Avandaryl Information
Avandaryl (Rosiglitazone maleate,glimepiride) Indications And Usage
After consultation with a healthcare professional who has considered and advised the patient of the risks and benefits of rosiglitazone, Avandaryl (Rosiglitazone maleate,glimepiride) is indicated as an adjunct to diet and exercise to improve glycemic control when treatment with both rosiglitazone and glimepiride is appropriate in adults with type 2 diabetes mellitus who either are:
Avandaryl (Rosiglitazone maleate,glimepiride) Dosage And Administration
Prior to prescribing Avandaryl (Rosiglitazone maleate,glimepiride) , refer to for appropriate patient selection. Only prescribers enrolled in the AVANDIA-Rosiglitazone Medicines Access Program can prescribe Avandaryl (Rosiglitazone maleate,glimepiride)
The recommended starting dose is 4 mg/1 mg administered once daily with the first meal of the day. For adults already treated with a sulfonylurea or rosiglitazone, a starting dose of 4 mg/2 mg may be considered.
All patients should start the rosiglitazone component of Avandaryl (Rosiglitazone maleate,glimepiride) at the lowest recommended dose. Further increases in the dose of rosiglitazone should be accompanied by careful monitoring for adverse events related to fluid retention .
When switching from combination therapy of rosiglitazone plus glimepiride as separate tablets, the usual starting dose of Avandaryl (Rosiglitazone maleate,glimepiride) is the dose of rosiglitazone and glimepiride already being taken.
Dose increases should be individualized according to the glycemic response of the patient. Patients who may be more sensitive to glimepiride , including the elderly, debilitated, or malnourished, and those with renal, hepatic, or adrenal insufficiency, should be carefully titrated to avoid hypoglycemia. If hypoglycemia occurs during up-titration of the dose or while maintained on therapy, a dosage reduction of the glimepiride component of Avandaryl (Rosiglitazone maleate,glimepiride) may be considered. Increases in the dose of rosiglitazone should be accompanied by careful monitoring for adverse events related to fluid retention .
To switch to Avandaryl (Rosiglitazone maleate,glimepiride) for adults currently treated with rosiglitazone,
To switch to Avandaryl (Rosiglitazone maleate,glimepiride) for adults currently treated with sulfonylurea,
Pregnancy and Lactation:
Pediatric Use:
Avandaryl (Rosiglitazone maleate,glimepiride) Dosage Forms And Strengths
Each rounded triangular tablet contains rosiglitazone maleate and glimepiride as follows:
Avandaryl (Rosiglitazone maleate,glimepiride) Contraindications
Initiation of Avandaryl (Rosiglitazone maleate,glimepiride) in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated .
Avandaryl (Rosiglitazone maleate,glimepiride) Warnings And Precautions
The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the trial conducted by the University Group Diabetes Program (UGDP), a long-term, prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The trial involved 823 patients who were randomly assigned to one of four treatment groups ( 1970;19[Suppl. 2]:747-830). UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the trial to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP trial provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of glimepiride-containing tablets and of alternative modes of therapy.
Although only one drug in the sulfonylurea class (tolbutamide) was included in this trial, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.
Rosiglitazone, like other thiazolidinediones, alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate or lead to heart failure. Patients should be observed for signs and symptoms of heart failure. If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of rosiglitazone must be considered .
Patients with congestive heart failure (CHF) NYHA Class I and II treated with rosiglitazone have an increased risk of cardiovascular events. A 52-week, double-blind, placebo-controlled echocardiographic trial was conducted in 224 patients with type 2 diabetes mellitus and NYHA Class I or II CHF (ejection fraction ≤45%) on background antidiabetic and CHF therapy. An independent committee conducted a blinded evaluation of fluid-related events (including congestive heart failure) and cardiovascular hospitalizations according to predefined criteria (adjudication). Separate from the adjudication, other cardiovascular adverse events were reported by investigators. Although no treatment difference in change from baseline of ejection fractions was observed, more cardiovascular adverse events were observed with rosiglitazone treatment compared to placebo during the 52-week trial. (See Table 1.)
a
Initiation of Avandaryl (Rosiglitazone maleate,glimepiride) in patients with established NYHA Class III or IV heart failure is contraindicated. Avandaryl (Rosiglitazone maleate,glimepiride) is not recommended in patients with symptomatic heart failure.
Patients experiencing acute coronary syndromes have not been studied in controlled clinical trials. In view of the potential for development of heart failure in patients having an acute coronary event, initiation of Avandaryl (Rosiglitazone maleate,glimepiride) is not recommended for patients experiencing an acute coronary event, and discontinuation of Avandaryl (Rosiglitazone maleate,glimepiride) during this acute phase should be considered.
Patients with NYHA Class III and IV cardiac status (with or without CHF) have not been studied in controlled clinical trials. Avandaryl (Rosiglitazone maleate,glimepiride) is not recommended in patients with NYHA Class III and IV cardiac status.
In 7 controlled, randomized, double-blind trials which had durations from 16 to 26 weeks and which were included in a meta-analysis , patients with type 2 diabetes mellitus were randomized to coadministration of rosiglitazone and insulin (N = 1,018) or insulin (N = 815). In these 7 trials, rosiglitazone was added to insulin. These trials included patients with long-standing diabetes (median duration of 12 years) and a high prevalence of pre-existing medical conditions, including peripheral neuropathy, retinopathy, ischemic heart disease, vascular disease, and congestive heart failure. The total number of patients with emergent congestive heart failure was 23 (2.3%) and 8 (1.0%) in the rosiglitazone plus insulin and insulin groups, respectively.
Cardiovascular adverse events have been evaluated in a meta-analysis of 52 clinical trials, in long-term, prospective, randomized, controlled trials, and in observational studies.
In this analysis, a statistically significant increased risk of myocardial infarction with rosiglitazone versus pooled comparators was observed. Analyses were performed using a composite of major adverse cardiovascular events (myocardial infarction, stroke, and cardiovascular death), referred to hereafter as MACE. Rosiglitazone had a statistically non-significant increased risk of MACE compared to the pooled comparators. A statistically significant increased risk of myocardial infarction and statistically non-significant increased risk of MACE with rosiglitazone was observed in the placebo-controlled trials. In the active-controlled trials, there was no increased risk of myocardial infarction or MACE. (See Figure 1 and Table 3.)
RSG = rosiglitazone
Of the placebo-controlled trials in the meta-analysis, 7 trials had patients randomized to rosiglitazone plus insulin or insulin. There were more patients in the rosiglitazone plus insulin group compared to the insulin group with myocardial infarctions, MACE, cardiovascular deaths, and all-cause deaths (see Table 4). The total number of patients with stroke was 5 (0.5%) and 4 (0.5%) in the rosiglitazone plus insulin and insulin groups, respectively. The use of rosiglitazone in combination with insulin may increase the risk of myocardial infarction
ND = not defined
In each of these trials, there was a statistically non-significant increase in the risk of myocardial infarction for rosiglitazone versus comparator medications.
In a long-term, randomized, placebo-controlled, 2x2 factorial trial intended to evaluate rosiglitazone, and separately ramipril (an angiotensin converting enzyme inhibitor [ACEI]), on progression to overt diabetes in 5,269 subjects with glucose intolerance, the incidence of myocardial infarction was higher in the subset of subjects who received rosiglitazone in combination with ramipril than among subjects who received ramipril alone but not in the subset of subjects who received rosiglitazone alone compared to placebo. The higher incidence of myocardial infarction among subjects who received rosiglitazone in combination with ramipril was not confirmed in the two other large (total N = 8,798) long-term, randomized, active-controlled clinical trials conducted in patients with type 2 diabetes, in which 30% and 40% of patients in the two trials reported angiotensin-converting enzyme inhibitor use at baseline.
There have been no adequately designed clinical trials directly comparing rosiglitazone to pioglitazone on cardiovascular risks. However, in a long-term, randomized, placebo-controlled cardiovascular outcomes trial comparing pioglitazone to placebo in patients with type 2 diabetes mellitus and prior macrovascular disease, pioglitazone was not associated with an increased risk of myocardial infarction or total mortality.
The increased risk of myocardial infarction observed in the meta-analysis and large, long-term controlled clinical trials, and the increased risk of MACE observed in the meta-analysis described above, have not translated into a consistent finding of excess mortality from controlled clinical trials or observational studies. Clinical trials have not shown any difference between rosiglitazone and comparator medications in overall mortality or CV-related mortality.
Because of the potential increased risk of myocardial infarction, Avandaryl (Rosiglitazone maleate,glimepiride) is available only through a restricted distribution program called the AVANDIA-Rosiglitazone Medicines Access Program . Both prescribers and patients must enroll in the program to be able to prescribe or receive Avandaryl (Rosiglitazone maleate,glimepiride) , respectively. Avandaryl (Rosiglitazone maleate,glimepiride) will be available only from specially certified pharmacies participating in the program. As part of the program, prescribers will be educated about the potential increased risk of myocardial infarction and the need to limit the use of Avandaryl (Rosiglitazone maleate,glimepiride) to eligible patients. Prescribers will need to discuss with patients the risks and benefits of taking Avandaryl (Rosiglitazone maleate,glimepiride) . To enroll, call 1-800-AVANDIA or visit www.AVANDIA.com.
Avandaryl (Rosiglitazone maleate,glimepiride) is a combination tablet containing rosiglitazone and glimepiride, a sulfonylurea. All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Elderly patients are particularly susceptible to hypoglycemic action of glucose-lowering drugs. Debilitated or malnourished patients, and those with adrenal, pituitary, renal, or hepatic insufficiency are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. A starting dose of 1 mg glimepiride, as contained in Avandaryl (Rosiglitazone maleate,glimepiride) 4 mg/1 mg, followed by appropriate dose titration is recommended in these patients. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs or other sympatholytic agents. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used.
Patients receiving rosiglitazone in combination with a sulfonylurea may be at risk for hypoglycemia, and a reduction in the dose of the sulfonylurea may be necessary .
Avandaryl (Rosiglitazone maleate,glimepiride) should be used with caution in patients with edema. In a clinical trial in healthy volunteers who received 8 mg of rosiglitazone once daily for 8 weeks, there was a statistically significant increase in median plasma volume compared to placebo.
Since thiazolidinediones, including rosiglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, Avandaryl (Rosiglitazone maleate,glimepiride) should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure .
In controlled clinical trials of patients with type 2 diabetes, mild to moderate edema was reported in patients treated with rosiglitazone, and may be dose-related. Patients with ongoing edema were more likely to have adverse events associated with edema if started on combination therapy with insulin and rosiglitazone . The use of Avandaryl (Rosiglitazone maleate,glimepiride) in combination with insulin is not recommended.
Dose-related weight gain was seen with Avandaryl (Rosiglitazone maleate,glimepiride) , rosiglitazone alone, and rosiglitazone together with other hypoglycemic agents (see Table 5). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.
In a 4- to 6-year, monotherapy, comparative trial (ADOPT) in patients recently diagnosed with type 2 diabetes not previously treated with antidiabetic medication, the median weight change (25, 75 percentiles) from baseline at 4 years was 3.5 kg (0.0, 8.1) for rosiglitazone, 2.0 kg (-1.0, 4.8) for glyburide, and -2.4 kg (-5.4, 0.5) for metformin.
In postmarketing experience with rosiglitazone alone or in combination with other hypoglycemic agents, there have been rare reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure.
With sulfonylureas, including glimepiride, there may be an elevation of liver enzyme levels in rare cases. In isolated instances, impairment of liver function (e.g., with cholestasis and jaundice), as well as hepatitis (which may also lead to liver failure) have been reported.
Liver enzymes should be measured prior to the initiation of therapy with Avandaryl (Rosiglitazone maleate,glimepiride) in all patients and periodically thereafter per the clinical judgment of the healthcare professional. Therapy with Avandaryl (Rosiglitazone maleate,glimepiride) should not be initiated in patients with increased baseline liver enzyme levels (ALT >2.5X upper limit of normal). Patients with mildly elevated liver enzymes (ALT levels ≤2.5X upper limit of normal) at baseline or during therapy with Avandaryl (Rosiglitazone maleate,glimepiride) should be evaluated to determine the cause of the liver enzyme elevation. Initiation of, or continuation of, therapy with Avandaryl (Rosiglitazone maleate,glimepiride) in patients with mild liver enzyme elevations should proceed with caution and include close clinical follow-up, including more frequent liver enzyme monitoring, to determine if the liver enzyme elevations resolve or worsen. If at any time ALT levels increase to >3X the upper limit of normal in patients on therapy with Avandaryl (Rosiglitazone maleate,glimepiride) , liver enzyme levels should be rechecked as soon as possible. If ALT levels remain >3X the upper limit of normal, therapy with Avandaryl (Rosiglitazone maleate,glimepiride) should be discontinued.
If any patient develops symptoms suggesting hepatic dysfunction, which may include unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, and/or dark urine, liver enzymes should be checked. The decision whether to continue the patient on therapy with Avandaryl (Rosiglitazone maleate,glimepiride) should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued.
When a patient stabilized on any antidiabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold Avandaryl (Rosiglitazone maleate,glimepiride) and temporarily administer insulin. Avandaryl (Rosiglitazone maleate,glimepiride) may be reinstituted after the acute episode is resolved.
Periodic fasting glucose and HbA1c measurements should be performed to monitor therapeutic response.
Therapy with rosiglitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking rosiglitazone . Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been specifically investigated in clinical trials; therefore the frequency of this occurrence is not known.
Although hormonal imbalance has been seen in preclinical studies , the clinical significance of this finding is not known. If unexpected menstrual dysfunction occurs, the benefits of continued therapy with Avandaryl (Rosiglitazone maleate,glimepiride) should be reviewed.
Avandaryl (Rosiglitazone maleate,glimepiride) Adverse Reactions
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Trials utilizing rosiglitazone in combination with a sulfonylurea provide support for the use of Avandaryl (Rosiglitazone maleate,glimepiride) . Adverse event data from these trials, in addition to adverse events reported with the use of rosiglitazone and glimepiride therapy, are presented below.
Rosiglitazone:
Events of anemia and edema tended to be reported more frequently at higher doses, and were generally mild to moderate in severity and usually did not require discontinuation of treatment with rosiglitazone.
Edema was reported by 4.8% of patients receiving rosiglitazone compared to 1.3% on placebo, and 1.0% on sulfonylurea monotherapy. The reporting rate of edema was higher for rosiglitazone 8 mg added to a sulfonylurea (12.4%) compared to other combinations, with the exception of insulin. Anemia was reported by 1.9% of patients receiving rosiglitazone compared to 0.7% on placebo, 0.6% on sulfonylurea monotherapy, and 2.3% on rosiglitazone in combination with a sulfonylurea. Overall, the types of adverse experiences reported when rosiglitazone was added to a sulfonylurea were similar to those during monotherapy with rosiglitazone.
In 26-week double-blind, fixed-dose trials, edema was reported with higher frequency in the rosiglitazone plus insulin combination trials (insulin, 5.4%; and rosiglitazone in combination with insulin, 14.7%). Reports of new onset or exacerbation of congestive heart failure occurred at rates of 1% for insulin alone, and 2% (4 mg) and 3% (8 mg) for insulin in combination with rosiglitazone . The use of rosiglitazone in combination with insulin may increase the risk of myocardial infarction .
Long-Term Trial of Rosiglitazone as Monotherapy:
In ADOPT, fractures were reported in a greater number of women treated with rosiglitazone (9.3%, 2.7/100 patient-years) compared to glyburide (3.5%, 1.3/100 patient-years) or metformin (5.1%, 1.5/100 patient-years). The majority of the fractures in the women who received rosiglitazone were reported in the upper arm, hand, and foot. The observed incidence of fractures for male patients was similar among the 3 treatment groups.
Serum Transaminase Levels:
In pre-approval controlled trials, 0.2% of patients treated with rosiglitazone had reversible elevations in ALT >3X the upper limit of normal compared to 0.2% on placebo and 0.5% on active comparators. The ALT elevations in patients treated with rosiglitazone were reversible. Hyperbilirubinemia was found in 0.3% of patients treated with rosiglitazone compared with 0.9% treated with placebo and 1% in patients treated with active comparators. In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure.
In the 4- to 6-year ADOPT trial, patients treated with rosiglitazone (4,954 patient-years exposure), glyburide (4,244 patient-years exposure) or metformin (4,906 patient-years exposure) as monotherapy had the same rate of ALT increase to >3X upper limit of normal (0.3 per 100 patient-years exposure).
In addition to adverse reactions reported from clinical trials, the events described below have been identified during post-approval use of Avandaryl (Rosiglitazone maleate,glimepiride) or its individual components. Because these events are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or to always establish a causal relationship to drug exposure.
In patients receiving thiazolidinedione therapy, serious adverse events with or without a fatal outcome, potentially related to volume expansion (e.g., congestive heart failure, pulmonary edema, and pleural effusions) have been reported .
There are postmarketing reports with rosiglitazone of hepatitis, hepatic enzyme elevations to 3 or more times the upper limit of normal, and hepatic failure with and without fatal outcome, although causality has not been established.
There are postmarketing reports with rosiglitazone of rash, pruritus, urticaria, angioedema, anaphylactic reaction, Stevens-Johnson syndrome, and new onset or worsening diabetic macular edema with decreased visual acuity .
Avandaryl (Rosiglitazone maleate,glimepiride) Drug Interactions
An inhibitor of CYP2C8 (e.g., gemfibrozil) may increase the AUC of rosiglitazone and an inducer of CYP2C8 (e.g., rifampin) may decrease the AUC of rosiglitazone. Therefore, if an inhibitor or an inducer of CYP2C8 is started or stopped during treatment with rosiglitazone, changes in diabetes treatment may be needed based upon clinical response.
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. Potential interactions of glimepiride with other drugs metabolized by cytochrome P450 2C9 also include phenytoin, diclofenac, ibuprofen, naproxen, and mefenamic acid.
Avandaryl (Rosiglitazone maleate,glimepiride) Use In Specific Populations
Pregnancy Category C.
All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Careful monitoring of glucose control is essential in such patients. Most experts recommend that insulin monotherapy be used during pregnancy to maintain blood glucose levels as close to normal as possible. Avandaryl (Rosiglitazone maleate,glimepiride) should not be used during pregnancy.
Human Data:
Animal Studies:
Rosiglitazone:
Glimepiride:
In some studies in rats, offspring of dams exposed to high levels of glimepiride during pregnancy and lactation developed skeletal deformities consisting of shortening, thickening, and bending of the humerus during the postnatal period. Significant concentrations of glimepiride were observed in the serum and breast milk of the dams as well as in the serum of the pups. These skeletal deformations were determined to be the result of nursing from mothers exposed to glimepiride. Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives.
No trials have been conducted with Avandaryl (Rosiglitazone maleate,glimepiride) . It is not known whether rosiglitazone or glimepiride is excreted in human milk. Because many drugs are excreted in human milk, Avandaryl (Rosiglitazone maleate,glimepiride) should not be administered to a nursing woman.
Rosiglitazone:
Glimepiride:
Glimepiride:
Comparison of glimepiride pharmacokinetics in type 2 diabetes patients ≤65 years (N = 49) and those >65 years (N = 42) 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 drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Elderly patients are particularly susceptible to hypoglycemic action of glucose-lowering drugs. In elderly, debilitated, or malnourished patients, or in patients with renal, hepatic or adrenal insufficiency, the starting dose, dose increments, and maintenance dosage should be conservative based upon blood glucose levels prior to and after initiation of treatment to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs or other sympatholytic agents .
Avandaryl (Rosiglitazone maleate,glimepiride) Description
Avandaryl (Rosiglitazone maleate,glimepiride) contains 2 oral antidiabetic drugs used in the management of type 2 diabetes: rosiglitazone maleate and glimepiride.
Rosiglitazone maleate is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity. Rosiglitazone maleate is not chemically or functionally related to the sulfonylureas, the biguanides, or the alpha-glucosidase inhibitors. Chemically, rosiglitazone maleate is (±)-5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, ()-2-butenedioate (1:1) with a molecular weight of 473.52 (357.44 free base). The molecule has a single chiral center and is present as a racemate. Due to rapid interconversion, the enantiomers are functionally indistinguishable. The molecular formula is CHNOS•CHO. Rosiglitazone maleate is a white to off-white solid with a melting point range of 122° to 123°C. The pK values of rosiglitazone maleate are 6.8 and 6.1. It is readily soluble in ethanol and a buffered aqueous solution with pH of 2.3; solubility decreases with increasing pH in the physiological range. The structural formula of rosiglitazone maleate is:
Glimepiride is an oral antidiabetic drug of the sulfonylurea class. Glimepiride is a white to yellowish-white, crystalline, odorless to practically odorless powder. Chemically, glimepiride is 1-[[p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea with a molecular weight of 490.62. The molecular formula for glimepiride is CHNOS. Glimepiride is practically insoluble in water. The structural formula of glimepiride is:
Avandaryl (Rosiglitazone maleate,glimepiride) is available for oral administration as tablets containing rosiglitazone maleate and glimepiride, respectively, in the following strengths (expressed as rosiglitazone maleate/glimepiride): 4 mg/1 mg, 4 mg/2 mg, 4 mg/4 mg, 8 mg/2 mg, and 8 mg/4 mg. Each tablet contains the following inactive ingredients: Hypromellose 2910, lactose monohydrate, macrogol (polyethylene glycol), magnesium stearate, microcrystalline cellulose, sodium starch glycolate, titanium dioxide, and 1 or more of the following: Yellow, red, or black iron oxides.
Avandaryl (Rosiglitazone maleate,glimepiride) Clinical Pharmacology
Avandaryl (Rosiglitazone maleate,glimepiride) 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:
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 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 (Rosiglitazone maleate,glimepiride) 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 (Rosiglitazone maleate,glimepiride) 4 mg/4 mg, the area under the curve (AUC) and maximum concentration (C) 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 C was 13% lower when administered as the combination tablet (see Table 7).
AUC = area under the curve; C = maximum concentration; T = terminal half-life; T = time of maximum concentration.
Regimen A = Avandaryl (Rosiglitazone maleate,glimepiride) 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 T which is presented as arithmetic mean (range) and T, which is presented as median (range).
The rate and extent of absorption of both the rosiglitazone component and glimepiride component of Avandaryl (Rosiglitazone maleate,glimepiride) 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:
Rosiglitazone:
max
Glimepiride:
max
ss
Glimepiride:
Glimepiride:
When [C]glimepiride was given orally, approximately 60% of the total radioactivity was recovered in the urine in 7 days and M1 (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 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 has been observed.
Special Populations:
Pediatric:
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 C were observed after repeat doses of rosiglitazone (8 mg once daily) for 8 days in healthy adult subjects.
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.
11
Glyburide:
Digoxin:
Warfarin:
Additional pharmacokinetic trials demonstrated no clinically relevant effect of acarbose, ranitidine, or metformin on the pharmacokinetics of rosiglitazone.
Glimepiride:
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:
Aspirin:
max
H-Receptor Antagonists:
Beta-Blockers:
Warfarin:
ACE Inhibitors:
Other:
2
Avandaryl (Rosiglitazone maleate,glimepiride) Nonclinical Toxicology
No animal studies have been conducted with Avandaryl (Rosiglitazone maleate,glimepiride) . The following data are based on findings in studies performed with rosiglitazone or glimepiride alone.
Rosiglitazone was not carcinogenic in the mouse. There was an increase in incidence of adipose hyperplasia in the mouse at doses ≥1.5 mg/kg/day (approximately 2 times human AUC at the maximum recommended human daily dose). In rats, there was a significant increase in the incidence of benign adipose tissue tumors (lipomas) at doses ≥0.3 mg/kg/day (approximately 2 times human AUC at the maximum recommended human daily dose). These proliferative changes in both species are considered due to the persistent pharmacological overstimulation of adipose tissue.
Impairment of Fertility:
Mutagenesis:
Impairment of Fertility:
Rosiglitazone:
Avandaryl (Rosiglitazone maleate,glimepiride) Clinical Studies
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 (Rosiglitazone maleate,glimepiride) 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 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.
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 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 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 to no change on the glipizide arm.
Avandaryl (Rosiglitazone maleate,glimepiride) How Supplied/storage And Handling
Each rounded triangular tablet contains rosiglitazone as the maleate and glimepiride as follows:
4 mg/1 mg – yellow, gsk debossed on one side and 4/1 on the other.
4 mg/2 mg – orange, gsk debossed on one side and 4/2 on the other.
4 mg/4 mg – pink, gsk debossed on one side and 4/4 on the other.
8 mg/2 mg – pale pink, gsk debossed on one side and 8/2 on the other.
8 mg/4 mg – red, gsk debossed on one side and 8/4 on the other.
4 mg/1 mg bottles of 30: NDC 0173-0841-13
4 mg/2 mg bottles of 30: NDC 0173-0842-13
4 mg/4 mg bottles of 30: NDC 0173-0843-13
8 mg/2 mg bottles of 30: NDC 0173-0844-13
8 mg/4 mg bottles of 30: NDC 0173-0845-13
Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). Dispense in a tight, light-resistant container.
Avandaryl (Rosiglitazone maleate,glimepiride) Patient Counseling Information
Avandaryl (Rosiglitazone maleate,glimepiride)
Avandaryl (Rosiglitazone maleate,glimepiride)
Avandaryl (Rosiglitazone maleate,glimepiride)
Avandaryl (Rosiglitazone maleate,glimepiride)
Avandaryl (Rosiglitazone maleate,glimepiride)
Avandaryl (Rosiglitazone maleate,glimepiride)
Avandaryl (Rosiglitazone maleate,glimepiride)
