"The U.S. Food and Drug Administration (FDA) is warning that the type 2 diabetes medicines canagliflozin, dapagliflozin, and empagliflozin may lead to ketoacidosis, a serious condition where the body produces high levels of blood acids called keto"...
Mechanism Of Action
AVANDAMET combines 2 antidiabetic agents with different mechanisms of action to improve glycemic control in patients with type 2 diabetes: Rosiglitazone, a member of the thiazolidinedione class, and metformin, a member of the biguanide class. Thiazolidinediones are insulin sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas biguanides act primarily by decreasing endogenous hepatic glucose production.
Rosiglitazone improves glycemic control by improving insulin sensitivity. Rosiglitazone is a highly selective and potent agonist for the peroxisome proliferatoractivated receptor-gamma (PPARy). 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, PPARy-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 tissue. 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.
Metformin is an antidiabetic agent, which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antidiabetic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and increases peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects except in special circumstances [see WARNINGS AND PRECAUTIONS] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
In all 26-week controlled trials, across the recommended dose range, rosiglitazone as monotherapy was associated with increases in total cholesterol, LDL-cholesterol and HDLcholesterol and decreases in free fatty acids.
The lipid profiles of AVANDAMET as well as rosiglitazone and metformin monotherapies in patients who have inadequate glycemic control on diet and exercise are shown in Table 8.
Table 8: Summary of Meana Lipid Changes in
a 32-Week Trial of AVANDAMET in Patients With Type 2 Diabetes Mellitus who Have
Inadequate Glycemic Control on Diet and Exercise
|Parameter||AVANDAMET Nb = 132||Rosiglitazone Nb = 128||Metformin Nb = 117|
|Total Cholesterol (mg/dL)|
|% Change from baseline (mean)||-2.2%||5.3%||-9.0%|
|% Change from baseline (mean)||-0.2%||4.5%||-10.7%|
|% Change from baseline (mean)||5.8%||3.1%||0.0%|
|Triglycerides (mg/dL) Baseline (mean) % Change from baseline (mean)||180.3 -18.7%||166.6 -4.8%||175.7 -15.4%|
|a Data presented as geometric means throughout
bN = number of subjects with a baseline and end of treatment value.
The pattern of LDL, HDL, and total cholesterol changes following therapy with rosiglitazone added to metformin was generally similar to those seen with rosiglitazone monotherapy, and a small decrease in mean triglycerides was observed with the combination therapy.
AVANDAMET: In a bioequivalence and dose-proportionality trial of AVANDAMET 4 mg/500 mg, both the rosiglitazone component and the metformin component were bioequivalent to coadministered 4-mg rosiglitazone tablet and 500-mg metformin tablet under fasted conditions (see Table 9). In this trial, dose proportionality of rosiglitazone in the combination formulations of 1 mg/500 mg and 4 mg/500 mg was demonstrated.
Table 9: Mean (SD) Pharmacokinetic Parameters for
Rosiglitazone and Metformin
|AUC0-inf (ng•h/mL)||Cmax (ng/mL)||Tmaxa (h)||T½ (h)|
|A||25||1,442 (324)||242 (70)||0.95 (0.48-2.47)||4.26 (118)|
|B||25||1,398 (340)||254 (69)||0.57 (0.43-2.58)||3.95 (0.81)|
|C||24||349 (91)||63.0 (15.0)||0.57 (0.47-1.45)||3.87 (0.88)|
|A||25||7,116 (2,096)||1,106 (329)||2.97 (1.02-4.02)||3.46 (0.96)|
|B||25||7,413 (1,838)||1,135 (253)||2.50 (1.03-3.98)||3.36 (0.54)|
|C||24||6,945 (2,045)||1,080 (327)||2.97 (1.00-5.98)||3.35 (0.59)|
|a Median and range presented for Tmax.
AUC = area under the curve; Cmax = maximum concentration; Ty2 = terminal half-life. Regimen A = 4 mg/500 mg AVANDAMET; Regimen B = 4-mg rosiglitazone tablet + 500-mg metformin tablet; Regimen C = 1 mg/500 mg AVANDAMET.
Administration of AVANDAMET 4 mg/500 mg with food resulted in no change in overall exposure (AUC) for either rosiglitazone or metformin. However, there were decreases in Cmax of both components (22% for rosiglitazone and 15% for metformin, respectively) and a delay in Tmax of both components (1.5 hours for rosiglitazone and 0.5 hours for metformin, respectively). These changes are not likely to be clinically significant. The pharmacokinetics of both the rosiglitazone component and the metformin component of AVANDAMET when taken with food were similar to the pharmacokinetics of rosiglitazone and metformin when administered concomitantly as separate tablets with food.
Rosiglitazone: The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations are observed about 1 hour after dosing. Maximum plasma concentration (Cmax) and the area under the curve (AUC) of rosiglitazone increase in a dose-proportional manner over the therapeutic dose range.
Metformin: The absolute bioavailability of a 500-mg metformin tablet given under fasting conditions is approximately 50% to 60%. Trials using single oral doses of metformin tablets of 500 mg to 1,500 mg, and 850 mg to 2,550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination.
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.
Metformin: The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg metformin averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin, steady-state plasma concentrations of metformin are reached within 24 to 48 hours and are generally < 1 mcg/mL. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.
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 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. The elimination half-life is 3 to 4 hours and is independent of dose.
Metabolism and Excretion
Metformin: Intravenous single-dose trials in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance is approximately 3.5 times greater than creatinine clearance which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
Renal Impairment: In subjects with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance [see WARNINGS AND PRECAUTIONS, GLUCOPHAGE prescribing information]. Since metformin is contraindicated in patients with renal impairment, administration of AVANDAMET is contraindicated in these patients.
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 AVANDAMET 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].
No pharmacokinetic trials of metformin have been conducted in subjects with hepatic insufficiency.
Geriatric: 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. However, limited data from controlled pharmacokinetic trials of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the halflife is prolonged, and Cmax is increased, compared with healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function [see Use In Specific Populations, GLUCOPHAGE prescribing information]. Metformin treatment and therefore treatment with AVANDAMET should not be initiated in patients >80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS].
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). In rosiglitazone and metformin combination trials, efficacy was demonstrated with no gender differences in glycemic response.
Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical trials in patients with type 2 diabetes, the antihyperglycemic effect of metformin tablets was comparable in males and females.
Race: 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.
No trials of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical trials of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (N = 249), blacks (N = 51), and Hispanics (N = 24).
Pediatric: No pharmacokinetic data from trials in pediatric subjects are available for AVANDAMET.
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.1 [See DRUG INTERACTIONS]
Cationic Drugs: Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both singleand multiple-dose, metformin-cimetidine drug interaction trials, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose trial. Metformin had no effect on cimetidine pharmacokinetics. [See WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS]
Furosemide: A single-dose, metformin-furosemide drug interaction trial in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when coadministered chronically.
Nifedipine: A single-dose, metformin-nifedipine drug interaction trial in normal healthy volunteers demonstrated that coadministration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. Tmax and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.
Other: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid.
In healthy volunteers, the pharmacokinetics of metformin and propranolol and metformin and ibuprofen were not affected when coadministered in single-dose interaction trials. Metformin is negligibly bound to plasma proteins and is therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid.
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 of the rosiglitazone component of AVANDAMET, 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.
Patients Who Have Inadequate Glycemic Control On Diet and Exercise
In a 32-week, randomized, double-blind clinical trial, 468 patients with type 2 diabetes mellitus inadequately controlled on diet and exercise alone (mean baseline FPG 198 mg/dL and mean baseline HbA1c 8.8%) were randomized to AVANDAMET 2 mg/500 mg, rosiglitazone 4 mg, or metformin 500 mg. Doses were increased at 4-week intervals up to a maximum of 8 mg/2,000 mg for AVANDAMET, 8 mg for rosiglitazone, and 2,000 mg for metformin to reach a target mean daily glucose of ≤ 110 mg/dL. Following the initial dosage level, AVANDAMET, rosiglitazone, and metformin were all administered as twice-daily regimens. Statistically significant improvements in FPG and HbA1c were observed in patients treated with AVANDAMET compared with either rosiglitazone or metformin alone (see Table 10). However, when considering the choice of therapy for drug-naive patients, the risk-benefit of initiating monotherapy or dual therapy should be considered.
Table 10: Glycemic Parameters in a 32-Week Trial of
AVANDAMET in Patients With Type 2 Diabetes Mellitus Inadequately Controlled on
Diet and Exercise
|Parameter||AVANDAMET Rosiglitazone Metformin|
|Mean Final Dose||7.2 mg/1,799 mg||7.7 mg||1,847 mg|
|Change from baseline (mean)||-74||-47||-51|
|Difference between AVANDAMET and monotherapy (adjusted mean)||-22a||-22a|
|% of patients with ≥30 mg/dL decrease from baseline||86%||68%||64%|
|Change from baseline (mean)||-2.3%||-1.6%||-1.8%|
|Difference between AVANDAMET and monotherapy (adjusted mean)||-0.6a||-0.4a|
|% of patients with HbA1c ≥0.7% decrease from baseline||92%||79%||84%|
|% of Patients with HbA1c < 7.0%||77%||58%||57%|
|a P < 0.001 AVANDAMET compared with rosiglitazone or metformin.|
Patients screened in the double-blind clinical trial described above with HbA1c >11% or FPG >270 mg/dL were not eligible for blinded treatment but were treated with open-label AVANDAMET (4 mg/1,000 mg up to a maximum dose of 8 mg/2,000 mg). Treatment with AVANDAMET reduced mean HbA1c from a baseline of 11.8% to 7.8% and mean FPG from a baseline of 305 mg/dL to 166 mg/dL. Given the lack of direct comparators in this evaluation, determination of the exact contribution of rosiglitazone and metformin as well as diet and exercise, to the observed improvement in glycemic control is not possible.
Patients Previously Treated With Metformin
AVANDAMET was not studied in patients previously treated with metformin monotherapy; however, the combination of rosiglitazone and metformin was compared with rosiglitazone and metformin monotherapies in clinical trials. Bioequivalence between AVANDAMET and coadministered rosiglitazone tablets and metformin tablets has been demonstrated [see CLINICAL PHARMACOLOGY].
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 rosiglitazone in combination with metformin. Rosiglitazone, administered in either once-daily or twice-daily dosing regimens, was added to the therapy of patients who were inadequately controlled on 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 rosiglitazone 4 mg once daily, rosiglitazone 8 mg 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 rosiglitazone 4 mg once daily and rosiglitazone 8 mg once daily, versus patients continued on metformin alone (see Table 11).
Table 11: Glycemic Parameters in a 26-Week Trial of
Rosiglitazone Added to Metformin Therapy
|Parameter||Metformin||Rosiglitazone 4 mg Once Daily + Metformin||Rosiglitazone 8 mg Once Daily + Metformin|
|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%|
|Change from baseline (mean)||0.5||-0.6||-0.8|
|Difference from metformin alone (adjusted mean)||-1.0a||-1.2a|
|% of patients with HbA1c ≥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 rosiglitazone 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 rosiglitazone resulted in lower levels of FPG and HbA1c than either agent alone.
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: 5/28/2014
This monograph has been modified to include the generic and brand name in many instances.
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