Avandia (Rosiglitazone Maleate)
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Avandia (Rosiglitazone Maleate)

AVANDIA
(rosiglitazone maleate) Tablets

WARNING: CONGESTIVE HEART FAILURE AND MYOCARDIAL INFARCTION

  • Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive heart failure in some patients [see WARNINGS AND PRECAUTIONS]. After initiation of AVANDIA, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of AVANDIA must be considered.
  • AVANDIA is not recommended in patients with symptomatic heart failure. Initiation of AVANDIA in patients with established NYHA Class III or IV heart failure is contraindicated. [See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS.]
  • A meta-analysis of 52 clinical trials (mean duration 6 months; 16,995 total patients), most of which compared AVANDIA to placebo, showed AVANDIA to be associated with a statistically significant increased risk of myocardial infarction. Three other trials (mean duration 46 months; 14,067 total patients), comparing AVANDIA to some other approved oral antidiabetic agents or placebo, showed a statistically non-significant increased risk of myocardial infarction, and a statistically non-significant decreased risk of death. There have been no clinical trials directly comparing cardiovascular risk of AVANDIA and ACTOS® (pioglitazone, another thiazolidinedione), but in a separate trial, pioglitazone (when compared to placebo) did not show an increased risk of myocardial infarction or death. [See WARNINGS AND PRECAUTIONS.]
  • Because of the potential increased risk of myocardial infarction, AVANDIA is available only through a restricted distribution program called the AVANDIA-Rosiglitazone Medicines Access Program. Both prescribers and patients need to enroll in the program. To enroll, call 1-800-AVANDIA or visit www.AVANDIA.com. [See WARNINGS AND PRECAUTIONS.]

DRUG 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, (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 structural formula of rosiglitazone maleate is:

AVANDIA
  (rosiglitazone maleate) Structural Formula Illustration

The molecular formula is C18H19N3O3S•C4H4O4. 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 are the possible side effects of rosiglitazone (Avandia)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using rosiglitazone and call your doctor at once if you have a serious side effect such as:

  • feeling short of breath, even with mild exertion;
  • swelling or rapid weight gain;
  • chest pain or heavy feeling, pain spreading to the arm or shoulder, sweating, general ill feeling;
  • nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the...

Read All Potential Side Effects and See Pictures of Avandia »

What are the precautions when taking rosiglitazone maleate (Avandia)?

Before taking rosiglitazone, tell your doctor or pharmacist if you are allergic to it; or to other "glitazones" such as pioglitazone; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Promptly talk with your doctor or pharmacist about the benefits and possible risks of this medication, even if you have been taking it for awhile, especially if you have heart problems. Do not stop taking it unless directed to do so.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: type 1 diabetes (insulin-dependent diabetes), very high blood glucose (diabetic...

Read All Potential Precautions of Avandia »

Last reviewed on RxList: 11/30/2011
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

After consultation with a healthcare professional who has considered and advised the patient of the risks and benefits of AVANDIA®, this drug is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who either are:

  • already taking AVANDIA, or
  • not already taking AVANDIA and are unable to achieve adequate glycemic control on other diabetes medications and, in consultation with their healthcare provider, have decided not to take pioglitazone (ACTOS®) for medical reasons.

Other Important Limitations of Use

DOSAGE AND ADMINISTRATION

Prior to prescribing AVANDIA, refer to INDICATIONS for appropriate patient selection. Only prescribers enrolled in the AVANDIA-Rosiglitazone Medicines Access Program can prescribe AVANDIA [see WARNINGS AND PRECAUTIONS.].

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. Increases in the dose of AVANDIA should be accompanied by careful monitoring for adverse events related to fluid retention [see BOXED WARNING and WARNINGS AND PRECAUTIONS.]. AVANDIA may be taken with or without food.

The total daily dose of AVANDIA should not exceed 8 mg.

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.

Specific Patient Populations

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. [See WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY.]

Pediatric: Data are insufficient to recommend pediatric use of AVANDIA [see Use In Specific Populations].

HOW SUPPLIED

Dosage Forms and Strengths

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

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 0173-0834-18
4 mg bottles of 30: NDC 0173-0835-13
8 mg bottles of 30: NDC 0173-0836-13

Store at 25°C (77°F); excursions 15° to 30°C (59° to 86°F). Dispense in a tight, light-resistant container.

Glaxo SmithKline, Research Triangle Park, NC 27709

Last reviewed on RxList: 11/30/2011
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

Clinical Trial Experience

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 6.

Table 6. Adverse Events ( ≥ 5% in Any Treatment Group) Reported by Patients in Short-Terma Double-Blind Clinical Trials With AVANDIA as Monotherapy

Preferred Term AVANDIA
Monotherapy
Placebo Metformin Sulfonylureasb
N = 2,526 N = 601 N = 225 N = 626
% % % %
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
a Short-term trials ranged from 8 weeks to 1 year.
b Includes patients receiving glyburide (N = 514), gliclazide (N = 91), or glipizide (N = 21).

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 trials, 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 trials.

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 [see BOXED WARNING and WARNINGS AND PRECAUTIONS.]. The use of AVANDIA in combination with insulin may increase the risk of myocardial infarction [see WARNINGS AND PRECAUTIONS.].

In controlled combination therapy trials with sulfonylureas, mild to moderate hypoglycemic symptoms, which appear to be dose related, were reported. Few patients were withdrawn for hypoglycemia ( < 1%) and few episodes of hypoglycemia were considered to be severe ( < 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 ≤ 50 mg/dL, were 6% for insulin alone and 12% (4 mg) and 14% (8 mg) for insulin in combination with AVANDIA. [See WARNINGS AND PRECAUTIONS.]

Long-Term Trial of AVANDIA as Monotherapy: A 4- to 6-year trial (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 7 presents adverse reactions without regard to causality; rates are expressed per 100 patient-years (PY) exposure to account for the differences in exposure to trial 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. [See WARNINGS AND PRECAUTIONS.] The observed incidence of fractures for male patients was similar among the 3 treatment groups.

Table 7. On-Therapy Adverse Events ( ≥ 5 Events/100 Patient-Years [PY]) in Any Treatment Group Reported in a 4- to 6-Year Clinical Trial of AVANDIA as Monotherapy (ADOPT)

  AVANDIA
N= 1,456
PY = 4,954
Glyburide
N= 1,441
PY = 4,244
Metformin
N= 1,454
PY = 4,906
Nasopharyngitis 6.3 6.9 6.6
Back pain 5.1 4.9 5.3
Arthralgia 5.0 4.8 4.2
Hypertension 4.4 6.0 6.1
Upper respiratory tract infection 4.3 5.0 4.7
Hypoglycemia 2.9 13.0 3.4
Diarrhea 2.5 3.2 6.8

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 ( > 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 trial, 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.

Laboratory Abnormalities

Hematologic: Decreases in mean hemoglobin and hematocrit occurred in a dose-related fashion in adult patients treated with AVANDIA (mean decreases in individual trials 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 trials and may have contributed to the higher reporting rate of anemia. In a single trial 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 [see CLINICAL PHARMACOLOGY]. Small changes in serum lipid parameters were reported in children treated with AVANDIA for 24 weeks.

Serum Transaminase Levels: In pre-approval clinical trials in 4,598 patients treated with AVANDIA (3,600 patient-years of exposure) and in a long-term 4- to 6-year trial 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. [See WARNINGS AND PRECAUTIONS.]

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 > 3X upper limit of normal (0.3 per 100 patient-years exposure).

Postmarketing Experience

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 [see BOXED WARNING and WARNINGS AND PRECAUTIONS.].

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 [see WARNINGS AND PRECAUTIONS.].

Read the Avandia (rosiglitazone maleate) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

CYP2C8 Inhibitors and Inducers

An inhibitor of CYP2C8 (e.g., gemfibrozil) may increase the AUC of rosiglitazone and an inducer of CYP2C8 (e.g., rifampin) may decrease the AUC of rosiglitazone. Therefore, if an inhibitor or an inducer of CYP2C8 is started or stopped during treatment with rosiglitazone, changes in diabetes treatment may be needed based upon clinical response. [See CLINICAL PHARMACOLOGY]

Last reviewed on RxList: 11/30/2011
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Cardiac Failure

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 [see BOXED WARNING].

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 trial 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 trial. (See Table 1.)

Table 1. Emergent Cardiovascular Adverse Events in Patients With Congestive Heart Failure (NYHA Class I and II) Treated With AVANDIA or Placebo (in Addition to Background Antidiabetic and CHF Therapy)

Events AVANDIA Placebo
N=110
n (%)
N=114
n (%)
Adjudicated    
Cardiovascular deaths 5 (5%) 4 (4%)
CHF worsening 7 (6%) 4 (4%)
- with overnight hospitalization 5 (5%) 4 (4%)
- without overnight hospitalization 2 (2%) 0 (0%)
New or worsening edema 28 (25%) 10 (9%)
New or worsening dyspnea 29 (26%) 19 (17%)
Increases in CHF medication 36 (33%) 20(18%)
Cardiovascular hospitalizationa 21 (19%) 15 (13%)
Investigator-reported, non-adjudicated    
Ischemic adverse events 10 (9%) 5 (4%)
  - Myocardial infarction 5 (5%) 2 (2%)
  -Angina 6 (5%) 3 (3%)
a Includes hospitalization for any cardiovascular reason.

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. [See BOXED WARNING.]

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.

Congestive Heart Failure During Coadministration of AVANDIA With Insulin: In trials in which AVANDIA was added to insulin, AVANDIA increased the risk of congestive heart failure. Coadministration of AVANDIA and insulin is not recommended. [See INDICATIONS

In 7 controlled, randomized, double-blind trials which had durations from 16 to 26 weeks and which were included in a meta-analysis1, patients with type 2 diabetes mellitus were randomized to coadministration of AVANDIA and insulin (N = 1,018) or insulin (N = 815). In these 7 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 23 (2.3%) and 8 (1.0%) in the AVANDIA plus insulin and insulin groups, respectively.

Heart Failure in Observational Studies of Elderly Diabetic Patients Comparing AVANDIA to AGIOS: Three observational studies2-4 in elderly diabetic patients (age 65 years and older) found that AVANDIA statistically significantly increased the risk of hospitalized heart failure compared to use of ACTOS. One other observational study5 in patients with a mean age of 54 years, which also included an analysis in a subpopulation of patients > 65 years of age, found no statistically significant increase in emergency department visits or hospitalization for heart failure in patients treated with AVANDIA compared to ACTOS in the older subgroup.

Major Adverse Cardiovascular Events

Cardiovascular adverse events have been evaluated in a meta-analysis of 52 clinical trials, in long-term, prospective, randomized, controlled trials, and in observational studies.

Meta-Analysis of Major Adverse Cardiovascular Events in a Group of 52 Clinical Trials: A meta-analysis was conducted retrospectively to assess cardiovascular adverse events reported across 52 double-blind, randomized, controlled clinical trials (mean duration 6 months).1 These trials had been conducted to assess glucose-lowering efficacy in type 2 diabetes. Prospectively planned adjudication of cardiovascular events did not occur in most of the trials. Some trials were placebo-controlled and some used active oral antidiabetic drugs as controls. Placebo-controlled trials included monotherapy trials (monotherapy with AVANDIA versus placebo monotherapy) and add-on trials (AVANDIA or placebo, added to sulfonylurea, metformin, or insulin). Active control trials 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 16,995 patients were included (10,039 in treatment groups containing AVANDIA, 6,956 in comparator groups), with 5,167 patient-years of exposure to AVANDIA and 3,637 patient-years of exposure to comparator. Cardiovascular events occurred more frequently for patients who received AVANDIA than for patients who received comparators (see Table 2).

Table 2. Occurrence of Cardiovascular Events in a Meta-Analysis of 52 Clinical Trials

Eventa AVANDIA
(Rosiglitazone)
(N = 10,039)
n (%)
Comparator
(N = 6,956)
n (%)
MACE (a composite of myocardial infarction, cardiovascular death, or stroke) 70 (0.7) 39 (0.6)
Myocardial Infarction 45 (0.4) 20 (0.3)
Cardiovascular Death 17 (0.2) 9(0.1)
Stroke 18(0.2) 16(0.2)
All-cause Death 29 (0.3) 17 (0.2)
a Events are not exclusive: i.e., a patient with a cardiovascular death due to a myocardial infarction would be counted in 4 event categories (myocardial infarction; myocardial infarction, cardiovascular death, or stroke; cardiovascular death; all-cause death).

In this analysis, a statistically significant increased risk of myocardial infarction with AVANDIA versus pooled comparators was observed. Analyses were performed using a composite of major adverse cardiovascular events (myocardial infarction, stroke, and cardiovascular death), referred to hereafter as MACE. AVANDIA had a statistically nonsignificant increased risk of MACE compared to the pooled comparators. A statistically significant increased risk of myocardial infarction and statistically non-significant increased risk of MACE with AVANDIA was observed in the placebo-controlled trials. In the active-controlled trials, there was no increased risk of myocardial infarction or MACE. (See Figure 1 and Table 3.)

Figure 1. Forest Plot of Odds Ratios (95% Confidence Intervals) for MACE and Myocardial Infarction in the Meta-Analysis of 52 Clinical Trials

Forest Plot of Odds Ratios - Illustration

Table 3. Occurrence of MACE and Myocardial Infarction in a Meta-Analysis of 52 Clinical Trials by Trial Type

    MACE Myocardial Infarction
N n (%) OR
(95% CI)
n (%) OR
(95% CI)
Active-Controlled Trials RSG 2,119 16 (0.8%) 1.05
(0.48, 2.34)
10 (0.5%) 1.00
(0.36, 2.82)
Control 1,918 14 (0.7%) 9 (0.5%)
Placebo-Controlled Trials RSG 8,124 54 (0.7%) 1.53
(0.94, 2.54)
35 (0.4%) 2.23
(1.14,4.64)
Placebo 5,636 28 (0.5%) 13 (0.2%)
Overall RSG 10,039 70 (0.7%) 1.44
(0.95, 2.20)
45 (0.4%) 1.8
(1.03,3.25)
Control 6,956 39 (0.6%) 20 (0.3%)
RSG = AVANDIA (rosiglitazone)

Of the placebo-controlled trials in the meta-analysis, 7 trials had patients randomized to ANDIA plus insulin or insulin. There were more patients in the AVANDIA plus insulin group compared to the insulin group with myocardial infarctions, MACE, cardiovascular deaths, and all-cause deaths (see Table 4). The total number of patients with stroke was 5 (0.5%) and 4 (0.5%) in the AVANDIA plus insulin and insulin groups, respectively. The use of AVANDIA in combination with insulin may increase the risk of myocardial infarction.

Table 4. Occurrence of Cardiovascular Events for AVANDIA in Combination With Insulin in a Meta-Analysis of 52 Clinical Trials

Eventa AVANDIA
(Rosiglitazone)
(N=l,018)
(%)
Insulin
(N = 815) (%)
OR
(95% CI)
MACE (a composite of myocardial infarction, cardiovascular death, or stroke) 1.3 0.6 2.14 (0.70, 7.83)
Myocardial infarction 0.6 0.1 5.6 (0.67, 262.7)
Cardiovascular death 0.4 0.0 ND, (0.47, ∞)
All cause death 0.6 0.2 2.19 (0.38, 22.61)
ND = not defined
a Events are not exclusive: i.e., a patient with a cardiovascular death due to a myocardial infarction would be counted in 4 event categories (myocardial infarction; myocardial infarction, cardiovascular death, or stroke; cardiovascular death; all-cause death).

Myocardial Infarction Events in Large, Long-Term, Prospective, Randomized, Controlled Trials of AVANDIA: Data from 3 large, long-term, prospective, randomized, controlled clinical trials of AVANDIA were assessed separately from the meta-analysis.6-8 These 3 trials included a total of 14,067 patients (treatment groups containing AVANDIA N = 6,311; comparator groups N = 7,756), with patient-year exposure of 24,534 patient-years for AVANDIA and 28,882 patient-years for comparator. Patient populations in the trials included patients with impaired glucose tolerance, patients with type 2 diabetes who were initiating oral agent monotherapy, and patients with type 2 diabetes who had failed monotherapy and were initiating dual oral agent therapy. Duration of follow-up exceeded 3 years in each trial.

In each of these trials, there was a statistically non-significant increase in the risk of myocardial infarction for AVANDIA versus comparator medications.

In a long-term, randomized, placebo-controlled, 2x2 factorial trial intended to evaluate AVANDIA, and separately ramipril (an angiotensin converting enzyme inhibitor [ACEI]), on progression to overt diabetes in 5,269 subjects with glucose intolerance, the incidence of myocardial infarction was higher in the subset of subjects who received AVANDIA in combination with ramipril than among subjects who received ramipril alone but not in the subset of subjects who received AVANDIA alone compared to placebo.6 The higher incidence of myocardial infarction among subjects who received AVANDIA in combination with ramipril was not confirmed in the two other large (total N = 8,798) long-term, randomized, active-controlled clinical trials conducted in patients with type 2 diabetes, in which 30% and 40% of patients in the two trials reported angiotensin-converting enzyme inhibitor use at baseline.7,8

There have been no adequately designed clinical trials directly comparing AVANDIA to ACTOS (pioglitazone) on cardiovascular risks. However, in a long-term, randomized, placebo-controlled cardiovascular outcomes trial comparing ACTOS (pioglitazone) to placebo in patients with type 2 diabetes mellitus and prior macrovascular disease, ACTOS (pioglitazone) was not associated with an increased risk of myocardial infarction or total mortality.9

The increased risk of myocardial infarction observed in the meta-analysis and large, long-term controlled clinical trials, and the increased risk of MACE observed in the meta-analysis described above, have not translated into a consistent finding of excess mortality from controlled clinical trials or observational studies. Clinical trials have not shown any difference between AVANDIA and comparator medications in overall mortality or CV-related mortality.

Mortality in Observational Studies of AVANDIA Compared to ACTOS: Three observational studies in elderly diabetic patients (age 65 years and older) found that AVANDIA statistically significantly increased the risk of all-cause mortality compared to use of ACTOS.2-4 One observational study5 in patients with a mean age of 54 years found no difference in all-cause mortality between patients treated with AVANDIA compared to ACTOS and reported similar results in the subpopulation of patients > 65 years of age. One additional small, prospective, observational study10 found no statistically significant differences for CV mortality and all-cause mortality in patients treated with AVANDIA compared to ACTOS.

Rosiglitazone REMS (Risk Evaluation and Mitigation Strategy) Program

Because of the potential increased risk of myocardial infarction, AVANDIA is available only through a restricted distribution program called the AVANDIA-Rosiglitazone Medicines Access Program [see INDICATIONS]. Both prescribers and patients must enroll in the program to be able to prescribe or receive AVANDIA, respectively. AVANDIA will be available only from specially certified pharmacies participating in the program. As part of the program, prescribers will be educated about the potential increased risk of myocardial infarction and the need to limit the use of AVANDIA to eligible patients. Prescribers will need to discuss with patients the risks and benefits of taking AVANDIA. To enroll, call 1-800-AVANDIA or visit www.AVANDIA.com.

Edema

AVANDIA should be used with caution in patients with edema. In a clinical trial 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 [see BOXED WARNING and PATIENT INFORMATION].

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 [see ADVERSE REACTIONS].

Weight Gain

Dose-related weight gain was seen with AVANDIA alone and in combination with other hypoglycemic agents (Table 5). 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 [see BOXED WARNING].

Table 5. Weight Changes (kg) From Baseline at Endpoint During Clinical Trials

    Control Group AVANDIA
4 ing
AVANDIA
8 ing
Monotherapy Duration   Median
(25th, 75* percentile)
Median
(25th, 75th percentile)
Median
(25th, 75th percentile)
  26 weeks placebo -0.9 (-2.8, 0.9)
N = 210
1.0 (-0.9, 3.6)
N = 436
3.1(1.1,5.8)
N = 439
  52 weeks Sulfonylurea 2.0 (0, 4.0)
N=173
2.0 (-0.6, 4.0)
N=150
2.6 (0, 5.3)
N=157
Combination therapy
Sulfonylurea 24-26 weeks Sulfonylurea 0 (-1.0, 1.3)
N= 1,155
2.2 (0.5, 4.0)
N = 613
3.5(1.4,5.9)
N=841
Metformin 26 weeks metformin -1.4 (-3.2, 0.2)
N=175
0.8 (-1.0, 2.6)
N=100
2.1(0,4.3)
N=184
Insulin 26 weeks insulin 0.9 (-0.5, 2.7)
N=162
4.1(1.4,6.3)
N=164
5.4 (3.4, 7.3)
N=150
Sulfonylurea + metformin 26 weeks Sulfonylurea + metformin 0.2 (-1.2, 1.6)
N = 272
2.5 (0.8, 4.6)
N = 275
4.5 (2.4, 7.3)
N = 276

In a 4- to 6-year, monotherapy, comparative trial (ADOPT) in patients recently diagnosed with type 2 diabetes not previously treated with antidiabetic medication [see Clinical Studies], the median weight change (25th, 75th 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 trial in pediatric patients aged 10 to 17 years treated with AVANDIA 4 to 8 mg daily, a median weight gain of 2.8 kg (25th, 75th percentiles: 0.0, 5.8) was reported.

Hepatic Effects

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. [See ADVERSE REACTIONS]

Macular Edema

Macular edema has been reported in postmarketing experience in some diabetic patients who were taking AVANDIA or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but some patients appear to have been diagnosed on routine ophthalmologic examination. Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of their thiazolidinedione. Patients with diabetes should have regular eye exams by an ophthalmologist, per the Standards of Care of the American Diabetes Association. Additionally, any diabetic who reports any kind of visual symptom should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings. [See ADVERSE REACTIONS]

Fractures

In a 4- to 6-year comparative trial (ADOPT) of glycemic control with monotherapy in drug-naive patients recently diagnosed with type 2 diabetes mellitus, an increased incidence of bone fracture was noted in female patients taking AVANDIA. Over the 4- to 6-year period, the incidence of bone fracture in females was 9.3% (60/645) for AVANDIA versus 3.5% (21/605) for glyburide and 5.1% (30/590) for metformin. This increased incidence was noted after the first year of treatment and persisted during the course of the trial. The majority of the fractures in the women who received AVANDIA occurred in the upper arm, hand, and foot. These sites of fracture are different from those usually associated with postmenopausal osteoporosis (e.g., hip or spine). Other trials suggest that this risk may also apply to men, although the risk of fracture among women appears higher than that among men. The risk of fracture should be considered in the care of patients treated with AVANDIA, and attention given to assessing and maintaining bone health according to current standards of care.

Hematologic Effects

Decreases in mean hemoglobin and hematocrit occurred in a dose-related fashion in adult patients treated with AVANDIA [see ADVERSE REACTIONS]. The observed changes may be related to the increased plasma volume observed with treatment with AVANDIA.

Diabetes and Blood Glucose Control

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 HbAlc measurements should be performed to monitor therapeutic response.

Ovulation

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 [see Use in Specific Populations]. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been specifically investigated in clinical trials; therefore, the frequency of this occurrence is not known.

Although hormonal imbalance has been seen in preclinical studies [see Nonclinical Toxicology], the clinical significance of this finding is not known. If unexpected menstrual dysfunction occurs, the benefits of continued therapy with AVANDIA should be reviewed.

Patient Counseling Information

See Medication Guide.

Patient Advice

There are multiple medications available to treat type 2 diabetes. The benefits and risks of each available diabetes medication should be taken into account when choosing a particular diabetes medication for a given patient.

Patients should be informed of the risks and benefits of AVANDIA. AVANDIA should only be taken by adults with type 2 diabetes who are already taking AVANDIA, or who are not already taking AVANDIA and are unable to achieve adequate glycemic control on other diabetes medications, and, in consultation with their healthcare provider, have decided not to take pioglitazone (ACTOS) for medical reasons. Inform patients that they must be enrolled in the AVANDIA-Rosiglitazone Medicines Access Program in order to receive AVANDIA.

Patients should be informed of the following:

  • AVANDIA is not recommended for patients with symptomatic heart failure.
  • Results of a set of clinical trials suggest that treatment with AVANDIA is associated with an increased risk for myocardial infarction (heart attack), especially in patients taking insulin. Clinical trials have not shown any difference between AVANDIA and comparator medications in overall mortality or CV-related mortality.
  • AVANDIA is not recommended for patients who are taking insulin.
  • 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. It can take 2 weeks to see a reduction in blood glucose and 2 to 3 months to see the full effect of AVANDIA.
  • Blood will be drawn to check their liver function prior to the start of therapy and periodically thereafter per the clinical judgment of the healthcare professional. Patients with unexplained symptoms of nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine should immediately report these symptoms to their physician.
  • Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on AVANDIA should immediately report these symptoms to their physician.
  • AVANDIA can be taken with or without meals.
  • When using AVANDIA in combination with other 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 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 trials so the frequency of this occurrence is not known.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: A 2-year carcinogenicity study was conducted in Charles River CD-I 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 juvenile rats dosed from 27 days of age through to sexual maturity (at up to 40 mg/kg/day), there was no effect on male reproductive performance, or on estrous cyclicity, mating performance or pregnancy incidence in females (approximately 68 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.

Use In Specific Populations

Pregnancy

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 trials 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.

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 AVANDLA is excreted in human milk. Because many drugs are excreted in human milk, AVANDIA should not be administered to a nursing woman.

Pediatric Use

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/m2, 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 naive 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 HbAlc was -0.14% with AVANDIA and -0.49% with metformin. There was an insufficient number of patients in this trial to establish statistically whether these observed mean treatment effects were similar or different. Treatment effects differed for patients naive to therapy with antidiabetic drugs and for patients previously treated with antidiabetic therapy (Table 8).

Table 8. Week 24 FPG and HbAlc Change From Baseline Last-Observation-Carried Forward in Children With Baseline HbAlc > 6.5%

  Naive Patients Previously-Treated Patients
Metformin Rosiglitazone Metformin Rosiglitazone
N = 40 N = 45 N = 43 N = 32
FPG (mg/dL)
Baseline (mean) 170 165 221 205
Change from baseline (mean) -21 -11 -33 -5
Adjusted treatment differencea (rosiglitazone-metformin)b (95% CI)   8
(-15, 30)
  21
(-9, 51)
% of patients with > 30 mg/dL decrease from baseline 43% 27% 44% 28%
HbAlc (%)
Baseline (mean) 8.3 8.2 8.8 8.5
Change from baseline (mean) -0.7 -0.5 -0.4 0.1
Adjusted treatment differencea (rosiglitazone-metformin)b (95% CI)   0.2
(-0.6, 0.9)
  0.5
(-0.2, 1.3)
% of patients with > 0.7% decrease from baseline 63% 52% 54% 31%
a Change from baseline means are least squares means adjusting for baseline HbAlc, gender, and region.
b Positive values for the difference favor metformin.

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 [see WARNINGS AND PRECAUTIONS.]. 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 trial.

Adverse events observed in this trial are described in ADVERSE REACTIONS.

Figure 2. Mean HbAlc Over Time in a 24-Week Trial of AVANDIA and Metformin in Pediatric Patients — Drug-Naive Subgroup

Mean HbAlc Over Time in a 24-Week Trial - Illustration

Geriatric Use

Results of the population pharmacokinetic analysis showed that age does not significantly affect the pharmacokinetics of rosiglitazone [see CLINICAL PHARMACOLOGY]. Therefore, no dosage adjustments are required for the elderly. In controlled clinical trials, no overall differences in safety and effectiveness between older ( ≥ 65 years) and younger ( < 65 years) patients were observed.

REFERENCES

1. Food and Drug Administration Briefing Document. Joint meeting of the Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management Advisory Committees. July 13-14, 2010.

2. Winkelmayer WC, et al. Comparison of cardiovascular outcomes in elderly patients with diabetes who initiated rosiglitazone vs pioglitazone therapy. Arch Intern Med 2008;168(21):2368-2375.

3. Juurlink DN, et al. Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study. BMJ 2009; 339.

4. Graham DJ, et al. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly medicare patients treated with rosiglitazone or pioglitazone. JAMA 2010;304:411-418.

5. Wertz DA, et al. Risk of cardiovascular events and all-cause mortality in patients with Thiazolidinediones in a managed-care population. Circ Cardiovasc Qual Outcomes 2010;3: 538-545.

6. DREAM Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006;368:1096-1105.

7. Kahn S, et al. Glycemic durability of rosiglitazone, metformin or glyburide monotherapy. New England Journal of Medicine 2006, 355:2427-2443.

8. Home P, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicenter, randomized, open-label trial. Lancet 2009, 373:2125-35.

9. Dormandy J et al. Secondary prevention of macro vascular events in patients with type 2 diabetes in the PROactive study (Prospective Pioglitazone Clinical Trial in Macrovascular Events): a randomized controlled trial. Lancet 2005, 366:1279-89.

10. Bilik D, et al. Thiazolidinediones, cardiovascular disease and cardiovascular mortality: translating research into action for diabetes (TRIAD). Pharmocoepidemiol Drug Saf 2010; 19:715-721.

Last reviewed on RxList: 11/30/2011
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

Limited data are available with regard to overdosage in humans. In clinical trials 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.

CONTRAINDICATIONS

Initiation of AVANDIA in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated [see BOXED WARNING].

Last reviewed on RxList: 11/30/2011
This monograph has been modified to include the generic and brand name in many instances.

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 (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.

Pharmacodynamics

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 9).

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 trial 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.

Table 9. Summary of Mean Lipid Changes in 26-Week Placebo-Controlled and 52-Week Glyburide-Controlled Monotherapy Trials

  Placebo-Controlled Trials
Week 26
Glyburide-Controlled Trial
Week 26 and Week 52
Placebo AVANDIA Glyburide Titration AVANDIA 8 mg
4mg dailya 8mg dailya Wk 26 Wk 52 Wk 26 Wk 52
Free fatty acids
  N 207 428 436 181 168 166 145
  Baseline (mean) 18.1 17.5 17.9 26.4 26.4 26.9 26.6
  % Change from baseline (mean) +0.2% -7.8% -14.7% -2.4% -4.7% -20.8% -21.5%
LDL
  N 190 400 374 175 160 161 133
  Baseline (mean) 123.7 126.8 125.3 142.7 141.9 142.1 142.1
  % Change from baseline (mean) +4.8% +14.1% +18.6% -0.9% -0.5% +11.9% +12.1%
HDL
  N 208 429 436 184 170 170 145
  Baseline (mean) 44.1 44.4 43.0 47.2 47.7 48.4 48.3
  % Change from baseline (mean) +8.0% +11.4% +14.2% +4.3% +8.7% +14.0% +18.5%
a Once daily and twice daily dosing groups were combined.

Pharmacokinetics

Maximum plasma concentration (Cmax) and the area under the curve (AUC) of rosiglitazone increase in a dose-proportional manner over the therapeutic dose range (Table 10). The elimination half-life is 3 to 4 hours and is independent of dose.

Table 10. Mean (SD) Pharmacokinetic Parameters for Rosiglitazone Following Single Oral Doses (N = 32)

Parameter 1 mg
Fasting
2 mg Fasting 8 mg Fasting 8 mg Fed
AUC0-inf
[ng•hr/mL]
358 (112) 733 (184) 2,971 (730) 2,890 (795)
Cmax
[ng/mL]
76 (13) 156 (42) 598 (117) 432 (92)
Half-life
[hr]
3.16 (0.72) 3.15 (0.39) 3.37 (0.63) 3.59 (0.70)
CL/Fa
[L/hr]
3.03 (0.87) 2.89 (0.71) 2.85 (0.69) 2.97 (0.81)
a CL/F = Oral clearance.

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 Cmax and a delay in Tmax (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 [14C]rosiglitazone maleate, approximately 64% and 23% of the dose was eliminated in the urine and in the feces, respectively. The plasma half-life of [14C]related material ranged from 103 to 158 hours.

Population Pharmacokinetics in Patients With Type 2 Diabetes: Population pharmacokinetic analyses from 3 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

Geriatric: 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, AVANDIA improved glycemic control in both males and females. In metformin combination trials, efficacy was demonstrated with no gender differences in glycemic response.

In monotherapy trials, 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 PPARy 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 Cmax and AUC0-inf were increased 2- and 3-fold, respectively. Elimination half-life for rosiglitazone was about 2 hours longer in patients with liver disease, compared to healthy subjects.

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 baseline [see WARNINGS AND PRECAUTIONS.].

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.

Drug-Drug Interactions

Drugs That Inhibit. Induce, or are Metabolized by Cvtochrome 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.11

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 Cmax of approximately 30%. In Japanese subjects, glyburide AUC and CmaX 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 Cmax 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.

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). Effects in juvenile rats were consistent with those seen in adults. 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.

Clinical Studies

Monotherapy

In clinical trials, treatment with AVANDIA resulted in an improvement in glycemic control, as measured by FPG and HbAlc, 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 trials suggested that no additional benefit was obtained with a total daily dose of 12 mg.

Short-Term Clinical Trials: A total of 2,315 patients with type 2 diabetes, previously treated with diet alone or antidiabetic medication(s), were treated with AVANDIA as monotherapy in 6 double-blind trials, which included two 26-week placebo-controlled trials, one 52-week glyburide-controlled trial, and 3 placebo-controlled dose-ranging trials 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 (n = 1,401) with inadequate glycemic control (mean baseline FPG approximately 228 mg/dL [101 to 425 mg/dL] and mean baseline HbAlc 8.9% [5.2% to 16.2%]), were conducted. Treatment with AVANDIA produced statistically significant improvements in FPG and HbAlc compared to baseline and relative to placebo. Data from one of these trials are summarized in Table 11.

Table 11. Glycemic Parameters in a 26-Week Placebo-Controlled Trial

  Placebo AVANDIA AVANDIA
4 mg once daily 2 mg twice daily 8 mg once daily 4 mg twice daily
N=173 N=180 N=186 N=181 N=187
FPG (mg/dL)
  Baseline (mean) 225 229 225 228 228
  Change from baseline (mean) 8 -25 -35 -42 -55
  Difference from placebo (adjusted mean) - -31a -43a -49a -62a
  % of patients with ≥ 30 mg/dL decrease from baseline 19% 45% 54% 58% 70%
HbAlc (%)
  Baseline (mean) 8.9 8.9 8.9 8.9 9.0
  Change from baseline (mean) 0.8 0.0 -0.1 -0.3 -0.7
  Difference from placebo (adjusted mean) - -0.8a -0.9a -1.1a -1.5a
  % of patients with ≥ 0.7% decrease from baseline 9% 28% 29% 39% 54%
a P < 0.0001 compared to placebo.

When administered at the same total daily dose, AVANDIA was generally more effective in reducing FPG and HbAlc when administered in divided doses twice daily compared to once daily doses. However, for HbAlc, the difference between the 4 mg once daily and 2 mg twice daily doses was not statistically significant.

Long-Term Clinical Trials: 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 AVANDIA 2 mg twice daily (N = 195) or AVANDIA 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 (Figure 3 and Figure 4). At the end of week 52, the reduction from baseline in FPG and HbAlc was -40.8 mg/dL and -0.53% with AVANDIA 4 mg twice daily; -25.4 mg/dL and -0.27% with AVANDIA 2 mg twice daily; and -30.0 mg/dL and -0.72% with glyburide. For HbAlc, the difference between AVANDIA 4 mg twice daily and glyburide was not statistically significant at week 52. The initial fall in FPG with glyburide was greater than with AVANDIA; however, this effect was less durable over time. The improvement in glycemic control seen with AVANDIA 4 mg twice daily at week 26 was maintained through week 52 of the trial.

Figure 3. Mean FPG Over Time in a 52-Week Glyburide-Controiled Trial

Mean FPG Over Time - Illustration

Figure 4. Mean HbAlc Over Time in a 52-Week Gly bur ide-Contr oiled Trial

Mean HbAlc Over Time - Illustration

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 AVANDIA. 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 AVANDIA, respectively, versus 1.9 kg in glyburide-treated patients. In patients treated with AVANDIA, 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.

A Diabetes Outcome Progression Trial (ADOPT) was a multicenter, double-blind, controlled trial (N = 4,351) conducted over 4 to 6 years to compare the safety and efficacy of AVANDIA, metformin, and glyburide monotherapy in patients recently diagnosed with type 2 diabetes mellitus ( ≤ 3 years) inadequately controlled with diet and exercise. The mean age of patients in this trial was 57 years and the majority of patients (83%) had no known history of cardiovascular disease. The mean baseline FPG and HbAlc were 152 mg/dL and 7.4%, respectively. Patients were randomized to receive either AVANDIA 4 mg once daily, glyburide 2.5 mg once daily, or metformin 500 mg once daily, and doses were titrated to optimal glycemic control up to a maximum of 4 mg twice daily for AVANDIA, 7.5 mg twice daily for glyburide, and 1,000 mg twice daily for metformin. The primary efficacy outcome was time to consecutive FPG > 180 mg/dL after at least 6 weeks of treatment at the maximum tolerated dose of study medication or time to inadequate glycemic control, as determined by an independent adjudication committee.

The cumulative incidence of the primary efficacy outcome at 5 years was 15% with AVANDIA, 21% with metformin, and 34% with glyburide (HR 0.68 [95% CI 0.55, 0.85] versus metformin, HR 0.37 [95% CI 0.30, 0.45] versus glyburide).

Cardiovascular and adverse event data (including effects on body weight and bone fracture) from ADOPT for AVANDIA, metformin, and glyburide are described in WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS, respectively. As with all medications, efficacy results must be considered together with safety information to assess the potential benefit and risk for an individual patient.

Combination With Metformin or Sulfonylurea

The addition of AVANDIA to either metformin or sulfonylurea resulted in significant reductions in hyperglycemia compared to either of these agents alone. These results are consistent with an additive effect on glycemic control when AVANDIA is used as combination therapy.

Combination With Metformin: A total of 670 patients with type 2 diabetes participated in two 26-week, randomized, double-blind, placebo/active-controlled trials designed to assess the efficacy of AVANDIA in combination with metformin. AVANDIA, 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 trial, patients inadequately controlled on 2.5 grams/day of metformin (mean baseline FPG 216 mg/dL and mean baseline HbAlc 8.8%) were randomized to receive 4 mg of AVANDIA once daily, 8 mg of AVANDIA once daily, or placebo in addition to metformin. A statistically significant improvement in FPG and HbAlc was observed in patients treated with the combinations of metformin and 4 mg of AVANDIA once daily and 8 mg of AVANDIA once daily, versus patients continued on metformin alone (Table 12).

Table 12. Glycemic Parameters in a 26-Week Combination Trial of AVANDIA Plus Metformin

  Metformin AVANDIA 4 mg once daily + metformin AVANDIA 8 mg once daily + metformin
N=113 N=116 N=110
FPG (mg/dL)
  Baseline (mean) 214 215 220
  Change from baseline (mean) 6 -33 -48
  Difference from metformin alone (adjusted mean) - -40a -53a
  % of patients with > 30 mg/dL decrease from baseline 20% 45% 61%
HbAlc (%)
  Baseline (mean) 8.6 8.9 8.9
  Change from baseline (mean) 0.5 -0.6 -0.8
  Difference from metformin alone (adjusted mean) - -1.0a -1.2a
  % of patients with > 0.7% decrease from baseline 11% 45% 52%
a P < 0.0001 compared to metformin.

In a second 26-week trial, patients with type 2 diabetes inadequately controlled on 2.5 grams/day of metformin who were randomized to receive the combination of AVANDIA 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 HbAlc of-0.8% over metformin alone. The combination of metformin and AVANDIA resulted in lower levels of FPG and HbAlc 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 AVANDIA demonstrated loss of glycemic control, as evidenced by increases in FPG and HbAlc. In this group, increases in LDL and VLDL were also seen.

Combination With a Sulfonylurea: A total of 3,457 patients with type 2 diabetes participated in ten 24- to 26-week randomized, double-blind, placebo/active-controlled trials and one 2-year double-blind, active-controlled trial in elderly patients designed to assess the efficacy and safety of AVANDIA in combination with a sulfonylurea. AVANDIA 2 mg, 4 mg, or 8 mg daily was administered, either once daily (3 trials) or in divided doses twice daily (7 trials), to patients inadequately controlled on a submaximal or maximal dose of sulfonylurea.

In these trials, the combination of AVANDIA 4 mg or 8 mg daily (administered as single or twice daily divided doses) and a sulfonylurea significantly reduced FPG and HbAlc compared to placebo plus sulfonylurea or further up-titration of the sulfonylurea. Table 13 shows pooled data for 8 trials in which AVANDIA added to sulfonylurea was compared to placebo plus sulfonylurea.

Table 13. Glycemic Parameters in 24- to 26-Week Combination Trials of AVANDIA Plus Sulfonylurea

Twice Daily Divided Dosing
(5 Trials)
Sulfonylurea AVANDIA
2 mg twice daily + sulfonylurea
Sulfonylurea AVANDIA
4 mg twice daily + sulfonylurea
N = 397 N = 497 N = 248 N = 346
FPG (mg/dL)
Baseline (mean) 204 198 188 187
Change from baseline (mean) 11 -29 8 -43
Difference from sulfonylurea alone (adjusted mean) - -42a - -53a
% of patients with ≥ 30 mg/dL decrease from baseline 17% 49% 15% 61%
HbAlc (%)
Baseline (mean) 9.4 9.5 9.3 9.6
Change from baseline (mean) 0.2 -1.0 0.0 -1.6
Difference from sulfonylurea alone (adjusted mean) - -l.1a - -1.4a
% of patients with ≥ 0.7% decrease from baseline 21% 60% 23% 75%
Once Daily Dosing
(3 Trials)
Sulfonylurea AVANDIA
4 mg once daily + sulfonylurea
Sulfonylurea AVANDIA
8 mg once daily + sulfonylurea
  N=172 N=172 N=173 N=176
FPG (mg/dL)
Baseline (mean) 198 206 188 192
Change from baseline (mean) 17 -25 17 -43
Difference from sulfonylurea alone (adjusted mean) - -47a - -66a
% of patients with ≥ 30 mg/dL decrease from baseline 17% 48% 19% 55%
HbAlc (%)
Baseline (mean) 8.6 8.8 8.9 8.9
Change from baseline (mean) 0.4 -0.5 0.1 -1.2
Difference from sulfonylurea alone (adjusted mean) - -0.9a - -1.4a
% of patients with ≥ 0.7% decrease from baseline 11% 36% 20% 68%
a P < 0.0001 compared to sulfonylurea alone.

One of the 24- to 26-week trials included patients who were inadequately controlled on maximal doses of glyburide and switched to 4 mg of AVANDIA daily as monotherapy; in this group, loss of glycemic control was demonstrated, as evidenced by increases in FPG and HbAlc.

In a 2-year double-blind trial, elderly patients (aged 59 to 89 years) on half-maximal sulfonylurea (glipizide 10 mg twice daily) were randomized to the addition of AVANDIA (n = 115, 4 mg once daily to 8 mg as needed) or to continued up-titration of glipizide (n = 110), to a maximum of 20 mg twice daily. Mean baseline FPG and HbAlc were 157 mg/dL and 7.72%, respectively, for the AVANDIA plus glipizide arm and 159 mg/dL and 7.65%, respectively, for the glipizide up-titration arm. Loss of glycemic control (FPG ≥ 180 mg/dL) occurred in a significantly lower proportion of patients (2%) on AVANDIA plus glipizide compared to patients in the glipizide up-titration arm (28.7%). About 78% of the patients on combination therapy completed the 2 years of therapy while only 51% completed on glipizide monotherapy. The effect of combination therapy on FPG and HbAlc was durable over the 2-year trial period, with patients achieving a mean of 132 mg/dL for FPG and a mean of 6.98% for HbAlc compared to no change on the glipizide arm.

Combination With Sulfonylurea Plus Metformin

In two 24- to 26-week, double-blind, placebo-controlled, trials designed to assess the efficacy and safety of AVANDIA in combination with sulfonylurea plus metformin, AVANDIA 4 mg or 8 mg daily, was administered in divided doses twice daily, to patients inadequately controlled on submaximal (10 mg) and maximal (20 mg) doses of glyburide and maximal dose of metformin (2 g/day). A statistically significant improvement in FPG and HbAlc was observed in patients treated with the combinations of sulfonylurea plus metformin and 4 mg of AVANDIA and 8 mg of AVANDIA versus patients continued on sulfonylurea plus metformin, as shown in Table 14.

Table 14. Glycemic Parameters in a 26-Week Combination Trial of AVANDIA Plus Sulfonylurea and Metformin

  Sulfonylurea + metformin AVANDIA
2 mg twice daily + sulfonylurea + metformin
AVANDIA
4 mg twice daily + sulfonylurea + metformin
N = 273 N = 276 N = 277
FPG (mg/dL)
  Baseline (mean) 189 190 192
  Change from baseline (mean) 14 -19 -40
  Difference from sulfonylurea plus metformin (adjusted mean) - -30a -52a
  % of patients with > 30 mg/dL decrease from baseline 16% 46% 62%
HbAlc (%)
  Baseline (mean) 8.7 8.6 8.7
  Change from baseline (mean) 0.2 -0.4 -0.9
  Difference from sulfonylurea plus metformin (adjusted mean) - -0.6a -l.1a
  % of patients with > 0.7% decrease from baseline 16% 39% 63%
a P < 0.0001 compared to placebo.

REFERENCES

11. Park JY, Kim KA, Kang MH, et al. Effect of rifampin on the pharmacokinetics of rosiglitazone in healthy subjects. Clin Pharmacol Ther 2004;75:157-162.

Last reviewed on RxList: 11/30/2011
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

MEDICATION GUIDE

AVANDIA®
(ah-VAN-dee-a)
(rosiglitazone maleate) Tablets

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.

What is the most important information I should know about AVANDIA?

AVANDIA is available only through the AVANDIA-Rosiglitazone Medicines Access Program. Both you and your doctor must be enrolled in the program so that you can get AVANDIA. To enroll, you must:

  • talk to your doctor,
  • understand the risks and benefits of AVANDIA, and
  • agree to enroll in the program.

AVANDIA may cause serious side effects, including:

New or worse heart failure

  • AVANDIA can cause your body to keep extra fluid (fluid retention), which leads to swelling (edema) and weight gain. Extra body fluid can make some heart problems worse or lead to heart failure. Heart failure means your heart does not pump blood well enough.
  • If you have severe heart failure, you cannot start AVANDIA.
  • If you have heart failure with symptoms (such as shortness of breath or swelling), even if these symptoms are not severe, AVANDIA may not be right for you.

Call your doctor right away if you have any of the following:

  • swelling or fluid retention, especially in the ankles or legs
  • shortness of breath or trouble breathing, especially when you lie down
  • an unusually fast increase in weight
  • unusual tiredness

Myocardial Infarction ("Heart Attack")

AVANDIA may raise the risk of a heart attack. The risk of having a heart attack may be higher in people who take AVANDIA with insulin. Most people who take insulin should not also take AVANDIA.

Symptoms of a heart attack can include the following:

  • chest discomfort in the center of your chest that lasts for more than a few minutes, or that goes away or comes back
  • chest discomfort that feels like uncomfortable pressure, squeezing, fullness or pain
  • pain or discomfort in your arms, back, neck, jaw or stomach
  • shortness of breath with or without chest discomfort
  • breaking out in a cold sweat
  • nausea or vomiting
  • feeling lightheaded

Call your doctor or go to the nearest hospital emergency room right away if you think you are having a heart attack.

People with diabetes have a greater risk for heart problems. It is important to work with your doctor to manage other conditions, such as high blood pressure or high cholesterol.

AVANDIA can have other serious side effects. Be sure to read the section below "What are possible side effects of AVANDIA?".

What is AVANDIA?

AVANDIA is a prescription medicine used with diet and exercise to treat certain adults with type 2 ("adult-onset" or "non-insulin dependent") diabetes mellitus ("high blood sugar") who are:

  • already taking AVANDIA or
  • unable to control their blood sugar on other diabetes medicines, and after talking with their doctor have decided not to take pioglitazone (ACTOS)

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.

AVANDIA is not for people with type 1 diabetes mellitus or to treat a condition called diabetic ketoacidosis.

It is not known if AVANDIA is safe and effective in children under 18 years old.

Who should not take AVANDIA?

Many people with heart failure should not start taking AVANDIA. See "What should

I tell my doctor before taking AVANDIA?".

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:

  • have heart problems or heart failure.
  • have type 1 ("juvenile") diabetes or had diabetic ketoacidosis. These conditions should be treated with insulin.
  • have a type of diabetic eye disease called macular edema (swelling of the back of the eye).
  • have liver problems. Your doctor should do blood tests to check your liver before you start taking AVANDIA and during treatment as needed.
  • had liver problems while taking REZULIN® (troglitazone), another medicine for diabetes.
  • are pregnant or plan to become pregnant. AVANDIA should not be used during pregnancy. It is not known if AVANDIA can harm your unborn baby. You and your doctor should talk about the best way to control your diabetes during pregnancy. If you are a premenopausal woman (before the "change of life") who does not have regular monthly periods, AVANDIA may increase your chances of becoming pregnant. Talk to your doctor about birth control choices while taking AVANDIA. Tell your doctor right away if you become pregnant while taking AVANDIA.
  • are breast-feeding or planning to breast-feed. It is not known if AVANDIA passes into breast milk. You should not use AVANDIA while breast-feeding.

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:

  • insulin.
  • any medicines for high blood pressure, high cholesterol or heart failure, or for prevention of heart disease or stroke.

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.

How should I take AVANDIA?

  • Take AVANDIA exactly as prescribed. Your doctor will tell you how many tablets to take and how often. The usual daily starting dose is 4 mg a day taken one time each day or 2 mg taken two times each day. Your doctor may need to adjust your dose until your blood sugar is better controlled.
  • AVANDIA may be prescribed alone or with other diabetes medicines. This will depend on how well your blood sugar is controlled.
  • Take AVANDIA with or without food.
  • It can take 2 weeks for AVANDIA to start lowering blood sugar. It may take 2 to 3 months to see the full effect on your blood sugar level.
  • If you miss a dose of AVANDIA, take it as soon as you remember, unless it is time to take your next dose. Take your next dose at the usual time. Do not take double doses to make up for a missed dose.
  • If you take too much AVANDIA, call your doctor or poison control center right away.
  • Test your blood sugar regularly as your doctor tells you.
  • Diet and exercise can help your body use its blood sugar better. It is important to stay on your recommended diet, lose extra weight, and get regular exercise while taking AVANDIA.
  • Your doctor should do blood tests to check your liver before you start AVANDIA and during treatment as needed. Your doctor should also do regular blood sugar tests (for example, "A1C") to monitor your response to AVANDIA.

What are possible side effects of AVANDIA?

AVANDIA may cause serious side effects including:

  • New or worse heart failure. See "What is the most important information I should know about AVANDIA?".
  • Heart attack. See "What is the most important information I should know about AVANDIA?".
  • Swelling (edema). AVANDIA can cause swelling due to fluid retention. See "What is the most important information I should know about AVANDIA?".
  • Weight gain. AVANDIA can cause weight gain that may be due to fluid retention or extra body fat. Weight gain can be a serious problem for people with certain conditions including heart problems. See "What is the most important information I should know about AVANDIA?".
  • Liver problems. It is important for your liver to be working normally when you take AVANDIA. Your doctor should do blood tests to check your liver before you start taking AVANDIA and during treatment as needed. Call your doctor right away if you have unexplained symptoms such as:
    • nausea or vomiting
    • stomach pain
    • unusual or unexplained tiredness
    • loss of appetite
    • dark urine
    • yellowing of your skin or the whites of your eyes.
  • Macular edema (a diabetic eye disease with swelling in the back of the eye). Tell your doctor right away if you have any changes in your vision. Your doctor should check your eyes regularly. Very rarely, some people have had vision changes due to swelling in the back of the eye while taking AVANDIA.
  • Fractures (broken bones), usually in the hand, upper arm or foot. Talk to your doctor for advice on how to keep your bones healthy.
  • Low red blood cell count (anemia).
  • Low blood sugar (hypoglycemia). Lightheadedness, dizziness, shakiness or hunger may mean that your blood sugar is too low. This can happen if you skip meals, if you use another medicine that lowers blood sugar, or if you have certain medical problems. Call your doctor if low blood sugar levels are a problem for you.
  • Ovulation (release of egg from an ovary in a woman) leading to pregnancy. Ovulation may happen in premenopausal women who do not have regular monthly periods. This can increase the chance of pregnancy. See "What should I tell my doctor before taking AVANDIA?".

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.

How should I store AVANDIA?

  • Store AVANDIA at room temperature, 59° to 86°F (15° to 30°C). Keep AVANDIA in the container it comes in.
  • Safely, throw away AVANDIA that is out of date or no longer needed.
  • Keep AVANDIA and all medicines out of the reach of children.

General information about AVANDIA

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.

What are the ingredients in AVANDIA?

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 - pink with "SB" on one side and "2" on the other.
4 mg - orange with "SB" on one side and "4" on the other.
8 mg - red-brown with "SB" on one side and "8" on the other.

AVANDIA is a registered trademark of GlaxoSmithKline. The other brands listed are trademarks of their respective owners and are not trademarks of GlaxoSmithKline. The makers of these brands are not affiliated with and do not endorse GlaxoSmithKline or its products.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Last reviewed on RxList: 11/30/2011
This monograph has been modified to include the generic and brand name in many instances.

>

PATIENT INFORMATION

MEDICATION GUIDE

AVANDIA®
(ah-VAN-dee-a)
(rosiglitazone maleate) Tablets

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.

What is the most important information I should know about AVANDIA?

AVANDIA is available only through the AVANDIA-Rosiglitazone Medicines Access Program. Both you and your doctor must be enrolled in the program so that you can get AVANDIA. To enroll, you must:

  • talk to your doctor,
  • understand the risks and benefits of AVANDIA, and
  • agree to enroll in the program.

AVANDIA may cause serious side effects, including:

New or worse heart failure

  • AVANDIA can cause your body to keep extra fluid (fluid retention), which leads to swelling (edema) and weight gain. Extra body fluid can make some heart problems worse or lead to heart failure. Heart failure means your heart does not pump blood well enough.
  • If you have severe heart failure, you cannot start AVANDIA.
  • If you have heart failure with symptoms (such as shortness of breath or swelling), even if these symptoms are not severe, AVANDIA may not be right for you.

Call your doctor right away if you have any of the following:

  • swelling or fluid retention, especially in the ankles or legs
  • shortness of breath or trouble breathing, especially when you lie down
  • an unusually fast increase in weight
  • unusual tiredness

Myocardial Infarction ("Heart Attack")

AVANDIA may raise the risk of a heart attack. The risk of having a heart attack may be higher in people who take AVANDIA with insulin. Most people who take insulin should not also take AVANDIA.

Symptoms of a heart attack can include the following:

  • chest discomfort in the center of your chest that lasts for more than a few minutes, or that goes away or comes back
  • chest discomfort that feels like uncomfortable pressure, squeezing, fullness or pain
  • pain or discomfort in your arms, back, neck, jaw or stomach
  • shortness of breath with or without chest discomfort
  • breaking out in a cold sweat
  • nausea or vomiting
  • feeling lightheaded

Call your doctor or go to the nearest hospital emergency room right away if you think you are having a heart attack.

People with diabetes have a greater risk for heart problems. It is important to work with your doctor to manage other conditions, such as high blood pressure or high cholesterol.

AVANDIA can have other serious side effects. Be sure to read the section below "What are possible side effects of AVANDIA?".

What is AVANDIA?

AVANDIA is a prescription medicine used with diet and exercise to treat certain adults with type 2 ("adult-onset" or "non-insulin dependent") diabetes mellitus ("high blood sugar") who are:

  • already taking AVANDIA or
  • unable to control their blood sugar on other diabetes medicines, and after talking with their doctor have decided not to take pioglitazone (ACTOS)

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.

AVANDIA is not for people with type 1 diabetes mellitus or to treat a condition called diabetic ketoacidosis.

It is not known if AVANDIA is safe and effective in children under 18 years old.

Who should not take AVANDIA?

Many people with heart failure should not start taking AVANDIA. See "What should

I tell my doctor before taking AVANDIA?".

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:

  • have heart problems or heart failure.
  • have type 1 ("juvenile") diabetes or had diabetic ketoacidosis. These conditions should be treated with insulin.
  • have a type of diabetic eye disease called macular edema (swelling of the back of the eye).
  • have liver problems. Your doctor should do blood tests to check your liver before you start taking AVANDIA and during treatment as needed.
  • had liver problems while taking REZULIN® (troglitazone), another medicine for diabetes.
  • are pregnant or plan to become pregnant. AVANDIA should not be used during pregnancy. It is not known if AVANDIA can harm your unborn baby. You and your doctor should talk about the best way to control your diabetes during pregnancy. If you are a premenopausal woman (before the "change of life") who does not have regular monthly periods, AVANDIA may increase your chances of becoming pregnant. Talk to your doctor about birth control choices while taking AVANDIA. Tell your doctor right away if you become pregnant while taking AVANDIA.
  • are breast-feeding or planning to breast-feed. It is not known if AVANDIA passes into breast milk. You should not use AVANDIA while breast-feeding.

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:

  • insulin.
  • any medicines for high blood pressure, high cholesterol or heart failure, or for prevention of heart disease or stroke.

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.

How should I take AVANDIA?

  • Take AVANDIA exactly as prescribed. Your doctor will tell you how many tablets to take and how often. The usual daily starting dose is 4 mg a day taken one time each day or 2 mg taken two times each day. Your doctor may need to adjust your dose until your blood sugar is better controlled.
  • AVANDIA may be prescribed alone or with other diabetes medicines. This will depend on how well your blood sugar is controlled.
  • Take AVANDIA with or without food.
  • It can take 2 weeks for AVANDIA to start lowering blood sugar. It may take 2 to 3 months to see the full effect on your blood sugar level.
  • If you miss a dose of AVANDIA, take it as soon as you remember, unless it is time to take your next dose. Take your next dose at the usual time. Do not take double doses to make up for a missed dose.
  • If you take too much AVANDIA, call your doctor or poison control center right away.
  • Test your blood sugar regularly as your doctor tells you.
  • Diet and exercise can help your body use its blood sugar better. It is important to stay on your recommended diet, lose extra weight, and get regular exercise while taking AVANDIA.
  • Your doctor should do blood tests to check your liver before you start AVANDIA and during treatment as needed. Your doctor should also do regular blood sugar tests (for example, "A1C") to monitor your response to AVANDIA.

What are possible side effects of AVANDIA?

AVANDIA may cause serious side effects including:

  • New or worse heart failure. See "What is the most important information I should know about AVANDIA?".
  • Heart attack. See "What is the most important information I should know about AVANDIA?".
  • Swelling (edema). AVANDIA can cause swelling due to fluid retention. See "What is the most important information I should know about AVANDIA?".
  • Weight gain. AVANDIA can cause weight gain that may be due to fluid retention or extra body fat. Weight gain can be a serious problem for people with certain conditions including heart problems. See "What is the most important information I should know about AVANDIA?".
  • Liver problems. It is important for your liver to be working normally when you take AVANDIA. Your doctor should do blood tests to check your liver before you start taking AVANDIA and during treatment as needed. Call your doctor right away if you have unexplained symptoms such as:
    • nausea or vomiting
    • stomach pain
    • unusual or unexplained tiredness
    • loss of appetite
    • dark urine
    • yellowing of your skin or the whites of your eyes.
  • Macular edema (a diabetic eye disease with swelling in the back of the eye). Tell your doctor right away if you have any changes in your vision. Your doctor should check your eyes regularly. Very rarely, some people have had vision changes due to swelling in the back of the eye while taking AVANDIA.
  • Fractures (broken bones), usually in the hand, upper arm or foot. Talk to your doctor for advice on how to keep your bones healthy.
  • Low red blood cell count (anemia).
  • Low blood sugar (hypoglycemia). Lightheadedness, dizziness, shakiness or hunger may mean that your blood sugar is too low. This can happen if you skip meals, if you use another medicine that lowers blood sugar, or if you have certain medical problems. Call your doctor if low blood sugar levels are a problem for you.
  • Ovulation (release of egg from an ovary in a woman) leading to pregnancy. Ovulation may happen in premenopausal women who do not have regular monthly periods. This can increase the chance of pregnancy. See "What should I tell my doctor before taking AVANDIA?".

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.

How should I store AVANDIA?

  • Store AVANDIA at room temperature, 59° to 86°F (15° to 30°C). Keep AVANDIA in the container it comes in.
  • Safely, throw away AVANDIA that is out of date or no longer needed.
  • Keep AVANDIA and all medicines out of the reach of children.

General information about AVANDIA

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.

What are the ingredients in AVANDIA?

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 - pink with "SB" on one side and "2" on the other.
4 mg - orange with "SB" on one side and "4" on the other.
8 mg - red-brown with "SB" on one side and "8" on the other.

AVANDIA is a registered trademark of GlaxoSmithKline. The other brands listed are trademarks of their respective owners and are not trademarks of GlaxoSmithKline. The makers of these brands are not affiliated with and do not endorse GlaxoSmithKline or its products.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Last reviewed on RxList: 11/30/2011
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Avandia Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

ROSIGLITAZONE - ORAL

(ROE-si-GLI-ta-zone)

COMMON BRAND NAME(S): Avandia

WARNING: This medication may infrequently cause or worsen certain heart problems (congestive heart failure, heart attack). Seek immediate medical attention if you notice any symptoms of heart problems, including: swelling of the hands/feet, unusual/sudden weight gain, trouble breathing, chest pain/discomfort.

USES: Rosiglitazone is an anti-diabetic drug (thiazolidinedione-type, also called "glitazones") used with a proper diet and exercise program to control high blood sugar in patients with type 2 diabetes (non-insulin-dependent diabetes). You should only begin taking rosiglitazone when other drugs have not worked well or cannot be taken, and you do not wish to take pioglitazone-containing medications. If you are currently taking rosiglitazone and have good control of your blood sugars and no new side effects/symptoms, continue to take this drug as directed. Ask your doctor promptly about the risks and benefits of this drug, since a small number of people have had serious side effects (see Warning Section).

After November 18, 2011, only patients enrolled in the Avandia-Rosiglitazone Medicines Access Program may obtain and use rosiglitazone-containing products. Your doctor will need to register you with this program before you can receive your prescription. Only physicians enrolled in the Avandia-Rosiglitazone Medicines Access Program may prescribe rosiglitazone-containing products, and only certified mail-order pharmacies enrolled in the program may dispense them. Talk to your doctor or pharmacist for more details about the program.

Rosiglitazone works by helping to restore your body's proper response to insulin, thereby lowering your blood sugar. Controlling high blood sugar helps prevent kidney damage, blindness, nerve problems, loss of limbs, and sexual function problems. Proper control of diabetes may also lessen your risk of a heart attack or stroke.

HOW TO USE: Read the Medication Guide and, if available, the Patient Information Leaflet provided by your pharmacist before you start using rosiglitazone and each time you get a refill. If you have any questions regarding the information, consult your doctor or pharmacist.

Take this medication by mouth, with or without food, usually once or twice daily, or as directed by your doctor. Dosage is based on your medical condition, response to therapy, and if you are taking other anti-diabetic drugs.

Use this medication regularly in order to get the most benefit from it. Remember to use it at the same time(s) each day. Monitor blood glucose levels on a regular basis.

It may take up to 2 to 3 months before the full benefit of this drug takes effect.

Take all other medications for diabetes as directed by your doctor.

Disclaimer

Avandia Consumer (continued)

SIDE EFFECTS: See also Warning section.

Headache or cough may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: fast/pounding heartbeat, changes in menstrual cycles, bone fracture.

Tell your doctor immediately if any of these highly unlikely but very serious side effects occur: dark urine, yellowing of eyes/skin, persistent nausea/vomiting, stomach/abdominal pain, vision changes (e.g., color or night vision problems).

This medication usually does not cause low blood sugar (hypoglycemia), but this effect may occur if you do not consume enough calories (from food, juices, fruit, etc.). The symptoms include chills, cold sweat, dizziness, drowsiness, shaking, rapid heart rate, weakness, headache, fainting, tingling of the hands or feet, or hunger. It is a good habit to carry glucose tablets or gel to treat low blood sugar. If you are in a situation where you don't have these reliable forms of glucose, eat a quick source of sugar such as table sugar, honey, or candy, or drink a glass of orange juice or non-diet soda to quickly raise your blood sugar level. Tell your doctor immediately about the reaction. To help prevent hypoglycemia, eat meals on a regular schedule and do not skip meals.

Symptoms of high blood sugar (hyperglycemia) include thirst, increased urination, confusion, drowsiness, flushing, rapid breathing, or fruity breath odor. If these symptoms occur, tell your doctor immediately. Your medication dosage may need to be increased.

A serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction include: rash, itching/swelling (especially of the face/tongue/throat), dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Avandia (rosiglitazone maleate) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before taking rosiglitazone, tell your doctor or pharmacist if you are allergic to it; or to other "glitazones" such as pioglitazone; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Promptly talk with your doctor or pharmacist about the benefits and possible risks of this medication, even if you have been taking it for awhile, especially if you have heart problems. Do not stop taking it unless directed to do so.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: type 1 diabetes (insulin-dependent diabetes), very high blood glucose (diabetic ketoacidosis), newly diagnosed or worsening heart failure (acute congestive heart failure), history of liver disease, active liver disease.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: heart disease (e.g., chronic congestive heart failure, heart attack, angina), fluid in your lungs, swelling (edema), anemia, high blood cholesterol, eye (retina) problems, bone problems (e.g., osteoporosis, osteopenia).

You may experience blurred vision, dizziness, or drowsiness due to extremely low or high blood sugar levels. Do not drive, use machinery, or do any activity that requires alertness or clear vision until you are sure you can perform such activities safely.

Limit alcohol while taking this medication because it can increase the risk of your blood sugar getting too low (hypoglycemia).

During times of stress, such as fever, infection, injury or surgery, it may be more difficult to control your blood sugar. Consult your doctor, as additional medication may be required.

This medication may increase the risk of bone fracture (upper arm, hand, foot) in female patients. To lower the chance of getting injured, use caution when doing activities such as contact sports.

This medication can cause changes in the menstrual cycle (ovulation) in women with certain fertility problems. Consult your doctor or pharmacist about the use of reliable birth control while taking this medication.

This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor. Your doctor may substitute insulin for this drug during your pregnancy. Follow all instructions carefully.

It is unknown if this medication passes into breast milk. Consult your doctor before breast-feeding.

Disclaimer

Avandia Consumer (continued)

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: insulin, gemfibrozil, herbal/natural products (e.g., fenugreek, ginseng, gymnema), nitrates (e.g., isosorbide dinitrate), quinolone antibiotics (e.g., ciprofloxacin).

Beta-blocker medications (e.g., metoprolol, propranolol, glaucoma eye drops such as timolol) may prevent the fast/pounding heartbeat you would usually feel when your blood sugar level falls too low (hypoglycemia). Other symptoms of low blood sugar such as dizziness, hunger, or sweating are unaffected by these drugs.

Many drugs can affect your blood sugar levels, making it more difficult to control your blood sugar. Before you start, stop, or change any medication, talk with your doctor or pharmacist about how the medication may affect your blood sugar. Check your blood sugar levels regularly as directed by your doctor. Tell your doctor about the results and of any symptoms of high or low blood sugar. (See also Side Effects section.) Your doctor may need to adjust your anti-diabetic medication, exercise program, or diet.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: Do not share this medication with others.

It is recommended you attend a diabetes education program to understand diabetes and all the important aspects of its treatment including meals/diet, exercise, personal hygiene, medications and getting regular eye, foot and medical exams.

Lifestyle changes that help promote healthy bones include increasing weight-bearing exercise, eating well-balanced meals containing adequate calcium and vitamin D, stopping smoking, and limiting alcohol. Consult your doctor to see if you need to take calcium/vitamin D supplements and discuss lifestyle changes that might benefit you.

Keep all medical appointments. Laboratory and/or medical tests (e.g., liver and kidney function tests, fasting blood glucose, hemoglobin A1c, complete blood counts, blood cholesterol levels) will be performed to monitor for side effects and response to therapy. Regularly check your blood or urine for sugar, as directed by your doctor or pharmacist.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised May 2012. Copyright(c) 2012 First Databank, Inc.

Avandia Patient Information Including Side Effects

Brand Names: Avandia

Generic Name: rosiglitazone (Pronunciation: row zi GLI ta zone)

What is rosiglitazone (Avandia)?

Rosiglitazone is an oral diabetes medicine that helps control blood sugar levels.

Rosiglitazone is for people with type 2 (non-insulin-dependent) diabetes. Rosiglitazone is sometimes used in combination with other medicines, but it is not for treating type 1 diabetes.

Rosiglitazone is not recommended for use with insulin.

Taking rosiglitazone may increase your risk of serious heart problems, such as heart attack or stroke. Therefore, rosiglitazone is available only to certain people with type 2 diabetes that cannot be controlled with other diabetes medications.

Rosiglitazone is available only under a special program called Avandia-Rosiglitazone Medicines Access Program. You must be registered in the program and sign documents stating that you understand the risks and benefits of taking this medication.

Rosiglitazone may also be used for purposes not listed in this medication guide.

Avandia 2 mg

pentagonal, pink, imprinted with SB, 2

Avandia 4 mg

pentagonal, orange, orange, imprinted with SB, 4

Avandia 8 mg

pentagonal, brown, imprinted with SB, 8, SKB

What are the possible side effects of rosiglitazone (Avandia)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using rosiglitazone and call your doctor at once if you have a serious side effect such as:

  • feeling short of breath, even with mild exertion;
  • swelling or rapid weight gain;
  • chest pain or heavy feeling, pain spreading to the arm or shoulder, sweating, general ill feeling;
  • nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
  • blurred vision;
  • increased thirst or hunger, urinating more than usual; or
  • pale skin, easy bruising or bleeding, weakness.

Less serious side effects may include:

  • cold symptoms such as stuffy nose, sneezing, sore throat;
  • headache; or
  • back pain.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Avandia (rosiglitazone maleate) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about rosiglitazone (Avandia)?

Taking rosiglitazone may increase your risk of serious heart problems, such as heart attack or stroke. Therefore, rosiglitazone is available only to certain people with type 2 diabetes that cannot be controlled with other diabetes medications.

Rosiglitazone is available only under a special program called Avandia-Rosiglitazone Medicines Access Program. You must be registered in the program and sign documents stating that you understand the risks and benefits of taking this medication.

Do not use rosiglitazone if you have type 1 diabetes, or if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin).

Before taking rosiglitazone, tell your doctor if you have congestive heart failure or heart disease, a history of heart attack or stroke, liver disease, or eye problems caused by diabetes.

Know the signs of low blood sugar (hypoglycemia) and how to recognize them: headache, hunger, weakness, sweating, tremors, irritability, or trouble concentrating.

Women may also be more likely than men to have bone fractures in the upper arm, hand, or foot while taking rosiglitazone. Talk with your doctor if you are concerned about this possibility.

Side Effects Centers

Avandia Patient Information including How Should I Take

What should I discuss with my healthcare provider before taking rosiglitazone (Avandia)?

Do not use rosiglitazone if you have type 1 diabetes, or if you are in a state of diabetic ketoacidosis (call your doctor for treatment with insulin).

To make sure you can safely take rosiglitazone, tell your doctor if you have any of these other conditions:

  • congestive heart failure or heart disease;
  • a history of heart attack or stroke;
  • liver disease; or
  • eye problems caused by diabetes.

Women may be more likely than men to have bone fractures in the upper arm, hand, or foot while taking rosiglitazone. Talk with your doctor if you are concerned about this possibility.

FDA pregnancy category C. It is not known whether rosiglitazone will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

Some women using rosiglitazone have started having menstrual periods, even after not having a period for a long time due to a medical condition. You may be able to get pregnant if your periods restart. Talk with your doctor about the need for birth control.

It is not known whether rosiglitazone passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take rosiglitazone (Avandia)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results.

Rosiglitazone is usually taken in the morning and evening. You may take the medicine with or without food.

Rosiglitazone is only part of a complete program of treatment that also includes diet, exercise, and weight control. Your doctor may also recommend other medicines to treat your diabetes.

Use rosiglitazone regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.

Your blood sugar will need to be checked often, and you may need other blood tests at your doctor's office. Visit your doctor regularly.

Your medication needs may change if you become sick or injured, if you have a serious infection, or if you have any type of surgery. Your doctor may want you to stop taking rosiglitazone for a short time if any of these situations affect you.

Take care not to let your blood sugar get too low. You may have hypoglycemia if you skip a meal, exercise too long, drink alcohol, or are under stress.

Know the signs of low blood sugar (hypoglycemia) and how to recognize them: headache, hunger, weakness, sweating, tremors, irritability, or trouble concentrating.

Always keep a source of sugar available in case you have symptoms of low blood sugar. Sugar sources include orange juice, glucose gel, candy, or milk. If you have severe hypoglycemia and cannot eat or drink, use an injection of glucagon. Your doctor can give you a prescription for a glucagon emergency injection kit and tell you how to give the injection.

Store at room temperature away from moisture, heat, and light.

Side Effects Centers

Avandia Patient Information including If I Miss a Dose

What happens if I miss a dose (Avandia)?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose (Avandia)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Symptoms of severe hypoglycemia include extreme weakness, confusion, tremors, sweating, trouble speaking, blurred vision, nausea, fainting, and seizure (convulsions).

What should I avoid while taking rosiglitazone (Avandia)?

Avoid drinking alcohol. It can lower your blood sugar.

What other drugs will affect rosiglitazone (Avandia)?

You may be more likely to have hyperglycemia (high blood sugar) if you take rosiglitazone with other drugs that can raise blood sugar, such as:

  • isoniazid;
  • diuretics (water pills);
  • steroids (prednisone and others);
  • phenothiazines (Compazine and others);
  • thyroid medicine (Synthroid and others);
  • birth control pills and other hormones;
  • seizure medicines (Dilantin and others); and
  • diet pills or medicines to treat asthma, colds, or allergies.

You may be more likely to have hypoglycemia (low blood sugar) if you take rosiglitazone with other drugs that can lower blood sugar, such as:

  • probenecid (Benemid);
  • some nonsteroidal anti-inflammatory drugs (NSAIDs);
  • aspirin or other salicylates (including Pepto-Bismol);
  • a blood thinner (warfarin, Coumadin, Jantoven, and others);
  • sulfa drugs (Bactrim, Septra, Sulfatrim, SMX-TMP, and others);
  • a monoamine oxidase inhibitor (MAOI); or
  • other oral diabetes medications, especially acarbose (Precose), metformin (Glucophage), miglitol (Glyset), pioglitazone (Actos, Duetact, Actoplus Met), or other drugs that contain rosiglitazone (Avandaryl, Avandamet).

Some medications may interact with rosiglitazone. Tell your doctor if you are using any of the following drugs:

  • delavirdine (Rescriptor);
  • gemfibrozil (Lopid);
  • tolbutamide (Orinase);
  • nicardipine (Cardene);
  • antifungal medications such as fluconazole (Diflucan), ketoconazole (Nizoral), or miconazole (Oravig);
  • pain or arthritis medicine such as flurbiprofen (Ansaid), ibuprofen (Advil, Motrin), indomethacin (Indocin), mefenamic acid (Ponstel), or piroxicam (Feldene);
  • antibiotics such as rifampin (Rifater, Rifadin, Rifamate) or sulfisoxazole (Pediazole, and others); or
  • seizure medicine such as carbamazepine (Carbatrol, Equetro, Tegretol) or phenobarbital (Solfoton).

This list is not complete and other drugs may interact with rosiglitazone. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

Your pharmacist has additional information about rosiglitazone written for health professionals that you may read.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 13.01. Revision date: 7/29/2011.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

Healthwise

Side Effects Centers

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