Avandia (Rosiglitazone Maleate) - Side Effects and Adverse Reactions

ADVERSE REACTIONS

Clinical Trial Experience

Adult

In clinical trials, approximately 8,400 patients with type 2 diabetes have been treated with AVANDIA; 6,000 patients were treated for 6 months or longer and 3,000 patients were treated for 12 months or longer.

Trials of AVANDIA as Monotherapy and in Combination With Other Hypoglycemic Agents

The incidence and types of adverse events reported in clinical trials of AVANDIA as monotherapy are shown in Table 4.

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

Preferred Term	AVANDIA 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
* 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 studies, anemia was reported in 1.9% of patients receiving AVANDIA as monotherapy compared to 0.7% on placebo, 0.6% on sulfonylureas, and 2.2% on metformin. Reports of anemia were greater in patients treated with a combination of AVANDIA and metformin (7.1%) and with a combination of AVANDIA and a sulfonylurea plus metformin (6.7%) compared to monotherapy with AVANDIA or in combination with a sulfonylurea (2.3%). Lower pre-treatment hemoglobin/hematocrit levels in patients enrolled in the metformin combination clinical trials may have contributed to the higher reporting rate of anemia in these studies [see Adverse Reactions].

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].

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 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 (5.10) and Dosage and Administration (2.2).]

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 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 AVANDIA monotherapy. Pre-treatment levels of hemoglobin and hematocrit were lower in patients in metformin combination studies and may have contributed to the higher reporting rate of anemia. In a single study in pediatric patients, decreases in hemoglobin and hematocrit (mean decreases of 0.29 g/dL and 0.95%, respectively) were reported. Small decreases in hemoglobin and hematocrit have also been reported in pediatric patients treated with AVANDIA. White blood cell counts also decreased slightly in adult patients treated with AVANDIA. Decreases in hematologic parameters may be related to increased plasma volume observed with treatment with AVANDIA.

Lipids

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

Serum Transaminase Levels

In clinical studies in 4,598 patients treated with AVANDIA encompassing approximately 3,600 patient years of exposure, there was no evidence of drug-induced hepatotoxicityor elevated ALT levels.

In controlled trials, 0.2% of patients treated with AVANDIA had reversible elevations in ALT >3X the upper limit of normal compared to 0.2% on placebo and 0.5% on active comparators. 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 the clinical program including long-term, open-label experience, the rate of ALT increase (to >3X the upper limit of normal), per 100 patient-years of AVANDIA exposure, was 0.35 for patients treated with AVANDIA, 0.59 for placebo-treated patients, and 0.78 for patients treated with active comparator agents.

In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure. In postmarketing experience with AVANDIA, reports of hepatic enzyme elevations 3 or more times the upper limit of normal and hepatitis have been received [see Warnings and Precautions].

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].

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].

REPORTS OF SIDE EFFECTS / ADVERSE REACTIONS RELATED TO AVANDIA

Possible Avandia side effects / adverse reactions in 87 year old male

Reported by a consumer/non-health professional from United States on 2007-01-04

Patient: 87 year old male weighing 54.5 kg (119.9 pounds)

Reactions: Weight Increased, Fracture

Adverse event resulted in: hospitalization

Suspect drug(s):
Avandia

Other drugs received by patient: Metformin HCL; Glipizide; Lipitor; Lisinopril; Vitamin D; Calcium; Ascorbic Acid; Vicodin; Ferrous Sulfate TAB; Glucosamine Chondroitin; Vitamin CAP

Possible Avandia side effects / adverse reactions in 55 year old female

Reported by a consumer/non-health professional from Finland on 2007-01-10

Patient: 55 year old female

Reactions: Weight Increased, Dyspnoea, Dysphagia, Swelling, Dizziness

Suspect drug(s):
Avandia

Other drugs received by patient: Green TEA

Possible Avandia side effects / adverse reactions in 47 year old male

Reported by a consumer/non-health professional from United States on 2007-01-15

Patient: 47 year old male

Reactions: Neovascularisation, Cataract, Retinal Detachment, Retinal Aneurysm, Retinal Haemorrhage, Vitreous Haemorrhage, Visual Acuity Reduced, Macular Oedema, Colour Blindness, Vitreous Floaters, Retinal Oedema, Diabetic Retinopathy, Vision Blurred

Adverse event resulted in: disablity

Suspect drug(s):
Avandia

Other drugs received by patient: Lipitor; Medication FOR High Blood Pressure; Altace; Glipizide; Pentoxifylline; Glucotrol XL; Moexipril HCL; Univasc; Metformin HCL; Enalapril Maleate; Lovastatin; Tramadol HCL