Pioglitazone is indicated for the treatment of patients with type 2 diabetes

In monotherapy

- in adults, particularly overweight, inadequately controlled by diet or exercise and in whom metformin is contraindicated or not, tolerated. Br>
In combination with orally in association with

- metformin in adults, in particular overweight, when a maximum tolerated dose of oral metformin monotherapy is insufficient to obtain adequate glycemic control
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- sulfonamide, hypoglycaemic, only in adults, intolerant to metformin or for which metformin is contraindicated, where a maximum tolerated dose of oral monotherapy with sulphonylurea hypoglycemic agent does not allow control Sufficient glycemic control.

In triple association, oral with

- metformin and a hypoglycemic sulphonylurea in adults, in particular overweight, in which the combinations in dual therapy do not permit sufficient glycemic control.
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Pioglitazone is also indicated in combination with insulin, in adults with type 2 diabetes insufficiently controlled by insulin and in whom metformin is contraindicated or poorly tolerated (see section 4. Warnings and Precautions; Of employment)

Dosage

Treatment with pioglitazone may be initiated at a dose of 15 mg or 30 mg in a single daily dose. The dose may be increased progressively up to the dose of 45 mg in a single daily dose.

In combination with insulin, the dose of insulin may be maintained upon initiation of treatment with pioglitazone. In case of hypoglycemia, the dose of insulin should be decreased.
Population, special

Subject: aged

No dosage adjustment is necessary in the elderly (see section Pharmacokinetic properties)

Insufficient, renal

No dose adjustment is required in patients with renal insufficiency (creatinine clearance> 4 ml / min) (see section Properties, Pharmacokinetics). Pioglitazone should not be administered to patients on dialysis because no information is available in this population

Insufficient liver disease

Pioglitazone should not be used in patients with hepatic impairment (see paragraphs, Contraindications and Warnings and Precautions for Use)

Population, pediatric

The safety and effectiveness of Actos in children and adolescents under 18 years of age have not been established. No data is available

Administration mode

Pioglitazone is administered orally in one dose per day, during or outside meals. The tablets should be swallowed with a glass of water.
The tablets are white to white, broken, round, flat and marked '30' on one side and 'ACTOS' on the other side.
Pharmacotherapeutic group: medicines, antidiabetics, hypoglycaemic agents, insulin

ATC code A10BG03.

Pioglitazone acts, probably via the reduction of insulin resistance. Pioglitazone is a selective agonist of PPAR-γ (peroxisomal proliferator activated receptor gamma receptors or gamma peroxisome-activating receptors) that induce increased sensitivity to insulin in the liver, Adipose tissue, and skeletal muscle. A decrease in hepatic production of glucose and an increased use of glucose peripheral insulin resistance were also observed

The control of fasting and postprandial glucose is improved in patients with type 2 diabetes and is associated with decreased plasma, fasting and postprandial insulin concentrations. A clinical study evaluating pioglitazone vs gliclazide monotherapy was extended to two years to evaluate the onset of treatment failure (defined as the onset of an HbA1c ≥8.0% after The first six months of treatment). The Kaplan-Meier analysis showed a shorter delay in the occurrence of treatment failure, in patients treated with gliclazide, compared to pioglitazone. At 2 years, glycemic control (defined as HbA1c
The effects of pioglitazone (45 mg monotherapy versus placebo) were studied in an 18-week trial in patients with type 2 diabetes. Significant weight gain was observed under pioglitazone. A significant decrease in abdominal fat was observed at the same time as an increase in subcutaneous fat. Similar changes in the body fat distribution observed under pioglitazone were accompanied by an improvement in insulin sensitivity. A decrease in plasma triglycerides and circulating free fatty acids as well as an increase in HDL-cholesterol were observed in most clinical trials as compared to placebo with a slight but not clinically significant increase in LDL-cholesterol.

In clinical trials up to two years of age, pioglitazone reduced plasma triglycerides, total plasma, free fatty acids, and increased, compared to placebo, metformin, or gliclazide; Rate of HDL-Cholesterol. Pioglitazone did not result in a statistically significant increase in LDL cholesterol compared to placebo, while reductions were observed with metformin and gliclazide. In a 20-week study, pioglitazone reduced postprandial hypertriglyceridemia, as well as fasting triglycerides, by an effect on the triglycerides absorbed and those synthesized by the liver. These effects were independent of the effects of pioglitazone on blood glucose and had a statistically significant difference from glibenclamide
In PROACTIVE, cardiovascular morbidity and mortality study, 5238 patients with type 2 diabetes with pre-existing major vascular involvement received randomized pioglitazone or placebo in combination with their pre-existing cardiovascular and antidiabetic treatments for Up to 3.5 years. The average age of the population studied was 62 years and the average age of diabetes was 9.5 years. Approximately one-third of patients received insulin in combination with metformin and / or a sulphonylurea, hypoglycemic.
To be included in the study, patients had one or more of the following histories: myocardial infarction, stroke, transcutaneous coronary artery bypass surgery, coronary artery bypass surgery, acute coronary syndrome, coronary artery disease, arterial disease obstructive device . Approximately 50% of patients had a history of myocardial infarction and 20% had stroke. Approximately 50% of the population studied had at least two of the cardiovascular histories selected as inclusion criteria. Almost all patients (95%) were receiving cardiovascular drugs (beta-blockers, ACE inhibitors, angiotensin II antagonists, calcium channel blockers, derivatives, nitrates, diuretics, aspirin, statins, fibrates). >

Although the study did not achieve its main objective, which was a composite criterion including all causes of mortality, non-fatal myocardial infarction, accident, cerebral vascular disease, acute coronary syndrome, major limb amputation, revascularization Coronary heart and revascularization of the leg, the results suggest that there is no cardiovascular risk related to the long-term use of pioglitazone. However, the incidence of edema, weight gain, and heart failure were increased. There was no observed increase in mortality from cardiac insufficiency.
Population, pediatric

The European Medicines Agency has granted a derogation to the obligation to submit the results of studies carried out with Actos in all subgroups of the pediatric population in type 2 diabetes. Mode of administration for information about use pediatric.

Actos has no or negligible effect on the ability to drive and use machines. However, patients with visual disturbances should be cautious when driving vehicles or when using machines

Pioglitazone is contraindicated in patients with

- hypersensitivity to the active substance or to any of the excipients

- heart failure or a history of heart failure (NYHA, stages I to IV)

- hepatic insufficiency

- ketoacidosis, diabetic.

Water retention and heart failure

Pioglitazone may cause fluid retention that may aggravate or accelerate the progression to cardiac insufficiency. In patients with at least one factor, risk of developing heart failure (eg, history of myocardial infarction, coronary disease, symptomatic), doctors should initiate pioglitazone at the lowest dose available, Increase, gradually

Signs and symptoms of heart failure, weight gain or edema should be investigated, especially in patients with reduced cardiac reserve. Heart failure was observed after marketing, when insulin was associated with pioglitazone, in patients with a history of heart failure. When pioglitazone is used in combination with insulin, the onset of signs or symptoms of heart failure, weight gain and edema should be monitored. Because insulin and pioglitazone are associated with fluid retention, concomitant administration may increase the risk of edema. Pioglitazone should be discontinued in the event of cardiac degradation

A study of cardiovascular morbidity and mortality with pioglitazone has been performed in patients with type 2 diabetes of less than 75 years of age with a pre-existing major macro vasculature. Pioglitazone or placebo has been added to pre-existing antidiabetic and cardiovascular therapies for up to 3.5 years. This study showed an increased incidence of heart failure reported, however, with no increase in mortality. Since the experiment is limited in patients older than 75 years of age in this study, special attention must be paid to these patients.


Rare cases of hepatocellular dysfunction have been reported post-marketing (see section, Adverse effects). Periodic monitoring of liver enzymes is therefore recommended. In all patients, a dosage of liver enzymes should be performed prior to initiation of treatment with pioglitazone. Treatment with pioglitazone should not be initiated in patients with elevated liver enzymes (ALT> 2.5 X upper limit of normal) or any other sign of hepatic disease

Following initiation of treatment with pioglitazone, it is recommended that liver enzymes be monitored periodically on the basis of clinical evaluation. If the ALT level is increased under treatment (more than 3 times the upper limit of normal), a new control should be performed as soon as possible. If the ALT level remains more than 3 times the upper limit of normal, treatment should be stopped. When a patient has symptoms suggestive of liver damage (nausea, unexplained origin, vomiting, abdominal pain, fatigue, anorexia and / or dark urine), the liver enzymes should be checked. In the expectation of the results, the decision to maintain the patient under pioglitazone will be based on clinical interpretation. In the event of jaundice, the medicinal product must be stopped.

Weight gain

Clinical trials with pioglitazone have demonstrated dose-dependent weight gain. This weight gain would be related to the accumulation of fat associated in some cases with water retention. In some cases, the increase in weight can be a symptom of heart failure. Therefore, the weight must be carefully monitored. Diabetes treatment, also based on diet, patients should carefully follow their prescription, diet.

Hematology

A decrease of 4.0% in mean hemoglobin and 4.1% in hematocrit was associated with treatment with pioglitazone. It may be explained by haemodilution. In controlled and comparative clinical trials with pioglitazone, similar changes were observed with metformin (decrease in hemoglobin 3-4% and hematocrit 3.6-4.1%) and And, to a lesser extent, sulphonylureas and insulin (decreased hemoglobin 1-2% and hematocrit 1-3.2%)
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Hypoglycemia

Due to the increase in insulin sensitivity, patients receiving pioglitazone under dual therapy or oral triple therapy with a sulphonylurea, or dual therapy with insulin, May present a risk of hypoglycemia, dose-dependent and a reduction in the dose of the sulphonylurea or insulin may then prove necessary.
Eye disorders

Cases of macular edema or aggravation with decreased visual acuity have been reported with thiazolidinediones, including pioglitazone, after they have been commercialized. Of these patients, several reported concomitant peripheral edema. A direct relationship between pioglitazone and macular edema has not been clearly established, however prescribers should be alerted to the possible occurrence of macular edema, in patients with visual acuity disorders, Ophthalmologic consultation should be considered.

Other

An increase in the incidence of bone fractures in women was observed in an adverse effects analysis from randomized, controlled, double-blind clinical trials involving more than 8100 patients treated with pioglitazone And more than 7400 patients treated with comparators followed up to 3.5 years

Fractures were observed in 2.6% of women treated with pioglitazone versus 1.7% of women treated with a comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.3%) versus a comparator (1.5%). >

The incidence of fractures calculated per 100 patient-years was 1.9 fractures in women treated with pioglitazone and 1.1 fractures in treated women by a comparator. In this analysis, the difference in fracture risk for women under pioglitazone is therefore 0.8 fractures per 100 patient-years in. More

In the study, PRO, a 3.5-year study of cardiovascular morbidity and mortality, 44/870 (5.1%, 1.0 fracture per 100, patient-years) of patients treated with pioglitazone showed fractures Compared with 23/905 (2.5%, 0.5 fracture per 100 patient-years) of patients, treated with a comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.7%) versus a comparator (2.1%). >
The risk of fracture should be taken into consideration when taking care of the long-term treatment of women treated with pioglitazone

Because of the increased sensitivity to insulin, ovulation resumption may occur in patients with polycystic ovary syndrome. There is then a risk of pregnancy. Patients should be informed of this risk of pregnancy. If a patient wishes to become pregnant or if a pregnancy occurs, treatment should be discontinued (see section Pregnancy and lactation).
Pioglitazone should be used with caution when administered concomitantly with inhibitors (eg gemfibrozil) or inducers (eg, rifampicin) of cytochrome P450 2C8. Glycemic control should be closely monitored. Adjustment of the dose of pioglitazone within the recommended dosage range or modifications of the antidiabetic treatment should be considered (see section Interactions with other medicinal products and other forms of interactions). Br>

Due to the presence of lactose monohydrate, Actos tablets should not be used in patients with rare hereditary disorders, galactose intolerance, lactase deficiency or malabsorption of glucose and galactose .

Interaction studies have shown that pioglitazone does not alter the pharmacokinetic or pharmacodynamic properties of digoxin, warfarin, phenprocoumone and metformin. Concomitant administration of pioglitazone and sulphonylureas does not appear to alter the pharmacokinetics of sulfonamides, hypoglycemic agents. Studies carried out in humans do not suggest any induction of the main inducible cytochrome P450 isoenzymes: 1A, 2C8 / 9 and 3A4. In vitro studies showed no inhibition of a cytochrome P450 subtype. Therefore, interactions with substances metabolised by these enzymes (oral contraceptives, cyclosporine, calcium channel blockers, and HMG CoA reductase inhibitors) are not expected.

In the concomitant administration of pioglitazone and gemfibrozil (a cytochrome P450 2C8 inhibitor), a 3-fold increase in the AUC area of ​​pioglitazone was observed. Given the potential risk of increased dose-dependent adverse events, a decrease in the dose of pioglitazone may be required when concomitant administration of gemfibrozil. Close monitoring of glycemic control should be considered (see Warnings and Precautions for Use). Conversely, during concomitant administration of pioglitazone and rifampicin (an inducer of cytochrome P450 2C8), a 54% decrease in the AUC of pioglitazone was observed. An increase in the dose of pioglitazone may be required and concomitant administration of rifampicin. Close monitoring of glycemic control should be considered (see Warnings and Precautions for Use).

Not applicable.

In clinical studies, patients took pioglitazone at daily doses greater than the maximum recommended dose of 45 mg.
The most important case of overdosage with pioglitazone was reported in a patient taking 120 mg / day for four days and 180 mg / day for seven days with no symptoms observed

An episode of hypoglycaemia may occur in association with hypoglycemic sulfonamides or insulin. In case of overdose, a treatment adapted to the patient's clinical condition should be established.

Pregnancy

In humans, there is no adequate data to assess the safety of pioglitazone during pregnancy. In animal studies, toxicity studies have shown decreased fetal growth in animals; Exposed fetuses. This toxicity is attributed to the action of pioglitazone which reduces hyper insulinemia in the mother and to insulin resistance which appears during pregnancy, thus reducing the use of metabolic substrates during fetal growth. The potential for such a phenomenon is not known in women. Pioglitazone should not be used during pregnancy

Breastfeeding

In animals (spleen), pioglitazone was detected in milk. In the absence of data concerning the passage of pioglitazone in breast milk, pioglitazone should not be used in breastfeeding women.

Fertility

In fertility studies in animals, no reproductive, fertility or fertility effects have been demonstrated.
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Undesirable effects reported at a frequency of more than 0.5% over placebo and more than one isolated case in patients receiving pioglitazone in double blind studies are listed below MedDRA classification (by organ and frequency class, absolute). Frequencies are defined as follows: very common (≥ 1/10), frequent (≥ 1/100,