Drug: Avandaryl

AVANDARYL 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, (Z)-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 C18H19N3O3S•C4H4O4. Rosiglitazone maleate is a white to off-white solid with a melting point range of 122° to 123°C. The pKa 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 C24H34N4O5S. Glimepiride is practically insoluble in water. The structural formula of glimepiride is: AVANDARYL 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.

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The following adverse reactions are discussed in more detail elsewhere in the labeling:
  • Increased Risk of Cardiovascular Mortality for Sulfonylurea Drugs [see WARNINGS AND PRECAUTIONS]
  • Cardiac Failure With Rosiglitazone [see WARNINGS AND PRECAUTIONS]
  • Major Adverse Cardiovascular Events [see WARNINGS AND PRECAUTIONS]
  • Hypoglycemia [see WARNINGS AND PRECAUTIONS]
  • Edema [see WARNINGS AND PRECAUTIONS]
  • Weight Gain [see WARNINGS AND PRECAUTIONS]
  • Hepatic Effects [see WARNINGS AND PRECAUTIONS]
  • Macular Edema [see WARNINGS AND PRECAUTIONS]
  • Fractures [see WARNINGS AND PRECAUTIONS]
  • Hematologic Effects [see WARNINGS AND PRECAUTIONS]
  • Hemolytic Anemia [see WARNINGS AND PRECAUTIONS]
  • Ovul ati on [see WARNINGS AND PRECAUTIONS]
Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Patients With Inadequate Glycemic Control on Diet and Exercise Table 3 summarizes adverse events occurring at a frequency of ≥ 5% in any treatment group in the 28-week, double-blind trial of AVANDARYL in patients with type 2 diabetes mellitus inadequately controlled on diet and exercise. Patients in this trial 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 maximum total daily dose of either 4 mg/4 mg or 8 mg/4 mg for AVANDARYL, 8 mg for rosiglitazone monotherapy, or 4 mg for glimepiride monotherapy. Table 3: Adverse Events ( ≥ 5% in any Treatment Group) Reported by Patients With Inadequate Glycemic Control on Diet and Exercise in a 28-Week, Double-blind Clinical Trial of AVANDARIYL
Preferred Term Glimepiride Monotherapy
N = 222
% Rosiglitazone Monotherapy
N = 230
% AVANDARYL 4 mg/4 mg
N = 224
% AVANDARYL 8 mg/4 mg
N = 218
% Headache 2.3 6.1 3.1 6.0 Nasopharyngitis 3.6 5.2 4.0 4.6 Hypertension 3.6 5.2 3.1 2.3 Hypoglycemiaa 4.1 0.4 3.6 5.5 a As documented by symptoms and a fingerstick blood glucose measurement of < 50 mg/dL. Hypoglycemia was reported to be generally mild to moderate in intensity and none of the reported events of hypoglycemia resulted in withdrawal from the trial. Hypoglycemia requiring parenteral treatment (i.e., intravenous glucose or glucagon injection) was observed in 3 (0.7%) patients treated with AVANDARYL. Edema was reported by 3.2% of patients on AVANDARYL, 3.0% on rosiglitazone alone, and 2.3% on glimepiride alone. Congestive heart failure was observed in 1 (0.2%) patient treated with AVANDARYL and in 1 (0.4%) patient treated with rosiglitazone monotherapy. Patients Treated With Rosiglitazone Added to Sulfonylurea Monotherapy and Other Experience With Rosiglitazone or Glimepiride Trials utilizing rosiglitazone in combination with a sulfonylurea provide support for the use of AVANDARYL. Adverse event data from these trials, in addition to adverse events reported with the use of rosiglitazone and glimepiride therapy, are presented below. Rosiglitazone: The most common adverse experiences with rosiglitazone monotherapy ( ≥ 5%) were upper respiratory tract infection, injury, and headache. Overall, the types of adverse experiences reported when rosiglitazone was added to a sulfonylurea were similar to those during monotherapy with rosiglitazone. In controlled combination therapy trials with sulfonylureas, mild to moderate hypoglycemic symptoms, which appear to be dose-related, were reported. Few patients were withdrawn for hypoglycemia ( < 1%) and few episodes of hypoglycemia were considered to be severe ( < 1%). 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 with 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 with other combinations, with the exception of insulin. Anemia was reported by 1.9% of patients receiving rosiglitazone compared with 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 [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Glimepiride: Hypoglycemia: The incidence of hypoglycemia with glimepiride, as documented by blood glucose values < 60 mg/dL, ranged from 0.9% to 1.7% in 2 large, wellcontrolled, 1-year trials. In patients treated with glimepiride in US placebo-controlled trials (N = 746), adverse events, other than hypoglycemia, considered to be possibly or probably related to trial drug that occurred in more than 1% of patients included dizziness (1.7%), asthenia (1.6%), headache (1.5%), and nausea (1.1%). Gastrointestinal Reactions: Vomiting, gastrointestinal pain, and diarrhea have been reported, but the incidence in placebo-controlled trials was less than 1%. In rare cases, there may be an elevation of liver enzyme levels. 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 with sulfonylureas, including glimepiride. Dermatologic Reactions: Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in less than 1% of treated patients. These may be transient and may disappear despite continued use of glimepiride. If those hypersensitivity reactions persist or worsen, the drug should be discontinued. Porphyria cutanea tarda, photosensitivity reactions, and allergic vasculitis have been reported with sulfonylureas, including glimepiride. Hematologic Reactions: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia [see WARNINGS AND PRECAUTIONS], aplastic anemia, and pancytopenia have been reported with sulfonylureas, including glimepiride. Metabolic Reactions: Hepatic porphyria reactions and disulfiram-like reactions have been reported with sulfonylureas, including glimepiride. Cases of hyponatremia have been reported with glimepiride and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone. The syndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with certain other sulfonylureas, including glimepiride, and it has been suggested that certain sulfonylureas may augment the peripheral (antidiuretic) action of ADH and/or increase release of ADH. Other Reactions: Changes in accommodation and/or blurred vision may occur with the use of glimepiride. This is thought to be due to changes in blood glucose, and may be more pronounced when treatment is initiated. This condition is also seen in untreated diabetic patients, and may actually be reduced by treatment. In placebo-controlled trials of glimepiride, the incidence of blurred vision was placebo, 0.7%, and glimepiride, 0.4%. Human Ophthalmology Data: Ophthalmic examinations were carried out in more than 500 subjects during long-term trials of glimepiride using the methodology of Taylor and West and Laties et al. No significant differences were seen between glimepiride and glyburide in the number of subjects with clinically important changes in visual acuity, intraocular tension, or in any of the 5 lens-related variables examined. Ophthalmic examinations were carried out during long-term trials using the method of Chylack et al. No significant or clinically meaningful differences were seen between glimepiride and glipizide with respect to cataract progression by subjective LOCS II grading and objective image analysis systems, visual acuity, intraocular pressure, and general ophthalmic examination [see Nonclinical Toxicology]. Long-term Trial of Rosiglitazone as Monotherapy A 4- to 6-year trial (ADOPT) compared the use of rosiglitazone (n = 1,456), glyburide (n = 1,441), and metformin (n = 1,454) as monotherapy in patients recently diagnosed with type 2 diabetes who were not previously treated with antidiabetic medication. Table 4 presents adverse reactions without regard to causality; rates are expressed per 100 patient-years (PY) exposure to account for the differences in exposure to trial medication across the 3 treatment groups. In ADOPT, fractures were reported in a greater number of women treated with rosiglitazone (9.3%, 2.7/100 patient-years) compared with glyburide (3.5%, 1.3/100 patientyears) 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. [See WARNINGS AND PRECAUTIONS] The observed incidence of fractures for male patients was similar among the 3 treatment groups. Table 4: On-therapy Adverse Events [ ≥ 5 Events/100 Patient-Years (PY)] in any Treatment Group Reported in a 4- to 6-Year Clinical Trial of Rosiglitazone as Monotherapy (ADOPT)
Preferred Term Rosiglitazone
N = 1,456
PY = 4,954 Glyburide
N = 1,441
PY = 4,244 Metformin
N = 1,454
PY = 4,906 Nasopharyngitis 6.3 6.9 6.6 Back pain 5.1 4.9 5.3 Arthralgia 5.0 4.8 4.2 Hypertension 4.4 6.0 6.1 Upper respiratory tract infection 4.3 5.0 4.7 Hypoglycemia 2.9 13.0 3.4 Diarrhea 2.5 3.2 6.8 Long-term Trial of Rosiglitazone as Combination Therapy (RECORD): RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes) was a multicenter, randomized, open-label, non-inferiority trial in subjects with type 2 diabetes inadequately controlled on maximum doses of metformin or sulfonylurea (glyburide, gliclazide, or glimepiride) to compare the time to reach the combined cardiovascular endpoint of cardiovascular death or cardiovascular hospitalization between patients randomized to the addition of rosiglitazone versus metformin or sulfonylurea. The trial included patients who have failed metformin or sulfonylurea monotherapy; those who failed metformin (n = 2,222) were randomized to receive either add-on rosiglitazone (n = 1,117) or add-on sulfonylurea (n = 1,105), and those who failed sulfonylurea (n = 2,225) were randomized to receive either add-on rosiglitazone (n = 1,103) or add-on metformin (n = 1,122). Patients were treated to target HbA1c ≤ 7% throughout the trial. The mean age of patients in this trial was 58 years, 52% were male, and the mean duration of follow-up was 5.5 years. Rosiglitazone demonstrated non-inferiority to active control for the primary endpoint of cardiovascular hospitalization or cardiovascular death (HR 0.99, 95% CI: 0.85-1.16). There were no significant differences between groups for secondary endpoints with the exception of congestive heart failure (see Table 5). The incidence of congestive heart failure was significantly greater among patients randomized to rosiglitazone. Table 5: Cardiovascular (CV) Outcomes for the RECORD Trial
Primary Endpoint Rosiglitazone
N = 2,220 Active Control
N = 2,227 Hazard Ratio 95% CI CV death or CV hospitalization 321 323 0.99 0.85-1.16 Secondary Endpoint All-cause death 136 157 0.86 0.68-1.08 CV death 60 71 0.84 0.59-1.18 Myocardial infarction 64 56 1.14 0.80-1.63 Stroke 46 63 0.72 0.49-1.06 CV death, myocardial infarction, or stroke 154 165 0.93 0.74-1.15 Heart failure 61 29 2.10 1.35-3.27 There was an increased incidence of bone fracture for subjects randomized to rosiglitazone in addition to metformin or sulfonylurea compared with those randomized to metformin plus sulfonylurea (8.3% versus 5.3%) [see WARNINGS AND PRECAUTIONS]. The majority of fractures were reported in the upper limbs and distal lower limbs. The risk of fracture appeared to be higher in females relative to control (11.5% versus 6.3%), than in males relative to control (5.3% versus 4.3%). Additional data are necessary to determine whether there is an increased risk of fracture in males after a longer period of follow-up. Laboratory Abnormalities Rosiglitazone Hematologic: Decreases in mean hemoglobin and hematocrit occurred in a dose-related fashion in adult patients treated with rosiglitazone (mean decreases in individual trials as much as 1.0 g/dL hemoglobin and as much as 3.3% hematocrit). The changes occurred primarily during the first 3 months following initiation of therapy with rosiglitazone or following a dose increase in rosiglitazone. The time course and magnitude of decreases were similar in patients treated with a combination of rosiglitazone and other hypoglycemic agents or monotherapy with rosiglitazone. White blood cell counts also decreased slightly in adult patients treated with rosiglitazone. Decreases in hematologic parameters may be related to increased plasma volume observed with treatment with rosiglitazone. Lipids: Changes in serum lipids have been observed following treatment with rosiglitazone in adults [see CLINICAL PHARMACOLOGY]. Serum Transaminase Levels: In pre-approval clinical trials in 4,598 patients treated with rosiglitazone encompassing approximately 3,600 patient-years of exposure, there was no evidence of drug-induced hepatotoxicity. In pre-approval controlled trials, 0.2% of patients treated with rosiglitazone had reversible elevations in ALT > 3X the upper limit of normal compared with 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. [See WARNINGS AND PRECAUTIONS] 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 the RECORD trial, patients randomized to rosiglitazone in addition to metformin or sulfonylurea (10,849 patient-years exposure) and to metformin plus sulfonylurea (10,209 patientyears exposure) had a rate of ALT increase to ≥ 3X upper limit of normal of approximately 0.2 and 0.3 per 100 patient-years exposure, respectively. Postmarketing Experience In addition to adverse reactions reported from clinical trials, the events described below have been identified during post-approval use of AVANDARYL 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 [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. 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 [see CONTRAINDICATIONS], and new onset or worsening diabetic macular edema with decreased visual acuity [see WARNINGS AND PRECAUTIONS]. Read the Avandaryl (rosiglitazone maleate and glimepiride) Side Effects Center for a complete guide to possible side effectsLearn More »

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Therapy with AVANDARYL should be individualized for each patient. The risk-benefit of initiating monotherapy versus dual therapy with AVANDARYL should be considered. No studies have been performed specifically examining the safety and efficacy of AVANDARYL in patients previously treated with other oral hypoglycemic agents and switched to AVANDARYL. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur. [See INDICATIONS AND USAGE] Starting Dose 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 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 [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. When switching from combination therapy of rosiglitazone plus glimepiride as separate tablets, the usual starting dose of AVANDARYL is the dose of rosiglitazone and glimepiride already being taken. Dose Titration Dose increases should be individualized according to the glycemic response of the patient. Patients who may be more sensitive to glimepiride [see WARNINGS AND PRECAUTIONS], 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 may be considered. Increases in the dose of rosiglitazone should be accompanied by careful monitoring for adverse events related to fluid retention [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. To switch to AVANDARYL for adults currently treated with rosiglitazone, dose titration of the glimepiride component of AVANDARYL is recommended if patients are not adequately controlled after 1 to 2 weeks. The glimepiride component may be increased in no more than 2 mg increments. After an increase in the dosage of the glimepiride component, dose titration of AVANDARYL is recommended if patients are not adequately controlled after 1 to 2 weeks. To switch to AVANDARYL for adults currently treated with sulfonylurea, it may take 2 weeks to see a reduction in blood glucose and 2 to 3 months to see the full effect of the rosiglitazone component. Therefore, dose titration of the rosiglitazone component of AVANDARYL is recommended if patients are not adequately controlled after 8 to 12 weeks. Patients should be observed carefully (1 to 2 weeks) for hypoglycemia when being transferred from longer half-life sulfonylureas (e.g., chlorpropamide) to AVANDARYL due to potential overlapping of drug effect. After an increase in the dosage of the rosiglitazone component, dose titration of AVANDARYL is recommended if patients are not adequately controlled after 2 to 3 months. Maximum Dose The maximum recommended daily dose is 8 mg rosiglitazone and 4 mg glimepiride. Specific Patient Populations Elderly and Malnourished Patients and Those With Renal, Hepatic, or Adrenal Insufficiency In elderly, debilitated, or malnourished patients, or in patients with renal, hepatic, or adrenal insufficiency, the starting dose, dose increments, and maintenance dosage of AVANDARYL should be conservative to avoid hypoglycemic reactions. [See WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY] Hepatic Impairment Liver enzymes should be measured prior to initiating treatment with AVANDARYL. 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 start of therapy). After initiation of AVANDARYL, liver enzymes should be monitored periodically per the clinical judgment of the healthcare professional. [See WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY] Pregnancy and Lactation AVANDARYL should not be used during pregnancy or in nursing mothers. Pediatric Use Safety and effectiveness of AVANDARYL in pediatric patients have not been established. AVANDARYL and its components, rosiglitazone and glimepiride, are not recommended for use in pediatric patients.

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Drugs Metabolized By Cytochrome P450 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. [See CLINICAL PHARMACOLOGY] 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. [See CLINICAL PHARMACOLOGY] Drugs That Produce Hyperglycemia 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. Read the Avandaryl Drug Interactions Center for a complete guide to possible interactions Learn More »

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AVANDARYL® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Important Limitations of Use
  • Due to its mechanism of action, rosiglitazone is active only in the presence of endogenous insulin. Therefore, AVANDARYL should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
  • Coadministration of AVANDARYL with insulin is not recommended [see WARNINGS AND PRECAUTIONS].

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Initiation of AVANDARYL in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated [see BOXED WARNING]. AVANDARYL is contraindicated in patients with a history of a hypersensitivity reaction to rosiglitazone or any of the product's ingredients. 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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Rosiglitazone Limited data are available with regard to overdosage in humans. In clinical trials in volunteers, rosiglitazone has been administered at single oral doses of up to 20 mg and was well tolerated. In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patient's clinical status. Glimepiride Overdosage of sulfonylureas, including glimepiride, can produce hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid IV injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours, because hypoglycemia may recur after apparent clinical recovery.

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Dosage Forms And Strengths Each rounded triangular tablet contains rosiglitazone 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.
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. GlaxoSmithKline, Research Triangle Park, NC 27709. May 2014 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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Increased Risk Of Cardiovascular Mortality For Sulfonylurea Drugs The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared with 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 (Diabetes 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 2 ½ 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. Cardiac Failure With Rosiglitazone 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 [see BOXED WARNING]. 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, placebocontrolled, 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 with placebo during the 52-week trial. (See Table 1.) Table 1: Emergent Cardiovascular Adverse Events in Patients With Congestive Heart Failure (NYHA Class I and II) Treated With Rosiglitazone or Placebo (in Addition to Background Antidiabetic and CHF Therapy)
Events Rosiglitazone
N = 110
n (%) Placebo
N = 114
n (%) Adjudicated Cardiovascular deaths 5(5%) 4(4%) CHF worsening 7(6%) 4(4%)   with overnight hospitalization 5 (5%) 4 (4%)    without overnight hospitalization 2 (2%) 0 (0%) New or worsening edema 28(25%) 10(9%) New or worsening dyspnea 29(26%) 19(17%) Increases in CHF medication 36(33%) 20(18%) Cardiovascular hospitalizationa 21(19%) 15(13%) Investigator-reported, non-adj udicated Ischemic adverse events 10(9%) 5(4%)   Myocardial infarction 5 (5%) 2 (2%)    Angina 6 (5%) 3 (3%) a Includes hospitalization for any cardiovascular reason. In a long-term, cardiovascular outcome trial (RECORD) in patients with type 2 diabetes [see ADVERSE REACTIONS], the incidence of heart failure was higher in patients treated with rosiglitazone [2.7% (61/2,220) compared with active control 1.3% (29/2,227), HR 2.10 (95% CI: 1.35, 3.27)]. Initiation of AVANDARYL in patients with established NYHA Class III or IV heart failure is contraindicated. AVANDARYL is not recommended in patients with symptomatic heart failure. [See BOXED WARNING.] 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 is not recommended for patients experiencing an acute coronary event, and discontinuation of AVANDARYL 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 is not recommended in patients with NYHA Class III and IV cardiac status. Congestive Heart Failure During Coadministration of Rosiglitazone With Insulin In trials in which rosiglitazone was added to insulin, rosiglitazone increased the risk of congestive heart failure. Coadministration of rosiglitazone and insulin is not recommended. [See INDICATIONS AND USAGE] 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. Heart Failure in Observational Studies of Elderly Diabetic Patients Comparing Rosiglitazone to Pioglitazone Three observational studies in elderly diabetic patients (age 65 years and older) found that rosiglitazone statistically significantly increased the risk of hospitalized heart failure compared to use of pioglitazone. One other observational study in patients with a mean age of 54 years, which also included an analysis in a subpopulation of patients > 65 years of age, found no statistically significant increase in emergency department visits or hospitalization for heart failure in patients treated with rosiglitazone compared to pioglitazone in the older subgroup. Major Adverse Cardiovascular Events Data from long-term, prospective, randomized, controlled clinical trials of rosiglitazone versus metformin or sulfonylureas, particularly a cardiovascular outcome trial (RECORD), observed no difference in overall mortality or in major adverse cardiovascular events (MACE) and its components. A meta-analysis of mostly short-term trials suggested an increased risk for myocardial infarction with rosiglitazone compared with placebo. Cardiovascular Events in Large, Long-term, Prospective, Randomized, Controlled Trials of Rosiglitazone RECORD, a prospectively designed cardiovascular outcome trial (mean follow-up 5.5 years; 4,447 patients), compared the addition of rosiglitazone to metformin or a sulfonylurea (N = 2,220) with a control group of metformin plus sulfonylurea (N = 2,227) in patients with type 2 diabetes [see ADVERSE REACTIONS]. Non-inferiority was demonstrated for the primary endpoint, cardiovascular hospitalization or cardiovascular death, for rosiglitazone compared with control [HR 0.99 (95% CI: 0.85, 1.16)] demonstrating no overall increased risk in cardiovascular morbidity or mortality. The hazard ratios for total mortality and MACE were consistent with the primary endpoint and the 95% CI similarly excluded a 20% increase in risk for rosiglitazone. The hazard ratios for the components of MACE were 0.72 (95% CI: 0.49, 1.06) for stroke, 1.14 (95% CI: 0.80, 1.63) for myocardial infarction, and 0.84 (95% CI: 0.59, 1.18) for cardiovascular death. The results of RECORD are consistent with the findings of 2 earlier long-term, prospective, randomized, controlled clinical trials (each trial > 3 years' duration; total of 9,620 patients) (see Figure 1). In patients with impaired glucose tolerance (DREAM trial), although the incidence of cardiovascular events was higher among subjects who were randomized to rosiglitazone in combination with ramipril than among subjects randomized to ramipril alone, no statistically significant differences were observed for MACE and its components between rosiglitazone and placebo. In type 2 diabetes patients who were initiating oral agent monotherapy (ADOPT trial), no statistically significant differences were observed for MACE and its components between rosiglitazone and metformin or a sulfonylurea. Figure 1: Hazard Ratios for the Risk of MACE, Myocardial Infarction, and Total Mortality With Rosiglitazone Compared With a Control Group in Long-term Trials
Cardiovascular Events in a Group of 52 Clinical Trials In a meta-analysis of 52 double-blind, randomized, controlled clinical trials designed to assess glucose-lowering efficacy in type 2 diabetes (mean duration 6 months), a statistically significant increased risk of myocardial infarction with rosiglitazone versus pooled comparators was observed [0.4% versus 0.3%; OR 1.8, (95% CI: 1.03, 3.25)]. A statistically non-significant increased risk of MACE was observed with rosiglitazone versus pooled comparators (OR 1.44, 95% CI: 0.95, 2.20). In the placebo-controlled trials, a statistically significant increased risk of myocardial infarction [0.4% versus 0.2%, OR 2.23 (95% CI: 1.14, 4.64)] and statistically non-significant increased risk of MACE [0.7% versus 0.5%, OR 1.53 (95% CI: 0.94, 2.54)] with rosiglitazone were observed. In the active-controlled trials, there was no increased risk of myocardial infarction or MACE. Mortality in Observational Studies of Rosiglitazone Compared to Pioglitazone Three observational studies in elderly diabetic patients (age 65 years and older) found that rosiglitazone statistically significantly increased the risk of all-cause mortality compared to use of pioglitazone. One observational study in patients with a mean age of 54 years found no difference in all-cause mortality between patients treated with rosiglitazone compared to pioglitazone and reported similar results in the subpopulation of patients > 65 years of age. One additional small, prospective, observational study found no statistically significant differences for CV mortality and all-cause mortality in patients treated with rosiglitazone compared to pioglitazone. Hypoglycemia AVANDARYL 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 4 mg/1 mg, followed by appropriate dose titration is recommended in these patients. [See CLINICAL PHARMACOLOGY] Hypoglycemia may be difficult to recognize in the elderly and in people who are taking betaadrenergic 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 [see DOSAGE AND ADMINISTRATION]. Edema AVANDARYL 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 with placebo. Since thiazolidinediones, including rosiglitazone, can cause fluid retention, which can exacerbate or lead to congestive heart failure, AVANDARYL should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure [see BOXED WARNING, PATIENT INFORMATION]. 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 [see ADVERSE REACTIONS]. The use of AVANDARYL in combination with insulin is not recommended. Weight Gain Dose-related weight gain was seen with AVANDARYL, rosiglitazone alone, and rosiglitazone together with other hypoglycemic agents (see Table 2). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation. Table 2: Weight Changes (kg) From Baseline at Endpoint During Clinical Trials [Median (25th, 75th Percentiles)
Monotherapy Duration Contro Group Rosiglitazone 4 mg Rosiglitazone 8 mg 26 weeks Placebo -0.9
(-2.8, 0.9)
N = 210 1.0
(-0.9, 3.6)
N = 436 3.1
(1.1, 5.8)
N = 439 52 weeks Sulfonylurea 2.0
(0, 4.0)
N = 173 2.0
(-0.6, 4.0)
N = 150 2.6
(0, 5.3)
N = 157 Combination Therapy Duration Contro Group Rosiglitazone + Control Therapy Rosiglitazone 4 mg Rosiglitazone 8 mg 24-26 weeks Sulfonylurea 0
(-1.0, 1.3)
N = 1,155 2.2
(0.5, 4.0)
N = 613 3.5
(1.4, 5.9)
N = 841 26 weeks Metformin -1.4
(-3.2, 0.2)
N = 175 0.8
(-1.0, 2.6)
N = 100 2.1
(0, 4.3)
N = 184 26 weeks Insulin 0.9
(-0.5, 2.7)
N = 162 4.1
(1.4, 6.3)
N = 164 5.4
(3.4, 7.3)
N = 150 AVANDARYL in Patients With Inadequate Control on Diet and Exercise Duration Contro Group AVANDARYL 4 mg/4 mg AVANDARYL 8 mg/4 mg 28 weeks Glimepiride 1.1
(-1.1, 3.2)
N = 222 2.2
(0, 4.5)
N = 221 2.9
(0, 5.8)
N = 217 Rosiglitazone 0.9
(-1.4, 3.2)
N = 228 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 (25th, 75th 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 [see BOXED WARNING]. Hepatic Effects 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 in all patients and periodically thereafter per the clinical judgment of the healthcare professional. Therapy with AVANDARYL 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 should be evaluated to determine the cause of the liver enzyme elevation. Initiation of, or continuation of, therapy with AVANDARYL 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, liver enzyme levels should be rechecked as soon as possible. If ALT levels remain > 3X the upper limit of normal, therapy with AVANDARYL 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 should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued. Macular Edema Macular edema has been reported in postmarketing experience in some diabetic patients who were taking rosiglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but some patients appear to have been diagnosed on routine ophthalmologic examination. Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of their thiazolidinedione. Patients with diabetes should have regular eye exams by an ophthalmologist, per the Standards of Care of the American Diabetes Association. Additionally, any diabetic who reports any kind of visual symptom should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings. [See ADVERSE REACTIONS] Fractures Long-term trials (ADOPT and RECORD) show an increased incidence of bone fracture in patients, particularly female patients, taking rosiglitazone [see ADVERSE REACTIONS]. This increased incidence was noted after the first year of treatment and persisted during the course of the trial. The majority of the fractures in the women who received rosiglitazone occurred in the upper arm, hand, and foot. These sites of fracture are different from those usually associated with postmenopausal osteoporosis (e.g., hip or spine). Other trials suggest that this risk may also apply to men, although the risk of fracture among women appears higher than that among men. The risk of fracture should be considered in the care of patients treated with rosiglitazone, and attention given to assessing and maintaining bone health according to current standards of care. Hematologic Effects Decreases in hemoglobin and hematocrit occurred in a dose-related fashion in adult patients treated with rosiglitazone [see ADVERSE REACTIONS]. The observed changes may be related to the increased plasma volume observed with treatment with rosiglitazone. Hemolytic Anemia Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because glimepiride, a component of AVANDARYL, belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered. In postmarketing experience, hemolytic anemia has also been reported in patients receiving sulfonylureas who did not have known G6PD deficiency [see ADVERSE REACTIONS]. Diabetes And Blood Glucose Control 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 and temporarily administer insulin. AVANDARYL may be reinstituted after the acute episode is resolved. Periodic fasting glucose and HbA1c measurements should be performed to monitor therapeutic response. Ovulation 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 [see Use In Specific Populations]. 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 [see Nonclinical Toxicology], the clinical significance of this finding is not known. If unexpected menstrual dysfunction occurs, the benefits of continued therapy with AVANDARYL should be reviewed. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Medication Guide). There are multiple medications available to treat type 2 diabetes. The benefits and risks of each available diabetes medication should be taken into account when choosing a particular diabetes medication for a given patient. Patients should be informed of the following:
  • AVANDARYL is not recommended in patients with symptomatic heart failure.
  • A meta-analysis of mostly short-term trials suggested an increased risk for myocardial infarction with rosiglitazone compared with placebo. Data from long-term clinical trials of rosiglitazone versus other antidiabetes agents (metformin or sulfonylureas), including a cardiovascular outcome trial (RECORD), observed no difference in overall mortality or in major adverse cardiovascular events (MACE) and its components.
  • AVANDARYL is not recommended for patients who are taking insulin.
  • Management of type 2 diabetes should include diet control. Caloric restriction, weight loss, and exercise are essential for the proper treatment of the diabetic patient because they help improve insulin sensitivity. This is important not only in the primary treatment of type 2 diabetes, but also in maintaining the efficacy of drug therapy.
  • It is important to adhere to dietary instructions and to regularly have blood glucose and glycosylated hemoglobin (HbA1c) tested. It can take 2 weeks to see a reduction in blood glucose and 2 to 3 months to see the full effect of AVANDARYL.
  • The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members.
  • Blood will be drawn to check their liver function prior to the start of therapy and periodically thereafter per the clinical judgment of the healthcare professional. Patients with unexplained symptoms of nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine should immediately report these symptoms to their physician.
  • Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on AVANDARYL should immediately report these symptoms to their physician.
AVANDARYL should be taken with the first meal of the day. 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 AVANDARYL. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been specifically investigated in clinical trials so the frequency of this occurrence is not known. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility No animal studies have been conducted with AVANDARYL. The following data are based on findings in studies performed with rosiglitazone or glimepiride alone. Rosiglitazone Carcinogenesis: A 2-year carcinogenicity study was conducted in Charles River CD-1 mice at doses of 0.4, 1.5, and 6 mg/kg/day in the diet (highest dose equivalent to approximately 12 times human AUC at the maximum recommended human daily dose). Sprague-Dawley rats were dosed for 2 years by oral gavage at doses of 0.05 mg/kg/day, 0.3 mg/kg/day, and 2 mg/kg/day (highest dose equivalent to approximately 10 and 20 times human AUC at the maximum recommended human daily dose for male and female rats, respectively). 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. Mutagenesis: Rosiglitazone was not mutagenic or clastogenic in the in vitro bacterial assays for gene mutation, the in vitro chromosome aberration test in human lymphocytes, the in vivo mouse micronucleus test, and the in vivo/in vitro rat UDS assay. There was a small (about 2-fold) increase in mutation in the in vitro mouse lymphoma assay in the presence of metabolic activation. Impairment of Fertility: Rosiglitazone had no effects on mating or fertility of male rats given up to 40 mg/kg/day (approximately 116 times human AUC at the maximum recommended human daily dose). Rosiglitazone altered estrous cyclicity (2 mg/kg/day) and reduced fertility (40 mg/kg/day) of female rats in association with lower plasma levels of progesterone and estradiol (approximately 20 and 200 times human AUC at the maximum recommended human daily dose, respectively). No such effects were noted at 0.2 mg/kg/day (approximately 3 times human AUC at the maximum recommended human daily dose). In juvenile rats dosed from 27 days of age through to sexual maturity (at up to 40 mg/kg/day), there was no effect on male reproductive performance, or on estrous cyclicity, mating performance or pregnancy incidence in females (approximately 68 times human AUC at the maximum recommended daily dose). In monkeys, rosiglitazone (0.6 and 4.6 mg/kg/day; approximately 3 and 15 times human AUC at the maximum recommended human daily dose, respectively) diminished the follicular phase rise in serum estradiol with consequential reduction in the luteinizing hormone surge, lower luteal phase progesterone levels, and amenorrhea. The mechanism for these effects appears to be direct inhibition of ovarian steroidogenesis. Glimepiride Carcinogenesis: Studies in rats at doses of up to 5,000 parts per million (ppm) in complete feed (approximately 340 times the maximum recommended human dose, based on surface area) for 30 months showed no evidence of carcinogenesis. In mice, administration of glimepiride for 24 months resulted in an increase in benign pancreatic adenoma formation which was dose-related and is thought to be the result of chronic pancreatic stimulation. The no-effect dose for adenoma formation in mice in this study was 320 ppm in complete feed, or 46 to 54 mg/kg body weight/day. This is about 35 times the maximum human recommended dose based on surface area. Mutagenesis: Glimepiride was non-mutagenic in a battery of in vitro and in vivo mutagenicity studies (Ames test, somatic cell mutation, chromosomal aberration, unscheduled DNA synthesis, mouse micronucleus test). Impairment of Fertility: There was no effect of glimepiride on male mouse fertility in animals exposed up to 2,500 mg/kg body weight ( > 1,700 times the maximum recommended human dose based on surface area). Glimepiride had no effect on the fertility of male and female rats administered up to 4,000 mg/kg body weight (approximately 4,000 times the maximum recommended human dose based on surface area). Use In Specific Populations Pregnancy 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 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Human Data There are no adequate and well-controlled trials with AVANDARYL or its individual components in pregnant women. Rosiglitazone has been reported to cross the human placenta and be detectable in fetal tissue. The clinical significance of these findings is unknown. Animal Studies No animal studies have been conducted with AVANDARYL. The following data are based on findings in studies performed with rosiglitazone or glimepiride individually. Rosiglitazone: There was no effect on implantation or the embryo with rosiglitazone treatment during early pregnancy in rats, but treatment during mid-late gestation was associated with fetal death and growth retardation in both rats and rabbits. Teratogenicity was not observed at doses up to 3 mg/kg in rats and 100 mg/kg in rabbits (approximately 20 and 75 times human AUC at the maximum recommended human daily dose, respectively). Rosiglitazone caused placental pathology in rats (3 mg/kg/day). Treatment of rats during gestation through lactation reduced litter size, neonatal viability, and postnatal growth, with growth retardation reversible after puberty. For effects on the placenta, embryo/fetus, and offspring, the no-effect dose was 0.2 mg/kg/day in rats and 15 mg/kg/day in rabbits. These no-effect levels are approximately 4 times human AUC at the maximum recommended human daily dose. Rosiglitazone reduced the number of uterine implantations and live offspring when juvenile female rats were treated at 40 mg/kg/day from 27 days of age through to sexual maturity (approximately 68 times human AUC at the maximum recommended daily dose). The no-effect level was 2 mg/kg/day (approximately 4 times human AUC at the maximum recommended daily dose). There was no effect on pre- or post-natal survival or growth. Glimepiride: Glimepiride did not produce teratogenic effects in rats exposed orally up to 4,000 mg/kg body weight (approximately 4,000 times the maximum recommended human dose based on surface area) or in rabbits exposed up to 32 mg/kg body weight (approximately 60 times the maximum recommended human dose based on surface area). Glimepiride has been shown to be associated with intrauterine fetal death in rats when given in doses as low as 50 times the human dose based on surface area and in rabbits when given in doses as low as 0.1 times the human dose based on surface area. This fetotoxicity, observed only at doses inducing maternal hypoglycemia, has been similarly noted with other sulfonylureas, and is believed to be directly related to the pharmacologic (hypoglycemic) action of 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. Labor And Delivery The effect of AVANDARYL or its components on labor and delivery in humans is unknown. Nursing Mothers No trials have been conducted with AVANDARYL. It is not known whether rosiglitazone or glimepiride is excreted in human milk. Because many drugs are excreted in human milk, a decision should be made whether to discontinue nursing or to discontinue AVANDARYL, taking into account the importance of the drug to the mother. Rosiglitazone Drug-related material was detected in milk from lactating rats. Glimepiride In rat reproduction studies, significant concentrations of glimepiride were observed in the serum and breast milk of the dams, as well as in the serum of the pups. Although it is not known whether glimepiride is excreted in human milk, other sulfonylureas are excreted in human milk. Pediatric Use Safety and effectiveness of AVANDARYL in pediatric patients have not been established. AVANDARYL and its components, rosiglitazone and glimepiride, are not indicated for use in pediatric patients. Geriatric Use Rosiglitazone Results of the population pharmacokinetic analysis showed that age does not significantly affect the pharmacokinetics of rosiglitazone [see CLINICAL PHARMACOLOGY]. Therefore, no dosage adjustments are required for the elderly. In controlled clinical trials, no overall differences in safety and effectiveness between older ( ≥ 65 years) and younger ( < 65 years) patients were observed. Glimepiride In US clinical trials of glimepiride, 608 of 1,986 patients were 65 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. 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 agegroups [see CLINICAL PHARMACOLOGY]. 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 [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY]. Last reviewed on RxList: 5/28/2014
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