Avandia Information
Avandia () Dosage And Administration
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.
Avandia () Dosage Forms And Strengths
Pentagonal film-coated TILTAB tablet contains rosiglitazone as the maleate as follows:
Avandia () Contraindications
Initiation of Avandia () in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated .
Avandia () Warnings And Precautions
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.
In studies in which Avandia () was added to insulin, Avandia () increased the risk of congestive heart failure and myocardial ischemia. (See Table 2.) Coadministration of Avandia () and insulin is not recommended.
In five, 26-week, controlled, randomized, double-blind trials which were included in the meta-analysis , patients with type 2 diabetes mellitus were randomized to coadministration of Avandia () and insulin (N = 867) or insulin (N = 663). In these 5 trials, Avandia () was added to insulin. These trials included patients with long-standing diabetes (median duration of 12 years) and a high prevalence of pre-existing medical conditions, including peripheral neuropathy, retinopathy, ischemic heart disease, vascular disease, and congestive heart failure. The total number of patients with emergent congestive heart failure was 21 (2.4%) and 7 (1.1%) in the Avandia () plus insulin and insulin groups, respectively. The total number of patients with emergent myocardial ischemia was 24 (2.8%) and 9 (1.4%) in the Avandia () plus insulin and insulin groups, respectively (OR 2.1 [95% CI 0.9, 5.1]). Although the event rate for congestive heart failure and myocardial ischemia was low in the studied population, consistently the event rate was 2-fold or higher with coadministration of Avandia () and insulin. These cardiovascular events were noted at both the 4 mg and 8 mg daily doses of Avandia () . (See Table 2.)
In a sixth, 24-week, controlled, randomized, double-blind trial of Avandia () and insulin coadministration, insulin was added to AVANDAMET (rosiglitazone maleate and metformin HCl) (n = 161) and compared to insulin plus placebo (n = 158), after a single-blind 8-week run-in with AVANDAMET. Patients with edema requiring pharmacologic therapy and those with congestive heart failure were excluded at baseline and during the run-in period. In the group receiving AVANDAMET plus insulin, there was one myocardial ischemic event and one sudden death. No myocardial ischemia was observed in the insulin group, and no congestive heart failure was reported in either treatment group.
Avandia () should be used with caution in patients with edema. In a clinical study in healthy volunteers who received 8 mg of Avandia () once daily for 8 weeks, there was a statistically significant increase in median plasma volume compared to placebo.
Since thiazolidinediones, including rosiglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, Avandia () should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure .
In controlled clinical trials of patients with type 2 diabetes, mild to moderate edema was reported in patients treated with Avandia () , and may be dose related. Patients with ongoing edema were more likely to have adverse events associated with edema if started on combination therapy with insulin and Avandia () .
Dose-related weight gain was seen with Avandia () alone and in combination with other hypoglycemic agents (Table 3). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.
In postmarketing experience, there have been reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure .
In a 4- to 6-year, monotherapy, comparative trial (ADOPT) in patients recently diagnosed with type 2 diabetes not previously treated with antidiabetic medication , the median weight change (25, 75 percentiles) from baseline at 4 years was 3.5 kg (0.0, 8.1) for Avandia () , 2.0 kg (-1.0, 4.8) for glyburide, and -2.4 kg (-5.4, 0.5) for metformin.
In a 24-week study in pediatric patients aged 10 to 17 years treated with Avandia () 4 to 8 mg daily, a median weight gain of 2.8 kg (25, 75 percentiles: 0.0, 5.8) was reported.
Liver enzymes should be measured prior to the initiation of therapy with Avandia () in all patients and periodically thereafter per the clinical judgment of the healthcare professional. Therapy with Avandia () should not be initiated in patients with increased baseline liver enzyme levels (ALT >2.5X upper limit of normal). Patients with mildly elevated liver enzymes (ALT levels ≤2.5X upper limit of normal) at baseline or during therapy with Avandia () should be evaluated to determine the cause of the liver enzyme elevation. Initiation of, or continuation of, therapy with Avandia () in patients with mild liver enzyme elevations should proceed with caution and include close clinical follow-up, including liver enzyme monitoring, to determine if the liver enzyme elevations resolve or worsen. If at any time ALT levels increase to >3X the upper limit of normal in patients on therapy with Avandia () , liver enzyme levels should be rechecked as soon as possible. If ALT levels remain >3X the upper limit of normal, therapy with Avandia () should be discontinued.
If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia and/or dark urine, liver enzymes should be checked. The decision whether to continue the patient on therapy with Avandia () should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued.
Patients receiving Avandia () in combination with other hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the dose of the concomitant agent may be necessary.
Periodic fasting blood glucose and HbA1c measurements should be performed to monitor therapeutic response.
Therapy with Avandia () , 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 Avandia () . Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been specifically investigated in clinical studies; therefore, the frequency of this occurrence is not known.
Although hormonal imbalance has been seen in preclinical studies , the clinical significance of this finding is not known. If unexpected menstrual dysfunction occurs, the benefits of continued therapy with Avandia () should be reviewed.
Avandia () Adverse Reactions
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 .
Avandia () Use In Specific Populations
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.
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).
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.
Adverse events observed in this study are described in .
Avandia () Overdosage
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.
Avandia () Description
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.
Chemically, rosiglitazone maleate is (±)-5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, ()-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 structural formula of rosiglitazone maleate is:
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.
Avandia () Clinical 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.
Avandia () Clinical Studies
In clinical studies, treatment with Avandia () resulted in an improvement in glycemic control, as measured by FPG and 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 Avandia () as an insulin sensitizer.
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.
Avandia () How Supplied/storage And Handling
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 60: NDC 0029-3158-18
4 mg bottles of 30: NDC 0029-3159-13
4 mg bottles of 90: NDC 0029-3159-00
8 mg bottles of 30: NDC 0029-3160-13
8 mg bottles of 90: NDC 0029-3160-59
Store at 25°C (77°F); excursions 15° to 30°C (59° to 86°F). Dispense in a tight, light-resistant container.
Avandia ()
Avandia () Medication Guide
Read this Medication Guide carefully before you start taking Avandia () and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about Avandia () , ask your doctor or pharmacist.
Avandia () is a prescription medicine to treat adults with diabetes. It helps to control high blood sugar. (See “What is Avandia () ?”). It is important that you take Avandia () exactly how it is prescribed by your doctor to best treat your diabetes.
Avandia () may cause serious side effects, including:
Call your doctor right away if you have any of the following:
Avandia () may raise the risk of heart problems related to reduced blood flow to the heart. These include possible increases in the risk of heart-related chest pain (angina) or "heart attack" (myocardial infarction). This risk seemed to be higher in people who took Avandia () with insulin or with nitrate medicines. Most people who take insulin or nitrate medicines should not also take Avandia () .
Avandia () can have other serious side effects. Be sure to read the section below “What are possible side effects of Avandia () ?”.
Avandia () is a prescription medicine used with diet and exercise to treat adults with type 2 (“adult-onset” or “non-insulin dependent”) diabetes mellitus (“high blood sugar”). Avandia () helps to control high blood sugar. Avandia () may be used alone or with other diabetes medicines. Avandia () can help your body respond better to insulin made in your body. Avandia () does not cause your body to make more insulin.
Many people with heart failure should not start taking Avandia () . See “What should I tell my doctor before taking Avandia () ?”.
Before starting Avandia () , ask your doctor about what the choices are for diabetes medicines, and what the expected benefits and possible risks are for you in particular.
Before taking Avandia () , tell your doctor about all your medical conditions, including if you:
Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins or herbal supplements. Avandia () and certain other medicines can affect each other and may lead to serious side effects including high or low blood sugar, or heart problems. Especially tell your doctor if you take:
Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist before you start a new medicine. They will tell you if it is alright to take Avandia () with other medicines.
The most common side effects of Avandia () reported in clinical trials included cold-like symptoms and headache.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Avandia () for a condition for which it was not prescribed. Do not give Avandia () to other people, even if they have the same symptoms you have. It may harm them.
This Medication Guide summarizes important information about Avandia () . If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Avandia () that is written for healthcare professionals. You can also find out more about Avandia () by calling 1-888-825-5249 or visiting the website www.Avandia () .com.
Active Ingredient: Rosiglitazone maleate.
Inactive Ingredients: 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.
Always check to make sure that the medicine you are taking is the correct one. Avandia () tablets are triangles with rounded corners and look like this:
2 mg strength tablets – pink with “SB” on one side and “2” on the other.
4 mg strength tablets – orange with “SB” on one side and “4” on the other.
8 mg strength tablets – red-brown with “SB” on one side and “8” on the other.
Avandia () is a registered trademark of GlaxoSmithKline.
REZULIN is a registered trademark of Parke-Davis Pharmaceuticals Ltd.
GlaxoSmithKline
Research Triangle Park, NC 27709
©2008, GlaxoSmithKline. All rights reserved.
October 2008
AVD:4MG
Avandia () 4 mg tablets are available from Cardinal Health in unit dose packages of 90.
4 mg, unit dose package of 90 tablets, NDC 55154-4513-3
Avandia () 8 mg tablets are available from Cardinal Health in unit dose packages of 30.
8 mg, unit dose package of 30 tablets, NDC 55154-4518-4
Cardinal Health
Zanesville OH 43701
IU37360481009
Avandia () Principal Display Panel-carton
NDC 55154-4513-3
Avandia () ®
(rosiglitazone maleate) Tablets
4 mg
90 Tiltab® Tablets
Each Tiltab® tablet contains: rosiglitazone maleate equivalent to 4 mg rosiglitazone.
See product insert for dosage, prescribing information, precautions and warnings.
STORAGE: Store at 25°C (77°F); excursions 15°-30°C (59°-86°F).
Dispense in a tight, light-resistant container.
IMPORTANT: Use safety closures when dispensing this product unless otherwise directed by physician or requested by purchaser.
Federal Law requires dispensing of Avandia () ® with the Medication Guide provided with this package.
RX ONLY
WARNING: This package is intended for institutional use only. This package is not child resistant. Keep this and all drugs out of the reach of children.
See window for lot number and expiration date.
GlaxoSmithKline
RTP, NC 27709
Made in Ireland
Repackaged by: Cardinal Health
Zanesville, OH 43701
LUC39797130610
Avandia () Principal Display Panel - Pouch
Avandia () ®
(rosiglitazone maleate)
Tiltab® Tablet
4 mg
Avandia () Principal Display Panel - Mg Bag
Avandia () ® 4 mg
Rosiglitazone MaleateTablets
10 Tiltab® Tablets
Avandia () Principal Display Panel - Carton
NDC 55154-4518-4
Avandia () ®
(rosiglitazone maleate) Tablets
8 mg
30 Tiltab® Tablets
Each Tiltab® tablet contains: rosiglitazone maleate equivalent to 8 mg rosiglitazone.
See product insert for dosage, prescribing information, precautions and warnings.
STORAGE: Store at 25°C (77°F); excursions 15°-30°C (59°-86°F).
RX ONLY
WARNING: This package is intended for institutional use only. This package is not child resistant. Keep this and all drugs out of the reach of children.
See window for lot number and expiration date.
GlaxoSmithKline
RTP, NC 27709
Made in Ireland
Repackaged by: Cardinal Health
Zanesville, OH 43701
LUC40835310610
Avandia () Principal Display Panel - Pouch
Avandia () ®
(rosiglitazone maleate)
Tiltab® Tablet
8 mg
Avandia () Principal Display Panel - Mg Bag
Avandia () ® 8 mg
Rosiglitazone Maleate Tablets
10 Tiltab® Tablet
