RU  UA  EN Home     Contact     Site Map    
     

GLUTAZON tablets


This information is intended for medical professionals only

APPROVED
Order of Ministry of
Healthcare of Ukraine
14.11.11 № 787
Registration certificate
№ UA/11871/01/01
№ UA/11871/01/02
№ UA/11871/01/03

INSTRUCTION
for medical use of drug
 
GLUTAZONE®


 
Composition:
active substance: pioglitazone;
1 tablet contains pioglitazone hydrochloride equivalent to pioglitazone 15 mg or 30 mg, or 45 mg;
excipients: lactose monohydrate, hydroxypropyl cellulose, carboxymethyl cellulose calcium, magnesium stearate.

Pharmaceutical form. Tablets.

Pharmacotherapeutic group.
Antidiabetic drugs. Hypoglycemic drugs, excluding insulins. Thiazolidinediones.
Code АТС А10В G03.

Clinical characteristics.
Indications.
Treatment of II type diabetes mellitus:
as monotherapy
– in patients (especially in obese patients) with contraindications and intolerance to metformin in case of inadequate control or glucose level with diet and exercises;
as double combined therapy with
– metformin in patients (especially in obese patients) with insufficient glycemic control despite using maximum tolerated dose of metformin;
– sulfonylurea derivatives only in patients with contraindications and intolerance to metformin in case of insufficient glycemic control despite using maximum tolerated dose of sulfonylurea derivatives;
as triple combined therapy with
– metformin and sulfonylurea derivatives in patients (especially in obese patients) with insufficient glycemic control despite using double combined therapy.
Glutazone® is also indicated in combination with insulin in patients with II type diabetes mellitus with insufficient glycemic control despite using insulin, who have contraindications or intolerance to metformin.
 
Contraindications.
Hypersensitivity to the active substance or any other component of the drug.
Heart failure (stages I - IV NYHA), severe hepatic dysfunction, diabetic keto-acidosis, diabetes mellitus type I.

Dosage and administration.
Adults take Glutazone® per os 1 time daily regardless of meal. The dose is adjusted individually. The initial dose of pioglitazone is 15 mg or 30 mg; if necessary, it may be increased to 30-45 mg 1 time daily.
Maximum daily dose is 45 mg.
When using combined therapy of pioglitazone and insulin, the dose of insulin either remains unchanged or is decreased if the patient reported hypoglycemia.
Elderly patients.
There is no need for dosage adjustment in elderly patients.
Patients with impaired renal function.
There is no need for dosage adjustment in patients with impaired renal function (creatinine clearance > 4 mL/min). Pioglitazone is not recommended in patients on dialysis.
Patients with impaired hepatic function.
Pioglitazone is not recommended in patients with impaired hepatic function.

Adverse reactions.

The adverse reactions are specified according to the frequency: very common (> 1/10),  common  (> 1/100, < 1/10),  uncommon  (> 1/1000,  < 1/100), rare (> 1/1000, < 1/100), very rare (< 1/10 000), unknown (cannot be estimated from available data).
Pioglitazone monotherapy:
organs of vision: common- visual disturbances;
infections: common – upper respiratory tract infections; uncommon - sinusitis;
nervous system: common – hypoesthesia; uncommon - insomnia;
other: common – weight gain.
Pioglitazone in combination with metformin:
blood system: common – anemia;
organs of vision: common – visual disturbances;
gastrointestinal tract: common – flatulence;
musculoskeletal system: common – arthralgia;
nervous system: common – headache;
urinary system: common – hematuria;
reproductive system: common – erectile dysfunction;
other: common – weight gain.
Pioglitazone in combination with sulfonylurea derivatives:
vestibular apparatus: uncommon - vertigo;
organs of vision: common – visual disturbances;
gastrointestinal tract: common – flatulence;
general disorders: uncommon - fatigue;
metabolic disorders: uncommon – increased appetite, hypoglycemia;
nervous system: common – dizziness; uncommon – headache;
urinary system: common – glycosuria, proteinuria;
skin: uncommon – increased perspiration;
other: common – weight gain; uncommon – increased lactic dehydrogenase.
Pioglitazone in triple combination with metformin and sulfonylurea derivatives:
metabolic disorders: very common – hypoglycemia;
musculoskeletal system: common – arthralgia;
other: common – weight gain, increased plasma level of creatinphosphokinase.
Pioglitazone in combination with insulin:
metabolic disorders: very common – hypoglycemia;
general disorders: very common – edema;
infections: common – bronchitis;
musculoskeletal system: common – arthralgia, back pain;
respiratory system: common – dyspnea;
cardiovascular system: common – heart failure;
other: common – weight gain.

Overdose.

Maximum reported dose of 120 mg daily for 4 days, and then 180 mg daily for 7 days was not associated with any symptoms.
Hypoglycemia may be observed when using a combination of pioglitazone with sulfonylurea derivatives or insulin.
Treatment: symptomatic and supporting therapy.

Pregnancy and lactation.

In the absence of clinical data, pioglitazone is not recommended during pregnancy or breast-feeding.

Children.
There is no data on using pioglitazone in children, therefore, it is not recommended in this population.

Peculiarities of use.
Fluid retention and heart failure.
Pioglitazone may cause fluid retention, which may lead to heart failure. Treatment of patients with at least one risk factor for development of chronic heart failure (e.g. myocardium infarction in anamnesis) should be started with minimum dose followed by its gradual increase. This population of patients should be constantly controlled for signs and symptoms of heart failure, weight gain and edema, especially in patients with reduced diastolic reserve. As insulin and pioglitazone are associated with fluid retention, their co-administration may increase the risk of edema. Patients using this combination should be carefully monitored for signs of heart failure, weight gain and occurrence of edema. In case of any deterioration of cardiac status, pioglitazone should be stopped.
When using pioglitazone in patients over 75 years old, caution should be exercised due to limited experience of use in this age group.
Liver function monitoring.
Before the start of treatment with pioglitazone, liver enzyme activity should be checked in all patients. Pioglitazone is not recommended in patients with clinical manifestations of liver disease in the active phase and with ALT level more than 2.5-fold upper limit of normal. In case of moderate increase of liver enzyme activity, caution should be exercised when starting or continuing treatment with pioglitazone. When receiving pioglitazone therapy, liver enzyme levels should be monitored in patients with hepatic pathology or in case of liver dysfunction symptoms (nausea, anorexia, abdominal pain, fatigue). In case of 3-fold increase of enzyme activity level (ALT) or jaundice, pioglitazone should be stopped.
Weight gain.
There are data on dose-dependent weight gain. Visceral fat had significantly decreased, whereas extra-abdominal fat mass increased. Such changes in distribution of fat mass in the body when receiving pioglitazone were accompanied by improvements in insulin sensitivity. In some cases, weight gain may be associated with fluid retention, and may be a symptom of heart failure, therefore, body weight should be controlled. The patients are recommended to strictly control caloric content of food.

Hematology.
During treatment with pioglitazone, slight decrease was observed in hemoglobin level (relative decrease 4%) and hematocrit (relative decrease 4.1%) due to increased volume of blood plasma. Similar changes were observed for metformin (relative decrease of hemoglobin was 3-4%, hematocrit 3.6-4.1%) and to a lesser extent for drugs sulfonylurea group (relative reduction of hemoglobin - 1-2% hematocrit - 1-3.2%).
Hypoglycemia.
As a result of increased tissue sensitivity to insulin, patients receiving pioglitazone as double or triple therapy with sulfonylurea derivatives and insulin, may be at increased risk of hypoglycemia. In case of risk or hypoglycemia, dose reduction may be required for sulfonylurea derivatives or insulin.
Organs of vision.
Macular edema may occur in case of visual impairment. In such case, consultation of ophthalmologist is necessary.
Other.
There is risk of fractures in women treated with pioglitazone, which has to be taken into account.
Due to increased tissue sensitivity to insulin, pioglitazone treatment in women with polycystic ovaries may result in reinitiation of ovulation. Such patients risk to get pregnant. The patients should be warned about the possibility of pregnancy. If pregnancy has already occurred, pioglitazone should be stopped.
Glutazone® contains lactose monohydrate; therefore it should not be prescribed in patients with such rare hereditary diseases as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome.

Effects on ability to drive and operate machinery.
The drug therapy may cause adverse effects which affect the ability to drive and operate other mechanisms.

Drug interactions and other kinds of interactions.
Interaction studies have shown that pioglitazone has no relevant effect on either the pharmacokinetics or pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin. Co-administration pioglitazone with sulfonylurea derivatives does not appear to affect the pharmacokinetics of these drugs. Studies in humans suggest no induction of the main inducible cytochrome P450, 1A, 2C8/9 and 3A4. Therefore, interactions with substances metabolized by these enzymes, e.g. oral contraceptives, cyclosporin, calcium channel blockers, and HMGCoA reductase inhibitors are not to be expected.
Co-administration of pioglitazone with gemfibrozil (an inhibitor of cytochrome P450 2C8) is reported to result in a 3-fold increase in area under the curve “concentration-time” (AUC) of pioglitazone. Since there is a potential for an increase in dose-related adverse events, a decrease in the dose of pioglitazone may be needed when gemfibrozil is concomitantly administered. Co-administration of pioglitazone with rifampicin (an inducer of cytochrome P450 2C8) is reported to result in a 54% decrease in AUC of pioglitazone. The pioglitazone dose may need to be increased when rifampicin is concomitantly administered. Close monitoring of glycaemic control should be considered.

Pharmacological properties.
Pharmacodynamics. Glutazone® is an oral hypoglycemic agent, which belongs to the class of thiazolidinediones. The effect of pioglitazone depends on the effect of insulin. Highly selective agonist of peroxisome proliferator-activated receptors-γ (PPAR-γ). PPAR-γ are detected in adipose tissue, muscle tissue and liver. Activation of nuclear PPAR-γ modulates the transcription of genes, sensitive to insulin, which are involved in controlling glucose and lipid metabolism. Glutazone® decreases insulin resistance in peripheral tissues and liver, which results in increased consumption of insulin dependent glucose and decreased release of glucose from the liver. Unlike sulfonylurea derivatives, pioglitazone does not stimulate insulin secretion of β-cells of the pancreas.
In type II diabetes mellitus, decrease of insulin resistance promoted by pioglitazone results in decreased blood glucose level, decreased plasma insulin level and     hemoglobin A1C (glycated hemoglobin, HbА1С). The drug used in combination with sulfonylurea derivatives, metformin or insulin improves glycemic control.
In patients with lipid metabolism disorders the application of pioglitazone, which also stimulates PPAR-α, results in activation of catabolism of inflammatory mediators, decrease in thickness of artery walls due to elimination of inflammatory and proliferative processes, decrease in plasma fibrinogen level and triglycerides level, and increase in HDL (high density lipoproteins) level, along with this, the level of LDL (low density lipoproteins) remains unaltered.
Pharmacokinetics.
Absorption. After oral administration, pioglitazone is rapidly absorbed; maximum plasma concentration of unchanged pioglitazone is usually achieved within 2 hours after ingestion. Proportional increase in plasma concentrations was observed for doses from 2 to 60 mg. Stable condition is achieved within 4-7 days of drug therapy. Multiple use does not result in accumulation of the drug or its metabolites. Food does not affect absorption of the drug. Absolute bioavailability of pioglitazone is > 80%.
Distribution. Estimated volume of distribution in humans is 1.25 L/kg. pioglitazone and all its active metabolites are extensively bound to plasma proteins (>99%).
Metabolism. Pioglitazone undergoes extensive hepatic metabolism by hydroxylation of aliphatic methylene groups. This usually involves cytochrome P450 2C8, tough other isoenzymes may also participate to a lesser extent. 3 of 6 identified metabolites are active (M-II, M-III and M-IV). Taking into account activity, concentration and protein binding, pioglitazone and its metabolite M-III have equal effect on efficacy. On this basis M-IV contribution to efficacy is approximately three-fold that of pioglitazone, whilst the relative efficacy of M-II is minimal.
In vitro studies have shown no evidence that pioglitazone inhibits any subtype of cytochrome P450. There is no induction of the main inducible P450 isoenzymes 1A, 2C8/9, and 3A4 in humans.
Elimination. 55% of pioglitazone is excreted in feces, and 45% in urine. Mean half-life of unchanged pioglitazone is 5-6 hours, and 16-23 hours for all its active metabolites. 
Elderly patients. Pharmacokinetic parameters are similar in patients aged ≥65 and in younger subjects.
Patients with impaired renal function. In patients with renal impairment, the concentration of pioglitazone and its active metabolites in plasma is lower than in patients with normal renal function, but clearance of parent compound is similar. Thus, concentration of free (unbound) pioglitazone remains unchanged.
Patients with impaired hepatic function. Total plasma concentration of pioglitazone is unchanged, but with an increased volume of distribution, clearance is reduced, coupled with a higher unbound fraction of pioglitazone.

Pharmaceutical characteristics.
Main physico-chemical properties:
tablets 15 mg: white, round flat tablets with “K” embossed «К» on one side and smooth on the other;
tablets 30 mg: white, round biconvex tablets, smooth on both sides;
tablets 45 mg: white, round biconvex tablets, smooth on both sides.

Shelf life. 3 years.

Storage conditions.

Store at ≤ 25 °С in a dry place. Protect from sunlight.
Keep out of reach of children.

Package.
14 tablets in a blister; 2 blisters in a carton.
10 tablets in a blister; 3 blisters in a carton.

Conditions of supply. On prescription.

Manufacturer. 
LLC “KUSUM PHARM”.

Address.
54 Skriabina St., Sumy 40030, Ukraine

Last revision date.

Information given on this site should not be used for self-diagnosis and treatment and can't be a replacement of doctor's advice.