Piouno (Tablets) Instructions for Use

Marketing Authorization Holder

Wockhardt Ltd. (India)

ATC Code

A10BG03 (Pioglitazone)

Active Substance

Pioglitazone (Rec.INN registered by WHO)

Dosage Forms

	Piouno	Tablets 15 mg: 30 pcs.
		Tablets 30 mg: 30 pcs.
		Tablets 45 mg: 30 pcs.

Dosage Form, Packaging, and Composition

15 pcs. – blister packs (2) – cardboard packs.

15 pcs. – blister packs (2) – cardboard packs.

15 pcs. – blister packs (2) – cardboard packs.

Clinical-Pharmacological Group

Oral hypoglycemic drug

Pharmacotherapeutic Group

Oral hypoglycemic agent

Pharmacological Action

Pioglitazone is a hypoglycemic agent of the thiazolidinedione class for oral administration.

Pioglitazone stimulates specific nuclear gamma receptors activated by peroxisome proliferator (PPARγ). It modulates the transcription of insulin-sensitive genes involved in the control of blood glucose concentration and lipid metabolism in adipose, muscle tissues and liver. Unlike sulfonylurea derivatives, Pioglitazone does not stimulate insulin secretion, but is active only when the insulin-synthetic function of the pancreas is preserved. Pioglitazone reduces insulin resistance of peripheral tissues and liver, increases the utilization of insulin-dependent glucose and reduces glucose release from the liver; reduces the concentration of glucose, insulin and glycosylated hemoglobin. During therapy with pioglitazone, the concentration of triglycerides and free fatty acids in blood plasma decreases, and the concentration of high-density lipoproteins increases.

For patients with type 2 diabetes, blood glucose control improves both fasting and after meals.

Pharmacokinetics

Absorption

Pioglitazone is rapidly absorbed, C_max of pioglitazone in blood plasma is usually reached 2 hours after oral administration. Within the range of therapeutic doses, plasma concentrations increase proportionally with increasing dose. With repeated administration, accumulation of pioglitazone and its metabolites does not occur. Food intake does not affect absorption. Bioavailability is over 80%.

Distribution

V_d is 0.25 l/kg of body weight and is achieved after 4-7 days of therapy. Binding to plasma proteins is more than 99% for pioglitazone and more than 98% for its metabolites.

Metabolism

Pioglitazone is metabolized by hydroxylation and oxidation. This process occurs primarily with the participation of cytochrome P450 isoenzymes (CYP2C8 and CYP3A4), and to a somewhat lesser extent, other isoenzymes. 3 of the 6 identified metabolites (M) exhibit pharmacological activity (M-II, M-III, M-IV). Taking into account pharmacological activity, concentrations and degree of binding to plasma proteins, Pioglitazone and metabolite M-III equally determine the overall activity, the contribution of metabolite M-IV to the overall activity of the drug is approximately 3 times greater than the contribution of pioglitazone, and the relative activity of metabolite M-II is minimal.

Results of in vitro studies have shown that Pioglitazone does not inhibit CYP1A, CYP2C8/9, CYP3A4 isoenzymes.

Excretion

It is excreted mainly through the intestines, as well as by the kidneys (15-30%) in the form of metabolites and their conjugates. T_1/2 of unchanged pioglitazone from blood plasma averages 3-7 hours, and for all active metabolites 16-24 hours.

The concentration of pioglitazone and active metabolites in blood plasma remains at a sufficiently high level for 24 hours after a single administration of the daily dose.

Pharmacokinetics in special clinical cases

No dose adjustment is required for elderly patients and/or in case of renal impairment.

In case of impaired liver function, the fraction of free pioglitazone is higher.

Indications

Type 2 diabetes mellitus:

• In monotherapy in overweight patients with ineffective diet and physical exercise, with intolerance to metformin or presence of contraindications to its use;
• As part of combination therapy

1. with metformin in overweight patients in the absence of adequate glycemic control during metformin monotherapy;

2. with sulfonylurea derivatives only in patients for whom metformin is contraindicated, in the absence of adequate glycemic control during sulfonylurea derivative monotherapy.

3. with insulin in the absence of adequate glycemic control during insulin therapy in patients for whom metformin is contraindicated.

ICD codes

Dosage Regimen

Orally, 1 time/day regardless of meals.

Recommended initial doses are 15 or 30 mg 1 time/day. The maximum daily dose for monotherapy is 45 mg, for combination therapy – 30 mg.

When prescribing pioglitazone in combination with metformin, metformin can be continued at the same dose.

In combination with sulfonylurea derivatives: at the beginning of treatment, their administration can be continued at the same dose. If hypoglycemia develops, it is recommended to reduce the dose of the sulfonylurea derivative.

In combination with insulin: the initial dose of pioglitazone is 15-30 mg/day, the insulin dose remains the same or is reduced by 10-25% if hypoglycemia occurs.

For elderly patients, no dose adjustment is required.

For patients with impaired renal function (creatinine clearance more than 4 ml/min), no dose adjustment is required. There are no data on the use of pioglitazone in patients undergoing hemodialysis. Therefore, Pioglitazone should not be used in this group of patients.

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

There are no data on the use of pioglitazone in patients under 18 years of age, therefore the use of pioglitazone in this age group is not recommended.

Adverse Reactions

Frequency: very common – more than 1/10, common – more than 1/100 and less than 1/10, uncommon – more than 1/1000 and less than 1/100, rare – more than 1/10,000 and less than 1/1000, very rare – less than 1/10,000, including isolated reports.

Pioglitazone monotherapy

From the sensory organs common – visual impairment.

From the respiratory system common – upper respiratory tract infections; uncommon – sinusitis.

From the metabolism common – weight gain.

From the nervous system common – hypoesthesia; uncommon – insomnia.

Combination of pioglitazone with metformin

From the hematopoietic organs common – anemia.

From the sensory organs : common – visual impairment.

From the digestive system uncommon – flatulence.

From the metabolism common – weight gain.

From the musculoskeletal system common – arthralgia.

From the nervous system common – headache.

From the genitourinary system : common – hematuria, erectile dysfunction.

Combination of pioglitazone with sulfonylurea derivatives

From the sensory organs uncommon – vertigo, visual impairment.

From the digestive system common – flatulence.

Other uncommon – fatigue.

From the metabolism common – weight gain; uncommon – increased LDH activity, increased appetite, hypoglycemia.

From the nervous system common – dizziness; uncommon – headache.

From the genitourinary system uncommon – glucosuria, proteinuria.

From the skin uncommon – increased sweating.

Combination of pioglitazone with metformin and sulfonylurea derivatives

From the metabolism very common – hypoglycemia; common – weight gain, increased creatine phosphokinase (CPK) activity.

From the musculoskeletal system common – arthralgia.

Combination of pioglitazone with insulin

From the metabolism common – hypoglycemia.

From the musculoskeletal system common – back pain, arthralgia.

From the respiratory system common – dyspnea, bronchitis.

From the cardiovascular system common – heart failure.

Other very common – edema.

Post-marketing experience

From the sensory organs frequency unknown – macular edema, bone fractures.

With long-term use of pioglitazone for more than 1 year, edema is observed in 6-9% of patients, mild or moderate and usually not requiring discontinuation of therapy.

Visual disturbances occur mainly at the beginning of therapy and are associated with changes in blood plasma glucose concentration, as with the use of other hypoglycemic agents.

Contraindications

• Type 1 diabetes mellitus;
• Diabetic ketoacidosis;
• Heart failure, including in history (NYHA class I-IV);
• Hepatic insufficiency (increase in liver enzyme activity 2.5 times above the upper limit of normal);
• Chronic renal failure (creatinine clearance less than 4 ml/min);
• Lactase deficiency, lactose intolerance, glucose-galactose malabsorption;
• Pregnancy;
• Lactation period;
• Children under 18 years of age (clinical studies of the safety and efficacy of pioglitazone in children have not been conducted);
• Hypersensitivity to pioglitazone or other components of the drug.

With caution – edematous syndrome, anemia.

Use during pregnancy and lactation. The efficacy and safety of pioglitazone in pregnant women has not been studied, so the use of the drug during pregnancy is contraindicated. It has been proven that Pioglitazone slows fetal growth. It is not known whether Pioglitazone is excreted in breast milk, so the drug should not be taken by women during lactation. If it is necessary to prescribe the drug during lactation, breastfeeding should be discontinued.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

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

Contraindicated

• Hepatic insufficiency (increase in liver enzyme activity 2.5 times above the upper limit of normal).

Use in Renal Impairment

For patients with impaired renal function (creatinine clearance more than 4 ml/min), no dose adjustment is required. There are no data on the use of pioglitazone in patients undergoing hemodialysis. Therefore, Pioglitazone should not be used in this group of patients.

Contraindicated

• Chronic renal failure (creatinine clearance less than 4 ml/min).

Pediatric Use

There are no data on the use of pioglitazone in patients under 18 years of age, therefore the use of pioglitazone in this age group is not recommended.

Geriatric Use

For elderly patients, no dose adjustment is required.

Special Precautions

When conducting therapy for type 2 diabetes, in addition to taking pioglitazone, it is recommended to follow a diet and perform physical exercises to maintain the effectiveness of drug therapy, as well as due to possible weight gain.

During the use of pioglitazone, fluid retention and an increase in plasma volume are possible, which can lead to the development or worsening of heart failure, therefore, if the condition of the cardiovascular system worsens, pioglitazone should be discontinued.

In patients who have at least one risk factor for the development of chronic heart failure (CHF), treatment should be started with a minimum dose and gradually increased. It is necessary to timely identify the initial symptoms of CHF, weight gain (may indicate the development of CHF) or the development of edema, especially in patients with reduced cardiac output. If CHF develops, the drug should be discontinued immediately.

Pioglitazone may cause impaired liver function. Before starting treatment and periodically during therapy, liver enzyme activity should be examined. If ALT activity exceeds 2.5 times the upper limit of normal, or if there are other symptoms of liver failure, the use of pioglitazone is contraindicated. If in 2 consecutive studies ALT activity exceeds the upper limit of normal by 3 times or the patient develops jaundice, treatment with pioglitazone should be stopped immediately. If the patient develops symptoms suggesting impaired liver function (unexplained nausea, vomiting, abdominal pain, weakness, anorexia, dark urine), liver enzyme activity should be examined immediately.

Pioglitazone may cause a decrease in hemoglobin or hematocrit by 4% and 4.1%, respectively, which may be a consequence of hemodilution (due to fluid retention).

Pioglitazone increases tissue sensitivity to insulin, which increases the risk of hypoglycemia in patients receiving combination therapy containing sulfonylurea derivatives or insulin. A reduction in the dose of the latter may be required.

Pioglitazone may cause or worsen macular edema, which may lead to decreased visual acuity.

Pioglitazone may increase the frequency of fractures in women.

In women with polycystic ovary syndrome, increased sensitivity to insulin may lead to resumption of ovulation and possible pregnancy. Women with polycystic ovary syndrome who do not wish to become pregnant should use reliable methods of contraception. If pregnancy occurs, treatment should be discontinued immediately.

Effect on ability to drive vehicles and operate machinery

Considering the side effects of the drug, caution should be exercised when driving vehicles and working with mechanisms requiring concentration.

Overdose

Symptoms hypoglycemia is possible when taking pioglitazone in combination with sulfonylurea derivatives and insulin.

Treatment symptomatic therapy.

Drug Interactions

When using pioglitazone in combination with other oral hypoglycemic drugs, hypoglycemia may develop. In this case, it may be necessary to reduce the dose of another oral hypoglycemic drug.

During combined use of pioglitazone with insulin, heart failure may develop.

Pioglitazone does not affect the pharmacokinetics and pharmacodynamics of glipizide, digoxin, warfarin, metformin.

Gemfibrozil increases the AUC value of pioglitazone by 3 times.

Rifampicin accelerates the metabolism of pioglitazone by 54%.

In vitro ketoconazole inhibits the metabolism of pioglitazone.

Storage Conditions

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

Shelf Life

Shelf life – 3 years. Do not use after the expiration date.

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.