Actos^® (Tablets) Instructions for Use

Marketing Authorization Holder

Eli Lilly and Company (USA)

ATC Code

A10BG03 (Pioglitazone)

Active Substance

Pioglitazone (Rec.INN registered by WHO)

Dosage Forms

	Actos®	Tablets 15 mg: 7 or 30 pcs.
		Tablets 30 mg: 7 or 30 pcs.
		Tablets 45 mg: 7 or 30 pcs.

Dosage Form, Packaging, and Composition

Tablets from white to almost white, round, biconvex, with “15” debossed on one side and “ACTOS” on the other.

Excipients: lactose monohydrate, hydroxypropylcellulose, calcium carboxymethylcellulose, magnesium stearate.

7 pcs. – polyethylene bottles.
30 pcs. – polyethylene bottles.

Tablets from white to almost white, round, flat, with “30” debossed on one side and “ACTOS” on the other.

Excipients: lactose monohydrate, hydroxypropylcellulose, calcium carboxymethylcellulose, magnesium stearate.

7 pcs. – polyethylene bottles.
30 pcs. – polyethylene bottles.

Tablets from white to almost white, round, flat, with “45” debossed on one side and “ACTOS” on the other.

Excipients: lactose monohydrate, hydroxypropylcellulose, calcium carboxymethylcellulose, magnesium stearate.

7 pcs. – polyethylene bottles.
30 pcs. – polyethylene bottles.

Clinical-Pharmacological Group

Oral hypoglycemic drug

Pharmacotherapeutic Group

Oral hypoglycemic agent

Pharmacological Action

An oral hypoglycemic drug of the thiazolidinedione class. The action of pioglitazone depends on the presence of insulin. It is a highly selective agonist of peroxisome proliferator-activated gamma receptors (PPARγ). PPARγ receptors are found in adipose tissue, muscle tissue, and the liver. Activation of nuclear PPARγ receptors modulates the transcription of a number of insulin-sensitive genes involved in blood glucose control and lipid metabolism. Actos^® reduces insulin resistance in peripheral tissues and the liver, resulting in increased insulin-dependent glucose uptake and decreased glucose output from the liver. Unlike sulfonylurea drugs, Pioglitazone does not stimulate insulin secretion by pancreatic beta cells.

In type 2 diabetes mellitus, the reduction in insulin resistance under the action of Actos^® causes a decrease in blood glucose concentration, a decrease in plasma insulin levels, and the HbA_1c (glycated hemoglobin) indicator. In combination with sulfonylureas, metformin, or insulin, the drug improves glycemic control.

In type 2 diabetes mellitus with lipid metabolism disorders, treatment with the drug leads to a decrease in triglyceride levels and an increase in HDL levels. At the same time, LDL and total cholesterol levels in such patients do not change.

Pharmacokinetics

Absorption

After oral administration on an empty stomach, Pioglitazone is detected in blood plasma within 30 minutes. C_max in plasma is reached within 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.

Distribution

After a single dose, the apparent V_d of pioglitazone averages 0.63±0.41 (mean ± SD) L/kg. Pioglitazone is highly bound to human serum proteins (>99%), mainly to albumin; to a lesser extent – to other serum proteins. Pioglitazone metabolites M-III and M-IV are also highly bound to serum albumin (>98%).

Metabolism

In both healthy volunteers and patients with type 2 non-insulin-dependent diabetes mellitus, the C_ss of pioglitazone is about 30-50% of the C_max of total pioglitazone in serum and 20-25% of the AUC.

Pioglitazone is extensively metabolized in the liver through hydroxylation and oxidation reactions to form metabolites M-II, M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglitazone). Metabolites M-III and M-IV are detected after repeated administration of the drug and are the main related compounds of pioglitazone. Metabolites are also partially converted to glucuronic and sulfuric acid conjugates.

The metabolism of pioglitazone in the liver occurs with the participation of the main cytochrome P450 isoenzymes (CYP2C8 and CYP3A4).

In an in vitro study, Pioglitazone did not inhibit the activity of P450 system isoenzymes. Studies of the effect of pioglitazone on the activity of these enzymes in humans have not been conducted.

Excretion

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

After oral administration, about 15-30% of the pioglitazone dose is found in the urine. A negligible amount of unchanged pioglitazone is excreted by the kidneys; it is mainly excreted as metabolites and their conjugates. When taken orally, most of the dose is excreted in the bile, both unchanged and as metabolites, and is eliminated from the body in the feces.

Serum concentrations of total pioglitazone and active metabolites remain at a sufficiently high level 24 hours after a single daily dose.

Indications

Type 2 diabetes mellitus

• For monotherapy or as part of combination therapy with sulfonylureas, metformin or insulin;
• As an adjunct to diet therapy and physical exercise.

ICD codes

Dosage Regimen

The dose is set individually.

Actos^® is prescribed orally once a day, regardless of meals.

For monotherapy in patients whose diabetes compensation is not achieved with diet therapy and physical exercise, Actos^® is prescribed at a dose of 15 mg or 30 mg once a day. If necessary, the dose can be gradually increased to 45 mg/day.

In monotherapy, the maximum dose of Actos^® is 45 mg once a day.

If monotherapy is ineffective, the possibility of combination therapy should be considered.

For combination therapy with sulfonylureas, Actos^® is prescribed at a dose of 15 mg or 30 mg once a day. At the start of treatment with Actos^®, the dose of the sulfonylurea derivative can be left unchanged; if hypoglycemia develops, the dose of the latter must be reduced.

In combination with metformin, Actos^® is prescribed at a dose of 15 mg or 30 mg once a day. At the start of treatment with Actos^®, the dose of metformin can be left unchanged. The risk of hypoglycemia with this combination is low, so the need for metformin dose adjustment is unlikely.

In combination with insulin, Actos^® is prescribed at a dose of 15 mg or 30 mg once a day. At the start of treatment with Actos^®, the insulin dose can be left unchanged. If hypoglycemia develops and plasma glucose levels fall below 100 mg/dL, the insulin dose can be reduced by 10-25%. Further adjustment of the insulin dose should be carried out individually, taking into account the level of glycemia.

For combination therapy, the maximum dose of Actos^® is 30 mg/day.

In patients with renal impairment, no dose adjustment of Actos^® is required.

There are no data on the use of Actos^® in combination with other thiazolidinedione drugs.

Adverse Reactions

Endocrine system: hypoglycemia (2% – in combination with a sulfonylurea drug, 8-15% – in combination with insulin).

Hematopoietic system: 1-1.6% – anemia (with monotherapy and combination therapy); decrease in hemoglobin (2-4%) and hematocrit, which are observed mainly 4-12 weeks after the start of treatment and remain relatively constant (not associated with any clinically significant hematological effects and are most often due to an increase in plasma volume).

Metabolism: edema (4.8% – with monotherapy, 15.3% – in combination with insulin); 5% – weight gain; rarely – increased CPK activity.

Digestive system: about 0.25% – increased ALT activity > 3 times ULN; rarely – hepatitis.

Organ of vision: very rarely – development or progression of diabetic macular edema, accompanied by decreased visual acuity. A direct relationship between the development of macular edema and pioglitazone intake has not been established. Physicians should consider the possibility of macular edema if patients complain of decreased visual acuity.

Cardiovascular system: in US placebo-controlled studies, the incidence of serious cardiovascular side effects associated with increased circulating blood volume did not differ between patients receiving Actos^® alone and Actos^® in combination with sulfonylurea, metformin, or placebo. In a clinical study with simultaneous administration of Actos^® and insulin, cases of congestive heart failure were noted in a small number of patients with a history of heart disease. Patients with heart failure of NYHA functional classes III and IV did not participate in clinical trials of the drug, therefore Actos^® is contraindicated for this group of patients.

According to post-marketing data, cases of congestive heart failure have been reported with the use of Actos^® in patients regardless of a history of pre-existing heart disease.

Contraindications

• Type 1 diabetes mellitus;
• Diabetic ketoacidosis;
• Severe heart failure of NYHA functional class III-IV;
• Pregnancy;
• Lactation (breastfeeding);
• Age under 18 years;
• Hypersensitivity to the components of the drug.

With caution, the drug should be used in patients with edematous syndrome, anemia, hepatic insufficiency (increase in liver enzyme activity 1-2.4 times above ULN), with mild and moderate heart failure.

Use in Pregnancy and Lactation

The use of the drug is contraindicated during pregnancy and lactation (breastfeeding).

Adequate and strictly controlled studies of the safety of Actos^® use during pregnancy have not been conducted.

It is not known whether Pioglitazone is excreted in breast milk, so if it is necessary to use Actos^® during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

The drug should be used with caution in patients with hepatic insufficiency.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

The complex of measures for the treatment of type 2 diabetes mellitus, in addition to taking Actos^®, must include recommended diet therapy and physical exercise. This is important not only at the beginning of therapy for type 2 diabetes mellitus, but also for maintaining the effectiveness of drug therapy.

The effectiveness of treatment with the drug is preferably assessed by the level of HbA_1c, which is the most adequate indicator of glycemic control over a long period of time, compared with determining only fasting glycemia. HbA_1c reflects the level of glycemia over the past 2-3 months. Treatment with Actos^® is recommended for a period sufficient to assess the change in HbA_1c level (3 months), if no deterioration in glycemic control is observed during this time.

In patients with insulin resistance and anovulatory cycle in the premenopausal period, treatment with thiazolidinediones, including Actos^®, may cause ovulation. The consequence of improved insulin sensitivity in these patients is the risk of pregnancy if adequate contraceptive measures are not used.

The drug should be used with caution in patients with edema.

Pioglitazone can cause fluid retention in the body both during monotherapy and in combination with other hypoglycemic drugs, including insulin. Fluid retention in the body can lead to the development or worsening of existing heart failure. It is necessary to monitor for symptoms of heart failure, especially in patients with reduced cardiac reserve. If cardiac function deteriorates, pioglitazone should be discontinued. Cases of heart failure have been described with the use of pioglitazone in combination with insulin.

Since NSAIDs and Pioglitazone cause fluid retention in the body, the combined use of these drugs may increase the risk of edema.

Special caution is required when prescribing the drug to patients with heart disease, including myocardial infarction, angina pectoris, cardiomyopathy, and hypertensive conditions that contribute to the development of heart failure.

Since an increase in circulating blood volume can quickly lead to the development of edematous syndrome and cause or enhance manifestations of heart failure, the following requirements must be observed.

1) Actos^® should not be prescribed to patients with active heart failure or a history of heart failure.

2) Patients taking Actos^® should be carefully monitored. If edema, sudden weight gain, or symptoms of heart failure occur, appropriate measures should be taken, such as discontinuing Actos^®, prescribing “loop” diuretics (including furosemide).

3) The patient should be instructed that if edema, sudden weight gain, or changes in symptoms occur during treatment, they should immediately stop taking the drug and consult a doctor.

Since Actos^® can cause ECG abnormalities and increase the cardio-thoracic ratio, periodic ECG monitoring is necessary. If such disorders develop, the drug regimen should be reviewed; temporary discontinuation or dose reduction of the drug may be required.

In all patients, ALT levels should be determined before starting treatment with Actos^®, and this control should be carried out every 2 months during the first year of treatment and periodically thereafter.

During treatment, if liver dysfunction is suspected (nausea, vomiting, abdominal pain, fatigue, lack of appetite, dark urine), liver function tests should be determined. The decision to continue therapy with Actos^® should be made based on clinical data, taking into account laboratory parameters. If jaundice occurs, treatment with the drug should be discontinued.

The drug should not be prescribed in the presence of clinical manifestations of active liver disease or with an increase in ALT activity 2.5 times above ULN. With moderately elevated liver enzyme activity (ALT < 2.5 times ULN) before starting treatment or during treatment with Actos^®, patients should be examined to determine the cause of the elevated parameters. With moderately elevated liver enzyme activity, treatment with Actos^® should be started or continued with caution. In this case, more frequent monitoring of the clinical picture and testing of liver enzyme activity levels is recommended.

In case of an increase in serum transaminase activity (ALT > 2.5 times ULN) during treatment with Actos^®, 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 ULN, a repeat ALT activity test should be performed as soon as possible. If ALT activity remains at a level 3 times ULN, treatment with Actos^® should be discontinued.

Before starting treatment with Actos^®, during the first year of treatment (every 2 months) and then periodically, ALT activity should be monitored.

In patients receiving ketoconazole simultaneously with Actos^®, blood glucose levels should be monitored regularly.

Overdose

Overdose of Actos^® in monotherapy is not accompanied by specific clinical symptoms.

Overdose of Actos^® in combination with a sulfonylurea drug may be accompanied by symptoms of hypoglycemia.

Treatment: symptomatic therapy depending on clinical manifestations (e.g., treatment of hypoglycemia). There is no specific antidote.

Drug Interactions

In patients taking Actos^® and oral contraceptives, a decrease in contraceptive effectiveness is possible.

No changes in pharmacokinetics and pharmacodynamics were observed with the simultaneous use of Actos^® with glipizide, digoxin, indirect anticoagulants, metformin.

In vitro, ketoconazole inhibits the metabolism of pioglitazone.

Data on the pharmacokinetic interaction of Actos^® with erythromycin, astemizole, calcium channel blockers, cisapride, corticosteroids, cyclosporine, lipid-lowering agents (statins), tacrolimus, triazolam, trimetrexate and itraconazole are not available.

Storage Conditions

List B. The drug should be stored out of the reach of children, in a dry place, protected from light, at a temperature from 15°C (59°F) to 30°C (86°F).

Shelf Life

Shelf life – 3 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.