Forxiga: Drug used in diabetes

2021-06-13 08:23 PM

Following the administration of Forxiga (dapagliflozin), an increase in urinary glucose excretion was observed in healthy subjects and in patients with type 2 diabetes mellitus, approximately 70 g of glucose was excreted in the urine per day.

Producer

AstraZeneca.

Ingredient

Each tablet: Dapagliflozin 5mg or 10mg.

Describe

Forxiga 5mg: Yellow, biconvex, round, film-coated tablets with a diameter of 0.7 cm, engraved with the number "5" on one side, and the number "1427" on the other side.

Forxiga 10mg: Yellow, biconvex, diamond-shaped, film-coated tablets with a diagonal of 1.1 x 0.8 cm, engraved with the number "10" on one side, and the number "1428" on the other side.

Pharmacodynamic properties

Group of therapeutic effects: Drugs used in diabetes, Na-glucose co-transporter protein 2 (SGLT2) inhibitors, ATC code: A10BK01.

Mechanism of action

Dapagliflozin has a strong (Ki: 0.55 nM), selective and reversible inhibitory effect on SGLT2.

SGLT2 occurs selectively in the kidney and is not detected in more than 70 other tissues including liver, skeletal muscle, adipose tissue, breast, bladder, and brain. SGLT2 is the major transporter for the reabsorption of glucose from the renal tubules into the circulation. Although blood glucose is elevated in type 2 diabetes, reabsorption of filtered glucose continues. Dapagliflozin improves both fasting and postprandial blood glucose levels by reducing renal glucose reabsorption leading to urinary glucose excretion. Glucose excretion (hyperglycaemic effect) was observed after the first dose, continued through 24 hours of dosing, and maintained throughout treatment. The amount of glucose excreted by the kidneys by this mechanism depends on the blood glucose concentration and the glomerular filtration rate (GFR). Dapagliflozin does not impair endogenous glucose production by reducing blood glucose. Dapagliflozin acts independently of insulin secretion and insulin action. Improvements in the homeostasis model of beta-cell function (HOMA beta-cell) have been reported in clinical studies with Forxiga.
 
Increased urinary glucose excretion (glucuresis) due to dapagliflozin has been associated with decreased energy and weight loss. Inhibition of glucose and sodium co-transportation by dapagliflozin has also been associated with mild diuresis and transient hypernatremia.

Dapagliflozin does not inhibit glucose transport factors important for the transport of glucose into peripheral tissues and is >1,400-fold more specific on SGLT2 than SGLT1 which is the major transporter for intestinal glucose absorption.

Pharmacokinetic effects

Following the administration of dapagliflozin, an increase in urinary glucose excretion was observed in healthy subjects and in patients with type 2 diabetes. Approximately 70 g of glucose was excreted in the urine per day (equivalent to 280 kCal/day) in dapagliflozin 10 mg/day in patients with type 2 diabetes mellitus for 12 weeks. There is evidence of glucose excretion in patients with type 2 diabetes who received dapagliflozin 10 mg/day for up to 2 years.

Urinary excretion of glucose by dapagliflozin also induces an osmotic diuretic effect and increases urine output in patients with type 2 diabetes. Increased urine volume in type 2 diabetic patients treated with dapagliflozin 10 mg for up to 12 weeks and in amounts of about 375 mL/day. Increased urine output associated with mild and transient hypernatremia does not alter serum sodium concentrations.

Uric acid excretion in the urine is also transiently increased (for 3-7 days) and is accompanied by a prolonged decrease in serum uric acid. At week 24, serum uric acid decreased from -48.3 to -18.3 micromol/L (-0.87 to -0.33 mg/dL).

Clinical efficacy and safety

14 double-blind, randomized, controlled clinical trials performed in 7,056 patients with type 2 diabetes to evaluate the efficacy and safety of Forxiga; 4,737 patients in these trials were treated with dapagliflozin. 12 studies had a treatment duration of 24 weeks, 8 were long-term extension studies of 24 to 80 weeks (total study duration was 104 weeks), one study had a treatment duration of 28 weeks, and one study had a treatment duration of 28 weeks. study 52 weeks long-term extension by 52 and 104 weeks (total study duration 208 weeks). The median duration of diabetes was 1.4 to 16.9 years. 50% of patients with mild renal impairment and 11% with moderate renal impairment. 51% of patients were male, 84% Caucasian, 8% Asian, 4% Colored, and 4% other races. 81% of patients had a body mass index (BMI) ≥27. Furthermore, two 12-week, placebo-controlled studies were performed in patients with poorly controlled type 2 diabetes and hypertension.

Control blood sugar

Monotherapy

A double-blind, placebo-controlled, 24-week study (with extension) was conducted to evaluate the safety and efficacy of Forxiga monotherapy in patients with poorly controlled type 2 diabetes. blood sugar. Treatment with dapagliflozin once daily resulted in a statistically significant (p<0.0001) decrease in HbA1c compared with placebo.

In the extended phase, the decrease in HbA1c was maintained for 102 weeks (adjusted mean change from baseline for dapagliflozin 10 mg and placebo -0.61% and -0.17%, respectively).

Complementary therapy

A 52-week, controlled, non-inferiority study (long-term extension by 52 weeks and 104 weeks) evaluated Forxiga as an add-on combination therapy to metformin versus an add-on sulfonylurea (glipizide) with metformin in patients with inadequate glycemic control (HbA1c >6.5% and ≤10%). Results showed that the mean decrease in HbA1c at week 52 from baseline was comparable to that of glipizide, demonstrating non-inferiority. At week 104, the baseline adjusted mean change in HbA1c was -0.32% for dapagliflozin and -0.14% for glipizide. At week 208, the baseline-corrected mean change in HbA1c was -0.10% for dapagliflozin and 0.20% for glipizide. At weeks 52, 104, and 208, the proportion of patients with at least 1 hypoglycemic event in the dapagliflozin group (3.5%, 4.3%, and 5.0%, respectively) was significantly lower. significant compared with glipizide treatment group (40.8%, 47.0% and 50.0%, respectively). The proportions of patients remaining in the study at 104 and 208 weeks in the dapagliflozin group were 56.2% and 39.7% and in the glipizide group 50.0% and 34.6% respectively.

Dapagliflozin in addition to metformin, glimepiride, metformin, and sulfonylurea, sitagliptin (with or without metformin), or insulin resulted in statistically significant reductions in HbA1c at week 24 compared with placebo (p<0.0001).

The decrease in HbA1c observed at week 24 was maintained in the add-on combination studies (with glimepiride and insulin) with data for 48 weeks (glimepiride) and data up to 104 weeks (insulin). At week 48 in combination with sitagliptin (with or without metformin), the baseline adjusted mean change for dapagliflozin 10 mg and placebo was -0.30% and 0.38, respectively. %. In the add-on combination study with metformin, the HbA1c reduction was maintained for up to 102 weeks (baseline-adjusted mean change for dapagliflozin 10 mg and placebo -0.78% and 0. 02%). At week 104 for insulin (with or without an oral glucose-lowering agent), baseline adjusted mean change in HbA1c reduction for dapagliflozin 10 mg and placebo was -0.71%, respectively. and -0.06%. At weeks 48 and 104, the insulin dose in the dapagliflozin 10 mg group remained stable at an average dose of 76 IU/day from baseline. In the placebo group at weeks 48 and 104, the mean increase from baseline was 10.5 IU/day and 18.3 IU/day, respectively (mean dose 84 and 92 IU/day). The proportion of patients remaining in the study at week 104 in the dapagliflozin 10 mg group was 72.4% and in the placebo group 54.8%.

Combination therapy with metformin in previously untreated patients

A total of 1,236 untreated types 2 diabetes patients (HbA1c 7.5% and 12%) enrolled in 2 24-week controlled studies to assess safety and efficacy. Efficacy of dapagliflozin (5 mg or 10 mg) in combination with metformin in previously untreated patients compared with monotherapy.

Co-administration of dapagliflozin 10 mg with metformin (dose up to 2000 mg/day) resulted in a significant improvement in HbA1c compared with treatment with either drug alone, with greater reductions in fasting glucose (FPG). (compared to individual drugs) and weight loss (compared to metformin).

Combination therapy with extended-release exenatide

A 28-week, double-blind, comparative controlled study to compare the efficacy of combination therapy of dapagliflozin and extended-release exenatide (GLP-1 receptor agonist) with dapagliflozin monotherapy and extended-release exenatide as monotherapy in patients with inadequate glycemic control on metformin monotherapy (HbA1c ≥8% and ≤12%). All treatment groups had decreased HbA1c from baseline. The combination therapy with dapagliflozin 10 mg and extended-release exenatide reduced HbA1c from baseline more strongly than dapagliflozin alone and extended-release exenatide alone.

Hungry glycemia

Treatment with dapagliflozin 10 mg as monotherapy or in addition to metformin, glimepiride, metformin and a sulfonylurea, sitagliptin (with or without metformin) or insulin resulted in statistically significant (-1, 90 to -1.20 mmol/L [-34.2 to -21.7 mg/dL]) versus placebo (-0.33 to 0.21 mmol/L [-6.0 to 3.8 mg) /dL]). This effect was observed at week 1 of treatment and maintained up to week 104 of the extended study.

At week 28, combination therapy of dapagliflozin 10 mg with extended-release exenatide resulted in a significantly higher reduction in the fasting blood glucose (FPG) index (FPG) of -3.66 mmol/L (-65.8 mg/dL) compared with dapagliflozin monotherapy [2.73 mmol/L (-49.2 mg/dL) (p<0.001)] and exenatide monotherapy group [-2.54 mmol/L] (-45.8 mg/dL) (p<0.001)].

Glycemia after eating

Treatment with dapagliflozin 10 mg in addition to glimepiride significantly reduced postprandial glycemia 2 hours at week 24 and maintained until week 48.

Treatment with dapagliflozin 10 mg in addition to sitagliptin (with or without metformin) reduced postprandial glycemia 2 hours at week 24 and maintained until week 48.

The combination therapy of dapagliflozin 10 mg with extended-release exenatide resulted in a significantly higher 2 h postprandial hypoglycemia compared with the monotherapy group at week 28.

Weight

Dapagliflozin 10 mg in addition to metformin, glimepiride, metformin, and sulfonylurea, sitagliptin (with or without metformin), or insulin was statistically significant after 24 weeks (p < 0.0001). This result is Sustained over longer tests. At week 48, the difference between dapagliflozin plus sitagliptin (with or without metformin) versus placebo was -2.22 kg. At week 102, the difference between dapagliflozin plus metformin versus placebo or add-on insulin differed from placebo by -2.14 and -2.88 kg, respectively.

As an add-on to metformin in a non-inferior, controlled study, dapagliflozin resulted in significant weight loss compared with glipizide, -4.65 kg at week 52 (p < 0.0001) and maintained up to 104 and 208 (-5.06kg and -4.38kg respectively).

Combination therapy of dapagliflozin 10 mg with extended-release exenatide resulted in much greater weight loss than would mean single-value use.

A 24-week study of 182 diabetic patients using dual-energy X-ray absorptiometry (DXA) to assess body composition for dapagliflozin 10 mg in combination with metformin reduced weight and body fat as measured by DXA compared with the descriptor or fluid loss with placebo and metformin. Treatment with Forxiga in combination with metformin gave visceral mean reduction compared with users and metformin in a magnetic resonance imaging study.

Blood pressure

A parser on 13 In a placebo-controlled study, treatment with dapagliflozin 10 mg resulted in a 3.7 mmHg reduction in systolic blood pressure and a 1.8 mmHg decrease in diastolic blood pressure compared with a 0.5 mmHg decrease in systolic blood pressure and a 0. 5 mmHg diastolic blood pressure in the placebo group at week 24 from baseline. Similar incidents were also recorded up to week 104.

At week 28, the combination of dapagliflozin 10 mg with extended-release exenatide resulted in a significantly greater reduction in systolic blood pressure (-4.3 mmHg) than in the dapagliflozin group alone (-1.8 mmHg, p < 0.05). ) and exenatide magnified long single value data (-1.2 mmHg, p < 0.01).

In 2 12-week placebo-controlled studies, 1,062 patients with type 2 diabetes were poorly monitored for blood glucose and blood pressure (despite prior stabilization with ACE-I or ARB in one Study). study and ACE-I or ARB plus a therapeutic pressure method in another) were treated with dapagliflozin 10 mg or placebo. At week 12 of both studies, dapagliflozin 10 mg in combination with a common antidiabetic drug improved HbA1c and reduced systolic blood pressure by 3.1 and 4.3 mmHg, respectively (after placebo adjusted, respectively. ).

Cardiovascular safety

An integrated pool of fixed variable cardiac circuits in clinical studies was performed. In this clinical study, at baseline 34.4% of patients had a history of cardiovascular disease (except hypertension) and 67.9% of patients had hypertension. Variable fixed circuits are reviewed by an independent board. The standard primary meeting at the first occurrence of the following events: cardiovascular death, activation, myocardial infarction, or hospitalization for lumbar instability. Attempts to change were 1.62% patient-years in the dapagliflozin arm and 2.06% patient-years in the comparator arm. The hazard ratio between dapagliflozin and comparator was 0.79 (95% CI [CI]: 0.58; 1.07), forxiga is found in this parsing in type 2 diabetic patients. Disease mortality. Cardiovascular, myocardial, or socket was scored with a hazard ratio of 0.77 (95% CI: 0.54; 1.10).

Type 2 diabetic patient with kidney

Patients with mild renal impairment (estimated glomerular filtration rate eGFR 60 to <90mL/min/1.73m2)

In a clinical trial of more than 3000 patients with mild renal impairment corrected with dapagliflozin. Efficacy was assessed based on an analysis obtained from 9 clinical studies performed in 2226 patients with mild renal impairment. At week 24, the mean change in hemoglobin A1c (HbA1c) from baseline and mean change in HbA1c after placebo adjusted was -1.03% and -0.54%, respectively, in the Forxiga 10mg trial. (n = 562). Safety data in mildly considered patients were similar to those obtained in the overall study.

Patients with moderate renal impairment (estimated glomerular filtration rate eGFR 30 to <60mL/min/1.73m2)

The efficacy and safety of Forxiga were evaluated in 2 specialized studies in patients with moderate renal impairment and in 2 subgroup analyzes of clinical studies.

In a randomized, double-blind, placebo-controlled study of a total of 321 adult patients with type 2 diabetes with eGFR 45 to <60 mL/min/1.73 m2 (the group of patients with moderate renal impairment). moderate - chronic kidney disease CKD 3A), treated with Forxiga 10 mg or placebo did not have good glycemic control with the current treatment regimen. At week 24, Forxiga 10mg (n=159) significantly improved HbA1c, fasting glycemic index (FPG), body weight, and systolic blood pressure (SBP) compared with placebo (n=161). Mean change from baseline in HbA1c and mean change in HbA1c after adjusted placebo were -0.37% and -0.34%, respectively. Mean change from baseline and mean change in FPG after placebo adjusted were -21.46 mg/dL and -16.59 mg/dL, respectively. Mean body weight loss (in %) and mean weight loss after placebo adjusted were -3.42% and -1.43%, respectively. Mean sitting systolic blood pressure (SBP) and mean SPB reductions after adjusted placebo were -4.8 mmHg and -3.1 mmHg, respectively.

The safety data of dapagliflozin in this study were similar to those obtained from the general population of patients with type 2 diabetes. Mean eGFR decreased during the initial treatment with dapagliflozin and remained stable thereafter. during 24 weeks of treatment (dapagliflozin: -3.39 mL/min/1.73m2 and placebo: -0.90 mL/min/1.73m2). After 3 weeks of discontinuing Forxiga, the mean change in eGFR from baseline in the dapagliflozin group was similar to that in the placebo group (Forxiga: 0.57 mL/min/1.73m2 and placebo: -0.04 mL). /min/1.73m2).

Efficacy in patients with moderate renal impairment was evaluated based on a meta-analysis obtained from 9 clinical studies (366 patients, 87% had eGFR ≥45 to <60 mL/min/1.73m2); These pooled data did not include 2 specific studies in patients with diabetes mellitus with moderate renal impairment. Mean change in HbA1c from baseline and mean change in HbA1c after placebo adjusted at week 24 were -0.87% and -0.39% when treated with Forxiga 10mg (n=85), respectively. ).

Safety of patients with moderate renal impairment was evaluated based on a meta-analysis of 12 clinical studies (384 patients, 88% had eGFR ≥45 to <60 mL/min/1.73m2); These pooled data did not include 2 specific studies in patients with diabetes mellitus with moderate renal impairment. At week 24, the safety data were similar to those observed in the review of the clinical trials except for the proportion of patients who reported at least one adverse event related to renal failure or renal disease. end-stage disease (7.9% in the Forxiga 10mg group versus 5.6% in the placebo group). Among these events, the most frequent was an increase in serum creatinine (6.7% in the Forxiga 10 mg group versus 2.8% in the placebo group). The mean increases in parathyroid hormone (PTH) and serum phosphorus observed in the Forxiga group in the clinical study review were similarly observed in the meta-analysis. Long-term and short-term safety data were pooled up to week 102, resulting in similar safety data.

Safety and efficacy of dapagliflozin were also evaluated based on 1 study of 252 diabetic patients with eGFR ≥30 to <60 mL/min/1.73m2 (moderate renal impairment subgroups CKD 3A and CKD 3B). . At week 24, treatment with Forxiga did not significantly change HbA1c (after adjusting for placebo) in the total study population (combined CKD 3A and CKD 3B groups). In the additional analysis of the CKD 3A subgroup, Forxiga 10mg (n=32) resulted in a -0.33% mean change in HbA1c after placebo adjusted at week 24. At week 52, Forxiga resulted in a mean change in eGFR from baseline (Forxiga 10mg -4.46 mL/min/1.73m2 and placebo -2.58 mL/min/1.73m2). This change remained until week 104 (eGFR: Forxiga 10mg -3.50 mL/min/1.73m2 and placebo -2.38 mL/min/1.73m2). Treatment with Forxiga 10 mg decreased eGFR at the first week of treatment and remained stable up to week 104, whereas the eGFR in placebo-treated patients decreased continuously until week 52 and remained stable until week 104.

At week 52 and extending through week 104, mean increases in mean serum PTH and phosphorus were observed in this study in the Forxiga 10 mg group than in the placebo group, where baseline values ​​were observed. of these analyses. Increases in potassium levels 6 mEq/L were more common in placebo-treated patients (12%) than in Forxiga 5 mg and 10 mg (4.8% at both concentrations) groups during the treatment period. Cumulative value up to 104 weeks. The proportion of patients discontinuing treatment when potassium levels were elevated or potassium levels corrected from baseline was higher in the placebo group (14.3%) than in the Forxiga group (6.9% and 6.9%, respectively). .7% for the 5mg and 10mg groups).

Overall, up to week 104, 13 patients had reported fracture adverse reactions in this study, of which 8 occurred in the Forxiga 10mg group and 5 in the Forxiga group. 5mg and none occurred in the placebo group. Eight of the 13 fractures occurred in patients with an estimated eGFR 30 to 45 mL/min/1.73 m2 and 10 of the 13 reported fractures occurred within the first 52 weeks of treatment. treat. There is no clear image of the fracture site. No imbalance in fractures was observed in the safety analysis from the pooled data of 12 studies, and no study-specific fractures were reported in patients with eGFR 45 to < 60 mL/min/1.73m2 (CKD group 3A).

Patients with baseline HbA1c 9%

In a pooled analysis of patients with HbA1c 9.0 %, treatment with dapagliflozin 10 mg as monotherapy resulted in a statistically significant decrease in HbA1c at week 24 (mean change from baseline in the dapagliflozin 10 group). mg and in the placebo group -2.04% and 0.19%, respectively) and in add-on to metformin (mean change from baseline in the dapagliflozin 10 mg and placebo groups respectively). respectively -1.32% and -0.53%).

Children

The efficacy and safety of dapagliflozin in children 0 to less than 18 years of age have not been established. No data currently available.

Pharmacokinetic properties

Absorb

Dapagliflozin is well and rapidly absorbed after oral administration. Maximum dapagliflozin plasma concentrations (Cmax) are usually reached within 2 hours of dosing in the fasted state. The mean Cmax and AUCτ at steady state after oral administration of dapagliflozin 10 mg once daily were 158 ng/mL and 628 ng h/mL, respectively. The absolute oral bioavailability of dapagliflozin after a 10 mg dose is 78%. Administration with a high-fat meal reduced dapagliflozin Cmax by 50% and prolonged Tmax by about 1 hour but had no effect on AUC compared with fasting dosing. These changes are of no clinical significance. Therefore, Forxiga can be taken with or without meals.

Distribution

Dapagliflozin is about 91% protein bound. Protein binding is not affected by various disease conditions (such as liver or kidney failure). The mean volume of distribution of dapagliflozin at steady-state is 118 liters.

Metabolism

Dapagliflozin is extensively and principally metabolized to dapagliflozin 3-O-glucuronide, an inactive metabolite. Dapagliflozin 3-O-glucuronide or other metabolites do not contribute to the hypoglycemic effect. Dapagliflozin 3-O-glucuronide is formed via UGT1A9, an enzyme found in the liver and kidneys, and metabolism by CYP is a secondary clearance pathway in humans.

Elimination

The mean elimination half-life (t½) of dapagliflozin in healthy subjects was 12.9 hours after a 10 mg dose of dapagliflozin. The mean total clearance of dapagliflozin when administered intravenously was 207 mL/min. Dapagliflozin and related metabolites are eliminated primarily by the kidneys in the urine with less than 2% unchanged dapagliflozin. Following administration of [14C]-dapagliflozin 50 mg, 96% were recovered, 75% in urine, and 21% in feces. In the feces, about 15% of the administered dose is excreted as the parent drug.

Linear

The concentration and duration of exposure of dapagliflozin increased proportionally with the dapagliflozin dose level in the range of 0.1 to 500 mg and the pharmacokinetics did not change with the duration of daily dosing up to 24 weeks.

Special object

Kidney failure

At steady state (20 mg dapagliflozin once daily for 7 days), patients with type 2 diabetes mellitus with mild, moderate, or severe renal impairment (as determined by serum iohexol clearance) had plasma concentrations and Mean exposure time of dapagliflozin was 32%, 60%, and 87% higher, respectively than in type 2 diabetic patients with normal renal function. The 24-hour steady-state urinary glucose excretion is highly dependent on renal function and the amount of glucose excreted in patients with type 2 diabetes mellitus with normal renal function, mild, moderate, or severe renal impairment. respectively 85, 52, 18, and 11 g glucose/day. The effect of hemodialysis on dapagliflozin exposure and exposure time is unknown.

Liver failure

In patients with mild and moderate hepatic impairment (Child-Pugh classifications A and B), the mean Cmax and AUC of dapagliflozin were 12% and 36% higher, respectively, than in healthy controls. These differences are not clinically significant. In patients with severe hepatic impairment (Child-Pugh class C), mean Cmax and AUC of dapagliflozin were 40% and 67% higher, respectively than in healthy controls.

Elderly (≥65 years old)

In patients less than 70 years of age, the concentrations and exposure times did not increase statistically with age. However, exposure and exposure times may increase due to age-related decline in renal function. There are insufficient data to conclude on concentrations and duration of exposure in patients >70 years of age.

Children

The pharmacokinetics of children have not been studied.

Sex

The estimated mean AUCss of dapagliflozin in women was about 22% higher than in men.

Race

Concentrations and duration of exposure in Caucasians, Blacks, or Asians were not clinically significant.

Weight

The exposure and exposure time of dapagliflozin decreased with increasing weight. Therefore, exposure and exposure time may be increased in low-weight patients and decreased in heavy-weight patients. However, the difference in concentration and exposure time was not clinically significant.

Indications and usage

Forxiga is indicated for the treatment of patients 18 years of age and older with type 2 diabetes mellitus to control blood glucose in:

Monotherapy: When diet and exercise do not provide adequate glycemic control in patients who are not suitable for metformin due to intolerance.

Add-on combination therapy: In combination with other hypoglycemic agents, including insulin, when these drugs in combination with diet and exercise do not provide adequate glycemic control.

Dosage

Monotherapy and add-on combination therapy

The recommended dose is 10 mg dapagliflozin once daily as monotherapy or in add-on therapy with other glucose-lowering agents including insulin. When dapagliflozin is used in combination with insulin or with an insulin secretagogue such as a sulfonylurea, a low dose of insulin or an insulin secretagogue should be used to limit the risk of hypoglycemia.

Special Objects

Kidneys falure

Forxiga is not recommended for the treatment of diabetes in patients with an estimated glomerular filtration rate eGFR continuously below 45 mL/min/1.73 m2 because efficacy in glycemic control is dependent on renal function.

No dose adjustment is required based on renal function.

Liver failure

No dose adjustment is required for patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, the recommended starting dose is 5 mg. If well tolerated, the dose can be increased to 10 mg.

Elderly (≥65 years old)

In general, no dose adjustment according to age is recommended. Renal function and the risk of hypovolemia should be considered.

Due to limited therapeutic experience in patients 75 years of age and older, initiation of treatment with dapagliflozin is not recommended.

Children

The efficacy and safety of dapagliflozin in children 0 to less than 18 years of age have not been established. No data currently available.

How to use

Forxiga can be taken once a day at any time of the day, with or without meals. The pill should be taken whole.

Use caution

Generality

Forxiga must not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Kidney failure

Before initiating therapy with Forxiga, renal function should be assessed and periodically thereafter. Forxiga is not recommended for the treatment of diabetes in patients with an estimated glomerular filtration rate eGFR continuously below 45 mL/min/1.73 m because the efficacy of dapagliflozin in glycemic control is dependent on renal function. Forxiga has not been studied in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) or end-stage renal disease (ESRD).

Renal function monitoring is recommended in the following cases:

Before starting dapagliflozin and then at least once a year.

Before initiating coadministration with drugs that may decrease renal function and periodically thereafter.

When renal function falls close to eGFR 45mL/min/1.73m2, monitor at least 2-4 times/year. If renal function continues to fall below the estimated glomerular filtration rate [eGFR] < 45 mL/min/1.73 m2, dapagliflozin therapy should be discontinued.

Patients with liver failure

Clinical experience in patients with hepatic impairment is limited. The exposure and exposure time of dapagliflozin are increased in patients with severe hepatic impairment.

Use in patients at risk of hypovolaemia, hypotension, and/or electrolyte imbalance

Due to its mechanism of action, dapagliflozin increases urinary excretion which is associated with a moderate decrease in blood pressure that may be more pronounced in patients with very high blood glucose concentrations.

The use of dapagliflozin is not recommended in patients receiving loop diuretics or in patients with hypovolemia due to acute illness (eg, gastrointestinal disease).

Caution should be exercised in patients at risk of hypotension due to dapagliflozin, such as patients with pre-existing cardiovascular disease, patients on antihypertensive therapy with a history of hypotension, or elderly patients.

For patients receiving dapagliflozin, in the event of conditions that may predispose to hypovolaemia, careful monitoring of volume status (eg, physical examination, blood pressure measurement, laboratory tests included) is recommended. hematocrit) and electrolytes. Treatment with dapagliflozin should be withheld in hypovolemic patients until the hypovolemia has corrected.

Diabetic ketoacidosis

Rare cases of diabetic ketoacidosis (DKA), including life-threatening and fatal cases, have been reported in patients treated with protein agonist inhibitors. Na-glucose transfer 2 (SGLT2), including dapagliflozin. In some cases, the disease presents atypically with only moderate elevations in blood glucose, below 14 mmol/L (250 mg/dL). It is not known whether DKA is more likely to occur with higher doses of dapagliflozin.

The risk of diabetic ketoacidosis must be considered in the presence of atypical symptoms such as nausea, vomiting, loss of appetite, abdominal pain, thirst, dyspnea, confusion, unusual fatigue. or sleepy. Patients should be evaluated for ketoacidosis immediately if these symptoms develop, regardless of blood glucose levels.

Dapagliflozin therapy should be discontinued immediately in patients with suspected or diagnosed ketoacidosis.

Treatment should be temporarily discontinued in patients hospitalized for major surgery or acute serious illness. In either case, dapagliflozin can be reintroduced once the patient's condition has stabilized.

Before initiating dapagliflozin, predisposing factors for ketoacidosis should be considered in the patient's history.

Patients who may be at high risk for ketoacidosis include patients with low beta-cell functional reserve (such as patients with low C-peptide type 2 diabetes or latent autoimmune diabetes in adults (LADA) or patients with a history of pancreatitis), patients with limited food intake or severe dehydration, patients with reduced insulin doses, and patients with increased insulin requirements due to acute illness, surgery, or Alcoholism. SGLT2 inhibitors should be used with caution in these patients.

The reintroduction of SGLT2 inhibitors is not recommended in patients with DKA on prior SGLT2 inhibitor therapy unless another obvious factor is identified and resolved.

The efficacy and safety of dapagliflozin in patients with type 1 diabetes have not been established and dapagliflozin should not be used in the treatment of patients with type 1 diabetes. Limited data from clinical trials suggest that DKA occurs. with common frequency in type 1 diabetic patients treated with SGLT2 inhibitors.

Urinary tract infections

In a 24-week meta-analysis, urinary tract infections were observed more frequently with dapagliflozin 10 mg than with placebo.

Pyelonephritis was uncommon and occurred with a similar frequency to the control group. Urinary glucose excretion may be associated with an increased risk of urinary tract infections; therefore, consideration should be given to temporarily discontinuing dapagliflozin while being treated for pyelonephritis or urinary tract infection.

Elderly (≥65 years old)

Elderly patients often have reduced renal function and/or use of antihypertensive drugs that may alter renal function such as angiotensin-converting enzyme (ACE-I) inhibitors and type 1 angiotensin II receptor blockers. (ARB). The recommendations for patients with renal impairment are also applicable to elderly patients and to all patient populations.

In patients ≥65 years of age, a higher proportion of dapagliflozin-treated patients experienced adverse events related to decreased renal function or renal failure compared with placebo. The most commonly reported adverse reaction related to renal function was an increase in serum creatinine, most of which were transient and reversible.

Elderly patients may be at higher risk of hypovolemia and are often treated with diuretics. In patients ≥65 years of age, a higher proportion of dapagliflozin-treated patients experienced volume depletion-related adverse events.

Treatment experience in patients 75 years of age and older is limited. Initiation of treatment with dapagliflozin is not recommended in this population.

Heart failure

Experience in patients with NYHA class I-II heart failure is limited and there is no experience in clinical studies with dapagliflozin in patients with NYHA class III-IV heart failure.

Use in patients treated with pioglitazone

While a causal relationship between dapagliflozin and bladder cancer is unclear, as a precaution, the concomitant use of dapagliflozin in patients treated with pioglitazone is not recommended. The available epidemiological data for pioglitazone indicate a small increased risk of bladder cancer in diabetic patients treated with pioglitazone.

Increased hematocrit

An increase in hematocrit has been reported during treatment with dapagliflozin. Therefore, extreme caution must be exercised in patients who already have elevated hematocrit.

Urine test

Due to the drug's mechanism of action, patients taking Forxiga will have a positive urine glucose test result.

Lactose

The tablet contains lactose (anhydrous). Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Effects on ability to drive and use machinery

Forxiga has no or negligible 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 sulfonylurea or insulin.

Overdose

Dapagliflozin did not show toxicity in healthy subjects taking single doses up to 500 mg (50 times the maximum recommended human dose). These subjects had detectable glucose in the urine for a dose-related period (at least 5 days for the 500 mg dose), with no reports of dehydration, hypotension, or electrolyte imbalances. resolved, and had no clinically significant effect on the QTc interval. The rate of hypoglycemia was comparable to that of placebo. In clinical studies using once-daily doses up to 100 mg (10 times the maximum recommended human dose) in healthy subjects and in patients with type 2 diabetes mellitus for 2 weeks, the incidence of hypoglycemia was high. than placebo and was not dose-related. Rates of adverse events including dehydration or hypotension were comparable to placebo, and laboratory parameters including serum electrolytes and biomarkers of renal function were not significantly changed. clinical significance is dose-related.

In the case of overdose, supportive treatment should be initiated according to the clinical condition of the patient. The exclusion of dapagliflozin by dialysis has not been studied.

Contraindications

Hypersensitivity to the active substance or to any of the excipients of the drug.

Use in pregnant and lactating women

Pregnant

There are no data on the use of dapagliflozin in pregnant women. Studies in rats have shown developing nephrotoxicity in the second and third trimesters of human pregnancy, respectively. Therefore, the use of dapagliflozin during the second and third trimesters of pregnancy is not recommended.

When pregnancy is detected, treatment with dapagliflozin should be discontinued.

Breastfeeding

It is not known whether dapagliflozin and/or its metabolites are excreted in human milk. Pharmacodynamic/toxicological data in animals indicate that dapagliflozin/metabolites are excreted in milk, as well as having a pharmacological effect on nursing infants. The risk to the infant/child cannot be ignored. Dapagliflozin should not be used while breastfeeding.

Fertility

The effects of dapagliflozin on fertility in humans have not been studied. In male and female rats, dapagliflozin had no effect on fertility at any of the doses tested.

Interactive

Diuretic

Dapagliflozin may enhance the diuretic effect of thiazides, loop diuretics and may increase the risk of dehydration and hypotension.

Insulin and insulin secretagogues

Insulin and insulin secretagogues such as sulfonylureas can cause hypoglycemia. Therefore, it is necessary to use low doses of insulin or insulin secretagogues to limit the risk of hypoglycemia when used in combination with dapagliflozin.

Dapagliflozin is metabolized primarily by the indirect glucuronide conjugation pathway via UDP glucuronosyltransferase 1A9 (UGT1A9).

In in vitro studies, dapagliflozin did not inhibit cytochrome P450 (CYP) 1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, nor induce CYP1A2, CYP2B6 or CYP3A4. Therefore, dapagliflozin does not affect the metabolic clearance of drugs metabolized by these enzymes when co-administered.

Effects of other drugs on dapagliflozin

Interaction studies conducted in healthy subjects, mainly using a single dose design, showed that the pharmacokinetics of dapagliflozin was not affected by metformin, pioglitazone, sitagliptin, glimepiride, voglibose, hydrochlorothiazide, bumetanide, valsartan, or simvastatin.

When dapagliflozin was co-administered with rifampicin (an inducer of multiple active transporters and drug-metabolizing enzymes), a 22% decrease in dapagliflozin exposure and time of exposure (AUC) was observed, but no effect was observed. clinically significant to 24-hour urinary glucose excretion. No dose adjustment is recommended. There were no clinically significant effects with other inducers (eg, carbamazepine, phenytoin, phenobarbital).

When dapagliflozin was co-administered with mefenamic acid (a UGT1A9 inhibitor), a 55% increase in dapagliflozin exposure and the exposure time was observed, but no clinically significant effect on urinary glucose excretion was observed 24 hours. No dose adjustment is recommended.

Effects of dapagliflozin on other drugs

In interaction studies conducted in healthy subjects, primarily using a single dose design, dapagliflozin had no effect on the pharmacokinetics of metformin, pioglitazone, sitagliptin, glimepiride, hydrochlorothiazide, bumetanide, valsartan, digoxin (one) substrate of P-gp) or warfarin (S-warfarin, a substrate of CYP2C9), or the anticoagulant effect of warfarin as measured by INR. A single dose combination of dapagliflozin 20 mg and simvastatin (a substrate of CYP3A4) resulted in a 19% increase in simvastatin AUC and a 31% increase in simvastatin acid AUC. Increases in exposure and exposure time of simvastatin and simvastatin acid were not clinically significant.

Quantitative assay of 1,5-anhydroglucitol (1.5-AG)

Monitoring of glycemic control with a quantitative 1.5-AG test is not recommended because the measurement of 1.5-AG is unreliable in the assessment of glycemic control in patients taking SGLT2 inhibitors. Recommend alternative methods for monitoring glycemic control.

Children

Interaction studies have only been performed in adults.

Side effects

Safety data summary

In a meta-analysis of 13 placebo-controlled studies, 2,360 patients received dapagliflozin 10 mg and 2,295 patients received placebo.

The most common adverse reaction was hypoglycemia, depending on the background therapy used in each study. The frequency of mild hypoglycaemic episodes was similar in the treatment groups, including the placebo group, except in the add-on sulfonylurea (SU) and insulin combination therapy studies. Combination therapy with sulfonylureas and in addition to insulin has a higher incidence of hypoglycemia.

Adverse reactions

The following adverse reactions have been reported in placebo-controlled clinical trials. There were no dose-related reactions. Adverse reactions were classified by frequency and system organ system (SOC). Frequency groups are conventionally defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (≤1/10,000), and unspecified (cannot be estimated from available data).

Description of selected adverse reactions

Hypoglycemia

The frequency of hypoglycemia depends on the background therapy used in each study.

In studies of dapagliflozin as monotherapy, as an add-on to metformin, or as an add-on to sitagliptin (with or without metformin) up to 102 weeks of treatment, the frequency of mild hypoglycaemic episodes was similar. <5%) between treatment groups, including the placebo group. In all studies, episodes of severe hypoglycemia were uncommon and were similar in the dapagliflozin or placebo groups. Add-on therapy studies with sulfonylureas (SU) and with insulin had a higher incidence of hypoglycemia.

In an add-on study with glimepiride, at weeks 24 and 48, episodes of mild hypoglycemia were more common in the dapagliflozin 10 mg and glimepiride groups (6.0% and 7.9%, respectively). compared with the placebo and glimepiride groups (2.1% and 2.1%, respectively).

In an additional insulin combination study, at weeks 24 and 104 episodes of severe hypoglycemia were 0.5% and 1.0% in the dapagliflozin 10 mg plus insulin group, respectively, and in the insulin group, respectively. placebo plus insulin was 0.5%. At weeks 24 and 104, episodes of mild hypoglycemia in the dapagliflozin 10 mg plus insulin group were 40.3% and 53.1%, respectively, and in the placebo plus insulin group, respectively. 34.0% and 41.6%.

In an add-on study with metformin and a sulfonylurea, up to 24 weeks, no episodes of severe hypoglycemia were observed. Mild episodes of hypoglycemia were observed in 12.8% of patients in the dapagliflozin 10 mg plus metformin and a sulfonylurea group and in 3.7% of patients in the placebo plus metformin and a sulfonylurea drug.

Decreased circulating volume

Volume depletion-related reactions (including dehydration, hypovolemia, or hypotension) were observed in the dapagliflozin 10 mg group and in the placebo group by 1.1% and 0, respectively. 7%; Serious reactions occurred in <0.2% of patients equally in the dapagliflozin 10 mg and placebo groups.

Vaginitis, balanitis, and genital infections

Vaginitis, balanitis, and genital tract infections were reported in the dapagliflozin 10 mg group and in the placebo group by 5.5% and 0.6%, respectively. Most infections are mild to moderate and patients respond to the initial course of treatment with standard therapy and rarely require discontinuation of dapagliflozin. These infections were more common in women (8.4% and 1.2% for dapagliflozin and placebo, respectively) and patients with a history of the disease were more likely to be reinfected.

Urinary tract infections

Urinary tract infections were reported more frequently for patients receiving dapagliflozin 10 mg than for placebo (4.7% and 3.5 percent, respectively). Most infections were mild to moderate and patients responded to the initial course of treatment with standard regimens and rarely required discontinuation of dapagliflozin. These infections are more common in women, and patients with a history of the disease are more likely to be reinfected.

Increase creatinine

Adverse drug reactions associated with increased creatinine are grouped (eg, decreased renal creatinine clearance, renal failure, increased serum creatinine, and decreased glomerular filtration rate). This group of adverse reactions was observed in patients receiving dapagliflozin 10 mg and in patients receiving placebo in 3.2% and 1.8%, respectively. In patients with normal renal function or mild renal impairment (baseline eGFR 60mL/min/1.73m2) this class of adverse reactions has been observed in patients receiving dapagliflozin 10 mg and in patients receiving 10 mg of dapagliflozin. placebo was 1.3% and 0.8%, respectively. These reactions commonly occurred in patients with baseline eGFR ≥30 and <60 mL/min/1.73m2 (18.5% in the dapagliflozin group and 9.3% in the placebo group).

Further evaluation of patients with renal adverse events showed that most had a change in serum creatinine ≤0.5 mg/dL from baseline. Creatinine elevations are usually transient during ongoing therapy or reversible upon discontinuation of therapy.

Parathyroid hormone (PTH)

Slight increases in serum PTH levels have been observed with greater increases in patients with higher baseline PTH levels. Bone density indices in patients with normal renal function or mild renal impairment did not show bone loss during the 2-year treatment period.

Melanoma

In clinical trials, the overall proportion of patients with malignancies or undetermined tumors in the dapagliflozin group (1.50%) was comparable to that in the placebo/comparative drug group (1.50%) ,50%), and there were no indications of carcinogenicity or mutagenicity from animal data. When considering tumors in different organ systems, the relative risk ratio for dapagliflozin was greater than one of several tumor types (bladder, prostate, breast) and small than one of several other tumor types (eg, hematopoietic and lymphatic neoplasms, uterine tumors, and urinary tract tumors), did not increase the overall risk of dapagliflozin for tumorigenesis. No statistically significant difference was observed in the increase or decrease in the risk of tumorigenesis in any organ system. Considering the lack of evidence of tumor occurrence in preclinical trials as well as the short latency period from initial administration to tumor diagnosis, cannot be established. There is a cause-and-effect relationship here. Significant differences in breast, bladder, and prostate tumor numbers should be considered with caution and will be followed up in post-marketing studies.

Special Objects

Elderly (≥65 years old)

In patients ≥65 years of age, adverse events related to decreased renal function or renal failure were observed in the dapagliflozin group in 7.7% and in the placebo group in 3.8%. The most common adverse reaction related to renal function was an increase in serum creatinine. The majority of adverse reactions were transient and reversible. In patients ≥65 years of age, hypovolemic adverse events, most commonly hypotension, were observed in the dapagliflozin and placebo groups of 1.7% and 0, respectively. 8%.

Report suspected adverse reactions

Reporting suspected adverse reactions after pharmaceutical products are authorized is important. This allows continuous monitoring of the balance of benefits and risks of pharmaceutical products. Healthcare professionals are required to report suspected adverse reactions.

Preservation

Store below 30°C.

Presentation and packaging

Film-coated tablets: Box of 2 blisters x 14 tablets.