Actos®

Pioglitazone HCl

Antidiabetic--Insulin Resistance Reducing Agent

Lilly

http://www.lilly.com/

Actos Monograph PDF download here.

 

 

 

 

Pharmacology

Actos (pioglitazone hydrochloride) 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 liver, resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output respectively.

     Actos improves glycemic control while reducing circulating insulin levels. Unlike sulfonylureas, Actos is not an insulin secretagogue. Actos 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 a number of insulin responsive genes involved in the control of glucose and lipid metabolism, and in the maturation of preadipocytes, predominantly of subcutaneous origin.

     Insulin resistance is a primary feature characterizing the pathogenesis of type 2 diabetes. Actos results in increased responsiveness of insulin-dependent tissues. Actos significantly improves hepatic and peripheral (muscle) tissue sensitivity to insulin in patients with type 2 diabetes. Actos also results in significant reductions in markers of beta cell hyperstimulation, such as fasting insulin and fasting C-peptide. In short term clinical studies of 16 weeks duration, Actos has also been shown to significantly improve biochemical markers of pancreatic beta cell function.

     In clinical studies in patients with type 2 diabetes, Actos reduces the hyperglycemia and hyperinsulinemia characteristic of insulin-resistant states, including type 2 diabetes.

     Actos significantly reduces hemoglobin A_1c (HbA_1c), a marker for long term glycemic control), and fasting blood glucose (FBG) in patients with type 2 diabetes. Inadequately controlled hyperglycemia is associated with an increased risk of diabetic complications, including cardiovascular disorders and diabetic nephropathy, retinopathy and neuropathy.

     Other risk factors for diabetic complications in patients with type 2 diabetes include dyslipidemias and hypertension. In addition, elevated microalbuminuria is an early indicator of diabetic nephropathy.

     Low HDL-C and elevated triglycerides are common in patients with type 2 diabetes. Actos significantly increases high density lipoprotein cholesterol (HDL-C) and reduces triglycerides in patients with type 2 diabetes. It also increases the particle size of low density lipoprotein.

     Actos significantly reduces carotid arterial intimal medial thickness.  It also results in modest, but significant, reductions in blood pressure. In addition, Actos significantly decreases microalbuminuria in patients with type 2 diabetes. See also Warnings and Precautions sections regarding use in patients with heart disease.

     Since Actos enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.

 

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, 2 of the pharmacologically active metabolites of pioglitazone, Metabolites III (M-III) and IV (M-IV), reach serum concentrations equal to or greater than pioglitazone. At steady state, 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 area under the serum concentration-time curve (AUC).

     Maximum serum concentration (C_max), AUC, and trough serum concentrations (C_min) for both pioglitazone and total pioglitazone increase proportionally at doses of 15 mg 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.

     Pioglitazone incubated with expressed human P450 or human liver microsomes results in the formation of M-IV and to a much lesser degree, M-II. The major cytochrome P450 isoforms involved in the hepatic metabolism of pioglitazone are CYP2C8 and CYP3A4 (>50% of metabolism) with contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. Ketoconazole inhibited up to 85% of hepatic pioglitazone metabolism in vitro at an equimolar concentration to pioglitazone. At higher than the therapeutic concentrations, pioglitazone had no effect on the reactions mediated by human liver microsomes expressing cytochrome P450 isoforms including CYP2C8 and CYP3A4. In vivo human studies have not been performed to investigate any induction of CYP3A4 by pioglitazone.

Excretion and Elimination: Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine as metabolites. Renal elimination of unchanged 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 0.5 to 1.0 mL/s [30 to 60 mL/min]) to severe (creatinine clearance <0.5 mL/s [30 mL/min]) renal impairment when compared to normal subjects. No dose adjustment in patients with renal dysfunction is recommended.

Hepatic Insufficiency: A single-dose, open-label study was conducted to investigate the effects of impaired hepatic function on pioglitazone. A group of 24 subjects was enrolled; 12 with normal hepatic function and 12 with abnormal hepatic function classified as Childs-Pugh Class B or C. Subjects received a 30 mg pioglitazone tablet 10 minutes after a diet-controlled meal, and changes in the serum pharmacokinetic profile and urinary excretion of pioglitazone and its metabolites were then studied. Compared with controls, subjects with impaired hepatic function have a 45% reduction in pioglitazone and total (pioglitazone plus active metabolites) mean peak concentrations but no change in the mean AUC values. The findings of this study showed that the extent of pioglitazone absorption, as indicated by AUC_0–24, was similar in both normal subjects and individuals with impaired hepatic function. No adverse events attributable to pioglitazone were reported in either group, and no clinically significant changes in baseline laboratory tests, including liver function tests, were observed.

     Although no adverse events attributed to drug were noted in any group, Actos should be used with caution in patients with hepatic disease (see Warnings, Hepatic Disease and Precautions, Hepatic Insufficiency).

Geriatrics

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.

Children

Pharmacokinetic data in the pediatric population are not available. Actos is not recommended for patients under 18 years of age.

Gender

Actos improved glycemic control in both males and females. In controlled clinical trials the mean C_max and AUC values were increased 20% to 60% in females. HbA_1c decreases from baseline were generally greater for females than for males (average mean absolute difference in HbA_1c 0.005). Since therapy should be individualized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone.

Pharmacodynamics and Clinical Effects

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 significantly lower blood glucose concentrations, lower plasma insulin levels, and lower HbA_1c values. Based on results from an open-label extension studies, the glucose lowering effects of Actos are sustained for more than 1 year, but some patients require titration to higher doses to maintain the response. The effect of Actos occurs in the absence of weight loss.

     Actos exerts its antihyperglycemic effect in the presence of insulin. Because Actos does not stimulate insulin secretion, hypoglycemia would not be expected in patients treated with Actos alone.

     In pharmacodynamic studies of both monotherapy and combination therapy, treatment with Actos was associated with decreases in free fatty acids.

     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-C levels increased to a greater extent in the Actos-treated patients than in the placebo-treated patients. There were no consistent differences for low density lipoprotein cholesterol (LDL-C) and total cholesterol in Actos-treated patients compared to placebo (see  Table 1).

CPS:Actos_t1Click here for Table 1

Table 1: Actos

Lipids in a 26-week, Multicentre, Placebo-controlled Dose-ranging Study

 

	Placebo	Actos 15 mg Once Daily	Actos 30 mg Once Daily	Actos 45 mg Once Daily
Triglycerides (mmol/L)	N=79	N=79	N=84	N=77
Baseline (mean)	2.97	3.20	2.95	2.93
Percent change from baseline (mean)	4.8%	-9.0%	-9.6%	-9.3%
HDL Cholesterol (mmol/L)	N=79	N=79	N=83	N=77
Baseline (mean)	1.08	1.04	1.06	1.05
Percent change from baseline (mean)	8.1%	14.1%	12.2%	19.1%
LDL Cholesterol (mmol/L)	N=65	N=63	N=74	N=62
Baseline (mean)	3.59	3.41	3.51	3.28
Percent change from baseline (mean)	4.8%	7.2%	5.2%	6.0%
Total Cholesterol (mmol/L)	N=79	N=79	N=84	N=77
Baseline (mean)	5.81	5.69	5.76	5.53
Percent change from baseline (mean)	4.4%	4.6%	3.3%	6.4%

 

     In two other monotherapy studies (study duration 24 weeks and 16 weeks), the results were generally consistent with the data above. For Actos-treated patients, the placebo-corrected mean changes from baseline decreased by 21 to 23% for triglycerides, and increased by 5 to 13% for HDL-C.

     Statistically significant increases in HDL-C and reductions in triglycerides were also observed with Actos in 2 controlled, combination therapy studies (each 16 weeks duration), in which patients with type 2 diabetes who were receiving therapy with a sulfonylurea or metformin were randomized to placebo or combination therapy with Actos.

     Patients taking statins were not excluded from clinical trials.  In these patients, the mean increases in HDL-C and reductions of triglycerides with Actos were observed in addition to the effects of the statin.

     Actos is also associated with weight gain (see Precautions and Adverse Effects). However, the weight gain observed in clinical studies with Actos was consistently associated with improved glycemic control.  In addition, Actos significantly decreases visceral (abdominal) fat stores while increasing extra-abdominal fat.   The reduction in visceral fat correlates with improved hepatic and peripheral tissue insulin sensitivity.  Abdominal obesity is a risk factor for cardiovascular disorders.

      Figure 1 plots the change in body weight for patients who had completed 48 weeks of treatment with pioglitazone in an open-label trial.

 

Figure 1:

Actos

Mean Change from Baseline for Body Weight by Visit for Patients who Completed 48 Weeks of Open-label Treatment

 

     As indicated in  Figure 1, at Week 48 the mean change from baseline in body weight was 5.55 kg for the de novo group, 6.34 kg for the roll-over placebo group, and 5.36 kg for the roll-over pioglitazone group. For the total patient group, the mean change from baseline in body weight was 5.56 kg. The maximum and minimum weight changes observed up to Week 48 from time of entry into this open-label trial for the total patient group were 21.77 kg and − 19.86 kg, respectively (median weight change: 4.54 kg).

     Two patients were withdrawn from the study due to reported weight increases of 15.6 kg and 20.8 kg, respectively. For the first patient, the investigator believed the weight gain was due to edema, and for the second, a dose of 60 mg of pioglitazone was used, and the patient had dietary factors that could have also contributed to the weight gain. Any abnormally large weight gain experienced by some patients may be due to fluid retention (see Warnings, Edema).

     During three placebo-controlled, 16 week, combination therapy studies the mean weight increased for all Actos treatment groups: for the sulfonulyrea combination therapy study the mean increase with Actos 15 mg and 30 mg was 1.9 and 2.9 kg, respectively; for the metformin study, the mean increase with Actos 30 mg was 0.95 kg and for the insulin study, the mean increase with Actos 15 and 30 mg was  2.3 and 3.7 kg, respectively.

     However, the individual weight change was highly variable. The range of weight changes during the study is shown in  Table 2 (see Precautions, Weight Gain).

CPS:Actos_t2Click here for Table 2

Table 2: Actos

Change In Weight During Double-Blind, Combination Therapy Studies

 

Combination Therapy:	Sulfonylurea				Metformin			Insulin
	Placebo	Actos 15 mg	Actos 30 mg	Placebo		Actos 30 mg	Placebo		Actos 15 mg	Actos 30 mg
N	160 (%)	157 (%)	168 (%)	112 (%)		137 (%)	162 (%)		165 (%)	174 (%)
>10 kg loss	1 (0.6)	-	-	-		1 (0.6)	1 (0.6)		-	-
≥ 5 to 10 kg loss	13 (8.1)	2 (1.3)	4 (2.4)	15 (13.4)		9 (6.6)	9 (5.6)		6 (3.6)	3 (1.7)
0 to <5 kg loss	76 (47.5)	23 (14.6)	16 (9.5)	54 (48.2)		21 (15.3)	59 (36.4)		19 (11.5)	13 (7.5)
0 kg	19 (11.9)	5 (3.2)	4 (2.4)	9 (8.0)		10 (7.3)	11 (6.3)		9 (5.5)	6 (3.4)
0 to ≤ 5 kg gain	49 (30.6)	110 (70.0)	106 (63.1)	33 (29.5)		81 (59.1)	78 (48.1)		100 (60.6)	96 (55.2)
>5 to 10 kg gain	2 (1.3)	16 (10.2)	36 (21.4)	1 (0.9)		15 (10.9)	4 (2.5)		30 (18.2)	49 (28.2)
>10 kg gain	-	1 (0.6)	2 (1.2)	-		-	-		1 (0.6)	7 (4.0)

 

     In patients receiving long-term combination therapy with sulfonylurea or metformin, median weight gain (5.40 kg after at least 60 weeks Actos therapy) was similar to that with Actos monotherapy (median weight gain 4.54 kg after 48 weeks).

     As with Actos monotherapy studies, weight gain in patients treated with Actos in combination with a sulfonylurea, metformin or insulin was associated with improved glycemic control.

Clinical Studies

Monotherapy: 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. All 3 studies included patients previously treated with another oral antidiabetic agent (sulfonylureas, n=524; metformin, n=170; acarbose, n=19) and patients who were previously untreated (n=268).

     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 HbA_1c and fasting blood glucose (FBG) at endpoint compared to placebo (see  Figure 2 and  Table 3).

      Figure 2 shows the time course for changes in FBG and HbA_1c for the entire study population in this 26-week study.

      Table 3 shows HbA_1c and FBG 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 4. 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 HbA_1c and FBG values from screening to baseline for the naive patients; however, for the previously-treated group, washout from previous anti-diabetic medication resulted in deterioration of glycemic control and increases in HbA_1c and FBG.

     In a 24-week study, 260 patients with type 2 diabetes were randomized to 1 of 2 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 4 weeks, the dose was increased to 15 mg once daily and after another 4 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 HbA_1c and FBG at endpoint compared to placebo (see  Table 5).

 

Figure 2:

Actos

Mean Change from Baseline for FBG and HbA_1c in a 26-week Placebo-controlled Dose-ranging Study

 

CPS:Actos_t3Click here for Table 3

Table 3: Actos

Glycemic Parameters in a 26-week Placebo-controlled Dose-ranging Study

 

	Placebo	Actos 15 mg Once Daily	Actos 30 mg Once Daily	Actos 45 mg Once Daily
Total Population
HbA1c	N=79	N=79	N=85	N=76
Baseline (mean)	0.104	0.102	0.102	0.103
Change from Baseline (adjusted meana )	0.007	-0.003	-0.003	-0.009
Difference from Placebob  (adjusted meana )		-0.01	-0.01	-0.016
FBG (mmol/L)	N=79	N=79	N=84	N=77
Baseline (mean)	14.9	14.8	14.9	15.3
Change from Baseline (adjusted meana )	0.5	-1.7	-1.8	-3.1
Difference from Placebob  (adjusted meana )		-2.2	-2.3	-3.6

 

 ^a Adjusted for baseline, pooled center, and pooled center by treatment interaction.

 ^b p≤.05 vs placebo.

 

 

CPS:Actos_t4Click here for Table 4

Table 4: Actos

Glycemic Parameters in a 26-week Placebo-controlled Dose-ranging Study

 

	Placebo	Actos 15 mg Once Daily	Actos 30 mg Once Daily	Actos 45 mg Once Daily
Naïve to Therapy
HbA1c	N=25	N=26	N=26	N=21
Screening (mean)	0.093	0.10	0.095	0.098
Baseline (mean)	0.09	0.099	0.093	0.10
Change from Baseline (adjusted  meana )	0.006	-0.008	-0.006	-0.019
Difference from Placebo (adjusted meana )		-0.014	-0.013	-0.026
FBG (mmol/L)	N=25	N=26	N=26	N=21
Screening (mean)	12.4	13.6	13.3	13.3
Baseline (mean)	12.7	13.9	12.5	13.0
Change from Baseline (adjusted meana )	0.9	-2.1	-2.3	-3.6
Difference from Placebo (adjusted meana )		-2.9	-3.1	-4.4
Previously Treated
HbA1c	N=54	N=53	N=59	N=55
Screening (mean)	0.093	0.090	0.091	0.090
Baseline (mean)	0.109	0.104	0.104	0.106
Change from Baseline (adjusted meana )	0.008	-0.001	0	-0.006
Difference from Placebo (adjusted meana )		-0.01	-0.009	-0.014
FBG (mmol/L)	N=54	N=53	N=58	N=56
Screening (mean)	12.3	11.6	12.8	11.9
Baseline (mean)	15.8	15.3	15.9	16.2
Change from Baseline (adjusted meana )	0.2	-1.8	-1.5	-3.1
Difference from Placebo (adjusted meana )		-2.0	-1.7	-3.3

 

 ^a Adjusted for baseline and pooled center.

 

 

CPS:Actos_t5Click here for Table 5

Table 5: Actos

Glycemic Parameters in a 24-week Placebo-controlled Forced-titration Study

 

	Placebo	Actos 30 mga  Once Daily	Actos 45 mga  Once Daily
Total Population
HbA1c	N=83	N=85	N=85
Baseline (mean)	0.108	0.103	0.108
Change from Baseline (adjusted meanb )	0.009	-0.006	-0.006
Difference from Placebo (adjusted meanb )		-0.015c	-0.015c
FBG (mmol/L)	N=78	N=82	N=85
Baseline (mean)	15.5	14.9	15.6
Change from Baseline (adjusted meanb )	1.0	-2.4	-2.8
Difference from Placebo (adjusted meanb )		-3.4c	-3.8c

 

 ^a Final dose in forced titration.

 ^b Adjusted for baseline, pooled center, and pooled center by treatment interaction.

 ^c p≤ 0.05 vs placebo.

 

 

     For patients who had not been previously treated with antidiabetic medication (24%), mean values at screening were 0.101 for HbA_1c and 13.2 mmol/L for FBG. At baseline, mean HbA_1c was 0.102 and mean FBG was 13.5 mmol/L. Compared with placebo, treatment with Actos titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbA_1c of 0.023 and 0.026 and mean FBG of 3.5 mmol/L and 5.3 mmol/L, respectively. For patients who had been previously treated with antidiabetic medication (76%), this medication was discontinued at screening. Mean values at screening were 0.094 for HbA_1c and 12.0 mmol/L for FBG. At baseline, mean HbA_1c was 0.107 and mean FBG was 16.1 mmol/L. Compared with placebo, treatment with Actos titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbA_1c of 0.013 and 0.014 and mean FBG of 3.1 mmol/L and 3.3 mmol/L, respectively. The decrease in percent mean HbA_1c was not greater in the group with a final dose of 45 mg compared to a final dose of 30 mg.

     For patients who had been previously treated with antidiabetic medication, 10% of patients in the final dose of 30 mg, and 4% of patients in the final dose of 45 mg groups did not complete the trial due to an insufficient therapeutic effect. For patients who had not been previously treated with antidiabetic medication, 5% of patients in both groups did not complete the trial due to an insufficient therapeutic effect.

     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 HbA_1c and FBG at endpoint compared to placebo (see  Table 6).

CPS:Actos_t6Click here for Table 6

Table 6: Actos

Glycemic Parameters in a 16-week Placebo-controlled Study

 

	Placebo	Actos 30 mg Once Daily
Total Population
HbA1c	N=93	N=100
Baseline (mean)	0.103	0.105
Change from Baseline (adjusted meana )	0.008	-0.006
Difference from Placebo (adjusted meana )		-0.014b
FBG (mmol/L)	N=91	N=99
Baseline (mean)	15	15.2
Change from Baseline (adjusted meana )	0.4	-2.8
Difference from Placebo (adjusted meana )		-3.2b

 

 ^a Adjusted for baseline, pooled center, and pooled center by treatment interaction.

 ^b p≤ 0.05 vs placebo.

 

 

     For patients who had not been previously treated with antidiabetic medication (40%), mean values at screening were 0.103 for HbA_1c and 13.3 mmol/L for FBG. At baseline, mean HbA_1c was 0.104 and mean FBG was 14.1 mmol/L. Compared with placebo, treatment with Actos 30 mg resulted in reductions from baseline in mean HbA_1c of 0.010 and mean FBG of 3.4 mmol/L. For patients who had been previously treated with antidiabetic medication (60%), this medication was discontinued at screening. Mean values at screening were 0.094 for HbA_1c and 12.0 mmol/L for FBG. At baseline, mean HbA_1c was 0.106 and mean FBG was 15.9 mmol/L. Compared with placebo, treatment with Actos 30 mg resulted in reductions from baseline in mean HbA_1c of 0.013 and mean FBG of 2.6 mmol/L. In this study, the response to Actos brought the patients previously treated with other agents back to the values used before entering the trial, i.e., it largely corrected the increase in HbA_1c seen during the run-in period.

      Figure 3 shows the time course for changes in FBG and HbA_1c in naive patients and previous users of antidiabetic medications, during this 16-week study.

 

Figure 3:

Actos

Mean Change from Baseline for FBG and HbA_1c in a 16-week Placebo-controlled Study

 

     A subset analysis was performed on the combined results of the above monotherapy studies to determine if the HbA_1c levels at study entry had an effect on the outcome of the results. There was no meaningful difference in the efficacy of Actos in lowering HbA_1c levels in patients entering the studies with HbA_1c values which were <0.09 compared to those entering with values which were ≥ 0.09.

Combination Therapy

Three 16-week, randomized, double-blind, placebo-controlled clinical studies were conducted to evaluate the effects of Actos on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA_1c≥ 0.08) despite current therapy with a sulfonylurea, metformin, or insulin. Previous diabetes treatment may have been monotherapy or combination therapy.

     In one double-blind combination study, 560 patients with type 2 diabetes on a sulfonylurea, either alone or combined with another antidiabetic agent, were randomized to receive either placebo or Actos 15 mg or 30 mg once daily in addition to their current sulfonylurea regimen. Any other antidiabetic agent was withdrawn.  Figure 4 shows the changes in HbA_1c over the 16 week study period. Compared with placebo, the addition of Actos to the sulfonylurea significantly reduced the mean HbA_1c by 0.009 and 0.013 for the 15 mg and 30 mg doses, respectively. Compared with placebo, mean FBG decreased by 2.2 mmol/L (15 mg dose) and 3.2 mmol/L (30 mg dose).

     Actos resulted in dose-dependent, significant increases in HDL-C (15 mg, 0.04; 30 mg, 0.10 mmol/L; p≤ 0.05) and decreases in triglycerides (15 mg, -0.44; 30 mg, -0.80 mmol/L; p≤ 0.05).  See also Pharmacodynamics and Clinical Effects,  Table 2; Precautions, Edema, Weight Gain; Adverse Effects.

     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 (<50%, 50%, or >50% of the recommended maximum daily dose). A number of different sufonylureas were used in this study including glyburide (55% of patients) and glipizide (19% of patients).

     In a second double-blind combination study, 328 patients with type 2 diabetes on metformin either alone or combined with another antidiabetic agent, were randomized to receive placebo or Actos 30 mg once daily in addition to their metformin. Any other antidiabetic agent was withdrawn. Compared to placebo, the addition of Actos to metformin significantly reduced the mean HbA_1c by 0.008 and decreased the mean FBG by 2.1 mmol/L (see  Figure 4). Actos also significantly increased HDL-C (0.08 mmol/L; p≤ 0.05) and decreased triglycerides (-0.72 mmol/L; p≤ 0.05).

 

Figure 4:

Actos

Mean Change from Baseline for HbA_1c (%) during Placebo-controlled, Actos Combination Therapy Studies

 

     See also Pharmacodynamics and Clinical Effects,  Table 2; Precautions, Edema, Weight Gain; Adverse Effects.

     The therapeutic effect of Actos in combination with metformin was observed in patients regardless of whether the patients were receiving lower or higher doses of metformin (<2000 mg per day or ≥ 2000 mg per day).

     In a third double blind combination study, 566 patients with type 2 diabetes receiving a median of 60.5 units per day of insulin, either alone or combined with another antidiabetic agent, were randomized to receive placebo or to Actos 15 mg or 30 mg once daily in addition to their insulin. Any other antidiabetic agent was discontinued. Compared to placebo, treatment with Actos in addition to insulin significantly reduced both HbA_1c (reduction of 0.007 for the 15 mg dose and 0.01 for the 30 mg dose) and FBG (1.9 mmol/L for the 15 mg dose and 2.7 mmol/L for the 30 mg dose). Adverse events most commonly reported were hypoglycemia (11.6%), upper respiratory tract infection (11.6%) and edema (11.3%); for the placebo plus insulin patients, the incidence of these adverse events was as follows: hypoglycemia, 4.8%; upper respiratory tract infection, 9.6%; edema, 7%. See also Pharmacodynamics and Clinical Effects, Table 2; Precautions, Edema, Weight Gain; Adverse Effects .

     The therapeutic effect of Actos in combination with insulin was observed in patients regardless of whether the patients were receiving lower or higher doses of insulin (<60.5 units per day or ≥ 60.5 units per day). Compared with the other groups, a significantly higher percentage of patients randomized to Actos 30 mg reduced their daily insulin dose by >25% (placebo, 2.1%; Actos 15 mg, 3.7%; Actos 30 mg, 16.0%).  One Actos 30 mg patient discontinued insulin.

     During an open label extension study, 236 patients received Actos in combination with sulfonylurea and 154 received Actos in combination with metformin.  Patients receiving sulfonylurea were initiated with Actos 15 mg daily whereas those receiving metformin were initiated with Actos 30 mg daily.  Based on the HbA_1c response, the Actos dose could be titrated up to 45 mg daily.  The median duration of open label Actos therapy was 67.6 weeks; the maximum duration was 84 weeks.

     The  mean changes for HbA_1c, FBG, triglycerides and HDL-C for the Actos treatment groups during the preceding double blind studies were sustained for at least 60 weeks open-label treatment.  For those patients who completed at least 60 weeks of open label treatment with Actos, the mean reduction from double-blind baseline for HbA_1c was 0.013 (p<0.0001). Mean FBG was reduced 3.7 mmol/L (mean change − 25.12%).  The mean change in triglycerides and HDL-C was − 10.4% and  +9.3%, respectively.  All mean changes were comparable for both combination therapies.

     The types of adverse events reported were, in general, similar to those in the double-blind studies (see Adverse Effects).

 

Indications

Actos (pioglitazone hydrochloride) is indicated as monotherapy in patients not controlled by diet and exercise alone, to decrease insulin resistance and blood glucose levels in patients with type 2 diabetes mellitus (non-insulin dependent diabetes mellitus, NIDDM).

     Actos is indicated for use in combination with a sulfonylurea or metformin when diet and exercise plus the single agent do not result in adequate glycemic control.

Clinical Use: It is recommended that patients be treated for an adequate period of time to evaluate change in HbA_1c unless glycemic control deteriorates.

     Management of type 2 diabetes should also include nutritional counselling, weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy.

     The long-term safety and efficacy of the use of Actos in combination with insulin is the subject of ongoing clinical studies.

 

Contraindications

Actos (pioglitazone hydrochloride) is contraindicated in patients with:

•  known hypersensitivity to this product or any of its components;

•  serious hepatic impairment (see Precautions, Hepatic Insufficiency);

•  acute heart failure (see Warnings, Heart Disease).

 

 

Warnings

Heart Disease: Treatment with thiazolidinediones has been associated with cases of heart failure which were difficult to treat unless the medication was discontinued. Thiazolidinediones can cause fluid retention, which can exacerbate congestive heart failure. Patients at risk for heart failure, particularly any patient also taking insulin, should be monitored for the signs and symptoms of heart failure. (Clinical evidence for the safety of Actos in combination with insulin is the subject of ongoing clinical trials.) (See Precautions, Use in Patients with Heart Disease.)

     Actos is not indicated in patients with NYHA Class II, III or IV cardiac status. Actos should be discontinued if  patients develop clinical heart failure (See Precautions, Use in Patients with Heart Disease).

Hepatic Disease: Rare cases of severe hepatocellular injury have been reported associated with thiazolidinediones (see Precautions, Hepatic Insufficiency).

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Actos should not be used during pregnancy. Current information strongly suggests that abnormally high blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies as well as increased neonatal morbidity and mortality. Most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.

     Pioglitazone was not teratogenic in rats at oral doses up to 80 mg/kg or in rabbits given up to 160 mg/kg during organogenesis (approximately 17 and 40 times the maximum recommended human oral dose based on mg/m², respectively). Delayed parturition and embryotoxicity (as evidenced by increased postimplantation losses, delayed development and reduced fetal weights) were observed in rats at oral doses of 40 mg/kg/day and above (approximately 10 times the maximum recommended human oral dose based on mg/m²). No functional or behavioral toxicity was observed in offspring of rats. In rabbits, embryotoxicity was observed at an oral dose of 160 mg/kg (approximately 40 times the maximum recommended human oral dose based on mg/m²). Delayed postnatal development, attributed to decreased body weight, was observed in offspring of rats at oral doses of 10 mg/kg and above during late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose based on mg/m²).

 

Precautions

 

General

The effect of Actos on morbidity and mortality has not been established.

     Actos (pioglitazone hydrochloride) exerts its antihyperglycemic effect only in the presence of insulin. Therefore, Actos should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Hypoglycemia: During the administration of Actos as monotherapy, documented hypoglycemia has not been observed, nor would it be expected based on the mechanism of action.

Ovulation: In premenopausal anovulatory patients with insulin resistance, treatment with thiazolidinediones, including Actos, may result in resumption of ovulation. These patients may be at risk for pregnancy if adequate contraception is not used.

Hematologic: Across all clinical studies, mean hemoglobin values declined by 2% to 4% in Actos-treated patients but remained within normal limits at all times (including up to 18 months of continuous therapy). In all studies, patients were excluded if they had a hemoglobin of less than 120 g/L for males or 100 g/L for females. In the monotherapy studies, the mean hemoglobin declined from 151 to 147 g/L, with the range in the bottom 10% of hemoglobin values 111 to 125 g/L. In a long-term open-label follow-up monotherapy study of an additional 84 weeks, the change in hemoglobin remained small, declining from 151 to 143 g/L. In the combination studies, the mean hemoglobin declined from 147 to 142 g/L, with the range in the bottom 10% of hemoglobin values 100 to 124 g/L. In a long-term open-label follow-up combination study, after an additional 72 weeks, the change in hemoglobin remained small, declining from 147 to 138g/L. These changes may be related to increased plasma volume and have not been associated with any significant hematologic clinical effects (see Adverse Effects, Laboratory Abnormalities).

Use in Patients with Heart Disease: In a 6-month placebo-controlled study of 334 patients with type 2 diabetes and a long-term (one year or more) open-label study of more than 350 patients with type 2 diabetes, echocardiographic evaluation revealed no increase in mean left ventricular mass index or decrease in mean cardiac index in patients treated with Actos. Preload-induced cardiac hypertrophy has been observed in some animal toxicology studies.

     In clinical trials that excluded patients with New York Heart Association (NYHA) Class III and IV cardiac status, electrocardiographic evidence of left ventricular hypertrophy, a history of myocardial infarction, coronary angioplasty, coronary bypass graft, unstable angina pectoris, transient ischemic attacks, or a documented cerebrovascular accident 6 months preceding the study, no increased incidence of serious cardiac adverse events potentially related to volume expansion (e.g., congestive heart failure) was observed. Patients with NYHA Class III and IV cardiac status were not studied in Actos clinical trials. There is limited exposure of Actos in patients with Class II cardiac status. Patients should be monitored for evidence of congestive heart failure.

Edema: Actos should be used with caution in patients with edema. In studies of 488 non-diabetic subjects, no cases of edema were reported except in 4 subjects with concomitant impaired hepatic function and 5 with renal dysfunction. However, in the placebo-controlled clinical studies, the incidence of edema is increased with Actos relative to the control groups (see Adverse Effects).

Weight Gain: Actos may be associated with weight gain. In the clinical studies, improvements in hyperglycemia were associated with weight gain. Mean weight gain in controlled monotherapy studies ranged from 0.5 to 2.8 kg. In combination therapy studies, the mean weight gain ranged from 0.95 to 3 kg. Patients who experience unusual or unexpected weight gain should be re-evaluated (see Pharmacology, Pharmacodynamics and Clinical Effects).

Hepatic Disease: Therapy with Actos should not be initiated in patients with increased baseline liver enzyme levels (ALT >2.5 times the upper limit of normal).

     Although available data from clinical studies show no evidence of Actos-induced hepatotoxicity or ALT elevations, pioglitazone has a common thiazolidinedione structure to troglitazone, which has been associated with idiosyncratic hepatotoxicity and rare cases of liver failure, liver transplants, and death. Pending the availability of the results of additional large, long-term controlled clinical trials and postmarket safety data following wide clinical use of Actos to more fully define its hepatic safety profile, it is recommended that patients treated with Actos undergo periodic monitoring of liver enzymes. Liver enzymes should be checked prior to the initiation of therapy with Actos in all patients. In patients with normal baseline liver enzymes, following initiation of therapy with Actos, it is recommended that liver enzymes be monitored every two months for the first twelve months, and periodically thereafter. Patients with mildly elevated liver enzymes (ALT levels one to 2.5 times the upper limit of normal) at baseline or during therapy with Actos should be evaluated to determine the cause of the liver enzyme elevation. Initiation of, or continuation of therapy with Actos in patients with mild liver enzyme elevations should proceed with caution and include appropriate close clinical follow-up, including more frequent liver enzyme monitoring, to determine if the liver enzyme elevations resolve or worsen. If at any time ALT levels increase to >3 times the upper limit of normal in patients on therapy with Actos, liver enzymes should be rechecked as soon as possible. If ALT levels remain >3 times the upper limit of normal, therapy with Actos should be discontinued. (For Use in Patients with Hepatic Insufficiency, see Pharmacology, Special Populations.)

 

Children

Safety and effectiveness of Actos in pediatric patients have not been established. Use in patients under 18 years of age is not recommended.

Geriatrics

Approximately 500 patients in placebo-controlled clinical trials of Actos were 65 and over. No significant differences in effectiveness and safety were observed between these patients and younger patients.

 

Lactation

Pioglitazone is secreted in the milk of lactating rats. It is not known whether Actos is secreted in human milk. Because many drugs are excreted in human milk, Actos should not be administered to a breast-feeding woman.

Information to Be Provided to the Patient

It is important to instruct patients to adhere to dietary instructions, caloric restrictions, weight loss and exercise programs and to have blood glucose and glycosylated hemoglobin tested regularly.

     Patients should be told to take Actos (pioglitazone hydrochloride) once daily. Actos can be taken with or without meals. If a dose is missed on one day, the patient should take the regular dose on the following day. The patient should not take a double dose to make up for a missed dose.

     Although Actos was not associated with hepatic toxicity during clinical trials, patients who develop nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine, jaundice or other symptoms and signs suggestive of hepatic dysfunction should immediately report these to their physician. Patients should be informed that a blood test will be drawn to check their liver function prior to the start of therapy and every two months for the first twelve months, and periodically thereafter.

     Since thiazolidinediones can cause fluid retention, which can exacerbate congestive heart failure, patients should be monitored for the signs and symptoms of heart failure. All patients should be told to inform their physician immediately if they develop edema, shortness of breath, weakness, fatigue, or rapid weight gain. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly.

     Patients should inform their physician if they are taking oral contraceptives. Since Actos may interfere with the metabolism of oral contraceptives, the patient's dose of oral contraceptive may need to be adjusted. Women of childbearing age should inform their physician if they are or intend to become pregnant. In anovulatory, premenopausal women with insulin resistance, therapy with Actos may cause resumption of ovulation and contraceptive measures may need to be considered. Patients who appear to be infertile, should discuss the question of contraceptives before starting therapy with Actos.

 

Drug Interactions

Oral Contraceptives: Administration of another thiazolidinedione with an oral contraceptive containing ethinyl estradiol and norethindrone reduced the plasma concentrations of both hormones by approximately 30%, which could result in loss of contraception. The pharmacokinetics of coadministration of Actos and oral contraceptives have not been evaluated in patients receiving Actos and an oral contraceptive. Therefore, additional caution regarding contraception should be exercised in patients receiving Actos and an oral contraceptive.

Glipizide: In healthy volunteers, coadministration of Actos (45 mg once daily) and glipizide (5 mg once daily) for seven days did not alter the steady-state pharmacokinetics of glipizide.

Digoxin: In healthy volunteers, coadministration of Actos (45 mg once daily) with digoxin (0.25 mg once daily) for seven days did not alter the steady-state pharmacokinetics of digoxin.

Warfarin: In healthy volunteers, coadministration of Actos (45 mg once daily) for seven days with warfarin did not alter the steady-state pharmacokinetics of warfarin. In addition, Actos has no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin therapy.

Metformin: In healthy volunteers, coadministration of metformin (1000 mg) and Actos (45 mg) after seven days of Actos (45 mg once daily) did not alter the pharmacokinetics of the single dose of metformin.

     Pioglitazone neither induced nor inhibited P450 activity when tested following chronic administration to rats or when incubated with human P450 liver microsomes indicating minimal effects of Actos on metabolic pathways of the liver. The cytochrome P450 isoform CYP3A4 is partially responsible for the metabolism of pioglitazone. Specific formal pharmacokinetic interaction studies have not been conducted with Actos and other drugs metabolized by this enzyme such as: erythromycin, astemizole, calcium channel blockers, cisapride, corticosteroids, cyclosporine, HMG-CoA reductase inhibitors, tacrolimus, trizolam, and trimetrexate, as well as inhibitory drugs such as ketoconazole and itraconazole. However, patients on drugs metabolized by cytochrome P450 enzymes including calcium channel blockers and HMG-CoA reductase inhibitors were permitted in clinical trials.

 

Adverse Effects

Controlled Clinical Trials: In worldwide clinical trials, over 3700 patients with type 2 diabetes have been treated with Actos (pioglitazone hydrochloride). The overall incidence and types of adverse events reported in placebo-controlled clinical trials of Actos monotherapy at doses of 7.5 mg, 15 mg, 30 mg, or 45 mg once daily are shown in  Table 7.

CPS:Actos_t7Click here for Table 7

Table 7: Actos

Placebo-controlled Clinical Studies of Actos Monotherapy: Adverse Events Reported at a Frequency >5% of Actos-treated Patients

 

	(% of Patients)
	Placebo n=259	Actos n=606
Upper Respiratory Tract Infection	8.5	13.2
Headache	6.9	9.1
Sinusitis	4.6	6.3
Myalgia	2.7	5.4
Tooth Disorder	2.3	5.3
Diabetes Mellitus Aggravated	8.1	5.1
Pharyngitis	0.8	5.1

 

     In addition, 4.8% of patients on Actos experienced edema, compared with 1.2% on placebo.  In a long-term, open-label followup study of monotherapy, a cumulative incidence of edema of 6.0% has been reported with Actos.

     The types of clinical adverse events reported when Actos was used in combination with sulfonylureas (N=373) or metformin (N=168) were generally similar to those reported during Actos monotherapy. The most commonly reported adverse events from the combination therapy studies with sulfonylureas or metformin are shown in  Table 8.

CPS:Actos_t8Click here for Table 8

Table 8: Actos

Placebo-controlled Studies of Actos in combination with a Sulfonylurea or Metformin: Adverse Events Reported at a Frequency >5% in any Group

 

Combination therapy	(% of Patients)
	Sulfonylurea		Metformin
Treatment group	Placebo n=187	Actos n=373	Placebo n=160	Actos n=168
Upper respiratory tract infection	15.5	16.6	15.6	15.4
Accidental injury	8.6	3.5	3.8	4.2
Peripheral edema	2.1	5.1	2.5	4.2
Diarrhea	3.7	1.6	6.3	4.8
Headache	3.7	4.8	1.9	6.0

 

     Mild to moderate hypoglycemia was reported during combination therapy with sulfonylurea. In double-blind, combination therapy studies with a sulfonylurea or insulin, the incidence of hypoglycemia was higher for patients initiated with Actos 30 mg than for those receiving placebo or Actos 15 mg ( Table 9).

     Edema also occurred more frequently in patients receiving Actos 30 mg  ( Table 9;  see also Precautions, Weight Gain, Edema).

CPS:Actos_t9Click here for Table 9

Table 9: Actos

Selected adverse events during controlled, combination therapy studies

 

Combination Therapy	Sulfonylurea			Metformin		Insulin
	Placebo	Actos 15 mg	Actos 30 mg	Placebo	Actos 30 mg	Placebo	Actos 15 mg	Actos 30 mg
N	187 (%)	184 (%)	189 (%)	160 (%)	168 (%)	187 (%)	191 (%)	188 (%)
Hypoglycemia	1 (0.5)	0	7 (3.7)	1 (0.6)	1 (0.6)	9 (4.8)	15 (7.9)	29 (15.4)
Edemaa	4 (2.1)	3 (1.6)	25 (13.2)	4 (2.5)	10 (6.0)	14 (7.5)	25 (13.1)	33 (17.6)
Hypertension	2 (1.1)	2 (1.1)	4 (2.1)	2 (1.3)	3 (1.79)	4 (2.1)	3 (1.6)	3 (1.6)
Cardiac disordersb	4 (2.1)	7 (3.8)	6 (3.2)	3 (1.9)	1 (0.6)	10 (5.3)	6 (3.1)	14 (7.4)
Ischemiac	3 (1.6)	1 (0.5)	5 (2.5)	0	1 (0.6)	2 (1.1)	2 (1.0)	4 (2.1)

 

 ^a Edema and peripheral edema

 ^b Chest pain and abnormal EGC

 ^c Angina pectoris, myocardial infarction, myocardial ischemia and transient ischemic attacks

 

 

     During an open-label extension study, Actos was added to the patient's sulfonylurea or metformin, and the dose titrated based on the HbA_1cresponse. Selected adverse events that occurred during this long-term study are shown in  Table 10. However, the study did not include a placebo group to control for the background rate of adverse events.

     The incidence of withdrawals from clinical trials due to an adverse event other than hyperglycemia was similar for patients treated with placebo (2.8%) or Actos (3.3%). In all clinical trials weight increased proportionately as the HbA_1c decreased, suggesting that weight gain was associated with improved glycemic control. However, excessive weight gain did result in 2 patients being withdrawn from the clinical trial (see Pharmacology, Pharmacodynamics and Clinical Effects, Precautions and Information to Be Provided to the Patient).

Post-marketing Reports: In post-marketing experience with Actos, cases of congestive heart failure have been reported primarily in patients with a history of reduced cardiac reserve. A causal relationship has not been established.

     In post-marketing experience with Actos, reports of hepatitis and of hepatic enzyme elevations to 3 or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established.

CPS:Actos_t10Click here for Table 10

Table 10: Actos

Selected adverse events during open label, combination therapy study (67.6 weeks median duration)

 

Combination Therapy	Sulfonylurea			Metformin
	15 mg	30mg	45 mg	15 mg	30 mg	45mg
N	46 (%)	81 (%)	109 (%)	5 (%)	75 (%)	74 (%)
Hypoglycemia	6 (13.0)	9 (11.1)	4 (3.7)	1 (20.0)	1 (1.3)	3 (4.1)
Edemaa	8 (17.4)	17(20.9)	24 (22.0)	0	13 (17.3)	11 (14.9)
Hypertension	2 (4.3)	5 (6.2)	9 (8.3)	0	5 (6.7)	3 (4.1)
Cardiac disordersb	4 (8.7)	8 (9.9)	12 (11.0)	0	5 (6.7)	7 (9.5)
Ischemiac	3 (6.5)	0	3 (2.8)	0	3 (4.0)	2 (2.7)

 

 ^a Edema and peripheral edema

 ^b Chest pain and abnormal ECG

 ^c Angina pectoris, myocardial infarction, myocardial ischemia and transient ischemic attacks

 

 

Laboratory Abnormalities: Hematologic: Across all clinical studies, mean hemoglobin values declined by 2% to 4% in Actos-treated patients. These changes generally occurred within the first 4 to 12 weeks of therapy and remained relatively stable thereafter. These changes may be related to increased plasma volume associated with Actos therapy and have not been associated with any significant hematologic clinical effects. Values remained within normal limits at all times (including up to 18 months of continuous therapy).

Serum Transaminase Levels: A total of 4 of 1526 (0.26%) Actos-treated patients and 2 of 793 (0.25%) placebo-treated patients had ALT values ≥ 3 times the upper limit of normal in double-blind, randomized clinical trials. During all clinical studies in the U.S., 11 of 2561 (0.43%) Actos-treated patients had ALT values ≥ 3 times the upper limit of normal. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with Actos, mean values for bilirubin, AST, ALT, alkaline phosphatase, and GGT were decreased at the final visit compared with baseline. Fewer than 0.12% of Actos-treated patients were withdrawn from clinical trials due to abnormal liver function tests.

     In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure.

 

Overdose

 

 

Symptoms

During controlled clinical trials, one case of overdose with Actos (pioglitazone hydrochloride) 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.

 

 

Treatment

In the event of overdosage, appropriate supportive treatment should be initiated according to patient's clinical signs and symptoms.

 

Dosage

The management of antidiabetic therapy should be individualized. Ideally, the response to therapy should be evaluated using HbA_1c, which is a better indicator of long-term glycemic control than FBG alone. HbA_1c reflects glycemia over the past two to three months. In clinical use, it is recommended that patients be treated with Actos for a period of time adequate to evaluate change in HbA_1c unless glycemic control deteriorates.

     Actos should be taken once daily without regard to meals.

Monotherapy

Actos 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 Actos, the dose can be increased in increments up to 45 mg once daily.

Combination Therapy

In patients not adequately controlled with a sulfonylurea or metformin, Actos may be initiated at 15 or 30 mg once daily. For patients who do not respond adequately to the initial dose, Actos  may be increased in increments up to 45 mg once daily.

     As adverse events such as edema and weight gain appear to be dose-related, the smallest effective dose should be used (see Precautions and Information to Be Provided to the Patient).

     In patients receiving a sulfonylurea, the dose of the sulfonylurea may need to be decreased if hypoglycemia occurs. It is unlikely that the metformin dose will require adjustment because of hypoglycemia.

     The dose of Actos (pioglitazone hydrochloride) should not exceed 45 mg once daily since doses higher than 45 mg once daily have not been studied in placebo-controlled clinical studies.

     Liver enzymes should be checked prior to the initiation of therapy with Actos in all patients. Therapy with Actos should not be initiated if a patient exhibits clinical evidence of liver disease or increased serum transaminase levels (ALT >2.5 times upper limit of normal). SeePrecautions, Hepatic Disease for additional information on liver enzyme monitoring. In cases where therapy is to be initiated, dose adjustment in patients with hepatic disease is not required (see Pharmacology, Special Populations).

     Dose adjustment in patients with renal insufficiency is not required (see Pharmacology, Special Populations).

 

Supplied

15 mg

Each white to off-white, round, convex, non-scored tablet, with “Actos” printed on one side and “15” on the other, contains: pioglitazone HCl equivalent to pioglitazone 15 mg. Nonmedicinal ingredients: carboxymethylcellulose calcium, hydroxypropylcellulose, lactose monohydrate and magnesium stearate. Bottles of 90.