`
` 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
`
` • Lactic acidosis can occur due to metformin accumulation. The
`
`
`
`
`risk increases with conditions such as sepsis, dehydration, excess
`
` alcohol intake, hepatic impairment, renal impairment, and acute
`
`
` congestive heart failure. (5.2)
` • Symptoms include malaise, myalgias, respiratory distress,
`
`
`
`
`
` increasing somnolence, and nonspecific abdominal distress.
` Laboratory abnormalities include low pH, increased anion gap,
`
`
` and elevated blood lactate. (5.2)
` • If acidosis is suspected, discontinue ACTOPLUS MET XR and
`
`
`
`
` hospitalize the patient immediately. (5.2)
` ----------------------------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 of ACTOPLUS MET XR based on the
`
`
`
` patient’s current regimen. (2)
`
`
`
` • May 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)
`
`
`
`
`
`
`
` • ACTOPLUS MET XR should be given in divided daily doses with meals
`
` to reduce the gastrointestinal (GI) side effects due to metformin. (2)
`
`
`
`
`
` • Dose increases should be accompanied by careful monitoring for
`
` adverse events related to fluid retention. (2)
`
`
`
`
`
` • Obtain liver tests before starting ACTOPLUS MET XR. If abnormal, use
`
`
` caution when treating with ACTOPLUS MET XR, investigate the
`
` probable cause, treat (if possible) and follow appropriately. Monitoring
`
`
`
` liver tests while on ACTOPLUS MET XR is not recommended in
`
`
`
` patients without liver disease. (2, 5.4)
`
`
` ------------------------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)
`
`
`
`
`
` • Renal impairment. (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: Warn against excessive alcohol intake.
`
`
` ACTOPLUS MET XR is not recommended in hepatic impairment
`
` and is contraindicated in renal impairment. Ensure normal renal
`
`
` function before initiating and at least annually thereafter. (5.2,
`
`
` 5.10)
`
`
`
` • 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: Preclinical and clinical trial data, and results
`
`
`
`
`
` from an observational study suggest an increased risk of bladder
` cancer in pioglitazone users. The observational data further
`
`
`
`
` suggest that the risk increases with duration of use. 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)
` • Temporarily discontinue in patients undergoing radiologic studies
`
`
`
`
` with intravascular iodinated contrast materials or any surgical
` procedures necessitating restricted intake of food and fluids.
`
`
` (5.12)
` • Vitamin B12 deficiency: Metformin may lower vitamin B12 levels.
`
`
`
` Monitor hematologic parameters annually. (5.14)
` • Macrovascular outcomes: There have been no clinical studies
`
`
`
`
`
` establishing conclusive evidence of macrovascular risk reduction
` with ACTOPLUS MET XR or any other antidiabetic drug. (5.15)
`
`
`
`
`-----------------------------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)
`
`
` • Cationic drugs: May reduce metformin elimination. Use with
`
`
`
` caution in patients who are taking cationic medications
` eliminated by renal tubular secretion. (7.4)
`
`
`
`
` -----------------------USE IN SPECIFIC POPULATIONS------------------­
` • Nursing mothers: Discontinue drug or nursing, taking into
`
`
`
`
` consideration the importance of the drug to the mother. (8.3)
`
`
` • Pediatrics: Not recommended for use in pediatric patients.(8.4)
`
`
`
`
` • Geriatric Use: Caution should be used when prescribing
`
` ACTOPLUS MET XR to elderly patients because reduced renal
`
` functions are associated with increasing age. (8.5)
`
`
` See 17 for PATIENT COUNSELING INFORMATION and
`
`
` Medication Guide
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Revised: 11/2013
`
`Reference ID: 3405461
`
`
`
`

`

`
` 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 Concomitant Use with an Insulin Secretagogue or
`
`
` Insulin
`
` 2.3 Concomitant Use with Strong CYP2C8 Inhibitors
`
`
`
`
`
`
` 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 Ovulation
`
`
`
` 5.10 Monitoring of Renal Function
`
`
`
` 5.11 Hypoxic States
`
`
`
` 5.12 Surgical Procedures
`
`
` 5.13 Alcohol Intake
`
`
`
` 5.14 Vitamin B12 Levels
`
`
`
`5.15 Macrovascular Outcomes
`
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Page 2 of 47
`
`
`
`6.2 Postmarketing Experience
`
`
`
`7 DRUG INTERACTIONS
`
`
`
`7.1 Strong CYP2C8 Inhibitors
`
`
`
`7.2 CYP2C8 Inducers
`
`
`
`7.3 Carbonic Anhydrase Inhibitors
`
`
`
`
`7.4 Cationic Drugs
`
`
`
`7.5 Drugs Affecting Glycemic Control
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`
`8.2 Labor and Delivery
`
`
`8.3 Nursing Mothers
`
`
`
`8.4 Pediatric Use
`
`
`
`8.5 Geriatric Use
`
`
`
`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: 3405461
`
`
`
`

`

`
`
`
`
` Page 3 of 47
`
`
`
`
`
`
`
`
`
` 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.
`
`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
`
`• Lactic acidosis is a rare, but serious complication that can occur due to
`
`
`metformin accumulation. The risk increases with conditions such as sepsis,
`
`
`dehydration, excess alcohol intake, hepatic impairment, renal impairment, and
`
`
`
`
`acute congestive heart failure [see Warnings and Precautions (5.2)].
`
`
`
`• The onset is often subtle, accompanied only by nonspecific symptoms such
`
`
`
`as malaise, myalgias, respiratory distress, increasing somnolence, and
`
`
`
`
`nonspecific abdominal distress. Laboratory abnormalities include low pH,
`
`
`increased anion gap and elevated blood lactate [see Warnings and
`
`
`Precautions (5.2)].
`
`If acidosis is suspected, ACTOPLUS MET XR should be discontinued and the
`
`
`
`patient hospitalized immediately [see Warnings and Precautions (5.2)].
`
`
`
`
`
`•
`
`
`•
`
`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)].
`
`
`
`
`Reference ID: 3405461
`
`
`
`

`

`
`
`
`
`
`
` Page 4 of 47
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`
`
`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: 3405461
`
`
`
`

`

`
`
`
`
` Page 5 of 47
`
`
`
` 2.2 Concomitant Use with an Insulin Secretagogue or Insulin
`
`
`
` If hypoglycemia occurs in a patient coadministered ACTOPLUS MET XR 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 XR 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.
` 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)].
`
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 4 CONTRAINDICATIONS
`
`
`
` Initiation in patients with established NYHA Class III or IV heart failure [see Boxed
`•
` Warning].
`
`
`
`
`
`
`
`
` • Renal impairment (e.g., serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL
`
`
`
` [females], or abnormal creatinine clearance) which may also result from conditions
`
`
`
`such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia
`
` [see Warnings and Precautions (5.2, 5.10)].
`
` • 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)].
`
`
`Reference ID: 3405461
`
`
`
`

`

`
`
`
`
` Page 6 of 47
`
`
`
`
`
` 5.2 Lactic Acidosis
`
`
` Metformin hydrochloride
`
` Lactic Acidosis
` Lactic acidosis is a serious, metabolic complication that can occur due to metformin
`
`
`
`
`
` accumulation during treatment with ACTOPLUS MET XR and it is fatal in approximately
` 50% of cases. Lactic acidosis may also occur in association with a number of
`
`
` pathophysiologic conditions, including diabetes mellitus, and whenever there is
`
`
`
`
` significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by
` elevated blood lactate concentrations (>5 mmol/L), decreased blood pH, electrolyte
`
`
`
` disturbances with an increased anion gap, and an increased lactate/pyruvate ratio.
` When metformin is implicated as the cause of lactic acidosis, metformin plasma levels
`
`
`
`
`
` >5 mcg/mL are generally found.
`
` The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is
`
` approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal
`
`
` cases/1000 patient-years. In more than 20,000 patient-years exposure to metformin in
`
` clinical trials, there were no reports of lactic acidosis. Reported cases have occurred
`
` primarily in diabetic patients with significant renal impairment, including both intrinsic
`
`
` renal disease and renal hypoperfusion, often in the setting of multiple concomitant
`
`
`
` medical/surgical problems and multiple concomitant medications. Patients with
`
`
` congestive heart failure requiring pharmacologic management, particularly when
`
`
`
` accompanied by hypoperfusion and hypoxemia, are at increased risk of lactic acidosis.
`
`
` The risk of lactic acidosis increases with the degree of renal dysfunction and the
`
`
`
` patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by
`
`
`
` regular monitoring of renal function in patients taking metformin. In particular, treatment
`
`
` of the elderly should be accompanied by careful monitoring of renal function.
`
` ACTOPLUS MET XR treatment should not be initiated in any patient unless
`
`
`
` measurement of creatinine clearance demonstrates that renal function is not reduced. In
`
` addition, metformin should be promptly withheld in the presence of any condition
`
`
`
` associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function
`
`
` may significantly limit the ability to clear lactate, metformin should generally be avoided
`
` in patients with clinical or laboratory evidence of hepatic impairment. Patients should be
`
`
`
` cautioned against excessive alcohol intake when taking metformin, because alcohol
`
`
`
`
` potentiates the effects of metformin on lactate metabolism. In addition, metformin
`
`
` should be temporarily discontinued prior to any intravascular radiocontrast study and for
`
` any surgical procedure necessitating restricted intake of food or fluids [see Warnings
`
`
`
`
` and Precautions (5.10, 5.11, 5.12, 5.13)]. Use of topiramate, a carbonic anhydrase
`
`
`
`
` inhibitor, in epilepsy and migraine prophylaxis may frequently cause dose-dependent
`
`
`
` metabolic acidosis and may exacerbate the risk of metformin-induced lactic acidosis
`
`
`
` [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
`
`
`
` The onset of lactic acidosis often is subtle, and accompanied only by nonspecific
`
`
`
` symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and
`
` nonspecific abdominal distress. There may be associated hypothermia, hypotension,
`
`
`
`
`
` and resistant bradyarrhythmias with more marked acidosis. Patients should be
`
`
` educated to promptly report these symptoms should they occur. If present, ACTOPLUS
`
`
`
` MET XR should be withdrawn until lactic acidosis is ruled out. Serum electrolytes,
`
`
`
`
`
`
` ketones, blood glucose, blood pH, lactate levels, and blood metformin levels may be
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3405461
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` Page 7 of 47
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`
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` useful. Once a patient is stabilized on any dose level of metformin, gastrointestinal
`
`
`
`
`
` symptoms, which are common during initiation of therapy, are unlikely to recur. Later
` occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious
`
`
` disease.
`
`
`
` Levels of fasting venous plasma lactate above the upper limit of normal but less than 5
` mmol/L in patients taking metformin do not necessarily indicate impending lactic
`
`acidosis and may be explainable by other mechanisms, such as poorly controlled
`diabetes or obesity, vigorous physical activity, or technical problems in sample handling
`
`
`
`
`[see Warnings and Precautions (5.10)].
`
`
`Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis
`
`
`lacking evidence of ketoacidosis (ketonuria and ketonemia).
`
`Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a
`
`
`
`
`
`patient with lactic acidosis who is taking metformin, the drug should be discontinued
`
`
`immediately and general supportive measures promptly instituted. Because metformin
`hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good
`hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis
`
`
`and remove the accumulated metformin. Such management often results in prompt
`
`reversal of symptoms and recovery [see Contraindications (4) and Warnings and
`
`
`
`
`Precautions (5.10)].
`
`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 Dosage and Administration (2.2)].
`
`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
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` Page 8 of 47
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` 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 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.
`
`
` Because impaired hepatic function has been associated with some cases of lactic
`
` acidosis ACTOPLUS MET XR should generally be avoided in patients with clinical or
`
`
` laboratory evidence of hepatic disease.
`
`
` 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 two 3-year trials in which
`
`
`
`
`
` pioglitazone was compared to placebo or glyburide, there were 16/3656 (0.44%) reports
`
` of bladder cancer in patients taking pioglitazone compared to 5/3679 (0.14%) in patients
`
` not taking pioglitazone. After excluding patients in whom exposure to study drug was
`
`
`
` less than one year at the time of diagnosis of bladder cancer, there were six (0.16%)
`
` cases on pioglitazone and two (0.05%) cases on placebo.
`
`
`
`
` A five-year interim report of an ongoing 10-year observational cohort study found a non­
` significant increase in the risk for bladder cancer in subjects ever exposed to
`
`
`
`
`
` pioglitazone, compared to subjects never exposed to pioglitazone (HR 1.2 [95% CI 0.9
`
`
`
` − 1.5]). Compared to never exposure, a duration of pioglitazone therapy longer than 12
`
`
`
` months was associated with an increase in risk (HR 1.4 [95% CI 0.9 − 2.1]), which
`
`
`
` reached statistical significance after more than 24 months of pioglitazone use (HR 1.4
`
`
`
` [95% CI 1.03 − 2.0]). Interim results from this study suggested that taking pioglitazone
`
`
`
` longer than 12 months increased the relative risk of developing bladder cancer in any
`
`
`
`
`
`
`
`
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`Reference ID: 3405461
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` Page 9 of 47
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` given year by 40% which equates to an absolute increase of three cases in 10,000
`
`
`
`
`
`
` (from approximately seven in 10,000 [without pioglitazone] to approximately 10 in
` 10,000 [with pioglitazone]).
`
`
` 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 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)].
`
`
`
`
`5.9 Ovulation
`
`
`Therapy with pioglitazone, like other thiazolidinediones, may result in ovulation in some
`
`
`premenopausal anovulatory women. As a result, these patients may be at an increased
`
`
`
`risk for pregnancy while taking ACTOPLUS MET XR [