Approved Drug Label (PDF)
Boxed Warning
Boxed Warning
(Physician Labeling Rule (PLR) Conversion)
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 GLUCOVANCE and institute
general supportive measures in a hospital setting. Prompt hemodialysis
is recommended.
4
Contraindications
4 CONTRAINDICATIONS
(Physician
Labeling Rule (PLR) Conversion; additions and/or revisions are underlined)
GLUCOVANCE
is
contraindicated in patients with:
Severe renal impairment (eGFR below 30 mL/min/1.73 m2).
Hypersensitivity to metformin or glyburide.
Acute or chronic metabolic acidosis, including diabetic
ketoacidosis, with or
without coma.
Concomitant administration of bosentan.
5
Warnings and Precautions
5.1 Lactic Acidosis
(Physician Labeling Rule (PLR) Conversion; additions
and/or revisions are 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, 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 GLUCOVANCE. In GLUCOVANCE treated patients
with a diagnosis
or strong suspicion
of lactic acidosis, prompt hemodialysis is recommended to correct
the acidosis and remove accumulated metformin (metformin HCl 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 GLUCOVANCE 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 GLUCOVANCE, obtain an estimated glomerular filtration rate
(eGFR).
GLUCOVANCE is contraindicated in patients with an
eGFR less
than 30
mL/min/1.73 m2.
Initiation of GLUCOVANCE is not recommended in patients
with eGFR between
30 to 45 mL/min/1.73 m2.
Obtain an eGFR at least annually
in all patient
taking GLUCOVANCE. In patients at risk for the development of renal impairment (e.g., the elderly),
renal function should be assessed more frequently.
In patients taking GLUCOVANCE whose eGFR falls below 45 mL/min/1.73 m2, assess
the benefit and risk of
continuing therapy.
Drug
interactions—The
concomitant
use of GLUCOVANCE 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, or cardiac
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 GLUCOVANCE 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. Reevaluate eGFR 48 hours after the
imaging procedure, and restart GLUCOVANCE 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. GLUCOVANCE 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
GLUCOVANCE.
Excessive Alcohol
intake—Alcohol potentiates the effect of metformin
on lactate metabolism. Patients should be warned against
excessive alcohol intake, acute or chronic, while
receiving GLUCOVANCE.
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 GLUCOVANCE in patients with
clinical or laboratory evidence of hepatic disease.
5.2 Hypoglycemia
(Physician Labeling
Rule (PLR) Conversion)
All
sulfonylurea
drugs, including
GLUCOVANCE, are capable of producing
severe hypoglycemia [see Adverse
Reactions (6)]. Concomitant use of GLUCOVANCE with other anti- diabetic medication can increase the risk of hypoglycemia. A lower dose of GLUCOVANCE may be required to minimize the risk of hypoglycemia when combining
it with other anti- diabetic medications.
Educate
patients
to recognize and manage hypoglycemia. When initiating and increasing GLUCOVANCE in patients who may be predisposed to hypoglycemia (e.g., the elderly, patients with renal impairment, patients on other anti-diabetic medications) start with a lower dose. Debilitated or malnourished patients, and those with adrenal,
pituitary, or hepatic
impairment are particularly susceptible to the hypoglycemic action of anti-diabetic medications. Hypoglycemia is also
more likely to occur when caloric
intake is deficient,
after severe or prolonged exercise, or when
alcohol is ingested.
The
patient's
ability to concentrate and react may be impaired
as a result of hypoglycemia. Early warning symptoms of hypoglycemia may be different
or less pronounced in patients with autonomic neuropathy, the elderly,
and in patients who are taking beta-adrenergic blocking medications or other sympatholytic agents. These situations may result in severe hypoglycemia before the patient is aware of the hypoglycemia.
These
impairments
may present
a risk in situations
where these abilities are especially important, such as driving or operating
other machinery. Severe hypoglycemia can lead to unconsciousness or
convulsions and may result
in temporary or permanent impairment of brain function or death.
5.3 Cardiovascular
Mortality
(Physician Labeling
Rule (PLR) Conversion; additions and/or revisions are underlined)
The
administration of oral hypoglycemic drugs has been reported
to be associated with increased cardiovascular mortality as compared to treatment
with diet alone or diet plus insulin.
This warning is based on the study conducted
by the University Group Diabetes Program (UGDP), a long-term
prospective clinical study designed
to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying
vascular complications in patients
with type 2 diabetes
mellitus. The study involved
823 patients who were randomly assigned to 1 of 4 treatment groups.
UGDP
reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet
alone. A significant increase in total mortality
was not observed,
but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall
mortality. Despite
controversy regarding the interpretation of these results, the findings
of the UGDP study provide an adequate basis for this warning.
The patient should be informed of the potential
risks and benefits
of glyburide and of
alternative modes of therapy.
Although
only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider
that this warning
may also apply to other hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.
5.4 Hemolytic Anemia
(Physician Labeling
Rule (PLR) Conversion; additions and/or revisions are underlined)
Treatment
of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents, including
GLUCOVANCE, can lead to hemolytic anemia. Avoid use of GLUCOVANCE in patients
with G6PD deficiency. In postmarketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.
5.5 Vitamin
B12 Deficiency
(Physician Labeling
Rule (PLR) Conversion; additions and/or revisions are underlined)
In clinical studies 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. Such decrease, possibly
due to interference with B12 absorption from the B12-intrinsic factor complex,
may
be associated
with anemia but appears to be
rapidly
reversible with discontinuation of metformin or vitamin
B12 supplementation. 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 GLUCOVANCE and manage any abnormalities.
5.6 Macrovascular
Outcomes
(Physician Labeling
Rule (PLR) Conversion)
There
have been no
clinical studies establishing conclusive evidence of macrovascular risk reduction
with GLUCOVANCE.
6
Adverse Reactions
6 Adverse Reactions
(Physician Labeling
Rule (PLR) Conversion)
The following adverse reactions are also discussed elsewhere in the labeling:
Lactic
Acidosis
Hypoglycemia
Cardiovascular
mortality
Hemolytic anemia
Vitamin B12 Deficiency
6.1 Clinical
Studies Experience
(Physician Labeling
Rule (PLR) Conversion; additions and/or revisions are underlined)
(Table 1 and 2 has
been revised; please refer to label)
Because
clinical studies are conducted under widely varying
conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly
compared to rates in the clinical studies
of another drug and may not reflect
the rates observed in practice.
In
double-blind clinical studies with GLUCOVANCE as initial therapy
or as second-line therapy of 20 and 14 weeks, respectively (see section 14), a total of 642 patients
received GLUCOVANCE, 312 received
metformin HCl, 324 received glyburide, and 161 received
placebo. Adverse
reactions are listed in Table 1.
Hypoglycemia
The
incidence of reported
symptoms of hypoglycemia (such as dizziness, shakiness, sweating, and hunger), in the initial therapy
study of GLUCOVANCE are summarized in Table 2. For patients with a baseline
HbA1c between 8% and 11% treated with GLUCOVANCE 2.5 mg/500
mg as initial therapy,
the frequency of hypoglycemic symptoms was 30% to 35%. As
second-line therapy in patients inadequately controlled on sulfonylurea alone, approximately 6.8% of all patients treated
with GLUCOVANCE experienced hypoglycemic
symptoms.
Gastrointestinal Reactions
The
incidence of gastrointestinal (GI) side effects (diarrhea, nausea/vomiting, and abdominal pain) in the GLUCOVANCE initial therapy study are summarized in Table 2. Across all GLUCOVANCE studies,
GI symptoms were the most common adverse events with GLUCOVANCE and were more frequent at higher
dose levels. In controlled studies, <2% of patients discontinued
GLUCOVANCE therapy due to
GI adverse
events.
Dermatologic
Reactions
Allergic
skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in 1.5% of glyburide-treated patients. These
may be transient and may disappear despite
continued use.
6.2 Postmarketing
Adverse Reactions
(Physician Labeling
Rule (PLR) Conversion; additions and/or revisions are underlined)
The
following
adverse reactions
have been identified during post-approval use of GLUCOVANCE. 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.
Allergic: Angioedema, arthralgia, myalgia, and vasculitis have been reported.
Dermatologic: Porphyria cutanea tarda and photosensitivity reactions have been reported
with sulfonylureas.
Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, which occasionally may present as purpura, hemolytic anemia, aplastic anemia, and pancytopenia, have been reported
with sulfonylureas.
Hepatic: Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with
postmarketing use of
metformin.
Cholestatic
jaundice
and
hepatitis
may occur rarely with glyburide, which may progress
to liver failure.
Liver
function
abnormalities,
including
isolated
transaminase
elevations,
have
been
reported.
Metabolic: Hepatic porphyria reactions have been reported
with sulfonylureas; however, these have not been reported with glyburide. Disulfiram-like reactions have been reported very rarely with glyburide. Cases of hyponatremia have been reported with glyburide and all other sulfonylureas, most often in patients
who are on other medications or have medical conditions known
to cause hyponatremia or
increase release
of antidiuretic hormone.
Other
Reactions:
Changes in accommodation and/or
blurred vision have been reported with glyburide and other sulfonylureas. These are thought to be related to fluctuation in glucose
levels.
7
Drug Interactions
7 DRUG INTERACTIONS
(Physician Labeling
Rule (PLR) Conversion; table 3 has been revised; please refer to label)
Table 3 presents clinically significant
drug interactions with GLUCOVANCE.
8
Use in Specific Populations
8.1 Pregnancy
(Physician Labeling
Rule (PLR) Conversion; additions and/or revisions are underlined)
Risk Summary
Available
data from a small
number of published studies and postmarketing experience with glyburide use in pregnancy
over decades have not identified any drug associated risks for major birth defects, miscarriage, or adverse maternal outcomes. However, sulfonylureas (including glyburide) cross the placenta
and have been associated with neonatal adverse reactions such as hypoglycemia. Therefore, GLUCOVANCE should be discontinued at least two weeks before expected delivery. Limited data with metformin
in pregnant women are not sufficient to determine
a drug-associated risk for major birth defects or miscarriage. Published studies
with metformin use during pregnancy
have not reported a clear association with metformin and major birth defect or miscarriage risk.. There are risks to the mother
and fetus associated with poorly
controlled diabetes mellitus in pregnancy.
No
evidence of harm to the fetus was observed
when doses up to 500 times the maximum
recommended human dose of 20 mg of glyburide, based on body surface area, were administered to rats and
rabbits in reproduction studies.
No
adverse developmental effects were observed when metformin was administered to pregnant
Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 3- and 6- times,
respectively, a 2000 mg
clinical dose, based on body surface area [see Data].
The
estimated background risk of major birth defects
is 6–10% in women with pre-gestational diabetes mellitus with an HbA1c >7 and has been reported
to be as high as 20–25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown.
In the U.S. general
population, the estimated
background risk of major birth defects and
miscarriage in clinically recognized
pregnancies is 2–4% and 15–20%, respectively.
Clinical Considerations
Disease-associated maternal and/or embryo/fetal
risk
Poorly controlled diabetes mellitus in pregnancy
increases the maternal
risk for diabetic
ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery
complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth,
and macrosomia related morbidity.
Fetal/Neonatal Adverse Reactions
Neonates
of women with gestational diabetes who are treated with sulfonylureas during pregnancy may be at increased risk for neonatal
intensive care admission and may develop respiratory distress, hypoglycemia, birth injury,
and
be large for gestational age. Prolonged severe hypoglycemia, lasting 4-10 days, has been reported
in neonates born to mothers
receiving a sulfonylurea at the time of delivery and has been reported with the use of agents with a prolonged half-life. Observe newborns for symptoms
of hypoglycemia and respiratory distress and
manage accordingly.
Dose adjustments during pregnancy and the postpartum period
Due
to reports
of prolonged severe hypoglycemia in neonates
born to mothers
receiving a sulfonylurea at the time of delivery,
GLUCOVANCE should be discontinued at least two weeks before expected
delivery.
Data
Human Data
Published
data from post-marketing studies have not reported
a clear association with metformin and major birth defects, miscarriage, or adverse maternal
or fetal outcomes
when metformin was used during
pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent
comparator groups.
Animal Data
Reproduction
studies
were
performed
in rats and rabbits at doses up to 500 times the maximum recommended human dose of 20 mg of glyburide based on body surface area comparisons and revealed
no evidence of harm
to the fetus.
Metformin did not adversely affect development outcomes when administered to pregnant
rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure
of about 3 and 6 times a
2000 mg clinical dose based on body surface area comparisons for rats and rabbits,
respectively.
Determination of fetal concentrations
demonstrated a partial placental barrier to metformin.
8.2 Lactation
(Physician Labeling
Rule (PLR) Conversion)
Risk Summary
Breastfed infants
of lactating women using GLUCOVANCE should be monitored for symptoms of
hypoglycemia [see Clinical Considerations]. Although glyburide was negligible
in human milk in one small clinical lactation study; this result is not conclusive
because of the limitations of the assay used in the study. There are no data on
the effects of glyburide on milk production. Limited published studies report
that metformin is present in human milk [see Data]. However, there is
insufficient information to determine the effects of metformin on the breastfed
infant and no available information on the effects of metformin on milk
production. Therefore, the developmental and health benefits of breastfeeding
should be considered along with the mother’s clinical need for GLUCOVANCE and
any potential adverse effects on the breastfed child from GLUCOVANCE or from
the underlying maternal condition.
Clinical
Considerations
Monitoring for
adverse reactions
Monitor breastfed
infants for signs of hypoglycemia (e.g., jitters, cyanosis, apnea, hypothermia,
excessive sleepiness, poor feeding, seizures).
Data
Published clinical
lactation studies report that metformin is present in human milk which resulted
in infant doses approximately 0.11% to 1% of the maternal weight-adjusted
dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies
were not designed to definitely establish the risk of use of metformin during
lactation because of small sample size and limited adverse event data collected
in infants.
8.3 Females
and Males of Reproductive Potential
(Physician Labeling
Rule (PLR) Conversion)
Discuss the potential for unintended pregnancy with premenopausal women as therapy with GLUCOVANCE
may result in ovulation
in some anovulatory women.
8.4 Pediatric
Use
(Physician Labeling
Rule (PLR) Conversion)
Safety
and effectiveness of GLUCOVANCE have not been
established in pediatric patients.
8.5 Geriatric
Use
(Physician Labeling
Rule (PLR) Conversion; additions and/or revisions are underlined)
Of
the 642 patients who received GLUCOVANCE in double-blind clinical studies, 23.8% were 65 and older while 2.8% were 75 and older. No overall
differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients are particularly susceptible to the hypoglycemic action
of anti-diabetic agents. Hypoglycemia may be difficult to recognize in these 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 hypoglycemia and lactic acidosis.
Assess renal function
more frequently in elderly patients.
8.6 Renal
Impairment
(Physician Labeling
Rule (PLR) Conversion)
Metformin is substantially excreted by the kidney, and the risk of
metformin accumulation and lactic acidosis increases with the degree of renal
impairment. GLUCOVANCE 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
(Physician Labeling
Rule (PLR) Conversion)
Use of metformin in patients with hepatic impairment has been
associated with some cases of lactic acidosis. GLUCOVANCE is not recommended in
patients with hepatic impairment.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(Physician Labeling
Rule (PLR) Conversion)
Advise the
patient to read the FDA-approved patient labeling (Patient Information).
Lactic Acidosis:
Explain the
risks of lactic acidosis, its symptoms, and conditions that predispose to its development.
Advise patients to discontinue GLUCOVANCE immediately and to promptly notify
their healthcare provider practitioner if unexplained hyperventilation,
myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur.
Counsel patients against excessive alcohol intake and inform patients about
importance of regular testing of renal function while receiving GLUCOVANCE.
Instruct patients to inform their doctor that they are taking GLUCOVANCE prior
to any surgical or radiological procedure, as temporary discontinuation may be
required.
Hypoglycemia:
Inform
patients that hypoglycemia may occur when taking GLUCOVANCE. Explain to
patients the risks of hypoglycemia, its symptoms and treatment, and conditions
that predispose to its development.
Cardiovascular Mortality:
Inform
patients that the administration of oral hypoglycemic drugs has been reported
to be associated with increased cardiovascular mortality as compared to
treatment with diet alone or diet plus insulin. Inform patients of the
potential risks and benefits of glyburide and of alternative modes of therapy.
Vitamin B12 Deficiency:
Inform
patients about importance of regular hematological testing while receiving GLUCOVANCE.
Females of Reproductive Age:
Inform
females that treatment with GLUCOVANCE may result in ovulation in some premenopausal
anovulatory women which may lead to unintended pregnancy.
Other
PATIENT INFORMATION
(Format changed, please refer to the
label)
Approved Drug Label (PDF)
4
Contraindications
(additions
underlined)
GLUCOVANCE
is contraindicated in patients with:
1. Severe renal impairment (eGFR below 30
mL/min/1.73m2)
2. Known hypersensitivity to metformin
hydrochloride or glyburide.
3. Acute or chronic metabolic acidosis,
including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis
should be treated with insulin.
4. Concomitant administration of bosentan.
5
Warnings and Precautions
PRECAUTIONS
(additions
underlined)
Lactic
Acidosis
There have been
post-marketing 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
GLUCOVANCE. In GLUCOVANCE 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 GLUCOVANCE 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 GLUCOVANCE, obtain an estimated glomerular filtration rate
(eGFR).
•
GLUCOVANCE is
contraindicated in patients
with an eGFR
less than 30 mL/min/1.73 m2
•
Initiation of GLUCOVANCE is
not recommended in
patients with eGFR
between
30-45 mL/min/1.73 m2.
•
Obtain an eGFR
at least annually in all patient taking GLUCOVANCE. In patients at risk for the
development of renal impairment (e.g., the elderly), renal function should be
assessed more frequently.
•
In patients
taking GLUCOVANCE whose eGFR falls below 45 mL/min/1.73 m2, assess the benefit
and risk of continuing therapy.
- Drug interactions—The concomitant use of GLUCOVANCE 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, or cardiac 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 GLUCOVANCE 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.
Reevaluate eGFR 48 hours after the imaging procedure, and restart
GLUCOVANCE 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. GLUCOVANCE
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 GLUCOVANCE.
- 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 GLUCOVANCE.
- 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 GLUCOVANCE in patients with clinical
or laboratory evidence of hepatic disease.
…
Macrovascular
Outcomes
There
have been no clinical studies
establishing conclusive evidence of macrovascular risk reduction
with GLUCOVANCE or any other antidiabetic drug.
WARNING
(subsection
revised, additions underlined)
Post-marketing 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.
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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
GLUCOVANCE and institute general supportive measures in a hospital setting.
Prompt hemodialysis is recommended
…
7
Drug Interactions
Alcohol
Alcohol
is known to potentiate the effects of metformin on lactate metabolism. Warn
patients against excessive alcohol intake while receiving GLUCOVANCE.
Carbonic Anhydrase Inhibitors
Topiramate
or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or
dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce
non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these
drugs with GLUCOVANCE may increase the risk for lactic acidosis. Consider more
frequent monitoring of these patients.
Drugs that reduce metformin clearance
(additions
underlined)
Concomitant
use of drugs that interfere with common renal tubular transport systems
involved in the renal elimination of metformin (e.g., organic cationic
transport-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 accumulation of metformin and 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.
8
Use in Specific Populations
Geriatric Use
(additions underlined)
Of
the 642 patients who received GLUCOVANCE in double-blind clinical studies,
23.8% were65 and older while 2.8% were 75 and older. Of the 1302 patients who
received GLUCOVANCE in open-label clinical studies, 20.7% were 65 and older
while 2.5% were 75 and older. No overall differences in effectiveness or safety
were observed between these patients and younger patients, and other reported
clinical experience has not identified differences in response between the
elderly and younger patients, but greater sensitivity of some older individuals
cannot be ruled out.
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
(revisions
and additions, please refer to label)
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