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Actos

ACTOS, aka, pioglitazone hydrochloride, is a once-a-day prescription pill for type 2 diabetes that along with healthy eating and physical activity helps your body more effectively use its own natural insulin or the insulin you take. When your necessary efforts at healthy eating and physical activity alone do not control your blood glucose levels, ACTOS can be used by itself or in combination with certain other diabetes pills (sulfonylureas, metformin) or insulin to lower blood glucose.

ACTOS is a member of the type of oral diabetes agents called thiazolidinediones (THIGH-ah-ZO-li-deen-DYE-owns; TZDs). These medications help reduce insulin resistance, which has been identified as one of the major problems in type 2 diabetes.

ACTOS side effects have been known to include Congestive Heart Failure CHF and Liver Damage. Due to Actos side effects Actos lawyers have begun to actively search for individuals that have sustained Actos side effects and are interested in pursuing Actos lawsuits. Below is some information pertaining to Actos side effects that have resulted in Actos attorneys starting Actos lawsuits. If you have been injured as a result of ACTOS side effects you may want to contact an ACTOS lawyer about an ACTOS lawsuit. Mass Tort Lawsuits are a common practice of many ACTOS attorneys. There are several Mass Tort Lawyers that may be able to handle an ACTOS lawsuit including:

Parker & Waichman - NY City

Ennis & Ennis, P.A. - Washington DC (National Mass Tort Lawyers)

The American Heart Association and American Diabetes Association issued recommendations to guide the use of glucose-lowering drugs known as thiazolidinediones (TZDs), including Actos .

Researchers say that in some people, Actos may cause fluid retention, a condition known as edema, and swelling of the feet. Edema is also a classic symptom of congestive heart failure. The increase in fluid retention and therefore weight gain is usually seen in the first weeks after initiating therapy and then plateaus.

Because edema is a well-known side effect of these drugs, especially when combined with insulin therapy, researchers say that patients and health-care providers should be aware of the risk of congestive heart failure when using Actos.

According to a consensus statement released by the AHA and ADA in the Dec. 9 issue of Circulation: Journal of the American Heart Association, people with moderate to severe congestive heart failure should not use these drugs.

The warning comes after a Mayo Clinic study was released that identified Congestive Heart Failure in Actos and Avandia patients. This study was published in the September 9 2004 issue of the Mayo Clinic Proceedings and reported on six cases of congestive heart failure in people taking these drugs.

The study concluded that diabetics who have mild heart disease or any problems with their kidneys could be at a greater risk of developing congestive heart failure if they take Actos or Avandia.

Below is the prescribing information provided by Eli-Lilly:

ACTOS®
(pioglitazone hydrochloride) Tablets
DESCRIPTION
ACTOS (pioglitazone hydrochloride) 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.
Pioglitazone [(±)-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. The structural
formula is as shown:
Pioglitazone hydrochloride is an odorless white crystalline powder that has a
molecular formula of C19H20N2O3S•HCl and a molecular weight of 392.90 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.
ACTOS is available as a tablet for oral administration containing 15 mg, 30 mg,
or 45 mg of pioglitazone (as the base) formulated with the following excipients:
lactose monohydrate NF, hydroxypropylcellulose NF, carboxymethylcellulose
calcium NF, and magnesium stearate NF.
CLINICAL PHARMACOLOGY
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 a 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.
Pharmacokinetics and Drug Metabolism
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 area under the serum concentration-time curve (AUC).
Maximum serum concentration (Cmax), AUC, and trough serum concentrations
(Cmin) 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. 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 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 Drug Interactions). Urinary 6ß-hydroxycortisol/
cortisol ratios measured in patients treated with ACTOS showed that pioglitazone
is not a strong CYP3A4 enzyme inducer.
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 AND 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 PRECAUTIONS, Hepatic Effects).
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,
N
O
CH3
S
NH
O
O
• HCl
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.
Drug-Drug Interactions
The following drugs were studied in healthy volunteers with a co-administration
of ACTOS 45 mg once daily. Listed below are the results:
Oral Contraceptives: Co-administration of ACTOS (45 mg once daily) and an
oral contraceptive (1 mg norethindrone plus 0.035 mg ethinyl estradiol once
daily) for 21 days, resulted in 11% and 11-14% decrease in ethinyl estradiol
AUC (0-24h) and Cmax respectively. There were no significant changes in
norethindrone AUC (0-24h) and Cmax. In view of the high variability of ethinyl
estradiol pharmacokinetics, the clinical significance of this finding is
unknown.
Fexofenadine HCI: Co-administration of ACTOS for 7 days with 60 mg fexofenadine
administered orally twice daily resulted in no significant effect on
pioglitazone pharmacokinetics. ACTOS had no significant effect on fexofenadine
pharmacokinetics.
Glipizide: Co-administration of ACTOS and 5 mg glipizide administered orally
once daily for 7 days did not alter the steady-state pharmacokinetics of glipizide.
Digoxin: Co-administration of ACTOS with 0.25 mg digoxin administered orally
once daily for 7 days did not alter the steady-state pharmacokinetics of
digoxin.
Warfarin: Co-administration of ACTOS for 7 days with warfarin did not alter
the steady-state pharmacokinetics of warfarin. ACTOS has no clinically significant
effect on prothrombin time when administered to patients receiving
chronic warfarin therapy.
Metformin: Co-administration of a single dose of metformin (1000 mg) and
ACTOS after 7 days of ACTOS did not alter the pharmacokinetics of the single
dose of metformin.
Midazolam: Administration of ACTOS for 15 days followed by a single 7.5 mg
dose of midazolam syrup resulted in a 26% reduction in midazolam Cmax and
AUC.
Ranitidine HCI: Co-administration of ACTOS for 7 days with ranitidine administered
orally twice daily for either 4 or 7 days resulted in no significant effect
on pioglitazone pharmacokinetics. ACTOS showed no significant effect on
ranitidine pharmacokinetics.
Nifedipine ER: Co-administration of ACTOS for 7 days with 30 mg nifedipine
ER administered orally once daily for 4 days to male and female volunteers
resulted in least square mean (90% Cl) values for unchanged nifedipine of
0.83 (0.73-0.95) for Cmax and 0.88 (0.80-0.96) for AUC. In view of the high
variability of nifedipine pharmacokinetics, the clinical significance of this finding
is unknown.
Ketoconazole: Co-administration of ACTOS for 7 days with ketoconazole
200 mg administered twice daily resulted in least square mean (90% Cl) values
for unchanged pioglitazone of 1.14 (1.06 - 1.23) for Cmax, 1.34 (1.26 - 1.41)
for AUC and 1.87 (1.71 - 2.04) for Cmin.
Atorvastatin Calcium: Co-administration of ACTOS for 7 days with atorvastatin
calcium (LIPITOR®) 80 mg once daily resulted in least square mean (90% Cl)
values for unchanged pioglitazone of 0.69 (0.57 - 0.85) for Cmax, 0.76 (0.65 -
0.88) for AUC and 0.96 (0.87 - 1.05) for Cmin. For unchanged atorvastatin
the least square mean (90% Cl) values were 0.77 (0.66 - 0.90) for Cmax, 0.86
(0.78 - 0.94) for AUC and 0.92 (0.82 - 1.02) for Cmin.
Theophylline: Co-administration of ACTOS for 7 days with theophylline 400 mg
administered twice daily resulted in no change in the pharmacokinetics of
either drug.
Cytochrome P450: See PRECAUTIONS.
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
lower plasma glucose concentrations, lower plasma insulin levels, and lower
HbA1c values. Based on 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 (Table 1).
Table 1 Lipids in a 26-Week Placebo-Controlled Monotherapy
Dose-Ranging Study
ACTOS ACTOS ACTOS
Placebo 15 mg 30 mg 45 mg
Once Daily Once Daily Once Daily
Triglycerides (mg/dL) N=79 N=79 N=84 N=77
Baseline (mean) 262.8% 283.8% 261.1% 259.7%
Percent change from 4.8% -9.0% -9.6% -9.3%
baseline (mean)
HDL Cholesterol (mg/dL) N=79 N=79 N=83 N=77
Baseline (mean) 41.7% 40.4% 40.8% 40.7%
Percent change from 8.1% 14.1% 12.2% 19.1%
baseline (mean)
LDL Cholesterol (mg/dL) N=65 N=63 N=74 N=62
Baseline (mean) 138.8% 131.9% 135.6% 126.8%
Percent change from 4.8% 7.2% 5.2% 6.0%
baseline (mean)
Total Cholesterol (mg/dL) N=79 N=79 N=84 N=77
Baseline (mean) 224.6% 220.0% 222.7% 213.7%
Percent change from 4.4% 4.6% 3.3% 6.4%
baseline (mean)
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 data above. In placebo-controlled trials, the placebo-corrected mean
changes from baseline decreased 5% to 26% for triglycerides and increased
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.
In a combination therapy study with insulin (16 weeks), the placebo-corrected
mean percent change from baseline in triglyceride values for patients
treated with ACTOS was also decreased. A placebo-corrected mean change
from baseline in LDL cholesterol of 7% was observed for the 15 mg dose
group. Similar results to those noted above for HDL and total cholesterol
were observed. A similar pattern of results was seen in a 24-week combination
therapy study with ACTOS with insulin.
Clinical Studies
Monotherapy
In the U.S., 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.
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 study.
Figure 1 Mean Change from Baseline for FPG and HbA1c in a
26-Week Placebo-Controlled Dose-Ranging Study
Table 2 shows HbA1c and FPG values for the entire study population.
Table 2 Glycemic Parameters in a 26-Week Placebo-Controlled
Dose-Ranging Study
ACTOS ACTOS ACTOS
Placebo 15 mg 30 mg 45 mg
Once Daily Once Daily Once Daily
Total Population
HbA1c (%) N=79 N=79 N=85 N=76
Baseline (mean) 10.4 10.2 10.2 10.3
Change from baseline 0.7 -0.3 -0.3 -0.9
(adjusted mean+)
Difference from placebo -1.0* -1.0* -1.6*
(adjusted mean+)
FPG (mg/dL) N=79 N=79 N=84 N=77
Baseline (mean) 268 267 269 276
Change from baseline 9 -30 -32 -56
(adjusted mean+)
Difference from placebo -39* -41* -65*
(adjusted mean+)
+Adjusted for baseline, pooled center, and pooled center by treatment interaction
*p ≤ 0.050 vs. placebo
The study population included patients not previously treated with antidiabetic
medication (naïve; 31%) and patients who were receiving antidiabetic medication
at the time of study enrollment (previously treated; 69%). The data for
the naïve 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 naïve 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.
Table 3 Glycemic Parameters in a 26-Week Placebo-Controlled
Dose-Ranging Study
ACTOS ACTOS ACTOS
Placebo 15 mg 30 mg 45 mg
Once Daily Once Daily Once Daily
Naïve to Therapy
HbA1c (%) N=25 N=26 N=26 N=21
Screening (mean) 9.3 10.0 9.5 9.8
Baseline (mean) 9.0 9.9 9.3 10.0
Change from baseline 0.6 -0.8 -0.6 -1.9
(adjusted mean*)
Difference from placebo -1.4 -1.3 -2.6
(adjusted mean*)
FPG (mg/dL) N=25 N=26 N=26 N=21
Screening (mean) 223 245 239 239
Baseline (mean) 229 251 225 235
Change from baseline 216 -37 -41 -64
(adjusted mean*)
Difference from placebo -52 -56 -80
(adjusted mean*)
Previously Treated
HbA1c (%) N=54 N=53 N=59 N=55
Screening (mean) 9.3 9.0 9.1 9.0
Baseline (mean) 10.9 10.4 10.4 10.6
Change from baseline 0.8 -0.1 -0.0 -0.6
(adjusted mean*)
Difference from placebo -1.0 -0.9 -1.4
(adjusted mean*)
FPG (mg/dL) N=54 N=53 N=58 N=56
Screening (mean) 222 209 230 215
Baseline (mean) 285 275 286 292
Change from baseline 224 -32 -27 -55
(adjusted mean*)
Difference from placebo -36 -31 -59
(adjusted mean*)
* Adjusted for baseline and pooled center
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).
Table 4 Glycemic Parameters in a 24-Week Placebo-Controlled
Forced-Titration Study
ACTOS ACTOS
Placebo +30 mg+ +45 mg+
Once Daily Once Daily
Total Population
HbA1c (%) N=83 N=85 N=85
Baseline (mean) 10.8 10.3 10.8
Change from baseline 0.9 -0.6 -0.6
(adjusted mean++)
Difference from placebo -1.5* -1.5*
(adjusted mean++)
FPG (mg/dL) N=78 N=82 N=85
Baseline (mean) 279 268 281
Change from baseline 218 -44 -50
(adjusted mean++)
Difference from placebo -62* -68*
(adjusted mean++)
\ +Final dose in forced titration
++ Adjusted for baseline, pooled center, and pooled center by treatment interaction
*p ≤ 0.050 vs. placebo
For 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 mg/dL 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.
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).
Table 5 Glycemic Parameters in a 16-Week Placebo-Controlled Study
ACTOS 30 mg
Placebo Once Daily
Total Population
HbA1c (%) N=93 N=100
Baseline (mean) 10.3 10.5
Change from baseline (adjusted mean+) 0.8 -0.6
Difference from placebo (adjusted mean+) -1.4*
FPG (mg/dL) N=91 N=99
Baseline (mean) 270.3 273
Change from baseline (adjusted mean+) 278.3 -50
Difference from placebo (adjusted mean+) -58*
+ Adjusted for baseline, pooled center, and pooled center by treatment interaction
* p ≤ 0.050 vs. placebo
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 1.0% 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.
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 mg/dL and 58 mg/dL for the 15 mg and
30 mg doses, respectively.
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. 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.
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 0.80% 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 effect of ACTOS in combination with metformin was
observed in patients regardless of whether the patients were receiving lower
or higher doses of metformin.
ACTOS Plus Insulin Studies
Two clinical studies were conducted with ACTOS in combination with
insulin. Both studies included patients with type 2 diabetes on insulin, either
alone or in combination with another antidiabetic agent. All other antidiabetic
agents were withdrawn prior to starting study treatment. In the first
study, 566 patients receiving a median of 60.5 units per day of insulin were
randomized to receive either 15 mg or 30 mg of ACTOS or placebo once
daily for 16 weeks in addition to their insulin regimen. When compared to
placebo at Week 16, the addition of ACTOS to insulin significantly reduced
both HbA1c by 0.7% and 1.0% and FPG by 35 mg/dL and 49 mg/dL for the
15 mg and 30 mg dose, respectively.
In the second study, 690 patients receiving a median of 60.0 units per day
of insulin received either 30 mg or 45 mg of ACTOS once daily for 24 weeks
in addition to their current insulin regimen. The mean reductions from baseline
at Week 24 in HbA1c were 1.17% and 1.46% for the 30 mg and 45 mg
doses, respectively. Mean reductions from baseline in FPG were 31.9 mg/dL
and 45.8 mg/dL. Improved glycemic control was accompanied by mean
decreases from baseline in insulin dose requirements of 6.0% and 9.4% per
day for the 30 mg and 45 mg dose, respectively.
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.
INDICATIONS AND USAGE
ACTOS 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). ACTOS is indicated for monotherapy. ACTOS 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.
Management of type 2 diabetes should also include nutritional counseling,
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.
CONTRAINDICATIONS
ACTOS is contraindicated in patients with known hypersensitivity to this product
or any of its components.
WARNINGS
Cardiac Failure and Other Cardiac Effects
ACTOS, like other thiazolidinediones, can cause fluid retention when used
alone or in combination with other antidiabetic agents, including insulin. Fluid
retention may lead to or exacerbate heart failure. Patients should be observed
for signs and symptoms of heart failure (see Information for Patients). ACTOS
should be discontinued if any deterioration in cardiac status occurs. Patients
with New York Heart Association (NYHA) Class III and IV cardiac status were
not studied during pre-approval clinical trials; ACTOS is not recommended in
these patients (see PRECAUTIONS, Cardiovascular).
In one 16-week U.S. double-blind, placebo-controlled clinical trial involving
566 patients with type 2 diabetes, ACTOS at doses of 15 mg and 30 mg in
combination with insulin was compared to insulin therapy alone. This trial
included patients with long-standing diabetes and a high prevalence of preexisting
medical conditions as follows: arterial hypertension (57.2%), peripheral
neuropathy (22.6%), coronary heart disease (19.6%), retinopathy
(13.1%), myocardial infarction (8.8%), vascular disease (6.4%), angina pectoris
(4.4%), stroke and/or transient ischemic attack (4.1%), and congestive
heart failure (2.3%).
In this study two of the 191 patients receiving 15 mg ACTOS plus insulin
(1.1%) and two of the 188 patients receiving 30 mg ACTOS plus insulin
(1.1%) developed congestive heart failure compared with none of the 187
patients on insulin therapy alone. All four of these patients had previous
histories of cardiovascular conditions including coronary artery disease,
previous CABG procedures, and myocardial infarction. In a 24-week dosecontrolled
study in which ACTOS was coadministered with insulin, 0.3% of
patients (1/345) on 30 mg and 0.9% (3/345) of patients on 45 mg reported
CHF as a serious adverse event.
Analysis of data from these studies did not identify specific factors that
predict increased risk of congestive heart failure on combination therapy with
insulin.
In type 2 diabetes and congestive heart failure (systolic dysfunction)
A 24-week post-marketing safety study was performed to compare ACTOS
(n=262) to glyburide (n=256) in uncontrolled diabetic patients (mean HbA1c
8.8% at baseline) with NYHA Class II and III heart failure and ejection fraction
less than 40% (mean EF 30% at baseline). Over the course of the study,
overnight hospitalization for congestive heart failure was reported in 9.9% of
patients on ACTOS compared to 4.7% of patients on glyburide with a treatment
difference observed from 6 weeks. This adverse event associated with
ACTOS was more marked in patients using insulin at baseline and in patients
over 64 years of age. No difference in cardiovascular mortality between the
treatment groups was observed.
ACTOS should be initiated at the lowest approved dose if it is prescribed
for patients with type 2 diabetes and systolic heart failure (NYHA Class II). If
subsequent dose escalation is necessary, the dose should be increased gradually
only after several months of treatment with careful monitoring for
weight gain, edema, or signs and symptoms of CHF exacerbation.
PRECAUTIONS
General
ACTOS 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: Patients receiving ACTOS in combination with insulin or oral
hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the
dose of the concomitant agent may be necessary.
Cardiovascular: In U.S. placebo-controlled clinical trials that excluded patients
with New York Heart Association (NYHA) Class III and IV cardiac status, the
incidence of serious cardiac adverse events related to volume expansion was
not increased in patients treated with ACTOS as monotherapy or in combination
with sulfonylureas or metformin vs. placebo-treated patients. In insulin
combination studies, a small number of patients with a history of previously
existing cardiac disease developed congestive heart failure when treated with
ACTOS in combination with insulin (see WARNINGS). Patients with NYHA
Class III and IV cardiac status were not studied in these ACTOS clinical trials.
ACTOS is not indicated in patients with NYHA Class III or IV cardiac
status.
In postmarketing experience with ACTOS, cases of congestive heart failure
have been reported in patients both with and without previously known heart
disease.
Edema: ACTOS should be used with caution in patients with edema. In all U.S.
clinical trials, edema was reported more frequently in patients treated with
ACTOS than in placebo-treated patients and appears to be dose related (see
ADVERSE REACTIONS). In postmarketing experience, reports of initiation or
worsening of edema have been received.
Weight Gain: Dose related weight gain was seen with ACTOS alone and in combination
with other hypoglycemic agents (Table 6). The mechanism of weight
gain is unclear but probably involves a combination of fluid retention and fat accumulation.
Table 6 Weight Changes (kg) from Baseline during Double-Blind
Clinical Trials with ACTOS
Control Group ACTOS ACTOS ACTOS
(Placebo) 15 mg 30 mg 45 mg
Median Median Median Median
(25th/75th (25th/75th (25th/75th (25th/75th
percentile) percentile) percentile) percentile)
Monotherapy -1.4 (-2.7/0.0) 0.9 (-0.5/3.4) 1.0 (-0.9/3.4) 2.6 (0.2/5.4)
n=256 n=79 n=188 n=79
Combination Sulfonylurea -0.5 (-1.8/0.7) 2.0 (0.2/3.2) 3.1 (1.1/5.4) 4.1 (1.8/7.3)
Therapy n=187 n=183 n=528 n=333
Metformin -1.4 (-3.2/0.3) N/A 0.9 (-0.3/3.2) 1.8 (-0.9/5.0)
n=160 n=567 n=407
Insulin 0.2 (-1.4/1.4) 2.3 (0.5/4.3) 3.3 (0.9/6.3) 4.1 (1.4/6.8)
n=182 n=190 n=522 n=338
Note: Trial durations of 16 to 26 weeks
Ovulation: Therapy with ACTOS, like other thiazolidinediones, may result in
ovulation in some premenopausal anovulatory women. As a result, these
patients may be at an increased risk for pregnancy while taking ACTOS. Thus,
adequate contraception in premenopausal women should be recommended.
This possible effect has not been investigated in clinical studies so the frequency
of this occurrence is not known.
Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit.
Across all clinical studies, mean hemoglobin values declined by 2% to 4% in
patients treated with ACTOS. 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 rarely been associated
with any significant hematologic clinical effects (see ADVERSE REACTIONS,
Laboratory Abnormalities).
Hepatic Effects: In pre-approval clinical studies worldwide, over 4500 subjects
were treated with ACTOS. In U.S. clinical studies, over 4700 patients with type
2 diabetes received ACTOS. There was no evidence of drug-induced hepatotoxicity
or elevation of ALT levels in the clinical studies.
During pre-approval placebo-controlled clinical trials in the U.S., a total of 4
of 1526 (0.26%) patients treated with ACTOS and 2 of 793 (0.25%) placebotreated
patients had ALT values ≥ 3 times the upper limit of normal. The ALT
elevations in patients treated with ACTOS were reversible and were not clearly
related to therapy with ACTOS.
In postmarketing 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.
Pioglitazone is structurally related to troglitazone, a thiazolidinedione no
longer marketed in the United States, which was associated with idiosyncratic
hepatotoxicity and cases of liver failure, liver transplants and death during
postmarketing clinical use. In pre-approval controlled clinical trials in
patients with type 2 diabetes, troglitazone was more frequently associated
with clinically significant elevations of hepatic enzymes (ALT > 3 times the
upper limit of normal) compared to placebo, and cases of reversible jaundice
were reported.
Pending the availability of the results of additional large, long-term controlled
clinical trials and additional postmarketing safety data, it is recommended
that patients treated with ACTOS undergo periodic monitoring of liver
enzymes.
Serum ALT (alanine aminotransferase) levels should be evaluated prior to the
initiation of therapy with ACTOS in all patients and periodically thereafter per
the clinical judgment of the health care professional. Liver function tests
should also be obtained for patients if symptoms suggestive of hepatic dysfunction
occur, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, or
dark urine. The decision whether to continue the patient on therapy with ACTOS
should be guided by clinical judgment pending laboratory evaluations. If jaundice
is observed, drug therapy should be discontinued.
Therapy with ACTOS should not be initiated if the patient exhibits clinical
evidence of active liver disease or the ALT levels exceed 2.5 times the upper
limit of normal. Patients with mildly elevated liver enzymes (ALT levels at 1 to
2.5 times the upper limit of normal) at baseline or any time during therapy
with ACTOS should be evaluated to determine the cause of the liver enzyme
elevation. Initiation or continuation of therapy with ACTOS in patients with
mildly elevated liver enzymes should proceed with caution and include appropriate
clinical follow-up which may include more frequent liver enzyme monitoring.
If serum transaminase levels are increased (ALT > 2.5 times the upper
limit of normal), liver function tests should be evaluated more frequently until
the levels return to normal or pretreatment values. If ALT levels exceed 3 times
the upper limit of normal, the test should be repeated as soon as possible. If
ALT levels remain > 3 times the upper limit of normal or if the patient is jaundiced,
ACTOS therapy should be discontinued.
There are no data available to evaluate the safety of ACTOS in patients who
experienced liver abnormalities, hepatic dysfunction, or jaundice while on
troglitazone. ACTOS should not be used in patients who experienced jaundice
while taking troglitazone.
Laboratory Tests
FPG and HbA1c measurements should be performed periodically to monitor
glycemic control and the therapeutic response to ACTOS.
Liver enzyme monitoring is recommended prior to initiation of therapy with
ACTOS in all patients and periodically thereafter per the clinical judgment of the
health care professional (see PRECAUTIONS, General, Hepatic Effects and
ADVERSE REACTIONS, Serum Transaminase Levels).
Information for Patients
It is important to instruct patients to adhere to dietary instructions and to
have blood glucose and glycosylated hemoglobin tested regularly. 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 who experience an unusually rapid increase in weight or edema or
who develop shortness of breath or other symptoms of heart failure while on
ACTOS should immediately report these symptoms to their physician.
Patients should be told that blood tests for liver function will be performed
prior to the start of therapy and periodically thereafter per the clinical judgment
of the health care professional. Patients should be told to seek immediate
medical advice for unexplained nausea, vomiting, abdominal pain, fatigue,
anorexia, or dark urine.
Patients should be told to take ACTOS once daily. ACTOS can be taken with
or without meals. If a dose is missed on one day, the dose should not be doubled
the following day.
When using combination therapy with insulin or oral hypoglycemic agents,
the risks of hypoglycemia, its symptoms and treatment, and conditions that
predispose to its development should be explained to patients and their family
members.
Therapy with ACTOS, like other thiazolidinediones, may result in ovulation
in some premenopausal anovulatory women. As a result, these patients may be
at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception
in premenopausal women should be recommended. This possible
effect has not been investigated in clinical studies so the frequency of this
occurrence is not known.
Drug Interactions
In vivo drug-drug interaction studies have suggested that pioglitazone may be
a weak inducer of CYP 450 isoform 3A4 substrate (see CLINICAL PHARMACOLOGY,
Metabolism and Drug-Drug Interactions).
Carcinogenesis, Mutagenesis, Impairment of Fertility
A two-year carcinogenicity study was conducted in male and female rats at oral
doses up to 63 mg/kg (approximately 14 times the maximum recommended
human oral dose of 45 mg based on mg/m2). Drug-induced tumors were not
observed in any organ except for the urinary bladder. Benign and/or malignant
transitional cell neoplasms were observed in male rats at 4 mg/kg/day and
above (approximately equal to the maximum recommended human oral dose
based on mg/m2). A two-year carcinogenicity study was conducted in male and
female mice at oral doses up to 100 mg/kg/day (approximately 11 times the
maximum recommended human oral dose based on mg/m2). No drug-induced
tumors were observed in any organ. Urinary tract tumors have been reported
in rodents taking experimental drugs with dual PPAR α/γ activity; however,
ACTOS is a selective agonist for PPARγ.
During prospective evaluation of urinary cytology involving more than
1800 patients receiving ACTOS in clinical trials up to one year in duration, no
new cases of bladder tumors were identified. Occasionally, abnormal urinary
cytology results indicating possible malignancy were observed in both patients
treated with ACTOS (0.72%) and patients treated with placebo (0.88%).
Pioglitazone HCl was not mutagenic in a battery of genetic toxicology studies,
including the Ames bacterial assay, a mammalian cell forward gene mutation
assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using
CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus
assay.
No adverse effects upon fertility were observed in male and female rats at
oral doses up to 40 mg/kg pioglitazone HCl daily prior to and throughout
mating and gestation (approximately 9 times the maximum recommended
human oral dose based on mg/m2).
Animal Toxicology
Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and
above) and dogs (3 mg/kg) treated orally with pioglitazone HCl (approximately
11, 1, and 2 times the maximum recommended human oral dose for mice,
rats, and dogs, respectively, based on mg/m2). In a one-year rat study, drugrelated
early death due to apparent heart dysfunction occurred at an oral dose
of 160 mg/kg/day (approximately 35 times the maximum recommended
human oral dose based on mg/m2). Heart enlargement was seen in a 13-week
study in monkeys at oral doses of 8.9 mg/kg and above (approximately 4
times the maximum recommended human oral dose based on mg/m2), but
not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times
the maximum recommended human oral dose based on mg/m2).
Pregnancy
Pregnancy Category C. 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).
There are no adequate and well-controlled studies in pregnant women.
ACTOS should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.
Because current information strongly suggests that abnormal 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.
Nursing Mothers
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.
Pediatric Use
Safety and effectiveness of ACTOS in pediatric patients have not been established.
Elderly Use
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.
ADVERSE REACTIONS
In worldwide clinical trials, over 5900 patients with type 2 diabetes have been
treated with ACTOS. In U.S. clinical trials, over 4700 patients have received
ACTOS, over 3300 patients have been treated for 6 months or longer, and over
450 patients for one year or longer.
The overall incidence and types of adverse events reported in placebocontrolled
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.
Table 7 Placebo-Controlled Clinical Studies of ACTOS
Monotherapy: Adverse Events Reported at a
Frequency ≥ 5% of Patients Treated with ACTOS
(% of Patients)
Placebo ACTOS
N=259 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
For most clinical adverse events the incidence was similar for groups treated
with ACTOS monotherapy and those treated in combination with sulfonylureas,
metformin, and insulin. There was an increase in the occurrence of edema in
the patients treated with ACTOS and insulin compared to insulin alone.
In a 16-week, placebo-controlled ACTOS plus insulin trial (n=379), 10 patients
treated with ACTOS plus insulin developed dyspnea and also, at some point
during their therapy, developed either weight change or edema. Seven of
these 10 patients received diuretics to treat these symptoms. This was not
reported in the insulin plus placebo group.
The incidence of withdrawals from placebo-controlled clinical trials due to
an adverse event other than hyperglycemia was similar for patients treated
with placebo (2.8%) or ACTOS (3.3%).
In controlled combination therapy studies with either a sulfonylurea or
insulin, mild to moderate hypoglycemia, which appears to be dose related,
was reported (see PRECAUTIONS, General, Hypoglycemia and DOSAGE and
ADMINISTRATION, Combination Therapy).
In U.S. double-blind studies, anemia was reported in ≤ 2% of patients treated
with ACTOS plus sulfonylurea, metformin or insulin (see PRECAUTIONS,
General, Hematologic).
In monotherapy studies, edema was reported for 4.8% of patients treated
with ACTOS versus 1.2% of placebo-treated patients. In combination therapy
studies, edema was reported for 7.2% of patients treated with ACTOS and
sulfonylureas compared to 2.1% of patients on sulfonylureas alone. In combination
therapy studies with metformin, edema was reported in 6.0% of
patients on combination therapy compared to 2.5% of patients on metformin
alone. In combination therapy studies with insulin, edema was reported in
15.3% of patients on combination therapy compared to 7.0% of patients on
insulin alone. Most of these events were considered mild or moderate in
intensity (see PRECAUTIONS, General, Edema).
In one 16-week clinical trial of insulin plus ACTOS combination therapy,
more patients developed congestive heart failure on combination therapy
(1.1%) compared to none on insulin alone (see WARNINGS, Cardiac Failure
and Other Cardiac Effects).
Laboratory Abnormalities
Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit.
The fall in hemoglobin and hematocrit with ACTOS appears to be dose related.
Across all clinical studies, mean hemoglobin values declined by 2% to
4% in patients treated with ACTOS. 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 rarely been associated with any significant hematologic
clinical effects.
Serum Transaminase Levels: During all clinical studies in the U.S., 14 of
4780 (0.30%) patients treated with ACTOS had ALT values ≥ 3 times the
upper limit of normal during treatment. 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 0.9% of
patients treated with ACTOS were withdrawn from clinical trials in the U.S.
due to abnormal liver function tests.
In pre-approval clinical trials, there were no cases of idiosyncratic drug
reactions leading to hepatic failure (see PRECAUTIONS, Hepatic Effects).
CPK Levels: During required laboratory testing in clinical trials, sporadic,
transient elevations in creatine phosphokinase levels (CPK) were observed.
An isolated elevation to greater than 10 times the upper limit of normal was
noted in 9 patients (values of 2150 to 11400 IU/L). Six of these patients continued
to receive ACTOS, two patients had completed receiving study medication
at the time of the elevated value and one patient discontinued study
medication due to the elevation. These elevations resolved without any
apparent clinical sequelae. The relationship of these events to ACTOS therapy
is unknown.
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 patient’s clinical signs and symptoms.
DOSAGE AND ADMINISTRATION
ACTOS should be taken once daily without regard to meals.
The management of antidiabetic therapy should be individualized. Ideally, the
response to therapy should be evaluated using HbA1c which is a better indicator
of long-term glycemic control than FPG alone. HbA1c 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
HbA1c (three months) unless glycemic control deteriorates.
Monotherapy
ACTOS 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 ACTOS, 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.
Combination Therapy
Sulfonylureas: ACTOS in combination with a sulfonylurea may be initiated at
15 mg or 30 mg once daily. The current sulfonylurea dose can be continued
upon initiation of ACTOS therapy. If patients report hypoglycemia, the dose of
the sulfonylurea should be decreased.
Metformin: ACTOS in combination with metformin may be initiated at 15 mg
or 30 mg once daily. The current metformin dose can be continued upon initiation
of ACTOS therapy. It is unlikely that the dose of metformin will require
adjustment due to hypoglycemia during combination therapy with ACTOS.
Insulin: ACTOS in combination with insulin may be initiated at 15 mg or 30 mg
once daily. The current insulin dose can be continued upon initiation of ACTOS
therapy. In patients receiving ACTOS and insulin, the insulin dose can be decreased
by 10% to 25% if the patient reports hypoglycemia or if plasma glucose
concentrations decrease to less than 100 mg/dL. Further adjustments should
be individualized based on glucose-lowering response.
Maximum Recommended Dose
The dose of ACTOS should not exceed 45 mg once daily in monotherapy or
in combination with sulfonylurea, metformin or insulin.
Dose adjustment in patients with renal insufficiency is not recommended
(see CLINICAL PHARMACOLOGY, Pharmacokinetics and Drug Metabolism).
Therapy with ACTOS should not be initiated if the patient exhibits clinical
evidence of active liver disease or increased serum transaminase levels (ALT
greater than 2.5 times the upper limit of normal) at start of therapy (see PRECAUTIONS,
General, Hepatic Effects and CLINICAL PHARMACOLOGY, Special
Populations, Hepatic Insufficiency). Liver enzyme monitoring is recommended
in all patients prior to initiation of therapy with ACTOS and periodically thereafter
(see PRECAUTIONS, General, Hepatic Effects).
There are no data on the use of ACTOS in patients under 18 years of age;
therefore, use of ACTOS in pediatric patients is not recommended.
No data are available on the use of ACTOS in combination with another
thiazolidinedione.
HOW SUPPLIED
ACTOS is available in 15 mg, 30 mg, and 45 mg tablets as follows:
15 mg Tablet: white to off-white, round, convex, non-scored tablet with
“ACTOS” on one side, and “15” on the other, available in:
NDC 64764-151-04 Bottles of 30
NDC 64764-151-05 Bottles of 90
NDC 64764-151-06 Bottles of 500
30 mg Tablet: white to off-white, round, flat, non-scored tablet with “ACTOS”
on one side, and “30” on the other, available in:
NDC 64764-301-14 Bottles of 30
NDC 64764-301-15 Bottles of 90
NDC 64764-301-16 Bottles of 500
45 mg Tablet: white to off-white, round, flat, non-scored tablet with “ACTOS”
on one side, and “45” on the other, available in:
NDC 64764-451-24 Bottles of 30
NDC 64764-451-25 Bottles of 90
NDC 64764-451-26 Bottles of 500
STORAGE
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP
Controlled Room Temperature]. Keep container tightly closed, and protect
from moisture and humidity.
Rx only
Manufactured by:
Takeda Pharmaceutical Company Limited
Osaka, Japan
Marketed by:
Takeda Pharmaceuticals America, Inc.
475 Half Day Road
Lincolnshire, IL 60069
and
Eli Lilly and Company
Lilly Corporate Center
Indianapolis, IN 46285
ACTOS® is a registered trademark of Takeda Pharmaceutical Company Limited
and used under license by Takeda Pharmaceuticals America, Inc. and Eli Lilly
and Co.
All other trademark names are the property of their respective owners.
05-1113 Revised: August 2004
PI01-0048-2