Forxiga, 30 pcs., 10 mg, film-coated tablets
Use in patients with impaired renal function
The effectiveness of dapagliflozin is dependent on renal function, and this effectiveness is reduced in patients with moderate renal impairment and is likely absent in patients with severe renal impairment. Among patients with moderate renal impairment (creatinine clearance <60 mL/min or estimated GFR <60 mL/min/1.73 m2), a greater proportion of patients receiving dapagliflozin experienced increased creatinine, phosphorus, PTH concentrations, and hypotension. patients receiving placebo. Forxiga™ is contraindicated in patients with moderate or severe renal impairment (creatinine clearance <60 mL/min or estimated GFR <60 mL/min/1.73 m2). Forxiga™ has not been studied in severe renal impairment (creatinine clearance <30 mL/min or estimated GFR <30 mL/min/1.73 m2) or end-stage renal disease.
It is recommended to monitor kidney function as follows:
- before starting therapy with dapagliflozin and at least once a year thereafter;
- before starting to take concomitant medications that may reduce renal function, and periodically thereafter;
- if kidney function is impaired, close to moderate severity, at least 2-4 times a year. If renal function decreases below a CK value <60 ml/min or an estimated GFR <60 ml/min/1.73 m2, it is necessary to stop taking dapagliflozin.
Use in patients with liver dysfunction
Clinical studies have provided limited data on the use of the drug in patients with impaired liver function. Exposure to dapagliflozin is increased in patients with severe hepatic impairment.
Use in patients at risk of reducing blood volume, developing arterial hypotension and/or electrolyte imbalance
In accordance with the mechanism of action, dapagliflozin increases diuresis, accompanied by a slight decrease in blood pressure. The diuretic effect may be more pronounced in patients with very high blood glucose concentrations.
Dapagliflozin is contraindicated in patients taking loop diuretics or in patients with decreased blood volume, for example due to acute illnesses (such as gastrointestinal diseases).
Caution should be exercised in patients for whom dapagliflozin-induced blood pressure reduction may pose a risk, such as patients with a history of cardiovascular disease, patients with a history of hypotension receiving antihypertensive therapy, or elderly patients.
When taking dapagliflozin, careful monitoring of blood volume and electrolyte concentrations (for example, physical examination, blood pressure measurement, laboratory tests, including hematocrit) is recommended against the background of concomitant conditions that may lead to a decrease in blood volume. If there is a decrease in blood volume, it is recommended to temporarily stop taking dapagliflozin until this condition is corrected.
Ketoacidosis
During post-marketing use of the drug, ketoacidosis has been reported, incl. diabetic ketoacidosis, in patients with type 1 and type 2 diabetes mellitus taking Forxiga™ and other SGLT2 inhibitors, although a cause-and-effect relationship has not been established. Forxiga™ is not indicated for the treatment of patients with type 1 diabetes mellitus.
Patients taking Forxiga™ with signs and symptoms suggestive of ketoacidosis, including nausea, vomiting, abdominal pain, malaise, and shortness of breath, should be monitored for ketoacidosis, even if blood glucose concentrations are below 14 mmol/L. If ketoacidosis is suspected, discontinuation or temporary discontinuation of Forxiga™ should be considered and the patient should be assessed immediately.
Factors predisposing to the development of ketoacidosis include low β-cell function due to impaired pancreatic function (eg, type 1 diabetes mellitus, pancreatitis, or history of pancreatic surgery), decreased insulin dosage, decreased calorie intake, or increased need for insulin due to infections, illness or surgery, or alcohol abuse. Forxiga® should be used with caution in such patients.
Urinary tract infections
In an analysis of pooled data from dapagliflozin use up to 24 weeks, urinary tract infections were reported more frequently with dapagliflozin 10 mg compared to placebo. The development of pyelonephritis was noted infrequently, with a similar frequency in the control group. Renal excretion of glucose may be accompanied by an increased risk of urinary tract infections, so temporary discontinuation of dapagliflozin therapy should be considered when treating pyelonephritis or urosepsis.
Urosepsis and pyelonephritis. Serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization in patients taking Forxiga and other SGLT2 inhibitors have been reported during post-marketing use of the drug. Therapy with SGLT2 inhibitors increases the risk of developing urinary tract infections. Patients should be monitored for signs and symptoms of urinary tract infections and treated promptly if indicated.
Elderly patients
Elderly patients are more likely to have impaired renal function and/or use of antihypertensive drugs that may affect renal function, such as ACE inhibitors and angiotensin II type 1 receptor antagonists (ARAs). For elderly patients, the same recommendations for renal impairment apply as for all patient populations.
In patients aged ≥65 years, a higher proportion of patients receiving dapagliflozin experienced adverse reactions related to renal impairment or renal failure compared with placebo. The most common adverse reaction associated with renal impairment was an increase in serum creatinine concentration, most cases were transient and reversible.
In elderly patients, the risk of a decrease in blood volume may be higher, and the use of diuretics is more likely. A larger proportion of patients aged ≥65 years who received dapagliflozin experienced adverse reactions associated with a decrease in blood volume.
Experience with the drug in patients aged 75 years and older is limited. It is contraindicated to initiate dapagliflozin therapy in this population.
Chronic heart failure
Experience with the drug in patients with NYHA class I-II chronic heart failure is limited, and during clinical trials, dapagliflozin was not used in patients with NYHA class III-IV chronic heart failure.
Increased hematocrit value
An increase in hematocrit has been observed with the use of dapagliflozin, and therefore caution should be exercised in patients with elevated hematocrit values.
Urine test results estimates
Due to the drug's mechanism of action, urine glucose test results will be positive in patients taking Forxiga™.
Effect on the determination of 1,5-anhydroglucitol
Assessing glycemic control by measuring 1,5-anhydroglucitol is not recommended because measuring 1,5-anhydroglucitol is unreliable in patients taking SGLT2 inhibitors. Alternative methods should be used to assess glycemic control.
Impact on the ability to drive vehicles and operate machinery
No studies have been conducted to study the effect of dapagliflozin on the ability to drive vehicles and operate machinery.
Forxiga
The safety profile of dapagliflozin was assessed in a clinical development program for T2DM and heart failure.
In clinical trials for T2DM, more than 15,000 patients were treated with dapagliflozin. The primary assessment of safety and tolerability was conducted in a preplanned analysis of pooled data from 13 short-term (up to 24 weeks) placebo-controlled studies in which 2360 patients received dapagliflozin 10 mg and 2295 patients received placebo.
In the Dapagliflozin on Cardiovascular Outcomes in T2DM (DECLARE) trial, 8574 patients received dapagliflozin 10 mg and 8569 received placebo (median exposure 48 months). In total, dapagliflozin exposure was 30,623 patient-years.
In the Dapagliflozin on Cardiovascular Outcomes in Patients with Heart Failure with Reduced Ejection Fraction (DAPA-HF) study, 2368 patients received dapagliflozin 10 mg and 2368 received placebo (median exposure 18 months). The population included patients with and without T2DM and patients with eGFR ≥ 30 ml/min/1.73 m2.
The safety profile of dapagliflozin across studies was generally similar across the indications studied. Severe hypoglycemia and diabetic ketoacidosis were noted only in patients with diabetes mellitus.
The following are HP observed in placebo-controlled clinical trials3 and post-marketing use. None of them depended on the dose of the drug. HP are classified by frequency and class of systems and organs. The frequency of HP is presented in the following gradation: very often (≥1/10), often (≥1/100, <1/10), infrequently (≥1/1000, <1/100), rarely (≥1/10000, <1/1000), very rare (<1/10000) and unspecified frequency (cannot be estimated from the data obtained).
Infectious and parasitic diseases: often* - vulvovaginitis, balanitis and associated genital infectionsb,c, urinary tract infectionb,d, infrequently** - vulvovaginal itching, fungal infectious diseases; very rarely - necrotizing fasciitis of the perineum (Fournier's gangrene)
Metabolic and nutritional disorders: very often - hypoglycemia (when used in combination with a sulfonylurea derivative or insulin)b; infrequently** - decrease in blood volume b, e, thirst; rarely - diabetic ketoacidosis (when used for type 2 diabetes)b,i
Nervous system disorders: often* - dizziness
Gastrointestinal disorders: uncommon** - constipation, dry mouth
Disorders of the skin and subcutaneous tissues: often* - rashj; very rarely - angioedema
Disorders of the musculoskeletal system and connective tissue: often* - back pain
Renal and urinary tract disorders: often* - dysuria, polyuriaf; uncommon** - nocturia
Laboratory and instrumental data: often* - dyslipidemiah, increased hematocritg, decreased renal creatinine clearance at the initial stage of therapyb; uncommon** - increased urea concentration in the blood, increased creatinine concentration in the blood at the initial stage of therapyb.
a Presents data on use of the drug for up to 24 weeks (short-term therapy), regardless of the use of an additional hypoglycemic drug.
b See the relevant subsection below for more information.
c Vulvovaginitis, balanitis and related genital infections include, for example, the following predefined preferred terms: vulvovaginal fungal infection, vaginal infection, balanitis, genital fungal infection, vulvovaginal candidiasis, vulvovaginitis, candidal balanitis, genital candidiasis, genital infection, infection genital organs in men, penile infection, vulvitis, bacterial vaginitis, vulvar abscess.
d Urinary tract infection includes the following preferred terms, listed in descending order of frequency: urinary tract infection, cystitis, Escherichia urinary tract infection, genitourinary tract infection, pyelonephritis, trigonitis, urethritis, kidney infection, and prostatitis.
e Decreased blood volume includes, for example, the following predefined preferred terms: dehydration, hypovolemia, hypotension.
f Polyuria includes the preferred terms: pollakiuria, polyuria, and increased diuresis.
g The mean change from baseline in hematocrit was 2.30% in the dapagliflozin 10 mg group compared with -0.33% in the placebo group. Hematocrit values >55% were observed in 1.3% of patients receiving dapagliflozin 10 mg compared with 0.4% of patients receiving placebo.
h The mean percentage changes from baseline in the dapagliflozin 10 mg group and placebo group, respectively, were: total cholesterol 2.5% versus 0.0%; HDL cholesterol 6.0% versus 2.7%; LDL cholesterol 2.9% versus -1.0%; triglycerides -2.7% compared to -0.7%.
i Noted in the DECLARE study. Frequency is based on an annual rate.
j HP noted during post-marketing surveillance. Rash includes the following preferred terms, listed in order of frequency of occurrence in clinical studies: rash, generalized rash, pruritic rash, macular rash, maculopapular rash, pustular rash, vesicular rash, erythematous rash. In placebo-controlled and active-controlled clinical trials (dapagliflozin group: 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%), which corresponds to the frequency category “often”.
*Occurred in ≥ 2% of patients treated with dapagliflozin 10 mg and > 1% more frequently than placebo.
**Occurred in ≥ 0.2% of patients and ≥ 0.1% more often and in at least 3 more patients (at least 3) in the dapagliflozin 10 mg group compared with the placebo group, regardless of the use of additional hypoglycemic drug.
Description of individual HP
Vulvovaginitis, balanitis and associated genital infections
In pooled safety data from 13 studies, vulvovaginitis, balanitis, and associated genital infections were reported in 5.5% and 0.6% of patients treated with dapagliflozin 10 mg and placebo, respectively. Most infections were mild or moderate; The initial course of standard therapy was effective, and patients rarely discontinued dapagliflozin. These infections occurred more frequently in women (8.4% and 1.2% with dapagliflozin and placebo, respectively) and were more likely to recur in patients with a history of such infections.
In the DECLARE study, the number of patients with serious adverse events of genital infections was small and balanced: 2 (<0.1%) patients each in the dapagliflozin group and the placebo group.
In the DAPA-HF study, there were no patients with serious adverse events such as 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 experienced adverse events leading to discontinuation of treatment due to genital infections, and no patients in the placebo group.
Necrotizing perineal fasciitis (Fournier's gangrene)
Post-marketing cases of Fournier's gangrene have been reported in patients taking SGLT2 inhibitors, including dapagliflozin (see section "Special Instructions").
In the DECLARE study, in 17,160 patients with T2DM and a median exposure of 48 months, a total of 6 cases of Fournier's gangrene were reported: one in the dapagliflozin group and 5 in the placebo group.
Hypoglycemia
The incidence of hypoglycemia depended on the type of background therapy used in clinical trials of T2DM.
In studies of dapagliflozin as monotherapy, combination therapy with metformin for up to 102 weeks, the incidence of mild hypoglycaemic episodes was similar (<5%) in treatment groups including placebo. In all studies, episodes of severe hypoglycemia were reported infrequently and their incidence was comparable between the dapagliflozin and placebo groups. In studies of dapagliflozin added to a sulfonylurea or insulin, a higher incidence of hypoglycemia was observed (see Interactions with Other Drugs). In a study of dapagliflozin 10 mg administered concomitantly with extended-release exenatide (concomitant with metformin), no episodes of severe or mild hypoglycemia were observed.
In the DECLARE study, there was no increased risk of severe hypoglycemia with dapagliflozin compared with placebo. Severe hypoglycemia was reported in 58 (0.7%) patients receiving dapagliflozin and in 83 (1.0%) patients receiving placebo.
In the DAPA-HF study, severe hypoglycemia was reported in 4 (0.2%) patients in both dapagliflozin and placebo groups and was observed only in patients with T2DM.
Decrease in BCC
In pooled safety data from 13 HP studies, evidence of decreased volume (including reports of dehydration, hypovolemia, or hypotension) was observed in 1.1% and 0.7% of patients receiving dapagliflozin 10 mg and placebo, respectively; Serious HP occurred in <0.2% of patients and was comparable between the dapagliflozin 10 mg and placebo groups (see section "Special Instructions").
In the DECLARE study, the number of patients with events indicating a decrease in blood volume 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. Events were generally balanced between treatment groups for age, diuretic use, blood pressure, and angiotensin-converting enzyme inhibitor (ACEI) use. Among patients with a baseline eGFR <60 ml/min/1.73 m2, there were 19 cases of serious adverse events indicating a decrease in blood volume in the dapagliflozin group and 13 in the placebo group.
In the DAPA-HF study, the number of patients with events indicating a decrease in volume was balanced between treatment groups: 170 (7.2%) and 153 (6.5%) in the dapagliflozin and placebo groups, respectively. There were fewer patients in the dapagliflozin group with severe symptoms indicating a decrease in volumetric volume compared to the placebo group: 23 (1.0%) and 38 (1.6%) patients, respectively. Similar results were observed in subgroup analyzes based on age, diabetes at baseline, baseline eGFR, and SBP.
Diabetic ketoacidosis in T2DM
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 evenly throughout the study period. In the dapagliflozin group, of the 27 patients with diabetic ketoacidosis, 22 were receiving concomitant insulin therapy at the time of the event.
Factors predisposing to the development of diabetic ketoacidosis were expected for the population with T2DM (see section "Special Instructions").
In the DAPA-HF study, diabetic ketoacidosis events were reported in 3 patients with T2DM in the dapagliflozin group and in no patients in the placebo group.
Urinary tract infections
In pooled safety data from 13 studies, urinary tract infections were reported more frequently with dapagliflozin 10 mg than with placebo (4.7% versus 3.5%, respectively; see Precautions). Most infections were mild or moderate; The initial course of standard therapy was effective, and patients rarely discontinued dapagliflozin. These infections occurred more frequently in women, and in patients with a history of such infections they were more likely to recur.
In the DECLARE study, serious urinary tract infections were reported less frequently with dapagliflozin 10 mg compared with placebo: 79 (0.9%) events versus 109 (1.3%) events, respectively.
In the DAPA-HF study, the number of patients with serious adverse events 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. In the dapagliflozin and placebo groups, there were 5 (0.2%) patients each with adverse events leading to discontinuation of treatment due to urinary tract infections.
Increased creatinine concentration
HP associated with increased creatinine concentrations were grouped (eg, decreased renal creatinine clearance, impaired renal function, increased blood creatinine concentrations, and decreased GFR). In pooled safety data from 13 studies, this group of reactions was observed in 3.2% and 1.8% of patients receiving dapagliflozin 10 mg and placebo, respectively. In patients with normal or mild renal impairment (eGFR ≥ 60 mL/min/1.73 m2 at baseline), 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 baseline eGFR ≥ 30 and < 60 ml/min/1.73 m2 (18.5% in the dapagliflozin 10 mg group versus 9.3% in the placebo group).
Additional evaluation of patients with adverse events related to renal function showed that the majority of these patients experienced a change in serum creatinine concentration of <0.5 mg/dL from baseline. The increase in creatinine concentrations was generally transient with continued therapy or reversible after discontinuation of therapy.
In the DECLARE study, which included older patients and patients with impaired renal function (eGFR less than 60 ml/min/1.73 m2), eGFR decreased over time in both treatment groups. At 1 year of therapy, mean eGFR was slightly lower in the dapagliflozin group and slightly higher at 4 years of therapy compared with the placebo group.
In the DAPA-HF study, a decrease in mean eGFR was observed, which was initially greater in the dapagliflozin group compared with the placebo group. At 20 months, the change from baseline in eGFR was similar between treatment groups.
Use of the drug Forxiga in patients with chronic heart failure
In 2021, The New England Journal of Medicine published an article on the use of Forxiga in patients with chronic heart failure.
Chronic heart failure is a serious, life-threatening, progressive disease with disabling, complex symptoms.
The antidiabetic drug Forxiga (dapagliflozin) has been shown to improve outcomes in patients with heart failure. This sodium-glucose cotransporter type 2 inhibitor may be the first in its class to break out of diabetes therapy alone.
Forxiga is now approved for the treatment of heart failure (class II - IV) with reduced ejection fraction in order to reduce the risk of death from cardiovascular complications or hospitalization due to heart failure. The drug can be used regardless of the presence or absence of type 2 diabetes mellitus. The corresponding approval was issued by the US Food and Drug Administration.
The phase III DAPA-HF clinical trial (randomized, placebo-controlled, multicenter, international) included patients (4744) with class II-IV heart failure with reduced left ventricular ejection fraction (≤40%) with both type 2 diabetes mellitus and not suffering.
Inclusion criteria: increased level of brain natriuretic peptide (NT-proBNP) to at least 600 pg/ml - or at least 400 pg/ml in case of hospitalization for heart failure in the last 12 months. In patients with atrial fibrillation or flutter, NT-proBNP levels were required to be at least 900 pg/ml, regardless of the presence or absence of a previous hospitalization.
Subjects were given daily dapagliflozin or placebo on top of standard drug therapy for heart failure.
In the dapagliflozin group, the study showed a 25% reduction in the likelihood of negative outcomes in patients with heart failure, regardless of the presence or absence of type 2 diabetes in the subjects.
A 30 percent reduction in the risk of a first episode of worsening heart failure and an 18 percent reduction in death from cardiovascular complications was found.
The specific mechanism of action of dapagliflozin in nondiabetic patients is unclear, but the drug is thought to have a protective effect on renal function and modify cardiometabolism.
Forxiga tab p/pl obol 10mg N30 (AstraZeneca)
Oral hypoglycemic drug. The mechanism of action of Dapagliflozin is a powerful (inhibition constant (Ki) 0.55 nM), selective reversible inhibitor of sodium-glucose cotransporter type 2 (SGLT2). SGLT2 is selectively expressed in the kidney and is not found in more than 70 other body tissues (including liver, skeletal muscle, adipose tissue, mammary glands, bladder and brain). SGLT2 is the main transporter involved in the process of glucose reabsorption in the renal tubules. Glucose reabsorption in the renal tubules in patients with type 2 diabetes mellitus (T2DM) continues despite hyperglycemia. By inhibiting the renal transport of glucose, dapagliflozin reduces its reabsorption in the renal tubules, which leads to the excretion of glucose by the kidneys. The effect of dapagliflozin is a decrease in fasting and postprandial glucose concentrations, as well as a decrease in the concentration of glycosylated hemoglobin in patients with type 2 diabetes. The removal of glucose (glucosuric effect) is observed after taking the first dose of the drug, persists for the next 24 hours and continues throughout therapy. The amount of glucose excreted by the kidneys through this mechanism depends on the concentration of glucose in the blood and on the glomerular filtration rate (GFR). Dapagliflozin does not interfere with normal endogenous glucose production in response to hypoglycemia. The action of dapagliflozin is independent of insulin secretion and insulin sensitivity. In clinical studies of Forxiga™, an improvement in β-cell function was noted (HOMA test, homeostasis model assessment). Renal glucose excretion induced by dapagliflozin is accompanied by calorie loss and weight loss. Inhibition of sodium-glucose cotransport by dapagliflozin is accompanied by weak diuretic and transient natriuretic effects. Dapagliflozin has no effect on other glucose transporters that transport glucose to peripheral tissues and exhibits more than 1400 times greater selectivity for SGLT2 than for SGLT1, the main intestinal transporter responsible for glucose absorption. Pharmacodynamics: After administration of dapagliflozin to healthy volunteers and patients with type 2 diabetes, an increase in the amount of glucose excreted by the kidneys was observed. When patients with T2DM took dapagliflozin at a dose of 10 mg/day for 12 weeks, approximately 70 g of glucose/day was excreted by the kidneys (corresponding to 280 kcal/day). In patients with T2DM who took dapagliflozin at a dose of 10 mg/day for a long time (up to 2 years), glucose excretion was maintained throughout the entire course of therapy. Renal excretion of glucose with dapagliflozin also leads to osmotic diuresis and an increase in urine volume. The increase in urine volume in patients with type 2 diabetes treated with dapagliflozin 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 sodium excretion by the kidneys, which did not lead to a change in serum sodium concentration. A planned analysis of 13 placebo-controlled studies demonstrated a reduction in systolic blood pressure (SBP) of 3.7 mmHg. and diastolic blood pressure (DBP) by 1.8 mm Hg. at week 24 of therapy with dapagliflozin at a dose of 10 mg/day compared with a decrease in SBP and DBP by 0.5 mm Hg. in the placebo group. A similar reduction in blood pressure was observed throughout 104 weeks of treatment. When using dapagliflozin at a dose of 10 mg/day in patients with type 2 diabetes with inadequate glycemic control and arterial hypertension, receiving angiotensin II receptor blockers, ACE inhibitors, incl. in combination with another antihypertensive drug, a decrease in glycosylated hemoglobin by 3.1% and a decrease in SBP by 4.3 mmHg were noted. after 12 weeks of therapy compared with placebo.
