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
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).