Gaudil

Gaudil® is a thiazolidinedione antidiabetic agent indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Important Limitations of Use

• Due to its mechanism of action, Gaudil is active only in the presence of endogenous insulin. Therefore, Gaudil should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
• The coadministration of Gaudil and insulin is not recommended.

Gaudil may be administered at a starting dose of 4 mg either as a single daily dose or in 2 divided doses. For patients who respond inadequately following 8 to 12 weeks of treatment, as determined by reduction in fasting plasma glucose (FPG), the dose may be increased to 8 mg daily. Increases in the dose of Gaudil should be accompanied by careful monitoring for adverse events related to fluid retention. Gaudil may be taken with or without food.

The total daily dose of Gaudil should not exceed 8 mg.

Patients receiving Gaudil 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.

Specific Patient Populations

Renal Impairment

No dosage adjustment is necessary when Gaudil is used as monotherapy in patients with renal impairment. Since metformin is contraindicated in such patients, concomitant administration of metformin and Gaudil is also contraindicated in patients with renal impairment.

Hepatic Impairment

Liver enzymes should be measured prior to initiating treatment with Gaudil. Therapy with Gaudil should not be initiated if the patient exhibits clinical evidence of active liver disease or increased serum transaminase levels (ALT >2.5X upper limit of normal at start of therapy). After initiation of Gaudil, liver enzymes should be monitored periodically per the clinical judgment of the healthcare professional.

Pediatric

Data are insufficient to recommend pediatric use of Gaudil.

• Initiation of Gaudil in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.
• Use in patients with a history of a hypersensitivity reaction to rosiglitazone or any of the product's ingredients.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Cardiac Failure

Gaudil, 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.

Patients with congestive heart failure (CHF) NYHA Class I and II treated with Gaudil 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 Gaudil 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 Gaudil or Placebo (in Addition to Background Antidiabetic and CHF Therapy)

In a long-term, cardiovascular outcome trial (RECORD) in patients with type 2 diabetes , the incidence of heart failure was higher in patients treated with Gaudil [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 Gaudil in patients with established NYHA Class III or IV heart failure is contraindicated. Gaudil is not recommended in patients with symptomatic heart failure.

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 Gaudil is not recommended for patients experiencing an acute coronary event, and discontinuation of Gaudil 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. Gaudil is not recommended in patients with NYHA Class III and IV cardiac status.

Congestive Heart Failure During Coadministration of Gaudil With Insulin

In trials in which Gaudil was added to insulin, Gaudil increased the risk of congestive heart failure. Coadministration of Gaudil and insulin is not recommended.

In 7 controlled, randomized, double-blind trials which had durations from 16 to 26 weeks and which were included in a meta-analysis , patients with type 2 diabetes mellitus were randomized to coadministration of Gaudil and insulin (N = 1,018) or insulin (N = 815). In these 7 trials, Gaudil 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 Gaudil plus insulin and the insulin group, respectively.

Heart Failure in Observational Studies of Elderly Diabetic Patients Comparing Gaudil to Pioglitazone

Three observational studies in elderly diabetic patients (age 65 years and older) found that Gaudil 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 Gaudil compared to pioglitazone in the older subgroup.

Major Adverse Cardiovascular Events

Data from long-term, prospective, randomized, controlled clinical trials of Gaudil 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 Gaudil compared with placebo.

Cardiovascular Events in Large, Long-term, Prospective, Randomized, Controlled Trials of Gaudil

RECORD, a prospectively designed cardiovascular outcome trial (mean follow-up 5.5 years; 4,447 patients), compared the addition of Gaudil 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. Non-inferiority was demonstrated for the primary endpoint, cardiovascular hospitalization or cardiovascular death, for Gaudil 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 Gaudil. 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 Gaudil in combination with ramipril than among subjects randomized to ramipril alone, no statistically significant differences were observed for MACE and its components between Gaudil 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 Gaudil and metformin or a sulfonylurea.

Figure 1: Hazard Ratios for the Risk of MACE, Myocardial Infarction, and Total Mortality With Gaudil 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 Gaudil 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 Gaudil 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 Gaudil were observed. In the active-controlled trials, there was no increased risk of myocardial infarction or MACE.

Mortality in Observational Studies of Gaudil Compared to Pioglitazone

Three observational studies in elderly diabetic patients (age 65 years and older) found that Gaudil 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 Gaudil 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 Gaudil compared to pioglitazone.

Edema

Gaudil should be used with caution in patients with edema. In a clinical trial in healthy volunteers who received 8 mg of Gaudil 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, Gaudil should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure.

In controlled clinical trials of patients with type 2 diabetes, mild to moderate edema was reported in patients treated with Gaudil, 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 Gaudil.

Weight Gain

Dose-related weight gain was seen with Gaudil 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.

Table 2: Weight Changes (kg) From Baseline at Endpoint During Clinical Trials

In a 4- to 6-year, monotherapy, comparative trial (ADOPT) in patients recently diagnosed with type 2 diabetes not previously treated with antidiabetic medication , the median weight change (25th, 75th percentiles) from baseline at 4 years was 3.5 kg (0.0, 8.1) for Gaudil, 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 Gaudil 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 Gaudil in all patients and periodically thereafter per the clinical judgment of the healthcare professional. Therapy with Gaudil 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 Gaudil should be evaluated to determine the cause of the liver enzyme elevation. Initiation of, or continuation of, therapy with Gaudil 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 Gaudil, liver enzyme levels should be rechecked as soon as possible. If ALT levels remain >3X the upper limit of normal, therapy with Gaudil 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 Gaudil should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued.

Macular Edema

Macular edema has been reported in postmarketing experience in some diabetic patients who were taking Gaudil 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.

Fractures

Long-term trials (ADOPT and RECORD) show an increased incidence of bone fracture in patients, particularly female patients, taking Gaudil. 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 Gaudil 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 Gaudil, 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 Gaudil. The observed changes may be related to the increased plasma volume observed with treatment with Gaudil.

Diabetes And Blood Glucose Control

Patients receiving Gaudil 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.

Ovulation

Therapy with Gaudil, 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 Gaudil. 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 , the clinical significance of this finding is not known. If unexpected menstrual dysfunction occurs, the benefits of continued therapy with Gaudil 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:

• Gaudil 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 Gaudil compared with placebo. Data from long-term clinical trials of Gaudil 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.
• Gaudil 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 Gaudil.
• 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 Gaudil should immediately report these symptoms to their physician.
• Gaudil can be taken with or without meals.
• When using Gaudil 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 Gaudil, 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 Gaudil. 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-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.

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. Gaudil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 Gaudil 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 Gaudil, taking into account the importance of the drug to the mother.

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/m , were randomized to treatment with 2 mg twice daily of Gaudil (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 Gaudil 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 Gaudil 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%

Treatment differences depended on baseline BMI or weight such that the effects of Gaudil 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. 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 Gaudil and Metformin in Pediatric Patients — Drug-naive Subgroup

Geriatric Use

Results of the population pharmacokinetic analysis showed that age does not significantly affect the pharmacokinetics of rosiglitazone. 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.

The following adverse reactions are discussed in more detail elsewhere in the labeling:

• 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 Gaudil.

Short-term Trials of Gaudil as Monotherapy and In Combination With Other Hypoglycemic Agents: The incidence and types of adverse events reported in short-term clinical trials of Gaudil 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 Gaudil as Monotherapy

Overall, the types of adverse reactions without regard to causality reported when Gaudil was used in combination with a sulfonylurea or metformin were similar to those during monotherapy with Gaudil.

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 Gaudil.

In double-blind trials, anemia was reported in 1.9% of patients receiving Gaudil 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 Gaudil and metformin (7.1%) and with a combination of Gaudil and a sulfonylurea plus metformin (6.7%) compared with monotherapy with Gaudil 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 Gaudil 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 Gaudil 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 Gaudil 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 Gaudil.

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 Gaudil 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 Gaudil.

Long-term Trial of Gaudil as Monotherapy: A 4- to 6-year trial (ADOPT) compared the use of Gaudil (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 Gaudil (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 Gaudil as Monotherapy (ADOPT)

Long-term Trial of Gaudil 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 Gaudil 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 Gaudil 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 Gaudil 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. Gaudil 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 Gaudil.

Table 5: Cardiovascular (CV) Outcomes for the RECORD Trial

There was an increased incidence of bone fracture for subjects randomized to Gaudil 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

Gaudil has been evaluated for safety in a single, active-controlled trial of pediatric patients with type 2 diabetes in which 99 were treated with Gaudil and 101 were treated with metformin. The most common adverse reactions (>10%) without regard to causality for either Gaudil 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 Gaudil (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 Gaudil or following a dose increase in Gaudil. The time course and magnitude of decreases were similar in patients treated with a combination of Gaudil and other hypoglycemic agents or monotherapy with Gaudil. 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 Gaudil. White blood cell counts also decreased slightly in adult patients treated with Gaudil. Decreases in hematologic parameters may be related to increased plasma volume observed with treatment with Gaudil.

Lipids

Changes in serum lipids have been observed following treatment with Gaudil in adults. Small changes in serum lipid parameters were reported in children treated with Gaudil for 24 weeks.

Serum Transaminase Levels

In pre-approval clinical trials in 4,598 patients treated with Gaudil (3,600 patient-years of exposure) and in a long-term 4- to 6-year trial in 1,456 patients treated with Gaudil (4,954 patient-years exposure), there was no evidence of druginduced hepatotoxicity.

In pre-approval controlled trials, 0.2% of patients treated with Gaudil 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 Gaudil were reversible. Hyperbilirubinemia was found in 0.3% of patients treated with Gaudil 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 Gaudil (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 Gaudil 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 Gaudil. 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 Gaudil 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 Gaudil of rash, pruritus, urticaria, angioedema, anaphylactic reaction, Stevens-Johnson syndrome.

Limited data are available with regard to overdosage in humans. In clinical trials in volunteers, Gaudil has been administered at single oral doses of up to 20 mg and was well tolerated. In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient's clinical status.

Patients with lipid abnormalities were not excluded from clinical trials of Gaudil. In all 26-week controlled trials, across the recommended dose range, Gaudil as monotherapy was associated with increases in total cholesterol, LDL, and HDL and decreases in free fatty acids. These changes were statistically significantly different from placebo or glyburide controls (Table 7).

Increases in LDL occurred primarily during the first 1 to 2 months of therapy with Gaudil and LDL levels remained elevated above baseline throughout the trials. In contrast, HDL continued to rise over time. As a result, the LDL/HDL ratio peaked after 2 months of therapy and then appeared to decrease over time. Because of the temporal nature of lipid changes, the 52-week, glyburide-controlled trial is most pertinent to assess long-term effects on lipids. At baseline, Week 26, and Week 52, mean LDL/HDL ratios were 3.1, 3.2, and 3.0, respectively, for Gaudil 4 mg twice daily. The corresponding values for glyburide were 3.2, 3.1, and 2.9. The differences in change from baseline between Gaudil and glyburide at Week 52 were statistically significant.

The pattern of LDL and HDL changes following therapy with Gaudil in combination with other hypoglycemic agents were generally similar to those seen with Gaudil in monotherapy.

The changes in triglycerides during therapy with Gaudil were variable and were generally not statistically different from placebo or glyburide controls.

Table 7: Summary of Mean Lipid Changes in 26-Week, Placebo-controlled and 52-Week, Glyburide-controlled Monotherapy Trials

Maximum plasma concentration (Cmax) and the area under the curve (AUC) of rosiglitazone increase in a dose-proportional manner over the therapeutic dose range (Table 8). The elimination half-life is 3 to 4 hours and is independent of dose.

Table 8: Mean (SD) Pharmacokinetic Parameters for Rosiglitazone Following Single Oral Doses (N = 32)

Absorption

The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations are observed about 1 hour after dosing. Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), but there was an approximately 28% decrease in Cmax and a delay in Tmax (1.75 hours). These changes are not likely to be clinically significant; therefore, Gaudil may be administered with or without food.

Distribution

The mean (CV%) oral volume of distribution (Vss/F) of rosiglitazone is approximately 17.6 (30%) liters, based on a population pharmacokinetic analysis. Rosiglitazone is approximately 99.8% bound to plasma proteins, primarily albumin.

Metabolism

Rosiglitazone is extensively metabolized with no unchanged drug excreted in the urine. The major routes of metabolism were N-demethylation and hydroxylation, followed by conjugation with sulfate and glucuronic acid. All the circulating metabolites are considerably less potent than parent and, therefore, are not expected to contribute to the insulin-sensitizing activity of rosiglitazone.

In vitro data demonstrate that rosiglitazone is predominantly metabolized by Cytochrome P450 (CYP) isoenzyme 2C8, with CYP2C9 contributing as a minor pathway.

Excretion

Following oral or intravenous administration of [¹⁴C]rosiglitazone maleate, approximately 64% and 23% of the dose was eliminated in the urine and in the feces, respectively. The plasma half-life of [¹⁴C]related material ranged from 103 to 158 hours.

Population Pharmacokinetics in Patients With Type 2 Diabetes

Population pharmacokinetic analyses from 3 large clinical trials including 642 men and 405 women with type 2 diabetes (aged 35 to 80 years) showed that the pharmacokinetics of rosiglitazone are not influenced by age, race, smoking, or alcohol consumption. Both oral clearance (CL/F) and oral steady-state volume of distribution (Vss/F) were shown to increase with increases in body weight. Over the weight range observed in these analyses (50 to 150 kg), the range of predicted CL/F and Vss/F values varied by < 1.7-fold and < 2.3-fold, respectively. Additionally, rosiglitazone CL/F was shown to be influenced by both weight and gender, being lower (about 15%) in female patients.