Expiration date: 11/2025

Active substance: Dapagliflozin

Testimony:

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

• Monotherapy,
  
• Add to metformin therapy in the absence of adequate glycemic control on this therapy,
  
• Starting the combined therapy with metformin therapy if appropriate this.
  

Dosage and administration:

Inside, regardless of meals.

Monotherapy: The recommended dose Forsiga drug is 10 mg 1 time per day.

Combination therapy: The recommended dose of the drug is 10 Forsiga 1 mg once daily in combination with metformin.

The starting combination therapy with metformin: the recommended dose of the drug Forsiga is 10 mg 1 time a day, the dose of metformin - 500 mg 1 time per day. In case of inadequate glycemic control, the dose of metformin should be increased.

Use in special patient groups

Patients with hepatic impairment

When violations of liver function or mild to moderate severity is not necessary to adjust the dose of the drug. Patients with impaired liver function severe recommended initial dose of 5 mg. With good endurance dose can be increased to 10 mg (see. Forums "Pharmacokinetics" and "Cautions").

Patients with impaired renal function

Efficacy dapagliflozin depends on renal function in patients with impaired renal function moderate severity reduced effectiveness of treatment and in patients with severe impairment - probably absent. Forsiga drug is contraindicated in patients with renal insufficiency, moderate and severe (creatinine clearance <60 mL / min or GFR <60 mL / min / 1.73 m2) or with end-stage renal disease (see. Sections "Contraindications", "Side effects "and" Cautions ").

When violations of mild renal function there is no need to adjust the dose of the drug.

Children

Safety and efficacy of dapagliflozin in patients under 18 years have not been studied (see. "Contraindications").

Elderly patients

In elderly patients there is no need to adjust the dose of the drug. However, when choosing the dose should be considered that these patients are more likely to impaired renal function and reduce the risk of BCC. Since clinical experience with the drug in patients 75 years and older is limited, start dapagliflozin therapy is contraindicated in this age group.

Side effect

Summary of the safety profile

The pre-planned analysis of pooled data included the results of 12 placebo-controlled trials in which 1,193 patients received dapagliflozin 10 mg and 1393 patients received placebo.

The overall incidence of adverse events (short-term therapy) in patients treated with dapagliflozin 10 mg, was similar to that in the placebo group. The number of adverse events that led to the cancellation of treatment, was small and balanced between treatment groups. The most common adverse events with withdrawal therapy dapagliflozin 10 mg, were increase in blood creatinine concentration (0.4%), urinary tract infection (0.3%), nausea (0.2%), dizziness (0, 2%), and rash (0.2%). One patient who took dapagliflozin, observed adverse events of the liver diagnosed with drug-induced hepatitis and / or autoimmune hepatitis. The most common adverse reaction was hypoglycemia, the development of which depended on the type of baseline therapy used in each study. The incidence of mild hypoglycemia episodes was similar in the treatment groups, including placebo.

The list of adverse reactions in the form of tables

Below are the adverse reactions noted in the placebo-controlled clinical trials. None of them was independent of dose. The frequency of adverse reactions represented by the following grading: very often (?1 / 10), often (?1 / 100 <1 10 = "" 1 = "" 1000 = "" 100 = "" 10000 = "" p = "">

Description of the individual adverse events

Hypoglycemia

Hypoglycemia frequency depended on the type of base treatment used in each study.

In studies of dapagliflozin as a monotherapy, combination therapy with metformin for up to 102 weeks, the incidence of mild hypoglycemia episodes was similar (<5%) in the treatment groups, including placebo. In all studies, episodes of severe hypoglycemia observed infrequently, and their incidence was comparable between dapagliflozin and placebo group.

Reducing the bcc

Adverse reactions associated with a decrease in the bcc (including reports of dehydration, hypovolemia or hypotension), were observed in 0.8% and 0.4% of patients treated with dapagliflozin 10 mg, and placebo, respectively, severe reactions were reported in <0.2 10% = "" p = "">,

Vulvovaginitis, balanitis and genital infections such

Vulvovaginitis, balanitis and the like genital infections were reported in 4.8% and 0.9% of patients treated with dapagliflozin 10 mg and placebo, respectively. Most infections were mild or moderate in intensity, the initial course of standard therapy was effective, and therefore patients rarely stopped receiving dapagliflozin. These infections are often developed in women (6.9% and 1.5% with dapagliflozin and placebo, respectively), and in patients with a history of such infections are often recur.

Infections mochevyvodyaschiih ways

Urinary tract infections are more marked when using dapagliflozin 10 mg than for placebo (4.3% compared with 3.7%, respectively, see. "special instructions" section). Most infections were mild or moderate in intensity, the initial course of standard therapy was effective, and therefore patients rarely discontinued use of dapagliflozin. These infections usually develop in women and in patients with a history of such infections, they often recur.

Parathyroid hormone (PTH)

There was a slight increase PTH concentration in blood serum, and to a greater degree in patients with higher baseline PTH concentrations. Studies of bone mineral density in patients with normal renal function or mild violation of renal function showed no bone loss within one year of therapy.

Malignant tumors

In clinical studies, the overall proportion of patients with malignant or unspecified tumors was similar in the group of dapagliflozin (1.47%) and the placebo / comparator product (1.35%). According to animal studies the drug did not show carcinogenic or mutagenic properties. When considering the incidence of tumors of various organ systems, the relative risk associated with dapagliflozin was above 1 for certain cancers (bladder, prostate gland, mammary gland) and less than 1 for the other (for example, blood and lymphatic system, ovaries, urinary system) generally without increasing the cancer risk associated with dapagliflozin. Increase / decrease the risk was not statistically significant for either one organ system. Given the lack of preclinical data on the development of tumors, as well as a short latency period between the first drug exposure and tumor diagnosis, causal relationship is assessed as unlikely. Since the numerical imbalance of breast tumors, bladder and prostate requires special attention, the study of this issue will continue in the framework of post-marketing studies.

Elderly patients (?65 years)

Adverse reactions associated with impaired renal function or renal insufficiency, reported in 2.5% of patients receiving dapagliflozin, and in 1.1% of patients receiving placebo, in patients ?65 years (see. "Special Instructions" section). The most common adverse reactions associated with renal dysfunction, were increased creatinine concentration in the serum. Most of these reactions were transient and reversible. Among patients aged ? 65 years, reduction of BCC, the most frequently reported as arterial hypotension was seen in 1.5% and 0.4% of patients taking dapagliflozin and placebo groups, respectively (see. "Special Instructions" section).

Contraindications

• Individual hypersensitivity to any component of the drug,
  
• Type 1 diabetes,
  
• Diabetic ketoacidosis,
  
• Renal failure secondary to severe (GFR <60 mL / min / 1.73 m2) or end-stage renal failure,
  
• Hereditary lactose intolerance, lactase deficiency and glucose-galactose intolerance,
  
• Pregnancy and lactation,
  
• Children up to age 18 years (safety and efficacy have not been studied)
  
• Patients taking "loop" diuretics (see section "Interaction with other medicinal products and other forms of drug interactions."), Or with a reduced volume of circulating blood, for example, due to acute illness (such as gastro-intestinal diseases)
  
• Elderly patients aged 75 years and older (to start therapy).
  
• Precautions: hepatic failure, severe, urinary tract infection, the risk of reducing the volume of circulating blood, elderly patients, chronic heart failure, increased hematocrit value.
  

Pregnancy and breast-feeding

Due to the fact that the use of dapagliflozin during pregnancy is not known, the drug is contraindicated in pregnancy. In the case of diagnosing pregnancy dapagliflozin therapy should be discontinued.

It is unknown whether dapagliflozin and / or its inactive metabolites in breast milk. It is impossible to eliminate the risk to newborns / infants. Dapagliflozin is contraindicated during breast-feeding.

Application for violations of liver function

When violations of liver function or mild to moderate severity is not necessary to adjust the dose of the drug. Patients with impaired liver function severe recommended initial dose of 5 mg. With good tolerance dose can be increased to 10 mg

Application for violations of renal function

Efficacy dapagliflozin depends on renal function in patients with impaired renal function moderate severity reduced effectiveness of treatment and in patients with severe impairment - probably absent. Forsiga drug is contraindicated in patients with renal insufficiency, moderate and severe (creatinine clearance <60 mL / min or GFR <60 mL / min / 1.73 m2) or with end-stage renal failure.

When violations of mild renal function there is no need to adjust the dose of the drug.

Use in children

Safety and efficacy of dapagliflozin in patients under 18 years have not been studied, so the purpose of the drug is contraindicated.

Use in elderly patients

In elderly patients there is no need to adjust the dose of the drug. However, when choosing the dose should be considered that these patients are more likely to impaired renal function and reduce the risk of BCC.

Since clinical experience with the drug in patients 75 years and older is limited, start dapagliflozin therapy is contraindicated in this age group.

Special instructions

Use in patients with impaired renal function

The effectiveness of dapagliflozin is dependent on renal function, and this efficiency is reduced in patients with renal insufficiency of moderate severity, and probably not in patients with impaired renal function, severe (see. "Dosage and Administration" section). Among patients with renal moderate impairment (creatinine clearance <60 mL / min or estimated glomerular filtration rate <60 mL / min / 1.73 m2), have a greater proportion of patients receiving dapagliflozin, was an increase in serum creatinine, phosphorus, and parathyroid hormone hypotension than patients receiving placebo. Forsiga drug is contraindicated in patients with renal insufficiency, moderate or severe (creatinine clearance <60 mL / min or estimated glomerular filtration rate <60 mL / min / 1.73 m2). The drug Forsiga not studied in patients with renal failure, severe (creatinine clearance <30 mL / min or estimated glomerular filtration rate <30 mL / min / 1.73 m2) or end-stage renal failure.

It is recommended to monitor renal function in the following way:

• Prior to initiating therapy dapagliflozin and at least once a year thereafter (see sections "Dosage and administration", "Side effects", "Pharmacodynamics" and "Pharmacokinetics".)
  
• Before receiving concomitant medications that may decrease renal function, and periodically thereafter,
  
• With impaired renal function, close to moderate severity, at least 2-4 times a year. By reducing kidney function below the creatinine clearance <60 mL / min or estimated glomerular filtration rate <60 mL / min / 1.73 m2, need to stop taking dapagliflozin.
  

Use in patients with impaired hepatic function

In clinical studies, received limited evidence of the drug in patients with impaired hepatic function. Exposure increased dapagliflozin in patients with impaired liver function severe (see. Sections "Dosage and administration", "Precautions" and "Pharmacokinetics").

Use in patients with BCC risk reduction of arterial hypotension and / or electrolyte imbalance

In accordance with dapagliflozin mechanism of action enhances diuresis, accompanied by a small decrease in blood pressure (see. "Pharmacodynamics" section). The diuretic effect may be more pronounced in patients with a very high concentration of blood glucose.

Dapagliflozin is contraindicated in patients receiving "loop" diuretics (see. Section "Interaction with other medicinal products and other forms of drug interactions"), or patients with reduced BCC, for example, due to acute illness (such as gastro-intestinal diseases).

Caution must be exercised in patients for whom dapagliflozin-induced decrease in blood pressure may be a risk, for example, in patients with cardiovascular disease history, in patients with a history of arterial hypertension receiving antihypertensive therapy, or in elderly patients.

When receiving dapagliflozin recommended careful monitoring of the state of the BCC and the concentration of electrolytes (eg, physical examination, blood pressure measurement, laboratory tests, including hematocrit) against comorbid conditions that may lead to a decrease in the bcc. By reducing the BCC recommended temporary discontinuation of dapagliflozin to correct this condition (see. "Side effects" section).

Urinary tract infections

In the analysis of pooled data from the use of up to 24 weeks of dapagliflozin urinary tract infections are more marked in the application of dapagliflozin 10 mg compared to placebo (see. "Side effects" section). The development of pyelonephritis infrequently observed, with a similar frequency in the control group. Excretion of glucose by the kidneys may be accompanied by an increased risk of urinary tract infections, so the treatment of pyelonephritis or urosepsis should consider temporary discontinuation dapagliflozin (see. "Side effects" section).

Elderly patients

Older patients are more likely to impaired renal function and / or the use of antihypertensive drugs that may affect renal function, such as angiotensin converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists of type 1 (APA). For elderly patients apply the same recommendations with impaired renal function, as well as for all patient populations (see. Sections "Dosage and administration", "Side effects" and "Pharmacodynamic"). In the group of> 65 years of age have a greater proportion of patients treated with dapagliflozin, developed adverse reactions associated with impaired renal function or renal failure as compared to placebo. The most common adverse reactions associated with impaired renal function, was to increase the concentration of creatinine in the blood serum, the majority of cases were transient and reversible ( "Side effect" see. Section).

In elderly patients, the risk reduction of BCC can be higher and more likely diuretics. Among patients aged> 65 years have a greater share of patients receiving dapagliflozin, marked adverse reactions associated with a decrease in the bcc (see. "Side effects" section).

The experience of the drug in patients aged 75 years and older is limited. Contraindicated begin dapagliflozin therapy in this population (see. Sections "Dosage and Administration" and "Pharmacokinetics").

Chronic heart failure

The experience of the drug in patients with chronic heart failure I-II NYHA functional class classification is limited, and in clinical trials dapagliflozin was not used in patients with chronic heart failure III-IV NYHA functional class.

Increased hematocrit values

In the application of dapagliflozin was an increase in hematocrit (see. Section "Side effects"), and therefore caution should be exercised in patients with elevated hematocrit value.

Estimates of urine analysis results

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

Effects on ability to drive vehicles and management mechanisms

Studies on the effect of dapagliflozin on the ability to drive vehicles and machinery was carried out.

Overdose

Dapagliflozin safe and well tolerated in healthy volunteers receiving single doses up to 500 mg (50 times the recommended dose). Glucose was determined in urine after dosing (at least 5 days after a dose of 500 mg), with no cases identified dehydration, hypotension, electrolyte imbalance, clinically significant effects on interval QTc. The frequency of hypoglycemia was similar to the frequency in the placebo. In clinical studies in healthy volunteers and patients with type 2 diabetes treated with drug once daily doses up to 100 mg (10 times the maximum recommended dose) for 2 weeks, the incidence of hypoglycemia was slightly higher than the placebo, and no dose-dependent . The incidence of adverse events, including dehydration or hypotension, was similar to the rate in the placebo group, while not clinically significant, dose-dependent changes in laboratory parameters including serum concentration of electrolytes and renal function biomarkers.

In case of overdose should be carried out maintenance therapy, given the condition of the patient. Excretion of dapagliflozin by hemodialysis has not been studied.

Drug interactions

Pharmacodynamic interactions

Diuretics

Dapagliflozin may enhance the effect of thiazide diuretic and a "loop" diuretics and increase the risk of dehydration and hypotension (see. "Special Instructions" section).

Pharmacokinetic interactions

Dapagliflozin metabolism, mainly carried out by the action glucuronide UGT1A9 conjugation.

During in vitro studies, dapagliflozin did not inhibit cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, or induce isozymes CYP1A2, CYP2B6 and CYP3A4. In this connection it is not expected to influence the metabolic clearance dapagliflozin concomitant drugs are metabolized by the action of these isoenzymes.

The influence of other drugs on dapagliflozin

Interaction studies in healthy volunteers, mostly 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 joint use of dapagliflozin and rifampin, an inducer of various active transporters and metabolizing enzymes medications decreased systemic exposure (AUC) dapagliflozin 22%, 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. Clinically significant effects when applied to other inducers (eg, carbamazepine, phenytoin, phenobarbital) is expected.

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

Dapagliflozin influence to other drugs

In studies of interactions involving healthy volunteers, mostly once taking the dose, dapagliflozin did not affect the pharmacokinetics of metformin, pioglitazone, sitagliptin, glimepiride, hydrochlorothiazide, bumetanide, valsartan, digoxin (P-gp substrate) or warfarin (S-warfarin, the substrate isoenzyme CYP2C9), or anticoagulant effect, as measured by international normalized ratio (MHO). The use of a single dose of dapagliflozin 20 mg and simvastatin (a substrate of isoenzyme CYP3A4) resulted in an increase by 19% the AUC of simvastatin and 31% AUC simvastatinovoy acid. Increasing the exposure of simvastatin acid and simvastatinovoy not considered clinically significant.

Other interactions

The effect of smoking, diet, herbal products, and acceptance of alcohol use on the pharmacokinetics of dapagliflozin parameters have not been studied.

Terms and Conditions of storage

The temperature is not above 30 ° C, out of reach of children. Shelf life - 3 years.