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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: The primary mechanism of action of glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. In addition, extrapancreatic effects may also play a role in the activity of sulfonylureas such as glimepiride. This is supported by both preclinical and clinical trials demonstrating that glimepiride administration can lead to increased sensitivity of peripheral tissues to insulin. These findings are consistent with the results of a long-term, randomized, placebo-controlled trial in which glimepiride therapy improved postprandial insulin/C-peptide responses and overall glycemic control without producing clinically meaningful increases in fasting insulin/C-peptide levels. However, as with other sulfonylureas, the mechanism by which glimepiride lowers blood glucose during long-term administration has not been clearly established.
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.
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)
|Regimen A||Regimen B||Regimen A||Regimen B|
|Cmax (ng/mL)|| 257
|T½ (hr)|| 3.53
|Tmax (hr)|| 1.00
|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.
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 to the fasted state. There was an increase in both AUC (19%) and CmaX (55%) of glimepiride in the fed state compared to 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: After oral administration, glimepiride is completely (100%) absorbed from the gastrointestinal tract. Trials with single oral doses in normal subjects and with multiple oral doses in patients with type 2 diabetes have shown significant absorption of glimepiride within 1 hour after administration and Cmax at 2 to 3 hours.
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 normal 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 (Ml) and the carboxyl derivative (M2). Cytochrome P450 2C9 has been shown to be involved in the biotransformation of glimepiride to Ml. Ml is further metabolized to M2 by one or several cytosolic enzymes. Ml, but not M2, possesses about 1/3 of the pharmacological activity as compared to its parent in an animal model; however, whether the glucose-lowering effect of Ml is clinically meaningful is not clear.
When [14C] glimepiride was given orally, approximately 60% of the total radioactivity was recovered in the urine in 7 days and Ml (predominant) and M2 accounted for 80 to 90% of that recovered in the urine. Approximately 40% of the total radioactivity was recovered in feces and Ml 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 Ml metabolite has been observed.
No pharmacokinetic data are available for AVANDARYL in the following special populations. Information is provided for the individual components of AVANDARYL.
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 to 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.
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: Comparison of glimepiride pharmacokinetics in type 2 diabetes patients 65 years and younger with those older than 65 years was performed in a trial using a dosing regimen of 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 about 13% lower than that for the younger patients; the mean weight-adjusted clearance for the older patients was about 11% higher than that for the younger patients. [See Use in Specific Populations]
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 to 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 to healthy subjects.
Glimepiride: No trials of glimepiride have been conducted in patients with hepatic insufficiency.
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 pharmacokinetic trials to assess the effects of race have been performed, but in placebo-controlled trials of glimepiride in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (N = 536), blacks (N = 63), and Hispanics (N = 63).
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 to subjects with normal renal function.
Glimepiride: A single-dose glimepiride, open-label trial was conducted in 15 patients with renal impairment. Glimepiride (3 mg) was administered to 3 groups of patients with different levels of mean creatinine clearance (CLcr); (Group I, CLcr = 77.7 mL/min, N = 5), (Group II, CLcr = 27.7 mL/min, N = 3), and (Group III, CLcr = 9.4 mL/min, N = 7). Glimepiride was found to be well tolerated in all 3 groups. The results showed that glimepiride serum levels decreased as renal function decreased. However, Ml and M2 serum levels (mean AUC values) increased 2.3 and 8.6 times from Group I to Group III. The apparent terminal half-life (Ti/2) for glimepiride did not change, while the half-lives for Ml and M2 increased as renal function decreased. Mean urinary excretion of Ml plus M2 as percent of dose, however, decreased (44.4%, 21.9%, and 9.3% for Groups I to III). A multiple-dose titration trial was also conducted in 16 type 2 diabetes patients with renal impairment using doses ranging from 1 to 8 mg daily for 3 months. The results were consistent with those observed after single doses. All patients with a CLcr less than 22 mL/min had adequate control of their glucose levels with a dosage regimen of only 1 mg daily. The results from this trial suggest that a starting dose of 1 mg glimepiride, as contained in AVANDARYL 4 mg/1 mg, may be given to type 2 diabetes patients with kidney disease, and the dose may be titrated based on fasting glucose levels.
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/hr 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 AUC0-last (338.8 ± 203.1 ng.hr/mL), Cmax (102.4 ± 47.7 ng/mL), and T1/2 (3.1 ± 1.7 hours) were comparable to those previously reported in adults (AUC0-last 315.2 ± 95.9 ng.hr/mL, Cmax 103.2 ± 34.3 ng/mL, and T1/2 5.3 ± 4.1 hours).
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.
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 CYP3 A4.
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 to 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 to the administration of rosiglitazone (8 mg) alone [see DRUG INTERACTIONS].11
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.
The hypoglycemic action of sulfonylureas may be potentiated by certain drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs) and other drugs that are highly protein bound, such as salicylates, sulfonamides, chloramphenicol, coumarins, probenecid, monoamine oxidase inhibitors, and beta-adrenergic blocking agents. When these drugs are administered to a patient receiving glimepiride, the patient should be observed closely for hypoglycemia. When these drugs are withdrawn from a patient receiving glimepiride, the patient should be observed closely for loss of glycemic control.
Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, and isoniazid. When these drugs are administered to a patient receiving glimepiride, the patient should be closely observed for loss of control. When these drugs are withdrawn from a patient receiving glimepiride, the patient should be observed closely for hypoglycemia.
Drugs Metabolized by Cytochrome P450: A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the IV, topical, or vaginal preparations of miconazole is not known. There is a potential interaction of glimepiride with inhibitors (e.g., fluconazole) and inducers (e.g., rifampicin) of cytochrome P450 2C9.
Aspirin: Coadministration of aspirin (1 g three times daily) and glimepiride led to a 34% decrease in the mean glimepiride AUC and, therefore, a 34% increase in the mean CL/F. The mean Cmax had a decrease of 4%. Blood glucose and serum C-peptide concentrations were unaffected and no hypoglycemic symptoms were reported.
H2-Receptor Antagonists: Coadministration of either cimetidine (800 mg once daily) or ranitidine (150 mg twice daily) with a single 4-mg oral dose of glimepiride did not significantly alter the absorption and disposition of glimepiride, and no differences were seen in hypoglycemic symptomatology.
Beta-Blockers: Concomitant administration of propranolol (40 mg three times daily) and glimepiride significantly increased Cmax, AUC, and T1/2 of glimepiride by 23%, 22%, and 15%, respectively, and it decreased CL/F by 18%. The recovery of Ml and M2 from urine, however, did not change. The pharmacodynamic responses to glimepiride were nearly identical in normal subjects receiving propranolol and placebo. Pooled data from clinical trials in patients with type 2 diabetes showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of beta-blockers. However, if beta-blockers are used, caution should be exercised and patients should be warned about the potential for hypoglycemia.
Warfarin: Concomitant administration of glimepiride tablets (4 mg once daily) did not alter the pharmacokinetic characteristics of R- and S-warfarin enantiomers following administration of a single dose (25 mg) of racemic warfarin to healthy subjects. No changes were observed in warfarin plasma protein binding. Glimepiride treatment did result in a slight, but 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 very small (3.3% and 9.9%, respectively) and are unlikely to be clinically important.
ACE Inhibitors: The responses of serum glucose, insulin, C-peptide, and plasma glucagon to 2 mg glimepiride were unaffected by Coadministration of ramipril (an ACE inhibitor) 5 mg once daily in normal subjects. No hypoglycemic symptoms were reported.
Other: Although no specific interaction trials were performed, pooled data from clinical trials showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of aspirin and other salicylates, H2-receptor antagonists, ACE inhibitors, calcium-channel blockers, estrogens, fibrates, NSAIDs, HMG CoA reductase inhibitors, sulfonamides, or thyroid hormone.
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.
Glimepiride: Reduced serum glucose values and degranulation of the pancreatic beta cells were observed in beagle dogs exposed to glimepiride 320 mg/kg/day for 12 months (approximately 1,000 times the recommended human dose based on surface area). No evidence of tumor formation was observed in any organ. One female and one male dog developed bilateral subcapsular cataracts. Non-GLP studies indicated that glimepiride was unlikely to exacerbate cataract formation. Evaluation of the co-cataractogenic potential of glimepiride in several diabetic and cataract rat models was negative and there was no adverse effect of glimepiride on bovine ocular lens metabolism in organ culture [see ADVERSE REACTIONS].
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 HbAlc compared to placebo plus sulfonylurea or further up-titration of the sulfonylurea. Table 8 shows pooled data for 8 trials in which rosiglitazone added to sulfonylurea was compared to placebo plus sulfonylurea.
Table 8. Glycemic Parameters in 24- to 26-Week Combination
Trials of Rosiglitazone Plus Sulfonylurea
| Twice Daily Divided Dosing
2 mg twice daily + sulfonylurea
4 mg twice daily + sulfonylurea
|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%|
|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
4 mg once daily + sulfonylurea
8 mg once daily + sulfonylurea
|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%|
|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 to 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 HbAlc.
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 HbAlc 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 to 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 HbAlc 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 HbAlc compared to no change on the glipizide arm.
11. 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: 12/5/2011
This monograph has been modified to include the generic and brand name in many instances.
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