PIOGLITAZONE HCl + METFORMIN HCl

PIOGLITAZONE HCl + METFORMIN HCl Pioplus 15 mg/500 mg Tablet Pioplus 30 mg/500 mg Tablet Oral Hypoglycemic FORMULATION Each tablet contains: Pioglitazone hydrochloride 15 mg or 30 mg Metformin hydrochloride (in sustained-release form). 500 mg PRODUCT DESCRIPTIONS Pioglitazone HCl + Metformin HCl (Pioplus ) 15 mg/500 mg is a capsule-shaped, biconvex, bilayered tablet, plain on both sides, one layer white in color and the other is orange. Pioglitazone HCl + Metformin HCl (Pioplus ) 30 mg/500 mg is a capsule-shaped, biconvex, bilayered tablet, plain on both sides, one layer white in color and the other is blue. CLINICAL PHARMACOLOGY Pharmacodynamics Pioglitazone + Metformin (SR) fixed-dose combination (FDC) tablet combines two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes mellitus. Pioglitazone HCl Pioglitazone, a potent and highly selective peroxisome proliferator-activated receptor gamma (PPARγ) agonist, is a thiazolidinedione (TZD) oral antidiabetic agent that acts primarily by reducing insulin resistance. It improves glycemic control by increasing insulin sensitivity in target tissues, primarily skeletal muscle and adipose tissue, and by decreasing hepatic gluconeogenesis. Activation of PPARγ nuclear receptors, which are found in key target tissues for insulin action (e.g., adipose tissue, skeletal muscle, liver), modulates the transcription of insulin-responsive genes involved in the control of glucose and lipid metabolism. Like other TZDs, pioglitazone minimizes the risk of hypoglycemia associated with the treatment of type 2 diabetes by decreasing insulin resistance without stimulating insulin release from pancreatic beta-cells. Metformin HCl Metformin is a biguanide antidiabetic agent that reduces both basal and postprandial plasma glucose concentrations in patients with type 2 diabetes mellitus by improving both peripheral and hepatic sensitivity to insulin. It does not stimulate insulin secretion and therefore does not produce hypoglycemia when given alone and in combination with TZDs. Fasting insulin levels and day-long insulin response remain the same or may even decrease with metformin therapy. Metformin may act via three mechanisms: It reduces hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis; increases insulin sensitivity in the skeletal muscles and adipocytes, improving peripheral glucose uptake and utilization; delays intestinal glucose absorption. 1 of 15

Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. It also increases the transport capacity of all types of membrane glucose transporters. Metformin has demonstrated modest favorable effects on lipid metabolism in patients with type 2 diabetes. It lowers total cholesterol, mean fasting serum triglycerides and low density lipoprotein cholesterol levels; it has no adverse effects on other lipid levels. Pharmacokinetics A bioequivalence study in healthy volunteers have shown the FDC of pioglitazone HCl 30 mg + metformin HCl 500 mg SR to be bioequivalent to pioglitazone HCl 30 mg and metformin HCl 500 mg SR given as separate tablets with no serious adverse events reported during the study period. The following are the important pharmacokinetic parameters of the pioglitazone HCl 30 mg + metformin HCl 500 mg SR FDC given as single dose under fasting conditions: Parameters Mean + SD Metformin SR Pioglitazone C max (ng/ml) 827.99 + 107.71 888.15 + 158.24 AUC 0-t (ng hr/ml) 6999.78 + 1023.83 8852.81 + 1206.2 AUC 0-inf (ng hr/ml) 7525.51 + 1013.15 9614.78 + 1201.72 T max (hrs) 5.5 + 0.86 3.69 + 0.63 K el (hrs -1 ) 0.15 + 0.04 0.09 + 0.02 T 1/2 (hrs) 4.8 + 1.27 8.26 + 2.02 Pioglitazone HCl Pioglitazone is absorbed rapidly with peak plasma concentrations occurring within two hours after oral administration (fasting state). Repeated dosing does not result in accumulation of pioglitazone or metabolites. Pioglitazone is more than 80% bioavailable. While food slightly delays pioglitazone s absorption, the extent of absorption is not altered. Pioglitazone is more than 99% plasma protein bound and its mean apparent volume of distribution after single-dose administration is about 0.63±0.41 L/kg body weight. Metabolites MIII and MIV are also extensively bound to serum albumin (>98%). Pioglitazone is extensively metabolized by hydroxylation and oxidation through the cytochrome P450 isoforms (mainly CYP2C8 and to a lesser degree CYP3A4, with additional contributions from other isoforms including the mainly extrahepatic CYP1A1); the metabolites are also partly converted to glucuronide or sulfate conjugates. M-II, M-III and M-IV are its pharmacologically active metabolites. Studies of pioglitazone in combination with P450 inhibitors and substrates have been performed and have shown that pioglitazone is not a strong CYP3A4 enzyme inducer. Steady state serum concentrations of both pioglitazone and total pioglitazone (pioglitazone plus active metabolites) are achieved within 7 days. At steady state, two of the pharmacologically active metabolites of pioglitazone, MIII and MIV, reach serum concentrations equal to or greater than pioglitazone. At steady state, in both healthy volunteers and in patients with type 2 diabetes, pioglitazone comprises approximately 30-50% of the peak total pioglitazone concentrations and 20-25% of the total area under the serum concentration-time-curve (AUC). Cmax, AUC and trough serum concentrations (Cmin) for both pioglitazone and total pioglitazone increase proportionally at doses of 15 mg and 30 mg per day. There is a slightly less than proportional increase for pioglitazone and total pioglitazone at a dose of 60 mg/day. Pioglitazone is primarily excreted through the bile as unchanged drug or as metabolites and eliminated in the feces. About 15-30% of an oral pioglitazone dose is recovered in the urine (as metabolites and its conjugates); its renal elimination is negligible. Pioglitazone s plasma elimination half-life is up to 7 hours while its active metabolites have a half-life of up to 24 hours. 2 of 15

Renal Insufficiency: Compared with normal subjects, the serum elimination half-life of pioglitazone, M-III and M-IV remains unchanged in patients with moderate (creatinine clearance 30-60 ml/min) to severe (creatinine clearance <30 ml/min) renal impairment. Hepatic Insufficiency: Compared with normal subjects, patients with hepatic dysfunction (Child- Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak plasma concentrations and no change in the mean AUC values. Pioglitazone + metformin FDC should not be given in patients with active liver disease or serum transaminase levels (ALT) levels of more than 2.5 times the upper limit of normal. Elderly: Peak serum concentrations of pioglitazone and total pioglitazone are not significantly different in healthy elderly subjects. However, the AUC values in these patients are slightly higher and the terminal half-life values slightly longer than for younger subjects. These changes are considered to be clinically irrelevant. Metformin HCl Metformin is slowly and incompletely absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability of metformin tablet under fasting conditions is approximately 50% to 60% with metformin doses of 500 mg to 1,500 mg. Single doses of metformin 500 mg to 1,500 mg show lack of dose proportionality with increasing doses which is due to decreased absorption rather than altered elimination. Metformin HCl in a sustained-release (SR) formulation is intended for once a day dosing. Once a day dosing is possible through control of metformin release rate prolonging absorption in the upper gastrointestinal tract. Metformin distributes rapidly to peripheral body tissues and fluids. It also appears to distribute slowly into erythrocytes and into a deep tissue compartment. Metformin is negligibly bound to plasma proteins. Steady-state plasma concentration of metformin is generally < 1 mcg/ml and is reached within 24-48 hours at usual clinical doses and dosing schedules. Metformin is not metabolized in the liver or GI tract. Renal elimination of metformin is via glomerular filtration and secretion by the proximal convoluted tubules as unchanged drug. About 90% of the total dose is cleared within 24 hours in patients with normal renal function. Patients with Type 2 Diabetes: There are no differences between single- or multiple-dose pharmacokinetics of metformin between normal subjects and patients with type 2 diabetes nor is there any accumulation of metformin in either group at usual clinical doses in the presence of normal renal function. Renal Insufficiency: The plasma and blood half-life of metformin is prolonged and the renal clearance decreased in proportion to the decrease in creatinine clearance in patients with decreased renal function (based on measured creatinine levels). Elderly: The limited pharmacokinetic data of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, half-life is prolonged, and Cmax is increased, compared to healthy young subjects. It appears that the change in metformin pharmacokinetics with aging is primarily related to a change in renal function. Children: After oral administration of a single metformin 500 mg tablet with food, Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years old) compared with healthy adults (20 45 years old), all with normal renal function. 3 of 15

INDICATIONS An adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus who: Have inadequate glycemic control with metformin or pioglitazone monotherapy; or Are switching to combination therapy from pioglitazone plus metformin as separate tablets. To maintain the efficacy of drug therapy, management of type 2 diabetes mellitus should also include nutritional counseling, exercise and weight reduction if obese or overweight. Secondary causes of poor glycemic control (e.g., infection) should be investigated and treated prior to initiation or escalation of oral antidiabetic therapy. DOSAGE AND ADMINISTRATION General Recommendations The dose of pioglitazone + metformin FDC will vary, depending on a number of factors such as: patient s glycemic control, underlying medical conditions and other medications currently being taken. The dose of pioglitazone + metformin FDC should be individualized based on effectiveness and tolerability but not exceeding the maximum recommended daily dose of pioglitazone (45 mg) and metformin SR (2000 mg). Selecting the dose of pioglitazone + metformin FDC should be based on the patient s current regimen of pioglitazone and/or metformin to be able to select the course of therapy. Dose titration with pioglitazone added to optimal dose of metformin should be considered before switching the patient to the FDC. When clinically appropriate, direct change from metformin monotherapy to pioglitazone + metformin FDC may be considered. Patients should be carefully monitored for adverse events related to fluid retention after initiation of the FDC or with dose increase. It is recommended to assess response to therapy by using glycosylated hemoglobin (HbA1c), a better indicator of long-term glycemic control which reflects glycemia over the past two to three months. The sustained-release (SR) tablet should be swallowed whole. Do not chew or crush or divide the SR tablet. Pioglitazone + Metformin SR FDC should be given with meals to reduce the gastrointestinal side effects associated with metformin. Usual starting dose: Pioglitazone 15 mg + Metformin 500 mg SR FDC tablet either once or twice a day. If glycemic control with the usual starting doses of pioglitazone 15 mg + metformin 500 mg SR FDC tablet remains unsatisfactory, a dose of pioglitazone 30 mg + metformin 500 mg SR FDC tablet may be considered, but should not exceed the maximum daily recommended adult oral dose for each component. Special Patient Populations Elderly The initial and maintenance dose of pioglitazone + metformin SR FDC should be conservative in elderly patients, due to the potential for decreased renal function in this population. Any dosage adjustment should be based on a careful assessment of renal function. Generally, elderly patients should not be titrated to the maximum dose of pioglitazone and metformin. Monitoring of renal function is necessary to aid in the prevention of metformin-associated lactic acidosis, particularly in the elderly. Patients with Renal Impairment Pioglitazone + Metformin FDC tablet should not be used in patients with renal failure or renal dysfunction (creatinine clearance <60 ml/min). 4 of 15

Patients with Hepatic Impairment Pioglitazone + Metformin FDC tablet should not be used in patients with hepatic impairment or active liver disease. CONTRAINDICATIONS Known hypersensitivity to pioglitazone and/or metformin or to any ingredient of the product. Patients with established New York Heart Association (NYHA) Class III or IV heart failure. Patients with a history of lactic acidosis irrespective of precipitating factors Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin. Renal disease or renal dysfunction Serum creatinine levels 1.5 mg/dl (males), Serum creatinine levels 1.4 mg/dl (females) Abnormal creatinine clearance (< 60 ml/ minute) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia. Acute or chronic disease which may cause tissue hypoxia such as: History of or existing cardiac and/or respiratory failure; Recent myocardial infarction; Shock Acute conditions with the potential to alter renal function such as: Dehydration due to persistent or severe diarrhea, recurrent vomiting; Severe infection Diagnostic examinations (e.g., intravenous urography, angiography) that would involve the use of iodinated contrast agents/media Hepatic impairment/presence of severe liver disease In chronic alcoholism with hepatic damage Pregnancy or breastfeeding WARNINGS AND PRECAUTIONS CONGESTIVE HEART FAILURE AND LACTIC ACIDOSIS Congestive Heart Failure Thiazolidinediones, including pioglitazone, which is a component of the FDC may cause or exacerbate congestive heart failure in some patients (see WARNINGS AND PRECAUTIONS). After initiation of pioglitazone + metformin FDC and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to the current standards of care. Furthermore, discontinuation or dose reduction of pioglitazone + metformin FDC must be considered. The product is not recommended in patients with symptomatic heart failure. Initiation of pioglitazone + metformin FDC in patients with established NYHA Class III or IV heart failure is contraindicated (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS). Lactic Acidosis Lactic acidosis is a rare but serious complication that can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufficiency, renal impairment, and acute congestive heart failure. The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, 5 of 15

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, pioglitazone + metformin FDC should be discontinued and the patient hospitalized immediately (see WARNINGS AND PRECAUTIONS). Fluid Retention and Congestive Heart Failure (see BOXED WARNING and CONTRAINDICATIONS) Like other TZDs, pioglitazone can cause fluid retention when used alone or in combination with other antidiabetic medicines and is most common when pioglitazone is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Pioglitazone + Metformin FDC should be used with caution in patients with existing edema or heart failure. The incidence of heart failure increases in patients with a history of cardiac disease such as coronary artery disease, previous coronary artery bypass graft procedures and myocardial infarction. Weight gain, usually dose-dependent and probably due to a combination of fluid retention and fat accumulation, has been reported. Patients who experience weight gain should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure. Initiate pioglitazone + metformin FDC therapy at the lowest approved dose when treating patients who have at least one risk factor for development of congestive heart failure. Monitor patients for signs and symptoms of heart failure and fluid retention. In particular, patients who are at risk for heart failure including those receiving concurrent therapy which increases insulin levels (i.e., insulin, sulfonylureas) should be closely monitored (see UNDESIRABLE EFFECTS). Lactic Acidosis (see BOXED WARNING) Lactic acidosis is a rare, but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can be reduced by also assessing other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency, and any condition associated with hypoxia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/l), reduced blood ph, electrolyte disturbance with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 µg/ml are generally found. Lactic acidosis is usually accompanied by nonspecific symptoms such as acidotic dyspnea, vomiting, abdominal pain with muscle cramps, and/or a general feeling of malaise with severe fatigue. Hypothermia followed by coma, hypotension, and resistant bradyarrhythmias may be seen with marked acidosis. Instruct patients to immediately alert their physicians if these symptoms occur. Serum electrolytes, ketones, blood glucose, and if indicated, blood ph, lactate levels, and even blood metformin levels may be useful. Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking pioglitazone + metformin FDC, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin HCl is dialyzable, prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery. 6 of 15

Do not use pioglitazone + metformin FDC in patients with congestive heart failure receiving drugs such as digoxin and furosemide because of the risk of hypoperfusion and hypoxemia which may lead to lactic acidosis. Urinary Bladder Tumors Do not use pioglitazone in patients with active bladder cancer Use pioglitazone with caution in patients with prior history of bladder cancer. The benefits of blood sugar control with pioglitazone should be weighed against the unknown risk for cancer recurrence. Results from a 5-year interim analysis of a 10-year observational cohort study showed a small increased risk of bladder cancer in diabetic patients treated with pioglitazone, in particular those who were treated for the longest durations and with the highest cumulative doses. The study suggest that the use of pioglitazone for more than one year increased the relative risk of developing bladder cancer in any given year by 40% (absolute risk of 3 cases in 10, 000). Although there is insufficient evidence to determine whether pioglitazone promotes the development of urinary bladder tumors, pioglitazone + metformin FDC should not be used in patients with active bladder cancer. In patients with a history of bladder cancer, the benefits of glycemic control versus unknown risks for cancer recurrence with pioglitazone should be considered. Counsel patients to report any signs or symptoms of blood in the urine, urinary urgency, pain on urination, back or abdominal pain, as these may be due to bladder cancer. Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with pioglitazone, metformin or any other antidiabetic medicine. Pioglitazone + metformin FDC should not be prescribed to lower the risk of cardiovascular diseases (i.e., myocardial infarction and stroke) or to lower cardiovascular mortality. Hypoglycemia Hypoglycemia does not occur in patients receiving metformin alone but patients receiving pioglitazone in dual therapy with insulin or other hypoglycemic agents may be at risk for dose related hypoglycemia; a reduction in the dose of the concomitant antidiabetic agent may be necessary. Under usual circumstances of use, hypoglycemia could also occur when caloric intake is deficient and when strenuous exercise is not compensated by caloric supplementation. Elderly, debilitated or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemia. It may be difficult to recognize hypoglycemic states in the elderly, and in people who are taking beta-adrenergic blocking drugs. Hepatic Effects Therapy with pioglitazone + metformin FDC should not be initiated in patients with increased baseline liver enzyme levels, i.e., ALT > 2.5 times the upper limit of normal (ULN), or active liver disease. There have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking pioglitazone. These reports, however, contain insufficient information necessary to establish the probable cause. Patients with type 2 diabetes may have fatty liver disease or cardiac disease with episodic congestive heart failure (both of which may cause liver test abnormalities). These patients may also have other forms of liver disease many of which can be treated or managed. It is therefore recommended that prior to therapy with pioglitazone + metformin FDC, a liver function test panel [i.e., aspartate aminotransferase (AST), alanine aminotransfease (ALT), alkaline phosphatase, and total bilirubin] be obtained and patient be assessed for liver disease. Pioglitazone + Metformin FDC should be initiated with caution in patients with abnormal liver tests. 7 of 15

Measure liver tests promptly if manifestations suggestive of liver injury (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine or jaundice) develop in patients receiving pioglitazone + metformin FDC. Discontinue therapy if ALT increases to >3 times the ULN during therapy and remains elevated, or if jaundice develops. Patients should be investigated and should not be restarted without establishing the probable cause of the liver injury. Do not restart pioglitazone + metformin FDC in patients with serum ALT elevations >3 times the ULN and serum total bilirubin >2 times the reference range without alternative etiologies since they are at risk for severe drug-induced liver injury. Initiation of, or continuation of therapy with pioglitazone + metformin FDC in patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, should proceed with caution. Pioglitazone HCl Ovulation Pioglitazone, like other TZDs, may cause ovulation in anovulatory premenopausal women with insulin resistance. These women have an increased possibility of pregnancy unless contraceptive methods are initiated. Hematologic Pioglitazone may cause dose-related decreases in hemoglobin and hematocrit which usually become evident within the first three months of starting treatment. These hematologic effects may be related to plasma volume expansion. Increased Risk of Fracture in Women In clinical trials, there were more reports of fractures in female patients taking TZDs, including pioglitazone, than those taking a comparator (either placebo or active). The incidence of bone fracture in females was 5.1% for pioglitazone versus 2.5% for placebo. The difference was noted after the first year of treatment and remained during the course of the study. Majority of fractures observed in female patients were nonvertebral fractures including fractures in the distal upper limb (forearm, hand and wrist) or distal lower limb (foot, ankle, fibula, and tibia). Consider the risk of fracture in the care of patients, especially female patients, being treated with pioglitazone + metformin FDC or when starting pioglitazone + metformin FDC treatment; attention should be given to assessing and monitoring bone health according to current standards of care. Macular Edema Macular edema, some with blurred vision or decreased visual acuity, has been reported in patients receiving pioglitazone or other TZDs. Most patients reported concurrent peripheral edema. In some patients, macular edema improved after discontinuation of TZD treatment. Although it is not known whether there is causal relationship between pioglitazone and macular edema, regular eye examination by an ophthalmologist is recommended for all diabetic patients. Promptly report and refer any visual symptom to an ophthalmologist. Type 1 Diabetes Mellitus or Diabetic Ketoacidosis Pioglitazone is active only in the presence of endogenous insulin and should therefore not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. 8 of 15

Metformin HCl Monitoring of Renal Function Impaired renal function would increase the risk of metformin accumulation and lactic acidosis. Patients with serum creatinine levels higher than the normal range should not initiate therapy with pioglitazone + metformin FDC. Renal function should be assessed and verified as normal before initiation of pioglitazone + metformin FDC therapy especially in elderly patients because aging is associated with reduced renal function. Medications which may affect renal function or result in significant hemodynamic change or interfere with the disposition of metformin (i.e., cationic drugs) should be used with caution since these drugs are eliminated by renal tubular secretion. Radiologic Studies Parenteral iodinated contrast media may alter renal function and increase the risk of lactic acidosis in patients receiving metformin. Temporarily discontinue pioglitazone + metformin FDC prior to or at the time of any procedure requiring parenteral iodine contrast media. Do not reinstitute pioglitazone + metformin FDC until 48 hours after such procedures and until renal function has been reevaluated and found to be normal. Hypoxic States Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. Promptly discontinue the drug when such events occur in patients on pioglitazone + metformin FDC therapy. Surgical Procedures Temporarily discontinue use of pioglitazone + metformin FDC in patients undergoing surgery associated with restricted food or fluid intake. Therapy may be reinstituted when the patient s oral intake has resumed and renal function has been found normal. Impaired Hepatic Function Pioglitazone + Metformin FDC should generally be avoided in patients with clinical or laboratory evidence of hepatic disease since impaired hepatic function has been associated with lactic acidosis. Alcohol Combined use of alcohol and metformin may increase the risk of hypoglycemia and lactic acidosis since alcohol decreases lactate clearance and hepatic gluconeogenesis and may increase insulin secretion. Excessive alcohol intake on an acute or chronic basis should be avoided in patients receiving pioglitazone + metformin FDC. Vitamin B 12 Levels Evaluate hematologic parameters prior to initiation of pioglitazone + metformin FDC therapy and at least annually since decreases in serum vitamin B 12 have been associated with metformin use. Maintaining Adequate Glycemic Control during Periods of Stress Temporary discontinuation of pioglitazone + metformin FDC and administration of insulin may be necessary in periods of stress such as fever, trauma, infection, or surgery to maintain adequate glucose control. Pioglitazone + Metformin FDC may be reinstituted after the acute episode is resolved. 9 of 15

INTERACTION WITH OTHER MEDICAMENTS Although pharmacokinetic interaction studies have been conducted with the individual components of pioglitazone and metformin, no studies have been conducted with the FDC. β-adrenergic Blocking Agents: β-adrenergic blocking agents may impair glucose tolerance and mask the true frequency or severity of hypoglycemia, block hypoglycemia-induced tachycardia but not hypoglycemic sweating, delay the rate of recovery of blood glucose concentration following drug-induced hypoglycemia, and impair peripheral circulation. Use these drugs with caution in patients with type 2 diabetes. Pioglitazone HCl Oral Contraceptives: Co-administration of pioglitazone (45 mg once daily) and an oral contraceptive (1 mg norethindrone plus 0.035 mg ethinyl estradiol once daily) resulted in 11% and 11-14% decrease in ethinyl estradiol AUC and Cmax, respectively. Clinical significance of a high variability on ethinyl estradiol pharmacokinetics is unknown. Insulin or insulin secretagogues: The dose of insulin and insulin secretagogues (e.g., sulfonylurea) should be reduced since concomitant administration may result in hypoglycemia. Midazolam: Administration of pioglitazone for 15 days followed by a 7.5 mg single dose of midazolam syrup resulted in a 26% reduction in midazolam Cmax and AUC. Strong CYP2C8 Inhibitors: Gemfibrozil (an inhibitor of CYP450 2C8) resulted in a 3- fold increase in the plasma concentration of parent pioglitazone and also inhibited the further metabolism of M-III and M-IV. Careful blood glucose monitoring and dosage adjustments are suggested during co-administration of pioglitazone and gemfibrozil. If used in combination with gemfibrozil or other strong CYP2C8 inhibitors, a maximum dose of 15 mg pioglitazone should not be exceeded. CYP2C8 Inducers: Co-administration of pioglitazone with rifampicin (an inducer of CYP450 2C8) resulted in a 54% reduction in pioglitazone s AUC. The dose of pioglitazone may need to be increased when rifampicin is co-administered and glycemic control closely monitored. If an inducer of CYP2C8 is started or stopped during treatment with pioglitazone, the maximum recommended dose of 45 mg should not be exceeded and changes in diabetes treatment may be needed based on the patient s clinical response. Drugs Metabolized via Cytochrome P450: The cytochrome P450 isoform, CYP3A4, is partially responsible for the metabolism of pioglitazone. There is potential pharmacokinetic interaction (reduction in peak plasma concentration and AUC) with CYP3A4 substrates (e.g., atorvastatin, nifedipine); the clinical significance of this finding is unknown. Peak plasma concentration and area under the concentration-time curve (AUC) of pioglitazone may increase when taken concomitantly with CYP3A4 inhibitors such as ketoconazole. However, pharmacokinetic interaction is unlikely with ranitidine which is a relatively weak CYP3A4 inhibitor. In vitro studies have shown no inhibition of any subtype of cytochrome P450. Interactions with substances metabolized by these enzymes are unlikely: Ciclosporin and HMGCoA reductase inhibitors. 10 of 15

Coadministration of pioglitazone with the following drugs did not show pharmacokinetic interactions: Metformin, glipizide, digoxin, phenprocoumon, fexofenadine, CYP2C9 substrates (e.g., warfarin), CYP1A2 substrates (e.g., theophylline) Metformin HCl Cationic Drugs: Cationic drugs such as amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin that are eliminated by renal tubular secretion, theoretically may cause an increase in metformin peak plasma concentrations, whole blood concentrations and whole blood AUC by competing with metformin for common renal tubular transport systems. Concomitant administration of metformin and cimetidine has been observed to result in reduced urinary metformin excretion and increased plasma metformin concentrations. Hypoglycemic Agents: Hypoglycemia may occur when metformin is used concomitantly with other hypoglycemic agents such as sulfonylureas or insulin. Diuretics: Thiazide diuretics may exacerbate diabetes mellitus and may result in increased requirements of oral antidiabetic agents, metformin included. Temporary loss of diabetic control, or secondary failure to the antidiabetic agent may also occur. Potassium-sparing diuretics, which are less diabetogenic, may be considered as substitute. Furosemide may increase metformin plasma and blood concentrations and blood AUC without significantly affecting metformin renal clearance. Nifedipine: Concomitant administration of metformin and nifedipine may result in increased plasma metformin concentration due to enhanced absorption. Nifedipine may also increase urinary metformin excretion. Metformin had minimal effects on nifedipine. Protein-Bound Drugs: Interaction of metformin and highly protein-bound drugs (e.g., salicylates, sulfonamides, chloramphenicol, probenecid) is unlikely because metformin is negligibly bound to plasma proteins. Angiotensin-Converting Enzyme (ACE) Inhibitors: ACE inhibitors such as captopril and enalapril may reduce fasting blood glucose concentrations. These drugs have also been associated with unexplained hypoglycemia in diabetic patients. Caution should be exercised when administering metformin together with ACE inhibitors to prevent severe hypoglycemia. Clomiphene: Ovulatory response may be increased when clomiphene and metformin are used concomitantly in premenopausal patients with polycystic ovary syndrome. Coumarin Anticoagulants: Concomitant intake with metformin may affect the pharmacokinetic properties of coumarin anticoagulants. An increase in prothrombin time may occur upon cessation of metformin therapy, with an increased risk of hemorrhage. Patients receiving phenprocumon or other vitamin K anticoagulants should be carefully monitored. Others: Drugs that may cause and exacerbate hyperglycemia or loss of glycemic control in patients with type 2 diabetes mellitus include corticosteroids, estrogen plus progestogen, oral contraceptives, phenytoin, thyroid products, sympathomimetics, phenothiazines, nicotinic acid, calcium-channel blocking agents, and isoniazid. When such drugs are added to or withdrawn from therapy in patients receiving oral antidiabetic 11 of 15

agents including metformin, patients should be observed closely for evidence of altered glycemic control. The pharmacokinetics of metformin and propranolol, metformin and ibuprofen were not affected when co-administered in single dose. STATEMENT ON USAGE FOR HIGH RISK GROUPS Pregnancy: Pregnancy Category C Pioglitazone + Metformin FDC tablet should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. Maintaining blood glucose levels as close to normal as possible is necessary during pregnancy since abnormal blood glucose levels are associated with a higher incidence of congenital abnormalities, as well as increased neonatal morbidity and mortality. Insulin is recommended during pregnancy. If a patient wishes to become pregnant or if a pregnancy occurs, treatment with Pioglitazone + Metformin FDC should be discontinued (see WARNINGS AND PRECAUTIONS). Lactation No studies have been conducted with combined pioglitazone and metformin. In studies performed on the individual components, both pioglitazone and metformin are secreted in the milk of lactating rats. It is not known whether pioglitazone and/or metformin is secreted in human milk or if breastfeeding will lead to exposure of the infant to the medicinal product. Pioglitazone + Metformin FDC must therefore not be used in women who are breastfeeding. Infants and Children The safety and efficacy of pioglitazone in children have not been established. Use in patients <18 years old is not recommended. The use of metformin hydrochloride immediate-release tablet has been established in pediatric patients 10 to 16 years old with type 2 diabetes. Studies have not been conducted with metformin SR tablets in these patients. Geriatric Use (> 65 years old) There are no significant differences in the pharmacokinetics, efficacy and safety of pioglitazone between geriatric and younger patients. Metformin is known to be substantially excreted in the kidney. The risk of serious adverse reactions to metformin is greater in patients with reduced/impaired renal function especially in the elderly. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, dose in elderly patients should not be titrated to the maximum dose. ADVERSE EFFECTS / UNDESIRABLE EFFECTS The following adverse reactions were reported with combined use of pioglitazone + metformin. Respiratory: Respiratory tract infection and sinusitis GIT: Diarrhea, nausea, increased weight Urogenital: Urinary tract infection CNS: Headache, dizziness 12 of 15

Others: Peripheral edema, edema of the lower limb and anemia Pioglitazone HCl Respiratory Effects: Upper respiratory tract infection, dyspnea, sinusitis, bronchitis, pulmonary edema, and pharyngitis Endocrine Effects: Aggravated diabetes mellitus, erectile dysfunction Dose-related mild to moderate hypoglycemia has been reported when pioglitazone was used in combination with either a sulfonylurea or insulin. Cardiovascular Effects: Congestive heart failure and edema/peripheral edema have been reported especially when pioglitazone is used in combination with insulin. Heart failure, chest pain, abnormal ECG, hypertension, ischemia, angina pectoris, myocardial infarction, myocardial ischemia, and transient ischemic attacks; heart rate and rhythm disorders CNS Effects: Headache, hypoesthesia, vertigo, dizziness, and insomnia Musculoskeletal Effects: Arthralgia, myalgia, back pain, and cramps (legs); increased risk of fractures in female patients taking pioglitazone (See Warnings and Precautions) Hepatic Effects: Fatal and non-fatal hepatic failure and hepatitis have been reported. During all clinical trials in the U.S., 11 of 2561 (0.43%) patients treated with pioglitazone had ALT values > 3 ULN. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with pioglitazone, mean values for bilirubin, AST, ALT, alkaline phosphatase, and Gamma-glutamyl transferase (GGT) were decreased at the final visit compared with baseline. Sporadic, transient elevations in creatine phosphokinase (CPK) levels have also occurred. Hematologic Effects: Anemia has been reported in patients taking pioglitazone in combination with sulfonylureas, metformin or insulin. Dose-related decreases in hemoglobin and hematocrit have been associated with pioglitazone use. Renal Effects: Urinary tract infection, hematuria, glycosuria, and proteinuria Gastrointestinal Effects: Flatulence, increased appetite and diarrhea Eye Disorders: New onset or worsening diabetic macular edema with decreased visual acuity has been reported. Tumors: Urinary bladder tumors (rare) Others: Tooth disorder, accidental injury, fatigue, sweating, pain in extremity, weight gain, increased lactic dehydrogenase levels. Metformin HCl Metformin may provoke or augment lactic acidosis particularly if it is present in high concentrations in the blood. Some of the symptoms of lactic acidosis may mimic certain adverse effects of metformin. Physicians should instruct their patients to recognize the onset of symptoms of lactic acidosis to avoid this adverse reaction. 13 of 15

Gastrointestinal: Adverse effects with metformin are principally gastrointestinal and appear to be dose-related and include diarrhea, loose stools, nausea, vomiting, abdominal discomfort (e.g., abdominal cramps or pain), abnormal stools, constipation, abdominal distention, dyspepsia, epigastric discomfort, flatulence, gastroenteritis (viral), taste disturbance specifically metallic taste in the mouth, toothache, tooth abscess. Most of these reactions are transient and can be controlled by taking metformin with meals, or by a temporary reduction in dosage. Body as a Whole: Chills, flu syndrome, fatigue, lethargy, asthenia, accidental injury, headache, infection Cardiovascular: Chest discomfort/chest pain, hypertension, palpitations Hematologic: Vitamin B 12 and folate malabsorption, thrombocytopenia, neutropenia, and rare reports of megaloblastic anemia Hepatic: Severe acute hepatitis associated with liver function tests abnormalities and cholestasis have been associated with long-term metformin therapy resolving upon discontinuation of metformin. Endocrine Effects: Hypoglycemia may occur when metformin is given concomitantly with sulfonylureas and/or alcohol; hyperglycemia (NOS) and sexual dysfunction Musculoskeletal: Asthenia, muscle cramp, muscle strain, myalgia, pain in limb Nervous System: Agitation, dizziness, migraine, paresthesia, syncope, sinus headache, hypoesthesia, lightheadedness, tremor Respiratory: Dyspnea, flu syndrome, nasal congestion, sinus congestion, rhinorrhea, rhinitis, tonsillitis, upper respiratory infection Skin and Appendages: contusion Rash, erythema, pruritus, urticaria, increased sweating, Others: Pneumonitis with vasculitis, edema (aggravated), peripheral edema, ear pain, blurred vision, fungal infection, flushing, nail disorder, and seasonal allergy The profile of adverse reactions in pediatric patients is similar to those observed in adults. Laboratory Findings: Decreased blood glucose, abnormal liver function test and increased white blood cell count OVERDOSAGE AND MANAGEMENT Overdose with pioglitazone + metformin would depend on a number of factors, including the amount of the medicine ingested and co-administration with other medicines and/or, alcohol. Pioglitazone HCl There is limited data on pioglitazone overdosage in humans. Pioglitazone doses of up to 180 mg per day for seven days have been taken without any clinical symptom. Hypoglycemia may occur in combination with sulfonylureas or insulin. Initiate appropriate supportive treatment dictated by the patient s clinical signs and symptoms if overdose occurs. 14 of 15

Metformin HCl There were no cases of overdose reported in clinical studies. Symptoms of metformin overdose include extensions of the common undesirable effects (e.g., epigastric discomfort, nausea, vomiting, diarrhea, drowsiness, weakness, dizziness, malaise, and headache). Should these symptoms occur, lactic acidosis should be excluded. Metformin therapy should be discontinued and proper supportive therapy should be instituted. Lactic acidosis has been reported in approximately 32% of metformin overdose cases. Metformin is dialyzable with a clearance of up to 170 ml/min under good hemodynamic conditions. Therefore, hemodialysis maybe useful for removal of accumulated drug from patients in whom metformin overdosage is suspected. STORE AT TEMPERATURES NOT EXCEEDING 30 C KEEP OUT OF SIGHT AND REACH OF CHILDREN CAUTION Foods, Drugs, Devices and Cosmetics Act prohibits dispensing without prescription. 15 of 15