WARNINGS
Metformin Hydrochloride
Lactic acidosis:
Lactic
acidosis is a rare, but serious, metabolic complication that can occur due
to metformin accumulation during treatment with GLUCOVANCE (Glyburide and
Metformin HCl) Tablets; when it occurs, it is fatal in approximately 50% of
cases. Lactic acidosis may also occur in association with a number of pathophysiologic
conditions, including diabetes mellitus, and whenever there is significant
tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated
blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances
with an increased anion gap, and an increased lactate/pyruvate ratio. When
metformin is implicated as the cause of lactic acidosis, metformin plasma
levels >5 µg/mL are generally found.
The
reported incidence of lactic acidosis in patients receiving metformin hydrochloride
is very low (approximately 0.03 cases/1000 patient-years, with approximately
0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure
to metformin in clinical trials, there were no reports of lactic acidosis.
Reported cases have occurred primarily in diabetic patients with significant
renal insufficiency, including both intrinsic renal disease and renal hypoperfusion,
often in the setting of multiple concomitant medical/surgical problems and
multiple concomitant medications. Patients with congestive heart failure requiring
pharmacologic management, in particular those with unstable or acute congestive
heart failure who are at risk of hypoperfusion and hypoxemia, are at increased
risk of lactic acidosis. The risk of lactic acidosis increases with the degree
of renal dysfunction and the patient's age. The risk of lactic acidosis may,
therefore, be significantly decreased by regular monitoring of renal function
in patients taking metformin and by use of the minimum effective dose of metformin.
In particular, treatment of the elderly should be accompanied by careful monitoring
of renal function. GLUCOVANCE treatment should not be initiated in patients
≥80 years of age unless measurement of creatinine clearance demonstrates that
renal function is not reduced, as these patients are more susceptible to developing
lactic acidosis. In addition, GLUCOVANCE should be promptly withheld in the
presence of any condition associated with hypoxemia, dehydration, or sepsis.
Because impaired hepatic function may significantly limit the ability to clear
lactate, GLUCOVANCE should generally be avoided in patients with clinical
or laboratory evidence of hepatic disease. Patients should be cautioned against
excessive alcohol intake, either acute or chronic, when taking GLUCOVANCE,
since alcohol potentiates the effects of metformin hydrochloride on lactate
metabolism. In addition, GLUCOVANCE should be temporarily discontinued prior
to any intravascular radiocontrast study and for any surgical procedure (see
also PRECAUTIONS).
The
onset of lactic acidosis often is subtle, and accompanied only by nonspecific
symptoms such as malaise, myalgias, respiratory distress, increasing somnolence,
and nonspecific abdominal distress. There may be associated hypothermia, hypotension,
and resistant bradyarrhythmias with more marked acidosis. The patient and
the patient's physician must be aware of the possible importance of such symptoms
and the patient should be instructed to notify the physician immediately if
they occur (see also PRECAUTIONS). GLUCOVANCE should
be withdrawn until the situation is clarified. Serum electrolytes, ketones,
blood glucose, and if indicated, blood pH, lactate levels, and even blood
metformin levels may be useful. Once a patient is stabilized on any dose level
of GLUCOVANCE, gastrointestinal symptoms, which are common during initiation
of therapy with metformin, are unlikely to be drug related. Later occurrence
of gastrointestinal symptoms could be due to lactic acidosis or other serious
disease.
Levels of fasting venous plasma
lactate above the upper limit of normal but less than 5 mmol/L
in patients taking GLUCOVANCE do not necessarily indicate impending lactic
acidosis and may be explainable by other mechanisms, such as poorly controlled
diabetes or obesity, vigorous physical activity, or technical problems in
sample handling. (See also PRECAUTIONS.)
Lactic
acidosis should be suspected in any diabetic patient with metabolic acidosis
lacking evidence of ketoacidosis (ketonuria and ketonemia).
Lactic
acidosis is a medical emergency that must be treated in a hospital setting.
In a patient with lactic acidosis who is taking GLUCOVANCE, the drug should
be discontinued immediately and general supportive measures promptly instituted.
Because metformin hydrochloride is dialyzable (with a clearance of up to 170
mL/min under good hemodynamic conditions), prompt hemodialysis is recommended
to correct the acidosis and remove the accumulated metformin. Such management
often results in prompt reversal of symptoms and recovery. (See also CONTRAINDICATIONS and PRECAUTIONS.)
SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY
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 trial designed to evaluate the effectiveness
of glucose-lowering drugs in preventing or delaying vascular complications
in patients with non-insulin-dependent diabetes. The study involved 823 patients
who were randomly assigned to 1 of 4 treatment groups (Diabetes 19
(Suppl. 2):747-830, 1970).
UGDP reported
that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide
(1.5 g 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 1 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.
PRECAUTIONS
General
Macrovascular Outcomes
There have been no clinical
studies establishing conclusive evidence of macrovascular risk reduction with
GLUCOVANCE or any other antidiabetic drug.
GLUCOVANCE
Hypoglycemia
GLUCOVANCE is capable of producing hypoglycemia
or hypoglycemic symptoms, therefore, proper patient selection, dosing, and
instructions are important to avoid potential hypoglycemic episodes. The risk
of hypoglycemia is increased when caloric intake is deficient, when strenuous
exercise is not compensated by caloric supplementation, or during concomitant
use with other glucose-lowering agents or ethanol. Renal or hepatic insufficiency
may cause elevated drug levels of both glyburide and metformin hydrochloride,
and the hepatic insufficiency may also diminish gluconeogenic capacity, both
of which increase the risk of hypoglycemic reactions. 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 people who are
taking beta-adrenergic blocking drugs.
Glyburide
Hemolytic anemia
Treatment of patients with glucose-6-phosphate
dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic
anemia. Because GLUCOVANCE belongs to the class of sulfonylurea agents, caution
should be used in patients with G6PD deficiency and a non-sulfonylurea alternative
should be considered. In postmarketing reports, hemolytic anemia has also
been reported in patients who did not have known G6PD deficiency.
Metformin Hydrochloride
Monitoring of renal function
Metformin is known to be substantially
excreted by the kidney, and the risk of metformin accumulation and lactic
acidosis increases with the degree of impairment of renal function. Thus,
patients with serum creatinine levels above the upper limit of normal for
their age should not receive GLUCOVANCE. In patients with advanced age, GLUCOVANCE
should be carefully titrated to establish the minimum dose for adequate glycemic
effect, because aging is associated with reduced renal function. In elderly
patients, particularly those ≥80 years of age, renal function should be monitored
regularly and, generally, GLUCOVANCE should not be titrated to the maximum
dose (see
WARNINGS
and
DOSAGE
AND ADMINISTRATION). Before initiation of GLUCOVANCE therapy
and at least annually thereafter, renal function should be assessed and verified
as normal. In patients in whom development of renal dysfunction is anticipated,
renal function should be assessed more frequently and GLUCOVANCE discontinued
if evidence of renal impairment is present.
Use of concomitant medications that may affect renal function or metformin disposition
Concomitant medication(s) that may affect
renal function or result in significant hemodynamic change or may interfere
with the disposition of metformin, such as cationic drugs that are eliminated
by renal tubular secretion (see
PRECAUTIONS: Drug
Interactions), should be used with caution.
Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials)
Intravascular contrast studies with iodinated
materials can lead to acute alteration of renal function and have been associated
with lactic acidosis in patients receiving metformin (see
CONTRAINDICATIONS).
Therefore, in patients in whom any such study is planned, GLUCOVANCE should
be temporarily discontinued at the time of or prior to the procedure, and
withheld for 48 hours subsequent to the procedure and reinstituted only after
renal function has been reevaluated and found to be normal.
Hypoxic states
Cardiovascular collapse (shock) from whatever
cause, acute congestive heart failure, acute myocardial infarction, and other
conditions characterized by hypoxemia have been associated with lactic acidosis
and may also cause prerenal azotemia. When such events occur in patients on
GLUCOVANCE therapy, the drug should be promptly discontinued.
Surgical procedures
GLUCOVANCE therapy should be temporarily
suspended for any surgical procedure (except minor procedures not associated
with restricted intake of food and fluids) and should not be restarted until
the patient's oral intake has resumed and renal function has been evaluated
as normal.
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.
Due to its effect on the gluconeogenic capacity of the liver, alcohol may
also increase the risk of hypoglycemia.
Impaired hepatic function
Since impaired hepatic function has been
associated with some cases of lactic acidosis, GLUCOVANCE should generally
be avoided in patients with clinical or laboratory evidence of hepatic disease.
Vitamin B12 levels
In controlled clinical trials with metformin
of 29 weeks duration, a decrease to subnormal levels of previously normal
serum vitamin B12, 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 metformin or vitamin B12 supplementation.
Measurement of hematologic parameters on an annual basis is advised in patients
on metformin and any apparent abnormalities should be appropriately investigated
and managed (see
PRECAUTIONS: Laboratory Tests).
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.
Change in clinical status of patients with previously controlled type 2 diabetes
A patient with type 2 diabetes previously
well controlled on metformin who develops laboratory abnormalities or clinical
illness (especially vague and poorly defined illness) should be evaluated
promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should
include serum electrolytes and ketones, blood glucose and, if indicated, blood
pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs,
GLUCOVANCE must be stopped immediately and other appropriate corrective measures
initiated (see also
WARNINGS).
Addition of Thiazolidinediones to GLUCOVANCE Therapy
Hypoglycemia
Patients receiving GLUCOVANCE in combination
with a thiazolidinedione may be at risk for hypoglycemia.
Weight gain
Weight gain was seen with the addition
of rosiglitazone to GLUCOVANCE, similar to that reported for thiazolidinedione
therapy alone.
Hepatic effects
When a thiazolidinedione is used in combination
with GLUCOVANCE, periodic monitoring of liver function tests should be performed
in compliance with the labeled recommendations for the thiazolidinedione.
Information for Patients
GLUCOVANCE
Patients should be informed of the potential
risks and benefits of GLUCOVANCE and alternative modes of therapy. They should
also be informed about the importance of adherence to dietary instructions;
a regular exercise program; and regular testing of blood glucose, glycosylated
hemoglobin, renal function, and hematologic parameters.
The
risks of lactic acidosis associated with metformin therapy, its symptoms,
and conditions that predispose to its development, as noted in the
WARNINGS
and
PRECAUTIONS
sections,
should be explained to patients. Patients should be advised to discontinue
GLUCOVANCE immediately and promptly notify their health practitioner if unexplained
hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific
symptoms occur. Once a patient is stabilized on any dose level of GLUCOVANCE,
gastrointestinal symptoms, which are common during initiation of metformin
therapy, are unlikely to be drug related. Later occurrence of gastrointestinal
symptoms could be due to lactic acidosis or other serious disease.
The
risks of hypoglycemia, its symptoms and treatment, and conditions that predispose
to its development should be explained to patients and responsible family
members.
Patients should be counseled against excessive
alcohol intake, either acute or chronic, while receiving GLUCOVANCE. (See
Patient Information
printed below.)
Laboratory Tests
Periodic fasting blood glucose (FBG) and HbA1c measurements
should be performed to monitor therapeutic response.
Initial
and periodic monitoring of hematologic parameters (eg, hemoglobin/hematocrit
and red blood cell indices) and renal function (serum creatinine) should be
performed, at least on an annual basis. While megaloblastic anemia has rarely
been seen with metformin therapy, if this is suspected, vitamin B12 deficiency
should be excluded.
Drug Interactions
GLUCOVANCE
Certain drugs tend to produce hyperglycemia
and may lead to loss of blood glucose control. These drugs include thiazides
and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens,
oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium
channel blocking drugs, and isoniazid. When such drugs are administered to
a patient receiving GLUCOVANCE, the patient should be closely observed for
loss of blood glucose control. When such drugs are withdrawn from a patient
receiving GLUCOVANCE, the patient should be observed closely for hypoglycemia.
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 sulfonylureas, which are extensively
bound to serum proteins.
Glyburide
The
hypoglycemic action of sulfonylureas may be potentiated by certain drugs,
including nonsteroidal anti-inflammatory agents and other drugs that are highly
protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins,
monoamine oxidase inhibitors, and beta-adrenergic blocking agents. When such
drugs are administered to a patient receiving GLUCOVANCE, the patient should
be observed closely for hypoglycemia. When such drugs are withdrawn from a
patient receiving GLUCOVANCE, the patient should be observed closely for loss
of blood glucose control.
A possible interaction between
glyburide and ciprofloxacin, a fluoroquinolone antibiotic, has been reported,
resulting in a potentiation of the hypoglycemic action of glyburide. The mechanism
for this interaction is not known.
A potential interaction
between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia
has been reported. Whether this interaction also occurs with the intravenous,
topical, or vaginal preparations of miconazole is not known.
Metformin Hydrochloride
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.
Nifedipine
A single-dose, metformin-nifedipine drug
interaction study in normal healthy volunteers demonstrated that coadministration
of nifedipine increased plasma metformin Cmax and AUC
by 20% and 9%, respectively, and increased the amount excreted in the urine.
Tmax and half-life were unaffected. Nifedipine appears
to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.
Cationic drugs
Cationic drugs (eg, amiloride, digoxin,
morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim,
or vancomycin) that are eliminated by renal tubular secretion theoretically
have the potential for interaction with metformin by competing for common
renal tubular transport systems. 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. Although such interactions remain theoretical (except for
cimetidine), careful patient monitoring and dose adjustment of GLUCOVANCE
and/or the interfering drug is recommended in patients who are taking cationic
medications that are excreted via the proximal renal tubular secretory system.
Other
In
healthy volunteers, the pharmacokinetics of metformin and propranolol and
metformin and ibuprofen were not affected when coadministered in single-dose
interaction studies.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No
animal studies have been conducted with the combined products in GLUCOVANCE.
The following data are based on findings in studies performed with the individual
products.
Glyburide
Studies
in rats with glyburide alone at doses up to 300 mg/kg/day (approximately 145
times the maximum recommended human daily [MRHD] dose of 20 mg for the glyburide
component of GLUCOVANCE based on body surface area comparisons) for 18 months
revealed no carcinogenic effects. In a 2-year oncogenicity study of glyburide
in mice, there was no evidence of treatment-related tumors.
There
was no evidence of mutagenic potential of glyburide alone in the following in
vitro tests: Salmonella microsome test (Ames test)
and in the DNA damage/alkaline elution assay.
Metformin Hydrochloride
Long-term carcinogenicity studies were
performed with metformin alone in rats (dosing duration of 104 weeks) and
mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day
and 1500 mg/kg/day, respectively. These doses are both approximately 4 times
the MRHD dose of 2000 mg of the metformin component of GLUCOVANCE based on
body surface area comparisons. No evidence of carcinogenicity with metformin
alone was found in either male or female mice. Similarly, there was no tumorigenic
potential observed with metformin alone in male rats. There was, however,
an increased incidence of benign stromal uterine polyps in female rats treated
with 900 mg/kg/day of metformin alone.
There was no
evidence of a mutagenic potential of metformin alone in the following in
vitro tests: Ames test (S. typhimurium), gene mutation
test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes).
Results in the in vivo mouse micronucleus test were also
negative.
Fertility of male or female rats was unaffected
by metformin alone when administered at doses as high as 600 mg/kg/day, which
is approximately 3 times the MRHD dose of the metformin component of GLUCOVANCE
based on body surface area comparisons.
Pregnancy
Teratogenic Effects: Pregnancy Category B
Recent information strongly
suggests that abnormal blood glucose levels during pregnancy are associated
with a higher incidence of congenital abnormalities. Most experts recommend
that insulin be used during pregnancy to maintain blood glucose as close to
normal as possible. Because animal reproduction studies are not always predictive
of human response, GLUCOVANCE should not be used during pregnancy unless clearly
needed. (See below.)
There are no adequate and well-controlled
studies in pregnant women with GLUCOVANCE or its individual components. No
animal studies have been conducted with the combined products in GLUCOVANCE.
The following data are based on findings in studies performed with the individual
products.
Glyburide
Reproduction studies were performed in
rats and rabbits at doses up to 500 times the MRHD dose of 20 mg of the glyburide
component of GLUCOVANCE based on body surface area comparisons and revealed
no evidence of impaired fertility or harm to the fetus due to glyburide.
Metformin Hydrochloride
Metformin alone was not teratogenic in
rats or rabbits at doses up to 600 mg/kg/day. This represents an exposure
of about 2 and 6 times the MRHD dose of 2000 mg of the metformin component
of GLUCOVANCE based on body surface area comparisons for rats and rabbits,
respectively. Determination of fetal concentrations demonstrated a partial
placental barrier to metformin.
Nonteratogenic Effects
Prolonged severe hypoglycemia (4-10 days)
has been reported in neonates born to mothers who were receiving a sulfonylurea
drug at the time of delivery. This has been reported more frequently with
the use of agents with prolonged half-lives. It is not recommended that GLUCOVANCE
be used during pregnancy. However, if it is used, GLUCOVANCE should be discontinued
at least 2 weeks before the expected delivery date. (See
Pregnancy:
Teratogenic Effects: Pregnancy Category B.)
Nursing Mothers
Although it is not known whether
glyburide is excreted in human milk, some sulfonylurea drugs are known to
be excreted in human milk. Studies in lactating rats show that metformin is
excreted into milk and reaches levels comparable to those in plasma. Similar
studies have not been conducted in nursing mothers. Because the potential
for hypoglycemia in nursing infants may exist, a decision should be made whether
to discontinue nursing or to discontinue GLUCOVANCE, taking into account the
importance of the drug to the mother. If GLUCOVANCE is discontinued, and if
diet alone is inadequate for controlling blood glucose, insulin therapy should
be considered.
Pediatric Use
The safety and efficacy
of GLUCOVANCE were evaluated in an active-controlled, double-blind, 26-week
randomized trial involving a total of 167 pediatric patients (ranging from
9-16 years of age) with type 2 diabetes. GLUCOVANCE was not shown statistically
to be superior to either metformin or glyburide with respect to reducing HbA1c from
baseline (see
Table 5). No unexpected
safety findings were associated with GLUCOVANCE in this trial.
Table 5: HbA1c (Percent) Change From Baseline
at 26 Weeks: Pediatric Study
|
Glyburide 2.5
mg tablets
|
Metformin 500
mg tablets
|
GLUCOVANCE 1.25
mg/250 mg tablets
|
Mean
Final Dose
|
6.5 mg |
1500 mg |
3.1 mg/623
mg |
Hemoglobin
A1c
|
N=49 |
N=54 |
N=57 |
Baseline
Mean (%) |
7.70 |
7.99 |
7.85 |
Mean
Change from Baseline |
−0.96 |
−0.48 |
−0.80 |
Difference
from Metformin |
|
|
−0.32 |
Difference
from Glyburide |
|
|
+0.16 |
Geriatric Use
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. 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.
Metformin
hydrochloride is known to be substantially excreted by the kidney and because
the risk of serious adverse reactions to the drug is greater in patients with
impaired renal function, GLUCOVANCE should only be used in patients with normal
renal function (see
CONTRAINDICATIONS,
WARNINGS, and
CLINICAL PHARMACOLOGY:
Pharmacokinetics). Because aging is associated with reduced
renal function, GLUCOVANCE should be used with caution as age increases. Care
should be taken in dose selection and should be based on careful and regular
monitoring of renal function. Generally, elderly patients should not be titrated
to the maximum dose of GLUCOVANCE (see also
WARNINGS
and
DOSAGE AND ADMINISTRATION).
|