Invokana pills 100mg №30

Active substance

Canagliflozin

Composition

Pills

Active substance: 102.0 mg kanagliflozin hemihydrate, equivalent to 100.0 mg kanagliflozin.

Auxiliary substances (core): microcrystalline cellulose 39.26 mg, anhydrous lactose 39.26 mg, croscarmellose sodium 12.00 mg, hyperrol 6.00 mg, Magnesium stearate 1.48 mg.

Mechanism of action

The near-neutral glucose transporter 2 (NZTG2) in the proximal renal tubules is responsible for most of the reabsorption of filtered glucose from the tubule lumen. Patients with diabetes have been shown to have increased renal glucose reabsorption, which may be one of the causes of constantly elevated glucose concentrations in the blood. Canagliflozin is an active inhibitor of NZTG2 for oral administration. By inhibiting NZTG2, kanagliflozin reduces the reabsorption of filtered glucose and reduces the renal threshold for glucose (NP G), increasing glucose excretion (EG) in the urine and reducing plasma glucose concentration using this insulin-independent mechanism in patients with type 2 diabetes. Increased excretion of glucose in the urine during the inhibition of NZTG2 also leads to osmotic diuresis, while the diuretic effect leads to a decrease in systolic blood pressure; loss of calories and weight loss are the result of an increase in urinary glucose excretion, as demonstrated in studies with patients with type 2 diabetes.

The ability of canagliflozin to increase EG with urine, directly reducing the level of glucose in the blood plasma, does not depend on insulin. In clinical trials with canagliflozin, there was an improvement in the homeostatic model for assessing β-cell function (HOMA β-cells) and an improvement in insulin secretion by beta cells in response to the mixed-food sample.

During studies of phase 3 of canagliflozin at a dose of 300 mg before meals, the level of postprandial glycemia decreased more than the use of a dose of 100 mg. This effect of a 300 mg dose of canagliflozin may partly be explained by local inhibition of intestinal NZTG1 (an important glucose transporter in the intestine) due to temporary high concentrations of canagliflozin in the intestinal cavity before drug absorption (canagliflozin is a weak inhibitor of NZTG1). Studies have not demonstrated glucose malabsorption when using kanagliflozin.

Indications

Type 2 diabetes in adults in combination with diet and exercise to improve glycemic control (as monotherapy, as part of combination therapy with other hypoglycemic drugs, including insulin).

Contraindications

• hypersensitivity to canaglyflozin or any excipient of the drug;
• type 1 diabetes;
• diabetic ketoacidosis;
• severe renal failure;
• severe liver failure;
• pregnancy;
• breastfeeding period;
• children's age up to 18 years.

Side effects

Data on adverse reactions observed during clinical studies1 of canagliflozin with a frequency of ≥2% are systematized with respect to each of the organ systems depending on the frequency of occurrence using the following classification: very frequent (≥1 / 10), frequent (≥1 / 100,

Violations of the gastrointestinal tract:
Frequent: constipation, thirst2, dry mouth.

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

Violations of the genital and breast organs:
Frequent: balanitis and balanoposthitis5, vulvovaginal candidiasis6, vaginal infections.

1 Including monotherapy and adjunct therapy with Metformin, metformin and sulfonylurea derivatives, as well as metformin and pioglitazone.
2 The category “thirst” includes the term “thirst”, this category also includes the term “polydipsia”.
3 The category “polyuria or pollakiuria” includes the terms “polyuria”, this category also includes the terms “an increase in the volume of urine released”, “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 “candidal balanitis” and “genital fungal infections”.
6 The category “vulvovaginal candidiasis” includes the terms “vulvovaginal candidiasis”, “vulvovaginal fungal infections”, “vulvovaginitis” as well as the terms “vulvitis” and “genital fungal infections”.
Other undesirable reactions that developed in placebo-controlled studies of canagliflozin with a frequency

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) was According to the results of a generalized analysis, patients who received "loop" diuretics, patients with moderate renal failure 30 to 2) and patients aged ≥75 years have a higher incidence of these adverse reactions. When conducting a study on cardiovascular risks, the frequency of serious adverse reactions associated with a decrease in intravascular volume did not increase with the use of kanagliflozin, cases of discontinuation of treatment due to the development of undesirable reactions of this type were infrequent.

Hypoglycemia when used as an adjunct to insulin therapy or by means of enhancing its secretion

When kanagliflozin was used as an adjunct to insulin or sulfonylurea therapy, the development of hypoglycemia was reported more frequently.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 increase its secretion (for example, a sulfonylurea derivative).

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 who received canagliflozin at a dose of 100 mg, and 7.0% of patients who received canagliflozin at a dose of 300 mg, and in 4.8% of patients receiving placebo. Occasionally there was a more pronounced increase in serum potassium concentration in patients with impaired moderate renal function, who previously had an increase in potassium concentration and / or who received several drugs that reduce potassium excretion (potassium-saving diuretics and angiotensin-converting enzyme inhibitors). In general, an 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 the concentration of creatinine (The proportion of patients with a more significant decrease in GFR (> 30%) compared with the initial level observed at any stage of treatment was 2.0% - when using kanagliflozin in a dose 100 mg, 4.1% - with the use of the drug in a dose of 300 mg and 2.1% - with placebo.These reductions in GFR were often transient, and by the end of the study, a similar decrease in GFR was observed in fewer patients. According to a combined analysis of patients with moderately severe renal failure, the proportion of patients with a more significant reduction in GFR (> 30%) compared with the baseline level observed at any stage of treatment was 9.3% - when using canagliflozin 100 mg, 12, 2% - when used at a dose of 300 mg, and 4.9% - when using a placebo. After discontinuation of canagliflozin, these changes in laboratory indices underwent a positive trend or returned to the initial level.

Increasing the concentration of low-density lipoprotein (LDL)
A dose-dependent increase in the concentration of LDL was observed when using kanagliflozin. 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 canagliflozin 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 with canagliflozin administered in doses of 100 and 300 mg and placebo, respectively.

Increased hemoglobin concentration
When using kanagliflozin 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%).There was a comparable small increase in the average percentage change in erythrocyte count and hematocrit from baseline. Most patients had 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 of the values ​​remained within the normal range.

Decreased serum uric acid concentration
When using kanagliflozin in doses of 100 mg and 300 mg, there was a moderate decrease in the average concentration of uric acid from the initial level (-10.1% and -10.6%, respectively) compared with placebo, with the use of which a slight increase in the average concentration from the initial (1.9%). The decrease in the serum uric acid concentration in the kanagliflozin groups was maximum or close to the maximum at week 6 and persisted throughout therapy. There was a transient increase in the concentration of uric acid in the urine. According to the results of the 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 kanagliflozin compared with the placebo group.

Interaction

Drug interactions (in vitro data)

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

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

Effects of other drugs on canagliflozin

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

Drugs that induce the enzymes of the family UDF-glucuronyl transferase (UGT) u drug carriers

Simultaneous 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 cangliflozin. Reducing the exposure to canagliflozin can lead to a decrease in its effectiveness. If an inducer of UGT family enzymes and drug carriers (for example, rifampicin, phenytoin, phenobarbital, ritonavir) is required at the same time as canagliflozin, it is necessary to control the concentration of glycated hemoglobin HbA1c in patients receiving canagliflozin in a dose of 100 mg 1 time / day, and consider increasing the dose Canagliflozina up to 300 mg 1 time / day,if additional glycemic control is needed.

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

Probenecid: The combined use of canagliflozin with probenecid, a non-selective inhibitor of several UGT family enzymes and drug carriers, including UGT1A9 and MRP2, did not have a clinically significant effect on the pharmacokinetics of canagliflozin. Since kanagliflozin undergoes glukuronirovaniyu two different enzymes of the UGT family, and glukuronirovanie characterized by high activity / low affinity, the development of clinically significant effects of other drugs on the pharmacokinetics of glyagloflozin by glucuronidation unlikely.

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

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

Adults (≥18 years old)
The recommended dose of canagliflozin is 100 mg or 300 mg once a day; reception is preferably carried out before breakfast.
If kanagliflozin is used as an adjunct to insulin therapy or agents that increase its secretion (for example, sulfonylurea derivatives), the possibility of using lower doses of the above drugs may be considered to reduce the risk of hypoglycemia.
Canagliflozin has a diuretic effect. In patients treated with diuretics, in patients with moderately severe renal dysfunction [with glomerular filtration rate (GFR) from 30 to 2] or in patients aged ≥75 years, more frequent development of adverse reactions associated with a decrease in intravascular volume was observed (for example, postural dizziness, orthostatic hypotension or arterial hypotension). Thus, in these patients, the use of kangagloflozin in the initial dose of 100 mg once a day is recommended. In patients with signs of hypovolemia, it is recommended that the condition be corrected before cangliflozin is started. In patients receiving canagliflozin in a dose of 100 mg with good tolerability, who need additional glycemic control, it is advisable to increase the dose to 300 mg.

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

Special patient categories

Children under 18
The safety and efficacy of canagliflozin in children have not been studied.

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

Renal dysfunction
In patients with impaired mild renal function (estimated glomerular filtration rate (GFR) from 60 to 2), dose adjustment is not required.
In patients with impaired renal function of moderate severity, it is recommended to use the drug in the initial dose of 100 mg once a day. With good dose tolerance of 100 mg, patients who need additional glycemic control, it is advisable to increase the dose to 300 mg.
Kanagliflozin is not recommended for patients with severe renal impairment (GFR 2), end-stage chronic renal failure (CRF) or in patients on dialysis, since it is expected that kanagliflozin will be ineffective in these patient populations.

Overdose

Symptoms:No cases of overdose of canagliflozin are known. Single doses of canagliflozin, which reached 1600 mg in healthy individuals and 300 mg twice a day for 12 weeks in patients with type 2 diabetes, were generally well tolerated.

Treatment:In the case of an overdose, it is necessary to carry out the usual supporting measures, for example, to remove an unabsorbed substance from the gastrointestinal tract, to carry out clinical observation and to carry out supportive treatment taking into account the clinical condition of the patient.Canagliflozin was not practically eliminated during 4-hour dialysis. Canaglyflozin is not expected to be cleared by peritoneal dialysis.

Special instructions

Are common

The use of canagliflozin in patients with type 1 diabetes has not been studied, therefore its use is contraindicated in this category of patients.
Canagliflozin is contraindicated in diabetic ketoacidosis, in patients with end-stage chronic renal failure (CRF) or in patients on dialysis, since such treatment will not be effective in these clinical cases.

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

Fertility
The effect of canagliflozin on fertility in humans has not been studied. No effect on fertility was observed in animal studies.

Hypoglycemia with simultaneous use with other hypoglycemic drugs
It was shown that the use of canagliflozin 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 increase its secretion (for example, sulfonylurea derivatives) cause the development of hypoglycemia.When canagliflozin was used as an adjunct to insulin therapy or agents that increase its secretion (for example, sulfonylurea derivatives), the incidence of hypoglycemia was higher than with placebo.
Thus, in order to reduce the risk of hypoglycemia, it is recommended to lower the dose of insulin or agents that increase its secretion.

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