`
`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)
`
`
`
`
`
`--------------------------RECENT MAJOR CHANGES--------------------------------­
`
`
`Warnings and Precautions
`
`
`
`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
`
`
`
`
`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
`
`
`
`
`
`2m
`
`o discontinue if eGFR falls below 30 mL/min/1.73 m2
`
`
`
`
`
`
`Reference ID: 4198896
`
`
`
`
`
`
`
`
`
`
`• 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. (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 reduce metformin clearance (such as ranolazine,
`
`vandetanib, dolutegravir, and cimetidine), may increase the
`
`
`
`accumulation of metformin. Consider the benefits and risks of
`
`
`concomitant use. (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)
`
`
`• Topiramate may decrease pioglitazone concentrations. (7.8)
`
`
`
`
`
`

`

`
`
`-----------------------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)
`
`
`
`
`
` Page 2 of 45
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`Medication Guide
`
`
`Revised: 12/2017
`
`Reference ID: 4198896
`
`
`
`

`

`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: CONGESTIVE HEART FAILURE AND LACTIC
`
`ACIDOSIS
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`
`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
`
`
`
`ADVERSE REACTIONS
`
`
`
`
`6.1 Clinical Trials Experience
`
`
`
`6.2 Postmarketing Experience
`
`
`
`
`7 DRUG INTERACTIONS
`
`
`7.1 Strong CYP2C8 Inhibitors
`
`
`
`6
`
`
`
`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
`
`
`
`7.8 Topiramate
`
`
`
`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.
`
`Reference ID: 4198896
`
`
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
` Page 4 of 45
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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)].
`
`
`•
`
`
`•
`
`
`
` 1
`
`
`
` INDICATIONS AND USAGE
`
`
` 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)].
`
`
`
`
`
`Reference ID: 4198896
`
`
`
`

`

` 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)].
`
`
`
`
`
`
` Page 5 of 45
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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 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)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`Reference ID: 4198896
`
`
`
`

`

`
` Page 6 of 45
`
`
`
`
`
`
`
` 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
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`15 mg/1000 mg tablets: White to off-white, round, film-coated tablets imprinted with
`•
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`“4833X” and “15/1000” in red on one side
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`30 mg/1000 mg tablets: White to off-white, round, film-coated tablets imprinted with
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`“4833X” and “30/1000” in light blue on one side
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`•
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`4 CONTRAINDICATIONS
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`Initiation in patients with established NYHA Class III or IV heart failure [see Boxed
`•
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`Warning].
`Severe renal impairment ( eGFR below 30 mL/min/1.73 m2) [see Warnings and
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`
`
` Precautions (5.2)].
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` Use in patients with known hypersensitivity to pioglitazone, metformin or any other
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` component of ACTOPLUS MET XR.
` • Metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be
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` treated with insulin.
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` 5 WARNINGS AND PRECAUTIONS
` 5.1 Congestive Heart Failure
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` Pioglitazone
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`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
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` pioglitazone is used in combination with insulin. Fluid retention may lead to or exacerbate
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`Reference ID: 4198896
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` Page 7 of 45
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` congestive heart failure. Patients treated with ACTOPLUS MET XR should be observed for
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` signs and symptoms of congestive heart failure. If congestive heart failure develops, it should
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` be managed according to current standards of care and discontinuation or dose reduction of
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` ACTOPLUS MET XR must be considered [see Boxed Warning, Contraindications (4), and
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` Adverse Reactions (6.1)].
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` 5.2 Lactic Acidosis
`
` Metformin hydrochloride
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` Lactic Acidosis
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` There have been post-marketing cases of metformin-associated lactic acidosis, including fatal
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`cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such
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`as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however,
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`hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis.
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`Metformin-associated lactic acidosis was characterized by elevated blood lactate
`concentrations (greater than 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria
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`or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally
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`greater than 5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood
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`levels which may increase the risk of lactic acidosis, especially in patients at risk.
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`If metformin-associated lactic acidosis is suspected, general supportive measures should be
`instituted promptly in a hospital setting, along with immediate discontinuation of ACTOPLUS
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`MET XR. Patients treated with ACTOPLUS MET XR with a diagnosis or strong suspicion of
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`lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove
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`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
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`symptoms and recovery.
`Educate patients and their families about the symptoms of lactic acidosis and if these
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`symptoms occur instruct them to discontinue ACTOPLUS MET XR and report these symptoms
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`to their healthcare provider.
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`For each of the known and possible risk factors for metformin-associated lactic acidosis,
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`recommendations to reduce the risk of and manage metformin-associated lactic acidosis are
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`provided below:
`Renal Impairment
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`The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients
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`with significant renal impairment. The risk of metformin accumulation and metformin­
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`associated lactic acidosis increases with the severity of renal impairment because metformin is
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`substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal
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`function include [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].
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`• Before initiating ACTOPLUS MET XR, obtain an eGFR.
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`• ACTOPLUS MET XR is contraindicated in patients with an eGFR less than
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`30 mL/min/1.73 m2. Initiation of ACTOPLUS MET XR is not recommended in patients
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`with eGFR between 30 – 45 mL/min/1.73 m2 [see Contraindications (4)].
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`• Obtain an eGFR at least annually in all patients taking ACTOPLUS MET XR. In patients
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`at increased risk for the development of renal impairment (e.g., the elderly), renal
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`function should be assessed more frequently.
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`In patients taking ACTOPLUS MET XR whose eGFR later falls below
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`45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy.
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`Reference ID: 4198896
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` Page 8 of 45
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` Drug Interactions
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` The concomitant use of ACTOPLUS MET XR with specific drugs may increase the risk of
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` metformin-associated lactic acidosis: those that impair renal function, result in significant
`hemodynamic change, interfere with acid-base balance or increase metformin accumulation
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` (e.g., cationic drugs) [see Drug Interactions (7)]. Therefore, consider more frequent monitoring
` of patients.
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` Age 65 or Greater
` The risk of metformin-associated lactic acidosis increases with the patient’s age because
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` 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
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`Populations (8.5)].
` Radiological Studies with Contrast
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` Administration of intravascular iodinated contrast agents in patients treated with metformin
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` 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
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`patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of
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`hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-
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`arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and
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`restart ACTOPLUS MET XR if renal function is stable.
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`Surgery and Other Procedures
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`Withholding of food and fluids during surgical or other procedures may increase the risk for
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`volume depletion, hypotension and renal impairment. ACTOPLUS MET XR should be
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`temporarily discontinued while patients have restricted food and fluid intake.
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`Hypoxic States
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`Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the
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`setting of acute congestive heart failure (particularly when accompanied by hypoperfusion
`and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and
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`other conditions associated with hypoxemia have been associated with lactic acidosis and
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`may also cause prerenal azotemia. When such events occur, discontinue ACTOPLUS MET
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`XR.
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`Excessive Alcohol Intake
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`Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the
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`risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake
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`while receiving ACTOPLUS MET XR.
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`Hepatic Impairment
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`Patients with hepatic impairment have developed with cases of metformin-associated lactic
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`acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels.
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`Therefore, avoid use of ACTOPLUS MET XR in patients with clinical or laboratory evidence of
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`hepatic disease.
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`5.3 Edema
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`In controlled clinical trials with pioglitazone, edema was reported more frequently in patients
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`treated with pioglitazone than in patients treated with placebo and is dose related [see Adverse
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`Reactions (6.1)]. In postmarketing experience, reports of new onset or worsening of edema
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`have been received. ACTOPLUS MET XR should be used with caution in patients with edema.
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`Because thiazolidinediones, including pioglitazone, can cause fluid retention, which can
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` Page 9 of 45
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` 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
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`
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` XR should be monitored for signs and symptoms of congestive heart failure [see Boxed
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` Warning, Warnings and Precautions (5.1), and Patient Counseling Information (17)].
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` 5.4 Hypoglycemia
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` Patients receiving ACTOPLUS MET XR in combination with insulin or other anti-diabetic
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` medications (particularly insulin secretagogues such as sulfonylureas) may be at risk for
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` hypoglycemia. A reduction in the dose of the concomitant anti-diabetic medication may be
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` necessary to reduce the risk of hypoglycemia [see Drug Interactions (7.7)]. Hypoglycemia can
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` also occur when caloric intake is deficient or when strenuous exercise is not compensated by
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` caloric supplement. Elderly, debilitated, or malnourished patients and those with adrenal or
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` pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic
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` effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking
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` beta-adrenergic blocking drugs.
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` 5.5 Hepatic Effects
` There have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking
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`pioglitazone, although the reports contain insufficient information necessary to establish the
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` 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)].
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` 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
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` have other forms of liver disease, many of which can be treated or managed. Therefore,
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` obtaining a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase
`
` [AST], alkaline phosphatase, and total bilirubin) and assessing the patient is recommended
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` before initiating ACTOPLUS MET XR therapy.
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` 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,
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` including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this
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` clinical context, if the patient is found to have abnormal liver tests (ALT greater than three
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` times the upper limit of the reference range), ACTOPLUS MET XR treatment should be
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` interrupted and investigation done to establish the probable cause. ACTOPLUS MET XR
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` should not be restarted in these patients without another explanation for the liver test
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` abnormalities.
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` 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
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` severe drug-induced liver injury, and should not be restarted on ACTOPLUS MET XR. For
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` 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.
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` 5.6 Urinary Bladder Tumors
` Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study
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`[see Nonclinical Toxicology (13.1)]. In addition, during the three year PROactive clinical trial,
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`14 patients out of 2605 (0.54%) randomized to pioglitazone and 5 out of 2633 (0.19%)
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`randomized to placebo were diagnosed with bladder cancer. After excluding patients in whom
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`exposure to study drug was less than one year at the time of diagnosis of bladder cancer,
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`there were 6 (0.23%) cases on pioglitazone and two (0.08%) cases on placebo. After
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`completion of the trial, a large subset of patients was observed for up to 10 additional years,
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` Page 10 of 45
` with little additional exposure to pioglitazone. During the 13 years of both PROactive and
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` 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]).
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`Findings regarding the risk of bladder cancer in patients exposed to pioglitazone vary among
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`observational studies; some did not find an increased risk of bladder cancer associated with
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`pioglitazone, while others did.
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`A large prospective 10-year observational cohort study conducted in the United States found
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`no statistically significant increase in the risk of bladder cancer in diabetic patients ever
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