Approved Drug Label (PDF)
Boxed Warning
(additions
underlined)
WARNING: CONGESTIVE HEART FAILURE and LACTIC ACIDOSIS
Rosiglitazone
maleate: CONGESTIVE HEART FAILURE
• Thiazolidinediones, including rosiglitazone, cause or
exacerbate congestive heart failure in some patients. After initiation of
AVANDAMET, and after dose increases, observe patients carefully for signs and
symptoms of heart failure (including excessive, rapid weight gain, dyspnea,
and/or edema). If these signs and symptoms
develop, the heart failure should be managed according to current standards of
care. Furthermore, discontinuation or dose reduction of AVANDAMET must be
considered.
• AVANDAMET is not recommended in patients with symptomatic
heart failure. Initiation of AVANDAMET in patients with established NYHA Class
III or IV heart failure is contraindicated.
Metformin
hydrochloride: LACTIC ACIDOSIS
• Postmarketing cases of metformin-associated lactic
acidosis have resulted in death, hypothermia, hypotension, and resistant
bradyarrhythmias. The onset of metformin- associated lactic acidosis often subtle,
accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory
distress, somnolence, and abdominalpain. Metformin- associated
lactic acidosis was characterized by elevated blood lactate levels (>5
mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and
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 in the Full Prescribing
Information.
• If metformin-associated lactic acidosis is
suspected, immediately discontinue AVANDAMET and institute
general supportive measures in a hospital setting. Prompt hemodialysis is
recommended.
4
Contraindications
(addition
underlined)
• Initiation in patients with established New York Heart
Association (NYHA) Class III or IV
heart failure [see Boxed Warning].
• Severe renal impairment (eGFR below 30 mL/minute/1.73
m2).
• Use in patients with acute or chronic metabolic acidosis,
including diabetic ketoacidosis, with or without coma.
• Use in patients with a history of a hypersensitivity
reaction to rosiglitazone or any of the product’s ingredients.
5
Warnings and Precautions
5.1 Lactic Acidosis
(subsection
revised, additions underlined)
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,
hypothermia, 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 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 AVANDAMET. In patients treated with AVANDAMET 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 to170 mL/minute 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 AVANDAMET 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 AVANDAMET, obtain an eGFR.
• AVANDAMET is contraindicated in patients with an eGFR
less than 30 mL/minute/1.73 m2
• Initiation of AVANDAMET is not recommended in patients
with eGFR between 30 –45 mL/minute/1.73 m2.
• Obtain an eGFR at least annually in all patients taking
AVANDAMET. In patients at increased risk for the development of renal
impairment (e.g., the elderly), renal function should be assessed more
frequently.
• In patients taking AVANDAMET eGFR later falls below 45
mL/minute/1.73 m2, assess the benefit and risk of continuing therapy.
Drug Interactions: The concomitant use of AVANDAMET 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. Therefore, 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.
Radiological 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 AVANDAMET at the time of,
or prior to, an iodinated contrast imaging procedure in patients with an eGFR
between 30 and 60 mL/minute/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 AVANDAMET 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. AVANDAMET 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
also cause prerenal azotemia. When such events occur, discontinue AVANDAMET.
Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and
this may increase the risk of metformin-associated lactic acidosis. Warn
patients against excessive alcohol intake while receiving AVANDAMET.Hepatic Impairment: Patients with
hepatic impairment have developed metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate
blood levels. Therefore, avoid
use of AVANDAMET in patients with clinical or laboratory evidence of hepatic
disease.
6
Adverse Reactions
6.3 Postmarketing Experience
(additions
underlined)
Cholestatic,
hepatocellular, and mixed hepatocellular liver injury have been reported with
postmarketing use of metformin.
7
Drug Interactions
7.2 Drugs that Reduce Metformin Clearance
(subsection
revised, 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.
7.3 Carbonic Anhydrase Inhibitors
(new
subsection added)
Topiramate or other carbonic anhydrase inhibitors
(e.g., zonisamide, acetazolamide, or dichlorphenamide) frequently cause a
decrease in serum bicarbonate and induce non-anion gap, hyperchloremic
metabolic acidosis. Concomitant use of these drugs with AVANDAMET may increase
the risk for lactic acidosis. Consider more frequent monitoring of these
patients.
7.4 Alcohol
(new subsection added)
Alcohol
is known to potentiate the effect of metformin on lactate metabolism. Warn
patients against excessive alcohol intake while receiving AVANDAMET.
8
Use in Specific Populations
8.5 Geriatric Use
(additions
underlined)
Because
reduced renal function is associated with increasing age, AVANDAMET should be
used with caution in elderly patients. In general, dose selection for
an elderly patient should 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.
8.6 Renal Impairment
(new
subsection added)
Metformin
is substantially excreted by the kidney, and the risk of metformin accumulation
and lactic acidosis increases with the degree of renal impairment. AVANDAMET is
contraindicated in severe renal impairment, patients with an eGFR below 30
mL/minute/1.73 m2.
8.7 Hepatic Impairment
(new
subsection added)
Use
of metformin in patients with hepatic impairment has been associated with some
cases of lactic acidosis. AVANDAMET is not recommended in patients with hepatic
impairment.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION
(additions
underlined)
Advise
the patient to read the FDA-approved patient labeling (Medication Guide).
There
are multiple medications available to treat type 2 diabetes. The benefits and
risks of each available diabetes
medication should be taken into account when choosing a particular diabetes
medication for a given patient.
Patients
should be informed of the following:
…
• Instruct patients to inform their doctor that they
are taking AVANDAMET prior to any surgical or radiological procedure, as
temporary discontinuation of AVANDAMET may be required until renal function has
been confirmed to be normal.
…
MEDICATION GUIDE
(additions
and revisions, please refer to label)