Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/4046
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METAGLIP (Tablet, Film Coated)
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General Considerations: Dosage of METAGLIP must be individualized on the basis of
both effectiveness and tolerance while not exceeding the maximum recommended
daily dose of 20 mg glipizide/2000 mg metformin. METAGLIP 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 glipizide), 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
METAGLIP 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 METAGLIP therapy in patients taking concomitant
glipizide (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/>METAGLIP in Patients with Inadequate Glycemic Control on Diet and Exercise Alone: For patients with type 2 diabetes whose
hyperglycemia cannot be satisfactorily managed with diet and exercise alone,
the recommended starting dose of METAGLIP is 2.5 mg/250 mg once a day with
a meal. For patients whose FPG is 280 mg/dL to 320 mg/dL a starting dose of
METAGLIP 2.5 mg/500 mg twice daily should be considered. The efficacy of METAGLIP
in patients whose FPG exceeds 320 mg/dL has not been established. Dosage increases
to achieve adequate glycemic control should be made in increments of one tablet
per day every two weeks up to maximum of 10 mg/1000 mg or 10 mg/2000 mg METAGLIP
per day given in divided doses. In clinical trials of METAGLIP as initial
therapy, there was no experience with total daily doses greater than 10 mg/2000
mg per day.<br/>METAGLIP in Patients with Inadequate Glycemic Control on a Sulfonylurea and/or Metformin: For patients not adequately controlled
on either glipizide (or another sulfonylurea) or metformin alone, the recommended
starting dose of METAGLIP 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 METAGLIP should not exceed the daily doses of glipizide
or metformin already being taken. The daily dose shouldbe 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. Patients previously
treated with combination therapy of glipizide (or another sulfonylurea) plus
metformin may be switched to METAGLIP 2.5 mg/500 mg or 5
mg/500 mg; the starting dose should not exceed the daily dose of glipizide
(or equivalent dose of another sulfonylurea) and metformin already being taken.
The decision to switch to the nearest equivalent dose or to titrate should
be based on clinical judgment. Patients should be monitored closely for signs
and symptoms of hypoglycemia following such a switch and the dose of METAGLIP
should be titrated as described above to achieve adequate control of blood
glucose.<br/>Specific Patient Populations: METAGLIP is not recommended for use during pregnancy or for use
in pediatric patients. The initial and maintenance dosing of METAGLIP 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 METAGLIP 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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METAGLIP(glipizide
and metformin HCl) Tablets contains two oral antihyperglycemic drugs used
in the management of type 2 diabetes, glipizide and metformin hydrochloride. Glipizide
is an oral antihyperglycemic drug of the sulfonylurea class. The chemical
name for glipizide is 1-cyclohexyl-3-[[p-[2-(5-methylpyrazinecarboxamido)ethyl]phenyl]sulfonyl]urea.
Glipizide is a whitish, odorless powder with a molecular formula of CHNOS, a molecular weight of 445.55 and a pKof
5.9. It is insoluble in water and alcohols, but soluble in 0.1 N NaOH;
it is freely soluble in dimethylformamide. 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 pKof metformin is 12.4. The pH
of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural
formula is as shown: METAGLIP is available for oral administration in tablets
containing 2.5 mg glipizide with 250 mg metformin hydrochloride,
2.5 mg glipizide with 500 mg metformin hydrochloride, and 5 mg
glipizide 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: METAGLIP combines glipizide and metformin hydrochloride, two antihyperglycemic
agents with complementary mechanisms of action, to improve glycemic control
in patients with type 2 diabetes. Glipizide 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. Extrapancreatic effects may play a part
in the mechanism of action of oral sulfonylurea hypoglycemic drugs. The mechanism
by which glipizide lowers blood glucose during long-term administration has
not been clearly established. In man, stimulation of insulin secretion by
glipizide in response to a meal is undoubtedly of major importance. Fasting
insulin levels are not elevated even on long-term glipizide administration,
but the postprandial insulinresponse continues to be enhanced after at least
6 months of treatment. 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: 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: The metabolism and excretion of glipizide may be slowed in patients
with impaired hepatic function .
No pharmacokinetic studies have been conducted in patients with hepatic insufficiency
for metformin.<br/>Renal Insufficiency: The metabolism and excretion of glipizide may be slowed in patients
with impaired renal function . 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 glipizide 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: No data from pharmacokinetic studies in pediatric subjects are
available for glipizide. 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: There is no information on the effect of gender on the pharmacokinetics
of glipizide. 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 glipizide. 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 24-week, double-blind, active-controlled,
multicenter international clinical trial, patients with type 2 diabetes, whose
hyperglycemia was not adequately controlled with diet and exercise alone (hemoglobin
A[HbA]>7.5% and���12% and
fasting plasma glucose [FPG]<300 mg/dL) were randomized to receive initial
therapy with glipizide 5 mg, metformin 500 mg, METAGLIP 2.5
mg/250 mg, or METAGLIP 2.5 mg/500 mg. After two weeks, the dose was progressively
increased (up to the 12-week visit) to a maximum of four tablets daily in
divided doses as needed to reach a target mean daily glucose (MDG) of���130
mg/dL. Trial data at 24 weeks are summarized in Table
2. After 24 weeks, treatment with METAGLIP 2.5 mg/250 mg
and 2.5 mg/500 mg resulted in significantly greater reduction in HbAcompared
to glipizide and to metformin therapy. Also, METAGLIP 2.5 mg/250 mg therapy
resulted in significant reductions in FPG versus metformin therapy. Increases
above fasting glucose and insulin levels were determined at baseline and final
study visits by measurement of plasma glucose and insulin for three hours
following a standard mixed liquid meal. Treatment with METAGLIP lowered the
three-hour postprandial glucose AUC, compared to baseline, to a significantly
greater extent than did the glipizide and the metformin therapies. Compared
to baseline, METAGLIP enhanced the postprandial insulin response, but did
not significantly affectfasting insulin levels. There
were no clinically meaningful differences in changes from baseline for all
lipid parameters between METAGLIP therapy and either metformin therapy or
glipizide therapy. The adjusted mean changes from baseline in body weight
were: METAGLIP 2.5 mg/250 mg,���0.4 kg; METAGLIP 2.5 mg/500 mg,���0.5 kg; glipizide,���0.2 kg; and metformin,���1.9 kg. Weight loss was greater with metformin than
with METAGLIP.<br/>Patients with Inadequate Glycemic Control on Sulfonylurea Monotherapy: In an 18-week, double-blind, active-controlled
U.S. clinical trial, a total of 247 patients with type 2 diabetes not adequately
controlled (HbA���7.5% and���12% and FPG<300 mg/dL)
while being treated with at least one-half the maximum labeled dose of a sulfonylurea
(eg, glyburide 10 mg, glipizide 20 mg) were randomized to receive glipizide
(fixed dose, 30 mg), metformin (500 mg), or METAGLIP 5 mg/500 mg. The doses
of metformin and METAGLIP were titrated (up to the eight-week visit) to a
maximum of four tablets daily as needed to achieve MDG���130 mg/dL. Trial data
at 18 weeks are summarized in Table 3. After 18 weeks, treatment with METAGLIP at doses up to
20 mg/2000 mg per day resulted in significantly lower mean final HbAand
significantly greater mean reductions in FPG compared to glipizide and to
metformin therapy. Treatment with METAGLIP lowered the three-hour postprandial
glucose AUC, compared to baseline, to a significantly greater extent than
did the glipizide and the metformin therapies. METAGLIP did not significantly
affect fasting insulin levels. There were no clinically
meaningful differences in changes from baseline for all lipid parameters between
METAGLIP therapy and either metformin therapy or glipizide therapy. The adjusted
mean changes from baseline in body weight were: METAGLIP 5 mg/500 mg,���0.3
kg; glipizide,���0.4 kg; and metformin,���2.7 kg. Weight
loss was greater with metformin than with METAGLIP.
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METAGLIP (glipizide and metformin HCl) Tablets is contraindicated
in patients with: METAGLIP 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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METAGLIP(glipizide
and metformin HCl) Tablets METAGLIP 2.5 mg/250 mg tablet is a pink oval-shaped,
biconvex film-coated tablet with "BMS" debossed on one side and
"6081" debossed on the opposite side. METAGLIP 2.5 mg/500 mg tablet is a white oval-shaped,
biconvex film-coated tablet with "BMS" debossed on one side and
"6077" debossed on the opposite side. METAGLIP 5 mg/500 mg tablet is a pink oval-shaped,
biconvex film-coated tablet with "BMS" debossed on one side and
"6078" debossed on the opposite side.<br/>STORAGE: Store at 20��C-25��C (68��F-77��F); excursions permitted
to 15��C-30��C (59��F-86��F). [See USP Controlled Room Temperature.]
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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 METAGLIP;
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 hypoperfusionand 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. METAGLIP 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, METAGLIP 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, METAGLIP 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 METAGLIP, since alcohol potentiates the effects of metformin hydrochloride
on lactate metabolism. In addition, METAGLIP 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 .
METAGLIP 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 METAGLIP, gastrointestinal symptoms, which are common during
initiation of therapy with metformin, are unlikely to be drug related. Later
occurrence of gastrointestinal symptoms could be due to lactic acidosis or
other serious disease. Levels of fasting venous plasma lactate above the upper
limit of normal but less than 5 mmol/L in patients taking
METAGLIP do not necessarily indicate impending lactic acidosis and may be
explainable by other mechanisms, such as poorly controlled diabetes or obesity,
vigorous physical activity, or technical problems in sample handling. (See
also PRECAUTIONS.) Lactic acidosis should be suspected in any diabetic patient
with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia). Lactic acidosis is a medical emergency that must be treated
in a hospital setting. In a patient with lactic acidosis who is taking METAGLIP,
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 METAGLIP or any other
anti-diabetic drug.<br/>METAGLIP:<br/>Glipizide:<br/>Metformin Hydrochloride:<br/>Information for Patients:<br/>METAGLIP: Patients should be informed of the potential risks and benefits
of METAGLIP 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
METAGLIP 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 METAGLIP,
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 METAGLIP. (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 (eg,
hemoglobin/hematocrit and red blood cell indices) and renal function (serum
creatinine) should be performed, at least on an annual basis. While megaloblastic
anemia has rarely been seen with metformin therapy, if this is suspected,
vitamin Bdeficiency should be excluded.<br/>Drug Interactions:<br/>METAGLIP: 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 METAGLIP,
the patient should be closely observed for loss of blood glucose control.
When such drugs are withdrawn from a patient receiving METAGLIP, 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/>Glipizide: The hypoglycemic action of sulfonylureas may be potentiated by
certain drugs including nonsteroidal anti-inflammatory agents, some azoles,
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 METAGLIP, the patient should be observed closely for hypoglycemia.
When such drugs are withdrawn from a patient receiving METAGLIP, the patient
should be observed closely for loss of blood glucose control. In vitro binding
studies with human serum proteins indicate that glipizide binds differently
than tolbutamide and does not interact with salicylate or dicumarol. However,
caution must be exercised in extrapolating these findings to the clinical
situation and in the use of METAGLIP with these drugs. 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. The effect of concomitant administration of fluconazole and
glipizide has been demonstrated in a placebo-controlled crossover study in
normal volunteers. All subjects received glipizide alone and following treatment
with 100 mg of fluconazole as a single oral daily dose for 7 days, the mean
percent increase in the glipizide AUC after fluconazole administration was
56.9% (range: 35% to 81%).<br/>Metformin Hydrochloride:<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: No animal studies have been conducted with the combined products
in METAGLIP. The following data are based on findings in studies performed
with the individual products.<br/>Glipizide: A 20-month study in rats and an 18-month study in mice at doses
up to 75 times the maximum human dose revealed no evidence of drug-related
carcinogenicity. Bacterial and in vivo mutagenicity tests
were uniformly negative. Studies in rats of both sexes at doses up to 75 times
the human dose showed no effects on fertility.<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 METAGLIP based on body
surface area comparisons. No evidence of carcinogenicity with metformin alone
wasfound 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 METAGLIP based on body surface area comparisons.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C: 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, METAGLIP should not be
used during pregnancy unless clearly needed. (See below.) There are no adequate and well-controlled studies in
pregnant women with METAGLIP or its individual components. No animal studies
have been conducted with the combined products in METAGLIP. 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 METAGLIP be used during
pregnancy. However, if it is used, METAGLIP should be discontinued at least
one month before the expected delivery date. (See Pregnancy:
Teratogenic Effects: Pregnancy Category C.)<br/>Nursing Mothers: Although it is not known whether glipizide 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 METAGLIP, taking into account the importance of the drug to the
mother. If METAGLIP is discontinued, and if diet alone is inadequate for controlling
blood glucose, insulin therapy should be considered.<br/>Pediatric Use: Safety and effectiveness of METAGLIP in pediatric patients have
not been established.<br/>Geriatric Use: Of the 345 patients who received METAGLIP 2.5 mg/250 mg and 2.5
mg/500 mg in the initial therapy trial, 67 (19.4%) were aged 65 and older
while 5 (1.4%) were aged 75 and older. Of the 87 patients who received METAGLIP
in the second-line therapy trial, 17 (19.5%) were aged 65 and older while
one (1.1%) was at least aged 75. No overall differences in effectiveness or
safety were observed between these patients and younger patients in either
the initial therapy trial or the second-line therapy trial, 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, METAGLIP 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, METAGLIP 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 METAGLIP .
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Glipizide: Overdosage of sulfonylureas, including glipizide, 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. Clearance of glipizide
from plasma would be prolonged in persons with liver disease. Because of the
extensive protein binding of glipizide, dialysis is unlikely to be of benefit.<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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GLIPIZIDE AND METFORMIN HYDROCHLORIDE
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METAGLIP (Tablet, Film Coated)
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METAGLIP: In
a double-blind 24-week clinical trial involving METAGLIP as initial therapy,
a total of 172 patients received METAGLIP 2.5 mg/250 mg, 173 received METAGLIP
2.5 mg/500 mg, 170 received glipizide, and 177 received metformin. The most
common clinical adverse events in these treatment groups are listed in Table 4. In a double-blind 18-week clinical trial involving METAGLIP
as second-line therapy, a total of 87 patients received METAGLIP, 84 received
glipizide, and 75 received metformin. The most common clinical adverse events
in this clinical trial are listed in Table 5.<br/>Hypoglycemia: In a controlled initial therapy trial of METAGLIP 2.5 mg/250 mg
and 2.5 mg/500 mg the numbers of patients with hypoglycemia documented by
symptoms (such as dizziness, shakiness, sweating, and hunger) and a fingerstick
blood glucose measurement���50 mg/dL were 5 (2.9%) for glipizide, 0 (0%) for
metformin, 13 (7.6%) for METAGLIP 2.5 mg/250 mg, and 16 (9.3%) for METAGLIP
2.5 mg/500 mg. Among patients taking either METAGLIP 2.5 mg/250
mg or METAGLIP 2.5 mg/500 mg, 9 (2.6%) patients discontinued METAGLIP due
to hypoglycemic symptoms and one required medical intervention due to hypoglycemia.
In a controlled second-line therapy trial of METAGLIP 5 mg/500 mg, the numbers
of patients with hypoglycemia documented by symptoms and a fingerstick blood
glucose measurement���50 mg/dL were 0 (0%) for glipizide,
1 (1.3%) for metformin, and 11 (12.6%) for METAGLIP. One (1.1%) patient discontinued
METAGLIP therapy due to hypoglycemic symptoms and none required medical intervention
due to hypoglycemia.<br/>Gastrointestinal Reactions: Among the most common clinical adverse events in the initial therapy
trial were diarrhea and nausea/vomiting; the incidences of these events were
lower with both METAGLIP dosage strengths than with metformin therapy. There
were 4 (1.2%) patients in the initial therapy trial who discontinued METAGLIP
therapy due to GI adverse events. Gastrointestinal symptoms of diarrhea, nausea/vomiting,
and abdominal pain were comparable among METAGLIP, glipizide and metformin
in the second-line therapy trial. There were 4 (4.6%) patients in the second-line
therapy trial who discontinued METAGLIP therapy due to GI adverse events.
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| dailymed-instance:warning |
Metformin Hydrochloride: Lactic acidosis: Lactic acidosis is a rare, but serious, metabolic complication
that can occur due to metformin accumulation during treatment with METAGLIP;
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 hypoperfusionand 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. METAGLIP 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, METAGLIP 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, METAGLIP 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 METAGLIP, since alcohol potentiates the effects of metformin hydrochloride
on lactate metabolism. In addition, METAGLIP 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 .
METAGLIP 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 METAGLIP, gastrointestinal symptoms, which are common during
initiation of therapy with metformin, are unlikely to be drug related. Later
occurrence of gastrointestinal symptoms could be due to lactic acidosis or
other serious disease. Levels of fasting venous plasma lactate above the upper
limit of normal but less than 5 mmol/L in patients taking
METAGLIP do not necessarily indicate impending lactic acidosis and may be
explainable by other mechanisms, such as poorly controlled diabetes or obesity,
vigorous physical activity, or technical problems in sample handling. (See
also PRECAUTIONS.) Lactic acidosis should be suspected in any diabetic patient
with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia). Lactic acidosis is a medical emergency that must be treated
in a hospital setting. In a patient with lactic acidosis who is taking METAGLIP,
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 grams per day) had a rate of cardiovascular
mortality approximately 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 glipizide 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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| dailymed-instance:indicatio... |
METAGLIP is indicated as an adjunct to
diet and exercise to improve glycemic control in adults with type 2 diabetes
mellitus.
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| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
METAGLIP
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