Pioglitazone Hydrochloride And Metformin Hydrochloride

• Thiazolidinediones, including pioglitazone, which is a component of pioglitazone and metformin hydrochloride, cause or exacerbate congestive heart failure in some patients

  [see

  5.1 Congestive Heart Failure

  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. Observe patients for signs and symptoms of congestive heart failure. If congestive heart failure develops while taking pioglitazone and metformin hydrochloride, consider discontinuation of pioglitazone and metformin hydrochloride or dosage reduction of pioglitazone in pioglitazone and metformin hydrochloride

  [see Boxed Warning

  ,

  Contraindications (4), Adverse Reactions (6.1)]

  .

  ]

  .
• After initiation of pioglitazone and metformin hydrochloride, 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

  congestive heart failure develops while taking pioglitazone and metformin hydrochloride, consider discontinuation of pioglitazone and metformin hydrochloride or dosage reduction of pioglitazone in pioglitazone and metformin hydrochloride

  [see

  5.1 Congestive Heart Failure

  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. Observe patients for signs and symptoms of congestive heart failure. If congestive heart failure develops while taking pioglitazone and metformin hydrochloride, consider discontinuation of pioglitazone and metformin hydrochloride or dosage reduction of pioglitazone in pioglitazone and metformin hydrochloride

  [see Boxed Warning

  ,

  Contraindications (4), Adverse Reactions (6.1)]

  .

  ]

  .
• Pioglitazone and metformin hydrochloride is not recommended in patients with symptomatic heart failure

  [see

  5.1 Congestive Heart Failure

  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. Observe patients for signs and symptoms of congestive heart failure. If congestive heart failure develops while taking pioglitazone and metformin hydrochloride, consider discontinuation of pioglitazone and metformin hydrochloride or dosage reduction of pioglitazone in pioglitazone and metformin hydrochloride

  [see Boxed Warning

  ,

  Contraindications (4), Adverse Reactions (6.1)]

  .

  ]

  .
• Initiation of pioglitazone and metformin hydrochloride in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated

  [see 

  4 CONTRAINDICATIONS

  Pioglitazone and metformin hydrochloride are contraindicated in patients with:

  • Established NYHA Class III or IV heart failure at the time of pioglitazone and metformin hydrochloride initiation
    [see Boxed Warning]
    .
  • Severe renal impairment (eGFR below 30 mL/min)
    [see Warnings and Precautions (5.2)]
    .
  • A history of serious hypersensitivity to pioglitazone, metformin hydrochloride, or any of the excipients in pioglitazone and metformin hydrochloride tablets.
  • Acute or chronic metabolic acidosis, including diabetic ketoacidosis
    [see Warnings and Precautions (5.2)].

  • In patients with established New York Heart Association (NYHA) Class III or IV heart failure at the time of pioglitazone and metformin hydrochloride initiation [see Boxed Warning].
  • In patients with severe renal impairment: (eGFR below 30 mL/min).
  • In patients with a history of serious hypersensitivity to pioglitazone, metformin hydrochloride, or any of the excepients in pioglitazone and metformin hydrochloride tablets.
  • In patients with acute or chronic metabolic acidosis, including diabetic ketoacidosis.

  , 

  5.1 Congestive Heart Failure

  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. Observe patients for signs and symptoms of congestive heart failure. If congestive heart failure develops while taking pioglitazone and metformin hydrochloride, consider discontinuation of pioglitazone and metformin hydrochloride or dosage reduction of pioglitazone in pioglitazone and metformin hydrochloride

  [see Boxed Warning

  ,

  Contraindications (4), Adverse Reactions (6.1)]

  .

  ]

  .

• Postmarketing 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

  5.2 Lactic Acidosis

  Lactic Acidosis

  
  
  

  There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate:pyruvate ratio, and metformin plasma levels generally greater than 5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

  
  
  

  If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of pioglitazone and metformin hydrochloride. In pioglitazone and metformin hydrochloride-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

  
  
  

  Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue pioglitazone and metformin hydrochloride and report these symptoms to their healthcare provider.

  
  
  

  For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

  
  
  

  Renal Impairment

  
  
  

  The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include

  [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

  • Before initiating pioglitazone and metformin hydrochloride, obtain an eGFR.
  • Pioglitazone and metformin hydrochloride is contraindicated in patients with an eGFR less than 30 mL/min. Initiation of pioglitazone and metformin hydrochloride is not recommended in patients with eGFR between 30 to 45 mL/min
    [see Contraindications (4)].
  • Obtain an eGFR at least annually in all patients taking pioglitazone and metformin hydrochloride. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
  • In patients taking pioglitazone and metformin hydrochloride whose eGFR later falls below 45 mL/min, assess the benefit and risk of continuing therapy.

  
  
  

  Drug Interactions

  
  
  

  The concomitant use of pioglitazone and metformin hydrochloride with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation (e.g., cationic drugs)

  [see Drug Interactions (7)].

  Therefore, consider more frequent monitoring of patients.

  
  
  

  Age 65 or Greater

  
  
  

  The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients

  [see Use in Specific Populations (8.5)].

  
  
  

  Radiological Studies with Contrast

  
  
  

  Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop pioglitazone and metformin hydrochloride at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart pioglitazone and metformin hydrochloride if renal function is stable.

  
  
  

  Surgery and Other Procedures

  
  
  

  Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. Pioglitazone and metformin hydrochloride should be temporarily discontinued while patients have restricted food and fluid intake.

  
  
  

  Hypoxic States

  
  
  

  Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue pioglitazone and metformin hydrochloride.

  
  
  

  Excessive Alcohol Intake

  
  
  

  Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving pioglitazone and metformin hydrochloride.

  
  
  

  Hepatic Impairment

  
  
  

  Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of pioglitazone and metformin hydrochloride in patients with clinical or laboratory evidence of hepatic disease.

  ]

  .
• 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

  2.3 Recommendations for Use in Patients with Renal Impairment

  • Assess renal function prior to initiation
    of
    pioglitazone and metformin hydrochloride tablets and periodically thereafter
    [see Use in Specific Populations (8.6)].
  • Pioglitazone and metformin hydrochloride tablets are contraindicated in patients with
    an
    estimated glomerular filtration rate (eGFR) below 30 mL/min.
  • Initiation of pioglitazone and metformin hydrochloride tablets in patients with
    an
    eGFR between 30 to 45 mL/min is not recommended.
  • In patients taking pioglitazone and metformin hydrochloride tablets whose eGFR later falls below
    45
    mL/min, assess the benefit and risk of continuing therapy.
  • Discontinue pioglitazone and metformin hydrochloride tablets
    if
    the patient's eGFR later falls below 30 mL/min
    [see Contraindications (4), Warnings and Precautions (5.2)].

  ,

  4 CONTRAINDICATIONS

  Pioglitazone and metformin hydrochloride are contraindicated in patients with:

  • Established NYHA Class III or IV heart failure at the time of pioglitazone and metformin hydrochloride initiation
    [see Boxed Warning]
    .
  • Severe renal impairment (eGFR below 30 mL/min)
    [see Warnings and Precautions (5.2)]
    .
  • A history of serious hypersensitivity to pioglitazone, metformin hydrochloride, or any of the excipients in pioglitazone and metformin hydrochloride tablets.
  • Acute or chronic metabolic acidosis, including diabetic ketoacidosis
    [see Warnings and Precautions (5.2)].

  • In patients with established New York Heart Association (NYHA) Class III or IV heart failure at the time of pioglitazone and metformin hydrochloride initiation [see Boxed Warning].
  • In patients with severe renal impairment: (eGFR below 30 mL/min).
  • In patients with a history of serious hypersensitivity to pioglitazone, metformin hydrochloride, or any of the excepients in pioglitazone and metformin hydrochloride tablets.
  • In patients with acute or chronic metabolic acidosis, including diabetic ketoacidosis.

  ,

  5.2 Lactic Acidosis

  Lactic Acidosis

  
  
  

  There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate:pyruvate ratio, and metformin plasma levels generally greater than 5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

  
  
  

  If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of pioglitazone and metformin hydrochloride. In pioglitazone and metformin hydrochloride-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

  
  
  

  Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue pioglitazone and metformin hydrochloride and report these symptoms to their healthcare provider.

  
  
  

  For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

  
  
  

  Renal Impairment

  
  
  

  The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include

  [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

  • Before initiating pioglitazone and metformin hydrochloride, obtain an eGFR.
  • Pioglitazone and metformin hydrochloride is contraindicated in patients with an eGFR less than 30 mL/min. Initiation of pioglitazone and metformin hydrochloride is not recommended in patients with eGFR between 30 to 45 mL/min
    [see Contraindications (4)].
  • Obtain an eGFR at least annually in all patients taking pioglitazone and metformin hydrochloride. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
  • In patients taking pioglitazone and metformin hydrochloride whose eGFR later falls below 45 mL/min, assess the benefit and risk of continuing therapy.

  
  
  

  Drug Interactions

  
  
  

  The concomitant use of pioglitazone and metformin hydrochloride with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation (e.g., cationic drugs)

  [see Drug Interactions (7)].

  Therefore, consider more frequent monitoring of patients.

  
  
  

  Age 65 or Greater

  
  
  

  The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients

  [see Use in Specific Populations (8.5)].

  
  
  

  Radiological Studies with Contrast

  
  
  

  Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop pioglitazone and metformin hydrochloride at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart pioglitazone and metformin hydrochloride if renal function is stable.

  
  
  

  Surgery and Other Procedures

  
  
  

  Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. Pioglitazone and metformin hydrochloride should be temporarily discontinued while patients have restricted food and fluid intake.

  
  
  

  Hypoxic States

  
  
  

  Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue pioglitazone and metformin hydrochloride.

  
  
  

  Excessive Alcohol Intake

  
  
  

  Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving pioglitazone and metformin hydrochloride.

  
  
  

  Hepatic Impairment

  
  
  

  Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of pioglitazone and metformin hydrochloride in patients with clinical or laboratory evidence of hepatic disease.

  ,

  7 DRUG INTERACTIONS

  • Strong CYP2C8 inhibitors (e.g., gemfibrozil): Limit pioglitazone and metformin hydrochloride dose to 15 mg/850 mg daily.
  • CYP2C8 inducers (e.g., rifampin) may decrease pioglitazone concentrations.
  • Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring.
  • 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.
  • Alcohol: Warn patients against excessive alcohol intake.
  • Use of insulin secretagogues or insulin use may increase the risk for hypoglycemia and may require dose reduction.
  • Topiramate may decrease pioglitazone concentrations. (7.8)

  7.1 Strong CYP2C8 Inhibitors

  An inhibitor of CYP2C8 (e.g., gemfibrozil) significantly increases the exposure (area under the serum concentration-time curve or AUC) and half-life (t_1/2) of pioglitazone. Therefore, the maximum recommended dosage of pioglitazone and metformin hydrochloride is 15 mg of pioglitazone and 850 mg of metformin hydrochloride once daily if used in combination with gemfibrozil or other strong CYP2C8 inhibitors

  [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)]

  .

  7.2 CYP2C8 Inducers

  An inducer of CYP2C8 (e.g., rifampin) may significantly decrease the exposure (AUC) of pioglitazone. Therefore, if an inducer of CYP2C8 is started or stopped during treatment with pioglitazone and metformin hydrochloride, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dosage of pioglitazone and metformin hydrochloride (45 mg of pioglitazone and 2,550 mg of metformin hydrochloride)

  [see Clinical Pharmacology (12.3)]

  .

  7.3 Carbonic Anhydrase Inhibitors

  Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with pioglitazone and metformin hydrochloride may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.

  7.4 Drugs that Reduce Metformin Clearance

  Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis

  [see Clinical Pharmacology (12.3)]

  . Consider the benefits and risks of concomitant use.

  7.5 Alcohol

  Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving pioglitazone and metformin hydrochloride.

  7.6 Insulin Secretagogues or Insulin

  Coadministration of pioglitazone and metformin hydrochloride with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia. If hypoglycemia occurs in a patient coadministered pioglitazone and metformin hydrochloride and an insulin secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be reduced.

  7.7 Drugs Affecting Glycemic Control

  Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to a patient receiving pioglitazone and metformin hydrochloride, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving pioglitazone and metformin hydrochloride, the patient should be observed closely for hypoglycemia.

  7.8 Topiramate

  A decrease in the exposure of pioglitazone and its active metabolites were noted with concomitant administration of pioglitazone and topiramate

  [see Clinical Pharmacology (12.3)].

  The clinical relevance of this decrease is unknown; however, when pioglitazone and metformin hydrochloride and topiramate are used concomitantly, monitor patients for adequate glycemic control.

  ,

  8.6 Renal Impairment

  Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Pioglitazone and metformin hydrochloride is contraindicated in severe renal impairment, which includes patients with an eGFR below 30 mL/min

  [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.2), Clinical Pharmacology (12.3)].

  ,

  8.7 Hepatic Impairment

  Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Pioglitazone and metformin hydrochloride is not recommended in patients with hepatic impairment

  [see Warnings and Precautions (5.2)]

  .

  ]

  .
• If metformin-associated lactic acidosis is suspected, immediately discontinue pioglitazone and metformin hydrochloride and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended

  [see

  5.2 Lactic Acidosis

  Lactic Acidosis

  
  
  

  There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate:pyruvate ratio, and metformin plasma levels generally greater than 5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

  
  
  

  If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of pioglitazone and metformin hydrochloride. In pioglitazone and metformin hydrochloride-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

  
  
  

  Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue pioglitazone and metformin hydrochloride and report these symptoms to their healthcare provider.

  
  
  

  For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

  
  
  

  Renal Impairment

  
  
  

  The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include

  [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

  • Before initiating pioglitazone and metformin hydrochloride, obtain an eGFR.
  • Pioglitazone and metformin hydrochloride is contraindicated in patients with an eGFR less than 30 mL/min. Initiation of pioglitazone and metformin hydrochloride is not recommended in patients with eGFR between 30 to 45 mL/min
    [see Contraindications (4)].
  • Obtain an eGFR at least annually in all patients taking pioglitazone and metformin hydrochloride. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
  • In patients taking pioglitazone and metformin hydrochloride whose eGFR later falls below 45 mL/min, assess the benefit and risk of continuing therapy.

  
  
  

  Drug Interactions

  
  
  

  The concomitant use of pioglitazone and metformin hydrochloride with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation (e.g., cationic drugs)

  [see Drug Interactions (7)].

  Therefore, consider more frequent monitoring of patients.

  
  
  

  Age 65 or Greater

  
  
  

  The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients

  [see Use in Specific Populations (8.5)].

  
  
  

  Radiological Studies with Contrast

  
  
  

  Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop pioglitazone and metformin hydrochloride at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart pioglitazone and metformin hydrochloride if renal function is stable.

  
  
  

  Surgery and Other Procedures

  
  
  

  Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. Pioglitazone and metformin hydrochloride should be temporarily discontinued while patients have restricted food and fluid intake.

  
  
  

  Hypoxic States

  
  
  

  Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue pioglitazone and metformin hydrochloride.

  
  
  

  Excessive Alcohol Intake

  
  
  

  Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving pioglitazone and metformin hydrochloride.

  
  
  

  Hepatic Impairment

  
  
  

  Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of pioglitazone and metformin hydrochloride in patients with clinical or laboratory evidence of hepatic disease.

  ]

  .

Dosage and Administration

Important Dosage and Administration Information (

Recommendations for Use in Patients with Renal

Impairment (

Recommendations for Congestive Heart Failure (

Coadministration with Strong CYP2C8 Inhibitors (

Pioglitazone and metformin hydrochloride tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Pioglitazone and metformin hydrochloride tablets are not recommended to treat type 1 diabetes mellitus or diabetic ketoacidosis.

• Obtain liver tests before initiation. If abnormal, use caution when treating with pioglitazone and metformin hydrochloride, investigate the probable cause, treat (if possible), and follow appropriately. (
  2.1 Important Dosage and Administration Information

  • Obtain liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) prior to initiating pioglitazone and metformin hydrochloride tablets
    [see Warnings and Precautions (5.5)].
  • Pioglitazone and metformin hydrochloride tablet contains 15 mg of pioglitazone and 500 mg of metformin hydrochloride or 15 mg of pioglitazone and 850 mg of metformin hydrochloride in each tablet.
  • Take pioglitazone and metformin hydrochloride tablets with meals to reduce gastrointestinal adverse reactions with metformin
    [see Adverse Reactions (6.1)].
  • If a dose is missed, do not double the next dose.
  )
• Take orally with meals to reduce gastrointestinal adverse reactions with metformin (2.10)
• Individualize the starting dose based on the patient’s current regimen and titrate the dosage gradually, as needed after assessing therapeutic response and tolerability. The maximum recommended total daily dosage is pioglitazone 45 mg and metformin 2,550 mg. (
  2.2 Recommended Dosage and Administration

  Recommended Starting Dosage Based

  on

  Current Regimen
  
  

  
  
  Individualize the starting dosage of pioglitazone and metformin hydrochloride tablets based

  on

  the patient's current regimen and the available strength of pioglitazone and metformin hydrochloride tablets (see Table 1).

  Table 1: Recommended Starting Dosage Based on the Patient’s Current Regimen

  *For dosage recommendations for patients with renal impairment and/or congestive heart failure, see Dosage and Administration (2.3, 2.4)
  Current Regimen	Starting Dosage of Pioglitazone and Metformin Hydrochloride tablets (15 mg of pioglitazone and 850 mg of metformin hydrochloride per tablet)*
  Not treated with either pioglitazone or metformin hydrochloride	One tablet orally once daily
  Metformin hydrochloride	One tablet orally once or twice daily. Select a dosage that is as close as possible to the current dosage of metformin hydrochloride
  Pioglitazone	One tablet orally once daily
  Pioglitazone and metformin hydrochloride	Select a dosage that is as close as possible to the current dosage of pioglitazone and metformin hydrochloride while not exceeding three tablets orally per day.

  Dosage Titration

  for

  Additional Glycemic Control
  
  

  
  
  Titrate the pioglitazone and metformin hydrochloride tablets dosage gradually,

  as

  needed, after assessing therapeutic response and tolerability.

  
  
  

  Pioglitazone and metformin hydrochloride tablets may be increased

  to

  a maximum recommended total daily dosage of three tablets per day (45 mg of pioglitazone and 2,550 mg of metformin hydrochloride). Total daily dosages of 2,550 mg of metformin hydrochloride may be taken in divided doses three times a day to reduce gastrointestinal adverse reactions

  [see Adverse Reactions (6.1)].
  )
• Recommended starting dosage in patients with NYHA Class I or Class II congestive heart failure is 15 mg of pioglitazone and 500 mg of metformin hydrochloride or 15 mg of pioglitazone and 850 mg of metformin hydrochloride orally once daily. (
  2.4 Recommendations for Congestive Heart Failure

  Starting Dosage in Patients with NYHA Class I or

  II

  Congestive Heart Failure
  
  

  
  
  For patients with preexisting NYHA Class I or II congestive heart failure, the recommended starting dosage of pioglitazone and metformin hydrochloride tablets are 15 mg of pioglitazone and 500 mg of metformin or 15 mg

  of

  pioglitazone and 850 mg of metformin

  [see Boxed Warningand Warnings and Precautions (5.1)].

  Monitoring for Fluid Retention and Dosage Modifications

  for

  Congestive Heart Failure
  
  

  
  
  After initiation of pioglitazone and metformin hydrochloride tablets or with dosage increase, monitor patients carefully

  for

  adverse reactions related to fluid retention as has been seen with pioglitazone (e.g., weight gain, edema and signs and symptoms of congestive heart failure).

  
  
  

  If congestive heart failure develops while taking pioglitazone and metformin hydrochloride tablets, consider discontinuation of pioglitazone and metformin hydrochloride tablets or dosage reduction of pioglitazone in pioglitazone

  and

  metformin hydrochloride tablets

  [see Boxed Warningand Warnings and Precautions (5.1)].
  )
• Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR). (
  2.2 Recommended Dosage and Administration

  Recommended Starting Dosage Based

  on

  Current Regimen
  
  

  
  
  Individualize the starting dosage of pioglitazone and metformin hydrochloride tablets based

  on

  the patient's current regimen and the available strength of pioglitazone and metformin hydrochloride tablets (see Table 1).

  Table 1: Recommended Starting Dosage Based on the Patient’s Current Regimen

  *For dosage recommendations for patients with renal impairment and/or congestive heart failure, see Dosage and Administration (2.3, 2.4)
  Current Regimen	Starting Dosage of Pioglitazone and Metformin Hydrochloride tablets (15 mg of pioglitazone and 850 mg of metformin hydrochloride per tablet)*
  Not treated with either pioglitazone or metformin hydrochloride	One tablet orally once daily
  Metformin hydrochloride	One tablet orally once or twice daily. Select a dosage that is as close as possible to the current dosage of metformin hydrochloride
  Pioglitazone	One tablet orally once daily
  Pioglitazone and metformin hydrochloride	Select a dosage that is as close as possible to the current dosage of pioglitazone and metformin hydrochloride while not exceeding three tablets orally per day.

  Dosage Titration

  for

  Additional Glycemic Control
  
  

  
  
  Titrate the pioglitazone and metformin hydrochloride tablets dosage gradually,

  as

  needed, after assessing therapeutic response and tolerability.

  
  
  

  Pioglitazone and metformin hydrochloride tablets may be increased

  to

  a maximum recommended total daily dosage of three tablets per day (45 mg of pioglitazone and 2,550 mg of metformin hydrochloride). Total daily dosages of 2,550 mg of metformin hydrochloride may be taken in divided doses three times a day to reduce gastrointestinal adverse reactions

  [see Adverse Reactions (6.1)].
  )
  • Contraindicated in patients with eGFR below 30 mL/min
  • Initiation is not recommended in patients with eGFR between 30 to 45 mL/min
  • Assess risk/benefit of continuing pioglitazone and metformin hydrochloride if eGFR falls below 45 mL/min
  • Discontinue if eGFR falls below 30 mL/min
• Monitor patients for adverse events related to fluid retention after initiation and dose increases. (
  2.4 Recommendations for Congestive Heart Failure

  Starting Dosage in Patients with NYHA Class I or

  II

  Congestive Heart Failure
  
  

  
  
  For patients with preexisting NYHA Class I or II congestive heart failure, the recommended starting dosage of pioglitazone and metformin hydrochloride tablets are 15 mg of pioglitazone and 500 mg of metformin or 15 mg

  of

  pioglitazone and 850 mg of metformin

  [see Boxed Warningand Warnings and Precautions (5.1)].

  Monitoring for Fluid Retention and Dosage Modifications

  for

  Congestive Heart Failure
  
  

  
  
  After initiation of pioglitazone and metformin hydrochloride tablets or with dosage increase, monitor patients carefully

  for

  adverse reactions related to fluid retention as has been seen with pioglitazone (e.g., weight gain, edema and signs and symptoms of congestive heart failure).

  
  
  

  If congestive heart failure develops while taking pioglitazone and metformin hydrochloride tablets, consider discontinuation of pioglitazone and metformin hydrochloride tablets or dosage reduction of pioglitazone in pioglitazone

  and

  metformin hydrochloride tablets

  [see Boxed Warningand Warnings and Precautions (5.1)].
  )
• Pioglitazone and metformin hydrochloride may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. (
  2.6 Discontinuation for Iodinated Contrast Imaging Procedures

  Discontinue pioglitazone and metformin hydrochloride tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min; 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 pioglitazone and metformin hydrochloride tablets if renal function is stable

  [see Warnings and Precautions (5.2)]

  .
  )

• 15 mg/500 mg tablets: White to off-white, oblong, biconvex film-coated tablets, debossed with ‘H’ on one side and ‘92’ on other side.
• 15 mg/850 mg tablets: White to off-white, oblong, biconvex film-coated tablets, debossed with ‘H’ on one side and ‘93’ on other side.

• Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. (
  8.3 Females and Males of Reproductive Potential

  Discuss the potential for unintended pregnancy with premenopausal women as therapy with pioglitazone and metformin hydrochloride, may result in ovulation in some anovulatory women.
  )
• Pediatrics: Safety and effectiveness have not been established. (
  8.4 Pediatric Use

  Safety and effectiveness of pioglitazone and metformin hydrochloride in pediatric patients have not been established.

  
  
  

  Pioglitazone and metformin hydrochloride is not recommended for use in pediatric patients based on adverse effects observed in adults, including fluid retention and congestive heart failure, fractures, and urinary bladder tumors

  [see Warnings and Precautions (5.1, 5.3, 5.6, 5.7)].
  )
• Geriatric Use: Assess renal function more frequently. (
  8.5 Geriatric Use

  Pioglitazone

  A total of 92 patients (15.2%) treated with pioglitazone in the three pooled 16 to 26 week double-blind, placebo-controlled, monotherapy trials were ≥65 years old and two patients (0.3%) were ≥75 years old. In the two pooled 16 to 24 week add-on to sulfonylurea trials, 201 patients (18.7%) treated with pioglitazone were ≥65 years old and 19 (1.8%) were ≥75 years old. In the two pooled 16 to 24 week add-on to metformin trials, 155 patients (15.5%) treated with pioglitazone were ≥65 years old and 19 (1.9%) were ≥75 years old. In the two pooled 16 to 24 week add-on to insulin trials, 272 patients (25.4%) treated with pioglitazone were ≥65 years old and 22 (2.1%) were ≥75 years old.

  
  
  

  In PROactive Trial, 1,068 patients (41%) treated with pioglitazone were ≥65 years old and 42 (1.6%) were ≥75 years old.

  
  
  

  In pharmacokinetic studies with pioglitazone, no significant differences were observed in pharmacokinetic parameters between elderly and younger patients

  [see Clinical Pharmacology (12.3)]

  .

  
  
  

  Although clinical experiences have not identified differences in effectiveness and safety between the elderly (≥65 years) and younger patients, these conclusions are limited by small sample sizes for patients ≥75 years old.

  
  
  

  Metformin hydrochloride

  Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients

  [see Warnings and Precautions (5.2), Dosage and Administration (2.2)].
  )
• Hepatic Impairment: Avoid use in patients with hepatic impairment. (
  8.7 Hepatic Impairment

  Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Pioglitazone and metformin hydrochloride is not recommended in patients with hepatic impairment

  [see Warnings and Precautions (5.2)]

  .
  )