68:20 Antidiabetic Agents

68:20.04 Biguanides
Metformin Hydrochloride
Introduction
C4 H11N5 HCl
Metformin hydrochloride is a biguanide antidiabetic agent.1 , 2 , 3 , 4 , 18, 20, 22, 23, 27,
28 29 30 33 72 146 243 245 246
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Uses
Diabetes Mellitus
Metformin is used as monotherapy as an adjunct to diet and exercise for the
management of type 2 (noninsulin-dependent) diabetes mellitus (NIDDM) in patients
whose hyperglycemia cannot be controlled by diet alone.1 , 3 , 4 , 6 , 8 , 15, 16, 17, 18, 19,
20 27 29 95 166 243 245 246
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Metformin may also be used in combination with a
sulfonylurea or a thiazolidinedione antidiabetic agent as an adjunct to diet and exercise
in patients with type 2 diabetes who do not achieve adequate glycemic control with
metformin, sulfonylurea, or thiazolidinedione monotherapy.1 , 3 , 6 , 15, 18, 20, 22, 27, 29,
30 48 59 78 88 95 97 99 112 134 166 191 234 237 239 241 242 243 245 246 250
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Metformin may be used with repaglinide in patients with type 2 diabetes mellitus who
have inadequate glycemic control with diet, exercise, and monotherapy with metformin,
a sulfonylurea, repaglinide, or a thiazolidinedione antidiabetic agent.238, 249 Metformin
also may be used concomitantly with nateglinide in patients who no longer respond
adequately to metformin despite appropriate diet, exercise, and metformin
monotherapy. Metformin is commercially available in fixed combination with glyburide or
glipizide for use as initial therapy in the management of patients with type 2 diabetes
mellitus whose hyperglycemia cannot be controlled by diet and exercise alone, or as
second-line therapy in patients who do not achieve adequate control of hyperglycemia
despite therapy with diet, exercise, and initial treatment with a sulfonylurea antidiabetic
agent or metformin. A thiazolidinedione may be added to metformin in fixed combination
with glyburide in patients who have inadequate glycemic control with fixed-combination
therapy. Metformin is commercially available in fixed combination with rosiglitazone for
the management of type 2 diabetes mellitus in patients who who have inadequate
glycemic control with metformin monotherapy or are already receiving therapy with
metformin and rosiglitazone as separate components. Metformin also may be used as
adjunctive therapy in patients with type 2 diabetes mellitus receiving insulin therapy to
improve glycemic control and/or decrease the dosage of insulin needed to obtain
optimal glycemic control.
The National Diabetes Data Group and the American Diabetes Association (ADA)

currently classify diabetes mellitus as type 1 (insulin dependent, IDDM), type 2

(noninsulin dependent, NIDDM), or that associated with certain conditions or syndromes
(e.g., drug- or chemical-induced, hormonal, that associated with pancreatic disease).7 ,
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Type 2 diabetes mellitus previously was described as maturity-onset (MOD) or
adult-onset (AODM) diabetes mellitus, since it usually occurs in patients older than 40
years of age.7 However, type 1 or 2 diabetes mellitus can occur at any age, and the
current classification is based on clinical presentation rather than on age of onset.7 , 12
Epidemiologic data indicate that the incidence of type 2 diabetes mellitus is increasing in
children and adolescents such that 8-45% of children with newly diagnosed diabetes
have nonimmune-mediated diabetes mellitus; most of these individuals have type 2
diabetes mellitus, although other types, including idiopathic or nonimmune-mediated
type 1 diabetes mellitus, also have been reported.235 Most individuals with type 2
diabetes mellitus (about 50-90%) are obese;7 , 12, 178, 179, 180, 236 obesity itself also
contributes to the insulin resistance and glucose intolerance observed in these
patients.8 , 9 , 11, 18, 27, 30, 59, 60, 73, 134, 145, 178, 179, 236 While children with
immune-mediated type 1 diabetes generally are not overweight, the incidence of obesity
in children with this form of diabetes is increasing with the increasing incidence of
obesity in the US population.235
Metformin is not effective as sole therapy in patients with type 1 diabetes mellitus;
insulin is necessary in these patients.6 , 30, 134, 146
Patients with type 2 diabetes mellitus are not dependent initially on insulin (although
many patients eventually require insulin for glycemic control)13, 18, 27, 28, 30, 78, 94, 95,
99 101 134 146 166 179 181 185 187
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nor are they prone to ketosis;7 , 12 however,
insulin occasionally may be required for correction of symptomatic or persistent
hyperglycemia that is not controlled by dietary regulation or oral antidiabetic agents
(e.g., sulfonylureas), and ketosis occasionally may develop during periods of severe
stress (e.g., acute infection, trauma, surgery). 7 , 12, 14, 146, 179 Type 2 diabetes mellitus
is a heterogeneous subclass of the disease; hyperglycemia in these patients often is
accompanied by other metabolic abnormalities such as obesity, hypertension,
hyperlipidemia, and impaired fibrinolysis.7 , 8 , 9 , 13, 14, 22, 27, 28, 73, 94, 102, 146, 178,
179 181
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Endogenous insulin is present in type 2 diabetic patients, although plasma
insulin concentrations may be decreased, increased, or normal.8 , 9 , 11, 18, 27, 28, 34, 71,
73 181 189
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In type 2 diabetic patients, glucose-stimulated secretion of endogenous
insulin is frequently, but not always, reduced and decreased peripheral sensitivity to
insulin is almost always associated with glucose intolerance.9 , 11, 28, 181
Glycemic Control and Microvascular Complications
Current evidence from epidemiologic and clinical studies supports an association
between chronic hyperglycemia and the pathogenesis of microvascular complications in
patients with diabetes mellitus,8 , 13, 146, 163, 181, 183, 185, 186, 194, 195, 196, 202 and
results of randomized, controlled studies in patients with type 1 diabetes mellitus
indicate that intensive management of hyperglycemia with near-normalization of blood
glucose and glycosylated hemoglobin (hemoglobin A1c [HbA1c ]) concentrations

provides substantial benefits in terms of reducing chronic microvascular (e.g.,

neuropathy, retinopathy, nephropathy) complications associated with the disease.8 , 14,
163 180 181 182 190
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Glycosylated hemoglobin reflects the glycosylation of other
proteins throughout the body as a result of recent hyperglycemia and is used as a
predictor of risk for the development of diabetic microvascular complications (e.g.,
neuropathy, retinopathy, nephropathy).134, 184, 188, 194, 195, 196, 202, 206
In the Diabetes Control and Complications Trial (DCCT), a reduction of approximately
50-75% in the risk of development or progression of retinopathy, nephropathy, and
neuropathy was demonstrated during an average 6.5 years of follow-up in patients with
type 1 diabetes mellitus receiving intensive insulin treatment (3 or more insulin injections
daily with dosage adjusted according to results of at least 4 daily blood glucose
determinations, dietary intake, and anticipated exercise) compared with that in patients
receiving conventional insulin treatment (1 or 2 insulin injections daily, self-monitoring of
blood or urine glucose values, education about diet and exercise).14, 182 However, the
incidence of severe hypoglycemia, including multiple episodes in some patients, was 3
times higher in the intensive-treatment group than in the conventional-treatment
group.182 The reduction in risk of microvascular complications in the DCCT study
correlated continuously with the reduction in glycosylated hemoglobin concentration
(hemoglobin A1c ) produced by intensive insulin treatment (e.g., a 40% reduction in risk
of microvascular disease for each 10% reduction in hemoglobin A1c ).13, 14, 134, 182,
185 206
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These data imply that any decrease in glycosylated hemoglobin levels is
beneficial and that complete normalization of blood glucose concentrations may prevent
diabetic microvascular complications.13, 14, 134, 182, 185, 206

The DCCT was terminated prematurely because of the pronounced benefits of intensive
insulin regimens,182, 255 and all treatment groups were encouraged to institute or
continue such intensive insulin therapy.255 In the Epidemiology of Diabetes
Interventions and Complications (EDIC) study, the long-term, open-label continuation
phase of the DCCT, the reduction in the risk of microvascular complications (e.g.,
retinopathy, nephropathy, neuropathy) associated with intensive insulin therapy has
been maintained throughout 7 years of follow-up.255 In addition, the prevalence of
hypertension (an important consequence of diabetic nephropathy) in those receiving
conventional therapy has exceeded that of those receiving intensive therapy.255
Patients receiving conventional insulin therapy in the DCCT were able to achieve a
lower glycosylated hemoglobin when switched to intensive therapy in the continuation
study, although the average glycosylated hemoglobin values achieved during the
continuation study were higher (i.e., worse) than those achieved during the DCCT with
intensive insulin therapy.255 Patients who remained on intensive insulin therapy during
the EDIC continuation study were not able to maintain the degree of glycemic control
achieved during the DCCT; by 5 years of follow-up in the EDIC study, glycosylated
hemoglobin values were similar in both intensive and conventional therapy groups.255
The EDIC study demonstrated that the greater the duration of chronically elevated
plasma glucose concentrations (as determined by glycosylated hemoglobin values), the
greater the risk of microvascular complications.255 Conversely, the longer patients can

maintain a target glycosylated hemoglobin of 7% of less, the greater the delay in the
onset of these complications.255
In another randomized, controlled study (Stockholm Diabetes Intervention Study) in
patients with type 1 diabetes mellitus who were evaluated for up to 7.5 years, blood
glucose control (as determined by glycosylated hemoglobin concentrations) was
improved, and the incidence of microvascular complications (e.g., decreased visual
acuity, retinopathy, nephropathy, decreased nerve conduction velocity) reduced, with
intensive insulin treatment (e.g., at least 3 insulin injections daily accompanied by
intensive educational efforts) compared with that in patients receiving standard
treatment (e.g., generally 2 insulin injections daily without intensive educational
efforts).190
Evidence from the United Kingdom Prospective Diabetes (UKPD) study216, 218, 219, 220
and other smaller studies51 in patients with type 2 diabetes mellitus generally is
consistent with the same benefits of oral hypoglycemic agents on microvascular
complications as those observed in type 1 diabetics receiving insulin therapy in the
DCCT. 182, 186, 216, 218, 219, 220, 221 The UKPD study evaluated more than 5000
middle-aged, newly diagnosed, overweight (exceeding 120% of ideal body weight) or
non-overweight patients with type 2 diabetes mellitus who received conventional or
intensive treatment regimens with an oral sulfonylurea agent and/or insulin; overweight
patients also could be allocated to metformin therapy in the same proportions as those
allocated to sulfonylureas and insulin.218, 219, 220, 222 Initial therapy consisted of an
oral antidiabetic agent (sulfonylurea or metformin) or insulin, with stepwise addition of
metformin (or glyburide in those initially allocated to metformin) in those poorly
controlled on initial therapy or conversion to insulin alone in patients not adequately
controlled with 2 oral agents.218, 219, 220, 222 Intensive treatment consisted of
antidiabetic therapy targeted to a fasting plasma glucose concentration of less than 108
mg/dL or, in patients receiving insulin, preprandial glucose concentrations of 72-126
mg/dL. 218, 219, 220, 222 Conventional treatment consisted of antidiabetic therapy
targeted to a fasting plasma glucose concentration of less than 270 mg/dL without
symptoms of hyperglycemia.218, 219, 220, 222 Results of the UKPD study indicate
beneficial effects on retinopathy, nephropathy, and possibly neuropathy with intensive
glucose-lowering therapy in type 2 diabetics, in whom a median glycosylated
hemoglobin of 7% was achieved compared with a value of 7.9% in the conventional
treatment group.219, 220 The overall incidence of microvascular complications was
reduced by 25% with intensive therapy.219, 200 Epidemiologic analysis of the UKPD
study results indicates a continuous relationship between the risks of microvascular
complications and glycemia, with a 35% reduction in risk for each 1% reduction in
glycosylated hemoglobin.219, 220 While an association between the risk of
macrovascular (e.g., cardiovascular) complications was also demonstrated by the
UKPD study, there was no statistically significant effect of lowering blood glucose on
cardiovascular complications.219, 220
In the UKPD study, fasting plasma glucose concentrations and percent glycosylated
hemoglobin values steadily increased over 10 years in the patients receiving

conventional therapy, and more than 80% of these patients eventually required
antidiabetic therapy in addition to diet to maintain fasting plasma glucose concentrations
within the desired goal of less than 270 mg/dL.216, 219, 220, 222 In patients receiving
intensive therapy initiated with chlorpropamide, glyburide, or insulin, fasting plasma
glucose concentrations and percent glycosylated hemoglobin values decreased during
the first year of the study.217, 219, 222 Subsequent increases in these indices of
glycemic control after the first year paralleled that in the conventional therapy group for
the remainder of the study, indicating slow decline of pancreatic -cell function and loss
of glycemic control regardless of intensity of therapy. 217, 219, 223, 224
The ADA currently recommends the same blood glucose and glycosylated hemoglobin
goals for all patients with type 1 or type 2 diabetes mellitus but states that less stringent
treatment goals may be appropriate for certain individuals.14 Based on target values for
blood glucose and glycosylated hemoglobin used in clinical trials (e.g., DCCT) for type 1
diabetic patients,182 modified somewhat to reduce the risk of severe hypoglycemia,
ADA currently recommends target preprandial (fasting) and peak postprandial plasma
glucose concentrations of 90-130 and less than 180 mg/dL, respectively, and
glycosylated hemoglobin concentrations of less than 7% (based on a nondiabetic range
of less than 6%) in patients with type 1 or 2 diabetes mellitus who are not pregnant. 14
Patients with diabetes mellitus who have elevated glycosylated hemoglobin
concentrations despite having adequate preprandial glucose concentrations should
monitor glucose concentrations 1-2 hours after the start of a meal.14 Treatment with
agents (e.g., a-glucosidase inhibitors) that principally lower postprandial glucose
concentrations to within target ranges also should reduce glycosylated hemoglobin.14,
244
The effect of adequate control of postprandial glucose concentrations on the
microvascular and macrovascular complications of diabetes mellitus is not known.14
Treatment goals should be individualized, and specific target values for blood glucose
and glycosylated hemoglobin appropriately adjusted, based on the patient's capacity to
understand and adhere to the treatment regimen, the risk of severe hypoglycemia, and
other patient factors that may increase risk or decrease benefit (e.g., very young or old
age, comorbid conditions, other diseases that materially shorten life expectancy).14
Strict glycemic control (e.g., maintenance of fasting blood glucose concentrations below
140 mg/dL) usually is not achieved in patients with type 2 diabetes mellitus who have
moderately severe to severe hyperglycemia prior to therapy; most patients with a
baseline fasting blood glucose concentration exceeding 200 mg/dL are unlikely to
experience a return to euglycemia with oral antidiabetic agent monotherapy.18, 78, 105,
134 146
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Data from the long-term UKPD study in middle-aged, newly diagnosed patients with
type 2 diabetes mellitus indicate that strict glycemic control (i.e., maintenance of fasting
blood glucose concentrations below 108 mg/dL) was not achieved with initial intensive
oral antidiabetic therapy in most patients; at 3 and 9 years, 50 and 75%, respectively, of
patients required combination therapy with sulfonylureas or initiation of insulin to
maintain adequate glycemic control.216, 220, 223, 231 While strict guidelines for insulin
dosage adjustments were used in the DCCT study, adjustments of antidiabetic therapy

dosage in the UKPD study were not as frequent (dosage adjustments allowed every 3
months); in addition, the definition of secondary treatment failure with sulfonylureas and
the time of institution of supplementary antidiabetic therapy changed as the study
progressed.182, 216, 219, 223, 225
Considerations in Initiating and Maintaining Antidiabetic Therapy
When initiating therapy for patients with type 2 diabetes mellitus who do not have
severe symptoms, diet should be emphasized as the primary form of treatment;10, 14,
18 24 25 95 123
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caloric restriction and weight reduction are essential in obese
14 24 25 26 88 95 123
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Although appropriate dietary management and weight
reduction alone may be effective in controlling blood glucose concentration and
symptoms of hyperglycemia, many patients receiving dietary advice fail to achieve and
maintain adequate glycemic control with dietary modification alone.13, 23, 24, 25, 26, 95,
134 146 184
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The importance of regular physical activity also should be emphasized, and
cardiovascular risk factors should be identified and corrective measures employed when
feasible.10, 14, 26 Efforts also should be aimed at blood pressure control, as reduction in
blood pressure to a mean of 144/82 mm Hg ("tight blood pressure control") in patients
with diabetes mellitus and uncomplicated mild to moderate hypertension in the UKPD
study substantially reduced the incidence of virtually all macrovascular (e.g., stroke,
heart failure) and microvascular (e.g., retinopathy, vitreous hemorrhage, renal failure)
outcomes and diabetes-related mortality.14, 217, 220, 222, 225, 228, 229
If this treatment program (dietary management, weight reduction, exercise, reduction of
cardiovascular risk factors) fails to reduce symptoms and/or blood glucose
concentrations within 2-3 months of diagnosis, initiation of monotherapy with an oral
antidiabetic agent (e.g., sulfonylurea, metformin, acarbose) or insulin should be
considered.10, 14, 15, 18, 19, 26, 72, 88, 95, 105, 113, 179 The patient and physician should
recognize that dietary management is the principal consideration in the management of
diabetes mellitus, and that oral antidiabetic therapy is used only as an adjunct to, and
not as a substitute for or a convenient means to avoid, proper dietary management.30,
95 189 191 192
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In addition, loss of blood glucose control on diet alone can be temporary
in some patients, requiring only short-term management with drug therapy.1 , 134, 243,
245 246
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Metformin Monotherapy
Clinical studies indicate that metformin is as effective as a sulfonylurea antidiabetic
agent (e.g., chlorpropamide,3 , 16, 17, 18, 19, 27, 29 glyburide,15, 18, 19, 27, 29, 45, 46, 57,
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glipizide,18 tolbutamide3 , 48, 118) for the management of type 2 diabetes mellitus.
Although metformin often has been used in patients who did not achieve adequate
glycemic control with sulfonylurea monotherapy and who did not have symptoms of
severe insulin deficiency (e.g., ketosis, uncontrolled weight loss),6 , 15, 18, 22, 48, 59, 78,
95 112 123 146 166
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either a sulfonylurea or metformin may be used as initial
monotherapy in patients with type 2 diabetes whose hyperglycemia is not controlled

despite dietary modification and exercise.1 , 15, 18, 19, 72, 88, 95, 105, 146, 243, 245, 246
Potential advantages of metformin compared with sulfonylurea antidiabetic agents or
insulin include a minimal risk of hypoglycemia, more favorable effects on serum lipids,
reduction of hyperinsulinemia, and weight loss or lack of weight gain.1 , 2 , 3 , 6 , 16, 17, 18,
19 20 27 30 42 60 68 102 134 146 166
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Type 2 diabetic patients who are very obese or
who have baseline fasting blood glucose concentrations exceeding 200 mg/dL may be
less likely to respond to therapy with sulfonylurea antidiabetic agents.197, 198 Therefore,
since metformin may stabilize or even decrease body weight,1 , 3 , 4 , 6 , 8 , 16, 17, 18, 19,
20 21 105 118 166 243 245 246
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the drug may be particularly useful as initial
monotherapy in obese individuals who might gain weight while receiving a
sulfonylurea.15, 16, 17 Metformin is equally effective in lean or obese patients with type 2
diabetes mellitus. 3 , 6 , 15, 16, 17, 18, 19, 31, 46, 105, 146 Metformin may be effective as
replacement monotherapy in some patients with primary or secondary failure to
sulfonylureas.1 , 30, 48, 78, 95, 134, 179 (See Diabetes Mellitus: Combination Therapy, in
Uses.)
In controlled studies of up to 8 months' duration in adults with type 2 diabetes mellitus,
therapy with metformin hydrochloride (0.5-3 g daily) reduced fasting and postprandial
glucose concentrations15, 31, 34, 35, 42, 60, 78, 85, 105 and glycosylated hemoglobin15,
35 42 68 78
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substantially more than did placebo. The antihyperglycemic effect of
metformin does not appear to correlate with duration of diabetes, age, obesity, race,
fasting insulin concentrations, or baseline plasma lipid concentrations.6 , 20, 78, 105 In a
placebo-controlled study in pediatric (10-16 years of age), treatment-naive (i.e., those
receiving diet therapy only), obese patients with type 2 diabetes mellitus, the net
difference in fasting plasma glucose concentrations in patients receiving metformin
hydrochloride (up to 2 g daily) or placebo for up to 16 weeks was 64.3 mg/dL, reflecting
an increase in fasting plasma glucose concentrations in the placebo group and an
improvement in glycemic control with metformin therapy. 1 The improvement in glycemic
control with metformin in these pediatric patients was similar to that observed in clinical
studies with the drug in adults.1 A small, similar weight loss occurred in patients
receiving either metformin or placebo in this study.1 In a multicenter, randomized,
controlled study in newly diagnosed, asymptomatic patients with type 2 diabetes
mellitus, the efficacy of metformin therapy in reducing fasting plasma glucose (target
value: less than 108 mg/dL) and glycosylated hemoglobin concentrations in a subgroup
of obese patients was similar to that of therapy with a sulfonylurea (chlorpropamide,
glyburide, or glipizide) or insulin in nonobese patients; all drug regimens improved
glycemic control compared with conventional (diet only) therapy.19, 166, 184 However,
unlike sulfonylurea or insulin therapy, metformin therapy generally decreased plasma
insulin concentrations and was not associated with weight gain or an increased
incidence of hypoglycemia.19, 166, 184 In this long-term study, gradual deterioration in
glycemic control occurred with all therapies over the study period despite increases in
drug dosage or combined drug therapy; glycosylated hemoglobin concentrations
generally had increased to baseline levels after 4-5 years of therapy with any of the drug
regimens. 184 Such deterioration in glycemic control has been attributed to a progressive
decline in pancreatic -cell function94, 95, 146, 166, 184 rather than a reduction in insulin

sensitivity.166
Combination Therapy
Metformin may be used concomitantly with one or more oral antidiabetic agents (e.g., a
sulfonylurea, a thiazolidinedione, a meglitinide, and/or an a-glucosidase inhibitor) or
insulin to improve glycemic control in patients with type 2 diabetes.1 , 3 , 6 , 15, 18, 20, 22,
27 29 30 48 59 78 88 90 94 95 97 99 112 134 146 166 191 237 238 239 240 241
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While metformin may be effective as replacement monotherapy in some patients who
develop primary or secondary failure to sulfonylurea antidiabetic agents, optimum
benefit generally is obtained by addition of metformin to existing sulfonylurea therapy as
soon as monotherapy no longer provides adequate glycemic control (i.e., before primary
or secondary failure with symptomatic hyperglycemia occurs).1 , 30, 48, 78, 95, 134, 179,
239 243 245 246
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Primary or secondary failure may occur with metformin as well as with
sulfonylurea therapy.6 , 16, 17, 18, 27, 78, 95, 99, 146, 166 In patients receiving initial
monotherapy with metformin, the incidence of primary and secondary failures appears
to be less than6 , 27, 166 or similar to6 , 16, 17, 18, 122 that in patients receiving
sulfonylurea monotherapy. Secondary failure to sulfonylurea antidiabetic agents or
metformin is characterized by progressively decreasing diabetic control following 1
month to several years of good control. 30, 134, 166, 184, 199 Combined therapy with
metformin and another oral antidiabetic agent generally is used in patients with
longstanding type 2 diabetes mellitus who have poor glycemic control with
monotherapy;15, 72, 95, 99, 216, 238, 240 the sequence in which metformin or a
sulfonylurea is used at initiation of therapy does not appear to alter the effectiveness of
combined therapy with the drugs.15, 95, 146
Metformin is commercially available in fixed combination with glyburide or glipizide for
use as initial therapy in the management of patients with type 2 diabetes mellitus whose
hyperglycemia cannot be controlled by diet and exercise alone. 234, 254 In several
comparative trials in such patients, therapy with metformin in fixed combination with
glyburide or glipizide was more effective in improving glycemic control (as determined
by glycosylated hemoglobin values, fasting plasma glucose concentrations) than
monotherapy with either component. 234, 254 A greater percentage of patients receiving
metformin in fixed combination with glipizide or glipizide achieved strict glycemic control
(e.g., glycosylated hemoglobin values less than 7%)14 than patients receiving
monotherapy with metformin, glyburide, or glipizide.234, 254
Metformin in fixed combination with glyburide or glipizide also is used to improve
glycemic control in patients with type 2 diabetes who are inadequately controlled with
either sulfonylurea or metformin monotherapy. 234, 254 In several comparative studies in
such patients, greater glycemic control (as determined by glycosylated hemoglobin
values, fasting plasma glucose concentrations) was achieved with the fixed combination
of metformin and glyburide or glipizide than with metformin, glyburide, or glipizide
monotherapy. 234, 254 Strict glycemic control (e.g., glycosylated hemoglobin values less

than 7%)14 was achieved in a greater percentage of patients receiving fixed

combinations of metformin with a sulfonylurea (glyburide or glipizide) than with
sulfonylurea or metformin monotherapy. 234, 254
Metformin also is used in combination with rosiglitazone (either as a fixed-combination
preparation or as individual drugs given concurrently) in patients with type 2 diabetes
who have inadequate glycemic control with metformin monotherapy or in those who are
already receiving metformin and rosiglitazone concurrently as separate components.
166 184 247 250
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In a controlled clinical trial, concurrent therapy with metformin
hydrochloride (2.5 g once daily) and rosiglitazone (4 or 8 mg once daily) in patients
inadequately controlled with metformin monotherapy reduced mean fasting plasma
glucose concentrations and glycosylated hemoglobin values compared with metformin
monotherapy.240 247 No clinical trials have evaluated the fixed combination of metformin
and rosiglitazone; efficacy and safety of the fixed combination has been established
based on concurrent administration of the 2 agents separately.247 Bioequivalence has
been demonstrated between the fixed combination of rosiglitazone and metformin and
each agent given concurrently.247 No clinical trials have evaluated metformin as add-on
therapy in patients inadequately controlled with rosiglitazone monotherapy or the
combination of the agents given separately as initial therapy in patients with type 2
diabetes mellitus. 247 In a dose-ranging trial evaluating rosiglitazone 4 or 8 mg as
add-on therapy to the maximum daily dosage of metformin hydrochloride, 28.1% of
patients receiving the higher dosage of rosiglitazone concurrently with metformin
achieved glycosylated hemoglobin values of 7% or less.240
Metformin may be used concomitantly with glyburide and a thiazolidinedione
antidiabetic agent to improve glycemic control in patients with type 2 diabetes who are
inadequately controlled with the fixed combination of metformin and glyburide. 234 In
such patients, the addition of rosiglitazone to combined therapy with metformin and
glyburide has reduced fasting glucose concentrations and glycosylated hemoglobin
values.234 Strict glycemic control (e.g., glycosylated hemoglobin values less than 7%)14
was achieved in 42.4% of patients of receiving the triple combination of metformin,
glyburide, and rosiglitazone compared with 13.5% of those receiving metformin and
glyburide.234
Metformin also is used in combination with other insulin secretagogues (e.g.,
meglitinides such as repaglinide or nateglinide), other thiazolidinediones (e.g.,
pioglitazone), or acarbose to improve glycemic control in patients with type 2 diabetes
mellitus.112, 237, 238, 244, 248, 249
In a clinical trial in patients who had inadequate glycemic control (glycosylated
hemoglobin exceeding 7.1%) with metformin monotherapy, addition of repaglinide to
metformin therapy produced reductions in fasting plasma glucose concentrations and
glycosylated hemoglobin averaging 39.6 mg/dL and 1.4%, respectively, compared with
reductions averaging 4.5 mg/dL and 0.33%, respectively, with metformin alone; patients
receiving repaglinide therapy alone had an increase in fasting plasma glucose
concentrations of 8.8 mg/dL and a reduction of 0.38% in glycosylated hemoglobin. 238,

249

In a clinical trial in treatment-naive patients or patients who had previously received

antidiabetic therapy (followed by a washout period of at least 2 months), combined
therapy with metformin hydrochloride and nateglinide resulted in greater reductions in
glycosylated hemoglobin and fasting plasma glucose concentrations than metformin or
nateglinide monotherapy.248, 252
In another clinical trial in patients with type 2 diabetes mellitus who had inadequate
glycemic control with metformin, a sulfonylurea, or insulin, the combination of
pioglitazone (30 mg daily) and metformin (and withdrawal of other antidiabetic therapy)
reduced fasting plasma glucose concentrations and glycosylated hemoglobin values
compared with metformin therapy alone, regardless of whether patients were receiving
lower (less than 2 g daily) or higher (2 g daily or more) dosages of metformin
hydrochloride.237, 251
In a multicenter, controlled study in patients whose hyperglycemia was inadequately
controlled by diet and metformin therapy, the addition of acarbose produced appreciable
improvement in postprandial plasma glucose concentrations and modest improvement
in glycosylated hemoglobin.112, 134, 244 Fasting plasma glucose concentrations
generally are not reduced by addition of acarbose to therapy with metformin since
acarbose acts principally during a meal to delay carbohydrate absorption.112, 113
Limited data suggest that combined therapy with metformin and a sulfonylurea is as
effective205 or more effective193 in reducing fasting blood glucose and glycosylated
hemoglobin concentrations than combined therapy with acarbose and a sulfonylurea;
however, acarbose may provide better control of postprandial blood glucose
concentrations.205
Combined therapy with metformin and other oral antidiabetic agents (e.g., sulfonylureas,
acarbose) in patients not adequately controlled with monotherapy may reduce
symptoms and delay or avoid institution of insulin or allow reduced insulin dosages.1 , 6 ,
18 20 21 22 23 73 94 95 99 100 101 104 112 122 146 179 193 237 239
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In patients
poorly controlled by diet and oral sulfonylurea therapy, the addition of metformin has
reduced fasting glucose concentrations by 25-40%; it has been suggested that up to
50% of patients who are not controlled by high-dose sulfonylurea therapy will improve
substantially with concomitant metformin therapy.15, 21, 22, 44, 78, 97, 179 However,
strict glycemic control (e.g., fasting blood glucose less than 140 mg/dL) has not been
achieved in most of these patients, and insulin therapy eventually is required for
control.15, 21, 22, 44, 78, 97, 134
Conflicting data regarding the long-term benefit of metformin as part of an intensive
antidiabetic regimen have been reported in the United Kingdom Prospective Diabetes
(UKPD) study, which consisted of middle-aged, newly diagnosed, overweight
(exceeding 120% of ideal body weight) or non-overweight patients with type 2 diabetes
mellitus who received long-term therapy (over 10 years) with intensive or conventional
treatment.218, 219, 220, 222 (See Glycemic Control and Microvascular Complications,
under Uses: Diabetes Mellitus.) In one UKPD study substudy, overweight patients
receiving metformin as initial therapy in a stepwise intensive regimen had a 32% lower

risk of developing any diabetes-related endpoint (including macrovascular and

microvascular complications) compared with those managed by dietary modification
alone; the reduction in any diabetes-related end point was greater in those receiving
metformin than in those receiving initial intensive therapy with a sulfonylurea or
insulin.216 The risk for diabetes-related death or myocardial infarction (39% lower) was
also lower with intensive therapy with metformin or sulfonylureas or insulin compared
with conventional therapy; no differences between the effects of intensive therapies
were noted. 216, 218, 220, 221 In contrast, a second UKPD substudy in which metformin
was added to sulfonylurea therapy to improve glycemic control resulted in an increase in
the risk of diabetes-related death or death from any cause compared with continuing
therapy with a sulfonylurea alone.216, 217, 218, 220, 221, 225 A pooled analysis of both
trials and epidemiologic analysis of other data from the UKPD study in patients who
received stepwise therapy with metformin and sulfonylurea therapy because of
progressive hyperglycemia showed a small reduction in diabetes-related death,
all-cause mortality, myocardial infarction, and stroke.216 Reasons for disparate results
of these trials are unclear but may be related to trial design, the relatively smaller
number of patients receiving metformin, analytical methods, or differences in response
between overweight and non-overweight patients.217, 218, 220 Pending the results of
additional studies, the American Diabetes Association (ADA) and other clinicians do not
recommend changing current guidelines regarding the use of metformin as
monotherapy or in combination with sulfonylureas.220, 221, 224
When glycemic control cannot be improved after 1-3 months of combined therapy with
oral antidiabetic agents at maximal doses or if the effectiveness of such combined
therapy declines, most clinicians recommend discontinuance of oral antidiabetic agents
and initiation of insulin therapy.1 , 3 , 88, 94, 95, 134, 179
Metformin may be used in combination with insulin to improve glycemic control and
reduce insulin requirements in patients with type 2 diabetes mellitus who no longer
respond to combinations of oral antidiabetic agents.1 , 3 , 6 , 88, 90, 94, 95, 146 Combined
therapy with insulin and one or more oral antidiabetic agents appears to increase
glycemic control with lower doses of insulin than would be required with insulin alone
and with a decreased potential for body weight gain associated with insulin therapy.1 ,
94 95 104 122 179
, ,
,
,
Data from a small, placebo-controlled, 24-week trial indicate that
addition of metformin improved glycemic control (as measured by a reduction in
glycosylated hemoglobin) in patients who failed to achieve adequate glycemic control
with insulin therapy; insulin dosage in patients receiving adjunctive metformin therapy
was decreased by 16%.1 In another small, placebo-controlled study in patients
adequately controlled with insulin therapy, insulin dosage requirements were reduced by
19% after addition of metformin.1 Limited data in patients who no longer respond to
monotherapy with a sulfonylurea or metformin suggest that combined therapy with
metformin and a sulfonylurea, with or without a single daily dose of intermediate-acting
insulin, is at least as effective in providing glycemic control as combined therapy with a
sulfonylurea and intermediate-acting insulin,104, 193 combined therapy with a
sulfonylurea and an a-glucosidase inhibitor (e.g., acarbose),193 or combined therapy
with intermediate- and short-acting insulins.94

Metformin has been used as an adjunct to insulin to reduce insulin requirements in a

limited number of patients with type 1 diabetes mellitus, but the potential benefits and
risks require further evaluation before such combined therapy can be recommended.6 ,
86 87 116 122 134
, ,
,
,
Oral antidiabetic agents, including metformin, are not effective as sole therapy in
patients with diabetes mellitus complicated by acidosis, ketosis, or coma; management
of these conditions requires the use of insulin.1 , 6 , 30, 146, 191, 192, 243, 245, 246
Misuse and Abuse
Dietary Supplements
Some herbal dietary supplements promoted for the treatment of diabetes mellitus and
purported to contain only natural Chinese herbal ingredients have been found to contain
phenformin (a biguanide similar to metformin but no longer commercially available in the
US) and glyburide.233 Adulteration of these dietary supplements was discovered after
use of one of the glyburide- and phenformin-containing dietary supplements by a patient
with diabetes mellitus resulted in several episodes of hypoglycemia, from which the
patient fully recovered. 233 Restrictions on the importation and sale of these dietary
supplements have been initiated by FDA.233
Dosage and Administration
Administration
Metformin is administered orally.1 , 3 , 18, 85, 243, 245, 246 In patients receiving a
metformin hydrochloride conventional tablets at a dosage of 2 g or less daily, the drug
usually can be given as 2 divided doses daily; however, in patients who require more
than 2 g daily, the drug usually should be administered as 3 divided doses daily.1 , 243,
245 246
,
Although food decreases the extent and slightly delays absorption of metformin
conventional tablets, the manufacturer states that the clinical importance of these
effects is not known and recommends that the drug be taken with meals to decrease
adverse GI effects.1 , 3 , 18, 243, 245, 246
Metformin hydrochloride extended-release tablets should be taken with the evening
meal.1 The matrix core of the tablets usually is broken up in the GI tract, but patients
should be advised that occasionally the biologically inert components of the tablet may
remain intact and be passed in the stool as a soft, hydrated mass. 1
Dosage
Dosage of metformin hydrochloride must be individualized carefully based on patient
response and tolerance.1 , 4 , 243, 245, 246 The goal of therapy should be to reduce both
fasting glucose and glycosylated hemoglobin (hemoglobin A1c [HbA1c ]) values to
normal or near normal using the lowest effective dosage of metformin hydrochloride,
either when used as monotherapy or combined with another oral antidiabetic agent
(e.g., sulfonylurea, acarbose).1 , 8 , 13, 14, 78, 85, 88, 105, 134, 146, 166, 234, 235, 243, 245,

246

Patients should be monitored with regular laboratory evaluations, including fasting

blood (or plasma) glucose determinations, to assess therapeutic response and the
minimum effective dosage of metformin hydrochloride.1 , 2 , 85, 243, 245, 246 (Glucose
concentrations in plasma generally are 10-15% higher than those in whole blood;
glucose concentrations also may vary according to the method and laboratory used for
these determinations.)204 Glucose determinations also should be monitored to detect
primary failure (inadequate lowering of glucose concentration at the maximum
recommended dosage) or secondary failure (loss of glycemic control following an initial
period of effectiveness) to the drug.1 , 3 , 243, 245, 246 If inadequate glycemic control
and/or secondary failure occurs during maintenance therapy with metformin or an oral
sulfonylurea alone, combined therapy may result in an adequate response.1 , 134, 243,
245 246
,
If secondary failure occurs with combined metformin and oral sulfonylurea
therapy, most clinicians currently recommend discontinuance of oral antidiabetic agents
and initiation of insulin therapy.1 , 3 , 13, 30, 88, 90, 94, 95, 134, 146, 179, 243, 245, 246
Following initiation of metformin therapy and dosage titration, determination of
glycosylated hemoglobin concentrations at intervals of approximately 3 months is useful
for assessing the patient's continued response to therapy.1 , 2 , 3 , 14, 134, 234, 243, 245,
246
Glycosylated hemoglobin is a better indicator of long-term glycemic control than
fasting plasma glucose concentrations alone.14, 234 In patients usually well controlled
by dietary management alone, short-term therapy with metformin may be sufficient
during periods of transient loss of diabetic control.1 , 134, 243, 245, 246
Since adverse GI effects with metformin appear to be dose related, it is recommended
that dosage of the drug be increased gradually and that the drug be taken with meals.1 ,
2 18 53 85 243 245 246
, , , ,
,
,
(See Cautions: GI Effects.)
Initial Dosage in Previously Untreated Patients
Adult Dosage
For the management of type 2 (noninsulin-dependent) diabetes mellitus (NIDDM) in
adults not previously receiving insulin or a sulfonylurea antidiabetic agent, the usual
initial dosage of metformin hydrochloride as conventional tablets is 500 mg twice daily
given in the morning and evening with meals.1 , 4 , 134, 243, 245, 246 Alternatively, a
metformin hydrochloride dosage of 500-850 mg daily (given in the morning) as
conventional tablets has been suggested.1 , 2 , 3 , 4 , 23, 30, 146, 243, 245, 246 When the
extended-release preparation of metformin hydrochloride is used, the usual initial
dosage in adults is 500 mg once daily with the evening meal.1 Subsequent dosage
should be adjusted according to the patient's therapeutic response, using the lowest
possible effective dosage.1 , 30, 243, 245, 246 Although satisfactory control of blood
glucose concentrations may be achieved within a few days after dosage adjustment, the
full effects of the drug may not be observed for up to 2 weeks.18, 134
Metformin should be used with caution in geriatric patients since aging is associated
with reduced renal function, and accumulation of the drug resulting in lactic acidosis
may occur in patients with renal impairment.1 , 3 , 4 , 165, 243, 245, 246 In addition, renal

function should be monitored regularly in geriatric patients to determine the appropriate

dosage of metformin hydrochloride.1 , 2 , 3 , 4 , 164, 165, 243, 245, 246 Metformin should not
be initiated in geriatric patients 80 years of age or older unless determinations of
creatinine clearance indicate normal renal function.1 , 209 Initial dosages of metformin
hydrochloride should be conservative and should be titrated carefully; dosage generally
should not be titrated to the maximum level recommended for younger adults.1 , 2 , 3 , 4 ,
165 243 245 246
,
,
,
It has been suggested, based on limited data, that initial dosages of
metformin hydrochloride in geriatric patients be reduced by approximately 33%
compared with such dosages in other patients with type 2 diabetes mellitus.30, 174
Pediatric Dosage
For the management of type 2 (noninsulin-dependent) diabetes mellitus (NIDDM) in
children 10 years of age or older, the usual initial dosage of metformin hydrochloride as
conventional tablets is 500 mg twice daily given in the morning and evening with
meals.1 , 246 Use of the extended-release tablets of metformin hydrochloride is not
recommended in children younger than 17 years of age.1
Transferring from Therapy with Other Antidiabetic Agents
When transferring from most sulfonylurea antidiabetic agents to metformin, a transition
period generally is not required, and administration of the sulfonylurea antidiabetic agent
may be abruptly discontinued.1 , 2 , 243, 245, 246 Because an exaggerated hypoglycemic
response may occur in some patients during the transition from a sulfonylurea
antidiabetic agent with a prolonged half-life (e.g., chlorpropamide) to metformin, patients
being transferred from such agents should be monitored closely for the occurrence of
hypoglycemia during the initial 2 weeks of the transition period.1 , 2 , 30, 243, 245, 246
Maintenance Dosage
Adult Dosage
The usual adult maintenance dosage of metformin hydrochloride as conventional tablets
is 850 mg twice daily with the morning and evening meals; when additional glycemic
control is necessary, patients may be given 850 mg 3 times daily with meals.1 , 243, 245,
246
In adults receiving an initial metformin hydrochloride dosage of 500 mg twice daily
as conventional tablets, dosage may be increased by 500 mg daily at weekly intervals
until the desired fasting blood glucose concentration (e.g., less than 140 mg/dL) is
achieved or up to 2 g daily.1 , 2 , 14, 18, 21, 30, 85, 134, 243, 245, 246 In adults receiving
500 mg of metformin hydrochloride twice daily as conventional tablets, dosage may be
increased to 850 mg twice daily (i.e., using the 850-mg tablets) after 2 weeks.1 , 243, 245,
246
Alternatively, in adults receiving an initial metformin hydrochloride dosage of 850 mg
daily as conventional tablets, dosage may be increased by 850 mg daily every other
week until the desired fasting blood glucose concentration (e.g., less than 140 mg/dL) is
achieved or up to a maximum dosage of 2.55 g daily.1 , 2 , 3 , 4 , 14, 18, 22, 85, 243, 245,
246

In adults receiving metformin hydrochloride extended-release tablets, dosage may be

increased by 500 mg daily at weekly intervals until the desired glycemic response is

achieved or a maximum dosage is 2 g daily is reached.1 If glycemic control is not

achieved with metformin hydrochloride extended-release tablets at a dosage of 2 g once
daily, a dosage of 1g twice daily should be considered.1 If a dosage exceeding 2 g daily
is needed in patients receiving metformin hydrochloride extended-release tablets,
patients should be switched to conventional metformin hydrochloride tablets and may
receive up to a maximum of 2.55 g of the drug daily in divided doses. 1 Conversely,
therapy with extended-release tablets can be substituted for conventional tablets at the
same total daily dosage of conventional tablets; dosage subsequently should be
adjusted according to glycemic response.1
Dosage in adults generally should not exceed 2.55 g daily as conventional tablets1 , 243,
245 246
,
or 2 g daily as extended-release tablets.1 Dosages exceeding 2 g of metformin
hydrochloride daily as conventional tablets may be better tolerated if given in 3 divided
doses daily with meals.1 , 243, 245, 246 Maintenance dosage of metformin hydrochloride
should be conservative in debilitated, malnourished, or geriatric patients because of an
increased risk of hypoglycemia in these patients.1 , 243, 245, 246 (See Cautions:
Precautions and Contraindications.)
Metformin should be used with caution in geriatric patients since aging is associated
with reduced renal function, and accumulation of the drug resulting in lactic acidosis
may occur in patients with renal impairment.1 , 3 , 4 , 165, 243, 245, 246 In addition, renal
function should be monitored periodically in geriatric patients to determine the
appropriate dosage of metformin hydrochloride.1 , 2 , 3 , 4 , 164, 165, 243, 245, 246
Maintenance dosage of metformin hydrochloride in geriatric patients generally should
not be titrated to the maximum level recommended for younger adults.1 , 2 , 3 , 4 , 165,
243 245 246
,
,
It has been suggested, based on limited data, that maximum dosages in
geriatric patients be reduced by approximately 33% compared with such dosages in
other patients with type 2 diabetes mellitus.30, 174
Pediatric Dosage
In children 10 years of age or older receiving metformin hydrochloride 500 mg twice
daily as conventional tablets, dosage may be increased by 500 mg daily at weekly
intervals until the desired glycemic response is achieved or up to a maximum dosage of
2 g daily.1 , 14, 246
Concomitant Therapy with Metformin and Sulfonylurea Antidiabetic Agents
In patients who do not respond to a 4-week trial of metformin hydrochloride therapy at
the maximum recommended dosage, the manufacturer suggests that gradual addition
of a sulfonylurea antidiabetic agent be considered even if prior primary or secondary
failure to a sulfonylurea antidiabetic agent has occurred.1 , 2 , 4 , 191, 243, 245, 246 The
manufacturer of glipizide states that other oral antidiabetic agents may be added to
glipizide therapy if glycemic control is inadequate with glipizide. 242 The manufacturers
of glimepiride or glyburide state that combination therapy with metformin may be used in
patients who no longer respond adequately to either antidiabetic agent alone, despite
appropriate antidiabetic monotherapy, diet, and exercise.191, 241, 246 With concomitant

metformin hydrochloride and sulfonylurea therapy, dosage of each drug should be

adjusted to obtain adequate glycemic control with the minimum effective dosage of each
drug.1 , 2 , 191, 243, 245, 246 In patients who do not respond to 1-3 months of concomitant
therapy at the maximum dosage of each oral antidiabetic agent, therapeutic alternatives
include use of insulin1 , 243, 245, 246 with or without concomitant metformin
hydrochloride therapy.1
The commercially available preparation containing metformin hydrochloride in fixed
combination with glyburide may be used as initial therapy in patients with type 2
diabetes mellitus whose blood glucose is not adequately controlled with diet and
exercise alone, or as second-line therapy in those in whom glycemic control with
glyburide or metformin monotherapy is not adequate. 234, 254 If the fixed combination of
metformin and glyburide is used as initial therapy, the recommended initial dosage is
250 mg of metformin hydrochloride and 1.25 mg of glyburide daily with a meal.234
Patients with more severe hyperglycemia (as determined by glycosylated hemoglobin
exceeding 9% or fasting plasma glucose concentrations exceeding 200 mg/dL) may
receive an initial dosage of 250 mg of metformin hydrochloride and 1.25 mg of glyburide
twice daily with the morning and evening meals.234 Dosage may be increased in
increments of 1.25 mg of glyburide and 250 mg of metformin hydrochloride daily at
2-week intervals until the minimum effective dosage required to achieve adequate blood
glucose control is reached.234 A total daily dosage exceeding 10 mg of glyburide and 2
g of metformin hydrochloride has not been evaluated in clinical trials in patients
receiving the fixed-combination preparation as initial therapy.234 The manufacturer
states that the fixed-combination preparation containing 5 mg of glyburide and 500 mg
of metformin hydrochloride should not be used as initial therapy in treatment-naive
patients because of the increased risk for hypoglycemia.234
If the fixed combination of metformin and glipizide is used as initial therapy, the
recommended initial dosage is 250 mg of metformin hydrochloride and 2.5 mg of
glipizide once daily with a meal. 254 Patients with more severe hyperglycemia (as
determined by fasting plasma glucose concentrations of 280-320 mg/dL) may receive
an initial dosage of 500 mg of metformin hydrochloride and 2.5 mg of glipizide twice
daily. 254 The efficacy of metformin in fixed combination with glipizide has not been
established in patients whose fasting plasma glucose concentrations exceed 320
mg/dL. 254Dosage may be increased in increments of one tablet (using the tablet
strength at which therapy was initiated, either 2.5 mg of glipizide and 250 mg of
metformin hydrochloride or 2.5 mg of glipizide and 500 mg of metformin in
hydrochloride) daily at 2-week intervals until the minimum effective dosage required to
achieve adequate blood glucose control is reached or the maximal dosage of 2 g of
metformin hydrochloride and 10 mg of glipizide is reached. 254, 256 A total daily dosage
exceeding 2 g of metformin hydrochloride and 10 mg of glipizide has not been evaluated
in clinical trials in patients receiving the fixed-combination preparation as initial therapy.
254

The commercially available preparation containing metformin hydrochloride in fixed

combination with glyburide or glipizide also may be used as second-line therapy in

patients with type 2 diabetes mellitus whose blood glucose is not adequately controlled
with either glyburide or glipizide (or another sulfonylurea antidiabetic agent) or
metformin alone.234, 254 The recommended initial dosage of the commercially available
fixed-combination tablets in previously treated patients is 500 mg of metformin
hydrochloride and 2.5 or 5 mg of glyburide or glipizide twice daily with the morning and
evening meals. 234, 254 In order to minimize the risk of hypoglycemia, the initial dosage
of glyburide and metformin hydrochloride in fixed combination should not exceed the
daily dosage of metformin hydrochloride, glyburide, or glipizide (or the equivalent
dosage of another sulfonylurea) previously received.234, 254 The dosage of the fixed
combination of metformin hydrochloride and glyburide or glipizide should be titrated
upward in increments not exceeding 500 mg of metformin hydrochloride and 5 mg of
glyburide or glipizide until adequate control of blood glucose is achieved or a maximum
daily dosage of 2 g of metformin hydrochloride and 20 mg of glyburide or glipizide is
reached. 234, 254
For patients being switched from combined therapy with separate preparations, the
initial dosage of the fixed-combination preparation of glyburide or glipizide and
metformin hydrochloride should not exceed the daily dosage of glyburide, glipizide (or
equivalent dosage of another sulfonylurea antidiabetic agent), and metformin
hydrochloride currently being taken.234, 254 Such patients should be monitored for signs
and symptoms of hypoglycemia following the switch.234, 254 In the transfer from
previous antidiabetic therapy to fixed combination of metformin hydrochloride, the
decision to switch to the nearest equivalent dosage or to titrate dosage should be based
on clinical judgment. 254 Hypoglycemia and hyperglycemia are possible in such patients,
and any change in the therapy of type 2 diabetic patients should be undertaken with
caution and appropriate monitoring.234 If blood glucose concentrations are not
adequately controlled following initial administration of the fixed-combination
preparation, the dose may be titrated in increments of no more than 5 mg of glyburide
and 500 mg of metformin hydrochloride until adequate control of blood glucose is
achieved or a maximum dosage of 20 mg of glyburide or glipizide and 2 g of metformin
hydrochloride is reached.234, 254 The safety and efficacy of switching from another
combined therapy with separate preparations of glyburide (or another sulfonylurea
antidiabetic agent) and metformin in the fixed-combination preparation have not been
established in clinical studies.234
For patients whose hyperglycemia is not adequately controlled on therapy with
metformin in fixed combination with glyburide, a thiazolidinedione (e.g., pioglitazone,
rosiglitazone) may be added at its recommended initial dosage and the dosage of the
fixed combination may be continued unchanged. 234 In patients requiring further
glycemic control, the dosage of the thiazolidinedione may be titrated upward, based on
the dosage regimen recommended by the manufacturer. 234 Triple therapy with
glyburide, metformin, and a thiazolidinedione may increase the potential for
hypoglycemia at any time of day.234 If hypoglycemia develops during such triple
therapy, consideration should be given to reducing the dosage of the glyburide
component; adjustment of the dosage of the other components of the antidiabetic
regimen also should be considered as clinically indicated.234

Therapy with metformin in fixed combination with glyburide should be used with caution
in geriatric patients, since aging is associated with reduced renal function.234 The initial
and maintenance dosages of metformin hydrochloride in fixed combination with
glyburide should be conservative and should be titrated carefully in such patients.234
Renal function should be assessed with initial dosage selection and with each dosage
adjustment, particularly in geriatric patients, to aid in prevention of lactic acidosis. 234 To
minimize the risk of hypoglycemia, maintenance dosage of the fixed combination of
metformin hydrochloride and glyburide in geriatric, debilitated, or malnourished patients
should not be titrated to the maximum dosage recommended for other patients.234
Combination Therapy with Metformin and a Thiazolidinedione
The manufacturers of pioglitazone or rosiglitazone state that combination therapy with
metformin hydrochloride may be used in patients who do not respond adequately to
either antidiabetic agent alone despite appropriate antidiabetic monotherapy, diet, and
exercise.237, 250 In patients with inadequate glycemic control receiving metformin
hydrochloride, the current dosage of metformin hydrochloride may be continued upon
initiation of thiazolidinedione therapy, as dosage adjustments of metformin
hydrochloride because of hypoglycemia are not likely to be needed.237, 250
The commercially available fixed-combination preparation containing metformin
hydrochloride and rosiglitazone is used as second-line therapy in patients who have
inadeqate glycemic control with metformin monotherapy.247 Metformin in fixed
combination with rosiglitazone also is used in patients with type 2 diabetes mellitus who
are already receiving each drug component separately. 247 Any change in the therapy
of type 2 diabetic patients should be undertaken with caution and appropriate
monitoring. 247
When the commercially available preparation containing metformin hydrochloride in
fixed combination with rosiglitazone is used as second-line therapy in patients
inadequately controlled on metformin or rosiglitazone monotherapy or to replace
concurrent therapy with the drugs given as separate tablets, dosage of the fixed
combination is based on the patient's current dosages of metformin hydrochloride
and/or rosiglitazone.247 In patients inadequately controlled on rosiglitazone
monotherapy, the usual initial dosage of metformin hydrochloride (in fixed combination
with rosiglitazone) is 1 g daily plus the patient's existing dosage of rosiglitazone, given in
2 divided doses. 247 In patients inadequately controlled with metformin hydrochloride
monotherapy, the usual initial dosage of rosiglitazone (in fixed combination with
metformin hydrochloride) is 4 mg daily plus the patient's existing dosage of metformin
hydrochloride, given in 2 divided doses. 247 The tablet strength of the fixed combination
that is selected should be the one that most closely provides the patient's existing
dosage of metformin hydrochloride or rosiglitazone, respectively. 247 (See Table.)
Initial Dosage of the Fixed Combination of Rosiglitazone and Metformin Hydrochloride (Avandamet)
Prior Therapy
Usual Initial Dosage of Avandamet

Total Daily Dosage

Tablet strength
Number of tablets
Metformin Hydrochloride
1g
2 mg/500 mg
1 tablet twice daily
2g
1 mg/500 mg
2 tablets twice daily
Rosiglitazone
4 mg
2 mg/500 mg
1 tablet twice daily
8 mg
4 mg/500 mg
1 tablet twice daily
Therapy should be individualized in patients already receiving metformin hydrochloride
at dosages not available in the fixed combination (i.e., dosages other than 1 or 2 g). 247
The safety and efficacy of transferring from therapy with other oral antidiabetic agents to
the fixed-combination of metformin hydrochloride and rosiglitazone have not been
established in clinical studies.247
For patients switching from combined therapy with separate preparations of metformin
hydrochloride and rosiglitazone, the initial dosage of the fixed-combination preparation
of metformin hydrochloride and rosiglitazone should be the same as the daily dosage of
metformin hydrochloride and rosiglitazone currently being taken. 247
If additional glycemic control is needed following initial therapy or transfer from other
antidiabetic therapy, the dosage of the fixed combination of metformin hydrochloride
and rosiglitazone may be titrated upward in increments not exceeding 500 mg of
metformin hydrochloride and/or 4 mg of rosiglitazone until adequate glycemic control is
achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 8 mg of
rosiglitazone is reached. 247
Therapy with metformin in fixed combination with rosiglitazone should be used with
caution in geriatric patients, since aging is associated with reduced renal function.247
The initial and maintenance dosages of metformin hydrochloride in fixed combination
with rosiglitazone should be conservative and should be titrated carefully in such
patients.247 Renal function should be assessed with initial dosage selection and with
each dosage adjustment, particularly in geriatric patients, to aid in prevention of lactic
acidosis.247 To minimize the risk of hypoglycemia, maintenance dosage of the fixed
combination of metformin hydrochloride and glyburide in geriatric, debilitated, or
malnourished patients should not be titrated to the maximum dosage recommended for
other patients. 247
Concomitant Therapy with Metformin and Insulin
Combination therapy with metformin and insulin may be used in patients who no longer
respond adequately to therapy with oral antidiabetic agents.1 In such patients, the
manufacturer recommends an initial metformin hydrochloride dosage of 500 mg once
daily; the daily dosage may be increased by 500 mg at weekly intervals up to a
maximum of 2.5 g daily or until the desired fasting blood glucose concentration is
achieved.1 Dosages up to 2 g may be given in 2 divided doses daily (e.g., 2 g daily
divided as 1 g with the morning and evening meal) and dosages exceeding 2 g of
metformin hydrochloride daily may be better tolerated if given in 3 divided doses daily

with meals.1 Concurrent insulin dosage should initially remain unchanged.1 Patients
should be monitored closely (e.g., with determination of fasting glucose concentrations)
during the dosage titration.1 When fasting plasma glucose concentrations decrease to
less than 120 mg/dL in patients receiving combined metformin and insulin therapy, the
insulin dosage may be decreased by 10-25%.1 Further dosage adjustments should be
individualized based on glycemic response.1 Periodic adjustments in dosage may be
necessary during continued combination therapy, as guided by monitoring of fasting
glucose and/or glycosylated hemoglobin concentrations.1
Dosage in Renal and Hepatic Impairment
Because of the risk of lactic acidosis, which often is fatal, metformin should not be used
in patients with renal disease or dysfunction and should be avoided in those with clinical
or laboratory evidence of hepatic disease.1 , 165, 243, 245, 246 (See Cautions: Lactic
Acidosis.)
Cautions
Adverse effects, principally GI effects, reportedly occur in about 5-50% of patients
receiving metformin therapy as conventional tablets in clinical trials and generally
required discontinuance of the drug in 6% or less of patients.1 , 6 , 18, 20, 23, 27, 134, 243,
245 246
,
When metformin in used in fixed combination with glyburide, glipizide, or
rosiglitazone, the cautions, precautions, and contraindications associated with these
concomitant agents must be considered in addition to those associated with
metformin. 234, 247, 254
GI Effects
Adverse GI effects such as diarrhea1 , 31, 48, 49, 53, 78, 109, 118, 122, 135, 234, 243, 245,
246 254
,
, nausea1 , 31, 53, 78, 109, 118, 122, 254, vomiting, 1 , 118, 122, 234, 243, 245, 246,
254
flatulence,1 , 243, 245, 246 indigestion,1 , 243, 245, 246 and abdominal discomfort (e.g.,
bloating, abdominal cramping or pain),1 , 31, 35, 42, 53, 118, 122, 234, 243, 245, 246 are the
most common adverse effects associated with metformin-containing therapy as
conventional tablets;1 , 2 , 18, 20, 234, 243, 245, 246, 247, 254 diarrhea or nausea/vomiting
are the most common adverse effects reported in clinical trials with the
extended-release tablets.1 Because substantial diarrhea and/or vomiting may cause
dehydration and prerenal azotemia, metformin should be discontinued in patients who
develop such potentially serious GI effects; persistent diarrhea resolves promptly upon
discontinuance of the drug.1 , 18 Unpleasant or metallic taste (taste
disorder/disturbance),1 , 18, 118, 122, 243, 245, 246 which usually resolves spontaneously,
has been reported in approximately 1-5% of patients receiving metformin conventional
or extended-release tablets.1 , 2 , 3 , 30 Other adverse GI effects reported in 1-5% of
patients receiving conventional or extended-release metformin tablets include abnormal
stools,1 , 243, 245, 246 distended abdomen,1 constipation, 49, 118 or
dyspepsia/heartburn.1 , 49, 118 Anorexia also has been reported with metformin
therapy.3 , 6 , 18

Metformin-induced adverse GI effects appear to be dose related, generally occur at

initiation of therapy, and usually subside spontaneously during continued metformin
therapy; in some cases, a reduction in metformin hydrochloride dosage may be useful in
hastening resolution of these effects.1 , 2 , 3 , 4 , 16, 21, 23, 30, 69, 85, 105, 134, 146
Diarrhea severe enough to require discontinuance of metformin occurred in about 6% of
patients receiving the conventional tablets and in about 0.6% of those receiving the
extended-release tablets in controlled clinical trials.1 , 30, 78, 243, 245, 246 Since adverse
GI effects occurring during initiation of metformin therapy appear to be dose related,
they may be reduced by gradual dosage escalation and administration of the drug with
meals.1 , 2 , 16, 18, 53, 85, 243, 245, 246
Hypoglycemia
Hypoglycemia is uncommon in patients receiving metformin as monotherapy; however,
it may occur when metformin is used concomitantly with an oral sulfonylurea antidiabetic
agent, a thiazolidinedione, or insulin, when caloric intake is deficient, or when strenuous
exercise is not accompanied by food intake.1 , 15, 30, 78, 94, 99, 234, 243, 245, 246, 247,
254
Symptoms of hypoglycemia (such as dizziness, shakiness, sweating, hunger) have
occurred in 21.3, 11.4, or 37.7% of patients receiving glyburide (5.3 mg), glyburide in
fixed combination with metformin hydrochloride (2.78 mg of glyburide, 557 mg of
metformin hydrochloride), or glyburide in fixed combination with metformin hydrochloride
at a final mean titrated dosage of 824 mg of metformin hydrochloride and 4.1 mg of
glyburide in controlled clinical trials. 234 In a controlled initial therapy trial of metformin
hydrochloride in fixed combination with glipizide, symptomatic hypoglycemia and blood
glucose concentrations 50 mg/dL or less occurred in 2.9, 0, 7.6, or 9.3% of patients
receiving glipizide monotherapy (final mean dosage of 16.7 mg), metformin
hydrochloride monotherapy (final mean dosage of 1.749 g of metformin hydrochloride),
the fixed combination with glipizide (final mean dosage of 791 mg of metformin
hydrochloride and 7.9 mg of glipizide), and the fixed combination with a higher dosage
of the metformin hydrochloride component (final mean dosage of 1.477 g of metformin
hydrochloride and 7.4 mg of glipizide). 254 In a controlled trial in patients inadequately
controlled by monotherapy with metformin hydrochloride or a sulfonylurea agent,
documented hypoglycemia (as determined by blood glucose concentrations of 50 mg/dL
or less) occurred in 0, 1.3, or 12.6% of patients receiving glipizide monotherapy (mean
final dosage of 30 mg), metformin hydrochloride monotherapy (mean final dosage of
1.927 g), or metformin hydrochloride in fixed combination with glipizide at a final mean
dosage of 1.747 g of metformin hydrochloride and 5 mg of glipizide. 254 When
rosiglitazone was added to fixed combination therapy of glyburide and metformin
hydrochloride, documented hypoglycemia occurred in 22% of such patients compared
to 3.3% of patients receiving glyburide in fixed combination with metformin
hydrochloride. 234 (See Cautions: Precautions and Contraindications.)
Hematologic Effects
Asymptomatic decreases in serum vitamin B12 concentration were reported in about
7-9% of patients receiving metformin alone,1 , 18, 243, 245, 246 and in about 6% of those
receiving metformin concomitantly with a sulfonylurea antidiabetic agent, during

29-week controlled clinical trials.1 , 18 Such decreases may be related to interference

with absorption of vitamin B12 from B12-intrinsic factor complex;1 , 70, 243, 245, 246
however, they rarely are associated with anemia and are rapidly reversible following
discontinuation of metformin or supplementation with vitamin B12.1 , 3 , 6 , 20, 30, 70, 77,
82 134 243 245 246

,
,
,
,
Serum folic acid concentrations do not appear to decrease
substantially in patients receiving metformin therapy.1 , 70, 82 Megaloblastic anemia has
been reported rarely (e.g., approximately 5 case reports outside the US to date) in
patients receiving metformin,1 , 2 , 18, 114, 243, 245, 246 and no increased incidence of
neuropathy has been observed in patients receiving the drug.1 , 18, 114, 123 Hematologic
parameters (e.g., hemoglobin, serum vitamin B 12 concentrations) should be monitored
annually in patients receiving metformin, and any apparent abnormalities appropriately
investigated and managed.1 , 243, 245, 246 Some clinicians have suggested that periodic
supplementation with parenteral vitamin B12 be considered in patients receiving
metformin who are at high risk for developing subnormal vitamin B12 levels (e.g.,
alcoholics, patients with low calcium or vitamin B12 intake or absorption).82, 114, 122,
134 148

(See Cautions: Precautions and Contraindications.)

Dermatologic Reactions
The manufacturer states that incidence of rash or dermatitis in patients receiving
metformin monotherapy is similar to that with placebo, and that the incidence of these
dermatologic effects in patients receiving metformin concomitantly with a sulfonylurea
antidiabetic agent is similar to that in individuals receiving a sulfonylurea antidiabetic
agent alone.1 , 30
Lactic Acidosis
Accumulation of metformin may occur in patients with renal impairment, and such
accumulation rarely can result in lactic acidosis, a serious, potentially fatal metabolic
disease.1 , 6 , 18, 20, 27, 29, 30, 62, 89, 96, 158 However, the risk of developing lactic
acidosis is less with metformin than with phenformin (no longer commercially available
in the US).3 , 6 , 20, 23(See Chemistry and Stability: Chemistry.) Lactic acidosis also may
occur in association with a variety of pathophysiologic conditions, including diabetes
mellitus, and may occur whenever substantial tissue hypoperfusion and hypoxemia
exist.1 , 32, 53, 63, 64, 93, 96, 123, 146 Lactic acidosis is characterized by elevated blood
lactate concentrations (exceeding 45 mg/dL), decreased blood pH (less than 7.35),
electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate
ratio.1 , 30
When metformin has been implicated as the cause of lactic acidosis, plasma drug
concentrations exceeding 5 mcg/mL generally have been observed.1 However, plasma
metformin concentrations may not be an accurate indication of tissue accumulation of
the drug in patients with metformin-induced lactic acidosis, and increased plasma
concentrations of lactic acid or lactic acidosis have been demonstrated during metformin
therapy despite normal plasma concentrations of the drug. 51, 64, 96, 146, 158 Patients
with lactic acidosis and normal plasma metformin concentrations also may have other

conditions contributing to the development of lactic acidosis (e.g., hypoxia,

dehydration).96, 134, 158
Fasting venous plasma lactate concentrations that exceed the upper limit of normal but
are less than 45 mg/dL do not necessarily indicate impending lactic acidosis in patients
receiving metformin.1 Such concentrations may be related to poorly controlled diabetes,
obesity, vigorous physical activity, or technical problems in handling samples for plasma
lactate determinations.1
The reported overall incidence of lactic acidosis in patients receiving metformin therapy
is low (approximately 0.03 cases per 1000 patient-years of metformin therapy);
approximately 50% of such cases have been fatal.1 , 2 , 3 , 4 , 33, 78, 95, 146, 158 It has
been suggested that in metformin-associated lactic acidosis not accompanied by
conditions predisposing to tissue anoxia (e.g., heart failure, renal or pulmonary disease),
techniques for the elimination of metformin from the body may allow a recovery rate
exceeding 80%.158 Lactic acidosis associated with metformin therapy generally has
occurred in diabetic patients with severe renal insufficiency, including those with both
intrinsic renal impairment and renal hypoperfusion; such patients frequently had
concomitant medical and/or surgical problems and were receiving multiple drugs.1 , 2 , 3 ,
20 50 62 64 76 96 123 158 164 165
, , , , , ,
,
,
,
The risk of lactic acidosis increases with the degree of renal impairment and the
patient's age; therefore, the risk of this condition can be minimized by periodic
monitoring of renal function and use of the minimum effective dosage of metformin
hydrochloride.1 , 32, 62, 63, 65, 76, 85, 91, 93, 96, 123, 124, 158, 164, 165, 234, 247 Metformin
therapy should be withheld promptly in patients with any condition associated with
hypoxemia, sepsis, or dehydration.1 , 2 , 62, 63, 93, 234, 247 Therapy with the drug alone
or in fixed combinations also should be avoided in patients with clinical or laboratory
evidence of hepatic impairment since elimination of lactate may be reduced
substantially in such patients.1 , 2 , 63, 65, 85, 91, 93, 156, 158, 234, 247 Patients should be
advised not to consume excessive amounts of alcohol, either acutely or chronically,
since alcohol may potentiate the effects of metformin on lactate metabolism by
decreasing hepatic gluconeogenesis.1 , 2 , 63, 76, 91, 93, 158, 234, 247 In addition, therapy
with metformin preparations should be withheld temporarily in patients undergoing
surgery or receiving parenteral iodinated radiographic contrast media.1 , 2 , 30, 62, 63, 93,
158 234 247 254
,
,
,
(See Cautions: Precautions and Contraindications.)
Lactic acidosis often has a subtle onset and may be accompanied only by nonspecific
symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and
nonspecific abdominal distress.1 , 32, 62, 119 Associated hypothermia, hypotension, and
resistant bradyarrhythmias with more marked acidosis also may occur.1 , 62, 117
Patients and clinicians should be aware of the possible importance of such symptoms,
and patients should be instructed to notify their clinician immediately if these symptoms
occur;1 , 2 metformin should be discontinued until the clinician has evaluated the
patient's condition.1 , 30 Once a patient is stabilized at any dosage of metformin

hydrochloride, GI symptoms, which are common during initiation of therapy, are unlikely
to be drug related; later occurrence of GI symptoms could be manifestations of lactic
acidosis or other serious disease.1 In diabetic patients, lactic acidosis may be
manifested as metabolic acidosis without ketoacidosis (ketonuria and ketonemia).1
Lactic acidosis constitutes a medical emergency requiring immediate hospitalization and
treatment;1 in such cases, metformin should be discontinued and general supportive
therapy (e.g., volume expansion, diuresis) should be initiated immediately.1 , 32, 62, 119
(See Acute Toxicity.)
Other Adverse Effects
Headache,118 agitation,118 dizziness,118 and tiredness118 were reported in a small
comparative study in geriatric diabetic patients receiving metformin.30, 85 Headache has
been reported in 9.3 or 8.9% of patients receiving metformin or metformin in fixed
combination with glyburide, respectively. 234 Headache has been reported in 5.3 or
12.6% of patients receiving metformin or metformin in fixed combination with glipizide,
respectively. 254 Dizziness has been reported in 3.8 or 5.5% of patients receiving
metformin or metformin in fixed combination with glyburide, respectively. 234 Dizziness
has been reported in 3.8 or 5.5% of patients receiving metformin or metformin in fixed
combination with glyburide, respectively. 234
Pneumonitis with vasculitis has been reported rarely with concomitant metformin and
oral sulfonylurea (e.g., glyburide) therapy.18, 74 Upper respiratory tract infection was
reported in 16.3 or 17.3% of patients receiving metformin or metformin in fixed
combination with glyburide, respectively. 234 Upper respiratory tract infection was
reported in 8.5 or 8.1-9.9% of patients receiving metformin or metformin in fixed
combination with glipizide, respectively, as initial therapy for type 2 diabetes mellitus.
254
Upper respiratory tract infection was reported in 10.7 or 10.3% of patients receiving
metformin or metformin in fixed combination with glipizide, respectively, as second-line
therapy for type 2 diabetes mellitus. 254 Urinary tract infection has been reported in 8 or
1.1% of patients receiving metformin alone or in fixed combination with glipizide,
respectively. 254 Hypertension has been reported in 5.6 or 2.9-3.5% of patients
receiving metformin alone or in fixed combination with glipizide, respectively. 254
Musculoskeletal pain has been reported in 6.7 or 8% of patients receiving metformin
alone or in fixed combination with glipizide, respectively. 254 Severe acute hepatitis
associated with marked elevations in serum hepatic aminotransferase values and
cholestasis has been reported following initiation of metformin therapy in a patient
receiving glipizide and enalapril.213
Precautions and Contraindications
When metformin in used in fixed combination with glyburide, the cautions, precautions,
and contraindications associated with glyburide must be considered in addition to those
associated with metformin.234
The diagnostic and therapeutic measures for managing diabetes mellitus that are

necessary to ensure optimum control of the disease with insulin are generally necessary
with metformin.12, 13, 14, 25, 26, 134, 179, 181 Clinicians who prescribe metformin should
be familiar with the indications, limitations, and patient-selection criteria for therapy with
oral antidiabetic agents to ensure appropriate patient management.10, 23, 30, 134, 187
Patients receiving metformin should be monitored with regular laboratory evaluations,
including blood glucose determinations, to determine the minimum effective dosage of
metformin hydrochloride when used either as monotherapy or in combination with a
sulfonylurea antidiabetic agent.1 , 2 , 14, 88, 179, 187 Glycosylated hemoglobin
(hemoglobin A1c [HbA1c ]) measurements also are useful, particularly for monitoring
long-term control of blood glucose concentration.1 , 2 , 134 Blood glucose determinations
are important to detect primary failure (inadequate lowering of blood glucose
concentration at the maximum recommended dosage) or secondary failure (loss of
control of blood glucose concentration following an initial period of effectiveness) to the
drug.1

Patients should be informed of the risks of lactic acidosis and conditions that predispose
to its development.1 (See Cautions: Lactic Acidosis.) Since metformin is excreted
substantially by the kidneys, accumulation of the drug resulting in lactic acidosis may
occur in patients with renal impairment;1 , 91, 93, 164 the risk of lactic acidosis increases
with degree of renal impairment.1 Therefore, the manufacturer states that renal function
should be evaluated prior to initiation of therapy with metformin preparations and at
least annually thereafter.1 , 2 , 77, 85, 234 The manufacturer also states that patients
whose serum creatinine concentrations exceed the upper limit of normal for their age
should not receive metformin.1 In patients in whom development of impaired renal
function is anticipated (e.g., those with blood glucose concentrations exceeding 300
mg/dL, who may develop renal dysfunction as a result of polyuria and volume
depletion),156 renal function should be monitored more frequently; the drug should be
discontinued if evidence of renal impairment is present.1 , 2 , 156, 164 In addition, drugs
that may affect renal function, produce substantial hemodynamic changes, or interfere
with metformin elimination (e.g., cimetidine) should be used with caution in patients
receiving metformin.1 , 134 Hemodialysis has been used in patients with lactic acidosis to
accelerate the clearance of metformin. (See Acute Toxicity.)
Metformin should not be used in patients with congestive heart failure requiring drug
therapy (e.g., digoxin, furosemide), such as those with unstable or acute congestive
heart failure. 1 , 209, 214, 215 These patients are at risk for hypoperfusion and hypoxemia,
which may lead to lactic acidosis.1 , 215 Some clinicians suggest that metformin may be
reinstituted once acute heart failure has resolved and renal function is normal (as
measured by creatinine clearance).215
Since administration of parenteral iodinated contrast media may lead to acute alteration
of renal function and has been associated with lactic acidosis in patients receiving
metformin, the manufacturer states that metformin should be discontinued at the time of
or prior to the procedure, and should not be reinstituted until 48 hours after such
procedures;1 , 234, 243, 245, 246, 247, 254 metformin should not be reinstituted until renal

function has been evaluated and found to be normal.1 , 234, 247 Metformin also should
be discontinued temporarily in patients undergoing surgery, except minor surgery that is
not associated with restricted food or fluid intake; the drug should be reinitiated only
when patient's oral intake has resumed and renal function has been shown to be
normal.1 , 254 In addition, any diabetic patient previously well controlled with metformin
therapy who develops a clinical illness (especially one that is vague and poorly defined)
or whose laboratory test results deviate from normal should be evaluated promptly for
evidence of ketoacidosis or lactic acidosis.1 , 88, 169 (See Cautions: Lactic Acidosis.)
Such evaluation should include determinations of serum electrolytes and ketones, blood
glucose, and if indicated, blood pH, lactate, pyruvate, and metformin concentrations.1 ,
88 134 156 169
,
,
,
Since cardiovascular collapse (shock), congestive heart failure,
ischemic heart disease (e.g., acute myocardial infarction), peripheral vascular disease
(e.g., claudication), obstructive airways disease, or other conditions that are likely to
cause central hypoxemia or reduced peripheral perfusion have been associated with
lactic acidosis and prerenal azotemia, metformin should be discontinued in patients
developing such conditions.1 , 18, 20, 30, 62, 76, 91, 93, 146, 156, 158, 254
The cardiovascular risks associated with use of oral antidiabetic agents have not been
fully determined.1 , 2 , 34, 136, 216 In 1970, the University Group Diabetes Program
(UGDP) reported that administration of oral antidiabetic agents (i.e., tolbutamide or
phenformin) was associated with increased cardiovascular mortality compared with
treatment with dietary regulation alone or with dietary regulation and insulin.1 , 191, 192,
200 234
,
The UGDP reported that type 2 diabetic patients who were treated for 5-8 years
with dietary regulation and a fixed dose (1.5 g daily) of tolbutamide or dietary regulation
and a fixed dose (100 mg daily) of phenformin (currently not commercially available in
the US) had a cardiovascular mortality rate approximately 2.5 times that of patients
treated with dietary regulation alone.1 , 191, 192, 200, 234 Although a substantial increase
in total mortality was observed only with phenformin, both tolbutamide and phenformin
were discontinued because of the increases in cardiovascular mortality.1 , 191, 192, 200,
234
The results of the UGDP study have been analyzed exhaustively, and there has
been general disagreement in the scientific and medical communities regarding the
study's validity and clinical importance. 1 , 10, 23, 180, 198, 200 The management of
patients with type 2 diabetes mellitus has changed substantially since the UGDP was
initiated in 1961.10, 180, 184, 198 Dietary management, weight reduction, better control
of blood glucose concentration, and regular physical activity have received greater
emphasis in the management of diabetes in these patients.8 , 10, 14, 24, 25, 26, 88, 179,
181
In addition, reduction of existing cardiovascular risk factors (e.g., management of
hypertension, discontinuance of smoking) has been emphasized.10, 14, 26, 88, 179, 181,
185 187
,
The American Diabetes Association (ADA) currently recommends that clinician
judgment in the management of type 2 diabetes mellitus be based on assessment of all
available therapeutic information, including data on cardiovascular risk factors, the
positive effect of metabolic control of diabetes on cardiovascular disease, the
importance of dietary management and weight reduction in obese diabetic patients, the
importance of regular physical activity, and objective reports in the scientific literature
that pertain to the UGDP study and to the long-term use of sulfonylureas. 10, 14, 26, 136

Results of several recent, long-term studies by the United Kingdom Prospective

Diabetes Study (UKPD study) group indicate that effects of metformin on mortality and
macrovascular outcomes vary considerably depending on the patient population
evaluated.216, 218 In one study, intensive therapy (target fasting plasma glucose of less
than 108 mg/dL) initiated with metformin or other antidiabetic agents (chlorpropamide,
glyburide, or insulin) was compared with conventional therapy (target fasting plasma
glucose of less than 270 mg/dL) consisting of diet and supplemental therapy with the
same antidiabetic agents for marked hyperglycemia in overweight (exceeding 120% of
ideal body weight) patients.216 In this study, cardiovascular disease accounted for 62%
of the total mortality observed in patients receiving conventional therapy.216 Intensive
therapy initiated with metformin in these overweight patients was associated with a 36%
reduction in all-cause mortality and a 30% lower risk of developing macrovascular
disease (myocardial infarction, sudden death, angina, stroke, peripheral vascular
disease) compared with conventional therapy; the reduction in macrovascular disease
was similar among intensive therapies employing other antidiabetic agents.216
In another study, metformin was given as supplemental therapy in overweight and
non-overweight patients who were poorly controlled on existing sulfonylurea therapy, or
sulfonylurea therapy alone was continued.216 In this study, intensive metformin and
sulfonylurea therapy was associated with an increase in the risk of diabetes-related
death or death from any cause compared with that in patients continuing to receive
sulfonylurea therapy alone.216 Similarly, another study by the UKPD Study Group found
no decrease in mortality when metformin was added to sulfonylurea therapy (i.e.,
chlorpropamide or glyburide) or insulin alone in an intensive regimen (target fasting
plasma glucose concentration of 108 mg/dL) in obese and non-obese patients.216, 220
A pooled analysis of both UKPD trials and epidemiologic analysis of other
non-overweight and overweight patients from UKPD studies who received metformin
and sulfonylurea therapy because of progressive hyperglycemia showed a small
reduction in diabetes-related death, all-cause mortality, myocardial infarction, and
stroke.216 As reasons for the inconsistent effects of metformin are unclear, further
comparative studies of metformin alone or in combination with a sulfonylurea are
needed to determine the long-term safety and efficacy of metformin in the treatment of
type 2 diabetes mellitus.217, 220, 221, 222, 225, 226 Pending the results of such studies,
the American Diabetes Association (ADA) and other clinicians do not recommend
changing current guidelines regarding the use of metformin as monotherapy or in
combination with sulfonylureas.220, 221, 224 ADA currently recommends that clinicians
continue to emphasize dietary management and weight reduction as the principal
therapy for the management of type 2 diabetes mellitus and that oral antidiabetic agents
or insulin be used only after these measures have failed; the decision to use an oral
antidiabetic agent or insulin should be made by the clinician in consultation with the
patient.1 , 10, 14, 26
Patients should be advised fully and completely about the nature of diabetes mellitus,
what they must do to prevent and detect complications, and how to control their
condition.14, 88, 179, 185 Patients should be informed of the potential risks and

advantages of metformin therapy and of alternative forms of treatment.1 Patients should

be instructed that dietary regulation is the principal consideration in the management of
diabetes, 1 , 24, 25, 26 and that metformin therapy is used only as an adjunct to,1 and not
a substitute for, proper dietary regulation.134, 187 Patients also should be advised that
they should not neglect dietary restrictions, develop a careless attitude about their
condition, or disregard instructions about body-weight control, exercise, hygiene, and
avoidance of infection.1 , 30, 134 The possibility of primary and secondary failure to
metformin therapy also should be explained to patients.1
Patients and responsible family members should be informed of the risks of
hypoglycemia, symptoms and treatment of hypoglycemic reactions, and conditions that
predispose to the development of such reactions, since these reactions occasionally
may occur during therapy with metformin.1 Hypoglycemia occurs infrequently in patients
receiving metformin therapy under usual conditions of use; the incidence of
hypoglycemia with metformin is much lower than that in patients receiving sulfonylureas
or insulin.1 , 2 , 19, 62, 78, 166 However, hypoglycemia may occur when the drug is used
concomitantly with a sulfonylurea antidiabetic agent and/or insulin.1 , 15, 78, 94, 99 In
addition, certain other factors (e.g., deficient caloric intake, strenuous exercise not
compensated by caloric supplementation, alcohol ingestion, adrenal or pituitary
insufficiency) may predispose patients to the development of hypoglycemia.1 , 2
Debilitated, malnourished, or geriatric patients also may be particularly susceptible to
hypoglycemia; 1 , 2 this condition may be difficult to recognize in geriatric patients or in
those receiving -adrenergic blocking agents or other sympatholytic agents.1 , 83, 91,
128 143 153 159
,
,
,
(See Drug Interactions: -Adrenergic Blocking Agents.)
To maintain control of diabetes during periods of stress (e.g., fever of any cause,
trauma, infection, surgery), temporary discontinuance of metformin and administration of
insulin may be required.1 Metformin therapy may be reinstituted after the acute episode
is resolved. 1
Since decreases in serum vitamin B12 concentrations have been reported in some
patients receiving metformin, hematologic parameters (e.g., hemoglobin, hematocrit,
erythrocyte indices) should be evaluated prior to initiation of metformin therapy and at
least annually during treatment and any abnormality properly investigated.1 , 2 , 3 , 30, 72,
85 243 245 246
,
,
,
Some patients (i.e., those with an inadequate absorption or intake of
vitamin B12 or calcium) appear to be predisposed to developing decreased vitamin B12
concentrations; vitamin B12 concentrations should be monitored every 2-3 years while
these patients are receiving metformin therapy.1 , 30, 134, 148, 168, 243, 245, 246

Metformin alone or in fixed combination with glyburide, glipizide, or rosiglitazone is

contraindicated in patients with renal impairment (e.g., men or women with serum
creatinine concentrations equal to or exceeding 1.5 or 1.4 mg/dL, respectively) or
abnormal creatinine clearance, which may result from conditions such as cardiovascular
collapse (shock), acute myocardial infarction, or septicemia.1 , 2 , 18, 20, 91, 234, 247, 254
Metformin alone or in fixed combination with glyburide, glipizide, or rosiglitazone is

contraindicated in patients with congestive heart failure requiring drug therapy.1 , 234,
247 254
,
Metformin-containing therapy also is contraindicated as sole therapy in patients
with type 1 diabetes and in patients with diabetes complicated by acute or chronic
metabolic acidosis, including diabetic ketoacidosis with or without coma.1 , 2 , 234, 247
Metformin alone or in fixed combination with glyburide, glipizide, or rosiglitazone also is
contraindicated in patients with known hypersensitivity any ingredient in the respective
formulations.
Pediatric Precautions
Safety and efficacy of metformin conventional or extended-release tablets in children
younger than 10 or younger than 17 years of age, respectively, have not been
established.1 , 3 , 4 , 30, 134, 243, 245, 246 Data from a placebo-controlled clinical trial
indicated a similar glycemic response and adverse effect profile in pediatric patients
(10-16 years of age) as in adults.1 , 246 (See Diabetes Mellitus: Metformin Monotherapy,
in Uses.) The safety and efficacy of metformin in fixed combination with glyburide,
glipizide, or rosiglitazone in pediatric patients have not been established. 234, 247, 254
The American Diabetes Association (ADA) states that most pediatric diabetologists use
oral antidiabetic agents in children with type 2 diabetes mellitus because of greater
patient compliance and convenience for the patient's family and a lack of evidence
demonstrating better efficacy of insulin as initial therapy for type 2 diabetes mellitus.235
Geriatric Precautions
It is not known whether geriatric patients respond differently to metformin than younger
patients.1 Data from controlled clinical trials with metformin in fixed combination with
glyburide or glipizide have not revealed age-related differences in safety and efficacy of
the combination, but greater sensitivity of geriatric patients to these fixed combinations
cannot be ruled out. 234, 254 Since metformin is excreted principally by the kidneys and
renal function declines with age, the drug should be used with caution in geriatric
patients.1 , 3 , 4 , 30, 85, 174 234, 247, 254 Metformin therapy should be used only in
patients with normal renal function. 1 , 234, 254 As geriatric patients are at risk for the
development of lactic acidosis, metformin therapy should not be initiated in geriatric
patients 80 years of age and older without confirmation of adequate renal function as
measured by creatinine clearance.209, 214, 234, 247, 254 In addition, renal function
should be monitored periodically and care should be taken in dosage selection for
geriatric patients; such patients generally should not receive the maximum
recommended dosage of metformin hydrochloride.1 , 2 , 3 , 4 , 30, 85, 174, 234, 247, 254
Mutagenicity and Carcinogenicity
No evidence of mutagenicity or chromosomal damage was observed in vivo in a
micronucleus test in mice or in in vitro test systems, including microbial (Ames test) and
mammalian (mouse lymphoma and human lymphocytes) assays.1
No evidence of carcinogenic potential was seen in a 104-week study in male and female
rats receiving metformin hydrochloride dosages up to and including 900 mg/kg daily or
in a 91-week study in male and female mice receiving metformin hydrochloride at
dosages up to and including 1500 mg/kg daily; these dosages are about 3 times the

maximum recommended human daily dosage based on body surface area.1 However,
an increased incidence of benign stromal uterine polyps was observed in female rats
treated with 900 mg/kg of metformin hydrochloride daily.1
Pregnancy, Fertitlity and Lactation
Reproduction studies in rats and rabbits given metformin hydrochloride dosages of 600
mg/kg daily (about twice the maximum recommended human daily dosage based on
body surface area or about 2 and 6 times the maximum recommended human daily
dosage of extended-release tablets [2 g] based on body surface area comparisons with
rats and rabbits, respectively)1 have not revealed evidence of harm to the fetus.1
Determination of fetal concentrations of metformin suggest that a partial placental
barrier to the drug exists. 1 , 3 Since abnormal maternal blood glucose concentrations
during pregnancy may be associated with a higher incidence of congenital
abnormalities, 1 , 115 most experts recommend that insulin be used during pregnancy to
maintain optimum control of blood glucose concentration.1 , 3 , 4 , 18, 72, 88, 92
There are no adequate and controlled studies to date using metformin in pregnant
women.1 Limited data from uncontrolled or retrospective studies are conflicting with
regard to the effects of long-term maternal therapy with metformin hydrochloride (1.5-3
g daily) on neonatal morbidity (e.g., congenital malformations) and mortality. 92, 115
Metformin should be used during pregnancy only when clearly needed.1 , 3 , 4
No evidence of impaired fertility was observed in rats following administration of
metformin hydrochloride dosages of 600 mg/kg daily (about twice the maximum
recommended human dosage based on body surface area).1
Metformin is distributed into milk of lactating rats and achieves concentrations
comparable to those attained in plasma.1 , 85 Since it is not known if metformin is
distributed into milk in humans, a decision should be made whether to discontinue
nursing or the drug, taking into account the importance of the drug to the woman. 1 , 3 , 4
If metformin is discontinued in a nursing mother and dietary therapy is inadequate for
glycemic control, insulin therapy should be considered.1
Drug Interactions
Antidiabetic Agents
Although hypoglycemia occurs infrequently in patients receiving metformin therapy
alone,1 , 19, 62, 78, 166 hypoglycemia may occur when the drug is used concomitantly
with a sulfonylurea antidiabetic agent (e.g., glyburide) and/or insulin.1 , 15, 78, 94, 99 (See
Cautions: Precautions and Contraindications.)
In a single-dose study in patients with type 2 diabetes mellitus, concomitant
administration of glyburide with metformin did not alter the pharmacokinetics or
pharmacodynamics of metformin.1 Although variable decreases in the area under the
blood concentration-time curve (AUC) and peak blood concentration of glyburide were

observed, the single-dose nature of this study and the lack of a relationship between
glyburide blood concentrations and pharmacodynamic effects preclude evaluation of the
clinical importance of these effects.1
In a single-dose study, administration of metformin concomitantly with an a-glucosidase
inhibitor (acarbose) resulted in an acute decrease in the bioavailability of metformin.138,
201
Coadministration of guar gum (10 g) and metformin hydrochloride (1.7 g) with a
standard meal in healthy individuals reduced and delayed the absorption of metformin
from the GI tract.18, 85, 99, 106
Diuretics
Thiazide diuretics can exacerbate diabetes mellitus, resulting in increased requirements
of oral antidiabetic agents, temporary loss of diabetic control, or secondary failure to the
antidiabetic agent.1 , 91, 139, 143, 151, 152, 153, 154, 159, 160 If control of diabetes is
impaired by a thiazide diuretic, clinicians may consider substituting a less diabetogenic
diuretic (e.g., potassium-sparing diuretic), reducing the dosage of or discontinuing the
diuretic, or increasing the dosage of the oral antidiabetic agent.73, 134, 152, 153, 154, 159,
160

In a single-dose study in healthy individuals, administration of furosemide concomitantly

with metformin increased peak plasma and blood concentrations of metformin by
approximately 22% and AUC of metformin by approximately 15%.1 Administration of
metformin concomitantly with furosemide increased peak plasma furosemide
concentrations by approximately 31% and AUC by approximately 12%.1 The renal
clearance of both drugs remained unchanged during such concomitant use, but the
half-life of furosemide was decreased by 32%.1 The manufacturer states that no
information is available on potential interactions between metformin and furosemide
during long-term administration.1
Nifedipine
Concomitant administration of single doses of metformin and nifedipine in healthy
individuals resulted in enhanced absorption of metformin, as indicated by increases of
20 and 9% in the peak plasma concentration and AUC, respectively, of metformin. 1
Nifedipine also increased the urinary excretion of metformin; half-life and time to peak
plasma concentration of metformin remained unchanged.1 Metformin appears to have
minimal effects on the pharmacokinetics of nifedipine.1
Cimetidine
Cimetidine may reduce the urinary excretion of metformin by competing for renal tubular
organic cationic transport systems.1 , 75 In single- and multiple-dose studies in healthy
individuals, concomitant administration of cimetidine and metformin increased the peak
plasma and whole blood concentrations of metformin by approximately 60-81% and the
area under the plasma or whole blood concentration-time curve (AUC) of metformin by
approximately 40-50%.1 , 75 Metformin has negligible effects on cimetidine
pharmacokinetics, possibly because cimetidine has a higher affinity for renal tubular

transport sites. 1 , 75 The manufacturer states that the possibility of other cationic drugs
that undergo substantial tubular secretion (e.g., amiloride, digoxin, morphine,
procainamide, quinidine, quinine, ranitidine, triamterene, vancomycin) decreasing the
urinary excretion of metformin should be considered.1 , 30 Patients receiving metformin
concomitantly with a cationic drug that is excreted by the proximal renal tubules should
be monitored carefully and the need for possible dosage adjustment of either agent
considered.1
-Adrenergic Blocking Agents
In single-dose studies in healthy individuals, concomitant administration of metformin
and propranolol did not alter the pharmacokinetics of either drug.1 However, several
potential interactions between -adrenergic blocking agents and oral antidiabetic agents
(e.g., sulfonylureas, metformin) exist.91, 127, 143, 153, 159, 160, 198 -Adrenergic
blocking agents may impair glucose tolerance;73, 143, 152, 153, 159 increase the
frequency or severity of hypoglycemia;127 block hypoglycemia-induced tachycardia but
not hypoglycemic sweating, which may actually be increased;91, 153, 159 delay the rate
of recovery of blood glucose concentration following drug-induced hypoglycemia;91, 127,
153
alter the hemodynamic response to hypoglycemia, possibly resulting in an
exaggerated hypertensive response;153 and possibly impair peripheral circulation.153
Nonselective - adrenergic blocking agents (e.g., propranolol, nadolol) without intrinsic
sympathomimetic activity are more likely to affect glucose metabolism than more
selective -adrenergic blocking agents (e.g., metoprolol, atenolol) or those with intrinsic
sympathomimetic activity (e.g., acebutolol, pindolol).36, 73, 91, 143, 152, 159, 160, 173
Signs of hypoglycemia (e.g., tachycardia, blood pressure changes, tremor, feelings of
anxiety) mediated by catecholamines may be masked by either nonselective or
selective -adrenergic blocking agents.128, 143, 153, 159 These drugs should be used
with caution in patients with type 2 diabetes mellitus who are receiving antidiabetic
agents, especially in those with labile disease or in those prone to hypoglycemia.36, 83,
91 127 128 153
,
,
,
Use of low-dose, selective 1 -adrenergic blockers (e.g., metoprolol) or
-adrenergic blocking agents with intrinsic sympathomimetic activity in patients
receiving oral antidiabetic agents may theoretically decrease the risk of affecting
glycemic control.36, 143, 152, 160, 173 When an oral antidiabetic agent and a
-adrenergic blocking agent are used concomitantly, the patient should be advised
about and monitored closely for altered antidiabetic response.134
Alcohol
Combined use of alcohol and metformin can increase the risk of hypoglycemia and
lactic acidosis, since alcohol decreases lactate clearance and hepatic gluconeogenesis
and may increase insulin secretion.1 , 2 , 18, 33, 63, 72, 76, 91, 93, 107, 143 (See Cautions:
Lactic Acidosis.) Excessive alcohol intake, on an acute or chronic basis, should be
avoided in patients receiving metformin therapy.1
Protein-Bound Drugs
Binding of metformin to plasma proteins is negligible; therefore, metformin is less likely
to interact with drugs that are highly protein bound compared with sulfonylurea

antidiabetic agents, which are extensively bound to plasma proteins.1

Angiotensin-Converting Enzyme Inhibitors
Angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril, enalapril) may reduce
fasting blood glucose concentrations in nondiabetic individuals132 and have been
associated with unexplained hypoglycemia in patients whose diabetes had been
controlled with insulin or oral antidiabetic agents, including combined therapy with
glyburide and metformin.73, 130, 131, 132, 155, 159, 160 Testing in some of these patients
indicated that the ACE inhibitor (e.g., captopril) apparently increased insulin sensitivity;
the mechanism of this effect is not known.131, 152, 159, 160 Other investigators have
reported no alterations in glycemic control with concomitant use of an ACE inhibitor and
oral antidiabetic agents or insulin in diabetic patients.133 The potential risk of
precipitating hypoglycemia or hyperglycemia appears to be low but should be
considered when therapy with an ACE inhibitor is initiated or withdrawn in diabetic
patients; blood glucose concentrations should be monitored during dosage adjustments
with either agent.130, 131, 132, 134, 152, 155, 160
Clomiphene
In premenopausal patients with polycystic ovary syndrome, therapy with certain oral
antidiabetic agents, including metformin, may result in the resumption of ovulation in a
modest number of women.210, 211, 212 Ovulatory response is further increased in
patients pretreated with metformin hydrochloride (500 mg 3 times daily for 35 days)
receiving additional low-dose clomiphene (50 mg daily for 5 days); ovulation was
associated with decreased insulin secretion and increased serum progesterone
concentrations.210
Other Drugs
Drugs that cause hyperglycemia and may exacerbate glycemic control in patients with
diabetes mellitus include corticosteroids, oral contraceptives, thiazide diuretics,
sympathomimetics, phenothiazines, niacin, calcium-channel blocking agents, and
isoniazid.1 , 80, 85, 91, 120, 121, 134, 139, 143, 151, 152, 153, 154, 159, 160 When such
drugs are added to or withdrawn from therapy in patients receiving oral antidiabetic
agents, patients should be observed closely for evidence of altered glycemic control.1 ,
30 134
,
Acute Toxcicity
Limited information is available on the acute toxicity of metformin.1 , 2 , 119
Hypoglycemia has not been observed even with acute oral ingestion of up to 85 g of
metformin hydrochloride; however, lactic acidosis has occurred in such circumstances.1 ,
2 62 119
, ,
(See Cautions: Lactic Acidosis.) Since metformin is eliminated by dialysis (with
a clearance of up to 170 mL per minute under good hemodynamic conditions), prompt
hemodialysis is recommended to correct acidosis and remove accumulated drug; such
management often results in rapid reversal of symptoms and recovery.1 , 23, 32, 62, 117,
119

Pharmacology
Antidiabetic Effects
Metformin hydrochloride, a biguanide antidiabetic agent, is chemically and
pharmacologically unrelated to sulfonylurea antidiabetic agents.1 , 2 , 18, 20, 27, 28, 29
Unlike sulfonylureas, biguanides such as metformin lower blood glucose concentrations
in patients with type 2 (noninsulin-dependent) diabetes mellitus (NIDDM) without
increasing insulin secretion from pancreatic cells;1 , 2 , 3 , 4 , 18, 20, 27, 31, 40, 60, 134
however, metformin is ineffective in the absence of some endogenous or exogenous
insulin.18, 27, 40, 71, 122 Biguanides usually do not produce hypoglycemia in diabetic
patients and do not affect normal blood glucose concentrations in nondiabetic
individuals; metformin, even in excessive dosage, normally does not lower glucose
concentrations below euglycemia.1 , 2 , 18, 20, 27, 28, 29, 72, 102, 103, 111 (See Acute
Toxicity.) Therefore, while biguanides as well as sulfonylureas historically have been
referred to as oral hypoglycemic agents,27, 28, 29 biguanides such as metformin are
more appropriately referred to as antihyperglycemic agents.1 , 6 , 18, 20, 157
Type 2 diabetes mellitus is characterized by insulin resistance (impaired uptake and
disposal of glucose by peripheral tissues and excessive glucose production by the liver),
and abnormal insulin secretion, which may result in insulin deficiency (impaired
secretion of insulin from pancreatic cells) during the late stage of the disease.8 , 18, 20,
24 25 27 28 31 40 41 42 44 71 81 134 145 146 161
, , , , , , , , , , ,
,
,
,
(See Uses.) Although the
underlying pathophysiology of type 2 diabetes mellitus may be similar in obese and
nonobese patients with the disease, severe peripheral and hepatic insulin resistance
appears to predominate in obese patients, while nonobese patients tend to have milder
degrees of insulin resistance but more marked insulin deficiency; however, both
abnormalities eventually occur in the course of the disease.8 , 9 , 18, 60, 134, 145, 178
Obesity itself often is associated with insulin resistance and an elevated rate of fatty
acid oxidation, which may contribute to the glucose intolerance observed in obese
patients with type 2 diabetes mellitus.9 , 11, 27, 59, 73, 134, 146, 178, 179
Metformin lowers both basal (fasting) and postprandial glucose concentrations in
patients with type 2 diabetes mellitus.1 , 2 , 18, 22 Although the precise mechanism(s) by
which metformin exerts its antihyperglycemic effect has not been fully established,
current evidence suggests that the drug improves both peripheral and hepatic sensitivity
to insulin.18, 31, 33, 40, 41, 42, 44, 52, 58, 60, 81, 146 Improved insulin sensitivity occurs
principally as a result of decreased hepatic glucose production and enhanced
insulin-stimulated uptake and utilization of glucose by peripheral tissues (e.g., skeletal
muscle, adipocytes);18, 31, 40, 41, 42, 44, 60, 81, 146, 149 the relative contribution of these
mechanisms to the antihyperglycemic effect of metformin has not been fully
elucidated.18, 42, 44, 71, 72, 135, 146, 161 Increases of 18-29% in the rate of
insulin-stimulated glucose uptake (principally by skeletal muscle) have been reported in
patients with type 2 diabetes mellitus with metformin hydrochloride and in
normoglycemic insulin-resistant individuals in whom glucose utilization during therapy
(0.5-3 g daily) generally was evaluated using a euglycemic, hyperinsulinemic clamp

technique (a high-dose, continuous IV infusion of insulin administered concurrently with

a glucose infusion titrated to maintain euglycemia).18, 20, 39, 41, 60, 68, 69, 146, 161
However, some studies in which insulin and/or glucose concentrations were not
regulated during metformin therapy have reported no increases and/or even decreases
in glucose uptake, 44, 81 possibly because of the nonphysiologic conditions inherent in
the euglycemic, hyperinsulinemic clamp technique.60, 102, 122
The apparent improvement in peripheral glucose disposal with metformin therapy has
been attributed principally to improved metabolism of glucose via nonoxidative
(anaerobic) pathways (e.g., glycogen formation in skeletal muscle, postprandial lactate
production in splanchnic tissues, lipogenesis in adipose tissue).3 , 4 , 6 , 18, 27, 31, 39, 68,
71 79 134 146 149
, ,
,
,
Studies in animals and humans indicate that metformin, unlike
phenformin, enhances glucose oxidation and does not affect fasting lactate production
in peripheral tissues.20, 53, 60, 61, 72, 78, 79, 81, 135, 146, 149 While increases in
postprandial plasma lactate concentrations have been demonstrated in type 2 diabetic
patients receiving metformin alone or in combination with a sulfonylurea (e.g.,
glyburide), plasma lactate concentrations generally remain within the normal range
during metformin therapy.31, 60, 61, 72, 84, 97, 146 Postprandial increases in serum
lactate concentration observed with metformin therapy may occur as a result of
increased conversion of glucose to lactate and glycogen in the splanchnic bed by
metformin. 6 , 44, 72, 145, 146, 158 While most of the lactate from the portal circulation
serves as a substrate for gluconeogenesis and is thus cleared, some may escape into
the systemic circulation as increased amounts are presented to the liver after a meal.6 ,
44 72 146
, ,
Metformin does not increase lactate production or alter lactate uptake or
release from skeletal muscle.23, 81, 149
Metformin reduces basal hepatic glucose production by decreasing gluconeogenesis
and possibly glycogenolysis, thereby lowering fasting plasma glucose concentrations.6 ,
20 23 31 37 39 61 72 81 134 135
, , , , , , , ,
,
Although some investigators have suggested that
reduction of hepatic glucose production may be the drug's principal antihyperglycemic
mechanism, 18, 27, 44, 61, 81, 134 this effect has not been demonstrated in all studies.18,
41 60 69
, ,
In vitro studies in hepatocytes indicate that metformin, at concentrations
similar to or higher than those observed with therapeutic dosages, enhances
insulin-induced suppression of gluconeogenesis and decreases glucagon-stimulated
gluconeogenesis.6 , 146, 175, 176, 177 Insulin secretion usually remains unchanged
during metformin therapy; fasting insulin concentrations and day-long plasma insulin
response remain the same or may even decrease. 1 , 2 , 3 , 18, 20, 42, 60, 68, 102, 166 The
magnitude of the decrease in fasting blood glucose concentrations generally is
proportional to the level of fasting baseline hyperglycemia.1 , 134, 146 Metformin also
may decrease plasma glucose concentrations by enhancing basal glucose disposal
through insulin-independent mechanisms (e.g., a decrease in free fatty acid oxidation),
but such effects appear to be modest.18, 42, 68, 72, 134, 146
Receptor binding of insulin is decreased in patients with type 2 diabetes mellitus, and
some studies using radiolabeled insulin in rat and human cell cultures have

demonstrated improved insulin binding with metformin.18, 54, 67, 84, 98, 145 However,
conflicting data also have been reported,40, 41, 42, 79, 84 and a direct correlation
between increases in insulin binding and decreases in blood glucose concentration has
not been observed.18, 20, 22, 37, 40, 41, 42, 71, 134 In in vitro studies in animal and
human skeletal muscle cells or adipocytes, metformin has increased glucose uptake
through enhancement of insulin-stimulated recruitment of specific glucose transporters
(e.g., GLUT-1, GLUT-4) to the plasma membrane of insulin target cells (e.g., adipose
tissue, skeletal muscle) and through increases in the activity of these glucose
transporters.4 , 33, 40, 47, 52 In in vitro studies using metformin concentrations within the
therapeutic range, metformin has not consistently enhanced basal glucose uptake,
which is noninsulin-mediated; however, in vitro data may not accurately reflect in vivo
actions of the drug, and further study is needed to determine whether metformin acts
through insulin-dependent or -independent pathways, or both, to affect basal glucose
uptake.37, 40, 47, 52, 134, 149, 150
Metformin accumulates in the walls of the intestine but does not appear to have
clinically important effects on glucose absorption.6 , 18, 28, 37, 44, 134, 146
Antilipemic Effects
Metformin has demonstrated modest favorable effects on serum lipids, which are often
abnormal in patients with type 2 diabetes mellitus.1 , 3 , 6 , 15, 18, 20, 34, 146 In clinical
studies, particularly in patients with elevated baseline serum lipid concentrations (e.g.,
patients with type II, type III, or type IV hyperlipoproteinemia), metformin alone or
combined with a sulfonylurea antidiabetic agent lowered fasting serum triglyceride
concentrations and total and LDL-cholesterol concentrations without adversely affecting
other serum lipids.1 , 3 , 4 , 6 , 15, 18, 20, 31, 34, 42, 46, 53, 58, 78, 81, 102, 135, 146 Modest
reductions (e.g., 10-20%) in serum triglyceride concentrations noted with metformin
therapy generally have been attributed to decreased hepatic synthesis of
VLDL-cholesterol, particularly in patients with elevated baseline triglyceride
concentrations.1 , 3 , 4 , 6 , 18, 20, 22, 31, 35, 42, 102, 146 Characteristics of patients who
are likely to exhibit a decrease in serum triglycerides with metformin therapy have not
been determined, and correlation of potential antilipemic effect with the degree of
glycemic control has been inconsistent.46, 49, 72, 78 Small reductions (e.g., 5-10%) in
serum total cholesterol also have been reported in some studies;15, 20, 31, 42, 46, 58, 78,
102
these effects may be attributed to decreased LDL- or VLDL-cholesterol
concentrations.6 , 15, 18, 31, 42, 46, 58, 78, 102 Increases in HDL-cholesterol also have
been reported with metformin therapy in nondiabetic patients18, 20 and in those with
type 2 diabetes mellitus.18, 31, 42, 102 Consistent changes in plasma glycerol and free
fatty acid concentrations have not been reported during metformin therapy in patients
with NIDDM or in nondiabetic individuals.20, 31, 35, 42, 44, 58, 61, 68, 81, 102, 135 A
reduction in free fatty oxidation has been suggested as a possible mechanism for the
decrease in plasma free fatty acids observed in some studies with metformin therapy.31,
35 42 68 102
, , ,
Hematologic Effects

Metformin may exert potentially beneficial effects on the fibrinolytic system by increasing
the activity of tissue-type plasminogen activator (t-PA) and/or reducing concentrations of
plasminogen activator inhibitor-1 (PAI-1) in nondiabetic, hypertensive patients and in
patients with type 2 diabetes mellitus; serum fibrinogen concentrations do not appear to
be affected by metformin therapy.18, 34, 55, 56, 58, 108, 109, 136 Patients with type 2
diabetes mellitus, hypertension, and obesity often have hyperinsulinemia and a high
incidence of vascular disease.55, 108 PAI-1 concentrations, which are regulated by
insulin, may be substantially increased in patients with type 2 diabetes mellitus and in
obese individuals,34, 55, 108, 136 and it has been suggested that the reduced fibrinolytic
activity associated with elevated PAI-1 concentrations may be important in the
pathogenesis of vascular disease in these individuals.34, 55, 108, 134, 136 Metformin has
been shown to increase fibrinolytic activity (as measured by blood clot lysis time,
euglobulin fibrinolytic activity, and by increases in t-PA activity) in patients with coronary
artery disease, obese individuals, and in patients with mild hypertension; increases in
fibrinolytic activity with metformin therapy generally occur in patients who have low
fibrinolytic activity at baseline.56, 58, 108 Reduced platelet density, activation, and/or
aggregation; 18, 73, 109 decreased blood pressure; and decreased peripheral arterial
resistance18, 57, 58 also have been reported in some normotensive patients with type 2
diabetes mellitus and in nondiabetic, mildly hypertensive patients receiving metformin;
however, whether these effects are associated with the drug or are secondary to
improvement in glycemic control or a reduction in body weight has not been
determined.18, 57, 58, 73, 109, 146
Other Effects
Therapy with metformin may be associated with weight stabilization19, 35, 41, 42, 46, 69
or loss.15, 31, 17, 45, 49, 57, 78, 81, 84, 118 Although the exact mechanism associated
with such alterations in weight has not been established,6 , 16, 17, 20, 30, 31, 81, 85
suggested mechanisms include the absence of a hyperinsulinemic effect (which if
present may increase appetite and/or lipogenesis)15, 17, 18, 72 and decreased dietary
intake associated with adverse GI effects of metformin. 17, 29, 85, 189 The
antihyperglycemic effect of the drug does not appear to be related to weight loss in
patients with type 2 diabetes mellitus receiving metformin, nor does weight loss appear
to be dose related.6 , 17, 20, 34 Limited data from studies comparing metformin therapy
with oral sulfonylurea (e.g., glyburide, chlorpropamide, tolbutamide) therapy indicate
that patients with type 2 diabetes mellitus receiving oral sulfonylureas gained weight or
lost less weight than patients receiving metformin.15, 16, 17, 20, 46, 57, 118, 134
Metformin has little or no effect on fasting plasma glucagon, somatostatin, serum growth
hormone, or serum cortisol concentration in patients with normal renal function;
glucagon, growth hormone, and cortisol concentrations are elevated in patients with
lactic acidosis and renal failure who have been receiving metformin.6 , 61, 62, 81, 135
Pharmacokinetics
The pharmacokinetics of metformin in patients with normal renal function do not appear

to be affected by gender, race, or the presence of diabetes mellitus.1 , 2 , 18, 89

Absorption
Metformin is slowly and incompletely absorbed from the GI tract, mainly from the small
intestine; absorption is complete within 6 hours.6 , 18, 43, 50, 51, 65, 72, 89 The absolute
oral bioavailability of the drug under fasting conditions is reported to be approximately
50-60% with metformin hydrochloride doses of 0.5-1.5 g;1 , 2 , 3 , 4 , 18, 33, 43, 50, 65, 72,
85 89
,
binding of the drug to the intestinal wall may explain the difference between the
amount of drug absorbed (as determined by the urinary and fecal excretion of
unchanged drug) and the amount bioavailable in some studies.6 , 18, 51, 72, 89, 129 In
single-dose studies with metformin hydrochloride doses of 0.5-1.5 g1 , 89 or 0.85-2.55
g,1 , 111 plasma metformin concentrations did not increase in proportion to increasing
doses, suggesting an active saturable absorption process.1 , 18, 65, 72, 89, 111, 126
However, limited data from studies in animals and in human intestinal cell cultures
suggest that transepithelial transfer of metformin in the intestine may occur through a
passive, nonsaturable mechanism, possibly involving a paracellular route.129, 134
Food decreases and slightly delays the absorption of metformin conventional tablets;
the clinical importance of these effects is unknown.1 , 2 , 3 , 4 , 18, 208 (See Dosage and
Administration: Administration.) Administration of metformin hydrochloride conventional
tablets with food reportedly has decreased peak plasma concentrations of the drug by
35-40%, reduced area under the plasma concentration-time curve (AUC) by 20-25%,
and delayed time to peak plasma drug concentration by 35-40 minutes compared with
these parameters in fasting individuals receiving this metformin preparation.1 , 126
However, in one study, concomitant administration of the drug as conventional tablets
with food had a less pronounced effect (average reduction in bioavailability of 10%) on
absorption.208 Following oral administration of metformin hydrochloride as an
extended-release tablet with food, the extent of absorption (as measured by AUC)
increased by approximately 50%, but peak plasma concentrations and time to achieve
peak plasma concentrations were not altered.1 The pharmacokinetics of metformin
extended-release tablets were not affected by the fat content of meals.1
Following oral administration of 0.5-1.5 g of metformin hydrochloride as conventional
tablets in healthy individuals or in patients with type 2 diabetes mellitus, peak plasma
drug concentrations of approximately 0.4-3 mcg/mL usually are attained within 2-4
hours.1 , 2 , 6 , 18, 33, 38, 43, 44, 50, 85, 125 Following oral administration of a single dose
(0.5-2 g) of metformin hydrochloride as extended-release tablets, peak plasma drug
concentrations of 0.6-1.8 mcg/mL usually are attained within a median of 7 hours
(range: 4-8 hours).1 Peak plasma drug concentrations following administration of
metformin extended-release tablets are approximately 20% lower than those following
administration of the same dose as conventional tablets.1 The extent of absorption of
metformin hydrochloride 2 g once daily as extended-release tablets is similar to that
following administration of 1 g of the drug twice daily as conventional tablets.1
Steady-state plasma concentrations with usual dosages of metformin hydrochloride as
conventional tablets (e.g., 1.5-2.55 g daily in 1 to 3 divided doses) are attained within

24-48 hours and generally average about 1 mcg/mL or less. 1 , 30, 38, 51 A precise
correlation between plasma metformin concentrations and the drug's antihyperglycemic
effect has not been established.5 , 51, 53, 72 In addition, plasma metformin
concentrations generally have shown no correlation with plasma lactate concentrations
during metformin therapy in patients with type 2 diabetes mellitus.5 , 30, 53, 64, 96, 134
Although metformin-associated lactic acidosis generally has been associated with
plasma metformin concentrations exceeding 5 mcg/mL1 , 2 , 62, 96, 119 (see Cautions:
Lactic Acidosis), such high concentrations reportedly were not observed during
controlled clinical trials with the drug, even at maximum dosage (2.5-2.55 g daily).1 , 134
Satisfactory control of blood or plasma glucose concentration may occur within a few
days to 1 week following initiation of metformin therapy in patients with type 2 diabetes
mellitus, but the maximum antihyperglycemic effect may be delayed for up to 2
weeks.18, 53, 72, 98, 134 Following discontinuance of metformin therapy, blood glucose
concentration increases within 2 weeks.53, 134
Distribution
Metformin is distributed rapidly in animals and humans into peripheral body tissues and
fluids, particularly the GI tract; the drug also appears to distribute slowly into
erythrocytes and into a deep tissue compartment (probably GI tissues).30, 50, 65, 72, 89,
134 162 167
,
,
The highest tissue concentrations of metformin (at least 10 times the
plasma concentration) occur in the GI tract (e.g., esophagus, stomach, duodenum,
jejunum, ileum), with lower concentrations (twice the plasma concentration) occurring in
kidney, liver, and salivary gland tissue. 6 , 18, 44, 50, 51, 65, 72, 162 The drug distributes
into salivary glands with a half-life of about 9 hours.50, 65 Metformin concentrations in
saliva are tenfold lower than those in plasma and may be responsible for the metallic
taste reported in some patients receiving the drug.50, 65 Any local effect of metformin on
glucose absorption in the GI tract may be associated with the relatively high GI
concentrations of the drug compared with those in other tissues.6 , 18, 43 It is not known
whether metformin crosses the blood-brain barrier or the placenta in humans or if the
drug is distributed into human milk; however, in lactating rats, metformin is distributed
into breast milk at levels comparable to those in plasma.1 , 2 , 85
Following oral administration of single 850-mg doses of metformin hydrochloride as
conventional tablets, the apparent volume of distribution has been reported to average
654 L.1 Volume of distribution reported after IV administration of the drug generally has
been smaller (e.g., 63-276 L) than that with oral administration, perhaps because of less
drug binding in the GI tract and/or different methods of determining volume of
distribution in various studies.30, 50, 51, 89, 134 Unlike oral sulfonylurea antidiabetic
agents, which are more than 90% bound to plasma proteins, metformin is negligibly
bound to plasma proteins.1 , 18, 50, 51, 65, 85, 89 Metformin equilibrates freely between
erythrocytes and plasma, most likely as a function of time; drug bound to erythrocytes is
approximately 5% of total blood concentration.1 , 2 , 3 , 18, 89
Elimination

Following oral administration of metformin hydrochloride (0.5-1.5 g) as conventional

tablets in healthy individuals or in patients with type 2 diabetes mellitus, plasma
concentrations decline in a triphasic manner.50, 89 Following multiple-dose
administration of metformin hydrochloride (500 mg twice daily for 7-14 days) as
conventional tablets in a limited number of patients with type 2 diabetes mellitus, peak
plasma concentrations remained unchanged, but trough drug concentrations were
higher than with single-dose administration, suggesting some drug accumulation in a
peripheral tissue compartment.89 (See Pharmacokinetics: Distribution.) No
accumulation of metformin appears to occur following repeated oral doses of the drug
as extended-release tablets.1 The principal plasma elimination half-life of metformin
ranges from 3-6 hours; 90% of the drug is cleared within 24 hours in patients with
normal renal function.1 , 2 , 6 , 18, 33, 38, 50, 51, 65, 85, 89, 125, 134 The decline in plasma
metformin concentrations is slower after oral than after IV administration of the drug,
indicating that elimination is absorption rate-limited.18, 50, 89 Urinary excretion data and
data from whole blood indicate a slower terminal-elimination phase of 8-20 hours
occurring 12 hours after the oral dose, but this phase represents only 0.4-5% of total
drug clearance and may represent elimination from a small, deep tissue compartment.3 ,
18 50 65 72 89 134 174
, , , , ,
,
Metformin is not metabolized in the liver or GI tract and is not excreted in bile; no
metabolites of the drug have been identified in humans.1 , 50, 51, 89 Renal elimination of
metformin involves glomerular filtration and secretion by the proximal convoluted
tubules as unchanged drug.1 , 2 , 6 , 33, 50, 63, 65, 75, 85, 89 Following single-dose oral
administration of metformin hydrochloride (0.5-1.5 g), urinary recovery ranges from
35-52% of the total dose.50, 51, 89 Approximately 20-33% of the total oral dose is
excreted in feces within 4-7 days.6 , 33, 43, 50, 72, 89 Total plasma clearance of
metformin hydrochloride following single-dose oral administration (0.5-1.5 g) has ranged
from 718-1552 mL/minute.33, 89 Metformin is removed by hemodialysis with a clearance
of up to 170 mL/minute under good hemodynamic conditions.1 , 23, 32, 33, 62, 117
Renal clearance is decreased (as measured by decreases in creatinine clearance) in
patients with renal impairment and, apparently because of reduced renal function with
age, in geriatric individuals.1 , 33, 51, 174 Following a single 850-mg oral dose of
metformin hydrochloride, renal clearance averaged 552, 491, or 412 mL/minute in
nondiabetic adults, diabetic adults, or healthy geriatric individuals, respectively.1 , 174
Renal impairment results in increased peak plasma concentrations of metformin, a
prolonged time to peak plasma concentration, and a decreased volume of distribution. 1 ,
3 51 174
, ,
In geriatric individuals, decreased renal clearance of metformin also results in
increased plasma concentrations of the drug; volume of distribution remains
unaffected.1 , 174 (See Cautions: Precautions and Contraindications.)
Chemistry and Stability
Chemistry

Metformin hydrochloride, a dimethylbiguanide, is an orally active antidiabetic agent

derived from guanidine.1 , 2 , 3 , 4 , 18, 20, 22, 23, 27, 28, 29, 30, 33, 72, 146 Guanidine
occurs naturally in Galega officinalis, a medieval European remedy for diabetes
mellitus.6 , 18, 20, 44, 72, 146
Metformin is structurally and pharmacologically related to phenformin, a
phenethylbiguanide (no longer commercially available in the US).18, 27, 28, 29 However,
the guanidinium group of metformin has 2 methyl substituents rather than a single
hydrophobic phenethyl substituent as in phenformin, giving metformin improved water
solubility and decreased binding affinity for biologic membranes (e.g., mitochondrial,
plasma membranes) compared with phenformin.2 , 6 , 20, 23, 38, 47 Consequently,
metformin causes less disturbance to mitochondrial-mediated glucose oxidative
pathways, resulting in a decrease in the formation of lactate from glucose via anaerobic
metabolism and a reduced potential for the development of lactic acidosis compared
with phenformin.3 , 6 , 20, 23
Metformin hydrochloride is commercially available as conventional tablets, extendedrelease tablets, and as conventional tablets in fixed combination with glyburide. 234, 1
The extended-release tablets contain dual hydrophilic polymers that form a swellable
gel matrix when in contact with gastric or intestinal fluids and release the drug slowly
over time.1
Metformin is a weak base; the pH of a 1% aqueous solution of metformin hydrochloride
is 6.68.1 , 47 The pKa of metformin base is 12.4. 1 , 2 , 30 Metformin hydrochloride is freely
soluble in water and practically insoluble in acetone, ether, and chloroform.1 , 2

Stability
Commercially available metformin hydrochloride conventional (including
fixed-combination preparations with glipizide or rosiglitazone) and extended-release
tablets should be stored at a controlled room temperature of 20-25C and protected
from light but may be exposed to temperatures ranging from 15-30C .1 , 247, 254
Fixed-combination preparations containing metformin hydrochloride and glyburide
should be stored at a controlled room temperature up to 25C and be protected from
light.234
Preparations
Metformin Hydrochloride
Oral
Tablets, film-

500 mg

Glucophage , (with povidone)

coated

Bristol-Myers Squibb
850 mg

Glucophage , (with
povidone) Bristol-Myers Squibb

1g

Glucophage , (with
povidone) Bristol-Myers Squibb

Tablets, extended- 500 mg

release
750 mg

Glucophage XR, BristolMyers Squibb

Glucophage XR,
Bristol- Myers Squibb

Metformin Hydrochloride Combinations

Oral
Tablets, filmcoated

250 mg with Glyburide 1.25

mg
Squibb

Glucovance, Bristol-Myers

500 mg with Glyburide 2.5 mg Glucovance, Bristol-Myers

Squibb
500 mg with Glyburide 5 mg
Squibb

Glucovance , Bristol-Myers

500 mg with Rosiglitazone 1 Avandamet

, mg
GlaxoSmithKline
500 mg with Rosiglitazone 2 Avandamet

, mg
GlaxoSmithKline
500 mg with Rosiglitazone 4 Avandamet

, mg
GlaxoSmithKline

References
1. Bristol-Myers Squibb Company. Glucophage (metformin hydrochloride) tablets and
Glucophage XR (metformin hydrochloride) extended-release tablets prescribing