Included as part of the PRECAUTIONS section.
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.
Metforminassociated lactic acidosis was characterized by elevated blood lactate
concentrations (> 5mmol/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 RIOMET. In RIOMET 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
RIOMET 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:
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, CLINICAL PHARMACOLOGY]:
- Before initiating RIOMET, obtain an estimated glomerular
filtration rate (eGFR).
- RIOMET is contraindicated in patients with an eGFR less
than 30 mL/min/1.73 m² [see CONTRAINDICATIONS].
- Initiation of RIOMET is not recommended in patients with
eGFR between 30 to 45 mL/min/1.73 m².
- Obtain an eGFR at least annually in all patients taking
RIOMET. In patients at risk for the development of renal impairment (e.g., the
elderly), renal function should be assessed more frequently.
- In patients taking RIOMET whose eGFR falls below 45
mL/min/1.73 m², assess the benefit and risk of continuing therapy.
The concomitant use of RIOMET 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 [see DRUG INTERACTIONS].
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 RIOMET 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 intraarterial iodinated
contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart RIOMET
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. RIOMET
should be temporarily discontinued while patients have restricted food and
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,
Excessive Alcohol Intake
Alcohol potentiates the effect of metformin on lactate
metabolism. Patients should be warned against excessive alcohol intake while
Patients with hepatic impairment have developed cases of
metforminassociated lactic acidosis. Thismay be due to impaired lactate
clearance resulting in higher lactate blood levels. Therefore, avoid use of
RIOMET in patients with clinical or laboratory evidence of hepatic disease.
Vitamin B12 Deficiency
In clinical trials of 29-week duration with metformin
hydrochloride (HCl) tablets, a decrease to subnormal levels of previously
normal serum vitamin B12 levels was observed in approximately 7% of patients.
Such decrease, possibly due to interference with B12 absorption from the
B12-intrinsic factor complex, may be associated with anemia but appears to be
rapidly reversible with discontinuation of metformin or vitamin B12
supplementation. Certain individuals (those with inadequate vitamin B12 or
calcium intake or absorption) appear to be predisposed to developing subnormal
vitamin B12 levels. Measure hematologic parameters on an annual basis and
vitamin B12 at 2 to 3 year intervals in patients on RIOMET and manage any
abnormalities [see ADVERSE REACTIONS].
Hypoglycemia With Concomitant Use With Insulin And
Insulin and insulin secretagogues (e.g., sulfonylurea)
are known to cause hypoglycemia. RIOMET may increase the risk of hypoglycemia
when combinedwith insulin and/or an insulin secretagogue. Therefore, a lower
dose of insulin or insulin secretagogue may be required to minimize the risk of
hypoglycemia when used in combination with RIOMET [see DRUG INTERACTIONS].
There have been no clinical studies establishing
conclusive evidence of macrovascular risk reduction with RIOMET.
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (PATIENT INFORMATION).
Instruct patients or caregivers to use the supplied
dosing cup to measure the prescribed amount of medication. Inform patients that
additional RIOMET dosing cups or oral dosing syringes may be obtained from
Explain the risks of lactic acidosis, its symptoms, and
conditions that predispose to its development. Advise patients to discontinue
RIOMET immediately and to promptly notify their healthcare provider if
unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific
symptoms occur. Counsel patients against excessive alcohol intake and inform
patients about importance of regular testing of renal function while receiving
RIOMET. Instruct patients to informtheir doctor that they are taking RIOMET
prior to any surgical or radiological procedure, as temporary discontinuation
may be required [see WARNINGS AND PRECAUTIONS].
Inform patients that hypoglycemia may occur when RIOMET
is coadministered with oral sulfonylureas and insulin. Explain to patients
receiving concomitant therapy the risks of hypoglycemia, its symptoms and
treatment, and conditions that predispose to its development [see WARNINGS
Vitamin B12 Deficiency
Inform patients about importance of regular hematological
parameters while receiving RIOMET [see WARNINGS AND PRECAUTIONS].
Females Of Reproductive Age
Inform females that treatment with RIOMET may result in
ovulation in some premenopausal anovulatory women which may lead to unintended
pregnancy [see Use In Specific Populations].
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 1,500 mg/kg/day, respectively.
These doses are both approximately 3 times the maximum recommended human daily
dose of 2,550 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
Fertility of male or female rats was unaffected by
metformin when administered at doses as high as 600 mg/kg/day, which is
approximately 2 times the maximum recommended human daily dose of 2,550 mg
based on body surface area comparisons.
Use In Specific Populations
Limited data with RIOMET in pregnant women are not
sufficient to determine a drug-associated risk for major birth defects or
miscarriage. Published studies with metformin use during pregnancy have not
reported a clear association with metformin and major birth defect or
miscarriage risk [see Data]. There are risks to the mother and fetus
associated with poorly controlled diabetes mellitus in pregnancy [see Clinical
No adverse developmental effects were observed when
metformin was administered to pregnant Sprague Dawley rats and rabbits during
the period of organogenesis at doses up to 2- and 5times, respectively, a 2,550
mg clinical dose, based on body surface area [see Data].
The estimated background risk of major birth defects is 6
to 10% in women with pre-gestational diabetes mellitus with an HbA1C >7 and
has been reported to be as high as 20 to 25% in women with a HbA1C >10. The
estimated background risk of miscarriage for the indicated population is unknown.
In the U.S. general population, the estimated background risk of major birth
defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15
to 20%, respectively.
Disease-Associated Maternal And/Or Embryo/Fetal Risk
Poorly-controlled diabetes mellitus in pregnancy
increases the maternal risk for diabetic ketoacidosis, pre-eclampsia,
spontaneous abortions, preterm delivery, stillbirth and delivery complications.
Poorly controlled diabetes mellitus increases the fetal risk for major birth
defects, stillbirth, and macrosomia related morbidity.
Published data from post-marketing studies have not
reported a clear association with metformin and major birth defects,
miscarriage, or adverse maternal or fetal outcomes when metformin was used during
pregnancy. However, these studies cannot definitely establish the absence of
any metforminassociated risk because of methodological limitations, including
small sample size and inconsistent comparator groups.
Metformin hydrochloride did not adversely affect
development outcomes when administered to pregnant rats and rabbits at doses up
to 600 mg/kg/day. This represents an exposure of about 2 and 5 times a 2,550 mg
clinical dose based on body surface area comparisons for rats and rabbits, respectively.
Determination of fetal concentrations demonstrated a partial placental barrier
Limited published studies report thatmetformin is present
in human milk [see Data]. However, there is insufficient information to
determine the effects of metformin on the breastfed infant and no available
information on the effects of metformin on milk production. Therefore, the
developmental and health benefits of breastfeeding should be considered along
with the mother's clinical need for RIOMET and any potential adverse effects on
the breastfed child from RIOMET or from the underlying maternal condition.
Published clinical lactation studies report that
metformin is present in human milk which resulted in infant doses approximately
0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio
ranging between 0.13 and 1. However, the studies were not designed to
definitely establish the risk of use of metformin during lactation because of
small sample size and limited adverse event data collected in infants.
Females And Males Of Reproductive Potential
Discuss the potential for unintended pregnancy with
premenopausal women as therapy with RIOMET may result in ovulation in some
The safety and effectiveness of RIOMET for the treatment
of type 2 diabetes mellitus have been established in pediatric patients 10 to
16 years old. Safety and effectiveness of RIOMET have not been established in
pediatric patients less than 10 years old.
Use of RIOMET in pediatric patients 10 to 16 years old
for the treatment of type 2 diabetes mellitus is supported by evidence from
adequate and well-controlled studies of metformin HCl tablets in adults with
additional data from a controlled clinical study of metformin HCl tablets in
pediatric patients 10 to 16 years old with type 2 diabetes mellitus, which
demonstrated a similar response in glycemic control to that seen in adults [see
Clinical Studies]. In this study, adverse reactions were similar to
those described in adults. A maximum daily dose of 2,000 mg of RIOMET is recommended.
[See DOSAGE AND ADMINISTRATION]
Controlled clinical studies of metformin HCl tablets did
not include sufficient numbers of elderly patients to determine whether they
respond differently from 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 [see WARNINGS AND PRECAUTIONS].
Metformin is substantially excreted by the kidney, and the
risk of metformin accumulation and lactic acidosis increases with the degree of
renal impairment. RIOMET is contraindicated in severe renal impairment,
patients with an estimated glomerular filtration rate (eGFR) below 30
mL/min/1.73 m² [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS,
WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY].
Use of metformin in patients with hepatic impairment has
been associated with some cases of lactic acidosis. RIOMET is not recommended
in patients with hepatic impairment. [see WARNINGS AND PRECAUTIONS].