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Glucovance Warnings, Precautions, Pregnancy, Nursing, Abuse - Glyburide and Metformin
Glucovance Warnings, Precautions, Pregnancy, Nursing, Abuse - Glyburide and Metformin
WARNINGS
Metformin Hydrochloride
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Lactic Acidosis
Lactic acidosis is a rare, but serious, metabolic complication that can
occur due to metformin accumulation during treatment with GLUCOVANCE;
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). 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.)
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PRECAUTIONS
General
GLUCOVANCE
Hypoglycemia --GLUCOVANCE (Glyburide and Metformin HCl Tablets) 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 in people who
are taking beta-adrenergic blocking drugs.
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 B 12 levels --In controlled clinical trials with
metformin of 29 weeks duration, a decrease to subnormal levels of previously
normal serum Vitamin B 12 , without clinical manifestations, was
observed in approximately 7% of patients. Such decrease, possibly due to interference
with B 12 absorption from the B 12 -intrinsic factor complex,
is, however, very rarely associated with anemia and appears to be rapidly reversible
with discontinuation of metformin or Vitamin B 12 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 B 12 or calcium
intake or absorption) appear to be predisposed to developing subnormal Vitamin
B 12 levels. In these patients, routine serum Vitamin B 12 measurements
at two- to three-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
).
Information for Patients
GLUCOVANCE
Patients should be informed of the potential risks and benefits of GLUCOVANCE
and of alternative modes of therapy. They should also be informed about the
importance of adherence to dietary instructions, of a regular exercise program,
and of 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 (Glyburide and Metformin HCl Tablets)
immediately and to 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.
(SeePatient INFORMATIONPrinted Below.)
Laboratory Tests
Periodic fasting blood glucose and glycosylated hemoglobin (HbA 1c )
measurements should be performed to monitor therapeutic response.
Initial and periodic monitoring of hematologic parameters (e.g., 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 B 12 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 the 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 co-administration. Furosemide increased the metformin plasma
and blood C max by 22% and blood AUC by 15%, without any significant
change in metformin renal clearance. When administered with metformin, the C
max 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 co-administered
chronically.
Nifedipine --A single-dose, metformin-nifedipine drug interaction study
in normal healthy volunteers demonstrated that co-administration of nifedipine
increased plasma metformin C max and AUC by 20% and 9%, respectively,
and increased the amount excreted in the urine. T max and half-life
were unaffected. Nifedipine appears to enhance the absorption of metformin.
Metformin had minimal effects on nifedipine.
Cationic drugs --Cationic drugs (e.g., 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 co-administered
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 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 two-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 four times the maximum recommended human daily dose of
2000 mg of the metformin component of GLUCOVANCE (Glyburide and Metformin HCl
Tablets) 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 three times the maximum
recommended human daily 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 maximum recommended human daily 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 two and six times the maximum recommended
human daily 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 to 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 two 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
Safety and effectiveness of GLUCOVANCE in pediatric patients have not been
established.
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 ).
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