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Avandia
Overview
What is Avandia?
AVANDIA (rosiglitazone maleate) is an oral antidiabetic agent
which acts primarily by increasing insulin sensitivity. AVANDIA improves
glycemic control while reducing circulating insulin levels.
Rosiglitazone maleate is not chemically or functionally related to the
sulfonylureas, the biguanides, or the alpha-glucosidase inhibitors.
The molecular formula is CHNOS•CHO.
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.
Each pentagonal film-coated TILTAB tablet contains rosiglitazone maleate
equivalent to rosiglitazone, 2 mg, 4 mg, or 8 mg, for oral administration.
Inactive ingredients are: Hypromellose 2910, lactose monohydrate, magnesium
stearate, microcrystalline cellulose, polyethylene glycol 3000, sodium starch
glycolate, titanium dioxide, triacetin, and 1 or more of the following:
Synthetic red and yellow iron oxides and talc.
What does Avandia look like?
What are the available doses of Avandia?
Pentagonal film-coated TILTAB tablet
contains rosiglitazone as the maleate as follows:
What should I talk to my health care provider before I take Avandia?
Pregnancy Category C.
All pregnancies have a background risk of birth defects, loss, or other
adverse outcome regardless of drug exposure. This background risk is increased
in pregnancies complicated by hyperglycemia and may be decreased with good
metabolic control. It is essential for patients with diabetes or history of
gestational diabetes to maintain good metabolic control before conception and
throughout pregnancy. Careful monitoring of glucose control is essential in such
patients. Most experts recommend that insulin monotherapy be used during
pregnancy to maintain blood glucose levels as close to normal as possible.
Human Data
Rosiglitazone has been reported to cross the human placenta and be detectable
in fetal tissue. The clinical significance of these findings is unknown. There
are no adequate and well-controlled studies in pregnant women. AVANDIA should
not be used during pregnancy.
Animal Studies
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. Rosiglitazone reduced the number of
uterine implantations and live offspring when juvenile female rats were treated
at 40 mg/kg/day from 27 days of age through to sexual maturity (approximately
68 times human AUC at the maximum recommended daily dose). The no-effect level
was 2 mg/kg/day (approximately 4 times human AUC at the maximum recommended
daily dose). There was no effect on pre- or post-natal survival or growth.
The effect of rosiglitazone on labor and delivery in humans is
not known.
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.
After placebo run-in including diet counseling, children with
type 2 diabetes mellitus, aged 10 to 17 years and with a baseline mean body mass
index (BMI) of 33 kg/m, were randomized to treatment
with 2 mg twice daily of AVANDIA (n = 99) or 500 mg twice daily of metformin
(n = 101) in a 24-week, double-blind clinical trial. As expected, FPG decreased
in patients naïve to diabetes medication (n = 104) and increased in patients
withdrawn from prior medication (usually metformin) (n = 90) during the run-in
period. After at least 8 weeks of treatment, 49% of patients treated with
AVANDIA and 55% of metformin-treated patients had their dose doubled if FPG
>126 mg/dL. For the overall intent-to-treat population, at week 24, the mean
change from baseline in HbA1c was -0.14% with AVANDIA and -0.49% with metformin.
There was an insufficient number of patients in this study to establish
statistically whether these observed mean treatment effects were similar or
different. Treatment effects differed for patients naïve to therapy with
antidiabetic drugs and for patients previously treated with antidiabetic therapy
(Table 6).
* Change from baseline means are least squares means adjusting for baseline HbA1c,
gender, and region.
†
Treatment differences depended on baseline BMI or weight such that the
effects of AVANDIA and metformin appeared more closely comparable among heavier
patients. The median weight gain was 2.8 kg with rosiglitazone and 0.2 kg with
metformin .
Fifty-four percent of patients treated with rosiglitazone and 32% of patients
treated with metformin gained ≥2 kg, and 33% of patients treated with
rosiglitazone and 7% of patients treated with metformin gained ≥5 kg on
study.
Figure 3. Mean HbA1c Over Time in a 24-Week Study of
AVANDIA and Metformin in Pediatric Patients — Drug-Naïve Subgroup
Results of the population pharmacokinetic analysis showed that
age does not significantly affect the pharmacokinetics of rosiglitazone . Therefore, no dosage
adjustments are required for the elderly. In controlled clinical trials, no
overall differences in safety and effectiveness between older (greater than or equal to 65 years) and
younger (less than 65 years) patients were observed.
How should I use Avandia?
AVANDIA is indicated as an adjunct to diet and exercise to
improve glycemic control in adults with type 2 diabetes mellitus.
The management of antidiabetic therapy should be individualized.
All patients should start AVANDIA at the lowest recommended dose. Further
increases in the dose of AVANDIA should be accompanied by careful monitoring for
adverse events related to fluid retention .
AVANDIA may be administered at a starting dose of 4 mg either as a single
daily dose or in 2 divided doses. For patients who respond inadequately
following 8 to 12 weeks of treatment, as determined by reduction in fasting
plasma glucose (FPG), the dose may be increased to 8 mg daily as monotherapy or
in combination with metformin, sulfonylurea, or sulfonylurea plus metformin.
Reductions in glycemic parameters by dose and regimen are described under . AVANDIA may be taken with or
without food.
The total daily dose of AVANDIA should not exceed 8 mg.
The usual starting dose of AVANDIA 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
hemoglobin A1c (HbA1c).
When AVANDIA is added to existing therapy, the current dose(s) of
the agent(s) can be continued upon initiation of therapy with AVANDIA.
Sulfonylurea
When used in combination with sulfonylurea, the usual starting dose of
AVANDIA 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 AVANDIA 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 AVANDIA.
The usual starting dose of AVANDIA in combination with a
sulfonylurea plus metformin is 4 mg administered as either a single dose once
daily or divided doses twice daily. If patients report hypoglycemia, the dose of
the sulfonylurea should be decreased.
Renal Impairment
No dosage adjustment is necessary when AVANDIA is used as monotherapy in
patients with renal impairment. Since metformin is contraindicated in such
patients, concomitant administration of metformin and AVANDIA is also
contraindicated in patients with renal impairment.
Hepatic Impairment
Liver enzymes should be measured prior to initiating treatment with AVANDIA.
Therapy with AVANDIA 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 start of therapy). After initiation of
AVANDIA, liver enzymes should be monitored periodically per the clinical
judgment of the healthcare professional.
Pediatric
Data are insufficient to recommend pediatric use of AVANDIA .
What interacts with Avandia?
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What are the warnings of Avandia?
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What are the precautions of Avandia?
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What are the side effects of Avandia?
Sorry No records found
What should I look out for while using Avandia?
Initiation of AVANDIA in patients with established New York Heart Association
(NYHA) Class III or IV heart failure is contraindicated .
What might happen if I take too much Avandia?
Limited data are available with regard to overdosage in humans. In clinical
studies in volunteers, AVANDIA 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’s clinical
status.
How should I store and handle Avandia?
Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container as defined in the USP/NF with a child-resistant closure.A Schedule CIII Narcotic.Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container as defined in the USP/NF with a child-resistant closure.A Schedule CIII Narcotic.Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].Dispense in a tight, light-resistant container as defined in the USP/NF with a child-resistant closure.A Schedule CIII Narcotic.Each pentagonal film-coated TILTAB tablet contains rosiglitazone as the maleate as follows: 2 mg–pink, debossed with SB on one side and 2 on the other; 4 mg–orange, debossed with SB on one side and 4 on the other; 8 mg–red-brown, debossed with SB on one side and 8 on the other.2 mg bottles of 30: NDC 54868-5249-02 mg bottles of 60: NDC 54868-5249-14 mg bottles of 30: NDC 54868-4198-04 mg bottles of 60: NDC 54868-4198-1 8 mg bottles of 30: NDC 54868-4221-0 Store at 25°C (77°F); excursions 15° to 30°C (59° to 86°F). Dispense in a tight, light-resistant container.Each pentagonal film-coated TILTAB tablet contains rosiglitazone as the maleate as follows: 2 mg–pink, debossed with SB on one side and 2 on the other; 4 mg–orange, debossed with SB on one side and 4 on the other; 8 mg–red-brown, debossed with SB on one side and 8 on the other.2 mg bottles of 30: NDC 54868-5249-02 mg bottles of 60: NDC 54868-5249-14 mg bottles of 30: NDC 54868-4198-04 mg bottles of 60: NDC 54868-4198-1 8 mg bottles of 30: NDC 54868-4221-0 Store at 25°C (77°F); excursions 15° to 30°C (59° to 86°F). Dispense in a tight, light-resistant container.Each pentagonal film-coated TILTAB tablet contains rosiglitazone as the maleate as follows: 2 mg–pink, debossed with SB on one side and 2 on the other; 4 mg–orange, debossed with SB on one side and 4 on the other; 8 mg–red-brown, debossed with SB on one side and 8 on the other.2 mg bottles of 30: NDC 54868-5249-02 mg bottles of 60: NDC 54868-5249-14 mg bottles of 30: NDC 54868-4198-04 mg bottles of 60: NDC 54868-4198-1 8 mg bottles of 30: NDC 54868-4221-0 Store at 25°C (77°F); excursions 15° to 30°C (59° to 86°F). Dispense in a tight, light-resistant container.Each pentagonal film-coated TILTAB tablet contains rosiglitazone as the maleate as follows: 2 mg–pink, debossed with SB on one side and 2 on the other; 4 mg–orange, debossed with SB on one side and 4 on the other; 8 mg–red-brown, debossed with SB on one side and 8 on the other.2 mg bottles of 30: NDC 54868-5249-02 mg bottles of 60: NDC 54868-5249-14 mg bottles of 30: NDC 54868-4198-04 mg bottles of 60: NDC 54868-4198-1 8 mg bottles of 30: NDC 54868-4221-0 Store at 25°C (77°F); excursions 15° to 30°C (59° to 86°F). Dispense in a tight, light-resistant container.Each pentagonal film-coated TILTAB tablet contains rosiglitazone as the maleate as follows: 2 mg–pink, debossed with SB on one side and 2 on the other; 4 mg–orange, debossed with SB on one side and 4 on the other; 8 mg–red-brown, debossed with SB on one side and 8 on the other.2 mg bottles of 30: NDC 54868-5249-02 mg bottles of 60: NDC 54868-5249-14 mg bottles of 30: NDC 54868-4198-04 mg bottles of 60: NDC 54868-4198-1 8 mg bottles of 30: NDC 54868-4221-0 Store at 25°C (77°F); excursions 15° to 30°C (59° to 86°F). Dispense in a tight, light-resistant container.
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
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 (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.
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.
In animal models, the antidiabetic activity of rosiglitazone was shown to be
mediated by increased sensitivity to insulin’s action in the liver, muscle, and
adipose tissues. Pharmacological studies in animal models indicate that
rosiglitazone inhibits hepatic gluconeogenesis. 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.
Patients with lipid abnormalities were not excluded from clinical
trials of AVANDIA. In all 26-week controlled trials, across the recommended dose
range, AVANDIA 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
7).
Increases in LDL occurred primarily during the first 1 to 2 months of therapy
with AVANDIA 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 AVANDIA 4 mg twice daily. The corresponding values
for glyburide were 3.2, 3.1, and 2.9. The differences in change from baseline
between AVANDIA and glyburide at week 52 were statistically significant.
The pattern of LDL and HDL changes following therapy with AVANDIA in
combination with other hypoglycemic agents were generally similar to those seen
with AVANDIA in monotherapy.
The changes in triglycerides during therapy with AVANDIA were variable and
were generally not statistically different from placebo or glyburide controls.
Maximum plasma concentration (C) and
the area under the curve (AUC) of rosiglitazone increase in a dose-proportional
manner over the therapeutic dose range (Table 8). 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 and a
delay in T (1.75 hours). These changes are not likely
to be clinically significant; therefore, AVANDIA 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
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 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 P450 (CYP) isoenzyme 2C8, with CYP2C9 contributing as a minor
pathway.
Excretion
Following oral or intravenous administration of [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 [C]related material ranged from 103 to
158 hours.
Population Pharmacokinetics in Patients
With Type 2 Diabetes
Population pharmacokinetic analyses from 3 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 less than 1.7-fold and less than 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
Geriatric
Results of the population pharmacokinetic analysis (n = 716 less than 65 years;
n = 331 greater than or equal to 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, AVANDIA 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 AVANDIA 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 and AUC 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 AVANDIA should not be initiated if the patient exhibits clinical
evidence of active liver disease or increased serum transaminase levels (ALT
greater than 2.5X upper limit of normal) at baseline .
Pediatric
Pharmacokinetic parameters of rosiglitazone in pediatric patients were
established using a population pharmacokinetic analysis with sparse data from 96
pediatric patients in a single pediatric clinical trial including 33 males and
63 females with ages ranging from 10 to 17 years (weights ranging from 35 to
178.3 kg). Population mean CL/F and V/F of rosiglitazone were 3.15 L/hr and 13.5
L, respectively. These estimates of CL/F and V/F were consistent with the
typical parameter estimates from a prior adult population analysis.
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 AVANDIA.
Since metformin is contraindicated in patients with renal impairment,
coadministration of metformin with AVANDIA 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.
Drugs That Inhibit, Induce, or are
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 (ethinyl estradiol and norethindrone), which are predominantly
metabolized by CYP3A4.
Gemfibrozil
Concomitant administration of gemfibrozil (600 mg twice daily), an inhibitor
of CYP2C8, and rosiglitazone (4 mg once daily) for 7 days increased
rosiglitazone AUC by 127%, compared to the administration of rosiglitazone (4 mg
once daily) alone. Given the potential for dose-related adverse events with
rosiglitazone, a decrease in the dose of rosiglitazone may be needed when
gemfibrozil is introduced .
Rifampin
Rifampin administration (600 mg once a day), an inducer of CYP2C8, for 6 days
is reported to decrease rosiglitazone AUC by 66%, compared to the administration
of rosiglitazone (8 mg) alone .
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. Repeat
doses of AVANDIA (8 mg once daily) for 8 days in healthy adult Caucasian
subjects caused a decrease in glyburide AUC and C of
approximately 30%. In Japanese subjects, glyburide AUC and C slightly increased following coadministration of
AVANDIA.
Glimepiride
Single oral doses of glimepiride in 14 healthy adult subjects had no
clinically significant effect on the steady-state pharmacokinetics of AVANDIA.
No clinically significant reductions in glimepiride AUC and C were observed after repeat doses of AVANDIA (8 mg once
daily) for 8 days in healthy adult subjects.
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.
Non-Clinical Toxicology
Initiation of AVANDIA in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated .Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use of amoxicillin and probenecid may result in increased and prolonged blood levels of amoxicillin.
Chloramphenicol, macrolides, sulfonamides, and tetracyclines may interfere with the bactericidal effects of penicillin. This has been demonstrated ; however, the clinical significance of this interaction is not well documented.
In common with other antibiotics, amoxicillin capsules, amoxicillin for oral suspension, or amoxicillin tablets (chewable) may affect the gut flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives.
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. If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of rosiglitazone must be considered .
Patients with congestive heart failure (CHF) NYHA Class I and II treated with AVANDIA have an increased risk of cardiovascular events. A 52-week, double-blind, placebo-controlled echocardiographic study was conducted in 224 patients with type 2 diabetes mellitus and NYHA Class I or II CHF (ejection fraction ≤45%) on background antidiabetic and CHF therapy. An independent committee conducted a blinded evaluation of fluid-related events (including congestive heart failure) and cardiovascular hospitalizations according to predefined criteria (adjudication). Separate from the adjudication, other cardiovascular adverse events were reported by investigators. Although no treatment difference in change from baseline of ejection fractions was observed, more cardiovascular adverse events were observed following treatment with AVANDIA compared to placebo during the 52-week study. (See Table 1.)
Initiation of AVANDIA in patients with established NYHA Class III or IV heart failure is contraindicated. AVANDIA is not recommended in patients with symptomatic heart failure.
Patients experiencing acute coronary syndromes have not been studied in controlled clinical trials. In view of the potential for development of heart failure in patients having an acute coronary event, initiation of AVANDIA is not recommended for patients experiencing an acute coronary event, and discontinuation of AVANDIA during this acute phase should be considered.
Patients with NYHA Class III and IV cardiac status (with or without CHF) have not been studied in controlled clinical trials. AVANDIA is not recommended in patients with NYHA Class III and IV cardiac status.
Meta-Analysis of Myocardial Ischemia in a Group of 42 Clinical Trials
A meta-analysis was conducted retrospectively to assess cardiovascular adverse events reported across 42 double-blind, randomized, controlled clinical trials (mean duration 6 months). These studies had been conducted to assess glucose-lowering efficacy in type 2 diabetes, and prospectively planned adjudication of cardiovascular events had not occurred in the trials. Some trials were placebo-controlled and some used active oral antidiabetic drugs as controls. Placebo-controlled studies included monotherapy trials (monotherapy with AVANDIA versus placebo monotherapy) and add-on trials (AVANDIA or placebo, added to sulfonylurea, metformin, or insulin). Active control studies included monotherapy trials (monotherapy with AVANDIA versus sulfonylurea or metformin monotherapy) and add-on trials (AVANDIA plus sulfonylurea or AVANDIA plus metformin, versus sulfonylurea plus metformin). A total of 14,237 patients were included (8,604 in treatment groups containing AVANDIA, 5,633 in comparator groups), with 4,143 patient-years of exposure to AVANDIA and 2,675 patient-years of exposure to comparator. Myocardial ischemic events included angina pectoris, angina pectoris aggravated, unstable angina, cardiac arrest, chest pain, coronary artery occlusion, dyspnea, myocardial infarction, coronary thrombosis, myocardial ischemia, coronary artery disease, and coronary artery disorder. In this analysis, an increased risk of myocardial ischemia with AVANDIA versus pooled comparators was observed (2% AVANDIA versus 1.5% comparators, odds ratio 1.4, 95% confidence interval [CI] 1.1, 1.8). An increased risk of myocardial ischemic events with AVANDIA was observed in the placebo-controlled studies, but not in the active-controlled studies. (See Figure 1.)
A greater increased risk of myocardial ischemic events was observed in studies where AVANDIA was added to insulin (2.8% for AVANDIA plus insulin versus 1.4% for placebo plus insulin, [OR 2.1, 95% CI 0.9, 5.1]). This increased risk reflects a difference of 3 events per 100 patient-years (95% CI -0.1, 6.3) between treatment groups.
Figure 1. Forest Plot of Odds Ratios (95% Confidence Intervals) for Myocardial Ischemic Events in the Meta-Analysis of 42 Clinical Trials
A greater increased risk of myocardial ischemia was also observed in patients who received AVANDIA and background nitrate therapy. For AVANDIA (N = 361) versus control (N = 244) in nitrate users, the odds ratio was 2.9 (95% CI 1.4, 5.9), while for non-nitrate users (about 14,000 patients total), the odds ratio was 1.3 (95% CI 0.9, 1.7). This increased risk represents a difference of 12 myocardial ischemic events per 100 patient-years (95% CI 3.3, 21.4). Most of the nitrate users had established coronary heart disease. Among patients with known coronary heart disease who were not on nitrate therapy, an increased risk of myocardial ischemic events for AVANDIA versus comparator was not demonstrated.
Adult
In clinical trials, approximately 9,900 patients with type 2 diabetes have been treated with AVANDIA.
Short-Term Trials of AVANDIA as Monotherapy and in Combination With Other Hypoglycemic Agents
The incidence and types of adverse events reported in short-term clinical trials of AVANDIA as monotherapy are shown in Table 4.
Overall, the types of adverse reactions without regard to causality reported when AVANDIA was used in combination with a sulfonylurea or metformin were similar to those during monotherapy with AVANDIA.
Events of anemia and edema tended to be reported more frequently at higher doses, and were generally mild to moderate in severity and usually did not require discontinuation of treatment with AVANDIA.
In double-blind studies, anemia was reported in 1.9% of patients receiving AVANDIA as monotherapy compared to 0.7% on placebo, 0.6% on sulfonylureas, and 2.2% on metformin. Reports of anemia were greater in patients treated with a combination of AVANDIA and metformin (7.1%) and with a combination of AVANDIA and a sulfonylurea plus metformin (6.7%) compared to monotherapy with AVANDIA or in combination with a sulfonylurea (2.3%). 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 .
In clinical trials, edema was reported in 4.8% of patients receiving AVANDIA as monotherapy compared to 1.3% on placebo, 1.0% on sulfonylureas, and 2.2% on metformin. The reporting rate of edema was higher for AVANDIA 8 mg in sulfonylurea combinations (12.4%) compared to other combinations, with the exception of insulin. Edema was reported in 14.7% of patients receiving AVANDIA in the insulin combination trials compared to 5.4% on insulin alone. Reports of new onset or exacerbation of congestive heart failure occurred at rates of 1% for insulin alone, and 2% (4 mg) and 3% (8 mg) for insulin in combination with AVANDIA .
In controlled combination therapy studies with sulfonylureas, mild to moderate hypoglycemic symptoms, which appear to be dose related, were reported. Few patients were withdrawn for hypoglycemia (less than 1%) and few episodes of hypoglycemia were considered to be severe (less than 1%). Hypoglycemia was the most frequently reported adverse event in the fixed-dose insulin combination trials, although few patients withdrew for hypoglycemia (4 of 408 for AVANDIA plus insulin and 1 of 203 for insulin alone). Rates of hypoglycemia, confirmed by capillary blood glucose concentration less than or equal to 50 mg/dL, were 6% for insulin alone and 12% (4 mg) and 14% (8 mg) for insulin in combination with AVANDIA.
Long-Term Trial of AVANDIA as Monotherapy
A 4- to 6-year study (ADOPT) compared the use of AVANDIA (n = 1,456), glyburide (n = 1,441), and metformin (n = 1,454) as monotherapy in patients recently diagnosed with type 2 diabetes who were not previously treated with antidiabetic medication. Table 5 presents adverse reactions without regard to causality; rates are expressed per 100 patient-years (PY) exposure to account for the differences in exposure to study medication across the 3 treatment groups.
In ADOPT, fractures were reported in a greater number of women treated with AVANDIA (9.3%, 2.7/100 patient-years) compared to glyburide (3.5%, 1.3/100 patient-years) or metformin (5.1%, 1.5/100 patient-years). The majority of the fractures in the women who received rosiglitazone were reported in the upper arm, hand, and foot. The observed incidence of fractures for male patients was similar among the 3 treatment groups.
Pediatric
AVANDIA has been evaluated for safety in a single, active-controlled trial of pediatric patients with type 2 diabetes in which 99 were treated with AVANDIA and 101 were treated with metformin. The most common adverse reactions (greater than 10%) without regard to causality for either AVANDIA or metformin were headache (17% versus 14%), nausea (4% versus 11%), nasopharyngitis (3% versus 12%), and diarrhea (1% versus 13%). In this study, one case of diabetic ketoacidosis was reported in the metformin group. In addition, there were 3 patients in the rosiglitazone group who had FPG of ∼300 mg/dL, 2+ ketonuria, and an elevated anion gap.
Hematologic
Decreases in mean hemoglobin and hematocrit occurred in a dose-related fashion in adult patients treated with AVANDIA (mean decreases in individual studies as much as 1.0 g/dL hemoglobin and as much as 3.3% hematocrit). The changes occurred primarily during the first 3 months following initiation of therapy with AVANDIA or following a dose increase in AVANDIA. The time course and magnitude of decreases were similar in patients treated with a combination of AVANDIA and other hypoglycemic agents or monotherapy with AVANDIA. 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. In a single study in pediatric patients, decreases in hemoglobin and hematocrit (mean decreases of 0.29 g/dL and 0.95%, respectively) were reported. Small decreases in hemoglobin and hematocrit have also been reported in pediatric patients treated with AVANDIA. White blood cell counts also decreased slightly in adult patients treated with AVANDIA. Decreases in hematologic parameters may be related to increased plasma volume observed with treatment with AVANDIA.
Lipids
Changes in serum lipids have been observed following treatment with AVANDIA in adults . Small changes in serum lipid parameters were reported in children treated with AVANDIA for 24 weeks.
Serum Transaminase Levels
In pre-approval clinical studies in 4,598 patients treated with AVANDIA (3,600 patient-years of exposure) and in a long-term 4- to 6-year study in 1,456 patients treated with AVANDIA (4,954 patient-years exposure), there was no evidence of drug-induced hepatotoxicity.
In pre-approval 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. Hyperbilirubinemia was found in 0.3% of patients treated with AVANDIA compared with 0.9% treated with placebo and 1% in patients treated with active comparators. In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure.
In the 4- to 6-year ADOPT trial, patients treated with AVANDIA (4,954 patient-years exposure), glyburide (4,244 patient-years exposure), or metformin (4,906 patient-years exposure), as monotherapy, had the same rate of ALT increase to greater than 3X upper limit of normal (0.3 per 100 patient-years exposure).
In addition to adverse reactions reported from clinical trials, the events described below have been identified during post-approval use of AVANDIA. Because these events are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or to always establish a causal relationship to drug exposure.
In patients receiving thiazolidinedione therapy, serious adverse events with or without a fatal outcome, potentially related to volume expansion (e.g., congestive heart failure, pulmonary edema, and pleural effusions) have been reported .
There are postmarketing reports with AVANDIA of hepatitis, hepatic enzyme elevations to 3 or more times the upper limit of normal, and hepatic failure with and without fatal outcome, although causality has not been established.
There are postmarketing reports with AVANDIA of rash, pruritus, urticaria, angioedema, anaphylactic reaction, Stevens-Johnson syndrome, and new onset or worsening diabetic macular edema with decreased visual acuity .
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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