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Invokana® [Canagliflozin]

Brand Johnson and johnson

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Available since: 2019-09-19

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Clinical Pharmacology

It has been shown that in patients with diabetes mellitus there is an increased renal reabsorption of glucose, which may contribute to a persistent increase in the concentration of glucose. The sodium glucose transport protein 2 (SGLT2), expressed in the proximal renal tubule, is responsible for most of the reabsorption of glucose from the lumen of the tubule.
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 the secretion of glucose in the urine, which leads to a decrease in glucose concentration in the blood plasma using insulin. independent mechanism in patients with type 2 diabetes.
An increase in 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, in which the tolerance test with a mixed breakfast was carried out, the use of canagliflozin at a dose of 300 mg resulted in 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 intestinal SGLT1 protein, taking into account transient high concentrations of canagliflozin in the intestinal lumen prior to absorption of the drug (canagliflozin is a low potential SGLT1 inhibitor). No malabsorption was detected in the use of kanagliflozin.
Pharmacodynamic effects:
In clinical trials, after single and repeated oral administration of kanagliflozin in patients with type 2 diabetes, the renal threshold for glucose was dose-dependently decreased, and urine excretion of glucose increased. The initial value of the renal threshold for glucose was about 13 mmol / l, the maximum decrease in the 24-hour average renal glucose threshold 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 at treatment background. In a clinical study of canagliflozin in doses of 100 to 300 mg 1 time per day by patients with type 2 diabetes mellitus for 16 days, a decrease in the renal threshold for glucose and an increase in urinary glucose excretion was constant. The concentration of glucose in the blood plasma decreased dose-dependently on the first day of use, followed by a steady decrease in plasma glucose concentration on an empty stomach and after eating.
The use of a single dose of 300 mg of canagliflozin before a mixed-calorie meal with patients with type 2 diabetes caused a delay in the absorption of glucose in the intestine and a decrease in postprandial glycemia by renal and extrarenal mechanisms.
In clinical studies, 60 healthy volunteers received once orally 300 mg of canagliflozin, 1200 mg of canagliflozin (4 times higher than the maximum recommended dose), moxifloxacin and placebo. There were no significant changes in the QT interval, either when using the recommended dose of 300 mg or when applying the dose of 1200 mg. At a dose of 1200 mg, the peak plasma concentration of kanagliflozin was about 1.4 times higher than the equilibrium peak concentration after taking a dose of 300 mg once a day.
Glycemia on an empty stomach:
In clinical studies, the use of canagliflozine as a monotherapy or supplement to therapy with one or two oral hypoglycemic drugs resulted in average changes in fasting glucose in comparison with the initial level with respect to placebo from -1.2 mmol / l to -1.9 mmol / l when using the dosage of 100 mg and from -1.9 mmol / l to -2.4 mmol / l - when applying the dosage of 300 mg, respectively. This effect was close to the maximum after the first day of therapy and persisted throughout the entire period of treatment.
Postprandial glycemia:
In clinical studies on the use of canagliflozin as monotherapy or adjunctive therapy to one or two oral hypoglycemic agents, postprandial glycemia was measured after applying a tolerance test with a standardized mixed breakfast. The use of canagliflozin resulted in 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 - using a dosage of 100 mg and from -2.1 mmol / l to -3.5 mmol / l - when using a dosage of 300 mg, respectively, due to a decrease in the concentration of glucose before a meal and a decrease in fluctuations in the level of postprandial glycemia.
Body mass:
Canagliflozin 100 mg and 300 mg as monotherapy and as double or triple adjunctive therapy caused a statistically significant reduction in the percentage of body weight over 26 weeks, compared with placebo. For two 52-week active controlled studies comparing canagliflozin with glimepiride and sitagliptin, a steady and statistically significant average reduction in the percentage of body weight for canagliflozine 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 placebo-controlled studies, treatment with kanagliflozin 100 mg and 300 mg caused an average decrease in systolic blood pressure of -3.9 mmHg. and -5.3 mm Hg 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 mm Hg accordingly, compared with placebo (-0.3 mm).
There were no significant changes in heart rate.
The function of beta cells:
Studies on the use of canagliflozin in patients with type 2 diabetes indicate an improvement in the function of beta cells, according to an assessment of the homeostasis model for the function of these cells (HOMA2-% B) and an improvement in the rate of insulin secretion using the mixed breakfast tolerance test.

Indications

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

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

Composition

1 tablet contains:

Active substance: 102.0 mg of canagliflozine hemihydrate, equivalent to 100.0 mg of canagliflozin.

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.

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Dosage and Administration

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 impaired renal function of moderate severity [with glomerular filtration rate (GFR) from 30 to2] or patients aged ≥75 years, more frequent development of adverse reactions associated with a decrease in intravascular volume (eg, postural dizziness, orthostatic hypotension, or arterial hypotension) was noted. 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 prior to treatment with cangliflozin. 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 to2), 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.
Canagliflozin is not recommended for patients with severe renal impairment (GFR2), end-stage chronic renal failure (CRF) or in patients on dialysis, since it is expected that kanagliflozin will be ineffective in these patient populations.

Adverse reactions

Evidence of adverse reactions observed during clinical trials¹ canagliflozin with a frequency of ≥2%, 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,

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

Kidney and urinary tract disorders:
Frequent: polyuria and pollakiuria³urgency to urinate, urinary tract infection⁴urosepsis.

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 have evolved in placenab 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) was According to the results of a generalized analysis in patients who received "loop" diuretics, patients with moderate renal insufficiency (GFR from 30 to2) and patients aged ≥75 years, there was a higher frequency 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 therapy with insulin or sulfonylurea derivatives, 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 enhance 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 renal function of moderate severity, 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% when using the drug at a dose of 300 mg and 2.1% when using placebo. These reductions in GFR were often transient, and by the end of the study a similar decrease in GFR was observed in a smaller number of patients. patients with renal failure of moderate severity, the proportion of patients with a more significant reduction in GFR (> 30%) compared with the initial level observed at any stage of treatment was 9.3% - when using canagliflozin in a dose of 100 mg, 12.2 % - when used at a dose of 300 mg, and 4.9% - when using 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 with the use of canagliflozin. 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 concentration values were 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 kanagliflozin in 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. In the majority of patients, an increase in hemoglobin concentration (> 20 g / l) was observed 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. A transient increase in uric acid concentration in the urine was noted. According to the results of the combined analysis of the use of kanagliflozin 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.

Contraindications

Hypersensitivity to cangaglofluin or any excipient of the drug; type 1 diabetes; diabetic ketoacidosis; severe renal failure; severe liver failure; pregnancy and breastfeeding; children's age up to 18 years.

Drug interactions

Drug interactions (in vitro data)

Canagliflozin did not induce the expression of CYP450 system isoenzymes (3A4, 2C9, 2C19, 2B6 and 1A2) in the culture of human hepatocytes. 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 cangliflozin exposure. Reducing the exposure of 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, along with canagliflozin, it is necessary to control the concentration of glycated hemoglobin HbA_1c in patients receiving canagliflozin in a dose of 100 mg 1 time / day, and to provide for the possibility of increasing the dose of canagliflozin up to 300 mg 1 time / day, if additional glycemia control is necessary.

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 is characterized by high activity / low affinity, the development of clinically significant effects of other drugs on the pharmacokinetics kanagliflozin through glukuronirovaniya unlikely.

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

Pregnancy and Lactation

Pregnancy
Studies of the use of kanaglflozina in pregnant women has not been conducted. Animal studies do not indicate a direct or indirect toxic effect on the reproductive system. The use of canagliflozina is contraindicated during pregnancy.

Breastfeeding period
Canagliflozin is contraindicated in women during breastfeeding, because, according to the available pharmacodynamic / toxicological data obtained during preclinical studies, canagliflozin passes into breast milk.

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 frequency 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 increase its secretion.

Decreased intravascular volume
Canagliflozin has a diuretic effect due to an increase in glucose excretion by the kidneys, causing osmotic diuresis, which can lead to a decrease in intravascular volume. In clinical studies of canagliflozin, an increase in the incidence 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 300 mg of canagliflozin. Patients who may be more susceptible to adverse reactions associated with a decrease in intravascular volume include patients who receive "loop" diuretics, patients with impaired renal function of moderate severity and patients aged ≥75 years.
Patients should report the clinical symptoms of intravascular volume reduction. These adverse reactions often led to the cessation of kanagliflozin and often with continued administration of kanagliflozin were corrected by changing the regimen of antihypertensive drugs (including diuretics). In patients with a decrease in intravascular volume, adjustment of this condition should be ensured prior to the start of treatment with canagliflozin.
During the first six weeks of treatment with canagliflozin, there were cases of a slight average decrease in the estimated glomerular filtration rate (GFR) due to a decrease in intravascular volume. In patients who are predisposed to a greater reduction in intravascular volume, as indicated above, sometimes there was a more significant decrease in GFR (> 30%), which was subsequently resolved and occasionally required interruptions in treatment with canagliflozin.

Fungal infections of the genitals
In clinical studies, the incidence of vulvovaginal candidiasis (including vulvovaginitis and vulvovaginal fungal infections) was higher in women who received canfliflozin compared with the placebo group. Patients with a vulvovaginal candidiasis in history, who received therapy with canagliflozin, 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 concerned the first four months after the start of treatment with canagliflozin. 0.7% of all patients stopped taking kanagliflozina due to vulvovaginal candidiasis. The diagnosis of vulvovaginal candidiasis, as a rule, was established only on the basis of symptoms. In clinical studies, the efficacy of local or oral antifungal treatment prescribed by a doctor or taken alone against the background of ongoing therapy with canagliflozin was noted.
In clinical studies, candidal balanitis or balanoposthitis was more common in patients treated with canagliflozin at doses of 100 mg and 300 mg compared with the placebo group. Balanitis or balanoposthitis developed, first of all, in men who were not circumcised, and more often developed in men with balanitis or balanoposthitis in history. More than one infection episode was observed in 0.9% of patients treated with kangagloflozin. 0.5% of all patients stopped taking kanagliflozin due to candidal balanitis or balanoposthitis. In clinical studies, in the majority of cases, the infection was treated with local antifungal agents prescribed by a doctor or taken alone against the background of ongoing therapy with kanagliflozin. Rare cases of phimosis have been reported, and sometimes a circumcision is performed.

Bone fractures
In a study of cardiovascular outcomes in 4327 patients with diagnosed cardiovascular disease or a 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 drug Invokan^® at doses of 100 mg and 300 mg and placebo, respectively. An imbalance in the incidence of fractures occurred during the first 26 weeks of therapy.
Cumulative analysis of other studies of the drug Invokana^®In which about 5800 patients with diabetes from the general population were included, the incidence of bone fractures was 10.8, 12.0 and 14.1 per 1,000 patient-years of use of the drug Invokan^® at doses of 100 mg and 300 mg and placebo, respectively.
During the 104 weeks of treatment, kanagliflozin did not adversely affect the bone mineral density.

Influence on ability to drive vehicles and mechanisms

It has not been established that canagliflozin may affect the ability to drive and operate machinery. However, patients should be aware of the risk of hypoglycemia in the case of canagliflozin as an adjunct to insulin therapy or drugs that increase its secretion, the increased risk of unwanted reactions associated with a decrease in intravascular volume (postural dizziness) and deterioration in the ability to manage vehicles and mechanisms in the development of undesirable reactions.

Overdosage

Symptoms:No cases of overdose of canagliflozin are known. Single doses of canagliflozin, reaching 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 the non-absorbed substance from the gastrointestinal tract, to carry out clinical observation and to carry out supportive treatment taking into account the patient's clinical condition. Canagliflozin was not practically eliminated during 4-hour dialysis. It is not expected that canagliflozin will be cleared by peritoneal dialysis.