Approved Drug Label (PDF)
4
Contraindications
Additions
and/or revisions underlined:
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:
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.
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).