FARXIGA PILL 10MG

Adverse reactions

The pre-planned analysis of pooled data included the results of 12 placebo-controlled studies in which 1,193 patients took dapagliflozin at a dose of 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 leading to discontinuation of therapy was small and balanced between treatment groups. The most frequent adverse events that led to the discontinuation of dapagliflozin therapy at a dose of 10 mg were an increase in the concentration of creatinine in the blood (0.4%), urinary tract infection (0.3%), nausea (0.2%), dizziness (0.2%) and rash (0.2% ). In one patient taking dapagliflozin, the development of an adverse event on the part of the liver was diagnosed with drug-induced hepatitis and / or autoimmune hepatitis.

Most frequent undesirable reaction was hypoglycemia, the development of which depended on the type of basic therapy used in each study. The incidence of mild hypoglycemia was similar in treatment groups, including placebo.

The adverse reactions reported in placebo-controlled clinical trials are presented below. None of them depended on the dose of the drug.The frequency of undesirable reactions is represented as the following grades: very often (≥1 / 10), often (≥1 / 100, <1/10), infrequently (≥1 / 1000, <1/100), rarely (≥1 / 10 000, <1/1000), very rarely (<1/10 000) and unspecified frequency (it is impossible to estimate from the data obtained).

Adverse reactions in placebo controlled studiesa

but The table presents data on the use of the drug up to 24 weeks (short-term therapy), regardless of the admission of an additional hypoglycemic drug.

b See the appropriate subsection below for more information.

c Vulvovaginitis, balanitis and similar genital infections include, for example, the following predetermined preferred terms: vulvovaginal fungal infection, vaginal infection, balanitis, fungal infection of the genital organs, vulvovaginal candidiasis, vulvovaginitis, candidal balanitis,genital candidiasis, infection of the genital organs, infection of the genital organs in men, infection of the penis, vulvitis, bacterial vaginitis, an abscess of the vulva.

d Polyuria includes the preferred terms: pollakiuria, polyuria, and increased diuresis.

e The reduction in bcc includes, for example, the following predefined preferred terms: dehydration, hypovolemia, arterial hypotension.

f The average change in the following indicators in percent of baseline values ​​in the dapagliflozin 10 mg group and the placebo group, respectively, was: total cholesterol 1.4% compared with -0.4%; cholesterol-HDL 5.5% compared with 3.8%; cholesterol-LDL 2.7% compared with -1.9%; triglycerides -5.4% compared with -0.7%.

g The mean change in hematocrit from baseline values ​​was 2.15% in the dapagliflozin 10 mg group compared with -0.40% in the placebo group.

* Marked in ≥ 2% of patients taking dapagliflozin at a dose of 10 mg, and ≥1% more often than in the placebo group.

** Marked in ≥ 0.2% of patients and ≥0.1% more often and in a larger number of patients (at least 3) in the 10 mg dapagliflozin group compared with the placebo group, regardless of the supplemental hypoglycemic drug.

Description of individual unwanted reactions

Hypoglycemia

The incidence of hypoglycemia depended on the type of basic therapy used in each study.

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

Decrease bcc

Adverse reactions associated with a decrease in BCC (including reports of dehydration, hypovolemia, or arterial hypotension) were noted in 0.8% and 0.4% of patients taking dapagliflozin 10 mg and placebo, respectively; severe reactions were observed in <0.2% 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 are noted in 4.8% and 0.9% of patients taking dapagliflozin 10 mg and placebo, respectively. Most infections were mild or moderate; the initial course of standard therapy was effective, and therefore patients rarely stopped taking dapagliflozin. These infections more often developed in women (6.9% and 1.5% with dapagliflozin and placebo, respectively), and in patients with such infections in history, they more often recurred.

Urinary tract infections

Urinary tract infections are more common with dapagliflozin 10 mg than with placebo (4.3% compared with 3.7%, respectively). Most infections were mild or moderate; the initial course of standard therapy was effective, and therefore patients rarely discontinued dapagliflozin. These infections more often developed in women, and in patients with such infections in history, they often recur.

Parathyroid hormone (PTH)

A slight increase in serum PTH concentration was noted, and to a greater extent in patients with higher initial PTH concentrations. 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 total proportion of patients with malignant or unspecified tumors was similar in the dapagliflozin group (1.47%) and the placebo / comparator group (1.35%). According to animal studies, the drug did not show carcinogenic or mutagenic properties. When considering cases of the development of tumors of various organ systems, the relative risk associated with dapagliflozin was above 1 for some tumors (bladder, prostate gland, mammary gland) and below 1 for others (for example, blood and lymphatic system, ovaries, urinary system), in general, without increasing the risk of developing tumors associated with dapagliflozin. The increased / decreased risk was not statistically significant for any organ system. Given the lack of information on the development of tumors in preclinical studies, as well as a short latent period between the first exposure of the drug and the diagnosis of the tumor, the causal relationship is assessed as unlikely. Since the numerical imbalance of breast, bladder and prostate tumors requires special attention, the study of this issue will be continued in the framework of post-registration studies.

Elderly patients (≥65 years)

Adverse reactions associated with impaired renal function or renal failure were reported in 2.5% of patients who received dapagliflozin and 1.1% of patients who received placebo in a group of patients aged ≥65 years. The most common adverse reaction associated with impaired renal function was an increase in serum creatinine concentration. 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.

- diabetes mellitus type 1;

- diabetic ketoacidosis;

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

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

- pregnancy;

- breastfeeding period;

- children's and teenage age till 18 years (safety and efficiency are not studied);

- patients taking "loopback" diuretics, or with a reduced BCC, for example, due to acute diseases (such as gastrointestinal diseases);

- Elderly patients aged 75 years and older (to start therapy);

- increased individual sensitivity to any component of the drug.

Carefully: severe liver failure, urinary tract infection, risk of diminished BCC, elderly patients, chronic heart failure, increased hematocrit.

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

It is not known whether dapagliflozin and / or its inactive metabolites into breast milk. Risk to newborns / babies cannot be excluded. Dapagliflozin contraindicated during breastfeeding.

When violations of the liver of mild or moderate severity there is no need to adjust the dose of the drug.

To use with caution in patients with severe liver failure, it is recommended that the initial dose of the drug 5 mg. With good tolerance, the dose can be increased to 10 mg.

In cases of mild renal impairment, there is no need to adjust the dose of the drug.

Drug FarxigaTm contraindicated in patients with moderate to severe renal failure (CK <60 ml / min or GFR <60 ml / min / 1.73 m2 ) or with end-stage renal disease.

The drug is contraindicated in children and adolescents under the age of 18 years.

Elderly patients do not need to adjust the dose of the drug.However, when choosing a dose, it should be borne in mind that this category of patients is more likely to have impaired renal function and the risk of lowering BCC.

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

Use in patients with impaired renal function

The effectiveness of dapagliflozin depends on the kidney function, and this efficiency is reduced in patients with moderate renal insufficiency and is probably absent in patients with severe renal impairment. Among patients with moderate renal failure (CC <60 ml / min or estimated GFR <60 ml / min / 1.73 m2), in a larger proportion of patients who received dapagliflozin, there was an increase in the concentration of creatinine, phosphorus, PTH and arterial hypotension than in patients who received placebo. Drug FarxigaTm contraindicated in patients with moderate to severe renal failure (CC <60 ml / min or estimated GFR <60 ml / min / 1.73 m2). Drug FarxigaTm not studied in severe renal failure (CC <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 the start of therapy with dapagliflozin and at least once a year thereafter;

- before the start of concomitant medications that can reduce kidney function, and periodically thereafter;

- in violation of renal function, close to moderate severity, at least 2-4 times a year.With a decrease in renal function below the CC value <60 ml / min or estimated GFR <60 ml / min / 1.73 m2, you must stop taking dapagliflozin.

Use in patients with impaired liver function

In clinical studies, limited data on the use of the drug in patients with impaired liver function were obtained. Dapagliflozin exposure is increased in patients with severely impaired liver function.

Use in patients with the risk of reducing the BCC development of 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 a very high concentration of glucose in the blood.

Dapagliflozin is contraindicated in patients taking "loopback" diuretics, or in patients with reduced BCC, for example, due to acute diseases (such as gastrointestinal diseases).

Care should be taken in patients for whom dapagliflozin-induced reduction in blood pressure may pose a risk, for example, in patients with a history of cardiovascular disease, in patients with a history of arterial hypotension who are receiving antihypertensive therapy, or in elderly patients.

When taking dapagliflozin, careful monitoring of the state of the BCC and the concentration of electrolytes (for example, physical examination, measurement of blood pressure, laboratory tests, including hematocrit) against the background of associated conditions that may lead to a decrease in the BCC is recommended.When reducing the BCC, it is recommended to temporarily stop taking dapagliflozin before correcting this condition.

Ketoacidosis

When postmarketing use of the drug, ketoacidosis has been reported, incl. diabetic ketoacidosis, in patients with type 1 and 2 diabetes mellitus, taking FarxigaTm and other SGLT2 inhibitors, although a causal relationship has not been established. Drug FarxigaTm not indicated for the treatment of patients with type 1 diabetes.

ForsighaTm Patients with signs and symptoms suggestive of ketoacidosis, including nausea, vomiting, abdominal pain, malaise and shortness of breath, should be checked for ketoacidosis even if the glucose concentration in the blood is below 14 mmol / l. If ketoacidosis is suspected, the possibility of withdrawing or temporarily discontinuing the use of Farxiga should be considered.Tm and immediately conduct an examination of the patient.

Factors predisposing to the development of ketoacidosis include low functional β-cell activity due to dysfunction of the pancreas (for example, diabetes mellitus type 1, pancreatitis or pancreatic surgery in history) insulin due to infection, disease or surgery, and alcohol abuse. Drug Farxiga® should be used with caution in these patients.

Urinary tract infection

When analyzing the combined data, the use of dapagliflozin up to 24 weeks of urinary tract infection is more often noted with the use of dapagliflozin at a dose of 10 mg compared with placebo. The development of pyelonephritis was noted infrequently, with a similar frequency in the control group. The excretion of glucose by the kidneys may be accompanied by an increased risk of developing urinary tract infections, therefore, when treating pyelonephritis or urosepsis, the possibility of temporary discontinuation of dapagliflozin therapy should be considered.

Urosepsis and pyelonephritis. With the post-marketing use of the drug, serious urinary tract infections, including urosepsis and pyelonephritis, have been reported, requiring hospitalization of patients taking FarxigaTm and other SGLT2 inhibitors. 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, if indicated, should be treated immediately.

Elderly patients

Older patients are more likely to have impaired renal function and / or use of antihypertensive drugs that can affect kidney function, such as ACE inhibitors and angiotensin II type 1 receptor antagonists (ARA). For older patients, the same recommendations apply for kidney dysfunction as for all patient populations.

In the group of patients aged ≥65 years, a greater proportion of patients who received dapagliflozin developed adverse reactions associated with impaired renal function or renal insufficiency compared with placebo.The most common adverse reaction associated with impaired renal function was an increase in serum creatinine, most cases were transient and reversible.

Elderly patients may have a higher risk of reducing BCC, and diuretics are more likely to be taken. A greater proportion of patients aged ≥65 years who received dapagliflozin had adverse reactions associated with a decrease in BCC.

Experience with the drug in patients aged 75 years and older is limited. It is contraindicated to begin therapy with dapagliflozin 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 NYHA.

Hematocrit increase

When using dapagliflozin, an increase in hematocrit was observed, and therefore care should be taken in patients with elevated hematocrit.

Evaluation results of urine analysis

Due to the mechanism of action of the drug, the results of urine glucose analysis in patients taking FarxigaTmwill be positive.

Effect on the determination of 1,5-anhydroglucitol

Evaluation of glycemic control using the determination of 1,5-anhydroglucitol is not recommended, since the measurement of 1,5-anhydroglucitol is an unreliable method for patients taking SGLT2 inhibitors.Alternative methods should be used to evaluate glycemic control.

Influence on ability to drive motor transport and control mechanisms

Studies on the effect of dapagliflozin on the ability to drive vehicles and mechanisms have been conducted.

Dapagliflozin is safe and well tolerated by healthy volunteers when taken once in doses up to 500 mg (50 times higher than the recommended dose). Glucose was determined in the urine after taking the drug (at least 5 days after taking a dose of 500 mg), while no cases of dehydration, arterial hypotension, electrolyte imbalance, or clinically significant effect on the QT interval were detected.c. The incidence of hypoglycemia was similar to the frequency with placebo. In clinical studies in healthy volunteers and patients with T2DM who took the drug once in doses up to 100 mg (10 times higher than the maximum recommended dose) for 2 weeks, the incidence of hypoglycemia was slightly higher than when taking placebo, and did not depend on the dose . The incidence of adverse events, including dehydration or hypotension, was similar to the frequency in the placebo group, with no clinically significant, dose-dependent changes in laboratory parameters, including serum electrolyte concentrations and kidney function biomarkers.

Treatment: in case of overdose, maintenance therapy is necessary, taking into account the patient's condition.Removal of dapagliflozin using hemodialysis has not been studied.

Pharmacodynamic interaction

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

Against the background of the application insulin and insulin secretion enhancershypoglycemia may occur. Therefore, in order to reduce the risk of hypoglycemia with the joint appointment of the drug FarxigaTm with an insulin preparation or a drug that increases insulin secretion, it may be necessary to lower the dose of the insulin preparation or the drug that increases insulin secretion.

Pharmacokinetic interaction

The metabolism of dapagliflozin is mainly carried out by glucuronide conjugation under the action of UGT1A9.

In the course of in vitro studies, dapagliflozin did not inhibit the cytochrome P450 isoenzymes of the CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and did not induce the CYP1A2 isoenzymes, CYP26, CYP2A6, CYP2A6, CYP2A6, CYP2A6. In this regard, the effect of dapagliflozin on the metabolic clearance of concomitant drugs that are metabolized by these isoenzymes is not expected.

Effects of other drugs on dapagliflozin

Studies of interactions involving healthy volunteers, mostly taking a single dose of the drug, have shown that metformin, pioglitazone, sitagliptin, Glimepiride, voglibose, hydrochlorothiazide, bumetanide, valsartan or Simvastatin do not affect the pharmacokinetics of dapagliflozine.

After joint 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 glucose excretion 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 (for example, Carbamazepine, phenytoin, phenobarbital).

After the combined use of dapagliflozin and mefenamic acid (an inhibitor of UGT1A9), a 55% increase in systemic exposure to dapagliflozin was noted, 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 drugs

In studies of interactions involving healthy volunteers, mainly taking a single dose of the drug, dapagliflozin had no effect on the pharmacokinetics of metformin, pioglitazone, sitagliptin, glimepiride, hydrochlorothiazide, bumetanide, valsartan, Digoxin (P-gp substrate or -tar or alphonfluidine, bumetanide, valsartan, digoxin (substrate P-gp or or), or var-pyridine, p-gp, or p-gp. CYP2C9 isoenzyme), or on the anticoagulant effect, as assessed by MHO. The use of dapagliflozin in a single dose of 20 mg and simvastatin (CYP3A4 isoenzyme substrate) resulted in an increase of 19% AUC of simvastatin and 31% AUC of simvastatinic acid. Increasing the exposure of simvastatin and simvastatinic acid is not considered clinically significant.

Other types of interaction

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

The drug should be stored out of the reach of children at a temperature not higher than 30 ° C.