WARNING: CONGESTIVE HEART FAILURE AND MYOCARDIAL ISCHEMIA
Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive
heart failure in some patients [see Warnings and Precautions
(5.1)]. After initiation of AVANDIA, 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 AVANDIA must be considered.
AVANDIA is not recommended in patients with symptomatic heart failure.
Initiation of AVANDIA in patients with established NYHA Class III or IV heart
failure is contraindicated. [See Contraindications (4) and
Warnings and Precautions (5.1).]
A meta-analysis of 42 clinical studies (mean duration 6 months; 14,237 total
patients), most of which compared AVANDIA to placebo, showed AVANDIA 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 AVANDIA 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 (5.2).]
WARNING: CONGESTIVE HEART FAILURE AND MYOCARDIAL ISCHEMIA
Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive
heart failure in some patients [see Warnings and Precautions
(5.1)]. After initiation of AVANDIA, 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 AVANDIA must be considered.
AVANDIA is not recommended in patients with symptomatic heart failure.
Initiation of AVANDIA in patients with established NYHA Class III or IV heart
failure is contraindicated. [See Contraindications (4) and
Warnings and Precautions (5.1).]
A meta-analysis of 42 clinical studies (mean duration 6 months; 14,237 total
patients), most of which compared AVANDIA to placebo, showed AVANDIA 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 AVANDIA 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 (5.2).]
1 Indications And Usage
1.1 Monotherapy and
Combination Therapy AVANDIA is indicated as an adjunct to diet and exercise to
improve glycemic control in adults with type 2 diabetes mellitus. 1.2 Important Limitations of
Use
Due to its mechanism of action, AVANDIA is active only in the presence of
endogenous insulin. Therefore, AVANDIA should not be used in patients with type
1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
The coadministration of AVANDIA and insulin is not recommended.
The use of AVANDIA with nitrates is not recommended.
2 Dosage And Administration
The management of antidiabetic therapy should be individualized.
All patients should start AVANDIA at the lowest recommended dose. Further
increases in the dose of AVANDIA should be accompanied by careful monitoring for
adverse events related to fluid retention [see Boxed Warning
and Warnings and Precautions (5.1)].
AVANDIA may be administered at a starting dose of 4Â mg either as a single
daily dose or in 2 divided doses. For patients who respond inadequately
following 8 to 12Â weeks of treatment, as determined by reduction in fasting
plasma glucose (FPG), the dose may be increased to 8Â mg daily as monotherapy or
in combination with metformin, sulfonylurea, or sulfonylurea plus metformin.
Reductions in glycemic parameters by dose and regimen are described under Clinical Studies (14.1). AVANDIA may be taken with or
without food.
The total daily dose of AVANDIA should not exceed 8Â mg. 2.1 Monotherapy The usual starting dose of AVANDIA is 4Â mg administered either as
a single dose once daily or in divided doses twice daily. In clinical trials,
the 4-mg twice-daily regimen resulted in the greatest reduction in FPG and
hemoglobin A1c (HbA1c). 2.2 Combination With
Sulfonylurea or Metformin When AVANDIA is added to existing therapy, the current dose(s) of
the agent(s) can be continued upon initiation of therapy with AVANDIA. Sulfonylurea
When used in combination with sulfonylurea, the usual starting dose of
AVANDIA is 4Â mg administered as either a single dose once daily or in divided
doses twice daily. If patients report hypoglycemia, the dose of the sulfonylurea
should be decreased. Metformin
The usual starting dose of AVANDIA in combination with metformin is 4Â mg
administered as either a single dose once daily or in divided doses twice daily.
It is unlikely that the dose of metformin will require adjustment due to
hypoglycemia during combination therapy with AVANDIA. 2.3 Combination With
Sulfonylurea Plus Metformin The usual starting dose of AVANDIA in combination with a
sulfonylurea plus metformin is 4Â mg administered as either a single dose once
daily or divided doses twice daily. If patients report hypoglycemia, the dose of
the sulfonylurea should be decreased. 2.4 Specific Patient
Populations Renal Impairment
No dosage adjustment is necessary when AVANDIA is used as monotherapy in
patients with renal impairment. Since metformin is contraindicated in such
patients, concomitant administration of metformin and AVANDIA is also
contraindicated in patients with renal impairment. Hepatic Impairment
Liver enzymes should be measured prior to initiating treatment with AVANDIA.
Therapy with AVANDIA 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
AVANDIA, liver enzymes should be monitored periodically per the clinical
judgment of the healthcare professional. [See Warnings and
Precautions (5.6) and Clinical Pharmacology (12.3).]
Pediatric
Data are insufficient to recommend pediatric use of AVANDIA [see Use in Specific Populations (8.4)].
3 Dosage Forms And Strengths
Pentagonal film-coated TILTAB® tablet
contains rosiglitazone as the maleate as follows:
2 mg - pink, debossed with SB on one side and 2 on the other
4 mg - orange, debossed with SB on one side and 4 on the other
8 mg - red-brown, debossed with SB on one side and 8 on the other
4 Contraindications
Initiation of AVANDIA in patients with established New York Heart Association
(NYHA) Class III or IV heart failure is contraindicated [see
Boxed Warning].
5 Warnings And Precautions
5.1 Cardiac Failure AVANDIA, like other thiazolidinediones, alone or in combination
with other antidiabetic agents, can cause fluid retention, which may exacerbate
or lead to heart failure. Patients should be observed for signs and symptoms of
heart failure. If these signs and symptoms develop, the heart failure should be
managed according to current standards of care. Furthermore, discontinuation or
dose reduction of rosiglitazone must be considered [see
Boxed Warning].
Patients with congestive heart failure (CHF) NYHA Class I and II treated with
AVANDIA have an increased risk of cardiovascular events. A 52-week,
double-blind, placebo-controlled echocardiographic study was conducted in 224
patients with type 2 diabetes mellitus and NYHA Class I or II CHF (ejection
fraction ≤45%) on background antidiabetic and CHF therapy. An independent
committee conducted a blinded evaluation of fluid-related events (including
congestive heart failure) and cardiovascular hospitalizations according to
predefined criteria (adjudication). Separate from the adjudication, other
cardiovascular adverse events were reported by investigators. Although no
treatment difference in change from baseline of ejection fractions was observed,
more cardiovascular adverse events were observed following treatment with
AVANDIA compared to placebo during the 52-week study. (See Table 1.)
Table 1. Emergent Cardiovascular Adverse Events in Patients With Congestive Heart Failure (NYHA Class I and II) Treated With AVANDIA or Placebo (in Addition to Background Antidiabetic and CHF Therapy)
Events
AVANDIA
Placebo
N = 110
n (%)
N = 114
n (%)
Adjudicated
Cardiovascular deaths
5 (5%)
4 (4%)
CHF worsening
7 (6%)
4 (4%)
- with overnight hospitalization
5 (5%)
4 (4%)
- without overnight hospitalization
2 (2%)
0 (0%)
New or worsening edema
28 (25%)
10 (9%)
New or worsening dyspnea
29 (26%)
19 (17%)
Increase in CHF medication
36 (33%)
20 (18%)
Cardiovascular hospitalization*
21 (19%)
15 (13%)
Investigator-reported, non-adjudicated
Ischemic adverse events
10 (9%)
5 (4%)
- Myocardial infarction
5 (5%)
2 (2%)
- Angina
6 (5%)
3 (3%)
* Includes hospitalization for any
cardiovascular reason.
Initiation of AVANDIA in patients with established NYHA Class III or IV heart
failure is contraindicated. AVANDIA is not recommended in patients with
symptomatic heart failure. [See Boxed Warning.]
Patients experiencing acute coronary syndromes have not been studied in
controlled clinical trials. In view of the potential for development of heart
failure in patients having an acute coronary event, initiation of AVANDIA is not
recommended for patients experiencing an acute coronary event, and
discontinuation of AVANDIA during this acute phase should be considered.
Patients with NYHA Class III and IV cardiac status (with or without CHF) have
not been studied in controlled clinical trials. AVANDIA is not recommended in
patients with NYHA Class III and IV cardiac status. 5.2 Myocardial
Ischemia Meta-Analysis of Myocardial Ischemia in a
Group of 42 Clinical Trials
A meta-analysis was conducted retrospectively to assess cardiovascular
adverse events reported across 42 double-blind, randomized, controlled clinical
trials (mean duration 6 months).1 These studies had been
conducted to assess glucose-lowering efficacy in type 2 diabetes, and
prospectively planned adjudication of cardiovascular events had not occurred in
the trials. Some trials were placebo-controlled and some used active oral
antidiabetic drugs as controls. Placebo-controlled studies included monotherapy
trials (monotherapy with AVANDIA versus placebo monotherapy) and add-on trials
(AVANDIA or placebo, added to sulfonylurea, metformin, or insulin). Active
control studies included monotherapy trials (monotherapy with AVANDIA versus
sulfonylurea or metformin monotherapy) and add-on trials (AVANDIA plus
sulfonylurea or AVANDIA plus metformin, versus sulfonylurea plus metformin). A
total of 14,237 patients were included (8,604 in treatment groups containing
AVANDIA, 5,633 in comparator groups), with 4,143 patient-years of exposure to
AVANDIA and 2,675 patient-years of exposure to comparator. Myocardial ischemic
events included angina pectoris, angina pectoris aggravated, unstable angina,
cardiac arrest, chest pain, coronary artery occlusion, dyspnea, myocardial
infarction, coronary thrombosis, myocardial ischemia, coronary artery disease,
and coronary artery disorder. In this analysis, an increased risk of myocardial
ischemia with AVANDIA versus pooled comparators was observed (2% AVANDIA versus
1.5% comparators, odds ratio 1.4, 95% confidence interval [CI] 1.1, 1.8). An
increased risk of myocardial ischemic events with AVANDIA was observed in the
placebo-controlled studies, but not in the active-controlled studies. (See
Figure 1.)
A greater increased risk of myocardial ischemic events was observed in
studies where AVANDIA was added to insulin (2.8% for AVANDIA plus insulin versus
1.4% for placebo plus insulin, [OR 2.1, 95% CI 0.9, 5.1]). This increased risk
reflects a difference of 3 events per 100 patient-years (95% CI -0.1, 6.3)
between treatment groups. [See Warnings and Precautions
(5.3).]
Figure 1. Forest Plot of Odds Ratios (95% Confidence
Intervals) for Myocardial Ischemic Events in the Meta-Analysis of 42 Clinical
Trials
A greater increased risk of myocardial ischemia was also observed in patients
who received AVANDIA and background nitrate therapy. For AVANDIA (N = 361)
versus control (N = 244) in nitrate users, the odds ratio was 2.9 (95% CI 1.4,
5.9), while for non-nitrate users (about 14,000 patients total), the odds ratio
was 1.3 (95% CI 0.9, 1.7). This increased risk represents a difference of 12
myocardial ischemic events per 100 patient-years (95% CI 3.3, 21.4). Most of the
nitrate users had established coronary heart disease. Among patients with known
coronary heart disease who were not on nitrate therapy, an increased risk of
myocardial ischemic events for AVANDIA versus comparator was not demonstrated.
Myocardial Ischemic Events in Large,
Long-Term, Prospective, Randomized, Controlled Trials of AVANDIA
Data from 3 other large, long-term, prospective, randomized, controlled
clinical trials of AVANDIA were assessed separately from the meta-analysis.
These 3 trials include a total of 14,067 patients (treatment groups containing
AVANDIA NÂ =Â 6,311, comparator groups NÂ =Â 7,756), with patient-year exposure of
21,803 patient-years for AVANDIA and 25,998 patient-years for comparator.
Duration of follow-up exceeded 3 years in each study. ADOPT (A Diabetes Outcomes
Progression Trial) was a 4- to 6-year randomized, active-controlled study in
recently diagnosed patients with type 2 diabetes naĂŻve to drug therapy. It was
an efficacy and general safety trial that was designed to examine the durability
of AVANDIA as monotherapy (NÂ =Â 1,456) for glycemic control in type 2 diabetes,
with comparator arms of sulfonylurea monotherapy (NÂ =Â 1,441) and metformin
monotherapy (NÂ =Â 1,454). DREAM (Diabetes Reduction Assessment with Rosiglitazone
and Ramipril Medication, published report2) was a 3- to
5-year randomized, placebo-controlled study in patients with impaired glucose
tolerance and/or impaired fasting glucose. It had a 2x2 factorial design,
intended to evaluate the effect of AVANDIA, and separately of ramipril (an
angiotensin converting enzyme inhibitor [ACEI]), on progression to overt
diabetes. In DREAM, 2,635 patients were in treatment groups containing AVANDIA,
and 2,634 were in treatment groups not containing AVANDIA. Interim results have
been published3 for RECORD (Rosiglitazone Evaluated for
Cardiac Outcomes and Regulation of Glycemia in Diabetes), an ongoing open-label,
6-year cardiovascular outcomes study in patients with type 2 diabetes with an
average treatment duration of 3.75 years. RECORD includes patients who have
failed metformin or sulfonylurea monotherapy; those who have failed metformin
are randomized to receive either add-on AVANDIA or add-on sulfonylurea, and
those who have failed sulfonylurea are randomized to receive either add-on
AVANDIA or add-on metformin. In RECORD, a total of 2,220 patients are receiving
add-on AVANDIA, and 2,227 patients are on one of the add-on regimens not
containing AVANDIA. For these 3 trials, analyses were performed using a composite of major
adverse cardiovascular events (myocardial infarction, cardiovascular death, or
stroke), referred to hereafter as MACE. This endpoint differed from the
meta-analysis’ broad endpoint of myocardial ischemic events, more than half of
which were angina. Myocardial infarction included adjudicated fatal and nonfatal
myocardial infarction plus sudden death. As shown in Figure 2, the results for
the 3 endpoints (MACE, MI, and Total Mortality) were not statistically
significantly different between AVANDIA and comparators. Figure 2. Hazard Ratios for the Risk of MACE
(Myocardial Infarction, Cardiovascular Death, or Stroke), Myocardial Infarction,
and Total Mortality With AVANDIA Compared With a Control Group
In preliminary analyses of the DREAM trial, the incidence of cardiovascular
events was higher among subjects who received AVANDIA in combination with
ramipril than among subjects who received ramipril alone, as illustrated in
Figure 2. This finding was not confirmed in ADOPT and RECORD (active-controlled
trials in patients with diabetes) in which 30% and 40% of patients respectively,
reported ACE-inhibitor use at baseline.
In their entirety, the available data on the risk of myocardial ischemia are
inconclusive. Definitive conclusions regarding this risk await completion of an
adequately-designed cardiovascular outcome study.
There have been no clinical studies establishing conclusive evidence of
macrovascular risk reduction with AVANDIA or any other oral antidiabetic
drug. 5.3 Congestive Heart Failure
and Myocardial Ischemia During Coadministration of AVANDIA With Insulin In studies in which AVANDIA was added to insulin, AVANDIA
increased the risk of congestive heart failure and myocardial ischemia. (See
Table 2.) Coadministration of AVANDIA and insulin is not recommended. [See Indications and Usage (1.2) and Warnings and Precautions
(5.1, 5.2).]
In five, 26-week, controlled, randomized, double-blind trials which were
included in the meta-analysis [see Warnings and Precautions
(5.2)], patients with type 2 diabetes mellitus were randomized to
coadministration of AVANDIA and insulin (NÂ =Â 867) or insulin (NÂ =Â 663). In these
5 trials, AVANDIA was added to insulin. These trials included patients with
long-standing diabetes (median duration of 12 years) and a high prevalence of
pre-existing medical conditions, including peripheral neuropathy, retinopathy,
ischemic heart disease, vascular disease, and congestive heart failure. The
total number of patients with emergent congestive heart failure was 21 (2.4%)
and 7 (1.1%) in the AVANDIA plus insulin and insulin groups, respectively. The
total number of patients with emergent myocardial ischemia was 24 (2.8%) and 9
(1.4%) in the AVANDIA plus insulin and insulin groups, respectively (OR 2.1 [95%
CI 0.9, 5.1]). Although the event rate for congestive heart failure and
myocardial ischemia was low in the studied population, consistently the event
rate was 2-fold or higher with coadministration of AVANDIA and insulin. These
cardiovascular events were noted at both the 4Â mg and 8Â mg daily doses of
AVANDIA. (See Table 2.)
Table 2. Occurrence of Cardiovascular Events in 5 Controlled Trials of Addition of AVANDIA to Established Insulin Treatment
Event*
AVANDIA + Insulin(n = 867)n (%)
Insulin(n = 663)n (%)
Congestive heart failure
21 (2.4%)
7 (1.1%)
Myocardial ischemia
24 (2.8%)
9 (1.4%)
Composite of cardiovascular death, myocardial infarction, or stroke
10 (1.2%)
5 (0.8%)
Stroke
5 (0.6%)
4 (0.6%)
Myocardial infarction
4 (0.5%)
1 (0.2%)
Cardiovascular death
4 (0.5%)
1 (0.2%)
All deaths
6 (0.7%)
1 (0.2%)
*Â Â Â Â Â Events are not exclusive; i.e., a patient with a cardiovascular death due to a
myocardial infarction would be counted in 4 event categories (myocardial
ischemia; cardiovascular death, myocardial infarction, or stroke; myocardial
infarction; cardiovascular death).
In a sixth, 24-week, controlled, randomized, double-blind trial of AVANDIA
and insulin coadministration, insulin was added to AVANDAMET® (rosiglitazone maleate and metformin HCl) (n = 161) and
compared to insulin plus placebo (n = 158), after a single-blind 8-week run-in
with AVANDAMET. Patients with edema requiring pharmacologic therapy and those
with congestive heart failure were excluded at baseline and during the run-in
period. In the group receiving AVANDAMET plus insulin, there was one myocardial
ischemic event and one sudden death. No myocardial ischemia was observed in the
insulin group, and no congestive heart failure was reported in either treatment
group. 5.4 Edema AVANDIA should be used with caution in patients with edema. In a
clinical study in healthy volunteers who received 8Â mg of AVANDIA once daily for
8Â weeks, there was a statistically significant increase in median plasma volume
compared to placebo.
Since thiazolidinediones, including rosiglitazone, can cause fluid retention,
which can exacerbate or lead to congestive heart failure, AVANDIA should be used
with caution in patients at risk for heart failure. Patients should be monitored
for signs and symptoms of heart failure [see Boxed Warning,
Warnings and Precautions (5.1), and Patient Counseling Information
(17.1)].
In controlled clinical trials of patients with type 2 diabetes, mild to
moderate edema was reported in patients treated with AVANDIA, and may be dose
related. Patients with ongoing edema were more likely to have adverse events
associated with edema if started on combination therapy with insulin and AVANDIA
[see Adverse Reactions (6.1)]. 5.5 Weight Gain Dose-related weight gain was seen with AVANDIA alone and in
combination with other hypoglycemic agents (Table 3). The mechanism of weight
gain is unclear but probably involves a combination of fluid retention and fat
accumulation.
In postmarketing experience, there have been reports of unusually rapid
increases in weight and increases in excess of that generally observed in
clinical trials. Patients who experience such increases should be assessed for
fluid accumulation and volume-related events such as excessive edema and
congestive heart failure [see Boxed Warning].
Table 3. Weight Changes (kg) From Baseline at Endpoint During Clinical
Trials
Control Group
AVANDIA
4 mg
AVANDIA
8 mg
Monotherapy
Duration
Median
(25th, 75th
percentile)
Median
(25th, 75th
percentile)
Median
(25th, 75th
percentile)
26 weeks
placebo
-0.9 (-2.8, 0.9)
NÂ =Â 210
1.0 (-0.9, 3.6)
NÂ =Â 436
3.1 (1.1, 5.8)
NÂ =Â 439
52 weeks
sulfonylurea
2.0 (0, 4.0)
NÂ =Â 173
2.0 (-0.6, 4.0)
NÂ =Â 150
2.6 (0, 5.3)
NÂ =Â 157
Combination therapy
Sulfonylurea
24-26 weeks
sulfonylurea
0 (-1.0, 1.3)
NÂ =Â 1,155
2.2 (0.5, 4.0)
NÂ =Â 613
3.5 (1.4, 5.9)
NÂ =Â 841
Metformin
26 weeks
metformin
-1.4 (-3.2, 0.2)
NÂ =Â 175
0.8 (-1.0, 2.6)
NÂ =Â 100
2.1 (0, 4.3)
NÂ =Â 184
Insulin
26 weeks
insulin
0.9 (-0.5, 2.7)
NÂ =Â 162
4.1 (1.4, 6.3)
NÂ =Â 164
5.4 (3.4, 7.3)
NÂ =Â 150
Sulfonylurea + metformin
26 weeks
sulfonylurea + metformin
0.2 (-1.2, 1.6)
NÂ =Â 272
2.5 (0.8, 4.6)
NÂ =Â 275
4.5 (2.4, 7.3)
NÂ =Â 276
In a 4- to 6-year, monotherapy, comparative trial (ADOPT) in patients
recently diagnosed with type 2 diabetes not previously treated with antidiabetic
medication [see Clinical Studies (14.1)], the median
weight change (25th, 75th
percentiles) from baseline at 4 years was 3.5 kg (0.0, 8.1) for AVANDIA, 2.0 kg
(-1.0, 4.8) for glyburide, and -2.4 kg (-5.4, 0.5) for metformin.
In a 24-week study in pediatric patients aged 10 to 17Â years treated with
AVANDIA 4 to 8Â mg daily, a median weight gain of 2.8Â kg (25th, 75th percentiles: 0.0, 5.8) was
reported. 5.6 Hepatic Effects Liver enzymes should be measured prior to the initiation of
therapy with AVANDIA in all patients and periodically thereafter per the
clinical judgment of the healthcare professional. Therapy with AVANDIA should
not be initiated in patients with increased baseline liver enzyme levels (ALT
>2.5X upper limit of normal). Patients with mildly elevated liver enzymes
(ALT levels ≤2.5X upper limit of normal) at baseline or during therapy with
AVANDIA should be evaluated to determine the cause of the liver enzyme
elevation. Initiation of, or continuation of, therapy with AVANDIA in patients
with mild liver enzyme elevations should proceed with caution and include close
clinical follow-up, including liver enzyme monitoring, to determine if the liver
enzyme elevations resolve or worsen. If at any time ALT levels increase to
>3X the upper limit of normal in patients on therapy with AVANDIA, liver
enzyme levels should be rechecked as soon as possible. If ALT levels remain
>3X the upper limit of normal, therapy with AVANDIA should be
discontinued.
If any patient develops symptoms suggesting hepatic dysfunction, which may
include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and/or
dark urine, liver enzymes should be checked. The decision whether to continue
the patient on therapy with AVANDIA should be guided by clinical judgment
pending laboratory evaluations. If jaundice is observed, drug therapy should be
discontinued. [See Adverse Reactions (6.2, 6.3).]
5.7 Macular Edema Macular edema has been reported in postmarketing experience in
some diabetic patients who were taking AVANDIA or another thiazolidinedione.
Some patients presented with blurred vision or decreased visual acuity, but some
patients appear to have been diagnosed on routine ophthalmologic examination.
Most patients had peripheral edema at the time macular edema was diagnosed. Some
patients had improvement in their macular edema after discontinuation of their
thiazolidinedione. Patients with diabetes should have regular eye exams by an
ophthalmologist, per the Standards of Care of the American Diabetes Association.
Additionally, any diabetic who reports any kind of visual symptom should be
promptly referred to an ophthalmologist, regardless of the patient’s underlying
medications or other physical findings. [See Adverse
Reactions (6.1).]
5.8 Fractures In a 4- to 6-year comparative study (ADOPT) of glycemic control
with monotherapy in drug-naĂŻve patients recently diagnosed with type 2 diabetes
mellitus, an increased incidence of bone fracture was noted in female patients
taking AVANDIA. Over the 4- to 6-year period, the incidence of bone fracture in
females was 9.3% (60/645) for AVANDIA versus 3.5% (21/605) for glyburide and
5.1% (30/590) for metformin. This increased incidence was noted after the first
year of treatment and persisted during the course of the study. The majority of
the fractures in the women who received AVANDIA occurred in the upper arm, hand,
and foot. These sites of fracture are different from those usually associated
with postmenopausal osteoporosis (e.g., hip or spine). No increase in fracture
rates was observed in men treated with AVANDIA. The risk of fracture should be
considered in the care of patients, especially female patients, treated with
AVANDIA, and attention given to assessing and maintaining bone health according
to current standards of care. 5.9 Hematologic Effects Decreases in mean hemoglobin and hematocrit occurred in a
dose-related fashion in adult patients treated with AVANDIA [see Adverse Reactions (6.2)]. The observed changes may be
related to the increased plasma volume observed with treatment with
AVANDIA. 5.10 Diabetes and Blood
Glucose Control Patients receiving AVANDIA in combination with other hypoglycemic
agents may be at risk for hypoglycemia, and a reduction in the dose of the
concomitant agent may be necessary.
Periodic fasting blood glucose and HbA1c measurements should be performed to
monitor therapeutic response. 5.11 Ovulation Therapy with AVANDIA, like other thiazolidinediones, may result
in ovulation in some premenopausal anovulatory women. As a result, these
patients may be at an increased risk for pregnancy while taking AVANDIA [see Use in Specific Populations (8.1)]. Thus, adequate
contraception in premenopausal women should be recommended. This possible effect
has not been specifically investigated in clinical studies; therefore, the
frequency of this occurrence is not known.
Although hormonal imbalance has been seen in preclinical studies [see Nonclinical Toxicology (13.1)], the clinical
significance of this finding is not known. If unexpected menstrual dysfunction
occurs, the benefits of continued therapy with AVANDIA should be reviewed.
6 Adverse Reactions
6.1 Clinical Trial
Experience Adult
In clinical trials, approximately 9,900 patients with type 2 diabetes have
been treated with AVANDIA. Short-Term Trials of AVANDIA as Monotherapy
and in Combination With Other Hypoglycemic Agents
The incidence and types of adverse events reported in short-term clinical
trials of AVANDIA as monotherapy are shown in Table 4.
Table 4. Adverse Events (≥5% in Any Treatment Group) Reported by Patients in Short-Term* Double-Blind Clinical Trials With AVANDIA as Monotherapy
Preferred Term
AVANDIA Monotherapy
N = 2,526%
Placebo
N = 601%
Metformin
N = 225%
Sulfonylureasâ€
N = 626%
Upper respiratory tract infection
9.9
8.7
8.9
7.3
Injury
7.6
43.3
7.6
6.1
Headache
5.9
5.0
8.9
5.4
Back pain
4.0
3.8
4.0
5.0
Hyperglycemia
3.9
5.7
4.4
8.1
Fatigue
3.6
5.0
4.0
1.9
Sinusitis
3.2
4.5
5.3
3.0
Diarrhea
2.3
3.3
15.6
3.0
Hypoglycemia
0.6
0.2
1.3
5.9
*Â Â Â Short-term trials ranged from 8 weeks to 1 year.
†Includes patients receiving glyburide (N = 514), gliclazide (N = 91), or glipizide
(NÂ =Â 21).
Overall, the types of adverse reactions without regard to causality reported
when AVANDIA was used in combination with a sulfonylurea or metformin were
similar to those during monotherapy with AVANDIA.
Events of anemia and edema tended to be reported more frequently at higher
doses, and were generally mild to moderate in severity and usually did not
require discontinuation of treatment with AVANDIA.
In double-blind studies, anemia was reported in 1.9% of patients receiving
AVANDIA as monotherapy compared to 0.7% on placebo, 0.6% on sulfonylureas, and
2.2% on metformin. Reports of anemia were greater in patients treated with a
combination of AVANDIA and metformin (7.1%) and with a combination of AVANDIA
and a sulfonylurea plus metformin (6.7%) compared to monotherapy with AVANDIA or
in combination with a sulfonylurea (2.3%). Lower pre-treatment
hemoglobin/hematocrit levels in patients enrolled in the metformin combination
clinical trials may have contributed to the higher reporting rate of anemia in
these studies [see Adverse Reactions (6.2)].
In clinical trials, edema was reported in 4.8% of patients receiving AVANDIA
as monotherapy compared to 1.3% on placebo, 1.0% on sulfonylureas, and 2.2% on
metformin. The reporting rate of edema was higher for AVANDIA 8Â mg in
sulfonylurea combinations (12.4%) compared to other combinations, with the
exception of insulin. Edema was reported in 14.7% of patients receiving AVANDIA
in the insulin combination trials compared to 5.4% on insulin alone. Reports of
new onset or exacerbation of congestive heart failure occurred at rates of 1%
for insulin alone, and 2% (4Â mg) and 3% (8Â mg) for insulin in combination with
AVANDIA [see Boxed Warning and Warnings and Precautions
(5.3)].
In controlled combination therapy studies with sulfonylureas, mild to
moderate hypoglycemic symptoms, which appear to be dose related, were reported.
Few patients were withdrawn for hypoglycemia (less than 1%) and few episodes of
hypoglycemia were considered to be severe (less than 1%). Hypoglycemia was the most
frequently reported adverse event in the fixed-dose insulin combination trials,
although few patients withdrew for hypoglycemia (4 of 408 for AVANDIA plus
insulin and 1 of 203 for insulin alone). Rates of hypoglycemia, confirmed by
capillary blood glucose concentration less than or equal to 50Â mg/dL, were 6% for insulin alone and
12% (4Â mg) and 14% (8Â mg) for insulin in combination with AVANDIA. [See Warnings and Precautions (5.10).]
Long-Term Trial of AVANDIA as
Monotherapy
A 4- to 6-year study (ADOPT) compared the use of AVANDIA (n = 1,456),
glyburide (n = 1,441), and metformin (n = 1,454) as monotherapy in patients
recently diagnosed with type 2 diabetes who were not previously treated with
antidiabetic medication. Table 5 presents adverse reactions without regard to
causality; rates are expressed per 100 patient-years (PY) exposure to account
for the differences in exposure to study medication across the 3 treatment
groups.
In ADOPT, fractures were reported in a greater number of women treated with
AVANDIA (9.3%, 2.7/100 patient-years) compared to glyburide (3.5%, 1.3/100
patient-years) or metformin (5.1%, 1.5/100 patient-years). The majority of the
fractures in the women who received rosiglitazone were reported in the upper
arm, hand, and foot. [See Warnings and Precautions
(5.7).] The observed incidence of fractures for male patients was similar
among the 3 treatment groups.
Table 5. On-Therapy Adverse Events (Greater Than or Equal To 5 Events/100 Patient-Years [PY])
in Any Treatment Group Reported in a 4- to 6-Year Clinical Trial of AVANDIA as
Monotherapy (ADOPT)
AVANDIA
Glyburide
Metformin
N = 1,456
N = 1,441
N = 1,454
PY = 4,954
PY = 4,244
PY = 4,906
Nasopharyngitis
6.3
6.9
6.6
Back pain
5.1
4.9
5.3
Arthralgia
5.0
4.8
4.2
Hypertension
4.4
6.0
6.1
Upper respiratory tract infection
4.3
5.0
4.7
Hypoglycemia
2.9
13.0
3.4
Diarrhea
2.5
3.2
6.8
Pediatric
AVANDIA has been evaluated for safety in a single, active-controlled trial of
pediatric patients with type 2 diabetes in which 99 were treated with AVANDIA
and 101 were treated with metformin. The most common adverse reactions (greater than 10%)
without regard to causality for either AVANDIA or metformin were headache (17%
versus 14%), nausea (4% versus 11%), nasopharyngitis (3% versus 12%), and
diarrhea (1% versus 13%). In this study, one case of diabetic ketoacidosis was
reported in the metformin group. In addition, there were 3 patients in the
rosiglitazone group who had FPG of âĽ300 mg/dL, 2+ ketonuria, and an elevated
anion gap. 6.2 Laboratory
Abnormalities Hematologic
Decreases in mean hemoglobin and hematocrit occurred in a dose-related
fashion in adult patients treated with AVANDIA (mean decreases in individual
studies as much as 1.0Â g/dL hemoglobin and as much as 3.3% hematocrit). The
changes occurred primarily during the first 3Â months following initiation of
therapy with AVANDIA or following a dose increase in AVANDIA. The time course
and magnitude of decreases were similar in patients treated with a combination
of AVANDIA and other hypoglycemic agents or monotherapy with AVANDIA.
Pre-treatment levels of hemoglobin and hematocrit were lower in patients in
metformin combination studies and may have contributed to the higher reporting
rate of anemia. In a single study in pediatric patients, decreases in hemoglobin
and hematocrit (mean decreases of 0.29Â g/dL and 0.95%, respectively) were
reported. Small decreases in hemoglobin and hematocrit have also been reported
in pediatric patients treated with AVANDIA. White blood cell counts also
decreased slightly in adult patients treated with AVANDIA. Decreases in
hematologic parameters may be related to increased plasma volume observed with
treatment with AVANDIA. Lipids
Changes in serum lipids have been observed following treatment with AVANDIA
in adults [see Clinical Pharmacology (12.2)]. Small
changes in serum lipid parameters were reported in children treated with AVANDIA
for 24Â weeks. Serum Transaminase Levels
In pre-approval clinical studies in 4,598Â patients treated with AVANDIA
(3,600Â patient-years of exposure) and in a long-term 4- to 6-year study in 1,456
patients treated with AVANDIA (4,954 patient-years exposure), there was no
evidence of drug-induced hepatotoxicity.
In pre-approval controlled trials, 0.2% of patients treated with AVANDIA had
elevations in ALT >3X the upper limit of normal compared to 0.2% on placebo
and 0.5% on active comparators. The ALT elevations in patients treated with
AVANDIA were reversible. Hyperbilirubinemia was found in 0.3% of patients
treated with AVANDIA compared with 0.9% treated with placebo and 1% in patients
treated with active comparators. In pre-approval clinical trials, there were no
cases of idiosyncratic drug reactions leading to hepatic failure. [See Warnings and Precautions (5.6).]
In the 4- to 6-year ADOPT trial, patients treated with AVANDIA (4,954
patient-years exposure), glyburide (4,244 patient-years exposure), or metformin
(4,906 patient-years exposure), as monotherapy, had the same rate of ALT
increase to greater than 3X upper limit of normal (0.3Â per 100 patient-years exposure).
6.3 Postmarketing
Experience In addition to adverse reactions reported from clinical trials,
the events described below have been identified during post-approval use of
AVANDIA. Because these events are reported voluntarily from a population of
unknown size, it is not possible to reliably estimate their frequency or to
always establish a causal relationship to drug exposure.
In patients receiving thiazolidinedione therapy, serious adverse events with
or without a fatal outcome, potentially related to volume expansion (e.g.,
congestive heart failure, pulmonary edema, and pleural effusions) have been
reported [see Boxed Warning and Warnings and Precautions
(5.1)].
There are postmarketing reports with AVANDIA of hepatitis, hepatic enzyme
elevations to 3 or more times the upper limit of normal, and hepatic failure
with and without fatal outcome, although causality has not been established.
There are postmarketing reports with AVANDIA of rash, pruritus, urticaria,
angioedema, anaphylactic reaction, Stevens-Johnson syndrome, and new onset or
worsening diabetic macular edema with decreased visual acuity [see Warnings and Precautions (5.7)].
7 Drug Interactions
7.1 CYP2C8 Inhibitors and
Inducers An inhibitor of CYP2C8 (e.g., gemfibrozil) may increase the AUC
of rosiglitazone and an inducer of CYP2C8 (e.g., rifampin) may decrease the AUC
of rosiglitazone. Therefore, if an inhibitor or an inducer of CYP2C8 is started
or stopped during treatment with rosiglitazone, changes in diabetes treatment
may be needed based upon clinical response. [See Clinical
Pharmacology (12.4).]
8 Use In Specific Populations
8.1 Pregnancy Pregnancy Category C.
All pregnancies have a background risk of birth defects, loss, or other
adverse outcome regardless of drug exposure. This background risk is increased
in pregnancies complicated by hyperglycemia and may be decreased with good
metabolic control. It is essential for patients with diabetes or history of
gestational diabetes to maintain good metabolic control before conception and
throughout pregnancy. Careful monitoring of glucose control is essential in such
patients. Most experts recommend that insulin monotherapy be used during
pregnancy to maintain blood glucose levels as close to normal as possible. Human Data
Rosiglitazone has been reported to cross the human placenta and be detectable
in fetal tissue. The clinical significance of these findings is unknown. There
are no adequate and well-controlled studies in pregnant women. AVANDIA should
not be used during pregnancy. Animal Studies
There was no effect on implantation or the embryo with rosiglitazone
treatment during early pregnancy in rats, but treatment during mid-late
gestation was associated with fetal death and growth retardation in both rats
and rabbits. Teratogenicity was not observed at doses up to 3Â mg/kg in rats and
100Â mg/kg in rabbits (approximately 20 and 75Â times human AUC at the maximum
recommended human daily dose, respectively). Rosiglitazone caused placental
pathology in rats (3Â mg/kg/day). Treatment of rats during gestation through
lactation reduced litter size, neonatal viability, and postnatal growth, with
growth retardation reversible after puberty. For effects on the placenta,
embryo/fetus, and offspring, the no-effect dose was 0.2Â mg/kg/day in rats and 15
mg/kg/day in rabbits. These no-effect levels are approximately 4Â times human AUC
at the maximum recommended human daily dose. Rosiglitazone reduced the number of
uterine implantations and live offspring when juvenile female rats were treated
at 40Â mg/kg/day from 27Â days of age through to sexual maturity (approximately
68Â times human AUC at the maximum recommended daily dose). The no-effect level
was 2Â mg/kg/day (approximately 4Â times human AUC at the maximum recommended
daily dose). There was no effect on pre- or post-natal survival or growth. 8.2 Labor and Delivery The effect of rosiglitazone on labor and delivery in humans is
not known. 8.3 Nursing Mothers Drug-related material was detected in milk from lactating rats.
It is not known whether AVANDIA is excreted in human milk. Because many drugs
are excreted in human milk, AVANDIA should not be administered to a nursing
woman. 8.4 Pediatric Use After placebo run-in including diet counseling, children with
type 2 diabetes mellitus, aged 10 to 17 years and with a baseline mean body mass
index (BMI) of 33Â kg/m2, were randomized to treatment
with 2 mg twice daily of AVANDIA (n = 99) or 500 mg twice daily of metformin
(n = 101) in a 24-week, double-blind clinical trial. As expected, FPG decreased
in patients naïve to diabetes medication (n = 104) and increased in patients
withdrawn from prior medication (usually metformin) (n = 90) during the run-in
period. After at least 8Â weeks of treatment, 49% of patients treated with
AVANDIA and 55% of metformin-treated patients had their dose doubled if FPG
>126 mg/dL. For the overall intent-to-treat population, at week 24, the mean
change from baseline in HbA1c was -0.14% with AVANDIA and -0.49% with metformin.
There was an insufficient number of patients in this study to establish
statistically whether these observed mean treatment effects were similar or
different. Treatment effects differed for patients naĂŻve to therapy with
antidiabetic drugs and for patients previously treated with antidiabetic therapy
(Table 6).
Table 6. Week 24 FPG and HbA1c Change From Baseline Last-Observation-Carried Forward in Children With Baseline HbA1c >6.5%
*Â Change from baseline means are least squares means adjusting for baseline HbA1c,
gender, and region.
†Positive values for the difference favor
metformin.
Treatment differences depended on baseline BMI or weight such that the
effects of AVANDIA and metformin appeared more closely comparable among heavier
patients. The median weight gain was 2.8Â kg with rosiglitazone and 0.2Â kg with
metformin [see Warnings and Precautions (5.4)].
Fifty-four percent of patients treated with rosiglitazone and 32% of patients
treated with metformin gained ≥2 kg, and 33% of patients treated with
rosiglitazone and 7% of patients treated with metformin gained ≥5 kg on
study. Adverse events observed in this study are described in Adverse Reactions (6.1). Figure 3. Mean HbA1c Over Time in a 24-Week Study of
AVANDIA and Metformin in Pediatric Patients — Drug-Naïve Subgroup 8.5 Geriatric Use Results of the population pharmacokinetic analysis showed that
age does not significantly affect the pharmacokinetics of rosiglitazone [see Clinical Pharmacology (12.3)]. Therefore, no dosage
adjustments are required for the elderly. In controlled clinical trials, no
overall differences in safety and effectiveness between older (greater than or equal to 65 years) and
younger (less than 65 years) patients were observed.
10 Overdosage
Limited data are available with regard to overdosage in humans. In clinical
studies in volunteers, AVANDIA has been administered at single oral doses of up
to 20Â mg and was well-tolerated. In the event of an overdose, appropriate
supportive treatment should be initiated as dictated by the patient’s clinical
status.
11 Description
AVANDIA (rosiglitazone maleate) is an oral antidiabetic agent
which acts primarily by increasing insulin sensitivity. AVANDIA improves
glycemic control while reducing circulating insulin levels.
Rosiglitazone maleate is not chemically or functionally related to the
sulfonylureas, the biguanides, or the alpha-glucosidase inhibitors. Chemically, rosiglitazone maleate is
(±)-5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione,
(Z)-2-butenedioate (1:1) with a molecular weight of
473.52 (357.44 free base). The molecule has a single chiral center and is
present as a racemate. Due to rapid interconversion, the enantiomers are
functionally indistinguishable. The structural formula of rosiglitazone maleate
is: The molecular formula is C18H19N3O3S•C4H4O4.
Rosiglitazone maleate is a white to off-white solid with a melting point range
of 122° to 123°C. The pKa values of rosiglitazone maleate are 6.8 and 6.1. It is
readily soluble in ethanol and a buffered aqueous solution with pH of 2.3;
solubility decreases with increasing pH in the physiological range.
Each pentagonal film-coated TILTAB tablet contains rosiglitazone maleate
equivalent to rosiglitazone, 2Â mg, 4Â mg, or 8Â mg, for oral administration.
Inactive ingredients are: Hypromellose 2910, lactose monohydrate, magnesium
stearate, microcrystalline cellulose, polyethylene glycol 3000, sodium starch
glycolate, titanium dioxide, triacetin, and 1 or more of the following:
Synthetic red and yellow iron oxides and talc.
12 Clinical Pharmacology
12.1 Mechanism of Action Rosiglitazone, a member of the thiazolidinedione class of
antidiabetic agents, improves glycemic control by improving insulin sensitivity.
Rosiglitazone is a highly selective and potent agonist for the peroxisome
proliferator-activated receptor-gamma (PPARÎł). In humans, PPAR receptors are
found in key target tissues for insulin action such as adipose tissue, skeletal
muscle, and liver. Activation of PPARÎł nuclear receptors regulates the
transcription of insulin-responsive genes involved in the control of glucose
production, transport, and utilization. In addition, PPARÎł-responsive genes also
participate in the regulation of fatty acid metabolism.
Insulin resistance is a common feature characterizing the pathogenesis of
type 2 diabetes. The antidiabetic activity of rosiglitazone has been
demonstrated in animal models of type 2 diabetes in which hyperglycemia and/or
impaired glucose tolerance is a consequence of insulin resistance in target
tissues. Rosiglitazone reduces blood glucose concentrations and reduces
hyperinsulinemia in the ob/ob obese mouse, db/db diabetic mouse, and fa/fa fatty
Zucker rat.
In animal models, the antidiabetic activity of rosiglitazone was shown to be
mediated by increased sensitivity to insulin’s action in the liver, muscle, and
adipose tissues. Pharmacological studies in animal models indicate that
rosiglitazone inhibits hepatic gluconeogenesis. The expression of the
insulin-regulated glucose transporter GLUT-4 was increased in adipose tissue.
Rosiglitazone did not induce hypoglycemia in animal models of type 2 diabetes
and/or impaired glucose tolerance. 12.2 Pharmacodynamics Patients with lipid abnormalities were not excluded from clinical
trials of AVANDIA. In all 26-week controlled trials, across the recommended dose
range, AVANDIA as monotherapy was associated with increases in total
cholesterol, LDL, and HDL and decreases in free fatty acids. These changes were
statistically significantly different from placebo or glyburide controls (Table
7).
Increases in LDL occurred primarily during the first 1 to 2Â months of therapy
with AVANDIA and LDL levels remained elevated above baseline throughout the
trials. In contrast, HDL continued to rise over time. As a result, the LDL/HDL
ratio peaked after 2Â months of therapy and then appeared to decrease over time.
Because of the temporal nature of lipid changes, the 52-week
glyburide-controlled study is most pertinent to assess long-term effects on
lipids. At baseline, week 26, and week 52, mean LDL/HDL ratios were 3.1, 3.2,
and 3.0, respectively, for AVANDIA 4Â mg twice daily. The corresponding values
for glyburide were 3.2, 3.1, and 2.9. The differences in change from baseline
between AVANDIA and glyburide at week 52 were statistically significant.
The pattern of LDL and HDL changes following therapy with AVANDIA in
combination with other hypoglycemic agents were generally similar to those seen
with AVANDIA in monotherapy.
The changes in triglycerides during therapy with AVANDIA were variable and
were generally not statistically different from placebo or glyburide controls.
Table 7. Summary of Mean Lipid Changes in 26-Week Placebo-Controlled and 52-Week Glyburide-Controlled Monotherapy Studies
Placebo-
ControlledWeek 26
Studies
Glyburide-Studyand
ControlledWeek 26Week 52
Placebo
AVANDIA
AVANDIA
Glyburide
Titration
AVANDIA
8 mg
4mg daily*
8 mg daily*
Wk 26
Wk 52
Wk 26
Wk 52
Free Fatty acids
N
207
428
436
181
168
166
145
Baselline (mean)
18.1
17.5
17.9
26.4
26.4
26.9
26.6
% Change from baseline (mean)
+0.2%
-7.8%
-14.7%
-2.4%
-4.7%
-20.8%
-21.5%
LDL
N
190
400
374
175
160
161
133
Baselline (mean)
123.7
126.8
125.3
142.7
141.9
142.1
142.1
% Change from baseline (mean)
+4.8%
+14.1%
+18.6%
-0.9%
-0.5%
+11.9%
+12.1%
HDL
N
208
429
436
184
170
170
145
Baselline (mean)
44.1
44.4
43.0
47.2
47.7
48.4
48.3
% Change from baseline (mean)
+8.0%
+11.4%
+14.2%
+4.3%
+8.7%
+14.0%
+18.5%
*Â Once daily and twice daily dosing groups were combined.
12.3 Pharmacokinetics Maximum plasma concentration (Cmax) and
the area under the curve (AUC) of rosiglitazone increase in a dose-proportional
manner over the therapeutic dose range (Table 8). The elimination half-life is 3
to 4Â hours and is independent of dose.
Table 8. Mean (SD) Pharmacokinetic Parameters for Rosiglitazone Following Single Oral Doses (N = 32)
Parameter
1 mgFasting
2 mgFasting
8 mgFasting
8 mgFed
AUC0-inf
[ng•hr/mL]
358(112)
733(184)
2,971(730)
2,890(795)
Cmax
[ng/mL]
76(13)
156(42)
598(117)
432(92)
Half-life
[hr]
3.16(0.72)
3.15(0.39)
3.37(0.63)
3.59(0.70)
CL/F*
[L/hr]
3.03(0.87)
2.89(0.71)
2.85(0.69)
2.97(0.81)
*Â Â CL/F = Oral clearance.
Absorption
The absolute bioavailability of rosiglitazone is 99%. Peak plasma
concentrations are observed about 1Â hour after dosing. Administration of
rosiglitazone with food resulted in no change in overall exposure (AUC), but
there was an approximately 28% decrease in Cmax and a
delay in Tmax (1.75Â hours). These changes are not likely
to be clinically significant; therefore, AVANDIA may be administered with or
without food. Distribution
The mean (CV%) oral volume of distribution (Vss/F) of rosiglitazone is
approximately 17.6 (30%) liters, based on a population pharmacokinetic analysis.
Rosiglitazone is approximately 99.8% bound to plasma proteins, primarily
albumin. Metabolism
Rosiglitazone is extensively metabolized with no unchanged drug excreted in
the urine. The major routes of metabolism were N-demethylation and
hydroxylation, followed by conjugation with sulfate and glucuronic acid. All the
circulating metabolites are considerably less potent than parent and, therefore,
are not expected to contribute to the insulin-sensitizing activity of
rosiglitazone.
In vitro data demonstrate that rosiglitazone is predominantly metabolized by
Cytochrome P450 (CYP) isoenzyme 2C8, with CYP2C9 contributing as a minor
pathway. Excretion
Following oral or intravenous administration of [14C]rosiglitazone maleate, approximately 64% and 23% of the
dose was eliminated in the urine and in the feces, respectively. The plasma
half-life of [14C]related material ranged from 103 to
158Â hours. Population Pharmacokinetics in Patients
With Type 2 Diabetes
Population pharmacokinetic analyses from 3 large clinical trials including
642 men and 405 women with type 2 diabetes (aged 35 to 80 years) showed that the
pharmacokinetics of rosiglitazone are not influenced by age, race, smoking, or
alcohol consumption. Both oral clearance (CL/F) and oral steady-state volume of
distribution (Vss/F) were shown to increase with increases in body weight. Over
the weight range observed in these analyses (50 to 150Â kg), the range of
predicted CL/F and Vss/F values varied by less than 1.7-fold and less than 2.3-fold,
respectively. Additionally, rosiglitazone CL/F was shown to be influenced by
both weight and gender, being lower (about 15%) in female patients. Special Populations Geriatric
Results of the population pharmacokinetic analysis (n = 716 less than 65 years;
n = 331 greater than or equal to 65 years) showed that age does not significantly affect the
pharmacokinetics of rosiglitazone. Gender
Results of the population pharmacokinetics analysis showed that the mean oral
clearance of rosiglitazone in female patients (n = 405) was approximately 6%
lower compared to male patients of the same body weight (n = 642).
As monotherapy and in combination with metformin, AVANDIA improved glycemic
control in both males and females. In metformin combination studies, efficacy
was demonstrated with no gender differences in glycemic response.
In monotherapy studies, a greater therapeutic response was observed in
females; however, in more obese patients, gender differences were less evident.
For a given body mass index (BMI), females tend to have a greater fat mass than
males. Since the molecular target PPARÎł is expressed in adipose tissues, this
differentiating characteristic may account, at least in part, for the greater
response to AVANDIA in females. Since therapy should be individualized, no dose
adjustments are necessary based on gender alone. Hepatic Impairment
Unbound oral clearance of rosiglitazone was significantly lower in patients
with moderate to severe liver disease (Child-Pugh Class B/C) compared to healthy
subjects. As a result, unbound Cmax and AUC0-inf were increased 2- and 3-fold, respectively. Elimination
half-life for rosiglitazone was about 2 hours longer in patients with liver
disease, compared to healthy subjects.
Therapy with AVANDIA should not be initiated if the patient exhibits clinical
evidence of active liver disease or increased serum transaminase levels (ALT
greater than 2.5X upper limit of normal) at baseline [see Warnings
and Precautions (5.6)]. Pediatric
Pharmacokinetic parameters of rosiglitazone in pediatric patients were
established using a population pharmacokinetic analysis with sparse data from 96
pediatric patients in a single pediatric clinical trial including 33 males and
63 females with ages ranging from 10 to 17Â years (weights ranging from 35 to
178.3Â kg). Population mean CL/F and V/F of rosiglitazone were 3.15 L/hr and 13.5
L, respectively. These estimates of CL/F and V/F were consistent with the
typical parameter estimates from a prior adult population analysis. Renal Impairment
There are no clinically relevant differences in the pharmacokinetics of
rosiglitazone in patients with mild to severe renal impairment or in
hemodialysis-dependent patients compared to subjects with normal renal function.
No dosage adjustment is therefore required in such patients receiving AVANDIA.
Since metformin is contraindicated in patients with renal impairment,
coadministration of metformin with AVANDIA is contraindicated in these
patients. Race
Results of a population pharmacokinetic analysis including subjects of
Caucasian, black, and other ethnic origins indicate that race has no influence
on the pharmacokinetics of rosiglitazone. 12.4 Drug-Drug
Interactions Drugs That Inhibit, Induce, or are
Metabolized by Cytochrome P450
In vitro drug metabolism studies suggest that rosiglitazone does not inhibit
any of the major P450 enzymes at clinically relevant concentrations. In vitro
data demonstrate that rosiglitazone is predominantly metabolized by CYP2C8, and
to a lesser extent, 2C9. AVANDIA (4Â mg twice daily) was shown to have no
clinically relevant effect on the pharmacokinetics of nifedipine and oral
contraceptives (ethinyl estradiol and norethindrone), which are predominantly
metabolized by CYP3A4. Gemfibrozil
Concomitant administration of gemfibrozil (600Â mg twice daily), an inhibitor
of CYP2C8, and rosiglitazone (4Â mg once daily) for 7Â days increased
rosiglitazone AUC by 127%, compared to the administration of rosiglitazone (4Â mg
once daily) alone. Given the potential for dose-related adverse events with
rosiglitazone, a decrease in the dose of rosiglitazone may be needed when
gemfibrozil is introduced [see Drug Interactions
(7.1)]. Rifampin
Rifampin administration (600 mg once a day), an inducer of CYP2C8, for 6 days
is reported to decrease rosiglitazone AUC by 66%, compared to the administration
of rosiglitazone (8 mg) alone [see Drug Interactions
(7.1)].4 Glyburide
AVANDIA (2Â mg twice daily) taken concomitantly with glyburide (3.75 to
10Â mg/day) for 7Â days did not alter the mean steady-state 24-hour plasma glucose
concentrations in diabetic patients stabilized on glyburide therapy. Repeat
doses of AVANDIA (8 mg once daily) for 8 days in healthy adult Caucasian
subjects caused a decrease in glyburide AUC and Cmax of
approximately 30%. In Japanese subjects, glyburide AUC and Cmax slightly increased following coadministration of
AVANDIA. Glimepiride
Single oral doses of glimepiride in 14 healthy adult subjects had no
clinically significant effect on the steady-state pharmacokinetics of AVANDIA.
No clinically significant reductions in glimepiride AUC and Cmax were observed after repeat doses of AVANDIA (8 mg once
daily) for 8 days in healthy adult subjects. Metformin
Concurrent administration of AVANDIA (2Â mg twice daily) and metformin (500Â mg
twice daily) in healthy volunteers for 4Â days had no effect on the steady-state
pharmacokinetics of either metformin or rosiglitazone. Acarbose
Coadministration of acarbose (100Â mg three times daily) for 7Â days in healthy
volunteers had no clinically relevant effect on the pharmacokinetics of a single
oral dose of AVANDIA. Digoxin
Repeat oral dosing of AVANDIA (8Â mg once daily) for 14Â days did not alter the
steady-state pharmacokinetics of digoxin (0.375Â mg once daily) in healthy
volunteers. Warfarin
Repeat dosing with AVANDIA had no clinically relevant effect on the
steady-state pharmacokinetics of warfarin enantiomers. Ethanol
A single administration of a moderate amount of alcohol did not increase the
risk of acute hypoglycemia in type 2 diabetes mellitus patients treated with
AVANDIA. Ranitidine
Pretreatment with ranitidine (150Â mg twice daily for 4Â days) did not alter
the pharmacokinetics of either single oral or intravenous doses of rosiglitazone
in healthy volunteers. These results suggest that the absorption of oral
rosiglitazone is not altered in conditions accompanied by increases in
gastrointestinal pH.
13 Nonclinical Toxicology
13.1 Carcinogenesis, Mutagenesis, Impairment of
Fertility Carcinogenesis
A 2-year carcinogenicity study was conducted in Charles River CD-1 mice at
doses of 0.4, 1.5, and 6Â mg/kg/day in the diet (highest dose equivalent to
approximately 12Â times human AUC at the maximum recommended human daily dose).
Sprague-Dawley rats were dosed for 2Â years by oral gavage at doses of 0.05, 0.3,
and 2Â mg/kg/day (highest dose equivalent to approximately 10 and 20Â times human
AUC at the maximum recommended human daily dose for male and female rats,
respectively).
Rosiglitazone was not carcinogenic in the mouse. There was an increase in
incidence of adipose hyperplasia in the mouse at doses ≥1.5 mg/kg/day
(approximately 2Â times human AUC at the maximum recommended human daily dose).
In rats, there was a significant increase in the incidence of benign adipose
tissue tumors (lipomas) at doses ≥0.3 mg/kg/day (approximately 2 times human AUC
at the maximum recommended human daily dose). These proliferative changes in
both species are considered due to the persistent pharmacological
overstimulation of adipose tissue. Mutagenesis
Rosiglitazone was not mutagenic or clastogenic in the in vitro bacterial
assays for gene mutation, the in vitro chromosome aberration test in human
lymphocytes, the in vivo mouse micronucleus test, and the in vivo/in vitro rat UDS assay. There was a small (about 2-fold)
increase in mutation in the in vitro mouse lymphoma assay in the presence of
metabolic activation. Impairment of Fertility
Rosiglitazone had no effects on mating or fertility of male rats given up to
40Â mg/kg/day (approximately 116Â times human AUC at the maximum recommended human
daily dose). Rosiglitazone altered estrous cyclicity (2Â mg/kg/day) and reduced
fertility (40Â mg/kg/day) of female rats in association with lower plasma levels
of progesterone and estradiol (approximately 20 and 200Â times human AUC at the
maximum recommended human daily dose, respectively). No such effects were noted
at 0.2Â mg/kg/day (approximately 3Â times human AUC at the maximum recommended
human daily dose). In juvenile rats dosed from 27Â days of age through to sexual
maturity (at up to 40Â mg/kg/day), there was no effect on male reproductive
performance, or on estrous cyclicity, mating performance or pregnancy incidence
in females (approximately 68Â times human AUC at the maximum recommended human
daily dose). In monkeys, rosiglitazone (0.6Â and 4.6Â mg/kg/day; approximately 3
and 15Â times human AUC at the maximum recommended human daily dose,
respectively) diminished the follicular phase rise in serum estradiol with
consequential reduction in the luteinizing hormone surge, lower luteal phase
progesterone levels, and amenorrhea. The mechanism for these effects appears to
be direct inhibition of ovarian steroidogenesis. 13.2 Animal Toxicology Heart weights were increased in mice (3Â mg/kg/day), rats
(5Â mg/kg/day), and dogs (2Â mg/kg/day) with rosiglitazone treatments
(approximately 5, 22, and 2Â times human AUC at the maximum recommended human
daily dose, respectively). Effects in juvenile rats were consistent with those
seen in adults. Morphometric measurement indicated that there was hypertrophy in
cardiac ventricular tissues, which may be due to increased heart work as a
result of plasma volume expansion.
14 Clinical Studies
14.1 Monotherapy In clinical studies, treatment with AVANDIA resulted in an
improvement in glycemic control, as measured by FPG and HbA1c, with a concurrent
reduction in insulin and C-peptide. Postprandial glucose and insulin were also
reduced. This is consistent with the mechanism of action of AVANDIA as an
insulin sensitizer.
The maximum recommended daily dose is 8Â mg. Dose-ranging studies suggested
that no additional benefit was obtained with a total daily dose of 12Â mg. Short-Term Clinical Studies
A total of 2,315 patients with type 2 diabetes, previously treated with diet
alone or antidiabetic medication(s), were treated with AVANDIA as monotherapy in
6 double-blind studies, which included two 26-week placebo-controlled studies,
one 52-week glyburide-controlled study, and 3 placebo-controlled dose-ranging
studies of 8 to 12Â weeks duration. Previous antidiabetic medication(s) were
withdrawn and patients entered a 2 to 4Â week placebo run-in period prior to
randomization.
Two 26-week, double-blind, placebo-controlled trials, in patients with type 2
diabetes (n = 1,401) with inadequate glycemic control (mean baseline FPG
approximately 228Â mg/dL [101 to 425Â mg/dL] and mean baseline HbA1c 8.9% [5.2% to
16.2%]), were conducted. Treatment with AVANDIA produced statistically
significant improvements in FPG and HbA1c compared to baseline and relative to
placebo. Data from one of these studies are summarized in Table 9.
Table 9. Glycemic Parameters in a 26-Week Placebo-Controlled Trial
Placebo
AVANDIA
AVANDIA
AVANDIA
AVANDIA
4 mg once daily
2 mg twice daily
8 mg once daily
4 mg twice daily
N = 173
N = 180
N = 186
N = 181
N = 187
FPG (mg/dL)
Baseline (mean)
225
229
225
228
228
Change from baseline (mean)
8
-25
-35
-42
-55
Difference from placebo (adjusted mean)
--
-31*
-43*
-49*
-62*
% of patients with ≥30 mg/dL decrease from baseline
19%
45%
54%
58%
70%
HbAlc (%)
Baseline (mean)
8.9
8.9
8.9
8.9
9.0
Change from baseline (mean)
0.8
0.0
-0.1
-0.3
-0.7
Difference from placebo (adjusted mean)
--
-0.8*
-0.9*
-1.1*
-1.5*
% of patients with ≥0.7% decrease from baseline
9%
28%
29%
39%
54%
*Â p less than 0.0001 compared to placebo.
When administered at the same total daily dose, AVANDIA was generally more
effective in reducing FPG and HbA1c when administered in divided doses twice
daily compared to once daily doses. However, for HbA1c, the difference between
the 4Â mg once daily and 2Â mg twice daily doses was not statistically
significant. Long-Term Clinical Studies
Long-term maintenance of effect was evaluated in a 52-week, double-blind,
glyburide-controlled trial in patients with type 2 diabetes. Patients were
randomized to treatment with AVANDIA 2Â mg twice daily (NÂ =Â 195) or AVANDIA 4Â mg
twice daily (NÂ =Â 189) or glyburide (NÂ =Â 202) for 52Â weeks. Patients receiving
glyburide were given an initial dosage of either 2.5Â mg/day or 5.0Â mg/day. The
dosage was then titrated in 2.5Â mg/day increments over the next 12Â weeks, to a
maximum dosage of 15.0Â mg/day in order to optimize glycemic control. Thereafter,
the glyburide dose was kept constant. The median titrated dose of glyburide was 7.5Â mg. All treatments resulted in
a statistically significant improvement in glycemic control from baseline
(Figure 4 and Figure 5). At the end of week 52, the reduction from baseline in
FPG and HbA1c was -40.8 mg/dL and -0.53% with AVANDIA 4Â mg twice daily;
-25.4Â mg/dL and -0.27% with AVANDIA 2Â mg twice daily; and -30.0Â mg/dL and -0.72%
with glyburide. For HbA1c, the difference between AVANDIA 4Â mg twice daily and
glyburide was not statistically significant at week 52. The initial fall in FPG
with glyburide was greater than with AVANDIA; however, this effect was less
durable over time. The improvement in glycemic control seen with AVANDIA 4 mg
twice daily at week 26 was maintained through week 52 of the study.Figure 4. Mean FPG Over Time in a 52-Week Glyburide-Controlled Study
Figure 5. Mean HbA1c Over Time in a 52-Week
Glyburide-Controlled Study
Hypoglycemia was reported in 12.1% of glyburide-treated patients versus 0.5%
(2Â mg twice daily) and 1.6% (4Â mg twice daily) of patients treated with AVANDIA.
The improvements in glycemic control were associated with a mean weight gain of
1.75Â kg and 2.95Â kg for patients treated with 2Â mg and 4Â mg twice daily of
AVANDIA, respectively, versus 1.9Â kg in glyburide-treated patients. In patients
treated with AVANDIA, C-peptide, insulin, pro-insulin, and pro-insulin split
products were significantly reduced in a dose-ordered fashion, compared to an
increase in the glyburide-treated patients.
A Diabetes Outcome Progression Trial (ADOPT) was a multicenter, double-blind,
controlled trial (NÂ =Â 4,351) conducted over 4 to 6 years to compare the safety
and efficacy of AVANDIA, metformin, and glyburide monotherapy in patients
recently diagnosed with type 2 diabetes mellitus (≤3 years) inadequately
controlled with diet and exercise. The mean age of patients in this trial was
57Â years and the majority of patients (83%) had no known history of
cardiovascular disease. The mean baseline FPG and HbA1c were 152Â mg/dL and 7.4%,
respectively. Patients were randomized to receive either AVANDIA 4Â mg once
daily, glyburide 2.5Â mg once daily, or metformin 500Â mg once daily, and doses
were titrated to optimal glycemic control up to a maximum of 4Â mg twice daily
for AVANDIA, 7.5Â mg twice daily for glyburide, and 1,000Â mg twice daily for
metformin. The primary efficacy outcome was time to consecutive FPG
>180Â mg/dL after at least 6Â weeks of treatment at the maximum tolerated dose
of study medication or time to inadequate glycemic control, as determined by an
independent adjudication committee.
The cumulative incidence of the primary efficacy outcome at 5Â years was 15%
with AVANDIA, 21% with metformin, and 34% with glyburide (hazard ratio 0.68 [95%
CI 0.55, 0.85] versus metformin, HR 0.37 [95% CI 0.30, 0.45] versus
glyburide).
Cardiovascular and adverse event data (including effects on body weight and
bone fracture) from ADOPT for AVANDIA, metformin, and glyburide are described in
Warnings and Precautions (5.2, 5.5, and 5.8) and
Adverse Reactions (6.1), respectively. As with all
medications, efficacy results must be considered together with safety
information to assess the potential benefit and risk for an individual
patient. 14.2 Combination With
Metformin or Sulfonylurea The addition of AVANDIA to either metformin or sulfonylurea
resulted in significant reductions in hyperglycemia compared to either of these
agents alone. These results are consistent with an additive effect on glycemic
control when AVANDIA is used as combination therapy. Combination With Metformin
A total of 670 patients with type 2 diabetes participated in two 26-week,
randomized, double-blind, placebo/active-controlled studies designed to assess
the efficacy of AVANDIA in combination with metformin. AVANDIA, administered in
either once daily or twice daily dosing regimens, was added to the therapy of
patients who were inadequately controlled on a maximum dose (2.5Â grams/day) of
metformin.
In one study, patients inadequately controlled on 2.5Â grams/day of metformin
(mean baseline FPG 216Â mg/dL and mean baseline HbA1c 8.8%) were randomized to
receive 4Â mg of AVANDIA once daily, 8Â mg of AVANDIA once daily, or placebo in
addition to metformin. A statistically significant improvement in FPG and HbA1c
was observed in patients treated with the combinations of metformin and 4Â mg of
AVANDIA once daily and 8Â mg of AVANDIA once daily, versus patients continued on
metformin alone (Table 10).
Table 10. Glycemic Parameters in a 26-Week Combination Study of AVANDIA Plus Metformin
Metformin
AVANDIA
AVANDIA
4 mg once daily + metformin
8 mg once daily + metformin
N = 113
N = 116
N = 110
FPG (mg/dL)
Baseline (mean)
214
215
220
Change from baseline (mean)
6
-33
-48
Difference from metformin alone (adjusted mean)
--
-40*
-53*
% of patients with ≥30 mg/dL decrease from baseline
20%
45%
61%
HbAlc (%)
Baseline (mean)
8.6
8.9
8.9
Change from baseline (mean)
0.5
-0.6
-0.8
Difference from metformin alone (adjusted mean)
--
-1.0*
-1.2*
% of patients with ≥0.7% decrease from baseline
11%
45%
52%
*Â p less than 0.0001 compared to metformin.
In a second 26-week study, patients with type 2 diabetes inadequately
controlled on 2.5Â grams/day of metformin who were randomized to receive the
combination of AVANDIA 4Â mg twice daily and metformin (NÂ =Â 105) showed a
statistically significant improvement in glycemic control with a mean treatment
effect for FPG of -56Â mg/dL and a mean treatment effect for HbA1c of -0.8% over
metformin alone. The combination of metformin and AVANDIA resulted in lower
levels of FPG and HbA1c than either agent alone.
Patients who were inadequately controlled on a maximum dose (2.5Â grams/day)
of metformin and who were switched to monotherapy with AVANDIA demonstrated loss
of glycemic control, as evidenced by increases in FPG and HbA1c. In this group,
increases in LDL and VLDL were also seen. Combination With a Sulfonylurea
A total of 3,457 patients with type 2 diabetes participated in ten 24- to
26-week randomized, double-blind, placebo/active-controlled studies and one
2-year double-blind, active-controlled study in elderly patients designed to
assess the efficacy and safety of AVANDIA in combination with a sulfonylurea.
AVANDIA 2Â mg, 4Â mg, or 8Â mg daily was administered, either once daily (3
studies) or in divided doses twice daily (7Â studies), to patients inadequately
controlled on a submaximal or maximal dose of sulfonylurea.
In these studies, the combination of AVANDIA 4Â mg or 8Â mg daily (administered
as single or twice daily divided doses) and a sulfonylurea significantly reduced
FPG and HbA1c compared to placebo plus sulfonylurea or further up-titration of
the sulfonylurea. Table 11 shows pooled data for 8 studies in which AVANDIA
added to sulfonylurea was compared to placebo plus sulfonylurea.
Table 11. Glycemic Parameters in 24- to 26-Week Combination Studies of AVANDIA Plus Sulfonylurea
Twice Daily Divided Dosing(5 Studies)
Sulfonylurea
AVANDIA2 mg twice daily +sulfonylurea
Sulfonylurea
AVANDIA4 mg twice daily +sulfonylurea
N = 397
N = 497
N = 248
N = 346
FPG (mg/dL)
Baseline (mean)
204
198
188
187
Change from baseline (mean)
11
-29
8
-43
Difference from sulfonylurea alone (adjusted mean)
--
-42*
--
-53*
% of patients with ≥30 mg/dL decrease from baseline
17%
49%
15%
61%
HbAlc (%)
Baseline (mean)
9.4
9.5
9.3
9.6
Change from baseline (mean)
0.2
-1.0
0.0
-1.6
Difference from sulfonylurea alone (adjusted mean)
--
-1.1*
--
-1.4*
% of patients with ≥0.7% decrease from baseline
21%
60%
23%
75%
Once Daily Dosing(3 Studies)
Sulfonylurea
AVANDIA4 mg once daily +sulfonylurea
Sulfonylurea
AVANDIA8 mg once daily +sulfonylurea
N = 172
N = 172
N = 173
N = 176
FPG (mg/dL)
Baseline (mean)
198
206
188
192
Change from baseline (mean)
17
-25
17
-43
Difference from sulfonylurea alone (adjusted mean)
--
-47*
--
-66*
% of patients with ≥30 mg/dL decrease from baseline
17%
48%
19%
55%
HbAlc (%)
Baseline (mean)
8.6
8.8
8.9
8.9
Change from baseline (mean)
0.4
-0.5
0.1
-1.2
Difference from sulfonylurea alone (adjusted mean)
--
-0.9*
--
-1.4*
% of patients with ≥0.7% decrease from baseline
11%
36%
20%
68%
*Â p less than 0.0001 compared to sulfonylurea alone.
One of the 24- to 26-week studies included patients who were inadequately
controlled on maximal doses of glyburide and switched to 4Â mg of AVANDIA daily
as monotherapy; in this group, loss of glycemic control was demonstrated, as
evidenced by increases in FPG and HbA1c.
In a 2-year double-blind study, elderly patients (aged 59 to 89Â years) on
half-maximal sulfonylurea (glipizide 10Â mg twice daily) were randomized to the
addition of AVANDIA (n = 115, 4 mg once daily to 8 mg as needed) or to continued
up-titration of glipizide (n = 110), to a maximum of 20 mg twice daily. Mean
baseline FPG and HbA1c were 157 mg/dL and 7.72%, respectively, for the AVANDIA
plus glipizide arm and 159 mg/dL and 7.65%, respectively, for the glipizide
up-titration arm. Loss of glycemic control (FPG ≥180 mg/dL) occurred in a
significantly lower proportion of patients (2%) on AVANDIA plus glipizide
compared to patients in the glipizide up-titration arm (28.7%). About 78% of the
patients on combination therapy completed the 2Â years of therapy while only 51%
completed on glipizide monotherapy. The effect of combination therapy on FPG and
HbA1c was durable over the 2-year study period, with patients achieving a mean
of 132 mg/dL for FPG and a mean of 6.98% for HbA1c compared to no change on the
glipizide arm. 14.3 Combination With
Sulfonylurea Plus Metformin In two 24- to 26-week, double-blind, placebo-controlled, studies
designed to assess the efficacy and safety of AVANDIA in combination with
sulfonylurea plus metformin, AVANDIA 4Â mg or 8Â mg daily, was administered in
divided doses twice daily, to patients inadequately controlled on submaximal
(10Â mg) and maximal (20Â mg) doses of glyburide and maximal dose of metformin
(2Â g/day). A statistically significant improvement in FPG and HbA1c was observed
in patients treated with the combinations of sulfonylurea plus metformin and
4Â mg of AVANDIA and 8Â mg of AVANDIA versus patients continued on sulfonylurea
plus metformin, as shown in Table 12.
Table 12. Glycemic Parameters in a 26-Week Combination Study of AVANDIA Plus Sulfonylurea and Metformin
Sulfonylurea +metformin
AVANDIA2 mg twice daily + sulfonylurea +metformin
AVANDIA4 mg twice daily + sulfonylurea +metformin
N = 273
N =276
N = 277
FPG (mg/dL)
Baseline (mean)
189
190
192
Change from baseline (mean)
14
-19
-40
Difference from sulfonylurea plus metformin(adjusted mean)
--
-30*
-52*
% of patients with ≥30 mg/dL decrease from baseline
16%
46%
62%
HbAlc (%)
Baseline (mean)
8.7
8.6
8.7
Change from baseline (mean)
0.2
-0.4
-0.9
Difference from sulfonylurea plus metforminadjusted mean)
--
-0.6*
-1.1*
% of patients with ≥0.7% decrease from baseline
16%
39%
63%
*Â Â p less than 0.0001 compared to placebo.
15 References
Food and Drug Administration Briefing Document. Joint meeting of the
Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management Advisory
Committees. July 30, 2007.
DREAM Trial Investigators. Effect of rosiglitazone on the frequency of
diabetes in patients with impaired glucose tolerance or impaired fasting
glucose: a randomised controlled trial. Lancet
2006;368:1096-1105.
Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for
cardiovascular outcomes – an interim analysis. NEJM
2007;357:1-11.
Park JY, Kim KA, Kang MH, et al. Effect of rifampin on the pharmacokinetics
of rosiglitazone in healthy subjects. Clin Pharmacol
Ther 2004;75:157-162.
16 How Supplied/storage And Handling
Each pentagonal film-coated TILTAB tablet contains rosiglitazone
as the maleate as follows: 2 mg–pink, debossed with SB on one side and 2 on the
other; 4 mg–orange, debossed with SB on one side and 4 on the other; 8
mg–red-brown, debossed with SB on one side and 8 on the other.
2 mg bottles of 30: NDC 54868-5249-02 mg bottles of 60: NDC 54868-5249-1
4 mg bottles of 30: NDC 54868-4198-04 mg bottles of 60: NDC 54868-4198-1
8 mg bottles of 30: NDC 54868-4221-0
Store at 25°C (77°F); excursions 15° to 30°C (59° to 86°F). Dispense in a
tight, light-resistant container.
17 Patient Counseling Information
17.1 Patient Advice Patients should be informed of the following:
AVANDIA is not recommended for patients with symptoms of heart failure.
Patients with more severe heart failure (NYHA Class 3 or 4) cannot start
AVANDIA as the risks exceed any potential benefits in such patients.
Results of a set of clinical studies suggest that treatment with AVANDIA is
associated with an increased risk for myocardial ischemic events, such as angina
or myocardial infarction (heart attack), especially in patients taking insulin
or nitrates. Because this risk has not been confirmed or excluded in different
long-term trials, definitive conclusions regarding this risk await completion of
an adequately-designed cardiovascular outcome study.
AVANDIA is not recommended for patients who are taking nitrates or insulin.
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.
There have been no clinical studies establishing conclusive evidence of
macrovascular risk reduction with AVANDIA or any other oral antidiabetic drug.
Management of type 2 diabetes should include diet control. Caloric
restriction, weight loss, and exercise are essential for the proper treatment of
the diabetic patient because they help improve insulin sensitivity. This is
important not only in the primary treatment of type 2 diabetes, but in
maintaining the efficacy of drug therapy.
It is important to adhere to dietary instructions and to regularly have
blood glucose and glycosylated hemoglobin tested. It can take 2Â weeks to see a
reduction in blood glucose and 2 to 3Â months to see the full effect of AVANDIA.
Blood will be drawn to check their liver function prior to the start of
therapy and periodically thereafter per the clinical judgment of the healthcare
professional. Patients with unexplained symptoms of nausea, vomiting, abdominal
pain, fatigue, anorexia, or dark urine should immediately report these symptoms
to their physician.
Patients who experience an unusually rapid increase in weight or edema or
who develop shortness of breath or other symptoms of heart failure while on
AVANDIA should immediately report these symptoms to their physician.
AVANDIA can be taken with or without meals.
When using AVANDIA in combination with other hypoglycemic agents, the risk
of hypoglycemia, its symptoms and treatment, and conditions that predispose to
its development should be explained to patients and their family members.
Therapy with AVANDIA, like other thiazolidinediones, may result in ovulation
in some premenopausal anovulatory women. As a result, these patients may be at
an increased risk for pregnancy while taking AVANDIA. Thus, adequate
contraception in premenopausal women should be recommended. This possible effect
has not been specifically investigated in clinical studies so the frequency of
this occurrence is not known.
17.2 FDA-Approved Medication
Guide See separate leaflet. AVANDIA and TILTAB are registered trademarks of
GlaxoSmithKline.
Read this Medication Guide carefully before you start taking AVANDIA and each
time you get a refill. There may be new information. This information does not
take the place of talking with your doctor about your medical condition or your
treatment. If you have any questions about AVANDIA, ask your doctor or
pharmacist.
What is the most important information I should know about
AVANDIA?
AVANDIA is a prescription medicine to treat adults with diabetes. It helps to
control high blood sugar. (See “What is AVANDIA?”). It is important that you
take AVANDIA exactly how it is prescribed by your doctor to best treat your
diabetes.
AVANDIA may cause serious side effects, including:
New or worse heart failure
AVANDIA can cause your body to keep extra fluid (fluid retention), which
leads to swelling (edema) and weight gain. Extra body fluid can make some heart
problems worse or lead to heart failure. Heart failure means your heart does not
pump blood well enough.
If you have severe heart failure, you cannot start AVANDIA.
If you have heart failure with symptoms (such as shortness of breath or
swelling), even if these symptoms are not severe, AVANDIA may not be right for
you.
Call your doctor right away if you have any of the following:
swelling or fluid retention, especially in the ankles or legs
shortness of breath or trouble breathing, especially when you lie down
an unusually fast increase in weight
unusual tiredness
Other heart problems
AVANDIA may raise the risk of heart problems related to reduced blood flow to
the heart. These include possible increases in the risk of heart-related chest
pain (angina) or "heart attack" (myocardial infarction). This risk seemed to be
higher in people who took AVANDIA with insulin or with nitrate medicines. Most
people who take insulin or nitrate medicines should not also take AVANDIA.
If you have chest pain or a feeling of chest pressure, get medical help
right away, no matter what diabetes medicines you are taking.
People with diabetes have a greater risk for heart problems. It is important
to work with your doctor to manage other conditions, such as high blood pressure
or high cholesterol.
AVANDIA can have other serious side effects. Be sure to read the section
below “What are possible side effects of AVANDIA?”.
What is AVANDIA?
AVANDIA is a prescription medicine used with diet and exercise to treat
adults with type 2 (“adult-onset” or “non-insulin dependent”) diabetes mellitus
(“high blood sugar”). AVANDIA helps to control high blood sugar. AVANDIA may be
used alone or with other diabetes medicines. AVANDIA can help your body respond
better to insulin made in your body. AVANDIA does not cause your body to make
more insulin.
For AVANDIA to work best, it is very important to exercise, lose extra
weight, and follow the diet recommended by your doctor.
AVANDIA has not been studied enough in children under 18 years of age to
know if it is safe or effective in children.
AVANDIA is not for people with type 1 diabetes mellitus or to treat a
condition called diabetic ketoacidosis.
Who should not take AVANDIA?
Many people with heart failure should not start taking AVANDIA. See “What
should I tell my doctor before taking AVANDIA?”.
What should I tell my doctor before taking AVANDIA?
Before starting AVANDIA, ask your doctor about what the choices are for
diabetes medicines, and what the expected benefits and possible risks are for
you in particular.
Before taking AVANDIA, tell your doctor about all your medical conditions,
including if you:
have heart problems or heart failure.
have type 1 (“juvenile”) diabetes or had diabetic
ketoacidosis. These conditions should be treated with insulin.
have a type of diabetic eye disease called macular
edema (swelling of the back of the eye).
have liver problems. Your doctor should do blood
tests to check your liver before you start taking AVANDIA and during treatment
as needed.
had liver problems while taking REZULIN® (troglitazone), another medicine for diabetes.
are pregnant or plan to become pregnant. AVANDIA
should not be used during pregnancy. It is not known if AVANDIA can harm your
unborn baby. You and your doctor should talk about the best way to control your
diabetes during pregnancy. If you are a premenopausal woman (before the “change
of life”) who does not have regular monthly periods, AVANDIA may increase your
chances of becoming pregnant. Talk to your doctor about birth control choices
while taking AVANDIA. Tell your doctor right away if you become pregnant while
taking AVANDIA.
are breast-feeding or planning to breast-feed. It is
not known if AVANDIA passes into breast milk. You should not use AVANDIA while
breast-feeding.
Tell your doctor about all the medicines you take including prescription and
non-prescription medicines, vitamins or herbal supplements. AVANDIA and certain
other medicines can affect each other and may lead to serious side effects
including high or low blood sugar, or heart problems. Especially tell your
doctor if you take:
insulin.
nitrate medicines such as nitroglycerin or
isosorbide to treat a type of chest pain called angina.
any medicines for high blood pressure, high cholesterol or
heart failure, or for prevention of heart disease or stroke.
Know the medicines you take. Keep a ul of your medicines and show it to
your doctor and pharmacist before you start a new medicine. They will tell you
if it is alright to take AVANDIA with other medicines.
How should I take AVANDIA?
Take AVANDIA exactly as prescribed. Your doctor will tell you how many
tablets to take and how often. The usual daily starting dose is 4 mg a day taken
one time each day or 2 mg taken two times each day. Your doctor may need to
adjust your dose until your blood sugar is better controlled.
AVANDIA may be prescribed alone or with other diabetes medicines. This will
depend on how well your blood sugar is controlled.
Take AVANDIA with or without food.
It can take 2 weeks for AVANDIA to start lowering blood sugar. It may take 2
to 3 months to see the full effect on your blood sugar level.
If you miss a dose of AVANDIA, take it as soon as you remember, unless it is
time to take your next dose. Take your next dose at the usual time. Do not take
double doses to make up for a missed dose.
If you take too much AVANDIA, call your doctor or poison control center
right away.
Test your blood sugar regularly as your doctor tells you.
Diet and exercise can help your body use its blood sugar better. It is
important to stay on your recommended diet, lose extra weight, and get regular
exercise while taking AVANDIA.
Your doctor should do blood tests to check your liver before you start
AVANDIA and during treatment as needed. Your doctor should also do regular blood
sugar tests (for example, “A1C”) to monitor your response to AVANDIA.
What are possible side effects of AVANDIA?
AVANDIA may cause serious side effects including:
New or worse heart failure. See “What is the most
important information I should know about AVANDIA?”.
Other heart problems. AVANDIA may increase the risk
of heart problems related to reduced blood flow to the heart. These include
possible increases in the risk of heart-related chest pain (angina) or "heart
attack" (myocardial infarction). See “What is the most important information I
should know about AVANDIA?”.
Swelling (edema). AVANDIA can cause swelling due to
fluid retention. See “What is the most important information I should know about
AVANDIA?”.
Weight gain. AVANDIA can cause weight gain that may
be due to fluid retention or extra body fat. Weight gain can be a serious
problem for people with certain conditions including heart problems. See “What
is the most important information I should know about AVANDIA?”.
Liver problems. It is important for your liver to be
working normally when you take AVANDIA. Your doctor should do blood tests to
check your liver before you start taking AVANDIA and during treatment as needed.
Call your doctor right away if you have unexplained symptoms such as:
nausea or vomiting
stomach pain
unusual or unexplained tiredness
loss of appetite
dark urine
yellowing of your skin or the whites of your eyes.
Macular edema (a diabetic eye disease with swelling
in the back of the eye). Tell your doctor right away if you have any changes in
your vision. Your doctor should check your eyes regularly. Very rarely, some
people have experienced vision changes due to swelling in the back of the eye
while taking AVANDIA.
Fractures (broken bones), usually in the hand, upper
arm or foot, in females. Talk to your doctor for advice on how to keep your
bones healthy.
Low red blood cell count (anemia).
Low blood sugar (hypoglycemia). Lightheadedness,
dizziness, shakiness or hunger may mean that your blood sugar is too low. This
can happen if you skip meals, if you use another medicine that lowers blood
sugar, or if you have certain medical problems. Call your doctor if low blood
sugar levels are a problem for you.
Ovulation (release of egg from an ovary in a woman)
leading to pregnancy. Ovulation may happen in premenopausal women who do not
have regular monthly periods. This can increase the chance of pregnancy. See
“What should I tell my doctor before taking AVANDIA?”.
The most common side effects of AVANDIA reported in clinical trials included
cold-like symptoms and headache.
Call your doctor for medical advice about side effects. You may report side
effects to FDA at 1-800-FDA-1088.
How should I store AVANDIA?
Store AVANDIA at room temperature, 59° to 86°F (15° to 30°C). Keep AVANDIA
in the container it comes in.
Safely, throw away AVANDIA that is out of date or no longer needed.
Keep AVANDIA and all medicines out of the reach of children.
General information about AVANDIA
Medicines are sometimes prescribed for purposes other than those uled in a
Medication Guide. Do not use AVANDIA for a condition for which it was not
prescribed. Do not give AVANDIA to other people, even if they have the same
symptoms you have. It may harm them.
This Medication Guide summarizes important information about AVANDIA. If you
would like more information, talk with your doctor. You can ask your doctor or
pharmacist for information about AVANDIA that is written for healthcare
professionals. You can also find out more about AVANDIA by calling
1-888-825-5249 or visiting the website www.avandia.com.
What are the ingredients in AVANDIA?
Active Ingredient:Â Rosiglitazone maleate.
Inactive Ingredients: Hypromellose 2910, lactose monohydrate, magnesium
stearate, microcrystalline cellulose, polyethylene glycol 3000, sodium starch
glycolate, titanium dioxide, triacetin, and 1 or more of the following:
Synthetic red and yellow iron oxides and talc.
Always check to make sure that the medicine you are taking is the correct
one. AVANDIA tablets are triangles with rounded corners and look like this:
2 mg strength tablets – pink with “SB” on one side and “2” on the other.
4 mg strength tablets – orange with “SB” on one side and “4” on the
other.
8 mg strength tablets – red-brown with “SB” on one side and “8” on the
other.
AVANDIA is a registered trademark of GlaxoSmithKline.
REZULIN is a registered trademark of Parke-Davis Pharmaceuticals Ltd.
This Medication Guide has been approved by the U.S. Food and
Drug Administration.
"This tool does not provide medical advice, and is for informational and educational purposes only, and is not a substitute for professional medical advice, treatment or diagnosis. Call your doctor to receive medical advice. If you think you may have a medical emergency, please dial 911."
"Do not rely on openFDA to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. We may limit or otherwise restrict your access to the API in line with our Terms of Service."
"This product uses publicly available data from the U.S. National Library of Medicine (NLM), National Institutes of Health, Department of Health and Human Services; NLM is not responsible for the product and does not endorse or recommend this or any other product."
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Figure 4. Mean FPG Over Time in a 52-Week Glyburide-Controlled Study
