Side Effects of Avandia (rosigliatazone)

Avandia (rosiglitazone) is a type of anti-diabetic drug called a thiazolidinedione that reduces the amount of sugar (glucose) in the blood used to treat patients with type 2 diabetes. 

Insulin is a hormone produced by the pancreas that is important for controlling levels of glucose in the blood. Insulin stimulates the cells of the body to remove glucose from the blood and thereby lowers the level of glucose in the blood. Patients with type 2 diabetes cannot make enough insulin or are resistant to the effects of insulin (insulin resistance). As a result, the cells in their bodies do not remove enough glucose from the blood, and the level of glucose rises.

Avandia often is referred to as an "insulin sensitizer" because it attaches to the insulin receptors on cells throughout the body and causes the cells to become more sensitive to insulin and remove more glucose from the blood. At least some insulin must be produced by the pancreas in order for Avandia to work.

Common side effects of Avandia include

• upper respiratory tract infection,
• headache,
• back pain,
• high blood sugar (hyperglycemia),
• fatigue,
• sinusitis,
• diarrhea,
• low blood sugar (hypoglycemia), and
• weight gain.

Serious side effects of Avandia include mild to moderate accumulation of fluid (edema) that can lead to heart failure, an increased risk of chest pain and heart attacks, anemia (with Avandia alone or combined with metformin), and an increased risk of bone fractures in women who received Avandia for four to six years.

Drug interactions of Avandia include rifampin, which decreases concentrations in the blood of Avandia by increasing its breakdown in the liver. Gemfibrozil increases the concentration of Avandia in the blood by reducing its breakdown in the liver and may increase the side effects of Avandia. Avandia should not be combined with nitrates because the risk of chest pain and heart attacks is greater in individuals on nitrate therapy.

There are no adequate studies of Avandia in pregnant women. Avandia crosses the placenta and is detectable in fetal tissue. It is unknown if Avandia passes into breast milk. The safety of Avandia to nursing infants is unknown. Consult your doctor before breastfeeding.

The most common side effects seen with rosiglitazone alone or in combination with metformin are:

• upper respiratory tract infection,
• headache,
• back pain,
• hyperglycemia (elevated blood sugar),
• fatigue,
• sinusitis,
• diarrhea, and
• hypoglycemia (low blood sugar).

Rosiglitazone has been shown to cause mild to moderate accumulation of fluid (edema) and can lead to heart failure. Patients who already have heart failure may develop worsening symptoms with rosiglitazone. Therefore, rosiglitazone should not be used by patients with heart failure. Rosiglitazone also has been associated with an increased risk of chest pain and heart attacks. The risk of heart attacks may be greater in those with established heart disease and taking nitrates or individuals receiving insulin.

Other important side effects include:

• anemia with rosiglitazone alone or combined with metformin.
• weight gain, and
• Increased risk of bone fractures in women who received rosiglitazone for 4 to 6 years.

• Cardiac Failure
• Major Adverse Cardiovascular Events
• Edema
• Weight Gain
• Hepatic Effects
• Macular Edema
• Fractures
• Hematologic Effects
• Ovul ati on

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.

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 3.

Table 3: Adverse Events (≥5% in any Treatment Group) Reported by Patients in Short term^a Double-blind Clinical Trials With Avandia as Monotherapy

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.

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.

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. 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)

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 Trial

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%) . 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.

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 approximately 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. 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.

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.

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.

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.

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.