Drug Safety-related Labeling Changes (SrLC)

Get Email Alerts | Guide

Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

GLUCOPHAGE XR (NDA-021202)

(METFORMIN HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

Download Data

Expand all

05/30/2018 (SUPPL-18)

Approved Drug Label (PDF)

Boxed Warning

PLR conversion; Lactic Acidosis warning is highlighted as box warning.

5 Warnings and Precautions

PLR conversion; subsections as below; please refer to label for complete information:

5.1 Lactic Acidosis

5.2 Vitamin B12 Deficiency

5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

5.4 Macrovascular Outcomes

6 Adverse Reactions

PLR conversion; please see label for complete information (including newly created subsection 6.2 Postmarketing Experience.

7 Drug Interactions

PLR conversion, inclusion of Table 3: Clinically Significant Drug Interactions with GLUCOPHAGE/GLUCOPHAGE XR; please refer to label for complete information.

8 Use in Specific Populations

PLR conversion and PLLR conversion; please refer to label for 8.1 Pregnancy and 8.2 Lactation complete information (including newly created subsection 8.3 Females and Males of Reproductive Potential)

8.4 Pediatric Use and 8.5 Geriatric Use have been altered in PLR conversion; please refer to label for complete information.

The following two sections have been completed revised by the PLR conversion; as below:

8.5 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. GLUCOPHAGE/GLUCOPHAGE XR is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2.

8.7 Hepatic Impairment

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. GLUCOPHAGE/GLUCOPHAGE XR is not recommended in patients with hepatic impairment.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

PLR conversion; newly created section, please see label for complete information.

PATIENT INFORMATION

PLR conversion; newly created section, please see label for complete information.

Other

PLR Conversion

04/05/2017 (SUPPL-21)

Approved Drug Label (PDF)

6 Adverse Reactions

(additions underlined)

Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.

04/05/2017 (SUPPL-23)

Approved Drug Label (PDF)

4 Contraindications

(additions underlined)

GLUCOPHAGE and GLUCOPHAGE XR are contraindicated in patients with:

1. Severe renal impairment (eGFR below 30 mL/min/1.73 m2)

2. Known hypersensitivity to metformin hydrochloride.

3. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

5 Warnings and Precautions

PRECAUTIONS

General

(additions underlined)

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, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels were 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 GLUCOPHAGE or GLUCOPHAGE XR. In GLUCOPHAGE or GLUCOPHAGE XR 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/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

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

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

Renal impairment—The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment.

The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include:

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

Drug interactions—The concomitant use of GLUCOPHAGE or GLUCOPHAGE XR 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. 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, orcardiac impairment than younger patients. Assess renal function more frequently in elderly patients.

Radiologic 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 GLUCOPHAGE or GLUCOPHAGE XR 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 heartfailure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart GLUCOPHAGE or GLUCOPHAGE XR 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. GLUCOPHAGE or GLUCOPHAGE XR 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 cause prerenal azotemia. When such an event occurs, discontinue GLUCOPHAGE or GLUCOPHAGE XR.

Excessive 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 GLUCOPHAGE or GLUCOPHAGE XR.

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 GLUCOPHAGE and GLUCOPHAGE XR in patients with clinical or laboratory evidence of hepatic disease.

Vitamin B12 levels—In controlled clinical trials of GLUCOPHAGE of 29 weeks duration, 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

GLUCOPHAGE or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on GLUCOPHAGE or GLUCOPHAGE XR 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 2- to 3-year intervals may be useful.

Hypoglycemia—Hypoglycemia does not occur in patients receiving GLUCOPHAGE or GLUCOPHAGE XR 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 GLUCOPHAGE or GLUCOPHAGE XR or any other antidiabetic drug.

WARNINGS

(additions underlined)

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin- associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin- associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided.

If metformin-associated lactic acidosis is suspected, immediately discontinue GLUCOPHAGE or

GLUCOPHAGE XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

7 Drug Interactions

(Clinical Evaluation of Drug Interactions Conducted with GLUCOPHAGE)

(additions Underlined)

Glyburide—In a single-dose interaction study in type 2 diabetes patients, coadministration of metformin and glyburide did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Decreases in glyburide AUC and Cmax were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide bloodlevels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain (see DOSAGE AND ADMINISTRATION: Concomitant GLUCOPHAGE or GLUCOPHAGE XR and Oral Sulfonylurea Therapy in Adult Patients).

Furosemide—A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when coadministered chronically.

…

Drugs that reduce metformin clearance—Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics.

In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when coadministered in single-dose interaction studies.

Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.

…

Carbonic anhydrase inhibitors—Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with GLUCOPHAGE or GLUCOPHAGE XR may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.

Alcohol—Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving GLUCOPHAGE OR GLUCOPHAGE XR.

8 Use in Specific Populations

Geriatric Use

(additions underlined)

Controlled clinical studies of GLUCOPHAGE and GLUCOPHAGE XR did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although 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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient Information

(new section added, please refer to label).