Drug Safety-related Labeling Changes (SrLC)

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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.

GLUMETZA (NDA-021748)

(METFORMIN HYDROCHLORIDE)

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

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11/07/2018 (SUPPL-25)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.

5 Warnings and Precautions

Additions and/or revisions underlined:

5.2 Vitamin B12 Deficiency

Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at 2 to 3 year intervals in patients on GLUMETZA and manage any abnormalities.

Newly added subsection:

5.3 Concomitant Use with Insulin and Insulin Secretagogues

Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. GLUMETZA may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with GLUMETZA.

6 Adverse Reactions

Revision underlined in the bulleted line listing:

Vitamin B12 Deficiency

6.1 Clinical Trials Experience

Following Table 1 Adverse Reactions Reported by >5%* of Patients for the Combined GLUMETZA Groups Versus Placebo Group, in which numerical data has been estimated in whole numbers (see label for complete information).

Laboratory Tests

Vitamin B12 Concentrations

Additions and/or revisions underlined:

In clinical trials of 29-week duration with metformin HCl tablets, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients

6.2 Postmarketing Experience

Additions and/or revisions underlined:

… during post-approval use of GLUMETZA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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

7 Drug Interactions

Table 2: Clinically Significant Drug Interactions with GLUMETZA Newly added table; please refer to label for complete information.

8 Use in Specific Populations

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

PLLR conversion. Extensive additions and/or revisions in the 3 subsections. Please refer to label for complete information.

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

PATIENT COUNSELING INFORMATION

Extensive changes; please refer to label for complete information.

04/05/2017 (SUPPL-20)

Approved Drug Label (PDF)

Boxed Warning

Lactic Acidosis

(addtions 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 in the full prescribing information.

If metformin-associated lactic acidosis is suspected, immediatelydiscontinue GLUMETZA and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

4 Contraindications

(additions underlined)

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

Known hypersensitivity to metformin hydrochloride.
Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin.

5 Warnings and Precautions

5.1 Lactic Acidosis

(subsection revised, additions underlined)

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:

• 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

• 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. Therefore, consider more frequent monitoring of patients.

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

Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop GLUMETZA at the time of, or prior to, an iodinated contrast imaging procedure in patientswith 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.

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

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

• Lactic acidosis

• Vitamin B12 Levels

• Hypoglycemia

6.2 Postmarketing Experience

(subsection added)

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.

7 Drug Interactions

7.1 Carbonic Anhydrase Inhibitors

(additions underlined)

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

7.2 Drugs that Reduce Metformin Clearance

(new subsection added)

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.

7.3 Alcohol

(new subsection added)

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

7.4 Insulin Secretagogues or Insulin

(new subsection added)

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.

8 Use in Specific Populations

8.5 Geriatric Use

(additions underlined)

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.

8.6 Renal Impairment

(new subsection added)

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.

8.7 Hepatic Impairment

(new subsection added)

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.

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

17 PATIENT COUNSELING INFORMATION

(additions underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Information for Patients

…

• Instruct patients to inform their doctor that they are taking GLUMETZA prior to any surgical or radiological procedure, as temporary discontinuation of GLUMETZA may be required until renal function has been confirmed to be normal

…

PATIENT INFORMATION

(additions and revisions, please refer to label).