Diab-Norm (Tablets) Instructions for Use

ATC Code

A10BG03 (Pioglitazone)

Active Substance

Pioglitazone (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Oral hypoglycemic drug

Pharmacotherapeutic Group

Oral hypoglycemic agent

Pharmacological Action

Oral hypoglycemic agent, a derivative of the thiazolidinedione series. It is a potent, selective agonist of gamma receptors activated by peroxisome proliferator (PPAR-gamma). PPAR-gamma receptors are found in adipose, muscle tissues and in the liver. Activation of nuclear PPAR-gamma receptors modulates the transcription of a number of insulin-sensitive genes involved in blood glucose control and lipid metabolism.

It reduces insulin resistance in peripheral tissues and in the liver, resulting in an increase in insulin-dependent glucose utilization and a decrease in glucose production in the liver. Unlike sulfonylurea derivatives, Pioglitazone does not stimulate insulin secretion by pancreatic beta-cells.

In type 2 diabetes mellitus (non-insulin-dependent), the reduction of insulin resistance under the action of pioglitazone leads to a decrease in blood glucose concentration, a decrease in plasma insulin levels and hemoglobin A_1c (glycated hemoglobin, HbA_1c).

In type 2 diabetes mellitus (non-insulin-dependent) with lipid metabolism disorders, the use of pioglitazone leads to a decrease in TG levels and an increase in HDL levels. At the same time, the levels of LDL and total cholesterol in such patients do not change.

Pharmacokinetics

After oral administration on an empty stomach, Pioglitazone is detected in blood plasma after 30 minutes. C_max in plasma is reached after 2 hours. When taken with food, a slight increase in the time to reach C_max to 3-4 hours was observed, but the extent of absorption did not change.

After a single dose, the apparent V_d of pioglitazone is on average 0.63±0.41 l/kg. Binding to human serum proteins, mainly albumin, is more than 99%; binding to other serum proteins is less pronounced. Pioglitazone metabolites M-III and M-IV also bind significantly to serum albumin – more than 98%.

Pioglitazone is intensively metabolized in the liver by hydroxylation and oxidation. Metabolites M-II, M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivatives of pioglitazone) exhibit pharmacological activity in models of type 2 diabetes mellitus in animals. Metabolites are also partially converted to glucuronic or sulfuric acid conjugates.

Metabolism of pioglitazone in the liver occurs with the participation of CYP2C8 and CYP3A4 isoenzymes.

T_1/2 of unchanged pioglitazone is 3-7 hours, total pioglitazone (Pioglitazone and active metabolites) is 16-24 hours. The clearance of pioglitazone is 5-7 l/h.

After oral administration, about 15-30% of the pioglitazone dose is found in the urine. The kidneys excrete an negligible amount of pioglitazone, mainly in the form of metabolites and their conjugates. It is believed that when taken orally, most of the dose is excreted in the bile both unchanged and in the form of metabolites and is eliminated from the body with feces.

The concentrations of pioglitazone and active metabolites in the blood serum remain at a sufficiently high level 24 hours after a single administration of the daily dose.

Indications

Type 2 diabetes mellitus (non-insulin-dependent).

ICD codes

Dosage Regimen

Administer orally once daily, with or without food. The initial dose is 15 mg or 30 mg.

For monotherapy, initiate at 15-30 mg. The maximum recommended daily dose is 45 mg.

When used in combination therapy with metformin, sulfonylureas, or insulin, start at 15-30 mg. Adjust the dose of the concomitant agent if there is a risk of hypoglycemia.

Titrate the dose based on glycemic response and tolerability. Allow several weeks to assess response to a given dose before further titration.

In patients with congestive heart failure (NYHA Class I or II), initiate therapy at the lowest dose, 15 mg. Monitor for signs and symptoms of heart failure.

Do not use in patients with active liver disease or if ALT levels exceed 2.5 times the upper limit of normal.

Monitor liver enzymes prior to initiation, periodically thereafter, and as clinically indicated.

Adverse Reactions

From the side of metabolism development of hypoglycemia (from mild to severe) is possible.

From the hematopoietic system anemia, decrease in hemoglobin and hematocrit are possible.

From the digestive system rarely – increased ALT activity.

Contraindications

Type 1 diabetes mellitus (insulin-dependent), diabetic ketoacidosis, pregnancy, lactation, hypersensitivity to pioglitazone.

Use in Pregnancy and Lactation

Pioglitazone is contraindicated for use during pregnancy and during lactation (breastfeeding).

In patients with insulin resistance and anovulatory cycle in the premenopausal period, treatment with thiazolidinediones, including Pioglitazone, may cause ovulation. This increases the risk of pregnancy if adequate contraceptive measures are not used.

Use in Hepatic Impairment

Pioglitazone should not be used in the presence of clinical manifestations of active liver disease or with an increase in ALT activity 2.5 times above the upper limit of normal (ULN). With moderately elevated liver enzyme activity (ALT less than 2.5 times above ULN) before starting or during treatment with pioglitazone, patients should be examined to determine the cause of the increase in indicators. With a moderate increase in liver enzyme activity, treatment should be started or continued with caution. In this case, more frequent monitoring of the clinical picture and study of the level of liver enzyme activity is recommended.

In case of an increase in serum transaminase activity (ALT >2.5 times above ULN), liver function should be monitored more frequently and until the level returns to normal or to the levels observed before treatment. If ALT activity is 3 times higher than ULN, a repeat test to determine ALT activity should be performed as soon as possible. If ALT activity remains at a level 3 times > ULN, Pioglitazone should be discontinued.

During treatment, if the development of liver dysfunction is suspected (appearance of nausea, vomiting, abdominal pain, fatigue, lack of appetite, dark urine), indicators of liver function tests should be determined. The decision on the continuation of pioglitazone therapy should be made on the basis of clinical data, taking into account laboratory parameters. In case of jaundice, Pioglitazone should be discontinued.

Pediatric Use

The use of pioglitazone in children is not recommended.

Special Precautions

Pioglitazone should not be used in the presence of clinical manifestations of active liver disease or with an increase in ALT activity 2.5 times above the upper limit of normal (ULN). With moderately elevated liver enzyme activity (ALT less than 2.5 times above ULN) before starting or during treatment with pioglitazone, patients should be examined to determine the cause of the increase in indicators. With a moderate increase in liver enzyme activity, treatment should be started or continued with caution. In this case, more frequent monitoring of the clinical picture and study of the level of liver enzyme activity is recommended.

In case of an increase in serum transaminase activity (ALT >2.5 times above ULN), liver function should be monitored more frequently and until the level returns to normal or to the levels observed before treatment. If ALT activity is 3 times higher than ULN, a repeat test to determine ALT activity should be performed as soon as possible. If ALT activity remains at a level 3 times > ULN, Pioglitazone should be discontinued.

During treatment, if the development of liver dysfunction is suspected (appearance of nausea, vomiting, abdominal pain, fatigue, lack of appetite, dark urine), indicators of liver function tests should be determined. The decision on the continuation of pioglitazone therapy should be made on the basis of clinical data, taking into account laboratory parameters. In case of jaundice, Pioglitazone should be discontinued.

Pioglitazone should be used with caution in patients with edema.

The use of pioglitazone in children is not recommended.

Drug Interactions

When another thiazolidinedione derivative was used simultaneously with oral contraceptives, a decrease in the plasma concentration of ethinyl estradiol and norethindrone by approximately 30% was observed. Therefore, with the simultaneous use of pioglitazone and oral contraceptives, a decrease in the effectiveness of contraception is possible.

Ketoconazole inhibits the metabolism of pioglitazone in the liver in vitro.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.