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| ## Rx only                                                            |
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**GLUCOPHAGE (metformin hydrochloride tablets)**

**GLUCOPHAGE XR (metformin hydrochloride extended-release tablets)**

DESCRIPTION

GLUCOPHAGE^®^ (metformin hydrochloride tablets) and GLUCOPHAGEXR
(metformin hydrochloride extended-release tablets) are oral
antihyperglycemic drugs used in the management of type 2 diabetes.
Metformin hydrochloride (*N,N*-dimethylimidodicarbonimidic diamide
hydrochloride) is not chemically or pharmacologically related to any
other classes of oral antihyperglycemic agents. The structural formula
is as shown:

![](media/image1.wmf){width="1.86875in" height="1.0361111111111112in"}

Metformin hydrochloride is a white to off-white crystalline compound
with a molecular formula of C~4~H~11~N~5~ • HCl and a molecular weight
of 165.63. Metformin hydrochloride is freely soluble in water and is­
practically insoluble in acetone, ether, and chloroform. The pK~a~ of
metformin is 12.4. The pH of a 1% aqueous solution of metformin
hydrochloride is 6.68.

GLUCOPHAGE tablets contain 500 mg, 850 mg, or 1000 mg of metformin
hydrochloride. Each tablet contains the inactive ingredients povidone
and magnesium stearate. In addition, the coating for the 500-mg and
850-mg tablets contains hydroxypropyl methylcellulose (hypromellose) and
the coating for the 1000-mg tablet contains hydroxypropyl
methylcellulose and polyethylene glycol.

GLUCOPHAGE XR (metformin hydrochloride extended-release tablets)
contains 500 mg of metformin hydrochloride as the active ingredient.
Each tablet contains the inactive ingredients sodium carboxymethyl
cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose,
and magnesium stearate.

**System Components and Performance.** GLUCOPHAGE XR (metformin
hydrochloride extended-release tablets) comprises a dual hydrophilic
polymer matrix system. Metformin hydrochloride is combined with a drug
release controlling polymer to form an \"inner\" phase, which is then
incorporated as discrete particles into an \"external\" phase of a
second polymer. After administration, fluid from the gastrointestinal
(GI) tract enters the tablet, causing the polymers to hydrate and swell.
Drug is released slowly from the dosage form by a process of diffusion
through the gel matrix that is essentially independent of pH. The
hydrated polymer system is not rigid and is expected to be broken up by
normal peristalsis in the GI tract. The biologically inert components of
the tablet may occasionally remain intact during GI transit and will be
eliminated in the feces as a soft, hydrated mass.

CLINICAL PHARMACOLOGY

Mechanism of Action

Metformin is an antihyperglycemic agent which improves glucose tolerance
in patients with type 2 diabetes, lowering both basal and postprandial
plasma glucose. Its pharmacologic mechanisms of action are different
from other classes of oral antihyperglycemic agents. Metformin decreases
hepatic glucose production, decreases intestinal absorption of glucose,
and improves insulin sensitivity by increasing peripheral glucose uptake
and utilization. Unlike sulfonylureas, metformin does not produce
hypoglycemia in either patients with type 2 diabetes or normal subjects
(except in special circumstances, see **PRECAUTIONS**) and does not
cause hyperinsulinemia. With metformin therapy, insulin secretion
remains unchanged while fasting insulin levels and day-long plasma
insulin response may actually decrease.

Pharmacokinetics

Absorption and Bioavailability

The absolute bioavailability of a GLUCOPHAGE 500-mg tablet given under
fasting conditions is approximately 50-60%. Studies using single oral
doses of GLUCOPHAGE 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate
that there is a lack of dose proportionality with increasing doses,
which is due to decreased absorption rather than an alteration in
elimination. Food decreases the extent of and slightly delays the
absorption of metformin, as shown by approximately a 40% lower mean peak
plasma concentration (C~max~), a 25% lower area under the plasma
concentration versus time curve (AUC), and a 35 minute prolongation of
time to peak plasma concentration (T~max~) following administration of a
single 850-mg tablet of metformin with food, compared to the same tablet
strength administered fasting. The clinical relevance of these decreases
is unknown.

Following a single oral dose of GLUCOPHAGE XR, C~max~ is achieved with a
median value of 7 hours and a range of 4 hours to 8 hours. Peak plasma
levels are approximately 20% lower compared to the same dose of
GLUCOPHAGE, however, the extent of absorption (as measured by AUC) is
similar to GLUCOPHAGE.

At steady state, the AUC and C~max~ are less than dose proportional for
GLUCOPHAGE XR within the range of 500 mg to 2000 mg administered once
daily. Peak plasma levels are approximately 0.6, 1.1, 1.4, and 1.8 g/mL
for 500, 1000, 1500, and 2000 mg once-daily doses, respectively. The
extent of metformin absorption (as measured by AUC) from GLUCOPHAGE XR
at a 2000 mg once-daily dose is similar to the same total daily dose
administered as GLUCOPHAGE tablets 1000 mg twice daily. After repeated
administration of GLUCOPHAGE XR, metformin did not accumulate in plasma.

Within-subject variability in C~max~ and AUC of metformin from
GLUCOPHAGE XR is comparable to that with GLUCOPHAGE.

Although the extent of metformin absorption (as measured by AUC) from
the GLUCOPHAGE XR tablet increased by approximately 50% when given with
food, there was no effect of food on C~max~ and T~max~ of metformin.
Both high and low fat meals had the same effect on the pharmacokinetics
of GLUCOPHAGE XR.

Distribution

The apparent volume of distribution (V/F) of metformin following single
oral doses of GLUCOPHAGE 850 mg averaged 654 ± 358 L. Metformin is
negligibly bound to plasma proteins, in contrast to sulfonylureas, which
are more than 90% protein bound. Metformin partitions into erythrocytes,
most likely as a function of time. At usual clinical doses and dosing
schedules of GLUCOPHAGE, steady state plasma concentrations of metformin
are reached within 24-48 hours and are generally \<1 μg/mL. During
controlled clinical trials of GLUCOPHAGE, maximum metformin plasma
levels did not exceed 5 μg/mL, even at maximum doses.

Metabolism and Elimination

Intravenous single-dose studies in normal subjects demonstrate that
metformin is excreted unchanged in the urine and does not undergo
hepatic metabolism (no metabolites have been identified in humans) nor
biliary excretion. Renal clearance (see **Table 1**) is approximately
3.5 times greater than creatinine clearance, which indicates that
tubular secretion is the major route of metformin elimination. Following
oral administration, approximately 90% of the absorbed drug is
eliminated via the renal route within the first 24 hours, with a ­plasma
elimination half-life of approximately 6.2 hours. In blood, the
elimination half-life is approximately 17.6 hours, suggesting that the
erythrocyte mass may be a compartment of distribution.

Special Populations

Patients with Type 2 Diabetes

In the presence of normal renal function, there are no differences
between single- or multiple-dose pharmacokinetics of metformin between
patients with type 2 diabetes and normal subjects (see **Table 1**), nor
is there any accumulation of metformin in either group at usual clinical
doses.

The pharmacokinetics of GLUCOPHAGE XR in patients with type 2 diabetes
are comparable to those in healthy normal adults.

Renal Insufficiency

In patients with decreased renal function (based on measured creatinine
clearance), the plasma and blood half-life of metformin is prolonged and
the renal clearance is decreased in proportion to the decrease in
creatinine clearance (see **Table 1;** also see **WARNINGS**).

Hepatic Insufficiency

No pharmacokinetic studies of metformin have been conducted in patients
with hepatic insufficiency.

Geriatrics

Limited data from controlled pharmacokinetic studies of GLUCOPHAGE in
healthy elderly subjects suggest that total plasma clearance of
metformin is decreased, the half-life is prolonged, and C~max~ is
increased, compared to healthy young subjects. From these data, it
appears that the change in metformin pharmacokinetics with aging is
primarily accounted for by a change in renal function (see **Table 1**).
GLUCOPHAGE and GLUCOPHAGE XR treatment should not be initiated in
patients 80 years of age unless measurement of creatinine clearance
demonstrates that renal function is not reduced (see **WARNINGS** and
**DOSAGE AND ADMINISTRATION**).

+-------------------------------+-----------+----------+--------------+
| **Table 1. Select Mean        |           |          |              |
| (±S.D.) Metformin             |           |          |              |
| Pharmacokinetic Parameters    |           |          |              |
| Following**                   |           |          |              |
|                               |           |          |              |
| **Single or Multiple Oral     |           |          |              |
| Doses of GLUCOPHAGE**         |           |          |              |
+-------------------------------+-----------+----------+--------------+
| **Subject Groups:             | **C~      | **T~m    | **Renal      |
| GLUCOPHAGE**                  | max~^b^** | ax~^c^** | Clearance**  |
|                               |           |          |              |
| **dose^a^ (number of          | (μg/mL)   | (hrs)    | (mL/min)     |
| subjects)**                   |           |          |              |
+-------------------------------+-----------+----------+--------------+
| **Healthy, nondiabetic        | 1.03      | 2.75     | 600 (±132)   |
| adults:**                     | (±0.33)   | (±0.81)  |              |
|                               |           |          | 552 (±139)   |
| 500 mg single dose (24)       | 1.60      | 2.64     |              |
|                               | (±0.38)   | (±0.82)  | 642 (±173)   |
| 850 mg single dose (74) ^d^   |           |          |              |
|                               | 2.01      | 1.79     |              |
| 850 mg three times daily for  | (±0.42)   | (±0.94)  |              |
| 19 doses ^e^ (9)              |           |          |              |
+-------------------------------+-----------+----------+--------------+
| **Adults with type 2          | 1.48      | 3.32     | 491 (±138)   |
| diabetes:**                   | (±0.5)    | (±1.08)  |              |
|                               |           |          | 550 (±160)   |
| 850 mg single dose (23)       | 1.90      | 2.01     |              |
|                               | (±0.62)   | (±1.22)  |              |
| 850 mg three times daily for  |           |          |              |
| 19 doses ^e^ (9)              |           |          |              |
+-------------------------------+-----------+----------+--------------+
| **Elderly ^f^, healthy        | 2.45      | 2.71     | 412 (±98)    |
| nondiabetic adults**:         | (±0.70)   | (±1.05)  |              |
|                               |           |          |              |
| 850 mg single dose (12)       |           |          |              |
+-------------------------------+-----------+----------+--------------+
| **Renal-impaired adults:**    | 1.86      | 3.20     | 384 (±122)   |
|                               | (±0.52)   | (±0.45)  |              |
| **850 mg single dose**        |           |          | 108 (±57)    |
|                               | 4.12      | 3.75     |              |
| **Mild** (CL~cr~ ^g^ 61-90    | (±1.83)   | (±0.50)  | 130 (±90)    |
| mL/min) (5)                   |           |          |              |
|                               | 3.93      | 4.01     |              |
| **Moderate** (CL~cr~ 31-60    | (±0.92)   | (±1.10)  |              |
| mL/min) (4)                   |           |          |              |
|                               |           |          |              |
| **Severe** (CL~cr~ 10-30      |           |          |              |
| mL/min) (6)                   |           |          |              |
+-------------------------------+-----------+----------+--------------+

^a^--All doses given fasting except the first 18 doses of the multiple
dose studies

^b^--Peak plasma concentration

^c^--Time to peak plasma concentration

^d^--Combined results (average means) of five studies: mean age 32 years
(range 23-

59 years)

^e^--Kinetic study done following dose 19, given fasting

^f^--Elderly subjects, mean age 71 years (range 65-81 years)

^g^--CL~cr~ = creatinine clearance normalized to body surface area of
1.73 m^2^

Pediatrics

No pharmacokinetic data from studies of pediatric patients are currently
available.

Gender

Metformin pharmacokinetic parameters did not differ significantly
between normal subjects and patients with type 2 diabetes when analyzed
according to gender (males = 19, females = 16). Similarly, in controlled
clinical studies in patients with type 2 diabetes, the antihyperglycemic
effect of GLUCOPHAGE was comparable in males and females.

Race

No studies of metformin pharmacokinetic parameters according to race
have been performed. In controlled clinical studies of GLUCOPHAGE in
patients with type 2 diabetes, the antihyperglycemic effect was
comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).

**Clinical Studies**

GLUCOPHAGE

In a double-blind, placebo-controlled, multicenter U.S. clinical trial
involving obese patients with type 2 diabetes whose hyperglycemia was
not adequately controlled with dietary management alone (baseline
fasting plasma glucose \[FPG\] of approximately 240 mg/dL), treatment
with GLUCOPHAGE (up to 2550 mg/day) for 29 weeks resulted in significant
mean net reductions in fasting and postprandial plasma glucose (PPG) and
hemoglobin A~1c~ (HbA~1c~) of 59 mg/dL, 83 mg/dL, and 1.8%,
respectively, compared to the placebo group (see **Table 2**).

+-----------------------------+---------------+---------+------------+
| **Table 2. GLUCOPHAGE vs    |               |         |            |
| Placebo**                   |               |         |            |
|                             |               |         |            |
| **Summary of Mean Changes   |               |         |            |
| from Baseline\* in Fasting  |               |         |            |
| Plasma Glucose, HbA~1c~,    |               |         |            |
| and Body Weight, at Final   |               |         |            |
| Visit (29-week study)**     |               |         |            |
+-----------------------------+---------------+---------+------------+
|                             | *             | **Pl    | **         |
|                             | *GLUCOPHAGE** | acebo** | p--Value** |
|                             |               |         |            |
|                             | **(n = 141)** | **(n =  |            |
|                             |               | 145)**  |            |
+-----------------------------+---------------+---------+------------+
| **FPG (mg/dL)**             | 241.5         | 237.7   | NS \*\*    |
|                             |               |         |            |
|   Baseline                  | --53.0        | 6.3     | 0.001      |
|                             |               |         |            |
| Change at FINAL VISIT       |               |         |            |
+-----------------------------+---------------+---------+------------+
| **Hemoglobin A~1c~ (%)**    | 8.4           | 8.2     | NS \*\*    |
|                             |               |         |            |
| Baseline                    | --1.4         | 0.4     | 0.001      |
|                             |               |         |            |
| Change at FINAL VISIT       |               |         |            |
+-----------------------------+---------------+---------+------------+
| **Body Weight (lbs)**       | 201.0         | 206.0   | NS \*\*    |
|                             |               |         |            |
| Baseline                    | --1.4         | --2.4   | NS \*\*    |
|                             |               |         |            |
| Change at FINAL VISIT       |               |         |            |
+-----------------------------+---------------+---------+------------+

\*All patients on diet therapy at Baseline     \*\*Not statistically
significant

A 29-week, double-blind, placebo-controlled study of GLUCOPHAGE and
glyburide, alone and in combination, was conducted in obese patients
with type 2 diabetes who had failed to achieve adequate glycemic control
while on maximum doses of glyburide (baseline FPG of approximately 250
mg/dL) (see **Table 3**). Patients randomized to continue on glyburide
experienced worsening of glycemic control, with mean increases in FPG,
PPG, and HbA~1c~ of 14 mg/dL, 3 mg/dL, and 0.2%, respectively. In
contrast, those randomized to GLUCOPHAGE (up to 2500 mg/day) experienced
a slight improvement, with mean reductions in FPG, PPG, and HbA~1c~ of 1
mg/dL, 6 mg/dL, and 0.4%, respectively. The combination of GLUCOPHAGE
and ­glyburide was effective in reducing FPG, PPG, and HbA~1c~ levels by
63 mg/dL, 65 mg/dL, and 1.7%, respectively. Compared to results of
glyburide treatment alone, the net differences with combination
treatment were --77 mg/dL, --68 mg/dL, and --1.9%, respectively (see
**Table 3**).

+-------------------+-------+-------+-------+-------+--------+---------+
| **Table 3.        |       |       |       |       |        |         |
| Combined          |       |       |       |       |        |         |
| GLU               |       |       |       |       |        |         |
| COPHAGE/Glyburide |       |       |       |       |        |         |
| (Comb) vs         |       |       |       |       |        |         |
| Glyburide         |       |       |       |       |        |         |
| (Glyb)**          |       |       |       |       |        |         |
|                   |       |       |       |       |        |         |
| **or GLUCOPHAGE   |       |       |       |       |        |         |
| (GLU)             |       |       |       |       |        |         |
| Monotherapy:      |       |       |       |       |        |         |
| Summary of Mean   |       |       |       |       |        |         |
| Changes from      |       |       |       |       |        |         |
| Baseline\***      |       |       |       |       |        |         |
|                   |       |       |       |       |        |         |
| **in Fasting      |       |       |       |       |        |         |
| Plasma Glucose,   |       |       |       |       |        |         |
| HbA~1c,~ and Body |       |       |       |       |        |         |
| Weight, at Final  |       |       |       |       |        |         |
| Visit (29-week    |       |       |       |       |        |         |
| study)**          |       |       |       |       |        |         |
+-------------------+-------+-------+-------+-------+--------+---------+
| **pvalues**       |       |       |       |       |        |         |
|                   |       |       |       |       |        |         |
| **Comb Glyb GLU   |       |       |       |       |        |         |
| Glyb vs GLU vs    |       |       |       |       |        |         |
| GLU vs**          |       |       |       |       |        |         |
|                   |       |       |       |       |        |         |
| **(n = 213) (n =  |       |       |       |       |        |         |
| 209) (n = 210)    |       |       |       |       |        |         |
| Comb Comb Glyb**  |       |       |       |       |        |         |
+-------------------+-------+-------+-------+-------+--------+---------+
| **Fasting         | 250.5 | 247.5 | 253.9 | N     | NS\*\* | NS\*\*  |
| Plasma**          |       |       |       | S\*\* |        |         |
|                   | -     | 13.7  | --0.9 |       | 0.001  | 0.025   |
| **  Glucose       | -63.5 |       |       | 0.001 |        |         |
| (mg/dL)**         |       |       |       |       |        |         |
|                   |       |       |       |       |        |         |
| Baseline          |       |       |       |       |        |         |
|                   |       |       |       |       |        |         |
| Change at FINAL   |       |       |       |       |        |         |
| VISIT             |       |       |       |       |        |         |
+-------------------+-------+-------+-------+-------+--------+---------+
| **Hemoglobin      | 8.8   | 8.5   | 8.9   | N     | NS\*\* | 0.007   |
| A~1c~ (%)**       |       |       |       | S\*\* |        |         |
|                   | --1.7 | 0.2   | --0.4 |       | 0.001  | 0.001   |
|   Baseline        |       |       |       | 0.001 |        |         |
|                   |       |       |       |       |        |         |
| Change at FINAL   |       |       |       |       |        |         |
| VISIT             |       |       |       |       |        |         |
+-------------------+-------+-------+-------+-------+--------+---------+
| **Body Weight     | 202.2 | 203.0 | 204.0 | N     | NS\*\* | NS\*\*  |
| (lbs)**           |       |       |       | S\*\* |        |         |
|                   | 0.9   | -0.7  | -8.4  |       | 0.001  | 0.001   |
| Baseline          |       |       |       | 0.011 |        |         |
|                   |       |       |       |       |        |         |
| Change at FINAL   |       |       |       |       |        |         |
| VISIT             |       |       |       |       |        |         |
+-------------------+-------+-------+-------+-------+--------+---------+

\*All patients on glyburide, 20 mg/day, at Baseline \*\*Not
statistically significant

The magnitude of the decline in fasting blood glucose concentration
following the institution of ­GLUCOPHAGE therapy was proportional to the
level of fasting hyperglycemia. Patients with type 2 diabetes with
higher fasting glucose concentrations experienced greater declines in
plasma glucose and glyco­sylated hemoglobin.

In clinical studies, GLUCOPHAGE, alone or in combination with a
sulfonylurea, lowered mean fasting serum triglycerides, total
cholesterol, and LDL cholesterol levels and had no adverse effects on
other lipid levels (see **Table 4**).

+---------+------------+--------+------------+---------------+--------+
| **Table |            |        |            |               |        |
| 4.      |            |        |            |               |        |
| Summary |            |        |            |               |        |
| of Mean |            |        |            |               |        |
| Percent |            |        |            |               |        |
| Change  |            |        |            |               |        |
| From    |            |        |            |               |        |
| B       |            |        |            |               |        |
| aseline |            |        |            |               |        |
| of      |            |        |            |               |        |
| Major   |            |        |            |               |        |
| Serum   |            |        |            |               |        |
| Lipid** |            |        |            |               |        |
|         |            |        |            |               |        |
| **Va    |            |        |            |               |        |
| riables |            |        |            |               |        |
| at      |            |        |            |               |        |
| Final   |            |        |            |               |        |
| Visit   |            |        |            |               |        |
| (       |            |        |            |               |        |
| 29-week |            |        |            |               |        |
| stu     |            |        |            |               |        |
| dies)** |            |        |            |               |        |
+---------+------------+--------+------------+---------------+--------+
|         | **         |        | **Combined |               |        |
|         | GLUCOPHAGE |        | GL         |               |        |
|         | vs         |        | UCOPHAGE/G |               |        |
|         | Placebo**  |        | lyburide** |               |        |
|         |            |        |            |               |        |
|         |            |        | **vs       |               |        |
|         |            |        | Mon        |               |        |
|         |            |        | otherapy** |               |        |
+---------+------------+--------+------------+---------------+--------+
|         | **GL       | **Pla  | **GL       | **            | *      |
|         | UCOPHAGE** | cebo** | UCOPHAGE** | GLUCOPHAGE/** | *Glybu |
|         |            |        |            |               | ride** |
|         | **(n =     | **(n = | **(n =     | **Glyburide** |        |
|         | 141)**     | 145)** | 210)**     |               | **(n = |
|         |            |        |            | **(n = 213)** | 209)** |
+---------+------------+--------+------------+---------------+--------+
| **Total | 211.0      | 212.3  | 213.1      | 215.6         | 219.6  |
| Chol    |            |        |            |               |        |
| esterol | -5%        | 1%     | -2%        | -4%           | 1%     |
| (m      |            |        |            |               |        |
| g/dL)** |            |        |            |               |        |
|         |            |        |            |               |        |
| B       |            |        |            |               |        |
| aseline |            |        |            |               |        |
|         |            |        |            |               |        |
| Mean %  |            |        |            |               |        |
| Change  |            |        |            |               |        |
| at      |            |        |            |               |        |
| FINAL   |            |        |            |               |        |
| VISIT   |            |        |            |               |        |
+---------+------------+--------+------------+---------------+--------+
| **Total | 236.1      | 203.5  | 242.5      | 215.0         | 266.1  |
| Trigly  |            |        |            |               |        |
| cerides | -16%       | 1%     | -3%        | -8%           | 4%     |
| (m      |            |        |            |               |        |
| g/dL)** |            |        |            |               |        |
|         |            |        |            |               |        |
| B       |            |        |            |               |        |
| aseline |            |        |            |               |        |
|         |            |        |            |               |        |
| > Mean  |            |        |            |               |        |
| > %     |            |        |            |               |        |
| >       |            |        |            |               |        |
|  Change |            |        |            |               |        |
| > at    |            |        |            |               |        |
| > FINAL |            |        |            |               |        |
| > VISIT |            |        |            |               |        |
+---------+------------+--------+------------+---------------+--------+
| **L     | 135.4      | 138.5  | 134.3      | 136.0         | 137.5  |
| DL-Chol |            |        |            |               |        |
| esterol | -8%        | 1%     | -4%        | -6%           | 3%     |
| (m      |            |        |            |               |        |
| g/dL)** |            |        |            |               |        |
|         |            |        |            |               |        |
| B       |            |        |            |               |        |
| aseline |            |        |            |               |        |
|         |            |        |            |               |        |
| Mean %  |            |        |            |               |        |
| Change  |            |        |            |               |        |
| at      |            |        |            |               |        |
| FINAL   |            |        |            |               |        |
| VISIT   |            |        |            |               |        |
+---------+------------+--------+------------+---------------+--------+
| **H     | 39.0       | 40.5   | 37.2       | 39.0          | 37.0   |
| DL-Chol |            |        |            |               |        |
| esterol | 2%         | -1%    | 5%         | 3%            | 1%     |
| (m      |            |        |            |               |        |
| g/dL)** |            |        |            |               |        |
|         |            |        |            |               |        |
| B       |            |        |            |               |        |
| aseline |            |        |            |               |        |
|         |            |        |            |               |        |
| Mean %  |            |        |            |               |        |
| Change  |            |        |            |               |        |
| at      |            |        |            |               |        |
| FINAL   |            |        |            |               |        |
| VISIT   |            |        |            |               |        |
+---------+------------+--------+------------+---------------+--------+

In contrast to sulfonylureas, body weight of individuals on GLUCOPHAGE
tended to remain stable or even decrease somewhat (see **Tables 2** and
**3**).

A 24-week, double-blind, placebo-controlled study of GLUCOPHAGE plus
insulin versus insulin plus placebo was conducted in patients with type
2 diabetes who failed to achieve adequate glycemic control on insulin
alone (see **Table 5**). Patients randomized to receive GLUCOPHAGE plus
insulin achieved a reduction in HbA~1c~ of 2.10%, compared to a 1.56%
reduction in HbA~1c~ achieved by insulin plus placebo. The improvement
in glycemic control was achieved at the final study visit with 16% less
insulin, 93.0 U/day vs 110.6 U/day, GLUCOPHAGE plus insulin versus
insulin plus placebo, respectively, p=0.04.

+-------------------------+---------------+------------+---------------+
| **Table 5. Combined     |               |            |               |
| GLUCOPHAGE/Insulin vs   |               |            |               |
| Placebo/Insulin**       |               |            |               |
|                         |               |            |               |
| **Summary of Mean       |               |            |               |
| Changes from Baseline   |               |            |               |
| in HbA~1c~ and Daily    |               |            |               |
| Insulin Dose**          |               |            |               |
+-------------------------+---------------+------------+---------------+
|                         | **            | **         | **Treatment** |
|                         | GLUCOPHAGE/** | Placebo/** |               |
|                         |               |            | *             |
|                         | **Insulin**   | *          | *Difference** |
|                         |               | *Insulin** |               |
|                         | **n = 26**    |            | **Mean        |
|                         |               | **n = 28** | [+            |
|                         |               |            | ]{.underline} |
|                         |               |            | SE**          |
+-------------------------+---------------+------------+---------------+
| **Hemoglobin A~1c~      | 8.95          | 9.32       | \- 0.54       |
| (%)**                   |               |            | [+            |
|                         | \- 2.10       | \- 1.56    | ]{.underline} |
| Baseline                |               |            | 0.43^a^       |
|                         |               |            |               |
| Change at FINAL VISIT   |               |            |               |
+-------------------------+---------------+------------+---------------+
| **Insulin Dose          | 93.12         | 94.64      | \- 16.08      |
| (U/day)**               |               | 15.93      | [+            |
|                         | \- 0.15       |            | ]{.underline} |
| Baseline                |               |            | 7.77^b^       |
|                         |               |            |               |
| Change at FINAL VISIT   |               |            |               |
+-------------------------+---------------+------------+---------------+

^a^ Statistically significant using analysis of covariance with baseline
as covariate (p=0.04) Not significant using analysis of variance (values
shown in table)

^b^ Statistically significant for insulin (p=0.04)

A second double-blind, placebo-controlled study (n=51), with 16 weeks of
randomized treatment, demonstrated that in patients with type 2 diabetes
controlled on insulin for 8 weeks with an average HbA~1c~ of 7.46
[+]{.underline} 0.97%, the addition of GLUCOPHAGE maintained similar
glycemic control (HbA~1c~ 7.15 [+]{.underline} 0.61 versus 6.97
[+]{.underline} 0.62 for GLUCOPHAGE plus insulin and placebo plus
insulin, respectively) with 19% less insulin versus baseline (reduction
of 23.68 [+]{.underline} 30.22 versus an increase of 0.43
[+]{.underline} 25.20 units for GLUCOPHAGE plus insulin and placebo plus
insulin, p0.01). In addition, this study demonstrated that the
combination of GLUCOPHAGE plus insulin resulted in reduction in body
weight of 3.11 [+]{.underline} 4.30 lbs, compared to an increase of 1.30
[+]{.underline} 6.08 lbs for placebo plus insulin, p=0.01.

GLUCOPHAGE XR

A 24-week, double-blind, placebo-controlled study of GLUCOPHAGE XR,
taken once daily with the evening meal, was conducted in patients with
type 2 diabetes who had failed to achieve glycemic control with diet and
exercise (HbA~1c~ 7.0-10.0%, FPG 126-270 mg/dL). Patients entering the
study had a mean baseline HbA~1c~ of 8.0% and a mean baseline FPG of 176
mg/dL. After 12 weeks treatment, mean HbA~1c~ had increased from
baseline by 0.1% and mean FPG decreased from baseline by 2 mg/dL in the
placebo group, compared with a decrease in mean HbA~1c~ of 0.6% and a
decrease in mean FPG of 23 mg/dL in patients treated with GLUCOPHAGE XR
1000 mg once daily. Subsequently, the treatment dose was increased to
1500 mg once daily if HbA~1c~ was 7.0% but \<8.0% (patients with HbA~1c~
8.0% were discontinued from the study). At the final visit (24-week),
mean HbA~1c~ had increased 0.2% from baseline in placebo patients and
decreased 0.6% with GLUCOPHAGE XR.

A 16-week, double-blind, placebo-controlled, dose-response study of
GLUCOPHAGE XR, taken once daily with the evening meal or twice daily
with meals, was conducted in patients with type 2 diabetes who had
failed to achieve glycemic control with diet and exercise (HbA~1c~
7.0-11.0%, FPG 126-280 mg/dL). Changes in glycemic control and body
weight are shown in **Table 6**.

<table style="width:100%;">
<colgroup>
<col style="width: 29%" />
<col style="width: 0%" />
<col style="width: 11%" />
<col style="width: 0%" />
<col style="width: 11%" />
<col style="width: 0%" />
<col style="width: 12%" />
<col style="width: 0%" />
<col style="width: 11%" />
<col style="width: 0%" />
<col style="width: 10%" />
<col style="width: 0%" />
<col style="width: 11%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="13"><p><strong>Table 6. Summary of Mean Changes from
Baseline</strong>* <strong>in HbA<sub>1c</sub>,</strong></p>
<p><strong>Fasting Plasma Glucose, and Body Weight at Final Visit
(16-week study)</strong></p></td>
</tr>
<tr class="even">
<td colspan="2" rowspan="2"></td>
<td colspan="9"><h1 id="glucophage-xr">GLUCOPHAGE XR</h1></td>
<td colspan="2" rowspan="2"><h1 id="section"></h1>
<h1 id="placebo">Placebo</h1></td>
</tr>
<tr class="odd">
<td colspan="2"><p><strong>500mg</strong></p>
<p><strong>Once Daily</strong></p></td>
<td colspan="2"><p><strong>1000mg</strong></p>
<p><strong>Once Daily</strong></p></td>
<td colspan="2"><p><strong>1500mg</strong></p>
<p><strong>Once Daily</strong></p></td>
<td colspan="3"><p><strong>2000mg 1000mg</strong></p>
<p><strong>Once Twice</strong></p>
<p><strong>Daily Daily</strong></p></td>
</tr>
<tr class="even">
<td><strong>Hemoglobin A<sub>1C</sub> (%)</strong></td>
<td colspan="2"><strong>(n = 115)</strong></td>
<td colspan="2"><strong>(n = 115)</strong></td>
<td colspan="2"><strong>(n = 111)</strong></td>
<td colspan="2" rowspan="5"><p><strong>(n = 125)</strong></p>
<p>8.4</p>
<p>-0.8</p>
<p>&lt;0.001</p></td>
<td colspan="2"><strong>(n=112)</strong></td>
<td colspan="2"><strong>(n = 111)</strong></td>
</tr>
<tr class="odd">
<td>Baseline</td>
<td colspan="2">8.2</td>
<td colspan="2">8.4</td>
<td colspan="2">8.3</td>
<td colspan="2">8.4</td>
<td colspan="2">8.4</td>
</tr>
<tr class="even">
<td>Change at FINAL VISIT</td>
<td colspan="2">-0.4</td>
<td colspan="2">-0.6</td>
<td colspan="2">-0.9</td>
<td colspan="2">-1.1</td>
<td colspan="2">0.1</td>
</tr>
<tr class="odd">
<td>p – value<sup>a</sup></td>
<td colspan="2">&lt;0.001</td>
<td colspan="2">&lt;0.001</td>
<td colspan="2">&lt;0.001</td>
<td colspan="2">&lt;0.001</td>
<td colspan="2">-</td>
</tr>
<tr class="even">
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td><h3 id="fpg-mgdl"><strong>FPG (mg/dL)</strong></h3></td>
<td colspan="2"><strong>(n = 126)</strong></td>
<td colspan="2"><strong>(n = 118)</strong></td>
<td colspan="2"><strong>(n = 120)</strong></td>
<td colspan="2" rowspan="5"><p><strong>(n = 132)</strong></p>
<p>181.0</p>
<p>-29.9</p>
<p>&lt;0.001</p></td>
<td colspan="2"><strong>(n=122)</strong></td>
<td colspan="2"><strong>(n = 113)</strong></td>
</tr>
<tr class="even">
<td>Baseline</td>
<td colspan="2">182.7</td>
<td colspan="2">183.7</td>
<td colspan="2">178.9</td>
<td colspan="2">181.6</td>
<td colspan="2">179.6</td>
</tr>
<tr class="odd">
<td>Change at FINAL VISIT</td>
<td colspan="2">-15.2</td>
<td colspan="2">-19.3</td>
<td colspan="2">-28.5</td>
<td colspan="2">-33.6</td>
<td colspan="2">7.6</td>
</tr>
<tr class="even">
<td>p – value<sup>a</sup></td>
<td colspan="2">&lt;0.001</td>
<td colspan="2">&lt;0.001</td>
<td colspan="2">&lt;0.001</td>
<td colspan="2">&lt;0.001</td>
<td colspan="2">-</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td><strong>Body Weight (lbs)</strong></td>
<td colspan="2"><strong>(n = 125)</strong></td>
<td colspan="2"><strong>(n = 119)</strong></td>
<td colspan="2"><strong>(n = 117)</strong></td>
<td colspan="2" rowspan="4"><p><strong>(n = 131)</strong></p>
<p>195.4</p>
<p>-1.5</p>
<p>NS**</p></td>
<td colspan="2"><strong>(n=119)</strong></td>
<td colspan="2"><strong>(n = 113)</strong></td>
</tr>
<tr class="odd">
<td>Baseline</td>
<td colspan="2">192.9</td>
<td colspan="2">191.8</td>
<td colspan="2">188.3</td>
<td colspan="2">192.5</td>
<td colspan="2">194.3</td>
</tr>
<tr class="even">
<td>Change at FINAL VISIT</td>
<td colspan="2">-1.3</td>
<td colspan="2">-1.3</td>
<td colspan="2">-0.7</td>
<td colspan="2">-2.2</td>
<td colspan="2">-1.8</td>
</tr>
<tr class="odd">
<td>p – value<sup>a</sup></td>
<td colspan="2">NS<sup>**</sup></td>
<td colspan="2">NS<sup>**</sup></td>
<td colspan="2">NS<sup>**</sup></td>
<td colspan="2" rowspan="2">NS**</td>
<td colspan="2">-</td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
<td></td>
<td></td>
</tr>
</tbody>
</table>

\*All patients on diet therapy at Baseline

^a^ All comparisons versus Placebo

^\*\*^ Not statistically significant

Compared with placebo, improvement in glycemic control was seen at all
dose levels of GLUCOPHAGE XR and treatment was not associated with any
significant change in weight (see **DOSAGE AND ADMINISTRATION** for
dosing recommendations for GLUCOPHAGE and GLUCOPHAGE XR).

A 24 week, double-blind, randomized study of GLUCOPHAGE XR, taken once
daily with the evening meal, and GLUCOPHAGE, taken twice daily (with
breakfast and evening meal), was conducted in patients with type 2
diabetes who had been treated with GLUCOPHAGE 500 mg twice daily for at
least 8 weeks prior to study entry. The GLUCOPHAGE dose had not
necessarily been titrated to achieve a specific level of glycemic
control prior to study entry. Patients qualified for the study if
HbA~1c~ was 8.5% and FPG was 200 mg/dL. Changes in glycemic control and
body weight are shown in **Table 7**.

+---------------------------+--------------+-------------+-------------+
| **Table 7. Summary of     |              |             |             |
| Mean Changes from         |              |             |             |
| Baseline**\* **in         |              |             |             |
| HbA~1c,~ Fasting Plasma   |              |             |             |
| Glucose, and Body Weight  |              |             |             |
| at Week 12 and at Final   |              |             |             |
| Visit (24-week study)**   |              |             |             |
+---------------------------+--------------+-------------+-------------+
|                           | # GLUCOPHAGE | #           |             |
|                           |              |  GLUCOPHAGE |             |
|                           | **500mg**    |  XR {#gluco |             |
|                           |              | phage-xr-1} |             |
|                           | **Twice      |             |             |
|                           | Daily**      |             |             |
+---------------------------+--------------+-------------+-------------+
|                           |              | **1000mg**  | **1500mg**  |
|                           |              |             |             |
|                           |              | **Once      | **Once      |
|                           |              | Daily**     | Daily**     |
+---------------------------+--------------+-------------+-------------+
| **Hemoglobin A~1c~ (%)**  | **(n = 67)** | **(n =      | **(n =      |
|                           |              | 72)**       | 66)**       |
| Baseline                  | 7.06         |             |             |
|                           |              | 6.99        | 7.02        |
| Change at 12 Weeks        | 0.14         |             |             |
|                           |              | 0.23        | 0.04        |
| (95% CI)                  | (-0.03,      |             |             |
|                           | 0.31)        | (0.10,      | (-0.08,     |
| Change at FINAL VISIT     |              | 0.36)       | 0.15)       |
|                           | 0.14^a^      |             |             |
| (95% CI)                  |              | 0.27        | 0.13        |
|                           | (-0.04,      |             |             |
|                           | 0.31)        | (0.11,      | (-0.02,     |
|                           |              | 0.43)       | 0.28)       |
+---------------------------+--------------+-------------+-------------+
| **FPG (mg/dL)**           | **(n = 69)** | **(n =      | **(n =      |
|                           |              | 72)**       | 70)**       |
| Baseline                  | 127.2        |             |             |
|                           |              | 131.0       | 131.4       |
| Change at 12 Weeks        | 12.9         |             |             |
|                           |              | 9.5         | 3.7         |
| (95% CI)                  | (6.5,19.4)   |             |             |
|                           |              | (4.4, 14.6) | (-0.4, 7.8) |
| Change at FINAL VISIT     | 14.0         |             |             |
|                           |              | 11.5        | 7.6         |
| (95% CI)                  | (7.0, 21.0)  |             |             |
|                           |              | (4.4, 18.6) | (1.0, 14.2) |
+---------------------------+--------------+-------------+-------------+
| **Body Weight (lbs)**     | **(n = 71)** | **(n =      | **(n =      |
|                           |              | 74)**       | 71)**       |
| Baseline                  | 210.3        |             |             |
|                           |              | 202.8       | 192.7       |
| Change at 12 Weeks        | 0.4          |             |             |
|                           |              | 0.9         | 0.7         |
| (95% CI)                  | (-0.4, 1.5)  |             |             |
|                           |              | (0.0, 2.0)  | (-0.4, 1.8) |
| Change at FINAL VISIT     | 0.9          |             |             |
|                           |              | 1.1         | 0.9         |
| (95% CI)                  | (-0.4, 2.2)  |             |             |
|                           |              | (-0.2, 2.4) | (-0.4, 2.0) |
+---------------------------+--------------+-------------+-------------+

> \* All patients on GLUCOPHAGE 500mg twice daily at Baseline

^a^ n = 68

After 12 weeks of treatment, there was an increase in mean HbA~1c~ in
all groups; in the GLUCOPHAGE XR 1000 mg group, the increase from
baseline of 0.23% was statistically significant (see **DOSAGE AND
ADMINISTRATION**)**.**

Changes in lipid parameters in the previously described
placebo-controlled dose-response study of GLUCOPHAGE XR are shown in
**Table 8**.

+-----------------------+------+-------+------+------+------+------+
| # Table 8             |      |       |      |      |      |      |
| . Summary of Mean Per |      |       |      |      |      |      |
| cent Changes from Bas |      |       |      |      |      |      |
| eline\* in Major Lipi |      |       |      |      |      |      |
| d Variables at Final  |      |       |      |      |      |      |
| Visit (16-week study) |      |       |      |      |      |      |
+-----------------------+------+-------+------+------+------+------+
|                       | #    |       |      |      |      |      |
|                       | GLUC |       |      |      |      |      |
|                       | OPHA |       |      |      |      |      |
|                       | GE X |       |      |      |      |      |
|                       | R {# |       |      |      |      |      |
|                       | gluc |       |      |      |      |      |
|                       | opha |       |      |      |      |      |
|                       | ge-x |       |      |      |      |      |
|                       | r-2} |       |      |      |      |      |
+-----------------------+------+-------+------+------+------+------+
|                       | *    | # 10  | **   | **   | **   | #### |
|                       | *500 | 00mg  | 1500 | 2000 | 1000 | ###  |
|                       | mg** |       | mg** | mg** | mg** | Plac |
|                       |      | #     |      |      |      | ebo  |
|                       | **On | ####  | **   | **   | **T  | {#pl |
|                       | ce** | Once  | Once | Once | wice | aceb |
|                       |      | Daily | Dai  | Dai  | Dai  | o-1} |
|                       | *    |       | ly** | ly** | ly** |      |
|                       | *Dai |       |      |      |      |      |
|                       | ly** |       |      |      |      |      |
+-----------------------+------+-------+------+------+------+------+
| **Total Cholesterol   | **(n | **(n  | **(n | **(n | **(n | **(n |
| (mg/dL)**             | =    | =     | =    | =    | =    | =    |
|                       | 12   | 1     | 11   | 12   | 11   | 11   |
| Baseline              | 0)** | 13)** | 0)** | 6)** | 7)** | 0)** |
|                       |      |       |      |      |      |      |
| Mean % Change at      | 2    | 218.1 | 2    | 2    | 2    | 2    |
| FINAL VISIT           | 10.3 |       | 14.6 | 04.4 | 08.2 | 08.6 |
|                       |      | 1.7%  |      |      |      |      |
|                       | 1.0% |       | 0.7% | \-   | \-   | 2.6% |
|                       |      |       |      | 1.6% | 2.6% |      |
+-----------------------+------+-------+------+------+------+------+
| **Total Triglycerides | **(n | **(n  | **(n | **(n | **(n | **(n |
| (mg/dL)**             | =    | =     | =    | =    | =    | =    |
|                       | 12   | 1     | 11   | 12   | 11   | 11   |
| Baseline              | 0)** | 13)** | 0)** | 6)** | 7)** | 0)** |
|                       |      |       |      |      |      |      |
| Mean % Change at      | 2    | 211.9 | 1    | 1    | 1    | 2    |
| FINAL VISIT           | 20.2 |       | 98.0 | 94.2 | 79.0 | 11.7 |
|                       |      | 9.4%  |      |      |      |      |
|                       | 1    |       | 1    | 1    | 9.4% | 1    |
|                       | 4.5% |       | 5.1% | 4.9% |      | 0.9% |
+-----------------------+------+-------+------+------+------+------+
| **LDL -- Cholesterol  | **(n | **(n  | **(n | **(n | **(n | **(n |
| (mg/dL)**             | =    | =     | =    | =    | =    | =    |
|                       | 11   | 1     | 10   | 12   | 11   | 10   |
| Baseline              | 9)** | 13)** | 9)** | 6)** | 7)** | 7)** |
|                       |      |       |      |      |      |      |
| Mean % Change at      | 1    | 134.9 | 1    | 1    | 1    | 1    |
| FINAL VISIT           | 31.0 |       | 35.8 | 25.8 | 31.4 | 31.9 |
|                       |      | \-    |      |      |      |      |
|                       | \-   | 1.6%  | \-   | \-   | \-   | 3.2% |
|                       | 1.4% |       | 3.5% | 3.3% | 5.5% |      |
+-----------------------+------+-------+------+------+------+------+
| **HDL -- Cholesterol  | **(n | **(n  | **(n | **(n | **(n | **(n |
| (mg/dL)**             | =    | =     | =    | =    | =    | =    |
|                       | 12   | 1     | 10   | 12   | 11   | 10   |
| Baseline              | 0)** | 08)** | 8)** | 5)** | 7)** | 8)** |
|                       |      |       |      |      |      |      |
| Mean % Change at      | 40.8 | 41.6  | 40.6 | 40.2 | 42.4 | 39.4 |
| FINAL VISIT           |      |       |      |      |      |      |
|                       | 6.2% | 8.6%  | 5.5% | 6.1% | 7.1% | 5.8% |
+-----------------------+------+-------+------+------+------+------+

\*All patients on diet therapy at Baseline

Changes in lipid parameters in the previously described study of
GLUCOPHAGE and GLUCOPHAGE XR are shown in **Table 9**.

+-------------------------------+------------+-----------+-----------+
| **Table 9. Summary of Mean    |            |           |           |
| Percent Changes from          |            |           |           |
| Baseline\* in Major**         |            |           |           |
|                               |            |           |           |
| **Lipid Variables at Final    |            |           |           |
| Visit (24-week study)**       |            |           |           |
+-------------------------------+------------+-----------+-----------+
|                               | #          | # Gluco   |           |
|                               | Glucophage | phage XR  |           |
|                               |            | {#glucoph |           |
|                               | **500mg**  | age-xr-3} |           |
|                               |            |           |           |
|                               | **Twice    |           |           |
|                               | Daily**    |           |           |
+-------------------------------+------------+-----------+-----------+
|                               |            | *         | *         |
|                               |            | *1000mg** | *1500mg** |
|                               |            |           |           |
|                               |            | **Once    | **Once    |
|                               |            | Daily**   | Daily**   |
+-------------------------------+------------+-----------+-----------+
| **Total Cholesterol (mg/dL)** | **(n =     | **(n =    | **(n =    |
|                               | 68)**      | 70)**     | 66)**     |
| Baseline                      |            |           |           |
|                               | 199.0      | 201.9     | 201.6     |
| Mean % Change at FINAL VISIT  |            |           |           |
|                               | 0.1%       | 1.3%      | 0.1%      |
+-------------------------------+------------+-----------+-----------+
| **Total Triglycerides         | **(n =     | **(n =    | **(n =    |
| (mg/dL)**                     | 68)**      | 70)**     | 66)**     |
|                               |            |           |           |
| Baseline                      | 178.0      | 169.2     | 206.8     |
|                               |            |           |           |
| Mean % Change at FINAL VISIT  | 6.3%       | 25.3%     | 33.4%     |
+-------------------------------+------------+-----------+-----------+
| **LDL -- Cholesterol          | **(n =     | **(n =    | **(n =    |
| (mg/dL)**                     | 68)**      | 70)**     | 66)**     |
|                               |            |           |           |
| Baseline                      | 122.1      | 126.2     | 115.7     |
|                               |            |           |           |
| Mean % Change at FINAL VISIT  | \- 1.3%    | \- 3.3%   | \- 3.7%   |
+-------------------------------+------------+-----------+-----------+
| **HDL -- Cholesterol          | **(n =     | **(n =    | **(n =    |
| (mg/dL)**                     | 68)**      | 70)**     | 65)**     |
|                               |            |           |           |
| Baseline                      | 41.9       | 41.7      | 44.6      |
|                               |            |           |           |
| Mean % Change at FINAL VISIT  | 4.8%       | 1.0%      | \- 2.1%   |
+-------------------------------+------------+-----------+-----------+

\*All patients on GLUCOPHAGE 500mg twice daily at Baseline

Pediatric Clinical Studies

In a double-blind, placebo-controlled study in pediatric patients aged
10 to 16 years with type 2 diabetes (mean FPG 182.2 mg/dL), treatment
with GLUCOPHAGE (up to 2000 mg/day) for up to 16 weeks (mean duration of
treatment 11 weeks) resulted in a significant mean net reduction in FPG
of 64.3 mg/dL, compared with placebo (see Table 10).

+-------------------------+---------------+------------+---------------+
| **Table 10. GLUCOPHAGE  |               |            |               |
| vs Placebo              |               |            |               |
| (Pediatrics^a^)**       |               |            |               |
|                         |               |            |               |
| **Summary of Mean       |               |            |               |
| Changes from            |               |            |               |
| Baseline**\* **in**     |               |            |               |
|                         |               |            |               |
| **Plasma Glucose and    |               |            |               |
| Body Weight at Final    |               |            |               |
| Visit**                 |               |            |               |
+-------------------------+---------------+------------+---------------+
|                         | *             | *          | **p-Value**   |
|                         | *GLUCOPHAGE** | *Placebo** |               |
+-------------------------+---------------+------------+---------------+
| **FPG (mg/dL)**         | **(n = 37)**  | **(n =     | \< 0.001      |
|                         |               | 36)**      |               |
| Baseline                | 162.4         |            |               |
|                         |               | 192.3      |               |
| Change at FINAL VISIT   | \- 42.9       |            |               |
|                         |               | 21.4       |               |
+-------------------------+---------------+------------+---------------+
| **Body Weight (lbs)**   | **(n = 39)**  | **(n =     | NS\*\*        |
|                         |               | 38)**      |               |
| Baseline                | 205.3         |            |               |
|                         |               | 189.0 -    |               |
| Change at FINAL VISIT   | \- 3.3        | 2.0        |               |
+-------------------------+---------------+------------+---------------+

^a^ Pediatric patients mean age 13.8 years (range 10-16 years)

\* All patients on diet therapy at Baseline

\*\* Not statistically significant

INDICATIONS AND USE

GLUCOPHAGE (metformin hydrochloride tablets) and GLUCOPHAGE XR
(metformin hydrochloride extended-release tablets), as monotherapy, are
indicated as an adjunct to diet and exercise to improve glycemic control
in patients with type 2 diabetes. GLUCOPHAGE is indicated in patients 10
years of age and older, and GLUCOPHAGE XR is indicated in patients 17
years of age and older.

GLUCOPHAGE or GLUCOPHAGE XR may be used concomitantly with a
sulfonylurea or insulin to improve glycemic control in adults (17 years
of age and older).

**CONTRAINDICATIONS**

GLUCOPHAGE and GLUCOPHAGE XR are contraindicated in patients with:

1.  Renal disease or renal dysfunction (e.g., as suggested by serum
    creatinine

levels ≥1.5 mg/dL \[males\], ≥1.4 mg/dL \[females\] or abnormal
creatinine

clearance) which may also result from conditions such as cardiovascular

collapse (shock), acute myocardial infarction, and septicemia

(see **WARNINGS** and **­ PRECAUTIONS**).

2.  Congestive heart failure requiring pharmacologic treatment.

3.  Known hypersensitivity to metformin hydrochloride.

> 4\. Acute or chronic metabolic acidosis, including diabetic
> ketoacidosis, with

4.  or without coma. Diabetic keto­acidosis should be treated with
    insulin.

GLUCOPHAGE and GLUCOPHAGE XR should be temporarily discontinued in
patients undergoing radiologic studies involving intravascular
administration of iodinated contrast materials, because use of such
products may result in acute alteration of renal function. (See also
**PRECAUTIONS**.)

**WARNINGS**

+-----------------------------------------------------------------------+
| **Lactic Acidosis:**                                                  |
|                                                                       |
| **Lactic acidosis is a rare, but serious, metabolic complication that |
| can occur due to metformin accumulation during treatment with         |
| GLUCOPHAGE or GLUCOPHAGE XR; when it occurs, it is fatal in           |
| approximately 50% of cases. Lactic acidosis may also occur in         |
| association with a number of pathophysiologic conditions, including   |
| diabetes mellitus, and whenever there is significant tissue           |
| hypoperfusion and hypoxemia. Lactic acidosis is characterized by      |
| ele­vated blood lactate levels (\>5 mmol/L), decreased blood pH,       |
| electrolyte disturbances with an increased anion gap, and an          |
| increased ­lactate/pyruvate ratio. When metformin is implicated as the |
| cause of lactic acidosis, metformin plasma levels \>5 µg/mL are       |
| generally found.**                                                    |
|                                                                       |
| **The reported incidence of lactic acidosis in patients receiving     |
| metformin hydrochloride is very low (approximately 0.03 cases/1000    |
| patient-years, with approximately 0.015 fatal cases/1000              |
| patient-years). Reported cases have occurred primarily in diabetic    |
| patients with significant renal insufficiency, including both         |
| intrinsic renal disease and renal hypoperfusion, often in the setting |
| of multiple concomitant medical/surgical problems and multiple        |
| concomitant medications. Patients with congestive heart failure       |
| requiring pharmacologic management, in particular those with unstable |
| or acute congestive heart failure who are at risk of hypoperfusion    |
| and hypoxemia, are at increased risk of lactic acidosis. The risk of  |
| lactic acidosis increases with the degree of renal dysfunction and    |
| the patient\'s age. The risk of lactic acidosis may, therefore, be    |
| significantly decreased by regular monitoring of renal function in    |
| patients taking GLUCOPHAGE or GLUCOPHAGE XR and by use of the minimum |
| effective dose of GLUCOPHAGE or GLUCOPHAGE XR. In particular,         |
| treatment of the elderly should be accompanied by careful monitoring  |
| of renal function. GLUCOPHAGE or GLUCOPHAGE XR treatment should not   |
| be initiated in patients ≥80 years of age unless measurement of       |
| creatinine clearance demonstrates that renal function is not reduced, |
| as these patients are more susceptible to developing lactic acidosis. |
| In addition, GLUCOPHAGE and GLUCOPHAGE XR should be promptly withheld |
| in the presence of any condition associated with hypoxemia,           |
| dehydration, or sepsis. Because impaired hepatic function may         |
| significantly limit the ability to clear lactate, GLUCOPHAGE and      |
| GLUCOPHAGE XR should generally be avoided in patients with clinical   |
| or laboratory evidence of hepatic disease. Patients should be         |
| cautioned against excessive alcohol intake, either acute or chronic,  |
| when taking GLUCOPHAGE or GLUCOPHAGE XR, since alcohol potentiates    |
| the effects of metformin hydrochloride on lactate metabolism. In      |
| addition, GLUCOPHAGE and GLUCOPHAGE XR should be temporarily          |
| discontinued prior to any intravascular radiocontrast study and for   |
| any surgical procedure (see also PRECAUTIONS).**                      |
|                                                                       |
| **The onset of lactic acidosis often is subtle, and accompanied only  |
| by nonspecific symptoms such as malaise, myalgias, respiratory        |
| distress, increasing somnolence, and nonspecific abdominal distress.  |
| There may be associated hypothermia, hypotension, and resistant       |
| bradyarrhythmias with more marked acidosis. The patient and the       |
| patient\'s physician must be aware of the possible importance of such |
| symptoms and the patient should be instructed to notify the physician |
| immediately if they occur (see also PRECAUTIONS). GLUCOPHAGE and      |
| GLUCOPHAGE XR should be withdrawn until the situation is clarified.   |
| Serum electrolytes, ketones, blood glucose, and if indicated, blood   |
| pH, lactate levels, and even blood metformin levels may be useful.    |
| Once a patient is stabilized on any dose level of GLUCOPHAGE or       |
| GLUCOPHAGE XR, gastrointestinal symptoms, which are common during     |
| initiation of therapy, are unlikely to be drug related. Later         |
| occurrence of gastrointestinal symptoms could be due to lactic        |
| acidosis or other serious disease.**                                  |
|                                                                       |
| > **Levels of fasting venous plasma lactate above the upper limit of  |
| > normal but less than 5 mmol/L in patients taking GLUCOPHAGE or      |
| > GLUCOPHAGE XR do not necessarily indicate impending lactic acidosis |
| > and may be explainable by other mechanisms, such as poorly          |
| > controlled diabetes or obesity, vigorous physical activity, or      |
| > technical problems in sample handling. (See also PRECAUTIONS.)**    |
| >                                                                     |
| > **Lactic acidosis should be suspected in any diabetic patient with  |
| > metabolic acidosis lacking evidence of ketoacidosis (ketonuria and  |
| > ketonemia).**                                                       |
| >                                                                     |
| > **Lactic acidosis is a medical emergency that must be treated in a  |
| > hospital setting. In a patient with lactic acidosis who is taking   |
| > GLUCOPHAGE or GLUCOPHAGE XR, the drug should be discontinued        |
| > immediately and general supportive measures promptly instituted.    |
| > Because metformin hydrochloride is dialyzable (with a clearance of  |
| > up to 170 mL/min under good hemodynamic conditions), prompt         |
| > hemodialysis is recommended to correct the acidosis and remove the  |
| > accumulated metformin. Such management often results in prompt      |
| > reversal of symptoms and recovery. (See also CONTRAINDICATIONS and  |
| > PRECAUTIONS.)**                                                     |
+-----------------------------------------------------------------------+

PRECAUTIONS

General

*Monitoring of renal function*---Metformin is known to be substantially
excreted by the kidney, and the risk of metformin accumulation and
lactic acidosis increases with the degree of impairment of renal
function. Thus, patients with serum creatinine levels above the upper
limit of normal for their age should not receive GLUCOPHAGE or
GLUCOPHAGE XR. In patients with advanced age, GLUCOPHAGE and GLUCOPHAGE
XR should be carefully titrated to establish the minimum dose for
adequate glycemic effect, because aging is associated with reduced renal
function. In elderly patients, particularly those 80 years of age, renal
function should be monitored regularly and, generally, GLUCOPHAGE and
GLUCOPHAGE XR should not be titrated to the maximum dose (see WARNINGS
and DOSAGE AND ADMINISTRATION).

Before initiation of GLUCOPHAGE or GLUCOPHAGE XR therapy and at least
annually thereafter, renal function should be assessed and verified as
normal. In patients in whom development of renal dysfunction is
anticipated, renal function should be assessed more frequently and
GLUCOPHAGE or GLUCOPHAGE XR discontinued if evidence of renal impairment
is present.

*Use of concomitant medications that may affect renal function or
metformin disposition***---**Concomitant medication(s) that may affect
renal function or result in significant hemodynamic change or may
interfere with the disposition of metformin, such as cationic drugs that
are eliminated by renal tubular secretion (see **PRECAUTIONS: Drug
Interactions**), should be used with caution.

*Radiologic studies involving the use of intravascular iodinated
contrast materials (for example, intravenous urogram, intravenous
cholangiography, angiography, and computed tomography (CT) scans with
intravascular contrast materials)***---**Intravascular contrast studies
with iodinated materials can lead to acute alteration of renal function
and have been associated with lactic acidosis in patients receiving
metformin (see **CONTRAINDICATIONS**). Therefore, in patients in whom
any such study is planned, GLUCOPHAGE or GLUCOPHAGE XR should be
temporarily discontinued at the time of or prior to the procedure, and
withheld for 48 hours subsequent to the procedure and reinstituted only
after renal function has been re-evaluated and found to be normal.

*Hypoxic states---*Cardiovascular collapse (shock) from whatever cause,
acute congestive heart failure, acute myocardial infarction and other
conditions characterized by hypoxemia have been associated with lactic
acidosis and may also cause prerenal azotemia. When such events occur in
patients on GLUCOPHAGE or GLUCOPHAGE XR therapy, the drug should be
promptly discontinued.

*Surgical procedures*---GLUCOPHAGE or GLUCOPHAGE XR therapy should be
temporarily suspended for any surgical procedure (except minor
procedures not associated with restricted intake of food and fluids) and
should not be restarted until the patient\'s oral intake has resumed and
renal function has been evaluated as normal.

*Alcohol intake*---Alcohol is known to potentiate the effect of
metformin on lactate metabolism. Patients, therefore, should be warned
against excessive alcohol intake, acute or chronic, while receiving
GLUCOPHAGE or GLUCOPHAGE XR.

*Impaired hepatic function*---Since impaired hepatic function has been
associated with some cases of ­ lactic acidosis, GLUCOPHAGE and
GLUCOPHAGE XR should generally be avoided in patients with clinical or
laboratory evidence of hepatic disease.

*Vitamin B~12~ levels*---In controlled clinical trials of GLUCOPHAGE of
29 weeks duration, a decrease to subnormal levels of previously normal
serum Vitamin B~12~ levels, without clinical manifestations, was
observed in approximately 7% of patients. Such decrease, possibly due to
interference with B~12~ absorption from the B~12~-intrinsic factor
complex, is, however, very rarely associated with anemia and appears to
be rapidly reversible with discontinuation of GLUCOPHAGE or Vitamin
B~12~ supplementation. Measurement of hematologic parameters on an
annual basis is advised in patients on GLUCOPHAGE or GLUCOPHAGE XR and
any apparent abnormalities should be appropriately investigated and
managed (see **PRECAUTIONS: Laboratory Tests**).

Certain individuals (those with inadequate Vitamin B~12~ or calcium
intake or absorption) appear to be predisposed to developing subnormal
Vitamin B~12~ levels. In these patients, routine serum Vitamin B~12~
measurements at two- to three-year intervals may be useful.

*Change in clinical status of patients with previously controlled type 2
diabetes*---A patient with type 2 diabetes previously well controlled on
GLUCOPHAGE or GLUCOPHAGE XR who develops laboratory abnormalities or
clinical illness (especially vague and poorly defined illness) should be
evaluated promptly for evidence of ketoacidosis or lactic acidosis.
Evaluation should include serum electrolytes and ketones, blood glucose
and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If
acidosis of either form occurs, GLUCOPHAGE or GLUCOPHAGE XR must be
stopped immediately and other appropriate corrective measures initiated
(see also **WARNINGS**).

*Hypoglycemia*---Hypoglycemia does not occur in patients receiving
GLUCOPHAGE or GLUCOPHAGE XR alone under usual circumstances of use, but
could occur when caloric intake is deficient, when strenuous exercise is
not compensated by caloric supplementation, or during concomitant use
with other glucose-lowering agents (such as sulfonylureas and insulin)
or ethanol.

Elderly, debilitated, or malnourished patients, and those with adrenal
or pituitary insufficiency or alcohol intoxication are particularly
susceptible to hypoglycemic effects. Hypoglycemia may be difficult to
recognize in the elderly, and in people who are taking beta-adrenergic
blocking drugs.

*Loss of control of blood glucose***---**When a patient stabilized on
any diabetic regimen is exposed to stress such as fever, trauma,
infection, or surgery, a temporary loss of glycemic control may occur.
At such times, it may be necessary to withhold GLUCOPHAGE or GLUCOPHAGE
XR and temporarily administer insulin. GLUCOPHAGE or GLUCOPHAGE XR may
be reinstituted after the acute episode is resolved.

The effectiveness of oral antidiabetic drugs in lowering blood glucose
to a targeted level decreases in many patients over a period of time.
This phenomenon, which may be due to progression of the underlying
disease or to diminished responsiveness to the drug, is known as
secondary failure, to distinguish it from primary failure in which the
drug is ineffective during initial therapy. Should secondary failure
occur with either GLUCOPHAGE or GLUCOPHAGE XR or sulfonylurea
monotherapy, combined therapy with GLUCOPHAGE or GLUCOPHAGE XR and
sulfonylurea may result in a response. Should secondary failure occur
with combined GLUCOPHAGE/sulfonylurea therapy or GLUCOPHAGE
XR/sulfonylurea therapy, it may be necessary to consider therapeutic
alternatives including initiation of insulin therapy.

Information for Patients

Patients should be informed of the potential risks and benefits of
GLUCOPHAGE or GLUCOPHAGE XR and of alternative modes of therapy. They
should also be informed about the importance of adherence to dietary
instructions, of a regular exercise program, and of regular testing of
blood glucose, glycosylated hemoglobin, renal function, and hematologic
parameters.

The risks of lactic acidosis, its symptoms, and conditions that
predispose to its development, as noted in the **WARNINGS** and
**PRECAUTIONS** sections, should be explained to patients. Patients
should be advised to discontinue GLUCOPHAGE or GLUCOPHAGE XR immediately
and to promptly notify their health practitioner if unexplained
hyperventilation, myalgia, malaise, unusual somnolence, or other
nonspecific symptoms occur. Once a patient is stabilized on any dose
level of GLUCOPHAGE or GLUCOPHAGE XR, gastrointestinal symptoms, which
are common during initiation of metformin therapy, are unlikely to be
drug related. Later occurrence of gastrointestinal symptoms could be due
to lactic acidosis or other serious disease.

Patients should be counselled against excessive alcohol intake, either
acute or chronic, while receiving ­GLUCOPHAGE or GLUCOPHAGE XR.

GLUCOPHAGE or GLUCOPHAGE XR alone does not usually cause hypoglycemia,
although it may occur when GLUCOPHAGE or GLUCOPHAGE XR is used in
conjunction with oral sulfonylureas and insulin. When initiating
combination therapy, the risks of hypoglycemia, its symptoms and
treatment, and conditions that predispose to its development should be
explained to patients and responsible family members. (See **Patient
Information** Printed Below.)

Laboratory Tests

Response to all diabetic therapies should be monitored by periodic
measurements of fasting blood glucose and glycosylated hemoglobin
levels, with a goal of decreasing these levels toward the normal range.
During initial dose titration, fasting glucose can be used to determine
the therapeutic response. Thereafter, both glucose and glycosylated
hemoglobin should be monitored. Measurements of glycosylated hemoglobin
may be especially useful for evaluating long-term control (see also
**DOSAGE AND ADMINISTRATION**).

Initial and periodic monitoring of hematologic parameters (e.g.,
hemoglobin/ hematocrit and red blood cell indices) and renal function
(serum creatinine) should be performed, at least on an annual basis.
While megaloblastic anemia has rarely been seen with GLUCOPHAGE therapy,
if this is suspected, Vitamin B~12~ deficiency should be excluded.

Drug Interactions (clinical evaluation of drug interactions conducted
with GLUCOPHAGE)

*Glyburide***\-\--**In a single-dose interaction study in type 2
diabetes patients, co-administration of metformin and glyburide did not
result in any changes in either metformin pharmacokinetics or
pharmacodynamics. Decreases in glyburide AUC and C~max~ were observed,
but were highly variable. The single-dose nature of this study and the
lack of correlation between glyburide blood levels and pharmacodynamic
effects, makes the clinical significance of this interaction uncertain
(see **DOSAGE AND ADMINISTRATION**: **Concomitant GLUCOPHAGE or**
**GLUCOPHAGE XR and** **Oral Sulfonylurea Therapy).**

*Furosemide***\-\--**A single-dose, metformin-furosemide drug
interaction study in healthy subjects demonstrated that pharmacokinetic
parameters of both compounds were affected by co-administration.
Furosemide increased the metformin plasma and blood C~max~ by 22% and
blood AUC by 15%, without any significant change in metformin renal
clearance. When administered with metformin, the C~max~ and AUC of
furosemide were 31% and 12% smaller, respectively, than when
administered alone, and the terminal half-life was decreased by 32%,
without any significant change in furosemide renal clearance. No
information is available about the interaction of metformin and
furosemide when co-administered chronically.

*Nifedipine***\-\--**A single-dose, metformin-nifedipine drug
interaction study in normal healthy volunteers demonstrated that
co-administration of nifedipine increased plasma metformin C~max~ and
AUC by 20% and 9%, respectively, and increased the amount excreted in
the urine. T~max~ and half-life were unaffected. Nifedipine appears to
enhance the absorption of metformin. Metformin had minimal effects on
nifedipine.

*Cationic drugs***\-\--**Cationic drugs (e.g., amiloride, digoxin,
morphine, procainamide, quinidine, quinine, ranitidine, triamterene,
trimethoprim, or vancomycin) that are eliminated by renal tubular
secretion theoretically have the potential for inter­action with
metformin by competing for common renal tubular transport systems. Such
interaction between metformin and oral cimetidine has been observed in
normal healthy volunteers in both single- and multiple-dose,
metformin-cimetidine drug interaction studies, with a 60% increase in
peak metformin plasma and whole blood concentrations and a 40% increase
in plasma and whole blood metformin AUC. There was no change in
­elimination half-life in the single-dose study. Metformin had no effect
on cimetidine pharmacokinetics. Although such interactions remain
theoretical (except for cimetidine), careful patient monitoring and dose
adjustment of GLUCOPHAGE or GLUCOPHAGE XR and/or the interfering drug is
recommended in patients who are taking cationic medications that are
excreted via the proximal renal tubular secretory system.

*Other***\-\--**Certain drugs tend to produce hyperglycemia and may lead
to loss of glycemic control. These drugs include the thiazides and other
diuretics, corticosteroids, phenothiazines, thyroid products, estrogens,
oral contraceptives, phenytoin, nicotinic acid, sympathomimetics,
calcium channel blocking drugs, and isoniazid. When such drugs are
administered to a patient receiving GLUCOPHAGE or GLUCOPHAGE XR, the
patient should be closely observed for loss of blood glucose control.
When such drugs are withdrawn from a patient receiving GLUCOPHAGE or
GLUCOPHAGE XR, the patient should be observed closely for hypoglycemia.

In healthy volunteers, the pharmacokinetics of metformin and
propranolol, and metformin and ibuprofen were not affected when
co-administered in single-dose interaction studies.

Metformin is negligibly bound to plasma proteins and is, therefore, less
likely to interact with highly protein-bound drugs such as salicylates,
sulfonamides, chloramphenicol, and probenecid, as compared to the
sulfonylureas, which are extensively bound to serum proteins.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term carcinogenicity studies have been performed in rats (dosing
duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses
up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively.
These doses are both approximately four times the maximum recommended
human daily dose of 2000 mg based on body surface area comparisons. No
evidence of carcinogenicity with metformin was found in either male or
female mice. Similarly, there was no tumorigenic potential observed with
metformin in male rats. There was, however, an increased incidence of
benign stromal uterine polyps in female rats treated with 900 mg/kg/day.

There was no evidence of a mutagenic potential of metformin in the
following *in vitro* tests: Ames test (*S. typhimurium*), gene mutation
test (mouse lymphoma cells), or chromosomal aberrations test (human
lymphocytes). Results in the *in vivo* mouse micronucleus test were also
negative.

Fertility of male or female rats was unaffected by metformin when
administered at doses as high as 600 mg/kg/day, which is approximately
three times the maximum recommended human daily dose based on body
surface area comparisons.

Pregnancy

Teratogenic Effects: Pregnancy Category B

Recent information strongly suggests that abnormal blood glucose levels
during pregnancy are associated with a higher incidence of congenital
abnormalities. Most experts recommend that insulin be used during
pregnancy to maintain blood glucose levels as close to normal as
possible. Because animal reproduction studies are not always predictive
of human response, GLUCOPHAGE and GLUCOPHAGE XR should not be used
during pregnancy unless clearly needed.

There are no adequate and well-controlled studies in pregnant women with
GLUCOPHAGE or GLUCOPHAGE XR. Metformin was not teratogenic in rats and
rabbits at doses up to 600 mg/kg/day. This represents an exposure of
about two and six times the maximum recommended human daily dose of 2000
mg based on body surface area comparisons for rats and rabbits,
respectively. Determination of fetal concentrations demonstrated a
partial placental ­barrier to metformin.

Nursing Mothers

Studies in lactating rats show that metformin is excreted into milk and
reaches levels comparable to those in plasma. Similar studies have not
been conducted in nursing mothers. Because the potential for
hypoglycemia in nursing infants may exist, a decision should be made
whether to discontinue nursing or to discontinue the drug, taking into
account the importance of the drug to the mother. If GLUCOPHAGE or
GLUCOPHAGE XR is discontinued, and if diet alone is inadequate for
controlling blood glucose, insulin therapy should be considered.

Pediatric Use

The safety and effectiveness of GLUCOPHAGE for the treatment of type 2
diabetes have been established in pediatric patients ages 10 to 16 years
(studies have not been conducted in pediatric patients below the age of
10 years). Use of GLUCOPHAGE in this age group is supported by evidence
from adequate and well-controlled studies of GLUCOPHAGE in adults with
additional data from a controlled clinical study in pediatric patients
ages 10-16 years with type 2 diabetes, which demonstrated a similar
response in glycemic control to that seen in adults. (See **CLINICAL
PHARMACOLOGY: Pediatric Clinical Studies**.) In this study, adverse
effects were similar to those described in adults. (See **ADVERSE
REACTIONS: Pediatric Patients**.) A maximum daily dose of 2000 mg is
recommended. (See **DOSAGE AND ADMINISTRATION: Recommended Dosing
Schedule: Pediatrics**.)

Safety and effectiveness of GLUCOPHAGE XR in pediatric patients have not
been established.

Geriatric Use

Controlled clinical studies of GLUCOPHAGE and GLUCOPHAGE XR did not
include sufficient numbers of elderly patients to determine whether they
respond differently from younger patients, although other reported
clinical experience has not identified differences in responses between
the elderly and younger patients. Metformin is known to be substantially
excreted by the kidney and because the risk of serious adverse reactions
to the drug is greater in patients with impaired renal function,
GLUCOPHAGE and GLUCOPHAGE XR should only be used in patients with normal
renal function (see **CONTRAINDICATIONS, WARNINGS,** and **CLINICAL
PHARMACOLOGY: Pharmacokinetics**). Because aging is associated with
reduced renal function, GLUCOPHAGE or GLUCOPHAGE XR should be used with
caution as age increases. Care should be taken in dose selection and
should be based on careful and regular monitoring of renal function.
Generally, elderly patients should not be titrated to the maximum dose
of GLUCOPHAGE or GLUCOPHAGE XR (see also **WARNINGS** and **DOSAGE AND
ADMINISTRATION**).

ADVERSE REACTIONS

In a US double-blind clinical study of GLUCOPHAGE in patients with type
2 diabetes, a total of 141 patients received GLUCOPHAGE therapy (up to
2550 mg per day) and 145 patients received placebo. Adverse reactions
reported in greater than 5% of the GLUCOPHAGE patients, and that were
more common in GLUCOPHAGE- than placebo-treated patients, are listed in
**Table 11**.

+--------------------------------------+--------------------+----------+
| ## Table 11                          |                    |          |
| . Most Common Adverse Reactions (\>5 |                    |          |
| .0%) in a Placebo-Controlled Clinica |                    |          |
| l Study of Glucophage Monotherapy\*  |                    |          |
+--------------------------------------+--------------------+----------+
| ####### Adverse Reaction             | # Glucophage       | # Plac   |
|                                      |                    | ebo {#pl |
|                                      | **Monotherapy**    | acebo-2} |
|                                      |                    |          |
|                                      | **n = 141**        | **n =    |
|                                      |                    | 145**    |
+--------------------------------------+--------------------+----------+
|                                      | **% of Patients**  |          |
+--------------------------------------+--------------------+----------+
| Diarrhea                             | 53.2               | 11.7     |
+--------------------------------------+--------------------+----------+
| Nausea/Vomiting                      | 25.5               | 8.3      |
+--------------------------------------+--------------------+----------+
| Flatulence                           | 12.1               | 5.5      |
+--------------------------------------+--------------------+----------+
| Asthenia                             | 9.2                | 5.5      |
+--------------------------------------+--------------------+----------+
| Indigestion                          | 7.1                | 4.1      |
+--------------------------------------+--------------------+----------+
| Abdominal Discomfort                 | 6.4                | 4.8      |
+--------------------------------------+--------------------+----------+
| Headache                             | 5.7                | 4.8      |
+--------------------------------------+--------------------+----------+

> \* Reactions that were more common in GLUCOPHAGE- than
>
> placebo-treated patients.

Diarrhea led to discontinuation of study medication in 6% of patients
treated with GLUCOPHAGE. Additionally, the following adverse reactions
were reported in % of GLUCOPHAGE patients and were more commonly
reported with GLUCOPHAGE than placebo: abnormal stools, hypoglycemia,
myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased,
taste disorder, chest discomfort, chills, flu syndrome, flushing,
palpitation.

In worldwide clinical trials over 900 patients with type 2 diabetes have
been treated with GLUCOPHAGE XR in placebo- and active-controlled
studies. In placebo-controlled trials, 781 patients were administered
GLUCOPHAGE XR and 195 patients received placebo. Adverse reactions
reported in greater than 5% of the GLUCOPHAGE XR patients, and that were
more common in GLUCOPHAGE XR- than placebo-treated patients, are listed
in **Table 12**.

+------------------------+--------------------------+------------------+
| **Table 12. Most       |                          |                  |
| Common Adverse         |                          |                  |
| Reactions (\>5.0%) in  |                          |                  |
| Placebo-Controlled     |                          |                  |
| Studies of GLUCOPHAGE  |                          |                  |
| XR**\*                 |                          |                  |
+------------------------+--------------------------+------------------+
|                        | **GLUCOPHAGE XR**        | **Placebo**      |
+------------------------+--------------------------+------------------+
|                        | **n=781**                | **n=195**        |
+------------------------+--------------------------+------------------+
| # Adverse Reaction     | **% of Patients**        |                  |
+------------------------+--------------------------+------------------+
| # Diarrhea             | 9.6                      | 2.6              |
+------------------------+--------------------------+------------------+
| ### Nausea/Vomiting    | 6.5                      | 1.5              |
+------------------------+--------------------------+------------------+
| ###  {#section-1}      |                          |                  |
+------------------------+--------------------------+------------------+

> \* Reactions that were more common in GLUCOPHAGE XR- than
>
> placebo-treated patients.

Diarrhea led to discontinuation of study medication in 0.6% of patients
treated with GLUCOPHAGE XR. Additionally, the following adverse
reactions were reported in 1.0% - 5.0% of GLUCOPHAGE XR patients and
were more commonly reported with GLUCOPHAGE XR than placebo: abdominal
pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence,
dizziness, headache, upper respiratory infection, taste disturbance.

**Pediatric Patients**

In clinical trials with GLUCOPHAGE in pediatric patients with type 2
diabetes, the profile of adverse reactions was similar to that observed
in adults.

**OVERDOSAGE**

Hypoglycemia has not been seen even with ingestion of up to 85 grams of
GLUCOPHAGE, although lactic acidosis has occurred in such circumstances
(see **WARNINGS**). Metformin is dialyzable with a clearance of up to
170 mL/min under good hemodynamic conditions. Therefore, hemodialysis
may be useful for removal of accumulated drug from patients in whom
metformin overdosage is suspected.

DOSAGE AND ADMINISTRATION

There is no fixed dosage regimen for the management of hyperglycemia in
patients with type 2 diabetes with GLUCOPHAGE or GLUCOPHAGE XR or any
other pharmacologic agent. Dosage of GLUCOPHAGE or GLUCOPHAGE XR must be
individualized on the basis of both ­effectiveness and tolerance, while
not exceeding the maximum recommended daily doses.­ The maximum
recommended daily dose of GLUCOPHAGE is 2550 mg in adults and 2000 mg in
pediatric patients (10-16 years of age); the maximum recommended daily
dose of GLUCOPHAGE XR in adults is 2000 mg.

GLUCOPHAGE should be given in divided doses with meals while GLUCOPHAGE
XR should generally be given once daily with the evening meal.
GLUCOPHAGE or GLUCOPHAGE XR should be started at a low dose, with
gradual dose escalation, both to reduce gastrointestinal side effects
and to permit identification of the minimum dose required for adequate
glycemic control of the patient.

During treatment initiation and dose titration (see **Recommended Dosing
Schedule),**

fasting plasma glucose should be used to determine the therapeutic
response to GLUCOPHAGE or GLUCOPHAGE XR and identify the minimum
effective dose for the patient. Thereafter, glycosylated hemoglobin
should be measured at intervals of approximately three months. **The
therapeutic goal should be to decrease both fasting plasma glucose and
glyco­sylated hemoglobin levels to normal or near normal by using the
lowest effective dose of GLUCOPHAGE or GLUCOPHAGE XR, either when used
as monotherapy or in combination with sulfonylurea or insulin.**

Monitoring of blood glucose and glycosylated hemoglobin will also permit
detection of primary failure, i.e., inadequate lowering of blood glucose
at the maximum recommended dose of medication, and secondary failure,
i.e., loss of an adequate blood glucose lowering response after an
initial period of effectiveness.

Short-term administration of GLUCOPHAGE or GLUCOPHAGE XR may be
sufficient during periods of transient loss of control in patients
usually well-controlled on diet alone.

Recommended Dosing Schedule

**Adults -** In general, clinically significant responses are not seen
at doses below 1500 mg per day. However, a lower recommended starting
dose and gradually increased dosage is advised to minimize
gastrointestinal symptoms.

The usual starting dose of GLUCOPHAGE (metformin hydrochloride tablets)
is 500 mg twice a day or 850 mg once a day, given with meals. Dosage
increases should be made in increments of 500 mg weekly or 850 mg every
2 weeks, up to a total of 2000 mg per day, given in divided doses.
Patients can also be titrated from 500 mg twice a day to 850 mg twice a
day after 2 weeks. For those patients requiring additional glycemic
control, GLUCOPHAGE may be given to a maximum daily dose of 2550 mg per
day. Doses above 2000 mg may be better tolerated given three times a day
with meals.

The usual starting dose of GLUCOPHAGE XR (metformin hydrochloride
extended-release tablets) is 500 mg once daily with the evening meal.
Dosage increases should be made in increments of 500 mg weekly, up to a
maximum of 2000 mg once daily with the evening meal. If glycemic control
is not achieved on GLUCOPHAGE XR 2000 mg once daily, a trial of
GLUCOPHAGE XR 1000 mg twice daily should be considered. If higher doses
of metformin are required, GLUCOPHAGE should be used at total daily
doses up to 2550 mg administered in divided daily doses, as described
above. (See CLINICAL PHARMACOLOGY, Clinical Studies.)

In a randomized trial, patients currently treated with GLUCOPHAGE were
switched to GLUCOPHAGE XR. Results of this trial suggest that patients
receiving GLUCOPHAGE treatment may be safely switched to GLUCOPHAGE XR
once daily at the same total daily dose, up to 2000 mg once daily.
Following a switch from GLUCOPHAGE to GLUCOPHAGE XR, glycemic control
should be closely monitored and dosage adjustments made accordingly (see
CLINICAL PHARMACOLOGY, Clinical Studies).

Pediatrics -- The usual starting dose of GLUCOPHAGE is 500 mg twice a
day, given with meals. Dosage increases should be made in increments of
500 mg weekly up to a maximum of 2000 mg per day, given in divided
doses. Safety and effectiveness of GLUCOPHAGE XR in pediatric patients
have not been established.

Transfer From Other Antidiabetic Therapy

When transferring patients from standard oral hypoglycemic agents other
than chlorpropamide to GLUCOPHAGE or GLUCOPHAGE XR, no transition period
generally is necessary. When transferring patients from chlorpropamide,
care should be exercised during the first two weeks because of the
prolonged retention of chlorpropamide in the body, leading to
overlapping drug effects and possible hypoglycemia.

Concomitant GLUCOPHAGE or GLUCOPHAGE XR and Oral Sulfonylurea Therapy in
Adult Patients

If patients have not responded to four weeks of the maximum dose of
GLUCOPHAGE or GLUCOPHAGE XR monotherapy, consideration should be given
to gradual addition of an oral sulfonylurea while continuing GLUCOPHAGE
or GLUCOPHAGE XR at the maximum dose, even if prior primary or secondary
failure to a sulfonylurea has occurred. Clinical and pharmacokinetic
drug-drug interaction data are currently available only for metformin
plus glyburide (glibenclamide).

With concomitant GLUCOPHAGE or GLUCOPHAGE XR and sulfonylurea therapy,
the desired control of blood glucose may be obtained by adjusting the
dose of each drug.

However, attempts should be made to identify the minimum effective dose
of each drug to achieve this goal. With concomitant GLUCOPHAGE or
GLUCOPHAGE XR and sulfonylurea therapy, the risk of hypoglycemia
associated with sulfonylurea therapy continues and may be increased.
Appropriate pre­cautions should be taken. (See Package Insert of the
respective sulfonylurea.)

If patients have not satisfactorily responded to one to three months of
concomitant

therapy with the maximum dose of GLUCOPHAGE or GLUCOPHAGE XR and the
maximum dose of an oral sulfonylurea, consider therapeutic alternatives
including switching to insulin with or without GLUCOPHAGE or GLUCOPHAGE
XR.

**Concomitant GLUCOPHAGE or GLUCOPHAGE XR and Insulin Therapy in Adult
Patients**

The current insulin dose should be continued upon initiation of
GLUCOPHAGE or GLUCOPHAGE XR therapy. GLUCOPHAGE or GLUCOPHAGE XR therapy
should be initiated at 500 mg once daily in patients on insulin therapy.
For patients not responding adequately, the dose of GLUCOPHAGE or
GLUCOPHAGE XR should be

increased by 500 mg after approximately 1 week and by 500 mg every week
thereafter until adequate glycemic control is achieved. The maximum
recommended daily dose is 2500 mg for GLUCOPHAGE and 2000 mg for
GLUCOPHAGE XR. It is recommended that the insulin dose be decreased by
10% to 25% when fasting plasma glucose concentrations decrease to less
than 120 mg/dL in patients receiving concomitant insulin and GLUCOPHAGE
or GLUCOPHAGE XR. Further adjustment should be individualized based on
glucose-lowering response.

Specific Patient Populations

GLUCOPHAGE or GLUCOPHAGE XR are not recommended for use in pregnancy.
GLUCOPHAGE is not recommended in patients below the age of 10 years.
GLUCOPHAGE XR is not recommended in pediatric patients (below the age of
17 years).

The initial and maintenance dosing of GLUCOPHAGE or GLUCOPHAGE XR should
be conservative in patients with advanced age, due to the potential for
decreased renal function in this population. Any dosage adjustment
should be based on a careful assessment of renal function. Generally,
elderly, debilitated, and malnourished patients should not be titrated
to the maximum dose of GLUCOPHAGE or GLUCOPHAGE XR.

Monitoring of renal function is necessary to aid in prevention of lactic
acidosis, particularly in the elderly. (See **WARNINGS**.)

HOW SUPPLIED

GLUCOPHAGE^®^ (metformin hydrochloride tablets)

500 mg      Bottles of 100      NDC 0087-6060-05

500 mg      Bottles of 500      NDC 0087-6060-10

850 mg      Bottles of 100      NDC 0087-6070-05

1000 mg Bottles of 100 NDC 0087-6071-11

GLUCOPHAGE 500-mg tablets are round, white to off-white, film coated
tablets debossed with BMS 6060 around the periphery of the tablet on one
side and 500 debossed across the face of the other side.

GLUCOPHAGE 850-mg tablets are round, white to off-white, film coated
tablets debossed with BMS 6070 around the periphery of the tablet on one
side and 850 debossed

across the face of the other side.

GLUCOPHAGE 1000-mg tablets are white, oval, biconvex, film coated
tablets with BMS 6071 debossed on one side and 1000 debossed on the
opposite side and with a bisect line on both sides.

GLUCOPHAGE XR (metformin hydrochloride extended-release tablets)

500 mg Bottles of 100 NDC 0087-6063-13

500 mg Bottles of 500 NDC 0087-6063-14

GLUCOPHAGE XR 500-mg tablets are white to off-white, capsule shaped,
biconvex tablets, with BMS 6063 debossed on one side and 500 debossed
across the face of the other side.

Storage

Store at 20 - 25C (68 - 77F); excursions permitted to 15 - 30C (59 -
86F). \[See USP Controlled Room Temperature.\]

Dispense in light-resistant containers.

Patient Information

**GLUCOPHAGE^®^(metformin hydrochloride tablets)**

**and**

**GLUCOPHAGE^®^XR (metformin hydrochloride extended-release tablets)**

Read this information carefully before you start taking this medicine
and each time you refill your prescription. There may be new
information. This information does not take the place of your doctor's
advice. Ask your doctor or pharmacist if you do not understand some of
this information or if you want to know more about this medicine.

**What are GLUCOPHAGE and GLUCOPHAGE XR?**

GLUCOPHAGE and GLUCOPHAGE XR are used to treat type 2 diabetes. This is
also known as non-insulin-dependent diabetes mellitus. People with type
2 diabetes are not able to make enough insulin or respond normally to
the insulin their bodies make. When this happens, sugar (glucose) builds
up in the blood. This can lead to serious medical problems including
kidney damage, amputations, and blindness. Diabetes is also closely
linked to heart disease. The main goal of treating diabetes is to lower
your blood sugar to a normal level.

High blood sugar can be lowered by diet and exercise, by a number of
medicines taken by mouth, and by insulin shots. Before you take
GLUCOPHAGE or GLUCOPHAGE XR, try to control your diabetes by exercise
and weight loss. While you take your diabetes medicine, continue to
exercise and follow the diet advised for your diabetes. No matter what
your recommended diabetes management plan is, studies have shown that
maintaining good blood sugar control can prevent or delay complications
of diabetes, such as blindness.

GLUCOPHAGE and GLUCOPHAGE XR have the same active ingredient. However,
GLUCOPHAGE XR works longer in your body. Both of these medicines help
control your blood sugar in a number of ways. These include helping your
body respond better to the insulin it makes naturally, decreasing the
amount of sugar your liver makes, and decreasing the amount of sugar
your intestines absorb. GLUCOPHAGE and GLUCOPHAGE XR do not cause your
body to make more insulin. Because of this, when taken alone, they
rarely cause hypoglycemia (low blood sugar), and usually do not cause
weight gain. However, when they are taken with a sulfonylurea or with
insulin, hypoglycemia is more likely to occur, as is weight gain.

**WARNING: A small number of people who have taken GLUCOPHAGE have
developed a serious condition called lactic acidosis. Lactic acidosis is
caused by a buildup of lactic acid in the blood. This happens more often
in people with kidney problems. Most people with kidney problems should
not take GLUCOPHAGE or GLUCOPHAGE XR. (See "What are the side effects of
GLUCOPHAGE and GLUCOPHAGE XR?")**

**Who should not take GLUCOPHAGE or GLUCOPHAGE XR?**

Some conditions increase your chance of getting lactic acidosis, or
cause other problems if you take either of these medicines. Most of the
conditions listed below can increase your chance of getting lactic
acidosis.

**Do not take GLUCOPHAGE or GLUCOPHAGE XR if you:**

-   have kidney problems

-   have liver problems

-   have heart failure that is treated with medicines, such as Lanoxin
    (digoxin) or Lasix (furosemide)

-   drink a lot of alcohol. This means you binge drink for short periods
    or drink all the time

-   are seriously dehydrated (have lost a lot of water from your body)

-   are going to have an x-ray procedure with injection of dyes
    (contrast agents)

-   are going to have surgery

-   develop a serious condition, such as heart attack, severe infection,
    or a stroke

-   are 80 years or older and you have NOT had your kidney function
    tested

Tell your doctor if you are pregnant or plan to become pregnant.
GLUCOPHAGE and GLUCOPHAGE XR may not be right for you. Talk with your
doctor about your choices. You should also discuss your choices with
your doctor if you are nursing a child.

**Can GLUCOPHAGE or GLUCOPHAGE XR be used in children?**

GLUCOPHAGE has been shown to effectively lower glucose levels in
children (ages 10 to 16 years) with type 2 diabetes. GLUCOPHAGE has not
been studied in children younger than 10 years old. GLUCOPHAGE has not
been studied in combination with other oral glucose-control medicines or
insulin in children. If you have any questions about the use of
GLUCOPHAGE in children, talk with your doctor or other healthcare
provider.

GLUCOPHAGE XR has not been studied in children.

**How should I take GLUCOPHAGE or GLUCOPHAGE XR?**

Your doctor will tell you how much medicine to take and when to take it.
You will probably start out with a low dose of the medicine. Your doctor
may slowly increase your dose until your blood sugar is better
controlled. You should take GLUCOPHAGE or GLUCOPHAGE XR with meals.

Your doctor may have you take other medicines along with GLUCOPHAGE or
GLUCOPHAGE XR to control your blood sugar. These medicines may include
insulin shots. Taking GLUCOPHAGE or GLUCOPHAGE XR with insulin may help
you better control your blood sugar while reducing the insulin dose .

Continue your exercise and diet program and test your blood sugar
regularly while taking GLUCOPHAGE or GLUCOPHAGE XR. Your doctor will
monitor your diabetes and may perform blood tests on you from time to
time to make sure your kidneys and your liver are functioning normally.
There is no evidence that GLUCOPHAGE or GLUCOPHAGE XR causes harm to the
liver or kidneys.

######## Tell your doctor if you

-   have an illness that causes severe vomiting, diarrhea or fever, or
    if you drink a much lower amount of liquid than normal. These
    conditions can lead to severe dehydration (loss of water in your
    body). You may need to stop taking GLUCOPHAGE or GLUCOPHAGE XR for a
    short time.

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-   plan to have surgery or an x-ray procedure with injection of dye
    (contrast agent). You may need to stop taking GLUCOPHAGE or
    GLUCOPHAGE XR for a short time.

-   start to take other medicines or change how you take a medicine.
    GLUCOPHAGE and GLUCOPHAGE XR can affect how well other drugs work,
    and some drugs can affect how well GLUCOPHAGE and GLUCOPHAGE XR
    work. Some medicines may cause high blood sugar.

**What should I avoid while taking GLUCOPHAGE or GLUCOPHAGE XR?**

Do not drink a lot of alcoholic drinks while taking GLUCOPHAGE or
GLUCOPHAGE XR. This means you should not binge drink for short periods,
and you should not drink a lot of alcohol on a regular basis. Alcohol
can increase the chance of getting lactic acidosis.

**What are the side effects of GLUCOPHAGE and GLUCOPHAGE XR?**

***Lactic Acidosis.* In rare cases, GLUCOPHAGE and GLUCOPHAGE XR can
cause a serious side effect called lactic acidosis. This is caused by a
buildup of lactic acid in your blood. This build-up can cause serious
damage.** Lactic acidosis caused by GLUCOPHAGE and GLUCOPHAGE XR is rare
and has occurred mostly in people whose kidneys were not working
normally. Lactic acidosis has been reported in about one in 33,000
patients taking GLUCOPHAGE over the course of a year. Although rare, if
lactic acidosis does occur, it can be fatal in up to half the people who
develop it.

It is also important for your liver to be working normally when you take
GLUCOPHAGE or GLUCOPHAGE XR. Your liver helps remove lactic acid from
your blood.

Make sure you tell your doctor before you use GLUCOPHAGE or GLUCOPHAGE
XR if you have kidney or liver problems. You should also **stop using
GLUCOPHAGE or GLUCOPHAGE XR and call your doctor right away if you have
signs of lactic acidosis. Lactic acidosis is a medical emergency that
must be treated in a hospital.**

**Signs of lactic acidosis are:**

-   feeling very weak, tired, or uncomfortable

-   unusual muscle pain

-   trouble breathing

-   unusual or unexpected stomach discomfort

-   feeling cold

-   feeling dizzy or lightheaded

-   suddenly developing a slow or irregular heartbeat

If your medical condition suddenly changes, stop taking GLUCOPHAGE or
GLUCOPHAGE XR and call your doctor right away. This may be a sign of
lactic acidosis or another serious side effect.

*Other Side Effects.* Common side effects of GLUCOPHAGE and GLUCOPHAGE
XR include diarrhea, nausea, and upset stomach. These side effects
generally go away after you take the medicine for a while. Taking your
medicine with meals can help reduce these side effects. Tell your doctor
if the side effects bother you a lot, last for more than a few weeks,
come back after they've gone away, or start later in therapy. You may
need a lower dose or need to stop taking the medicine for a short period
or for good.

About 3 out of every 100 people who take GLUCOPHAGE or GLUCOPHAGE XR
have an unpleasant metallic taste when they start taking the medicine.
It lasts for a short time.

GLUCOPHAGE and GLUCOPHAGE XR rarely cause hypoglycemia (low blood sugar)
by themselves. However, hypoglycemia can happen if you do not eat
enough, if you drink alcohol, or if you take other medicines to lower
blood sugar.

**General advice about prescription medicines**

If you have questions or problems, talk with your doctor or other
healthcare provider. You can ask your doctor or pharmacist for the
information about GLUCOPHAGE and GLUCOPHAGE XR that is written for
health care professionals. Medicines are sometimes prescribed for
purposes other than those listed in a patient information leaflet. Do
not use GLUCOPHAGE or GLUCOPHAGE XR for a condition for which it was not
prescribed. Do not share your medicine with other people.

GLUCOPHAGE is a registered trademark of LIPHA s.a.

Licensed to Bristol-Myers Squibb Company.

Distributed by

Bristol-Myers Squibb Company

Princeton, NJ 08543 USA

N3912-00 1125492 Revised October 2000

N3887-00 1125283