IMPORTANT SAFETY INFORMATION

Indications and Usage

ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

ACTOplus met and ACTOplus met XR are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with pioglitazone and metformin or who have inadequate glycemic control on pioglitazone alone or metformin alone.

duetact is a thiazolidinedione and sulfonylurea combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with a thiazolidinedione and a sulfonylurea or who have inadequate glycemic control on a thiazolidinedione alone or a sulfonylurea alone.

ACTOS, ACTOplus met, ACTOplus met XR, and duetact are not for treatment of type 1 diabetes or diabetic ketoacidosis (DKA).

Important Safety Information

WARNING: CONGESTIVE HEART FAILURE

  • Thiazolidinediones, including pioglitazone, which is a component of ACTOS, ACTOplus met, ACTOplus met XR, and duetact cause or exacerbate congestive heart failure (CHF) in some patients.
  • After initiation of pioglitazone, 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 pioglitazone must be considered.
  • Pioglitazone is not recommended in patients with symptomatic heart failure.
  • Initiation of pioglitazone in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.

WARNING: LACTIC ACIDOSIS for ACTOplus met and ACTOplus met XR

  • 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 insufficiency, renal impairment, and acute congestive heart failure.
  • 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.
  • If acidosis is suspected, ACTOplus met or ACTOplus met XR should be discontinued and the patient hospitalized immediately.

Contraindications

ACTOS, ACTOplus met, ACTOplus met XR, and duetact:

  • Do not initiate in patients with NYHA Class III or IV heart failure.
  • Do not use in patients with a history of serious hypersensitivity reaction to any of the ingredients of these products.

ACTOplus met and ACTOplus met XR:

  • Do not use in patients with renal disease or dysfunction (as suggested by 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.
  • Do not use in patients with acute or chronic metabolic acidosis, including DKA, with or without coma.
  • Temporarily discontinue in patients administered intravascular iodinated contrast materials, because such materials may acutely alter renal function.

Warnings and Precautions

ACTOS, ACTOplus met, ACTOplus met XR, and duetact:

  • Congestive Heart Failure: May cause fluid retention which 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.
  • Edema: Dose-related edema may occur. Use with caution in patients with edema.
  • Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal, have been received. Causality cannot be excluded. Obtain liver tests before starting treatment. Use caution in patients with liver disease. If liver injury is detected, promptly interrupt treatment and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart treatment if liver injury is confirmed and no alternate etiology can be found.
  • Fractures: An increased incidence of bone fracture has been noted in female patients.
  • Bladder cancer: Data suggest an increased risk of bladder cancer in ACTOS users. Data also suggest that the risk increases with duration of use. Do not use ACTOS, ACTOplus met, ACTOplus met XR, or duetact in patients with active bladder cancer. Use caution when using in patients with a prior history of bladder cancer. Tell patients to promptly report any sign of hematuria or other symptoms such as dysuria or urinary urgency as these may be due to bladder cancer.
  • Hypoglycemia: When used with insulin or insulin secretagogues, hypoglycemia may occur and a lower dose of the insulin or insulin secretagogue may be needed to reduce the risk.
  • Macular edema: Macular edema has been reported in some patients. Recommend regular eye exams. Instruct patients to report any visual changes promptly.
  • Ovulation: Ovulation in premenopausal anovulatory women may occur.
  • Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with these, or any other anti-diabetic drugs.
  • Use with CYP2C8 inducers or strong inhibitors may require dose adjustment.

Additional Warnings and Precautions

ACTOplus met and ACTOplus met XR:

  • Lactic acidosis due to metformin accumulation during therapy is rare. However, when it occurs, it is fatal in approximately 50% of cases. The risk increases in patients with renal dysfunction, congestive heart failure requiring drug treatment, and with increasing age.
    • Risk may be significantly decreased by regular monitoring of renal function, and by using the minimum effective dose. Monitor renal function, particularly in the elderly. Do not initiate in patients ≥80 years of age, unless creatinine clearance is normal.
    • Tell patients that subtle and nonspecific symptoms, such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress, may be important and should be reported immediately. Caution against excessive alcohol intake.
  • Avoid in patients with evidence of hepatic disease, hypoxemia, dehydration, or sepsis, and temporarily discontinue use prior to any surgical procedure.
  • A reversible decrease in vitamin B12 level, without clinical effects, is possible. Measure hematologic parameters annually.

duetact:

  • Cardiac Mortality: The University Group Diabetes Program (UGDP) trial found that tolbutamide, a sulfonylurea, was associated with an increased risk of cardiovascular mortality. Glimepiride was not studied in this trial; however, it is prudent to consider that this warning may apply to all sulfonylureas.
  • Severe hypoglycemia may occur with sulfonylurea use. Dosing should be conservative for elderly, debilitated, or malnourished patients, or patients with adrenal, pituitary, renal, or hepatic insufficiency.
  • Sulfonylurea treatment can lead to hemolytic anemia in patients with, or without, known glucose-6-phosphate dehydrogenase (G6PD) deficiency. Use caution in patients with G6PD deficiency.

Adverse Reactions

The most common adverse events (≥5% and greater than placebo) seen with ACTOS in monotherapy include upper respiratory tract infection, headache, sinusitis, myalgia, and pharyngitis. Use of ACTOS may be associated with weight gain.

The most common adverse events (≥5%) seen with ACTOS in combination with metformin include upper respiratory tract infection, diarrhea, nausea, headache, urinary tract infection, sinusitis, dizziness, lower limb edema, and increased weight.

The most common adverse events (≥5%) seen with ACTOS in combination with a sulfonylurea include hypoglycemia, upper respiratory tract infection, weight increase, lower limb edema, headache, urinary tract infection, diarrhea, nausea, and pain in limb.

Please see ACTOS Complete Prescribing Information, including boxed warning about congestive heart failure, and Medication Guide.

Please see ACTOplus met Complete Prescribing Information, including boxed warnings about congestive heart failure and lactic acidosis, and Medication Guide.

Please see ACTOplus met XR Complete Prescribing Information, including boxed warnings about congestive heart failure and lactic acidosis, and Medication Guide.

Please see duetact Complete Prescribing Information, including boxed warning about congestive heart failure, and Medication Guide.

PIVOTAL SHORT-TERM STUDY

ACTOS significantly reduces A1C across a range of doses in a short-term clinical study*1

  • Across all patients, ACTOS 45 mg once daily significantly reduced A1C by 1.6% points vs placebo in a 26-week study.*1
  • Across all patients, ACTOS 15 mg once daily reduced A1C by 1.0% point vs placebo in a 26-week study.*1

*Results from a 26-week, double-blind, randomized, multicenter, placebo-controlled study. A1C data: patients not previously treated with diabetes medications and not adequately controlled by diet and exercise alone and receiving ACTOS 45 mg QD, n=21, baseline A1C: 10.0%; 15 mg QD, n=26, baseline A1C: 9.9%. Across all patients receiving ACTOS 45 mg QD, n=76, baseline A1C: 10.3%; 15 mg QD, n=79, baseline A1C: 10.2% (P≤0.05). Values indicate the difference between the changes from baseline of ACTOS and placebo.

Indications and Usage

  • ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ACTOS is not for treatment of type 1 diabetes or diabetic ketoacidosis (DKA)2

Important Safety Information

  • Do not initiate in patients with NYHA Class III or IV heart failure
  • Do not use in patients with a history of a serious hypersensitivity reaction to ACTOS or any of its ingredients
  • ACTOS may cause fluid retention which 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
  • The most common adverse events (≥5% and greater than placebo) seen with ACTOS in monotherapy include upper respiratory tract infection, headache, sinusitis, myalgia, and pharyngitis. Use of ACTOS may be associated with weight gain

Please see Important Safety Information, including boxed warnings about congestive heart failure and lactic acidosis, below.

A1C REDUCTIONS IN LONG-TERM STUDIES

ACTOS durability: clinical trials show A1C reductions3-10

  • In two 52-week studies, ACTOS monotherapy provided sustained A1C reductions of up to 1.4%.*
  • Mean A1C levels reached the ADA goal of <7% starting at week 24 and continued until the end of the monotherapy study.†
  • ACTOS in combination with metformin maintained A1C reductions ≥1.0% out to 2 years.‡
  • ACTOS added to other conventional glucose-lowering agents resulted in an additional 0.9% point decrease in A1C sustained over 34.5 months.§
  • In a 42-month open-label study, ACTOS added to metformin continued to provide a 1.0% point A1C reduction.||

*Results from two 52-week, double-blind, randomized, double-dummy, multicenter, parallel-group studies using ACTOS 30 or 45 mg QD monotherapy. Study 404 Intent-to-treat, n=588, baseline A1C: 8.7%. Study 405 Intent-to-treat, n=616, baseline A1C: 8.7%.
†Results from a 104-week, double-blind, randomized, double-dummy, multicenter, parallel-group study using ACTOS 30 or 45 mg QD monotherapy. Completer analysis, n=147. Mean change at endpoint statistically significant vs baseline at P<0.0001. Baseline A1C: 8.4%.
‡Results from the per-protocol population of a 104-week, double-blind, randomized, double-dummy, multicenter, parallel-group study using ACTOS 15–45 mg once daily plus metformin. The per-protocol population comprised those patients with available A1C data at week 72 or later (n=229).
§Post-hoc analysis results from a randomized, double-blind, placebo-controlled safety trial in 5238 patients with type 2 diabetes and evidence of macrovascular disease. Baseline A1C: 8.1%. The primary endpoint was a composite of all-cause mortality, nonfatal myocardial infarction, stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. There was no statistically significant difference between ACTOS and placebo (standard of care) for the primary endpoint.
||Results from a 3.5-year, open-label, observational, primary care study. Patients on metformin monotherapy received ACTOS 30 mg QD, n=250, baseline A1C: 8.5% as add-on therapy.

Important Safety Information

  • ACTOS and ACTOplus met may cause fluid retention which 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
  • Lactic acidosis due to metformin accumulation during therapy is rare. However, when it occurs, it is fatal in approximately 50% of cases. The risk increases in patients with renal dysfunction, congestive heart failure requiring drug treatment, and with increasing age
  • Dose-related edema may occur. Use with caution in patients with edema
  • Postmarketing reports of hepatic failure, sometimes fatal, have been received. Causality cannot be excluded. Obtain liver tests before starting treatment. Use caution in patients with liver disease. If liver injury is detected, promptly interrupt treatment and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart treatment if liver injury is confirmed and no alternate etiology can be found
  • An increased incidence of bone fracture has been noted in female patients
  • Data suggest an increased risk of bladder cancer in ACTOS users. Data also suggest that the risk increases with duration of use. Do not use ACTOS, ACTOplus met, ACTOplus met XR, or duetact in patients with active bladder cancer. Use caution when using in patients with a prior history of bladder cancer. Tell patients to promptly report any sign of hematuria or other symptoms such as dysuria or urinary urgency as these may be due to bladder cancer
  • When used with insulin or insulin secretagogues, hypoglycemia may occur and a lower dose of the insulin or insulin secretagogue may be needed to reduce the risk
  • Macular edema has been reported in some patients. Recommend regular eye exams. Instruct patients to report any visual changes promptly
  • Ovulation in premenopausal anovulatory women may occur

Please see Important Safety Information, including boxed warnings about congestive heart failure and lactic acidosis, below.

ADDITIONAL A1C REDUCTIONS

Additional A1C reductions when ACTOS was added to metformin*3,11

  • The addition of ACTOS 30 mg to metformin significantly decreased A1C by another 0.8% point after 24 weeks.*3,11

*Results from a 24-week, double-blind, randomized, multicenter study. Mean change statistically significant vs baseline at P≤0.05. ACTOS 45 mg–baseline A1C: 9.8%, n=416; ACTOS 30 mg–baseline A1C: 9.9%, n=411.

In a 26-week study, patients achieved A1C goal ≤7.0%

55% of patients taking ACTOS added to metformin reached an A1C goal of ≤7.0% after 26 weeks†12

†Results from a 26-week, randomized, multicenter, parallel-group, open-label, forced-titration study. ACTOS or a sulfonylurea was added to failing metformin monotherapy in patients with type 2 diabetes. ACTOS baseline A1C: 8.3%, n=107. 56.3% of patients taking a sulfonylurea achieved A1C goal of ≤7% (baseline A1C 8.4%, n=96).

Indications and Usage

  • ACTOplus met and ACTOplus met XR are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with pioglitazone and metformin or who have inadequate glycemic control on pioglitazone alone or metformin alone.3 ACTOplus met and ACTOplus met XR are not for treatment of type 1 diabetes or diabetic ketoacidosis (DKA)

Important Safety Information

  • Do not initiate in patients with NYHA Class III or IV heart failure
  • Do not use in patients with a history of a serious hypersensitivity reaction to any of the ingredients of these products
  • Do not use in patients with renal disease or dysfunction (as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females], or abnormal creatinine clearance)
  • Do not use in patients with acute or chronic metabolic acidosis, including DKA, with or without coma
  • The most common adverse events (≥5%) seen with ACTOS in combination with metformin include upper respiratory tract infection, diarrhea, nausea, headache, urinary tract infection, sinusitis, dizziness, lower limb edema, and increased weight

Please see Important Safety Information, including boxed warnings about congestive heart failure and lactic acidosis, below.

ACTOS AND THE DEFECTS OF TYPE 2 DIABETES

ACTOS improves certain defects of type 2 diabetes

ACTOS reduced insulin resistance and improved beta-cell function (HOMA)*2,13-16

*HOMA is based on the following calculations: HOMA–IR=(fasting insulin x fasting glucose)/22.5; HOMA–BCF=(20 x fasting insulin)/(fasting glucose – 3.5).

Please see Important Safety Information, including boxed warnings about congestive heart failure and lactic acidosis, below.

Indications and Usage

ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

ACTOplus met and ACTOplus met XR are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with pioglitazone and metformin or who have inadequate glycemic control on pioglitazone alone or metformin alone.

duetact is a thiazolidinedione and sulfonylurea combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with a thiazolidinedione and a sulfonylurea or who have inadequate glycemic control on a thiazolidinedione alone or a sulfonylurea alone.

ACTOS, ACTOplus met, ACTOplus met XR, and duetact are not for treatment of type 1 diabetes or diabetic ketoacidosis (DKA).

Important Safety Information

WARNING: CONGESTIVE HEART FAILURE

  • Thiazolidinediones, including pioglitazone, which is a component of ACTOS, ACTOplus met, ACTOplus met XR, and duetact cause or exacerbate congestive heart failure (CHF) in some patients.
  • After initiation of pioglitazone, 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 pioglitazone must be considered.
  • Pioglitazone is not recommended in patients with symptomatic heart failure.
  • Initiation of pioglitazone in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.

WARNING: LACTIC ACIDOSIS for ACTOplus met and ACTOplus met XR

  • 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 insufficiency, renal impairment, and acute congestive heart failure.
  • 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.
  • If acidosis is suspected, ACTOplus met or ACTOplus met XR should be discontinued and the patient hospitalized immediately.

Contraindications

ACTOS, ACTOplus met, ACTOplus met XR, and duetact:

  • Do not initiate in patients with NYHA Class III or IV heart failure.
  • Do not use in patients with a history of serious hypersensitivity reaction to any of the ingredients of these products.

ACTOplus met and ACTOplus met XR:

  • Do not use in patients with renal disease or dysfunction (as suggested by 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.
  • Do not use in patients with acute or chronic metabolic acidosis, including DKA, with or without coma.
  • Temporarily discontinue in patients administered intravascular iodinated contrast materials, because such materials may acutely alter renal function.

Warnings and Precautions

ACTOS, ACTOplus met, ACTOplus met XR, and duetact:

  • Congestive Heart Failure: May cause fluid retention which 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.
  • Edema: Dose-related edema may occur. Use with caution in patients with edema.
  • Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal, have been received. Causality cannot be excluded. Obtain liver tests before starting treatment. Use caution in patients with liver disease. If liver injury is detected, promptly interrupt treatment and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart treatment if liver injury is confirmed and no alternate etiology can be found.
  • Fractures: An increased incidence of bone fracture has been noted in female patients.
  • Bladder cancer: Data suggest an increased risk of bladder cancer in ACTOS users. Data also suggest that the risk increases with duration of use. Do not use ACTOS, ACTOplus met, ACTOplus met XR, or duetact in patients with active bladder cancer. Use caution when using in patients with a prior history of bladder cancer. Tell patients to promptly report any sign of hematuria or other symptoms such as dysuria or urinary urgency as these may be due to bladder cancer.
  • Hypoglycemia: When used with insulin or insulin secretagogues, hypoglycemia may occur and a lower dose of the insulin or insulin secretagogue may be needed to reduce the risk.
  • Macular edema: Macular edema has been reported in some patients. Recommend regular eye exams. Instruct patients to report any visual changes promptly.
  • Ovulation: Ovulation in premenopausal anovulatory women may occur.
  • Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with these, or any other anti-diabetic drugs.
  • Use with CYP2C8 inducers or strong inhibitors may require dose adjustment.

Additional Warnings and Precautions

ACTOplus met and ACTOplus met XR:

  • Lactic acidosis due to metformin accumulation during therapy is rare. However, when it occurs, it is fatal in approximately 50% of cases. The risk increases in patients with renal dysfunction, congestive heart failure requiring drug treatment, and with increasing age.
    • Risk may be significantly decreased by regular monitoring of renal function, and by using the minimum effective dose. Monitor renal function, particularly in the elderly. Do not initiate in patients ≥80 years of age, unless creatinine clearance is normal.
    • Tell patients that subtle and nonspecific symptoms, such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress, may be important and should be reported immediately. Caution against excessive alcohol intake.
  • Avoid in patients with evidence of hepatic disease, hypoxemia, dehydration, or sepsis, and temporarily discontinue use prior to any surgical procedure.
  • A reversible decrease in vitamin B12 level, without clinical effects, is possible. Measure hematologic parameters annually.

duetact:

  • Cardiac Mortality: The University Group Diabetes Program (UGDP) trial found that tolbutamide, a sulfonylurea, was associated with an increased risk of cardiovascular mortality. Glimepiride was not studied in this trial; however, it is prudent to consider that this warning may apply to all sulfonylureas.
  • Severe hypoglycemia may occur with sulfonylurea use. Dosing should be conservative for elderly, debilitated, or malnourished patients, or patients with adrenal, pituitary, renal, or hepatic insufficiency.
  • Sulfonylurea treatment can lead to hemolytic anemia in patients with, or without, known glucose-6-phosphate dehydrogenase (G6PD) deficiency. Use caution in patients with G6PD deficiency.

Adverse Reactions

The most common adverse events (≥5% and greater than placebo) seen with ACTOS in monotherapy include upper respiratory tract infection, headache, sinusitis, myalgia, and pharyngitis. Use of ACTOS may be associated with weight gain.

The most common adverse events (≥5%) seen with ACTOS in combination with metformin include upper respiratory tract infection, diarrhea, nausea, headache, urinary tract infection, sinusitis, dizziness, lower limb edema, and increased weight.

The most common adverse events (≥5%) seen with ACTOS in combination with a sulfonylurea include hypoglycemia, upper respiratory tract infection, weight increase, lower limb edema, headache, urinary tract infection, diarrhea, nausea, and pain in limb.

Please see ACTOS Complete Prescribing Information, including boxed warning about congestive heart failure, and Medication Guide.

Please see ACTOplus met Complete Prescribing Information, including boxed warnings about congestive heart failure and lactic acidosis, and Medication Guide.

Please see ACTOplus met XR Complete Prescribing Information, including boxed warnings about congestive heart failure and lactic acidosis, and Medication Guide.

Please see duetact Complete Prescribing Information, including boxed warning about congestive heart failure, and Medication Guide.

Copyright ©1999, 2012 Takeda Pharmaceuticals U.S.A., Inc.

This site is intended for use by U.S. residents only.
ACTOS, ACTOplus met, ACTOplus met XR, and duetact are trademarks of
Takeda Pharmaceutical Company Limited registered with the U.S. Patent and
Trademark Office and used under license by Takeda Pharmaceuticals U.S.A., Inc.

Important Safety Information

WARNING: CONGESTIVE HEART FAILURE

  • Thiazolidinediones, including pioglitazone, which is a component of ACTOS, ACTOplus met, ACTOplus met XR, and duetact cause or exacerbate congestive heart failure (CHF) in some patients.
  • After initiation of pioglitazone, 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 pioglitazone must be considered.
  • Pioglitazone is not recommended in patients with symptomatic heart failure.
  • Initiation of pioglitazone in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.

WARNING: LACTIC ACIDOSIS for ACTOplus met and ACTOplus met XR

  • 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 insufficiency, renal impairment, and acute congestive heart failure.
  • 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.
  • If acidosis is suspected, ACTOplus met or ACTOplus met XR should be discontinued and the patient hospitalized immediately.

Contraindications

ACTOS, ACTOplus met, ACTOplus met XR, and duetact:

  • Do not initiate in patients with NYHA Class III or IV heart failure.
  • Do not use in patients with a history of serious hypersensitivity reaction to any of the ingredients of these products.

ACTOplus met and ACTOplus met XR:

  • Do not use in patients with renal disease or dysfunction (as suggested by 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.
  • Do not use in patients with acute or chronic metabolic acidosis, including DKA, with or without coma.
  • Temporarily discontinue in patients administered intravascular iodinated contrast materials, because such materials may acutely alter renal function.

Warnings and Precautions

ACTOS, ACTOplus met, ACTOplus met XR, and duetact:

  • Congestive Heart Failure: May cause fluid retention which 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.
  • Edema: Dose-related edema may occur. Use with caution in patients with edema.
  • Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal, have been received. Causality cannot be excluded. Obtain liver tests before starting treatment. Use caution in patients with liver disease. If liver injury is detected, promptly interrupt treatment and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart treatment if liver injury is confirmed and no alternate etiology can be found.
  • Fractures: An increased incidence of bone fracture has been noted in female patients.
  • Bladder cancer: Data suggest an increased risk of bladder cancer in ACTOS users. Data also suggest that the risk increases with duration of use. Do not use ACTOS, ACTOplus met, ACTOplus met XR, or duetact in patients with active bladder cancer. Use caution when using in patients with a prior history of bladder cancer. Tell patients to promptly report any sign of hematuria or other symptoms such as dysuria or urinary urgency as these may be due to bladder cancer.
  • Hypoglycemia: When used with insulin or insulin secretagogues, hypoglycemia may occur and a lower dose of the insulin or insulin secretagogue may be needed to reduce the risk.
  • Macular edema: Macular edema has been reported in some patients. Recommend regular eye exams. Instruct patients to report any visual changes promptly.
  • Ovulation: Ovulation in premenopausal anovulatory women may occur.
  • Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with these, or any other anti-diabetic drugs.
  • Use with CYP2C8 inducers or strong inhibitors may require dose adjustment.

Additional Warnings and Precautions

ACTOplus met and ACTOplus met XR:

  • Lactic acidosis due to metformin accumulation during therapy is rare. However, when it occurs, it is fatal in approximately 50% of cases. The risk increases in patients with renal dysfunction, congestive heart failure requiring drug treatment, and with increasing age.
    • Risk may be significantly decreased by regular monitoring of renal function, and by using the minimum effective dose. Monitor renal function, particularly in the elderly. Do not initiate in patients ≥80 years of age, unless creatinine clearance is normal.
    • Tell patients that subtle and nonspecific symptoms, such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress, may be important and should be reported immediately. Caution against excessive alcohol intake.
  • Avoid in patients with evidence of hepatic disease, hypoxemia, dehydration, or sepsis, and temporarily discontinue use prior to any surgical procedure.
  • A reversible decrease in vitamin B12 level, without clinical effects, is possible. Measure hematologic parameters annually.

duetact:

  • Cardiac Mortality: The University Group Diabetes Program (UGDP) trial found that tolbutamide, a sulfonylurea, was associated with an increased risk of cardiovascular mortality. Glimepiride was not studied in this trial; however, it is prudent to consider that this warning may apply to all sulfonylureas.
  • Severe hypoglycemia may occur with sulfonylurea use. Dosing should be conservative for elderly, debilitated, or malnourished patients, or patients with adrenal, pituitary, renal, or hepatic insufficiency.
  • Sulfonylurea treatment can lead to hemolytic anemia in patients with, or without, known glucose-6-phosphate dehydrogenase (G6PD) deficiency. Use caution in patients with G6PD deficiency.

Adverse Reactions

The most common adverse events (≥5% and greater than placebo) seen with ACTOS in monotherapy include upper respiratory tract infection, headache, sinusitis, myalgia, and pharyngitis. Use of ACTOS may be associated with weight gain.

The most common adverse events (≥5%) seen with ACTOS in combination with metformin include upper respiratory tract infection, diarrhea, nausea, headache, urinary tract infection, sinusitis, dizziness, lower limb edema, and increased weight.

The most common adverse events (≥5%) seen with ACTOS in combination with a sulfonylurea include hypoglycemia, upper respiratory tract infection, weight increase, lower limb edema, headache, urinary tract infection, diarrhea, nausea, and pain in limb.

Please see ACTOS Complete Prescribing Information, including boxed warning about congestive heart failure, and Medication Guide.

Please see ACTOplus met Complete Prescribing Information, including boxed warnings about congestive heart failure and lactic acidosis, and Medication Guide.

Please see ACTOplus met XR Complete Prescribing Information, including boxed warnings about congestive heart failure and lactic acidosis, and Medication Guide.

Please see duetact Complete Prescribing Information, including boxed warning about congestive heart failure, and Medication Guide.

Indications and Usage

ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

ACTOplus met and ACTOplus met XR are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with pioglitazone and metformin or who have inadequate glycemic control on pioglitazone alone or metformin alone.

duetact is a thiazolidinedione and sulfonylurea combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with a thiazolidinedione and a sulfonylurea or who have inadequate glycemic control on a thiazolidinedione alone or a sulfonylurea alone.

ACTOS, ACTOplus met, ACTOplus met XR, and duetact are not for treatment of type 1 diabetes or diabetic ketoacidosis (DKA).