Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3855
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GLUCOVANCE (Tablet, Film Coated)
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General Considerations: Dosage of GLUCOVANCE must be individualized
on the basis of both effectiveness and tolerance while not exceeding the maximum
recommended daily dose of 20 mg glyburide/2000 mg metformin. GLUCOVANCE
should be given with meals and should be initiated at a low dose, with gradual
dose escalation as described below, in order to avoid hypoglycemia (largely
due to glyburide), to reduce GI side effects (largely due to metformin), and
to permit determination of the minimum effective dose for adequate control
of blood glucose for the individual patient. With
initial treatment and during dose titration, appropriate blood glucose monitoring
should be used to determine the therapeutic response to GLUCOVANCE and to
identify the minimum effective dose for the patient. Thereafter, HbAshould
be measured at intervals of approximately 3 months to assess the effectiveness
of therapy. The therapeutic goal in all patients with type 2 diabetes is to
decrease FPG, PPG, and HbAto normal or as near normal
as possible. Ideally, the response to therapy should be evaluated using HbA(glycosylated
hemoglobin), which is a better indicator of long-term glycemic control than
FPG alone. No studies have been performed specifically
examining the safety and efficacy of switching to GLUCOVANCE therapy in patients
taking concomitant glyburide (or other sulfonylurea) plus metformin. Changes
in glycemic control may occur in such patients, with either hyperglycemia
or hypoglycemia possible. Any change in therapy of type 2 diabetes should
be undertaken with care and appropriate monitoring.<br/>GLUCOVANCE in Patients with Inadequate Glycemic Control on Diet and Exercise: Recommended starting dose: 1.25
mg/250 mg once or twice daily with meals. For
patients with type 2 diabetes whose hyperglycemia cannot be satisfactorily
managed with diet and exercise alone, the recommended starting dose of GLUCOVANCE
is 1.25 mg/250 mg once a day with a meal. As initial therapy in patients with
baseline HbA>9% or an FPG>200 mg/dL,
a starting dose of GLUCOVANCE 1.25 mg/250 mg twice daily with the morning
and evening meals may be used. Dosage increases should be made in increments
of 1.25 mg/250 mg per day every two weeks
up to the minimum effective dose necessary to achieve adequate control of
blood glucose. In clinical trials of GLUCOVANCE as initial therapy, there
was no experience with total daily doses greater than 10 mg/2000 mg per day.GLUCOVANCE
5 mg/500 mg should not be used as initial therapy due to
an increased risk of hypoglycemia.<br/>GLUCOVANCE Use in Patients with Inadequate Glycemic Control on a Sulfonylurea and/or Metformin: Recommended starting dose: 2.5
mg/500 mg or 5 mg/500 mg twice daily with meals. For
patients not adequately controlled on either glyburide (or another sulfonylurea)
or metformin alone, the recommended starting dose of GLUCOVANCE is 2.5 mg/500
mg or 5 mg/500 mg twice daily with the morning and evening
meals. In order to avoid hypoglycemia, the starting dose of GLUCOVANCE should
not exceed the daily doses of glyburide or metformin already being taken.
The daily dose should be titrated in increments of no more than 5 mg/500 mg
up to the minimum effective dose to achieve adequate control of blood glucose
or to a maximum dose of 20 mg/2000 mg per day. For
patients previously treated with combination therapy of glyburide (or another
sulfonylurea) plus metformin, if switched to GLUCOVANCE, the starting dose
should not exceed the daily dose of glyburide (or equivalent dose of another
sulfonylurea) and metformin already being taken. Patients should be monitored
closely for signs and symptoms ofhypoglycemia following such a switch and
the dose of GLUCOVANCE should be titrated as described above to achieve adequate
control of blood glucose.<br/>Addition of Thiazolidinediones to GLUCOVANCE Therapy: For patients not adequately controlled
on GLUCOVANCE, a thiazolidinedione can be added to GLUCOVANCE therapy. When
a thiazolidinedione is added to GLUCOVANCE therapy, the current dose of GLUCOVANCE
can be continued and the thiazolidinedione initiated at its recommended starting
dose. For patients needing additional glycemic control, the dose of the thiazolidinedione
can be increased based on its recommended titration schedule. The increased
glycemic control attainable with GLUCOVANCE plus a thiazolidinedione may increase
the potential for hypoglycemia at any time of day. In patients who develop
hypoglycemia when receiving GLUCOVANCE and a thiazolidinedione, consideration
should be given to reducing the dose of the glyburide component of GLUCOVANCE.
As clinically warranted, adjustment of the dosages of the other components
of the antidiabetic regimen should also be considered.<br/>Specific Patient Populations: GLUCOVANCE is not recommended for use
during pregnancy. The initial and maintenance dosing of GLUCOVANCE should
be conservative in patients with advanced age, due to the potential for decreased
renal function in this population. Any dosage adjustment requires a careful
assessment of renal function. Generally, elderly, debilitated, and malnourished
patients should not be titrated to the maximum dose of GLUCOVANCE to avoid
the risk of hypoglycemia. Monitoring of renal function is necessary to aid
in prevention of metformin-associated lactic acidosis, particularly in the
elderly.
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GLUCOVANCE (Glyburide
and Metformin HCl Tablets) contains two oral antihyperglycemic drugs used
in the management of type 2 diabetes, glyburide and metformin hydrochloride. Glyburide
is an oral antihyperglycemic drug of the sulfonylurea class. The chemical
name for glyburide is 1-[[p-[2-(5-chloro-o-anisamido)ethyl]phenyl]sulfonyl]-3-cyclo-hexylurea.
Glyburide is a white to off-white crystalline compound with a molecular formula
of CHClNOS
and a molecular weight of 494.01. The glyburide used in GLUCOVANCE has a particle
size distribution of 25% undersize value not more than 6��m, 50% undersize
value not more than 7-10��m, and 75% undersize value not more than 21��m.
The structural formula is represented below. Metformin
hydrochloride is an oral antihyperglycemic drug used in the management of
type 2 diabetes. Metformin hydrochloride (N,N-dimethylimidodicarbonimidic
diamide monohydrochloride) is not chemically or pharmacologically related
to sulfonylureas, thiazolidinediones, or��-glucosidase inhibitors. It is a
white to off-white crystalline compound with a molecular formula of CHClN(monohydrochloride) and a molecular weight of 165.63. Metformin hydrochloride
is freely soluble in water and is practically insoluble in acetone, ether,
and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution
of metformin hydrochloride is 6.68. The structural formula is as shown: GLUCOVANCE is available for oral administration
in tablets containing 1.25 mg glyburide with 250 mg metformin hydrochloride,
2.5 mg glyburide with 500 mg metformin hydrochloride, and 5 mg glyburide with
500 mg metformin hydrochloride. In addition, each tablet contains the following
inactive ingredients: microcrystalline cellulose, povidone, croscarmellose
sodium, and magnesium stearate. The tablets are film coated, which provides
color differentiation.
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Mechanism of Action: GLUCOVANCE combines glyburide and metformin
hydrochloride, two antihyperglycemic agents with complementary mechanisms
of action, to improve glycemic control in patients with type 2 diabetes. Glyburide appears to lower blood glucose
acutely by stimulating the release of insulin from the pancreas, an effect
dependent upon functioning beta cells in the pancreatic islets. The mechanism
by which glyburide lowers blood glucose during long-term administration has
not been clearly established. With chronic administration in patients with
type 2 diabetes, the blood glucose lowering effect persists despite a gradual
decline in the insulin secretory response to the drug. Extrapancreatic effects
may be involved in the mechanism of action of oral sulfonylurea hypoglycemic
drugs. Metformin hydrochloride is an antihyperglycemic
agent that improves glucose tolerance in patients with type 2 diabetes, lowering
both basal and postprandial plasma glucose. Metformin hydrochloride decreases
hepatic glucose production, decreases intestinal absorption of glucose, and
improves insulin sensitivity by increasing peripheral glucose uptake and utilization.<br/>Pharmacokinetics:<br/>Absorption and Bioavailability:<br/>Distribution:<br/>Metabolism and Elimination:<br/>Special Populations:<br/>Patients With Type 2 Diabetes: Multiple-dose studies with glyburide
in patients with type 2 diabetes demonstrate drug level concentration-time
curves similar to single-dose studies, indicating no buildup of drug in tissue
depots. In the presence of normal renal function, there
are no differences between single- or multiple-dose pharmacokinetics of metformin
between patients with type 2 diabetes and normal subjects (see Table 1), nor is there any accumulation of metformin
in either group at usual clinical doses.<br/>Hepatic Insufficiency: No pharmacokinetic studies have been
conducted in patients with hepatic insufficiency for either glyburide or metformin.<br/>Renal Insufficiency: No information is available on the pharmacokinetics
of glyburide in patients with renal insufficiency. In
patients with decreased renal function (based on creatinine clearance), the
plasma and blood half-life of metformin is prolonged and the renal clearance
is decreased in proportion to the decrease in creatinine clearance (see Table 1; also, see WARNINGS).<br/>Geriatrics: There is no information on the pharmacokinetics
of glyburide in elderly patients. Limited data from
controlled pharmacokinetic studies of metformin in healthy elderly subjects
suggest that total plasma clearance is decreased, the half-life is prolonged,
and Cis increased, compared to healthy young subjects.
From these data, it appears that the change in metformin pharmacokinetics
with aging is primarily accounted for by a change in renal function (see Table 1). Metformin treatment should not be initiated
in patients���80 years of age unless measurement of creatinine clearance demonstrates
that renal function is not reduced.<br/>Pediatrics: After administration of a single oral
GLUCOPHAGE (metformin hydrochloride) 500 mg tablet
with food, geometric mean metformin Cand AUC differed
less than 5% between pediatric type 2 diabetic patients (12 to 16 years of
age) and gender- and weight-matched healthy adults (20 to 45 years of age),
all with normal renal function. After administration
of a single oral GLUCOVANCE tablet with food, dose-normalized geometric mean
glyburide Cand AUC in pediatric patients with type
2 diabetes (11 to 16 years of age, n=28, mean body weight of 97 kg) differed
less than 6% from historical values in healthy adults.<br/>Gender: There
is no information on the effect of gender on the pharmacokinetics of glyburide. Metformin
pharmacokinetic parameters did not differ significantly in subjects with or
without type 2 diabetes when analyzed according to gender (males=19, females=16).
Similarly, in controlled clinical studies in patients with type 2 diabetes,
the antihyperglycemic effect of metformin was comparable in males and females.<br/>Race: No
information is available on race differences in the pharmacokinetics of glyburide. No
studies of metformin pharmacokinetic parameters according to race have been
performed. In controlled clinical studies of metformin in patients with type
2 diabetes, the antihyperglycemic effect was comparable in whites (n=249),
blacks (n=51), and Hispanics (n=24).<br/>Clinical Studies:<br/>Patients with Inadequate Glycemic Control on Diet and Exercise Alone: In a 20-week, double-blind, multicenter
U.S. clinical trial, a total of 806 drug-naive patients with type 2 diabetes,
whose hyperglycemia was not adequately controlled with diet and exercise alone
(baseline fasting plasma glucose [FPG]<240 mg/dL, baseline hemoglobin
A[HbA] between 7% and 11%),
were randomized to receive initial therapy with placebo, 2.5 mg
glyburide, 500 mg metformin, GLUCOVANCE 1.25 mg/250 mg, or GLUCOVANCE 2.5 mg/500
mg. After four weeks, the dose was progressively increased (up to the eight-week
visit) to a maximum of four tablets daily as needed to reach a target FPG
of 126 mg/dL. Trial data at 20 weeks are summarized in Table 2. Treatment with GLUCOVANCE resulted in significantly greater
reduction in HbAand postprandial plasma glucose
(PPG) compared to glyburide, metformin, or placebo. Also, GLUCOVANCE therapy
resulted in greater reduction in FPG compared to glyburide, metformin, or
placebo, but the differences from glyburide and metformin did not reach statistical
significance. Changes in the lipid profile associated
with GLUCOVANCE treatment were similar to those seen with glyburide, metformin,
and placebo. The double-blind, placebo-controlled trial
described above restricted enrollment to patients with HbA<11%
or FPG<240 mg/dL. Screened patients ineligible for the first trial because
of HbAand/or FPG exceeding these limits were treated
directly with GLUCOVANCE 2.5 mg/500 mg in an open-label,
uncontrolled protocol. In this study, three out of 173 patients (1.7%) discontinued
because of inadequate therapeutic response. Across the group of 144 patients
who completed 26 weeks of treatment, mean HbAwas
reduced from a baseline of 10.6% to 7.1%. The mean baseline FPG was 283 mg/dL
and was reduced to 164 and 161 mg/dL after 2 and 26 weeks,
respectively. The mean final titrated dose of GLUCOVANCE was 7.85 mg/1569
mg (equivalent to approximately three GLUCOVANCE 2.5 mg/500 mg tablets per
day).<br/>Patients with Inadequate Glycemic Control on Sulfonylurea Alone: In a 16-week, double-blind, active-controlled
U.S. clinical trial, a total of 639 patients with type 2 diabetes not adequately
controlled (mean baseline HbA9.5%, mean baseline
FPG 213 mg/dL) while being treated with at least one-half
the maximum dose of a sulfonylurea (e.g., glyburide 10 mg, glipizide 20 mg)
were randomized to receive glyburide (fixed dose, 20 mg),
metformin (500 mg), GLUCOVANCE 2.5 mg/500 mg,
or GLUCOVANCE 5 mg/500 mg.
The doses of metformin and GLUCOVANCE were titrated to a maximum of four tablets
daily as needed to achieve FPG<140 mg/dL. Trial data at 16 weeks are summarized
in Table 3. After 16 weeks, there was no significant change in the
mean HbAin patients randomized to glyburide or to
metformin therapy. Treatment with GLUCOVANCE at doses up to 20 mg/2000 mg
per day resulted in significant lowering of HbA,
FPG, and PPG from baseline compared to glyburide or metformin alone.<br/>Addition of Thiazolidinediones to GLUCOVANCE Therapy: In a 24-week, double-blind, multicenter
U.S. clinical trial, patients with type 2 diabetes not adequately controlled
on current oral antihyperglycemic therapy (either monotherapy or combination
therapy) were first switched to open label GLUCOVANCE 2.5 mg/500 mg tablets
and titrated to a maximum daily dose of 10 mg/2000 mg. A total of 365 patients
inadequately controlled (HbA>7.0% and���10%) after
10 to 12 weeks of a daily GLUCOVANCE dose of at least 7.5 mg/1500 mg were
randomized to receive add-on therapy with rosiglitazone 4 mg or placebo once
daily. After eight weeks, the rosiglitazone dose was increased to a maximum
of 8 mg daily as needed to reach a target mean daily glucose
of 126 mg/dL or HbA<7%. Trial data at 24 weeks
or at the last prior visit are summarized in Table 4. For patients who did not achieve adequate glycemic control
on GLUCOVANCE, the addition of rosiglitazone, compared to placebo, resulted
in significant lowering of HbAand FPG.
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GLUCOVANCE (Glyburide and Metformin HCl
Tablets) is contraindicated in patients with: GLUCOVANCE should be temporarily discontinued in patients
undergoing radiologic studies involving intravascular administration of iodinated
contrast materials, because use of such products may result in acute alteration
of renal function.
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GLUCOVANCE (Glyburide
and Metformin HCl Tablets) GLUCOVANCE 1.25
mg/250 mg tablet is a pale yellow, capsule-shaped, bevel-edged, biconvex,
film-coated tablet with "BMS" debossed on one side and "6072"
debossed on the opposite side. GLUCOVANCE 2.5
mg/500 mg tablet is a pale orange, capsule-shaped, bevel-edged, biconvex,
film-coated tablet with "BMS" debossed on one side and "6073"
debossed on the opposite side. GLUCOVANCE 5
mg/500 mg tablet is a yellow, capsule-shaped, bevel-edged, biconvex,
film-coated tablet with "BMS" debossed on one side and "6074"
debossed on the opposite side.<br/>STORAGE: Store
at temperatures up to 25��C (77��F). [See USP Controlled Room Temperature.] Dispense
in light-resistant containers.
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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��g/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 . 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, gastrointestinalsymptoms, 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. 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.
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General:<br/>Macrovascular Outcomes: There have been no clinical
studies establishing conclusive evidence of macrovascular risk reduction with
GLUCOVANCE or any other anti-diabetic drug.<br/>GLUCOVANCE:<br/>Metformin Hydrochloride:<br/>Addition of Thiazolidinediones to GLUCOVANCE Therapy:<br/>Information for Patients:<br/>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 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. (See Patient Information printed
below.)<br/>Laboratory Tests: Periodic fasting blood glucose and glycosylated
hemoglobin (HbA) 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 Bdeficiency
should be excluded.<br/>Drug Interactions:<br/>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.<br/>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.<br/>Metformin Hydrochloride:<br/>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.<br/>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.<br/>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 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.<br/>Pregnancy:<br/>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.<br/>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.)<br/>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.<br/>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 to 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 HbAfrom
baseline (see Table 5). No unexpected
safety findings were associated with GLUCOVANCE in this trial.<br/>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 .
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Glyburide: Overdosage
of sulfonylureas, including glyburide tablets, can produce hypoglycemia. Mild
hypoglycemic symptoms, without loss of consciousness or neurological findings,
should be treated aggressively with oral glucose and adjustments in drug dosage
and/or meal patterns. Close monitoring should continue until the physician
is assured that the patient is out of danger. Severe hypoglycemic reactions
with coma, seizure, or other neurological impairment occur infrequently, but
constitute medical emergencies requiring immediate hospitalization. If hypoglycemic
coma is diagnosed or suspected, the patient should be given a rapid intravenous
injection of concentrated (50%) glucose solution. This should be followed
by a continuous infusion of a more dilute (10%) glucose solution at a rate
that will maintain the blood glucose at a level above 100 mg/dL. Patients
should be closely monitored for a minimum of 24 to 48 hours, since hypoglycemia
may recur after apparent clinical recovery.<br/>Metformin Hydrochloride: Overdose of metformin hydrochloride has
occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia
was reported in approximately 10% of cases, but no causal association with
metformin hydrochloride has been established. Lactic acidosis has been reported
in approximately 32% of metformin overdose cases .
Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic
conditions. Therefore, hemodialysis may be useful for removal of accumulated
drug from patients in whom metformin overdosage is suspected.
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GLYBURIDE AND METFORMIN HYDROCHLORIDE
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GLUCOVANCE (Tablet, Film Coated)
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GLUCOVANCE: In
double-blind clinical trials involving GLUCOVANCE as initial therapy or as
second-line therapy, a total of 642 patients received GLUCOVANCE, 312 received
metformin therapy, 324 received glyburide therapy, and 161 received placebo.
The percent of patients reporting events and types of adverse events reported
in clinical trials of GLUCOVANCE (all strengths) as initial therapy and second-line
therapy are listed in Table 6. In a controlled clinical trial of rosiglitazone versus
placebo in patients treated with GLUCOVANCE (n=365), 181 patients received
GLUCOVANCE with rosiglitazone and 184 received GLUCOVANCE with placebo. Edema
was reported in 7.7% (14/181) of patients treated with rosiglitazone compared
to 2.2% (4/184) of patients treated with placebo. A mean weight gain of 3
kg was observed in rosiglitazone-treated patients. Disulfiram-like
reactions have very rarely been reported in patients treated with glyburide
tablets.<br/>Hypoglycemia: In controlled clinical trials of GLUCOVANCE
there were no hypoglycemic episodes requiring medical intervention and/or
pharmacologic therapy; all events were managed by the patients. The incidence
of reported symptoms of hypoglycemia (such as dizziness, shakiness, sweating,
and hunger), in the initial therapy trial of GLUCOVANCE are summarized in Table
7. The frequency of hypoglycemic symptoms in patients treated with
GLUCOVANCE 1.25 mg/250 mg was highest in
patients with a baseline HbA<7%, lower in those
with a baseline HbAof between 7% and 8%, and was
comparable to placebo and metformin in those with a baseline HbA>8%.
For patients with a baseline HbAbetween 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. When rosiglitazone was
added to GLUCOVANCE therapy, 22% of patients reported one or more fingerstick
glucose measurements���50 mg/dL compared to 3.3% of placebo-treated patients.
All hypoglycemic events were managed by the patients and only one patient
discontinued for hypoglycemia. (See PRECAUTIONS:
General: Addition of Thiazolidinediones to GLUCOVANCE Therapy.)<br/>Gastrointestinal Reactions: The incidence of GI side effects (diarrhea,
nausea/vomiting, and abdominal pain) in the initial therapy trial are summarized
in Table 7. Across all GLUCOVANCE trials, GI symptoms were the
most common adverse events with GLUCOVANCE and were more frequent at higher
dose levels. In controlled trials,<2% of patients discontinued GLUCOVANCE
therapy due to GI adverse events.
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Metformin Hydrochloride: 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��g/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 . 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, gastrointestinalsymptoms, 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. 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.<br/>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 one of four 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 2-1/2
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.
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GLUCOVANCE is indicated as an adjunct
to diet and exercise to improve glycemic control in adults with type 2 diabetes
mellitus.
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GLUCOVANCE
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