Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1121
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GLUCOPHAGE (Tablet, Film Coated)
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There is no fixed dosage regimen for the management of hyperglycemia
in patients with type 2 diabetes with GLUCOPHAGE or GLUCOPHAGE XR or any other
pharmacologic agent. Dosage of GLUCOPHAGE or GLUCOPHAGE XR must be individualized
on the basis of both effectiveness and tolerance, while not exceeding the
maximum recommended daily doses. The maximum recommended daily dose of GLUCOPHAGE
is 2550 mg in adults and 2000 mg in pediatric patients (10-16 years of age);
the maximum recommended daily dose of GLUCOPHAGE XR in adults is 2000 mg. GLUCOPHAGE should be given in divided doses with meals while GLUCOPHAGE
XR should generally be given once daily with the evening meal. GLUCOPHAGE
or GLUCOPHAGE XR should be started at a low dose, with gradual dose escalation,
both to reduce gastrointestinal side effects and to permit identification
of the minimum dose required for adequate glycemic control of the patient. During treatment initiation and dose titration (see Recommended Dosing Schedule), fasting plasma glucose
should be used to determine the therapeutic response to GLUCOPHAGE or GLUCOPHAGE
XR and identify the minimum effective dose for the patient. Thereafter, glycosylated
hemoglobin should be measured at intervals of approximately three months. The
therapeutic goal should be to decrease both fasting plasma glucose and glycosylated
hemoglobin levels to normal or near normal by using the lowest effective dose
of GLUCOPHAGE or GLUCOPHAGE XR, either when used as monotherapy or in combination
with sulfonylurea or insulin. Monitoring of blood glucose and glycosylated hemoglobin will also
permit detection of primary failure, i.e., inadequate lowering of blood glucose
at the maximum recommended dose of medication, and secondary failure, i.e.,
loss of an adequate blood glucose lowering response after an initial period
of effectiveness. Short-term administration of GLUCOPHAGE or GLUCOPHAGE XR may be
sufficient during periods of transient loss of control in patients usually
well-controlled on diet alone. GLUCOPHAGE XR tablets must be swallowed whole and never crushed
or chewed. Occasionally, the inactive ingredients of GLUCOPHAGE XR
will be eliminated in the feces as a soft, hydrated mass. (See Patient Information printed below.)<br/>Recommended Dosing Schedule: Adults - In general, clinically significant responses
are not seen at doses below 1500 mg per day. However, a lower recommended
starting dose and gradually increased dosage is advised to minimize gastrointestinal
symptoms. The usual starting dose of GLUCOPHAGE (metformin hydrochloride
tablets) is 500 mg twice a day or 850 mg once a day, given with meals. Dosage
increases should be made in increments of 500 mg weekly or 850 mg every 2
weeks, up to a total of 2000 mg per day, given in divided doses. Patients
can also be titrated from 500 mg twice a day to 850 mg twice a day after 2
weeks. For those patients requiring additional glycemic control, GLUCOPHAGE
may be given to a maximum daily dose of 2550 mg per day. Doses above 2000
mg may be better tolerated given three times a day with meals. The usual starting dose of GLUCOPHAGE XR (metformin hydrochloride
extended-release tablets) is 500 mg once daily with the evening meal. Dosage
increases should be made in increments of 500 mg weekly, up to a maximum of
2000 mg once daily with the evening meal. If glycemic control is not achieved
on GLUCOPHAGE XR 2000 mg once daily, a trial of GLUCOPHAGE XR 1000 mg twice
daily should be considered. If higher doses of metformin are required, GLUCOPHAGE
should be used at total daily doses up to 2550 mg administered in divided
daily doses, as described above. (See CLINICAL PHARMACOLOGY:
Clinical Studies.) In a randomized trial, patients currently treated with GLUCOPHAGE
were switched to GLUCOPHAGE XR. Results of this trial suggest that patients
receiving GLUCOPHAGE treatment may be safely switched to GLUCOPHAGE XR once
daily at the same total daily dose, up to 2000 mg once daily. Following a
switch from GLUCOPHAGE to GLUCOPHAGE XR, glycemic control should be closely
monitored and dosage adjustments made accordingly (see CLINICAL
PHARMACOLOGY: Clinical Studies). Pediatrics - The usual starting dose of GLUCOPHAGE
is 500 mg twice a day, given with meals. Dosage increases should be made in
increments of 500 mg weekly up to a maximum of 2000 mg per day, given in divided
doses. Safety and effectiveness of GLUCOPHAGE XR in pediatric patients have
not been established.<br/>Transfer From Other Antidiabetic Therapy: When transferring patients from standard oral hypoglycemic agents
other than chlorpropamide to GLUCOPHAGE or GLUCOPHAGE XR, no transition period
generally is necessary. When transferring patients from chlorpropamide, care
should be exercised during the first two weeks because of the prolonged retention
of chlorpropamide in the body, leading to overlapping drug effects and possible
hypoglycemia.<br/>Concomitant GLUCOPHAGE or GLUCOPHAGE XR and Oral Sulfonylurea Therapy in Adult Patients: If patients have not responded to four weeks of the maximum dose
of GLUCOPHAGE or GLUCOPHAGE XR monotherapy, consideration should be given
to gradual addition of an oral sulfonylurea while continuing GLUCOPHAGE or
GLUCOPHAGE XR at the maximum dose, even if prior primary or secondary failure
to a sulfonylurea has occurred. Clinical and pharmacokinetic drug-drug interaction
data are currently available only for metformin plus glyburide (glibenclamide). With concomitant GLUCOPHAGE or GLUCOPHAGE XR and sulfonylurea therapy,
the desired control of blood glucose may be obtained by adjusting the dose
of each drug. In a clinical trial of patients with type 2 diabetes and prior
failure on glyburide, patients started on GLUCOPHAGE 500 mg and glyburide
20 mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg or 2500/20 mg of
GLUCOPHAGE and glyburide, respectively, to reach the goal of glycemic control
as measured by FPG, HbAand plasma glucose response
.
However, attempts should be made to identify the minimum effective dose of
each drug to achieve this goal. With concomitant GLUCOPHAGE or GLUCOPHAGE
XR and sulfonylurea therapy, the risk of hypoglycemia associated with sulfonylurea
therapy continues and may be increased. Appropriate precautions should be
taken. (See Package Insert of the respective sulfonylurea.) If patients have not satisfactorily responded to one to three months
of concomitant therapy with the maximum dose of GLUCOPHAGE or GLUCOPHAGE XR
and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives
including switching to insulin with or without GLUCOPHAGE or GLUCOPHAGE XR.<br/>Concomitant GLUCOPHAGE or GLUCOPHAGE XR and Insulin Therapy in Adult Patients: The current insulin dose should be continued upon initiation of
GLUCOPHAGE or GLUCOPHAGE XR therapy. GLUCOPHAGE or GLUCOPHAGE XR therapy should
be initiated at 500 mg once daily in patients on insulin therapy. For patients
not responding adequately, the dose of GLUCOPHAGE or GLUCOPHAGE XR should
be increased by 500 mg after approximately 1 week and by
500 mg every week thereafter until adequate glycemic control is achieved.The maximum recommended daily dose is 2500 mg for GLUCOPHAGE and 2000 mg for
GLUCOPHAGE XR. It is recommended that the insulin dose be decreased by 10%
to 25% when fasting plasma glucose concentrations decrease to less than 120
mg/dL in patients receiving concomitant insulin and GLUCOPHAGE or GLUCOPHAGE
XR. Further adjustment should be individualized based on glucose-lowering
response.<br/>Specific Patient Populations: GLUCOPHAGE or GLUCOPHAGE XR are not recommended
for use in pregnancy. GLUCOPHAGE is not recommended in patients below the
age of 10 years. GLUCOPHAGE XR is not recommended in pediatric patients (below
the age of 17 years). The initial and maintenance dosing
of GLUCOPHAGE or GLUCOPHAGE XR should be conservative in patients with advanced
age, due to the potential for decreased renal function in this population.
Any dosage adjustment should be based on a careful assessment of renal function.
Generally, elderly, debilitated, and malnourished patients should not be titrated
to the maximum dose of GLUCOPHAGE or GLUCOPHAGE XR. Monitoring
of renal function is necessary to aid in prevention of lactic acidosis, particularly
in the elderly.
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GLUCOPHAGE (metformin
hydrochloride tablets) and GLUCOPHAGE XR (metformin
hydrochloride extended-release tablets) are oral antihyperglycemic drugs used
in the management of type 2 diabetes. Metformin hydrochloride (N,N-dimethylimidodicarbonimidic
diamide hydrochloride) is not chemically or pharmacologically related to any
other classes of oral antihyperglycemic agents. The structural formula is
as shown: Metformin hydrochloride is a white to off-white crystalline
compound with a molecular formula of CHN���HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble
in water and is practically insoluble in acetone, ether, and chloroform. The
pKof metformin is 12.4. The pH of a 1% aqueous solution
of metformin hydrochloride is 6.68. GLUCOPHAGE tablets
contain 500 mg, 850 mg, or 1000 mg of metformin hydrochloride. Each tablet
contains the inactive ingredients povidone and magnesium stearate. In addition,
the coating for the 500 mg and 850 mg tablets contains hypromellose and the
coating for the 1000 mg tablet contains hypromellose and
polyethylene glycol. GLUCOPHAGE XR contains 500 mg
or 750 mg of metformin hydrochloride as the active ingredient. GLUCOPHAGE
XR 500 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose,
hypromellose, microcrystalline cellulose, and magnesium stearate. GLUCOPHAGE
XR 750 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose,
hypromellose, and magnesium stearate. System
Components and Performance - GLUCOPHAGE XR comprises a dual hydrophilic
polymer matrix system. Metformin hydrochloride is combined with a drug release
controlling polymer to form an "inner" phase, which is then incorporated as
discrete particles into an "external" phase of a second polymer. After administration,
fluid from the gastrointestinal (GI) tract enters the tablet, causing the
polymers to hydrate and swell. Drug is released slowly from the dosage form
by a process of diffusion through the gel matrix that is essentially independent
of pH. The hydrated polymer system is not rigid and is expected to be broken
up by normal peristalsis in the GI tract. The biologically inert components
of the tablet may occasionally remain intact during GI transit and will be
eliminated in the feces as a soft, hydrated mass.
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Mechanism of Action: Metformin is an antihyperglycemic agent which improves glucose
tolerance in patients with type 2 diabetes, lowering both basal and postprandial
plasma glucose. Its pharmacologic mechanisms of action are different from
other classes of oral antihyperglycemic agents. Metformin decreases hepatic
glucose production, decreases intestinal absorption of glucose, and improves
insulin sensitivity by increasing peripheral glucose uptake and utilization.
Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients
with type 2 diabetes or normal subjects (except in special circumstances,
see PRECAUTIONS) and does not cause
hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged
while fasting insulin levels and day-long plasma insulin response may actually
decrease.<br/>Pharmacokinetics:<br/>Absorption and Bioavailability: The absolute bioavailability of a GLUCOPHAGE 500 mg tablet given
under fasting conditions is approximately 50% to 60%. Studies using single
oral doses of GLUCOPHAGE 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate
that there is a lack of dose proportionality with increasing doses, which
is due to decreased absorption rather than an alteration in elimination. Food
decreases the extent of and slightly delays the absorption of metformin, as
shown by approximately a 40% lower mean peak plasma concentration (C),
a 25% lower area under the plasma concentration versus time curve (AUC), and
a 35-minute prolongation of time to peak plasma concentration (T)
following administration of a single 850 mg tablet of metformin with food,
compared to the same tablet strength administered fasting. The clinical relevance
of these decreases is unknown. Following a single oral dose of GLUCOPHAGE XR, Cis
achieved with a median value of 7 hours and a range of 4 hours to 8 hours.
Peak plasma levels are approximately 20% lower compared to the same dose of
GLUCOPHAGE, however, the extent of absorption (as measured by AUC) is similar
to GLUCOPHAGE. At steady state, the AUC and Care less
than dose proportional for GLUCOPHAGE XR within the range of 500 mg to 2000
mg administered once daily. Peak plasma levels are approximately 0.6, 1.1,
1.4, and 1.8��g/mL for 500, 1000, 1500, and 2000 mg once-daily doses, respectively.
The extent of metformin absorption (as measured by AUC) from GLUCOPHAGE XR
at a 2000 mg once-daily dose is similar to the same total daily dose administered
as GLUCOPHAGE tablets 1000 mg twice daily. After repeated administration of
GLUCOPHAGE XR, metformin did not accumulate in plasma. Within-subject variability in Cand AUC
of metformin from GLUCOPHAGE XR is comparable to that with GLUCOPHAGE. Although the extent of metformin absorption (as measured by AUC)
from the GLUCOPHAGE XR tablet increased by approximately 50% when given with
food, there was no effect of food on Cand Tof
metformin. Both high and low fat meals had the same effect on the pharmacokinetics
of GLUCOPHAGE XR.<br/>Distribution: The apparent volume of distribution (V/F) of metformin following
single oral doses of GLUCOPHAGE 850 mg averaged 654��358 L. Metformin is
negligibly bound to plasma proteins, in contrast to sulfonylureas, which are
more than 90% protein bound. Metformin partitions into erythrocytes, most
likely as a function of time. At usual clinical doses and dosing schedules
of GLUCOPHAGE, steady state plasma concentrations of metformin are reached
within 24 to 48 hours and are generally<1��g/mL. During controlled clinical
trials of GLUCOPHAGE, maximum metformin plasma levels did not exceed 5��g/mL,
even at maximum doses.<br/>Metabolism and Elimination: Intravenous single-dose studies in normal subjects demonstrate
that metformin is excreted unchanged in the urine and does not undergo hepatic
metabolism (no metabolites have been identified in humans) nor biliary excretion.
Renal clearance (see Table 1) is
approximately 3.5 times greater than creatinine clearance, which indicates
that tubular secretion is the major route of metformin elimination. Following
oral administration, approximately 90% of the absorbed drug is eliminated
via the renal route within the first 24 hours, with a plasma elimination half-life
of approximately 6.2 hours. In blood, the elimination half-life is approximately
17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.<br/>Special Populations:<br/>Patients with Type 2 Diabetes: 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. The pharmacokinetics of GLUCOPHAGE XR in patients with type 2 diabetes
are comparable to those in healthy normal adults.<br/>Renal Insufficiency: In patients with decreased renal function (based on measured 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/>Hepatic Insufficiency: No pharmacokinetic studies of metformin have been conducted in
patients with hepatic insufficiency.<br/>Geriatrics: Limited data from controlled pharmacokinetic
studies of GLUCOPHAGE in healthy elderly subjects suggest that total plasma
clearance of metformin 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).
GLUCOPHAGE (metformin hydrochloride tablets) and GLUCOPHAGE XR (metformin
hydrochloride extended-release tablets) 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 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.<br/>Gender: Metformin pharmacokinetic parameters did not differ significantly
between normal subjects and patients with 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 GLUCOPHAGE
was comparable in males and females.<br/>Race: No studies of metformin pharmacokinetic parameters according to
race have been performed. In controlled clinical studies of GLUCOPHAGE 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/>GLUCOPHAGE: In a double-blind, placebo-controlled,
multicenter U.S. clinical trial involving obese patients with type 2 diabetes
whose hyperglycemia was not adequately controlled with dietary management
alone (baseline fasting plasma glucose [FPG] of approximately 240 mg/dL),
treatment with GLUCOPHAGE (up to 2550 mg/day) for 29 weeks resulted in significant
mean net reductions in fasting and postprandial plasma glucose (PPG) and hemoglobin
A(HbA) of 59 mg/dL, 83
mg/dL, and 1.8%, respectively, compared to the placebo group (see Table 2). A 29-week, double-blind, placebo-controlled study of GLUCOPHAGE
and glyburide, alone and in combination, was conducted in obese patients with
type 2 diabetes who had failed to achieve adequate glycemic control while
on maximum doses of glyburide (baseline FPG of approximately 250 mg/dL) (see Table 3). Patients randomized to the combination
arm started therapy with GLUCOPHAGE 500 mg and glyburide 20 mg. At the end
of each week of the first four weeks of the trial, these patients had their
dosages of GLUCOPHAGE increased by 500 mg if they had failed to reach target
fasting plasma glucose. After week four, such dosage adjustments were made
monthly, although no patient was allowed to exceed GLUCOPHAGE 2500 mg. Patients
in the GLUCOPHAGE only arm (metformin plus placebo) followed the same titration
schedule. At the end of the trial, approximately 70% of the patients in the
combination group were taking GLUCOPHAGE 2000 mg/glyburide 20 mg or GLUCOPHAGE
2500 mg/glyburide 20 mg. Patients randomized to continue on glyburide experienced
worsening of glycemic control, with mean increases in FPG, PPG, and HbAof
14 mg/dL, 3 mg/dL, and 0.2%, respectively. In contrast, those
randomized to GLUCOPHAGE (up to 2500 mg/day) experienced
a slight improvement, with mean reductions in FPG, PPG, and HbAof
1 mg/dL, 6 mg/dL, and 0.4%, respectively. The combination of GLUCOPHAGE and
glyburide was effective in reducing FPG, PPG, and HbAlevels
by 63 mg/dL, 65 mg/dL, and 1.7%, respectively. Compared to results of glyburide
treatment alone, the net differences with combination treatment were���77 mg/dL,���68 mg/dL, and���1.9%, respectively (see Table
3). The magnitude of the decline in fasting blood glucose
concentration following the institution of GLUCOPHAGE (metformin hydrochloride
tablets) therapy was proportional to the level of fasting hyperglycemia. Patients
with type 2 diabetes with higher fasting glucose concentrations experienced
greater declines in plasma glucose and glycosylated hemoglobin. In
clinical studies, GLUCOPHAGE, alone or in combination with a sulfonylurea,
lowered mean fasting serum triglycerides, total cholesterol, and LDL cholesterol
levels and had no adverse effects on other lipid levels (see Table
4). In contrast to sulfonylureas, body weight of individuals
on GLUCOPHAGE tended to remain stable or even decrease somewhat (see Tables 2 and 3). A
24-week, double-blind, placebo-controlled study of GLUCOPHAGE plus insulin
versus insulin plus placebo was conducted in patients with type 2 diabetes
who failed to achieve adequate glycemic control on insulin alone (see Table 5). Patients randomized to receive GLUCOPHAGE
plus insulin achieved a reduction in HbAof 2.10%,
compared to a 1.56% reduction in HbAachieved by
insulin plus placebo. The improvement in glycemic control was achieved at
the final study visit with 16% less insulin, 93.0 U/day vs 110.6 U/day, GLUCOPHAGE
plus insulin versus insulin plus placebo, respectively, p=0.04. A second double-blind, placebo-controlled study (n=51),
with 16 weeks of randomized treatment, demonstrated that in patients with
type 2 diabetes controlled on insulin for 8 weeks with an average HbAof
7.46��0.97%, the addition of GLUCOPHAGE maintained similar glycemic control
(HbA7.15��0.61 versus 6.97��0.62 for GLUCOPHAGE
plus insulin and placebo plus insulin, respectively) with 19% less insulin
versus baseline (reduction of 23.68��30.22 versus an increase of 0.43��25.20
units for GLUCOPHAGE plus insulin and placebo plus insulin, p<0.01). In
addition, this study demonstrated that the combination of GLUCOPHAGE plus
insulin resulted in reduction in body weight of 3.11��4.30 lbs, compared
to an increase of 1.30��6.08 lbs for placebo plus insulin, p=0.01.<br/>GLUCOPHAGE XR: A 24-week, double-blind, placebo-controlled
study of GLUCOPHAGE XR, taken once daily with the evening meal, was conducted
in patients with type 2 diabetes who had failed to achieve glycemic control
with diet and exercise (HbA7.0-10.0%, FPG 126-270
mg/dL). Patients entering the study had a mean baseline HbAof
8.0% and a mean baseline FPG of 176 mg/dL. After 12 weeks treatment, mean
HbAhad increased from baseline by 0.1% and mean
FPG decreased from baseline by 2 mg/dL in the placebo group, compared with
a decrease in mean HbAof 0.6% and a decrease in
mean FPG of 23 mg/dL in patients treated with GLUCOPHAGE XR 1000 mg once daily.
Subsequently, the treatment dose was increased to 1500 mg once daily if HbAwas���7.0% but<8.0% (patients with HbA���8.0% were
discontinued from the study). At the final visit (24-week), mean HbAhad
increased 0.2% from baseline in placebo patients and decreased 0.6% with GLUCOPHAGE
XR. A 16-week, double-blind, placebo-controlled, dose-response
study of GLUCOPHAGE XR, taken once daily with the evening meal or twice daily
with meals, was conducted in patients with type 2 diabetes who had failed
to achieve glycemic control with diet and exercise (HbA7.0-11.0%,
FPG 126-280 mg/dL). Changes in glycemic control and body weight are shown
in Table 6. Compared with placebo, improvement in glycemic control
was seen at all dose levels of GLUCOPHAGE XR (metformin hydrochloride extended-release
tablets) and treatment was not associated with any significant change in weight
(see DOSAGE AND ADMINISTRATION for dosing
recommendations for GLUCOPHAGE and GLUCOPHAGE XR). A
24-week, double-blind, randomized study of GLUCOPHAGE XR, taken once daily
with the evening meal, and GLUCOPHAGE (metformin hydrochloride tablets), taken
twice daily (with breakfast and evening meal), was conducted in patients with
type 2 diabetes who had been treated with GLUCOPHAGE 500 mg twice daily for
at least 8 weeks prior to study entry. The GLUCOPHAGE dose had not necessarily
been titrated to achieve a specific level of glycemic control prior to study
entry. Patients qualified for the study if HbAwas���8.5% and FPG was���200 mg/dL. Changes in glycemic control and body weight
are shown in Table 7. After 12 weeks of treatment, there was an increase in
mean HbAin all groups; in the GLUCOPHAGE XR 1000
mg group, the increase from baseline of 0.23% was statistically significant
. Changes
in lipid parameters in the previously described placebo-controlled dose-response
study of GLUCOPHAGE XR are shown in Table 8. Changes in lipid parameters in the previously described
study of GLUCOPHAGE and GLUCOPHAGE XR are shown in Table
9.<br/>Pediatric Clinical Studies: In a double-blind, placebo-controlled
study in pediatric patients aged 10 to 16 years with type 2 diabetes (mean
FPG 182.2 mg/dL), treatment with GLUCOPHAGE (up to 2000 mg/day) for up to
16 weeks (mean duration of treatment 11 weeks) resulted in a significant mean
net reduction in FPG of 64.3 mg/dL, compared with placebo (see Table 10).
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GLUCOPHAGE and GLUCOPHAGE XR are contraindicated in patients with: GLUCOPHAGE and GLUCOPHAGE XR 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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GLUCOPHAGE(metformin
hydrochloride tablets) GLUCOPHAGE 500 mg tablets are round, white to off-white,
film coated tablets debossed with "BMS 6060" around the periphery of the
tablet on one side and "500" debossed across the face of the other side. GLUCOPHAGE
850 mg tablets are round, white to off-white, film coated tablets debossed
with "BMS 6070" around the periphery of the tablet on one side and "850"
debossed across the face of the other side. GLUCOPHAGE1000 mg tablets are white, oval, biconvex, film coated tablets with "BMS
6071" debossed on one side and "1000" debossed on the opposite side and with
a bisect line on both sides. GLUCOPHAGE XR
(metformin hydrochloride extended-release tablets) GLUCOPHAGE XR 500 mg tablets are white to off-white, capsule
shaped, biconvex tablets, with "BMS 6063" debossed on one side and "500"
debossed across the face of the other side. GLUCOPHAGE
XR 750 mg tablets are capsule shaped, biconvex tablets, with "BMS 6064" debossed
on one side and "750" debossed on the other side. The tablets are pale red
and may have a mottled appearance.<br/>Storage: Store
at 20�����25��C (68�����77��F); excursions permitted to 15�����30��C (59�����86��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 GLUCOPHAGE
or GLUCOPHAGE XR; 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 GLUCOPHAGE or GLUCOPHAGE XR and by use
of the minimum effective dose of GLUCOPHAGE or GLUCOPHAGE XR. In particular,
treatment of the elderly should be accompanied by careful monitoring of renal
function. GLUCOPHAGE or GLUCOPHAGE XR 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, GLUCOPHAGE and GLUCOPHAGE XR 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, GLUCOPHAGE and GLUCOPHAGE XR 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 GLUCOPHAGE or GLUCOPHAGE XR, since alcohol potentiates
the effects of metformin hydrochloride on lactate metabolism. In addition,
GLUCOPHAGE and GLUCOPHAGE XR should be temporarily discontinued prior to any
intravascular radiocontrast study and for any surgical procedure . 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 .
GLUCOPHAGE and GLUCOPHAGE XR should be withdrawnuntil 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 GLUCOPHAGE or GLUCOPHAGE XR, gastrointestinal symptoms,
which are common during initiation of therapy, 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 GLUCOPHAGE or GLUCOPHAGE XR 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 GLUCOPHAGE
or GLUCOPHAGE XR, 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: Macrovascular
Outcomes���There have been no clinical studies establishing conclusive
evidence of macrovascular risk reduction with GLUCOPHAGE or GLUCOPHAGE XR
or any other anti-diabetic drug. 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 GLUCOPHAGE or GLUCOPHAGE
XR. In patients with advanced age, GLUCOPHAGE and GLUCOPHAGE XR 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, GLUCOPHAGE and GLUCOPHAGE XR should not be titrated to the
maximum dose . Before
initiation of GLUCOPHAGE or GLUCOPHAGE XR 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 GLUCOPHAGE or GLUCOPHAGE XR 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 .
Therefore, in patients in whom any such study is planned, GLUCOPHAGE or GLUCOPHAGE
XR 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 re-evaluated 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 GLUCOPHAGE or GLUCOPHAGE XR therapy, the drug should be promptly
discontinued. Surgical procedures���GLUCOPHAGE or GLUCOPHAGE XR
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
GLUCOPHAGE or GLUCOPHAGE XR. Impaired hepatic function���Since impaired hepatic
function has been associated with some cases of lactic acidosis, GLUCOPHAGE
and GLUCOPHAGE XR should generally be avoided in patients with clinical or
laboratory evidence of hepatic disease. Vitamin Blevels���In controlled
clinical trials of GLUCOPHAGE of 29 weeks duration, a decrease to subnormal
levels of previously normal serum vitamin Blevels,
without clinical manifestations, was observed in approximately 7% of patients.
Such decrease, possibly due to interference with Babsorption
from the B-intrinsic factor complex, is, however,
very rarely associated with anemia and appears to be rapidly reversible with
discontinuation of GLUCOPHAGE or vitamin Bsupplementation.
Measurement of hematologic parameters on an annual basis is advised in patients
on GLUCOPHAGE or GLUCOPHAGE XR and any apparent abnormalities should be appropriately
investigated and managed (see PRECAUTIONS: Laboratory
Tests). Certain individuals (those with inadequate vitamin Bor
calcium intake or absorption) appear to be predisposed to developing subnormal
vitamin Blevels. In these patients, routine serum
vitamin Bmeasurements 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 GLUCOPHAGE or GLUCOPHAGE XR 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,
GLUCOPHAGE or GLUCOPHAGE XR must be stopped immediately and other appropriate
corrective measures initiated. Hypoglycemia���Hypoglycemia does not occur in patients
receiving GLUCOPHAGE or GLUCOPHAGE XR alone under usual circumstances of use,
but could occur when caloric intake is deficient, when strenuous exercise
is not compensated by caloric supplementation, or during concomitant use with
other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with
adrenal or pituitary insufficiency or alcohol intoxication are particularly
susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize
in the elderly, and in people who are taking beta-adrenergic blocking drugs. Loss of control of blood glucose���When a patient
stabilized on any diabetic regimen is exposed to stress such as fever, trauma,
infection, or surgery, a temporary loss of glycemic control may occur. At
such times, it may be necessary to withhold GLUCOPHAGE or GLUCOPHAGE XR and
temporarily administer insulin. GLUCOPHAGE or GLUCOPHAGE XR may be reinstituted
after the acute episode is resolved. The effectiveness of oral antidiabetic drugs in lowering blood
glucose to a targeted level decreases in many patients over a period of time.
This phenomenon, which may be due to progression of the underlying disease
or to diminished responsiveness to the drug, is known as secondary failure,
to distinguish it from primary failure in which the drug is ineffective during
initial therapy. Should secondary failure occur with either GLUCOPHAGE or
GLUCOPHAGE XR or sulfonylurea monotherapy, combined therapy with GLUCOPHAGE
or GLUCOPHAGE XR and sulfonylurea may result in a response. Should secondary
failure occur with combined GLUCOPHAGE/sulfonylurea therapy or GLUCOPHAGE
XR/sulfonylurea therapy, it may be necessary to consider therapeutic alternatives
including initiation of insulin therapy.<br/>Information for Patients: Patients should be informed of the potential risks and benefits
of GLUCOPHAGE or GLUCOPHAGE XR 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, 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 GLUCOPHAGE or GLUCOPHAGE XR 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 GLUCOPHAGE or GLUCOPHAGE
XR, 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. Patients should be counselled against excessive alcohol intake,
either acute or chronic, while receiving GLUCOPHAGE or GLUCOPHAGE XR. GLUCOPHAGE or GLUCOPHAGE XR alone does not usually cause hypoglycemia,
although it may occur when GLUCOPHAGE or GLUCOPHAGE XR is used in conjunction
with oral sulfonylureas and insulin. When initiating combination therapy,
the risks of hypoglycemia, its symptoms and treatment, and conditions that
predispose to its development should be explained to patients and responsible
family members. (See Patient Information printed
below.) Patients should be informed that GLUCOPHAGE XR must be swallowed
whole and not crushed or chewed, and that the inactive ingredients may occasionally
be eliminated in the feces as a soft mass that may resemble the original tablet.<br/>Laboratory Tests: Response to all diabetic therapies should be monitored by periodic
measurements of fasting blood glucose and glycosylated hemoglobin levels,
with a goal of decreasing these levels toward the normal range. During initial
dose titration, fasting glucose can be used to determine the therapeutic response.
Thereafter, both glucose and glycosylated hemoglobin should be monitored.
Measurements of glycosylated hemoglobin may be especially useful for evaluating
long-term control . 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 GLUCOPHAGE therapy, if this is suspected,
vitamin Bdeficiency should be excluded.<br/>Drug Interactions (Clinical Evaluation of Drug Interactions Conducted with GLUCOPHAGE): Glyburide���In a single-dose interaction study in
type 2 diabetes patients, coadministration of metformin and glyburide did
not result in any changes in either metformin pharmacokinetics or pharmacodynamics.
Decreases in glyburide AUC and Cwere observed,
but were highly variable. The single-dose nature of this study and the lack
of correlation between glyburide blood levels and pharmacodynamic effects,
makes the clinical significance of this interaction uncertain (see DOSAGE AND ADMINISTRATION: Concomitant GLUCOPHAGE or GLUCOPHAGE
XR and Oral Sulfonylurea Therapy in Adult Patients). Furosemide���A single-dose, metformin-furosemide
drug interaction study in healthy subjects demonstrated that pharmacokinetic
parameters of both compounds were affected by coadministration. Furosemide
increased the metformin plasma and blood Cby 22%
and blood AUC by 15%, without any significant change in metformin renal clearance.
When administered with metformin, the Cand 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 Cand AUC
by 20% and 9%, respectively, and increased the amount excreted in the urine.
Tand 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
GLUCOPHAGE or GLUCOPHAGE XR 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���Certain drugs tend to produce hyperglycemia
and may lead to loss of glycemic 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 GLUCOPHAGE or GLUCOPHAGE XR, the patient should be closely
observed for loss of blood glucose control. When such drugs are withdrawn
from a patient receiving GLUCOPHAGE or GLUCOPHAGE XR, the patient should be
observed closely for hypoglycemia. In healthy volunteers, the pharmacokinetics of metformin and propranolol,
and metformin and ibuprofen were not affected when coadministered in single-dose
interaction studies. Metformin is negligibly bound to plasma proteins and is, therefore,
less likely to interact with highly protein-bound drugs such as salicylates,
sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas,
which are extensively bound to serum proteins.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term carcinogenicity studies have been performed 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 based on body surface area comparisons. No evidence
of carcinogenicity with metformin was found in either male or female mice.
Similarly, there was no tumorigenic potential observed with metformin in male
rats. There was, however, an increased incidence of benign stromal uterine
polyps in female rats treated with 900 mg/kg/day. There was no evidence of a mutagenic potential of metformin 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 when
administered at doses as high as 600 mg/kg/day, which is approximately three
times the maximum recommended human daily dose 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 levels as close to normal as possible. Because animal
reproduction studies are not always predictive of human response, GLUCOPHAGE
and GLUCOPHAGE XR should not be used during pregnancy unless clearly needed. There are no adequate and well-controlled studies in pregnant women
with GLUCOPHAGE or GLUCOPHAGE XR. Metformin was not teratogenic in rats and
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 based on body surface area comparisons for rats and rabbits, respectively.
Determination of fetal concentrations demonstrated a partial placental barrier
to metformin.<br/>Nursing Mothers: 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 orto discontinue the drug, taking into account the importance of
the drug to the mother. If GLUCOPHAGE or GLUCOPHAGE XR is discontinued, and
if diet alone is inadequate for controlling blood glucose, insulin therapy
should be considered.<br/>Pediatric Use: The safety and effectiveness of GLUCOPHAGE for the treatment of
type 2 diabetes have been established in pediatric patients ages 10 to 16
years (studies have not been conducted in pediatric patients below the age
of 10 years). Use of GLUCOPHAGE in this age group is supported by evidence
from adequate and well-controlled studies of GLUCOPHAGE in adults with additional
data from a controlled clinical study in pediatric patients ages 10 to 16
years with type 2 diabetes, which demonstrated a similar response in glycemic
control to that seen in adults. (See CLINICAL PHARMACOLOGY:
Pediatric Clinical Studies.) In this study, adverse effects
were similar to those described in adults. (See ADVERSE
REACTIONS: Pediatric Patients.) A maximum daily dose of 2000
mg is recommended. (See DOSAGE AND ADMINISTRATION:
Recommended Dosing Schedule: Pediatrics.) Safety and effectiveness of GLUCOPHAGE XR in pediatric patients
have not been established.<br/>Geriatric Use: Controlled clinical studies of GLUCOPHAGE and GLUCOPHAGE XR did
not include sufficient numbers of elderly patients to determine whether they
respond differently from younger patients, although other reported clinical
experience has not identified differences in responses between the elderly
and younger patients. Metformin 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, GLUCOPHAGE and GLUCOPHAGE XR 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, GLUCOPHAGE or GLUCOPHAGE XR shouldbe 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 GLUCOPHAGE or GLUCOPHAGE XR
(see also WARNINGS and DOSAGE
AND ADMINISTRATION).
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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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METFORMIN HYDROCHLORIDE
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GLUCOPHAGE (Tablet, Film Coated)
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In a US double-blind clinical study
of GLUCOPHAGE in patients with type 2 diabetes, a total of 141 patients received
GLUCOPHAGE therapy (up to 2550 mg per day) and 145 patients received placebo.
Adverse reactions reported in greater than 5% of the GLUCOPHAGE patients,
and that were more common in GLUCOPHAGE- than placebo-treated patients, are
listed in Table 11. Diarrhea led to discontinuation of study medication in
6% of patients treated with GLUCOPHAGE. Additionally, the following adverse
reactions were reported in���1.0 -���5.0% of GLUCOPHAGE patients and were more
commonly reported with GLUCOPHAGE than placebo: abnormal stools, hypoglycemia,
myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste
disorder, chest discomfort, chills, flu syndrome, flushing, palpitation. In
worldwide clinical trials over 900 patients with type 2 diabetes have been
treated with GLUCOPHAGE XR in placebo- and active-controlled studies. In placebo-controlled
trials, 781 patients were administered GLUCOPHAGE XR and 195 patients received
placebo. Adverse reactions reported in greater than 5% of the GLUCOPHAGE XR
patients, and that were more common in GLUCOPHAGE XR- than placebo-treated
patients, are listed in Table 12. Diarrhea led to discontinuation of study medication in
0.6% of patients treated with GLUCOPHAGE XR. Additionally, the following adverse
reactions were reported in���1.0% -���5.0% of GLUCOPHAGE XR patients and were
more commonly reported with GLUCOPHAGE XR than placebo: abdominal pain, constipation,
distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache,
upper respiratory infection, taste disturbance.<br/>Pediatric Patients: In clinical trials with GLUCOPHAGE in pediatric patients with type
2 diabetes, the profile of adverse reactions was similar to that observed
in adults.
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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 GLUCOPHAGE
or GLUCOPHAGE XR; 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 GLUCOPHAGE or GLUCOPHAGE XR and by use
of the minimum effective dose of GLUCOPHAGE or GLUCOPHAGE XR. In particular,
treatment of the elderly should be accompanied by careful monitoring of renal
function. GLUCOPHAGE or GLUCOPHAGE XR 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, GLUCOPHAGE and GLUCOPHAGE XR 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, GLUCOPHAGE and GLUCOPHAGE XR 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 GLUCOPHAGE or GLUCOPHAGE XR, since alcohol potentiates
the effects of metformin hydrochloride on lactate metabolism. In addition,
GLUCOPHAGE and GLUCOPHAGE XR should be temporarily discontinued prior to any
intravascular radiocontrast study and for any surgical procedure . 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 .
GLUCOPHAGE and GLUCOPHAGE XR should be withdrawnuntil 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 GLUCOPHAGE or GLUCOPHAGE XR, gastrointestinal symptoms,
which are common during initiation of therapy, 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 GLUCOPHAGE or GLUCOPHAGE XR 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 GLUCOPHAGE
or GLUCOPHAGE XR, 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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GLUCOPHAGE (metformin hydrochloride tablets)
is indicated as an adjunct to diet and exercise to improve glycemic control
in adults and children with type 2 diabetes mellitus. GLUCOPHAGE
XR (metformin hydrochloride extended-release tablets) is indicated as an adjunct
to diet and exercise to improve glycemic control in adults with type 2 diabetes
mellitus.
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GLUCOPHAGE
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