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
Rezulin Side Effects, and Drug Interactions - Troglitazone (removed from the US market 3/21/00)
Rezulin Side Effects, and Drug Interactions - Troglitazone (removed from the US market 3/21/00)
SIDE EFFECTS
Two patients in the clinical
studies developed reversible
jaundice: one of these patients had a liver
biopsy which was consistent
with an idiosyncraticdrug reaction. An
additional patient had
a liver biopsy
associated which was also consistent with an Idiosyncratic drug
reaction. Symptoms that are with hepatic
dysfunction have
been reported, including: nausea,
vomitin abdominal pain,
fatigue, anorexia,
dark urine, abnormal
liver function tests (including
increased ALT, AST, LDH, alkaline
phosphatase, bilirubin). Also see WARNINGS.
The overall incidence
and types of adverse reactions reported in placebo- controlled clinical
trials for Rezulin- treated patients and placebo- treated patients
are shown in Table 6. In
patients treated with Rezulin in glyburide- controlled studies (N=
550) or uncontrolled studies (N= 510), the safety profile of Rezulin
appeared similar to that displayed in Table 6. The incidence of
withdrawals during clinical
trials was similar for patients treated with placebo
or Rezulin (4%).
TABLE 6.
|
North American Placebo- Controlled Clinical Studies:
Adverse Events Reported at a Frequency > 5% of
Rezulin- Treated Patients
% of Patients
|
| |
Placebo
N = 492
|
Rezulin
N = 1450
|
|
Placebo
N = 492
|
Rezulin
N = 1450
|
| Infection |
22
|
18
|
Nausea |
4
|
6
|
| Headache |
11
|
11
|
Rhinitis |
7
|
5
|
| Pain |
14
|
10
|
Diarrhea |
6
|
5
|
| Accidental Injury |
6
|
8
|
Urinary Tract Infection
|
6
|
5
|
| Asthenia |
5
|
6
|
Peripheral Edema |
5
|
5
|
| Dizziness |
5
|
6
|
Pharyngitis |
4
|
5
|
| Back Pain |
4
|
6
|
. |
. |
. |
Types of adverse events seen when Rezulin was used concomitantly
with insulin (N= 543) were similar to those during Rezulin monotherapy
(N= 1731), although hypoglycemia
occurred on insulin
combination therapy
(see PRECAUTIONS).
Laboratory Abnormalities
Hematologic: Small decreases in hemoglobin,
hematocrit, and neutrophil
counts (within the normal
range) were more common in Rezulin-treated than placebo-treated
patients and may be related to increased plasma
volume observed with Rezulin treatment. Hemoglobin decreases to
below the normal range occurred in 5% of Rezulin-treated and 4 %
of placebo-treated patients.
Lipids: Small changes in serum
lipids have been observed (see CLINICAL
PHARMACOLOGY, Pharmacodynamics and Clinical effects).
Serum Transaminase Levels: During all clinical
studies in North America, a total of 48 of 2510 (1.9%) Rezulin-treated
patients and 3 of 475 (0.6%) placebo-treated patients had ALT
levels greater than 3 times the upp er limit
of normal. During controlled clinical
trials. 2.2% of Rezulintreated patients had reversible
elevations in AST or ALT
greater than 3 times the upper limit
of normal, compared with
0.6% of patients receiving placebo. Hyperbilirubinemia (> 1.25
upper limit of normal)
was found in 0.7% of Rezulin-treated patients compared with 1.7%
of patients receiving placebo. In
the population of
patients treated with Rezulin, mean and median
values for bilirubin,
AST, ALT, alkaline
phosphatase, and GGT were decreased at the final visit
compared with baseline,
while values or LDH were
increased slightly (see WARNINGS).
Postintroduction Reports
Adverse events associated with Rezulin that have been reported
since market introduction, that are not listed above, and for which
causal relationship to drug
has not been established include the following congestive heart
failure, weight gain,
edema, fever,
abnormal lab
tests including increased CPK and creatinine,
hyperglycemia,
syncope, anemia,
malaise.
DRUG INTERACTIONS
Oral Contraceptives: Administration of Rezulin with
an oral contraceptive
containing ethinyl estradiol
and norethindrone
reduced the plasma concentrations
of both by approximately 30% which could result in loss
of contraception. Therefore, a higher dose
of oral contraceptive or
an alternative method
of contraception
should be considered.
Terfenadine: Coadministration of Rezulin with terfenadine
decreases the plasma
concentration
of both terfenadine and its active metabolite by 50-70% and may
result in decreased efficacy
of terfenadine.
Cholestyramine: Concomitant administration
of cholestyramine with Rezulin reduces the absorption
of troglitazone
by 70%; thus, coadministration of cholestyramine and Rezulin is
not recommended.
Glyburide: Coadministration of Rezulin and glyburide
does not appear to alter troglitazone
or glyburide pharmacokinetics.
Digoxin: Coadministratjon of Rezulin with digoxin
does not alter the steady-state pharmacokinetics
of digoxin.
Warfarin: Rezulin has no
clinically significant
effect on prothrombin
time when administered
to patients receiving chronic
warfarin therapy.
Acetaminophen: Coadministration of acetaminophen
and Rezulin does not alter the pharmacokinetics
of either drug.
Metformin: No information is available on the use
of Rezulin with metformin.
Ethanol: A single administration
of a moderate amount of alcohol
did not increase the risk
of acute hypoglycemia
in Rezulin-treated patients with type
II diabetes mellitus.
The above interactions with terfenadine and oral
contraceptives suggest that troglitazone
may induce drug metabolism
by CYP3A4. Studies have not been performed with other drugs metabolized
by this enzyme such
as: astemizole, calcium channel
blockers, cisapride, corticosteroids cyclosporine. HMG-CoA reductase
inhibitors, tacrolimus, triazolam, and trimetrexate. The possi bility
of altered safety and efficacy
should be considered when Rezulin is used concomitantly with these
drugs.
Patients stable on one
or more of these agents when Rezulin is started should be closely
monitored and their therapy
adjusted as necessary.
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