Invokana, 100 mg 30 pcs.

The glucose transporter 2 (NZTG2) in the proximal renal tubules is responsible for most of the reabsorption of filtered glucose from the tubule lumen.It is proven that diabetic patients have increased renal glucose reabsorption, may be one of the causes of consistently elevated blood glucose concentrations.

Canagliflozin is an active oral NZTG2 inhibitor. By inhibiting NZTG2, canagliflozin reduces filtered glucose reabsorption and lowers the renal threshold for glucose (RTH ), increasing urinary glucose excretion (EG) and reducing plasma glucose concentration through this insulin-independent mechanism in patients with type 2 diabetes. Increased glucose excretion with urine when NZTG2 is inhibited also leads to osmotic diuresis, with diuretic effect leading to lower systolic blood pressure; calorie loss and weight loss are the result of increased glucose excretion with urine, which has been demonstrated in studies in patients with type 2 diabetes.

The ability of canagliflozin to increase EH with urine by directly reducing plasma glucose levels is independent of insulin. In clinical trials, canagliflozin has been observed to improve the homeostatic model of β-cell function assessment (NOMA of β-cells) and improve insulin secretion by beta-cells in response to a mixed food trial.

In phase 3 studies, administration of a 300-mg dose of canagliflozinu before meals reduced postprandial glycemia more than administration of a 100-mg dose. This effect of the 300 mg dose of canagliflozinu may be due in part to local inhibition of intestinal NZTG1 (an important glucose transporter in the gut) due to temporarily high concentrations of canagliflozinu in the intestine before absorption of the drug (canagliflozin is a weak NZTG1 inhibitor). Studies have not demonstrated glucose malabsorption when canagliflozinu is used.

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).

Active ingredient

Composition

Tablets

Active ingredient:

102.0 mg canagliflozin hemihydrate, which is equivalent to 100.0 mg canagliflozin.

Auxiliary substances (core):

Microcrystalline cellulose 39.26 mg,

Lactose anhydrous 39.26 mg,
.

croscarmellose sodium 12.00 mg,

hyprolose 6.00 mg,

magnesium stearate 1.48 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 renal dysfunction of moderate severity [with glomerular filtration rate (GFR) 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 dysfunction it is recommended to use the drug in an initial dose of 100 mg once a day. 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 in patients on dialysis, as canagliflozin is expected to be ineffective 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 via 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, as this treatment will not be effective in these clinical cases.

Cancerogenicity and Mutagenicity
Preclinical data show no specific hazard to humans, according to pharmacological safety studies, 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
The use of canagliflozin as monotherapy or in addition to hypoglycemic agents (whose use is not accompanied by the development of hypoglycemia) has rarely been shown to result in 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 agents that increase its secretion (e.g., sulfonylurea derivatives), the incidence of hypoglycemia was higher than when using placebo.
Thus, to reduce the risk of hypoglycemia, a reduction in the dose of insulin or agents that enhance its secretion is recommended.

Lowering 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.
During 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 discontinuation of canagliflozin treatment.

Genital fungal 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 background of ongoing therapy with canagliflozin.
In clinical trials, candidiasis 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 4,327 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 incidence 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.
At 104 weeks of treatment, canagliflozin had no adverse effect on bone mineral density.

Influence on ability to drive and operate vehicles

Canagliflozin has not been found to affect the ability to drive and operate machinery. However, patients should be aware of the risk of hypoglycemia when canagliflozin is used as an adjunct 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 when developing adverse reactions.

Contraindications

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 tract disorders:
Frequent: constipation, thirst2 , dry mouth.

Kidney 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 (30 to 2 GFR), 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 was more frequently reported when canagliflozin was 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
In 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 an increase in potassium concentration 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.

Elevations in serum creatinine and urea concentration
In the first six weeks after initiation of treatment, there was a slight average increase in creatinine concentration (The proportion of patients with more significant decreases 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 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.

Elevation of low-density lipoprotein (LDL) concentrations
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.

Elevation of hemoglobin concentration
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 at doses of 100 mg and 300 mg, 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
. Canagliflozin at doses of 100 mg and 300 mg showed a moderate decrease in mean uric acid concentration from baseline (-10.1% and -10.6%, respectively) compared to 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 case of overdose, the usual supportive measures should be implemented, such as removal of unabsorbed substance from the gastrointestinal tract, clinical monitoring, and supportive treatment based on the clinical condition of the patient. Canagliflozin was practically not excreted during 4-hour dialysis. Canagliflozin is not expected to be excreted by peritoneal dialysis.