Actos

Actos

pioglitazone

Manufacturer:

Takeda

Distributor:

DKSH
Full Prescribing Info
Contents
Pioglitazone hydrochloride.
Description
Pioglitazone is [(±)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-] thiazolidinedione monohydrochloride belongs to a different chemical class and has a different pharmacological action than the sulfonylureas, metformin or the α-glucosidase inhibitors. The molecule contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo. No differences were found in the pharmacologic activity between the two enantiomers.
Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular formula of C19H20N2O3S·HCl and a molecular weight of 392.9 daltons. It is soluble in N,N-dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether.
Action
Pharmacology: Actos is an oral antidiabetic agent that acts primarily by decreasing insulin resistance. Actos is used in the management of type 2 diabetes mellitus [also known as non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes]. Pharmacological studies indicate that actos improves sensitivity to insulin in muscle and adipose tissue, and inhibits hepatic gluconeogenesis. Actos improves glycemic control while reducing circulating insulin levels.
Mechanism of Action: Actos is a thiazolidinedione antidiabetic agent that depends on the presence of insulin for its mechanism of action. Actos decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle and liver. Activation of PPARγ nuclear receptors modulates the transcription of number of insulin responsive genes involved in the control of glucose and lipid metabolism.
In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin dependent tissues and are observed in numerous animal models of insulin resistance.
Since pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.
Pharmacodynamics: Clinical studies demonstrate that Actos improves insulin sensitivity in insulin-resistant patients. Actos enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, improves hepatic sensitivity to insulin, and improves dysfunctional glucose homeostasis. In patients with type 2 diabetes, the decreased insulin resistance produced by Actos results in lower plasma glucose concentrations, lower plasma insulin levels, and lower HbA1C values. Based on the results from an open-label extension study, the glucose lowering effects of Actos appear to persist for at least one year. In controlled clinical trials, Actos in combination with sulfonylurea, metformin, or insulin had an additive effect on glycemic control.
Patients with lipid abnormalities were included in clinical trials with Actos. Overall, patients treated with Actos had mean decreases in triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol.
In a 26-week, placebo-controlled, dose-ranging study, mean triglyceride levels decreased in the 15 mg, 30 mg and 45 mg Actos dose groups compared to a mean increase in the placebo group. Mean HDL levels increased to a greater extent in patients treated with Actos than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with Actos compared to placebo (see Table 1).

Click on icon to see table/diagram/image

In the two other monotherapy studies (24 weeks and 16 weeks) and in combination therapy studies with sulfonylurea (24 weeks and 16 weeks) and metformin (24 weeks and 16 weeks), the results were generally consistent with the previously mentioned data. In placebo-controlled trials, the placebo-corrected mean changes from baseline decreased by 5% to 26% for triglycerides and increased by 6% to 13% for HDL in patients treated with Actos. A similar pattern of results was seen in 24-week combination therapy studies of Actos with sulfonylurea or metformin.
Clinical Studies: Monotherapy: In the US, three randomized, double-blind, placebo-controlled trials with durations from 16 to 26 weeks were conducted to evaluate the use of Actos as monotherapy in patients with type 2 diabetes. These studies examined Actos at doses up to 45 mg or placebo once daily in 865 patients.
A Dose Ranging Study (Study PNFP-001): In a 26-week dose-ranging study, 408 patients with type 2 diabetes were randomized to receive 7.5 mg, 15 mg, 30 mg or 45 mg of Actos, or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 8 weeks prior to the double-blind period. Treatment with 15 mg, 30 mg, and 45 mg of Actos produced statistically significant improvements in HbA1c and fasting plasma glucose (FPG) at endpoint compared to placebo (see Figure 1, Table 2). Figure 1 shows the time course for changes in FPG and HbA1c for the entire study population in this 26-week. (See figure and Table 2.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Table 2 shows HbA1c and FPG values for the entire study population.
The study population included patients not previously treated with antidiabetic medication (naive; 31%) and patients who were receiving antidiabetic medication at the time of study enrollment (previously treated; 69%). The data for the naive and previously treated patient subsets are shown in Table 3. All patients entered an 8-week washout/run-in period prior to double-blind treatment. This run-in period was associated with little change in HbA1c and FPG values from screening to baseline for the naive patients; however, for the previously-treated group, washout from previous antidiabetic medication resulted in deterioration of glycemic control and increases in HbA1c and FPG. Although most patients in the previously-treated group had a decrease from baseline in HbA1c and FPG with Actos, in many cases, the values did not return to screening levels by the end of the study. The study design did not permit the evaluation of patients who switched directly to Actos from another antidiabetic agent. (See Table 3.)

Click on icon to see table/diagram/image

A Dose-Titration Study (Study PNFP-012): In a 24-week placebo-controlled study, 260 patients with type 2 diabetes were randomized to one of two forced-titration Actos treatment groups or a mock titration placebo group. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double-blind period. In one Actos treatment group, patients received an initial dose of 7.5 mg once daily. After four weeks, the dose was increased to 15 mg once daily and after another four weeks, the dose was increased to 30 mg once daily for the remainder of the study (16 weeks). In the second Actos treatment group, patients received an initial dose of 15 mg once daily and were titrated to 30 mg once daily and 45 mg once daily in a similar manner. Treatment with Actos, as described, produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (see Table 4).

Click on icon to see table/diagram/image

Patients who had not been previously treated with antidiabetic medication (24%), mean values at screening were 10.1% for HbA1c and 238 mg/dL for FPG. At baseline, mean HbA1c was 10.2% and mean FPG was 243 mg/dL. Compared with placebo, treatment with Actos titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbA1c of 2.3% and 2.6% and mean FPG of 63 mg/dL and 95 mg/dL, respectively. For patients who had been previously treated with antidiabetic medication (76%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbA1c and 216 mg/dL for FPG. At baseline, mean HbA1c was 10.7% and mean FPG was 290 mg/dL. Compared with placebo, treatment with Actos titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbA1c of 1.3% and 1.4% and mean FPG of 55 and 60 mg/dL, respectively. For many previously treated patients, HbA1c and FPG had not returned to screening levels by the end of the study.
A 16-Week Monotherapy Study (study PNFP-026): In a 16-week study, 197 patients with type 2 diabetes were randomized to treatment with 30 mg of Actos or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double-blind period. Treatment with 30 mg of Actos produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (see Table 5).

Click on icon to see table/diagram/image

For patients who had not been previously treated with antidiabetic medication (40%), mean values at screening were 10.3% for HbA1c and 240 mg/dL for FPG. At baseline, mean HbA1c was 10.4% and mean FPG was 254 mg/dL. Compared with placebo, treatment with Actos 30 mg resulted in reductions from baseline in mean HbA1c of 1% and mean FPG of 62 mg/dL. For patients who had been previously treated with antidiabetic medication (60%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbA1c and 216 mg/dL for FPG. At baseline, mean HbA1c was 10.6% and mean FPG was 287 mg/dL. Compared with placebo, treatment with Actos 30 mg resulted in reductions from baseline in mean HbA1c of 1.3% and mean FPG of 46 mg/dL. For many previously treated patients, HbA1c and FPG had not returned to screening levels by the end of the study.
Combination Therapy: Three 16-week, randomized, double-blind, placebo-controlled clinical studies and three 24-week randomized, double-blind, dose-controlled clinical studies were conducted to evaluate the effects of Actos on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c ≥8%) despite current therapy with a sulfonylurea, metformin or insulin. Previous diabetes treatment may have been monotherapy or combination therapy.
Actos Plus Sulfonylurea Studies: Two clinical studies were conducted with Actos in combination with a sulfonylurea. Both studies included patients with type 2 diabetes on a sulfonylurea, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment.
A 16-Week Add-on to Sulfonylurea Study (Study PNFP-010): In the first study, 560 patients were randomized to receive 15 mg or 30 mg of Actos or placebo once daily for 16 weeks in addition to their current sulfonylurea regimen. When compared to placebo at Week 16, the addition of Actos to the sulfonylurea significantly reduced the mean HbA1c by 0.9% and 1.3% and mean FPG by 39 and 58 mg/dL for the 15 mg and 30 mg doses, respectively.
A 24-Week Add-on to Sulfonylurea Study (Study PNFP-341): In the second study, 702 patients were randomized to receive 30 mg or 45 mg of Actos once daily for 24 weeks in addition to their current sulfonylurea regimen. The mean reductions from baseline at Week 24 in HbA1c were 1.55% and 1.67% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 51.5 mg/dl and 56.1 mg/dl.
The therapeutic effect of Actos in combination with sulfonylurea was observed in patients regardless of whether the patients were receiving low, medium, or high doses of sulfonylurea.
Actos Plus Metformin Studies: Two clinical studies were conducted with Actos in combination with metformin. Both studies included patients with type 2 diabetes on metformin, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment.
A 16-Week Add-on to Metformin Study (Study PNFP-027): In the first study, 328 patients were randomized to receive either 30 mg of Actos or placebo once daily for 16 weeks in addition to their current metformin regimen. When compared to placebo at Week 16, the addition of Actos to metformin significantly reduced the mean HbA1c by 0.8% and decreased the mean FPG by 38 mg/dL.
A 24-Week Add-on to Metformin Study (Study PNFP-342): In the second study, 827 patients were randomized to receive either 30 mg or 45 mg of Actos once daily for 24 weeks in addition to their current metformin regimen. The mean reductions from baseline at Week 24 in HbA1c were 0.8% and 1.01% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 38.2 mg/dl and 50.7 mg/dl.
The therapeutic effects of Actos in combination with metformin was observed in patients regardless of whether the patients were receiving lower or higher doses of metformin.
Pharmacokinetics: Serum concentrations of total pioglitazone (pioglitazone plus active metabolites) remain elevated 24 hours after once daily dosing. Steady-state serum concentrations of both pioglitazone and total pioglitazone are achieved within 7 days. At steady-state, two of the pharmacologically active metabolites of pioglitazone, metabolites III (M-III) and IV (M-IV), reach serum concentrations equal to or greater than pioglitazone. In both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the peak total pioglitazone serum concentrations and 20% to 25% of the total areas under the serum concentration-time curve (AUC).
Maximum serum concentration (Cmax), AUC and trough serum concentrations (Cmin) for both pioglitazone and total pioglitazone increased proportionally at doses of 15 and 30 mg per day. There is a slightly less than proportional increase for pioglitazone and total pioglitazone at a dose of 60 mg per day.
Absorption: Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption.
Distribution: The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63 ± 0.41 (mean ± SD) L/kg of body weight. Pioglitazone is extensively protein bound (>99%) in human serum, principally to serum albumin. Pioglitazone also binds to other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound (>98%) to serum albumin.
Metabolism: Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy derivatives of pioglitazone) and M-III (keto derivative of pioglitazone) are pharmacologically active in animal models of type 2 diabetes.
In addition to pioglitazone, M-III and M-IV are the principal drug-related species found in human serum following multiple dosing. At steady state, in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the total peak serum concentrations and 20% to 25% of the total AUC.
In vitro data demonstrate that multiple cytochrome P-450 (CYP) isoforms are involved in the metabolism of pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo studies of pioglitazone in combination with P450 inhibitors and substrates have been performed (see Interactions). Urinary 6β-hydroxycortisol/cortisol ratios measured in patients treated with Actos showed that pioglitazone is not a strong CYP3A4 enzyme inducer.
Interaction studies have shown that pioglitazone has no relevant effect on either the pharmacokinetics or pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin. Concomitant administration of pioglitazone with gemfibrozil (an inhibitor of CYP 2C8) or with rifampicin, (an inducer of CYP 2C8) is reported to increase or decrease, respectively, the plasma concentration of pioglitazone.
Excretion and Elimination: Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces.
The mean serum half-life of pioglitazone and total pioglitazone ranges from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr.
Special Populations: Renal Insufficiency: The serum elimination half-life of pioglitazone, M-III and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 60 mL/min) to severe (creatinine clearance <30 mL/min) renal impairment when compared to normal subjects. No dose adjustment in patients with renal dysfunction is recommended (see DOSAGE & ADMINISTRATION).
Hepatic Insufficiency: Compared with normal controls, subjects with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak concentrations but no change in the mean AUC values.
Actos therapy should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2.5 times the upper limit of normal (see Hepatic Effects under Precautions).
Elderly: In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are slightly higher and the terminal half-life values slightly longer than for younger subjects. These changes were not of a magnitude that would be considered clinically relevant.
Pediatrics: Pharmacokinetic data in the pediatric population are not available.
Gender: The mean Cmax and AUC values were increased 20% to 60% in females. As monotherapy and in combination with sulfonylurea, metformin, or insulin, Actos improved glycemic control in both males and females. In controlled clinical trials, hemoglobin A1c (HbA1c) decreases from baseline were generally greater for females than for males (average mean difference in HbA1c 0.5%). Since therapy should be individualized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone.
Ethnicity: Pharmacokinetic data among various ethnic groups are not available.
Indications/Uses
Actos is indicated as oral monotherapy in type 2 diabetes mellitus patients, particularly overweight patients, inadequately controlled by diet and exercise for whom metformin is inappropriate because of contraindications or intolerance.
Actos is also indicated for oral combination treatment in type 2 diabetes mellitus patients with insufficient glycaemic control despite maximal tolerated dose of oral monotherapy with either metformin or sulphonylurea: In combination with metformin particularly in overweight patients; In combination with a sulphonylurea only in patients who show intolerance to metformin or for whom metformin is contraindicated.
Dosage/Direction for Use
Actos should be taken orally once daily with or without food.
Dosage in Adults: Actos may be initiated at 15 mg or 30 mg once daily. The dose may be increased in increments up to 45mg once daily.
In combination with metformin, the current metformin dose can be continued upon initiation of pioglitazone therapy.
In combination with sulfonylurea, the current sulfonylurea dose can be continued upon initiation of pioglitazone therapy. If patients report hypoglycaemia, the dose of sulfonylurea should be decreased.
Elderly: No dosage adjustment is necessary for elderly patients.
Patients with renal impairment: No dosage adjustment is necessary in patients with impaired renal function (creatinine clearance >4 mL/min). No information is available from dialysed patients, therefore pioglitazone should not be used in such patients.
Patients with hepatic impairment: Pioglitazone should not be used in patients with hepatic impairment.
Children and adolescents: There are no data available on the use of pioglitazone in patients under 18 years of age, and therefore its use is not recommended in this age group.
Overdosage
During controlled clinical trials, one case of overdose with Actos was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days. The patient denied any clinical symptoms during this period.
In the event of overdosage, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.
Contraindications
Actos is contraindicated in patients with the following conditions: known hypersensitivity to pioglitazone or to any of the excipients of the tablet; cardiac failure or history of cardiac failure (NYHA stages I to IV); hepatic impairment; Diabetic ketoacidosis; Current bladder cancer or a history of bladder cancer; Uninvestigated macroscopic haematuria.
Special Precautions
Fluid retention and cardiac failure: Pioglitazone can cause fluid retention, which may exacerbate or precipitate heart failure. When treating patients who have at least one risk factor for development of congestive heart failure (e.g. prior myocardial infarction or symptomatic coronary artery disease or the elderly), physicians should start with the lowest available dose and increase the dose gradually. Patients should be observed for signs and symptoms of heart failure, weight gain or oedema; particularly those with reduced cardiac reserve. There have been post-marketing cases of cardiac failure reported when pioglitazone was used in combination with insulin or in patients with a history of cardiac failure. Patients should be observed for signs and symptoms of heart failure, weight gain and oedema when pioglitazone is used in combination with insulin. Since insulin and pioglitazone are both associated with fluid retention, concomitant administration may increase the risk of oedema. Post marketing cases of peripheral oedema and cardiac failure have also been reported in patients with concomitant use of pioglitazone and nonsteroidal anti-inflammatory drugs, including selective COX-2 inhibitors. Pioglitazone should be discontinued if any deterioration in cardiac status occurs.
A cardiovascular outcome study of pioglitazone has been performed in patients under 75 years with type 2 diabetes mellitus and pre-existing major macrovascular disease. Pioglitazone or placebo was added to existing antidiabetic and cardiovascular therapy for up to 3.5 years. This study showed an increase in reports of heart failure, however this did not lead to an increase in mortality in this study.
Bladder Cancer: Cases of bladder cancer were reported more frequently in a meta-analysis of controlled clinical trials with pioglitazone (19 cases from 12506 patients, 0.15%) than in control groups (7 cases from 10212 patients, 0.07%) HR=2.64 (95% CI 1.11-6.31, P=0.029). After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 7 cases (0.06%) on pioglitazone and 2 cases (0.02%) in control groups. Available epidemiological data also suggest a small increased risk of bladder cancer in diabetic patients treated with pioglitazone, although not all studies identified a statistically significant increased risk.
Risk factors for bladder cancer should be assessed before initiating pioglitazone treatment (risks include age, smoking history, exposure to some occupational or chemotherapy agents e.g. cyclophosphamide or prior radiation treatment in the pelvic region). Any macroscopic haematuria should be investigated before starting pioglitazone therapy.
Patients should be advised to promptly seek the attention of their physician if macrosopic haematuria or other symptoms such as dysuria or urinary urgency develop during treatment.
Monitoring of liver function: There have been rare reports of hepatocellular dysfunction during post-marketing experience (see section 4.8). It is recommended, therefore, that patients treated with pioglitazone undergo periodic monitoring of liver enzymes. Liver enzymes should be checked prior to the initiation of therapy with pioglitazone in all patients. Therapy with pioglitazone should not be initiated in patients with increased baseline liver enzyme levels (ALT > 2.5 X upper limit of normal) or with any other evidence of liver disease.
Following initiation of therapy with pioglitazone, it is recommended that liver enzymes be monitored periodically based on clinical judgement. If ALT levels are increased to 3 X upper limit of normal during pioglitazone therapy, liver enzyme levels should be reassessed as soon as possible. If ALT levels remain > 3 X the upper limit of normal, therapy should be discontinued. If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and/or dark urine, liver enzymes should be checked. The decision whether to continue the patient on therapy with pioglitazone should be guided by clinical judgement pending laboratory evaluations. If jaundice is observed, the medicinal product should be discontinued.
Weight gain: In clinical trials with pioglitazone there was evidence of dose related weight gain, which may be due to fat accumulation and in some cases associated with fluid retention. In some cases weight increase may be a symptom of cardiac failure, therefore weight should be closely monitored. Part of the treatment of diabetes is dietary control. Patients should be advised to adhere strictly to a calorie-controlled diet.
Haematology: There was a small reduction in mean haemoglobin (4% relative reduction) and haematocrit (4.1% relative reduction) during therapy with pioglitazone, consistent with haemodilution.
Similar changes were seen in metformin (haemoglobin 3-4% and haematocrit 3.6–4.1% relative reductions) and to a lesser extent sulphonylurea and insulin (haemoglobin 1–2% and haematocrit 1–3.2% relative reductions) treated patients in comparative controlled trials with pioglitazone.
Hypoglycaemia: As a consequence of increased insulin sensitivity, patients receiving pioglitazone in dual or triple oral therapy with a sulphonylurea or in dual therapy with insulin may be at risk for dose-related hypoglycaemia, and a reduction in the dose of the sulphonylurea or insulin may be necessary.
Eye disorders: Post-marketing reports of new-onset or worsening diabetic macular oedema with decreased visual acuity have been reported with thiazolidinediones, including pioglitazone. Many of these patients reported concurrent peripheral oedema. It is unclear whether or not there is a direct association between pioglitazone and macular oedema but prescribers should be alert to the possibility of macular oedema if patients report disturbances in visual acuity; an appropriate ophthalmological referral should be considered.
Others: Pioglitazone exerts its anti-hyperglycemic affect only in the presence of insulin and should therefore not be used in patients with type I diabetes or for the treatment of diabetic ketoacidosis.
An increased incidence in bone fractures in women was seen in a pooled analysis of adverse reactions of bone fracture from randomised, controlled, double blind clinical trials in over 8100 pioglitazone and 7400 comparator treated patients, on treatment for up to 3.5 years.
Fractures were observed in 2.6% of women taking pioglitazone compared to 1.7% of women treated with a comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.3%) versus comparator (1.5%).
The fracture incidence calculated was 1.9 fractures per 100 patient years in women treated with pioglitazone and 1.1 fractures per 100 patient years in women treated with a comparator. The observed excess risk of fractures for women in this dataset on pioglitazone is therefore 0.8 fractures per 100 patient years of use.
In the 3.5 year cardiovascular risk PROactive study, 44/870 (5.1%; 1.0 fractures per 100 patient years) of pioglitazone-treated female patients experienced fractures compared to 23/905 (2.5%; 0.5 fractures per 100 patient years) of female patients treated with comparator. No increase in fracture rates was observed in men treated with pioglitazone (1.7%) versus comparator (2.1%).
Some epidemiological studies have suggested a similarly increased risk of fracture in both men and women.
The risk of fractures should be considered in the long term care of patients treated with pioglitazone.
As a consequence of enhancing insulin action, pioglitazone treatment in patients with polycystic ovarian syndrome may result in resumption of ovulation. These patients may be at risk of pregnancy. Patients should be aware of the risk of pregnancy and if a patient wishes to become pregnant or if pregnancy occurs, the treatment should be discontinued.
Pioglitazone should be used with caution during concomitant administration of cytochrome P450 2C8 inhibitors (e.g. gemfibrozil) or inducers (e.g. rifampicin). Glycaemic control should be monitored closely. Pioglitazone dose adjustment within the recommended posology or changes in diabetic treatment should be considered.
Actos tablets contain lactose monohydrate and therefore should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
Effects on ability to drive and use machines: Actos has no or negligible influence on the ability to drive and use machines. However patients who experience visual disturbance should be cautious when driving or using machines.
Use in Elderly: Combination use with insulin should be considered with caution in the elderly because of increased risk of serious heart failure. In light of age- related risks (especially bladder cancer, fractures and heart failure), the balance of benefits and risks should be considered carefully both before and during treatment in the elderly. Patients should be advised to promptly seek the attention of their physician if macroscopic haematuria or other symptoms such as dysuria or urinary urgency develop during treatment.
Use In Pregnancy & Lactation
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.
Breast-feeding: 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.
Fertility: In animal fertility studies there was no effect on copulation, impregnation or fertility index.
Adverse Reactions
Tabulated list of adverse reactions: Adverse reactions reported in excess (> 0.5%) of placebo and as more than an isolated case in patients receiving pioglitazone in double-blind studies are listed below as MedDRA preferred term by system organ class and absolute frequency. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). Within each system organ class, adverse reactions are presented in order of decreasing incidence followed by decreasing seriousness. (See Table 6.)

Click on icon to see table/diagram/image
Drug 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 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 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 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.
Storage
Store below 30°C.
Shelf-Life: 3 years.
MIMS Class
ATC Classification
A10BG03 - pioglitazone ; Belongs to the class of thiazolidinediones. Used in the treatment of diabetes.
Presentation/Packing
Tab 15 mg (white to yellowish-white) x 30's. 30 mg x 30's.
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in