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Forxiga 10 mg 30 pcs. film-coated tablets

pharmachologic effect

An oral hypoglycemic agent is an inhibitor of sodium-dependent glucose transporter type 2.

Composition and release form Forxiga 10 mg 30 pcs. film-coated tablets

1 film-coated tablet, Forxiga 5 mg contains:

Active substance: dapagliflozin propanediol monohydrate 6.150 mg, equivalent to dapagliflozin 5 mg;
Excipients: microcrystalline cellulose 85.725 mg, anhydrous lactose 25.000 mg, crospovidone 5.000 mg, silicon dioxide 1.875 mg, magnesium stearate 1.250 mg;
Tablet shell: Opadry II yellow 5,000 mg (partially hydrolyzed polyvinyl alcohol 2,000 mg, titanium dioxide 1,177 mg, macrogol 3350 1,010 mg, talc 0,740 mg, yellow iron oxide dye 0,073 mg).

1 film-coated tablet Forxiga 10 mg contains:

Active substance: dapagliflozin propanediol monohydrate 12.30 mg, equivalent to dapagliflozin 10 mg;
Excipients: microcrystalline cellulose 171.45 mg, anhydrous lactose 50.00 mg, crospovidone 10.00 mg, silicon dioxide 3.75 mg, magnesium stearate 2.50 mg;
Tablet shell: Opadry® II yellow 10.00 mg (partially hydrolyzed polyvinyl alcohol 4.00 mg, titanium dioxide 2.35 mg, macrogol 3350 2.02 mg, talc 1.48 mg, yellow iron oxide dye 0.15 mg) .

Forxiga - film-coated tablets, 5 mg, 10 mg.

14 tablets in a blister made of aluminum foil; 2 or 4 blisters in a cardboard box with instructions for use or 10 tablets in a perforated blister made of aluminum foil; 3 or 9 perforated blisters in a cardboard box with instructions for use.

Description of the dosage form

Diamond-shaped, biconvex, yellow film-coated tablets, engraved with “10” on one side and “1428” on the other side.

Characteristic

Forxiga is an oral hypoglycemic agent that is an inhibitor of sodium-dependent glucose transporter type 2.

Dapagliflozin is a potent (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 tissues in the body (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™, improvements in beta cell function were 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 transporter in the intestine responsible for glucose absorption.

After administration of dapagliflozin to healthy volunteers and patients with T2DM, 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 per 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 T2DM 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.

Directions for use and doses

Inside, regardless of food intake.

Monotherapy: the recommended dose of Forxiga is 10 mg once a day.

Combination therapy: the recommended dose of Forxiga is 10 mg once daily in combination with metformin.

Initial combination therapy with metformin: the recommended dose of Forxiga is 10 mg once daily, the dose of metformin is 500 mg once daily.

In case of inadequate glycemic control, the dose of metformin should be increased.

Pharmacodynamics

Forxiga is an oral hypoglycemic agent that is an inhibitor of sodium-dependent glucose transporter type 2.

Pharmacokinetics

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

Dapagliflozin is approximately 91% protein bound. In patients with various diseases, for example, impaired renal or liver function, this indicator did not change.

Dapagliflozin is a C-linked glucoside, the aglycone of which is linked to glucose by a carbon-carbon bond, which ensures its resistance to glucosidases. The mean plasma half-life (T½) in healthy volunteers was 12.9 hours after a single 10 mg oral dose of dapagliflozin. Dapagliflozin is metabolized to form primarily 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 (according to 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 the total plasma radioactivity. Dapagliflozin-3-O-glucuronide and other metabolites do not have pharmacological effects. Dapagliflozin-3-O-glucuronide is formed under the action of the enzyme uridine diphosphate glucuronosyltransferase 1A9 (UGT1A9), present in the liver and kidneys; cytochrome CYP isoenzymes are involved in metabolism to a lesser extent.

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

Dapagliflozin is metabolized primarily through glucuronide conjugation by UGT1A9.

In in vitro studies, dapagliflozin did not inhibit the cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and did not induce CYP1A2, CYP2B6 or CYP3A4. Therefore, dapagliflozin is not expected to affect the metabolic clearance of concomitant medications that are metabolized by these isoenzymes.

Indications for use: Forxiga 10 mg 30 pcs. film-coated tablets

Forxiga is intended for use in type 2 diabetes mellitus in addition to diet and exercise to improve glycemic control as: monotherapy; addition to metformin therapy in the absence of adequate glycemic control on this therapy; starting combination therapy with metformin, if this therapy is appropriate.

Contraindications

Increased individual sensitivity to any component of the drug.
Diabetes mellitus type 1.
Diabetic ketoacidosis.
Moderate to severe renal failure (GFR)
Hereditary lactose intolerance, lactase deficiency and glucose-galactose intolerance.
Pregnancy and breastfeeding period.
Children under 18 years of age (safety and effectiveness have not been studied).
Patients taking loop diuretics or with reduced circulating blood volume, for example due to acute illnesses (such as gastrointestinal diseases).
Elderly patients aged 75 years and older (to initiate therapy).

With caution: severe liver failure, urinary tract infections, risk of decreased circulating blood volume, elderly patients, chronic heart failure, increased hematocrit.

Application of Forsiga 10 mg 30 pcs. film-coated tablets during pregnancy and breastfeeding

Due to the fact that the use of dapagliflozin during pregnancy has not been studied, the drug is contraindicated during pregnancy. If pregnancy is diagnosed, dapagliflozin therapy should be discontinued.

It is unknown whether dapagliflozin and/or its inactive metabolites are excreted in breast milk. A risk to newborns/infants cannot be excluded. Dapagliflozin is contraindicated during breastfeeding.

special instructions

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 failure (MC

It is recommended to monitor kidney function as follows:

before starting dapagliflozin therapy and at least once a year thereafter;
before starting concomitant medications that may reduce renal function, and periodically thereafter;
for renal dysfunction close to moderate severity, at least 2-4 times a year. When renal function decreases below the CC value

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 decreased blood volume, development of arterial hypotension and/or electrolyte imbalance

According to its 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 reductions in blood pressure 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. Urinary tract infections In an analysis of pooled data from dapagliflozin 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.

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 angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor antagonists (ARAs). For elderly patients, the same recommendations for renal impairment apply as for all patient populations. In the group >65 years of age, 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. Among patients aged > 65 years, a greater proportion of patients receiving 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 chronic heart failure of functional class I-II according to the NYHA classification is limited, and during clinical trials, dapagliflozin was not used in patients with chronic heart failure of functional class III-IV according to the NYHA.

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™.

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.

Overdose

Dapagliflozin is safe and well tolerated in healthy volunteers when administered in single doses up to 500 mg (50 times the recommended dose).

Glucose was determined in urine after taking the drug (at least for 5 days after taking a dose of 500 mg), and no cases of dehydration, hypotension, electrolyte imbalance, or clinically significant effect on the QTc interval were detected. The incidence of hypoglycemia was similar to that observed with placebo.

In clinical studies in healthy volunteers and patients with T2DM who took the drug in single doses up to 100 mg (10 times the maximum recommended dose) for 2 weeks, the incidence of hypoglycemia was slightly higher than with placebo and was not dose dependent. . The incidence of adverse events, including dehydration or hypotension, was similar to the placebo group, and there were no clinically significant, dose-related changes in laboratory parameters, including serum concentrations of electrolytes and biomarkers of renal function.

In case of overdose, it is necessary to carry out maintenance therapy, taking into account the patient's condition. Elimination of dapagliflozin by hemodialysis has not been studied.

Side effects of Forxiga 10 mg 30 pcs. film-coated tablets

The preplanned pooled data analysis included results from 12 placebo-controlled studies in which 1193 patients received dapagliflozin 10 mg and 1393 patients received placebo.

The overall incidence of adverse events (short-term therapy) in patients taking dapagliflozin 10 mg was similar to that in the placebo group.

The number of adverse events leading to discontinuation of therapy was small and balanced between treatment groups. The most common adverse events leading to discontinuation of therapy with dapagliflozin at a dose of 10 mg were increased creatinine concentration in the blood (0.4%), urinary tract infections (0.3%), nausea (0.2%), dizziness (0. 2%) and rash (0.2%). One patient taking dapagliflozin experienced an adverse liver event with a diagnosis of drug-induced hepatitis and/or autoimmune hepatitis.

The most common adverse reaction was hypoglycemia, the incidence of which depended on the type of background therapy used in each study. The incidence of mild hypoglycemia was similar between treatment groups, including placebo.

List of adverse reactions in table form

The following are adverse reactions observed in placebo-controlled clinical studies. None of them depended on the dose of the drug. The frequency of adverse reactions is presented in the following gradation: very often (>1/10), often (>1/100.1/1000.1/10000,

Infections and infestations: vulvovaginitis, balanitis and similar infections of the genital organs.

Urinary tract infection: vulvovaginal itching.

Metabolic and nutritional disorders: hypoglycemia (when used in combination with a sulfonylurea derivative or insulin) b, decreased blood volume, thirst.

Gastrointestinal disorders: constipation.

Skin and subcutaneous tissue disorders: increased sweating.

Musculoskeletal and connective tissue disorders: back pain.

Renal and urinary tract disorders: dysuria, polyuria, nocturia.

Laboratory and instrumental data: dyslipidemia, increased hematocrit, increased creatinine concentration in the blood, increased urea concentration in the blood.

Drug interactions

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

Interaction studies in healthy volunteers, mostly given a single dose of the drug, showed that metformin, pioglitazone, sitagliptin, glimepiride, voglibose, hydrochlorothiazide, bumetanide, valsartan or simvastatin did not affect the pharmacokinetics of dapagliflozin. After combined use of dapagliflozin and rifampicin, an inducer of various active transporters and drug-metabolizing enzymes, a decrease in systemic exposure (AUC) of dapagliflozin by 22% was observed, with no clinically significant effect on daily renal glucose excretion. It is not recommended to adjust the dose of the drug. Clinically significant effects are not expected when used with other inducers (for example, carbamazepine, phenytoin, phenobarbital).

Following co-administration of dapagliflozin and mefenamic acid (a UGT1A9 inhibitor), a 55% increase in systemic exposure to dapagliflozin was observed, but without a clinically significant effect on 24-hour renal glucose excretion. It is not recommended to adjust the dose of the drug.

Effect of dapagliflozin on other drugs

In interaction studies in mostly single-dose healthy volunteers, dapagliflozin did not affect the pharmacokinetics of metformin, pioglitazone, sitagliptin, glimepiride, hydrochlorothiazide, bumetanide, valsartan, digoxin (P-gp substrate), or warfarin (S-warfarin, substrate isoenzyme CYP2C9), or on the anticoagulation effect, assessed by the International Normalized Ratio (IHO).

A single dose of dapagliflozin 20 mg and simvastatin (a CYP3A4 substrate) resulted in a 19% increase in the AUC of simvastatin and a 31% increase in the AUC of simvastatin acid. Increased exposure to simvastatin and simvastatin acid is not considered clinically significant.

The effects of smoking, diet, herbal medications and alcohol consumption on the pharmacokinetic parameters of dapagliflozin have not been studied.