Invokana, 300 mg 30 pcs.

It has been shown that diabetic patients have increased renal glucose reabsorption, which may contribute to persistent elevated glucose concentrations. Sodium-glucose transporter protein 2 (SGLT2), expressed in the proximal renal tubules, is responsible for most of the glucose reabsorption from the tubule lumen.

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

The increase in glucose excretion with urine through inhibition of SGLT2 also leads to osmotic diuresis, diuretic effect leads to lower systolic blood pressure; increased glucose excretion with urine leads to loss of calories and, consequently, reduction in body weight.

In phase III studies in which a tolerance test with a mixed breakfast was performed, the use of canagliflozin at a dose of 300 mg resulted in a more pronounced reduction in postprandial glycemic fluctuations than when a dose of 100 mg was used. This effect may be due in part to local inhibition of the intestinal protein SGLT1, given the transient high concentrations of canagliflozin in the intestinal lumen before drug absorption (canagliflozin is a low potency SGLT1 inhibitor). Studies have shown no malabsorption when canagliflozin is used.

Pharmacodynamic effects:

In clinical studies after single and repeated oral administration of canagliflozin to patients with type 2 diabetes, the renal threshold for glucose was dose-dependently decreased and urinary glucose excretion was increased. The initial value of renal threshold for glucose was about 13 mmol/l, the maximum reduction of 24-hour average renal glucose threshold was observed when using 300 mg once a day and was 4 to 5 mmol/l, indicating a low risk of hypoglycemia during treatment. During a clinical study of canagliflozin administration in doses from 100 to 300 mg once a day in patients with type 2 diabetes for 16 days, the decrease in the renal threshold for glucose and the increase in glucose excretion with urine was constant. Plasma glucose concentrations decreased in a dose-dependent manner on the first day of use, followed by a steady decrease in plasma glucose concentrations on an empty stomach and after meals.

The administration of a single dose of 300 mg of canagliflozin before a mixed-calorie meal in patients with type 2 diabetes caused delayed intestinal glucose absorption and reduced 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 observed with either the recommended 300 mg dose or the 1200 mg dose. With the 1200 mg dose, the peak plasma concentration of canagliflozin was approximately 1.4 times the equilibrium peak concentration after the 300 mg dose once daily.

The fasting glycemia:

. In clinical trials, use of canagliflozin as monotherapy or as an adjunct to therapy with one or two oral hypoglycemic agents resulted in mean changes in fasting glycemia from baseline to placebo of -1.2 mmol/L to -1.9 mmol/L with the 100 mg dose and from -1.9 mmol/L to -2.4 mmol/L with the 300 mg dose, respectively. This effect was close to maximum after the first day of therapy and persisted throughout the treatment period.

Postprandial glycemia:

In clinical trials of canagliflozin as monotherapy or additional therapy to one or two oral hypoglycemic agents, postprandial glycemia was measured after a tolerance test with a standardized mixed breakfast. Administration of canagliflozin resulted in a mean decrease in postprandial glycemia from -1.5 mmol/L to -2.7 mmol/L using the 100 mg dose and from -2.1 mmol/L to -3.5 mmol/L using the 300 mg dose, respectively, due to a decrease in pre-meal glucose concentration and a decrease in postprandial glycemic fluctuation, compared with baseline levels with placebo.

Body weight:

Canagliflozin 100 mg and 300 mg as monotherapy and as dual or triple complementary therapy caused a statistically significant reduction in percent body weight over 26 weeks, compared with placebo. Over two 52-week active controlled trials comparing canagliflozin with glimepiride and sitagliptin, the sustained and statistically significant mean percentage body weight reduction for canagliflozin as adjunctive therapy 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 placebo-controlled studies, treatment with canagliflozin 100 mg and 300 mg caused a mean reduction in systolic blood pressure of -3.9 mm Hg and -5.3 mm Hg. respectively, compared with placebo (-0.1 mm Hg), and a smaller effect on diastolic blood pressure with a mean change for canagliflozin 100 mg and 300 mg of -2.1 mm Hg and -2.5 mm Hg, respectively, compared with placebo (-0.3 mm Hg).

There were no significant changes in heart rate.

Beta cell function:

Studies of canagliflozin use in patients with type 2 diabetes indicate improved beta cell function, according to homeostasis model assessment of these cell function (HOMA2-%B) and improved insulin secretion rate using a mixed breakfast tolerance test.

Indications

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

Active ingredient

Composition

1 film-coated tablet 300 mg contains:

306.0 mg canagliflozin hemihydrate, which is equivalent to 300.0 mg canagliflozin.

Auxiliary substances (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.

Auxiliary substances (shell):

Opadray II dye 85F18422 white (contains polyvinyl alcohol, partially hydrolyzed, 40.00% titanium dioxide 25.00%, macrogol 3350 20.20%, talc 14.80%) – 18.00 mg.

How to take, the dosage

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

Adults (≥18 years)
The recommended dose of canagliflozin is 100 mg or 300 mg once daily; preferably before breakfast.
When canagliflozin is used as an adjunct to therapy with insulin 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. In patients treated with diuretics, patients with moderate renal dysfunction [with a glomerular filtration rate (GFR) of 30 to 2] or patients aged ≥75 years had a higher frequency of adverse reactions associated with decreased intravascular volume (e.g., postural dizziness, orthostatic hypotension or arterial hypotension). Thus, in these patients, the use of canagliflozin at an initial dose of 100 mg once daily is recommended. In patients with signs of hypovolemia, it is recommended to correct this condition before starting treatment with canagliflozin. In patients receiving canagliflozin at a dose of 100 mg with good tolerability who require additional glycemic control, it is reasonable to increase the dose to 300 mg.

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

Special categories of patients

Children under 18 years
The safety and effectiveness of canagliflozin in children has not been studied.

Elderly patients
Patients aged ≥75 years should be given 100 mg once daily as an initial dose. If the 100 mg dose is well tolerated, it is appropriate to increase the dose to 300 mg in patients who require additional glycemic control.

Kidney function impairment
In patients with mild renal function impairment (estimated glomerular filtration rate (GFR) of 60 to 2), no dose adjustment is necessary.

In patients with moderate renal impairment, a starting dose of 100 mg once daily is recommended. If the 100 mg dose is well tolerated, it is reasonable to increase the dose to 300 mg in patients who need additional glycemic control.

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

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. It also did not inhibit cytochrome P450 isoenzymes (1A2, 2A6, 2C19, 2D6, or 2E1) and weakly inhibited CYP2B6, CYP2C8, CYP2C9, and CYP3A4, according to laboratory studies using human liver microsomes. In in vitro studies, canagliflozin has been shown to be a substrate of the drug metabolizing enzymes UGT1A9 and UGT2B4 and the drug transporters P-glycoprotein (P-gp) and MRP2. Canagliflozin is a weak P-gp inhibitor.

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

The effect of other drugs on canagliflozin

The clinical data indicate that the risk of significant interactions with concomitant drugs is low.

Drugs inducing UDF-glucuronyl transferase (UGT) family enzymes and drug transporters

Simultaneous use with rifampicin, a non-selective inducer of several UGT family enzymes and drug transporters, includingUGT1A9, UGT2B4, P-gp, and MRP2, reduced canagliflozin exposure. Decreased canagliflozin exposure may result in decreased efficacy. If an inducer of UGT family enzymes and drug transporters (e.g., rifampicin, phenytoin, phenobarbital, ritonavir) must be administered concomitantly with canagliflozin, the glycated hemoglobin HbA1c concentration in patients receiving canagliflozin at a dose of 100 mg once daily should be monitored and provision made for increasing the canagliflozin dose to 300 mg once daily in the event that additional glycemic control is required.

Drugs that inhibit UDF-glucuronyl transferase (UGT) family enzymes and drug transporters

Probenecid: Co-administration of canagliflozin with probenecid, a nonselective inhibitor of several UGT family enzymes and drug transporters, including UGT1A9 and MRP2, had no clinically significant effect on canagliflozin pharmacokinetics. Because canagliflozin undergoes glucuronidation by two different UGT family enzymes and glucuronidation is characterized by high activity/low affinity, the development of clinically significant effects of other drugs on the pharmacokinetics of canagliflozin through glucuronidation is unlikely.

Cyclosporine: No clinically significant pharmacokinetic interactions have been observed with concomitant use of canagliflozin with cyclosporine, P-glycoprotein inhibitor (P-gp), CYP3A and several drug transporters, including MRP2. The development of mild, transient “flushes” when concomitant use of canagliflozin and cyclosporine has been observed. It is not recommended to adjust the dose of canagliflozin. No significant drug interactions with other P-gp inhibitors are expected.

Special Instructions

General

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

Carcinogenicity and mutagenicity
Preclinical data show no specific hazards to humans, according to pharmacological studies of safety, repeat dose toxicity, genotoxicity, reproductive and ontogenetic toxicity.

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

Hypoglycemia when used concomitantly with other hypoglycemic drugs
It has been shown that the use of canagliflozin as monotherapy or in addition to hypoglycemic agents (whose use is not accompanied by the development of hypoglycemia), rarely led to the development of hypoglycemia. Insulin and hypoglycemic agents that increase its secretion (e.g., sulfonylurea derivatives) are known to cause hypoglycemia. When canagliflozin was used as an adjunct to therapy with insulin or with agents that increase its secretion (e.g., sulfonylurea derivatives), the rate of hypoglycemia was higher than when using placebo.
Thus, to reduce the risk of hypoglycemia, it is recommended to decrease the dose of insulin or agents that enhance its secretion.

Lower intravascular volume
Canagliflozin has a diuretic effect by increasing glucose excretion by the kidneys, causing osmotic diuresis, which may lead to lower intravascular volume. In clinical trials of canagliflozin, increased incidence of adverse reactions associated with decreased intravascular volume (e.g., postural dizziness, orthostatic hypotension, or arterial hypotension) was more frequently observed during the first three months when canagliflozin was used at a 300 mg dose. Patients who may be more susceptible to adverse reactions associated with decreased intravascular volume include patients receiving “loop” diuretics, patients with moderate renal dysfunction, and patients aged ≥75 years.

Patients should report clinical symptoms of decreased intravascular volume. These adverse reactions often led to discontinuation of canagliflozin and were often corrected by changing the regimen of hypotensive drugs (including diuretics) when canagliflozin was continued. In patients with decreased intravascular volume, this condition should be corrected before starting treatment with canagliflozin.

In the first six weeks of treatment with canagliflozin, there were cases of a slight average decrease in calculated glomerular filtration rate (GFR) due to decreased intravascular volume. Patients predisposed to a greater decrease in intravascular volume, as described above, sometimes experienced a greater decrease in GFR (>30%), which subsequently resolved and occasionally required a break in treatment with canagliflozin.

Fungal genital infections

In clinical trials, the incidence of candidal vulvovaginitis (including vulvovaginitis and vulvovaginal fungal infections) was higher in women who received canagliflozin compared to the placebo group. Patients with a history of candidal vulvovaginitis who received canagliflozin therapy were more prone to develop this infection. Among patients treated with canagliflozin, 2.3% had more than one episode of infection. Most reports of candidal vulvovaginitis concerned the first four months after starting canagliflozin treatment. 0.7% of all patients discontinued canagliflozin due to candidiasis vulvovaginitis. The diagnosis of candidiasis vulvovaginitis was usually made based on symptoms alone. Clinical studies have noted the efficacy of topical or oral antifungal treatment prescribed by a physician or taken alone on the basis of ongoing therapy with canagliflozin.

In clinical studies, candidal balanitis or balanopostitis was observed more frequently in patients treated with canagliflozin at doses of 100 mg and 300 mg compared to the placebo group. Balanitis or balanopostitis developed primarily in men who were not circumcised and developed more frequently in men with a history of balanitis or balanopostitis. 0.9% of patients treated with canagliflozin had more than one episode of infection. 0.5% of all patients discontinued canagliflozin due to candida balanitis or balanopostitis. In clinical trials, most cases of infection were treated with topical antifungal agents prescribed by a physician or taken independently against the background of ongoing therapy with canagliflozin. Rare cases of phimosis have been reported, and sometimes circumcision surgery was performed.

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

In a pooled analysis of other studies of Invokana® that included approximately 5,800 patients with diabetes from the general population, the prevalence of bone fractures was 10.8, 12.0 and 14.1 per 1,000 patient-years of Invokana® doses of 100 mg and 300 mg and placebo, respectively.

Canagliflozin had no adverse effect on bone mineral density over 104 weeks of treatment.

The effect on the ability to drive and operate vehicles

It has not been found that canagliflozin may affect the ability to drive and operate machinery. However, patients should be aware of the risk of hypoglycemia when canagliflozin is used in addition to therapy with insulin or drugs that enhance its secretion, the increased risk of adverse reactions associated with decreased intravascular volume (postural dizziness) and impaired ability to drive vehicles and mechanisms if adverse reactions develop.

Contraindications

Hypersensitivity to canagliflozin or any excipient of the drug;

Type 1 diabetes mellitus;

Diabetic ketoacidosis;

severe renal impairment;

severe hepatic impairment;

pregnancy and the period of breastfeeding;

children under 18 years of age.

Side effects

The data on adverse reactions observed in clinical trials1 of canagliflozin with a frequency of ≥2% are systematized with respect to each of the organ systems according to the frequency of occurrence using the following classification: Very frequent (≥1/10), Frequent (≥1/100,

Gastrointestinal disorders:
Frequent: constipation, thirst,2 dry mouth.

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

Genital and mammary disorders:
Frequent: balanitis and balanopostitis5, vulvovaginal candidiasis6, vaginal infections.

1 Including monotherapy and in addition to therapy with metformin, metformin and sulfonylurea derivatives, and 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 “increased volume of urine excreted” , “nycturia” are also included in this category.
4 The category “urinary tract infections” includes the term “urinary tract infections” and also includes the terms “cystitis” and “renal infections.
5 The category “balanitis or balanopostitis” includes the terms “balanitis” and “balanopostitis” as well as the terms “candidiasis 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 adverse reactions that developed in placebo-controlled studies of canagliflozin with frequency

Adverse reactions associated with decreased intravascular volume

The frequency of all adverse reactions associated with decreased intravascular volume (postural dizziness, orthostatic hypotension, arterial hypotension, dehydration, and syncope) was According to a pooled analysis, patients receiving “loop” diuretics, patients with moderate renal impairment (GFR 30 to 2), and patients aged ≥75 years had a higher frequency of these adverse reactions. In a study regarding cardiovascular risks, the incidence of serious adverse reactions associated with decreased intravascular volume did not increase with canagliflozin; cases of treatment discontinuation 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

Hypoglycemia has been reported more frequently when canagliflozin is used as an adjunct to therapy with insulin or sulfonylurea derivatives. This is consistent with the expected increased incidence of hypoglycemia when the drug, whose use is not accompanied by the development of this condition, is added to insulin or drugs that enhance its secretion (e.g., sulfonylurea derivatives).

Changes in laboratory parameters

Elevated serum potassium concentration
Cases of elevated serum potassium concentration (>5.4 mEq/L and 15% above baseline 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 in 4.8% of patients receiving placebo. Occasionally, a more pronounced increase in serum potassium concentration was observed in patients with moderate renal dysfunction who had previously experienced elevated potassium concentrations and/or were receiving several drugs that reduce potassium excretion (potassium-saving diuretics and angiotensin-converting enzyme (ACE) inhibitors). In general, the increase in potassium concentration was transient and did not require special treatment.

Elevation of serum creatinine and urea concentrations
During the first six weeks after initiation of treatment, there was a slight average increase in creatinine concentration (The proportion of patients with a greater decrease in FFR (>30%) from baseline noted at any stage of treatment were 2.0% with canagliflozin at a dose of 100 mg, 4.1% with the drug at a dose of 300 mg, and 2.1% with placebo. These reductions in FFR were often transient, with fewer patients experiencing similar reductions in FFR by the end of the study. In a pooled analysis of patients with moderate renal insufficiency, the proportion of patients with a greater decrease in FFR (>30%) from baseline noted at any stage of treatment was 9.3% with canagliflozin 100 mg, 12.2% with 300 mg, and 4.9% with placebo. After discontinuation of canagliflozin, these changes in laboratory parameters had a positive trend or returned to baseline levels.

Low-density lipoprotein (LDL) concentrations increased
A dose-dependent increase in LDL concentrations was observed with canagliflozin. The mean changes in LDL as a percentage of baseline concentration compared with placebo were 0.11 mmol/L (4.5%) and 0.21 mmol/L (8.0%) when canagliflozin was used at doses of 100 mg and 300 mg, respectively. Mean baseline LDL concentrations were 2.76 mmol/L, 2.70 mmol/L, and 2.83 mmol/L with canagliflozin doses of 100 and 300 mg and placebo, respectively.

Hemoglobin concentration increase
There was a slight increase in the mean percentage change in hemoglobin concentration from baseline (3.5% and 3.8%, respectively) when canagliflozin was used in the 100 mg and 300 mg doses, compared with a slight decrease in the placebo group (-1.1%). There was a comparable small increase in the mean percentage change in erythrocyte count and hematocrit from baseline. Most patients showed an increase in hemoglobin concentration (>20 g/L), occurring 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 normal limits.

Decrease in serum uric acid concentration
A moderate decrease in mean uric acid concentration from baseline (-10.1% and -10.6%, respectively) was observed with canagliflozin doses of 100 mg and 300 mg compared with placebo, which showed a slight increase in mean concentration from baseline (1.9%). The decrease in serum uric acid concentration in the canagliflozin groups was maximal or close to maximal at week 6 and was maintained throughout therapy. There was a transient increase in uric acid concentration in the urine. A pooled analysis of canagliflozin at doses of 100 mg and 300 mg showed that the incidence of nephrolithiasis was not increased.

Cardiovascular safety
No increase in cardiovascular risk was found with canagliflozin compared to the placebo group.

Overdose

Symptoms
No cases of canagliflozin overdose are known. Single doses of canagliflozin as high as 1600 mg in healthy individuals and 300 mg twice daily for 12 weeks in patients with type 2 diabetes mellitus were generally well tolerated.

Treatment
In cases of overdose, the usual supportive measures, such as removal of non-absorbed substance from the gastrointestinal tract, clinical observation, and supportive treatment based on the patient’s clinical condition should be implemented. Canagliflozin was practically not excreted during 4-hour dialysis. Canagliflozin is not expected to be excreted by peritoneal dialysis.