There have been postmarketing cases of metformin-associated lactic acidosis,
including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms
such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however,
hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated
lactic acidosis was characterized by elevated blood lactate concentrations (> 5 mmol/L), anion gap
acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin
plasma levels were generally > 5 mcg/mL. Metformin decreases liver uptake of lactate increasing
lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.
If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted
promptly in a hospital setting, along with immediate discontinuation of FORTAMET®. In
FORTAMET® treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt
hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin
hydrochloride is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions).
Hemodialysis has often resulted in reversal of symptoms and recovery.
Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur,
instruct them to discontinue FORTAMET® and report these symptoms to their healthcare provider.
For each of the known and possible risk factors for metformin-associated lactic acidosis,
recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided
The postmarketing metformin-associated lactic acidosis cases primarily
occurred in patients with significant renal impairment. The risk of metformin accumulation and
metformin-associated lactic acidosis increases with the severity of renal impairment because
metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's
renal function include (see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY):
- Before initiating FORTAMET®, obtain an estimated glomerular filtration rate (eGFR)
- FORTAMET® is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 (see CONTRAINDICATIONS).
- Initiation of FORTAMET® is not recommended in patients with eGFR between
30-45 mL/min/1.73 m2 .
- Obtain an eGFR at least annually in all patients taking FORTAMET®. In patients at risk for the
development of renal impairment (e.g., the elderly), renal function should be assessed more
- In patients taking FORTAMET® whose eGFR falls below 45 mL/min/1.73 m2 , assess the benefit
and risk of continuing therapy.
The concomitant use of FORTAMET® with specific drugs may increase the
risk of metformin-associated lactic acidosis: those that impair renal function, result in significant
hemodynamic change, interfere with acid-base balance, or increase metformin accumulation.
Consider more frequent monitoring of patients.
Age 65 Or Greater
The risk of metformin-associated lactic acidosis increases with the patient's
age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac
impairment than younger patients. Assess renal function more frequently in elderly patients.
Radiologic studies with contrast—Administration of intravascular iodinated contrast agents in
metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic
acidosis. Stop FORTAMET® at the time of, or prior to, an iodinated contrast imaging procedure in
patients with an eGFR between 30 and 60 mL/min/1.73 m2 ; in patients with a history of hepatic
impairment, alcoholism or heart failure, or in patients who will be administered intra-arterial
iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart
FORTAMET® if renal function is stable.
Surgery And Other Procedures
Withholding of food and fluids during surgical or other procedures
may increase the risk for volume depletion, hypotension, and renal impairment. FORTAMET®
should be temporarily discontinued while patients have restricted food and fluid intake.
Several of the postmarketing cases of metformin-associated lactic acidosis
occurred in the setting of acute congestive heart failure (particularly when accompanied by
hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction,
sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis
and may cause prerenal azotemia. When such an event occurs, discontinue FORTAMET®.
Excessive 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 FORTAMET®.
Patients with hepatic impairment have developed cases of metforminassociated
lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate
blood levels. Therefore, avoid use of FORTAMET® in patients with clinical or laboratory
evidence of hepatic disease.
Vitamin B12 Levels
In controlled clinical trials of immediate-release metformin of 29 weeks duration,
a decrease to subnormal levels of previously normal serum Vitamin B12 levels, without clinical
manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to
interference with B12 absorption from the B12 -intrinsic factor complex, is, however, very rarely
associated with anemia and appears to be rapidly reversible with discontinuation of immediate-release
metformin or Vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis
is advised in patients on FORTAMET® and any apparent abnormalities should be appropriately
investigated and managed (see PRECAUTIONS: Laboratory Tests ). Certain individuals (those with
inadequate Vitamin B12 or calcium intake or absorption) appear to be predisposed to developing
subnormal Vitamin B12 levels. In these patients, routine serum Vitamin B12 measurements at two- to
three-year intervals may be useful.
Hypoglycemia does not occur in patients receiving FORTAMET® 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.
There have been no clinical studies establishing conclusive evidence of
macrovascular risk reduction with FORTAMET® or any other anti-diabetic drug.
Information For Patients
Patients should be informed of the potential risks and benefits of FORTAMET® 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 FORTAMET® 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 FORTAMET® , 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 counseled against excessive alcohol intake, either acute or chronic, while receiving
FORTAMET® alone does not usually cause hypoglycemia, although it may occur when FORTAMET®
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).
Patients should be informed that FORTAMET® must be swallowed whole and not chewed, cut, or
crushed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that
may resemble the original tablet (see PATIENT INFORMATION).
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 immediate-release metformin therapy, if this is
suspected, Vitamin B12 deficiency should be excluded.
Instruct patients to inform their doctor that they are taking FORTAMET® prior to any surgical or
radiological procedure, as temporary discontinuation of FORTAMET® may be required until renal
function has been confirmed to be normal (see PRECAUTIONS).
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term carcinogenicity studies with metformin 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 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 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, FORTAMET® should not be used
during pregnancy unless clearly needed.
There are no adequate and well-controlled studies in pregnant women with immediate-release metformin
or FORTAMET® . 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.
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 FORTAMET®
is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be
No pediatric clinical studies have been conducted with FORTAMET® . The safety and effectiveness of
immediate-release metformin 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 immediate-release metformin in this age group is supported by evidence from adequate
and well-controlled studies of immediate-release metformin 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 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 of immediate-release metformin is recommended.
The safety and efficacy of FORTAMET® has not been evaluated in pediatric patients.
Of the 389 patients who received FORTAMET® in controlled Phase III clinical studies, 26.5%
[103/389] were 65 years and older. No overall differences in effectiveness or safety were observed
between these patients and younger patients.
Controlled clinical studies of immediate-release metformin 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
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the
dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of
concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function
more frequently in elderly patients (see WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).