ROSIGLITAZONE
DESCRIPTION
Rosizon (rosiglitazone maleate) is an oral antidiabetic agent which acts
primarily by increasing insulin sensitivity. Rosizon is used in the management
of type 2 diabetes mellitus (also known as non-insulin-dependent diabetes
mellitus [NIDDM] or adult-onset diabetes). Rosizon improves glycemic control
while reducing circulating insulin levels.
Pharmacological studies in animal models indicate that rosiglitazone improves
sensitivity to insulin in muscle and adipose tissue and inhibits hepatic
gluconeogenesis. Rosiglitazone maleate is not chemically or functionally related
to the sulfonylureas, the biguanides, or the alpha-glucosidase inhibitors.
Chemically, rosiglitazone maleate is (±)-5-[[4-[2-(methyl-2-
pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, ( Z )-2-butenedioate
(1:1) with a molecular weight of 473.52 (357.44 free base). The molecule has a
single chiral center and is present as a racemate. Due to rapid interconversion,
the enantiomers are functionally indistinguishable.
The molecular formula is C 18 H 19 N 3 O 3 S·C 4 H 4 O 4 . Rosiglitazone maleate
is a white to off-white solid with a melting point range of 122° to 123° C. The
pKa values of rosiglitazone maleate are 6.8 and 6.1. It is readily soluble in
ethanol and a buffered aqueous solution with pH of 2.3; solubility decreases
with increasing pH in the physiological range.
CLINICAL PHARMACOLOGY
Mechanism of Action
Rosiglitazone, a member of the thiazolidinedione class of antidiabetic agents,
improves glycemic control by improving insulin sensitivity. Rosiglitazone is a
highly selective and potent agonist for the peroxisome proliferator-activated
receptor-gamma (PPAR(gamma)). In humans, PPAR receptors are found in key target
tissues for insulin action such as adipose tissue, skeletal muscle, and liver.
Activation of PPAR(gamma) nuclear receptors regulates the transcription of
insulin-responsive genes involved in the control of glucose production,
transport, and utilization. In addition, PPAR(gamma)-responsive genes also
participate in the regulation of fatty acid metabolism.
Insulin resistance is a common feature characterizing the pathogenesis of type 2
diabetes. The antidiabetic activity of rosiglitazone has been demonstrated in
animal models of type 2 diabetes in which hyperglycemia and/or impaired glucose
tolerance is a consequence of insulin resistance in target tissues.
Rosiglitazone reduces 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 rat models.
In animal models, rosiglitazone's antidiabetic activity was shown to be mediated
by increased sensitivity to insulin' 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 and Drug Metabolism
Maximum plasma concentration (C max ) and the area under the curve (AUC) of
rosiglitazone increase in a dose-proportional manner over the therapeutic dose
range. The elimination half-life is 3 to 4 hours and is independent of dose.
Absorption
The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations
are observed about 1 hour after dosing. Administration of rosiglitazone with
food resulted in no change in overall exposure (AUC), but there was an
approximately 28% decrease in C max and a delay in T max (1.75 hours). These
changes are not likely to be clinically significant; therefore, Rosizon
(rosiglitazone maleate) may be administered with or without food.
Distribution
The mean (CV%) oral volume of distribution (Vss/F) of rosiglitazone is
approximately 17.6 (30%) liters, based on a population pharmacokinetic analysis.
Rosiglitazone is approximately 99.8% bound to plasma proteins, primarily
albumin.
Metabolism
Rosiglizatone 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 parent 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 P 450 (CYP) isoenzyme 2C8, with CYP2C9 contributing as a minor
pathway.
Excretion
Following oral or intravenous administration of [ 14 C]rosiglitazone maleate,
approximately 64% and 23% of the dose was eliminated in the urine and in the
feces, respectively. The plasma half-life of [ 14 C]related material ranged from
103 to 158 hours.
Population Pharmacokinetics in Patients with Type 2 Diabetes
Population pharmacokinetic analyses from three large clinical 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 influenced by both weight and
gender, being lower (about 15%) in female patients.
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 pharmacokinetics analysis showed that the
mean oral clearance of rosiglitazone in female patients (n=405) was
approximately 6% lower compared to male patients of the same body weight
(n=642).
As monotherapy and in combination with metformin, Rosizon 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 PPAR(gamma) is expressed in adipose tissues, this
differentiating characteristic may account, at least in part, for the greater
response to Rosizon in females. Since therapy should be individualized, no dose
adjustments are necessary based on gender alone.
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 C max and AUC 0-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.
Therapy with Rosizon (rosiglitazone maleate) should not be initiated if the
patient exhibits clinical evidence of active liver disease or increased serum
transaminase levels (ALT >2.5X upper limit of normal) at baseline (see
PRECAUTIONS , Hepatic Effects ).
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 receiving Rosizon . Since metformin is contraindicated in patients with
renal impairment, co-administration of metformin with Rosizon is contraindicated
in 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.
Pediatric Use: The safety and effectiveness of Rosizon in pediatric patients
have not been established.
Pharmacodynamics and Clinical Effects
In clinical studies, treatment with Rosizon 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 were also reduced. This is consistent with the mechanism of
action of Rosizon as an insulin sensitizer. The improvement in glycemic control
was durable, with maintenance of effect for 52 weeks. The maximum recommended
daily dose is 8 mg. Dose-ranging studies suggested that no additional benefit
was obtained with a total daily dose of 12 mg.
The addition of Rosizon to either metformin or a sulfonylurea resulted in
significant reductions in hyperglycemia compared to any of these agents alone.
These results are consistent with an additive effect on glycemic control when
Rosizon is used as combination therapy.
Reduction in hyperglycemia was associated with increases in weight. In the 26-
week clinical trials, the mean weight gain in patients treated with Rosizon was
1.2 kg (4 mg daily) to 3.5 kg (8 mg daily) when administered as monotherapy, 0.7
kg (4 mg daily) and 2.3 kg (8 mg daily) when administered in combination with
metformin, and 1.8 kg (4 mg daily) when administered in combination with a
sulfonylurea. A mean weight loss of about 1 kg was seen for both placebo and
metformin alone in these studies. The mean change in weight was negligible for
patients treated with a sulfonylurea alone in these studies. In the 52-week
glyburide-controlled study, there was a mean weight gain of 1.75 kg and 2.95 kg
for patients treated with 4 mg and 8 mg of Rosizon daily, respectively, versus
1.9 kg in glyburide-treated patients.
Patients with lipid abnormalities were not excluded from clinical trials of
Rosizon . In all 26-week controlled trials, across the recommended dose range,
Rosizon 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 (Table 2).
Increases in LDL occurred primarily during the first 1 to 2 months of therapy
with Rosizon and LDL levels remained 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, mean LDL/HDL ratios were 3.1, 3.2, and 3.0,
respectively, for Rosizon 4 mg twice daily. The corresponding values for
glyburide were 3.2, 3.1, and 2.9. The differences in change from baseline
between Rosizon and glyburide at week 52 were statistically significant.
The pattern of LDL and HDL changes following therapy with Rosizon in combination
with a sulfonylurea or metformin were generally similar to those seen with
Rosizon in monotherapy.
The changes in triglycerides during therapy with Rosizon (rosiglitazone maleate)
were variable and were generally not statistically different from placebo or
glyburide controls.
Clinical Studies
Monotherapy
A total of 2315 patients with type 2 diabetes, previously treated with diet
alone or antidiabetic medication(s), were treated with Rosizon as monotherapy in
six double-blind studies, which included two 26-week placebo-controlled studies,
one 52-week glyburide-controlled study, and three placebo-controlled dose-
ranging studies of 8 to 12 weeks duration. Previous antidiabetic medication(s)
were withdrawn and patients entered a 2 to 4 week placebo run-in period prior to
randomization.
Two 26-week, double-blind, placebo-controlled trials, in patients with type 2
diabetes with inadequate glycemic control (mean baseline FPG approximately 228
mg/dL and mean baseline HbA1c 8.9%), were conducted. Treatment with Rosizon
produced statistically significant improvements in FPG and HbA1c compared to
baseline and relative to placebo
When administered at the same total daily dose, Rosizon was generally more
effective in reducing FPG and HbA1c when administered in divided doses twice
daily compared to once daily doses. However, for HbA1c, the difference between
the 4 mg once daily and 2 mg twice daily doses was not statistically
significant.
Long-term maintenance of effect was evaluated in a 52-week, double-blind,
glyburide-controlled trial in patients with type 2 diabetes. Patients were
randomized to treatment with Rosizon (rosiglitazone maleate) 2 mg twice daily
(N=195) or Rosizon 4 mg twice daily (N=189) or glyburide (N=202) for 52 weeks.
Patients receiving glyburide were given an initial dosage of either 2.5 mg/day
or 5.0 mg/day. The dosage was then titrated in 2.5 mg/day increments over the
next 12 weeks, to a maximum dosage of 15.0 mg/day in order to optimize glycemic
control. Thereafter the glyburide dose was kept constant.
The median titrated dose of glyburide was 7.5 mg. All treatments resulted in a
statistically significant improvement in glycemic control from baseline (Figures
1 and 2). At the end of week 52, the reduction from baseline in FPG and HbA1c
was -40.8 mg/dL and -0.53% with Rosizon 4 mg twice daily; -25.4 mg/dL and -0.27%
with Rosizon 2 mg twice daily; and -30.0 mg/dL and -0.72% with glyburide. For
HbA1c, the difference between Rosizon 4 mg twice daily and glyburide was not
statistically significant at week 52. The initial fall in FPG with glyburide was
greater than with Rosizon ; however, this effect was less durable over time. The
improvement in glycemic control seen with Rosizon 4 mg twice daily at week 26
was maintained through week 52 of the study.
Hypoglycemia was reported in 12.1% of glyburide-treated patients versus 0.5% (2
mg twice daily) and 1.6% (4 mg twice daily) of patients treated with Rosizon .
The improvements in glycemic control were associated with a mean weight gain of
1.75 kg and 2.95 kg for patients treated with 2 mg and 4 mg twice daily of
Rosizon , respectively, versus 1.9 kg in glyburide-treated patients. In patients
treated with Rosizon , C-peptide, insulin, pro-insulin, and pro-insulin split
products were significantly reduced in a dose-ordered fashion, compared to an
increase in the glyburide-treated patients.
Combination with Metformin
A total of 670 patients with type 2 diabetes participated in two 26-week,
randomized, double-blind, placebo/active-controlled studies designed to assess
the efficacy of Rosizon (rosiglitazone maleate) in combination with metformin.
Rosizon , administered in either once daily or twice daily dosing regimens, was
added to the therapy of patients who were inadequately controlled on a maximum
dose (2.5 grams/day) of metformin.
In one study, patients inadequately controlled on 2.5 grams/day of metformin
(mean baseline FPG 216 mg/dL and mean baseline HbA1c 8.8%) were randomized to
receive Rosizon 4 mg once daily, Rosizon 8 mg once daily, or placebo in addition
to metformin. A statistically significant improvement in FPG and HbA1c was
observed in patients treated with the combinations of metformin and Rosizon 4 mg
once daily and Rosizon 8 mg once daily, versus patients continued on metformin
alone
In a second 26-week study, patients with type 2 diabetes inadequately controlled
on 2.5 grams/day of metformin who were randomized to receive the combination of
Rosizon 4 mg twice daily and metformin (N=105) showed a statistically
significant improvement in glycemic control with a mean treatment effect for FPG
of -56 mg/dL and a mean treatment effect for HbA1c of -0.8% over metformin
alone. The combination of metformin and Rosizon resulted in lower levels of FPG
and HbA1c than either agent alone.
Patients who were inadequately controlled on a maximum dose (2.5 grams/day) of
metformin and who were switched to monotherapy with Rosizon (rosiglitazone
maleate) demonstrated loss of glycemic control, as evidenced by increases in FPG
and HbA1c. In this group, increases in LDL and VLDL were also seen.
Combination with a Sulfonylurea
A total of 1216 patients with type 2 diabetes participated in three 26-week
randomized, double-blind, placebo/active-controlled studies designed to assess
the efficacy and safety of Rosizon in combination with a sulfonylurea. Rosizon 2
mg or 4 mg daily, was administered either once daily or in divided doses twice
daily, to patients inadequately controlled on a sulfonylurea.
In the two placebo-controlled studies, patients inadequately controlled on
sulfonylureas that were randomized to single dose or divided doses of Rosizon 4
mg daily plus a sulfonylurea showed significantly reduced FPG and HbA1c compared
to sulfonylurea plus placebo .
In the third study, including patients on prior single or multiple therapies, in
patients inadequately controlled on the maximal dose of glyburide (20 mg daily),
Rosizon 2 mg twice daily plus sulfonylurea significantly reduced FPG (n=98, mean
change from baseline of -31 mg/dL) and HbA1c (mean change from baseline of -
0.5%) compared to sulfonylurea plus placebo (n=99, mean change from baseline of
FPG of + 24 mg/dL and of HbA1c of + 0.9%). The combination of sulfonylurea and
Rosizon resulted in lower levels of FPG and HbA1c than either agent alone.
Patients who were switched from maximal dose of glyburide to 2 mg twice daily
Rosizon monotherapy demonstrated loss of glycemic control, as evidenced by
increases in FPG and HbA1c.
INDICATIONS AND USAGE
Rosizon is indicated as an adjunct to diet and exercise to improve glycemic
control in patients with type 2 diabetes mellitus. Rosizon is indicated as
monotherapy.
Rosizon is also indicated for use in combination with a sulfonylurea or
metformin when diet, exercise and Rosizon alone or diet, exercise plus the
single agent do not result in adequate glycemic control. For patients
inadequately controlled with a maximum dose of a sulfonylurea or metformin,
Rosizon should be added to, rather than substituted for, a sulfonylurea or
metformin.
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 also in maintaining the
efficacy of drug therapy. Prior to initiation of therapy with Rosizon
(rosiglitazone maleate), secondary causes of poor glycemic control, e.g.,
infection, should be investigated and treated.
CONTRAINDICATIONS
Rosizon is contraindicated in patients with known hypersensitivity to this
product or any of its components.
PRECAUTIONS
General
Due to its mechanism of action, Rosizon is active only in the presence of
insulin. Therefore, Rosizon should not be used in patients with type 1 diabetes
or for the treatment of diabetic ketoacidosis.
Patients receiving Rosizon in combination with other oral hypoglycemic agents
may be at risk for hypoglycemia, and a reduction in the dose of the concomitant
agent may be necessary.
Ovulation: Therapy with Rosizon , like other thiazolidinediones, may result in
ovulation in some premenopausal anovulatory women. As a result, these patients
may be at an increased risk for pregnancy while taking Rosizon . (See
PRECAUTIONS, Pregnancy, Pregnancy Category C .) Thus, adequate contraception in
premenopausal women should be recommended. This possible effect has not been
specifically investigated in clinical studies so the frequency of this
occurrence is not known.
Although hormonal imbalance has been seen in preclinical studies (see
Carcinogenesis, Mutagenesis, Impairment of Fertility ), the clinical
significance of this finding is not known. If unexpected menstrual dysfunction
occurs, the benefits of continued therapy with Rosizon 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 Rosizon alone and in combination with a
sulfonylurea or 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 Rosizon . The observed
changes may be related to the increased plasma volume observed with treatment
with Rosizon and have not been associated with any significant hematologic
clinical effects (see ADVERSE REACTIONS , Laboratory Abnormalities ).
Edema: Rosizon should be used with caution in patients with edema. In a
clinical study in healthy volunteers who received Rosizon 8 mg once daily for 8
weeks, there was a small, 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 Rosizon (See ADVERSE REACTIONS ).
Since thiazolidinediones can cause fluid retention, which can exacerbate
congestive heart failure, patients at risk for heart failure (particularly those
on insulin) should be monitored for signs and symptoms of heart failure (See
PRECAUTIONS , Use in Patients with Heart Failure ).
Use in Patients with Heart Failure: In preclinical studies, thiazolidinediones,
including rosiglitazone, caused plasma volume expansion and pre-load-induced
cardiac hypertrophy. Two ongoing echocardiography studies in patients with type
2 diabetes (a 52-week study with Rosizon 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. Rosizon 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, rosiglitazone was more frequently associated with
clinically significant elevations in liver 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 Rosizon , 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 Rosizon 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 Rosizon were reversible
and were not clearly causally related to therapy with Rosizon (rosiglitazone
maleate).
Although available clinical data show no evidence of Rosizon -induced
hepatotoxicity or ALT elevations, rosiglitazone is structurally related 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 Rosizon to
more fully define its hepatic safety profile, it is recommended that patients
treated with Rosizon undergo periodic monitoring of liver enzymes. Liver enzymes
should be checked prior to the initiation of therapy with Rosizon in all
patients. Therapy with Rosizon 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 Rosizon , it is recommended that liver enzymes be monitored every 2 months
for the first 12 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 Rosizon should be evaluated to determine the
cause of the liver enzyme elevation. Initiation of, or continuation of, therapy
with Rosizon in patients with mild liver enzyme elevations should proceed with
caution and include 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 Rosizon , liver enzyme levels should be rechecked as
soon as possible. If ALT levels remain >3X the upper limit of normal, therapy
with Rosizon should be discontinued.
There are no data available to evaluate the safety of Rosizon in patients who
experience liver abnormalities, hepatic dysfunction, or jaundice while on
troglitazone. Rosizon (rosiglitazone maleate) should not be used in patients who
experienced jaundice while taking troglitazone. For patients with normal hepatic
enzymes who are switched from troglitazone to Rosizon , a 1-week washout is
recommended before starting therapy with Rosizon .
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 Rosizon 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
Rosizon in all patients and periodically thereafter (See PRECAUTIONS , Hepatic
Effects 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 advised that it
can take 2 weeks to see a reduction in blood glucose and 2 to 3 months to see
full effect. Patients should be informed that blood will be drawn to check their
liver function prior to the start of therapy and every 2 months for the first 12
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.
Rosizon can be taken with or without meals.
When using Rosizon in combination with other oral hypoglycemic 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.
Therapy with Rosizon , like other thiazolidinediones, may result in ovulation in
some premenopausal anovulatory women. As a result, these patients may be at an
increased risk for pregnancy while taking Rosizon . (See PRECAUTIONS, Pregnancy,
Pregnancy Category C .) Thus, adequate contraception in premenopausal women
should be recommended. This possible effect has not been specifically
investigated in clinical studies so the frequency of this occurrence is not
known.
Drug Interactions
Drugs Metabolized by Cytochrome P 450
In vitro drug metabolism studies suggest that rosiglitazone does not inhibit any
of the major P 450 enzymes at clinically relevant concentrations. In vitro data
demonstrate that rosiglitazone is predominantly metabolized by CYP2C8, and to a
lesser extent, 2C9.
Rosizon (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 Rosizon (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 Rosizon (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 Rosizon .
Digoxin Repeat oral dosing of Rosizon (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 Rosizon 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
Rosizon (rosiglitazone maleate).
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 2-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 2 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 >/=1.5 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 >/=0.3 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. Rosizon
(rosiglitazone maleate) 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 monotherapy 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 Rosizon is excreted in human milk. Because many drugs are excreted in
human milk, Rosizon should not be administered to a nursing woman.
ADVERSE REACTIONS
In clinical trials, approximately 4600 patients with type 2 diabetes have been
treated with Rosizon ; 3300 patients were treated for 6 months or longer and
2000 patients were treated for 12 months or longer.
Rosizon Monotherapy and Oral Combination Therapy Studies
The incidence and types of adverse events reported in clinical trials of Rosizon
as monotherapy are shown in Table 6.
Table 6. Adverse Events (>/=5% in Any Treatment Group) Reported by Patients in
Double-blind Clinical Trials with Rosizon as Monotherapy Rosizon
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 Rosizon 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 Rosizon .
In double-blind studies, anemia was reported in 1.9% of patients receiving
Rosizon compared to 0.7% on placebo, 0.6% on sulfonylureas and 2.2% on
metformin. Edema was reported in 4.8% of patients receiving Rosizon compared to
1.3% on placebo, 1.0% on sulfonylureas, and 2.2% on metformin. Overall, the
types of adverse experiences reported when Rosizon was used in combination with
a sulfonylurea or metformin were similar to those during monotherapy with
Rosizon . Reports of anemia (7.1%) were greater in patients treated with a
combination of Rosizon and metformin compared to monotherapy with Rosizon 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 Laboratory Abnormalities ,
Hematologic ).
Laboratory Abnormalities
Hematologic: Decreases in mean hemoglobin and hematocrit occurred in a dose-
related fashion in patients treated with Rosizon (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 Rosizon and a sulfonylurea or metformin, or Rosizon 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 Rosizon . Decreases in hematologic parameters may be related to
increased plasma volume observed with treatment with Rosizon .
Lipids: Changes in serum lipids have been observed following treatment with
Rosizon (see CLINICAL PHARMACOLOGY , Pharmacodynamics and Clinical Effects ).
Serum Transaminase Levels: In clinical studies in 4598 patients treated with
Rosizon (rosiglitazone maleate) 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 Rosizon 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 Rosizon 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 Rosizon , 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 ).
DOSAGE AND ADMINISTRATION
The management of antidiabetic therapy should be individualized. Rosizon may be
administered either at a starting dose of 4 mg as a single daily dose or divided
and administered in the morning and evening. For patients who respond
inadequately following 8 to 12 weeks of treatment, as determined by reduction in
FPG, the dose may be increased to 8 mg daily as indicated below. Reductions in
glycemic parameters by dose and regimen are described under CLINICAL
PHARMACOLOGY, Clinical Studies . Rosizon may be taken with or without food.
Monotherapy
The usual starting dose of Rosizon is 4 mg administered either as a single dose
once daily or in divided doses twice daily. In clinical trials, the 4 mg twice
daily regimen resulted in the greatest reduction in FPG and HbA1c.
Combination Therapy with a Sulfonylurea or Metformin
When Rosizon is added to existing therapy, the current dose of sulfonylurea or
metformin can be continued upon initiation of Rosizon therapy
Sulfonylurea:
When used in combination with sulfonylurea, the recommended dose of Rosizon is 4
mg administered as either a single dose once daily or in divided doses twice
daily. If patients report hypoglycemia, the dose of the sulfonylurea should be
decreased.
Metformin
The usual starting dose of Rosizon in combination with metformin is 4 mg
administered as either a single dose once daily or in divided doses twice daily.
It is unlikely that the dose of metformin will require adjustment due to
hypoglycemia during combination therapy with Rosizon .
Maximum Recommended Dose:
The dose of Rosizon should not exceed 8 mg daily, as a single dose or divided
twice daily. The 8 mg daily dose has been shown to be safe and effective in
clinical studies as monotherapy and in combination with metformin. Doses of
Rosizon greater than 4 mg daily in combination with a sulfonylurea have not been
studied in adequate and well-controlled clinical trials. In clinical trials, the
8 mg daily regimen resulted in the greatest reduction in FPG and HbA1c.
Rosizon may be taken with or without food.
No dosage adjustments are required for the elderly.
No dosage adjustment is necessary when Rosizon is used as monotherapy in
patients with renal impairment. Since metformin is contraindicated in such
patients, concomitant administration of metformin and Rosizon is also
contraindicated in patients with renal impairment.
Therapy with Rosizon should not be initiated if the patient exhibits clinical
evidence of active liver disease or increased serum transaminase levels (ALT
>2.5X the upper limit of normal at start of therapy) (See PRECAUTIONS , Hepatic
Effects and CLINICAL PHARMACOLOGY , Hepatic Impairment ). Liver enzyme
monitoring is recommended in all patients prior to initiation of therapy with
Rosizon and periodically thereafter (See PRECAUTIONS , Hepatic Effects ).
There are no data on the use of Rosizon in patients under 18 years of age;
therefore, use of Rosizon in pediatric patients is not recommended.
OVERDOSAGE
Limited data are available with regard to overdosage in humans. In clinical
studies in volunteers, Rosizon (rosiglitazone maleate) has been administered at
single oral doses of up to 20 mg and was well-tolerated. In the event of an
overdose, appropriate supportive treatment should be initiated as dictated by
the patient' clinical status.