Farxiga® [Dapagliflozin]

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Farxiga® [Dapagliflozin]

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The drug is taken orally, regardless of the meal.

Monotherapy: the recommended dose of Farxiga ™ is 10 mg 1 time / day.

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

In order to reduce the risk of hypoglycemia with co-administration of the Farxiga®z® drug 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.

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

When violations of the liver of mild or moderate severity there is no need to adjust the dose. For patients with severely impaired liver function, an initial dose of 5 mg is recommended. With good tolerance, the dose can be increased to 10 mg.

The effectiveness of dapagliflozin depends on the function of the kidneys. In patients with impaired renal function of moderate severity, the effectiveness of treatment is reduced, and in patients with severe impairment, most likely, is absent. Farxiga ™ is contraindicated in patients with moderate to severe renal failure (CC <60 ml="" min="" or="" gfr="" 60="" 1="" 73="" m2="" with="" end-stage="" renal="" disease="" when="" violations="" of="" the="" kidney="" mild="" dose="" adjustment="" is="" not="" required="" p="">

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

Elderly patients dose adjustment is not required. 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 diminishing BCC. Since the clinical experience of the drug in patients aged 75 years and older is limited, it is contraindicated to begin therapy with dapagliflozin in this age group.

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 who took dapagliflozin, the development of an adverse event on the part of the liver was diagnosed with drug-induced hepatitis and / or autoimmune hepatitis.

The most frequent adverse 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.

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 placebo.

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 stopped using dapagliflozin. These infections more often developed in women, and in patients with such infections in history, they more often recurred.

Parathyroid hormone (PTH)

A slight increase in serum PTH concentration was noted, and to a greater extent in patients with higher baseline 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 studies, the overall 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 the development of tumors of various organ systems, the relative risk associated with dapagliflozin was above 1 for some tumors (bladder, prostate, breast) and below 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 / 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 the 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.

Contraindications

- diabetes mellitus type 1;

- diabetic ketoacidosis;

- moderate to severe renal failure (GFR <60 ml="" min="" 1="" 73="" m2="" or="" end-stage="" renal="" disease="" p="">

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

- pregnancy;

- breastfeeding period;

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

- patients taking "loop" 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.

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

Drug interactions

Pharmacodynamic interaction

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

Against the background of the use of insulin and drugs that increase insulin secretion, hypoglycemia may occur. Therefore, in order to reduce the risk of hypoglycemia with a joint appointment of the drug Farxiga ™ 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.

During in vitro studies, dapagliflozin did not inhibit cytochrome P450 isoenzymes of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and did not induce CYP1A2, CYP22 isoenzymes, CYP2A6, CYP3A4, 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

Interaction studies involving healthy volunteers, mainly 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 the 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 joint use of dapagliflozin and mefenamic acid (UGT1A9 inhibitor), 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.

The effect of dapagliflozin on other drugs

In studies of interactions involving healthy volunteers, mainly taking a single dose of the drug, dapagliflozin did not interfere with aphromine pharmacokinetics of metformin, pioglitazone, sitagliptin, glimepiride, hydrochlorothiazide, bumetanide, valsartan, digoxin (P-gp substrate), or orp, bumetanide, valsartan, digoxin (substrate P-gl or, or -tromide, bumetanide, valsartan, digoxin (substrate P-gl or, or), or pimlitrid, hydrochlorothiazide, bumetanide, valsartan, digoxin (substrate P-gl or, or). 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% in the AUC of simvastatin and in a 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, taking herbal remedies and drinking alcohol on the parameters of dapagliflozin pharmacokinetics have not been studied.

Pregnancy and Lactation

Special instructions

Overdosage