise, and shortness of breath, should be evaluated for ketoacidosis, even with blood glucose concentrations below 14 mmol/L. If ketoacidosis is suspected, consideration should be given to withdrawing or temporarily discontinuing Forciga, and the patient should be evaluated immediately.

Factors predisposing to the development of ketoacidosis include low functional activity of beta cells due to pancreatic dysfunction (e.g., type 1 diabetes, pancreatitis or a history of pancreatic surgery), decreased insulin dose, reduced caloric intake or increased insulin requirement due to infections, disease or surgery, and alcohol abuse. Forciga should be used with caution in these patients.

Necrotizing fasciitis of the perineum (Fournier’s gangrene)

. Post-histamine cases of necrotizing fasciitis of the perineum (Fournier’s gangrene) have been reported in women and men taking SGLT2 inhibitors (see

Section “Side effects”). This is a rare, potentially serious and life-threatening condition that requires emergency surgery and antibiotics. Patients should consult a physician if they experience symptoms of pain, sensitivity to touch, erythema or swelling in the genital or perineal area accompanied by fever and malaise. It is known that either a urogenital infection or a perineal abscess may precede necrotizing fasciitis.

If Fournier’s gangrene is suspected, the use of Forciga should be discontinued and immediate treatment (including antibiotics and surgery) initiated.

Urinary tract infections

. Cases of serious urinary tract infections, including urosepsis and pyelonephritis, that required hospitalization have been reported in patients taking SGLT2 inhibitors, including Forciga. Therapy with SGLT2 inhibitors increases the risk of urinary tract infections. Patients should be monitored for possible signs and symptoms of urinary tract infections and, if indicated, treatment should be started immediately (see section “Side effects”). If pyelonephritis or urosepsis is treated, temporary withdrawal of therapy with dapagliflozin should be considered.

Lower limb amputation

. An increase in lower limb amputation (primarily toes) has been observed in an ongoing long-term clinical trial in DM2 with another SGLT2 inhibitor. It is unknown whether this is an effect of SGLT2 class drugs. It is important to recommend continuous preventive foot care for diabetic patients taking SGLT2 inhibitors.

Chronic Heart Failure

The experience with dapagliflozin in patients with NYHA functional class IV chronic heart failure is limited.

Evaluations of urine test results

Due to the mechanism of action of the drug, urine test results for glucose in patients taking Forciga will be positive.

Influence on 1,5-Anhydroglucitol determination

. Assessment of glycemic control using 1,5-anhydroglucitol determination is not recommended because measurement of 1,5-anhydroglucitol is an unreliable method for patients taking SGLT2 inhibitors. Alternative methods should be used to assess glycemic control.

Hypoglycemia on concomitant use of insulin and secretion stimulants insulin

Insulin and insulin secretion stimulants may cause hypoglycemia. The drug Forcega may increase the risk of hypoglycemia when used in combination with insulin or insulin secretion stimulants (see section “Side effects”). It may be necessary to reduce the dose of insulin or insulin secretion stimulants to reduce the risk of hypoglycemia when they are used concomitantly with the drug Forsiga.

Fungal genital infections

Forsiga increases the risk of fungal genital infections. Patients with a history of fungal genital infections are more likely to develop these infections (see section “Side effects”). Patients should be monitored and appropriate treatment in case of such infections.

Influence on the ability to drive and operate vehiclesThere have been no studies on the effect of dapagliflozin on the ability to drive and operate vehicles.

Synopsis

Contraindications

Side effects

The safety profile of dapagliflozin was evaluated in clinical studies1 of the safety and efficacy of dapagliflozin when used for therapy of DM2, chronic heart failure and chronic kidney disease, during post-registration follow-up.

The safety profile of dapagliflozin in the indications studied in the studies was comparable. Severe hypoglycemia and diabetic ketoacidosis were observed only in diabetic patients. Adverse reactions were not dose-dependent.

Possible adverse reactions during therapy with dapagliflozin are divided into systemic organ classes with indication of their frequency according to WHO recommendations: Very common (≥1/10), common (≥1/100, < 1/10), infrequent (≥1/1000, < 1/100), rare (≥1/10000, < 1/1000), very rare (< 1/10000) and unspecified frequency (cannot be estimated from available data).

Infectious and parasitic diseases: frequent* – vulvovaginitis, balanitis, and related genital infections2,3, urinary tract infection2,4; infrequent** – vulvovaginal pruritus, fungal infectious diseases; very rare – necrotizing fasciitis of the perineum (Fournier’s gangrene)

Disorders of metabolism and nutrition: very common – hypoglycemia (when used in combination with a sulfonylurea derivative or insulin)2; infrequent** – Decreased RBC2.5, thirst; rarely diabetic ketoacidosis (when used in DM2)2.9

Nervous system disorders: often* – dizziness

Gastrointestinal tract disorders: infrequently** – constipation, dry mouth Skin and subcutaneous tissue disorders: frequently* – rash10; very rarely – angioedema

Musculoskeletal and connective tissue disorders: often* – back pain

Disorders of the kidneys and urinary tract: frequent* – dysuria, polyuria6; infrequent** – nycturia

Laboratory and instrumental findings: frequent* – dyslipidemia8, increased hematocrit value7, decreased renal creatinine clearance during initial therapy2; infrequent** – increased blood urea concentration, increased blood creatinine concentration during initial therapy2.

1 Presented data on use of the drug up to 24 weeks (short-term therapy) regardless of taking an additional hypoglycemic drug.

2 See the corresponding subsection below for more information.

3 Vulvovaginitis, balanitis, and related genital infections include, for example, the following predefined preferred terms: vulvovaginal fungal infection, vaginal infection, balanitis, fungal genital infection, vulvovaginal candidiasis, vulvovaginitis, candidal balanitis, genital candidiasis, genital infection, male genital infection, penile infection, vulvitis, bacterial vaginitis, vulvar abscess.

4 Urinary tract infection includes the following preferred terms, listed in descending order of frequency: Urinary tract infection, cystitis, urinary tract infection caused by bacteria of the genus Escherichia, urogenital tract infection, pyelonephritis, trigonitis, urethritis, kidney infection, and prostatitis.

5 Decreased CPR includes, for example, the following predefined preferred terms: dehydration, hypovolemia, arterial hypotension.

6 Polyuria includes the preferred terms: pollakiuria, polyuria, and increased diuresis.

7 The mean change in hematocrit values from baseline was 2.30% in the dapagliflozin 10 mg group compared with -0.33% in the placebo group. Hematocrit values of >55% were noted in 1.3% of patients receiving dapagliflozin 10 mg compared with 0.4% of patients receiving placebo.

The 8 mean change in the following parameters as a percentage of baseline values in the dapagliflozin 10 mg group and placebo group, respectively, was: total cholesterol 2.5% vs. 0.0%; HDL cholesterol 6.0% vs. 2.7%; LDL cholesterol

2.9% vs. -1.0%; triglycerides -2.7% vs. -0.7%.

9 Noted in the DECLARE study. Frequency is based on an annualized rate.

10 Adverse reactions were noted at post-registration follow-up. Rash includes the following preferred terms listed in order of frequency of development in clinical trials: rash, generalized rash, pruritic rash, maculopapular rash, maculopapular rash, pustular rash, vesicular rash, erythematous rash. In placebo-controlled and active-controlled clinical trials (group receiving dapagliflozin: n=5936, control group: n=3403), the incidence of rash was similar in patients receiving dapagliflozin (1.4%) and patients in the control group (1.4%), consistent with the “often” frequency category.

* were noted in ≥ 2% of patients receiving dapagliflozin at a dose of 10 mg and ≥ 1% more frequently than in the placebo group.

** Reported in ≥0.2% of patients and ≥0.1% more often and in more patients (by at least 3) in the dapagliflozin 10 mg group compared with the placebo group, regardless of taking an additional hypoglycemic drug.

Description of individual adverse reactions

.Vulvovaginitis, balanitis, and related genital infections

. In pooled safety data from 13 studies, vulvovaginitis, balanitis, and related genital infections were reported in 5.5% and 0.6% of patients taking dapagliflozin 10 mg and placebo, respectively. Most infections were mild to moderate; the initial course of standard therapy was effective, and patients rarely discontinued dapagliflozin. These infections were more frequent in women (8.4% and 1.2% with dapagliflozin and placebo, respectively), and patients with a history of such infections were more likely to have recurrent infections.

In the DECLARE trial, the number of patients with serious adverse events in the form of genital infections was small and balanced: 2 (< 0.1%) each in the dapagliflozin group and placebo group.

In the DAPA-HF study, there were no patients with serious adverse events in the form of genital infections in the dapagliflozin group; in the placebo group, a serious adverse event was reported in 1 patient. In the dapagliflozin group, 7 (0.3%) patients had adverse events leading to discontinuation of treatment due to genital infections, and no patient in the placebo group.

In the DAPA-CKD study, there were 3 (0.1%) patients with serious adverse events in the form of genital infections in the dapagliflozin group and no patients with such events in the placebo group. In the dapagliflozin group, 3 (0.1%) patients had adverse events leading to discontinuation of treatment due to genital infections, while there were no patients with such events in the placebo group. No serious adverse events or adverse events leading to treatment discontinuation due to genital infections were reported in patients without diabetes mellitus.

Necrotizing fasciitis of the perineum (Fournier’s gangrene)

. Post-registration cases of Fournier’s gangrene have been reported in patients taking SGLT2 inhibitors, including dapagliflozin (see See section “Special Indications”).

In the DECLARE study, a total of 6 cases of Fournier’s gangrene were reported in 17160 patients with DM2 and a median exposure of 48 months: one in the group receiving dapagliflozin and five in the placebo group.

Hypoglycemia

The incidence of hypoglycemia depended on the type of baseline therapy used in the DM2 clinical trials.

In studies of dapagliflozin as monotherapy, combination therapy with metformin lasting up to 102 weeks, the incidence of episodes of mild hypoglycemia was similar (< 5%) in treatment groups including placebo. In all studies, episodes of severe hypoglycemia were infrequent and their frequency was comparable between the dapagliflozin and placebo groups. In the studies of dapagliflozin as addition to sulfonylurea drug or insulin drug, a higher incidence of hypoglycemia was noted (see section “Interaction with other medicinal products”). In the study of dapagliflozin 10 mg, administered simultaneously with prolonged-acting exenatide (against the background of metformin use), no episodes of severe or mild hypoglycemia were noted.

The DECLARE study showed no increased risk of severe hypoglycemia with dapagliflozin therapy compared with placebo. Severe hypoglycemia was reported in 58 (0.7%) patients receiving dapagliflozin and 83 (1.0%) patients receiving placebo.

In the DAPA-HF study, severe hypoglycemia was reported in 4 (0.2%) patients in both the dapagliflozin and placebo groups and was seen only in patients with DM2.

In the DAPA-CKD study, severe hypoglycemia was reported in 14 (0.7%) patients in the dapagliflozin group and in 28 (1.3%) patients in the placebo group and was observed only in patients with DM2.

CPU reduction

. In pooled safety data from 13 studies, adverse reactions indicating decreased CPR (including reports of dehydration, hypovolemia, or arterial hypotension) were noted in 1.1% and 0.7% of patients taking dapagliflozin 10 mg and placebo, respectively; serious adverse reactions were noted in < 0.2% of patients, and they were comparable in the dapagliflozin 10 mg and placebo groups (see See section “Special Indications”).

In the DECLARE study, the number of patients with events indicative of decreased CPR was balanced between treatment groups: 213 (2.5%) and 207 (2.4%) in the dapagliflozin and placebo groups, respectively. Serious adverse events were reported in 81 (0.9%) and 70 (0.8%) patients in the dapagliflozin and placebo groups, respectively. The events were generally balanced between treatment groups in terms of age, diuretic use, blood pressure, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use. Among patients with a baseline rSFR < 60 mL/min/1.73 m2, 19 cases of serious adverse events indicative of decreased RBC were noted in the dapagliflozin group and 13 in the placebo group.

In the DAPA-HF study, the number of patients with events indicative of decreased CPR was balanced between treatment groups: 170 (7.2%) and 153 (6.5%) in the dapagliflozin and placebo groups, respectively. The dapagliflozin group had fewer patients with serious phenomena in the form of symptoms indicative of decreased CPR compared with the placebo group: 23 (1.0%) and 38 (1.6%) patients, respectively. Similar results were observed in subgroup analyses by age, presence of diabetes mellitus at baseline, baseline rCF and BP.

In the DAPA-CKD study, the number of patients with phenomena suggestive of decreased ROC 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 phenomena in the form of symptoms indicative of decreased OCC, and 15 (0.7%) patients in the placebo group.

Diabetic ketoacidosis in DM2

. In the DECLARE study with a median exposure of 48 months, diabetic ketoacidosis events were reported in 27 patients in the dapagliflozin 10 mg group and 12 patients in the placebo group. These phenomena occurred uniformly during the study period. In the dapagliflozin group, out of 27 patients with diabetic ketoacidosis

22 were receiving concomitant insulin therapy at the time the phenomenon developed. Predisposing factors for the development of diabetic ketoacidosis were expected in the DM2 population (see “Special Indications”).

In the DAPA-HF study, diabetic ketoacidosis events were reported in 3 patients with DM2 in the dapagliflozin group and none in the placebo group.

In the DAPA-CKD study, diabetic ketoacidosis was not reported in any patient in the dapagliflozin group, but was reported in 2 patients with DM2 in the placebo group.

Urinary tract infections

. In pooled safety data from 13 studies, urinary tract infections were more frequently reported with dapagliflozin 10 mg than with placebo (4.7% vs. 3.5%, respectively; see See section “Special Indications”). Most infections were mild to moderate; the initial course of standard therapy was effective, and patients rarely discontinued dapagliflozin. These infections were more frequent in women, and patients with a history of such infections were more likely to have recurrent infections.

In the DECLARE study, serious urinary tract infections were reported less frequently for dapagliflozin 10 mg compared with placebo: 79 (0.9%) events compared with 109 (1.3%) events, respectively.

In the DAPA-HF study, the number of patients with serious adverse events in the form of urinary tract infections was small and balanced: 14 (0.6%) patients in the dapagliflozin group and 17 (0.7%) patients in the placebo group. The dapagliflozin and placebo groups each had 5 (0.2%) patients with adverse events leading to discontinuation of treatment because of urinary tract infections.

In the DAPA-CKD trial, serious adverse events in the form of urinary tract infections were noted in 29 (1.3%) patients in the dapagliflozin group and in 18 (0.8%) patients in the placebo group. There were 8 (0.4%) patients in the dapagliflozin group with adverse events leading to discontinuation of treatment due to urinary tract infections and 3 (0.1%) patients in the placebo group. The number of patients who had serious adverse events or adverse events leading to discontinuation of treatment because of urinary tract infections was small and similar between treatment groups (6 [0.9%] compared with 4 [0.6%] for serious adverse events; 1 [0.1%] compared with 0 for adverse events leading to discontinuation of treatment) among patients without diabetes.

Elevated creatinine concentration

. The adverse reactions associated with increased creatinine concentrations were grouped (e.g., decreased renal clearance of creatinine, impaired renal function, increased blood creatinine concentration, and decreased GFR). In pooled safety data from 13 studies, this group of reactions was reported in 3.2% and 1.8% of patients receiving dapagliflozin 10 mg and placebo, respectively. In patients with normal or mild renal function impairment (baseline rCFR ≥60 mL/min/1.73 m2), this group of reactions was reported in 1.3% and 0.8% of patients receiving dapagliflozin 10 mg and placebo, respectively. These reactions were more common in patients with a baseline rSFR ≥30 and < 60 mL/min/1.73 m2 (18.5% in the dapagliflozin 10 mg group compared with 9.3% in the placebo group).

Additional evaluation of patients with adverse events related to renal function showed that most of these patients showed a change in serum creatinine concentration of ≤0.5 mg/dL from baseline. The increase in creatinine concentration was generally temporary with continuation of therapy or reversible after discontinuation of therapy.

In the DECLARE study, which included elderly patients and patients with impaired renal function (rCF less than 60 mL/min/1.73 m2), rCF decreased over time in both treatment groups. After 1 year of therapy, the mean rSKF value was slightly lower in the dapagliflozin group and slightly higher after 4 years of therapy compared with the placebo group.

In the DAPA-HF study, there was a decrease in mean rSKF, which was initially more pronounced in the dapagliflozin group compared to the placebo group. After 20 months, the change in rGFR relative to baseline was similar between treatment groups.

Overdose

Pregnancy use