Glumetza

No cases of overdose were reported during GLUMETZA clinical trials. It would be expected that adverse reactions of a more intense character including epigastric discomfort, nausea, and vomiting followed by diarrhea, drowsiness, weakness, dizziness, malaise and headache might be seen. Should those symptoms persist, lactic acidosis should be excluded.

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases. (See WARNINGS AND PRECAUTIONS) Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

Glumetza is part of the drug class:

• Biguanides

If you take too much Glumetza, call your local Poison Control Center or seek emergency medical attention right away.

WARNINGS

Lactic Acidosis:

Lactic acidosis is a rare, but serious, metabolic complication that can occur due to Glumetza accumulation during treatment with Glumetza; 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 Glumetza is implicated as the cause of lactic acidosis, Glumetza plasma levels >5 μg/mL are generally found.

 

You should not use this medication if you are allergic to metformin, or if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin).

If you need to have any type of x-ray or CT scan using a dye that is injected into your veins, you will need to temporarily stop taking metformin.

Before taking metformin, tell your doctor if you have liver disease or a history of heart disease.

Some people develop lactic acidosis while taking metformin. Early symptoms may get worse over time and this condition can be fatal. Get emergency medical help if you have even mild symptoms such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, slow or uneven heart rate, dizziness, or feeling very weak or tired.

• Diabetes (Type 1 and Type 2)
• Diabetes Treatment (Type 1 and Type 2 Medications and Diet)
• Oral Diabetes Prescription Medications
• Tips for Managing Type 1 and 2 Diabetes at Home
• Urinary Tract Infections (UTIs)

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of metformin oral solution and tablets in children 10 to 16 years of age. However, safety and efficacy of metformin extended-release tablets in the pediatric population have not been established.

Geriatric

Although appropriate studies on the relationship of age to the effects of metformin have not been performed in the geriatric population, geriatric-specific problems are not expected to limit the usefulness of metformin in the elderly. However, elderly patients are more likely to have age-related kidney problems, which may require caution in patients receiving metformin. This medicine is not recommended in patients 80 years of age and older who have kidney problems.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	B	Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate studies in pregnant women OR animal studies have shown an adverse effect, but adequate studies in pregnant women have failed to demonstrate a risk to the fetus.

Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Acetrizoic Acid
• Diatrizoate
• Ethiodized Oil
• Iobenzamic Acid
• Iobitridol
• Iocarmic Acid
• Iocetamic Acid
• Iodamide
• Iodipamide
• Iodixanol
• Iodohippuric Acid
• Iodopyracet
• Iodoxamic Acid
• Ioglicic Acid
• Ioglycamic Acid
• Iohexol
• Iomeprol
• Iopamidol
• Iopanoic Acid
• Iopentol
• Iophendylate
• Iopromide
• Iopronic Acid
• Ioseric Acid
• Iosimide
• Iotasul
• Iothalamate
• Iotrolan
• Iotroxic Acid
• Ioxaglate
• Ioxitalamic Acid
• Ipodate
• Metrizamide
• Metrizoic Acid
• Tyropanoate Sodium

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Aspirin
• Balofloxacin
• Besifloxacin
• Bupropion
• Ciprofloxacin
• Dasabuvir
• Dofetilide
• Dolutegravir
• Enoxacin
• Fleroxacin
• Flumequine
• Gatifloxacin
• Gemifloxacin
• Ioversol
• Lanreotide
• Levofloxacin
• Lomefloxacin
• Moxifloxacin
• Nadifloxacin
• Norfloxacin
• Octreotide
• Ofloxacin
• Ombitasvir
• Paritaprevir
• Pasireotide
• Pazufloxacin
• Pefloxacin
• Pioglitazone
• Prulifloxacin
• Ritonavir
• Rufloxacin
• Sparfloxacin
• Thioctic Acid
• Tosufloxacin
• Vandetanib

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acebutolol
• Atenolol
• Betaxolol
• Bisoprolol
• Bitter Melon
• Carteolol
• Carvedilol
• Celiprolol
• Esmolol
• Fenugreek
• Furazolidone
• Glucomannan
• Guar Gum
• Iproniazid
• Isocarboxazid
• Labetalol
• Levobunolol
• Linezolid
• Methylene Blue
• Metipranolol
• Metoprolol
• Moclobemide
• Nadolol
• Nebivolol
• Nialamide
• Oxprenolol
• Patiromer
• Penbutolol
• Phenelzine
• Pindolol
• Practolol
• Procarbazine
• Propranolol
• Psyllium
• Ranolazine
• Rasagiline
• Rifampin
• Safinamide
• Selegiline
• Sotalol
• Timolol
• Tranylcypromine
• Verapamil

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol, excessive use or
• Underactive adrenal glands or
• Underactive pituitary gland or
• Undernourished condition or
• Weakened physical condition or
• Any other condition that causes low blood sugar—Patients with these conditions may be more likely to develop low blood sugar while taking metformin.

• Anemia (low levels of red blood cells) or
• Vitamin B12 deficiency—Use with caution. May make these conditions worse.

• Congestive heart failure, acute or unstable or
• Dehydration or
• Heart attack, acute or
• Hypoxemia (decreased oxygen in the blood) or
• Kidney disease or
• Liver disease or
• Sepsis (blood poisoning) or
• Shock (low blood pressure, blood circulation is poor)—A rare condition called lactic acidosis can occur. Talk with your doctor if you have concerns about this.

• Diabetic ketoacidosis (ketones in the blood) or
• Kidney disease, severe or
• Metabolic acidosis (extra acids in the blood) or
• Type 1 diabetes—Should not be used in patients with these conditions.

• Fever or
• Infection or
• Surgery or
• Trauma—These conditions may cause temporary problems with blood sugar control and your doctor may want to treat you with insulin.

It is very important that your doctor check your progress at regular visits, especially during the first few weeks that you take this medicine. Blood and urine tests may be needed to check for unwanted effects.

This medicine may interact with the dye used for an X-ray or CT scan. Your doctor should advise you to stop taking it before you have any medical exams or diagnostic tests that might cause less urine output than usual. You may be advised to start taking the medicine again 48 hours after the exams or tests if your kidney function is tested and found to be normal.

Make sure any doctor or dentist who treats you knows that you are using this medicine. You may need to stop using this medicine several days before having surgery or medical tests.

It is very important to carefully follow any instructions from your health care team about:

• Alcohol—Drinking alcohol may cause severe low blood sugar. Discuss this with your health care team.
• Other medicines—Do not take other medicines unless they have been discussed with your doctor. This especially includes nonprescription medicines such as aspirin, and medicines for appetite control, asthma, colds, cough, hay fever, or sinus problems.
• Counseling—Other family members need to learn how to prevent side effects or help with side effects if they occur. Also, patients with diabetes may need special counseling about diabetes medicine dosing changes that might occur with lifestyle changes, such as changes in exercise or diet. Counseling on birth control and pregnancy may be needed because of the problems that can occur in pregnancy for patients with diabetes.
• Travel—Keep a recent prescription and your medical history with you. Be prepared for an emergency as you would normally. Make allowances for changing time zones and keep your meal times as close as possible to your usual meal times.
• In case of emergency—There may be a time when you need emergency help for a problem caused by your diabetes. You need to be prepared for these emergencies. It is a good idea to wear a medical identification (ID) bracelet or neck chain at all times. Also, carry an ID card in your wallet or purse that says that you have diabetes and a list of all of your medicines.

Under certain conditions, too much metformin can cause lactic acidosis. The symptoms of lactic acidosis are severe and quick to appear, and usually occur when other health problems not related to the medicine are present and are very severe, such as a heart attack or kidney failure. Symptoms of lactic acidosis include abdominal or stomach discomfort, decreased appetite, diarrhea, fast or shallow breathing, a general feeling of discomfort, severe muscle pain or cramping, and unusual sleepiness, tiredness, or weakness.

If symptoms of lactic acidosis occur, you should get immediate emergency medical help.

This medicine may cause hypoglycemia (low blood sugar). This is more common when this medicine is taken together with certain medicines. Low blood sugar must be treated before it causes you to pass out (unconsciousness). People feel different symptoms of low blood sugar. It is important that you learn which symptoms you usually have so you can treat it quickly. Talk to your doctor about the best way to treat low blood sugar.

Hyperglycemia (high blood sugar) may occur if you do not take enough or skip a dose of your medicine, overeat or do not follow your meal plan, have a fever or infection, or do not exercise as much as usual. High blood sugar can be very serious and must be treated right away. It is important that you learn which symptoms you have in order to treat it quickly. Talk to your doctor about the best way to treat high blood sugar.

High blood sugar may occur if you do not exercise as much as usual, have a fever or infection, do not take enough or skip a dose of your diabetes medicine, or overeat or do not follow your meal plan.

Lactic Acidosis

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

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

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

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

Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]:

• Before initiating Glumetza, obtain an estimated glomerular filtration rate (eGFR). • Glumetza is contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m2 [see Contraindications (4)]. • Initiation of Glumetza is not recommended in patients with eGFR between 30–45 mL/minute/1.73 m2. • Obtain an eGFR at least annually in all patients taking Glumetza. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. • In patients taking Glumetza whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy.

Drug Interactions: The concomitant use of Glumetza with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see Drug Interactions (7)]. Therefore, consider more frequent monitoring of patients.

Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5)].

Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop Glumetza at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart Glumetza if renal function is stable.

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

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

Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism, and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving Glumetza.

Hepatic Impairment: Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of Glumetza 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 or Vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on Glumetza, and any apparent abnormalities should be appropriately investigated and managed. 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.

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.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Glumetza or any other oral antidiabetic drug.

Clinical Trials Experience

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Lactic acidosis [see Warnings and Precautions (5.1)] • Vitamin B12 Levels [see Warnings and Precautions (5.2)] • Hypoglycemia [see Warnings and Precautions (5.3)]

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 to 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 >5%* of Patients for the Combined Glumetza Groups Versus Placebo Group

* ARs that were more common in the Glumetza-treated than in the placebo-treated patients.
Adverse Reaction	Glumetza + Glyburide (n=431)	Placebo + Glyburide (n=144)
Hypoglycemia	13.7%	4.9%
Diarrhea	12.5%	5.6%
Nausea	6.7%	4.2%

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 (5.2).]

Postmarketing Experience

The following adverse reactions have been identified during post-approval use. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cholestatic, hepatocellular, and mixed hepatocellular liver injury.

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.

Labor and Delivery

The safety and effectiveness of Glumetza used during labor and delivery has not been evaluated in human studies.

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. Glumetza is not recommended in pediatric patients below the age of 18 years.

Geriatric Use

Clinical studies of Glumetza 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 and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients. [See Warnings and Precautions (5.1) and Dosage and Administration (2.2).]

Renal Impairment

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Glumetza is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2. [See Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3).]

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 (5.1).]

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 (5)] 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 mcg/mL. During controlled clinical trials, which served as the basis of approval for metformin, maximum metformin plasma levels did not exceed 5 mcg/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.

Special Populations

Renal Impairment: Following a single-dose administration of Glumetza 500 mg in subjects with mild and moderate renal impairment, the oral and renal clearance of metformin were decreased by 33% and 50% and 16% and 53%, respectively. Metformin peak and systemic exposure was 27% and 61% greater, respectively in subjects with mild renal impairment and 74% and 2.36-fold greater in subjects with moderate renal impairment as compared to healthy subjects. [See Dosage and Administration (2.2), Contraindications (4), and Warnings and Precautions (5.1).]

Hepatic Impairment: No pharmacokinetic studies of Glumetza have been conducted in subjects with hepatic impairment. [See Warnings and Precautions (5.1).]

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. [See Warnings and Precautions (5.1) and Dosage and Administration (2).]

Gender: In the pharmacokinetic studies in healthy volunteers, there were no important differences between male and female subjects with respect to metformin AUC and t1/2. 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.

Table 2: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure

* All metformin and coadministered drugs were given as single doses. † AUC=AUC0-∞ ‡ Glumetza (metformin hydrochloride extended-release tablets) 500 mg § Ratio of arithmetic means ¶ At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC=AUC0-12h
Coadministered Drug	Dose of Coadministered Drug*	Dose of Metformin*	Geometric Mean Ratio (ratio with/without coadministered drug) No effect=1.00
			AUC†	Cmax
No dosing adjustments required for the following:
Glyburide	5 mg	500 mg‡	0.98§	0.99§
Furosemide	40 mg	850 mg	1.09§	1.22§
Nifedipine	10 mg	850 mg	1.16	1.21
Propranolol	40 mg	850 mg	0.90	0.94
Ibuprofen	400 mg	850 mg	1.05§	1.07§
Drugs that are eliminated by renal tubular secretion may increase the accumulation of metformin: [see Warnings and Precautions (5) and Drug Interactions (7)].
Cimetidine	400 mg	850 mg	1.40	1.61
Carbonic anhydrase inhibitors may cause metabolic acidosis: [see Warnings and Precautions (5) and Drug Interactions (7)].
Topiramate	100 mg¶	500 mg¶	1.25¶	1.17

Table 3: Effect of Metformin on Coadministered Drug Systemic Exposure

* All metformin and coadministered drugs were given as single doses. † AUC=AUC0–∞ ‡ AUC0-24 hr reported § Ratio of arithmetic means, p-value of difference <0.05 ¶ Ratio of arithmetic means
Coadministered Drug	Dose of Coadministered Drug*	Dose of Metformin*	Geometric Mean Ratio (ratio with/without coadministered drug) No effect=1.00
			AUC†	Cmax
No dosing adjustments required for the following:
Glyburide	5 mg	500 mg‡	0.78§	0.63§
Furosemide	40 mg	850 mg	0.87§	0.69§
Nifedipine	10 mg	850 mg	1.10‡	1.08
Propranolol	40 mg	850 mg	1.01‡	0.94
Ibuprofen	400 mg	850 mg	0.97¶	1.01¶
Cimetidine	400 mg	850 mg	0.95‡	1.01

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, one of the medicines 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.

Call your doctor right away if you have any of the following symptoms, which could be signs of lactic acidosis:

• you feel cold in your hands or feet • you feel dizzy or lightheaded • you have a slow or irregular heartbeat • you feel very weak or tired • you have unusual (not normal) muscle pain • you have trouble breathing • you feel sleepy or drowsy • you have stomach pains, nausea or vomiting

Most people who have had lactic acidosis with metformin have other things that, combined with the metformin, led to the lactic acidosis. Tell your doctor if you have any of the following, because you have a higher chance for getting lactic acidosis with Glumetza if you:

• have severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye • have liver problems • drink alcohol very often, or drink a lot of alcohol in 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 surgery • have a heart attack, severe infection, or stroke

The best way to keep from having a problem with lactic acidosis from metformin is to tell your doctor if you have any of the problems in the list above. Your doctor may decide to stop your Glumetza for a while if you have any of these things.

Glumetza can have other serious side effects. See “What are the possible side effects of Glumetza?”

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 severe 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. • 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 severe kidney problems • are going to get an injection of dye or contrast agents for an x-ray procedure, Glumetza may 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 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 over-the-counter 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 possible 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 happen 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 68° to 77°F (20° to 25°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.

Manufactured for:
Salix Pharmaceuticals, a division of Valeant
Pharmaceuticals North America LLC
Bridgewater, NJ 08807 USA

www.GlumetzaXR.com

For prescription only

U.S. Patent Numbers: 6,488,962; 6,723,340; 7,780,987; 8,323,692

Glumetza is a trademark of Valeant
Pharmaceuticals International, Inc. or
its affiliates.

©Valeant Pharmaceuticals North America LLC

  Rev. 04/2017
500 mg:
9599000
70012758

1000 mg:
9519103
20001996

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL 500 MG

NDC 68012-002-13

Rx only

Glumetza®
(metformin hydrochloride
extended-release tablets)

500 mg

ONCE DAILY

100 Tablets

Salix

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL 1000 MG

NDC 68012-003-16

Rx only

Glumetza®

(metformin hydrochloride
extended-release tablets)

1000 mg

ONCE
DAILY

90 Tablets

Salix

Glumetza  metformin hydrochloride tablet, film coated, extended release

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:68012-002 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength METFORMIN HYDROCHLORIDE (METFORMIN) METFORMIN HYDROCHLORIDE 500 mg

Inactive Ingredients Ingredient Name Strength HYPROMELLOSE, UNSPECIFIED   MAGNESIUM STEARATE   MICROCRYSTALLINE CELLULOSE   POLYETHYLENE GLYCOL, UNSPECIFIED

Product Characteristics Color BLUE (blue) Score no score Shape OVAL (oval) Size 18mm Flavor Imprint Code GMZ;500 Contains

Packaging # Item Code Package Description 1 NDC:68012-002-13 100 TABLET, FILM COATED, EXTENDED RELEASE in 1 BOTTLE 2 NDC:68012-002-92 21 TABLET, FILM COATED, EXTENDED RELEASE in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021748 08/01/2006

Glumetza  metformin hydrochloride tablet, film coated, extended release

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:68012-003 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength METFORMIN HYDROCHLORIDE (METFORMIN) METFORMIN HYDROCHLORIDE 1000 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE   POLYVINYL ALCOHOL, UNSPECIFIED   CROSPOVIDONE (15 MPA.S AT 5%)   GLYCERYL DIBEHENATE   HYPROMELLOSE, UNSPECIFIED   TALC   POLYETHYLENE GLYCOL, UNSPECIFIED   TITANIUM DIOXIDE   POLYSORBATE 80

Product Characteristics Color WHITE (white) Score no score Shape OVAL (oval) Size 20mm Flavor Imprint Code M1000 Contains

Packaging # Item Code Package Description 1 NDC:68012-003-16 90 TABLET, FILM COATED, EXTENDED RELEASE in 1 BOTTLE 2 NDC:68012-003-97 7 TABLET, FILM COATED, EXTENDED RELEASE in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021748 06/17/2008

Labeler - Santarus, Inc. (104286369)

Establishment
Name	Address	ID/FEI	Operations
Patheon Puerto Rico, Inc.		143814544	MANUFACTURE(68012-002)

Establishment
Name	Address	ID/FEI	Operations
Valeant Pharmaceuticals International, Inc.		253292734	MANUFACTURE(68012-003), PACK(68012-003), LABEL(68012-003)

Establishment
Name	Address	ID/FEI	Operations
Carton Service, Incorporated		928861723	PACK(68012-002), LABEL(68012-002)

Revised: 04/2017   Santarus, Inc.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Some people develop lactic acidosis while taking metformin. Early symptoms may get worse over time and this condition can be fatal. Get emergency medical help if you have even mild symptoms such as:

• muscle pain or weakness;

• numb or cold feeling in your arms and legs;

• trouble breathing;

• feeling dizzy, light-headed, tired, or very weak;

• stomach pain, nausea with vomiting; or

• slow or uneven heart rate.

Common side effects may include:

• nausea, vomiting, upset stomach; or

• diarrhea.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

• If you have an allergy to metformin or any other part of Glumetza (metformin extended-release tablets).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: Acidic blood problem, kidney disease, or liver disease.
• If you have had a recent heart attack or stroke.
• If you are not able to eat or drink like normal, including before certain procedures or surgery.
• If you are having an exam or test with contrast or have had one within the past 48 hours, talk with your doctor.

This is not a list of all drugs or health problems that interact with Glumetza (metformin extended-release tablets).

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Glumetza (metformin extended-release tablets) with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Use Glumetza (metformin extended-release tablets) as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with meals.
• Take with a full glass of water.
• This medicine may be used alone or with other high blood sugar (diabetes) drugs.
• To gain the most benefit, do not miss doses.
• Keep taking Glumetza (metformin extended-release tablets) as you have been told by your doctor or other health care provider, even if you feel well.
• Take with the evening meal if taking once daily.
• Swallow whole. Do not chew, break, or crush.
• If you have trouble swallowing, talk with your doctor.

What do I do if I miss a dose?

• Skip the missed dose and go back to your normal time unless your doctor tells you to do something else.
• Do not take 2 doses at the same time or extra doses.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Very bad belly pain.
• It is common to have stomach problems like upset stomach, throwing up, or loose stools (diarrhea) when you start taking Glumetza (metformin extended-release tablets). If you have stomach problems later during care, call your doctor right away. This may be a sign of an acid health problem in the blood (lactic acidosis).
• Low blood sugar can happen. The chance of low blood sugar may be raised when Glumetza (metformin extended-release tablets) is used with other drugs for high blood sugar (diabetes). Signs may be dizziness, headache, feeling sleepy, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating. Call your doctor right away if you have any of these signs. Follow what you have been told to do if you get low blood sugar. This may include taking glucose tablets, liquid glucose, or some fruit juices.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Medical Disclaimer