HIGHLIGHTS OF PRESCRIBING INFORMATION o Discontinue if eGFR falls below 30 mL/min/1.

73 m2
These highlights do not include all the information needed to use • ACTOPLUS MET may need to be discontinued at time of, or
ACTOPLUS MET safely and effectively. See full prescribing prior to, iodinated contrast imaging procedures (2.4)
information for ACTOPLUS MET.
-------------------DOSAGE FORMS AND STRENGTHS-------------------
ACTOPLUS MET (pioglitazone and metformin hydrochloride) tablets Tablets: 15 mg pioglitazone/500 mg metformin HCl and 15 mg
for oral use pioglitazone/850 mg metformin HCl (3)
Initial U.S. Approval: 2005
-----------------------------CONTRAINDICATIONS----------------------------
WARNING: CONGESTIVE HEART FAILURE AND LACTIC ACIDOSIS • Initiation in patients with established New York Heart Association
See full prescribing information for complete boxed warning (NYHA) Class III or IV heart failure [see Boxed Warning]. (4)
Congestive Heart Failure • Severe renal impairment: (eGFR below 30mL/min/1.73 m2). (4)
• Thiazolidinediones, including pioglitazone, which is a component • Use in patients with known hypersensitivity to pioglitazone,
of ACTOPLUS MET, cause or exacerbate congestive heart failure metformin or any other component of ACTOPLUS MET. (4)
in some patients. (5.1) • Metabolic acidosis, including diabetic ketoacidosis. (4, 5.2)
• After initiation of ACTOPLUS MET, and after dose increases,
monitor patients carefully for signs and symptoms of heart failure -----------------------WARNINGS AND PRECAUTIONS--------------------
(e.g., excessive, rapid weight gain, dyspnea, and/or edema). If • Congestive heart failure: Fluid retention may occur and can
heart failure develops, it should be managed according to current exacerbate or lead to congestive heart failure. Combination use with
standards of care and discontinuation or dose reduction of insulin and use in congestive heart failure NYHA Class I and II may
ACTOPLUS MET must be considered. (5.1) increase risk. Monitor patients for signs and symptoms. (5.1)
• ACTOPLUS MET is not recommended in patients with • Lactic acidosis: See boxed warning. (5.2)
symptomatic heart failure. (5.1) • Edema: Dose-related edema may occur. (5.3)
• Initiation of ACTOPLUS MET in patients with established New • Hypoglycemia: When used with insulin or an insulin secretagogue, a
York Heart Association (NYHA) Class III or IV heart failure is lower dose of the insulin or insulin secretagogue may be needed to
contraindicated. (4, 5.1) reduce the risk of hypoglycemia. (5.4)
Lactic Acidosis • Hepatic effects: Postmarketing reports of hepatic failure, sometimes
• Post-marketing cases of metformin-associated lactic acidosis fatal. Causality cannot be excluded. If liver injury is detected,
have resulted in death, hypothermia, hypotension, and resistant promptly interrupt ACTOPLUS MET and assess patient for probable
bradyarrhythmias. Symptoms included malaise, myalgias, cause, then treat cause if possible, to resolution or stabilization. Do
respiratory distress, somnolence, and abdominal pain. not restart ACTOPLUS MET if liver injury is confirmed and no
Laboratory abnormalities included elevated blood lactate levels, alternate etiology can be found. (5.5)
anion gap acidosis, increased lactate:pyruvate ratio; and • Bladder cancer: May increase the risk of bladder cancer. Do not use
metformin plasma levels generally greater than 5 mcg/mL. (5.2) in patients with active bladder cancer. Use caution when using in
• Risk factors include renal impairment, concomitant use of patients with a prior history of bladder cancer. (5.6)
certain drugs, age ≥65 years old, radiological studies with • Fractures: Increased incidence in female patients. Apply current
contrast, surgery and other procedures, hypoxic states, standards of care for assessing and maintaining bone health. (5.7)
excessive alcohol intake, and hepatic impairment. Steps to • Macular edema: Postmarketing reports. Recommend regular eye
reduce the risk of and manage metformin-associated lactic exams in all patients with diabetes according to current standards of
acidosis in these high risk groups are provided in the Full care with prompt evaluation for acute visual changes. (5.8)
Prescribing Information. (5.2) • Vitamin B12 deficiency: Metformin may lower vitamin B12 levels.
• If lactic acidosis is suspected, discontinue ACTOPLUS MET and Monitor hematologic parameters annually. (5.9)
institute general supportive measures in a hospital setting. • Macrovascular outcomes: There have been no clinical studies
Prompt hemodialysis is recommended. (5.2) establishing conclusive evidence of macrovascular risk reduction
with ACTOPLUS MET. (5.10)
--------------------------RECENT MAJOR CHANGES---------------------------------
-------------------------------ADVERSE REACTIONS-------------------------
Warnings and Precautions
Most common adverse reactions (>5%) are upper respiratory tract
Urinary Bladder Tumors (5.6) 12/2016
infection, edema, diarrhea, headache and weight gain. (6.1)
-----------------------------INDICATIONS AND USAGE------------------------------- To report SUSPECTED ADVERSE REACTIONS, contact Takeda
ACTOPLUS MET is a thiazolidinedione and biguanide combination Pharmaceuticals America, Inc. at 1-877-825-3327 and the
product indicated as an adjunct to diet and exercise to improve glycemic ACTOPLUS MET website at: www.actoplusmet.com or FDA at 1-
control in adults with type 2 diabetes mellitus when treatment with both 800-FDA-1088 or www.fda.gov/medwatch.
pioglitazone and metformin is appropriate. (1, 14)
--------------------------------DRUG INTERACTIONS-------------------------
Important Limitations of Use: • Strong CYP2C8 inhibitors (e.g., gemfibrozil) increase pioglitazone
• Not for treatment of type 1 diabetes or diabetic ketoacidosis. (1) concentrations. Limit ACTOPLUS MET dose to 15 mg/850 mg daily.
------------------------DOSAGE AND ADMINISTRATION-------------------------- (2.3, 7.1)
• Individualize the starting dose based on the patient’s current regimen • CYP2C8 inducers (e.g., rifampin) may decrease pioglitazone
and adjust the dosing based on effectiveness and tolerability while not concentrations. (7.2)
exceeding the maximum recommended daily dose of pioglitazone • Carbonic anhydrase inhibitors may increase risk of lactic acidosis.
45 mg and metformin 2550 mg. (2.1) Consider more frequent monitoring. (7.3)
• Give in divided daily doses with meals to reduce the gastrointestinal • Drugs that reduce metformin clearance (such as ranolazine,
effects due to metformin. (2.1) vandetanib, dolutegravir, and cimetidine), may increase the
• Monitor patients for adverse events related to fluid retention after accumulation of metformin. Consider the benefits and risks of
initiation and dose increases. (2.1) concomitant use. (7.4)
• Obtain liver tests before initiation. If abnormal, use caution when • Alcohol can potentiate the effect of metformin on lactate metabolism.
treating with ACTOPLUS MET, investigate the probable cause, treat (if Warn patients against excessive alcohol intake. (7.5)
possible), and follow appropriately. (2.1, 5.5) • Use of insulin secretagogues or insulin use may increase the risk for
• Prior to initiation, assess renal function with estimated glomerular hypoglycemia and may require dose reduction. (7.6)
filtration rate (eGFR) (2.2) • Topiramate may decrease pioglitazone concentrations. (7.8)
o Do not use in patients with eGFR below 30 mL/min/1.73 m2
--------------------------USE IN SPECIFIC POPULATIONS----------------
o Initiation is not recommended in patients with eGFR between 30 –
• Females and Males of Reproductive Potential: Advise
45 mL/min/1.73 m2
premenopausal females of the potential for an unintended
o Assess risk/benefit of continuing ACTOPLUS MET if eGFR falls
pregnancy. (8.3)
below 45 mL/min/1.73 m2
• Pediatrics: Not recommended for use in pediatric patients. (8.4)
 Page 2 of 45
• Geriatric Use: Assess renal function more frequently. (8.5) See 17 for PATIENT COUNSELING INFORMATION and
• Hepatic Impairment: Avoid use in patients with hepatic impairment. (8.7) Medication Guide
Revised: 06/2020
 Page 3 of 45

FULL PRESCRIBING INFORMATION: CONTENTS* 7.4 Drugs that Reduce Metformin Clearance
WARNING: CONGESTIVE HEART FAILURE AND LACTIC 7.5 Alcohol
ACIDOSIS 7.6 Insulin Secretagogues or Insulin
1 INDICATIONS AND USAGE 7.7 Drugs Affecting Glycemic Control
2 DOSAGE AND ADMINISTRATION 7.8 Topiramate
2.1 Recommendations for All Patients 8 USE IN SPECIFIC POPULATIONS
2.2 Recommendations for Use in Renal Impairment 8.1 Pregnancy
2.3 Concomitant Use with Strong CYP2C8 Inhibitors 8.2 Lactation
2.4 Discontinuation for Iodinated Contrast Imaging 8.3 Females and Males of Reproductive Potential
Procedures 8.4 Pediatric Use
3 DOSAGE FORMS AND STRENGTHS 8.5 Geriatric Use
4 CONTRAINDICATIONS
8.6 Renal Impairment
5 WARNINGS AND PRECAUTIONS 8.7 Hepatic Impairment
5.1 Congestive Heart Failure 10 OVERDOSAGE
5.2 Lactic Acidosis
11 DESCRIPTION
5.3 Edema 12 CLINICAL PHARMACOLOGY
5.4 Hypoglycemia 12.1 Mechanism of Action
5.5 Hepatic Effects
12.2 Pharmacodynamics
5.6 Urinary Bladder Tumors 12.3 Pharmacokinetics
5.7 Fractures 13 NONCLINICAL TOXICOLOGY
5.8 Macular Edema
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
5.9 Vitamin B12 Levels 13.2 Animal Toxicology and/or Pharmacology
5.10 Macrovascular Outcomes 14 CLINICAL STUDIES
6 ADVERSE REACTIONS 14.1 Patients Who Have Inadequate Glycemic Control with
6.1 Clinical Trials Experience Diet and Exercise Alone
6.2 Postmarketing Experience 14.2 Patients Previously Treated with Metformin
7 DRUG INTERACTIONS 16 HOW SUPPLIED/STORAGE AND HANDLING
7.1 Strong CYP2C8 Inhibitors 17 PATIENT COUNSELING INFORMATION
7.2 CYP2C8 Inducers *Sections or subsections omitted from the full prescribing information
7.3 Carbonic Anhydrase Inhibitors are not listed.
 Page 4 of 45

FULL PRESCRIBING INFORMATION

WARNING: CONGESTIVE HEART FAILURE AND LACTIC ACIDOSIS

Congestive Heart Failure
• Thiazolidinediones, including pioglitazone, which is a component of ACTOPLUS
MET, cause or exacerbate congestive heart failure in some patients [see
Warnings and Precautions (5.1)].
• After initiation of ACTOPLUS MET, and after dose increases, monitor patients
carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight
gain, dyspnea, and/or edema). If heart failure develops, it should be managed
according to current standards of care and discontinuation or dose reduction of
ACTOPLUS MET must be considered [see Warnings and Precautions (5.1)].
• ACTOPLUS MET is not recommended in patients with symptomatic heart failure
[see Warnings and Precautions (5.1)].
• Initiation of ACTOPLUS MET in patients with established New York Heart
Association (NYHA) Class III or IV heart failure is contraindicated [see
Contraindications (4) and Warnings and Precautions (5.1)].
Lactic Acidosis
• Post-marketing cases of metformin-associated lactic acidosis have resulted in
death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of
metformin-associated lactic acidosis is often subtle, accompanied only by
nonspecific symptoms such as malaise, myalgias, respiratory distress,
somnolence, and abdominal pain. Metformin-associated lactic acidosis was
characterized by elevated blood lactate levels (greater than 5 mmol/L), anion gap
acidosis (without evidence of ketonuria or ketonemia), an increased
lactate:pyruvate ratio; and metformin plasma levels generally greater than 5
mcg/mL [see Warnings and Precautions (5.2)].
• Risk factors for metformin-associated lactic acidosis include renal impairment,
concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as
topiramate), age 65 years old or greater, having a radiological study with contrast,
surgery and other procedures, hypoxic states (e.g., acute congestive heart
failure), excessive alcohol intake, and hepatic impairment.
• Steps to reduce the risk of and manage metformin-associated lactic acidosis in
these high risk groups are provided in the Full Prescribing Information [see
Dosage and Administration (2.2), Contraindications (4), Warnings and
Precautions (5.2), Drug Interactions (7), and Use in Specific Populations (8.6,
8.7)].
• If metformin-associated lactic acidosis is suspected, immediately discontinue
ACTOPLUS MET and institute general supportive measures in a hospital setting.
Prompt hemodialysis is recommended [see Warnings and Precautions (5.2)].

1 INDICATIONS AND USAGE

ACTOPLUS MET is indicated as an adjunct to diet and exercise to improve glycemic control in
adults with type 2 diabetes mellitus when treatment with both pioglitazone and metformin is
appropriate [see Clinical Studies (14)].
 Page 5 of 45
Important Limitations of Use
Pioglitazone exerts its antihyperglycemic effect only in the presence of endogenous insulin.
ACTOPLUS MET should not be used to treat type 1 diabetes or diabetic ketoacidosis, as it
would not be effective in these settings.
Use caution in patients with liver disease [see Warnings and Precautions (5.5)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommendations for All Patients
ACTOPLUS MET should be taken with meals to reduce the gastrointestinal side effects
associated with metformin.
If therapy with a combination tablet containing pioglitazone and metformin is considered
appropriate the recommended starting dose is:
• 15 mg/500 mg twice daily or 15 mg/850 mg once daily and gradually titrated, as needed,
after assessing adequacy of therapeutic response and tolerability,
• for patients with New York Heart Association (NYHA) Class I or Class II congestive heart
failure: 15 mg/500 mg or 15 mg/850 mg once daily and gradually titrated, as needed, after
assessing adequacy of therapeutic response and tolerability,
• for patients inadequately controlled on metformin monotherapy: 15 mg/500 mg twice daily
or 15 mg/850 mg once or twice daily (depending on the dose of metformin already being
taken) and gradually titrated, as needed, after assessing adequacy of therapeutic response
and tolerability,
• for patients inadequately controlled on pioglitazone monotherapy: 15 mg/500 mg twice daily
or 15 mg/850 mg once daily and gradually titrated, as needed, after assessing adequacy of
therapeutic response and tolerability,
• for patients who are changing from combination therapy of pioglitazone plus metformin as
separate tablets: ACTOPLUS MET should be taken at doses that are as close as possible
to the dose of pioglitazone and metformin already being taken.
ACTOPLUS MET may be titrated up to a maximum daily dose of 45 mg of pioglitazone and
2550 mg of metformin.
Metformin doses above 2000 mg may be better tolerated given three times a day.
After initiation of ACTOPLUS MET or with dose increase, monitor patients carefully for adverse
reactions related to fluid retention such as weight gain, edema, and signs and symptoms of
congestive heart failure [see Boxed Warning and Warnings and Precautions (5.1)]. Liver tests
(serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin)
should be obtained prior to initiating ACTOPLUS MET. Routine periodic monitoring of liver
tests during treatment with ACTOPLUS MET is not recommended in patients without liver
disease. Patients who have liver test abnormalities prior to initiation of ACTOPLUS MET or
who are found to have abnormal liver tests while taking ACTOPLUS MET should be managed
as described under Warnings and Precautions [see Warnings and Precautions (5.5) and
Clinical Pharmacology (12.3)].
2.2 Recommendations for Use in Renal Impairment
Assess renal function prior to initiation of ACTOPLUS MET and periodically thereafter.
ACTOPLUS MET is contraindicated in patients with an estimated glomerular filtration rate
(eGFR) below 30 mL/min/1.73 m2.
 Page 6 of 45
Initiation of ACTOPLUS MET in patients with an eGFR between 30 – 45 mL/min/1.73 m2 is not
recommended.
In patients taking ACTOPLUS MET whose eGFR later falls below 45 mL/min/1.73 m2, assess
the benefit risk of continuing therapy.
Discontinue ACTOPLUS MET if the patient’s eGFR later falls below 30 mL/min/1.73 m2 [see
Contraindications (4) and Warnings and Precautions (5.2)].
2.3 Concomitant Use with Strong CYP2C8 Inhibitors
Coadministration of pioglitazone (one of the ingredients in ACTOPLUS MET) and gemfibrozil,
a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3-fold. Therefore,
the maximum recommended dose of ACTOPLUS MET is 15 mg/850 mg daily when used in
combination with gemfibrozil or other strong CYP2C8 inhibitors [see Drug Interactions (7.1)
and Clinical Pharmacology (12.3)].
2.4 Discontinuation for Iodinated Contrast Imaging Procedures
Discontinue ACTOPLUS MET at the time of, or prior to, an iodinated contrast imaging
procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a
history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-
arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart
ACTOPLUS MET if renal function is stable [see Warnings and Precautions (5.2)].

3 DOSAGE FORMS AND STRENGTHS

• 15 mg/500 mg tablets: White to off-white, oblong, film-coated tablets debossed with
“4833M” on one side and “15/500” on the other
• 15 mg/850 mg tablets: White to off-white, oblong, film-coated tablets debossed with
“4833M” on one side and “15/850” on the other

4 CONTRAINDICATIONS
• Initiation in patients with established NYHA Class III or IV heart failure [see Boxed
Warning].
• Severe renal impairment (eGFR below 30 mL/min/1.73 m2) [see Warnings and Precautions
(5.2)].
• Use in patients with known hypersensitivity to pioglitazone, metformin, or any other
component of ACTOPLUS MET.
• Metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated
with insulin.

5 WARNINGS AND PRECAUTIONS

5.1 Congestive Heart Failure
Pioglitazone
Pioglitazone, like other thiazolidinediones, can cause dose-related fluid retention when used
alone or in combination with other antidiabetic medications and is most common when
pioglitazone is used in combination with insulin. Fluid retention may lead to or exacerbate
congestive heart failure. Patients treated with ACTOPLUS MET should be observed for signs
and symptoms of congestive heart failure. If congestive heart failure develops, it should be
managed according to current standards of care and discontinuation or dose reduction of
 Page 7 of 45
ACTOPLUS MET must be considered [see Boxed Warning, Contraindications (4), and
Adverse Reactions (6.1)].
5.2 Lactic Acidosis
Metformin hydrochloride
Lactic Acidosis
There have been post-marketing cases of metformin-associated lactic acidosis, including fatal
cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such
as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however,
hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis.
Metformin-associated lactic acidosis was characterized by elevated blood lactate
concentrations (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or
ketonemia), and an increased lactate:pyruvate ratio;metformin plasma levels generally greater
than 5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels
which may increase the risk of lactic acidosis, especially in patients at risk.
If metformin-associated lactic acidosis is suspected, general supportive measures should be
instituted promptly in a hospital setting, along with immediate discontinuation of ACTOPLUS
MET. In ACTOPLUS MET-treated patients with a diagnosis or strong suspicion of lactic
acidosis, prompt hemodialysis is recommended to correct the acidosis and remove
accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170
mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of
symptoms and recovery.
Educate patients and their families about the symptoms of lactic acidosis and if these
symptoms occur instruct them to discontinue ACTOPLUS MET and report these symptoms to
their healthcare provider.
For each of the known and possible risk factors for metformin-associated lactic acidosis,
recommendations to reduce the risk of and manage metformin-associated lactic acidosis are
provided below:
Renal Impairment
The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients
with significant renal impairment. The risk of metformin accumulation and metformin-
associated lactic acidosis increases with the severity of renal impairment because metformin is
substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal
function include [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].
• Before initiating ACTOPLUS MET, obtain an eGFR.
• ACTOPLUS MET is contraindicated in patients with an eGFR less than 30mL/min /1.73
m2. Initiation of ACTOPLUS MET is not recommended in patients with eGFR between 30
– 45 mL/min/1.73 m2 [see Contraindications (4)].
• Obtain an eGFR at least annually in all patients taking ACTOPLUS MET. In patients at
increased risk for the development of renal impairment (e.g., the elderly), renal function
should be assessed more frequently.
• In patients taking ACTOPLUS MET whose eGFR later falls below 45 mL/min/1.73 m2,
assess the benefit and risk of continuing therapy.
Drug Interactions
The concomitant use of ACTOPLUS MET with specific drugs may increase the risk of
metformin-associated lactic acidosis: those that impair renal function, result in significant
hemodynamic change, interfere with acid-base balance or increase metformin accumulation
 Page 8 of 45
(e.g. cationic drugs) [see Drug Interactions (7)]. Therefore, consider more frequent monitoring
of patients.
Age 65 or Greater
The risk of metformin-associated lactic acidosis increases with the patient’s age because
elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than
younger patients. Assess renal function more frequently in elderly patients [see Use in Specific
Populations (8.5)].
Radiological Studies with Contrast
Administration of intravascular iodinated contrast agents in metformin-treated patients has led
to an acute decrease in renal function and the occurrence of lactic acidosis. Stop ACTOPLUS
MET at the time of, or prior to, an iodinated contrast imaging procedure in patients with an
eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment,
alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated
contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart ACTOPLUS
MET if renal function is stable.
Surgery and Other Procedures
Withholding of food and fluids during surgical or other procedures may increase the risk for
volume depletion, hypotension and renal impairment. ACTOPLUS MET should be temporarily
discontinued while patients have restricted food and fluid intake.
Hypoxic States
Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the
setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and
hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other
conditions associated with hypoxemia have been associated with lactic acidosis and may also
cause prerenal azotemia. When such events occur, discontinue ACTOPLUS MET.
Excessive Alcohol Intake
Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the
risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake
while receiving ACTOPLUS MET.
Hepatic Impairment
Patients with hepatic impairment have developed with cases of metformin-associated lactic
acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels.
Therefore, avoid use of ACTOPLUS MET in patients with clinical or laboratory evidence of
hepatic disease.
5.3 Edema
In controlled clinical trials with pioglitazone, edema was reported more frequently in patients
treated with pioglitazone than in placebo-treated patients and is dose related [see Adverse
Reactions (6.1)]. In postmarketing experience, reports of new onset or worsening of edema
have been received.
ACTOPLUS MET should be used with caution in patients with edema. Because
thiazolidinediones, including pioglitazone, can cause fluid retention, which can exacerbate or
lead to congestive heart failure, ACTOPLUS MET should be used with caution in patients at
risk for congestive heart failure. Patients treated with ACTOPLUS MET should be monitored
for signs and symptoms of congestive heart failure [see Boxed Warning, Warnings and
Precautions (5.1), and Patient Counseling Information (17.1)].
 Page 9 of 45
5.4 Hypoglycemia
Patients receiving ACTOPLUS MET in combination with insulin or other antidiabetic
medications (particularly insulin secretagogues such as sulfonylureas) may be at risk for
hypoglycemia. A reduction in the dose of the concomitant antidiabetic medication may be
necessary to reduce the risk of hypoglycemia [see Drug Interactions (7.7)]. Hypoglycemia can
also occur when caloric intake is deficient or when strenuous exercise is not compensated by
caloric supplement. Elderly, debilitated, or malnourished patients, and those with adrenal or
pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic
effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking
beta-adrenergic blocking drugs.
5.5 Hepatic Effects
There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking
pioglitazone, although the reports contain insufficient information necessary to establish the
probable cause. There has been no evidence of drug-induced hepatotoxicity in the
pioglitazone controlled clinical trial database to date [see Adverse Reactions (6.1)].
Patients with type 2 diabetes may have fatty liver disease or cardiac disease with episodic
congestive heart failure, both of which may cause liver test abnormalities, and they may also
have other forms of liver disease, many of which can be treated or managed. Therefore,
obtaining a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase
[AST], alkaline phosphatase, and total bilirubin) and assessing the patient is recommended
before initiating ACTOPLUS MET therapy.
In patients with abnormal liver tests, ACTOPLUS MET should be initiated with caution.
Measure liver tests promptly in patients who report symptoms that may indicate liver injury,
including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this
clinical context, if the patient is found to have abnormal liver tests (ALT greater than three
times the upper limit of the reference range), ACTOPLUS MET treatment should be interrupted
and investigation done to establish the probable cause. ACTOPLUS MET should not be
restarted in these patients without another explanation for the liver test abnormalities.
Patients who have serum ALT greater than three times the reference range with serum total
bilirubin greater than two times the reference range without alternative etiologies are at risk for
severe drug-induced liver injury, and should not be restarted on ACTOPLUS MET. For patients
with lesser elevations of serum ALT or bilirubin and with an alternate probable cause,
treatment with ACTOPLUS MET can be used with caution.
5.6 Urinary Bladder Tumors
Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study
[see Nonclinical Toxicology (13.1)]. In addition, during the three year PROactive clinical trial,
14 patients out of 2605 (0.54%) randomized to pioglitazone and 5 out of 2633 (0.19%)
randomized to placebo were diagnosed with bladder cancer. After excluding patients in whom
exposure to study drug was less than one year at the time of diagnosis of bladder cancer,
there were 6 (0.23%) cases on pioglitazone and two (0.08%) cases on placebo. After
completion of the trial, a large subset of patients was observed for up to 10 additional years,
with little additional exposure to pioglitazone. During the 13 years of both PROactive and
observational follow-up, the occurrence of bladder cancer did not differ between patients
randomized to pioglitazone or placebo (HR =1.00; [95% CI: 0.59–1.72]).
 Page 10 of 45
Findings regarding the risk of bladder cancer in patients exposed to pioglitazone vary among
observational studies; some did not find an increased risk of bladder cancer associated with
pioglitazone, while others did.
A large prospective10-year observational cohort study conducted in the United States found no
statistically significant increase in the risk of bladder cancer in diabetic patients ever exposed
to pioglitazone, compared to those never exposed to pioglitazone (HR =1.06 [95% CI 0.89–
1.26]).
A retrospective cohort study conducted with data from the United Kingdom found a statistically
significant association between ever exposure to pioglitazone and bladder cancer (HR: 1.63;
[95% CI: 1.22–2.19]).
Associations between cumulative dose or cumulative duration of exposure to pioglitazone and
bladder cancer were not detected in some studies including the 10-year observational study in
the U.S., but were in others. Inconsistent findings and limitations inherent in these and other
studies preclude conclusive interpretations of the observational data.
Pioglitazone may be associated with an increase in the risk of urinary bladder tumors. There
are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder
tumors.
Consequently, ACTOPLUS MET should not be used in patients with active bladder cancer and
the benefits of glycemic control versus unknown risks for cancer recurrence with ACTOPLUS
MET should be considered in patients with a prior history of bladder cancer.
5.7 Fractures
In PROactive (the Prospective Pioglitazone Clinical Trial in Macrovascular Events), 5238
patients with type 2 diabetes and a history of macrovascular disease were randomized to
pioglitazone (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to
standard of care. During a mean follow-up of 34.5 months, the incidence of bone fracture in
females was 5.1% (44/870) for pioglitazone versus 2.5% (23/905) for placebo. This difference
was noted after the first year of treatment and persisted during the course of the study. The
majority of fractures observed in female patients were nonvertebral fractures including lower
limb and distal upper limb. No increase in the incidence of fracture was observed in men
treated with pioglitazone (1.7%) versus placebo (2.1%). The risk of fracture should be
considered in the care of patients, especially female patients, treated with ACTOPLUS MET
and attention should be given to assessing and maintaining bone health according to current
standards of care.
5.8 Macular Edema
Macular edema has been reported in postmarketing experience in diabetic patients who were
taking pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or
decreased visual acuity, but others were diagnosed on routine ophthalmologic examination.
Most patients had peripheral edema at the time macular edema was diagnosed. Some patients
had improvement in their macular edema after discontinuation of the thiazolidinedione.
Patients with diabetes should have regular eye exams by an ophthalmologist according to
current standards of care. Patients with diabetes who report any visual symptoms should be
promptly referred to an ophthalmologist, regardless of the patient's underlying medications or
other physical findings [see Adverse Reactions (6.1)].
 Page 11 of 45
5.9 Vitamin B12 Levels
In controlled clinical trials of metformin of 29 weeks’ duration, a decrease to subnormal levels
of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in
approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption
from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and
appears to be rapidly reversible with discontinuation of metformin or vitamin B 12
supplementation. Measurement of hematologic parameters on an annual basis is advised in
patients on ACTOPLUS MET and any apparent abnormalities should be appropriately
investigated and managed. Certain individuals (those with inadequate vitamin B 12 or calcium
intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In
these patients, routine serum vitamin B12 measurements at two- to three-year intervals may be
useful.
5.10 Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk
reduction with ACTOPLUS MET.

6 ADVERSE REACTIONS
The following serious adverse reactions are discussed elsewhere in the labeling:
• Congestive heart failure [see Boxed Warning and Warnings and Precautions (5.1)]
• Lactic acidosis [see Boxed Warning and Warnings and Precautions (5.2)]
• Edema [see Warnings and Precautions (5.3)]
• Fractures [see Warnings and Precautions (5.7)]
6.1 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.
Pioglitazone
Over 8500 patients with type 2 diabetes have been treated with pioglitazone in randomized,
double-blind, controlled clinical trials, including 2605 patients with type 2 diabetes and
macrovascular disease treated with pioglitazone from the PROactive clinical trial. In these
trials, over 6000 patients have been treated with pioglitazone for six months or longer, over
4500 patients have been treated with pioglitazone for one year or longer, and over 3000
patients have been treated with pioglitazone 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 pioglitazone 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 pioglitazone than with placebo (3.0%).
In the PROactive trial, the incidence of withdrawals due to adverse events was 9.0% for
patients treated with pioglitazone 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 pioglitazone 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 pioglitazone is provided in Table 1. Terms
 Page 12 of 45
that are reported represent those that occurred at an incidence of >5% and more commonly in
patients treated with pioglitazone than in patients who received placebo. None of these
adverse events were related to the pioglitazone dose.

Table 1. Three Pooled 16- to 26-Week Placebo-Controlled Clinical Trials of

Pioglitazone Monotherapy: Adverse Events Reported at an
Incidence >5% and More Commonly in Patients Treated with
Pioglitazone than in Patients Treated with Placebo
% of Patients
Placebo Pioglitazone
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

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
pioglitazone add-on to metformin 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 pioglitazone.
 Page 13 of 45

Table 2. 16- to 24-Week Clinical Trials of Pioglitazone Add-on to Metformin

16-Week Placebo-Controlled Trial
Adverse Events Reported in >5% of Patients and More Commonly in
Patients Treated with Pioglitazone + Metformin
than in Patients Treated with Placebo + Metformin
% of Patients
Placebo Pioglitazone 30 mg
+ Metformin + Metformin
N=160 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 Pioglitazone
45 mg + Metformin than in Patients Treated with Pioglitazone 30 mg
+ Metformin
% of Patients

Pioglitazone 30 mg Pioglitazone 45 mg
+ Metformin + Metformin
N=411 N=416
Upper Respiratory
12.4 13.5
Tract Infection
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.”

Common Adverse Events: 24-Week ACTOPLUS MET Clinical Trial

Table 3 summarizes the incidence and types of adverse reactions reported in a controlled, 24-
week double-blind clinical trial of ACTOPLUS MET dosed twice daily in patients with
inadequate glycemic control on diet and exercise (N=600).

Table 3. Adverse Events (≥5% for ACTOPLUS MET) Reported by Patients with
Inadequate Glycemic Control on Diet and Exercise in a 24-Week Double-Blind
Clinical Trial of ACTOPLUS MET Administered Twice Daily
% of Patients
ACTOPLUS MET Pioglitazone Metformin
15/850 mg 15 mg 850 mg
Twice Daily Twice Daily Twice Daily
N=201 N=190 N=209
Diarrhea 9.0 2.6 15.3
Headache 5.5 2.6 4.8
 Page 14 of 45
In this 24-week trial, abdominal pain was reported in 2.0% of patients in the ACTOPLUS MET
group, 1.6% in the pioglitazone monotherapy group and 3.3% in the metformin monotherapy
group.
Common Adverse Events: PROactive Trial
A summary of the overall incidence and types of common adverse events reported in the
PROactive trial is provided in Table 4. Terms that are reported represent those that occurred at
an incidence of >5% and more commonly in patients treated with pioglitazone than in patients
who received placebo.

Table 4. PROactive Trial: Incidence and Types of Adverse Events

Reported in >5% of Patients Treated with Pioglitazone and
More Commonly than Placebo
% of Patients
Placebo Pioglitazone
N=2633 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 5 for the 16- to 24-week add-on to metformin trials. None of the events were fatal.

Table 5. Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) Patients

Treated with Pioglitazone or Placebo Added on to Metformin
Number (%) of Patients

Placebo-Controlled Trial Non-Controlled

(16 weeks) Double-Blind Trial
(24 weeks)
Pioglitazone Pioglitazone Pioglitazone
Placebo 30 mg 30 mg 45 mg
+ Metformin + Metformin + Metformin + Metformin
N=160 N=168 N=411 N=416
At least one
congestive heart 0 1 (0.6%) 0 1 (0.2%)
failure event
Hospitalized 0 1 (0.6%) 0 1 (0.2%)
 Page 15 of 45

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

Patients Treated with Pioglitazone or Placebo Added on to a Sulfonylurea
Number (%) of Patients

Placebo-Controlled Trial Non-Controlled Double-Blind Trial

(16 weeks) (24 weeks)
Pioglitazone Pioglitazone Pioglitazone Pioglitazone
Placebo
15 mg 30 mg 30 mg 45 mg
+ Sulfonylurea
+ Sulfonylurea + Sulfonylurea + Sulfonylurea + Sulfonylurea
N=187
N=184 N=189 N=351 N=351
At least one
congestive heart 2 (1.1%) 0 0 1 (0.3%) 6 (1.7%)
failure event
Hospitalized 2 (1.1%) 0 0 0 2 (0.6%)
Patients Treated with Pioglitazone or Placebo Added on to Insulin
Number (%) of Patients

Placebo-Controlled Trial Non-Controlled Double-Blind Trial

(16 weeks) (24 weeks)

Pioglitazone Pioglitazone Pioglitazone Pioglitazone

Placebo
15 mg 30 mg 30 mg 45 mg
+ Insulin
+ Insulin + Insulin + Insulin + Insulin
N=187
N=191 N=188 N=345 N=345
At least one
congestive heart 0 2 (1.0%) 2 (1.1%) 3 (0.9%) 5 (1.4%)
failure event
Hospitalized 0 2 (1.0%) 1 (0.5%) 1 (0.3%) 3 (0.9%)
Patients Treated with Pioglitazone or Placebo Added on to Metformin
Number (%) of Patients

Placebo-Controlled Trial Non-Controlled Double-Blind Trial

(16 weeks) (24 weeks)

Pioglitazone Pioglitazone Pioglitazone

Placebo
30 mg 30 mg 45 mg
+ Metformin
+ Metformin + Metformin + Metformin
N=160
N=168 N=411 N=416
At least one
congestive heart 0 1 (0.6%) 0 1 (0.2%)
failure event
Hospitalized 0 1 (0.6%) 0 1 (0.2%)
 Page 16 of 45

Table 7. Treatment-Emergent Adverse Events of Congestive Heart Failure

(CHF) in Patients with NYHA Class II or III Congestive Heart Failure
Treated with Pioglitazone or Glyburide
Number (%) of Subjects

Pioglitazone Glyburide
N=262 N=256
Death due to cardiovascular causes
5 (1.9%) 6 (2.3%)
(adjudicated)
Overnight hospitalization for worsening
26 (9.9%) 12 (4.7%)
CHF (adjudicated)
Emergency room visit for CHF
4 (1.5%) 3 (1.2%)
(adjudicated)
Patients experiencing CHF
35 (13.4%) 21 (8.2%)
progression during study

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 Pioglitazone
N=2633 N=2605
At least one hospitalized
108 (4.1%) 149 (5.7%)
congestive heart failure event
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 pioglitazone (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 pioglitazone 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 pioglitazone and 572 (21.7%) placebo-treated patients
 Page 17 of 45
experienced at least one event from the primary composite endpoint (HR 0.90; 95% CI: 0.80,
1.02; p=0.10).
Although there was no statistically significant difference between pioglitazone 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 pioglitazone. The number of first occurrences
and total individual events contributing to the primary composite endpoint is shown in Table 9.

Table 9. PROactive Trial: Number of First and Total Events for Each Component Within
the Cardiovascular Composite Endpoint

Placebo Pioglitazone
N=2633 N=2605

First Total First Total

Events events Events events
n (%) n n (%) n
Cardiovascular Events
Any event 572 (21.7) 900 514 (19.7) 803
All-cause mortality 122 (4.6) 186 110 (4.2) 177
Nonfatal myocardial
118 (4.5) 157 105 (4.0) 131
infarction (MI)
Stroke 96 (3.6) 119 76 (2.9) 92
Acute coronary syndrome 63 (2.4) 78 42 (1.6) 65
Cardiac intervention
101 (3.8) 240 101 (3.9) 195
(CABG/PCI)
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 pioglitazone 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, 11, and 12 summarize the changes in body weight with pioglitazone and placebo in
the 16- to 26-week randomized, double-blind monotherapy and 16- to 24-week combination
add-on therapy trials, the PROactive trial, and the 24-week ACTOPLUS MET trial.
 Page 18 of 45

Table 10. Weight Changes (kg) from Baseline During Randomized, Double-Blind Clinical Trials
Control
Pioglitazone Pioglitazone Pioglitazone
Group
15 mg 30 mg 45 mg
(Placebo)
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)
(16 to 26 weeks) N=256 N=79 N=188 N=79

-0.5 (-1.8, 0.7) 2.0 (0.2, 3.2) 3.1 (1.1, 5.4) 4.1 (1.8, 7.3)
Combination Sulfonylurea
N=187 N=183 N=528 N=333
Therapy
(16 to 24 weeks) -1.4 (-3.2, 0.3) 0.9 (-1.3, 3.2) 1.8 (-0.9, 5.0)
Metformin N/A
N=160 N=567 N=407
0.2 (-1.4, 1.4) 2.3 (0.5, 4.3) 3.3 (0.9, 6.3) 4.1 (1.4, 6.8)
Insulin
N=182 N=190 N=522 N=338

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

Placebo Pioglitazone
Median Median
(25th, 75th (25th, 75th
percentile) percentile)
-0.5 (-3.3, 2.0) +3.6 (0.0, 7.5)
Change from baseline to final visit (kg)
N=2581 N=2560
Note: Median exposure for both pioglitazone and placebo was 2.7 years.

Table 12. Weight Changes (kg) from Baseline During Double-Blind Clinical Trial with
ACTOPLUS MET in Patients with Inadequate Glycemic Control on Diet and
Exercise
ACTOPLUS MET Pioglitazone Metformin
15/850 mg 15 mg 850 mg
Twice Daily Twice Daily Twice Daily
Median Median Median
(25th , 75th (25th , 75th (25th , 75th
percentile) percentile) percentile)
Change from baseline to 1.00 (-1.0, 3.0) 1.35 (-0.7, 4.1) -1.00 (-2.6, 0.4)
final visit (kg) N=198 N=178 N=203
Note: Trial duration of 24 weeks.
 Page 19 of 45
Edema
Edema induced from taking pioglitazone is reversible when pioglitazone is discontinued. The
edema usually does not require hospitalization unless there is coexisting congestive heart
failure.
In the 24-week ACTOPLUS MET trial, edema was reported in 3.0% of patients in the
ACTOPLUS MET group, 4.2% in the pioglitazone monotherapy group, and 1.4% in the
metformin monotherapy group.
A summary of the frequency and types of edema adverse events occurring in clinical
investigations of pioglitazone is provided in Table 13.

Table 13. Adverse Events of Edema in Patients Treated with Pioglitazone

Number (%) of Patients
Pioglitazone Pioglitazone Pioglitazone
Placebo
15 mg 30 mg 45 mg
Monotherapy 3 (1.2%) 2 (2.5%) 13 (4.7%) 11 (6.5%)
(16 to 26 weeks) N=259 N= 81 N= 275 N=169
4 (2.1%) 3 (1.6%) 61 (11.3%) 81 (23.1%)
Sulfonylurea
N=187 N=184 N=540 N=351
Combined Therapy 4 (2.5%) 34 (5.9%) 58 (13.9%)
Metformin N/A
(16 to 24 weeks) N=160 N=579 N=416
13 (7.0%) 24 (12.6%) 109 (20.5%) 90 (26.1%)
Insulin
N=187 N=191 N=533 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 14. Adverse Events of Edema in Patients in the

PROactive Trial
Number (%) of Patients
Placebo Pioglitazone
N=2633 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 pioglitazone-induced hepatotoxicity in the pioglitazone
controlled clinical trial database to date. One randomized, double-blind, three-year trial
comparing pioglitazone 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
pioglitazone 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
 Page 20 of 45
pioglitazone in the pioglitazone 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 pioglitazone 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 pioglitazone 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 pioglitazone 15 mg, 15.4% with
pioglitazone 30 mg, and 4.8% with placebo.
The incidence of reported hypoglycemia was higher with pioglitazone 45 mg compared to
pioglitazone 30 mg in both the 24-week add-on to sulfonylurea trial (15.7% versus 13.4%) and
in the 24-week add-on to insulin trial (47.8% versus 43.5%).
Three patients in these four trials were hospitalized due to hypoglycemia. All three patients
were receiving pioglitazone 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
pioglitazone 45 mg in combination with sulfonylurea (n=2) or pioglitazone 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 (13.1)]. During the three year PROactive clinical trial, 14 patients
out of 2605 (0.54%) randomized to pioglitazone and 5 out of 2633 (0.19%) randomized to
placebo were diagnosed with bladder cancer. After excluding patients in whom exposure to
study drug was less than one year at the time of diagnosis of bladder cancer, there were 6
(0.23%) cases on pioglitazone and two (0.08%) cases on placebo. After completion of the
trial, a large subset of patients was observed for up to 10 additional years, with little additional
exposure to pioglitazone. During the 13 years of both PROactive and observational follow-up,
the occurrence of bladder cancer did not differ between patients randomized to pioglitazone or
placebo (HR =1.00; 95% CI: 0.59-1.72) [see Warnings and Precautions (5.6)].
Metformin hydrochloride
In a double-blind clinical study of metformin in patients with type 2 diabetes, a total of 141
patients received metformin therapy (up to 2550 mg per day) and 145 patients received
placebo. Adverse reactions reported in greater than 5% of the metformin patients, and that
were more common in metformin than placebo-treated patients, are listed in Table 15. In this
trial, diarrhea led to discontinuation of study medication in 6% of patients treated with
metformin.
 Page 21 of 45

Table 15. Most Common Adverse Reactions (>5.0%) in a Placebo-Controlled

Clinical Study of Metformin Monotherapy*

Metformin
Placebo
Monotherapy
(n=145)
(n=141)

Adverse Reaction % of Patients

Diarrhea 53.2 11.7

Nausea/Vomiting 25.5 8.3

Flatulence 12.1 5.5

Asthenia 9.2 5.5

Indigestion 7.1 4.1

Abdominal Discomfort 6.4 4.8

Headache 5.7 4.8

*Reactions that were more common in metformin than placebo-treated patients.

Laboratory Abnormalities
Hematologic Effects
Pioglitazone may cause decreases in hemoglobin and hematocrit. In placebo-controlled
monotherapy trials, mean hemoglobin values declined by 2% to 4% in patients treated with
pioglitazone compared with a mean change in hemoglobin of -1% to +1% in placebo-treated
patients. These changes primarily occurred within the first four to 12 weeks of therapy and
remained relatively constant thereafter. These changes may be related to increased plasma
volume associated with pioglitazone therapy and are not likely to be associated with any
clinically significant hematologic effects.
Vitamin B12 Concentrations
Metformin may lower serum vitamin B12 concentrations. Measurement of hematologic
parameters on an annual basis is advised in patients on ACTOPLUS MET and any apparent
abnormalities should be appropriately investigated and managed [see Warnings and
Precautions (5.9)].
Creatine Phosphokinase
During protocol-specified measurement of serum creatine phosphokinase (CPK) in
pioglitazone 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 pioglitazone (values of
2150 to 11400 IU/L) and in no comparator-treated patients. Six of these nine patients
continued to receive pioglitazone, two patients were noted to have the CPK elevation on the
last day of dosing, and one patient discontinued pioglitazone due to the elevation. These
elevations resolved without any apparent clinical sequelae. The relationship of these events to
pioglitazone therapy is unknown.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of pioglitazone.
Because these reactions are reported voluntarily from a population of uncertain size, it is
 Page 22 of 45
generally not possible to reliably estimate their frequency or establish a causal relationship to
drug exposure.
Pioglitazone
• New onset or worsening diabetic macular edema with decreased visual acuity [see
Warnings and Precautions (5.8)].
• Fatal and nonfatal hepatic failure [see Warnings and Precautions (5.5)].
Postmarketing reports of congestive heart failure have been reported in patients treated with
pioglitazone, 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 (5.1)].
Metformin
Cholestatic, hepatocellular, and mixed hepatocellular liver injury.

7 DRUG INTERACTIONS
7.1 Strong CYP2C8 Inhibitors
An inhibitor of CYP2C8 (e.g., gemfibrozil) significantly increases the exposure (area under the
serum concentration-time curve or AUC) and half-life (t1/2) of pioglitazone. Therefore, the
maximum recommended dose of pioglitazone is 15 mg daily if used in combination with
gemfibrozil or other strong CYP2C8 inhibitors [see Dosage and Administration (2.3) and
Clinical Pharmacology (12.3)].
7.2 CYP2C8 Inducers
An inducer of CYP2C8 (e.g., rifampin) may significantly decrease the exposure (AUC) of
pioglitazone. Therefore, if an inducer of CYP2C8 is started or stopped during treatment with
pioglitazone, changes in diabetes treatment may be needed based on clinical response without
exceeding the maximum recommended daily dose of 45 mg for pioglitazone [see Clinical
Pharmacology (12.3)].
7.3 Carbonic Anhydrase Inhibitors
Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or
dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce
non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with
ACTOPLUS MET may increase the risk for lactic acidosis. Consider more frequent
monitoring of these patients.
7.4 Drugs that Reduce Metformin Clearance
Concomitant use of drugs that interfere with common renal tubular transport systems involved
in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and
toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine)
could increase systemic exposure to metformin and may increase the risk for lactic acidosis
[see Clinical Pharmacology (12.3)]. Consider the benefits and risks of concomitant use.
7.5 Alcohol
Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn
patients against excessive alcohol intake while receiving ACTOPLUS MET.
 Page 23 of 45
7.6 Insulin Secretagogues or Insulin
If hypoglycemia occurs in a patient coadministered ACTOPLUS MET and an insulin
secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be
reduced.
If hypoglycemia occurs in a patient coadministered ACTOPLUS MET and insulin, the
dose of insulin should be decreased by 10% to 25%. Further adjustments to the insulin dose
should be individualized based on glycemic response.
7.7 Drugs Affecting Glycemic Control
Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These
drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid
products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium
channel blockers, and isoniazid. When such drugs are administered to a patient receiving
ACTOPLUS MET, the patient should be closely observed for loss of blood glucose control.
When such drugs are withdrawn from a patient receiving ACTOPLUS MET, the patient should
be observed closely for hypoglycemia.
7.8 Topiramate
A decrease in the exposure of pioglitazone and its active metabolites were noted with
concomitant administration of pioglitazone and topiramate [see Clinical Pharmacology (12.3)].
The clinical relevance of this decrease is unknown; however, when ACTOPLUS MET and
topiramate are used concomitantly, monitor patients for adequate glycemic control.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy
Risk Summary
Limited data with ACTOPLUS MET or pioglitazone in pregnant women are not sufficient to
determine a drug-associated risk for major birth defects or miscarriage. Published studies with
metformin use during pregnancy have not reported a clear association with metformin and
major birth defect or miscarriage risk [see Data]. There are risks to the mother and fetus
associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].
In animal reproduction studies, no adverse developmental effects were observed when
pioglitazone was administered to pregnant rats and rabbits during organogenesis at exposures
up to 5- and 35-times the 45 mg clinical dose, respectively, based on body surface area. No
adverse developmental effects were observed when metformin was administered to pregnant
Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- to 6-
times, respectively, a 2000 mg clinical dose, based on body surface area [see Data].
The estimated background risk of major birth defects is 6-10% in women with pre-gestational
diabetes with a HbA1c >7 and has been reported to be as high as 20-25% in women with a
HbA1c >10. The estimated background risk of miscarriage for the indicated population is
unknown. In the U.S. general population, the estimated background risk of major birth defects
and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk
Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis,
pre-eclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications.
Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and
macrosomia related morbidity.
 Page 24 of 45
Data
Human Data
Published data from post-marketing studies have not reported a clear association with
metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when
metformin was used during pregnancy. However, these studies cannot definitely establish the
absence of any metformin-associated risk because of methodological limitations, including
small sample size and inconsistent comparator groups.
Animal Data
Pioglitazone and Metformin hydrochloride
Animal reproduction studies were not conducted with the combined products in ACTOPLUS
MET. The following data are based on studies conducted with the individual components of
ACTOPLUS MET.
Pioglitazone
Pioglitazone administered to pregnant rats during organogenesis did not cause adverse
developmental effects at a dose of 20 mg/kg (~5-times the 45 mg clinical dose), but delayed
parturition and reduced embryofetal viability at 40 and 80 mg/kg, or ≥9-times the 45 mg clinical
dose, by body surface area. In pregnant rabbits administered pioglitazone during
organogenesis, no adverse developmental effects were observed at 80 mg/kg (~35-times the
45 mg clinical dose), but reduced embryofetal viability at 160 mg/kg, or ~69-times the 45 mg
clinical dose, by body surface area. When pregnant rats received pioglitazone during late
gestation and lactation, delayed postnatal development, attributed to decreased body weight,
occurred in offspring at maternal doses of 10 mg/kg and above or ≥2-times the 45 mg clinical
dose, by body surface area.
Metformin hydrochloride
Metformin hydrochloride did not cause adverse developmental effects when administered to
pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of
organogenesis. This represents an exposure of about 2- to 6-times a 2000 mg clinical dose
based on body surface area (mg/m2) for rats and rabbits, respectively.
8.2 Lactation
Risk Summary
There is no information regarding the presence of ACTOPLUS MET or pioglitazone in human
milk, the effects on the breastfed infant, or the effects on milk production. Pioglitazone is
present in rat milk; however, due to species-specific differences in lactation physiology, animal
data may not reliably predict drug levels in human milk. Limited published studies report that
metformin is present in human milk [see Data]. However, there is insufficient information on the
effects of metformin on the breastfed infant and no available information on the effects of
metformin on milk production. The developmental and health benefits of breastfeeding should
be considered along with the mother’s clinical need for ACTOPLUS MET and any potential
adverse effects on the breastfed infant from ACTOPLUS MET or from the underlying maternal
condition.
Data
Published clinical lactation studies report that metformin is present in human milk which
resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage
and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed
to definitely establish the risk of use of metformin during lactation because of small sample
size and limited adverse event data collected in infants.
 Page 25 of 45
8.3 Females and Males of Reproductive Potential
Discuss the potential for unintended pregnancy with premenopausal women as therapy with
ACTOPLUS MET, may result in ovulation in some anovulatory women.
8.4 Pediatric Use
Safety and effectiveness of ACTOPLUS MET in pediatric patients have not been established.
ACTOPLUS MET is not recommended for use in pediatric patients based on adverse effects
observed in adults, including fluid retention and congestive heart failure, fractures, and urinary
bladder tumors [see Warnings and Precautions (5.1, 5.3, 5.6, 5.7)].
8.5 Geriatric Use
Pioglitazone
A total of 92 patients (15.2%) treated with pioglitazone in the three pooled 16- to 26-week
double-blind, placebo-controlled, monotherapy trials were ≥65 years old and two patients
(0.3%) were ≥75 years old. In the two pooled 16- to 24-week add-on to sulfonylurea trials, 201
patients (18.7%) treated with pioglitazone were ≥65 years old and 19 (1.8%) were ≥75 years
old. In the two pooled 16- to 24-week add-on to metformin trials, 155 patients (15.5%) treated
with pioglitazone were ≥65 years old and 19 (1.9%) were ≥75 years old. In the two pooled 16-
to 24-week add-on to insulin trials, 272 patients (25.4%) treated with pioglitazone were ≥65
years old and 22 (2.1%) were ≥75 years old.
In PROactive Trial, 1068 patients (41.0%) treated with pioglitazone were ≥65 years old and 42
(1.6%) were ≥75 years old.
In pharmacokinetic studies with pioglitazone, no significant differences were observed in
pharmacokinetic parameters between elderly and younger patients [see Clinical Pharmacology
(12.3)].
Although clinical experiences have not identified differences in effectiveness and safety
between the elderly (≥65 years) and younger patients, these conclusions are limited by small
sample sizes for patients ≥75 years old.
Metformin hydrochloride
Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to
determine whether they respond differently from younger patients, although other reported
clinical experience has not identified differences in responses between the elderly and young
patients. In general, dose selection for an elderly patient should be cautious, usually starting at
the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal,
or cardiac function, and of concomitant disease or other drug therapy and the higher risk of
lactic acidosis. Assess renal function more frequently in elderly patients [see Warnings and
Precautions (5.2) and Dosage and Administration (2.2)].
8.6 Renal Impairment
Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and
lactic acidosis increases with the degree of renal impairment. ACTOPLUS MET is
contraindicated in severe renal impairment, patients with an eGFR below 30 mL/min/1.73 m2
[see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.2)
and Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
Use of metformin in patients with hepatic impairment has been associated with some cases of
lactic acidosis. ACTOPLUS MET is not recommended in patients with hepatic impairment [see
Warnings and Precautions (5.2)].
 Page 26 of 45
10 OVERDOSAGE
Pioglitazone
During controlled clinical trials, one case of overdose with pioglitazone was reported. A male
patient took 120 mg per day for four days, then 180 mg per day for seven days. The patient
denied any clinical symptoms during this period.
In the event of overdosage, appropriate supportive treatment should be initiated according to
the patient’s clinical signs and symptoms.
Metformin hydrochloride
Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater
than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal
association with metformin hydrochloride has been established. Lactic acidosis has been
reported in approximately 32% of metformin overdose cases [see Warnings and Precautions
(5.2)]. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic
conditions. Therefore, hemodialysis may be useful for removal of accumulated metformin from
patients in whom metformin overdosage is suspected.

11 DESCRIPTION
ACTOPLUS MET tablets are a thiazolidinediones and biguanide combination product that
contains two oral antidiabetic medications: pioglitazone hydrochloride and metformin
hydrochloride.
Pioglitazone [(±)-5-[[4-[2-(5-ethyl-2-pyridinyl) ethoxy]phenyl]methyl]-2,4-] thiazolidinedione
monohydrochloride 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:

S O
C H3 N
• HCl
NH
O O

pioglitazone hydrochloride

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.
Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is a white
crystalline powder with a molecular formula of C4H11N5•HCl and a molecular weight of 165.62.
Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether,
and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin
hydrochloride is 6.68. The structural formula is as shown:
CH3
H
N N NH2
H3C · HCl

NH NH
metformin hydrochloride
 Page 27 of 45
ACTOPLUS MET is available as a tablet for oral administration containing 15 mg pioglitazone
(as the base) with 500 mg metformin hydrochloride (15 mg/500 mg) or 15 mg pioglitazone (as
the base) with 850 mg metformin hydrochloride (15 mg/850 mg) formulated with the following
excipients: povidone USP, microcrystalline cellulose NF, croscarmellose sodium NF,
magnesium stearate NF, hypromellose 2910 USP, polyethylene glycol 8000 NF, titanium
dioxide USP, and talc USP.

12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
ACTOPLUS MET combines two antidiabetic medications with different mechanisms of action
to improve glycemic control in adults with type 2 diabetes: pioglitazone, a thiazolidinedione,
and metformin hydrochloride, a biguanide. Thiazolidinediones are insulin-sensitizing agents
that act primarily by enhancing peripheral glucose utilization, whereas biguanides act primarily
by decreasing endogenous hepatic glucose production.
Pioglitazone
Pioglitazone is a thiazolidinedione that depends on the presence of insulin for its mechanism of
action. Pioglitazone decreases insulin resistance in the periphery and in the liver resulting in
increased insulin-dependent glucose disposal and decreased hepatic glucose output.
Pioglitazone is not an insulin secretagogue. Pioglitazone is an 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.
Because pioglitazone enhances the effects of circulating insulin (by decreasing insulin
resistance), it does not lower blood glucose in animal models that lack endogenous insulin.
Metformin hydrochloride
Metformin hydrochloride improves glucose tolerance in patients with type 2 diabetes, lowering
both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production,
decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing
peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in either
patients with type 2 diabetes or healthy subjects [except in specific circumstances, see
Warnings and Precautions (5.4)] and does not cause hyperinsulinemia. With metformin
therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma
insulin response may actually decrease.
12.2 Pharmacodynamics
Pioglitazone
Clinical studies demonstrate that pioglitazone improves insulin sensitivity in insulin-resistant
patients. Pioglitazone enhances cellular responsiveness to insulin, increases insulin-
dependent glucose disposal and improves hepatic sensitivity to insulin. In patients with type 2
diabetes, the decreased insulin resistance produced by pioglitazone results in lower plasma
glucose concentrations, lower plasma insulin concentrations, and lower HbA1c values. In
controlled clinical trials, pioglitazone had an additive effect on glycemic control when used in
combination with a sulfonylurea, metformin, or insulin [see Clinical Studies (14)].
 Page 28 of 45
Patients with lipid abnormalities were included in clinical trials with pioglitazone. Overall,
patients treated with pioglitazone had mean decreases in serum triglycerides, mean increases
in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. There is no
conclusive evidence of macrovascular benefit with pioglitazone [see Warnings and Precautions
(5.10) and Adverse Reactions (6.1)].
In a 26-week, placebo-controlled, dose-ranging monotherapy study, mean serum triglycerides
decreased in the 15-mg, 30-mg, and 45-mg pioglitazone dose groups compared to a mean
increase in the placebo group. Mean HDL cholesterol increased to a greater extent in patients
treated with pioglitazone than in the placebo-treated patients. There were no consistent
differences for LDL and total cholesterol in patients treated with pioglitazone compared to
placebo (see Table 16).

Table 16. Lipids in a 26-Week Placebo-Controlled Monotherapy Dose-Ranging Study

Pioglitazone Pioglitazone Pioglitazone

Placebo 15 mg 30 mg 45 mg
Once Once Once
Daily Daily Daily
Triglycerides (mg/dL) N=79 N=79 N=84 N=77
Baseline (mean) 263 284 261 260
Percent change from baseline
4.8% -9.0%† -9.6%† -9.3%†
(adjusted mean*)
HDL Cholesterol (mg/dL) N=79 N=79 N=83 N=77
Baseline (mean) 42 40 41 41
Percent change from baseline
8.1% 14.1%† 12.2% 19.1%†
(adjusted mean*)
LDL Cholesterol (mg/dL) N=65 N=63 N=74 N=62
Baseline (mean) 139 132 136 127
Percent change from baseline
4.8% 7.2% 5.2% 6.0%
(adjusted mean*)
Total Cholesterol (mg/dL) N=79 N=79 N=84 N=77
Baseline (mean) 225 220 223 214
Percent change from baseline
4.4% 4.6% 3.3% 6.4%
(adjusted mean*)
*Adjusted for baseline, pooled center, and pooled center by treatment interaction
†p <0.05 versus placebo

In the two other monotherapy studies (16 weeks and 24 weeks) and in combination therapy
studies with metformin (16 weeks and 24 weeks), the results were generally consistent with
the data above.
12.3 Pharmacokinetics
Absorption
ACTOPLUS MET
In bioequivalence studies of ACTOPLUS MET 15 mg/500 mg and 15 mg/850 mg, the area
under the curve (AUC) and maximum concentration (Cmax) of both the pioglitazone and the
metformin component following a single dose of the combination tablet were bioequivalent to
 Page 29 of 45
ACTOS 15 mg concomitantly administered with Glucophage (500 mg or 850 mg respectively)
tablets under fasted conditions in healthy subjects.
Administration of ACTOPLUS MET 15 mg/850 mg with food resulted in no change in overall
exposure of pioglitazone. With metformin there was no change in AUC; however, mean peak
serum concentration of metformin was decreased by 28% when administered with food. A
delayed time to peak serum concentration was observed for both components (1.9 hours for
pioglitazone and 0.8 hours for metformin) under fed conditions. These changes are not likely to
be clinically significant.
Pioglitazone
Following once-daily administration of pioglitazone, steady-state serum concentrations of both
pioglitazone and its major active metabolites, M-III (keto derivative of pioglitazone) and M-IV
(hydroxyl derivative of pioglitazone), are achieved within seven days. At steady-state, M-III and
M-IV reach serum concentrations equal to or greater than that of pioglitazone. At steady-state,
in both healthy volunteers and patients with type 2 diabetes, pioglitazone comprises
approximately 30% to 50% of the peak total pioglitazone serum concentrations (pioglitazone
plus active metabolites) and 20% to 25% of the total AUC.
Cmax, AUC, and trough serum concentrations (Cmin) for pioglitazone and M-III and M-IV,
increased proportionally with administered doses of 15 mg and 30 mg per day.
Following oral administration of pioglitazone, Tmax of pioglitazone was within two hours. Food
delays the Tmax to three to four hours, but does not alter the extent of absorption (AUC).
Metformin hydrochloride
The absolute bioavailability of a 500 mg metformin tablet given under fasting conditions is
approximately 50% - 60%. Studies using single oral doses of metformin tablets of 500 mg to
1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with
increasing doses, which is due to decreased absorption rather than an alteration in elimination.
At usual clinical doses and dosing schedules of metformin, steady-state plasma concentrations
of metformin are reached within 24 to 48 hours and are generally <1 mcg/mL. During
controlled clinical trials, maximum metformin plasma levels did not exceed 5 mcg/mL, even at
maximum doses.
Food decreases the rate and extent of metformin absorption, as shown by a 40% lower mean
Cmax, a 25% lower AUC, and a 35-minute prolongation of Tmax following administration of a
single 850 mg tablet of metformin with food, compared to the same tablet strength
administered fasting. The clinical relevance of these decreases is unknown.
Distribution
Pioglitazone
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. M-III and M-IV are also extensively bound (>98%)
to serum albumin.
Metformin hydrochloride
The Vd/F of metformin following single oral doses of 850 mg immediate-release metformin
averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions
into erythrocytes, most likely as a function of time.
 Page 30 of 45
Metabolism
Pioglitazone
Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also
partly convert to glucuronide or sulfate conjugates. Metabolites M-III and M-IV are the major
circulating active metabolites in humans.
In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of
pioglitazone which include CYP2C8 and, to a lesser degree, CYP3A4 with additional
contributions from a variety of other isoforms, including the mainly extrahepatic CYP1A1. In
vivo study of pioglitazone in combination with gemfibrozil, a strong CYP2C8 inhibitor, showed
that pioglitazone is a CYP2C8 substrate [see Dosage and Administration (2.3) and Drug
Interactions (7.1)]. Urinary 6ß-hydroxycortisol/cortisol ratios measured in patients treated with
pioglitazone showed that pioglitazone is not a strong CYP3A4 enzyme inducer.
Metformin hydrochloride
Intravenous single-dose studies in healthy subjects demonstrate that metformin is excreted
unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been
identified in humans) nor biliary excretion.
Excretion and Elimination
Pioglitazone
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 (t1/2) of pioglitazone and its metabolites (M-III and M-IV) range from
three to seven hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance,
CL/F, calculated to be five to seven L/hr.
Metformin hydrochloride
Renal clearance is approximately 3.5 times greater than creatinine clearance (CLcr), which
indicates that tubular secretion is the major route of metformin elimination. Following oral
administration, approximately 90% of the absorbed drug is eliminated via the renal route within
the first 24 hours, with a plasma elimination t1/2 of approximately 6.2 hours. In blood, the
elimination t1/2 is approximately 17.6 hours, suggesting that the erythrocyte mass may be a
compartment of distribution.
Specific Populations
Renal Impairment
Pioglitazone
The serum elimination half-life of pioglitazone, M-III and M-IV remains unchanged in patients
with moderate (CLcr 30 to 50 mL/min) and severe (CLcr <30 mL/min) renal impairment when
compared to subjects with normal renal function. Therefore, no dose adjustment in patients
with renal impairment is required.
Metformin hydrochloride
In patients with decreased renal function, the plasma and blood t1/2 of metformin is prolonged
and the renal clearance is decreased [see Dosage and Administration (2.2), Contraindications
(4) and Warnings and Precautions (5.2)].
 Page 31 of 45
Hepatic Impairment
Pioglitazone
Compared with healthy controls, subjects with impaired hepatic function (Child-Turcotte-Pugh
Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone
(pioglitazone, M-III, and M-IV) mean Cmax but no change in the mean AUC values. Therefore,
no dose adjustment in patients with hepatic impairment is required.
There are postmarketing reports of liver failure with pioglitazone and clinical trials have
generally excluded patients with serum ALT >2.5 times the upper limit of the reference range.
Use ACTOPLUS MET with caution in patients with liver disease [see Warnings and
Precautions (5.5)].
Metformin hydrochloride
No pharmacokinetic studies of metformin have been conducted in subjects with hepatic
impairment [see Warnings and Precautions (5.5)].
Geriatric Patients
Pioglitazone
In healthy elderly subjects, Cmax of pioglitazone was not significantly different, but AUC values
were approximately 21% higher than those achieved in younger subjects. The mean t1/2 of
pioglitazone was also prolonged in elderly subjects (about ten hours) as compared to younger
subjects (about seven hours). These changes were not of a magnitude that would be
considered clinically relevant.
Metformin hydrochloride
Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects
suggest that total CL/F is decreased, the t1/2 is prolonged, and Cmax is increased, compared to
healthy young subjects. From these data, it appears that the change in metformin
pharmacokinetics with aging is primarily accounted for by a change in renal function.
Pediatrics
Pioglitazone
Safety and efficacy of pioglitazone in pediatric patients have not been established. ACTOPLUS
MET is not recommended for use in pediatric patients [see Use in Specific Populations (8.4)].
Metformin hydrochloride
After administration of a single oral metformin 500 mg tablet with food, geometric mean
metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12
to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age),
and all with normal renal function.
Gender
Pioglitazone
The mean Cmax and AUC values of pioglitazone were increased 20% to 60% in women
compared to men. In controlled clinical trials, HbA1c decreases from baseline were generally
greater for females than for males (average mean difference in HbA1c 0.5%). Because therapy
should be individualized for each patient to achieve glycemic control, no dose adjustment is
recommended based on gender alone.
Metformin hydrochloride
Metformin pharmacokinetic parameters did not differ significantly between normal subjects and
patients with type 2 diabetes when analyzed according to gender (males=19, females=16).
Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic
effect of metformin was comparable in males and females.
 Page 32 of 45
Ethnicity
Pioglitazone
Pharmacokinetic data among various ethnic groups are not available.
Metformin hydrochloride
No studies of metformin pharmacokinetic parameters according to race have been performed.
In controlled clinical studies of metformin in patients with type 2 diabetes, the
antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics
(n=24).
Drug-Drug Interactions
Specific pharmacokinetic drug interaction studies with ACTOPLUS MET have not been
performed, although such studies have been conducted with the individual pioglitazone and
metformin components.
 Page 33 of 45

Pioglitazone
Table 17. Effect of Pioglitazone Coadministration on Systemic Exposure of Other Drugs
Coadministered Drug
Pioglitazone Change
Change
Dosage Name and Dose Regimens in Cmax†
in AUC†
Regimen (mg)*
Warfarin‡
45 mg Daily loading then maintenance doses R-Warfarin 3% R-Warfarin 2%
(N = 12) based PT and INR values
Quick's Value = 35 ± 5% S-Warfarin 1% S-Warfarin 1%
Digoxin
45 mg
(N = 12) 0.200 mg twice daily (loading dose) then
15% 17%
0.250 mg daily (maintenance dose, 7 days)
45 mg daily Oral Contraceptive
for 21 days [Ethinyl Estradiol (EE) 0.035 mg plus EE 11% EE 13%
(N = 35) Norethindrone (NE) 1 mg] for 21 days NE 3% NE 7%
45 mg Fexofenadine
(N = 23) 60 mg twice daily for 7 days 30% 37%
45 mg Glipizide
(N = 14) 5 mg daily for 7 days 3% 8%
45 mg daily Metformin
for 8 days
(N = 16) 1000 mg single dose on Day 8 3% 5%

45 mg Midazolam
(N = 21) 7.5 mg single dose on Day 15 26% 26%

45 mg Ranitidine
(N = 24) 150 mg twice daily for 7 days 1% 1%
45 mg daily Nifedipine ER
for 4 days
(N = 24) 30 mg daily for 4 days 13% 17%
45 mg Atorvastatin Ca
(N = 25) 80 mg daily for 7 days 14%  23%
45 mg Theophylline
(N = 22) 400 mg twice daily for 7 days 2% 5%
*Daily for 7 days unless otherwise noted
†% change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase

and decrease, respectively

‡Pioglitazone had no clinically significant effect on prothrombin time
 Page 34 of 45
Table 18. Effect of Coadministered Drugs on Pioglitazone Systemic Exposure
Pioglitazone
Coadministered Drug and
Dosage Regimen Dose Regimen Change Change
(mg)* in AUC† in Cmax†

Gemfibrozil 600 mg
15-mg
twice daily for 2 days 3.2-fold‡ 6%
single dose
(N = 12)
Ketoconazole 200 mg
twice daily for 7 days 45 mg 34% 14%
(N = 28)
Rifampin 600 mg
30-mg
daily for 5 days 54% 5%
single dose
(N = 10)
Fexofenadine 60 mg
twice daily for 7 days 45 mg 1% 0%
(N = 23)
Ranitidine 150 mg
twice daily for 4 days 45 mg 13% 16%
(N = 23)
Nifedipine ER 30 mg
daily for 7 days 45 mg 5% 4%
(N = 23)
Atorvastatin Ca 80 mg
daily for 7 days 45 mg 24% 31%
(N = 24)
Theophylline 400 mg
twice daily for 7 days 45 mg 4% 2%
(N = 22)
Topiramate 96 mg
twice daily for 7 days§ 30 mg§ 15%¶ 0%
(N = 26)
*Daily for 7 days unless otherwise noted
†Mean ratio (with/without coadministered drug and no change = 1-fold) % change (with/without

coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure
increase and decrease, respectively
‡The half-life of pioglitazone increased from 8.3 hours to 22.7 hours in the presence of

gemfibrozil [see Dosage and Administration (2.3) and Drug Interactions (7.1)]
§Indicates duration of concomitant administration with highest twice-daily dose of topiramate

from Day 14 onwards over the 22 days of study

¶Additional decrease in active metabolites; 60% for M-III and 16% for M-IV
 Page 35 of 45

Metformin hydrochloride

Table 19. Effect of Coadministered Drug on Plasma Metformin Systemic Exposure

Geometric Mean Ratio
Dose of (ratio with/without
Coadministered Dose of coadministered drug)
Coadministered
Drug Metformin* No effect = 1.00
Drug*
AUC† Cmax
No dosing adjustments required for the following:
Glyburide 5 mg 500 mg§ 0.98‡ 0.99‡
Furosemide 40 mg 850 mg 1.09‡ 1.22‡
Nifedipine 10 mg 850 mg 1.16 1.21
Propranolol 40 mg 850 mg 0.90 0.94
Ibuprofen 400 mg 850 mg 1.05‡ 1.07‡
Drugs that are eliminated by renal tubular secretion may increase the accumulation of metformin
[see Warnings and Precautions (5) and Drug Interactions (7)].
Cimetidine 400 mg 850 mg 1.40 1.61
Carbonic anhydrase inhibitors may cause metabolic acidosis [see Warnings and Precautions (5)
and Drug Interactions (7)].
Topiramate 100 mg¶ 500 mg¶ 1.25¶ 1.17
*All metformin and coadministered drugs were given as single doses
†AUC = AUC
0–∞
‡Ratio of arithmetic means
§Metformin hydrochloride extended-release tablets, 500 mg
¶At steady-state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours;

AUC = AUC0-12h

Table 20. Effect of Metformin on Coadministered Drug Systemic Exposure

Geometric Mean Ratio
Dose of (ratio with/without
Coadministered Dose of coadministered drug)
Coadministered
Drug Metformin* No effect = 1.00
Drug*
AUC† Cmax
No dosing adjustments required for the following:
Glyburide 5 mg 500 mg§ 0.78‡ 0.63‡
Furosemide 40 mg 850 mg 0.87‡ 0.69‡
Nifedipine 10 mg 850 mg 1.10§ 1.08
Propranolol 40 mg 850 mg 1.01§ 0.94
Ibuprofen 400 mg 850 mg 0.97¶ 1.01¶
Cimetidine 400 mg 850 mg 0.95§ 1.01
*All metformin and coadministered drugs were given as single doses
†AUC = AUC
0–∞
‡Ratio of arithmetic means, p-value of difference <0.05
§AUC
0-24hr reported
¶Ratio of arithmetic means
 Page 36 of 45
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
ACTOPLUS MET
No animal studies have been conducted with ACTOPLUS MET. The following data are based
on findings in studies performed with pioglitazone or metformin individually.
Pioglitazone
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 of male rats. 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). Urinary calculi with subsequent irritation and hyperplasia
were postulated as the mechanism for bladder tumors observed in male rats. A two-year
mechanistic study in male rats utilizing dietary acidification to reduce calculi formation was
completed in 2009. Dietary acidification decreased but did not abolish the hyperplastic
changes in the bladder. The presence of calculi exacerbated the hyperplastic response to
pioglitazone but was not considered the primary cause of the hyperplastic changes.
The relevance to humans of the bladder findings in the male rat cannot be excluded.
A two-year carcinogenicity study was also 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.
Pioglitazone hydrochloride 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 hydrochloride daily prior to and throughout mating and gestation
(approximately nine times the maximum recommended human oral dose based on mg/m 2).
Metformin hydrochloride
Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks)
and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and
1500 mg/kg/day, respectively. These doses are both approximately four times a human daily
dose of 2000 mg of the metformin component of ACTOPLUS MET based on body surface
area comparisons. No evidence of carcinogenicity with metformin was found in either male or
female mice. Similarly, there was no tumorigenic potential observed with metformin in male
rats. There was, however, an increased incidence of benign stromal uterine polyps in female
rats treated with 900 mg/kg/day.
There was no evidence of mutagenic potential of metformin in the following in vitro tests: Ames
test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal
aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were
also negative.
Fertility of male or female rats was unaffected by metformin when administered at doses as
high as 600 mg/kg/day, which is approximately three times the maximum recommended
human daily dose of the metformin component of ACTOPLUS MET based on body surface
area comparisons.
 Page 37 of 45
13.2 Animal Toxicology and/or Pharmacology
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 hydrochloride (approximately 11, one, and two
times the maximum recommended human oral dose for mice, rats, and dogs, respectively,
based on mg/m2). In a one-year rat study, drug-related 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 four times the
maximum recommended human oral dose based on mg/m 2), 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).

14 CLINICAL STUDIES
14.1 Patients Who Have Inadequate Glycemic Control with Diet and Exercise Alone
In a 24-week, randomized, double-blind clinical trial, 600 patients with type 2 diabetes mellitus
inadequately controlled with diet and exercise alone (mean baseline HbA1c 8.7%) were
randomized to ACTOPLUS MET 15/850 mg, pioglitazone 15 mg, or metformin 850 mg twice
daily. Statistically significant improvements in HbA1c and fasting plasma glucose (FPG) were
observed in patients treated with ACTOPLUS MET compared to either pioglitazone or
metformin alone (see Table 21).

Table 21. Glycemic Parameters in 24-Week Study of ACTOPLUS MET in Patients with Type
2 Diabetes Mellitus Inadequately Controlled with Diet and Exercise

Treatment Group
ACTOPLUS MET Pioglitazone Metformin
15/850 mg 15 mg 850 mg
Parameter Twice Daily Twice Daily Twice Daily
HbA1c (%) N=188 N=162 N=193
Baseline (mean) 8.9 8.7 8.7
Change from Baseline
-1.8 -1.0 -1.0
(adjusted mean*)
Difference between
ACTOPLUS MET 0.9† 0.8†
(adjusted mean*) (0.5, 1.2) (0.5, 1.2)
95% Confidence Interval
% of patients with HbA1c 7% 64 47 39
Fasting Plasma Glucose (mg/dL) N=196 N=176 N=202
Baseline (mean) 177 171 171
Change from Baseline
(adjusted mean*) -40 -22 -25
Difference between
ACTOPLUS MET 18† 15†
(adjusted mean*) (8, 28) (6, 25)
95% Confidence Interval
*Adjusted for baseline
†p ≤0.05 versus ACTOPLUS MET
 Page 38 of 45
14.2 Patients Previously Treated with Metformin
The efficacy and safety of pioglitazone as add-on to metformin therapy have been established
in two clinical studies. Bioequivalence of ACTOPLUS MET with coadministered pioglitazone
and metformin tablets was demonstrated for both ACTOPLUS MET strengths [see Clinical
Pharmacology (12.3)].
The two clinical trials testing pioglitazone as add-on to metformin therapy included patients
with type 2 diabetes on any dose of metformin, either alone or in combination with another
antidiabetic agent. All other antidiabetic agents were withdrawn at least three weeks prior to
starting study treatment.
In the first trial, 328 patients were randomized to receive either 30 mg of pioglitazone or
placebo once daily for 16 weeks in addition to their current metformin regimen. Treatment with
pioglitazone as add-on to metformin produced statistically significant improvements in HbA1c
and FPG at endpoint compared to placebo add-on to metformin (see Table 22).
Table 22. Glycemic Parameters in a 16-Week Placebo-Controlled, Add-on to
Metformin Trial

Pioglitazone
Placebo
30 mg
+ Metformin
+ Metformin

Total Population
HbA1c (%) N=153 N=161
Baseline (mean) 9.8 9.9
Change from baseline (adjusted mean*) 0.2 -0.6
Difference from placebo + metformin
-0.8†
(adjusted mean*)
(-1.2, -0.5)
95% Confidence Interval
Fasting Plasma Glucose (mg/dL) N=157 N=165
Baseline (mean) 260 254
Change from baseline (adjusted mean*) -5 -43
Difference from placebo + metformin
-38†
(adjusted mean*)
(-49, -26)
95% Confidence Interval
*Adjusted for baseline, pooled center, and pooled center by treatment interaction
†p 0.05 vs. placebo + metformin

In the second trial, 827 patients were randomized to receive either 30 mg or 45 mg of

pioglitazone once daily for 24 weeks in addition to their current metformin regimen. The mean
reduction from baseline at Week 24 in HbA1c was 0.8% for the 30 mg dose and 1.0% for the
45 mg dose (see Table 23). The mean reduction from baseline at Week 24 in FPG was
38 mg/dL for the 30 mg dose and 51 mg/dL for the 45 mg dose.
 Page 39 of 45

Table 23. Glycemic Parameters in a 24-Week Add-on to Metformin Study

Pioglitazone Pioglitazone
30 mg 45 mg
+ Metformin + Metformin
Total Population
HbA1c (%) N=400 N=398
Baseline (mean) 9.9 9.8
Change from baseline
-0.8 -1.0
(adjusted mean*)
Difference from 30 mg daily pioglitazone -0.2
+ metformin (adjusted mean*) (95% CI) (-0.5, 0.1)
Fasting Plasma Glucose (mg/dL) N=398 N=399
Baseline (mean) 233 232
Change from baseline
-38 -51
(adjusted mean*)
Difference from 30 mg daily pioglitazone -12†
+ metformin (adjusted mean*) (95% CI) (-21, -4)
95% CI = 95% confidence interval
*Adjusted for baseline, pooled center, and pooled center by treatment interaction
†p 0.05 vs. 30 mg daily pioglitazone + metformin

The therapeutic effect of pioglitazone in combination with metformin was observed in patients
regardless of the metformin dose.

16 HOW SUPPLIED/STORAGE AND HANDLING

ACTOPLUS MET is available in 15 mg pioglitazone (as the base)/500 mg metformin
hydrochloride and 15 mg pioglitazone (as the base)/850 mg metformin hydrochloride tablets as
follows:
15 mg/500 mg tablet: white to off-white, oblong, film-coated tablet with “4833M” on one side
and “15/500” on the other, available in:
Bottles of 60 NDC 64764-155-60
Bottles of 180 NDC 64764-155-18
15 mg/850 mg tablet: white to off-white, oblong, film-coated tablet with “4833M” on one side
and “15/850” on the other, available in:
Bottles of 60 NDC 64764-158-60
Bottles of 180 NDC 64764-158-18

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.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling (Medication Guide).
• 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
 Page 40 of 45
fever, trauma, infection, or surgery, medication requirements may change and patients
should be reminded to seek medical advice promptly.
• Tell patients to promptly report any sign of macroscopic hematuria or other symptoms such
as dysuria or urinary urgency that develop or increase during treatment as these may be
due to bladder cancer.
• Explain to patients the risks of lactic acidosis, its symptoms and conditions that predispose
to its development, as noted in the Warnings and Precautions (5.2) section. Advise
patients to discontinue ACTOPLUS MET immediately and to promptly notify their
healthcare professional if unexplained hyperventilation, myalgia, gastrointestinal
symptoms, malaise, unusual somnolence, or other nonspecific symptoms occur. Instruct
patients to inform their doctor that they are taking ACTOPLUS MET prior to any surgical or
radiological procedure, as temporary discontinuation of ACTOPLUS MET may be required
until renal function has been confirmed to be normal.
• Counsel patients against excessive alcohol intake while receiving ACTOPLUS MET.
• Inform patients to immediately report symptoms of an unusually rapid increase in weight or
edema, shortness of breath, or other symptoms of heart failure while receiving ACTOPLUS
MET.
• Tell patients to promptly stop taking ACTOPLUS MET and seek immediate medical advice
if there is unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine
as these symptoms may be due to hepatotoxicity.
• Inform patients about the importance of regular testing of renal function and hematologic
parameters when receiving treatment with ACTOPLUS MET.
• Inform female patients that treatment with ACTOPLUS MET may result in an unintended
pregnancy in some premenopausal anovulatory females due to its effect on ovulation [see
Use in Specific Populations (8.3)].
• Patients should be advised to notify their health practitioner or call the Poison Control
Center immediately in case of ACTOPLUS MET overdose.
• Combination antihyperglycemic therapy may cause hypoglycemia. When initiating
ACTOPLUS MET, the risks of hypoglycemia, its symptoms and treatment, and conditions
that predispose to its development should be explained to patients and their family
members.
• Patients should be told to take ACTOPLUS MET as prescribed and instructed that any
change in dosing should only be done if directed by their physician. If a dose is missed on
one day, the dose should not be doubled the following day.
Distributed by:
Takeda Pharmaceuticals America, Inc.
Lexington, MA 02421
ACTOS and ACTOPLUS MET are trademarks of Takeda Pharmaceutical Company Limited
registered with the U.S. Patent and Trademark Office and used under license by Takeda
Pharmaceuticals America, Inc.
All other trademarks are the property of their respective owners.
©2009 - 2020 Takeda Pharmaceuticals America, Inc.
APM001 R16
 Page 41 of 45
MEDICATION GUIDE
ACTOPLUS MET (ak-TŌ-plus-met)
(pioglitazone and metformin hydrochloride) tablets

Read this Medication Guide carefully before you start taking ACTOPLUS MET and each
time you get a refill. There may be new information. This information does not take the
place of talking with your doctor about your medical condition or your treatment. If you
have any questions about ACTOPLUS MET, ask your doctor or pharmacist.
What is the most important information I should know about ACTOPLUS MET?
ACTOPLUS MET can cause serious side effects, including:
• new or worse heart failure. Pioglitazone, one of the medicines in ACTOPLUS MET,
can cause your body to keep extra fluid (fluid retention), which leads to swelling
(edema) and weight gain. Extra body fluid can make some heart problems worse or
lead to heart failure. Heart failure means your heart does not pump blood well enough.
o Do not take ACTOPLUS MET if you have severe heart failure
o If you have heart failure with symptoms (such as shortness of breath or swelling),
even if these symptoms are not severe, ACTOPLUS MET may not be right for you.
Call your doctor right away if you have any of the following:
o swelling or fluid retention, especially in the ankles or legs
o shortness of breath or trouble breathing, especially when you lie down
o an unusually fast increase in weight
o unusual tiredness
• lactic acidosis. Metformin, one of the medicines in ACTOPLUS MET, can cause
a rare but serious condition called lactic acidosis (a buildup of an acid in the
blood) that can cause death. Lactic acidosis is a medical emergency and must
be treated in the hospital.
Call your doctor right away if you have any of the following symptoms, which could be
signs of lactic acidosis:
o you feel cold in your hands or feet
o you feel dizzy or lightheaded
o you have a slow or irregular heartbeat
o you feel very weak or tired
o you have unusual (not normal) muscle pain
o you have trouble breathing
o you feel sleepy or drowsy
o you have stomach pains, nausea, or vomiting
Most people who have had lactic acidosis with metformin have other things that,
combined with the metformin, led to the lactic acidosis. Tell your doctor if you have any of
the following, because you have a higher chance for getting lactic acidosis with ACTOPLUS
MET if you:
o have severe kidney problems or your kidneys are affected by certain x-ray tests
that use injectable dye. have liver problems
o drink alcohol very often, or drink a lot of alcohol in short-term "binge" drinking
 Page 42 of 45
o get dehydrated (lose a large amount of body fluids). This can happen if you are
sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you
sweat a lot with activity or exercise and do not drink enough fluids
o have surgery
o have a heart attack, severe infection, or stroke
The best way to keep from having a problem with lactic acidosis from metformin is to tell
your doctor if you have any of the problems in the list above. Your doctor may decide to
stop your ACTOPLUS MET for a while if you have any of these things.
ACTOPLUS MET can have other serious side effects. See “What are the possible side
effects of ACTOPLUS MET?”
What is ACTOPLUS MET?
ACTOPLUS MET contains two prescription diabetes medicines called pioglitazone (ACTOS)
and metformin hydrochloride (GLUCOPHAGE). ACTOPLUS MET can be used with diet and
exercise to improve blood sugar (glucose) control in adults with type 2 diabetes.
ACTOPLUS MET is not for people with type 1 diabetes.
ACTOPLUS MET is not for people with diabetic ketoacidosis (increased ketones in your
blood or urine).
It is not known if ACTOPLUS MET is safe and effective in children under the age of 18.
ACTOPLUS MET is not recommended for use in children.
Who should not take ACTOPLUS MET?
See “What is the most important information I should know about ACTOPLUS MET?”
Do not take ACTOPLUS MET if you:
• have severe heart failure
• are allergic to pioglitazone, metformin, or any of the ingredients in ACTOPLUS MET.
See the end of this Medication Guide for a complete list of ingredients in ACTOPLUS
MET
• have severe kidney problems
• have a condition called metabolic acidosis, including diabetic ketoacidosis. Diabetic
ketoacidosis should be treated with insulin
Tell your doctor before taking ACTOPLUS MET if you have any of these conditions.
What should I tell my doctor before taking ACTOPLUS MET?
Before you take ACTOPLUS MET, tell your doctor if you:
• have heart failure
• have severe kidney problems
• are going to have dye injected into a vein for an x-ray, CAT scan, heart study,
or other type of scanning
• will be undergoing a surgical procedure
• drink a lot of alcohol (all the time or short binge drinking)
• have type 1 (“juvenile”) diabetes or had diabetic ketoacidosis
• have a type of diabetic eye disease that causes swelling in the back of the eye
(macular edema)
• have liver problems
• have or have had cancer of the bladder
 Page 43 of 45
• are pregnant or plan to become pregnant. It is not known if ACTOPLUS MET can
harm your unborn baby. Talk to your doctor if you are pregnant or plan to become
pregnant about the best way to control your blood glucose levels while pregnant
• are a premenopausal woman (before the “change of life”) who does not have
periods regularly or at all. ACTOPLUS MET may increase your chance of becoming
pregnant. Talk to your doctor about birth control choices while taking ACTOPLUS MET.
Tell your doctor right away if you become pregnant while taking ACTOPLUS MET
• are breastfeeding or plan to breastfeed. It is not known if ACTOPLUS MET passes
into your milk and if it can harm your baby. Talk to your doctor about the best way to
control your blood glucose levels while breastfeeding
Tell your doctor about all the medicines you take, including prescription and over
the counter medicines, vitamins, and herbal supplements.
ACTOPLUS MET and some of your other medicines can affect each other. You may need to
have your dose of ACTOPLUS MET or certain other medicines changed.
Know the medicines you take. Keep a list of your medicines and show it to your doctor
and pharmacist before you start a new medicine. They will tell you if it is okay to take
ACTOPLUS MET with other medicines.
How should I take ACTOPLUS MET?
• Take ACTOPLUS MET exactly as your doctor tells you to take it
• Your doctor may need to change your dose of ACTOPLUS MET. Do not change your
ACTOPLUS MET dose unless your doctor tells you to
• ACTOPLUS MET may be prescribed alone or with other diabetes medicines. This will
depend on how well your blood sugar is controlled
• Take ACTOPLUS MET with meals to lower your chance of an upset stomach
• If you miss a dose of ACTOPLUS MET, take your next dose as prescribed unless your
doctor tells you differently. Do not take two doses at one time the next day
• If you take too much ACTOPLUS MET, call your doctor or go to the nearest hospital
emergency room right away
• If your body is under stress such as from a fever, infection, accident, or surgery, the
dose of your diabetes medicines may need to be changed. Call your doctor right away
• Stay on your diet and exercise programs and test your blood sugar regularly while
taking ACTOPLUS MET
• Your doctor should do certain blood tests before you start and while you take
ACTOPLUS MET
• Your doctor should also do hemoglobin A1C testing to check how well your blood sugar
is controlled with ACTOPLUS MET
• Your doctor should check your eyes regularly while you take ACTOPLUS MET
What are the possible side effects of ACTOPLUS MET?
ACTOPLUS MET may cause serious side effects, including:
• See “What is the most important information I should know about
ACTOPLUS MET?”
• low blood sugar (hypoglycemia). This can happen if you skip meals, if you also use
another medicine that lowers blood sugar, or if you have certain medical problems.
Lightheadedness, dizziness, shakiness, or hunger may happen if your blood sugar is
too low. Call your doctor if low blood sugar levels are a problem for you
 Page 44 of 45
• liver problems. Call your doctor right away if you have:
o nausea or vomiting
o stomach pain
o unusual or unexplained tiredness
o loss of appetite
o dark urine
o yellowing of your skin or the whites of your eyes
• bladder cancer. There may be an increased chance of having bladder cancer when
you take ACTOPLUS MET. You should not take ACTOPLUS MET if you are receiving
treatment for bladder cancer. Tell your doctor right away if you have any of the
following symptoms of bladder cancer:
o blood or a red color in your urine
o an increased need to urinate
o pain while you urinate
• broken bones (fractures). Usually in the hand, upper arm, or foot in women. Talk to
your doctor for advice on how to keep your bones healthy
• diabetic eye disease with swelling in the back of the eye (macular edema).
Tell your doctor right away if you have any changes in your vision. Your doctor should
check your eyes regularly
• release of an egg from an ovary in a woman (ovulation) leading to pregnancy.
Ovulation may happen when premenopausal women who do not have regular monthly
periods take ACTOPLUS MET. This can increase your chance of getting pregnant.
• low red blood cell count (anemia).
The most common side effects of ACTOPLUS MET include:
o cold-like symptoms (upper respiratory tract infection)
o swelling (edema)
o diarrhea
o headache
o increased weight
Tell your doctor if you have any side effect that bothers you or that does not go away.
These are not all the side effects of ACTOPLUS MET. For more information, ask your
doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.
How should I store ACTOPLUS MET?
• Store ACTOPLUS MET at 68°F to 77°F (20°C to 25°C). Keep ACTOPLUS MET in the
original container and protect from light
Keep the ACTOPLUS MET bottle tightly closed and keep tablets dry
Keep ACTOPLUS MET and all medicines out of the reach of children.
General information about the safe and effective use of ACTOPLUS MET
Medicines are sometimes prescribed for purposes other than those listed in a Medication
Guide. Do not use ACTOPLUS MET for a condition for which it was not prescribed. Do not
give ACTOPLUS MET to other people, even if they have the same symptoms you have. It
may harm them.
 Page 45 of 45
This Medication Guide summarizes the most important information about ACTOPLUS MET.
If you would like more information, talk with your doctor. You can ask your doctor or
pharmacist for information about ACTOPLUS MET that is written for healthcare
professionals.
For more information, go to www.actoplusmet.com or call 1-877-825-3327.
What are the ingredients in ACTOPLUS MET?
Active Ingredients: pioglitazone hydrochloride and metformin hydrochloride
Inactive Ingredients: povidone, microcrystalline cellulose, croscarmellose sodium,
magnesium stearate, hypromellose 2910, polyethylene glycol 8000, titanium dioxide, and
talc
ACTOS and ACTOPLUS MET are trademarks of Takeda Pharmaceutical Company Limited
registered with the U.S. Patent and Trademark Office and used under license by Takeda
Pharmaceuticals America, Inc.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Distributed by:
Takeda Pharmaceuticals America, Inc.
Lexington, MA 02421
Revised: December 2016
©2009 - 2020 Takeda Pharmaceuticals America, Inc.
APM001 R16
FPI-0198