SIDE EFFECTS
In clinical trials, approximately 4600 patients
with type 2 diabetes have been treated with Avandia; 3300
patients were treated for 6 months or longer and 2000 patients
were treated for 12 months or longer.
The incidence and types of adverse events reported in clinical
trials of Avandia as monotherapy are shown in Table 5.
Table 5: Adverse Events (³5%
in Any Treatment Group) Reported by Patients in Double-blind
Clinical Trials with Avandia as Monotherapy
| |
Avandia
Monotherapy
N=2526
|
Placebo
N=601
|
Metformin
N=225
|
Sulfonylureas
N=626
|
|
Preferred Term
|
%
|
%
|
%
|
%
|
| 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 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.
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 Laboratory Abnormalities, Hematologic
below).
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 metformin
or 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
PHARMACOLOGY, Pharmacodynamics and Clinical Effects).
Serum Transaminase Levels: In clinical
studies in 4598 patients treated with Avandia encompassing
approximately 3600 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
(see PRECAUTIONS, 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.
Avandia (4 mg twice daily) was shown to have no clinically
relevant effect on the pharmacokinetics of nifedipine and
oral contraceptives (ethinylestradiol 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.
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