Diaglitazon^® (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

Hypoglycemic drug for oral administration, a derivative of the thiazolidinedione series. It selectively stimulates gamma receptors activated by peroxisome proliferator (PPARγ). PPARγ receptors are found in tissues that play an important role in the mechanism of insulin action (adipose, skeletal muscle tissue, and liver).

Activation of nuclear PPARγ receptors modulates the transcription of a number of insulin-sensitive genes involved in the control of blood glucose concentration and lipid metabolism. By reducing insulin resistance, it increases the utilization of insulin-dependent glucose and reduces the release of glucose from the liver.

It reduces triglyceride levels, increases HDL and cholesterol concentration. Unlike sulfonylurea derivatives, it does not stimulate insulin secretion.

Pharmacokinetics

Absorption

After oral administration, absorption is high. Pioglitazone is detected in blood plasma after 30 minutes. C_max in blood plasma is reached after 2 hours, after a meal – after 3-4 hours.

Distribution and Metabolism

V_d is 0.22-1.04 L/kg. Plasma protein binding is 99%.

The concentration of total pioglitazone (Pioglitazone with active metabolites) in plasma is achieved after 24 hours with daily single use. C_ss in plasma for both pioglitazone and total pioglitazone is reached after 7 days.

It is intensively metabolized by hydroxylation and oxidation. Metabolites are also partially converted into glucuronide or sulfate conjugates. Metabolites M-II and M-IV (pioglitazone hydroxide derivatives) and M-III (keto-derivatives of pioglitazone) exhibit pharmacological activity. The main cytochrome P450 isoenzymes involved in hepatic metabolism are CYP2C8 and CYP3A4. Metabolism also occurs with the participation of many other isoenzymes, including mainly the extrahepatic isoenzyme CYP1A1.

Excretion

T_1/2 of pioglitazone and total pioglitazone is 3-7 hours and 16-24 hours, respectively.

It is excreted mainly with bile unchanged or in the form of metabolites and is removed with feces; by the kidneys – 15-30% in the form of metabolites and their conjugates.

Indications

Type 2 diabetes mellitus (non-insulin-dependent)

• As monotherapy;
• In combination with sulfonylurea derivatives, metformin or insulin in cases where diet, physical exercise, and monotherapy with one of the above hypoglycemic agents do not achieve adequate glycemic control.

ICD codes

Dosage Regimen

Tablets

Diaglitazon^® is prescribed orally, once a day (regardless of meals).

In monotherapy, the dose is 15-30 mg; the maximum daily dose is 45 mg.

In combination therapy with sulfonylurea derivatives or with metformin, treatment with pioglitazone begins with a dose of 15 mg or 30 mg (if hypoglycemia occurs, the dose of sulfonylurea drugs or metformin is reduced).

When treating in combination with insulin, the initial dose is 15-30 mg/day. The insulin dose is left unchanged or reduced by 10-25% (if the patient reports hypoglycemia, or the plasma glucose concentration decreases to a level below 100 mg/dL).

Adverse Reactions

From the CNS: dizziness, headache, hypoesthesia, insomnia.

From the sensory organs: visual disturbances, which are noted mainly at the beginning of therapy and are associated with changes in plasma glucose levels, as with the use of other hypoglycemic agents.

From the respiratory system: pharyngitis, sinusitis.

From the metabolism: weight gain, increased CPK activity; with long-term use for more than 1 year, edema, mild or moderate and usually not requiring discontinuation of therapy, are observed in 6-9% of cases.

From the endocrine system: hypoglycemia.

From the hematopoietic system: clinically insignificant decrease in hematocrit and hemoglobin, anemia.

From the digestive system: flatulence, increased ALT activity.

From the musculoskeletal system: arthralgia, myalgia.

Other: rarely – heart failure.

Contraindications

• Type 1 diabetes mellitus (insulin-dependent);
• Diabetic ketoacidosis;
• Heart failure of III-IV functional class (according to NYHA classification);
• Severe hepatic insufficiency (increase in liver enzyme activity 2.5 times above ULN);
• Pregnancy;
• Lactation period (breastfeeding);
• Children under 18 years of age (clinical studies of the safety and efficacy of pioglitazone in children have not been conducted);
• Hypersensitivity to the components of the drug.

With caution, the drug should be used in case of edematous syndrome, anemia, heart failure of I-II functional class, impaired liver function (increase in hepatic transaminase activity 1-2.5 times above ULN).

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Contraindication: severe hepatic insufficiency (increase in liver enzyme activity 2.5 times above ULN).

Pediatric Use

Contraindication: children under 18 years of age (clinical studies of the safety and efficacy of pioglitazone in children have not been conducted).

Special Precautions

Patients receiving Pioglitazone in combination with insulin or oral hypoglycemic agents are at risk of developing hypoglycemic conditions. In this case, it may be necessary to reduce the dose of co-administered hypoglycemic drugs.

In female patients with insulin resistance and anovulatory cycle in the premenopausal period, treatment with thiazolidinediones, including Pioglitazone, may cause ovulation. The consequence of improved sensitivity of these patients to insulin is the risk of pregnancy if adequate contraceptive means are not used. If pregnancy occurs or is planned, pioglitazone therapy should be discontinued.

The use of pioglitazone may cause a decrease in hemoglobin and hematocrit levels. These changes may be associated with an increase in plasma volume and are not associated with other significant hematological clinical effects.

In preclinical studies, thiazolidinediones, including Pioglitazone, caused an increase in plasma volume and the development of cardiac muscle hypertrophy (due to preload). In clinical studies that excluded patients with heart failure of III and IV functional class (according to NYHA classification), no increase in the frequency of serious cardiovascular side effects potentially associated with increased plasma volume (e.g., chronic heart failure) was detected.

It is recommended to regularly monitor the activity of liver enzymes in the blood during pioglitazone therapy. ALT levels should be determined in all patients before starting pioglitazone therapy, every 2 months during the first year of treatment, and periodically during subsequent years of drug use. Liver function should also be determined in patients if symptoms suspicious for liver failure symptoms (nausea, vomiting, abdominal pain, weakness, anorexia, dark urine) occur. The decision on the possibility of further use of pioglitazone should be based on laboratory test results. If jaundice develops, the drug should be discontinued.

Pioglitazone therapy should not be initiated in patients with active liver disease, or with ALT levels more than 2.5 times the upper limit of normal. In patients with baseline slight elevation of ALT (1-2.5 times the upper limit of normal) or at any time during pioglitazone therapy, an examination should be performed to identify the causes of increased liver enzyme activity. Initiation or continuation of pioglitazone therapy in patients with a slight increase in liver enzyme activity may be carried out with caution, while liver transaminase activity should be checked more frequently. If an increase in liver transaminase activity occurs (ALT > 2.5 times the upper limit of normal), liver enzyme activity should be determined more frequently until the levels decrease to normal and pre-therapy baseline. If the ALT level is more than 3 times the upper limit of normal, laboratory tests should be performed as soon as possible. If ALT levels remain more than 3 times the upper limit of normal or if the patient develops jaundice, pioglitazone should be discontinued.

Effect on ability to drive vehicles and mechanisms

There are no data on the effect of pioglitazone on the ability to drive vehicles and other mechanisms.

Overdose

Symptoms: overdose of pioglitazone in monotherapy is not accompanied by specific clinical symptoms; overdose of pioglitazone in combination with a sulfonylurea drug may be accompanied by the development of hypoglycemia symptoms.

Treatment: there is no specific treatment for overdose. If necessary, symptomatic therapy is carried out (e.g., treatment of hypoglycemia).

Drug Interactions

Pharmacokinetic studies on the combined use of pioglitazone and oral contraceptives have not been conducted.

The use of other thiazolidinediones in combination with oral contraceptives containing ethinyl estradiol or norethisterone was accompanied by a 30% decrease in the plasma concentration of both hormones, which may lead to a significant decrease in the contraceptive effect.

Therefore, caution should be exercised when using pioglitazone and oral contraceptives concomitantly.

No changes in pharmacokinetics are observed with simultaneous administration with glipizide, digoxin, warfarin, metformin.

In vitro studies have found that ketoconazole significantly inhibits the metabolism of pioglitazone. More careful monitoring of blood glucose levels should be carried out in patients receiving Pioglitazone and ketoconazole simultaneously.

There are no data on the use of pioglitazone in triple combination with other oral hypoglycemic drugs.

Storage Conditions

The drug should be stored out of the reach of children, in a dry, light-protected place at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 2 years.

Dispensing Status

The drug is dispensed by prescription.

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.