Resume

Metformin (Systemic)
Introductory Information
Antidiabetic agent; a biguanide, chemically and pharmacologically unrelated to sulfonylurea

antidiabetic agents.1, 2, 3, 4, 18, 20, 22, 23, 27, 28, 29, 30, 33, 72, 146, 243, 245, 246
Class: 68:20.04 Biguanides; hs502 (VA primary)
Brands*: Actoplus Met® (combination), Avandamet® (combination), Fortamet®, Glucophage®,

Glucophage® XR®, Glucovance® (combination), Glumetza®, Metaglip® (combination),
Riomet®
*
also available generically
Generic Name: Metformin Hydrochloride

CAS Number: 1115-70-4
Chemical Name: 1,1-Dimethylbiguanide monohydrochloride
Molecular Formula: C4H11N5•HCl
Investigational Drug Number: AI3-51264
Synonym: Dimethylbiguanide Hydrochloride
Special Alerts:
[UPDATED 02/04/2011] FDA notified healthcare professionals and patients that information
on the cardiovascular risks (including heart attack) of rosiglitazone has been added to the
physician labeling and patient Medication Guide. This information was first announced by
FDA on September 23, 2010 as part of new restrictions for prescribing and use of this drug.
Rosiglitazone is sold as a single-ingredient product under the brand name Avandia.

Rosiglitazone is also sold as a combination product under the brand name Avandamet
(contains rosiglitazone and metformin) and under the brand name Avandaryl (contains
rosiglitazone and glimepiride).
In addition to describing the cardiovascular risks, the drug labels have been revised to state
that rosiglitazone and rosiglitazone-containing medicines should only be used:
In patients already being treated with these medicines

In patients whose blood sugar cannot be controlled with other anti-diabetic medicines and
who, after consulting with their healthcare professional, do not wish to use pioglitazone-
containing medicines (Actos, Actoplus Met, Actoplus Met XR, or Duetact).
For more information visit the FDA website at: [Web] and [Web].
[Posted 09/23/2010] ISSUE: FDA notified healthcare professionals and patients that it will
significantly restrict the use of the diabetes drug rosiglitazone (Avandia) to patients with
Type 2 diabetes who cannot control their diabetes on other medications. These new
restrictions are in response to data that suggest an elevated risk of cardiovascular events, such
as heart attack and stroke, in patients treated with rosiglitazone
BACKGROUND: Rosiglitazone is in a class of drugs known as thiazolidinediones, or

TZDs. It is intended to be used in conjunction with diet and exercise to improve glucose
(blood sugar) control in patients with Type 2 diabetes mellitus. Rosiglitazone also is available
in combination with other diabetes medications, metformin under the brand name Avandamet
or glimepiride under the brand name Avandaryl.
RECOMMENDATION: FDA will require that GSK develop a restricted access program for
rosiglitazone under a risk evaluation and mitigation strategy, or REMS. Under the REMS,
rosiglitazone will be available to new patients only if they are unable to achieve glucose
control on other medications and are unable to take pioglitazone (Actos), the only other drug
in this class. Current users of rosiglitazone who are benefiting from the drug will be able to
continue using the medication if they choose to do so.
Doctors will have to attest to and document their patients' eligibility; patients will have to
review statements describing the cardiovascular safety concerns associated with this drug and
acknowledge they understand the risks. The agency anticipates that the REMS will limit use
of rosiglitazone significantly. For more information visit the FDA website at: [Web] and
[Web].
Boxed Warning
Lactic acidosis rare but potentially fatal.1, 6, 18, 20, 27, 29, 30, 62, 89, 96, 158 Increased risk of lactic
acidosis in patients with renal impairment, advanced age, metformin plasma concentrations
>5 mcg/mL.1, 2, 62, 96, 119
Generally has occurred in diabetic patients with severe renal insufficiency who 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
Periodically monitor renal function and use the minimum effective dosage.1, 32, 62, 63, 65, 76, 85, 91,
93, 96, 123, 124, 158, 164, 165
Withhold promptly in patients with any condition associated with
hypoxemia, sepsis, or dehydration.1, 2, 62, 63, 93 Avoid use in patients with clinical or laboratory
evidence of hepatic impairment.1, 2, 63, 65, 85, 91, 93, 156, 158 Discontinue therapy temporarily in
patients undergoing surgery or receiving parenteral iodinated radiographic contrast media.1, 2,
30, 62, 63, 93, 158
Drugs that may affect renal function or alter metformin elimination should be
used with caution.1
Advise patients not to consume excessive amounts of alcohol.1, 2, 63, 76, 91, 93, 158
If lactic acidosis occurs, discontinue metformin.1, 30 Immediate hospitalization and treatment
required.1
Uses
Pending revision, the material in this section should be considered in light of more recently
available information in the MEDWATCH notification at the beginning of this monograph.
Diabetes Mellitus
Used as monotherapy for the management of patients with type 2 diabetes mellitus that
cannot be controlled by diet alone.1, 3, 4, 6, 8, 15, 16, 17, 18, 19, 20, 27, 29, 95, 166
Used in combination with a sulfonylurea, repaglinide, or thiazolidinedione antidiabetic agent

for the management of patients with type 2 diabetes who do not achieve adequate glycemic
control on monotherapy with metformin or any of these drugs.1, 3, 6, 15, 18, 20, 22, 27, 29, 30, 48, 59, 78, 88,
95, 97, 99, 112, 134, 166, 191, 234, 237, 238, 239, 241, 242, 243, 245, 246, 249, 250
Used concomitantly with nateglinide in
patients who no longer respond adequately to metformin despite appropriate diet, exercise,
and metformin monotherapy.248
May be used with insulin to improve glycemic control and/or decrease the required dosage of
insulin.1, 3, 6, 88, 90, 94, 95, 146
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
Fixed combinations with glyburide or glipizide used 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.234, 254
Add a thiazolidinedione antidiabetic agent to metformin in fixed combination with glyburide

in patients who have inadequate glycemic control with the fixed combination.234
Commercially available in fixed combination with rosiglitazone for use when treatment with
rosiglitazone and metformin is appropriate (i.e., as initial therapy in patients whose
hyperglycemia cannot be controlled by diet and exercise alone and as second-line therapy in
patients who do not achieve adequate control of hyperglycemia despite therapy with diet,
exercise, and treatment with rosiglitazone or metformin).a
Metformin is the preferred initial oral antidiabetic agent for patients with type 2 diabetes
mellitus.264
Not effective as sole therapy in patients with diabetes mellitus complicated by acidosis,
ketosis, or coma.1, 6, 30, 146, 191, 192
Dosage and Administration
General
• Sulfonylurea agent may be abruptly discontinued (no transition period generally required)
when therapy is transferred from most sulfonylurea antidiabetic agents to metformin.1, 2
• Patients whose therapy is transferred from chlorpropamide to metformin should be monitored
closely for hypoglycemia during the initial 2 weeks following transfer.1, 2, 30
• 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
Administration
Oral Administration
Administer orally with meals to reduce adverse GI effects.1, 2, 3, 18, 53, 85
Administer conventional tablets 2 or 3 times daily.1 Administer in 2 divided doses if total

dosage ≤2 g daily or in 3 divided doses if total dosage is >2 g daily.1
Administer extended-release tablets once daily with the evening meal.1
Dosage
Available as metformin hydrochloride; dosage expressed in terms of the salt.1
Individualize dosage carefully based on patient's glycemic response and tolerance.1, 4, 243, 245,
246
Pediatric Patients
Diabetes Mellitus
Oral: Conventional tablets or oral solution in children 10-16 years of age: Initially, 500 mg
twice daily with meals as monotherapy.1, 257, 258 Titrate dosage in increments of 500 mg daily
at weekly intervals to a maximum of 2 g daily given in divided doses.1, 257, 258
Adults
Diabetes Mellitus
>Initial Dosage in Previously Untreated Patients
Oral: Conventional tablets or oral solution: Initially, 500 mg twice daily with the morning
and evening meal.1, 4, 134, 243, 245, 246, 257, 259 Titrate dosage by 500 mg daily at weekly intervals to
a total of 2 g daily1, 2, 14, 18, 21, 30, 85, 134, 257 or to 850 mg twice daily after 2 weeks.1, 257 Clinically
important responses generally not observed at dosages <1.5 g daily.1, 257 Usual maintenance
dosage is 850 mg twice daily.1, 259
Alternatively, give initial dosage of 500-850 mg once daily in the morning.1, 2, 3, 4, 23, 30, 146, 243,
245, 246
If initial dosage is 850 mg daily, titrate dosage by 850 mg daily every other week to a
total of 2 g daily.1, 2, 3, 4, 18, 22, 85, 243, 245, 246
For additional glycemic control, administer up to a maximum daily dosage of 2.55 g given in
divided doses.1, 257
Extended-release tablets (Glucophage® XR) in patients ≥17 years of age: Initially, 500 mg
once daily with the evening meal.1, 259 Titrate dosage by 500 mg daily at weekly intervals to a
maximum of 2 g daily.1, 259 If glycemic control is not achieved with 2 g once daily, consider
administering 1 g twice daily.1, 259 If >2 g daily is required, switch to conventional tablet
formulation and increase dosage up to 2.55 g daily in divided doses (preferably 3 doses for
daily dosages >2 g).1, 259
Extended-release tablets (Fortamet®) in patients ≥17 years of age: Initially, 1 g daily with the
evening meal; 500 mg daily may be used when clinically appropriate.258 Titrate dosage by 500
mg daily at weekly intervals to a maximum of 2.5 g daily with the evening meal.258
>Initial Dosage of Metformin Hydrochloride in Fixed Combination with Glipizide

(Metaglip®)
Oral: Initially, 250 mg of metformin hydrochloride and 2.5 mg of glipizide once daily with a
meal.254 For more severe hyperglycemia (fasting plasma glucose concentrations of 280-320
mg/dL), 500 mg of metformin hydrochloride and 2.5 mg of glipizide twice daily.254 Titrate in
increments of one tablet (using the tablet strength at which therapy was initiated) daily at 2-
week intervals until adequate blood glucose control is achieved or maximum daily dosage of
2 g of metformin hydrochloride and 10 mg of glipizide is reached.254, 256
Efficacy of metformin hydrochloride and glipizide in fixed combination not established in
patients with fasting plasma glucose concentrations >320 mg/dL.254 No experience with total
initial daily dosages exceeding 2 g of metformin hydrochloride and 10 mg of glipizide.254
>Initial Dosage of Metformin Hydrochloride in Fixed Combination with Glyburide
(Glucovance®)
Oral: Initially, 250 mg of metformin hydrochloride and 1.25 mg of glyburide once daily with
a meal.234 For more severe hyperglycemia (i.e., fasting plasma glucose concentrations >200
mg/dL or glycosylated hemoglobin >9%), 250 mg of metformin hydrochloride and 1.25 mg
of glyburide twice daily with the morning and evening meal.234 Titrate dosage in increments
of 250 mg of metformin hydrochloride and 1.25 mg of glyburide daily at 2-week intervals
adequate control of blood glucose is achieved or a maximum daily dosage of 2 g of
metformin hydrochloride and 10 mg of glyburide.234
The fixed combination of metformin hydrochloride 500 mg and glyburide 5 mg should not be
used as initial therapy due to an increased risk of hypoglycemia.234
>Initial Dosage of Metformin Hydrochloride in Fixed Combination with Rosiglitazone

(Avandamet®)
Oral: Initially, 500 mg of metformin hydrochloride and 2 mg of rosiglitazone once or twice

daily.a For more severe hyperglycemia (i.e., HbA1c >11% or fasting plasma glucose
concentrations >270 mg/dL), consider 500 mg of metformin hydrochloride and 2 mg of
rosiglitazone twice daily.a If additional glycemic control needed after 4 weeks, titrate dosage
upward in increments of 500 mg of metformin hydrochloride and 2 mg of rosiglitazone per
day until adequate glycemic control is achieved or a maximum daily dosage of 2 g of
metformin hydrochloride and 8 mg of rosiglitazone is reached.a
>Initial Dosage in Patients Transferred to Metformin Hydrochloride in Fixed

Combination with Glipizide (Metaglip®)
Oral: In previously treated patients, 500 mg of metformin hydrochloride and 2.5 or 5 mg of
glipizide twice daily with the morning and evening meals.254 The initial dosage of glipizide
and metformin hydrochloride in fixed combination should not exceed the daily dosage of
metformin hydrochloride or glipizide (or the equivalent dosage of another sulfonylurea)
previously received.254 Titrate dosage in increments not exceeding 500 mg of metformin
hydrochloride and 5 mg of glipizide until adequate control of blood glucose is achieved or a
maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of glipizide is
reached.254
For patients switching from combined therapy with separate preparations, the initial dosage
of the fixed-combination preparation of glipizide and metformin hydrochloride should not
exceed the daily dosages of glipizide (or equivalent dosage of another sulfonylurea
antidiabetic agent) and metformin hydrochloride currently being taken.254 Use clinical
judgment regarding whether to switch to the nearest equivalent dosage or to titrate dosage.254
Titrate dosage in increments of not more than 5 mg of glipizide and 500 mg of metformin
hydrochloride until adequate control of blood glucose is achieved or maximum daily dosage
of 20 mg of glipizide and 2 g of metformin hydrochloride is reached.254

Combination with Glyburide (Glucovance®)
Oral: Initially, 500 mg of metformin hydrochloride and 2.5 or 5 mg of glyburide twice daily
with the morning and evening meal.234 For patients previously receiving metformin
hydrochloride or glyburide (or another sulfonylurea agent), the initial dosage of metformin
hydrochloride or glyburide should not exceed the dosage (or equivalent dosage) received
previously.234 For patients previously receiving both metformin hydrochloride and glyburide
(or another sulfonylurea agent) separately, the initial dosage should not exceed the previous
dosage of metformin hydrochloride and glyburide (or the equivalent dosage of the other
sulfonylurea) administered separately.234 Titrate dosage in increments not exceeding 500 mg
of metformin hydrochloride and 5 mg of glyburide until adequate control of blood glucose is
achieved or a maximum daily dosage of 2 g of metformin hydrochloride and 20 mg of
glyburide is reached.158, 234
For patients whose hyperglycemia is not adequately controlled on therapy with metformin
hydrochloride 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,
titrate thiazolidinedione dosage upward as recommended.234

Combination with Rosiglitazone (Avandamet®)
Oral: In patients not adequately controlled on monotherapy with metformin hydrochloride or
rosiglitazone, dosage of the fixed combination is based on the patient's current dosages of
metformin hydrochloride and/or rosiglitazone.247 (See Table.)
In patients inadequately controlled on metformin monotherapy, the usual initial dosage of
rosiglitazone is 4 mg daily given with patient's existing dosage of metformin hydrochloride.a
In patients inadequately controlled on rosiglitazone monotherapy, the usual initial dosage of
metformin hydrochloride is 1 g daily given with patient's existing dosage of rosiglitazone.a
>Table 1. Initial Dosage of the Fixed Combination of Metformin Hydrochloride and

Rosiglitazone (Avandamet®)a
Prior Therapy Usual Initial Dosage of Avandamet®
Total Daily Dosage Tablet strength Number of tablets
Metformin Hydrochloridea
1g 2 mg/500 mg 1 tablet twice daily
2g 2 mg/1 g 1 tablet twice daily
Rosiglitazone
4 mg 2 mg/500 mg 1 tablet twice daily
8 mg 4 mg/500 mg 1 tablet twice daily
a
Individualize therapy 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 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.)
If additional glycemic control is needed following transfer, titrate dosage upward in
increments of 500 mg of metformin hydrochloride and/or 4 mg of rosiglitazone per day until
adequate glycemic control is achieved or a maximum daily dosage of 2 g of metformin
hydrochloride and 8 mg of rosiglitazone is reached.a Following increase in dosage of
metformin hydrochloride, further dosage adjustment recommended if adequate glycemic
control not achieved in 1-2 weeks.a Following increase in dosage of rosiglitazone, further
dosage adjustment recommended if adequate glycemic control not achieved in 8-12 weeks.a
For patients switching from combined therapy with separate preparations, 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
>Initial Metformin Hydrochloride Dosage in Patients Transferred from Insulin
Oral: Initially, 500 mg once daily; increase dosage by 500 mg daily at weekly intervals
adequate control of blood glucose is achieved or a maximum daily dosage of 2.5 g
(conventional tablets) or 2 g (extended-release tablets) is reached.1 Concurrent insulin dosage
initially remains unchanged.1 When fasting plasma glucose concentration decreases to <120
mg/dL, decrease insulin dosage by 10-25%.1
Prescribing Limits
Pediatric Patients
Oral
Children 10-16 years of age: Maximum 2 g daily as conventional tablets or oral solution.1, 257
Adults
Oral
Maximum 2.55 g daily (conventional tablets or oral solution; 2.5 g daily as Fortamet®
extended-release tablets; or 2 g daily as certain other extended-release tablets (e.g.,
Glucophage®).1, 2, 3, 4, 14, 18, 22, 85, 257, 258, 259 Switch to conventional tablets for further dosage
titration if required dosage exceeds 2 g daily while on extended-release tablets.1, 259
For the fixed combination with glyburide, maximum daily dosage as second-line therapy is 2
g of metformin hydrochloride and 20 mg of glyburide.234 For the fixed combination with
glipizide, maximum daily dosage is 2 g of metformin hydrochloride and 20 mg of
glipizide.254, 256 For the fixed combination with rosiglitazone, maximum daily dosage is 2 g of
metformin hydrochloride and 8 mg of rosiglitazone.247
Special Populations
Geriatric Patients
Maintenance dosage generally should not be titrated to the maximum recommended for
younger adults;1, 2, 3, 4, 165, 1 limited data suggest reducing initial dosage by approximately 33%
in geriatric patients.30, 174
Cautions
Contraindications
• 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
• Renal impairment (e.g., ≥1.5 or 1.4 mg/dL in men or women, respectively) or abnormal Scr.1, 2,
18, 20, 91, 234
Renal impairment may result from conditions such as cardiovascular collapse
(shock), AMI, or septicemia.1, 2, 18, 20, 91, 234
• Congestive heart failure requiring drug therapy (e.g., digoxin, furosemide).1, 209, 214, 215
• Known hypersensitivity to metformin hydrochloride or any ingredient in the formulations.1, 2,
234, 247, 254
Warnings/Precautions
Warnings
Lactic Acidosis
See Boxed Warning.
General Precautions
Hypoglycemia
Uncommon in patients receiving metformin as monotherapy.1, 15, 30, 78, 94, 99 Debilitated,
malnourished, or geriatric patients and patients with renal or hepatic impairment or adrenal or
pituitary insufficiency may be particularly susceptible.1, 2 Strenuous exercise, alcohol
ingestion, insufficient caloric intake, or use in combination with other antidiabetic agents may
increase risk.1, 2 Hypoglycemia may be difficult to recognize in geriatric patients or in those
receiving β-adrenergic blocking agents.1, 83, 91, 128, 143, 153, 159 (See Specific Drugs under
Interactions.)
Hematologic Effects
Decreased serum vitamin B12 concentrations, 1, 18 with or without clinical manifestations (e.g.,
anemia).1
Symptoms rapidly reversible following discontinuation of metformin or supplementation

with vitamin B12.1, 3, 6, 20, 30, 70, 77, 82, 134 Monitor hematologic parameters (e.g., hemoglobin,
serum vitamin B12 concentrations)1, 82, 114, 122, 134, 148 prior to initiation of therapy and at least
annually during treatment and any abnormality properly investigated.
Consider periodic supplementation with parenteral vitamin B12 in patients at high risk for
developing subnormal serum vitamin B12 concentrations (e.g., alcoholics, patients with low
calcium or vitamin B12 intake or absorption).1, 82, 114, 122, 134, 148
Cardiovascular Effects
Possible increased cardiovascular mortality associated with other biguanide antidiabetic
agents (i.e., phenformin).1, 191, 192, 200 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 pending the results of further studies of
metformin alone or in combination with sulfonylureas.220, 221, 224
Use of metformin in combination with rosiglitazone and insulin is not indicated; adverse
cardiovascular events (e.g., edema, heart failure) have occurred with combined rosiglitazone
and insulin therapy.247
Concurrent Illness
Evaluate serum electrolytes and ketones, blood glucose, and if indicated, blood pH, lactate,
pyruvate, and metformin concentrations for evidence of ketoacidosis or lactic acidosis.1, 88, 134,
156, 169
Temporary withdrawal of metformin therapy and administration of insulin may be required to

maintain glycemic control during periods of stress.1
Use of Fixed Combinations

When used in fixed combination with glipizide, glimepiride, or rosiglitazone, consider the
cautions, precautions, and contraindications associated with the concomitant agent.234, 247, 254
Specific Populations
Pregnancy
Category B.1
Most clinicians recommend use of insulin during pregnancy in diabetic patients to maintain
optimum control of blood glucose concentrations.1, 3, 4, 18, 72, 88, 92
Lactation
Distributed into milk in rats; not known if distributed into milk in humans.1, 85 Discontinue
nursing or the drug.1, 3, 4
Pediatric Use
Safety and efficacy of metformin as conventional tablets or oral solution in children <10
years of age have not been established.1, 257
Safety and efficacy of metformin as extended-release tablets in children <17 years of age
have not been established.1, 258, 259
Safety and efficacy of metformin in fixed combination with glipizide or rosiglitazone in

children have not been established.1, 3, 4, 30, 134, 234, 247, 254 Data from a clinical trial in children 9-
16 years of age comparing combined therapy with metformin and glyburide (Glucovance®)
with each drug as monotherapy did not reveal unexpected safety findings.234
Geriatric Use
Insufficient number of geriatric patients in controlled clinical trials of metformin
hydrochloride conventional (Glucophage®) and extended-release tablets (Glucophage® XR) to
determine if such patients respond differently than younger adults.1 With another extended-
release preparation of metformin hydrochloride (Fortamet®), no overall differences in safety
or efficacy in geriatric patients were observed compared with younger adults.258
Use with caution, since renal function declines with age.1, 3, 4, 30, 85, 174
Monitor renal function periodically.1, 2, 3, 4, 164, 165
Do not initiate in patients ≥80 years of age without confirmation of adequate renal function as
measured by Clcr.1, 209, 214
Geriatric patients particularly susceptible to hypoglycemia,1, 2 which may be difficult to

recognize.1, 83, 91, 128, 143, 153, 159
Renal Impairment
Evaluate renal function prior to initiation of therapy and at least annually thereafter.1, 2, 77, 85,
234
Monitor more frequently if development of impaired renal function is anticipated (e.g., those
with blood glucose concentrations >300 mg/dL, those who may develop renal dysfunction as
a result of polyuria and volume depletion).156
Discontinue metformin if evidence of renal impairment is present.1, 2, 156, 164
Patients whose serum creatinine concentrations exceed the upper limit of normal for their age
should not receive metformin.1
Hepatic Impairment
Avoid use.1, 165 Elimination of lactate may be substantially reduced.1 (See Boxed Warning.)
Common Adverse Effects
Diarrhea,1, 31, 48, 49, 53, 78, 109, 118, 122, 135 nausea,1, 31, 53, 78, 109, 118, 122 vomiting,1, 118, 122 abdominal
bloating, abdominal cramping or pain,1, 31, 35, 42, 53, 118, 122 flatulence,1 anorexia.1, 3, 6, 18
Interactions
Cationic Agents Secreted by Proximal Renal Tubules
Pharmacokinetic interaction with cimetidine (decreased excretion of metformin).1, 75
Potential pharmacokinetic interaction with other cationic drugs that undergo substantial
tubular secretion (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine,
ranitidine, triamterene, vancomycin).1, 30
Monitor carefully; consider dosage adjustment of either agent.1
Protein-bound Drugs
Pharmacokinetic interaction unlikely.1
Drugs That May Antagonize Hypoglycemic Effects
Calcium-channel blocking agents, corticosteroids, thiazide diuretics, estrogens and progestins

(e.g., oral contraceptives), isoniazid, niacin, phenothiazines, sympathomimetic agents (e.g.,
albuterol, epinephrine, terbutaline); observe patient closely for evidence of altered glycemic
control when such drugs are added to or withdrawn from therapy.1, 30, 80, 85, 91, 120, 121, 134, 139, 143,
151, 152, 153, 154, 159, 160
Specific Drugs
Drug Interaction Comments

Potential risk of Monitor blood glucose
ACE hypoglycemia/hyperglycemia when ACE concentrations during dosage
inhibitors inhibitor therapy is initiated/withdrawn131, adjustments with either agent130, 131,
132, 134, 152, 155, 160 132, 134, 152, 155, 160
Increased risk of hypoglycemia and lactic

Alcohol Avoid excessive alcohol intake1
acidosis1, 2, 18, 33, 63, 72, 76, 91, 93, 107, 143
β-Adrenergic Impaired glucose tolerance; 73, 143, 152, 153, If concomitant therapy necessary, a
159
blocking Increased frequency or severity of β1-selective adrenergic blocking
agent or β-adrenergic blocking
hypoglycemia and hypoglycemia-induced agents with intrinsic
agents
complications91, 127, 153, 159 sympathomimetic activity
preferred36, 143, 152, 160, 173
Possible decreased excretion of
Cimetidine
metformin
Possible resumption of ovulation in
Clomiphene premenopausal patients with polycystic
ovary syndrome210
Increased plasma concentrations of
Furosemide
metformin and furosemide237, 1
Variable decreases in AUC and peak
Glyburide Clinical importance uncertain1
blood concentration of glyburide1
Enhanced absorption and increased
Nifedipine
urinary excretion of metformin1
Consider using less diabetogenic
diuretic (e.g., potassium-sparing
Thiazide May exacerbate diabetes mellitus1, 91, 139, diuretic), reducing dosage of or
143, 151, 152, 153, 154, 159, 160
diuretics discontinuing diuretic, or increasing
dosage of oral antidiabetic agent73,
134, 152, 153, 154, 159, 160
Pharmacokinetics
Absorption
Bioavailability
Approximately 50-60% (absolute) with dosages of 0.5-1.5 g.1, 2, 3, 4, 18, 33, 43, 50, 65, 72, 85, 89
Fixed-combination preparation containing 500 mg of metformin hydrochloride and 4 mg of

rosiglitazone is bioequivalent to mg-equivalent dosages of individual components
administered separately under fasted conditions.a
Onset
Therapeutic response usually apparent within a few days to 1 week.18, 53, 72, 98, 134 Maximal
glycemic response within 2 weeks.18, 53, 72, 98, 134
Duration
Blood glucose concentrations increase within 2 weeks following discontinuance of metformin
therapy.53, 134
Food
Food decreases and slightly delays absorption of conventional tablets.1, 2, 3, 4, 18, 208
Food increases the extent of absorption of extended-release tablets (Glucophage® XR,

Fortamet®).1, 258 Peak plasma concentrations and time to achieve peak plasma concentrations
not altered by administration of one extended-release preparation (Glucophage® XR) with
food; 1 food increases peak plasma concentrations and prolongs time to peak plasma
concentrations of another extended-release tablet preparation (Fortamet®).258
Food increases the extent of absorption and delays the time to peak plasma concentrations of
the oral solution.257 Fat content of meals does not appreciably affect the pharmacokinetics of
metformin hydrochloride oral solution.257
Distribution
Extent
Rapidly distributed into peripheral body tissues and fluids, particularly GI tract.30, 50, 65, 72, 89,
134, 162, 167
Slowly distributed into erythrocytes and a deep tissue compartment (probably GI tissue).30, 50,
65, 72, 89, 134, 162, 167
Plasma Protein Binding

Negligible.1, 18, 50, 51, 65, 85, 89
Elimination
Metabolism
Not metabolized in the liver or GI tract and not excreted into bile.1, 50, 51, 89 No metabolites
identified in humans.1, 50, 51, 89
Elimination Route
Excreted in urine (approximately 35-52%)50, 51, 89 and feces (20-33%).6, 33, 43, 50, 72, 89
Eliminated as unchanged drug.1, 2, 6, 33, 50, 63, 65, 75, 85, 89
Half-life
3-6 hours.1, 2, 6, 18, 33, 38, 50, 51, 65, 85, 89, 125, 134
Special Populations
Renal impairment may reduce clearance, including in geriatric patients with age-related
decline in renal function.1, 33, 51, 174 Renal impairment results in increased peak plasma
concentrations, prolonged time to peak plasma concentration and half-life, and decreased
volume of distribution.1, 3, 51, 174
Stability
Storage
Oral
Tablets
Conventional tablets: tight, light resistant containers at 20-25°C (may be exposed to 15-
30°C).1
Extended-release tablets: tight, light resistant containers at 20-25° C (may be exposed to 15-
30°C).1, 258
Fixed-combination preparations with glipizide or rosiglitazone: tight, light resistant

containers at 20-25° C (may be exposed to 15-30°C).247, 254
Solution
15-30°C.257
Actions
• Lowers blood glucose concentrations in patients with type 2 (non-insulin-dependent) diabetes

mellitus (NIDDM) without increasing insulin secretion from pancreatic β cells.1, 2, 3, 4, 18, 20, 27,
31, 40, 60, 134
Ineffective in the absence of some endogenous or exogenous insulin.18, 27, 40, 71, 122
• Usually does not lower glucose concentrations below euglycemia, but hypoglycemia
occasionally may occur with overdosage.1, 2, 18, 20, 27, 28, 29, 72, 102, 103, 111
• Lowers both basal (fasting) and postprandial glucose concentrations in patients with type 2
diabetes mellitus.1, 2, 18, 22 Improves insulin sensitivity by decreasing hepatic glucose
production and enhancing 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 Insulin secretion usually
remains unchanged.1, 2, 3, 18, 20, 42, 60, 68, 102, 166
Advice to Patients
• Importance of informing clinicians of existing or contemplated therapy, including prescription

and OTC drugs, dietary or herbal supplements, and alcohol consumption, as well as any
concomitant illnesses (e.g., renal disease).1 Importance of avoiding excessive alcohol
consumption.1
• Importance of women informing clinicians if they are or plan to become pregnant or plan to
breast-feed.1
• Importance of adherence to diet and exercise regimens.1
• Possibility of primary and secondary failure with metformin therapy.1
• Risks of hypoglycemia, symptoms and treatment of hypoglycemic reactions, and conditions
that predispose to the development of such reactions.1
• Importance of regular laboratory evaluations, including fasting blood (or plasma) glucose
determinations.1, 2, 85
• Risks of lactic acidosis and conditions that predispose to its development.1
• Importance of informing patients of other important precautionary information.1 (See
Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects
in some individuals; consult specific product labeling for details.
Metformin Hydrochloride
Routes Dosage Forms Strengths Brand Names Manufacturer
500 mg/5
Oral Solution Riomet® Ranbaxy
mL
Tablets, film- Glucophage® (with
500 mg* Bristol-Myers Squibb
coated povidone)
Alphapharm, Amneal,
Metformin Tablets Aurobindo, Barr, Caraco,
Watson
625 mg Goldline
Tablets
750 mg Goldline
Tablets
Glucophage® (with
850 mg* Bristol-Myers Squibb
povidone)
Alphapharm, Amneal,
Watson
Glucophage® (with
1 g* Bristol-Myers Squibb
povidone)
Alphapharm, Amneal,
Watson
Tablets,
extended- 500 mg* Fortamet® First Horizon
release
Glucophage® XR® Bristol-Myers Squibb
®
Glumetza (with
Depomed
crospovidone)
Metformin Hydrochloride Actavis, Apotex, Barr,
Extended-Release Tablets Cobalt, Impax, Watson
750 mg* Glucophage® XR® Bristol-Myers Squibb
Metformin Hydrochloride Actavis, Apotex, Barr,
Extended-Release Tablets Cobalt, Impax, Watson
1 g* Fortamet® First Horizon
®
Glumetza (with
Depomed
crospovidone)
* available from one or more manufacturer, distributor, and/or repackager by generic
(nonproprietary) name
Metformin Hydrochloride Combinations

Dosage
Routes Strengths Brand Names Manufacturer
Forms
Tablets, 250 mg with Glipizide 2.5 Metaglip® Bristol-Myers
Oral
film-coated mg* (combination) Squibb
Metformin
Hydrochloride and CorePharma, Teva
Glipizide Tablets
250 mg with Glyburide 1.25 Glucovance® Bristol-Myers
mg* (combination) Squibb
Metformin
Actavis,
Hydrochloride and
CorePharma, Teva
Glyburide Tablets
500 mg with Glipizide 2.5 Metaglip® Bristol-Myers
Metformin CorePharma, Teva
Hydrochloride and
Glipizide Tablets
500 mg with Glipizide 5 Metaglip® Bristol-Myers
Metformin
Hydrochloride and CorePharma, Teva
Glipizide Tablets
500 mg with Glyburide 2.5 Glucovance® Bristol-Myers
Metformin
Actavis,
Hydrochloride and
CorePharma, Teva
Glyburide Tablets
500 mg with Glyburide 5 Glucovance® Bristol-Myers
Metformin
Actavis,
Hydrochloride and
CorePharma, Teva
Glyburide Tablets
500 mg with Pioglitazone Actoplus Met®
Hydrochloride 15 mg (of (combination) (with Takeda
pioglitazone) povidone)
500 mg with Rosiglitazone
Avandamet®
Maleate 2 mg (of GlaxoSmithKline
(combination)
rosiglitazone)
500 mg with Rosiglitazone
Avandamet®
(combination)
rosiglitazone)
850 mg with Pioglitazone Actoplus Met®
Hydrochloride 15 mg (of (combination) (with Takeda
pioglitazone) povidone)
1 g with Rosiglitazone
Avandamet®
(combination)
rosiglitazone)
1 g with Rosiglitazone
Avandamet®
(combination)
rosiglitazone)
* available from one or more manufacturer, distributor, and/or repackager by generic
(nonproprietary) name
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This
pricing information was updated 03/2011. For the most current and up-to-date pricing
information, please visit www.drugstore.com. Actual costs to patients will vary depending on
the use of specific retail or mail-order locations and health insurance copays.
Actoplus Met 15-500MG Tablets (TAKEDA PHARMACEUTICALS): 30/$129.66 or

90/$368.65
Actoplus Met 15-850MG Tablets (TAKEDA PHARMACEUTICALS): 30/$128.39 or

90/$368.65
Avandamet 2-1000MG Tablets (GLAXO SMITH KLINE): 60/$161.64 or 180/$455.07
Fortamet 1000MG 24-hr Tablets (SHIONOGI PHARMA): 60/$409.99 or 180/$1209.97
Fortamet 500MG 24-hr Tablets (SHIONOGI PHARMA): 60/$179.99 or 180/$519.97
Glucophage 1000MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 60/$141.08 or

180/$383.29

180/$179.96

180/$315.48
Glucophage XR 500MG 24-hr Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 60/$69.99
or 180/$180.97
Glucophage XR 750MG 24-hr Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$53.99
or 90/$139.96
Glucovance 2.5-500MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 60/$85.99 or

180/$249.98
Glucovance 5-500MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 60/$92 or

180/$246.06
Glumetza 500MG 24-hr Tablets (DEPOMED): 100/$239.99 or 300/$698.97
GlyBURIDE-MetFORMIN 2.5-500MG Tablets (IVAX PHARMACEUTICALS INC.):

60/$45.99 or 180/$125.96
GlyBURIDE-MetFORMIN 5-500MG Tablets (TEVA PHARMACEUTICALS USA):

100/$83.99 or 300/$246.97
Janumet 50-1000MG Tablets (MERCK SHARP & DOHME): 60/$215.64 or

180/$618.24
Janumet 50-500MG Tablets (MERCK SHARP & DOHME): 60/$216.89 or 180/$629.52
Metaglip 2.5-250MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$33.99 or

90/$97.97
Metaglip 5-500MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$42.99 or

90/$109.97
MetFORMIN HCl 1000MG Tablets (ZYDUS PHARMACEUTICALS (USA)): 30/$17.99 or
60/$31.97
MetFORMIN HCl 500MG 24-hr Tablets (TEVA PHARMACEUTICALS USA): 90/$18.99

or 180/$29.99
MetFORMIN HCl 500MG Tablets (ZYDUS PHARMACEUTICALS (USA)): 60/$12.99 or

120/$19.98
MetFORMIN HCl 750MG 24-hr Tablets (TEVA PHARMACEUTICALS USA): 30/$32.99

or 90/$89.99
MetFORMIN HCl 850MG Tablets (TEVA PHARMACEUTICALS USA): 90/$77.99 or

180/$130.99
Riomet 500MG/5ML Solution (RANBAXY LABORATORIES): 473/$179.99 or

1419/$519.97
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Metformin (Systemic)

Antidiabetic agent; a biguanide, chemically and pharmacologically unrelated to sulfonylurea

Class: 68:20.04 Biguanides; hs502 (VA primary)

Brands*: Actoplus Met® (combination), Avandamet® (combination), Fortamet®, Glucophage®,

Generic Name: Metformin Hydrochloride

Rosiglitazone is sold as a single-ingredient product under the brand name Avandia.

In patients already being treated with these medicines

BACKGROUND: Rosiglitazone is in a class of drugs known as thiazolidinediones, or

Used in combination with a sulfonylurea, repaglinide, or thiazolidinedione antidiabetic agent

Add a thiazolidinedione antidiabetic agent to metformin in fixed combination with glyburide

Dosage and Administration

Administer conventional tablets 2 or 3 times daily.1 Administer in 2 divided doses if total

Available as metformin hydrochloride; dosage expressed in terms of the salt.1

>Initial Dosage of Metformin Hydrochloride in Fixed Combination with Glipizide

>Initial Dosage of Metformin Hydrochloride in Fixed Combination with Rosiglitazone

Oral: Initially, 500 mg of metformin hydrochloride and 2 mg of rosiglitazone once or twice

>Initial Dosage in Patients Transferred to Metformin Hydrochloride in Fixed

>Initial Dosage in Patients Transferred to Metformin Hydrochloride in Fixed

>Initial Dosage in Patients Transferred to Metformin Hydrochloride in Fixed

>Table 1. Initial Dosage of the Fixed Combination of Metformin Hydrochloride and

Symptoms rapidly reversible following discontinuation of metformin or supplementation

Temporary withdrawal of metformin therapy and administration of insulin may be required to

Use of Fixed Combinations

Safety and efficacy of metformin in fixed combination with glipizide or rosiglitazone in

Monitor renal function periodically.1, 2, 3, 4, 164, 165

Geriatric patients particularly susceptible to hypoglycemia,1, 2 which may be difficult to

Discontinue metformin if evidence of renal impairment is present.1, 2, 156, 164

Common Adverse Effects

Cationic Agents Secreted by Proximal Renal Tubules

Pharmacokinetic interaction with cimetidine (decreased excretion of metformin).1, 75

Monitor carefully; consider dosage adjustment of either agent.1

Pharmacokinetic interaction unlikely.1

Drugs That May Antagonize Hypoglycemic Effects

Calcium-channel blocking agents, corticosteroids, thiazide diuretics, estrogens and progestins

Drug Interaction Comments

Increased risk of hypoglycemia and lactic

Fixed-combination preparation containing 500 mg of metformin hydrochloride and 4 mg of

Food increases the extent of absorption of extended-release tablets (Glucophage® XR,

Plasma Protein Binding

Fixed-combination preparations with glipizide or rosiglitazone: tight, light resistant

• Lowers blood glucose concentrations in patients with type 2 (non-insulin-dependent) diabetes

• Importance of informing clinicians of existing or contemplated therapy, including prescription

Metformin Hydrochloride Combinations

Actoplus Met 15-500MG Tablets (TAKEDA PHARMACEUTICALS): 30/$129.66 or

Actoplus Met 15-850MG Tablets (TAKEDA PHARMACEUTICALS): 30/$128.39 or

Avandamet 2-500MG Tablets (GLAXO SMITH KLINE): 60/$174.07 or 180/$472.47

Avandamet 4-1000MG Tablets (GLAXO SMITH KLINE): 60/$281.02 or 180/$808.28

Avandamet 4-500MG Tablets (GLAXO SMITH KLINE): 60/$281.02 or 180/$783.41

Fortamet 1000MG 24-hr Tablets (SHIONOGI PHARMA): 60/$409.99 or 180/$1209.97

Fortamet 500MG 24-hr Tablets (SHIONOGI PHARMA): 60/$179.99 or 180/$519.97

Glucophage 1000MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 60/$141.08 or

Glucophage 500MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 60/$69.99 or

Glucophage 850MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 60/$113.29 or

Glucovance 2.5-500MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 60/$85.99 or

Glucovance 5-500MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 60/$92 or

Glumetza 500MG 24-hr Tablets (DEPOMED): 100/$239.99 or 300/$698.97

GlyBURIDE-MetFORMIN 2.5-500MG Tablets (IVAX PHARMACEUTICALS INC.):

GlyBURIDE-MetFORMIN 5-500MG Tablets (TEVA PHARMACEUTICALS USA):

Janumet 50-1000MG Tablets (MERCK SHARP &amp; DOHME): 60/$215.64 or

Janumet 50-500MG Tablets (MERCK SHARP &amp; DOHME): 60/$216.89 or 180/$629.52

Metaglip 2.5-250MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$33.99 or

Metaglip 5-500MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$42.99 or

MetFORMIN HCl 500MG 24-hr Tablets (TEVA PHARMACEUTICALS USA): 90/$18.99

MetFORMIN HCl 500MG Tablets (ZYDUS PHARMACEUTICALS (USA)): 60/$12.99 or

Janumet 50-1000MG Tablets (MERCK SHARP & DOHME): 60/$215.64 or

Janumet 50-500MG Tablets (MERCK SHARP & DOHME): 60/$216.89 or 180/$629.52