WARNINGS
Cardiac Failure and Other Cardiac Effects: 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. Avandia
should be discontinued if any deterioration in cardiac status
occurs.
Patients with New York Heart Association (NYHA) Class 3
and 4 cardiac status were not studied during the clinical
trials. Avandia is not recommended in patients with NYHA
Class 3 and 4 cardiac status.
In two 26-week U.S. trials involving 611 patients with type
2 diabetes, Avandia plus insulin therapy was compared with
insulin therapy alone. These trials included patients with
long-standing diabetes and a high prevalence of pre-existing
medical conditions, including peripheral neuropathy (34%),
retinopathy (19%), ischemic heart disease (14%), vascular
disease (9%), and congestive heart failure (2.5%). In these
clinical studies an increased incidence of cardiac failure
and other cardiovascular adverse events were seen in patients
on Avandia and insulin combination therapy compared to insulin
and placebo. Patients who experienced heart failure were
on average older, had a longer duration of diabetes, and
were mostly on the higher 8 mg daily dose of Avandia. In
this population, however, it was not possible to determine
specific risk factors that could be used to identify all
patients at risk of heart failure on combination therapy.
Three of 10 who developed cardiac failure on combination
therapy during the double blind part of the studies had
no known prior evidence of congestive heart failure, or
pre-existing cardiac condition. The use of Avandia in combination
therapy with insulin is not currently indicated. (See ADVERSE
REACTIONS).
PRECAUTIONS
General
Due to its mechanism of action, Avandia is active
only in the presence of insulin. Therefore, Avandia should
not be used in patients with type 1 diabetes or for the
treatment of diabetic ketoacidosis.
Hypoglycemia: 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.
Edema: Avandia should be used with caution
in patients with edema. In a clinical study in healthy volunteers
who received Avandia 8 mg once daily for 8 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
WARNINGS
, Cardiac Failure and Other Cardiac Effects and
PRECAUTIONS
, Information for Patients).
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 are more likely to have adverse events associated
with edema if started on combination therapy with insulin
and Avandia. (See ADVERSE REACTIONS).
Weight Gain: Dose-related weight gain
was seen with Avandia alone and in combination with other
hypoglycemic agents (Table 6). The mechanism of weight gain
is unclear but probably involves a combination of fluid
retention and fat accumulation.
Table 6. Weight Changes (kg) from Baseline During
Clinical Trials with Avandia
|
|
|
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)
|
1.0 (-0.9, 3.6)
|
3.1 (1.1, 5.8)
|
| |
52 weeks
|
sulfonylurea
|
2.0 (0, 4.0)
|
2.0 (-0.6, 4.0)
|
2.6 (0, 5.3)
|
|
Combination
therapy
|
|
|
|
|
|
|
sulfonylurea
|
26 weeks
|
sulfonylurea
|
0 (-1.3, 1.2)
|
1.8 (0, 3.1)
|
--
|
|
metformin
|
26 weeks
|
metformin
|
-1.4 (-3.2, 0.2)
|
0.8 (-1.0, 2.6)
|
2.1 (0, 4.3)
|
|
insulin
|
26 weeks
|
insulin
|
0.9 (-0.5, 2.7)
|
4.1 (1.4, 6.3)
|
5.4 (3.4, 7.3)
|
Hematologic: Across all controlled clinical
studies, decreases in hemoglobin and hematocrit (mean decreases
in individual studies £1.0 gram/dL and £3.3%,
respectively) were observed for Avandia alone and in combination
with other hypoglycemic agents. The changes occurred primarily
during the first 3 months following initiation of Avandia
therapy or following an increase in Avandia dose. White
blood cell counts also decreased slightly in patients treated
with Avandia. The observed changes may be related to the
increased plasma volume observed with treatment with Avandia
and may be dose realated. (See ADVERSE REACTIONS, Laboratory
Abnormalities).
Ovulation: Avandia, like other thiazolidinediones,
may result in resumption of ovulation in premenopausal,
anovulatory women with insulin resistance. As a consequence
of their improved insulin sensitivity, these patients may
be at risk for pregnancy if adequate contraception is not
used.
Although hormonal imbalance has been seen in preclinical
studies (see Carcinogenesis, Mutagenesis, Impairment of
Fertility below), the clinical significance of this finding
is not known. If unexpected menstrual dysfunction occurs,
the benefits of continued therapy with Avandia should be
reviewed.
Hematologic: Across all controlled clinical
studies, decreases in hemoglobin and hematocrit (mean decreases
in individual studies £1.0 gram/dL and £3.3%,
respectively) were observed for both Avandia alone and in
combination with metformin. The changes occurred primarily
during the first 4 to 8 weeks of therapy and remained relatively
constant thereafter. White blood cell counts also decreased
slightly in patients treated with Avandia. The observed
changes 356 may be related to the increased plasma volume
observed with treatment with
Avandia and have not been associated with any significant
hematologic clinical effects (see ADVERSE REACTIONS, Laboratory
Abnormalities).
Edema: Avandia should be used with caution
in patients with edema. In a clinical study in healthy volunteers
who received Avandia 8 mg once daily for 8 weeks, there
was a statistically significant increase in median plasma
volume (1.8 mL/kg) compared to placebo.
In controlled clinical trials of patients with type 2 diabetes,
mild to moderate edema was reported in patients treated
with Avandia (see ADVERSE REACTIONS).
Use in Patients with Heart Failure: In preclinical studies,
thiazolidinediones, including rosiglitazone, cause plasma
volume expansion and pre-load-induced cardiac hypertrophy.
Two ongoing echocardiography studies in patients with type
2 diabetes (a 52-week study with Avandia 4 mg twice daily
[n= 86] and a 26-week study with 8 mg once daily [n= 90]),
have shown no deleterious alteration in cardiac structure
or function. These studies were designed to detect a change
in left ventricular mass of 10% or more.
Patients with New York Heart Association (NYHA) Class 3
and 4 cardiac status were not studied during the clinical
trials. Avandia is not indicated in patients with NYHA Class
3 and 4 cardiac status unless the expected benefit is judged
to outweigh the potential risk.
Hepatic Effects: Another drug of the thiazolidinedione
class, troglitazone, has been associated with idiosyncratic
hepatotoxicity, and very rare cases of liver failure, liver
transplants, and death have been reported during postmarketing
clinical use. In pre-approval controlled clinical trials
in patients with type 2 diabetes, troglitazone was more
frequently associated with clinically significant elevations
of hepatic enzymes (ALT 3X upper limit of normal) compared
to placebo, and very rare cases of reversible jaundice were
reported.
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
elevation of ALT levels.
In 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
and were not clearly causally related to therapy with Avandia.
Although available clinical data show no evidence of Avandia
induced hepatotoxicity or ALT elevations, rosiglitazone
is structurally very similar to troglitazone, which has
been associated with idiosyncratic hepatotoxicity and rare
cases of liver failure, liver transplants, and death. Pending
the availability of the results of additional large, long-term
controlled clinical trials and postmarketing safety data
following wide clinical use of Avandia to more fully define
its hepatic safety profile, it is recommended that patients
treated with Avandia undergo periodic monitoring of liver
enzymes. Liver enzymes should be checked prior to the initiation
of therapy with Avandia in all patients. Therapy with Avandia
should not be initiated in patients with increased baseline
liver enzyme levels (ALT 2.5X upper limit of normal). In
patients with normal baseline liver enzymes, following initiation
of therapy with Avandia, it is recommended that liver enzymes
be monitored every two months for the first twelve months,
and periodically thereafter. Patients with mildly elevated
liver enzymes (ALT levels one to 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 appropriate close clinical follow-up, including
more frequent liver enzyme monitoring, to determine if the
liver enzyme elevations resolve or worsen. If at any time
ALT levels increase to 3X 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.
There are no data available to evaluate the safety of Avandia
in patients who experience liver abnormalities, hepatic
dysfunction, or jaundice while on troglitazone. Avandia
should not be used in patients who experienced jaundice
while taking troglitazone. For patients with normal hepatic
enzymes who are switched from troglitazone to Avandia, a
one week washout is recommended before starting therapy
with Avandia.
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.
Laboratory Tests
Periodic fasting blood glucose and HbA1c measurements
should be performed to monitor therapeutic response.
Liver enzyme monitoring is recommended prior to initiation
of therapy with Avandia in all patients and periodically
thereafter (See Hepatic Effects - above and ADVERSE REACTIONS,
Serum Transaminase Levels).
Information for Patients
Patients should be informed of the following:
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. Patients should be informed that blood will be drawn
to check their liver function prior to the start of therapy
and every two months for the first twelve months, and periodically
thereafter. Patients with unexplained symptoms of nausea,
vomiting, abdominal pain, fatigue, anorexia, or dark urine
should immediately report these symptoms to their physician.
Avandia can be taken with or without meals.
Use of Avandia may cause resumption of ovulation in premenopausal,
anovulatory women with insulin resistance. Therefore, contraceptive
measures may need to be considered.
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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: A two-year carcinogenicity
study was conducted in Charles River CD-1 mice at doses
of 0.4, 1.5, and 6 mg/kg/day in the diet (highest dose equivalent
to approximately 12 times human AUC at the maximum recommended
human daily dose). Sprague-Dawley rats were dosed for two
years by oral gavage at doses of 0.05, 0.3, and 2 mg/kg/day
(highest dose equivalent to approximately 10 and 20 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 ³1.5 mg/kg/day (approximately 2 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 ³0.3 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 40 mg/kg/day (approximately 116 times human AUC at
the maximum recommended human daily dose). Rosiglitazone
altered estrous cyclicity (2 mg/kg/day) and reduced fertility
(40 mg/kg/day) of female rats in association with lower
plasma levels of progesterone and estradiol (approximately
20 and 200 times human AUC at the maximum recommended human
daily dose, respectively). No such effects were noted at
0.2 mg/kg/day (approximately 3 times human AUC at the maximum
recommended human daily dose). In monkeys, rosiglitazone
(0.6 and 4.6 mg/kg/day; approximately 3 and 15 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.
Animal Toxicology
Heart weights were increased in mice (3 mg/kg/day),
rats (5 mg/kg/day), and dogs (2 mg/kg/day) with rosiglitazone
treatments (approximately 5, 22, and 2 times human AUC
at the maximum recommended human daily dose, respectively).
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.
Pregnancy
Pregnancy Category C: 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 3 mg/kg in rats and 100 mg/kg in rabbits
(approximately 20 and 75 times human AUC at the maximum
recommended human daily dose, respectively). Rosiglitazone
caused placental pathology in rats (3 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 0.2 mg/kg/day in rats and 15 mg/kg/day in rabbits.
These no-effect levels are approximately 4 times human
AUC at the maximum recommended human daily dose.
There are no adequate and well-controlled studies in pregnant
women. Avandia should not be used during pregnancy unless
the potential benefit justifies the potential risk to
the fetus.
Because current information strongly suggests that abnormal
blood glucose levels during pregnancy are associated with
a higher incidence of congenital anomalies as well as
increased neonatal morbidity and mortality, most experts
recommend that insulin be used during pregnancy to maintain
blood glucose levels as close to normal as possible.
Labor and Delivery
The effect of rosiglitazone on labor and delivery
in humans is not known.
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.
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