Glucophage Information
Glucophage (Metformin hydrochloride) Description
Glucophage (Metformin hydrochloride) (metformin
hydrochloride) Tablets and Glucophage (Metformin hydrochloride) XR (metformin
hydrochloride) Extended-Release Tablets are oral antihyperglycemic drugs used
in the management of type 2 diabetes. Metformin hydrochloride (-dimethylimidodicarbonimidic
diamide hydrochloride) is not chemically or pharmacologically related to any
other classes of oral antihyperglycemic agents. The structural formula is
as shown:
Metformin hydrochloride is a white to off-white crystalline
compound with a molecular formula of CHN •
HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble
in water and is practically insoluble in acetone, ether, and chloroform. The
pK of metformin is 12.4. The pH of a 1% aqueous solution
of metformin hydrochloride is 6.68.
Glucophage (Metformin hydrochloride) tablets
contain 500 mg, 850 mg, or 1000 mg of metformin hydrochloride. Each tablet
contains the inactive ingredients povidone and magnesium stearate. In addition,
the coating for the 500 mg and 850 mg tablets contains hypromellose and the
coating for the 1000 mg tablet contains hypromellose and
polyethylene glycol.
Glucophage (Metformin hydrochloride) XR contains 500 mg
or 750 mg of metformin hydrochloride as the active ingredient.
Glucophage (Metformin hydrochloride)
XR 500 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose,
hypromellose, microcrystalline cellulose, and magnesium stearate.
Glucophage (Metformin hydrochloride)
XR 750 mg tablets contain the inactive ingredients sodium carboxymethyl cellulose,
hypromellose, and magnesium stearate.
Glucophage (Metformin hydrochloride) Indications And Usage
Glucophage (Metformin hydrochloride) (metformin hydrochloride)
Tablets is indicated as an adjunct to diet and exercise to improve glycemic
control in adults and children with type 2 diabetes mellitus.
Glucophage (Metformin hydrochloride)
XR (metformin hydrochloride) Extended-Release Tablets is indicated as an adjunct
to diet and exercise to improve glycemic control in adults with type 2 diabetes
mellitus.
Glucophage (Metformin hydrochloride) Contraindications
Glucophage (Metformin hydrochloride) and Glucophage (Metformin hydrochloride) XR are contraindicated in patients with:
Glucophage (Metformin hydrochloride) and Glucophage (Metformin hydrochloride) 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 .)
Glucophage (Metformin hydrochloride) Precautions
Patients should be informed of the potential risks and benefits
of Glucophage (Metformin hydrochloride) or Glucophage (Metformin hydrochloride) 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 and sections, should be explained to patients.
Patients should be advised to discontinue Glucophage (Metformin hydrochloride) or Glucophage (Metformin hydrochloride) 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 (Metformin hydrochloride) or Glucophage (Metformin hydrochloride)
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 (Metformin hydrochloride) or Glucophage (Metformin hydrochloride) XR.
Glucophage (Metformin hydrochloride) or Glucophage (Metformin hydrochloride) XR alone does not usually cause hypoglycemia,
although it may occur when Glucophage (Metformin hydrochloride) or Glucophage (Metformin hydrochloride) 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 printed
below.)
Patients should be informed that Glucophage (Metformin hydrochloride) XR must be swallowed
whole and not crushed or chewed, and that the inactive ingredients may occasionally
be eliminated in the feces as a soft mass that may resemble the original tablet.
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 ).
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 (Metformin hydrochloride) therapy, if this is suspected,
vitamin B deficiency should be excluded.
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 4 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 tests:
Ames test (), gene mutation test (mouse lymphoma
cells), or chromosomal aberrations test (human lymphocytes). Results in the 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 3 times the maximum recommended
human daily dose based on body surface area comparisons.
The safety and effectiveness of Glucophage (Metformin hydrochloride) 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 (Metformin hydrochloride) in this age group is supported by evidence
from adequate and well-controlled studies of Glucophage (Metformin hydrochloride) in adults with additional
data from a controlled clinical study in pediatric patients ages 10 to 16
years with type 2 diabetes, which demonstrated a similar response in glycemic
control to that seen in adults. (See .) In this study, adverse effects
were similar to those described in adults. (See .) A maximum daily dose of 2000
mg is recommended. (See .)
Safety and effectiveness of Glucophage (Metformin hydrochloride) XR in pediatric patients
have not been established.
Glucophage (Metformin hydrochloride) Adverse Reactions
In a US double-blind clinical study
of Glucophage (Metformin hydrochloride) in patients with type 2 diabetes, a total of 141 patients received
Glucophage (Metformin hydrochloride) therapy (up to 2550 mg per day) and 145 patients received placebo.
Adverse reactions reported in greater than 5% of the Glucophage (Metformin hydrochloride) patients,
and that were more common in Glucophage (Metformin hydrochloride) - than placebo-treated patients, are
listed in .
Diarrhea led to discontinuation of study medication in
6% of patients treated with Glucophage (Metformin hydrochloride) . Additionally, the following adverse
reactions were reported in ≥1.0% to ≤5.0% of Glucophage (Metformin hydrochloride) patients and were
more commonly reported with Glucophage (Metformin hydrochloride) 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 (Metformin hydrochloride) XR in placebo- and active-controlled studies. In placebo-controlled
trials, 781 patients were administered Glucophage (Metformin hydrochloride) XR and 195 patients received
placebo. Adverse reactions reported in greater than 5% of the Glucophage (Metformin hydrochloride) XR
patients, and that were more common in Glucophage (Metformin hydrochloride) XR- than placebo-treated
patients, are listed in .
Diarrhea led to discontinuation of study medication in
0.6% of patients treated with Glucophage (Metformin hydrochloride) XR. Additionally, the following adverse
reactions were reported in ≥1.0% to ≤5.0% of Glucophage (Metformin hydrochloride) XR patients and were
more commonly reported with Glucophage (Metformin hydrochloride) XR than placebo: abdominal pain, constipation,
distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache,
upper respiratory infection, taste disturbance.
Glucophage (Metformin hydrochloride) Overdosage
Overdose of metformin hydrochloride has occurred, including ingestion
of amounts greater than 50 grams. Hypoglycemia was reported in approximately
10% of cases, but no causal association with metformin hydrochloride has been
established. Lactic acidosis has been reported in approximately 32% of metformin
overdose cases (see ). 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.
Glucophage (Metformin hydrochloride) Dosage And Administration
There is no fixed dosage regimen for
the management of hyperglycemia in patients with type 2 diabetes with Glucophage (Metformin hydrochloride)
or Glucophage (Metformin hydrochloride) XR or any other pharmacologic agent. Dosage of Glucophage (Metformin hydrochloride) or
Glucophage (Metformin hydrochloride) 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 (Metformin hydrochloride) is 2550 mg in adults and 2000 mg in pediatric
patients (10-16 years of age); the maximum recommended daily dose of Glucophage (Metformin hydrochloride)
XR in adults is 2000 mg.
Glucophage (Metformin hydrochloride) should be given
in divided doses with meals while Glucophage (Metformin hydrochloride) XR should generally be given
once daily with the evening meal. Glucophage (Metformin hydrochloride) or Glucophage (Metformin hydrochloride) 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 ), fasting plasma glucose should be used to determine
the therapeutic response to Glucophage (Metformin hydrochloride) or Glucophage (Metformin hydrochloride) XR and identify the minimum
effective dose for the patient. Thereafter, glycosylated hemoglobin should
be measured at intervals of approximately 3 months.
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 (Metformin hydrochloride) or Glucophage (Metformin hydrochloride) XR may be sufficient during periods
of transient loss of control in patients usually well-controlled on diet alone.
If patients have not responded to 4 weeks
of the maximum dose of Glucophage (Metformin hydrochloride) or Glucophage (Metformin hydrochloride) XR monotherapy, consideration
should be given to gradual addition of an oral sulfonylurea while continuing
Glucophage (Metformin hydrochloride) or Glucophage (Metformin hydrochloride) 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 (Metformin hydrochloride)
or Glucophage (Metformin hydrochloride) XR and sulfonylurea therapy, the desired control of blood glucose
may be obtained by adjusting the dose of each drug. In a clinical trial of
patients with type 2 diabetes and prior failure on glyburide, patients started
on Glucophage (Metformin hydrochloride) 500 mg and glyburide 20 mg were titrated to 1000/20 mg, 1500/20
mg, 2000/20 mg, or 2500/20 mg of Glucophage (Metformin hydrochloride) and glyburide, respectively, to
reach the goal of glycemic control as measured by FPG, HbA,
and plasma glucose response (see ). However, attempts should be made to identify
the minimum effective dose of each drug to achieve this goal. With concomitant
Glucophage (Metformin hydrochloride) or Glucophage (Metformin hydrochloride) 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 1 to 3 months of concomitant
therapy with the maximum dose of Glucophage (Metformin hydrochloride) or Glucophage (Metformin hydrochloride) XR and the maximum
dose of an oral sulfonylurea, consider therapeutic alternatives including
switching to insulin with or without Glucophage (Metformin hydrochloride) or Glucophage (Metformin hydrochloride) XR.
Glucophage (Metformin hydrochloride) or Glucophage (Metformin hydrochloride) XR are not recommended
for use in pregnancy. Glucophage (Metformin hydrochloride) is not recommended in patients below the
age of 10 years. Glucophage (Metformin hydrochloride) XR is not recommended in pediatric patients (below
the age of 17 years).
The initial and maintenance dosing
of Glucophage (Metformin hydrochloride) or Glucophage (Metformin hydrochloride) 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 (Metformin hydrochloride) or Glucophage (Metformin hydrochloride) XR.
Monitoring
of renal function is necessary to aid in prevention of lactic acidosis, particularly
in the elderly. (See .)
Glucophage (Metformin hydrochloride) How Supplied
Glucophage (Metformin hydrochloride) (metformin
hydrochloride) Tablets
Glucophage (Metformin hydrochloride) 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 (Metformin hydrochloride)
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 (Metformin hydrochloride)
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 (Metformin hydrochloride) XR
(metformin hydrochloride) Extended-Release Tablets
Glucophage (Metformin hydrochloride) XR 500 mg tablets are white to off-white, capsule
shaped, biconvex tablets, with "BMS 6063" debossed on one side and "500"
debossed across the face of the other side.
Glucophage (Metformin hydrochloride)
XR 750 mg tablets are capsule shaped, biconvex tablets, with "BMS 6064" debossed
on one side and "750" debossed on the other side. The tablets are pale red
and may have a mottled appearance.
Glucophage (Metformin hydrochloride)
Glucophage (Metformin hydrochloride)
Glucophage (Metformin hydrochloride)
Glucophage (Metformin hydrochloride)
Glucophage (Metformin hydrochloride)
