ACTOPLUS MET tablets are a thiazolidinediones and biguanide combination product that contains two oral antidiabetic medications: pioglitazone HCl and metformin HCl. Pioglitazone [(±)-5-[[4-[2-(5-ethyl-2-pyridinyl) ethoxy]phenyl]methyl]-2,4-] thiazolidinedione monohydrochloride contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo . No differences were found in the pharmacologic activity between the two enantiomers. The structural formula is as shown: pioglitazone HCl Pioglitazone HCl is an odorless white crystalline powder that has a molecular formula of C 19 H 20 N 2 O 3 S•HCl and a molecular weight of 392.90 daltons. It is soluble in N,N -dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether. Metformin HCl ( N,N -dimethylimidodicarbonimidic diamide HCl) is a white crystalline powder with a molecular formula of C 4 H 11 N 5 •HCl and a molecular weight of 165.62. Metformin HCl is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin HCl is 6.68. The structural formula is as shown: metformin HCl ACTOPLUS MET is available as a tablet for oral administration containing 15 mg pioglitazone (as the base) with 850 mg metformin HCl (15 mg/850 mg) formulated with the following excipients: povidone USP, microcrystalline cellulose NF, croscarmellose sodium NF, magnesium stearate NF, hypromellose 2910 USP, polyethylene glycol 8000 NF, titanium dioxide USP, and talc USP. Chemical Structure Chemical Structure

ACTOPLUS MET is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use ACTOPLUS MET is not recommended to treat type 1 diabetes mellitus or diabetic ketoacidosis. ACTOPLUS MET is a combination of pioglitazone, a thiazolidinedione agonist of peroxisome proliferator receptor gamma, and metformin hydrochloride (HCl), a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use : Not recommended for treatment of type 1 diabetes or diabetic ketoacidosis.

15 mg of pioglitazone and 850 mg of metformin HCl tablets: White to off-white, oblong, film-coated tablets debossed with “4833M” on one side and “15/850” on the other Tablets: 15 mg pioglitazone/850 mg metformin HCl.

Obtain liver tests before initiation. If abnormal, use caution when treating with ACTOPLUS MET, investigate the probable cause, treat (if possible), and follow appropriately. Take orally with meals to reduce gastrointestinal adverse reactions with metformin 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. Recommended starting dosage in patients with NYHA Class I or Class II congestive heart failure is 15 mg of pioglitazone and 850 mg of metformin HCl orally once daily. Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR). 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 ACTOPLUS MET 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. ACTOPLUS MET may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures

Important Dosage and Administration Information Obtain liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) prior to initiating ACTOPLUS MET . ACTOPLUS MET contains 15 mg of pioglitazone and 850 mg of metformin hydrochloride (HCl) in each tablet. Take ACTOPLUS MET with meals to reduce gastrointestinal adverse reactions with metformin . If a dose is missed, do not double the next dose

Recommended Dosage and Administration Recommended Starting Dosage Based on Current Regimen Individualize the starting dosage of ACTOPLUS MET based on the patient's current regimen and the available strength of ACTOPLUS MET . Table 1: Recommended Starting Dosage Based on the Patient’s Current Regimen Current Regimen Starting Dosage of ACTOPLUS MET (15 mg of pioglitazone and 850 mg of metformin HCl per tablet) For dosage recommendations for patients with renal impairment and/or congestive heart failure, see Dosage and Administration (2.3 , 2.4) Not treated with either pioglitazone or metformin HCl One tablet orally once daily Metformin HCl One tablet orally once or twice daily. Select a dosage that is as close as possible to the current dosage of metformin HCl Pioglitazone One tablet orally once daily Pioglitazone and metformin HCl Select a dosage that is as close as possible to the current dosage of pioglitazone and metformin HCl while not exceeding three tablets orally per day. Dosage Titration for Additional Glycemic Control Titrate the ACTOPLUS MET dosage gradually, as needed, after assessing therapeutic response and tolerability. ACTOPLUS MET 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 HCl). Total daily dosages of 2,550 mg of metformin HCl may be taken in divided doses three times a day to reduce gastrointestinal adverse reactions

Recommendations for Use in Patients with Renal Impairment Assess renal function prior to initiation of ACTOPLUS MET and periodically thereafter . ACTOPLUS MET is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min. Initiation of ACTOPLUS MET in patients with an eGFR between 30 to 45 mL/min is not recommended. In patients taking ACTOPLUS MET whose eGFR later falls below 45 mL/min, assess the benefit and risk of continuing therapy. Discontinue ACTOPLUS MET if the patient’s eGFR later falls below 30 mL/min

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 ACTOPLUS MET is 15 mg of pioglitazone and 850 mg of metformin . Monitoring for Fluid Retention and Dosage Modifications for Congestive Heart Failure After initiation of ACTOPLUS MET 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 ACTOPLUS MET, consider discontinuation of ACTOPLUS MET or dosage reduction of pioglitazone in ACTOPLUS MET

Coadministration with Strong CYP2C8 Inhibitors The maximum recommended dosage of ACTOPLUS MET is one tablet (15 mg of pioglitazone and 850 mg of metformin HCl) once daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors

Discontinuation for Iodinated Contrast Imaging Procedures Discontinue ACTOPLUS MET 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 ACTOPLUS MET if renal function is stable .

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 ACTOPLUS MET. Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly interrupt ACTOPLUS MET and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart ACTOPLUS MET 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 B 12 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 ACTOPLUS MET, consider discontinuation of ACTOPLUS MET or dosage reduction of pioglitazone in ACTOPLUS MET

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 ACTOPLUS MET. In ACTOPLUS MET-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 ACTOPLUS MET 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 . Before initiating ACTOPLUS MET, obtain an eGFR. ACTOPLUS MET is contraindicated in patients with an eGFR less than 30 mL/min. Initiation of ACTOPLUS MET is not recommended in patients with eGFR between 30 to 45 mL/min . Obtain an eGFR at least annually in all patients taking ACTOPLUS MET. 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 ACTOPLUS MET whose eGFR later falls below 45 mL/min, assess the benefit and risk of continuing therapy . Drug Interactions The concomitant use of ACTOPLUS MET 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) . 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 . 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 ACTOPLUS MET 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 ACTOPLUS MET 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. ACTOPLUS MET 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 ACTOPLUS MET. 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 ACTOPLUS MET. 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 ACTOPLUS MET in patients with clinical or laboratory evidence of hepatic disease

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 . In postmarketing experience, reports of new onset or worsening of edema have been received. ACTOPLUS MET 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 should be used with caution in patients at risk for congestive heart failure. Patients treated with ACTOPLUS MET should be monitored for signs and symptoms of congestive heart failure

Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia. Therefore, a lower dosage of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with ACTOPLUS MET

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 establish the probable cause. There has been no evidence of drug-induced hepatotoxicity in the pioglitazone controlled clinical trial database to date . Patients with type 2 diabetes mellitus 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 therapy. In patients with abnormal liver tests, ACTOPLUS MET 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 clinically significant liver enzyme elevations (serum ALT greater than three times the ULN) and if abnormal liver tests persist or worsen, ACTOPLUS MET should be interrupted and investigation done to establish the probable cause. ACTOPLUS MET should not be restarted in these patients without another explanation for the liver test abnormalities

Urinary Bladder Tumors Tumors were observed in the urinary bladder of male rats in the two year carcinogenicity study . In addition, during the three year PROactive clinical trial, 14 patients out of 2,605 (0.54%) randomized to pioglitazone and 5 out of 2,633 (0.19%) randomized to placebo were diagnosed with bladder cancer. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 6 (0.23%) cases on pioglitazone and 2 (0.08%) cases on placebo. After completion of the trial, a large subset of patients was observed for up to 10 additional years, with little additional exposure to pioglitazone. During the 13 years of both PROactive and observational follow-up, the occurrence of bladder cancer did not differ between patients randomized to pioglitazone or placebo [Hazard Ratio (HR) = 1.00; (95% Confidence Interval (CI) : 0.59, 1.72)]. Findings regarding the risk of bladder cancer in patients exposed to pioglitazone vary among observational studies; some did not find an increased risk of bladder cancer associated with pioglitazone, while others did. A large prospective10 year observational cohort study conducted in the United States (U.S) found no statistically significant increase in the risk of bladder cancer in diabetic patients ever exposed to pioglitazone, compared to those never exposed to pioglitazone [HR = 1.06; (95% CI: 0.89, 1.26)]. A retrospective cohort study conducted with data from the United Kingdom found a statistically significant association between ever exposure to pioglitazone and bladder cancer [HR = 1.63; (95% CI: 1.22, 2.19)]. Associations between cumulative dose or cumulative duration of exposure to pioglitazone and bladder cancer were not detected in some studies including the 10 year observational study in the U.S., but were in others. Inconsistent findings and limitations inherent in these and other studies preclude conclusive interpretations of the observational data. Pioglitazone may be associated with an increase in the risk of urinary bladder tumors. There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors. Consequently, ACTOPLUS MET 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 should be considered in patients with a prior history of bladder cancer

Fractures In PROactive (the Prospective Pioglitazone Clinical Trial in Macrovascular Events), 5,238 patients with type 2 diabetes mellitus and a history of macrovascular disease were randomized to pioglitazone (N=2,605), force-titrated up to 45 mg daily or placebo (N=2,633) 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 and attention should be given to assessing and maintaining bone health according to current standards of care

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

Vitamin B 12 Levels In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. Measure hematologic parameters on an annual basis and vitamin B 12 at 2 to 3 year intervals in patients on ACTOPLUS MET and manage any abnormalities .

Strong CYP2C8 inhibitors (e.g., gemfibrozil): Limit ACTOPLUS MET 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

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 ½ ) of pioglitazone. Therefore, the maximum recommended dosage of ACTOPLUS MET is 15 mg of pioglitazone and 850 mg of metformin HCl once daily if used in combination with gemfibrozil or other strong CYP2C8 inhibitors

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 ACTOPLUS MET, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dosage of ACTOPLUS MET (45 mg of pioglitazone and 2,550 mg of metformin HCl)

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 ACTOPLUS MET may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients

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 . Consider the benefits and risks of concomitant use

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

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

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 ACTOPLUS MET, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving ACTOPLUS MET, the patient should be observed closely for hypoglycemia

Topiramate A decrease in the exposure of pioglitazone and its active metabolites were noted with concomitant administration of pioglitazone and topiramate . The clinical relevance of this decrease is unknown; however, when ACTOPLUS MET and topiramate are used concomitantly, monitor patients for adequate glycemic control.