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Actos (Pioglitazone Hydrochloride) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in the labeling:

  • • Congestive heart failure [see Boxed Warning and Warnings and Precautions]
  • • Edema [see Warnings and Precautions ]
  • • Fractures [see Warnings and Precautions ]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Over 8500 patients with type 2 diabetes have been treated with ACTOS in randomized, double-blind, controlled clinical trials, including 2605 patients with type 2 diabetes and macrovascular disease treated with ACTOS in the PROactive clinical trial. In these trials, over 6000 patients have been treated with ACTOS for six months or longer, over 4500 patients have been treated with ACTOS for one year or longer, and over 3000 patients have been treated with ACTOS for at least two years.

In six pooled 16- to 26-week placebo-controlled monotherapy and 16- to 24-week add-on combination therapy trials, the incidence of withdrawals due to adverse events was 4.5% for patients treated with ACTOS and 5.8% for comparator-treated patients. The most common adverse events leading to withdrawal were related to inadequate glycemic control, although the incidence of these events was lower (1.5%) with ACTOS than with placebo (3.0%).

In the PROactive trial, the incidence of withdrawals due to adverse events was 9.0% for patients treated with ACTOS and 7.7% for placebo-treated patients. Congestive heart failure was the most common serious adverse event leading to withdrawal occurring in 1.3% of patients treated with ACTOS and 0.6% of patients treated with placebo.

Common Adverse Events: 16- to 26-Week Monotherapy Trials

A summary of the incidence and type of common adverse events reported in three pooled 16- to 26-week placebo-controlled monotherapy trials of ACTOS is provided in Table 1. Terms that are reported represent those that occurred at an incidence of >5% and more commonly in patients treated with ACTOS than in patients who received placebo. None of these adverse events were related to ACTOS dose.

Table 1. Three Pooled 16- to 26-Week Placebo-Controlled Clinical Trials of ACTOS Monotherapy: Adverse Events Reported at an Incidence >5% and More Commonly in Patients Treated with ACTOS than in Patients Treated with Placebo
% 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

Pharyngitis

0.8

5.1

Common Adverse Events: 16- to 24-Week Add-on Combination Therapy Trials

A summary of the overall incidence and types of common adverse events reported in trials of ACTOS add-on to sulfonylurea is provided in Table 2. Terms that are reported represent those that occurred at an incidence of >5% and more commonly with the highest tested dose of ACTOS.

Table 2. 16- to 24-Week Clinical Trials of ACTOS Add-on to Sulfonylurea

16-Week Placebo-Controlled Trial
Adverse Events Reported in >5% of Patients and More Commonly in Patients Treated with ACTOS 30 mg + Sulfonylurea than in Patients Treated with Placebo + Sulfonylurea

% of Patients

Placebo
+ Sulfonylurea
N=187

ACTOS 15 mg
+ Sulfonylurea
N=184

ACTOS 30 mg
+ Sulfonylurea
N=189

Edema

2.1

1.6

12.7

Headache

3.7

4.3

5.3

Flatulence

0.5

2.7

6.3

Weight Increased

0

2.7

5.3

24-Week Non-Controlled Double-Blind Trial
Adverse Events Reported in >5% of Patients and More Commonly in Patients Treated with ACTOS 45 mg + Sulfonylurea than in Patients Treated with ACTOS 30 mg + Sulfonylurea

% of Patients

ACTOS 30 mg
+ Sulfonylurea
N=351

ACTOS 45 mg
+ Sulfonylurea
N=351

Hypoglycemia

13.4

15.7

Edema

10.5

23.1

Upper Respiratory Tract Infection

12.3

14.8

Weight Increased

9.1

13.4

Urinary Tract Infection

5.7

6.8

Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of "edema."

A summary of the overall incidence and types of common adverse events reported in trials of ACTOS add-on to metformin is provided in Table 3. Terms that are reported represent those that occurred at an incidence of >5% and more commonly with the highest tested dose of ACTOS.

Table 3. 16- to 24-Week Clinical Trials of ACTOS Add-on to Metformin

16-Week Placebo-Controlled Trial
Adverse Events Reported in >5% of Patients and More Commonly in Patients Treated with ACTOS + Metformin than in Patients Treated with Placebo + Metformin

% of Patients

Placebo
+ Metformin
N=160

ACTOS 30 mg
+ Metformin
N=168

Edema

2.5

6.0

Headache

1.9

6.0

24-Week Non-Controlled Double-Blind Trial

Adverse Events Reported in >5% of Patients and More Commonly in Patients Treated with ACTOS 45 mg + Metformin than in Patients Treated with ACTOS 30 mg + Metformin

% of Patients

ACTOS 30 mg
+ Metformin
N=411

ACTOS 45 mg
+ Metformin
N=416

Upper Respiratory Tract Infection

12.4

13.5

Edema

5.8

13.9

Headache

5.4

5.8

Weight Increased

2.9

6.7

Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of "edema."

Table 4 summarizes the incidence and types of common adverse events reported in trials of ACTOS add-on to insulin. Terms that are reported represent those that occurred at an incidence of >5% and more commonly with the highest tested dose of ACTOS.

Table 4. 16- to 24-Week Clinical Trials of ACTOS Add-on to Insulin

16-Week Placebo-Controlled Trial
Adverse Events Reported in >5% of Patients and More Commonly in Patients Treated with ACTOS 30 mg + Insulin than in Patients Treated with Placebo + Insulin

% of Patients

Placebo
+ Insulin
N=187

ACTOS 15 mg
+ Insulin
N=191

ACTOS 30 mg
+ Insulin
N=188

Hypoglycemia

4.8

7.9

15.4

Edema

7.0

12.6

17.6

Upper Respiratory Tract Infection

9.6

8.4

14.9

Headache

3.2

3.1

6.9

Weight Increased

0.5

5.2

6.4

Back Pain

4.3

2.1

5.3

Dizziness

3.7

2.6

5.3

Flatulence

1.6

3.7

5.3

24-Week Non-Controlled Double-Blind Trial
Adverse Events Reported in >5% of Patients and More Commonly in Patients Treated with ACTOS 45 mg + Insulin than in Patients Treated with ACTOS 30 mg + Insulin

% of Patients

ACTOS 30 mg
+ Insulin
N=345

ACTOS 45 mg
+ Insulin
N=345

Hypoglycemia

43.5

47.8

Edema

22.0

26.1

Weight Increased

7.2

13.9

Urinary Tract Infection

4.9

8.7

Diarrhea

5.5

5.8

Back Pain

3.8

6.4

Blood Creatine Phosphokinase Increased

4.6

5.5

Sinusitis

4.6

5.5

Hypertension

4.1

5.5

Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of "edema."

A summary of the overall incidence and types of common adverse events reported in the PROactive trial is provided in Table 5. Terms that are reported represent those that occurred at an incidence of >5% and more commonly in patients treated with ACTOS than in patients who received placebo.

Table 5. PROactive Trial: Incidence and Types of Adverse Events Reported in >5% of Patients Treated with ACTOS and More Commonly than Placebo
% of Patients
Placebo
N=2633
ACTOS
N=2605

Hypoglycemia

18.8

27.3

Edema

15.3

26.7

Cardiac Failure

6.1

8.1

Pain in Extremity

5.7

6.4

Back Pain

5.1

5.5

Chest Pain

5.0

5.1

Mean duration of patient follow-up was 34.5 months.

Congestive Heart Failure

A summary of the incidence of adverse events related to congestive heart failure is provided in Table 6 for the 16- to 24-week add-on to sulfonylurea trials, for the 16- to 24-week add-on to insulin trials, and for the 16- to 24-week add-on to metformin trials. None of the events were fatal.

Table 6. Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF)

Patients Treated with ACTOS or Placebo Added on to a Sulfonylurea

Number (%) of Patients

Placebo-Controlled Trial
(16 weeks)

Non-Controlled

Double-Blind Trial
(24 weeks)

Placebo
+ Sulfonylurea
N=187

ACTOS 15 mg
+ Sulfonylurea
N=184

ACTOS 30 mg
+ Sulfonylurea
N=189

ACTOS 30 mg
+ Sulfonylurea
N=351

ACTOS 45 mg
+ Sulfonylurea
N=351

At least one congestive
heart failure event

2 (1.1%)

0

0

1 (0.3%)

6 (1.7%)

Hospitalized

2 (1.1%)

0

0

0

2 (0.6%)

Patients Treated with ACTOS or Placebo Added on to Insulin

Number (%) of Patients

Placebo-Controlled Trial
(16 weeks)

Non-Controlled
Double-Blind Trial
(24 weeks)

Placebo
+ Insulin
N=187

ACTOS 15 mg
+ Insulin
N=191

ACTOS 30 mg
+ Insulin
N=188

ACTOS 30 mg
+ Insulin
N=345

ACTOS 45 mg
+ Insulin
N=345

At least one congestive heart failure event

0

2 (1.0%)

2 (1.1%)

3 (0.9%)

5 (1.4%)

Hospitalized

0

2 (1.0%)

1 (0.5%)

1 (0.3%)

3 (0.9%)

Patients Treated with ACTOS or Placebo Added on to Metformin

Number (%) of Patients

Placebo-Controlled Trial
(16 weeks)

Non-Controlled
Double-Blind Trial
(24 weeks)

Placebo
+ Metformin
N=160

ACTOS 30 mg
+ Metformin
N=168

ACTOS 30 mg
+ Metformin
N=411

ACTOS 45 mg
+ Metformin
N=416

At least one congestive heart failure event

0

1 (0.6%)

0

1 (0.2%)

Hospitalized

0

1 (0.6%)

0

1 (0.2%)

Patients with type 2 diabetes and NYHA class II or early class III congestive heart failure were randomized to receive 24 weeks of double-blind treatment with either ACTOS at daily doses of 30 mg to 45 mg (n=262) or glyburide at daily doses of 10 mg to 15 mg (n=256). A summary of the incidence of adverse events related to congestive heart failure reported in this study is provided in Table 7.

Table 7. Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) in Patients with NYHA Class II or III Congestive Heart Failure Treated with ACTOS or Glyburide
Number (%) of Subjects
ACTOS
N=262
Glyburide
N=256

Death due to cardiovascular causes (adjudicated)

5 (1.9%)

6 (2.3%)

Overnight hospitalization for worsening CHF (adjudicated)

26 (9.9%)

12 (4.7%)

Emergency room visit for CHF (adjudicated)

4 (1.5%)

3 (1.2%)

Patients experiencing CHF progression during study

35 (13.4%)

21 (8.2%)

Congestive heart failure events leading to hospitalization that occurred during the PROactive trial are summarized in Table 8.

Table 8. Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) in PROactive Trial
Number (%) of Patients
Placebo
N=2633
ACTOS
N=2605

At least one hospitalized congestive heart failure event

108 (4.1%)

149 (5.7%)

Fatal

22 (0.8%)

25 (1.0%)

Hospitalized, nonfatal

86 (3.3%)

124 (4.7%)

Cardiovascular Safety

In the PROactive trial, 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to ACTOS (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care. Almost all patients (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, angiotensin II receptor blockers, calcium channel blockers, nitrates, diuretics, aspirin, statins and fibrates). At baseline, patients had a mean age of 62 years, mean duration of diabetes of 9.5 years, and mean HbA1c of 8.1%. Mean duration of follow-up was 34.5 months.

The primary objective of this trial was to examine the effect of ACTOS on mortality and macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk for macrovascular events. The primary efficacy variable was the time to the first occurrence of any event in a cardiovascular composite endpoint that included all-cause mortality, nonfatal myocardial infarction (MI) including silent MI, stroke, acute coronary syndrome, cardiac intervention including coronary artery bypass grafting or percutaneous intervention, major leg amputation above the ankle, and bypass surgery or revascularization in the leg. A total of 514 (19.7%) patients treated with ACTOS and 572 (21.7%) placebo-treated patients experienced at least one event from the primary composite endpoint (hazard ratio 0.90; 95% Confidence Interval: 0.80, 1.02; p=0.10).

Although there was no statistically significant difference between ACTOS and placebo for the three-year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with ACTOS. The number of first occurrences and total individual events contributing to the primary composite endpoint is shown in Table 9.

Table 9. PROactive: Number of First and Total Events for Each Component within the Cardiovascular Composite Endpoint
Cardiovascular Events Placebo
N=2633
ACTOS
N=2605
First Events
n (%)
Total events
n
First Events
n (%)
Total events
n

Any event

572

900

514 (19.7)

803

    All-cause mortality

122 (4.6)

186

110 (4.2)

177

    Nonfatal myocardial infarction (MI)

118 (4.5)

157

105 (4.0)

131

    Stroke

96 (3.6)

119

76 (2.9)

92

    Acute coronary syndrome

63 (2.4)

78

42 (1.6)

65

    Cardiac intervention (CABG/PCI)

101 (3.8)

240

101 (3.9)

195

    Major leg amputation

15 (0.6)

28

9 (0.3)

28

    Leg revascularization

57 (2.2)

92

71 (2.7)

115

CABG = coronary artery bypass grafting; PCI = percutaneous intervention

Weight Gain

Dose-related weight gain occurs when ACTOS is used alone or in combination with other antidiabetic medications. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

Tables 10 and 11 summarize the changes in body weight with ACTOS and placebo in the 16- to 26-week randomized, double-blind monotherapy and 16- to 24-week combination add-on therapy trials and in the PROactive trial.

Table 10. Weight Changes (kg) from Baseline During Randomized, Double-Blind Clinical Trials
Control Group
(Placebo)
ACTOS
15 mg
ACTOS
30 mg
ACTOS
45 mg
Median
(25th/75th percentile)
Median
(25th/75th percentile)
Median
(25th/75th percentile)
Median
(25th/75th percentile)

Monotherapy
(16 to 26 weeks)

-1.4 (-2.7/0.0)
N=256

0.9 (-0.5/3.4)
N=79

1.0 (-0.9/3.4)
N=188

2.6 (0.2/5.4)
N=79


Combination Therapy
(16 to 24 weeks)

Sulfonylurea

-0.5 (-1.8/0.7)
N=187

2.0 (0.2/3.2)
N=183

3.1 (1.1/5.4)
N=528

4.1 (1.8/7.3)
N=333

Metformin

-1.4 (-3.2/0.3)
N=160

N/A

0.9 (-1.3/3.2)
N=567

1.8 (-0.9/5.0)
N=407

Insulin

0.2 (-1.4/1.4)
N=182

2.3 (0.5/4.3)
N=190

3.3 (0.9/6.3)
N=522

4.1 (1.4/6.8)
N=338

Table 11. Median Change in Body Weight in Patients Treated with ACTOS Versus Patients Treated with Placebo During the Double-Blind Treatment Period in the PROactive Trial

Placebo

ACTOS

Median

(25th/75th

percentile)

Median

(25th/75th

percentile)

Change from baseline to final visit (kg)

-0.5 (-3.3, 2.0)

N=2581

+3.6 (0.0, 7.5)

N=2560

Note: Median exposure for both ACTOS and Placebo was 2.7 years.

Edema

Edema induced from taking ACTOS is reversible when ACTOS is discontinued. The edema usually does not require hospitalization unless there is coexisting congestive heart failure. A summary of the frequency and types of edema adverse events occurring in clinical investigations of ACTOS is provided in Table 12.

Table 12. Adverse Events of Edema in Patients Treated with ACTOS
Number (%) of Patients
Placebo ACTOS
15 mg
ACTOS
30 mg
ACTOS
45 mg

Monotherapy (16 to 26 weeks)

3 (1.2%)
N=259

2 (2.5%)
N= 81

13 (4.7%)
N= 275

11 (6.5%)
N=169

Combined Therapy
(16 to 24 weeks)

Sulfonylurea

4 (2.1%)
N=187

3 (1.6%)
N=184

61 (11.3%)
N=540

81 (23.1%)
N=351

Metformin

4 (2.5%)
N=160

N/A

34 (5.9%)
N=579

58 (13.9%)
N=416

Insulin

13 (7.0%)
N=187

24 (12.6%)
N=191

109 (20.5%)
N=533

90 (26.1%)
N=345

Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of "edema."

Table 13. Adverse Events of Edema in Patients in the PROactive Trial
Number (%) of Patients
Placebo
N=2633
ACTOS
N=2605

419 (15.9%)

712 (27.3%)

Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of "edema."

Hepatic Effects

There has been no evidence of induced hepatotoxicity with ACTOS in the ACTOS controlled clinical trial database to date. One randomized, double-blind 3-year trial comparing ACTOS to glyburide as add-on to metformin and insulin therapy was specifically designed to evaluate the incidence of serum ALT elevation to greater than three times the upper limit of the reference range, measured every eight weeks for the first 48 weeks of the trial then every 12 weeks thereafter. A total of 3/1051 (0.3%) patients treated with ACTOS and 9/1046 (0.9%) patients treated with glyburide developed ALT values greater than three times the upper limit of the reference range. None of the patients treated with ACTOS in the ACTOS controlled clinical trial database to date have had a serum ALT greater than three times the upper limit of the reference range and a corresponding total bilirubin greater than two times the upper limit of the reference range, a combination predictive of the potential for severe drug-induced liver injury.

Hypoglycemia

In the ACTOS clinical trials, adverse events of hypoglycemia were reported based on clinical judgment of the investigators and did not require confirmation with fingerstick glucose testing.

In the 16-week add-on to sulfonylurea trial, the incidence of reported hypoglycemia was 3.7% with ACTOS 30 mg and 0.5% with placebo. In the 16-week add-on to insulin trial, the incidence of reported hypoglycemia was 7.9% with ACTOS 15 mg, 15.4% with ACTOS 30 mg, and 4.8% with placebo.

The incidence of reported hypoglycemia was higher with ACTOS 45 mg compared to ACTOS 30 mg in both the 24-week add-on to sulfonylurea trial (15.7% vs. 13.4%) and in the 24-week add-on to insulin trial (47.8% vs. 43.5%).

Three patients in these four trials were hospitalized due to hypoglycemia. All three patients were receiving ACTOS 30 mg (0.9%) in the 24-week add-on to insulin trial. An additional 14 patients reported severe hypoglycemia (defined as causing considerable interference with patient's usual activities) that did not require hospitalization. These patients were receiving ACTOS 45 mg in combination with sulfonylurea (n=2) or ACTOS 30 mg or 45 mg in combination with insulin (n=12).

Urinary Bladder Tumors

Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study [see Nonclinical Toxicology]. In two 3-year trials in which ACTOS was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking ACTOS compared to 5/3679 (0.14%) in patients not taking ACTOS. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on ACTOS and two (0.05%) cases on placebo. There are too few events of bladder cancer to establish causality.

Laboratory Abnormalities

Hematologic Effects

ACTOS may cause decreases in hemoglobin and hematocrit. In placebo-controlled monotherapy trials, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS compared with a mean change in hemoglobin of -1% to +1% in placebo-treated patients. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume associated with ACTOS therapy and are not likely to be associated with any clinically significant hematologic effects.

Creatine Phosphokinase

During protocol-specified measurement of serum creatine phosphokinase (CPK) in ACTOS clinical trials, an isolated elevation in CPK to greater than 10 times the upper limit of the reference range was noted in nine (0.2%) patients treated with ACTOS (values of 2150 to 11400 IU/L) and in no comparator-treated patients. Six of these nine patients continued to receive ACTOS, two patients were noted to have the CPK elevation on the last day of dosing and one patient discontinued ACTOS due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to ACTOS therapy is unknown.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ACTOS. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

  • •New onset or worsening diabetic macular edema with decreased visual acuity [see Warnings and Precautions ].
  • •Fatal and nonfatal hepatic failure [see Warnings and Precautions].

Postmarketing reports of congestive heart failure have been reported in patients treated with ACTOS, both with and without previously known heart disease and both with and without concomitant insulin administration.

In postmarketing experience, there have been reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure [see Boxed Warning and Warnings and Precautions].



REPORTS OF SUSPECTED ACTOS SIDE EFFECTS / ADVERSE REACTIONS

Below is a sample of reports where side effects / adverse reactions may be related to Actos. The information is not vetted and should not be considered as verified clinical evidence.

Possible Actos side effects / adverse reactions in 79 year old male

Reported by a health professional (non-physician/pharmacist) from United Kingdom on 2011-09-15

Patient: 79 year old male

Reactions: Bladder Transitional Cell Carcinoma Stage III

Adverse event resulted in: life threatening event

Suspect drug(s):
Actos

Other drugs received by patient: Ramipril; Simvastatin; Solifenacin Succinate (Solifenacin Succinate); Salamol (Salbutamol); Aspirin; Nateglinide; Furosemide; Acetaminophen and Codeine Phosphate; Metformin HCL; Zopiclone (Zopiclone); Omeprazole



Possible Actos side effects / adverse reactions in 81 year old male

Reported by a individual with unspecified qualification from Japan on 2011-10-04

Patient: 81 year old male

Reactions: Bladder Cancer

Adverse event resulted in: life threatening event

Suspect drug(s):
Livalo
    Dosage: 1 mg (1 mg, 1 in 1 d), per oral
    Administration route: Oral
    Indication: Hyperlipidaemia
    Start date: 2006-06-24

Magmitt (Magnesium Oxide)
    Dosage: 1500 mg (500 mg, 3 in 1 d), per oral
    Administration route: Oral
    Indication: Constipation
    Start date: 2006-06-24

Micardis
    Dosage: 40 mg (40 mg, 1 in 1 d), per oral
    Administration route: Oral
    Indication: Hypertension
    Start date: 2006-06-24

Actos
    Dosage: 15 mg (15 mg, 1 in 1 d), per oral;
    Indication: Blood Glucose Abnormal
    Start date: 2006-06-24
    End date: 2008-05-16

Actos
    Dosage: 15 mg (15 mg, 1 in 1 d), per oral;
    Indication: Blood Glucose Abnormal
    Start date: 2008-10-10
    End date: 2010-08-21



Possible Actos side effects / adverse reactions in 50 year old male

Reported by a consumer/non-health professional from United States on 2011-10-04

Patient: 50 year old male weighing 104.3 kg (229.5 pounds)

Reactions: Metastasis, Myocardial Infarction, Bladder Cancer

Suspect drug(s):
Actos



See index of all Actos side effect reports >>

Drug label data at the top of this Page last updated: 2013-11-21

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