Approved Drug Label (PDF)
4
Contraindications
(addition
underlined)
FORTAMET® is contraindicated in
patients with:
1. Severe renal impairment (eGFR below 30
mL/min/1.73 m2)
2. Known hypersensitivity to metformin.
3. Acute or chronic metabolic acidosis,
including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis
should be treated with insulin.
5
Warnings and Precautions
PRECAUTIONS General
(section
revised, additions underlined)
Lactic Acidosis—There have been post-marketing 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 increases 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 below:
- Renal Impairment—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 :
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
Initiation of
FORTAME is not recommended in patients with eGFR between 30- 45mL/min/1.73
m2.
Obtain an eGFR at least annually in all patient taking
FORTAMET. In patients at risk for the development of renal impairment
(e.g., the elderly), renal function should be assessed more frequently
In patients
taking FORTAMET whose eGFR falls below 45 mL/min/1.73 m2, assess the benefit
and risk of continuing therapy.
- Drug interactions—The concomitantuse of FORTAMET with
specific drugs may increase the risk of metformin-associated lactic
acidosis: those that mpair renal function, result in significant hemodynamic
change interfere with -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.
- Hypoxic states—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.
- Hepatic impairment—Patients with hepatic impairment have developed cases of
metformin- associated 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. 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.
Macrovascular
Outcomes –There have been no
clinical studies establishing conclusive evidence of macrovascular risk
reduction with FORTAMET® or any other anti-diabetic drug.
WARNING
(section
revised, additions underlined)
LACTIC ACIDOSIS
Post-marketing
cases of metformin-associated lactic acidosis have resulted in death,
hypothermia, hypotension, and resistant bradyarrhythmias. The onset of
metformin-associated lactic acidosis is often subtle, accompanied only by
nonspecific symptoms such as malaise, myalgias, respiratory distress,
somnolence, and abdominal pain. Metformin-associated lactic acidosis was
characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap
acidosis (without evidence of ketonuria or ketonemia), an increased
lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.
Risk factors for
metformin-associated lactic acidosis include renal impairment, concomitant use
of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age
65 years old or greater, having a radiological study with contrast, surgery and
other procedures, hypoxic states (e.g., acute congestive heart failure),
excessive alcohol intake, and hepatic impairment.
Steps to reduce the
risk of and manage metformin-associated lactic acidosis in these high risk
groups are provided.
If
metformin-associated lactic acidosis is suspected, immediately discontinue
FORTAMET and institute general supportive measures in a hospital setting.
Prompt hemodialysis is recommended.
6
Adverse Reactions
Pediatric Patients
(additions
underlined)
No pediatric
clinical studies have
been conducted with
FORTAMET®. In clinical
trials with immediate-release metformin
in pediatric patients
with type 2
diabetes, the profile
of adverse reactions was similar
to that observed in adults.
Cholestatic,
hepatocellular, and mixed
hepatocellular liver injury
have been reported
with postmarketing use of metformin.
7
Drug Interactions
Alcohol
(new
subsection added)
Alcohol is known to potentiate
the effect of metformin on lactate metabolism. Warn patients against excessive
alcohol intake while receiving FORTAMET.
Carbonic Anhydrase Inhibitors
(new
subsection added)
Topiramate or other carbonic
anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide)
frequently causes a decrease in serum bicarbonate and induce non- anion gap,
hyperchloremic metabolic acidosis. Concomitant use of these drugs with FORTAMET
may increase the risk for lactic acidosis. Consider more frequent monitoring of
these patients.
Drugs that reduce metformin clearance
(additions
underlined)
Concomitant use of
drugs that interfere with common renal tubular transport systems involved in
the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]
/ multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could
increase systemic exposure to metformin and may increase the risk for lactic
acidosis. Consider the benefits and risks of concomitant use. 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
In healthy
volunteers, the pharmacokinetics of metformin and propranolol, and metformin
and ibuprofen were not affected when coadministered 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.
8
Use in Specific Populations
Geriatric Use
(additions
underlined)
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 younger patients.
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
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Patient Information
(additions
and revisions, please refer to label)
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