A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Avandia Side Effects, and Drug Interactions - Rosiglitazone Maleate
Avandia Side Effects, and Drug Interactions - Rosiglitazone Maleate
SIDE EFFECTS
In clinical trials, approximately 4,600 patients with type
2 diabetes have been treated with AVANDIA; 3,300 patients were treated for 6
months or longer and 2,000 patients were treated for 12 months or longer.
Trials of AVANDIA as Monotherapy and in Combination With Other
Hypoglycemic Agents
The incidence and types of adverse events reported in clinical
trials of AVANDIA as monotherapy are shown in Table 7.
|
Table 7. Adverse Events (³5%
in Any Treatment Group) Reported by Patients in Double-blind Clinical
Trials With AVANDIA as Monotherapy
|
|
Preferred Term
|
AVANDIA Monotherapy N = 2,526
|
Placebo N = 601
|
Metformin N = 225
|
Sulfonylureas* N = 626
|
| |
%
|
%
|
%
|
%
|
|
Upper respiratory tract infection
|
9.9
|
8.7
|
8.9
|
7.3
|
|
Injury
|
7.6
|
4.3
|
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
|
|
*Includes patients receiving glyburide (N
= 514), gliclazide (N = 91) or glipizide (N = 21).
|
There were a small number of patients treated with AVANDIA
who had adverse events of anemia and edema. Overall, these events 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 compared to 0.7% on placebo, 0.6% on sulfonylureas, and 2.2%
on metformin. Edema was reported in 4.8% of patients receiving AVANDIA compared
to 1.3% on placebo, 1.0% on sulfonylureas, and 2.2% on metformin. Overall, the
types of adverse experiences reported when AVANDIA was used in combination with
a sulfonylurea or metformin were similar to those during monotherapy with AVANDIA.
Reports of anemia (7.1%) were greater in patients treated with a combination
of AVANDIA and metformin compared to monotherapy with AVANDIA or in combination
with a sulfonylurea.
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, Laboratory Abnormalities, Hematologic).
In 26-week double-blind, fixed-dose studies, edema was reported
with higher frequency in the AVANDIA plus insulin combination trials (insulin,
5.4%; and AVANDIA in combination with insulin, 14.7%). Reports of new onset
or exacerbation of congestive heart failure occurred at rates of 1% for insulin
alone, and 2% (4 mg) and 3% (8 mg) for insulin in combination with AVANDIA (see
WARNINGS, Cardiac Failure and Other Cardiac
Effects).
In postmarketing experience with AVANDIA, adverse events potentially
related to volume expansion (e.g., congestive heart failure, pulmonary edema,
and pleural effusions) have been reported.
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
£50 mg/dL, were 6% for insulin alone and 12% (4 mg)
and 14% (8 mg) for insulin in combination with AVANDIA.
In postmarketing experience with AVANDIA, angioedema and urticaria
have been reported rarely.
Laboratory Abnormalities
Hematologic
Decreases in mean hemoglobin and hematocrit occurred in a dose-related
fashion in patients treated with AVANDIA (mean decreases in individual studies
up to 1.0 gram/dL hemoglobin and up to 3.3% hematocrit). The time course and
magnitude of decreases were similar in patients treated with a combination of
AVANDIA and other hypoglycemic agents or AVANDIA monotherapy. 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. White
blood cell counts also decreased slightly in 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 (see CLINICAL STUDIES).
Serum Transaminase Levels
In clinical studies in 4,598 patients treated with
AVANDIA encompassing approximately 3,600 patient years of exposure,
there was no evidence of drug-induced hepatotoxicity or elevated ALT levels.
In controlled trials, 0.2% of patients treated with AVANDIA
had reversible elevations in ALT >3X the upper limit of normal compared to
0.2% on placebo and 0.5% on active comparators. 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 the clinical program including long-term, open-label experience,
the rate per 100 patient years exposure of ALT increase to >3X the upper
limit of normal was 0.35 for patients treated with AVANDIA, 0.59 for placebo-treated
patients, and 0.78 for patients treated with active comparator agents.
In pre-approval clinical trials, there were no cases of idiosyncratic
drug reactions leading to hepatic failure. In postmarketing experience with
AVANDIA, reports of hepatic enzyme elevations 3 or more times the upper limit
of normal and hepatitis have been received (see PRECAUTIONS,
General, Hepatic Effects).
DRUG INTERACTIONS
Drugs 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. An inhibitor of CYP2C8 (such
as gemfibrozil) may decrease the metabolism of rosiglitazone and an inducer
of CYP2C8 (such as rifampin) may increase the metabolism 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.
AVANDIA (4 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.
Glyburide
AVANDIA (2 mg twice daily) taken concomitantly with glyburide
(3.75 to 10 mg/day) for 7 days did not alter the mean steady-state 24-hour plasma
glucose concentrations in diabetic patients stabilized on glyburide therapy.
Metformin
Concurrent administration of AVANDIA (2 mg twice daily) and
metformin (500 mg twice daily) in healthy volunteers for 4 days had no effect
on the steady-state pharmacokinetics of either metformin or rosiglitazone.
Acarbose
Coadministration of acarbose (100 mg three times daily) for
7 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 (8 mg once daily) for 14 days
did not alter the steady-state pharmacokinetics of digoxin (0.375 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 (150 mg twice daily for 4 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.
Gemfibrozil
Concomitant administration of gemfibrozil (600 mg twice daily),
an inhibitor of CYP2C8, and rosiglitazone (4 mg once daily) for 7 days increased
rosiglitazone AUC by 2 fold, compared to the administration of rosiglitazone
(4 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.
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