Invokana - instructions for use, dose, side effects, contraindications

Active substanceKanagliflozinKanagliflozin

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Invokana®

pills inwards

Johnson & Johnson, LLC Russia

Dosage form: & nbspfilm coated tablets

Composition:

In 1 tablet, film-coated 100 mg, contains:

Active substance:

102.0 mg of cannagliflozin hemihydrate, equivalent to 100.0 mg of cannagliflozin.

Excipients (core): cellulose microcrystalline 39.26 mg, lactose anhydrous 39.26 mg, croscarmellose sodium 12.00 mg, giprolose 6.00 mg, magnesium stearate 1.48 mg.

Auxiliary substances (shell): dye Opadry II 85F92209 yellow (the composition includes polyvinyl alcohol, partially hydrolysed, 40.00%, titanium dioxide 24.25%, macrogol 3350 20.20%, talc 14.80%, iron oxide yellow (E172) 0.75%) - 8, 00 mg.

In 1 tablet, film-coated 300 mg, contains:

306.0 mg of cannagliflozin hemihydrate, equivalent to 300.0 mg of cannagliflozin.

Excipients (core): cellulose microcrystalline 117.78 mg, lactose anhydrous 117.78 mg, croscarmellose sodium 36.00 mg, giprolase 18,00 mg, magnesium stearate 4.44 mg.

Auxiliary substances (shell): coloring Opadrai II 85F1 8422 white (composed of polyvinyl alcohol, partially hydrolysed, 40.00% titanium dioxide 25.00%, macrogol 3350 20.20%, talc 14.80%) - 18.00 mg.

Description:

Dosage of 100 mg: capsule-shaped tablets *, covered with a film coating of yellow color, with engraving on one side "CFZ", and on the other = "100".

* On the cross-section, the core of the tablet is white or almost white in color.

Dosage of 300 mg: capsule-shaped tablets coated with a white or nearly white-colored film shell, engraved on one side "CFZ", and on the other - "300".

Pharmacotherapeutic group:Hypoglycemic agent for oral use is an inhibitor of the sodium-dependent glucose transporter of type 2

ATX: & nbsp

A.10.B.X.11 Kanagliflozin

Pharmacodynamics:

Mechanism of action

It was shown that in patients with diabetes there is increased renal glucose reabsorption, which can contribute to a steady increase in glucose concentration. Sodium-glucose cotransporter type 2 (SGLT2), expressed in the proximal renal tubules, is responsible for most of the glucose reabsorption from the tubule lumen.

Kanagliflozin is an inhibitor of sodium-glucose cotransporter type 2. Inhibiting SGLT2, cannagliflozin reduces the reabsorption of the filtered glucose and reduces the renal threshold for glucose (BCP), thereby increasing the excretion of glucose by the kidneys, which leads to a decrease in the concentration of glucose in the blood plasma with the help of an insulin-independent mechanism in patients with type 2 diabetes mellitus. Increase in the excretion of glucose by the kidneys by inhibition SGLT2 also leads to osmotic diuresis, diuretic effect leads to a decrease in systolic blood pressure; increasing the excretion of glucose by the kidneys leads to a loss of calories and, as a result, a decrease in body weight.

In studies III phase, the use of cannaroglofosin 300 mg before meals resulted in a more pronounced decrease in postprandial increase in glucose concentration than when applied at a dose of 100 mg. This effect may be partly due to local inhibition of the intestinal transporter SGLT1 taking into account transiently high concentrations of cannagliflozin in the lumen of the intestine prior to absorption of the drugcannagloflozin is an inhibitor SGLT1 with low activity). In studies, malabsorption of glucose was not detected with the use of cannagliflozin.

Pharmacodynamic effects

In clinical trials after single and multiple oral administration of cannagliflozin in patients with type 2 diabetes mellitus, the renal threshold for glucose was dose-dependent decreased, the excretion of glucose by the kidneys increased. The initial value of the renal threshold for glucose was about 13 mmol / l,the maximum decrease in the 24-hour mean renal glucose threshold was observed with the use of cannaroglofosin 300 mg once a day and was 4 to 5 mmol / l, indicating a low risk of hypoglycemia in the background of treatment. In a clinical study of the use of cannagliflozin in doses of 100 mg to 300 mg 1 time per day in patients with type 2 diabetes mellitus within 16 days, the decrease in the renal threshold for glucose and the increase in glucose excretion by the kidneys were constant. At the same time, the concentration of glucose in the blood plasma decreased dose-dependent on the first day of administration, followed by a steady decrease in fasting plasma glucose and after eating.

The use of cannagliflozin once in a dose of 300 mg before receiving mixed food in patients with type 2 diabetes mellitus caused a delay in the absorption of glucose in the intestine and a decrease in postprandial glycemia through renal and adrenal mechanisms.

In clinical trials, 60 healthy volunteers were given a single oral dose cannagloflozin in a dose of 300 mg, cannagloflozin in a dose of 1200 mg (4 times higher than the maximum recommended dose), moxifloxacin and placebo.Hc, there were significant changes in the interval QTc nor with the use of cannagliflozin at the recommended dose of 300 mg, nor with the use of cannagliflozin at a dose of 1200 mg. With the use of cannagliflozin in a dose of 1200 mg, the maximum concentration of cannagliflozin in the blood plasma was approximately 1.4 times higher than the equilibrium maximum concentration after administration of cannaminoglobin at a dose of 300 mg once a day.

Fasting glycemia

In clinical trials, the use of cannagliflozin as monotherapy or supplementation to therapy with one or two oral hypoglycemic drugs resulted in an average change in fasting glycemia from baseline versus placebo from -1.2 mmol / L to -1.9 mmol / L when applied kanagliflozin in a dose of 100 mg and from -1.9 mmol / l to -2.4 mmol / l - with the use of cannagliflozin at a dose of 300 mg, respectively. This effect was close to the maximum after the first day of therapy and persisted throughout the treatment period.

Postprandial Glycemia

In clinical studies of the use of cannagliflozin as monotherapy or complementary therapy, one or two oral hypoglycemic agents were measuredpostprandial glycemia after a glucose tolerance test with a standardized mixed breakfast. The use of cannagliflozin led to an average decrease in the level of postprandial glycemia compared with the baseline level with respect to placebo from -1.5 mmol / L to -2.7 mmol / L - with the use of cannagliflozin at a dose of 100 mg and -2.1 mmol / l to -3.5 mmol / l - with the use of cannagliflozin at a dose of 300 mg, respectively, due to a decrease in glucose concentration before meals and a decrease in the level of postprandial glycemia.

Function of beta cells

Studies of the use of cannagliflozin in patients with type 2 diabetes indicate an improvement in beta-cell function, according to the estimation of the homeostasis model for beta-cell function (homeostatic model-2 assessment index %B; NOMA2-% B) and an improvement in the rate of insulin secretion in a glucose tolerance test with a mixed breakfast.

Pharmacokinetics:

The pharmacokinetics of cannagliflozin in healthy subjects is similar to the pharmacokinetics of cannagliflozin in patients with type 2 diabetes mellitus. After a single oral administration of cannagliflozin in doses of 100 mg and 300 mg by healthy volunteers cannagloflozin quickly absorbed, the maximum concentration in the blood plasma (mean T_m_Oh) is achieved in 1-2 hours. Plasma C_m_Oh and AUC cannaroglofosin increased dose-proportional when the drug is used in doses from 50 mg to 300 mg. Apparent terminal half-life (t_1/2) was 10.6 hours and 13.1 hours with the use of cannagliflozin in doses of 100 mg and 300 mg, respectively. The equilibrium state was achieved 4-5 days after the initiation of therapy with cannacryphlosin at a dose of 100 mg or 300 mg once daily.

Pharmacokinetics of cannagliflozin does not depend on time, the accumulation of the drug in the plasma reaches 36% after repeated administration.

Suction

The average absolute bioavailability of cannagliflozin is approximately 65%. Eating high-fat foods did not affect the pharmacokinetics of cannagliflozin; so cannagloflozin can be taken with or without food. However, given the ability of cannagliflozin to reduce the increase in postprandial glycemia due to a slowdown in glucose absorption in the intestine, cannagloflozin before first eating.

Distribution

The average volume of distribution of cannagliflozin in the equilibrium state after a single intravenous infusion in healthy individuals was 119 liters, indicating a large distribution in tissues. Kanagliflozin largely binds to plasma proteins (99%), mainly with albumin. The connection with proteins does not depend on the concentration of cannagliflozin in the plasma. The association with plasma proteins does not significantly change in patients with renal or hepatic insufficiency.

Metabolism

O-glucuronation is the main pathway of the metabolism of cannagliflozin. Glucuronation occurs mainly with participation UGT1A9 and UGT2I34 up to two inactive O-glucuronide metabolites. SURZA4-mediated (oxidative) metabolism of cannagliflozin in the human body is minimal (about 7%).

Excretion

After taking a single dose ¹⁴C-cannagliflozin by orally healthy volunteers 41.5%, 7.0% and 3.2% of the administered radioactive dose was found in feces in the form of cannagliflozin, hydroxylated metabolite and O-glucuronide metabolite, respectively. The intestinal and hepatic circulation of cannagliflozin was insignificant.

Approximately 33% of the administered radioactive dose was detected in urine, mainly in the form of O-glucuronide metabolites (30.5%). Less than 1% of the dose is excreted in the form of unchanged kanagliflozin by the kidneys. Kidney clearance with the use of cannagliflozin in doses of 100 mg and 300 mg ranged from 1.30 to 1.55 ml / min.

Kanagliflozin refers to drugs with low clearance, the average systemic clearance is approximately 192 ml / min in healthy individuals after intravenous administration.

Special patient groups

Patients with impaired renal function

Renal failure did not affect C_m_Oh cannagloflosin. Compared to healthy volunteers, the serum index AUC cannaroglofosin increased by approximately 15%, 29% and 53% in patients with mild, moderate and severe renal failure, respectively, but was the same in healthy volunteers and patients with terminal chronic renal failure (HG1N). This increase AUC cannagliflozin was not regarded as clinically significant.

It is not recommended the use of cannagliflozin in patients with severe renal failure, terminal stage of chronic renal failure, patients on dialysis, since it is not expected that cannagloflozin will be effective in these patients.

Removal of cannagliflozin by dialysis was minimal.

Patients with impaired hepatic function

After the application of cannagliflozin at a dose of 300 mg once in comparison with patients with normal liver function in patients with impaired liver function of Class A but on the Child-Pugh scale (a malfunction of the liver of mild severity), the C_m_Oh and AUC_∞increased by 7% and 10%, respectively, and decreased by 4% and increased by 11%, respectively, in patients with impaired hepatic class B function on the Child-Pugh scale (impaired liver function of moderate severity). These differences are not regarded as clinically significant. Dose adjustments in patients with mild or moderate hepatic insufficiency do not it takes. Clinical use of the drug in patients with severe impairment of liver function (class C on the scale Child-Pugh) is absent, so the use of cannagliflozin in this group of patients is contraindicated.

Elderly patients (≥65 years old)

According to the results of population pharmacokinetic analysis, age had no clinically significant effect on the pharmacokinetics of cannagliflozin.

Children (<18 years old)

Studies of the pharmacokinetics of cannagliflozin in children have not been conducted.

Other patient groups

Dose adjustments for sex, race / ethnicity or body mass index are not required. These characteristics did not have a clinically significant effect on the pharmacokinetics of cannagliflozin, according to the results of the pharmacokinetic population analysis.

Indications:

Diabetes mellitus type 2 in adults combined with diet and exercise to improve glycemic control as:

- Monotherapy

- In combination therapy with other hypoglycemic drugs, including insulin.

Contraindications:

Hypersensitivity to kanagliflozin or any auxiliary substance of the drug; type 1 diabetes mellitus; diabetic ketoacidosis; severe renal insufficiency; severe hepatic impairment; pregnancy and the period of breastfeeding; children's age till 18 years.

Pregnancy and lactation:

Pregnancy

Studies of the use of cannagliflozin in pregnant women have not been conducted. Animal studies do not indicate a direct or indirect adverse toxic effect on reproductive system.

The use of cannagliflozin is contraindicated during pregnancy.

Breastfeeding period

Contraindicated in the use of cannagliflozin in women during breastfeeding, because, according to available pharmacodynamic / toxicological data obtained during preclinical studies, cannagloflozin penetrates into breast milk.

Dosing and Administration:

Kanagliflozin should be taken orally once a day, preferably before breakfast.

Adults (> 18 years)

The recommended dose of cannagliflozin is 100 mg or 300 mg once a day; preferably before breakfast.

With the use of cannagliflozin as an adjunct to insulin therapy or agents that enhance its secretion (for example, derivatives of sulfonylureas), the possibility of using lower doses of the above drugs may be considered to reduce the risk of hypoglycemia.

Kanagliflozin has a diuretic effect. In patients who received diuretics, in patients with impaired renal function of moderate severity [with a glomerular filtration rate (GFR) from 30 to <60 ml / min / 1.73 m²] or patients> 75 years of age, there was a more frequent development of unwanted reactions associated with a decrease in intravascular volume (eg, postural dizziness, orthostatic hypotension or arterial hypotension). Thus, these patients recommend the use of cannaroglofosin in an initial dose of 100 mg once a day. Patients with signs of hypovolemia are recommended to correct this condition before the beginning of treatment with cannagliflozin. In patients receiving cannagloflozin in a dose of 100 mg with good tolerance, which require additional control of glycemia, it is advisable to increase the dose to 300 mg.

Dose skip

If a dose is missed, it should be taken as soon as possible; however, do not take a double dose for one day.

Special categories of patients

Children under 18 years old

Safety and effectiveness of the use of cannagliflozin in children have not been studied.

Elderly patients

Patients aged ≥75 years as the initial dose should be administered 100 mg once a day. With a good dose tolerance of 100 mg, patients who need additional control of glycemia, it is advisable to increase the dose to 300 mg.

Impaired renal function

In patients with impaired renal function of mild degree (calculated glomerular filtration rate (GFR) from 60 to <90 ml / min / 1.73 m²), dose adjustment is not required.

In patients with impaired renal function of moderate severity, the use of the drug in an initial dose of 100 mg once a day is recommended. With a good dose tolerance of 100 mg, patients who need additional control of glycemia, it is advisable to increase the dose to 300 mg. Kanagliflozin It is not recommended for patients with impaired renal function of severe degree (GFR <30 ml / min / 1.73 m²), terminal stage of chronic renal failure (CRF), or in patients on dialysis, as it is expected that in these populations of patients cannagloflozin will be ineffective.

Side effects:

Data on adverse reactions observed during clinical trials¹ (≥1 / 10), frequent (≥1 / 100, <1/10), infrequent (≥1 / 10), frequent (≥1 / 100, <1/10), infrequent 1000, <1/100), rare (≥1 / 10000, <1/1000).

Disorders from the gastrointestinal tract:

Frequent: constipation, thirst², dry mouth.

Disorders from the kidneys and urinary tract:

Frequent: polyuria and pollakiuria³, compulsive urge to urinate, urinary tract infection⁴, urosepsis.

Violations of the genitals and breast:

Frequent: balanitis and balanoposthitis⁵, vulvovaginal candidiasis⁶, vaginal infections.

¹Including monotherapy and addition to metformin, metformin and sulfonylureas, as well as metformin and pioglitazone.

²The category "thirst" includes the term "thirst", the term "polydipsia" also refers to this category.

³ The category "polyuria or pollakiuria" includes the terms "polyuria", this category also includes the terms "increased volume of excreted urine", "nocturia".

⁴The category of "urinary tract infection" includes the term "urinary tract infection", and also includes the terms "cystitis" and "kidney infections."

⁵ The category "balanitis or balanoposthitis" includes the terms "balanitis" and "balanoposthitis", as well as the terms "candidal balanitis" and "genital fungal infections."

⁶ The category "vulvovaginal candidiasis" includes the terms "vulvovaginal candidiasis", "vulvovaginal fungal infections", "vulvovaginitis" and the terms "vulvitis" and "genital fungal infections."

Other undesirable reactions that developed in placebo-controlled studies of <2% Kanagliflozin were unwanted reactions associated with a decrease in intravascular volume (postural dizziness, orthostatic hypotension, arterial hypotension, dehydration and fainting), skin rash and urticaria.

Adverse reactions associated with a decrease in intravascular volume

The incidence of all adverse reactions associated with a decrease in intravascular volume (postural dizziness, orthostatic hypotension, arterial hypotension, dehydration and fainting) was <2% with the use of cannagliflozin in doses of 100 mg and 300 mg.

But the results of generalized analysis, in patients who received "loop" diuretics, patients with moderate renal insufficiency (GFR from 30 to <60 ml / min / 1.73 m²) and patients aged ≥ 75 years, there was a higher incidence of these undesirable reactions. In carrying out studies on cardiovascular risks, the frequency of serious adverse reactions associated with a decrease in intravascular volume, with the use of cannagliflozin did not increase, the cessation of treatment due to the development of undesirable reactions of this type were infrequent.

Hypoglycemia when used as an adjunct to insulin therapy or agents that enhance its secretion

With the use of cannagliflozin as a supplement to the therapy with insulin or sulfonylurea derivatives, the development of hypoglycemia has been reported more often. This is consistent with the expected increase in the incidence of hypoglycemia in cases where a drug whose use is not accompanied by the development of this condition is added to insulin or drugs that enhance its secretion (for example, sulfonylurea derivatives).

Changes in laboratory indicators

Increase in serum potassium concentration

The cases of potassium concentration increase in the serum (> 5.4 mEq / L and 15% higher than the initial concentration) were observed in 4.4% of patients receiving cannagloflozin in a dose of 100 mg, in 7.0% of patients who received cannagloflozin in a dose of 300 mg, and in 4.8% of patients receiving a placebo.Occasionally, there was a more pronounced increase in potassium concentration in the serum in patients with impaired renal function of moderate severity, who previously had an increase in potassium concentration and / or who received several drugs that reduce potassium excretion (potassium-sparing diuretics and angiotensin-converting enzyme (ACE) inhibitors). In general, the increase in potassium concentration was transient and did not require special treatment.

Increased serum creatinine and urea concentrations

During the first six weeks after the start of treatment, there was a slight average increase in creatinine concentration (<5%) with a commensurate decrease in GFR, after which there was a general tendency for the indicators to return to their baseline values. Within six weeks after the initiation of therapy with cannagliflozin, there was a moderate increase in the urea concentration (15-20%), which subsequently remained stable. In patients with impaired renal function of medium degree the severity of the increase in the concentration of creatinine and urea was noted in 10-11% and approximately 12% of cases, respectively.

The proportion of patients with a significant decrease in GFR (> 30%) compared with the baseline observed at any etan treatment was 2.0% - with the use of cannagliflozin at a dose of 100 mg, 4.1% - with the drug at a dose of 300 mg and 2.1% for placebo. These reductions in GFR were often transient, with a similar reduction in GFR by the end of the study in fewer patients. According to the combined analysis of patients with moderate renal insufficiency, the proportion of patients with a greater reduction in GFR (> 30%) compared with the baseline observed at any stage of treatment was 9.3% - with the use of cannagliflozin at a dose of 100 mg, 12 , 2% - when administered at a dose of 300 mg, and 4.9% - with placebo. After stopping the reception of cannagliflozin, these changes in laboratory parameters underwent positive dynamics or returned to the initial level.

Increase in the concentration of low density lipoproteins (LDL)

A dose-dependent increase in LDL-C concentration was observed with the use of cannagliflozin. The mean changes in LDL as a percentage of the initial concentration compared with placebo were 0.11 mmol / L (4.5%) and 0.21 mmol / L (8.0%) with the use of cannagliflozin at doses of 100 mg and 300 mg, respectively .The mean baseline LDL concentrations were 2.76 mmol / L, 2.70 mmol / L, and 2.83 mmol / L when administered with 100 mg and 300 mg of cannaminoglobin and placebo, respectively.

Increase in hemoglobin concentration

With the use of cannagliflozin in doses of 100 mg and 300 mg, there was a slight increase in the mean percentage change in hemoglobin concentration from the baseline (3.5% and 3.8%, respectively) compared with a slight decrease in the placebo group (-1.1%). A comparable slight increase in the mean percentage change in the number of erythrocytes and hematocrit from the basal level was observed. The greater part of the patients had an increase in hemoglobin concentration (> 20 g / l), which occurred in 6.0% of patients who received cannagloflozin in a dose of 100 mg, in 5.5% of patients who received cannagloflozin in a dose of 300 mg, and in 1.0% of patients receiving a placebo. Most of the values remained within normal limits.

Reduction of serum uric acid concentration

With the use of cannagliflozin in doses of 100 mg and 300 mg, there was a moderate decrease in the average concentration of uric acid from the baseline (-10.1% and -10.6%, respectively), compared with placebo, with a slight increase in the average concentration from the initial (1.9%).The decrease in serum uric acid concentration in the groups of cannagliflozin was maximal or close to the maximum at 6 weeks and persisted throughout therapy. There was a transient increase in the concentration of uric acid in the urine. Based on the results of a combined analysis of the use of cannagliflozin in doses of 100 mg and 300 mg, it was shown that the incidence of nephrolithiasis was not increased.

Safety in relation to the cardiovascular system

There was no increase in cardiovascular risk in the use of cannagliflozin compared with the placebo group.

Overdose:

Symptoms

There are no known cases of overdose of cannagliflozin. Single doses of cannagliflozin that reached 1600 mg in healthy subjects and 300 mg twice daily for 12 weeks in patients with type 2 diabetes mellitus were generally well tolerated.

Treatment

In case of an overdose, it is necessary to carry out the usual supporting measures, for example, to remove the absorbed substance from the gastrointestinal tract, to carry out clinical observation and to carry out maintenance treatment taking into account the clinical condition of the patient. Kanagliflozin was hardly excreted when carrying out a 4-hour dialysis. It is not expected that cannagloflozin will be excreted by peritoneal dialysis.

Interaction:

Drug interactions (data in vitro)

Kanagliflozin did not induce the expression of isoenzymes of the system CYP450 (ЗА4, 2С9, 2C19, 2B6 and 1A2) in the culture of human hepatocytes. It also did not inhibit cytochrome P450 isoenzymes (IA2, 2A6, 2C19, 2B6 or 2E1) and slightly inhibited CYP2B6, CYP2C8, CYP2C9, CYP3A4, according to laboratory studies using human liver microsomes. In studies in vitro it was shown that cannagloflozin is a substrate of enzymes UGTIA9 and UGT2B4, metabolizing drugs, and drug carriers of P-glycoprotein (P-gp) and MRP2. Kanagliflozin is a weak inhibitor P-gp.

Kanagliflozin is minimally exposed to oxidative metabolism. Thus, the clinically significant effect of other drugs on the pharmacokinetics of cannagliflozin via the cytochrome P450 system is unlikely.

The effect of other drugs on cannagliflozin

Clinical evidence indicates that the risk of significant interactions with concomitant medications are low.

Drugs that induce enzymes of the UDF-glucuronyl transferase family (UGT) and medicinal carriers

Simultaneous use with rifampicin, a nonselective inducer of a number of enzymes of the family UGT and medicinal vectors, including UGTIA9, UGT2B4, P-gp, and MRP2, reduced the exposure of cannagliflozin. Reducing the exposure of cannagliflozin can lead to a decrease in its effectiveness. If an inducer of family enzymes is desired UGT and medicinal vectors (eg, rifampicin, phenytoin, phenobarbital, ritonavir) simultaneously with kanagliflozin, it is necessary to control the concentration of glycated hemoglobin HbA_1c in patients receiving cannagloflozin in a dose of 100 mg once a day, and provide for the possibility of increasing the dose of cannagliflozin to 300 mg once a day, if additional control of glycemia is required.

Drugs that inhibit the enzymes of the UDF-glucuronyl transferase family (UGT) and medicinal carriers

Probenecid: The combined use of cannagliflozin with probenecid, nonselective inhibitor of several enzymes of the family UGT and medicinal vectors, including UGT1A9 and MRP2, had no clinically significant effect on the pharmacokinetics of kanagliflozin.Because the cannagloflozin is subjected to glucuronidation with two different enzymes of the family UGT, and glucuronidation is characterized by high activity / low affinity, the development of clinically significant effects of other drugs on the pharmacokinetics of cannagliflozin by glucuronation is unlikely.

Ciclosporin: Clinically significant pharmacokinetic interaction with simultaneous application of cannagliflozin with cyclosporin, an inhibitor of P-glycoprotein (P-gp), CYP3A and several drug vectors, including MRP2, was not observed. Development of non-expressed, transient "tides" with simultaneous application of cannagliflozin and cyclosporine was noted. Do not adjust the dose of cannagliflozin. Not expected significant drug interactions with other inhibitors P-gp.

Table 1: Impact of joint applications preparations for exposition cannagloflosin

Associated		Dose	Dose	Attitude	averages
drugs		accompanying	Kanaglyflozin¹	geometric
		drugs¹		(ratio	indicators
				at	appointment
				concomitant
				treatment / without it)
				Lack of Effect = 1.0
				AUC²	FROMmah (90%
				(90% CI)	DI)
In the following cases, a dose adjustment of cannagliflozin is required:
Cyclosporin		400 mg	300 mg once	1,23	1,01
			per day for	(1.19-1.27)	(0,91-
			8 days		1,11
Ethinylestra		0.03 mg	200 mg once	0,91	0,92
ol and		ethynylestradio	per day for	(0,88-0,94)	(0,84-
levonorgestra		la and 0.15 mg	6 days		0,99)
l		levonorgs
Hydrochlorothia		25 mg once a day	300 mg once	1,12	1,15
zid		day during	per day for	(1,08-1,17)	(1,06-
		35 days	7 days		1,25)
Metformin	2000 mg		300 mg once daily for 8 days	1,10 (1,05-1,15)	1,05 (0,96- 1,16)
Probenecid	500 mg twice		300 mg once	1,21	1,13
	per day for		per day for	(1,16-1,25)	(1,00-
	3 days		17 days		1,28)
Rifampicin	600 mg once		300 mg	0,49	0,72
	per day for			(0,44-0,54)	(0,61-
	8 days				0.84)

¹ Single vines, unless otherwise specified

² AUC_inf for drugs administered as single doses, and AUC₂₄ - for drugs administered in the form of multiple doses

Effects of cannaroglofosin on other drugs

In clinical trials cannagloflozin ns significant effect on the pharmacokinetics of metformin, oral contraceptives [ethinyl estradiol (EE) and levonorgestrel], glibenclamide, simvastatin, paracetamol or warfarin, based on the data obtained in vivo and indicating a low ability to induce drug interactions with substrates of isoenzymes CYP3A4, CYP2C9, CYP2C8 and an organic cationic transporter (OCT).

Digoxin: cannagloflozin had a negligible effect on plasma concentrations of digoxin. For patients receiving digoxin, proper monitoring should be conducted.

Table 2: Influence of cannagliflozin on the exposure of accompanying drugs

Associate	Dose	Dose	Attitude		averages
the	accompanying	cankerfly	geometric (ratio
medication	drugs¹	ina¹	indicators	when appointing
you			concomitant treatment / without it)
			Lack of Effect = 1.0
				AUC²	FROM max
				(90%	(90%
				DI)	DI)

In the following cases, there is no need to adjust the doses of concomitant drugs

Digoxin		0.5 mg once the first day, then 0.25 mg once a day for 6 days		300 mg once daily for 7 days		digoxin		1,20 (1,12- 1,28)		1,36 (1,21- 1,53)
Ethynyl-		0.03 mg		200 mg one		Ethinylest		1,07		1,22
estradiol		ethynylestradio		once a day in		radio		(0,99-		(1,10-
		la and 0.15 mg		current 6				1,15)		1,35)
and		levonorgestrel		days		levonorgue		1,06		1,22
Levonor-						arrows		(1,00-		(1, I-
ghost								1,13)		1,35)
Glybincle		1.25 mg		200 mg one		glibenclamide		1,02		0,93
amide				once a day in				(0,98-		(0,85-
				current 6				1,07)		1,01)
				days		3-cis-		1,01		0,99
						hydroxy		(0,96-		(0,91-
						libenclum		1,07)		1,08)
						id
						3-trans-		1,03		0,96
						hydroxy		(0,97-		(0,88-
						libenclum		1,09)		1,04)
						id
Hydrochloro		25 mg once		300 mg one		hydrochloride		0,99		0,94
rotiazide		per day in		once a day in		othiazide		(0,95-		(0,87-
		within 35		current 7				1,04)		1,01)
		days		days
Metform		2000 mg		300 mg one		metformin		1,20		1,06
in				once a day in				(1,08-		(0,93-
				current 8				1,34)		1,20)
				days
Paracete		1000 mg		300 mg two		paraceta-		l, 06³		1,00
pier			once a day for 25 days		pier		(0,98- 1,14)		(0,92- 1,09)
Simvasta	40 mg		300 mg one		symbol		1,12		1,09
tin			once a day in		statin		(0,94-		(0,91-
			current 7				1,33)		1,31)
			days		symbol		1,18		1,26
					statin		(1,03-		(1,10-
					nitric acid		1.35)		1,45)
Warfarin	30 mg		300 mg one		(R) -		1,01		1,03
			once a day in		warfarin		(0,96-		(0,94-
			current 12				1,06)		1,13)
			days		(S) -		1,06		1,01
					warfarin		(1,00-		(0,90-
							1,12)		1,13)
					Ml 10		1,00		1,05
							(0,98-		(0,99-
							1,03)		1,12)

¹Single doses, unless otherwise specified

²AUC_inf for drugs administered as single doses, and AUC₂₄_h - for drugs administered in the form of multiple doses

³AUC_0-12_h

Special instructions:

Are common

The use of cannagliflozin in patients with type 1 diabetes mellitus has not been studied, and therefore its use in this category of patients is contraindicated.

Kanagliflozina use contraindicated in diabetic ketoacidosis, patients with terminal chronic renal failure (CRF) or patients on dialysis, as such treatment would not be effective in these clinical situations.

Carcinogenicity and mutagenicity

Pre-clinical data show no particular hazard for humans, according to the results of pharmacological safety studies, repeated dose toxicity, genotoxicity, reproductive and developmental toxicity.

Fertility

The effect of kanagliflozin on fertility in humans has not been studied. There were no effects on fertility in animal studies.

Hypoglycemia with simultaneous use with other hypoglycemic drugs

It was shown that the use of cannagliflozin as a monotherapy or supplement to hypoglycemic agents (the use of which is not accompanied by the development of hypoglycemia), rarely led to the development of hypoglycemia. It is known that insulin and hypoglycemic agents that enhance its secretion (for example, derivatives of sulfonylureas) cause hypoglycemia. With the use of cannagliflozin as an adjunct to insulin therapy or agents that enhance its secretion (for example, derivatives of sulfonylureas), the incidence of hypoglycemia was higher than with placebo.

Thus, in order to reduce the risk of hypoglycemia, it is recommended to reduce the dose of insulin or agents that enhance its secretion.

Decreased intravascular volume

Kanagliflozin has a diuretic effect by increasing the excretion of glucose by the kidneys, causing osmotic diuresis, which can lead to a decrease in intravascular volume.In clinical trials cannagliflozin increase in the frequency of unwanted reactions associated with a decrease in intravascular volume (for example, postural dizziness, orthostatic hypotension or arterial hypotension), was more often observed during the first three months with the use of cannaroglofosin at a dose of 300 mg. Patients who may be more susceptible to adverse reactions associated with reduced intravascular volume include patients receiving loop diuretics, patients with impaired renal function of moderate severity, and patients aged ≥75 years.

Patients should report clinical symptoms of decreased intravascular volume. These adverse reactions often led to the cessation of the use of cannagliflozin and often with the continued use of cannagliflozin were corrected by changing the regimen for taking antihypertensive drugs (including diuretics). In patients with a decrease in intravascular volume, this condition should be adjusted before treatment with cannagliflozin.

During the first six weeks of treatment with cannagliflozin, there were cases of a slight average decrease in the estimated rateglomerular filtration (GFR) due to a decrease in intravascular volume. Patients with a predisposition to a larger decrease in intravascular volume, as indicated above, sometimes experienced a greater reduction in GFR (> 30%), which was subsequently resolved and occasionally required interruptions in the treatment with cannagliflozin.

Fungal infections of genital organs

In clinical studies, the incidence of vulvovaginal candidiasis (including vulvovaginitis and vulvovaginal fungal infections) was higher in women who received cannagloflozin, compared with the placebo group. Patients with a history of vulvovaginal candidiasis who received cannagliflozin therapy were more likely to develop this infection. Among patients treated with cannagliflozin, 2.3% had more than one episode of infection. Most of the reports of vulvovaginal candidiasis relate to the first four months after initiation of treatment with cannagliflozin. 0.7% of all patients discontinued the use of cannagliflozin in connection with candidal vulvovaginitis. The diagnosis of candidal vulvovaginitis, as a rule, was established only on the basis of symptoms.In clinical trials, the efficacy of topical or oral antifungal treatment, prescribed by a doctor or taken alone, against the background of ongoing therapy with cannagliflozin was noted.

In clinical trials, candidiasis balanitis or balanoposthitis was noted more often in patients treated with cannaraflozin at doses of 100 mg and 300 mg, compared with the placebo group. Balanitis or balanoposthitis developed, first of all, in men who did not have circumcision, and more often developed in men with balanitis or balanoposthitis in the anamnesis. In 0.9% of patients treated with cannagliflozin, more than one episode of infection was noted. 0.5% of all patients stopped taking gangliflozin in association with candida balanitis or balanoposthitis. In clinical studies, in most cases, the infection was treated with local antifungal medications prescribed by a doctor or taken alone on the background of ongoing therapy with cannagliflozin. There were reports of rare cases of phimosis, sometimes circumcision was performed.

Fractures of bones

In a study of cardiovascular outcomes in 4327 patients with diagnosed cardiovascular disease or highcardiovascular risk, the prevalence of bone fracture was 16.3, 16.4 and 10.8 per 1,000 patient-years of use of the drug Invocana® at doses of 100 mg and 300 mg and placebo, respectively. An imbalance in the prevalence of fractures occurred in the first 26 weeks of therapy.

In a combined analysis of other Inovokan® studies, in which about 5800 patients with diabetes mellitus were included in the general population, the prevalence of bone fracture was 10.8, 12.0 and 14.1 per 1,000 patient-years of Invokan® doses of 100 mg and 300 mi^- and placebo, respectively.

During 104 weeks of treatment cannagloflozin did not adversely affect the bone mineral density.

Effect on the ability to drive transp. cf. and fur:

It was not established that cannagloflozin can affect the ability to drive vehicles and work with machinery. Nevertheless, patients should be aware of the risk of hypoglycemia in the case of cannagliflozin as a supplement to insulin therapy or drugs that enhance its secretion, an increased risk of developing adverse reactions,associated with a decrease in intravascular volume (postural dizziness) and a deterioration in the ability to control vehicles and mechanisms when unwanted reactions develop.

Form release / dosage:

Tablets, film-coated 100 mg and 300 mg.

Packaging:

10 tablets per polyvinyl chloride / aluminum blisters.

1, 3, 9 or 10 blisters together with instructions for use in a cardboard bundle.

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Shelf life:2 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002977

Date of registration:28.04.2015

The owner of the registration certificate:Johnson & Johnson, LLC Johnson & Johnson, LLC Russia

Manufacturer: & nbsp

JANSSEN ORTHO, LLC Puerto Rico

Information update date: & nbsp16.02.2016

Illustrated instructions

Instructions

Invokana® (Invokana®)