Forxiga pills 10mg, 30pcs

Composition

of 1 tab. dapagliflozin propanediol monohydrate 12.3 mg, which corresponds to the content of dapagliflozin 10 mg

Auxiliary substances:

microcrystalline cellulose – 171.45 mg,

anhydrous lactose-50 mg,

crospovidone-10 mg,

silicon dioxide-3.75 mg,

magnesium stearate-2.5 mg.

Shell composition:

Opadray ® II yellow – 10 mg (partially hydrolyzed polyvinyl alcohol-4 mg, titanium dioxide-2.35 mg, macrogol 3350-2.02 mg, talc-1.48 mg, iron oxide yellow dye-0.15 mg).

Pharmacological action

Oral hypoglycemic drug.

Mechanism of action

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 kidneys and is not detected 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.

Reabsorption of glucose in the renal tubules in patients with type 2 diabetes mellitus (DM2) continues despite hyperglycemia. By inhibiting the renal transport of glucose, dapagliflozin reduces its reabsorption in the renal tubules, which leads to the elimination 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 DM2.

Glucose elimination (glucosuric effect) is observed after 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 the normal production of endogenous glucose in response to hypoglycemia. The effect of dapagliflozin is independent of insulin secretion and insulin sensitivity. In clinical trials of Forxiga™ There was an improvement in the function of beta-cells (HOMA test, homeostasis model assessment).

The elimination of glucose by the kidneys caused by dapagliflozin is accompanied by a loss of calories and a decrease in body weight. Dapagliflozin inhibition of sodium-glucose cotransport is accompanied by weak diuretic and transient natriuretic effects.

Dapagliflozin has no effect on other glucose transporters that transport glucose to peripheral tissues, and shows more than 1400 times greater selectivity for SGLT2 than for SGLT1, the main intestinal transporter responsible for glucose absorption.

Pharmacodynamics

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

Excretion of glucose by the kidneys with dapagliflozin also leads to osmotic diuresis and an increase in urine volume. The increase in urine volume in patients with DM2 treated with dapagliflozin at a dose of 10 mg/day persisted for 12 weeks and was approximately 375 ml / day. The increase in urine volume was accompanied by a small and transient increase in the excretion of sodium by the kidneys, which did not lead to a change in the concentration of sodium in the blood serum.

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

When using dapagliflozin at a dose of 10 mg / day in patients with DM2 with inadequate glycemic control and arterial hypertension, receiving angiotensin II receptor blockers, ACE inhibitors, including in combination with another antihypertensive drug, there was a decrease in glycosylated hemoglobin by 3.1% and a decrease in SBP by 4.3 mm Hg after 12 weeks of therapy compared with placebo.

Indications

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

— monotherapy;

— add to the therapy with Metformin, sulfonylureas (including in combination with Metformin), thiazolidinediones, inhibitors of dipeptidyl peptidase 4 (DPP-4) (including in combination with Metformin), insulin preparations (incl. combinations with one or two hypoglycemic drugs for oral use) in the absence of adequate glycemic control in this treatment;

— initial combination therapy with Metformin, when the appropriateness of this therapy.

Contraindications

diabetes mellitus type 1;

diabetic ketoacidosis;

— renal failure of moderate and severe severity (GFR <60 ml/min/1.73 m2) or end-stage renal disease;

hereditary lactose intolerance, lactase deficiency and glucose-galactose intolerance;

— pregnancy;

— the period of breastfeeding;

— children’s and teenage age up to 18 years (safety and effectiveness has not been studied);

— patients receiving loop diuretics, or with reduced BCC, for example, as a result of acute diseases (such as gastrointestinal diseases);

elderly patients aged 75 years and over (to start of therapy);

— increased individual sensitivity to any component of the drug.

With caution:  severe hepatic insufficiency, urinary tract infections, risk of BCC reduction, elderly patients, chronic heart failure, increased hematocrit.

Side effects

A pre-planned pooled data analysis included the results of 12 placebo-controlled trials in which 1,193 patients received dapagliflozin 10 mg and 1,393 patients received placebo.

The overall incidence of adverse events (short-term therapy) in patients taking dapagliflozin at a dose of 10 mg was similar to that in the placebo group. The number of adverse events that led to discontinuation of therapy was small and balanced between the treatment groups. The most common adverse events that led to discontinuation of 10 mg dapagliflozin therapy were increased blood creatinine (0.4%), urinary tract infections (0.3%), nausea (0.2%), dizziness (0.2%), and rash (0.2%). One patient treated with dapagliflozin developed a liver adverse event with a diagnosis of drug-induced hepatitis and / or autoimmune hepatitis.

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

Description of individual adverse reactions

Hypoglycaemia

The incidence of hypoglycaemia depended on the type of baseline therapy used in each study.

In studies of dapagliflozin as monotherapy, combined therapy with metformin lasting up to 102 weeks, the incidence of episodes of mild hypoglycemia was similar ( In all studies, episodes of severe hypoglycemia were infrequent, and their frequency was comparable between the dapagliflozin group and placebo.

BCC reduction

Adverse reactions associated with a decrease in BCC (including reports of dehydration, hypovolemia, or hypotension) were reported in 0.8% and 0.4% of patients treated with dapagliflozin 10 mg and placebo, respectively; serious reactions were reported in2% of patients, and they were comparable in the dapagliflozin 10 mg and placebo groups.

Vulvovaginitis, balanitis and similar genital infections

Vulvovaginitis, balanitis, and similar genital infections were reported in 4.8% and 0.9% of patients treated with dapagliflozin 10 mg and placebo, respectively. Most infections were mild to moderate; the initial course of standard therapy was effective, and patients rarely stopped taking dapagliflozin. These infections were more likely to occur in women (6.9% and 1.5% with dapagliflozin and placebo, respectively), and in patients with a history of such infections, they were more likely to recur.

Urinary tract infections

Urinary tract infections were more frequently reported with dapagliflozin 10 mg than with placebo (4.3% vs. 3.7%, respectively). Most infections were mild or moderate; the initial course of standard therapy was effective, and patients rarely stopped using dapagliflozin. These infections were more likely to develop in women, and in patients with a history of such infections, they were more likely to recur.

Parathyroid hormone (PTH)

There was a slight increase in the concentration of PTH in the blood serum, and to a greater extent in patients with higher initial concentrations of PTH. Studies of bone mineral density in patients with normal renal function or mild renal impairment did not reveal bone loss during one year of therapy.

Malignant tumors

In clinical trials, the overall proportion of patients with malignant or unspecified tumors was similar in the dapagliflozin group (1.47%) and the placebo/comparison drug group (1.35%). According to animal studies, the drug showed no carcinogenic or mutagenic properties. When considering the development of tumors of various organ systems, the relative risk associated with dapagliflozin was higher than 1 for some tumors (bladder, prostate, breast) and lower than 1 for others (for example, blood and lymphatic system, ovaries, urinary system), generally without increasing the risk of developing tumors associated with dapagliflozin. The increased / reduced risk was not statistically significant for any organ system. Given the lack of data on the development of tumors in preclinical studies, as well as the short latent period between the first drug exposure and the diagnosis of the tumor, a causal relationship is considered unlikely. Since the numerical imbalance of breast, bladder and prostate tumors requires special attention, the study of this issue will continue in post-marketing studies.

Elderly patients (≥65 years)

Adverse reactions associated with impaired renal function or renal insufficiency were reported in 2.5% of patients treated with dapagliflozin and 1.1% of patients treated with placebo in the group of patients aged ≥65 years. The most common adverse reaction associated with impaired renal function was an increase in serum creatinine. Most of these reactions were transient and reversible. Among patients aged ≥65 years, a decrease in BCC, most often recorded as arterial hypotension, was observed in 1.5% and 0.4% of patients taking dapagliflozin and placebo, respectively.

Interaction

Pharmacodynamic interaction

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

Hypoglycemia may occur with the use of insulin and drugs that increase insulin secretion. Therefore, in order to reduce the risk of hypoglycemia, when co-prescribing Forxiga™ with an insulin preparation or a drug that increases insulin secretion, it may be necessary to reduce the dose of an insulin preparation or a drug that increases insulin secretion.

Pharmacokinetic interaction

Dapagliflozin is mainly metabolized by glucuronide conjugation under the action of UGT1A9.

In vitro studies, dapagliflozin did not inhibit the cytochrome P 450 isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4, nor did it induce the isoenzymes CYP1A2, CYP2B6, or CYP3A4. Therefore, dapagliflozin is not expected to affect the metabolic clearance of concomitant drugs that are metabolized by these isoenzymes.

Effect of other drugs on dapagliflozin

Interaction studies involving healthy volunteers, mainly taking 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 the combined use of dapagliflozin and rifampicin, an inducer of various active transporters and drug-metabolizing enzymes, a 22% decrease in systemic exposure (AUC) of dapagliflozin was observed, with no clinically significant effect on the daily excretion of glucose by the kidneys. It is not recommended to adjust the dose of the drug. No clinically significant effect is expected when used with other inducers (e. g. carbamazepine, phenytoin, phenobarbital).

After the combined use of dapagliflozin and mefenamic acid (an inhibitor of UGT1A9), there was a 55% increase in systemic exposure to dapagliflozin, but without a clinically significant effect on the daily excretion of glucose by the kidneys. It is not recommended to adjust the dose of the drug.

Effect of dapagliflozin on other medications

Dapagliflozin did not affect the pharmacokinetics of metformin, pioglitazone, sitagliptin, glimepiride, hydrochlorothiazide, bumetanide, valsartan, digoxin (a P-gp substrate) or warfarin (S-warfarin, a substrate of the CYP2C9 isoenzyme), or the anticoagulant effect of dapagliflozin in interaction studies in healthy volunteers, mainly taking a single dose of the drug. rated by MHO. The use of dapagliflozin in a single dose of 20 mg and simvastatin (a substrate of the CYP3A4 isoenzyme) resulted in a 19% increase in the AUC of simvastatin and 31% increase in the AUC of simvastatin acid. Increased exposure to simvastatin and simvastatin acid is not considered clinically significant.

Other types of interaction

The effect of smoking, diet, herbal medications, and alcohol consumption on the pharmacokinetics of dapagliflozin has not been studied.

How to take, course of use and dosage

The drug is taken orally, regardless of food intake.

Monotherapy: recommended dose of Forxiga™ it is 10 mg 1 time/day.

Combination therapy: recommended dose of Forxiga™ It is 10 mg 1 time / day in combination with metformin, sulfonylurea derivatives (including in combination with metformin), thiazolidinediones, DPP-4 inhibitors (including in combination with metformin), insulin preparations (including in combination with one or two hypoglycemic drugs for oral use).

In order to reduce the risk of hypoglycemia, when co-prescribing Forxiga™ with insulin preparations or drugs that increase insulin secretion (for example, with a sulfonylurea derivative), it may be necessary to reduce the dose of insulin preparations or drugs that increase insulin secretion.

Initial combination therapy with metformin: recommended dose of Forxiga™ The dose of metformin is 10 mg 1 time/day, the dose of metformin is 500 mg 1 time/day. In case of inadequate glycemic control, the metformin dose should be increased.

In patients with mild or moderate hepatic impairment, there is no need to adjust the dose of the drug. In patients with severe hepatic impairment, an initial dose of 5 mg is recommended. With good tolerability, the dose can be increased to 10 mg.

The effectiveness of dapagliflozin depends on renal function. In patients with moderate renal impairment, the effectiveness of treatment is reduced, while in patients with severe renal impairment, it is most likely absent. Forxiga™ is contraindicated in patients with moderate to severe renal insufficiency (creatinine clearance <60 ml / min or GFR or with end-stage renal failure. No dose adjustment is required for mild renal impairment.

The safety and efficacy of dapagliflozin in children and adolescents under 18 years of age have not been studied.

No dose adjustment is required in elderly patients. However, when choosing the dose, it should be taken into account that this category of patients is more likely to have impaired renal function and the risk of BCC reduction. Since the clinical experience of using the drug in patients aged 75 years and older is limited, it is contraindicated to start therapy with dapagliflozin in this age group.

Overdose

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

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

In clinical trials in healthy volunteers and patients with DM2 who took the drug once in 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 did not depend on the dose.

The incidence of adverse events, including dehydration or hypotension, was similar to that in the placebo group, but there were no clinically significant, dose-dependent changes in laboratory parameters, including serum electrolyte concentrations and biomarkers of renal function.

Treatment: in case of overdose, maintenance therapy should be carried out, taking into account the patient’s condition. Elimination of dapagliflozin by hemodialysis has not been studied.

Special instructions

Use in patients with impaired renal function

The efficacy of dapagliflozin depends on renal function, and this efficacy is reduced in patients with moderate renal insufficiency and probably absent in patients with severe renal impairment. Among patients with moderate renal insufficiency (creatinine clearance <60 ml / min or estimated GFR Forxiga™ is contraindicated in patients with moderate or severe renal insufficiency (creatinine clearance <60 ml / min or estimated GFR Forxiga™preparation not studied in severe renal insufficiency (creatinine clearance <30 ml / min or estimated GFR

It is recommended to monitor renal function as follows:

— before starting therapy with dapagliflozin and at least once a year afterwards;

– before taking concomitant medications that may reduce renal function, and periodically afterwards;

– with impaired renal function, close to moderate severity, at least 2-4 times a year. If renal function decreases below the creatinine clearance <60 ml / min or the estimated GFR

Use in patients with impaired liver function

In clinical studies, limited data on the use of the drug in patients with impaired liver function have been obtained. Dapagliflozin exposure is increased in patients with severe hepatic impairment.

Use in patients at risk of BCC reduction, 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 reduced BCC, for example, due to acute diseases (such as gastrointestinal diseases).

Caution should be exercised in patients for whom a reduction in blood pressure caused by dapagliflozin may pose a risk, for example, in patients with a history of cardiovascular diseases, in patients with a history of arterial hypotension, receiving antihypertensive therapy, or in elderly patients.

When taking dapagliflozin, careful monitoring of BCC 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 BCC. With a decrease in BCC, it is recommended to temporarily stop taking dapagliflozin until this condition is corrected.

Ketoacidosis

Ketoacidosis, including diabetic ketoacidosis, has been reported in patients with type 1 and type 2 diabetes mellitus taking Forxiga™ and other SGLT2 inhibitors, although no causal relationship has been established. Forxiga™preparation It is not indicated for the treatment of patients with type 1 diabetes mellitus.

Patients taking Forxiga™ with signs and symptoms that indicate ketoacidosis, including nausea, vomiting, abdominal pain, malaise, and shortness of breath, should be checked for ketoacidosis, even if the blood glucose concentration is below 14 mmol/l. If ketoacidosis is suspected, discontinuation or temporary discontinuation of Forxiga™ should be considered and the patient should be evaluated immediately.

Factors predisposing to the development of ketoacidosis include low functional activity of β-cells due to dysfunction of the pancreas (e. g., diabetes type 1 diabetes, pancreatitis or surgery on the pancreas in history), reduce the dose of insulin, reducing the calorie content of food intake or increased need for insulin due to infections, diseases or surgery, as well as alcohol abuse. Forxiga should be used with caution in these patients.

Urinary tract infections

In an analysis of pooled data on dapagliflozin use up to 24 weeks, urinary tract infections were more frequently reported when dapagliflozin was administered at a dose of 10 mg compared to placebo. The development of pyelonephritis was noted infrequently, with a similar frequency in the control group. Renal glucose excretion may be associated with an increased risk of urinary tract infections, so temporary discontinuation of dapagliflozin therapy should be considered in the treatment of pyelonephritis or urosepsis.

Urosepsis and pyelonephritis. Serious urinary tract infections, including urosepsis and pyelonephritis, have been reported with post-marketing use of the drug, requiring hospitalization in patients taking Forxiga™ and other SGLT2 inhibitors. Therapy with SGLT2 inhibitors increases the risk of urinary tract infections. Patients should be monitored for signs and symptoms of urinary tract infections and, if indicated, treated immediately.

Elderly patients

Elderly patients are more likely to have impaired renal function and/or use antihypertensive medications that may affect renal function, such as ACE inhibitors and angiotensin II type 1 receptor antagonists (ARA). The same recommendations apply for elderly patients with impaired renal function as for all patient populations.

In the group of patients aged ≥65 years, a larger proportion of patients treated with dapagliflozin developed adverse reactions associated with impaired renal function or renal failure compared to placebo. The most common adverse reaction associated with impaired renal function was an increase in serum creatinine, most of which were transient and reversible.

Elderly patients may have a higher risk of BCC reduction and may be more likely to take diuretics. In a larger proportion of patients aged ≥65 years treated with dapagliflozin, adverse reactions associated with a decrease in BCC were observed.

The experience of using the drug in patients aged 75 years and older is limited. It is contraindicated to start dapagliflozin therapy in this population.

Chronic heart failure

The experience of using the drug in patients with chronic heart failure I-II FC according to the NYHA classification is limited, and in clinical studies dapagliflozin was not used in patients with chronic heart failure III-IV FC according to the NYHA.

Increased hematocrit

When using dapagliflozin, an increase in hematocrit was observed, and therefore caution should be exercised in patients with an increased hematocrit value.

Evaluation of urinalysis results

Due to the mechanism of action of the drug, the results of a urine glucose test in patients taking Forxiga™ will be positive.

Effect on the determination of 1,5-anhydroglucitol

Evaluation of glycemic control by measuring 1.5-anhydroglucitol is not recommended, as measuring 1.5-anhydroglucitol is an unreliable method for patients taking SGLT2 inhibitors. Alternative methods should be used to assess glycemic control.

Influence on the ability to drive motor vehicles and manage mechanisms

Studies on the effect of dapagliflozin on the ability to drive vehicles and mechanisms have not been conducted.

Form of production

Yellow film-coated tablets, diamond-shaped, biconvex, with the inscription “10” on one side and “1428” on the other side.

Active ingredient

Dapagliflozin

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For adults as directed by your doctor

Indications

Type 2 Diabetes