Invokana
Invokana: instructions for use and reviews
- 1. Release form and composition
- 2. Pharmacological properties
- 3. Indications for use
- 4. Contraindications
- 5. Method of application and dosage
- 6. Side effects
- 7. Overdose
- 8. Special instructions
- 9. Application during pregnancy and lactation
- 10. Use in childhood
- 11. In case of impaired renal function
- 12. For violations of liver function
- 13. Use in the elderly
- 14. Drug interactions
- 15. Analogs
- 16. Terms and conditions of storage
- 17. Terms of dispensing from pharmacies
- 18. Reviews
- 19. Price in pharmacies
Latin name: Invokana
ATX code: A10BX11
Active ingredient: canagliflozin (Canagliflozin)
Producer: Janssen Ortho, LLS (Janssen Ortho, LLC) (Puerto Rico), Janssen-Cilag (Italy)
Description and photo update: 2019-11-07
Prices in pharmacies: from 2479 rubles.
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Invokana is an oral hypoglycemic drug used in adults with type 2 diabetes.
Release form and composition
Dosage form - tablets, film-coated: capsule-shaped, engraved on one side "CFZ", the core in the cross section is almost white or white; dosage 100 mg - yellow, engraved with "100" on the other side; dosage of 300 mg - almost white or white, with an engraving "300" on the other side (in a cardboard box 1, 3, 9 or 10 blisters of 10 tablets and instructions for use of Invokana).
Composition of 1 tablet:
- active substance: canagliflozin - 100 or 300 mg (in the form of canagliflozin hemihydrate - 102 or 306 mg, respectively);
- auxiliary components (100/300 mg): microcrystalline cellulose - 39.26 / 117.78 mg; croscarmellose sodium - 12/36 mg; anhydrous lactose - 39.26 / 117.78 mg; magnesium stearate - 1.48 / 4.44 mg; hyprolosis - 6/18 mg;
- film shell: dosage 100 mg - Opadry II 85F92209 yellow dye (partially hydrolyzed polyvinyl alcohol - 40%; macrogol 3350 - 20.2%; titanium dioxide - 24.25%; talc - 14.8%; iron oxide yellow - 0, 75%) - 8 mg; dosage 300 mg - Opadry II 85F18422 white dye (partially hydrolyzed polyvinyl alcohol - 40%; macrogol 3350 - 20.2%; titanium dioxide - 25%; talc - 14.8%) - 18 mg.
Pharmacological properties
Pharmacodynamics
It was found that against the background of diabetes mellitus, there is an increased renal reabsorption of glucose, which can cause a persistent increase in glucose concentration. SGLT2 (sodium glucose cotransporter type 2), which is expressed in the proximal renal tubules, is responsible for most of the reabsorption of glucose from the tubular lumen.
Canagliflozin, the active ingredient of Invokana, is one of the SGLT2 inhibitors. With inhibition of SGLT2, a decrease in the reabsorption of filtered glucose and a decrease in PPG (renal threshold for glucose) are observed, this contributes to an increase in the excretion of glucose by the kidneys, which leads to a decrease in the plasma glucose concentration in the blood using an insulin-independent mechanism in patients with type 2 diabetes mellitus. Also, by increasing the excretion of glucose by the kidneys through inhibition of SGLT2, the development of osmotic diuresis is noted, the diuretic effect helps to reduce systolic pressure. In addition, against the background of an increase in the excretion of glucose by the kidneys, there is a loss of calories and, as a result, weight loss.
In phase III studies, the use of a 300 mg dose of Invokana before meals leads to a more pronounced decrease in the postprandial increase in glucose concentration than when taking a dose of 100 mg. Given the transiently high concentrations of the substance in the intestinal lumen before its absorption, this effect may be partly associated with local inhibition of the intestinal transporter SGLT1 (canagliflozin is a low activity SGLT1 inhibitor). In studies with canagliflozin, glucose malabsorption was not detected.
After a single / multiple oral administration of canagliflozin in clinical trials in patients with type 2 diabetes mellitus, a dose-dependent decrease in the renal threshold for glucose and an increase in the excretion of glucose by the kidneys were observed. For glucose, the initial value of the renal threshold is approximately 13 mmol / L, the maximum decrease in the daily mean renal glucose threshold is observed when 300 mg of canagliflozin is used once a day and is 4–5 mmol / L. This indicates a low risk of hypoglycemia during therapy.
When used for 16 days, 100-300 mg of canagliflozin 1 time per day in patients with type 2 diabetes mellitus, there was a constant decrease in the renal threshold for glucose and an increase in the excretion of glucose by the kidneys. The decrease in the plasma glucose concentration in the blood occurred in a dose-dependent manner on the first day of therapy and had a stable tendency in the future on an empty stomach and after eating.
A single application of a dose of Invokana 300 mg before a mixed meal led to a delay in the absorption of glucose in the intestine and a decrease in postprandial glycemia through extrarenal and renal mechanisms.
In a study involving 60 healthy volunteers, it was found that taking a dose of 300 and 1200 mg (4 times higher than the maximum therapeutic dose) does not lead to significant changes in the QTc interval. The maximum plasma concentration of canagliflozin in the blood with a dose of 1200 mg exceeded that after a single dose of 300 mg by approximately 1.4 times.
The use of canagliflozin as monotherapy or as part of a combination treatment (with the use of 1-2 oral hypoglycemic agents), in comparison with placebo, on average leads to a change in fasting glycemia from the initial level from –1.2 to –1.9 mmol / L and from –1.9 to –2.4 mmol / l when taking 100 and 300 mg, respectively. This effect after the first day of therapy was close to maximum and persisted throughout the entire treatment period.
The use of canagliflozin as monotherapy or as part of a combination treatment (using 1–2 oral hypoglycemic agents) was also investigated to measure postprandial glycemia after a glucose tolerance test against the background of a standardized mixed breakfast. Therapy, compared with baseline, contributed to an average decrease in the level of postprandial glycemia relative to placebo from –1.5 to –2.7 mmol / L and from –2.1 to –3.5 mmol / L when taking 100 and 300 mg, respectively, which is associated with a decrease in glucose concentration before meals and a decrease in fluctuations in the level of postprandial glycemia.
According to studies in patients with type 2 diabetes mellitus, the use of canagliflozin improves the function of beta cells (assessed by the model of homeostasis in relation to the function of beta cells) and the rate of insulin secretion (assessed by the glucose tolerance test with a mixed breakfast).
Pharmacokinetics
In healthy subjects, the pharmacokinetics of canagliflozin is similar to the pharmacokinetic parameters of the substance in patients with type 2 diabetes mellitus. After a single oral administration of 100 and 300 mg of Invokana, canagliflozin is rapidly absorbed by healthy volunteers, T max (time to reach the maximum concentration of the substance) in the blood plasma averages 1–2 hours. Plasma C max (maximum concentration of the substance) and AUC (area under the concentration-time curve) increase dose proportionally when using canagliflozin in the dose range of 50-300 mg. The apparent final T 1/2 (half-life) when using 100 and 300 mg of canagliflozin is 10.6 and 13.1 hours, respectively. The equilibrium state is reached 4–5 days after the start of therapy.
The pharmacokinetics of canagliflozin does not depend on time; after repeated use, the accumulation of the substance in the plasma reaches 36%.
The average absolute bioavailability of canagliflozin is about 65%. Eating food with a high fat content does not affect the pharmacokinetics of canagliflozin, therefore Invokana can be used with or without food. However, given the ability of canagliflozin to reduce the increase in postprandial glycemia due to the slowing down of glucose absorption in the intestine, it is recommended to take it before the first meal.
In healthy individuals, after a single intravenous infusion, the average V d (volume of distribution) of canagliflozin in the equilibrium state is 119 liters, which is evidence of an extensive distribution in tissues. The substance binds to plasma proteins, mainly albumin, to a large extent (at the level of 99%). The connection with proteins does not depend on the plasma concentration of canagliflozin. Against the background of renal / hepatic insufficiency, the connection with plasma proteins does not significantly change.
The main metabolic pathway of canagliflozin is O-glucuronidation. The process occurs mainly with the participation of UGT1A9 and UGT2I34 with the formation of two inactive O-glucuronide metabolites. In the human body, the oxidative (CYPZA4-mediated) metabolism of canagliflozin is minimal (approximately 7%).
After oral administration of a single dose of 14 C-kanagliflozina healthy volunteers was detected in the feces of 3.2; 7 and 41.5% of the administered radioactive dose in the form of O-glucuronide metabolite, hydroxylated metabolite and canagliflozin, respectively. The intestinal hepatic circulation of the substance is negligible.
About 33% of the radioactive dose is found in urine, mainly in the form of O-glucuronide metabolites (30.5%). Less than 1% of the dose is excreted by the kidneys in the form of an unchanged substance. When 100 and 300 mg of canagliflozin are used, renal clearance is in the range of 1.3–1.55 ml / min.
Canagliflozin is a drug with low clearance, after intravenous administration in healthy individuals, the average systemic clearance is approximately 192 ml / min.
The use of canagliflozin in severe renal failure, end-stage chronic renal failure, as well as in dialysis patients is not recommended, since the drug is not expected to be effective in this group of patients. With dialysis, there is a minimal excretion of canagliflozin.
In case of mild to moderate hepatic impairment, dose adjustment of Invokana is not required. Patients with severely impaired liver function (on the Child - Pugh scale - class C) are not prescribed the drug, which is due to the lack of clinical experience of its use in this category of patients.
The pharmacokinetic parameters of canagliflozin in children have not been studied.
Indications for use
Invokana is prescribed to improve glycemic control as monotherapy and as part of combined treatment (with other hypoglycemic agents, including insulin) for type 2 diabetes mellitus in adults in combination with exercise and diet.
Contraindications
- type 1 diabetes mellitus;
- severe renal / hepatic impairment;
- diabetic ketoacidosis;
- pregnancy and lactation;
- age up to 18 years;
- individual intolerance to the components of Invokana.
Invokana, instructions for use: method and dosage
Invokan tablets should be taken orally, preferably before breakfast, once a day.
The recommended daily dose is 100 or 300 mg.
If Invokana is used as an adjunct to insulin or drugs that increase its secretion (in particular, sulfonylurea derivatives), in order to reduce the risk of hypoglycemia, these drugs can be prescribed at a lower dose.
Canagliflozin has a diuretic effect. In patients treated with diuretics, as well as in persons with moderate renal function impairment (at a glomerular filtration rate of 30 to 60 ml / min / 1.73 m 2) and in patients over 75 years of age, there is a more frequent development of side effects that are associated with a decrease in intravascular volume (for example, arterial / orthostatic hypotension, postural dizziness). For this group of patients, it is recommended to start therapy with a daily dose of 100 mg. Patients with signs of hypovolemia were advised to correct this condition before starting canagliflozin treatment. If the 100 mg dose is well tolerated and additional glycemic control is required, it is advisable to increase the dose to 300 mg.
If you skip taking the next dose of Invokana, you should take it as soon as possible, but you should not take a double dose within one day.
Side effects
Undesirable effects observed in clinical studies (monotherapy and combined use with metformin, sulfonylurea derivatives and metformin, as well as metformin and pioglitazone) with a frequency of ≥ 2% (systematized depending on the frequency of occurrence according to the following classification: very often - ≥ 1/10, often - ≥ 1/100 and <1/10, infrequently - ≥ 1/1000 and <1/100, rarely - ≥ 1/10 000 and <1/1000, very rarely - <1/10 000, including isolated cases):
- gastrointestinal tract: often - thirst (including pathologically strong - polydipsia), constipation, xerostomia;
- genitals and mammary gland: often - balanitis and balanoposthitis, vulvovaginal candidiasis, vaginal infections;
- kidneys and urinary tract: often - polyuria and pollakiuria (including nocturia), urosepsis, urge to urinate, urinary tract infection (including cystitis and kidney infections).
In placebo-controlled studies of canagliflozin at a dose of 100 and 300 mg with a frequency of <2%, the development of adverse reactions associated with a decrease in intravascular volume (postural dizziness, arterial / orthostatic hypotension, fainting and dehydration), urticaria and skin rash were noted.
The incidence of these disorders in elderly patients (≥ 75 years), patients with moderate renal failure (with a glomerular filtration rate of 30 to 60 ml / min / 1.73 m 2), as well as in combination with loop diuretics is higher. 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 Invokana. These undesirable phenomena did not often lead to the need to discontinue therapy.
The development of hypoglycemia during therapy with Invokana in addition to insulin or sulfonylurea derivatives was reported more often, which is consistent with the expected increase in the incidence 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.
In 4.4% of patients receiving 100 mg of canagliflozin, in 7% of patients receiving 300 mg of canagliflozin, and in 4.8% of patients receiving placebo, there were cases of an increase in serum potassium concentration (> 5.4 mEq / L and above the initial concentration by fifteen%). In patients with moderate renal impairment, occasionally a more pronounced increase in serum potassium concentration was observed (usually in this group of patients there was an increase in potassium concentration, and / or they received several drugs that reduce the excretion of potassium - potassium-sparing diuretics and angiotensin-converting enzyme inhibitors). In general, this disorder is transient and does not require special treatment.
During the first six weeks of therapy, there is an insignificant (<5%) average increase in creatinine concentration with a commensurate decrease in the glomerular filtration rate, after which there is a general trend characterized by a return to baseline values. Also, during this period, the concentration of urea will increase moderately (15–20%), in the future the value of this indicator remains stable. Against the background of moderately impaired renal function, an increase in the concentration of creatinine and urea was observed in 10–11 and ~ 12% of cases, respectively.
The proportion of patients with a more significant decrease in the glomerular filtration rate (> 30%), in comparison with the baseline level observed at any stage of therapy, was 2 and 4.1% with the use of 100 and 300 mg of canagliflozin, respectively, with the use of placebo - 2.1 %. This disorder was often transient, with fewer patients having it by the end of the study. Based on a pooled analysis of patients with moderate renal failure, the proportion of patients with a more significant decrease in glomerular filtration rate (> 30%), compared with the baseline level observed at any stage of therapy, was 9.3% and 12.2% when using 100 and 300 mg of canagliflozin, respectively, with placebo - 4.9%. These changes in laboratory parameters after discontinuation of Invokana administration had a positive trend or returned to baseline values.
During therapy with canagliflozin, a dose-dependent increase in the concentration of LDL (low density lipoproteins) was observed. The average changes in this indicator as a percentage of the initial concentration, in comparison with placebo, were 0.11 mmol / L (4.5%) and 0.21 mmol / L (8%) when using 100 and 300 mg of canagliflozin, respectively. The mean baseline LDL concentrations with 100 and 300 mg canagliflozin and placebo were 2.76; 2.7 and 2.83 mmol / L, respectively.
Acceptance of 100 and 300 mg of canagliflozin led to a slight increase in the average percentage change in hemoglobin concentration (3.5 and 3.8%, respectively), compared with a slight decrease in the group of patients who used placebo (by 1.1%). There was a comparable small increase in the mean percent change in RBC and hematocrit. In most of the patients, the hemoglobin concentration increased (> 20 g / l), this violation was observed in 6% of patients receiving 100 mg of canagliflozin, and in 5.5% of patients receiving 300 mg of canagliflozin, as well as in 1% of patients receiving placebo. Most of the values did not go beyond the normal range.
The use of 100 and 300 mg of canagliflozin caused a moderate decrease in the average concentration of uric acid (by 10.1 and 10.6%, respectively), compared with placebo, which showed an increase in the average concentration of 1.9% from the initial one. These violations were maximal or close to maximal at the sixth week of therapy and persisted throughout the entire use of Invokana. A transient increase in the concentration of uric acid in the urine was also observed. According to the results of the pooled analysis of the use of canagliflozin in the recommended doses, the incidence of nephrolithiasis was not increased.
Overdose
Overdose cases of Invokana are not known. The intake of single doses of canagliflozin in healthy individuals, reaching 1600 mg, and in patients with type 2 diabetes mellitus, 600 mg per day in 2 divided doses for 12 weeks was usually well tolerated.
Therapy: the usual supportive measures are indicated, for example, the removal of non-absorbed substances from the gastrointestinal tract, the implementation of clinical observation and maintenance treatment taking into account the clinical condition of the patient.
During a four-hour dialysis, canagliflozin is practically not excreted. The substance is not expected to be cleared by peritoneal dialysis.
special instructions
The use of Invokana in patients with type 1 diabetes mellitus has not been studied, therefore its appointment to patients in this category is contraindicated.
According to the results of pharmacological studies of safety, toxicity of repeated doses, genotoxicity, ontogenetic and reproductive toxicity, Invokana does not pose a particular danger to humans.
The effect of canagliflozin on human fertility has not been studied. No effect on fertility has been observed in animal studies.
It has been shown that canagliflozin, when used as monotherapy or in addition to hypoglycemic drugs, which are not accompanied by the development of hypoglycemia, rarely leads to hypoglycemia. It has been found that insulin and hypoglycemic agents, which increase its secretion, contribute to the occurrence of hypoglycemia. With Invokana therapy as an adjunct to such drugs, the incidence of hypoglycemia is higher than with placebo. Thus, to reduce the likelihood of hypoglycemia, it is recommended to reduce the dose of insulin or drugs that increase its secretion.
Canagliflozin, by increasing the excretion of glucose by the kidneys, has a diuretic effect and causes osmotic diuresis, which can cause a decrease in intravascular volume. In clinical studies of canagliflozin, an increase in the incidence of adverse reactions associated with this disorder was more often observed during the first three months of treatment with 300 mg of Invokana. Patients more susceptible to intravascular volume reduction associated with adverse reactions include patients over 75 years of age, patients receiving loop diuretics, and patients with moderate renal impairment.
Clinical signs of decreased intravascular volume should be reported to the doctor. This often leads to the cancellation of Invokana. With continued administration of canagliflozin, correction of the antihypertensive drug regimen (including diuretics) is often required. Before starting treatment, patients with a decrease in intravascular volume need to correct this condition.
The incidence of vulvovaginal candidiasis (including vulvovaginal fungal infections and vulvovaginitis) observed in clinical studies in women treated with canagliflozin was higher than in the placebo group. Patients with a history of vulvovaginal candidiasis were more likely to develop this infection. Among women treated with canagliflozin, 2.3% of them developed more than one episode of infection. Most often, this disorder developed during the first four months of treatment with Invokana. Discontinued the drug due to vulvovaginal candidiasis 0.7% of all patients. In clinical studies, the effectiveness of oral or local antifungal therapy, prescribed by a doctor or carried out independently, against the background of continued intake of canagliflozin, has been noted.
Candidal balanoposthitis or balanitis was more common in patients who received Invokana at the recommended doses compared with placebo. First of all, these diseases developed in men who did not undergo circumcision, and more often in patients with a burdened history. During therapy, 0.9% of patients had more than one episode of infection. In 0.5% of all cases, the administration of canagliflozin was canceled due to candidal balanoposthitis or balanitis. In clinical trials, the infection was most often treated with topical antifungal drugs prescribed by a doctor or taken alone, without canceling Invokana. There is information about rare cases of phimosis, sometimes a circumcision operation was required.
When conducting studies of cardiovascular outcomes in 4327 patients with confirmed cardiovascular diseases or high cardiovascular risk, the prevalence of bone fractures was 16.3; 16.4 and 10.8 per 1000 patient-years of use of Invokana in doses of 100 and 300 mg and in the placebo group, respectively. An imbalance in relation to the incidence of fractures occurred during the first 26 weeks of treatment.
In a pooled analysis of other studies of the drug, which included approximately 5800 patients with diabetes from the general population, with Invokana therapy at doses of 100 and 300 mg and placebo, the incidence of bone fractures was 10.8; 12 and 14.1 per 1000 patient-years, respectively.
During 104 weeks of therapy, the drug had no negative effect on bone mineral density.
Influence on the ability to drive vehicles and complex mechanisms
When driving motor vehicles, it is necessary to take into account the risk of hypoglycemia if Invokana is used in addition to insulin or drugs that increase its secretion, an increased risk of adverse effects associated with a decrease in intravascular volume (including postural dizziness), and a deterioration in the ability to drive vehicles with the development of unwanted reactions.
Application during pregnancy and lactation
The use of canagliflozin in pregnant women has not been studied. In animal studies, direct or indirect adverse toxic effects on the reproductive system have not been established. However, Invokana is not prescribed during pregnancy.
Canagliflozin, according to the available pharmacodynamic / toxicological data, which were obtained in the course of preclinical studies, passes into breast milk. In this regard, the use of Invokana is contraindicated during the period of breastfeeding.
Pediatric use
The safety profile of Invokana in patients under 18 years of age has not been studied, therefore, the drug is contraindicated in this group of patients.
With impaired renal function
It is contraindicated to use Invokan tablets in severe renal failure.
In diabetic ketoacidosis, end-stage chronic renal failure and in patients on dialysis, the use of Invokana will be ineffective, therefore, its appointment for this group of patients is inappropriate.
For violations of liver function
It is contraindicated to use Invokan in case of severe hepatic insufficiency.
Use in the elderly
The initial daily dose for elderly patients (from 75 years) is 100 mg. If additional glycemic control is necessary, it can be increased to 300 mg, but only if the previous dose is well tolerated.
Drug interactions
Canagliflozin does not induce the expression of isoenzymes of the CYP450 system (3A4, 2C9, 2C19, 1A2 and 2B6) in the culture of human hepatocytes. It also, according to laboratory studies using human liver microsomes, does not inhibit cytochrome P 450 isoenzymes (IA2, 2A6, 2C19, 2E1 or 2B6) and weakly inhibits CYP2B6, CYP2C8, CYP3A4, CYP2C9. Canagliflozin is a substrate for drug-metabolizing enzymes UGT2B4 and UGTIA9, and drug transporters P-gp (P-glycoprotein) and MRP2. Canagliflozin is one of the weak P-gp inhibitors. The substance undergoes oxidative metabolism to a minimum. Therefore, a clinically significant effect of other drugs through the cytochrome P 450 system on the pharmacokinetics of canagliflozin is unlikely.
Based on clinical data, it can be assumed that the likelihood of significant interactions with drugs taken in combination with Invokana is low.
With simultaneous use with rifampicin, the exposure of canagliflozin and, as a result, its effectiveness decreases. If it is necessary to use it simultaneously with rifampicin and other inducers of the UGT family of enzymes and drug carriers (including phenytoin, phenobarbital, ritonavir) in patients receiving 100 mg of canagliflozin, it is necessary to control the concentration of glycated hemoglobin Hb A1c. If additional glycemic control is required, the possibility of increasing the dose of canagliflozin to 300 mg should be considered.
Canagliflozin in clinical studies did not have a significant effect on the pharmacokinetic parameters of metformin, oral contraceptives (ethinyl estradiol and levonorgestrel), simvastatin, glibenclamide, warfarin or paracetamol.
Canagliflozin, when combined with digoxin, insignificantly affects its plasma concentrations, which requires proper monitoring.
Analogs
Forsiga and Jardins are analogues of Invokana.
Terms and conditions of storage
Store at temperatures up to 30 ° C. Keep out of the reach of children.
Shelf life is 2 years.
Terms of dispensing from pharmacies
Dispensed by prescription.
Reviews about Invokan
Reviews about Invokan are few. Usually, patients indicate the high efficiency of the drug, while the main disadvantage is considered to be its high cost.
Price for Invokana in pharmacies
The approximate price for Invokana is 2000–3245 rubles. (in a package of 30 tablets of 100 mg) or 4300-5430 rubles. (in a package of 30 tablets of 300 mg).
Invokana: prices in online pharmacies
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Drug name Price Pharmacy |
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Invokana 100 mg film-coated tablets 30 pcs. 2479 RUB Buy |
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Invokana 300 mg film-coated tablets 30 pcs. 2698 RUB Buy |
Maria Kulkes Medical journalist About the author
Education: First Moscow State Medical University named after I. M. Sechenov, specialty "General Medicine".
Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!
