April 25, 2017
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Avandaryl

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Avandaryl




CLINICAL PHARMACOLOGY

Mechanism Of Action

AVANDARYL combines 2 antidiabetic agents with different mechanisms of action to improve glycemic control in patients with type 2 diabetes: Rosiglitazone maleate, a member of the thiazolidinedione class, and glimepiride, a member of the sulfonylurea class. Thiazolidinediones are insulin-sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas sulfonylureas act primarily by stimulating release of insulin from functioning pancreatic beta cells.

Rosiglitazone: Rosiglitazone 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 PPARγ 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. Pharmacologic studies in animal models indicate that rosiglitazone improves sensitivity to insulin in muscle and adipose tissue and 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.

Glimepiride: Glimepiride primarily lowers blood glucose by stimulating the release of insulin from pancreatic beta cells. Sulfonylureas bind to the sulfonylurea receptor in the pancreatic beta-cell plasma membrane, leading to closure of the ATP-sensitive potassium channel, thereby stimulating the release of insulin.

Pharmacodynamics

The lipid profiles of rosiglitazone and glimepiride in a clinical trial of patients with inadequate glycemic control on diet and exercise were consistent with the known profile of each monotherapy. AVANDARYL was associated with increases in HDL and LDL (3% to 4% for each) and decreases in triglycerides (-4%), that were not considered to be clinically meaningful.

The pattern of LDL and HDL changes following therapy with rosiglitazone in patients previously treated with a sulfonylurea was generally similar to those seen with rosiglitazone in monotherapy. Rosiglitazone as monotherapy was associated with increases in total cholesterol, LDL, and HDL and decreases in free fatty acids. The changes in triglycerides during therapy with rosiglitazone were variable and were generally not statistically different from placebo or glyburide controls.

Pharmacokinetics

In a bioequivalence trial of AVANDARYL 4 mg/4 mg, the area under the curve (AUC) and maximum concentration (Cmax) of rosiglitazone following a single dose of the combination tablet were bioequivalent to rosiglitazone 4 mg concomitantly administered with glimepiride 4 mg under fasted conditions. The AUC of glimepiride following a single fasted 4 mg/4 mg dose was equivalent to glimepiride concomitantly administered with rosiglitazone, while the Cmax was 13% lower when administered as the combination tablet (see Table 7).

Table 7: Pharmacokinetic Parameters for Rosiglitazone and Glimepiride (N = 28)

Parameter (Units) Rosiglitazone Glimepiride
Regimen A Regimen B Regimen A Regimen B
AUC 0-inf (ng•h/mL) 1,259(833-2,060) 1,253(756-2,758) 1,052(643-2,117) 1,101(648-2,555)
AUC0-t (ng•h/mL) 1,231(810-2,019) 1,224(744-2,654) 944(511-1,898) 1,038(606-2,337)
Cmax (ng/mL) 257(157-352) 251(77.3-434) 151(63.2-345) 173(70.5-329)
T½(h) 3.53(2.60-4.57) 3.54(2.10-5.03) 7.63(4.42-12.4) 5.08(1.80-11.31)
Tmax(h) 1.00(0.48-3.02) 0.98(0.48-5.97) 3.02(1.50-8.00) 2.53(1.00-8.03)
AUC = area under the curve; Cmax = maximum concentration; T½ = terminal half-life; Tmax = time of maximum concentration.
Regimen A = AVANDARYL 4 mg/4 mg tablet; Regimen B = Concomitant dosing of a rosiglitazone 4-mg tablet AND a glimepiride 4-mg tablet.
Data presented as geometric mean (range), except T½ which is presented as arithmetic mean (range) and Tmax, which is presented as median (range).

The rate and extent of absorption of both the rosiglitazone component and glimepiride component of AVANDARYL when taken with food were equivalent to the rate and extent of absorption of rosiglitazone and glimepiride when administered concomitantly as separate tablets with food.

Absorption

The AUC and Cmax of glimepiride increased in a dose-proportional manner following administration of AVANDARYL 4 mg/1 mg, 4 mg/2 mg, and 4 mg/4 mg. Administration of AVANDARYL in the fed state resulted in no change in the overall exposure of rosiglitazone; however, the Cmax of rosiglitazone decreased by 32% compared with the fasted state. There was an increase in both AUC (19%) and Cmax (55%) of glimepiride in the fed state compared with the fasted state.

Rosiglitazone: The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations are observed about 1 hour after dosing. The Cmax and AUC of rosiglitazone increase in a dose-proportional manner over the therapeutic dose range.

Glimepiride: Studies with single oral doses of glimepiride in healthy subjects and with multiple oral doses in patients with type 2 diabetes showed peak drug concentrations (Cmax) 2 to 3 hours post-dose. When glimepiride was given with meals, the mean Cmax and AUC were decreased by 8% and 9%, respectively.

Glimepiride does not accumulate in serum following multiple dosing. The pharmacokinetics of glimepiride does not differ between healthy subjects and patients with type 2 diabetes. Clearance of glimepiride after oral administration does not change over the 1 mg to 8 mg dose range, indicating linear pharmacokinetics.

In healthy subjects, the intra- and inter-individual variabilities of glimepiride pharmacokinetic parameters were 15 to 23% and 24 to 29%, respectively.

Distribution

Rosiglitazone: 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.

Glimepiride: After intravenous (IV) dosing in healthy subjects, the volume of distribution (Vd) was 8.8 L (113 mL/kg), and the total body clearance (CL) was 47.8 mL/min. Protein binding was greater than 99.5%.

Metabolism And Excretion

Rosiglitazone: 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. Following oral or IV 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. The elimination half-life is 3 to 4 hours and is independent of dose.

Glimepiride: Glimepiride is completely metabolized by oxidative biotransformation after either an IV or oral dose. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). Cytochrome P450 2C9 is involved in the biotransformation of glimepiride to M1. M1 is further metabolized to M2 by one or several cytosolic enzymes. M2 is inactive. In animals, M1 possesses about 1/3 of the pharmacological activity of glimepiride, but it is unclear whether M1 results in clinically meaningful effects on blood glucose in humans.

When [14C]glimepiride was given orally to 3 healthy male subjects, approximately 60% of the total radioactivity was recovered in the urine in 7 days. M1 and M2 accounted for 80% to 90% of the radioactivity recovered in the urine. The ratio of M1 to M2 in the urine was approximately 3:2 in two subjects and 4:1 in one subject. Approximately 40% of the total radioactivity was recovered in feces and M1 and M2 (predominant) accounted for about 70% of that recovered in feces. No parent drug was recovered from urine or feces. After IV dosing in patients, no significant biliary excretion of glimepiride or its M1 metabolite was observed.

Special Populations

No pharmacokinetic data are available for AVANDARYL in the following special populations. Information is provided for the individual components of AVANDARYL.

Gender

Rosiglitazone: 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). Combination therapy with rosiglitazone and sulfonylureas improved glycemic control in both males and females with a greater therapeutic response observed in females. For a given body mass index (BMI), females tend to have a greater fat mass than males. Since the molecular target of rosiglitazone, PPARγ, is expressed in adipose tissues, this differentiating characteristic may account, at least in part, for the greater response to rosiglitazone in combination with sulfonylureas in females. Since therapy should be individualized, no dose adjustments are necessary based on gender alone.

Glimepiride: There were no differences between males and females in the pharmacokinetics of glimepiride when adjustment was made for differences in body weight.

Geriatric

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

Glimepiride: A comparison of glimepiride pharmacokinetics in patients with type 2 diabetes ≤ 65 years and those > 65 years was evaluated in a multiple-dose study using glimepiride 6 mg daily. There were no significant differences in glimepiride pharmacokinetics between the 2 age groups. The mean AUC at steady state for the older patients was approximately 13% lower than that for the younger patients; the mean weight-adjusted clearance for the older patients was approximately 11% higher than that for the younger patients. [See Use in Specific Populations]

Hepatic Impairment

Therapy with AVANDARYL 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].

Rosiglitazone: 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.

Glimepiride: It is unknown whether there is an effect of hepatic impairment on glimepiride pharmacokinetics because the pharmacokinetics of glimepiride has not been adequately evaluated in patients with hepatic impairment.

Obese Patients

Glimepiride: The pharmacokinetics of glimepiride and its metabolites were measured in a single-dose study involving 28 patients with type 2 diabetes who either had normal body weight or were morbidly obese. While the Tmax, Cl, and Vd of glimepiride in the morbidly obese patients were similar to those in the normal weight group, the morbidly obese had lower Cmax and AUC than those of normal body weight. The mean Cmax, AUC0-24, AUC0-∞ values of glimepiride in normal versus morbidly obese patients were 547 ± 218 ng/mL versus 410 ± 124 ng/mL, 3,210 ± 1,030 hours.ng/mL versus 2,820 ± 1,110 hours.ng/mL and 4,000 ± 1,320 hours.ng/mL versus 3,280 ± 1,360 hours.ng/mL, respectively.

Race

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

Glimepiride: No studies have been conducted to assess the effects of race on glimepiride pharmacokinetics, but in placebo-controlled trials of glimepiride in patients with type 2 diabetes, the reduction in HbA1c was comparable in whites (N = 536), blacks (N = 63), and Hispanics (N = 63).

Renal Impairment

Rosiglitazone: 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.

Glimepiride: In a single-dose, open-label study, glimepiride 3 mg was administered to patients with mild, moderate, and severe renal impairment as estimated by creatinine clearance (Clcr): Group I consisted of 5 patients with mild renal impairment (CLcr > 50 mL/min), Group II consisted of 3 patients with moderate renal impairment (CLcr = 20 to 50 mL/min), and Group III consisted of 7 patients with severe renal impairment (CLcr < 20 mL/min). Although glimepiride serum concentrations decreased with decreasing renal function, Group III had a 2.3-fold higher mean AUC for M1 and an 8.6-fold higher mean AUC for M2 compared to corresponding mean AUCs in Group I. The apparent terminal half-life (T½) for glimepiride did not change, while the half-lives for M1 and M2 increased as renal function decreased. Mean urinary excretion of M1 plus M2 as a percentage of dose decreased from 44.4% for Group I to 21.9% for Group II and 9.3% for Group III).

Pediatric

No pharmacokinetic data from trials in pediatric subjects are available for AVANDARYL.

Rosiglitazone: 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.

Glimepiride: The pharmacokinetics of glimepiride (1 mg) were evaluated in a single-dose trial conducted in 30 type 2 diabetic patients (male = 7; female = 23) between ages 10 and 17 years. The mean (±SD) AUC0-last (339 ± 203 ng.h/mL), Cmax (102 ± 48 ng/mL), and t½ (3.1 ± 1.7 hours) were comparable to historical data from adults (AUC0-last 315 ± 96 ng.h/mL, Cmax 103 ± 34 ng/mL, and t½ 5.3 ± 4.1 hours).

Drug-drug Interactions

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

Rosiglitazone

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. [See DRUG INTERACTIONS]

Rosiglitazone (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: Rosiglitazone (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 rosiglitazone (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 rosiglitazone.

Digoxin: Repeat oral dosing of rosiglitazone (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 rosiglitazone had no clinically relevant effect on the steady-state pharmacokinetics of warfarin enantiomers.

Additional pharmacokinetic trials demonstrated no clinically relevant effect of acarbose, ranitidine, or metformin on the pharmacokinetics of rosiglitazone.

Glimepiride

Aspirin: In a randomized, double-blind, two-period, crossover study, healthy subjects were given either placebo or aspirin 1 gram three times daily for a total treatment period of 5 days. On Day 4 of each study period, a single 1 mg dose of glimepiride was administered. The glimepiride doses were separated by a 14-day washout period. Coadministration of aspirin and glimepiride resulted in a 34% decrease in the mean glimepiride AUC and a 4% decrease in the mean glimepiride Cmax.

Colesevelam: Concomitant administration of colesevelam and glimepiride resulted in reductions in glimepiride AUC0-∞ and Cmax of 18% and 8%, respectively. When glimepiride was administered 4 hours prior to colesevelam, there was no significant change in glimepiride AUC0-∞ or Cmax, -6% and 3%, respectively. [See DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS]

Cimetidine and Ranitidine: In a randomized, open-label, 3-way, crossover study, healthy subjects received either a single 4 mg dose of glimepiride alone, glimepiride with ranitidine (150 mg twice daily for 4 days; glimepiride was administered on Day 3), or glimepiride with cimetidine (800 mg daily for 4 days; glimepiride was administered on Day 3). Coadministration of cimetidine or ranitidine with a single 4-mg oral dose of glimepiride did not significantly alter the absorption and disposition of glimepiride.

Propranolol: In a randomized, double-blind, two-period, crossover study, healthy subjects were given either placebo or propranolol 40 mg three times daily for a total treatment period of 5 days. On Day 4 of each study period, a single 2 mg dose of glimepiride was administered. The glimepiride doses were separated by a 14-day washout period. Concomitant administration of propranolol and glimepiride significantly increased glimepiride Cmax, AUC, and T½ by 23%, 22%, and 15%, respectively, and decreased glimepiride CL/F by 18%. The recovery of M1 and M2 from urine was not changed.

Warfarin: In an open-label, two-way, crossover study, healthy subjects received 4 mg of glimepiride daily for 10 days. Single 25 mg doses of warfarin were administered 6 days before starting glimepiride and on Day 4 of glimepiride administration. The concomitant administration of glimepiride did not alter the pharmacokinetics of R- and S-warfarin enantiomers. No changes were observed in warfarin plasma protein binding. Glimepiride resulted in a statistically significant decrease in the pharmacodynamic response to warfarin. The reductions in mean area under the prothrombin time (PT) curve and maximum PT values during glimepiride treatment were 3.3% and 9.9%, respectively, and are unlikely to be clinically relevant.

Animal Toxicology And/Or Pharmacology

Rosiglitazone

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

Patients Inadequately Controlled On Diet And Exercise

In a 28-week, randomized, double-blind, clinical trial, 901 patients with type 2 diabetes inadequately controlled on diet and exercise alone (baseline mean fasting plasma glucose [FPG] 211 mg/dL and baseline mean HbA1c 9.1%) were started on AVANDARYL 4 mg/1 mg, rosiglitazone 4 mg, or glimepiride 1 mg. Doses could be increased at 4-week intervals to reach a target mean daily glucose of ≤ 110 mg/dL. Patients who received AVANDARYL were randomized to 1 of 2 titration schemes differing in the maximum total daily dose (4 mg/4 mg or 8 mg/4 mg). The maximum total daily dose was 8 mg for rosiglitazone monotherapy and 4 mg for glimepiride monotherapy. All treatments were administered as a once-daily regimen. Improvements in FPG and HbA1c were observed in patients treated with AVANDARYL compared with either rosiglitazone or glimepiride alone (see Table 8).

Table 8: Glycemic Parameters in a 28-Week Trial of AVANDARYL in Patients With Type 2 Diabetes Mellitus Inadequately Controlled on Diet and Exercise

Parameter Glimepiride Rosiglitazone AVANDARYL 4 mg/4 mg AVANDARYL 8 mg/4 mg
Mean Final Dose 3.5 mg 7.5 mg 4.0 mg/3.2 mg 6.8 mg/2.9 mg
N 221 227 221 214
FPG (mg/dL) [mean (SD)]
  Baseline 211 (70) 212 (66) 207 (58) 214 (61)
  Change from baseline -42 (66) -57 (58) -70 (57) -80 (57)
  Treatment difference between 
  - AVANDARYL and glimepiride -30a -37a
  - AVANDARYL and rosiglitazone % of patients with > 30 mg/dL decrease from baseline 56% 64% -16a 77% -23a 85%
HbA1c (%) [mean (SD)]
  Baseline 9.0 (1.3) 9.1 (1.3) 9.0 (1.3) 9.2 (1.4)
  Change from baseline -1.7 (1.4) -1.8 (1.5) -2.4 (1.4) -2.5 (1.4)
  Treatment difference between
  - AVANDARYL and glimepiride -0.6a -0.7a
  - AVANDARYL and rosiglitazone -0.7a -0.8a
  % of patients with > 0.7% decrease from baseline 82% 76% 93% 93%
  % of patients at HbAlc Target < 7.0%b 49% 46% 75% 72%
a Least squared means, P < 0.0001 compared with monotherapy.
b Response is related to baseline HbA1c.

Treatment with AVANDARYL resulted in statistically significant improvements in FPG and HbA1c compared with each of the monotherapies. However, when considering choice of therapy for drug-na´ve patients, the risk-benefit of initiating monotherapy or dual therapy should be considered. In particular, the risk of hypoglycemia and weight gain with dual therapy should be taken into account. [See WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS]

Patients Previously Treated With Sulfonylureas

The safety and efficacy of rosiglitazone added to a sulfonylurea have been studied in clinical trials in patients with type 2 diabetes inadequately controlled on sulfonylureas alone. No clinical trials have been conducted with the fixed-dose combination of AVANDARYL in patients inadequately controlled on a sulfonylurea or who have initially responded to rosiglitazone alone and require additional glycemic control.

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 rosiglitazone in combination with a sulfonylurea. Rosiglitazone 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 rosiglitazone 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 9 shows pooled data for 8 trials in which rosiglitazone added to sulfonylurea was compared with placebo plus sulfonylurea.

Table 9: Glycemic Parameters in 24- to 26-Week Combination Trials of Rosiglitazone Plus Sulfonylurea

Twice-Daily Divided Dosing (5 Trials) Sulfonylurea Rosiglitazone 2 mg Twice Daily + Sulfonylurea Sulfonylurea Rosiglitazone 4 mg Twice Daily + Sulfonylurea
N 397 497 248 346
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 Rosiglitazone 4 mg Once Daily +Sulfonylurea Sulfonylurea Rosiglitazone 8 mg Once Daily + Sulfonylurea
N 172 172 173 176
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 rosiglitazone 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 rosiglitazone (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 rosiglitazone plus glipizide arm 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 rosiglitazone 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.

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.

Last reviewed on RxList: 12/19/2016
This monograph has been modified to include the generic and brand name in many instances.

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