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Avandia

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Avandia

Avandia

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Cardiac Failure

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, placebo-controlled 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 to 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)

Events AVANDIA Placebo
N=110
n (%)
N=114
n (%)
Adjudicated    
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%)
Investigator-reported, non-adjudicated    
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.

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

In 7 controlled, randomized, double-blind trials which had durations from 16 to 26 weeks and which were included in a meta-analysis1, 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 AVANDIA plus insulin and insulin groups, respectively.

Heart Failure in Observational Studies of Elderly Diabetic Patients Comparing AVANDIA to AGIOS: Three observational studies2-4 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 ACTOS. One other observational study5 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 ACTOS in the older subgroup.

Major Adverse Cardiovascular Events

Cardiovascular adverse events have been evaluated in a meta-analysis of 52 clinical trials, in long-term, prospective, randomized, controlled trials, and in observational studies.

Meta-Analysis of Major Adverse Cardiovascular Events in a Group of 52 Clinical Trials: A meta-analysis was conducted retrospectively to assess cardiovascular adverse events reported across 52 double-blind, randomized, controlled clinical trials (mean duration 6 months).1 These trials had been conducted to assess glucose-lowering efficacy in type 2 diabetes. Prospectively planned adjudication of cardiovascular events did not occur in most of the trials. Some trials were placebo-controlled and some used active oral antidiabetic drugs as controls. Placebo-controlled trials included monotherapy trials (monotherapy with AVANDIA versus placebo monotherapy) and add-on trials (AVANDIA or placebo, added to sulfonylurea, metformin, or insulin). Active control trials included monotherapy trials (monotherapy with AVANDIA versus sulfonylurea or metformin monotherapy) and add-on trials (AVANDIA plus sulfonylurea or AVANDIA plus metformin, versus sulfonylurea plus metformin). A total of 16,995 patients were included (10,039 in treatment groups containing AVANDIA, 6,956 in comparator groups), with 5,167 patient-years of exposure to AVANDIA and 3,637 patient-years of exposure to comparator. Cardiovascular events occurred more frequently for patients who received AVANDIA than for patients who received comparators (see Table 2).

Table 2. Occurrence of Cardiovascular Events in a Meta-Analysis of 52 Clinical Trials

Eventa AVANDIA
(Rosiglitazone)
(N = 10,039)
n (%)
Comparator
(N = 6,956)
n (%)
MACE (a composite of myocardial infarction, cardiovascular death, or stroke) 70 (0.7) 39 (0.6)
Myocardial Infarction 45 (0.4) 20 (0.3)
Cardiovascular Death 17 (0.2) 9(0.1)
Stroke 18(0.2) 16(0.2)
All-cause Death 29 (0.3) 17 (0.2)
a Events are not exclusive: i.e., a patient with a cardiovascular death due to a myocardial infarction would be counted in 4 event categories (myocardial infarction; myocardial infarction, cardiovascular death, or stroke; cardiovascular death; all-cause death).

In this analysis, a statistically significant increased risk of myocardial infarction with AVANDIA versus pooled comparators was observed. Analyses were performed using a composite of major adverse cardiovascular events (myocardial infarction, stroke, and cardiovascular death), referred to hereafter as MACE. AVANDIA had a statistically nonsignificant increased risk of MACE compared to the pooled comparators. A statistically significant increased risk of myocardial infarction and statistically non-significant increased risk of MACE with AVANDIA was observed in the placebo-controlled trials. In the active-controlled trials, there was no increased risk of myocardial infarction or MACE. (See Figure 1 and Table 3.)

Figure 1. Forest Plot of Odds Ratios (95% Confidence Intervals) for MACE and Myocardial Infarction in the Meta-Analysis of 52 Clinical Trials

Forest Plot of Odds Ratios - Illustration

Table 3. Occurrence of MACE and Myocardial Infarction in a Meta-Analysis of 52 Clinical Trials by Trial Type

    MACE Myocardial Infarction
N n (%) OR
(95% CI)
n (%) OR
(95% CI)
Active-Controlled Trials RSG 2,119 16 (0.8%) 1.05
(0.48, 2.34)
10 (0.5%) 1.00
(0.36, 2.82)
Control 1,918 14 (0.7%) 9 (0.5%)
Placebo-Controlled Trials RSG 8,124 54 (0.7%) 1.53
(0.94, 2.54)
35 (0.4%) 2.23
(1.14,4.64)
Placebo 5,636 28 (0.5%) 13 (0.2%)
Overall RSG 10,039 70 (0.7%) 1.44
(0.95, 2.20)
45 (0.4%) 1.8
(1.03,3.25)
Control 6,956 39 (0.6%) 20 (0.3%)
RSG = AVANDIA (rosiglitazone)

Of the placebo-controlled trials in the meta-analysis, 7 trials had patients randomized to ANDIA plus insulin or insulin. There were more patients in the AVANDIA plus insulin group compared to the insulin group with myocardial infarctions, MACE, cardiovascular deaths, and all-cause deaths (see Table 4). The total number of patients with stroke was 5 (0.5%) and 4 (0.5%) in the AVANDIA plus insulin and insulin groups, respectively. The use of AVANDIA in combination with insulin may increase the risk of myocardial infarction.

Table 4. Occurrence of Cardiovascular Events for AVANDIA in Combination With Insulin in a Meta-Analysis of 52 Clinical Trials

Eventa AVANDIA
(Rosiglitazone)
(N=l,018)
(%)
Insulin
(N = 815) (%)
OR
(95% CI)
MACE (a composite of myocardial infarction, cardiovascular death, or stroke) 1.3 0.6 2.14 (0.70, 7.83)
Myocardial infarction 0.6 0.1 5.6 (0.67, 262.7)
Cardiovascular death 0.4 0.0 ND, (0.47, ∞)
All cause death 0.6 0.2 2.19 (0.38, 22.61)
ND = not defined
a Events are not exclusive: i.e., a patient with a cardiovascular death due to a myocardial infarction would be counted in 4 event categories (myocardial infarction; myocardial infarction, cardiovascular death, or stroke; cardiovascular death; all-cause death).

Myocardial Infarction Events in Large, Long-Term, Prospective, Randomized, Controlled Trials of AVANDIA: Data from 3 large, long-term, prospective, randomized, controlled clinical trials of AVANDIA were assessed separately from the meta-analysis.6-8 These 3 trials included a total of 14,067 patients (treatment groups containing AVANDIA N = 6,311; comparator groups N = 7,756), with patient-year exposure of 24,534 patient-years for AVANDIA and 28,882 patient-years for comparator. Patient populations in the trials included patients with impaired glucose tolerance, patients with type 2 diabetes who were initiating oral agent monotherapy, and patients with type 2 diabetes who had failed monotherapy and were initiating dual oral agent therapy. Duration of follow-up exceeded 3 years in each trial.

In each of these trials, there was a statistically non-significant increase in the risk of myocardial infarction for AVANDIA versus comparator medications.

In a long-term, randomized, placebo-controlled, 2x2 factorial trial intended to evaluate AVANDIA, and separately ramipril (an angiotensin converting enzyme inhibitor [ACEI]), on progression to overt diabetes in 5,269 subjects with glucose intolerance, the incidence of myocardial infarction was higher in the subset of subjects who received AVANDIA in combination with ramipril than among subjects who received ramipril alone but not in the subset of subjects who received AVANDIA alone compared to placebo.6 The higher incidence of myocardial infarction among subjects who received AVANDIA in combination with ramipril was not confirmed in the two other large (total N = 8,798) long-term, randomized, active-controlled clinical trials conducted in patients with type 2 diabetes, in which 30% and 40% of patients in the two trials reported angiotensin-converting enzyme inhibitor use at baseline.7,8

There have been no adequately designed clinical trials directly comparing AVANDIA to ACTOS (pioglitazone) on cardiovascular risks. However, in a long-term, randomized, placebo-controlled cardiovascular outcomes trial comparing ACTOS (pioglitazone) to placebo in patients with type 2 diabetes mellitus and prior macrovascular disease, ACTOS (pioglitazone) was not associated with an increased risk of myocardial infarction or total mortality.9

The increased risk of myocardial infarction observed in the meta-analysis and large, long-term controlled clinical trials, and the increased risk of MACE observed in the meta-analysis described above, have not translated into a consistent finding of excess mortality from controlled clinical trials or observational studies. Clinical trials have not shown any difference between AVANDIA and comparator medications in overall mortality or CV-related mortality.

Mortality in Observational Studies of AVANDIA Compared to ACTOS: 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 ACTOS.2-4 One observational study5 in patients with a mean age of 54 years found no difference in all-cause mortality between patients treated with AVANDIA compared to ACTOS and reported similar results in the subpopulation of patients > 65 years of age. One additional small, prospective, observational study10 found no statistically significant differences for CV mortality and all-cause mortality in patients treated with AVANDIA compared to ACTOS.

Rosiglitazone REMS (Risk Evaluation and Mitigation Strategy) Program

Because of the potential increased risk of myocardial infarction, AVANDIA is available only through a restricted distribution program called the AVANDIA-Rosiglitazone Medicines Access Program [see INDICATIONS]. Both prescribers and patients must enroll in the program to be able to prescribe or receive AVANDIA, respectively. AVANDIA will be available only from specially certified pharmacies participating in the program. As part of the program, prescribers will be educated about the potential increased risk of myocardial infarction and the need to limit the use of AVANDIA to eligible patients. Prescribers will need to discuss with patients the risks and benefits of taking AVANDIA. To enroll, call 1-800-AVANDIA or visit www.AVANDIA.com.

Edema

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 to 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 and 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].

Weight Gain

Dose-related weight gain was seen with AVANDIA alone and in combination with other hypoglycemic agents (Table 5). 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 5. Weight Changes (kg) From Baseline at Endpoint During Clinical Trials

    Control Group AVANDIA
4 ing
AVANDIA
8 ing
Monotherapy Duration   Median
(25th, 75* percentile)
Median
(25th, 75th percentile)
Median
(25th, 75th percentile)
  26 weeks placebo -0.9 (-2.8, 0.9)
N = 210
1.0 (-0.9, 3.6)
N = 436
3.1(1.1,5.8)
N = 439
  52 weeks Sulfonylurea 2.0 (0, 4.0)
N=173
2.0 (-0.6, 4.0)
N=150
2.6 (0, 5.3)
N=157
Combination therapy
Sulfonylurea 24-26 weeks Sulfonylurea 0 (-1.0, 1.3)
N= 1,155
2.2 (0.5, 4.0)
N = 613
3.5(1.4,5.9)
N=841
Metformin 26 weeks metformin -1.4 (-3.2, 0.2)
N=175
0.8 (-1.0, 2.6)
N=100
2.1(0,4.3)
N=184
Insulin 26 weeks insulin 0.9 (-0.5, 2.7)
N=162
4.1(1.4,6.3)
N=164
5.4 (3.4, 7.3)
N=150
Sulfonylurea + metformin 26 weeks Sulfonylurea + metformin 0.2 (-1.2, 1.6)
N = 272
2.5 (0.8, 4.6)
N = 275
4.5 (2.4, 7.3)
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.

Hepatic Effects

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

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 their thiazolidinedione. 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]

Fractures

In a 4- to 6-year comparative trial (ADOPT) of glycemic control with monotherapy in drug-naive patients recently diagnosed with type 2 diabetes mellitus, an increased incidence of bone fracture was noted in female patients taking AVANDIA. Over the 4- to 6-year period, the incidence of bone fracture in females was 9.3% (60/645) for AVANDIA versus 3.5% (21/605) for glyburide and 5.1% (30/590) for metformin. 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.

Hematologic Effects

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 HbAlc measurements should be performed to monitor therapeutic response.

Ovulation

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

See Medication Guide.

Patient Advice

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 risks and benefits of AVANDIA. AVANDIA should only be taken by adults with type 2 diabetes who are already taking AVANDIA, or who are not already taking AVANDIA and are unable to achieve adequate glycemic control on other diabetes medications, and, in consultation with their healthcare provider, have decided not to take pioglitazone (ACTOS) for medical reasons. Inform patients that they must be enrolled in the AVANDIA-Rosiglitazone Medicines Access Program in order to receive AVANDIA.

Patients should be informed of the following:

  • AVANDIA is not recommended for patients with symptomatic heart failure.
  • Results of a set of clinical trials suggest that treatment with AVANDIA is associated with an increased risk for myocardial infarction (heart attack), especially in patients taking insulin. Clinical trials have not shown any difference between AVANDIA and comparator medications in overall mortality or CV-related mortality.
  • 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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: A 2-year carcinogenicity study was conducted in Charles River CD-I 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.

Mutagenesis: 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

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.

Human Data: 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 not be used during pregnancy.

Animal Studies: 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.

Nursing Mothers

Drug-related material was detected in milk from lactating rats. It is not known whether AVANDLA is excreted in human milk. Because many drugs are excreted in human milk, AVANDIA should not be administered to a nursing woman.

Pediatric Use

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/m2, 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 HbAlc 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 8).

Table 8. Week 24 FPG and HbAlc Change From Baseline Last-Observation-Carried Forward in Children With Baseline HbAlc > 6.5%

  Naive Patients Previously-Treated Patients
Metformin Rosiglitazone Metformin Rosiglitazone
N = 40 N = 45 N = 43 N = 32
FPG (mg/dL)
Baseline (mean) 170 165 221 205
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%
HbAlc (%)
Baseline (mean) 8.3 8.2 8.8 8.5
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 HbAlc, gender, and region.
b Positive 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

Mean HbAlc Over Time in a 24-Week Trial - Illustration

Geriatric Use

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.

REFERENCES

1. Food and Drug Administration Briefing Document. Joint meeting of the Endocrinologic and Metabolic Drugs and Drug Safety and Risk Management Advisory Committees. July 13-14, 2010.

2. Winkelmayer WC, et al. Comparison of cardiovascular outcomes in elderly patients with diabetes who initiated rosiglitazone vs pioglitazone therapy. Arch Intern Med 2008;168(21):2368-2375.

3. Juurlink DN, et al. Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study. BMJ 2009; 339.

4. Graham DJ, et al. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly medicare patients treated with rosiglitazone or pioglitazone. JAMA 2010;304:411-418.

5. Wertz DA, et al. Risk of cardiovascular events and all-cause mortality in patients with Thiazolidinediones in a managed-care population. Circ Cardiovasc Qual Outcomes 2010;3: 538-545.

6. DREAM Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006;368:1096-1105.

7. Kahn S, et al. Glycemic durability of rosiglitazone, metformin or glyburide monotherapy. New England Journal of Medicine 2006, 355:2427-2443.

8. Home P, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicenter, randomized, open-label trial. Lancet 2009, 373:2125-35.

9. Dormandy J et al. Secondary prevention of macro vascular events in patients with type 2 diabetes in the PROactive study (Prospective Pioglitazone Clinical Trial in Macrovascular Events): a randomized controlled trial. Lancet 2005, 366:1279-89.

10. Bilik D, et al. Thiazolidinediones, cardiovascular disease and cardiovascular mortality: translating research into action for diabetes (TRIAD). Pharmocoepidemiol Drug Saf 2010; 19:715-721.

Last reviewed on RxList: 11/30/2011
This monograph has been modified to include the generic and brand name in many instances.

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