"June 28, 2010 -- Older patients who take Avandia have a higher risk of death, heart failure, and stroke than patients taking Actos, a similar diabetes drug, a new study finds.
It's far from the first study to address Avandia safety, but"...
Avandia Side Effects Center
Medical Editor: John P. Cunha, DO, FACOEP
Avandia (rosiglitazone maleate) is an oral diabetes medicine that helps control blood sugar levels. It is for people with type 2 (non-insulin-dependent) diabetes. Avandia is sometimes used in combination with insulin or other medications, but it is not for treating type 1 diabetes. Avandia is not recommended for use with insulin. Common side effects include headache or cough.
Avandia is administered at a starting dose of 4 mg either as a single daily dose or in 2 divided doses. The dose may be increased by a physician to 8 mg daily in patients who did not respond to lower doses. Drugs that can raise blood sugar such as isoniazid, diuretics (water pills), steroids, phenothiazines, thyroid medicine, birth control pills and other hormones, seizure medicines, and diet pills or medicines to treat asthma, colds or allergies can lead to hyperglycemia (high blood sugar) when taken with Avandia. Drugs that lower blood sugar such as non-steroidal anti-inflammatory drugs (NSAIDs), aspirin or other salicylates, sulfa drugs, monoamine oxidase inhibitors (MAOIs), beta-blockers, or probenecid may lead to hypoglycemia (low blood sugar) when taken with Avandia. Other medications that may interfere with Avandia include gemfibrozil, rifampin, and nitrate drugs for chest pain or heart problems. Tell your doctor all medications you are taking. Avandia should be used only when prescribed during pregnancy. It is unknown if this medication passes into breast milk. Consult your doctor before breast-feeding.
Our Avandia (rosiglitazone maleate) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.
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.
What is Patient Information in Detail?
Easy-to-read and understand detailed drug information and pill images for the patient or caregiver from Cerner Multum.
Avandia in Detail - Patient Information: Side Effects
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 entire detailed patient monograph for Avandia (Rosiglitazone Maleate) »
What is Patient Information Overview?
A concise overview of the drug for the patient or caregiver from First DataBank.
Avandia Overview - Patient Information: Side Effects
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 entire patient information overview for Avandia (Rosiglitazone Maleate)»
What is Prescribing information?
The FDA package insert formatted in easy-to-find categories for health professionals and clinicians.
Avandia FDA Prescribing Information: Side Effects
The following adverse reactions are discussed in more detail elsewhere in the labeling:
- Cardiac Failure [see WARNINGS AND PRECAUTIONS]
- Major Adverse Cardiovascular Events [see WARNINGS AND PRECAUTIONS]
- Edema [see WARNINGS AND PRECAUTIONS]
- Weight Gain [see WARNINGS AND PRECAUTIONS]
- Hepatic Effects [see WARNINGS AND PRECAUTIONS]
- Macular Edema [see WARNINGS AND PRECAUTIONS]
- Fractures [see WARNINGS AND PRECAUTIONS]
- Hematologic Effects [see WARNINGS AND PRECAUTIONS]
- Ovul ati on [see WARNINGS AND PRECAUTIONS]
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
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 3.
Table 3: Adverse Events (≥5% in any Treatment
Group) Reported by Patients in Short terma Double-blind Clinical Trials With AVANDIA as Monotherapy
|Preferred Term||Clinical Trials With AVANDIA as Monotherapy|
N = 2,526 %
N = 601 %
N = 225 %
N = 626 %
|Upper respiratory tract infection||9.9||8.7||8.9||7.3|
|a Short-term trials ranged from 8 weeks to 1
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 with 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 with 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 with 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 with other combinations, with the exception of insulin. Edema was reported in 14.7% of patients receiving AVANDIA in the insulin combination trials compared with 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, 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 4 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 with 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 4: 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)
N = 1,456
PY = 4,954
N = 1,441
PY = 4,244
N = 1,454
PY = 4,906
|Upper respiratory tract infection||4.3||5.0||4.7|
Long-term Trial of AVANDIA as Combination Therapy (RECORD): RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes) was a multicenter, randomized, open-label, non-inferiority trial in subjects with type 2 diabetes inadequately controlled on maximum doses of metformin or sulfonylurea (glyburide, gliclazide, or glimepiride) to compare the time to reach the combined cardiovascular endpoint of cardiovascular death or cardiovascular hospitalization between patients randomized to the addition of AVANDIA versus metformin or sulfonylurea. The trial included patients who have failed metformin or sulfonylurea monotherapy; those who failed metformin (n = 2,222) were randomized to receive either AVANDIA as add-on therapy (n = 1,117) or add-on sulfonylurea (n = 1,105), and those who failed sulfonylurea (n = 2,225) were randomized to receive either AVANDIA as add-on therapy (n = 1,103) or add-on metformin (n = 1,122). Patients were treated to target HbA1c ≤ 7% throughout the trial.
The mean age of patients in this trial was 58 years, 52% were male, and the mean duration of follow-up was 5.5 years. AVANDIA demonstrated non-inferiority to active control for the primary endpoint of cardiovascular hospitalization or cardiovascular death (HR 0.99, 95% CI: 0.85-1.16). There were no significant differences between groups for secondary endpoints with the exception of congestive heart failure (see Table 5). The incidence of congestive heart failure was significantly greater among patients randomized to AVANDIA.
Table 5: Cardiovascular (CV) Outcomes for the RECORD
N = 2,220
l N = 2,227
|Hazard Ratio||95% CI|
|CV death or CV hospitalization||321||323||0.99||0.85-1.16|
|CV death, myocardial infarction, or stroke||154||165||0.93||0.74-1.15|
There was an increased incidence of bone fracture for subjects randomized to AVANDIA in addition to metformin or sulfonylurea compared with those randomized to metformin plus sulfonylurea (8.3% versus 5.3%) [see WARNINGS AND PRECAUTIONS]. The majority of fractures were reported in the upper limbs and distal lower limbs. The risk of fracture appeared to be higher in females relative to control (11.5% versus 6.3%), than in males relative to control (5.3% versus 4.3%). Additional data are necessary to determine whether there is an increased risk of fracture in males after a longer period of follow-up.
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 approximately 300 mg/dL, 2+ ketonuria, and an elevated anion gap.
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.
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 druginduced hepatotoxicity.
In pre-approval controlled trials, 0.2% of patients treated with AVANDIA had elevations in ALT >3X the upper limit of normal compared with 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).
In the RECORD trial, patients randomized to AVANDIA in addition to metformin or sulfonylurea (10,849 patient-years exposure) and to metformin plus sulfonylurea (10,209 patientyears exposure) had a rate of ALT increase to ≥3X upper limit of normal of approximately 0.2 and 0.3 per 100 patient-years exposure, respectively.
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, 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 [see CONTRAINDICATIONS, and new onset or worsening diabetic macular edema with decreased visual acuity [see WARNINGS AND PRECAUTIONS].
Read the entire FDA prescribing information for Avandia (Rosiglitazone Maleate) »
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