Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism Of Action Metformin is a biguanide that improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in patients with type 2 diabetes or in healthy subjects except in special circumstances, (see WARNINGS AND PRECAUTIONS) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and daylong plasma insulin response may actually decrease. Pharmacokinetics Absorption Following a single oral dose of 1000 mg (2x500 mg tablets) GLUMETZA after a meal, the time to reach maximum plasma metformin concentration (Tmax) is achieved at approximately 7-8 hours. In both single and multiple-dose studies in healthy subjects, once daily 1000 mg (2x500 mg tablets) dosing provides equivalent systemic exposure, as measured by area-under-the-curve (AUC), and up to 35% higher Cmax, of metformin relative to the immediate release given as 500 mg twice daily. GLUMETZA tablets must be administered immediately after a meal to maximize therapeutic benefit. Single oral doses of GLUMETZA from 500 mg to 2500 mg resulted in less than proportional increase in both AUC and Cmax. Low-fat and high-fat meals increased the systemic exposure (as measured by AUC) from GLUMETZA tablets by about 38% and 73%, respectively, relative to fasting. Both meals prolonged metformin Tmax by approximately 3 hours but Cmax was not affected. In a two-way, single-dose crossover study in healthy volunteers, the 1000 mg tablet was found to be bioequivalent to two 500 mg tablets under fed conditions based on equivalent Cmax and AUCs for the two formulations. Distribution The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg immediate-release metformin hydrochloride averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin, steady state plasma concentrations of metformin are reached within 24- 48 hours and are generally < 1 μg/mL. During controlled clinical trials, which served as the basis of approval for metformin, maximum metformin plasma levels did not exceed 5μg/mL, even at maximum doses. Metabolism Intravenous single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans), nor biliary excretion. Metabolism studies with extended-release metformin tablets have not been conducted. Excretion Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. Specific Populations Renal Impairment Following a single dose administration of GLUMETZA 500 mg in patients with mild and moderate renal failure (based on measured creatinine clearance), the oral and renal clearance of metformin were decreased by 33% and 50% and 16% and 53%, respectively (see WARNINGS AND PRECAUTIONS). Metformin peak and systemic exposure was 27% and 61% greater, respectively in mild renal impaired and 74% and 2.36-fold greater in moderate renal impaired patients as compared to healthy subjects. Use of metformin in patients with renal impairment increases the risk for lactic acidosis. GLUMETZA is contraindicated in patients with renal impairment. (See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS) Hepatic Impairment No pharmacokinetic studies of GLUMETZA have been conducted in subjects with hepatic impairment. Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. GLUMETZA is not recommended in patients with hepatic impairment. (See WARNINGS AND PRECAUTIONS) Geriatrics Limited data from controlled pharmacokinetic studies of metformin hydrochloride in healthy elderly subjects suggest that total plasma clearance of metformin is decreased by 35%, the half-life is prolonged by 64% and Cmax is increased by 76%, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function. Metformin treatment should not be initiated in patients of any age unless measurement of creatinine clearance demonstrates that renal function is normal. (See WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION) Gender In the pharmacokinetic studies in healthy volunteers, there were no important differences between male and female subjects with respect to metformin AUC and t½. However, Cmax for metformin was 40% higher in female subjects as compared to males. The gender differences for Cmax are unlikely to be clinically important. Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin hydrochloride tablets was comparable in males and females. Race There were no definitive conclusions on the differences between the races with respect to the pharmacokinetics of metformin because of the imbalance in the respective sizes of the racial groups. However, the data suggest a trend towards higher metformin Cmax and AUC values for metformin are obtained in Asian subjects when compared to Caucasian, Hispanic and Black subjects. The differences between the Asian and Caucasian groups are unlikely to be clinically important. In controlled clinical studies of metformin hydrochloride in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n = 249), blacks (n = 51) and Hispanics (n = 24). Pediatrics No pharmacokinetic data from studies of GLUMETZA in pediatric subjects are available. Drug Interactions Specific pharmacokinetic drug interaction studies with GLUMETZA have not been performed except for one with glyburide. However, such studies have been performed on metformin. Co- administered Drug Dose of Coadministered Drug1 Dose of .Metformin1 Geometric Mean Ratio (ratio with without coadministered drug) No effect = 1.00 AUC2 Cmax No dosing adjustments required for the following: Glybunde 5 mg 500 mg4 0.983 0.993 Furosemide 40 mg 850 mg 1.093 1.223 Nifedipine 10 mg 850 mg 1.16 1.21 Propranolol 40 mg 850 mg 0.90 0.94 Ibuprofen 400 mg 850 mg 1.053 1.073 Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination: use with caution. (See WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS) Cunetidme 400 mg 850 mg 1.40 1.61 C arbonic anhydrase inhibitors may cause metabolic acidosis: use with caution (See WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS) Topiramate 100 mg5 500 mg5 1.255 1.17 1 All metformin and coadministered drugs were given as single doses 2.AUC-AUC0-∞ 3. Ratio of anthmetic means 4. GLUMETZA (metformin hydrochloride extended-release tablets) 500 me 5. At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours: AUC “ AUC0-12h Table 3: Effect of Metformin on Coadministered Drug Systemic Exposure Coadminister ed Drug Dose of Coadministered Drug1 Dose of Metformin1 Geometric Mean Ratio (ratio trith without coadministered drug) No effect - 1.00 AUC2 Cmax No dosing adjustments required for the following Glybunde 5 mg 500 mg4 0.783 0.633 Furosemide 40 mg 850 mg 0.873 0.693 Nifedipine 10 mg 850 mg 1.104 1.08 Propranolol 40 mg 850 mg 1.014 0.94 Ibuprofen 400 mg 850 mg 0.975 1.015 Cimendine 400 mg 850 mg 0.954 1.01 1 All metformin and coadministered drug were given as single doses 2 AUC – AUC0-∞ 3 Ratio of anthmetic means, p-value of difference < 0 05 4 AUC0-24hr reported 5 Ratio of anthmetic means Clinical Studies GLUMETZA has been studied as monotherapy and in combination with a sulfonylurea and insulin. Other formulations of metformin have been studied with other classes of antihyperglycemic agents, either as immediate or as extended release tablets. Double-Blind, Randomized, Parallel Group Clinical Trial to Compare the Efficacy, Safety, and Tolerability of Metformin ER (M-ER) Tablets and Metformin Immediate Release (M-IR) Tablets in the Treatment of Type 2 Diabetes Mellitus In a multicenter, randomized, double-blind, activecontrolled, dose-ranging, parallel group trial GLUMETZA 1500 mg once daily, GLUMETZA 1500mg per day in divided doses (500 mg in the morning and 1000 mg in the evening), and GLUMETZA 2000 mg once daily were compared to immediate-release metformin 1500 mg per day in divided doses (500 mg in the morning and 1000 mg in the evening). This trial enrolled patients (n = 338) who were newly diagnosed with diabetes, patients treated only with diet and exercise, patients treated with a single antidiabetic medication (sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, or meglinitides ), and patients (n = 368) receiving metformin up to 1500 mg/day plus a sulfonylurea at a dose equal to or less than one-half the maximum dose. Patients who were enrolled on monotherapy or combination anti-diabetic therapy underwent a 6-week washout. Patients randomized to GLUMETZA began titration from 1000 mg/day up to their assigned treatment dose over 3 weeks. Patients randomized to immediate-release metformin initiated 500 mg twice daily for 1week followed by 500 mg with breakfast and 1000 mg with dinner for the second week. The 3-week treatment period was followed by an additional 21-week period at the randomized dose. For HbA1c and fasting plasma glucose, each of the GLUMETZA regimens was at least as effective as immediate-release metformin. Additionally, once daily dosing of GLUMETZA was as effective as twice daily dosing of the immediate release metformin formulation. Table 4: Mean±SE Changer from Barline to Final Visit in  HbA1c, Fasting Plasma Glucose and Body Weight for the GLUMETZA and Metformin Immediate-Release Treatment Groups (First 24-Week Study) Parameter GLUMETZA Metformin immediate- release 1500 mg in dhided doses (n=174) 1500 mg once daily (n= 178) 1500 mg in dhided doses (n =182) 2000 mg once daily (n = 172) HbA1c(%) N 169 175 159 170 Baseline 8.2 ± 03 8.5 ± 0.2 8.3 ± 0 2 8.7 ± 0.3 Mean Change ± SE at Final Visit -0.7 ±0.1 -0.7 ± 0.1 -1.1 ± 0.1 -0.7 ± 0.1 Mean Difference ± SE from Metformin IR 98 4% CI for Difference 0 ± 0.1 (-0.3,0.3) 0 ± 0.1 (-0 .3, 0.3) -0.4 ± 0.1 (-0.7, -0.1) N/A Fasting Plasma Glucose (mg dL) N 175 179 170 172 Baseline 190 ± 10 192.3 ± 10 184 ± 10 197 ± 11 Mean Change ± SE at Final Visit -39 ± 4 -32 ± 4 -42 ± 5 -32 ± 5 Mean Difference ± SE from Metformin IR 95% CI for Difference -6±4 (-15, 2) 0±4 (-8,9) -10 ± 4 (-19, -1) N/A Body Weight (kg) N 176 180 171 173 Baseline 88.2 ± 3.7 90.5 ± 3.7 87.7 ± 3 7 88.7 ± 3.9 Mean Change ± SE at Final Visit -0.9 ± 0.4 -0.7 ± 0.4 -1.1 ± 0.4 -0 9 ± 0 4 Mean Difference ± SE from Metformin IR 95% CI for Difference -0.1 ± 04 (-0.9,0.7) 0.2 ± 0.4 (-0.6, 0.9) -0.3 ± 0.4 (-1.0, 0.5) N/A A Double-Blind, Randomized, Parallel-Group Study to Compare the Safety, Efficacy, and Tolerability of Metformin Extended Release (M-ER) Tablets in Combination with a Sulfonylurea (SU) and SU Alone in the Management of Patients with Type 2 Diabetes Mellitus In a double-blind, randomized, placebo-controlled (glyburide add-on) multicenter trial, patients with type 2 diabetes mellitus who were newly diagnosed or treated with diet and exercise (n = 144), or who were receiving monotherapy with metformin, sulfonylureas, alphaglucosidase inhibitors, thiazolidinediones, or meglinitides, or treated with combination therapy consisting of metformin/glyburide at doses up to 1000 mg metformin + 10 mg glyburide per day (or equivalent doses of glipizide or glimepiride up to half the maximum therapeutic dose) (n = 431) were enrolled. All patients were stabilized on glyburide for a 6-week run-in period, and then randomized to 1 of 4 treatments: placebo + glyburide (glyburide alone); GLUMETZA 1500 mg once a day + glyburide, GLUMETZA 2000 mg once a day + glyburide, or GLUMETZA 1000 mg twice a day + glyburide. A 3-week GLUMETZA titration phase was followed by a 21-week maintenance treatment phase. Use of insulin and oral hypoglycemic agents other than the study drugs were prohibited. The difference in the change from Baseline in HbA1c levels between the combined GLUMETZA + glyburide groups and the glyburide only group was statistically significant at week 24 (p < 0.001). The changes in glycemic control across the three GLUMETZA + glyburide groups were comparable. Table 5: Mean±SE Changes from Baselie to Final Visit in HbA1c Fasting Plasma Glucose and Body Weight for the GLUMETZA/ Glyburide Groups and Placebo /Glyburide Treatment Group (Second 24-Week Study) Parameter GLUMETZA - Glyburide Placebo/ Ghbaridt* (n = 141) 1500 mg QD (n = 144) 1000 mg BID (n= 141) 2000 mg QD (n = 146) HbA(%) N 134 136 144 141 Baseline 7.9 ± 0.1 7.8 ± 0.1 7.7 ± 01 81 ± 0.1 Mean Change ± SE at Final Visit -0.7 ± 0.1 -0 8 ± 01 -0.7 ± 01 -0.1 ± 0.1 Mean Difference ± SE from Glyburide Alone -0.8 ± 0.1 -0.9 ± 0.1 -0.8 ± 0.1 N/A 95% CI for Difference (-1.0,-0.6) (-1.1, -0.7) (-1.0,- 0.6) p-value for pairwise comparison - 0 001 < 0.001 < 0.001 Fasting Pasma Glucose (mg/dL) N 143 141 145 144 Baseline 163 ± 5 163 ± 5 159 ± 5 164 ± 5 Mean Change± SE at Final Visit -14 ± 4 -16 ± 4 -9 ± 4 16 ± 4 Mean Difference± SE from Glyburide Alone -29.2 ± 4. 9 -31.2 ± 40.9 -24.9 ± 4.9 N/A 95% CI for Difference (-39,- 20) (41,-22) (-35,- 15) p-value for pairwise comparision < 0.001 < 0.001 < 0.001 Body Weight (kg) N 143 141 146 144 Baseline 89.4± 11.2 103.7± 11.2 102.9± 11.2 95.6± 8.0 Mean Change± SE at Final Visit 0.3 ± 1.1 0.1 ± 1.1 0 ± 1.1 0.7 ± 1.0 Mean Difference± SE from Glyburide Alone -0.4 ± 0.5 -0.6 ± 0.5 -0.7 ± 0.5 N/A 95% CI for Difference (-1.5, 0.6) (-1.7,0.4) (-1.8,0.3) p-value for pairwise comparision 0.410 0.230 0.154 * -Glyburide was administered as 10 mg at breakfast and 5mg at dinner. A 24-week, double-blind, placebo-controlled trial of immediate-release metformin plus insulin versus insulin plus placebo was conducted in patients with type 2 diabetes who failed to achieve adequate glycemic control on insulin alone. Patients randomized to receive metformin plus insulin achieved a mean reduction in HbA1c of 2.10%, compared to a 1.56% reduction in HbA1c achieved by insulin plus placebo. The improvement in glycemic control was achieved at the final study visit with 16% less insulin, 93.0 U/day vs. 110.6 U/day, metformin plus insulin versus insulin plus placebo, respectively, p=0.04. A second double-blind, placebo-controlled study (n=51), with 16 weeks of randomized treatment, demonstrated that in patients with type 2 diabetes controlled on insulin for 8 weeks with an average HbA1c of 7.46 ± 0.97%, the addition of metformin maintained similar glycemic control (HbA1c 7.15 ± 0.61 versus 6.97 ± 0.62 for metformin plus insulin and placebo plus insulin, respectively) with 19% less insulin versus baseline (reduction of 23.68 ± 30.22 versus an increase of 0.43 ± 25.20 units for metformin plus insulin and placebo plus insulin, p < 0.01). In addition, this study demonstrated that the combination of metformin plus insulin resulted in reduction in body weight of 3.11 ± 4.30 lbs, compared to an increase of 1.30 ± 6.08 lbs for placebo plus insulin, p=0.01.

Find Lowest Prices on GLUMETZA® (metformin hydrochloride) Extended-release Tablets WARNING 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 impairment, renal impairment, and acute congestive heart failure. The onset of lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate. If acidosis is suspected, GLUMETZA (metformin hydrochloride extended-release tablets), should be discontinued and the patient hospitalized immediately. (See WARNINGS AND PRECAUTIONS) DESCRIPTION GLUMETZA (metformin hydrochloride) extended-release tablet is an oral antihyperglycemic medication used in the management of type 2 diabetes. Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The structural formula of metformin hydrochloride (metformin HCl) is as shown: Metformin HCl is a white to off-white crystalline compound with a molecular formula of C4H11N5•HCl and a molecular weight of 165.63. 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 hydrochloride is 6.68. GLUMETZA tablets are modified release dosage forms that contain 500 mg or 1000 mg of metformin HCl. Each 500 mg tablet contains coloring, hypromellose, magnesium stearate, microcrystalline cellulose and polyethylene oxide. Each 1000 mg tablet contains colloidal silicon dioxide, polyvinyl alcohol, crospovidone, glyceryl behenate, polyacrylate dispersion, hypromellose, talc, polyethylene glycol, eudragit, titanium dioxide, simethicone emulsion, polysorbate and coloring. GLUMETZA 500 mg and 1000 mg tablets are formulated to gradually release metformin to the upper gastrointestinal (GI) tract.

INDICATIONS GLUMETZA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Important Limitations Of Use GLUMETZA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. DOSAGE AND ADMINISTRATION Recommended Dosing GLUMETZA should be taken once daily with the evening meal. The dosage of GLUMETZA must be individualized on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended daily dose of 2000 mg. The starting dose of GLUMETZA in patients who are not currently taking metformin is 500 mg once daily, with the evening meal. The dose can be uptitrated in 500 mg increments no sooner than every 1-2 weeks if a higher dose of GLUMETZA is needed and there are no gastrointestinal adverse reactions. If GLUMETZA is considered appropriate for a patient already receiving immediate-release metformin, the patient can be switched to GLUMETZA once daily at the same total daily dose, up to 2000 mg once daily. GLUMETZA tablets must be swallowed whole and never split, crushed or chewed. Occasionally, the inactive ingredients of GLUMETZA 500 mg may be eliminated in the feces as a soft, hydrated mass, while the 1000 mg may leave an insoluble shell that may resemble the original tablet. If a dose of GLUMETZA is missed, patients should be cautioned against taking two doses of 2000 mg the same day. Resume dosing as according to prescribing recommendations. (See PATIENT INFORMATION) Patients Treated With An Insulin Secretagogue Or Insulin Co-administration of GLUMETZA with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia HOW SUPPLIED Dosage Forms And Strengths GLUMETZA (metformin hydrochloride extended-release tablets) 500 mg are available as blue, film coated, ovalshaped tablets debossed with “GMZ” on one side and “500” on the other side. GLUMETZA (metformin hydrochloride extended-release tablets) 1000 mg are available as white, film coated, ovalshaped tablets with “M1000” on one side. Storage And Handling GLUMETZA tablets - 500 mg are available as blue, film coated, oval-shaped tablets debossed with “GMZ” on one side and “500” on the other side. GLUMETZA tablets 1000 mg are available as white, film coated, oval-shaped tablets with “M1000” on one side. They are supplied as follows: Package Strength NDC Bottles of 100 500 mg 68012-002-13 Bottles of 90 1000 mg 68012-003-16 Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F); see [USP Controlled Room Temperature]. Manufactured for Santarus, Inc., a wholly owned subsidiary of Salix Pharmaceuticals, Raleigh, NC 27615. Revised: Sep 2014

PATIENT INFORMATION GLUMETZA (Gloo-met-za) (metformin hydrochloride) Extended-release Tablets Read the patient information that comes with GLUMETZA before you start taking this medicine and each time you refill your prescription. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment. Ask your doctor or pharmacist if you do not understand some of this information or if you want to know more about this medicine. What is the most important information I should know about GLUMETZA? Serious side effects can happen in people taking GLUMETZA, including: Lactic Acidosis. Metformin hydrochloride, the medicine in GLUMETZA can cause a rare, but serious condition called lactic acidosis (a buildup of an acid in the blood) that can cause death. Lactic acidosis is a medical emergency and must be treated in the hospital. Stop taking GLUMETZA and call your doctor right away if you get any of the following symptoms of lactic acidosis: feel very weak or tired have unusual (not normal) muscle pain have trouble breathing have unusual sleepiness or sleep longer than usual have unexplained stomach or intestinal problems with nausea and vomiting, or diarrhea feel cold, especially in your arms and legs feel dizzy or lightheaded have a slow or irregular heartbeat You have a higher chance for getting lactic acidosis with GLUMETZA if you: have kidney problems. People whose kidneys are not working properly should not take GLUMETZA. have liver problems have congestive heart failure that requires treatments with medicines drink a lot of alcohol (very often or short-term “binge” drinking) get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough fluids. have certain x-ray tests with injectable dyes or contrast agent have surgery have a heart attack, severe infection, or stroke What is GLUMETZA? GLUMETZA is a prescription medicine that contains metformin hydrochloride used with diet and exercise to help control high blood sugar in adults with type 2 diabetes. GLUMETZA is not for people with type 1 diabetes. GLUMETZA is not for people with diabetic ketoacidosis (increased ketones in your blood or urine). It is not known if GLUMETZA is safe and effective in children younger than 18 years old. Who should not take GLUMETZA? Do not take GLUMETZA if you: have kidney problems are allergic to the metformin hydrochloride in GLUMETZA or any of the ingredients in GLUMETZA. See the end of this leaflet for a list of ingredients in GLUMETZA. you are going to get an injection of dye or contrast agents for an x-ray procedure, GLUMETZA will need to be stopped for a short time. Talk to your doctor about when you should stop GLUMETZA and when you should start GLUMETZA again. See “What is the most important information I should know about GLUMETZA?” have a condition called metabolic acidosis or diabetic ketoacidosis (increased ketones in your blood or urine). What should I tell my doctor before taking GLUMETZA? Before you take GLUMETZA, tell your doctor if you: have type 1 diabetes. GLUMETZA should not be used to treat people with type 1 diabetes. have a history or risk for diabetic ketoacidosis (high levels of certain acids, known as ketones, in the blood or urine). GLUMETZA should not be used for the treatment of diabetic ketoacidosis. have kidney problems have liver problems have heart problems, including congestive heart failure. drink alcohol very often, or drink a lot of alcohol in short-term (binge) drinking are taking insulin have any other medical conditions are pregnant or planning to become pregnant. It is not known if GLUMETZA can harm your unborn baby. If you are pregnant, talk with your doctor about the best way to control your blood sugar while you are pregnant. are breastfeeding or plan to breastfeed. It is not known if GLUMETZA passes into your breast milk. Talk with your doctor about the best way to feed your baby while you take GLUMETZA. Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins and herbal supplements. Know the medicines you take. Keep a list of them to show your doctor and pharmacist. Talk to your doctor before you start any new medicine. GLUMETZA may affect the way other medicines work, and other medicines may affect how GLUMETZA works. How should I take GLUMETZA? Take GLUMETZA exactly as your doctor tells you. GLUMETZA should be taken 1 time per day with your evening meal. Swallow GLUMETZA tablets whole. Do not crush, cut, dissolve, or chew GLUMETZA. Tell your doctor if you cannot swallow tablets whole. Your doctor may prescribe a different medicine for you. You may sometimes pass a soft mass in your stools (bowel movement) that looks like GLUMETZA tablets. It is normal to see this in your stool. When your body is under some type of stress, such as fever, trauma (such as a car accident), infection, or surgery, the amount of diabetes medicine that you need may change. Tell your doctor right away if you have any of these problems. Your doctor should do blood tests to check how well your kidneys and liver are working before and during your treatment with GLUMETZA. Your healthcare provider will check your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A1C. Follow your doctor's instructions for treating blood sugar that is too low (hypoglycemia). Talk to your doctor if low blood sugar is a problem for you. See “What are the possible side effects of GLUMETZA?” Check your blood sugar regularly and as your doctor tells you to. Stay on your prescribed diet and exercise program and test your blood sugar regularly while taking GLUMETZA. If you miss a dose of GLUMETZA, resume dosing according to schedule. If you take too much GLUMETZA, call your doctor, or go to the nearest hospital emergency room right away. What are the side effects of GLUMETZA? GLUMETZA can cause serious side effects, including: See “What is the most important information I should know about GLUMETZA?” Low blood sugar (hypoglycemia). If you take GLUMETZA with another medicine that can cause low blood sugar, such as sulfonylureas or insulin, you have a higher risk of having low blood sugar. Tell your doctor if you take other diabetes medicines. If you have symptoms of low blood sugar, you should check your blood sugar and treat if low, then call your doctor. Symptoms of low blood sugar include: Shaking Sweating rapid heartbeat change in vision hunger headache change in mood Common side effects of GLUMETZA include: hypoglycemia diarrhea nausea upset stomach or stomach pain Taking GLUMETZA with your evening meal can help lessen the common stomach side effects of metformin that usually happens at the beginning of treatment. If you have unexplained stomach problems, tell your doctor. Stomach problems that start later, during treatment may be a sign of something more serious. Tell your doctor if these symptoms return, as they may be symptoms of lactic acidosis. Tell your doctor if you have side effects that bother you or that do not go away. These are not all of the possible side effects of GLUMETZA. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store GLUMETZA? Store GLUMETZA at 59°F to 86°F (15°C to 30°C). Keep GLUMETZA and all medicines out of the reach of children. General information about the safe and effective use of GLUMETZA. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use GLUMETZA for a condition for which it was not prescribed. Do not give GLUMETZA to other people, even if they have the same symptoms you have. It may harm them. This Patient Information summarizes the most important information about GLUMETZA. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about GLUMETZA that is written for health professionals. For more information, go to www.GlumetzaXR.com or call 1-800-508-0024. What are the ingredients in GLUMETZA? Active Ingredient: metformin hydrochloride Inactive Ingredient: 500 mg tablet: coloring, hypromellose, magnesium stearate, microcrystalline cellulose and polyethylene oxide. 1000 mg tablet: colloidal silicon dioxide, polyvinyl alcohol, crospovidone, glyceryl behenate, polyacrylate dispersion, hypromellose, talc, polyethylene glycol, eudragit, titanium dioxide, simethicone emulsion, polysorbate and coloring. What is type 2 diabetes? Type 2 diabetes is a condition in which your body does not make enough insulin, and the insulin that your body produces does not work as well as it should. Your body can also make too much sugar. When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems. The main goal of treating diabetes is to lower your blood sugar to a normal level. High blood sugar can be lowered by diet and exercise, and by certain medicines when necessary. Talk to your doctor about how to prevent, recognize, and take care of low blood sugar (hypoglycemia), high blood sugar (hyperglycemia), and problems you have because of your diabetes.

SIDE EFFECTS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In clinical trials conducted in the U.S., over 1000 patients with type 2 diabetes mellitus have been treated with GLUMETZA 1500–2000 mg/day in active-controlled and placebo-controlled studies with the 500 mg dosage form. In the 24-week monotherapy trial comparing GLUMETZA to immediate-release metformin, serious adverse reactions were reported in 3.6% (19/528) of the GLUMETZA-treated patients compared to 2.9% (5/174) of the patients treated with immediate-release metformin. In the add-on to sulfonylurea study, patients receiving background glyburide therapy were randomized to receive add-on treatment of either one of three different regimens of GLUMETZA or placebo. In total, 431 patients received GLUMETZA and glyburide and 144 patients received placebo and glyburide. A serious adverse reaction was reported in 2.1% (9/431) of the GLUMETZA and glyburide-treated patients compared to 1.4% (2/144) of the placebo and glyburide-treated patients. When the data from the monotherapy and add-on to sulfonylurea clinical trials were combined, the most frequently (incidence ≥ 0.5 %) reported serious adverse reactions classified by system organ class were gastrointestinal disorders (1.0% of GLUMETZA-treated patients compared to 0% of patients not treated with GLUMETZA) and cardiac disorders (0.4% of GLUMETZA-treated patients compared to 0.5% of patients not treated with GLUMETZA). Only 2 serious adverse reactions (unstable angina [n=2] and pancreatitis [n=2]) were reported in more than one GLUMETZA-treated patient. Adverse reactions reported in greater than 5% of patients treated with GLUMETZA that were more common in the combined GLUMETZA and glyburide group than in the placebo and glyburide group are shown in Table 1. In 0.7% of patients treated with GLUMETZA and glyburide, diarrhea was responsible for discontinuation of study medication compared to no patients in the placebo and glyburide group. Table 1: Treatment-Emergent Adverse Reactions Reported By >5H* of Patients for the Combined GLUMETZA Groups Venus Placebo Group Adverse Reaction GLUMETZA + Ghburide (n =431) Placebo + Glyburide (n = 144) Hypoglycemia 13.7% 4.9% Dianhea 12.5% 5.6% Nausea 6.7% 4.2% * ARs that were more common in the GLUMETZA-treated than in the placebo- treated patients Laboratory Tests Vitamin B12 concentrations Metformin may lower serum vitamin B12 concentrations. Measurement of hematologic parameters on an annual basis is advised in patients on GLUMETZA and any apparent abnormalities should be appropriately investigated and managed. (See WARNINGS AND PRECAUTIONS) DRUG INTERACTIONS Carbonic Anhydrase Inhibitors Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently decrease serum bicarbonate and induce nonunion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs may induce metabolic acidosis. Use these drugs with caution in patients treated with metformin, as the risk of lactic acidosis may increase. Cationic Drugs Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of GLUMETZA and/or the interfering drug is recommendedin patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system. 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 GLUMETZA, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving GLUMETZA, the patient should be observed closely for hypoglycemia.

WARNINGS Lactic Acidosis Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with GLUMETZA (metformin hcl) ; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels ( > 5 mmol/L), decreased blood pH, electrolyte disturbances 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. The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking GLUMETZA (metformin hcl) and by use of the minimum effective dose of GLUMETZA (metformin hcl) . In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. GLUMETZA (metformin hcl) treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, GLUMETZA (metformin hcl) should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, GLUMETZA (metformin hcl) should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking GLUMETZA (metformin hcl) , since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, GLUMETZA (metformin hcl) should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see also PRECAUTIONS). The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. These may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's physician must be aware of the possible importance of such symptoms and the patient should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose and, if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of GLUMETZA (metformin hcl) , gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking GLUMETZA (metformin hcl) do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling. (See also PRECAUTIONS.) Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia). Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking GLUMETZA (metformin hcl) , the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery. (See also CONTRAINDICATIONS and PRECAUTIONS.) PRECAUTIONS General There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with GLUMETZA (metformin hcl) or any other oral anti-diabetic drug. Monitoring of renal function Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive GLUMETZA (metformin hcl) . In patients with advanced age, GLUMETZA (metformin hcl) should be carefully titrated to establish the minimum dose for adequate glycemic effect, because aging is associated with reduced renal function. In elderly patients, particularly those ≥ 80 years of age, renal function should be monitored regularly and GLUMETZA (metformin hcl) should generally not be titrated to the maximum dose (see WARNINGS and DOSAGE AND ADMINISTRATION). Before initiation of GLUMETZA (metformin hcl) therapy and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and GLUMETZA (metformin hcl) discontinued if evidence of renal impairment is present. Use of concomitant medications that may affect renal function or metformin disposition — Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion (see PRECAUTIONS: DRUG INTERACTIONS), should be used with caution. Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials) — Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see CONTRAINDICATIONS). Therefore, in patients in whom any such study is planned, GLUMETZA (metformin hcl) should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated 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. When such events occur in patients on GLUMETZA (metformin hcl) therapy, the drug should be promptly discontinued. Surgical procedures — GLUMETZA (metformin hcl) therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal. Alcohol intake — Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving GLUMETZA (metformin hcl) . Impaired hepatic function — Since impaired hepatic function has been associated with some cases of lactic acidosis GLUMETZA (metformin hcl) should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Vitamin B12 levels — In controlled, 29-week clinical trials of immediate release metformin, a decrease to subnormal levels of previously normal serum Vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of GLUMETZA (metformin hcl) or Vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on GLUMETZA (metformin hcl) and any apparent abnormalities should be appropriately investigated and managed (see PRECAUTIONS: Laboratory Tests). Certain individuals (those with inadequate Vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal Vitamin B12 levels. In these patients, routine serum Vitamin B12 measurements at two-to three-year intervals may be useful. Change in clinical status of patients with previously controlled type 2 diabetes — A patient with type 2 diabetes previously well controlled on GLUMETZA (metformin hcl) who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, GLUMETZA (metformin hcl) must be stopped immediately and other appropriate corrective measures initiated (see also WARNINGS). Hypoglycemia — Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs. Loss of control of blood glucose — When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold GLUMETZA (metformin hcl) and temporarily administer insulin. GLUMETZA (metformin hcl) may be reinstituted after the acute episode is resolved. The effectiveness of oral antidiabetic drugs in lowering blood glucose to a targeted level decreases in many patients over a period of time. This phenomenon, which may be due to progression of the underlying disease or to diminished responsiveness to the drug, is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective during initial therapy. Should secondary failure occur with either GLUMETZA (metformin hcl) or sulfonylurea monotherapy, combined therapy with GLUMETZA (metformin hcl) and sulfonylurea may result in a response. Should secondary failure occur with combined GLUMETZA (metformin hcl) /sulfonylurea therapy, it may be necessary to consider therapeutic alternatives including initiation of insulin therapy. Information for Patients Patients should be informed of the potential risks and benefits of GLUMETZA (metformin hcl) and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic parameters. The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in the GLUMETZA (metformin hcl) sections, should be explained to patients. Patients should be advised to discontinue GLUMETZA (metformin hcl) immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of GLUMETZA (metformin hcl) , gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving GLUMETZA. GLUMETZA (metformin hydrochloride extended-release tablets) alone does not usually cause hypoglycemia, although it may occur when GLUMETZA (metformin hcl) is used in conjunction with oral sulfonylureas and insulin. When initiating combination therapy, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. Patients should be informed that GLUMETZA (metformin hcl) must be swallowed whole and not crushed or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet. (See PATIENT INFORMATION.) Laboratory Tests Response to all diabetic therapies should be monitored by periodic measurements of fasting blood glucose and glycosylated hemoglobin levels, with a goal of decreasing these levels toward the normal range. During initial dose titration, fasting glucose can be used to determine the therapeutic response. Thereafter, both glucose and glycosylated hemoglobin should be monitored. Measurements of glycosylated hemoglobin may be especially useful for evaluating long-term control (see also DOSAGE AND ADMINISTRATION). Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metformin therapy, if this is suspected, Vitamin B12 deficiency should be excluded. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term carcinogenicity studies have been performed in Sprague Dawley rats at doses of 150, 300, and 450 mg/kg/day in males and 150, 450, 900, and 1200 mg/kg/day in females. These doses are approximately 2, 4, and 8 times in males, and 3, 7, 12, and 16 times in females of the maximum recommended human daily dose of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female rats. A carcinogenicity study was also performed in Tg.AC transgenic mice at doses up to 2000 mg applied dermally. No evidence of carcinogenicity was observed in male or female mice. Genotoxicity assessments in the Ames test, gene mutation test (mouse lymphoma cells), chromosomal aberrations test (human lyhpocytes) and in vivo mouse micronucleus tests were negative. Fertility of male or female rats was not affected by metformin when administered at dose up to 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose based on body surface area comparisons. Pregnancy Teratogenic Effects Pregnancy Category B. Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day, which represent 3 and 6 times the maximum recommended human daily dose of 2000 mg based on body surface area comparison for rats and rabbits, respectively. However, because animal reproduction studies are not always predictive of human response, Metformin HCl should not be used during pregnancy unless clearly needed. Nursing Mothers Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Thus, the potential for hypoglycemia in nursing infants after Metformin HCl Oral Solution may exist. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of GLUMETZA (metformin hcl) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger 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. This drug may be known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See WARNINGS: Lactic Acidosis.)