Invokana tablets are covered.pl.ob. 300 mg 30 pcs. pack (Kanahlyflozyn)

Release form

Film-coated tablets

Packing

10 pcs. - blisters (3) - packs of cardboard.

The pharmacological action of

has been shown that in patients with diabetes mellitus there is an increased renal reabsorption of glucose, which can contribute to a persistent increase in glucose concentration. Sodium glucose transport protein 2 (SGLT2), expressed in the proximal renal tubules, is responsible for most of the reabsorption of glucose from the tubule lumen.

Canagliflozin is an inhibitor of sodium glucose transport protein 2. By inhibiting SGLT2, canagliflozin reduces the reabsorption of filtered glucose and reduces the renal threshold for glucose (PPG), thereby increasing urinary glucose excretion, which leads to a decrease in plasma glucose concentration with insulin -independent mechanism in patients with type 2 diabetes.

Increased urinary glucose excretion through inhibition of SGLT2 also leads to osmotic diuresis. the diuretic effect leads to a decrease in systolic blood pressure, an increase in the excretion of glucose in the urine leads to a loss of calories and, consequently, a decrease in body weight.

In phase III studies that conducted a mixed breakfast tolerance test, the use of canagliflozin at a dose of 300 mg led to a more pronounced decrease in fluctuations in the level of postprandial glycemia than with a dose of 100 mg. This effect may be partly due to local inhibition of the intestinal protein SGLT1, taking into account transient high concentrations of canagliflosin in the intestinal lumen before drug absorption (canagliflosin is a low potential SGLT1 inhibitor). In studies, malabsorption was not detected with the use of canagliflozin.

Pharmacodynamic effects: In clinical studies, after single and multiple oral administration of canagliflozin by patients with type 2 diabetes, the renal threshold for glucose was dose-dependently reduced, and urinary glucose excretion increased. The initial value of the renal threshold for glucose was about 13 mmol / L, the maximum decrease in the 24-hour average renal threshold for glucose was observed with a dosage of 300 mg once a day and ranged from 4 to 5 mmol / L, which indicates a low risk of hypoglycemia on treatment background. In a clinical study of the use of canagliflozin in doses from 100 to 300 mg once a day by patients with type 2 diabetes for 16 days, the decrease in the renal threshold for glucose and the increase in urinary glucose excretion were constant. In this case, the concentration of glucose in the blood plasma decreased dose-dependently on the first day of use, followed by a steady decrease in the concentration of glucose in the blood plasma on an empty stomach and after eating.

The use of a single dose of 300 mg of canagliflozin before meals of mixed calorie content in patients with type 2 diabetes caused a delay in intestinal glucose absorption and a decrease in postprandial glycemia through renal and extrarenal mechanisms.

In clinical trials, 60 healthy volunteers received a single oral dose of 300 mg of canagliflozin, 1200 mg of canagliflozin (4 times the maximum recommended dose), moxifloxacin, and placebo. No significant changes in the QT interval were noted either with a recommended dose of 300 mg or with a dose of 1200 mg. When applying a dose of 1200 mg, the peak plasma concentration of canagliflozin was approximately 1.4 times higher than the equilibrium peak concentration after taking a dose of 300 mg once a day.

Fasting glycemia: In clinical trials, the use of canagliflozin as a monotherapy or as an adjunct to therapy with one or two oral hypoglycemic drugs led to average fasting glycemia changes compared with the initial level with respect to placebo from -1.2 mmol / L to -1 9 mmol / L when applying a dosage of 100 mg and from -1.9 mmol / L to -2.4 mmol / L - when applying a dosage of 300 mg, respectively. This effect was close to maximum after the first day of therapy and persisted throughout the treatment period.

Postprandial glycemia: In clinical studies of the use of canagliflozin as monotherapy or as adjunctive therapy for one or two oral hypoglycemic agents, postprandial glycemia was measured after applying the tolerance test with a standardized mixed breakfast. The use of canagliflozin led to an average decrease in the level of postprandial glycemia compared with the initial level relative to placebo from -1.5 mmol / L to -2.7 mmol / L - when using a dosage of 100 mg and from -2.1 mmol / L -3.5 mmol / l - when using a dosage of 300 mg, respectively, due to a decrease in glucose concentration before meals and a decrease in fluctuations in the level of postprandial glycemia.

body weight: Canagliflozin 100 mg and 300 mg as a monotherapy and as a double or triple additional therapy caused a statistically significant reduction in the percentage of body weight over 26 weeks, compared with placebo. For two 52-week active controlled trials comparing canagliflozin with glimepiride and sitagliptin, a sustained and statistically significant mean decrease in body percentage for canagliflozin as an adjunct to metformin was -4.2% and -4.7% for canagliflozin 100 mg and 300 mg, respectively, compared with the combination of glimepiride and metformin (1.0%) and -2.5% for canagliflozin 300 mg in combination with metformin and sulfonylurea, compared with sitagliptin in combination with metformin and sulfonylurea (0.3%).

Blood Pressure: In a placebo-controlled study, treatment with canagliflozin 100 mg and 300 mg caused an average decrease in systolic blood pressure of -3.9 mm Hg and -5.3 mmHg respectively, compared with placebo (-0.1 mm), and a smaller effect on diastolic blood pressure with a change in the average value for canagliflozin 100 mg and 300 mg -2.1 mm Hg and -2.5 mmHg respectively, compared with placebo (-0.3 mm).

There were no significant changes in heart rate.

Beta-cell function: Studies of the use of canagliflozin in patients with type 2 diabetes indicate an improvement in beta-cell function according to an assessment of the homeostasis model with respect to the function of these cells (HOMA2-% B) and an improvement in the rate of insulin secretion using the tolerance test mixed breakfast.

Indications

Type 2 diabetes mellitus in adults combined with diet and exercise to improve glycemic control as:

monotherapy As part of combination therapy with other hypoglycemic drugs, including insulin.

Contraindications

Hypersensitivity to canagliflozin or any excipient of the drug diabetes mellitus type 1 diabetic ketoacidosis severe renal failure severe liver failure pregnancy and lactation, children under 18 years of age.

Pregnancy and lactation

Pregnancy

Canagliflozin has not been studied in pregnant women. Animal studies do not indicate direct or indirect adverse toxic effects on the reproductive system. The use of canagliflozin is contraindicated during pregnancy.

Breastfeeding period

Canagliflozin is contraindicated for women during breastfeeding, because, according to available pharmacodynamic / toxicological data obtained during preclinical studies, canagliflosin passes into breast milk.

Special instructions

General

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

The use of canagliflozin is contraindicated in diabetic ketoacidosis, in patients with end-stage chronic renal failure (CRF), or in patients undergoing dialysis, as such treatment will not be effective in these clinical cases.

Carcinogenicity and mutagenicity

Preclinical data do not show a specific hazard to humans, according to the results of pharmacological studies of safety, toxicity of repeated doses, genotoxicity, reproductive and ontogenetic toxicity.

Fertility

The effect of canagliflozin on human fertility has not been studied. No effects on fertility were observed in animal studies.

Hypoglycemia with simultaneous use with other hypoglycemic drugs

It was shown that the use of canagliflozin as monotherapy or as an adjunct 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, sulfonylurea derivatives) cause the development of hypoglycemia. When using canagliflozin as an adjunct to insulin therapy or by means of enhancing its secretion (for example, sulfonylurea derivatives), the incidence of hypoglycemia was higher than with placebo.

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

Decreased intravascular volume

Canagliflozin 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 studies of canagliflozin, an increase in the frequency of adverse 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 canagliflozin at a dose of 300 mg. Patients who may be more susceptible to adverse reactions associated with a decrease in 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 canagliflozin and often with continued use of canagliflozin were corrected by a change in the regimen of taking antihypertensive drugs (including diuretics). In patients with a decrease in intravascular volume, this condition should be adjusted before treatment with canagliflozin.

During the first six weeks of canagliflozin treatment, there were cases of a slight average decrease in the estimated glomerular filtration rate (GFR) due to a decrease in intravascular volume. In patients predisposed to a greater decrease in intravascular volume, as described above, sometimes there was a more significant decrease in GFR (> 30%), which was subsequently resolved and occasionally required interruptions in canagliflozin treatment.

Fungal infections of the genital organs

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

In clinical trials, candida balanitis or balanoposthitis was more common in patients treated with canagliflozin in doses of 100 mg and 300 mg, compared with the placebo group. Balanitis or balanoposthitis developed primarily in men who did not undergo circumcision, and more often developed in men with balanitis or balanoposthitis in the anamnesis. In 0.9% of patients treated with canagliflozin, more than one episode of infection was noted. 0 5% of all patients stopped taking canagliflozin due to candida balanitis or balanoposthitis. In clinical trials, in most cases, the infection was treated with local antifungal agents prescribed by a doctor or taken alone on the background of continued therapy with canagliflozin. Rare cases of phimosis were reported, sometimes circumcision was performed.

Bone fractures

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

In a combined analysis of other studies of InvocanaВ®, which included about 5800 patients with diabetes from the general population, the incidence of bone fractures was 10.8, 12.0, and 14.1 per 1,000 patient-years of using InvocanaВ® in doses of 100 mg and 300 mg and placebo, respectively.

Within 104 weeks of treatment, canagliflozin did not adversely affect bone mineral density.

Influence on the ability to drive vehicles and mechanisms

It has not been established that canagliflozin may affect the ability to drive vehicles and operate machinery. However, patients should be aware of the risk of hypoglycemia if canagliflozin is used as an adjunct to insulin or drug therapy. enhancing its secretion, about the increased risk of developing unwanted reactions associated with a decrease in intravascular volume (postural dizziness) and a deterioration in the ability to drive vehicles and mechanisms when developing unwanted reactions.

Composition of

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

306, 0 mg canagliflozin hemihydrate, which is equivalent to 300.0 mg canagliflozin.

Excipients (core): microcrystalline cellulose 117.78 mg, anhydrous lactose 117.78 mg, croscarmellose sodium 36.00 mg, hyprolose 18.00 mg, magnesium stearate 4.44 mg.

Excipients (shell): Opadry II dye 85F18422 white (polyvinyl alcohol, partially hydrolyzed, 40.00% titanium dioxide 25.00%, macrogol 3350 20.20%, talc 14.80%) - 18.00 mg

Dosage and Administration

Canagliflozin is recommended to be taken orally once a day, preferably before breakfast.

Adults (? 18 years of age)

The recommended dose of canagliflozin is 100 mg or 300 mg once daily, preferably before breakfast.

When using canagliflozin as an adjunct to insulin therapy or agents that enhance its secretion (e.g. sulfonylurea derivatives), lower doses of the above drugs may be considered to reduce the risk of hypoglycemia.

Canagliflozin has a diuretic effect. Patients treated with diuretics, patients with impaired renal function of moderate severity [with glomerular filtration rate (GFR) from 30 to 2], or patients? 75 years of age, showed a more frequent development of adverse reactions associated with a decrease in intravascular volume (for example, postural dizziness, orthostatic hypotension or arterial hypotension). Thus, in these patients, the use of canagliflozin in an initial dose of 100 mg once a day is recommended. In patients with signs of hypovolemia, it is recommended that this condition be adjusted before treatment with canagliflozin. In patients receiving canagliflozin at a dose of 100 mg with good tolerance, who need additional glycemic control, it is advisable to increase the dose to 300 mg.

Skipping a dose of

If you skip a dose, you should take it as soon as possible however, you should not take a double dose for one day.

Special patient categories

Children under 18

Safety and efficacy of canagliflozin in children have not been studied.

Elderly patients

Patients ≥75 years of age should be given 100 mg once daily as an initial dose. With good dose tolerance of 100 mg, it is advisable for patients who need additional glycemic control to increase the dose to 300 mg.

Impaired renal function

In patients with mild renal impairment (estimated glomerular filtration rate (GFR) 60 to 2), dose adjustment is not required.

In patients with moderate renal impairment, the use of the drug in an initial dose of 100 mg once a day is recommended. With good dose tolerance of 100 mg, it is advisable for patients who need additional glycemic control to increase the dose to 300 mg.

Canagliflozin is not recommended for use in patients with severe renal impairment (GFR 2), end-stage chronic renal failure (CRF), or in patients on dialysis, as canagliflozin is expected to be ineffective in these patient populations.

Side effects

Data on adverse reactions observed during clinical trials1 of canagliflozin with a frequency of? 2%, systematized relative to each of the organ systems depending on the frequency of occurrence using the following classification: very frequent (? 1/10), frequent (? 1/100,

Gastrointestinal disorders:

Frequent: constipation, thirst2, dryness

Disorders of the kidneys and urinary tract:

Frequent: polyuria and pollakiuria3, peremptory urination, urinary tract infection4, urosepsis

Disorders of the genitals and mammary gland:

Frequent: balanitis and balanitis candidiasis6, vaginal infections.

1 Including monotherapy and addition to therapy with metformin, metformin and sulfonylurea derivatives, as well as metformin and pioglitazone.

2 The category “thirst” includes the term “thirst”, The term "polydipsia" also falls into this category.

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

4 The category “urinary tract infections” includes the term “urinary tract infections” 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 “candida balanitis” and “genital fungal infections”.

6 The category “vulvovaginal candidiasis” includes the terms “vulvovaginal candidiasis”, “vulvovaginal fungal infections”, “vulvovaginitis” as well as the terms “vulvovaginal and genital fungal infections”.

Other adverse reactions, that developed in placebo-controlled studies of canagliflozin with a frequency of

Adverse reactions associated with a decrease in intravascular volume

The frequency of all adverse reactions associated with a decrease in intravascular volume (postural dizziness, orthostatic hypotension, arterial hypotension, dehydration and fainting analysis) was According to the results , in patients receiving “loop” diuretics, patients with moderate renal failure (GFR 30 to 2), and patients āste? 75 years of age had a higher incidence of these adverse reactions. When conducting research on cardiovascular risks, the frequency of serious adverse reactions associated with a decrease in intravascular volume did not increase with the use of canagliflozin, Cessation of treatment due to the development of adverse reactions of this type were infrequent.

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

When using canagliflozin as an adjunct to therapy with insulin or sulfonylurea derivatives, the development of hypoglycemia was reported more often. This is consistent with the expected increase in the frequency of hypoglycemia in cases where a drug, the use of which 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 parameters

Increased serum potassium concentration

Cases of increased serum potassium concentration (> 5.4 mEq / L and 15% higher than the initial concentration) were observed in 4, 4% of patients receiving canagliflozin at a dose of 100 mg, in 7.0% of patients receiving canagliflozin at a dose of 300 mg, and 4.8% of patients receiving placebo. Occasionally, a more pronounced increase in serum potassium concentration was observed 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 inhibitors (ACE)). In general, the increase in potassium concentration was transient and did not require special treatment.

Increased serum creatinine and urea

There was a slight average increase in creatinine concentration during the first six weeks after starting treatment (The proportion of patients with a more significant decrease in GFR (> 30%) compared with the initial level observed at any stage of treatment, amounted to 2.0% when using canagliflozin at a dose of 100 mg, 4.1% when using the drug at a dose of 300 mg and 2.1% when using placebo . These reductions in GFR were often transient, with a similar decrease in GFR observed in fewer patients by the end of the study. According to a joint analysis of patients with moderate renal failure, the proportion of patients with a more significant decrease in GFR (> 30%) compared with the initial level observed at any stage of treatment was 9.3% - with the use of canagliflozin at a dose of 100 mg, 12 , 2% when using a dose of 300 mg, and 4.9% when using a placebo. After stopping canagliflozin, these changes in laboratory parameters underwent positive dynamics or returned to their original level.

Increased low-density lipoprotein (LDL) concentration

A dose-dependent increase in LDL concentration was observed with canagliflozin. The average 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%) when using canagliflozin in doses of 100 mg and 300 mg, respectively . The average initial LDL concentration was 2.76 mmol / L, 2.70 mmol / L and 2.83 mmol / L with canagliflozin at doses of 100 and 300 mg and placebo, respectively.

Increased hemoglobin concentration

When using canagliflozin at doses of 100 mg and 300 mg, there was a slight increase in the average percentage change in hemoglobin concentration from baseline (3.5% and 3.8%, respectively) compared with a slight decrease in the placebo group (? 1 ,1%). A comparable slight increase in the average percentage change in the number of red blood cells and hematocrit from the baseline was observed. Most patients showed an increase in hemoglobin concentration (> 20 g / l), which occurred in 6.0% of patients receiving canagliflozin at a dose of 100 mg, in 5.5% of patients receiving canagliflozin at a dose of 300 mg, and in 1, 0% of patients receiving placebo. Most values ​​remained within the normal range.

Decreased serum uric acid concentration

With the use of canagliflozin at doses of 100 mg and 300 mg, there was a moderate decrease in the average uric acid concentration from the initial level (? 10.1% and? 10.6%, respectively) compared with placebo, which there was a slight increase in the average concentration from the initial (1.9%). The decrease in serum uric acid concentration in the canagliflozin groups was maximal or close to maximal at 6 weeks and persisted during therapy. A transient increase in uric acid concentration in urine was noted. According to the results of a combined analysis of the use of canagliflozin in doses of 100 mg and 300 mg, it was shown that the incidence of nephrolithiasis was not increased.

Cardiovascular safety

There was no increase in cardiovascular risk with canagliflozin compared with the placebo group.

Drug Interactions

Drug Interactions (in vitro data)

Canagliflozin did not induce the expression of CYP450 isoenzymes (3A4, 2C9, 2C19, 2B6 and 1A2) in human hepatocyte culture. He also did not inhibit isoenzymes of cytochrome P450 (1A2, 2A6, 2C19, 2D6 or 2E1) and slightly inhibited CYP2B6, CYP2C8, CYP2C9, CYP3A4, according to laboratory studies using human liver microsomes. In vitro studies have shown that canagliflozin is a substrate of drug metabolizing enzymes UGT1A9 and UGT2B4 and drug carriers of P-glycoprotein (P-gp) and MRP2. Canagliflozin is a weak inhibitor of P-gp.

Canagliflozin undergoes minimal oxidative metabolism. Thus, the clinically significant effect of other drugs on the pharmacokinetics of canagliflozin through the P450 cytochrome system is unlikely.

The effects of other drugs on canagliflozin

Clinical evidence indicates that the risk of meaningful interactions with concomitant drugs is low.

drugs, inducing enzymes of the UDF-glucuronyl transferase (UGT) family and drug carriers

Concomitant use with rifampicin, a non-selective inducer of a number of UGT family enzymes and drug carriers, including UGT1A9, UGT2B4, P-gp, and MRP2 reduced the exposure of canagliflozin. Decreased exposure to canagliflozin can lead to a decrease in its effectiveness. If it is necessary to prescribe an inducer of UGT family enzymes and drug carriers (for example, rifampicin, phenytoin, phenobarbital, ritonavir) simultaneously with canagliflozin, it is necessary to monitor the concentration of glycated hemoglobin НbА1c in patients receiving canagliflozin in a dose of 100 mg 1 time / day and consider the possibility of increasing the dose canagliflozin up to 300 mg 1 time / day, if additional glycemic control is necessary.

drugs, inhibiting enzymes of the UDF-glucuronyl transferase (UGT) family and drug carriers

Probenecid: The combined use of canagliflozin with probenecid, a nonselective inhibitor of several UGT family enzymes and drug carriers, including UGT1A9 and MRP2, did not have a clinically significant effect on pharmacokinet. Since canagliflozin is glucuronidated by two different enzymes of the UGT family, and glucuronidation is characterized by high activity / low affinity, the development of the clinically significant effect of other drugs on the pharmacokinetics of canagliflosin by glucuronidation is unlikely.

Cyclosporine: Clinically significant pharmacokinetic interaction with the simultaneous use of canagliflozin with cyclosporine, an inhibitor of P-glycoprotein (P-gp), CYP3A and several drug carriers, including MRP2 was not observed. The development of unexpressed, transient hot flashes was noted with the simultaneous use of canagliflozin and cyclosporine. A dose adjustment of canagliflozin is not recommended. No significant drug interactions with other P-gp inhibitors are expected.



overdose Symptoms of

Canagliflozin overdose is unknown. Single doses of canagliflozin reaching 1600 mg in healthy subjects and 300 mg twice daily for 12 weeks in patients with type 2 diabetes are generally well tolerated.

Treatment For

In the event of an overdose, routine supportive measures should be taken, such as removing the non-absorbed substance from the gastrointestinal tract, to carry out clinical supervision and to carry out supportive treatment taking into account the clinical condition of the patient. Canagliflozin was practically not eliminated during 4-hour dialysis. Canagliflozin is not expected to be excreted by peritoneal dialysis.

Storage conditions

Do not store above 30 ° C.

Keep out of the reach and sight of children.

Shelf life

2 years.

Do not use after expiration date.

Deystvuyushtee substance

Kanagliflozin

Terms and conditions

prescription

dosage form

tablets

Possible product names

Invokana tablets coated. 300 mg 30 pcs.

Johnson and Johnson, USA



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