Rosiglitazone Maleate

Name: Rosiglitazone Maleate

Clinical pharmacology

Mechanism Of Action

Rosiglitazone, a member of the thiazolidinedione class of antidiabetic agents, improves glycemic control by improving insulin sensitivity. Rosiglitazone is a highly selective and potent agonist for the peroxisome proliferator-activated receptor-gamma (PPARγ). In humans, PPAR receptors are found in key target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARy nuclear receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In addition, PPARγ-responsive genes also participate in the regulation of fatty acid metabolism.

Insulin resistance is a common feature characterizing the pathogenesis of type 2 diabetes. The antidiabetic activity of rosiglitazone has been demonstrated in animal models of type 2 diabetes in which hyperglycemia and/or impaired glucose tolerance is a consequence of insulin resistance in target tissues. Rosiglitazone reduces blood glucose concentrations and reduces hyperinsulinemia in the ob/ob obese mouse, db/db diabetic mouse, and fa/fa fatty Zucker rat.

In animal models, the antidiabetic activity of rosiglitazone was shown to be mediated by increased sensitivity to insulin's action in the liver, muscle, and adipose tissues. Pharmacological studies in animal models indicate that rosiglitazone inhibits hepatic gluconeogenesis. The expression of the insulin-regulated glucose transporter GLUT-4 was increased in adipose tissue. Rosiglitazone did not induce hypoglycemia in animal models of type 2 diabetes and/or impaired glucose tolerance.

Pharmacodynamics

Patients with lipid abnormalities were not excluded from clinical trials of AVANDIA. In all 26-week controlled trials, across the recommended dose range, AVANDIA 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 AVANDIA 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 AVANDIA 4 mg twice daily. The corresponding values for glyburide were 3.2, 3.1, and 2.9. The differences in change from baseline between AVANDIA and glyburide at Week 52 were statistically significant.

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

The changes in triglycerides during therapy with AVANDIA 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

Parameter Placebo-controlled Trials Week 26 Glyburide-controlled Trial Week 26 and Week 52
Placebo AVANDIA Glyburide Titration AVANDIA 8 mg
  4 mg Dailya 8 mg Dailya Week 26 Week 52 Week 26 Week 52
Free fatty acids
  N 207 428 436 181 168 166 145
  Baseline (mean) % 18.1 17.5 17.9 26.4 26.4 26.9 26.6
  Change from baseline(mean) +0.2% -7.8% -14.7% -2.4% -4.7% -20.8% -21.5%
LDL
  N 190 400 374 175 160 161 133
  Baseline (mean) % 123.7 126.8 125.3 142.7 141.9 142.1 142.1
  Change from baseline(mean) +4.8% +14.1% +18.6% -0.9% -0.5% +11.9% +12.1%
HDL
  N 208 429 436 184 170 170 145
  Baseline (mean) % 44.1 44.4 43.0 47.2 47.7 48.4 48.3
  Change from baseline(mean) +8.0% +11.4% +14.2% +4.3% +8.7% +14.0% +18.5%
a Once-daily and twice-daily dosing groups were combined.

Pharmacokinetics

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)

Parameter 1 mg Fasting 2 mg Fasting 8 mg Fasting 8 mg Fed
AUC0-inf (ng.h/mL) 358 (112) 733 (184) 2,971 (730) 2,890 (795)
Cmax (ng/mL) 76 (13) 156 (42) 598 (117) 432 (92)
T½ (h) 3.16 (0.72) 3.15 (0.39) 3.37 (0.63) 3.59 (0.70)
CL/F (L/h) 3.03 (0.87) 2.89 (0.71) 2.85 (0.69) 2.97 (0.81)
AUC = area under the curve; Cmax = maximum concentration; T½ = terminal half-life; CL/F = Oral clearance.

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, AVANDIA 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.

Special Populations

Geriatric: Results of the population pharmacokinetic analysis (n = 716 < 65 years; n = 331 ≥65 years) showed that age does not significantly affect the pharmacokinetics of rosiglitazone.

Gender: Results of the population pharmacokinetics analysis showed that the mean oral clearance of rosiglitazone in female patients (n = 405) was approximately 6% lower compared with male patients of the same body weight (n = 642).

As monotherapy and in combination with metformin, AVANDIA improved glycemic control in both males and females. In metformin combination trials, efficacy was demonstrated with no gender differences in glycemic response.

In monotherapy trials, a greater therapeutic response was observed in females; however, in more obese patients, gender differences were less evident. For a given body mass index (BMI), females tend to have a greater fat mass than males. Since the molecular target PPARy is expressed in adipose tissues, this differentiating characteristic may account, at least in part, for the greater response to AVANDIA in females. Since therapy should be individualized, no dose adjustments are necessary based on gender alone.

Hepatic Impairment: Unbound oral clearance of rosiglitazone was significantly lower in patients with moderate to severe liver disease (Child-Pugh Class B/C) compared with healthy subjects. As a result, unbound Cmax and AUC0-inf were increased 2- and 3-fold, respectively. Elimination half-life for rosiglitazone was about 2 hours longer in patients with liver disease, compared with healthy subjects.

Therapy with AVANDIA 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 baseline [see WARNINGS AND PRECAUTIONS].

Pediatric: Pharmacokinetic parameters of rosiglitazone in pediatric patients were established using a population pharmacokinetic analysis with sparse data from 96 pediatric patients in a single pediatric clinical trial including 33 males and 63 females with ages ranging from 10 to 17 years (weights ranging from 35 to 178.3 kg). Population mean CL/F and V/F of rosiglitazone were 3.15 L/h and 13.5 L, respectively. These estimates of CL/F and V/F were consistent with the typical parameter estimates from a prior adult population analysis.

Renal Impairment: There are no clinically relevant differences in the pharmacokinetics of rosiglitazone in patients with mild to severe renal impairment or in hemodialysis-dependent patients compared with subjects with normal renal function. No dosage adjustment is therefore required in such patients receiving AVANDIA. Since metformin is contraindicated in patients with renal impairment, coadministration of metformin with AVANDIA is contraindicated in these patients.

Race: Results of a population pharmacokinetic analysis including subjects of Caucasian, black, and other ethnic origins indicate that race has no influence on the pharmacokinetics of rosiglitazone.

Drug-drug Interactions

Drugs That Inhibit, Induce, or are Metabolized by Cytochrome P450

In vitro drug metabolism studies suggest that rosiglitazone does not inhibit any of the major P450 enzymes at clinically relevant concentrations. In vitro data demonstrate that rosiglitazone is predominantly metabolized by CYP2C8, and to a lesser extent, 2C9. AVANDIA (4 mg twice daily) was shown to have no clinically relevant effect on the pharmacokinetics of nifedipine and oral contraceptives (ethinyl estradiol and norethindrone), which are predominantly metabolized by CYP3A4.

Gemfibrozil: Concomitant administration of gemfibrozil (600 mg twice daily), an inhibitor of CYP2C8, and rosiglitazone (4 mg once daily) for 7 days increased rosiglitazone AUC by 127%, compared with the administration of rosiglitazone (4 mg once daily) alone. Given the potential for dose-related adverse events with rosiglitazone, a decrease in the dose of rosiglitazone may be needed when gemfibrozil is introduced [see DRUG INTERACTIONS].

Rifampin: Rifampin administration (600 mg once a day), an inducer of CYP2C8, for 6 days is reported to decrease rosiglitazone AUC by 66%, compared with the administration of rosiglitazone (8 mg) alone [see DRUG INTERACTIONS].1

Glyburide

AVANDIA (2 mg twice daily) taken concomitantly with glyburide (3.75 to 10 mg/day) for 7 days did not alter the mean steady-state 24-hour plasma glucose concentrations in diabetic patients stabilized on glyburide therapy. Repeat doses of AVANDIA (8 mg once daily) for 8 days in healthy adult Caucasian subjects caused a decrease in glyburide AUC and Cmax of approximately 30%. In Japanese subjects, glyburide AUC and Cmax slightly increased following coadministration of AVANDIA.

Glimepiride

Single oral doses of glimepiride in 14 healthy adult subjects had no clinically significant effect on the steady-state pharmacokinetics of AVANDIA. No clinically significant reductions in glimepiride AUC and Cmax were observed after repeat doses of AVANDIA (8 mg once daily) for 8 days in healthy adult subjects.

Metformin

Concurrent administration of AVANDIA (2 mg twice daily) and metformin (500 mg twice daily) in healthy volunteers for 4 days had no effect on the steady-state pharmacokinetics of either metformin or rosiglitazone.

Acarbose

Coadministration of acarbose (100 mg three times daily) for 7 days in healthy volunteers had no clinically relevant effect on the pharmacokinetics of a single oral dose of AVANDIA.

Digoxin

Repeat oral dosing of AVANDIA (8 mg once daily) for 14 days did not alter the steady-state pharmacokinetics of digoxin (0.375 mg once daily) in healthy volunteers.

Warfarin

Repeat dosing with AVANDIA had no clinically relevant effect on the steadystate pharmacokinetics of warfarin enantiomers.

Ethanol

A single administration of a moderate amount of alcohol did not increase the risk of acute hypoglycemia in type 2 diabetes mellitus patients treated with AVANDIA.

Ranitidine

Pre-treatment with ranitidine (150 mg twice daily for 4 days) did not alter the pharmacokinetics of either single oral or intravenous doses of rosiglitazone in healthy volunteers. These results suggest that the absorption of oral rosiglitazone is not altered in conditions accompanied by increases in gastrointestinal pH.

Animal Toxicology

Heart weights were increased in mice (3 mg/kg/day), rats (5 mg/kg/day), and dogs (2 mg/kg/day) with rosiglitazone treatments (approximately 5, 22, and 2 times human AUC at the maximum recommended human daily dose, respectively). Effects in juvenile rats were consistent with those seen in adults. Morphometric measurement indicated that there was hypertrophy in cardiac ventricular tissues, which may be due to increased heart work as a result of plasma volume expansion.

Clinical Studies

Monotherapy

In clinical trials, treatment with AVANDIA resulted in an improvement in glycemic control, as measured by FPG and HbA1c, with a concurrent reduction in insulin and C-peptide. Postprandial glucose and insulin were also reduced. This is consistent with the mechanism of action of AVANDIA as an insulin sensitizer.

The maximum recommended daily dose is 8 mg. Dose-ranging trials suggested that no additional benefit was obtained with a total daily dose of 12 mg.

Short-term Clinical Trials

A total of 2,315 patients with type 2 diabetes, previously treated with diet alone or antidiabetic medication(s), were treated with AVANDIA as monotherapy in 6 double-blind trials, which included two 26-week, placebo-controlled trials; one 52-week, glyburide-controlled trial; and 3 placebo-controlled, dose-ranging trials of 8 to 12 weeks' duration. Previous antidiabetic medication(s) were withdrawn and patients entered a 2- to 4-week placebo run-in period prior to randomization.

Two 26-week, double-blind, placebo-controlled trials, in patients with type 2 diabetes (n = 1,401) with inadequate glycemic control [mean baseline FPG approximately 228 mg/dL (101 to 425 mg/dL) and mean baseline HbA1c 8.9% (5.2% to 16.2%)], were conducted. Treatment with AVANDIA produced statistically significant improvements in FPG and HbA1c compared with baseline and relative to placebo. Data from one of these trials are summarized in Table 9.

Table 9: Glycemic Parameters in a 26-Week, Placebo-controlled Trial

Parameter Placebo AVANDIA AVANDIA
N = 173 4 mg Once Daily
N = 180
2 mg Twice Daily
N = 186
8 mg Once Daily
N = 181
4 mg Twice Daily
N = 187
FPG (mg/dL)
  Baseline (mean) 225 229 225 228 228
  Change from baseline (mean) 8 -25 -35 -42 -55
  Difference from placebo (adjusted mean) - -31a -43a -49a -62a
  % of patients with ≥30 mg/dL decrease from baseline 19% 45% 54% 58% 70%
HbA1c (%)
  Baseline (mean) 8.9 8.9 8.9 8.9 9.0
Change from baseline (mean) 0.8 0.0 -0.1 -0.3 -0.7
  Difference from placebo (adjusted mean) - -0.8a -0.9a -1.1a -1.5a
  % of patients with ≥0.7% decrease from baseline 9% 28% 29% 39% 54%
a P < 0.0001 compared with placebo.

When administered at the same total daily dose, AVANDIA was generally more effective in reducing FPG and HbA1c when administered in divided doses twice daily compared with once-daily doses. However, for HbA1c, the difference between the 4 mg once-daily and 2 mg twice-daily doses was not statistically significant.

Long-term Clinical Trials

Long-term maintenance of effect was evaluated in a 52- week, double-blind, glyburide-controlled trial in patients with type 2 diabetes. Patients were randomized to treatment with AVANDIA 2 mg twice daily (N = 195) or AVANDIA 4 mg twice daily (N = 189) or glyburide (N = 202) for 52 weeks. Patients receiving glyburide were given an initial dosage of either 2.5 mg/day or 5.0 mg/day. The dosage was then titrated in 2.5-mg/day increments over the next 12 weeks, to a maximum dosage of 15.0 mg/day in order to optimize glycemic control. Thereafter, the glyburide dose was kept constant.

The median titrated dose of glyburide was 7.5 mg. All treatments resulted in a statistically significant improvement in glycemic control from baseline (Figure 3 and Figure 4).  At the end of Week 52, the reduction from baseline in FPG and HbA1c was -40.8 mg/dL and-0.53% with AVANDIA 4 mg twice daily; -25.4 mg/dL and -0.27% with AVANDIA 2 mg twice daily; and -30.0 mg/dL and -0.72% with glyburide. For HbA1c, the difference between AVANDIA 4 mg twice daily and glyburide was not statistically significant at Week 52. The initial fall in FPG with glyburide was greater than with AVANDIA; however, this effect was less durable over time. The improvement in glycemic control seen with AVANDIA 4 mg twice daily at Week 26 was maintained through Week 52 of the trial.

Figure 3: Mean FPG Over Time in a 52-Week, Glyburide-controlled Trial

Figure 4: Mean HbAlc Over Time in a 52-Week, Glyburide-controlled Trial

Hypoglycemia was reported in 12.1% of glyburide-treated patients versus 0.5% (2 mg twice daily) and 1.6% (4 mg twice daily) of patients treated with AVANDIA. The improvements in glycemic control were associated with a mean weight gain of 1.75 kg and 2.95 kg for patients treated with 2 mg and 4 mg twice daily of AVANDIA, respectively, versus 1.9 kg in glyburidetreated patients. In patients treated with AVANDIA, C-peptide, insulin, pro-insulin, and proinsulin split products were significantly reduced in a dose-ordered fashion, compared with an increase in the glyburide-treated patients.

A Diabetes Outcome Progression Trial (ADOPT) was a multicenter, double-blind, controlled trial (N = 4,351) conducted over 4 to 6 years to compare the safety and efficacy of AVANDIA, metformin, and glyburide monotherapy in patients recently diagnosed with type 2 diabetes mellitus ( ≤ 3 years) inadequately controlled with diet and exercise. The mean age of patients in this trial was 57 years and the majority of patients (83%) had no known history of cardiovascular disease. The mean baseline FPG and HbA1c were 152 mg/dL and 7.4%, respectively. Patients were randomized to receive either AVANDIA 4 mg once daily, glyburide 2.5 mg once daily, or metformin 500 mg once daily, and doses were titrated to optimal glycemic control up to a maximum of 4 mg twice daily for AVANDIA, 7.5 mg twice daily for glyburide, and 1,000 mg twice daily for metformin. The primary efficacy outcome was time to consecutive FPG >180 mg/dL after at least 6 weeks of treatment at the maximum tolerated dose of study medication or time to inadequate glycemic control, as determined by an independent adjudication committee.

The cumulative incidence of the primary efficacy outcome at 5 years was 15% with AVANDIA, 21% with metformin, and 34% with glyburide (HR 0.68 [95% CI: 0.55, 0.85] versus metformin, HR 0.37 [95% CI: 0.30, 0.45] versus glyburide).

Cardiovascular and adverse event data (including effects on body weight and bone fracture) from ADOPT for AVANDIA, metformin, and glyburide are described in WARNINGS AND PRECAUTIONS (5.2, 5.4, and 5.7) and Adverse Reactions (6.1), respectively. As with all medications, efficacy results must be considered together with safety information to assess the potential benefit and risk for an individual patient.

Combination With Metformin Or Sulfonylurea

The addition of AVANDIA to either metformin or sulfonylurea resulted in significant reductions in hyperglycemia compared with either of these agents alone. These results are consistent with an additive effect on glycemic control when AVANDIA is used as combination therapy.

Combination With Metformin

A total of 670 patients with type 2 diabetes participated in two 26-week, randomized, double-blind, placebo/active-controlled trials designed to assess the efficacy of AVANDIA in combination with metformin. AVANDIA, administered in either oncedaily or twice-daily dosing regimens, was added to the therapy of patients who were inadequately controlled on a maximum dose (2.5 grams/day) of metformin.

In one trial, patients inadequately controlled on 2.5 grams/day of metformin (mean baseline FPG 216 mg/dL and mean baseline HbA1c 8.8%) were randomized to receive 4 mg of AVANDIA once daily, 8 mg of AVANDIA once daily, or placebo in addition to metformin. A statistically significant improvement in FPG and HbA1c was observed in patients treated with the combinations of metformin and 4 mg of AVANDIA once daily and 8 mg of AVANDIA once daily, versus patients continued on metformin alone (Table 10).

Table 10: Glycemic Parameters in a 26-Week Combination Trial of AVANDIA Plus Metformin

Parameter Metformin
N = 113
AVANDIA 4 mg Once Daily + Metformin
N = 116
AVANDIA 8 mg Once Daily +Metformin
N = 110
FPG (mg/dL)
  Baseline (mean) 214 215 220
  Change from baseline (mean) 6 -33 -48
  Difference from metformin alone (adjusted mean) - -40a -53a
  % of patients with ≥30 mg/dL decrease from baseline 20% 45% 61%
HbAlc (%)
  Baseline (mean) 8.6 8.9 8.9
  Change from baseline (mean) 0.5 -0.6 -0.8
  Difference from metformin alone (adjusted mean) - -1.0a -1.2a
  % of patients with ≥0.7% decrease from baseline 11% 45% 52%
a P < 0.0001 compared with metformin.

In a second 26-week trial, patients with type 2 diabetes inadequately controlled on 2.5 grams/day of metformin who were randomized to receive the combination of AVANDIA 4 mg twice daily and metformin (N = 105) showed a statistically significant improvement in glycemic control with a mean treatment effect for FPG of -56 mg/dL and a mean treatment effect for HbA1c of -0.8% over metformin alone. The combination of metformin and AVANDIA resulted in lower levels of FPG and HbA1c than either agent alone.

Patients who were inadequately controlled on a maximum dose (2.5 grams/day) of metformin and who were switched to monotherapy with AVANDIA demonstrated loss of glycemic control, as evidenced by increases in FPG and HbA1c. In this group, increases in LDL and VLDL were also seen.

Combination With a Sulfonylurea

A total of 3,457 patients with type 2 diabetes participated in ten 24- to 26-week randomized, double-blind, placebo/active-controlled trials and one 2-year double-blind, active-controlled trial in elderly patients designed to assess the efficacy and safety of AVANDIA in combination with a sulfonylurea. AVANDIA 2 mg, 4 mg, or 8 mg daily was administered, either once daily (3 trials) or in divided doses twice daily (7 trials), to patients inadequately controlled on a submaximal or maximal dose of sulfonylurea.

In these trials, the combination of AVANDIA 4 mg or 8 mg daily (administered as single-or twice-daily divided doses) and a sulfonylurea significantly reduced FPG and HbA1c compared with placebo plus sulfonylurea or further up-titration of the sulfonylurea. Table 11 shows pooled data for 8 trials in which AVANDIA added to sulfonylurea was compared with placebo plus sulfonylurea.

Table 11: Glycemic Parameters in 24- to 26-Week Combination Trials of AVANDIA Plus Sulfonylurea

Twice-Daily Divided Dosing (5 Trials) Sulfonylurea
N = 397
AVANDIA 2 mg Twice Daily + Sulfonylurea
N = 497
Sulfonylurea
N = 248
AVANDIA 4 mg Twice Daily + Sulfonylurea
N = 346
FPG (mg/dL)
  Baseline (mean) 204 198 188 187
  Change from baseline (mean) 11 -29 8 -43
  Difference from sulfonylurea alone(adjusted mean) - -42a - -53a
  % of patients with ≥30 mg/dL decrease from baseline 17% 49% 15% 61%
HbA1c (%) 
  Baseline (mean) 9.4 9.5 9.3 9.6
  Change from baseline (mean) 0.2 -1.0 0.0 -1.6
  Difference from sulfonylurea alone(adjusted mean) - -1.1a - -1.4a
  % of patients with ≥0.7% decrease from baseline 21% 60% 23% 75%
Once-Daily Dosing (3 Trials) Sulfonylurea
N = 172
AVANDIA 4 mg Once Daily +Sulfonylurea
N = 172
Sulfonylurea
N = 173
AVANDIA 8 mg Once Daily + Sulfonylurea
N = 176
FPG (mg/dL)
  Baseline (mean) 198 206 188 192
  Change from baseline (mean) 17 -25 17 -43
  Difference from sulfonylurea alone(adjusted mean) - -47a - -66a
  % of patients with ≥ 30 mg/dL decrease from baseline 17% 48% 19% 55%
HbA1c (%)
  Baseline (mean) 8.6 8.8 8.9 8.9
  Change from baseline (mean) 0.4 -0.5 0.1 -1.2
  Difference from sulfonylurea alone(adjusted mean) - -0.9a - -1.4a
  % of patients with ≥ 0.7% decrease from baseline 11% 36% 20% 68%
a P < 0.0001 compared with sulfonylurea alone.

One of the 24- to 26-week trials included patients who were inadequately controlled on maximal doses of glyburide and switched to 4 mg of AVANDIA daily as monotherapy; in this group, loss of glycemic control was demonstrated, as evidenced by increases in FPG and HbA1c.

In a 2-year, double-blind trial, elderly patients (aged 59 to 89 years) on half-maximal sulfonylurea (glipizide 10 mg twice daily) were randomized to the addition of AVANDIA (n = 115, 4 mg once daily to 8 mg as needed) or to continued up-titration of glipizide (n = 110), to a maximum of 20 mg twice daily. Mean baseline FPG and HbA1c were 157 mg/dL and 7.72%, respectively, for the arm receiving AVANDIA plus glipizide and 159 mg/dL and 7.65%, respectively, for the glipizide up-titration arm. Loss of glycemic control (FPG >180 mg/dL) occurred in a significantly lower proportion of patients (2%) on AVANDIA plus glipizide compared with patients in the glipizide up-titration arm (28.7%). About 78% of the patients on combination therapy completed the 2 years of therapy while only 51% completed on glipizide monotherapy. The effect of combination therapy on FPG and HbA1c was durable over the 2-year trial period, with patients achieving a mean of 132 mg/dL for FPG and a mean of 6.98% for HbA1c compared with no change on the glipizide arm.

Combination With Sulfonylurea Plus Metformin

In two 24- to 26-week, double-blind, placebo-controlled trials designed to assess the efficacy and safety of AVANDIA in combination with sulfonylurea plus metformin, AVANDIA 4 mg or 8 mg daily, was administered in divided doses twice daily, to patients inadequately controlled on submaximal (10 mg) and maximal (20 mg) doses of glyburide and maximal dose of metformin (2 g/day). A statistically significant improvement in FPG and HbA1c was observed in patients treated with the combinations of sulfonylurea plus metformin and 4 mg of AVANDIA and 8 mg of AVANDIA versus patients continued on sulfonylurea plus metformin, as shown in Table 12.

Table 12: Glycemic Parameters in a 26-Week Combination Trial of AVANDIA Plus Sulfonylurea and Metformin

Parameter Sulfonylurea + Metformin
N = 273
AVANDIA 2 mg Twice Daily + Sulfonylurea + Metformin
N = 276
AVANDIA 4 mg Twice Daily + Sulfonylurea + Metformin
N = 277
FPG (mg/dL)
  Baseline (mean) 189 190 192
  Change from baseline (mean) 14 -19 -40
  Difference from sulfonylurea plus metformin (adjusted mean) - -30a -52a
  % of patients with ≥30 mg/dL decrease from baseline 16% 46% 62%
HbA1c (%)
  Baseline (mean) 8.7 8.6 8.7
  Change from baseline (mean) 0.2 -0.4 -0.9
  Difference from sulfonylurea plus metformin (adjusted mean) - -0.6a -1.1a
  % of patients with ≥ 0.7% decrease from baseline 16% 39% 63%
a P < 0.0001 compared with placebo.

REFERENCES

1. Park JY, Kim KA, Kang MH, et al. Effect of rifampin on the pharmacokinetics of rosiglitazone in healthy subjects. Clin Pharmacol Ther 2004;75:157-162.

Patient information

AVANDIA®
(ah-VAN-dee-a)
(rosiglitazone maleate) Tablets

Read this Medication Guide carefully before you start taking AVANDIA and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about AVANDIA, ask your doctor or pharmacist.

What is the most important information I should know about AVANDIA?

AVANDIA may cause serious side effects, including:

New or worse heart failure

  • The risk of heart failure may be higher in people who take AVANDIA with insulin. Most people who take insulin should not also take AVANDIA.
  • AVANDIA can cause your body to keep extra fluid (fluid retention), which leads to swelling (edema) and weight gain. Extra body fluid can make some heart problems worse or lead to heart failure. Heart failure means your heart does not pump blood well enough.
  • If you have severe heart failure, you cannot start AVANDIA.
  • If you have heart failure with symptoms (such as shortness of breath or swelling), even if these symptoms are not severe, AVANDIA may not be right for you.

Call your doctor right away if you have any of the following:

  • swelling or fluid retention, especially in the ankles or legs
  • shortness of breath or trouble breathing, especially when you lie down
  • an unusually fast increase in weight
  • unusual tiredness

AVANDIA can have other serious side effects. Be sure to read the section below “What are possible side effects of AVANDIA?”

What is AVANDIA?

AVANDIA is a prescription medicine used with diet and exercise to treat adults with type 2 (“adult-onset” or “non-insulin dependent”) diabetes mellitus (“high blood sugar”).

AVANDIA helps to control high blood sugar. AVANDIA may be used alone or with other diabetes medicines. AVANDIA can help your body respond better to insulin made in your body. AVANDIA does not cause your body to make more insulin.

AVANDIA is not for people with type 1 diabetes mellitus or to treat a condition called diabetic ketoacidosis.

It is not known if AVANDIA is safe and effective in children younger than 18 years old.

Who should not take AVANDIA?

Many people with heart failure should not start taking AVANDIA. See “What should I tell my doctor before taking AVANDIA?”

Do not take AVANDIA if you are allergic to rosiglitazone or any of the ingredients in AVANDIA. See the end of this leaflet for a complete list of ingredients in AVANDIA.

Symptoms of a severe allergic reaction with AVANDIA may include:

  • swelling of your face, lips, tongue, or throat
  • problems with breathing or swallowing
  • skin rash or itching
  • raised red areas on your skin (hives)
  • blisters on your skin or in your mouth, nose, or eyes
  • peeling of your skin
  • fainting or feeling dizzy
  • very rapid heartbeat

What should I tell my doctor before taking AVANDIA?

Before starting AVANDIA, ask your doctor about what the choices are for diabetes medicines, and what the expected benefits and possible risks are for you in particular.

Before taking AVANDIA, tell your doctor about all of your medical conditions, including if you:

  • have heart problems or heart failure.
  • have type 1 (“juvenile”) diabetes or had diabetic ketoacidosis. These conditions should be treated with insulin.
  • have a type of diabetic eye disease called macular edema (swelling of the back of the eye).
  • have liver problems. Your doctor should do blood tests to check your liver before you start taking AVANDIA and during treatment as needed.
  • had liver problems while taking REZULIN™ (troglitazone), another medicine for diabetes.
  • are pregnant or plan to become pregnant. It is not known if AVANDIA can harm your unborn baby. You and your doctor should talk about the best way to control your diabetes during pregnancy. If you are a premenopausal woman (before the “change of life”) who does not have regular monthly periods, AVANDIA may increase your chances of becoming pregnant. Talk to your doctor about birth control choices while taking AVANDIA. Tell your doctor right away if you become pregnant while taking AVANDIA.
  • are breastfeeding or planning to breastfeed. It is not known if AVANDIA passes into breast milk. You and your doctor should decide if you will take AVANDIA or breastfeed. You should not do both.

Tell your doctor about all of the medicines you take including prescription and nonprescription medicines, vitamins or herbal supplements. AVANDIA and certain other medicines can affect each other and may lead to serious side effects including high or low blood sugar, or heart problems. Especially tell your doctor if you take:

  • insulin.
  • any medicines for high blood pressure, high cholesterol or heart failure, or for prevention of heart disease or stroke.

Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist before you start a new medicine. They will tell you if it is

alright to take AVANDIA with other medicines.

How should I take AVANDIA?

  • Take AVANDIA exactly as prescribed. Your doctor will tell you how many tablets to take and how often. The usual daily starting dose is 4 mg a day taken one time each day or 2 mg taken two times each day. Your doctor may need to adjust your dose until your blood sugar is better controlled.
  • AVANDIA may be prescribed alone or with other diabetes medicines. This will depend on how well your blood sugar is controlled.
  • Take AVANDIA with or without food.
  • It can take 2 weeks for AVANDIA to start lowering blood sugar. It may take 2 to 3 months to see the full effect on your blood sugar level.
  • If you miss a dose of AVANDIA, take it as soon as you remember, unless it is time to take your next dose. Take your next dose at the usual time. Do not take double doses to make up for a missed dose.
  • If you take too much AVANDIA, call your doctor or poison control center right away.
  • Test your blood sugar regularly as your doctor tells you.
  • Diet and exercise can help your body use its blood sugar better. It is important to stay on your recommended diet, lose extra weight, and get regular exercise while taking AVANDIA.
  • Your doctor should do blood tests to check your liver before you start AVANDIA and during treatment as needed. Your doctor should also do regular blood sugar tests (for example, “A1C”) to monitor your response to AVANDIA.

What are possible side effects of AVANDIA?

AVANDIA may cause serious side effects including:

  • New or worse heart failure. See “What is the most important information I should know about AVANDIA?”
  • Heart attack. AVANDIA may increase the risk of a heart attack. Talk to your doctor about what this means to you.
    Symptoms of a heart attack can include the following:
    • chest discomfort in the center of your chest that lasts for more than a few minutes, or that goes away or comes back
    • chest discomfort that feels like uncomfortable pressure, squeezing, fullness, or pain
    • pain or discomfort in your arms, back, neck, jaw, or stomach
    • shortness of breath with or without chest discomfort
    • breaking out in a cold sweat
    • nausea or vomiting
    • feeling lightheaded

Call your doctor or go to the nearest hospital emergency room right away if you think you are having a heart attack.

  • Swelling (edema). AVANDIA can cause swelling due to fluid retention. See “What is the most important information I should know about AVANDIA?”
  • Weight gain. AVANDIA can cause weight gain that may be due to fluid retention or extra body fat. Weight gain can be a serious problem for people with certain conditions including heart problems. See “What is the most important information I should know about AVANDIA?”
  • Liver problems. It is important for your liver to be working normally when you take AVANDIA. Your doctor should do blood tests to check your liver before you start taking AVANDIA and during treatment as needed. Call your doctor right away if you have unexplained symptoms such as:
    • nausea or vomiting
    • stomach pain
    • unusual or unexplained tiredness
    • loss of appetite
    • dark urine
    • yellowing of your skin or the whites of your eyes.
  • Macular edema (a diabetic eye disease with swelling in the back of the eye). Tell your doctor right away if you have any changes in your vision. Your doctor should check your eyes regularly. Very rarely, some people have had vision changes due to swelling in the back of the eye while taking AVANDIA.
  • Fractures (broken bones), usually in the hand, upper arm, or foot. Talk to your doctor for advice on how to keep your bones healthy.
  • Low red blood cell count (anemia).
  • Low blood sugar (hypoglycemia). Lightheadedness, dizziness, shakiness, or hunger may mean that your blood sugar is too low. This can happen if you skip meals, if you use another medicine that lowers blood sugar, or if you have certain medical problems. Call your doctor if low blood sugar levels are a problem for you.
  • Ovulation (release of egg from an ovary in a woman) leading to pregnancy. Ovulation may happen in premenopausal women who do not have regular monthly periods. This can increase the chance of pregnancy. See “What should I tell my doctor before taking AVANDIA?”

The most common side effects of AVANDIA reported in clinical trials included coldlike symptoms and headache.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store AVANDIA?

  • Store AVANDIA at room temperature, 59°F to 86°F (15°C to 30°C). Keep AVANDIA in the container it comes in.
  • Safely, throw away AVANDIA that is out of date or no longer needed.
  • Keep AVANDIA and all medicines out of the reach of children.

General information about AVANDIA

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use AVANDIA for a condition for which it was not prescribed. Do not give AVANDIA to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes important information about AVANDIA. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about AVANDIA that is written for healthcare professionals. You can also find out more about AVANDIA by calling 1-888-8255249.

What are the ingredients in AVANDIA?

Active Ingredient: rosiglitazone maleate.

Inactive Ingredients: hypromellose 2910, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 3000, sodium starch glycolate, titanium dioxide, triacetin, and 1 or more of the following: synthetic red and yellow iron oxides and talc.

Always check to make sure that the medicine you are taking is the correct one.

AVANDIA tablets are triangles with rounded corners and look like this:

2 mg - pink with “GSK” on one side and “2” on the other.

4 mg - orange with “GSK” on one side and “4” on the other.

8 mg - red-brown with “GSK” on one side and “8” on the other.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

What is rosiglitazone (avandia)?

Rosiglitazone is an oral diabetes medicine that helps control blood sugar levels.

Rosiglitazone is for people with type 2 diabetes. Rosiglitazone is sometimes used in combination with other medicines, but it is not for treating type 1 diabetes.

Rosiglitazone is not recommended for use with insulin.

Taking rosiglitazone may increase your risk of serious heart problems, such as heart attack or stroke. Therefore, rosiglitazone is available only to certain people with type 2 diabetes that cannot be controlled with other diabetes medications.

Rosiglitazone is available only under a special program called Avandia-Rosiglitazone Medicines Access Program. You must be registered in the program and sign documents stating that you understand the risks and benefits of taking this medication.

Rosiglitazone may also be used for purposes not listed in this medication guide.

What should i avoid while taking rosiglitazone (avandia)?

Avoid drinking alcohol. It can lower your blood sugar.

Where can i get more information?

Your pharmacist has additional information about rosiglitazone written for health professionals that you may read.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2013 Cerner Multum, Inc. Version: 13.02. Revision date: 11/23/2011.

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Rosiglitazone Maleate Dosage and Administration

General

  • Monitor regularly (e.g., fasting blood glucose concentrations, HbA1c) to determine therapeutic response.1 110 118 146

  • Carefully monitor for fluid retention after dosage increases.1 110 118

  • Allow sufficient time to assess therapeutic response (8–12 weeks) to rosiglitazone.1 110 118

Administration

Oral Administration

Administer rosiglitazone once or twice daily without regard to meals.1 25 146

Administer rosiglitazone/metformin hydrochloride fixed-combination preparation in divided doses with meals.110

Administer rosiglitazone/glimepiride fixed-combination preparation once daily with the first meal of the day.118 137

If a dose is missed, take the missed dose as soon as it is remembered.136 137 146 If the missed dose is remembered at the time of the next dose, skip missed dose and resume the regular schedule.136 137 146 Do not double dose to replace missed dose.136 137 146

Dosage

Available as rosiglitazone maleate; dosage expressed in terms of rosiglitazone.1

Adults

Treatment of Diabetes Mellitus Monotherapy Oral

Usual initial dosage is 4 mg daily in 1 or 2 divided doses.1 146 If response is inadequate after 8–12 weeks, may increase dosage to a maximum of 8 mg daily.1

Rosiglitazone/Metformin Hydrochloride Fixed-combination Therapy (Avandamet) Oral

Dosage of the fixed combination is based on the patient’s current dosage of metformin hydrochloride and/or rosiglitazone.110 (See Table 1.) Initiate rosiglitazone component at the lowest recommended dosage.110

Patients currently receiving metformin monotherapy: Usual initial dosage of rosiglitazone is 4 mg daily given with patient's existing dosage of metformin hydrochloride.110

Patients currently receiving rosiglitazone monotherapy: Usual initial dosage of metformin hydrochloride is 1 g daily given with patient's existing dosage of rosiglitazone.110

Individualize therapy in patients already receiving metformin hydrochloride in doses not available in the fixed combination (i.e., doses other than 1 or 2 g).110

Table 1. Initial Dosage of the Fixed Combination of Rosiglitazone and Metformin Hydrochloride (Avandamet)110

Prior Therapy

Usual Initial Dosage of Avandamet

Total Daily Dosage

Tablet Strength

Number of Tablets

Metformin Hydrochloride

1 g

2 mg/500 mg

1 tablet twice daily

2 g

2 mg/1 g

1 tablet twice daily

Rosiglitazone

4 mg

2 mg/500 mg

1 tablet twice daily

8 mg

4 mg/500 mg

1 tablet twice daily

Patients switching from combined therapy with separate rosiglitazone and metformin preparations: Usual initial dosage of the fixed combination is the same as the patient's existing dosage of the individual drugs.110

If additional glycemic control is needed following transfer, increase dosage in increments of 4 mg of rosiglitazone and/or 500 mg of metformin hydrochloride per day.110 Following increase in dosage of metformin hydrochloride, further dosage adjustment recommended if adequate glycemic control not achieved in 1–2 weeks.110 Following increase in dosage of rosiglitazone, further dosage adjustment recommended if adequate glycemic control not achieved in 8–12 weeks.110

Rosiglitazone/Glimepiride Fixed-combination Therapy (Avandaryl) Oral

Initially, 4 mg of rosiglitazone and 1 mg of glimepiride once daily.118 May consider initial dosage of 4 mg of rosiglitazone and 2 mg of glimepiride once daily in patients already receiving a sulfonylurea or rosiglitazone.118

Initiate rosiglitazone component at the lowest recommended dosage.118

Patients switching from combined therapy with separate rosiglitazone and glimepiride preparations: Usual initial dosage of the fixed-combination is the same as the patient's existing dosage of the individual drugs.118

In patients previously receiving rosiglitazone monotherapy, allow approximately 1–2 weeks to assess therapeutic response.118 If additional glycemic control is needed after 1–2 weeks, increase dosage of the glimepiride component in increments of ≤2 mg.118 Assess response to increase in glimepiride component after 1–2 weeks to determine need for further dosage adjustment.118

In patients previously receiving sulfonylurea monotherapy, allow 2 weeks to observe reduction in blood glucose concentrations and 2–3 months to observe full therapeutic response to newly initiated rosiglitazone component.118 If additional glycemic control is needed after 8–12 weeks, increase dosage of the rosiglitazone component.118 If additional glycemic control is needed 2–3 months after an increase in rosiglitazone component, further titrate dosage.118

During transfer from therapy with a sulfonylurea with a long half-life (e.g., chlorpropamide), closely monitor for hypoglycemia during the initial 1–2 weeks of the transition period.118

If hypoglycemia occurs, consider dosage reduction of the glimepiride component. 118

Prescribing Limits

Adults

Treatment of Diabetes Mellitus Oral

Rosiglitazone monotherapy: Maximum 8 mg daily.1

Fixed-combination preparation with metformin hydrochloride: Maximum 8 mg of rosiglitazone and 2 g of metformin hydrochloride daily.110

Fixed-combination preparation with glimepiride: Maximum 8 mg of rosiglitazone and 4 mg of glimepiride daily.118

Special Populations

Hepatic Impairment

Rosiglitazone monotherapy: Do not initiate therapy in patients with clinical evidence of active liver disease or elevated serum aminotransferase concentrations (ALT >2.5 times ULN).1

Fixed-combination preparation with metformin hydrochloride: Do not initiate therapy in patients with clinical evidence of active liver disease or elevated serum aminotransferase concentrations (ALT >2.5 times ULN).110

Fixed-combination preparation with glimepiride: Conservative initial and maintenance dosages recommended; individuals with hepatic impairment may be particularly sensitive to the hypoglycemic effects of glimepiride.118 Do not initiate therapy in patients with clinical evidence of active liver disease or elevated serum aminotransferase concentrations (ALT >2.5 times ULN).118

Renal Impairment

Rosiglitazone monotherapy: No dosage adjustment necessary.1

Fixed-combination preparation with metformin hydrochloride: Base any dosage adjustment on careful assessment of renal function.110

Fixed-combination preparation with glimepiride: Conservative initial and maintenance dosages recommended; individuals with renal impairment may be particularly sensitive to the hypoglycemic effects of glimepiride.118

Geriatric Patients

Rosiglitazone monotherapy: No dosage adjustment necessary.1

Fixed-combination preparation with metformin hydrochloride: Conservative initial and maintenance dosages recommended.110 Generally, do not titrate to maximum recommended dosage.110

Fixed-combination preparation with glimepiride: Conservative initial and maintenance dosages recommended; geriatric individuals may be particularly sensitive to the hypoglycemic effects of glimepiride.118

Other Populations

Fixed-combination preparation with metformin hydrochloride: Do not titrate to maximum recommended dosage in debilitated or malnourished patients.110

Fixed-combination preparation with glimepiride: Conservative initial and maintenance dosages recommended in debilitated or malnourished patients or patients with adrenal insufficiency; these individuals may be particularly sensitive to the hypoglycemic effects of glimepiride.118

Cautions for Rosiglitazone Maleate

Contraindications

  • Initiation of therapy in patients with NYHA class III or IV CHF.1 110 118 128 157 (See Boxed Warning.)

  • History of hypersensitivity to the drug or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Congestive Heart Failure

Risk of fluid retention; may cause or exacerbate CHF.1 116 117 128 141 143 Use of thiazolidinediones associated with approximately twofold increased risk of CHF.131 143 148 151 155 (See Boxed Warning and also see Edema under Cautions.)

Use with caution in patients with edema and in those who are at risk for CHF.1 110 117 148 Initiation of rosiglitazone not recommended in patients experiencing an acute coronary event.1 If an acute coronary event occurs, consider discontinuance of rosiglitazone during the acute phase.1 Use not recommended in patients with NYHA class III or IV cardiac status or those with symptomatic heart failure.1 110 113 118 149 150 Thiazolidinedione therapy should not be initiated in hospitalized patients with diabetes mellitus because of delayed onset of action and potential for increased vascular volume and CHF.114

Increased incidence of adverse cardiovascular events (e.g., edema, need for additional CHF therapy) reported in patients with NYHA class I or II heart failure receiving rosiglitazone in addition to other antidiabetic and CHF therapy.1 110 118 128 142 No change in left ventricular ejection fraction observed.1 110 118 128 142

Increased risk of CHF observed in patients receiving rosiglitazone and insulin compared with those receiving insulin alone.1 110 118 128 (See Specific Drugs under Interactions.)

General Precautions

Other Cardiovascular Effects

Findings from several meta-analyses of principally short-term trials and observational studies suggested a possible association between rosiglitazone and an increased risk of MI.1 110 118 128 130 132 144 148 151 155 217 220 However, these findings have not been confirmed in long-term (>3 years), prospective randomized studies.1 220 These studies, which include a cardiovascular outcomes trial (RECORD), generally have found no evidence of an increased risk of mortality or major adverse cardiovascular effects (MACE) with rosiglitazone compared with metformin and/or a sulfonylurea.1

Although some uncertainty remains regarding the cardiovascular risk of rosiglitazone, FDA states that concerns have been substantially reduced based on current evidence.220 223

Edema

Fluid retention reported; may lead to or exacerbate CHF.1 110 116 117 118 128 Weight gain reported; may involve fluid retention and fat accumulation.1 110 117 118

Use with caution in patients with edema and in those at risk for CHF.1 110 117 148 Monitor for weight gain and edema.1 117 Evaluate any patient developing edema within first few months of therapy for possible CHF.117 (See Congestive Heart Failure under Cautions.)

Musculoskeletal Effects

Risk of bone loss and fractures in women, and possibly men.1 110 118 125 126 127 139 145 147 151 Fractures reported more frequently in women receiving long-term therapy (4–6 years) with rosiglitazone (9.3%) than in women receiving metformin (5.1%) or glyburide (3.5%).1 110 118 125 126 147 Effects noted after first year of treatment and persisted throughout treatment.1 110 118 Majority of fractures were in upper limb (upper arm, hand, wrist) or distal lower limb (foot, ankle, fibula, tibia).1 110 118 125 127 147 Although increased risk of fracture may also apply to men, risk appears higher among women than men.1

Consider risk of fracture.1 110 118 125 127 147 Assess and maintain bone health according to current standards of care.1 110 125 147

Hematologic Effects

Possible dose-related decreases in hemoglobin (≤1 g/dL) and hematocrit (≤3.3%); usually evident within 3 months after initiation of therapy or dosage increase.1 30 110 Possible modest decreases in leukocyte counts.1 Hematologic effects may be related to plasma volume expansion.1 30

Ocular Effects

New-onset or worsening (diabetic) macular edema with decreased visual acuity reported; some patients reported concurrent peripheral edema.1 110 118 119 Some patients were symptomatic (e.g., blurred vision, decreased visual acuity); other cases were detected by routine ophthalmologic examination.1 110 118 Symptoms improved in some patients after discontinuance or rarely after dosage reduction.1 110 118 119

Regular eye examinations by an ophthalmologist recommended in patients with diabetes mellitus.1 110 114 118 Patients with any visual symptoms should be promptly evaluated by an ophthalmologist.1 110 118

Ovulatory Effects

Possible ovulation in premenopausal anovulatory women; risk of pregnancy unless contraceptive measures initiated.1 If unexpected menstrual dysfunction occurs, weigh risks versus benefits of continued therapy.1

Hepatic Effects

No evidence of hepatotoxicity in clinical studies to date.1 30 104 109 126 However, hepatitis, elevations in hepatic enzymes, and hepatic failure associated with fatalities reported during postmarketing experience.1

Monitor liver function tests prior to initiation of therapy and periodically thereafter according to clinician judgment.1 Do not initiate therapy if baseline ALT concentrations >2.5 times ULN.1 Evaluate patients with mildly elevated liver enzymes (e.g., ALT ≤2.5 ULN) prior to or during therapy to determine cause; initiate or continue drug with caution and close clinical monitoring.1 (See Hepatic Impairment under Cautions.)

Recheck liver enzymes as soon as possible if ALT increases to >3 times the ULN.1 Discontinue therapy if ALT remains elevated at >3 times ULN.1 Check liver function if manifestations suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine) occur.1 Decision to continue therapy pending results of laboratory tests should be guided by clinician judgment.1 Discontinue if jaundice develops.1 110

Use of Fixed Combinations

When used in fixed combination with metformin hydrochloride or glimepiride, consider the cautions, precautions, and contraindications associated with the concomitant agent.110 118

Specific Populations

Pregnancy

Category C.1 110 Risk of birth defects, pregnancy loss, or other adverse outcomes increases in pregnancies complicated by hyperglycemia and may decrease with good glycemic control.1 110 118 Use during pregnancy only when potential benefits justify possible risk to the fetus.1 110 118 Most clinicians recommend use of insulin during pregnancy to maintain optimum control of blood glucose concentrations.1 110 118

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 110 118 146 Discontinue nursing or the drug.1 110 118 146

Pediatric Use

Rosiglitazone: Has been evaluated in children and adolescents 10–17 years of age.1 Manufacturer states that data are insufficient to recommend use in pediatric patients <18 years of age.1

Fixed combination with glimepiride: Safety and efficacy not established in pediatric patients <18 years of age.118 137

Fixed combination with metformin hydrochloride: Safety and efficacy not established in pediatric patients.110

ADA states that use of oral antidiabetic agents may be considered in children with type 2 diabetes mellitus because of the greater compliance and convenience and lack of evidence demonstrating better efficacy of insulin for type 2 diabetes mellitus.107

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.1 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Use with caution in patients with mild hepatic impairment (ALT ≤2.5 times the ULN).1 110 118 Use not recommended in patients with ALT >2.5 times ULN.1 110 118 (See Hepatic Effects under Cautions.)

Common Adverse Effects

Upper respiratory tract infection,1 30 injury,1 headache.1

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Rosiglitazone Maleate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

2 mg (of rosiglitazone)

Avandia

GlaxoSmithKline

4 mg (of rosiglitazone)

Avandia

GlaxoSmithKline

8 mg (of rosiglitazone)

Avandia

GlaxoSmithKline

Rosiglitazone Maleate Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

2 mg (of rosiglitazone) with 500 mg Metformin Hydrochloride

Avandamet

GlaxoSmithKline

2 mg (of rosiglitazone) with 1 g Metformin Hydrochloride

Avandamet

GlaxoSmithKline

4 mg (of rosiglitazone) with 1 mg Glimepiride

Avandaryl

GlaxoSmithKline

4 mg (of rosiglitazone) with 2 mg Glimepiride

Avandaryl

GlaxoSmithKline

4 mg of (rosiglitazone) with 4 mg Glimepiride

Avandaryl

GlaxoSmithKline

4 mg (of rosiglitazone) with 500 mg Metformin Hydrochloride

Avandamet

GlaxoSmithKline

4 mg (of rosiglitazone) with 1 g Metformin Hydrochloride

Avandamet

GlaxoSmithKline

8 mg of (rosiglitazone) with 2 mg Glimepiride

Avandaryl

GlaxoSmithKline

8 mg of (rosiglitazone) with 4 mg Glimepiride

Avandaryl

GlaxoSmithKline

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