Glutazone® [Pioglitazone]

Pharmacological properties

glutazone is an oral hypoglycemic drug of the thiazolidinedione series. the effect of pioglitazone depends on the presence of insulin. highly selective agonist of γ receptors activated by peroxisome proliferator (γ-ppar). γ-ppar receptors are detected in adipose, muscle tissue and in the liver. activation of γ-ppar nuclear receptors modulates the transcription of insulin-sensitive genes involved in glucose control and lipid metabolism. glutazone reduces insulin resistance in peripheral tissues and in the liver, as a result of this, the consumption of insulin-dependent glucose increases and the release of glucose from the liver decreases. unlike sulfonylurea derivatives, pioglitazone does not stimulate insulin secretion by pancreatic β-cells.

In type II diabetes mellitus, a decrease in insulin resistance under the action of pioglitazone leads to a decrease in the concentration of glucose in the blood, the level of insulin in the blood plasma and hemoglobin A1c (glycated hemoglobin - HbA1c). In combination with sulfonylurea derivatives, metformin or insulin, the drug improves glycemic control.

In patients with impaired lipid metabolism when using pioglitazone, also due to stimulation of PPAR-alpha, the catabolism of inflammatory mediators is activated, the thickness of the inner wall of the arteries decreases due to the elimination of inflammatory and proliferative processes, the level of fibrinogen in the blood plasma decreases, as well as the level of TG and the level of HDL increases, while the level of LDL and total cholesterol does not change.

Pharmacokinetics

Suction. After oral administration, pioglitazone is rapidly absorbed; C_max in blood plasma, unchanged pioglitazone is usually reached within 2 hours after administration. A proportional increase in plasma concentration was noted at a dose of 2-60 mg. A stable state is achieved after taking the drug for 4-7 days. Repeated use does not lead to cumulation of the drug or its metabolites. Eating does not affect absorption. The absolute bioavailability of pioglitazone exceeds 80%.

Distribution. The estimated volume of distribution in humans is 1.25 l / kg. Pioglitazone and all its active metabolites extensively bind to plasma proteins (99%).

Metabolism. Pioglitazone is extensively metabolized in the liver by hydroxylation of aliphatic methylene groups. This is usually carried out with the participation of the 2C8 enzyme of the cytochrome P450 system, although other isoenzymes may be involved to a lesser extent. 3 out of 6 identified metabolites are active (M-II, M-III and M-IV). Given activity, concentration and protein binding, pioglitazone and its metabolite M-III equally affect effectiveness. On this basis, the contribution of M-IV to efficiency is approximately three times higher than the contribution of pioglitazone, while the relative contribution of M-II is minimal.

In vitro studies have not demonstrated that pioglitazone inhibits any subtype of the cytochrome P450 system. In humans, the induction of the main isoenzymes of the cytochrome P450 1A, 2C8.9 and 3A4 system does not occur.

55% of pioglitazone is excreted in feces and 45% in urine. Medium T_½ unchanged pioglitazone is 5–6 hours, and for all its active metabolites, 16–23 hours.

Elderly patients. Pharmacokinetic parameters in patients aged 65 years and older and similar in young patients.

Patients with impaired renal function. In patients with impaired renal function, the concentration of pioglitazone and its active metabolites in the blood plasma is lower than in patients with normal renal function, but the clearance of the parent compound is similar. Thus, the concentration of free (unbound) pioglitazone is unchanged.

Patients with impaired liver function.The total concentration of pioglitazone in the blood plasma does not change, but with an increased volume of distribution, clearance is reduced along with an increased fraction of unbound pioglitazone.

Indications

Type II diabetes mellitus treatment:

like monotherapy

• in patients (especially overweight) with contraindications and intolerance to metformin in case of inadequate control of blood glucose levels by diet and exercise;

as a double combination therapy with

• metformin in patients (especially overweight) with inadequate glycemic control, despite the use of the maximum tolerated dose of metformin;
• sulfonylurea derivatives only in patients with intolerance and contraindication to metformin with insufficient glycemic control, despite the use of the maximum tolerated dose of sulfonylurea derivatives;

as a triple combination therapy with

• metformin and sulfonylurea derivatives in patients (especially overweight) with inadequate glycemic control, despite the use of double combination therapy.

Glutazone is also indicated in combination with insulin for type II diabetes mellitus in patients with inadequate glycemic control when using insulin for which metformin is contraindicated or is intolerant of metformin.

After the start of treatment with pioglitazone, the effectiveness of therapy should be carefully assessed every 3-6 months (for example, by the degree of decrease in HbA1c level). If an adequate response to pioglitazone therapy is not received, its use should be discontinued. Given the potential risks of long-term therapy with pioglitazone, doctors who prescribe the drug should, using routine examinations, confirm the presence of a favorable safety profile of pioglitazone (see SPECIAL INSTRUCTIONS).

Application

Glutazone is taken by adults orally 1 time per day, regardless of food intake. the tablet should be taken without chewing, with a glass of water. the initial dose of pioglitazone is 15 or 30 mg, if necessary, the dose can be increased to 45 mg once a day.

The maximum daily dose is 45 mg.

With the combination therapy of pioglitazone with insulin, the dose of insulin either remains the same or decreases when the patient informs about hypoglycemia.

Elderly patients. Pioglitazone dose adjustment in elderly patients is not required. Treatment should be started with the lowest available dose. The dose should be increased gradually, especially in the case of pioglitazone in combination with insulin.

Patients with impaired renal function. Pioglitazone dose adjustment in patients with impaired renal function (creatinine clearance of 4 ml / min) is not required. Pioglitazone is not recommended for patients who are on dialysis.

Patients with impaired liver function. Pioglitazone should not be used in patients with impaired liver function.

Contraindications

Hypersensitivity to the active substance or any other component of the drug.

Insulin-dependent type I diabetes mellitus, diabetic ketoacidosis, severe liver dysfunction, heart failure (NYHA stages I – IV), a history of bladder cancer, macroscopic hematuria of unknown etiology.

Side effects

Adverse reactions are listed by this frequency: very often (1/10); often (1/100, 1/10); sometimes (1/1000, 1/100); rarely (1/10 000, 1/1000); very rarely (1/10 000); unknown (frequency cannot be estimated from the available data).

Pioglitazone monotherapy

From the side of the organ of vision: visual impairment, swelling of the macula.

Infections and infestations: upper respiratory tract infections, sinusitis.

From the immune system: hypersensitivity reactions and allergic reactions, including anaphylaxis, angioedema, urticaria.

From the nervous system: hypesthesia, insomnia.

Benign, malignant, and unspecified neoplasms (including cysts and polyps): bladder cancer.

From the musculoskeletal system: bone fractures.

Research results: weight gain, increased ALAT.

Pioglitazone in combination therapy with metformin

From the side of the organ of vision: visual impairment, swelling of the macula.

Infections and infestations: upper respiratory tract infections, sinusitis.

On the part of the blood system and lymphatic system: anemia.

From the immune system: hypersensitivity reactions and allergic reactions, including anaphylaxis, angioedema, urticaria.

From the nervous system: hypesthesia, headache, insomnia.

Benign, malignant, and unspecified neoplasms (including cysts and polyps): bladder cancer.

From the digestive tract: flatulence.

From the musculoskeletal system: bone fractures, arthralgia.

From the urinary system: hematuria.

From the reproductive system: erectile dysfunction.

Research results: weight gain, increased ALAT.

Pioglitazone in combination therapy with sulfonylureas

From the side of the organ of vision: visual impairment, swelling of the macula.

Infections and infestations: upper respiratory tract infections, sinusitis.

From the immune system: hypersensitivity reactions and allergic reactions, including anaphylaxis, angioedema, urticaria.

Metabolic disorders: hypoglycemia, increased appetite.

From the nervous system: hypesthesia, headache, dizziness, insomnia.

On the part of the organ of hearing and the vestibular apparatus: vertigo.

Benign, malignant, and unspecified neoplasms (including cysts and polyps): bladder cancer.

From the digestive tract: flatulence.

On the part of the skin: increased sweating.

From the musculoskeletal system: bone fractures.

From the urinary system: glucosuria, proteinuria.

General disorders: fatigue.

Research results: increase in body weight, increase in ALAT, increase in LDH levels.

Pioglitazone in triple combination therapy with metformin and sulfonylureas

From the side of the organ of vision: swelling of the macula.

Infections and infestations: upper respiratory tract infections, sinusitis.

From the immune system: hypersensitivity reactions and allergic reactions, including anaphylaxis, angioedema, urticaria.

Metabolic disorders: hypoglycemia.

From the nervous system: hypesthesia, insomnia.

Benign, malignant, and unspecified neoplasms (including cysts and polyps): bladder cancer.

From the musculoskeletal system: bone fractures, arthralgia.

Research results: an increase in body weight, an increase in ALAT, an increase in LDH levels, an increase in CPK in blood plasma.

Pioglitazone in combination therapy with insulin

From the side of the organ of vision: macular edema.

Infections and infestations: upper respiratory tract infections, sinusitis, bronchitis.

From the immune system: hypersensitivity reactions and allergic reactions, including anaphylaxis, angioedema, urticaria.

Metabolic disorders: hypoglycemia.

From the nervous system: hypesthesia, insomnia.

From the cardiovascular system: heart failure.

Benign, malignant, and unspecified neoplasms (including cysts and polyps): bladder cancer.

From the respiratory system: shortness of breath.

From the musculoskeletal system: bone fractures, arthralgia, back pain.

General disorders: edema.

Research results: increase in body weight, increased CPK in blood plasma.

special instructions

Fluid retention and heart failure.pioglitazone can cause fluid retention, which can exacerbate heart failure. treatment of patients with at least one risk factor for the development of chronic heart failure (for example, a history of myocardial infarction) should begin with a minimum dose followed by a gradual increase. this group of patients should be constantly monitored for signs and symptoms of heart failure, weight gain or the appearance of edema, especially in patients with reduced diastolic reserve. since insulin and pioglitazone are associated with fluid retention, their simultaneous use increases the risk of edema. Patients who take a combination of these drugs should be carefully monitored for signs of heart failure, weight gain, and swelling. there is evidence of peripheral edema and heart failure in patients taking pioglitazone in combination with NSAIDs, including selective cog-2 inhibitors. for any deterioration of the patient’s condition from the cardiovascular system, pioglitazone should be discontinued.

Elderly patients. When prescribing pioglitazone, patients over 75 years of age should be careful because of the limited experience in this age group. Pioglitazone should be used in combination with insulin in elderly patients with caution because of the increased risk of severe heart failure. Also, as a result of the existence of age-related risk factors (especially bladder cancer, fractures, and heart failure), the risk / benefit ratio should be carefully evaluated before and during pioglitazone therapy.

Bladder cancer Data from a meta-analysis of controlled clinical trials indicate an increased risk of developing bladder cancer in patients receiving pioglitazone. So, the bladder cancer detection rate was 0.06% in the study group (versus 0.02% in the control group). Available epidemiological evidence also suggests a slight increase in the risk of bladder cancer in patients with diabetes who received pioglitazone for a long time and in high total doses. It should be noted that at present, the risk of developing bladder cancer after a short-term use of pioglitazone cannot be completely excluded. Therefore, prior to starting pioglitazone therapy, any risk factors for bladder cancer (age, smoking, occupational hazards, chemotherapy (e.g. cyclophosphamide), pelvic radiation, etc.) should be carefully evaluated. In addition, before starting pioglitazone therapy, all patients with macroscopic hematuria of unknown origin should be carefully examined. Patients taking pioglitazone should be warned about the need to immediately consult a doctor if they show signs of macroscopic hematuria or other symptoms of the genitourinary system during therapy.

Monitoring liver function. Before starting treatment with pioglitazone, the level of activity of liver enzymes in all patients should be determined. Pioglitazone should not be prescribed to patients in the presence of clinical manifestations of liver disease in the active phase and with an increase in ALAT levels more than 2.5 times higher than the upper limit of normal. With a moderate increase in the activity of liver enzymes, caution should be started or continued with treatment with pioglitazone. During treatment with pioglitazone, patients with liver pathology or with the development of symptoms of liver dysfunction (nausea, anorexia, abdominal pain, fatigue) should regularly monitor the level of liver enzymes.With a three-fold increase in the level of enzyme activity (ALAT) or the development of jaundice, treatment with pioglitazone should be discontinued.

Weight gain. There is evidence of a dose-dependent increase in body weight. The volume of visceral fat decreased significantly, while extra-abdominal fat mass increased. Similar changes in the distribution of fat mass in the body when taking pioglitazone were accompanied by an improvement in insulin sensitivity. In some cases, weight gain may be associated with fluid retention, be a symptom of heart failure, so body weight should be carefully monitored. Patients are advised to strictly control the calorie content of food.

Hematology. During treatment with pioglitazone, a slight decrease in the levels of hemoglobin (relative decrease of 4%) and hematocrit (relative decrease of 4.1%) was observed due to an increase in blood plasma volume. Similar changes were detected for metformin (a relative decrease in hemoglobin - 3-4%, hematocrit - 3.6-4.1%) and to a lesser extent for drugs of the sulfonylurea group (a relative decrease in hemoglobin - 1-2%, hematocrit - 1-3, 2%).

Hypoglycemia. As a result of increased tissue sensitivity to insulin in patients taking pioglitazone in the form of double or triple therapy with sulfonylurea and insulin, an increased risk of hypoglycemia may be noted. At a risk of hypoglycemia, a dose reduction of sulfonylurea or insulin may be required.

From the side of the organ of vision. There is evidence of the occurrence or worsening of macular edema, which is accompanied by visual impairment in patients receiving thiazolidinediones, including pioglitazone. Most of these patients also have peripheral edema. It is not known whether there is a direct relationship between pioglitazone and macular edema. Therefore, the doctor should keep in mind that visual impairment in patients receiving pioglitazone therapy may be due to macular edema.

Others. There is clinical evidence regarding the risk of fractures in women with pioglitazone therapy, which must be considered with long-term treatment. Also, epidemiological data indicate the same incidence of fractures in both women and men during pioglitazone therapy. Therefore, the doctor should take into account the risk of fractures in patients receiving pioglitazone.

Due to increased tissue sensitivity to insulin, the result of treatment with pioglitazone in women with polycystic ovary syndrome may be the resumption of ovulation. Such patients are at risk of becoming pregnant. Patients should be warned about the possibility of pregnancy. If pregnancy has already occurred, pioglitazone should be discontinued.

Pioglitazone should be used with caution during the concomitant administration of inhibitors (e.g. gemfibrozil) or inducers (e.g. rifampicin) of cytochrome P450 2C8. In such cases, glycemic control should be carefully carried out and, if necessary, adjust the dose of pioglitazone or hypoglycemic therapy regimen.

Glutazone contains lactose monohydrate, therefore, it should not be prescribed to patients with rare hereditary diseases such as galactose intolerance, Lapp lactase deficiency or impaired glucose-galactose absorption.

Use during pregnancy and lactation. Due to the lack of clinical data, the use of pioglitazone during pregnancy and lactation is not recommended.

It is not known whether pioglitazone passes into breast milk. Animal studies have shown that it is excreted in breast milk, so the drug should not be prescribed for breastfeeding.

Fertility. During studies in laboratory animals, no negative effect of pioglitazone on fertility was revealed.

Children.The use of the drug Glutazone is contraindicated in children and adolescents under the age of 18 years.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. When using the drug, adverse reactions may occur that can affect the ability to drive vehicles or work with other mechanisms.

Interactions

Interaction studies have shown that pioglitazone does not significantly affect the pharmacokinetics and pharmacodynamics of digoxin, warfarin, fenprocoumone and metformin. the simultaneous use of pioglitazone with sulfonylurea derivatives does not affect the pharmacokinetics of these drugs. human studies do not suggest the induction of the main enzymes cyp 1a, 2c8 / 9 and 3a4. therefore, one can expect a lack of interaction with substances that are metabolized by these enzymes, for example, oral contraceptives, cyclosporin, calcium channel blockers, and GMA-COA reductase inhibitors.

There were reports that the simultaneous use of pioglitazone with gemfibrozil (a CYP 2C8 inhibitor) leads to a three-fold increase in the AUC of pioglitazone. Since there is potential to increase the risk of dose-related side effects, a dose reduction of pioglitazone may be required while it is used with gemfibrozil.

The simultaneous use of pioglitazone with rifampicin (inducer of CYP 2C8) leads to a 54% decrease in AUC of pioglitazone. It may be necessary to increase the dose of pioglitazone while using it with rifampicin, provided that glycemic control is carefully monitored.

Overdose

The reported maximum dose, 120 mg / day for 4 days, followed by 180 mg / day for 7 days, was not associated with any symptoms.

Hypoglycemia can occur with a combination of pioglitazone with sulfonylureas or insulin.

Treatment: symptomatic and supportive therapy.

Storage conditions

At a temperature not exceeding 25 ° C.