proviron cycle

08/24/2016

In clinical studies, after single and multiple oral kanagliflozina patients with type 2 diabetes mellitus, renal threshold for glucose dose-dependently decreased, increased excretion of glucose by the kidneys.The initial value of the renal threshold proviron cycle for glucose was approximately  the maximum reduction in the 24 hour mean renal glucose threshold observed when applying kanagliflozina 300 mg 1 time per day and varied from , which indicates a low risk of a hypoglycemia during treatment. In phase I trials in patients with type 2 diabetes treated kanagliflozin 100 mg or 300 mg, reduced renal threshold for glucose resulted in increased renal excretion of glucose at day; observed glucose excretion by the kidneys corresponds to a loss of day. Reduced renal threshold for glucose and increasing renal excretion of glucose was maintained throughout the 26-week treatment period in patients with type 2 diabetes. There was a moderate increase in the daily urine volume , which was reduced after a few days of preparation. There was a transient increase renal excretion of uric acid by the action kanagliflozina . This was accompanied by a persistent decrease proviron cycle in plasma uric acid concentration of about 20%.
The use kanagliflozina single dose of 300 mg before the mixed meal patients with type 2 diabetes caused a delay glucose absorption in the gut, and lowering postprandial glucose by the kidney and extrarenal mechanisms.
During clinical research 60 healthy volunteers received single oral kanagliflozin 300 mg, kanagliflozin a dose of 1200 mg (4-fold higher than the maximum recommended dose) or placebo, moxifloxacin. There were no significant changes in QTc interval kanagliflozina under application at the recommended dose of 300 mg, nor proviron cycle at kanagliflozina applying a dose of 1200 mg. Kanagliflozina When applied in a dose of  kanagliflozina after administration at a dose of 300 mg once a day.

Fasting
during the clinical trials application kanagliflozina as monotherapy or in addition to therapy with one or two oral hypoglycemic drugs has led to a change in the average fasting glucose from baseline compared to placebo from -1.2 mmol / L to 1.9 mmol / L kanagliflozina when used at a dose of 100 mg and 1.9 mmol / l to 2,4 mg / l – in applying kanagliflozina 300 mg, respectively. This effect was close to the maximum of the day after the first treatment and was maintained throughout the treatment period.

Postprandial glycemia
in clinical trials of kanagliflozina as monotherapy or adjunctive therapy to one or two oral hypoglycemic agents we measured postprandial blood glucose after a glucose tolerance test with a standardized mixed breakfast. Application kanagliflozina resulted in average reductions in postprandial blood glucose from baseline relative to placebo -1.5 mmol / L to -2.7 mmol / l – kanagliflozina when used at a dose of 100 mg and -2.1 mmol / l -3.5 mmol / l – application kanagliflozina at a dose of 300 mg, respectively, due to lower glucose concentration before meal and decrease postprandial glucose fluctuations.

Beta cell function
studies kanagliflozina use in patients with type 2 diabetes indicate improved beta-cell function, according to the homeostasis assessment model for beta-cell function (homeostatic model-2 assessment index% B; HOMA2-% B ), and speed improvements in insulin secretion during OGTT mixed breakfast.

Pharmacokinetic properties
Pharmacokinetics kanagliflozina in healthy subjects similar to the pharmacokinetics kanagliflozina in patients with type 2 diabetes. After a single oral kanagliflozina in doses of 100 mg and 300 mg in healthy volunteers kanagliflozin rapidly absorbed, the maximum plasma concentration (average value of the T max is reached after 1-2 hours). Plasma C max and AUC increased kanagliflozina dozoproportsionalno when used in doses from 50 mg to 300 mg. The apparent terminal half-life (t1 / 2) was 10.6 hours and 13.1 hours kanagliflozina when applied at doses of 100 mg and 300 mg, respectively. An equilibrium state was reached within 4-5 days after initiation of therapy kanagliflozinom 100 mg or 300 mg once a day.
Pharmacokinetics kanagliflozina not time dependent accumulation of drug in plasma of up to 36% after multiple dose.

Absorption
Mean absolute bioavailability kanagliflozina is approximately 65%. Eating foods high in fat did not affect the pharmacokinetics of kanagliflozina; kanagliflozin therefore can be taken with food or without it.However, given the increase in capacity kanagliflozina reduce postprandial blood glucose due to slow absorption of glucose in the intestines, it is recommended to take kanagliflozin before the first use of food.

Distribution
The mean volume of distribution at steady state kanagliflozina after a single intravenous infusion in healthy subjects was 83.5 liters, which indicates extensive tissue distribution. Kanagliflozin largely bound to plasma proteins (99%), mostly to albumin. Communication with proteins kanagliflozina independent of the plasma concentration. Communication to plasma proteins was not significantly altered in patients with renal or hepatic insufficiency.

Metabolism
O-glucuronidation is a major route of metabolism kanagliflozina. Glucuronidation occurs primarily involving UGT1A9 and UGT2B4 inactive to two O-glucuronide metabolites. Increased AUC kanagliflozina (26% and 18%) was observed in patients carriers of alleles UGT1A9 * UGT2B4 * 3 and 2, respectively. It is not expected that this effect will have clinical relevance. CYP3A4-mediated (oxidative) kanagliflozina metabolism in humans is minimal (about 7%).

Excretion
After a single dose of 14C-kanagliflozina orally to healthy volunteers 41.5%, 7.0% and 3.2% of the administered radioactive dose was detected in the feces in the form kanagliflozina, hydroxylated metabolite, and O-glucuronide metabolite, respectively. Enterohepatic circulation kanagliflozina was negligible.
Approximately 33% of the administered dose of radioactivity was detected in the urine, mainly as metabolites of O-glucuronide (30.5%). Less than 1% of the dose is excreted as unchanged kanagliflozina kidneys. Renal clearance kanagliflozina when used in doses 100 mg and 300 mg ranged from 1.30 to 1.55 ml / min.
Kanagliflozin relates to preparations with low clearance, mean systemic clearance is approximately 192 mL / min in healthy volunteers after intravenous administration.

Special patient groups Patients with impaired renal function, the C max kanagliflozina increased moderately by 13%, 29% and 29% in patients with impaired renal function mild, moderate and severe, respectively, but not in patients on hemodialysis. Compared to healthy volunteers, the serum component AUC kanagliflozina increased by approximately 17%, 63% and 50% in patients with mild, moderate and severe renal impairment, respectively, but was similar in healthy volunteers and patients with terminal chronic renal failure (CRF ). Removing kanagliflozina by dialysis was minimal.

 

Patients with impaired liver function
After applying kanagliflozina at a dose of 300 mg once daily compared to patients with normal liver function in patients with impaired hepatic function of class A on a scale Child-Pugh (dysfunction of the liver mild) indicators C max and AUC ∞ were raised on 7% and 10%, respectively, and decreased by 4% and rose by 11%, respectively, in patients with impaired liver function in class for Child-Pugh (impaired liver function moderate). These differences are not considered clinically significant. Dose adjustment in patients with hepatic impairment or mild to moderate severity is not required. Clinical experience with the drug in patients with severe hepatic impairment (class C Child-Pugh) is absent, so the use of kanagliflozina contraindicated in these patients.

Elderly patients (≥65 years)
According to the results of a population pharmacokinetic analysis, age had no clinically meaningful effect on the pharmacokinetics of kanagliflozina.

Children (<18 years)
Pharmacokinetic studies have not been conducted kanagliflozina children.

Other groups of patients
No dose adjustment based on gender, race / ethnicity, or body mass index is not required. These characteristics do not have a clinically meaningful effect on the pharmacokinetics of kanagliflozina, according to the results of a pharmacokinetic population analysis.

testimony

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

  • monotherapy;
  • in a combination therapy with other hypoglycemic drugs, including insulin.

Contraindications

  • Hypersensitivity to kanagliflozinu or any excipient of the drug;
  • type 1 diabetes;
  • diabetic ketoacidosis;
  • renal insufficiency with a glomerular filtration rate (GFR) <45 ml / min / 1.73 m 2 ;
  • severe hepatic impairment;
  • lactose intolerance, lactase deficiency, glucose-galactose malabsorption;
  • chronic heart failure III – IV functional class (classification NYHA);
  • Pregnancy and breast-feeding; Children up to age 18 years.

The caution
in diabetic ketoacidosis history

Application of pregnancy and during breastfeeding

Pregnancy
kanagliflozina application studies in pregnant women have been conducted. Animal studies indicate no direct or indirect adverse toxic effects in the reproductive system. Application kanagliflozina contraindicated during pregnancy.

Breast-feeding period
is contraindicated use of kanagliflozina women during breastfeeding. According to available pharmacodynamic / toxicological data obtained in animal studies, kanagliflozin passes into breast milk. It is unknown whether kanagliflozin penetrates human milk.

Dosing and Administration

Kanagliflozin recommended ingested once daily at a dose of 100 mg or 300 mg, preferably before breakfast. The tablets should be swallowed whole.
In applying kanagliflozina as an adjunct to insulin therapy or a means of augmenting the secretion (eg sulfonylureas), to reduce the risk of hypoglycemia may be considered the use of lower doses of the above drugs.
Kanagliflozin diuretic. In patients treated with diuretics, patients with impaired moderate renal function [GFR from 45 to 60 ml / min / 1.73 m 2 ] or patients aged > 75 years have seen more frequent development of unwanted reactions associated with a decrease in intravascular volume (eg, postural dizziness, orthostatic hypotension, or hypotension). Thus, in these patients it is recommended to use kanagliflozina at an initial dose of 100 mg once a day. Patients with signs of reduced intravascular volume adjustment is recommended this condition prior to initiating treatment kanagliflozinom. Patients receiving kanagliflozin 100 mg with good tolerability and need for additional glycemic control, it is appropriate to increase the dose up to 300 mg.

Skipping doses
If you skip the dose should be taken as soon as possible; but it should not take a double dose in one day.

Special patient population Children under 18 years of age The safety and efficacy of kanagliflozina in children have not been studied.

Elderly patients
Patients aged > 75 years as an initial dose of 100 mg should be administered once a day. It is necessary to take into account the function of the kidneys and the risk of hypovolemia.

Impaired Renal Function
In patients with impaired renal function mild (the calculated glomerular filtration rate (GFR) of 60 to 90 mL / min / 1.73 m 2 ) dose adjustment is not required.
In patients with renal impairment with a glomerular filtration rate of 45 to 60 ml / min / 1.73 m 2 is recommended to use the drug at a dose of 100 mg once a day.
Kanagliflozin not recommended for use in patients with impaired renal function with a GFR <45 mL / min / 1.73 m 2 , end-stage chronic renal failure (CRF), or in patients undergoing dialysis, as expected, it would be ineffective in these patient populations kanagliflozin.

Side effect

Data on adverse drug reactions observed during clinical studies (including monotherapy and addition to metformin, metformin and a sulfonylurea, and metformin and pioglitazone) kanagliflozina 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 common ( > 1/10), frequent ( > 1/100, <1/10), infrequent ( > 1/1000, <1/100), rare ( > 1/10000, <1/1000) . Violations of the gastrointestinal tract: Common: constipation, nausea, thirst 1 . Uncommon: dry mouth. Violations of the kidney and urinary tract infections: Frequent: polyuria and pollakiuria 2 , urinary tract infection 3 . Infrequent: urgency to urinate ., urosepsis Violations of the genital organs and the breast: Very frequent: vulvovaginal candidiasis 4 .frequent: balanitis and balanoposthitis 5 . Infrequent:. vaginal infections 1. Category “thirst” includes the term “thirst” and “polydipsia.” 2 . “polyuria or pollakiuria” category includes the terms “polyuria”, “increase in urine volume” and “nocturia”. 3. Category “urinary tract infection” includes the term “urinary tract infection,” “cystitis” and “infection kidney “. 4. The category” vulvovaginal candidiasis “includes the terms” vulvovaginal candidiasis “,” vulvovaginal fungal infection, “” vulvovaginitis “” vulvitis “and” genital fungal infections. ” 5. Category” balanitis and balanoposthitis “includes The terms “balanitis”, “balanoposthitis ‘,’ candida balanitis” and “genital fungal infections.” in other adverse reactions that have been developed in the placebo-controlled studies kanagliflozina with a frequency of <2%, were the adverse reactions associated with a decrease in intravascular volume (postural dizziness , orthostatic hypotension, hypotension, dehydration, and syncope), skin rash, and urticaria. therapy for low testosterone hcg phase 2 food list treatment for male hypogonadism