Rosiglitazone Side Effects

Brand Names: Avandia

Please note - some side effects for Rosiglitazone may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Rosiglitazone - for the Consumer

Rosiglitazone

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Rosiglitazone:

Cold-like symptoms; headache.

Seek medical attention right away if any of these SEVERE side effects occur when using Rosiglitazone:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); blurred vision or other vision changes; chest, jaw, or arm pain or discomfort; fainting; lightheadedness; numbness of an arm or leg; red, swollen, blistered, or peeling skin; severe headache, stomach pain, or vomiting; symptoms of heart failure (eg, shortness of breath; sudden, unexplained weight gain; swelling of the hands, ankles, legs, or feet); symptoms of liver problems (eg, dark urine; yellowing of the skin or eyes; unexplained nausea, vomiting, or loss of appetite; stomach pain); symptoms of low blood sugar (eg, anxiety, increased sweating, dizziness or drowsiness, headache, chills, tremors, increased hunger); unusual bone pain (especially in the hand, foot, or upper arm); unusual tiredness or weakness.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

Rosiglitazone/Metformin

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Rosiglitazone/Metformin:

Back or joint pain; cold-like symptoms; diarrhea; dizziness; headache; indigestion; nausea; stomach upset; tiredness.

Seek medical attention right away if any of these SEVERE side effects occur when using Rosiglitazone/Metformin:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); blurred vision or other vision changes; chest, jaw, or arm pain or discomfort; dark urine; fainting; fast or difficult breathing; feeling of being unusually cold; fever, chills, or persistent sore throat; general feeling of being unwell; lightheadedness; muscle pain or weakness; numbness of an arm or leg; persistent loss of appetite; red, swollen, blistered, or peeling skin; severe or persistent nausea or vomiting; shortness of breath; slow or irregular heartbeat; sudden, severe headache or dizziness; sudden, unexplained weight gain; swelling of the hands, ankles, legs, or feet; symptoms of low blood sugar (eg, anxiety, increased sweating, dizziness or drowsiness, headache, chills, tremors, increased hunger); unusual bone pain (especially in the hand, foot, or upper arm); unusual stomach pain or discomfort; unusual tiredness or weakness; yellowing of the eyes or skin.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Rosiglitazone Side Effects - for the Professional

Rosiglitazone

Clinical Trial Experience

Adult

In clinical trials, approximately 9,900 patients with type 2 diabetes have been treated with Rosiglitazone maleate.

Short-Term Trials of Rosiglitazone Maleate as Monotherapy and in Combination With Other Hypoglycemic Agents

The incidence and types of adverse events reported in short-term clinical trials of Rosiglitazone maleate as monotherapy are shown in Table 4.

Table 4. Adverse Events (≥5% in Any Treatment Group) Reported by Patients in Short-Term* Double-Blind Clinical Trials With Rosiglitazone Maleate as Monotherapy

Preferred Term	Rosiglitazone maleate  Monotherapy	Placebo	Metformin	Sulfonylureas†
	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
* Short-term trials ranged from 8 weeks to 1 year.
† 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 Rosiglitazone maleate was used in combination with a sulfonylurea or metformin were similar to those during monotherapy with Rosiglitazone maleate.

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 Rosiglitazone maleate.

In double-blind studies, anemia was reported in 1.9% of patients receiving Rosiglitazone maleate 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 ARosiglitazone maleate or in combination with a sulfonylurea (2.3%). Lower pre-treatment hemoglobin/hematocrit levels in patients enrolled in the metformin combination clinical trials may have contributed to the higher reporting rate of anemia in these studies [see Adverse Reactions (6.2)]. 

In clinical trials, edema was reported in 4.8% of patients receiving Rosiglitazone maleate 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 Rosiglitazone maleate 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 Rosiglitazone maleate 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 Rosiglitazone maleate [see Boxed Warning  and Warnings and Precautions (5.3 )].

In controlled combination therapy studies with sulfonylureas, mild to moderate hypoglycemic symptoms, which appear to be dose related, were reported. Few patients were withdrawn for hypoglycemia (<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 Rosiglitazone maleate 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 Rosiglitazone maleate. [See Warnings and Precautions (5.10) .]

Long-Term Trial of Rosiglitazone Maleate as Monotherapy

A 4- to 6-year study (ADOPT) compared the use of Rosiglitazone maleate (n = 1,456), glyburide (n = 1,441), and metformin (n = 1,454) as monotherapy in patients recently diagnosed with type 2 diabetes who were not previously treated with antidiabetic medication. Table 5 presents adverse reactions without regard to causality; rates are expressed per 100 patient-years (PY) exposure to account for the differences in exposure to study medication across the 3 treatment groups.

In ADOPT, fractures were reported in a greater number of women treated with Rosiglitazone maleate (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 (5.7 ).] The observed incidence of fractures for male patients was similar among the 3 treatment groups.

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

	Rosiglitazone Maleate	Glyburide	Metformin
	N = 1,456	N = 1,441	N = 1,454
	PY = 4,954	PY = 4,244	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

Rosiglitazone maleate has been evaluated for safety in a single, active-controlled trial of pediatric patients with type 2 diabetes in which 99 were treated with Rosiglitazone maleate and 101 were treated with metformin. The most common adverse reactions (>10%) without regard to causality for either Rosiglitazone maleate or metformin were headache (17% versus 14%), nausea (4% versus 11%), nasopharyngitis (3% versus 12%), and diarrhea (1% versus 13%). In this study, one case of diabetic ketoacidosis was reported in the metformin group. In addition, there were 3 patients in the Rosiglitazone group who had FPG of ∼300 mg/dL, 2+ ketonuria, and an elevated anion gap.

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 studies as much as 1.0 g/dL hemoglobin and as much as 3.3% hematocrit). The changes occurred primarily during the first 3 months following initiation of therapy with AVANDIA or following a dose increase in AVANDIA. The time course and magnitude of decreases were similar in patients treated with a combination of AVANDIA and other hypoglycemic agents or monotherapy with AVANDIA. Pre-treatment levels of hemoglobin and hematocrit were lower in patients in metformin combination studies and may have contributed to the higher reporting rate of anemia. In a single study in pediatric patients, decreases in hemoglobin and hematocrit (mean decreases of 0.29 g/dL and 0.95%, respectively) were reported. Small decreases in hemoglobin and hematocrit have also been reported in pediatric patients treated with AVANDIA. White blood cell counts also decreased slightly in adult patients treated with AVANDIA. Decreases in hematologic parameters may be related to increased plasma volume observed with treatment with AVANDIA.

Lipids

Changes in serum lipids have been observed following treatment with Rosiglitazone maleate in adults [see Clinical Pharmacology (12.2) ]. Small changes in serum lipid parameters were reported in children treated with Rosiglitazone maleate for 24 weeks.

Serum Transaminase Levels

In pre-approval clinical studies in 4,598 patients treated with Rosiglitazone maleate (3,600 patient-years of exposure) and in a long-term 4- to 6-year study in 1,456 patients treated with Rosiglitazone maleate (4,954 patient-years exposure), there was no evidence of drug-induced hepatotoxicity.

In pre-approval controlled trials, 0.2% of patients treated with Rosiglitazone maleate 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 Rosiglitazone maleate were reversible. Hyperbilirubinemia was found in 0.3% of patients treated with Rosiglitazone maleate 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 (5.6).] 

In the 4- to 6-year ADOPT trial, patients treated with Rosiglitazone maleate (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 Rosiglitazone maleate. 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 (5.1)]. 

There are postmarketing reports with Rosiglitazone maleate 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.

Rash, pruritus, urticaria, angioedema, anaphylactic reaction, and Stevens-Johnson syndrome have been reported rarely.

Reports of new onset or worsening diabetic macular edema with decreased visual acuity have also been received [see Warnings and Precautions (5.7)]. 

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Side Effects by Body System - for Healthcare Professionals

General

Rosiglitazone is generally well tolerated with the incidence of adverse effects similar to placebo. Upper respiratory tract infections, injury, headache, back pain and hypoglycemia were reported slightly more frequently than placebo in clinical trials.

Cardiovascular

Healthy volunteers receiving rosiglitazone 8 mg once daily for 8 weeks experienced a statistically significant increase in median plasma volume compared to placebo. Patients with ongoing edema are more likely to have adverse events associated with edema if started on combination therapy with insulin and rosiglitazone.

Dose-related weight gain was seen with rosiglitazone alone and in combination with other hypoglycemic agents. The mechanism is unclear but probably involves a combination of fluid retention and fat accumulation.

In a 26-week study, edema was reported with higher frequency in the rosiglitazone plus insulin combination trials (insulin, 5.4%; and rosiglitazone with insulin 14.7%). Reports of new onset or exacerbation of congestive heart failure occurred at a rate of 1% for insulin alone, and 2% (4 mg) and 3% (8 mg) for insulin in combination with rosiglitazone.

In postmarketing experience, there have been rare reports of usually rapid increases in weight. Patients should be assessed for fluid accumulation and volume-related events such as edema and congestive heart failure.

Cardiovascular side effects have included mild to moderate edema. Patients with congestive heart failure have experienced new or worsening edema. Hypertension has also been reported.

Hematologic

Hematologic side effects have included decreases in hemoglobin and hematocrit. White blood cell counts also decreased slightly.

These changes may be related to the increased plasma volume observed during treatment with rosiglitazone and have not been associated with any significant hematologic clinical effects.

Hepatic

Hepatic side effects have included postmarketing reports of hepatitis and of hepatic enzyme elevations to three or more time the upper limit of normal. Very rarely, reports have involved hepatic failure with and without fatal outcome. Rosiglitazone is structurally related to troglitazone, a thiazolidinedione no longer marketed in the United States, which was associated with idiosyncratic hepatotoxicity and rare cases of liver failure, liver transplants, and death during clinical use. It is recommended that liver enzymes be checked in all patients prior to the initiation of therapy and every two months for the first twelve months and periodically thereafter.

Metabolic

Metabolic side effects have included increases in total cholesterol, LDL, and HDL and decreases in free fatty acids. These changes were statistically significantly different from placebo or glyburide controls. Dose related weight gain has been reported in patients treated with rosiglitazone alone and in combination with other hypoglycemic agents.

Endocrine

Endocrine side effects have included the resumption of ovulation in premenopausal, anovulatory women with insulin resistance. These patients may be at risk for pregnancy if adequate contraception is not used.

Hypersensitivity

Hypersensitivity side effects have included rare postmarketing reports of urticaria and angioedema. Postmarketing experience has included rare reports of anaphylactic reactions.

Ocular

Ocular side effects have included rare postmarketing reports of new onset or worsening (diabetic) macular edema with decreased visual acuity. In some cases, symptoms improved following discontinuation of rosiglitazone. Physicians should consider the possibility of macular edema if a patient reports decreased visual acuity. There is a case report of rosiglitazone induced proptosis.

Dermatologic

Dermatologic side effects have included angioedema and urticaria. Rash, pruritus, and Stevens-Johnson syndrome have been reported rarely postmarketing.

Respiratory

Respiratory side effects have included new or worsening dyspnea in patients with congestive heart failure.

Gastrointestinal

Gastrointestinal side effects have included diarrhea.

Musculoskeletal

Musculoskeletal side effects have included arthralgia and fractures of the upper arm, hand and foot in women.

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