"The U.S. Food and Drug Administration today announced it has begun a safety review of the diabetes drug Actos (pioglitazone), after receiving preliminary results from a long-term observational study designed to evaluate the risk of bladder cancer"...
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, placebocontrolled, 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 with 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)
N = 110
N = 114
|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%)|
|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.|
In a long-term, cardiovascular outcome trial (RECORD) in patients with type 2 diabetes [see ADVERSE REACTIONS], the incidence of heart failure was higher in patients treated with AVANDIA [2.7% (61/2,220) compared with active control 1.3% (29/2,227), HR 2.10 (95% CI: 1.35, 3.27)].
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 AND USAGE, Major Adverse Cardiovascular Events]
In 7 controlled, randomized, double-blind trials which had durations from 16 to 26 weeks and which were included in a meta-analysis [see Major Adverse Cardiovascular Events], 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 group receiving AVANDIA plus insulin and the insulin group, respectively.
Heart Failure in Observational Studies of Elderly Diabetic Patients Comparing AVANDIA to Pioglitazone
Three observational studies 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 pioglitazone. One other observational study 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 pioglitazone in the older subgroup.
Major Adverse Cardiovascular Events
Data from long-term, prospective, randomized, controlled clinical trials of AVANDIA versus metformin or sulfonylureas, particularly a cardiovascular outcome trial (RECORD), observed no difference in overall mortality or in major adverse cardiovascular events (MACE) and its components. A meta-analysis of mostly short-term trials suggested an increased risk for myocardial infarction with AVANDIA compared with placebo.
Cardiovascular Events in Large, Long-term, Prospective, Randomized, Controlled Trials of AVANDIA
RECORD, a prospectively designed cardiovascular outcome trial (mean follow-up 5.5 years; 4,447 patients), compared the addition of AVANDIA to metformin or a sulfonylurea (N = 2,220) with a control group of metformin plus sulfonylurea (N = 2,227) in patients with type 2 diabetes [see ADVERSE REACTIONS]. Non-inferiority was demonstrated for the primary endpoint, cardiovascular hospitalization or cardiovascular death, for AVANDIA compared with control [HR 0.99 (95% CI: 0.85, 1.16)] demonstrating no overall increased risk in cardiovascular morbidity or mortality. The hazard ratios for total mortality and MACE were consistent with the primary endpoint and the 95% CI similarly excluded a 20% increase in risk for AVANDIA. The hazard ratios for the components of MACE were 0.72 (95% CI: 0.49, 1.06) for stroke, 1.14 (95% CI: 0.80, 1.63) for myocardial infarction, and 0.84 (95% CI: 0.59, 1.18) for cardiovascular death.
The results of RECORD are consistent with the findings of 2 earlier long-term, prospective, randomized, controlled clinical trials (each trial >3 years' duration; total of 9,620 patients) (see Figure 1). In patients with impaired glucose tolerance (DREAM trial), although the incidence of cardiovascular events was higher among subjects who were randomized to AVANDIA in combination with ramipril than among subjects randomized to ramipril alone, no statistically significant differences were observed for MACE and its components between AVANDIA and placebo. In type 2 diabetes patients who were initiating oral agent monotherapy (ADOPT trial), no statistically significant differences were observed for MACE and its components between AVANDIA and metformin or a sulfonylurea.
Figure 1: Hazard Ratios for the Risk of MACE,
Myocardial Infarction, and Total Mortality With AVANDIA Compared With a Control
Group in Long-term Trials
Cardiovascular Events in a Group of 52 Clinical Trials
In a meta-analysis of 52 double-blind, randomized, controlled clinical trials designed to assess glucose-lowering efficacy in type 2 diabetes (mean duration 6 months), a statistically significant increased risk of myocardial infarction with AVANDIA versus pooled comparators was observed [0.4% versus 0.3%; OR 1.8, (95% CI: 1.03, 3.25)]. A statistically non-significant increased risk of MACE was observed with AVANDIA versus pooled comparators (OR 1.44, 95% CI: 0.95, 2.20). In the placebo-controlled trials, a statistically significant increased risk of myocardial infarction [0.4% versus 0.2%, OR 2.23 (95% CI: 1.14, 4.64)] and statistically non-significant increased risk of MACE [0.7% versus 0.5%, OR 1.53 (95% CI: 0.94, 2.54)] with AVANDIA were observed. In the active-controlled trials, there was no increased risk of myocardial infarction or MACE.
Mortality in Observational Studies of AVANDIA Compared to Pioglitazone
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 pioglitazone. One observational study in patients with a mean age of 54 years found no difference in all-cause mortality between patients treated with AVANDIA compared to pioglitazone and reported similar results in the subpopulation of patients >65 years of age. One additional small, prospective, observational study found no statistically significant differences for CV mortality and all-cause mortality in patients treated with AVANDIA compared to pioglitazone.
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 with 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, Cardiac Failure, 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].
Dose-related weight gain was seen with AVANDIA alone and in combination with other hypoglycemic agents (Table 2). 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 2: Weight Changes (kg) From Baseline at Endpoint
During Clinical Trials
|Monotherapy||Duration||Control Group||AVANDIA 4 mg||AVANDIA 8 mg|
(25th, 75th percentiles)
(25th, 75th percentiles)
(25th, 75th percentiles)
N = 210
N = 436
N = 439
N = 173
N = 150
N = 157
N = 1,155
N = 613
N = 841
N = 175
N = 100
N = 184
N = 162
N = 164
N = 150
|Sulfonylurea + metformin||26 weeks||sulfonylurea + metformin||0.2
N = 272
N = 275
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.
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 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 theirthiazolidinedione. 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]
Long-term trials (ADOPT and RECORD) show an increased incidence of bone fracture in patients, particularly female patients, taking AVANDIA [see ADVERSE REACTIONS]. 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.
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 HbA1c measurements should be performed to monitor therapeutic response.
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
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
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 following:
- AVANDIA is not recommended for patients with symptomatic heart failure.
- A meta-analysis of mostly short-term trials suggested an increased risk for myocardial infarction with AVANDIA compared with placebo. Data from long-term clinical trials of AVANDIA versus other antidiabetes agents (metformin or sulfonylureas), including a cardiovascular outcome trial (RECORD), observed no difference in overall mortality or in major adverse cardiovascular events (MACE) and its components.
- 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.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
A 2-year carcinogenicity study was conducted in Charles River CD-1 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.
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 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.
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 be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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.
Drug-related material was detected in milk from lactating rats. It is not known whether AVANDIA is excreted in human milk. Because many drugs are excreted in human milk, a decision should be made whether to discontinue nursing or to discontinue AVANDIA, taking into account the importance of the drug to the mother.
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/m , 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 HbA1c 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 6).
Table 6:Week 24 FPG and HbA1c Change From Baseline
Last-observation—carried Forward in Children With Baseline HbA1c >6.5%
|Parameter||Naive Patients||Previously-treated Patients|
N = 40
N = 45
N = 43
N = 32
|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%|
|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 HbA1c, gender, and region.
bPositive 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
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.
Last reviewed on RxList: 5/27/2014
This monograph has been modified to include the generic and brand name in many instances.
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