Avandia®
Rosiglitazone Maleate
Antidiabetic Agent--Insulin Resistance Reducing
Agent
GlaxoSmithKline
http://www.gsk.com/index.htm
Avandia Monograph PDF download here.
CPS:PIS_m074250
Date of Preparation: July 5, 2001
Date of Revision: June 24, 2004
Pharmacology
Rosiglitazone is an oral antidiabetic agent
which acts primarily by increasing insulin sensitivity in type 2 diabetes.
Rosiglitazone, a member of the thiazolidinedione class of antidiabetic agents,
improves glycemic control while reducing circulating insulin levels. It
improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic
gluconeogenesis. Rosiglitazone is not chemically or functionally related to the
sulphonylureas, the biguanides or the alpha-glucosidase inhibitors.
Rosiglitazone is a highly selective and potent agonist for the peroxisome
proliferator-activated receptor- gamma (PPARγ ). In humans, PPAR receptors
are found in key target tissues for insulin action such as adipose tissue,
skeletal muscle and liver. Activation of PPARγ nuclear receptors
regulates the transcription of insulin-responsive genes involved in the control
of glucose production, transport and utilization. In addition, PPARγ
-responsive genes also participate in the regulation of fatty acid metabolism,
and in the maturation of preadipocytes, predominantly of subcutaneous origin.
Insulin resistance is a
primary feature characterizing the pathogenesis of type 2 diabetes. The
antidiabetic activity of rosiglitazone has been demonstrated in a number of
animal models of type 2 diabetes in which hyperglycemia and/or impaired glucose
tolerance is a consequence of insulin resistance in target tissues.
Rosiglitazone normalizes blood glucose concentrations and reduces
hyperinsulinemia in the ob/ob obese mouse, db/db diabetic mouse and fa/fa fatty
Zucker rat. Rosiglitazone also prevents the development of overt diabetes in
both the db/db mouse and Zucker fa/fa Diabetic Fatty (ZDF) rat models. In
addition, rosiglitazone prevents the development of systolic hypertension,
proteinuria, renal morphologic abnormalities and renal dysfunction in the
Zucker rat, and prevents the deleterious changes in pancreatic morphology seen
in untreated db/db mice, ZDF rats and Zucker fa/fa rats.
In animal models,
rosiglitazone's antidiabetic activity was shown to be mediated by increased
sensitivity to insulin's action in the liver, muscle and adipose tissues. 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.
Pharmacokinetics
Maximum plasma concentration (Cmax)
and the area under the curve (AUC0-inf) of rosiglitazone increase in
a dose-proportional manner over the therapeutic dose range (see Table 1). The
elimination half-life is 3 to 4 hours and is independent of dose.
CPS:Avandia_t1Click here for Table 1
Table 1: Avandia
Mean (SD) Pharmacokinetic Parameters for
Rosiglitazone Following Single Oral Doses (n=32)
|
Parameter
|
1 mg Fasting
|
2 mg Fasting
|
8 mg Fasting
|
8 mg Fed
|
|
AUC0-inf
[ng·h/mL]
|
358
(112)
|
733
(184)
|
2971
(730)
|
2890
(795)
|
|
Cmax
[ng/mL]
|
76
(13)
|
156
(42)
|
598
(117)
|
432
(92)
|
|
Tmax
[h]a
|
0.5
(0.5–1.5)
|
1.0
(0.5–2.0)
|
1.0
(0.5–1.5)
|
2.0
(1.0–5.0)
|
|
Half-life
[h]
|
3.16
(0.72)
|
3.15
(0.39)
|
3.37
(0.63)
|
3.59
(0.70)
|
|
CL/Fb
[L/h]
|
3.03
(0.87)
|
2.89
(0.71)
|
2.85
(0.69)
|
2.97
(0.81)
|
a Tmax presented as
median (range).
b CL/F=Oral Clearance.
Absorption: Rosiglitazone is rapidly and
completely absorbed after oral administration with negligible first-pass
metabolism. The absolute bioavailability of rosiglitazone is 99%. Peak plasma
concentrations are observed by 1 hour after dosing. Administration of
rosiglitazone with food resulted in no change in overall exposure (AUC), but
there was a decrease in the Cmax (about 28%) and a delay in Tmax
of 1.75 hours. These changes are not likely to be clinically significant and
rosiglitazone may be administered with or without food.
Distribution: The mean (SD) volume of
distribution (Vss) of rosiglitazone after i.v. administration to healthy
subjects is approximately 14.1 (3.1) L. 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 the parent drug 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 only a minor pathway.
Excretion: Following oral or i.v. administration
of [14C]rosiglitazone, 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 158 hours.
Population Pharmacokinetics in Patients with
Type 2 Diabetes: Population pharmacokinetic analyses from 3 Phase III 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 150 kg), the range of predicted CL/F and Vss/F values varied by <1.7-fold
and 2.3-fold, respectively. Additionally, rosiglitazone CL/F was shown to be
lower (about 6%) in female patients compared to males of the same body weight.
The population mean CL/F of rosiglitazone for a typical male weighing 84 kg was
2.48 L/h. The Vss/F in an 84 kg patient was 17.9 L. The inter-patient
variability in CL/F and Vss/F were 31% and 23%, respectively.
Special Populations: Age: Results of the
population pharmacokinetic analysis (n=716 <65 years; n=331 ≥ 65
years) showed that age does not significantly affect the pharmacokinetics of
rosiglitazone.
Gender: Results of the population
pharmacokinetic analysis showed that the mean oral clearance of rosiglitazone
in female patients (n=405) was 15% lower compared to male patients (n=642),
primarily related to lower body weight in females.
As monotherapy and in combination
with metformin, rosiglitazone 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 PPARγ is expressed in adipose tissues, this differentiating
characteristic may account, at least in part, for the greater response to
rosiglitazone in females. Since safety profiles were similar between male and
female patients in clinical studies and, as therapy should be individualized, no
dose adjustments are necessary based on gender.
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 (see Precautions,
Hepatic Disease).
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. Since metformin is contraindicated in patients with
renal impairment, metformin in combination with rosiglitazone should not be
given to 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.
Children: The safety and effectiveness of
rosiglitazone have not been established in patients younger than 18 years of
age, therefore, rosiglitazone is not indicated in patients younger than 18
years of age. Thiazolidinediones promote the maturation of preadipocytes and
have been associated with weight gain. Obesity is a major problem in
adolescents with type 2 diabetes.
Pharmacodynamics and Clinical Effects
In clinical studies, treatment with
rosiglitazone resulted in an improvement in glycemic control, as measured by
fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c), with a concurrent
reduction in insulin and C-peptide. Postprandial glucose and insulin levels
were also reduced. This is consistent with the mechanism of action of
rosiglitazone as an insulin sensitizer. The improvement in glycemic control was
durable, with maintenance of effect for at least 52 weeks. The maximum
recommended daily dose is 8 mg. Phase II studies indicated that no additional
benefit was obtained with a total daily dose of 12 mg.
Rosiglitazone is
believed to act primarily on muscle and adipose tissue, whereas metformin acts
primarily on the liver to decrease hepatic glucose output. The coadministration
of rosiglitazone with either metformin or sulfonylurea resulted in
significantly improved glycemic control compared to any of these agents alone.
These results are consistent with a synergistic effect on glycemic control when
rosiglitazone is used in combination therapy.
While improvement in
glycemic control was associated with increases in weight, changes were highly
variable. In 26-week clinical trials, the mean weight gain in patients treated
with rosiglitazone was 1.2 kg (range: − 11.6 to 12.7) (4 mg daily) and
3.5 kg (range: − 6.8 to 13.9) (8 mg daily) when administered as
monotherapy and 0.7 kg (range: − 6.8 to 9.8) (4 mg daily) and 2.3 kg
(range: − 5.4 to 13.1) (8 mg daily) when administered in combination with
metformin and 1.8 kg (range: − 5 to 11.5) (4 mg daily) when administered
in combination with sulfonylurea. In a 52-week glyburide-controlled study,
there was a mean weight gain of 1.75 kg (range: − 7.0 to 16.0) and 2.95
kg (range: − 11.0 to 22.0) for patients treated with 4 mg and 8 mg
of rosiglitazone daily, respectively, versus 1.9 kg (range: − 11.5 to
12.2) in glyburide-treated patients. Weight gain with thiazolidinediones can
result from increases in subcutaneous adipose tissue and/or from fluid retention.
Treatment should be re-evaluated in patients with excessive weight gain (see
Precautions and Adverse Effects).
Patients with lipid
abnormalities were not excluded from clinical trials of rosiglitazone. In all
26-week controlled trials, across the recommended dose range, rosiglitazone 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 (see Table 2).
Increases in LDL
occurred primarily during the first 1 to 2 months of therapy with rosiglitazone
and LDL levels remained stable, but elevated above baseline, throughout the
trials. In contrast, HDL continued to rise over time. As a result, the LDL/HDL
ratio peaked after 2 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, median LDL/HDL ratios were 3.0, 2.9,
and 2.8, respectively, for rosiglitazone 4 mg twice daily and the median total
cholesterol/HDL ratios were 4.76, 4.52 and 4.35, respectively. The
corresponding values for glyburide were 3.2, 2.9, and 2.7 for the median
LDL/HDL ratios and 4.90, 4.61 and 4.36 for the median total cholesterol/HDL
ratios.
The pattern of LDL and
HDL changes following therapy with rosiglitazone in combination with
sulfonylurea or metformin were generally similar to those seen with
rosiglitazone in monotherapy.
The changes in
triglycerides during therapy with rosiglitazone were variable and were
generally not statistically different from placebo or glyburide controls.
CPS:Avandia_t2Click here for Table 2
Table 2: Avandia
Summary of Lipid Changes in 26-Week
Placebo-Controlled and 52-Week Glyburide-Controlled Monotherapy Studies
|
|
Placebo-controlled
Studies
Week 26
|
Glyburide-controlled
Study
Week 26 and Week 52
|
|
|
Placebo
|
Avandia
|
Glyburide titration
|
Avandia 8 mg
|
|
|
4 mg daily
|
8 mg daily
|
wk 26
|
wk 52
|
wk 26
|
wk 52
|
|
|
Free Fatty Acids (mmol/L)
|
|
N
|
207
|
428
|
436
|
181
|
168
|
166
|
145
|
|
|
Baseline (median)
|
0.61
|
0.58
|
0.61
|
0.92
|
0.92
|
0.93
|
0.93
|
|
|
% change from baseline (median)
|
− 4.0
|
− 15.6
|
− 23.5
|
− 5.5
|
− 9.7
|
− 26.7
|
− 24.7
|
|
|
LDL-cholesterol (mmol/L)
|
|
N
|
190
|
400
|
374
|
175
|
160
|
161
|
133
|
|
|
Baseline (median)
|
3.15
|
3.26
|
3.19
|
3.68
|
3.55
|
3.62
|
3.62
|
|
|
% change from baseline (median)
|
+2.5
|
+10.3
|
+14.8
|
− 3.7
|
− 3.3
|
+7.1
|
+7.3
|
|
|
HDL-cholesterol (mmol/L)
|
|
N
|
208
|
429
|
436
|
184
|
170
|
170
|
145
|
|
|
Baseline (median)
|
1.06
|
1.14
|
1.09
|
1.17
|
1.18
|
1.19
|
1.19
|
|
|
% change from baseline (median)
|
+8.2
|
+10.3
|
+11.3
|
+4.7
|
+8.0
|
+13.2
|
+17.4
|
|
The long-term
significance of the lipid changes is not known.
Because rosiglitazone
does not stimulate insulin secretion, hypoglycemia is not expected to occur
when rosiglitazone is prescribed as monotherapy. Patients receiving
rosiglitazone in combination with other hypoglycemic agents (e.g.,
insulin-secreting agents) may be at risk for hypoglycemia, and a reduction in
the dose of the concomitant agent may be necessary.
As insulin sensitizers
can only work in the presence of insulin, rosiglitazone should not be used in
patients with type 1 diabetes.
Indications
As monotherapy, in patients not controlled by
diet and exercise alone, to reduce insulin resistance and lower elevated blood
glucose in patients with type 2 diabetes mellitus (see Dosage).
Rosiglitazone is
indicated for use in combination with metformin when, in addition to diet and
exercise, rosiglitazone or metformin alone does not result in adequate glycemic
control in patients with Type 2 diabetes. For patients inadequately controlled
by a maximum dose of metformin, rosiglitazone should be added to, not
substituted for, metformin.
Rosiglitazone is
indicated for use in combination with sulfonylurea when, in addition to diet
and exercise, rosiglitazone or the sulfonylurea alone does not result in
adequate glycemic control in patients with type 2 diabetes. For patients
inadequately controlled by a maximum dose of sulfonylurea, rosiglitazone should
be added to, not substituted for, sulfonylurea.
Caloric restriction,
weight loss, and exercise improve insulin sensitivity and are essential for the
proper treatment of a diabetic patient. These measures are important not only
in the primary treatment of type 2 diabetes, but also in maintaining the
efficacy of drug therapy. Prior to initiation of therapy with rosiglitazone,
secondary causes of poor glycemic control (e.g., infection) should be
investigated and treated.
Contraindications
In patients with known hypersensitivity to this
product or any of its components.
Rosiglitazone is
contraindicated in patients with serious hepatic impairment (see Precautions).
Thiazolidinediones,
including rosiglitazone, are contraindicated in patients with acute heart
failure.
Warnings
Thiazolidinediones can cause fluid retention,
which can exacerbate or lead to congestive heart failure. The fluid retention
may very rarely present as rapid and excessive weight gain. Patients at risk
for heart failure (particularly those on insulin) should be monitored for signs
and symptoms of heart failure. Treatment with thiazolidinediones has been
associated with cases of congestive heart failure, some of which were difficult
to treat unless the medication was discontinued (see Precautions, Patients with
Heart Disease). Rosiglitazone should be discontinued if any deterioration in
the cardiac status occurs.
Patients with New York
Heart Association (NYHA) Class III and IV cardiac status were not studied
during the clinical trials. Rosiglitazone is not indicated in patients with
NYHA Class III and IV cardiac status.
In two 26-week US
trials involving 611 patients with type 2 diabetes, rosiglitazone 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 rosiglitazone 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 rosiglitazone.
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
insulin combination therapy. Three of 10 patients who developed cardiac failure
on insulin combination therapy during the double-blind part of the studies had
no known prior evidence of congestive heart failure, or pre-existing cardiac
condition.
Rosiglitazone is not
currently indicated for combination use with insulin.
Rare cases of severe
hepatocellular injury have been reported with thiazolidinediones (see
Precautions, Hepatic Disease).
Pregnancy
There are no controlled trials of rosiglitazone
in pregnant women. Rosiglitazone should not be used and is not indicated for
use in pregnant women. 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 mortality, most
experts recommend that insulin be used during pregnancy. In animal studies,
rosiglitazone was not teratogenic but treatment during mid-late gestation caused
fetal death and growth retardation in both rats and rabbits at 19- and 73-fold
clinical systemic exposure, respectively.
Precautions
General
Rosiglitazone is active only in the presence of
insulin due to its mechanism of action. Therefore, rosiglitazone should not be
used in type 1 diabetes or for the treatment of diabetic ketoacidosis.
Hypoglycemia
Because rosiglitazone does not stimulate insulin
secretion, hypoglycemia is not expected to occur when rosiglitazone is
prescribed as monotherapy. Patients receiving rosiglitazone in combination with
other hypoglycemic agents (e.g., insulin-secreting agents) may be at risk for
hypoglycemia, and a reduction in the dose of the concomitant agent may be
necessary.
Ovulation
In common with other thiazolidinediones,
rosiglitazone may result in resumption of ovulation in premenopausal,
anovulatory women with insulin resistance (e.g., patients with polycystic ovary
syndrome). As a consequence of their improved insulin sensitivity, these
patients may be at risk of pregnancy if adequate contraception is not used.
Although hormonal
imbalance has been seen in preclinical studies, no significant adverse
experiences associated with menstrual disorders have been reported in clinical
trial participants, including premenopausal women. If unexpected menstrual
dysfunction occurs, the benefits of continued therapy should be reviewed.
Hematologic
In controlled trials, there were dose-related
decreases in hemoglobin and hematocrit. The magnitude of the decreases (≤
11 g/L for hemoglobin and ≤ 0.034 for hematocrit) was small for
rosiglitazone alone and rosiglitazone in combination with metformin or in
combination with sulfonylurea. The changes occurred primarily during the first
3 months of therapy or following an increase in rosiglitazone dose and remained
relatively constant thereafter. Decreases may be related to increased plasma
volume observed during treatment with rosiglitazone and have not been
associated with any significant hematologic clinical effects (see Adverse
Effects, Laboratory Abnormalities). Patients with a hemoglobin value of
<110 g/L for males and <100 g/L for females were excluded from
the clinical trials.
Edema
Rosiglitazone should be used with caution in
patients with edema. In healthy volunteers who received rosiglitazone 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 observed
at a greater frequency in patients treated with rosiglitazone 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
rosiglitazone (see Adverse Effects).
Weight Gain
Dose-related weight gain was seen with
rosiglitazone alone and in combination with other hypoglycemic agents. Weight
gain with thiazolidinediones can result from increases in subcutaneous adipose
tissue and/or from fluid retention. Treatment should be re-evaluated in
patients with excessive weight gain (see Pharmacology and Adverse Effects).
Patients with Heart Disease
In preclinical studies, thiazolidinediones
caused plasma volume expansion and preload-induced cardiac hypertrophy. Two
ongoing echocardiography studies in type 2 diabetic patients (a 52-week study
with rosiglitazone 4 mg twice daily and a 26-week study with 8 mg once
daily), designed to detect a change in left ventricular mass of 10% or more,
showed no deleterious alteration in cardiac structure or function. Compared to
placebo, there was a small, statistically significant increase in median plasma
volume (1.8 mL/kg) in healthy volunteers treated with rosiglitazone 8 mg once
daily for 8 weeks. No increased incidence of adverse events potentially related
to volume expansion (e.g., congestive heart failure) have been observed during
controlled clinical trials with rosiglitazone as monotherapy or in combination
with metformin or sulfonylurea. See Adverse Effects for experience concerning
serious cardiovascular adverse events.
Hepatic Disease
In pre-approval clinical studies in 4598
patients treated with rosiglitazone, representing approximately 3600 patient
years of exposure, there was no evidence of drug-induced hepatotoxicity or
elevation of ALT levels.
In the pre-approval
controlled trials, 0.2% of patients treated with rosiglitazone had elevations
in ALT >3 times the upper limit of normal, compared to 0.2% on placebo and
0.5% on active comparators. The ALT elevations in patients treated with
rosiglitazone were reversible and were not clearly causally related to therapy
with rosiglitazone. In the clinical program including long-term, open-label
experience, the rate per 100 patient-years exposure of ALT increase to >3 times
the upper limit of normal was 0.35 for patients treated with rosiglitazone,
0.59 for placebo-treated patients, and 0.78 for patients treated with active
comparator agents.
Although available
clinical data show no evidence of rosiglitazone induced hepatotoxicity or ALT
elevations, rosiglitazone has a common thiazolidinedione structure to
troglitazone, which has been associated with idiosyncratic hepatotoxicity and
rare cases of liver failure, liver transplants, and death during clinical use.
In postmarketing
experience with rosiglitazone, reports of hepatitis and of hepatic enzyme
elevations to 3 or more times the upper limit of normal have been
received. Very rarely, these reports have involved hepatic failure with and
without fatal outcome, although causality has not been established. Pending the
availability of the results of additional large, long-term controlled clinical
trials and additional postmarketing safety data following wide clinical use of
rosiglitazone to more fully define its hepatic safety profile, it is
recommended that patients treated with rosiglitazone undergo periodic
monitoring of liver enzymes.
Liver enzymes should be
checked prior to the initiation of therapy with rosiglitazone in all patients
and periodically thereafter per the clinical judgement of the healthcare
professional. Therapy with rosiglitazone should not be initiated in patients
with increased baseline liver enzyme levels (ALT >2.5 times the upper limit
of normal). Patients with mildly elevated liver enzymes (ALT levels ≤
2.5 times the upper limit of normal) at baseline or during therapy
with rosiglitazone should be evaluated to determine the cause of the liver
enzyme elevation.
Initiation of, or
continuation of, therapy with rosiglitazone 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 >3 times the upper limit of normal in patients on therapy with
rosiglitazone, liver enzyme levels should be rechecked as soon as possible. If
ALT levels remain >3 times the upper limit of normal, therapy with
rosiglitazone should be discontinued (see Dosage).
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
rosiglitazone 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 rosiglitazone in all
patients and periodically thereafter (see Precautions).
Information to Be Provided to the Patient
Physicians are advised to use the Information
for the Patient section to assist in the communication of the safe and
effective use of rosiglitazone to their patients.
Patients should be
informed of the following: Rosiglitazone can be taken with or without meals.
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 regularly have blood glucose and
glycosylated hemoglobin tested.
Use of rosiglitazone
may cause resumption of ovulation in women with polycystic ovary disease.
Therefore, contraceptive measures may need to be considered for these women.
Patients should be
advised to tell their physician if they are taking oral contraceptives and, if
they are of childbearing age, to inform their physician if they are, or intend
to become pregnant.
Patients should be
informed that blood will be drawn to check their liver function prior to the
start of therapy, and periodically thereafter per the clinical judgement of the
healthcare professional. Patients with unexplained symptoms of nausea,
vomiting, abdominal pain, fatigue, anorexia, dark urine, or unusual changes in
weight should immediately report these symptoms to their physician.
Patients should be
advised to immediately inform their physician if edema, shortness of breath,
weakness, fatigue or unusual weight gain develops because these symptoms,
although not specific, may signal heart problems.
When using
rosiglitazone in combination with other hypoglycemic agents (e.g.,
insulin-secreting 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.
If a dose of
rosiglitazone is missed with once-a-day dosing, the patient should be advised
to take 1 tablet as soon as they remember, anytime during the day. If a dose is
missed with twice-a-day dosing, the patient should be advised to take 1 tablet
as soon as they remember and the next tablet at the usual time. Three doses
should never be taken in one day to make up for a missed dose the day before.
If a whole day of rosiglitazone is missed, the usual dosing schedule should be
followed the next day without making up for the missed doses.
Drug Interactions
Drugs Metabolized by Cytochrome P450: It has been
shown in vitro that rosiglitazone does not inhibit any of the major P450
enzymes at clinically relevant concentrations. In vitro studies demonstrate
that rosiglitazone is predominantly metabolized by CYP2C8, with CYP2C9 as only
a minor pathway. No in vivo interaction studies have been performed with CYP2C8
substrates (cerivastatin and paclitaxel). The potential for a clinically
relevant interaction with cerivastatin is considered to be low. Although
rosiglitazone is not anticipated to affect the pharmacokinetics of paclitaxel,
concomitant use is likely to result in inhibition of the metabolism of
rosiglitazone. Clinically significant interactions with CYP2C9 substrates or
inhibitors are not anticipated.
CYP3A4 Substrates: Rosiglitazone (8 mg once
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. The results of these two drug
interaction studies suggest that rosiglitazone is unlikely to cause clinically
important drug interactions with other drugs metabolized via CYP3A4.
Oral Contraceptives: In 32 healthy women,
rosiglitazone (8 mg once daily) was shown to have no statistically significant
effect on the pharmacokinetics of oral contraceptives (ethinylestradiol and
norethindrone). Breakthrough bleeding occurred in 5 individuals when
rosiglitazone was coadministered with an oral contraceptive. In one of these
subjects, a 40% decrease in ethinylestradiol exposure (AUC) was recorded. This
was not correlated with a reduction in exposure to norethindrone, nor was there
a consistent relationship between the occurrence of breakthrough bleeding and
the pharmacokinetics of either ethinylestradiol or norethindrone in individual
subjects.
Glyburide: Rosiglitazone (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
rosiglitazone (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 3
times daily) for 7 days in healthy volunteers had no clinically relevant effect
on the pharmacokinetics of a single oral dose of rosiglitazone.
Digoxin: Repeat oral dosing of rosiglitazone (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: Coadministration of rosiglitazone (4
mg twice daily for 7 days) did not alter the anticoagulant response of
steady-state warfarin in healthy volunteers with baseline values of INR of
<2.75. Repeat dosing with rosiglitazone had no clinically relevant effect on
the steady-state pharmacokinetics of warfarin.
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 rosiglitazone.
Ranitidine: Pretreatment with ranitidine (150 mg
twice daily for 4 days) did not alter the pharmacokinetics of either
single oral or i.v. 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.
Concomitant Medications in Phase III Clinical
Trials: Results of the population pharmacokinetic analysis indicated that none
of the following classes of concomitant medications (oral hypoglycemics,
analgesics, calcium channel blockers, hypolipidemics, ACE inhibitors and
steroid hormones) appear to alter the oral clearance or oral steady-state
volume of distribution of rosiglitazone.
Geriatrics
In the pooled population pharmacokinetic
analysis, there were no marked differences in the pharmacokinetics of
rosiglitazone between elderly and non-elderly patients.
Children
There are no data on the use of rosiglitazone in
patients under 18 years of age; therefore, rosiglitazone is not indicated for
use in patients under 18 years of age.
Pregnancy
There are no controlled studies in pregnant
women. Rosiglitazone should not be used and is not indicated for use during
pregnancy.
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.
Lactation
It is not known whether rosiglitazone is
excreted in human milk. Because many drugs are excreted in human milk,
rosiglitazone should not be administered to a nursing woman.
Adverse Effects
In clinical trials, approximately 4600 type 2
diabetic patients have been treated with rosiglitazone as monotherapy or
concomitantly with metformin, sulfonylureas or insulin; 3300 patients were
treated for 6 months or longer and 2000 patients were treated for 12 months or
longer. In general, rosiglitazone was well tolerated. The overall incidence and
types of adverse experiences reported in clinical trials are shown in Table 3.
CPS:Avandia_t3Click here for Table 3
Table 3: Avandia
Adverse Experiences (≥ 5% in any treatment
group) Reported by Patients in Double-blind Clinical Trials with Avandia
|
Preferred Term
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Avandia Monotherapy
N=2526
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