us avandamet, rosiglitazon [ Pobierz całość w formacie PDF ]
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
AVANDAMET safely and effectively. See full prescribing information
for AVANDAMET.
•
Give in divided doses with meals with gradual dose escalation to reduce
the gastrointestinal side effects. (2.2)
•
Do not exceed the maximum recommended daily dose of 8 mg
rosiglitazone and 2,000 mg metformin. (2.3)
•
Do not initiate if the patient exhibits clinical evidence of active liver
disease or increased serum transaminase levels. (2.4)
--------------------- DOSAGE FORMS AND STRENGTHS --------------
Oval, film-coated tablets containing rosiglitazone/metformin hydrochloride:
2 mg/500 mg, 4 mg/500 mg, 2 mg/1,000 mg, and 4 mg/1,000 mg (3)
-------------------------------CONTRAINDICATIONS------------------------
•
Initiation in patients with established NYHA Class III or IV heart failure. (4)
•
Use in significant renal disease or renal dysfunction. (4)
•
Use in acute or chronic metabolic acidosis. (4)
•
Use in patients undergoing radiologic studies involving intravascular
administration of iodinated contrast materials. (4, 5.1)
----------------------- WARNINGS AND PRECAUTIONS ----------------
•
Fluid retention, which may exacerbate or lead to heart failure, may occur.
Combination use with insulin and use in congestive heart failure NYHA Class
I and II may increase risk of other cardiovascular effects. (5.2, 5.3, 5.5)
•
Increased risk of myocardial ischemic events has been observed in a meta-
analysis of 42 clinical trials of rosiglitazone (incidence rate 2% versus 1.5%).
(5.3)
•
Use with nitrates is not recommended. (5.3)
•
Coadministration with insulin is not recommended. (1.1, 5.3, 5.4)
•
Assess renal function before starting therapy and at least annually. (5.1)
•
Avoid use in patients with evidence of hepatic disease. (2.4, 5.1)
•
Warn patients against excessive alcohol intake. (5.1)
•
Promptly evaluate patients who develop laboratory abnormalities or clinical
illness for evidence of ketoacidosis or lactic acidosis. (5.1)
•
Dose-related edema (5.5), weight gain (5.6), and anemia (5.10) may occur.
•
Macular edema has been reported. (5.8)
•
Increased incidence of bone fracture in female patients. (5.9)
•
Measure hematologic parameters annually. (5.10)
•
There have been no clinical studies establishing conclusive evidence of
macrovascular risk reduction with AVANDAMET or any other antidiabetic
drug. (5.3)
------------------------------ ADVERSE REACTIONS -----------------------
The most common adverse reactions (≥10%) include nausea/vomiting,
diarrhea, headache, and dyspepsia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact
GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or
-------------------------------DRUG INTERACTIONS ------------------------
•
Inhibitors of CYP2C8 (e.g., gemfibrozil) may increase rosiglitazone levels.
(7.1)
•
Inducers of CYP2C8 (e.g., rifampin) may decrease rosiglitazone levels. (7.1)
•
Cationic drugs eliminated by renal tubular secretion; use with caution. (7.2)
----------------------- USE IN SPECIFIC POPULATIONS ----------------
•
Do not use during pregnancy. No human or animal data. (8.1)
•
Safety and effectiveness in children under 18 years have not been
established. (8.4)
•
Because reduced renal function is associated with increasing age, use with
caution in elderly patients. (8.5)
AVANDAMET
®
(rosiglitazone maleate and metformin hydrochloride)
Tablets
Initial U.S. Approval: 2002
WARNINGS
See full prescribing information for complete boxed warning.
Rosiglitazone maleate: CONGESTIVE HEART FAILURE AND
MYOCARDIAL ISCHEMIA
•
Thiazolidinediones, including rosiglitazone, cause or exacerbate heart
failure in some patients (5.2). 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 must be considered. (5.2)
•
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. (4, 5.2)
•
A meta-analysis of 42 studies (mean duration 6 months; 14,237 total
patients), most of which compared rosiglitazone to placebo, showed
rosiglitazone to be associated with an increased risk of myocardial ischemic
events. Three other studies (mean duration 41 months; 14,067 total
patients), comparing rosiglitazone to some other approved oral antidiabetic
agents or placebo, have not confirmed or excluded this risk. Available data
on the risk of myocardial ischemia are inconclusive. (5.3)
Metformin hydrochloride:
LACTIC ACIDOSIS
•
Lactic acidosis can occur due to metformin accumulation. The risk
increases with conditions such as sepsis, dehydration, excess alcohol intake,
hepatic insufficiency, renal impairment and acute congestive heart failure.
(5.1)
•
Symptoms include malaise, myalgias, respiratory distress, increasing
somnolence and nonspecific abdominal distress. Laboratory abnormalities
include low pH, increased anion gap and elevated blood lactate. (5.1)
•
If acidosis is suspected, discontinue AVANDAMET and hospitalize the
patient immediately. (5.1)
---------------------------RECENT MAJOR CHANGES --------------------
Boxed Warning
12/2008
Indications and Usage, Important Limitations of Use (1.1)
12/2008
Warnings and Precautions, Cardiac Failure (5.2)
12/2008
Warnings and Precautions, Myocardial Ischemia (5.3)
12/2008
Warnings and Precautions, Coadministration of Rosiglitazone
with Insulin (5.4)
12/2008
Warnings and Precautions, Edema (5.5) 12/2008
----------------------------INDICATIONS AND USAGE ---------------------
AVANDAMET is indicated as an adjunct to diet and exercise to improve
glycemic control in adults with type 2 diabetes mellitus when treatment with
both rosiglitazone and metformin is appropriate.
Important Limitations of Use:
•
Should not be used in patients with type 1 diabetes or for the treatment of
diabetic ketoacidosis. (1.1)
•
Use with nitrates is not recommended. (1.1, 5.3)
•
Coadministration with insulin is not recommended.
(1.1, 5.4)
----------------------- DOSAGE AND ADMINISTRATION ----------------
•
Individualize the starting dose based on the patient’s current regimen. (2.1)
•
Dose increases should be accompanied by careful monitoring for adverse
events related to fluid retention. (2.1)
See 17 for PATIENT COUNSELING INFORMATION and FDA-
approved Medication Guide.
Revised: December 2008
AVM:18PI
FULL PRESCRIBING INFORMATION: CONTENTS*
1
S AND PRECAUTIONS
WA
c
V
C
*
Sections or subsections omitted from the full prescribing information are not
listed.
c
C
r
2
______________________________________________________________________
FULL PRESCRIBING INFORMATION
WARNINGS
Rosiglitazone maleate
: CONGESTIVE HEART FAILURE AND MYOCARDIAL
ISCHEMIA
•
Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive heart failure
in some patients
[see Warnings and Precautions (5.2)]
. 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.
[See Contraindications (4) and Warnings and Precautions
(5.2).]
•
A meta-analysis of 42 clinical studies (mean duration 6 months; 14,237 total patients),
most of which compared rosiglitazone to placebo, showed rosiglitazone to be associated
with an increased risk of myocardial ischemic events such as angina or myocardial
infarction. Three other studies (mean duration 41 months; 14,067 total patients),
comparing rosiglitazone to some other approved oral antidiabetic agents or placebo,
have not confirmed or excluded this risk. In their entirety, the available data on the risk
of myocardial ischemia are inconclusive.
[See Warnings and Precautions (5.3).]
Metformin hydrochloride:
LACTIC ACIDOSIS
•
Lactic acidosis is a rare, but serious complication that can occur due to metformin
accumulation. The risk increases with conditions such as sepsis, dehydration, excess
alcohol intake, hepatic insufficiency, renal impairment, and acute congestive heart
failure.
[See Warnings and Precautions (5.1).]
•
Symptoms include malaise, myalgias, respiratory distress, increasing somnolence, and
nonspecific abdominal distress. Laboratory abnormalities include low pH, increased
anion gap and elevated blood lactate.
[See Warnings and Precautions (5.1).]
•
If acidosis is suspected, discontinue AVANDAMET and hospitalize the patient
immediately
[see Warnings and Precautions (5.1)]
.
1 INDICATIONS AND USAGE
AVANDAMET is indicated as an adjunct to diet and exercise to improve glycemic
control in adults with type 2 diabetes mellitus when treatment with both rosiglitazone and
metformin is appropriate.
[See Clinical Studies (14).]
3
 1.1 Important Limitations of Use
•
Due to its mechanism of action, rosiglitazone is active only in the presence of endogenous
insulin. Therefore, AVANDAMET should not be used in patients with type 1 diabetes.
•
The use of AVANDAMET with nitrates is not recommended
[see Warnings and Precautions
(5.3)]
.
•
Coadministration of AVANDAMET with insulin is not recommended
[see Warnings and
Precautions (5.4)]
.
2 DOSAGE AND ADMINISTRATION
The dosage of antidiabetic therapy with AVANDAMET should be individualized on the
basis of effectiveness and tolerability. The risk-benefit of initiating monotherapy versus dual
therapy with AVANDAMET should be considered.
2.1 Starting Dose
AVANDAMET is generally given in divided doses with meals.
All patients should start the rosiglitazone component of AVANDAMET at the lowest
recommended dose. Further increases in the dose of rosiglitazone should be accompanied by
careful monitoring for adverse events related to fluid retention
[see
Boxed Warning
and
Warnings and Precautions (5.5)]
.
Patients Inadequately Controlled With Diet and Exercise:
If therapy with a
combination tablet containing rosiglitazone and metformin is considered appropriate for a patient
with type 2 diabetes mellitus inadequately controlled with diet and exercise alone, the
recommended starting dose of AVANDAMET is 2 mg/500 mg administered once or twice daily.
For patients with HbA1c >11% or fasting plasma glucose (FPG) >270 mg/dL, a starting dose of
2 mg/500 mg twice daily may be considered. The dose of AVANDAMET may be increased in
increments of 2 mg/500 mg per day given in divided doses if patients are not adequately
controlled after 4 weeks. The maximum dose of AVANDAMET is 8 mg/2,000 mg per day.
Patients Inadequately Controlled With Rosiglitazone or Metformin Monotherapy:
If therapy with a combination tablet containing rosiglitazone and metformin is considered
appropriate for a patient with type 2 diabetes mellitus inadequately controlled on rosiglitazone or
metformin monotherapy, then the selection of the dose of AVANDAMET should be based on
the patient’s current doses of rosiglitazone and/or metformin.
For patients inadequately controlled on metformin monotherapy,
the usual starting
dose of AVANDAMET is 4 mg rosiglitazone (total daily dose) plus the dose of metformin
already being taken (see Table 1).
For patients inadequately controlled on rosiglitazone monotherapy,
the usual starting
dose of AVANDAMET is 1,000 mg metformin (total daily dose) plus the dose of rosiglitazone
already being taken (see Table 1).
When switching from combination therapy of rosiglitazone plus metformin as separate
tablets, the usual starting dose of AVANDAMET is the dose of rosiglitazone and metformin
already being taken.
4
 Table 1. AVANDAMET Starting Dose for Patients Treated with Metformin and/or
Rosiglitazone
PRIOR THERAPY
Usual AVANDAMET Starting Dose
Total daily dose
Tablet strength
Number of tablets
Metformin
*
1,000 mg/day
2 mg/500 mg
1 tablet twice a day
2,000 mg/day
2 mg/1,000 mg
1 tablet twice a day
Rosiglitazone
4 mg/day
2 mg/500 mg
1 tablet twice a day
8 mg/day
4 mg/500 mg
1 tablet twice a day
*
For patients on doses of metformin between 1,000 and 2,000 mg/day, initiation of
AVANDAMET requires individualization of therapy.
2.2 Dose Titration
AVANDAMET is generally given in divided doses with meals, with gradual dose
escalation. This reduces gastrointestinal side effects (largely due to metformin) and permits
determination of the minimum effective dose for the individual patient.
Sufficient time should be given to assess adequacy of therapeutic response. FPG should
be used initially to determine the therapeutic response to AVANDAMET. If additional glycemic
control is needed, the daily dose of AVANDAMET may be increased by increments of 4 mg
rosiglitazone and/or 500 mg metformin.
After an increase in metformin dosage, dose titration is recommended if patients are not
adequately controlled after 1 to 2 weeks. After an increase in rosiglitazone dosage, dose titration
is recommended if patients are not adequately controlled after 8 to 12 weeks.
2.3 Maximum Dose
The maximum recommended total daily dose of AVANDAMET is 8 mg rosiglitazone
(taken as 4 mg twice daily) and 2,000 mg metformin (taken as 1,000 mg twice daily).
2.4 Specific Patient Populations
Renal Impairment:
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 AVANDAMET. Monitoring of renal function is necessary to aid in
prevention of metformin-associated lactic acidosis, particularly in the elderly
[see Warnings and
Precautions (5.1)]
.
Hepatic Impairment:
Liver enzymes should be measured prior to initiating treatment
with AVANDAMET. Therapy with AVANDAMET should not be initiated if the patient exhibits
clinical evidence of active liver disease or increased serum transaminase levels (ALT >2.5X
upper limit of normal at start of therapy). After initiation of AVANDAMET, liver enzymes
should be monitored periodically per the clinical judgment of the healthcare professional
[see
5
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