Amalvia (Tablets) Instructions for Use

Marketing Authorization Holder

Pliva Hrvatska, d.o.o. (Croatia)

ATC Code

A10BG03 (Pioglitazone)

Active Substance

Pioglitazone (Rec.INN registered by WHO)

Dosage Forms

	Amalvia	Tablets 15 mg: 30 pcs.
		Tablets 30 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Tablets are light pink in color, round, biconvex, with an engraving “PG” on one side and “15” on the other; marbling is allowed.

Excipients: microcrystalline cellulose, crospovidone, polysorbate 80, hypromellose, magnesium stearate, colloidal silicon dioxide, red iron oxide dye.

10 pcs. – blisters (3) – cardboard packs.

Tablets are light pink in color, round, biconvex, with an engraving “PG” on one side and “30” on the other; marbling is allowed.

Excipients: microcrystalline cellulose, crospovidone, polysorbate 80, hypromellose, magnesium stearate, colloidal silicon dioxide, red iron oxide dye.

10 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Oral hypoglycemic drug

Pharmacotherapeutic Group

Oral hypoglycemic agent

Pharmacological Action

Pioglitazone is a hypoglycemic drug 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 the 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 the 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 level of triglycerides and free fatty acids in the blood plasma decreases, and the level 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. The 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.

Steady-state concentration is achieved 4-7 days after the start of therapy. With repeated administration, accumulation of the drug and its metabolites does not occur. Food intake does not affect absorption. Bioavailability is over 80%.

Distribution

The V_d averages 0.63 L/kg of body weight. Plasma protein binding of pioglitazone is more than 99%, and that of its metabolites is more than 98%.

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 exhibit pharmacological activity (M-II, M-III, M-IV). Taking into account pharmacological activity, concentrations and the degree of plasma protein binding, Pioglitazone and metabolite M-III equally determine the overall efficacy, the contribution of metabolite M-IV to the overall efficacy of the drug is approximately 3 times greater than the contribution of pioglitazone, and the relative efficacy of metabolite M-II is minimal.

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

Excretion

It is excreted primarily through the intestines, as well as by the kidneys (15-30%) in the form of metabolites and their conjugates. The 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 the 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 impaired renal function.

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

Indications

Type 2 diabetes mellitus in monotherapy

• In patients with excess body weight when diet and physical exercise are ineffective, as well as in case of metformin intolerance or contraindications to its use;

Type 2 diabetes mellitus as part of combination therapy

• With metformin in patients with excess body weight in the absence of adequate glycemic control during metformin monotherapy;
• With sulfonylurea derivatives only for patients for whom metformin is contraindicated, in the absence of adequate glycemic control during sulfonylurea derivative monotherapy;
• With metformin and sulfonylurea derivatives in the absence of adequate glycemic control during combination therapy of pioglitazone with one of the above hypoglycemic agents.

Pioglitazone is indicated in combination with insulin for the treatment of type 2 diabetes mellitus in patients in the absence of adequate glycemic control during insulin therapy and for whom metformin is contraindicated.

ICD codes

Dosage Regimen

Orally, once a day, regardless of meals.

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

When prescribing pioglitazonein combination with metformin, metformin can be continued at the same dose. The risk of hypoglycemia with this combination is low, so dose adjustment of metformin is unlikely to be necessary.

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

When prescribing pioglitazonein 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 greater than 4 ml/min), no dose adjustment is required.

Pioglitazone should not be used in patients with severe hepatic impairment.

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

The frequency of adverse effects is classified as follows: very common (≥10%); common (≥1% and < 10%); uncommon (≥0.1% and <1%); rare (≥0.01% and <0.1%); very rare (<0.01%, including isolated cases).

Pioglitazone monotherapy

Nervous system disorders: common – hypoesthesia; uncommon – insomnia.

General disorders: common – weight gain.

Infections and infestations: common – upper respiratory tract infections; uncommon – sinusitis.

Eye disorders: common – visual disturbances.

Pioglitazone in combination with metformin

Blood and lymphatic system disorders: common – anemia.

Eye disorders: common – visual disturbances.

Gastrointestinal disorders: uncommon – flatulence.

General disorders: common – weight gain.

Musculoskeletal and connective tissue disorders: common – arthralgia, myalgia.

Nervous system disorders: common – headache.

Renal and urinary disorders: common – hematuria.

Reproductive system and breast disorders: common – erectile dysfunction.

Pioglitazone in combination with sulfonylurea derivatives

Ear and labyrinth disorders: uncommon – dizziness.

Eye disorders: uncommon – visual disturbances.

Gastrointestinal disorders: common – flatulence.

General disorders: common – weight gain; uncommon – asthenia.

Investigations: increased plasma LDH activity.

Metabolism and nutrition disorders: uncommon – increased appetite, hypoglycemia.

Nervous system disorders: common – dizziness; uncommon – headache.

Renal and urinary disorders: uncommon – glucosuria, proteinuria.

Skin and subcutaneous tissue disorders: uncommon – hyperhidrosis.

Pioglitazone in combination with metformin and sulfonylurea derivatives

Investigations: increased ALT activity, CPK activity, decreased hematocrit and hemoglobin.

Metabolism and nutrition disorders: very common – hypoglycemia.

Musculoskeletal and connective tissue disorders: common – arthralgia, myalgia.

Pioglitazone in combination with insulin

Metabolism and nutrition disorders: common – hypoglycemia.

General disorders: very common – edema; common – weight gain.

Infections and infestations: common – bronchitis.

Musculoskeletal and connective tissue disorders: common – back pain, arthralgia.

Respiratory, thoracic and mediastinal disorders: common – dyspnea.

Cardiac disorders: common – heart failure.

With long-term use of pioglitazone for more than 1 year, edema is observed in 6-9% of cases, 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;
• Severe heart failure, including in the anamnesis (NYHA class III and IV);
• Hepatic failure (transaminase activity increased 2.5 times above the upper limit of normal);
• 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 pioglitazone or other components of the drug;

Due to the lack of data on the use of pioglitazone in patients with renal failure undergoing hemodialysis treatment, it should not be used in this group of patients.

The drug should be used with caution in edematous syndrome, anemia, heart failure (NYHA class I and II), impaired liver function.

Use in Pregnancy and Lactation

The efficacy and safety of pioglitazone during pregnancy have not been studied, so the use of the drug in pregnant women 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 breastfeeding. If it is necessary to prescribe the drug during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Contraindicated: hepatic failure (transaminase activity increased 2.5 times above the upper limit of normal).

Use in Renal Impairment

Due to the lack of data on the use of pioglitazone in patients with renal failure undergoing hemodialysis treatment, it should not be used in this group of patients.

Pediatric Use

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

Geriatric Use

For elderly patients, no dose adjustment is required.

Special Precautions

When treating type 2 diabetes mellitus, 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 cause the development of heart failure, therefore, if the condition of the cardiovascular system worsens, pioglitazone should be discontinued.

Before starting and during therapy with pioglitazone, it is recommended to monitor transaminase activity every 2 months during the first 12 months of administration, and then periodically. If ALT activity increases more than 2.5 times the upper limit of normal, or if there are other indicators of impaired liver function/liver disease, therapy with pioglitazone should not be started.

If during therapy with pioglitazone the serum ALT activity increases more than 3 times the upper limit of normal, the transaminase activity in the serum should be re-analyzed as soon as possible and if the indicator is confirmed, Pioglitazone should be discontinued. If symptoms suggesting impaired liver function develop (unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine), the possibility of continuing therapy should be discussed with a doctor depending on laboratory parameters. If jaundice develops, pioglitazone therapy should be discontinued.

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

Effect on ability to drive vehicles and operate machinery

There are no data on the effect of pioglitazone on the ability to drive vehicles or operate other machinery.

Overdose

Overdose of pioglitazone in monotherapy is not accompanied by the occurrence of specific clinical symptoms. Hypoglycemia is possible when taking pioglitazone in combination with sulfonylurea derivatives and insulin.

Treatment: symptomatic therapy is carried out.

Drug Interactions

When using pioglitazone in combination with oral hypoglycemic drugs, hypoglycemia may develop. In this case, a reduction in the dose of the concomitant drug may be required.

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.

When used concomitantly with oral contraceptives containing ethinyl estradiol and/or norethisterone, a decrease in the effectiveness of the latter is possible.

Storage Conditions

The drug should be stored out of the reach of children 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.