Pioglitazone - Warnings and Precautions

5 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. • Edema: Dose-related edema may occur. • Hypoglycemia: Consider a lower dose of insulin or insulin secretagogue to reduce risk of hypoglycemia when used in combination with pioglitazone and metformin hydrochloride tablets. • Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal.

Causality cannot be excluded.

If liver injury is detected, promptly interrupt pioglitazone and metformin hydrochloride tablets and assess patient for probable cause, then treat cause if possible, to resolution or stabilization.

Do not restart pioglitazone and metformin hydrochloride tablets if liver injury is confirmed and no alternate etiology can be found. • Urinary Bladder Tumors: May increase the risk of bladder cancer.

Do not use in patients with active bladder cancer.

Use caution when using in patients with a prior history of bladder cancer. • Fractures: Increased incidence in female patients.

Apply current standards of care for assessing and maintaining bone health. • 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. • Vitamin B12 deficiency: Metformin may lower vitamin B 12 levels.

Monitor hematologic parameters annually and vitamin B 12 at 2 to 3 year intervals and manage any abnormalities.

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 tablets, consider discontinuation of pioglitazone and metformin hydrochloride tablets or dosage reduction of pioglitazone in pioglitazone and metformin hydrochloride [see Boxed Warning, Contraindications , Adverse Reactions ] .

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 tablets.

In pioglitazone and metformin hydrochloride tablets-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin HCl 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 tablets 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.