HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`ACTOPLUS MET XR safely and effectively. See full prescribing
`information for ACTOPLUS MET XR.
`ACTOPLUS MET XR (pioglitazone and metformin hydrochloride
`extended-release) tablets for oral use
`Initial U.S. Approval: 2009
`WARNING: CONGESTIVE HEART FAILURE AND LACTIC ACIDOSIS
`See full prescribing information for complete boxed warning
`Congestive Heart Failure
`• Thiazolidinediones, including pioglitazone, which is a component
`of ACTOPLUS MET XR, cause or exacerbate congestive heart
`failure in some patients. (5.1)
`• After initiation of ACTOPLUS MET XR, 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 XR must be considered. (5.1)
`• ACTOPLUS MET XR is not recommended in patients with
`symptomatic heart failure. (5.1)
`• Initiation of ACTOPLUS MET XR in patients with established New
`York Heart Association (NYHA) Class III or IV heart failure is
`contraindicated. (4, 5.1)
`Lactic Acidosis
`• Post-marketing cases of metformin-associated lactic acidosis
`have resulted in death, hypothermia, hypotension, and resistant
`bradyarrhythmias. Symptoms included malaise, myalgias,
`respiratory distress, somnolence, and abdominal pain. Laboratory
`abnormalities included elevated blood lactate levels, anion gap
`acidosis, increased lactate/pyruvate ratio; and metformin plasma
`levels generally greater than 5 mcg/mL. (5.2)
`• Risk factors include renal impairment, concomitant use of certain
`drugs, age ≥65 years old, radiological studies with contrast,
`surgery and other procedures, hypoxic states, 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. (5.2)
`• If lactic acidosis is suspected, discontinue ACTOPLUS MET XR
`and institute general supportive measures in a hospital setting.
`Prompt hemodialysis is recommended. (5.2)
`
`5/2016
`
`5/2016
`5/2016
`
`--------------------------RECENT MAJOR CHANGES---------------------------------
`Boxed Warning
`5/2016
`Dosage and Administration
`Recommendations for Use in Renal Impairment (2.2)
`Discontinuation for Iodinated Contrast Imaging
`Procedures (2.4)
`Contraindications (4)
`Warnings and Precautions
`5/2016
`Lactic Acidosis (5.2)
`5/2016
`Hepatic Effects (5.5)
`12/2016
`Urinary Bladder Tumors (5.6)
`----------------------------INDICATIONS AND USAGE--------------------------------
`ACTOPLUS MET XR is a thiazolidinedione and biguanide combination
`product 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. (1)
`Important Limitations of Use:
`• Not for treatment of type 1 diabetes or diabetic ketoacidosis. (1)
`-------------------------DOSAGE AND ADMINISTRATION--------------------------
`• Individualize the starting dose based on the patient’s current regimen
`and adjust the dosing based on effectiveness and tolerability while not
`exceeding the maximum recommended daily dose of pioglitazone 45
`mg and extended-release metformin 2000 mg. (2.1)
`• Give in divided daily doses with meals to reduce gastrointestinal effects.
`(2.1)
`• Monitor patients for adverse events related to fluid retention after
`initiation and dose increases. (2.1)
`• Obtain liver tests before initiation. If abnormal, use caution when
`treating with ACTOPLUS MET XR, investigate the probable cause, treat
`(if possible) and follow appropriately. (2.1, 5.4)
`• Prior to initiation, assess renal function with estimated glomerular
`filtration rate (eGFR) (2.2)
`o Do not use in patients with eGFR below 30 mL/min/1.73 m2
`
`Reference ID: 4026186
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`o Initiation is not recommended in patients with eGFR between
`30 - 45 mL/min/1.73 m2
`o Assess risk/benefit of continuing if eGFR falls below
`45 mL/min/1.73 m2
`o discontinue if eGFR falls below 30 mL/min/1.73 m2
`• ACTOPLUS MET XR may need to be discontinued at time of, or
`prior to, iodinated contrast imaging procedures (2.4)
`-------------------DOSAGE FORMS AND STRENGTHS-------------------
`•
`Tablets: 15 mg pioglitazone/1000 mg metformin HCl. (3)
`•
`Tablets: 30 mg pioglitazone/1000 mg metformin HCl. (3)
`----------------------------CONTRAINDICATIONS-----------------------------
`• Initiation in patients with established New York Heart Association
`(NYHA) Class III or IV heart failure [see Boxed Warning]. (4)
`• Severe renal impairment (eGFR below 30 mL/min/1.73 m2). (4)
`• Use in patients with known hypersensitivity to pioglitazone,
`metformin or any other component of ACTOPLUS MET XR. (4)
`• Metabolic acidosis, including diabetic ketoacidosis. (4, 5.2)
`-----------------------WARNINGS AND PRECAUTIONS--------------------
`• Congestive heart failure: Fluid retention may occur and can
`exacerbate or lead to congestive heart failure. Combination use
`with insulin and use in congestive heart failure NYHA Class I and
`II may increase risk. Monitor patients for signs and symptoms.
`(5.1)
`• Lactic acidosis: See boxed warning. (5.2)
`• Edema: Dose-related edema may occur. (5.3)
`• Hypoglycemia: When used with insulin or an insulin
`secretagogue, a lower dose of the insulin or insulin secretagogue
`may be needed to reduce the risk of hypoglycemia. (5.4)
`• Hepatic effects: Postmarketing reports of hepatic failure,
`sometimes fatal. Causality cannot be excluded. If liver injury is
`detected, promptly interrupt ACTOPLUS MET XR and assess
`patient for probable cause, then treat cause if possible, to
`resolution or stabilization. Do not restart ACTOPLUS MET XR if
`liver injury is confirmed and no alternate etiology can be found.
`(5.5)
`• Bladder cancer: May increase the risk of bladder cancer. Do not
`use in patients with active bladder cancer. Use caution when
`using in patients with a prior history of bladder cancer. (5.6)
`• Fractures: Increased incidence in female patients. Apply current
`standards of care for assessing and maintaining bone health.
`(5.7)
`• Macular edema: Postmarketing reports. Recommend regular eye
`exams in all patients with diabetes according to current
`standards of care with prompt evaluation for acute visual
`changes. (5.8)
`• Vitamin B12 deficiency: Metformin may lower vitamin B12 levels.
`Monitor hematologic parameters annually. (5.9)
`• Macrovascular outcomes: There have been no clinical studies
`establishing conclusive evidence of macrovascular risk reduction
`with ACTOPLUS MET XR or any other antidiabetic drug. (5.10)
`-----------------------------ADVERSE REACTIONS---------------------------
`Most common adverse reactions (>5%) are upper respiratory tract
`infection, edema, diarrhea, headache and weight gain. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Takeda
`Pharmaceuticals at 1-877-825-3327 or FDA at 1-800-FDA-1088
`or www.fda.gov/medwatch.
`------------------------------DRUG INTERACTIONS---------------------------
`• Strong CYP2C8 inhibitors (e.g., gemfibrozil) increase
`pioglitazone concentrations. Limit ACTOPLUS MET XR dose to
`15 mg/1000 mg daily. (2.3, 7.1)
`• CYP2C8 inducers (e.g., rifampin) may decrease pioglitazone
`concentrations. (7.2)
`• Carbonic anhydrase inhibitors may increase risk of lactic
`acidosis. Consider more frequent monitoring. (7.3)
`• Drugs that are eliminated by renal tubular secretion (e.g.,
`cationic drugs such as cimetidine), may increase the
`accumulation of metformin. Consider more frequent monitoring.
`(7.4)
`• Alcohol can potentiate the effect of metformin on lactate
`metabolism. Warn patients against excessive alcohol intake.
`(7.5)
`• Use of insulin secretagogues or insulin use may increase the risk
`for hypoglycemia and may require dose reduction. (7.6)
`
`

`

`
`
`-----------------------USE IN SPECIFIC POPULATIONS-------------------
`• Females and Males of Reproductive Potential: Advise premenopausal
`females of the potential for an unintended pregnancy. (8.3)
`• Pediatrics: Not recommended for use in pediatric patients.(8.4)
`• Geriatric Use: Assess renal function more frequently. (8.5)
`• Hepatic impairment: Avoid use in patients with hepatic impairment. (8.7)
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: CONGESTIVE HEART FAILURE AND LACTIC
`ACIDOSIS
`1
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommendations for All Patients
`2.2 Recommendations for Use in Renal Impairment
`2.3 Concomitant Use with Strong CYP2C8 Inhibitors.
`2.4 Discontinuation for Iodinated Contrast Imaging
`Procedures
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Congestive Heart Failure
`5.2 Lactic Acidosis
`5.3 Edema
`5.4 Hypoglycemia
`5.5 Hepatic Effects
`5.6 Urinary Bladder Tumors
`5.7 Fractures
`5.8 Macular Edema
`5.9 Vitamin B12 Levels
`5.10 Macrovascular Outcomes
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`
`Page 2 of 48
`
`See 17 for PATIENT COUNSELING INFORMATION and
`Medication Guide
`
`Revised: 12/2016
`
`7 DRUG INTERACTIONS
`7.1 Strong CYP2C8 Inhibitors
`7.2 CYP2C8 Inducers
`7.3 Carbonic Anhydrase Inhibitors
`7.4 Drugs that Reduce Metformin Clearance
`7.5 Alcohol
`7.6
`Insulin Secretagogues or Insulin
`7.7 Drugs Affecting Glycemic Control
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.3 Females and Males of Reproductive Potential
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`* Sections or subsections omitted from the full prescribing information
`are not listed.
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`FULL PRESCRIBING INFORMATION
`
`•
`
`WARNING: CONGESTIVE HEART FAILURE AND LACTIC ACIDOSIS
`Congestive Heart Failure
`• Thiazolidinediones, including pioglitazone, which is a component of
`ACTOPLUS MET XR, cause or exacerbate congestive heart failure in some
`patients [see Warnings and Precautions (5.1)].
`• After initiation of ACTOPLUS MET XR, 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 XR must be
`considered [see Warnings and Precautions (5.1)].
`• ACTOPLUS MET XR is not recommended in patients with symptomatic
`heart failure [see Warnings and Precautions (5.1)].
`Initiation of ACTOPLUS MET XR 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 XR and institute general supportive
`measures in a hospital setting. Prompt hemodialysis is recommended [see
`Warnings and Precautions (5.2)].
`
`•
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`INDICATIONS AND USAGE
`1
` ACTOPLUS MET XR 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)].
`Important Limitations of Use
`Pioglitazone exerts its antihyperglycemic effect only in the presence of endogenous
`insulin. ACTOPLUS MET XR 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 XR should be taken with meals to reduce the gastrointestinal side
`effects associated with metformin.
`If therapy with a combination tablet containing pioglitazone and extended-release
`metformin is considered appropriate the recommended starting dose is:
`• 15 mg/1000 mg or 30 mg/1000 mg once daily and gradually titrated as needed, after
`assessing adequacy of therapeutic response and tolerability,
`for patients with NYHA Class I or Class II congestive heart failure: 15 mg/1000 mg or
`30 mg/1000 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/1000 mg
`twice daily or 30 mg/1000 mg once 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/1000 mg
`twice daily or 30 mg/1000 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 XR should be taken at doses that
`are as close as possible to the dose of pioglitazone and metformin already being
`taken.
`ACTOPLUS MET XR may be titrated up to a maximum daily dose of 45 mg/2000 mg of
`pioglitazone/extended-release metformin.
`Metformin doses above 2000 mg may be better tolerated given three times a day.
`Patients should be informed that ACTOPLUS MET XR must be swallowed whole
`and not chewed, cut, or crushed, and that the inactive ingredients may
`occasionally be eliminated in the feces as a soft mass that may resemble the
`original tablet.
`After initiation of ACTOPLUS MET XR or with dose increase, monitor patients carefully
`for adverse reactions related to fluid retention such as weight gain, edema, and signs
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`Page 5 of 48
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`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
`XR. Routine periodic monitoring of liver tests during treatment with ACTOPLUS MET
`XR is not recommended in patients without liver disease. Patients who have liver test
`abnormalities prior to initiation of ACTOPLUS MET XR or who are found to have
`abnormal liver tests while taking ACTOPLUS MET XR 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 XR and periodically
`thereafter.
`ACTOPLUS MET XR is contraindicated in patients with an estimated glomerular
`filtration rate (eGFR) below 30 mL/min/1.73 m2.
`Initiation of ACTOPLUS MET XR in patients with an eGFR between 30 –
`45 mL/min/1.73 m2 is not recommended.
`In patients taking ACTOPLUS MET XR whose eGFR later falls below
`45 mL/min/1.73 m2, assess the benefit risk of continuing therapy.
`Discontinue ACTOPLUS MET XR if the patient’s eGFR later falls below
`30 mL/min/1.73 m2 [see Contraindications (4) and Warnings and Precautions (5.12)].
`2.3 Concomitant Use with Strong CYP2C8 Inhibitors
`Coadministration of pioglitazone (one of the ingredients in ACTOPLUS MET XR) and
`gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure by
`approximately 3-fold. Therefore, the maximum recommended dose of ACTOPLUS MET
`XR is 15 mg/1000 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 XR 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 XR if renal function is stable [see
`Warnings and Precautions (5.2)].
`
`3 DOSAGE FORMS AND STRENGTHS
`• 15 mg/1000 mg tablets: White to off-white, round, film-coated tablets debossed with
`“4833X” on one side and “15/1000” on the other
`• 30 mg/1000 mg tablets: White to off-white, oblong, film-coated tablets debossed with
`“4833X” on one side and “30/1000” on the other
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`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 XR.
`• 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 XR 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 ACTOPLUS MET XR 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/Liter), 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 XR. ACTOPLUS MET XR-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 XR and report these
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`•
`
`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 [see Clinical Pharmacology
`(12.3)].
`• Before initiating ACTOPLUS MET XR, obtain an eGFR.
`• ACTOPLUS MET XR is contraindicated in patients with an eGFR less than
`30 mL/min/1.73 m2. Initiation of ACTOPLUS MET XR is not recommended in
`patients with eGFR between 30 – 45 mL/min/1.73 m2.
`• Obtain an eGFR at least annually in all patients taking ACTOPLUS MET XR. 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 XR whose eGFR later falls below
`45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy [see
`Dosage and Administration (2.2), Contraindications (4) and Clinical
`Pharmacology (12.3)].
`Drug Interactions
`The concomitant use of ACTOPLUS MET XR 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 (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 XR 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 XR if renal function is stable.
`Surgery and Other Procedures
`Withholding of food and fluids during surgical or other procedures may increase the
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`risk for volume depletion, hypotension and renal impairment. ACTOPLUS MET XR
`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 XR.
`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 XR.
`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 XR 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 XR 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 XR should be used with caution in patients at risk for congestive heart
`failure. Patients treated with ACTOPLUS MET XR should be monitored for signs and
`symptoms of congestive heart failure [see Boxed Warning, Warnings and Precautions
`(5.1), and Patient Counseling Information (17)].
`5.4 Hypoglycemia
`Patients receiving ACTOPLUS MET XR in combination with insulin or other anti-diabetic
`medications (particularly insulin secretagogues such as sulfonylureas) may be at risk for
`hypoglycemia. A reduction in the dose of the concomitant anti-diabetic 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 non-fatal 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
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`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 XR therapy.
`In patients with abnormal liver tests, ACTOPLUS MET XR 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 XR
`treatment should be interrupted and investigation done to establish the probable cause.
`ACTOPLUS MET XR 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 XR. For patients with lesser elevations of serum ALT or bilirubin and
`with an alternate probable cause, treatment with ACTOPLUS MET XR 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]).
`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 prospective 10-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]).
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`Reference ID: 4026186
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`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 XR 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 XR 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 XR 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 other