Actazone

Pioglitazone 15 mg Tablet: White circular, biconvex uncoated tablet.
Pioglitazone 30 mg Tablet: White, circular, biconvex uncoated tablet, having break line mark on one side plain on other side.
Each uncoated tablet contains: Pioglitazone (as hydrochloride) equivalent to Pioglitazone 15 mg or 30 mg, Excipients q.s.

Pharmacotherapeutic group: Drugs used in diabetes, blood glucose lowering drugs, excl. insulins.
Pharmacology: Pioglitazone is a thiazolidinedione antidiabetic agent that depends on the presence of insulin for its mechanism of action. Pioglitazone decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator activated receptor-gamma (PPARγ).
PPARγ receptor are found in tissues important for insulin action such as adipose tissue, skeletal muscles and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. Since, Pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance). It does not lower blood glucose in absence of endogenous insulin.
Pharmacodynamics: Pioglitazone effects may be mediated by a reduction of insulin resistance. Pioglitazone appears to act via activation of specific nuclear receptors (peroxisome proliferator activated receptor gamma) leading to increased insulin sensitivity of liver, fat and skeletal muscle cells in animals. Treatment with pioglitazone has been shown to reduce hepatic glucose output and to increase peripheral glucose disposal in the case of insulin resistance.
Fasting and postprandial glycaemic control is improved in patients with type 2 diabetes mellitus. The improved glycaemic control is associated with a reduction in both fasting and postprandial plasma insulin concentrations. A clinical trial of pioglitazone vs. gliclazide as monotherapy was extended to two years in order to assess time to treatment failure (defined as appearance of HbA1c ≥ 8.0% after the first six months of therapy). Kaplan-Meier analysis showed shorter time to treatment failure in patients treated with gliclazide, compared with pioglitazone. At two years, glycaemic control (defined as HbA1c < 8.0%) was sustained in 69% of patients treated with pioglitazone, compared with 50% of patients on gliclazide. In a two-year study of combination therapy comparing pioglitazone with gliclazide when added to metformin, glycaemic control measured as mean change from baseline in HbA1c was similar between treatment groups after one year. The rate of deterioration of HbA1c during the second year was less with pioglitazone than with gliclazide.
In a placebo controlled trial, patients with inadequate glycaemic control despite a three month insulin optimisation period were randomised to pioglitazone or placebo for 12 months. Patients receiving pioglitazone had a mean reduction in HbA1c of 0.45% compared with those continuing on insulin alone, and a reduction of insulin dose in the pioglitazone treated group.
HOMA analysis shows that pioglitazone improves beta cell function as well as increasing insulin sensitivity. Two-year clinical studies have shown maintenance of this effect.
In one year clinical trials, pioglitazone consistently gave a statistically significant reduction in the albumin/creatinine ratio compared to baseline.
The effect of pioglitazone (45 mg monotherapy vs. placebo) was studied in a small 18-week trial in type 2 diabetics. Pioglitazone was associated with significant weight gain. Visceral fat was significantly decreased, while there was an increase in extra-abdominal fat mass. Similar changes in body fat distribution on pioglitazone have been accompanied by an improvement in insulin sensitivity. In most clinical trials, reduced total plasma triglycerides and free fatty acids, and increased HDL-cholesterol levels were observed as compared to placebo, with small, but not clinically significant increases in LDL-cholesterol levels.
In clinical trials of up to two years duration, pioglitazone reduced total plasma triglycerides and free fatty acids, and increased HDL cholesterol levels, compared with placebo, metformin or gliclazide. Pioglitazone did not cause statistically significant increases in LDL cholesterol levels compared with placebo, whilst reductions were observed with metformin and gliclazide. In a 20-week study, as well as reducing fasting triglycerides, pioglitazone reduced post prandial hypertriglyceridaemia through an effect on both absorbed and hepatically synthesised triglycerides. These effects were independent of pioglitazone's effects on glycaemia and were statistically significantly different to glibenclamide.
In proactive, a cardiovascular outcome study, 5,238 patients with type 2 diabetes mellitus and pre-existing major macrovascular disease were randomised to pioglitazone or placebo in addition to existing antidiabetic and cardiovascular therapy, for up to 3.5 years. The study population had an average age of 62 years; the average duration of diabetes was 9.5 years. Approximately one third of patients were receiving insulin in combination with metformin and/or a sulphonylurea. To be eligible patients had to have had one or more of the following: myocardial infarction, stroke, percutaneous cardiac intervention or coronary artery bypass graft, acute coronary syndrome, coronary artery disease, or peripheral arterial obstructive disease. Almost half of the patients had a previous myocardial infarction and approximately 20% had a stroke. Approximately half of the study population had at least two of the cardiovascular history entry criteria. Almost all subjects (95%) were receiving cardiovascular medicinal products (beta blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II antagonists, calcium channel blockers, nitrates, diuretics, acetylsalicylic acid, statins, fibrates).
Although the study failed regarding its primary endpoint, which was a composite of all-cause mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, major leg amputation, coronary revascularisation and leg revascularisation, the results suggest that there are no long-term cardiovascular concerns regarding use of pioglitazone. However, the incidences of oedema, weight gain and heart failure were increased. No increase in mortality from heart failure was observed.
Pharmacokinetics: Pioglitazone is rapidly absorbed after oral administration. Peak plasma concentrations are obtained within 2 hours and bioavailability exceed 80%. Pioglitazone is more than 99% bound to plasma proteins.
It is extensively metabolized by cytochrome P450 isoenzymes CYP3A4 and CYP2C9 to both active and inactive metabolites. It is excreted in the urine and feces and has a plasma half-life of up to 7 hours.
The active metabolites have a half-life of up to 24 hours.

Pioglitazone is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin dependent diabetes mellitus, NIDDM).
Pioglitazone is indicated for monotherapy.
Pioglitazone is also indicated for use in combination with a sulfonylurea, metformin, or insulin when diet and exercise plus the single agent does not result in adequate glycemic control.

Pioglitazone monotherapy in patients not adequately controlled with diet and exercise may be initiated at 15 mg or 30 mg once daily. For patients who respond inadequately to the initial dose of Pioglitazone, the dose can be increased in increments up to 45 mg once daily. For patients not responding adequately to monotherapy, combination therapy should be considered. Pioglitazone can be combined with sulfonylurea, metformin or insulin.
Dosage in Hepatic Insufficiency: Therapy with Pioglitazone should not be initiated if the patients exhibits clinical evidence of active liver disease or increase serum transaminase levels (ALT greater than 2.5 times the upper limit of normal) at start of therapy. Liver enzyme monitoring is recommended in all patients prior to initiation of therapy with Pioglitazone and periodically thereafter. Or as prescribed by the physician.

In clinical studies, patients have taken pioglitazone at higher than the recommended highest dose of 45 mg daily. The maximum reported dose of 120 mg/day for four days, then 180 mg/day for seven days was not associated with any symptoms.
Hypoglycaemia may occur in combination with sulphonylureas or insulin. Symptomatic and general supportive measures should be taken in case of overdose.

Pioglitazone is contraindicated in patients with known hypersensitivity to this product or any of its components.

Bladder Cancer: Do not use Pioglitazone in patients with active bladder cancer.
Use Pioglitazone with caution in patients with a prior history of bladder cancer. The benefits of blood sugar control with Pioglitazone should be weighed against the unknown risks for cancer recurrence.
General: Pioglitazone exerts its antihyperglycemic effect only in the presence of insulin. Therefore, Pioglitazone should not be used in patients with type 1 diabetes or for the treatment of diabetic keto-acidosis.
Hyperglycemia: Patients receiving Pioglitazone in combination with insulin or oral hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the dose or the concomitant agent may be necessary.
Ovulation: In pre-menopausal anovulatory patients with insulin resistance, treatment with thiazolidinediones, including Pioglitazone may result in resumption of ovulation. As a consequence of their improved insulin sensitivity, these patients may be at risk for pregnancy if adequate contraception is not used.
Hematological: Pioglitazone may cause decreases in hemoglobin and hematocrit. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in Pioglitazone treated patients. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter.
These changes may be related to increased plasma volume and have not been associated with any significant haematologic clinical effects.

Pregnancy: There are no adequate human data to determine the safety of pioglitazone during pregnancy. Foetal growth restriction was apparent in animal studies with pioglitazone. This was attributable to the action of pioglitazone in diminishing the maternal hyperinsulinaemia and increased insulin resistance that occurs during pregnancy thereby reducing the availability of metabolic substrates for foetal growth. The relevance of such a mechanism in humans is unclear and pioglitazone should not be used in pregnancy.
Lactation: Pioglitazone has been shown to be present in the milk of lactating rats. It is not known whether pioglitazone is secreted in human milk. Therefore, pioglitazone should not be administered to breast-feeding women.

Adverse effects that have been commonly reported in placebo controlled clinical studies of Pioglitazone monotherapy are headache, upper respiratory tract infections, myalgia, sinusitis and pharyngitis.
In monotherapy studies, edema has been reported in 4.8% of Pioglitazone treated patients versus 1.2% in placebo treated patients.
Cases of anemia have been reported, although infrequently, in patients receiving Pioglitazone.

Interaction studies have shown that pioglitazone has no relevant effect on either the pharmacokinetics or pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin. Co-administration of pioglitazone with sulphonylureas does not appear to affect the pharmacokinetics of the sulphonylurea. Studies in man suggest no induction of the main inducible cytochrome P450, 1A, 2C8/9 and 3A4. In vitro studies have shown no inhibition of any subtype of cytochrome P450. Interactions with substances metabolised by these enzymes, e.g. oral contraceptives, cyclosporin, calcium channel blockers, and HMG-CoA 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 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. Close monitoring of glycaemic control should be considered. 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.

Store at temperatures not exceeding 30°C.

Antidiabetic Agents

A10BG03 - pioglitazone ; Belongs to the class of thiazolidinediones. Used in the treatment of diabetes.

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