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"value" : "AVANDARYL is indicated as an adjunct to diet and\nexercise, to improve glycemic control in patients with type 2\ndiabetes mellitus when treatment with dual rosiglitazone and glimepiride\ntherapy is appropriate. Management of type 2\ndiabetes should include diet control. Caloric restriction, weight\nloss, and exercise are essential for the proper treatment of the diabetic\npatient because they help improve insulin sensitivity. This is important\nnot only in the primary treatment of type 2 diabetes, but also\nin maintaining the efficacy of drug therapy. Prior to initiation of\ntherapy with AVANDARYL, secondary causes of poor glycemic control,\ne.g., infection, should be investigated and treated.",
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"value" : "Tablets: Each tablet contains rosiglitazone\nas the maleate and glimepiride as follows: 4\nmg/1 mg���yellow, rounded triangular tablet, gsk debossed on\none side and 4/1 on the other. 4 mg/2 mg���orange, rounded triangular tablet, gsk debossed on one side and 4/2\non the other. 4 mg/4 mg���pink, rounded\ntriangular tablet, gsk debossed on one side and 4/4 on the other. 8 mg/2 mg���pale pink, rounded triangular tablet,\ngsk debossed on one side and 8/2 on the other. 8 mg/4 mg���red, rounded triangular tablet, gsk debossed on\none side and 8/4 on the other. 4 mg/1 mg bottles\nof 30: NDC 0007-3151-13 4 mg/2 mg bottles of\n30: NDC 0007-3152-13 4 mg/4 mg bottles of 30:\nNDC 0007-3153-13 8 mg/2 mg bottles of 30: NDC\n0007-3148-13 8 mg/4 mg bottles of 30: NDC 0007-3149-13",
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"value" : "Mechanism of Action: AVANDARYL combines\n2 antidiabetic agents with complementary mechanisms of action to improve\nglycemic control in patients with type 2 diabetes: Rosiglitazone\nmaleate, a member of the thiazolidinedione class, and glimepiride,\na member of the sulfonylurea class. Thiazolidinediones are insulin-sensitizing\nagents that act primarily by enhancing peripheral glucose utilization,\nwhereassulfonylureas act primarily by stimulating release of insulin\nfrom functioning pancreatic beta cells. Rosiglitazone\nimproves glycemic control by improving insulin sensitivity. Rosiglitazone\nis a highly selective and potent agonist for the peroxisome proliferator-activated\nreceptor-gamma (PPAR��). In humans, PPAR receptors are found\nin key target tissues for insulin action such as adipose tissue, skeletal\nmuscle, and liver. Activation of PPAR��nuclear receptors regulates\nthe transcription of insulin-responsive genes involved in the control\nof glucose production, transport, and utilization. In addition, PPAR��-responsive\ngenes also participate in the regulation of fatty acid metabolism. Insulin resistance is a common feature characterizing\nthe pathogenesis of type 2 diabetes. The antidiabetic activity\nof rosiglitazone has been demonstrated in animal models of type 2\ndiabetes in which hyperglycemia and/or impaired glucose tolerance\nis a consequence of insulin resistance in target tissues. Rosiglitazone\nreduces blood glucose concentrations and reduces hyperinsulinemia\nin the ob/ob obese mouse, db/db diabetic mouse, and fa/fa fatty Zucker\nrat. In animal models, the antidiabetic activity\nof rosiglitazone was shown to be mediated by increased sensitivity\nto insulin's action in the liver, muscle, and adipose tissues.\nThe expression of the insulin-regulated glucose transporter GLUT-4\nwas increased in adipose tissue. Rosiglitazone did not induce hypoglycemia\nin animal models of type 2 diabetes and/or impaired glucose tolerance. The primary mechanism of action of glimepiride in lowering\nblood glucose appears to be dependent on stimulating the release of\ninsulin from functioning pancreatic beta cells. In addition, extrapancreatic\neffects may also play a role in the activity of sulfonylureas such\nas glimepiride. This is supported by both preclinical and clinical\nstudies demonstrating that glimepiride administration can lead to\nincreased sensitivity of peripheral tissues to insulin. These findings\nare consistent with the results of a long-term, randomized, placebo-controlled\ntrial in which glimepiride therapy improved postprandial insulin/C-peptide\nresponses and overall glycemic control without producing clinically\nmeaningful increases in fasting insulin/C-peptide levels. However,\nas with other sulfonylureas, the mechanism by which glimepiride lowers\nblood glucose during long-term administration has not been clearly\nestablished.
Pharmacokinetics: In a bioequivalence\nstudy of AVANDARYL 4 mg/4 mg, the area under the curve (AUC)\nand maximum concentration (C) of rosiglitazone following\na single dose of the combination tablet were bioequivalent to rosiglitazone\n4 mg concomitantly administered with glimepiride 4 mg under\nfasted conditions. The AUC of glimepiride following a single fasted\n4 mg/4 mg dose was equivalent to glimepiride concomitantly\nadministered with rosiglitazone, while the Cwas 13%\nlower when administered as the combination tablet (see Table 1). AUC = area under\nthe curve; C= maximum concentration; T= terminal half-life; T= time\nof maximum concentration. Regimen A = AVANDARYL 4 mg/4 mg tablet; Regimen\nB = Concomitant dosing of a rosiglitazone 4 mg tablet\nAND a glimepiride 4 mg tablet. Data presented as geometric mean (range), except\nTwhich is presented as arithmetic mean (range) and\nT, which is presented as median (range). The rate and extent of absorption of both the rosiglitazone\ncomponent and glimepiride component of AVANDARYL when taken with food\nwere equivalent to the rate and extent of absorption of rosiglitazone\nand glimepiride when administered concomitantly as separate tablets\nwith food.
Absorption: The AUC\nand Cof glimepiride increased in a dose-proportional\nmanner following administration of AVANDARYL 4 mg/1 mg,\n4 mg/2 mg, and 4 mg/4 mg. Administration of AVANDARYL\nin the fed state resulted in no change in the overall exposure of\nrosiglitazone; however, the Cof rosiglitazone decreased\nby 32% compared to the fasted state. There was an increase in both\nAUC (19%) and C(55%) of glimepiride in the fed state\ncompared to the fasted state.
Distribution:
Metabolism and Excretion:
Special Populations: No pharmacokinetic\ndata are available for AVANDARYL in the following special populations.\nInformation is provided for the individual components of AVANDARYL.
Gender:
Geriatric:
Hepatic Impairment: Therapy with\nAVANDARYL should not be initiated if the patient exhibits clinical\nevidence of active liver disease or increased serum transaminase levels\n(ALT>2.5X upper limit of normal) at baseline (see PRECAUTIONS, Hepatic\nEffects).
Race:
Renal Impairment:
Pediatric: No pharmacokinetic data from studies in pediatric\nsubjects are available for AVANDARYL.
Drug Interactions: Single oral doses\nof glimepiride in 14 healthy adult subjects had no clinically significant\neffect on the steady-state pharmacokinetics of rosiglitazone. No clinically\nsignificant reductions in glimepiride AUC and Cwere\nobserved after repeat doses of rosiglitazone (8 mg once daily) for\n8 days in healthy adult subjects.
Rosiglitazone:
Glimepiride: The hypoglycemic\naction of sulfonylureas may be potentiated by certain drugs, including\nnonsteroidal anti-inflammatory drugs (NSAIDs) and other drugs that\nare highly protein bound, such as salicylates, sulfonamides, chloramphenicol,\ncoumarins, probenecid, monoamine oxidase inhibitors, and beta-adrenergic\nblocking agents. When these drugs are administered to a patient receiving\nglimepiride, the patient should be observed closely for hypoglycemia.\nWhen these drugs are withdrawn from a patient receiving glimepiride,\nthe patient should be observed closely for loss of glycemic control. Certain drugs tend to produce hyperglycemia and may lead\nto loss of control. These drugs include the thiazides and other diuretics,corticosteroids, phenothiazines, thyroid products, estrogens, oral\ncontraceptives, phenytoin, nicotinic acid, sympathomimetics, and isoniazid.\nWhen these drugs are administered to a patient receiving glimepiride,\nthe patient should be closely observed for loss of control. When these\ndrugs are withdrawn from a patient receiving glimepiride, the patient\nshould be observed closely for hypoglycemia.",
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"value" : "Glimepiride: SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY The administration\nof oral hypoglycemic drugs has been reported to be associated with\nincreased cardiovascular mortality as compared to treatment with diet\nalone or diet plus insulin. This warning is based on the study conducted\nby the University Group Diabetes Program (UGDP), a long-term, prospective\nclinical trialdesigned to evaluate the effectiveness of glucose-lowering\ndrugs in preventing or delaying vascular complications in patients\nwith non-insulin-dependent diabetes. The study involved 823 patients\nwho were randomly assigned to one of four treatment groups (Diabetes 1970;19[Suppl. 2]:747-830). UGDP reported that patients\ntreated for 5 to 8 years with diet plus a fixed dose of tolbutamide\n(1.5 grams per day) had a rate of cardiovascular mortality approximately\n2��times that of patients treated with diet alone. A significant\nincrease in total mortality was not observed, but the use of tolbutamide\nwas discontinued based on the increase in cardiovascular mortality,\nthus limiting the opportunity for the study to show an increase in\noverall mortality. Despite controversy regarding the interpretation\nof these results, the findings of the UGDP study provide an adequate\nbasis for this warning. The patient should be informed of the potential\nrisks and advantages of glimepiride-containing tablets and of alternativemodes of therapy. Although only one drug in the sulfonylurea class\n(tolbutamide) was included in this study, it is prudent from a safety\nstandpoint to consider that this warning may also apply to other oral\nhypoglycemic drugs in this class, in view of their close similarities\nin mode of action and chemical structure.
Rosiglitazone:
Cardiac Failure and Other\nCardiac Effects: Rosiglitazone,\nlike other thiazolidinediones, alone or in combination with other\nantidiabetic agents, can cause fluid retention, which may exacerbate\nor lead to heart failure. Patients should be observed for signs and\nsymptoms of heart failure. If these signs and symptoms develop, the\nheart failure should be managed according to current standards of\ncare. Furthermore, discontinuation or dose reduction of rosiglitazone\nmust be considered (see BOXED WARNING). In combination with insulin,\nthiazolidinediones may also increase the risk of other cardiovascular\nadverse events. Rosiglitazone should be discontinued if any deterioration\nin cardiac status occurs. Patients with congestive\nheart failure (CHF) NYHA Class I and II treated with rosiglitazone\nhave an increased risk of cardiovascular events. A 52-week, double-blind,\nplacebo-controlled echocardiographic study was conducted in 224 patients\nwith type 2 diabetes mellitus and NYHA Class I or II CHF (ejection\nfraction���45%) on background antidiabetic and CHF therapy.\nAn independent committee conducted a blinded evaluation of fluid-related\nevents (including congestive heart failure) and cardiovascular hospitalizations\naccording to predefined criteria (adjudication). Separate from the\nadjudication, other cardiovascular adverse events were reported by\ninvestigators. Although no treatment difference in change from baseline\nof ejection fractions was observed, more cardiovascular adverse events\nwere observed with rosiglitazone treatment compared to placebo during\nthe 52-week study. (See Table 4.) Table 4. Emergent Cardiovascular Adverse Events in\nPatients with Congestive Heart Failure (NYHA Class I and II) treated\nwith Rosiglitazone or Placebo (in Addition to Background Antidiabetic\nand CHF Therapy) Includes hospitalization\nfor any cardiovascular reason. Initiation of\nAVANDARYL in patients with established NYHA Class III or IV heart\nfailure is contraindicated. AVANDARYL is not recommended in patients\nwith symptomatic heart failure. (See BOXED WARNING.) Patients with NYHA Class III and IV cardiac status were not\nstudied during the clinical trials. Rosiglitazone is not recommended\nin patients with NYHA Class III and IV cardiac status. In three 26-week trials in patients with type 2 diabetes,\n216 received 4 mg of rosiglitazone plus insulin, 322 received\n8 mg of rosiglitazone plus insulin, and 338 received insulin\nalone. These trials included patients with long-standing diabetes\nand a high prevalence of pre-existing medical conditions, including\nperipheral neuropathy, retinopathy, ischemic heart disease, vascular\ndisease, and congestive heart failure. In these clinical studies an\nincreased incidence of edema, cardiac failure, and other cardiovascular\nadverse events was seen in patients on rosiglitazone and insulin combination\ntherapy compared to insulin and placebo. Patients who experienced\ncardiovascular events were on average older and had a longer duration\nof diabetes. These cardiovascular events were noted at both the 4 mg\nand 8 mg daily doses of rosiglitazone. In this population, however,\nit was not possible to determine specific risk factors that could\nbe used to identify all patients at risk of heart failure and other\ncardiovascular events on combination therapy. Three of 10 patients\nwho developed cardiac failure on combination therapy during the double-blind\npart of the fixed-dose studies had no known prior evidence of congestive\nheart failure, or pre-existing cardiac condition. In a double-blind study in type 2 diabetes patients with chronic\nrenal failure (112 received 4 mg or 8 mg of rosiglitazone\nplus insulin and 108 received insulin control), there was no difference\nin cardiovascular adverse events with rosiglitazone in combination\nwith insulin compared to insulin control. Patientstreated with combination rosiglitazone and insulin should be monitored\nfor cardiovascular adverse events. This combination therapy should\nbe discontinued in patients who do not respond as manifested by a\nreduction in HbA1c or insulin dose after 4 to 5 months of therapy\nor who develop any significant adverse events. (See ADVERSE REACTIONS.) There are no studies that have evaluated the safety or\neffectiveness of AVANDARYL in combination with insulin. Therefore,\nthe use of AVANDARYL in combination with insulin is not recommended.",
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"value" : "Starting Dose:
Dose Titration:
Maximum Dose: No studies have been performed specifically examining\nthe safety and efficacy of AVANDARYL in patients previously treated\nwith other oral hypoglycemic agents and switched to AVANDARYL. Any\nchange in therapy of type 2 diabetes should be undertaken with\ncare and appropriate monitoring as changes in glycemic control can\noccur. (See INDICATIONS AND USAGE.)
Specific Patient Populations:",
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"value" : "Adverse events occurring at a frequency of���5%\nin any treatment group in the 28-week double-blind trial of AVANDARYL\nin drug-na��ve patients with type 2 diabetes mellitus are presented\nin Table 6. Patients in this trial were started on AVANDARYL 4 mg/1 mg,\nrosiglitazone 4 mg, or glimepiride 1 mg. Doses could be\nincreased at 4-week intervals to reach a maximum total daily dose\nof either 4 mg/4 mg or 8 mg/4 mg for AVANDARYL,\n8 mg for rosiglitazone monotherapy or 4 mg for glimepiride\nmonotherapy. Table\n6. Adverse Events (���5% in Any Treatment Group) Reported by\nDrug-Na��ve Patients in a 28-Week Double-Blind Clinical Trial of AVANDARYL As documented\nby symptoms and a fingerstick blood glucose measurement of<50\nmg/dL. Hypoglycemia was reported to be generally\nmild to moderate in intensity and none of the reported events of hypoglycemia\nresulted in withdrawal from the study. Hypoglycemia requiring parenteral\ntreatment (i.e., intravenous glucose or glucagon injection) was observed\nin 3 (0.7%) patients treated with AVANDARYL. Edema was reported by 3.2% of patients on AVANDARYL, 3.0% on rosiglitazone\nalone, and 2.3% on glimepiride alone. Congestive\nheart failure was observed in 1 (0.2%) patient treated with AVANDARYL\nand in 1 (0.4%) patient treated with rosiglitazone monotherapy. Studies utilizing rosiglitazone in combination with a\nsulfonylurea provide support for the use of AVANDARYL. Adverse event\ndata from these trials, in addition to adverse events reported with\nthe use of rosiglitazone and glimepiride as monotherapy, are presented\nbelow.
Rosiglitazone: The most common adverse experiences with rosiglitazone\nmonotherapy (���5%) were upper respiratory tract infection, injury,\nand headache. Overall, the types of adverse experiences reported when\nrosiglitazone was added to a sulfonylurea were similar to those during\nmonotherapy with rosiglitazone. In controlled combination therapy\nstudies with sulfonylureas, mild to moderate hypoglycemic symptoms,\nwhich appear to be dose related, were reported. Few patients were\nwithdrawn for hypoglycemia (<1%) and few episodes of hypoglycemia\nwere considered to be severe (<1%). Events\nof anemia and edema tended to be reported more frequently at higher\ndoses, and were generally mild to moderate in severity and usually\ndid not require discontinuation of treatment with rosiglitazone. Edema was reported by 4.8% of patients receiving rosiglitazone\ncompared to 1.3% on placebo, and 1.0% on sulfonylurea monotherapy.\nThe reporting rate of edema was higher for rosiglitazone 8 mg\nadded to a sulfonylurea (12.4%) compared to other combinations, with\nthe exception of insulin. Anemia was reported by 1.9% of patients\nreceiving rosiglitazone compared to 0.7% on placebo, 0.6% on sulfonylurea\nmonotherapy, and 2.3% on rosiglitazone in combination with a sulfonylurea.\nOverall, the types of adverse experiences reported when rosiglitazone\nwas added to a sulfonylurea were similar to those during monotherapy\nwith rosiglitazone. In 26-week double-blind,\nfixed-dose studies, edema was reported with higher frequency in the\nrosiglitazone plus insulin combination trials (insulin, 5.4%; and\nrosiglitazone in combination with insulin, 14.7%). Reports of new\nonset or exacerbation of congestive heart failure occurred at rates\nof 1% for insulin alone, and 2% (4 mg) and 3% (8 mg) for insulin in\ncombination with rosiglitazone (see BOXED WARNING and WARNINGS, Rosiglitazone). In postmarketing experience in patients receiving thiazolidinedione\ntherapy, serious adverse events potentially related to volume expansion\n(e.g., congestive heart failure, pulmonary edema with or without a\nfatal outcome, and pleural effusions) have been reported (see BOXED\nWARNING and WARNINGS, Rosiglitazone). In postmarketing\nexperience with rosiglitazone, rash, pruritus, urticaria, angioedema\nand anaphylactic reaction have been reported rarely. Postmarketing reports of new onset or worsening diabetic macular\nedema with decreased visual acuity have also been received (see PRECAUTIONS,\nMacular Edema).
Glimepiride:
Hypoglycemia: The incidence of hypoglycemia with glimepiride, as\ndocumented by blood glucose values<60 mg/dL, ranged from 0.9%\nto 1.7% in 2 large, well-controlled, 1-year studies. In patients treated\nwith glimepiride in US placebo-controlled trials (n = 746),\nadverse events, other than hypoglycemia, considered to be possibly\nor probably related to study drug that occurred in more than 1% of\npatients included dizziness (1.7%), asthenia (1.6%), headache (1.5%),\nand nausea (1.1%).
Gastrointestinal Reactions: Vomiting, gastrointestinal pain, and diarrhea have\nbeen reported, but the incidence in placebo-controlled trials was\nless than 1%. In rare cases, there may be an elevation of liver enzyme\nlevels. In isolated instances, impairment of liver function (e.g.,\nwith cholestasis and jaundice), as well as hepatitis, which may also\nlead to liver failure have been reported with sulfonylureas, including\nglimepiride.
Dermatologic Reactions: Allergic skin reactions, e.g., pruritus, erythema,\nurticaria, and morbilliform or maculopapular eruptions, occur in less\nthan 1% of treated patients. These may be transient and may disappear\ndespite continued use of glimepiride. If those hypersensitivity reactions\npersist or worsen, the drug should be discontinued. Porphyria cutanea\ntarda, photosensitivity reactions, and allergic vasculitis have been\nreportedwith sulfonylureas, including glimepiride.
Hematologic Reactions: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic\nanemia, aplastic anemia, and pancytopenia have been reported with\nsulfonylureas, including glimepiride.
Metabolic Reactions: Hepatic porphyria reactions and disulfiram-like reactions\nhave been reported with sulfonylureas, including glimepiride. Cases\nof hyponatremia have been reported with glimepiride and all other\nsulfonylureas, most often in patients who are on other medications\nor have medical conditions known to cause hyponatremia or increaserelease of antidiuretic hormone. The syndrome of inappropriate antidiuretic\nhormone (SIADH) secretion has been reported with certain other sulfonylureas,\nincluding glimepiride, and it has been suggested that certain sulfonylureas\nmay augment the peripheral (antidiuretic) action of ADH and/or increase\nrelease of ADH.
Other Reactions: Changes in accommodation and/or blurred vision may\noccur with the use of glimepiride. This is thought to be due to changes\nin blood glucose, and may be more pronounced when treatment is initiated.\nThis condition is also seen in untreated diabetic patients, and may\nactually be reduced by treatment. In placebo-controlled trials of\nglimepiride, the incidence of blurred vision was placebo, 0.7%, and\nglimepiride, 0.4%.
Human Ophthalmology Data: Ophthalmic examinations were carried out in more\nthan 500 subjects during long-term studies of glimepiride using the\nmethodology of Taylor and West and Laties et al. No significant differences\nwere seen between glimepiride and glyburide in the number of subjects\nwith clinically important changes in visual acuity, intraocular tension,\nor in any of the 5 lens-related variables examined. Ophthalmic examinations\nwere carried out during long-term studies using the method of Chylack\net al. No significant or clinically meaningful differences were seen\nbetween glimepiride and glipizide with respect to cataract progression\nby subjective LOCS II grading and objective image analysis systems,\nvisual acuity, intraocular pressure, and general ophthalmic examination\n(see PRECAUTIONS, Animal Toxicology, Glimepiride).
Pediatric Use: Safety and effectiveness of AVANDARYL in pediatric\npatients have not been established. AVANDARYL and its individual components,\nrosiglitazone and glimepiride, are not indicated for use in pediatric\npatients.",
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"value" : "Initiation of AVANDARYL in patients with established\nNew York Heart Association (NYHA) Class III or IV heart failure is\ncontraindicated (see BOXED WARNING). AVANDARYL is contraindicated in patients\nwith known hypersensitivity to rosiglitazone or glimepiride or any\nof the components of AVANDARYL. AVANDARYL is\ncontraindicated in patients with diabetic ketoacidosis, with or without\ncoma. This condition should be treated with insulin.",
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"value" : "General: Due to the mechanisms\nof action, rosiglitazone and glimepiride are active only in the presence\nof endogenous insulin. Therefore, AVANDARYL should not be used in\npatients with type 1 diabetes or for the treatment of diabetic\nketoacidosis.
Hypoglycemia: AVANDARYL is\na combination tablet containing rosiglitazone and glimepiride, a sulfonylurea.\nAll sulfonylurea drugs are capable of producing severe hypoglycemia.\nProper patient selection, dosage, and instructions are important to\navoid hypoglycemic episodes. Elderly patients are particularly susceptible\nto hypoglycemic action of glucose-lowering drugs. Debilitated or malnourished\npatients, and those with adrenal, pituitary, renal, or hepatic insufficiency\nare particularly susceptible to the hypoglycemic action of glucose-lowering\ndrugs. A starting dose of 1 mg glimepiride, as contained in AVANDARYL\n4 mg/1 mg, followed by appropriate dose titration is recommended\nin these patients. (See CLINICAL PHARMACOLOGY, Special Populations, Renal Impairment.) Hypoglycemia may\nbe difficult to recognize in the elderly and in people who are taking\nbeta-adrenergic blocking drugs or other sympatholytic agents. Hypoglycemia\nis more likely to occur when caloric intake is deficient, after severe\nor prolonged exercise, when alcohol is ingested, or when more than\none glucose-lowering drug is used. Patients receiving rosiglitazone in\ncombination with a sulfonylurea may be at risk for hypoglycemia, and\na reduction in the dose of the sulfonylurea may be necessary (see\nDOSAGE AND ADMINISTRATION, Specific Patient Populations).
Loss of Control of Blood Glucose: When a patient\nstabilized on any antidiabetic regimen is exposed to stress such as\nfever, trauma, infection, or surgery, a temporary loss of glycemic\ncontrol may occur. At such times, it may be necessary to withhold\nAVANDARYL and temporarily administer insulin. AVANDARYL may be reinstituted\nafter the acute episode is resolved.
Edema: AVANDARYL should be used with caution in patients\nwith edema. In a clinical study in healthy volunteers who received\n8 mg of rosiglitazone once daily for 8 weeks, there was\na statistically significant increase in median plasma volume compared\nto placebo. Since thiazolidinediones, including\nrosiglitazone, can cause fluid retention, which can exacerbate or\nlead to congestive heart failure, AVANDARYL should be used with caution\nin patients at risk for heart failure. Patients should be monitored\nfor signs and symptoms of heart failure (see BOXED WARNING, WARNINGS,\nRosiglitazone, and PRECAUTIONS). In controlled\nclinical trials of patients with type 2 diabetes, mild to moderate\nedema was reported in patients treated with rosiglitazone, and may\nbe dose related. Patients with ongoing edema are more likely to have\nadverse events associated with edema if started on combination therapy\nwith insulin and rosiglitazone (see ADVERSE REACTIONS). The use of\nAVANDARYL in combination with insulin is not recommended (see WARNINGS,\nRosiglitazone).
Macular Edema: Macular edema has been reported in postmarketing\nexperience in some diabetic patients who were taking rosiglitazone\nor another thiazolidinedione. Some patients presented with blurred\nvision or decreased visual acuity, but some patients appear to have\nbeen diagnosed on routine ophthalmologic examination. Most patients\nhad peripheral edema at the time macular edema was diagnosed. Some\npatients had improvement in their macular edema after discontinuation\nof their thiazolidinedione. Patients with diabetes should have regular\neye exams by an ophthalmologist, per the Standards of Care of the\nAmerican Diabetes Association. Additionally, any diabetic who reports\nany kind of visual symptom should be promptly referred to an ophthalmologist,\nregardless of the patient's underlying medications or other\nphysical findings. (See ADVERSE REACTIONS, Rosiglitazone.)
Fractures: In a 4- to 6-year comparative study (ADOPT) of glycemic\ncontrol with monotherapy in drug-na��ve patients recently diagnosed\nwith type 2 diabetes mellitus, an increased incidence of bone fracture\nwas noted in female patients taking rosiglitazone. Over the 4- to\n6-year period, the incidence of bone fracture in females was 9.3%\n(60/645) for rosiglitazone versus 3.5% (21/605) for glyburide and\n5.1% (30/590) for metformin. This increased incidence was noted after\nthe first year of treatment and persisted during the course of the\nstudy. The majority of the fractures in the women who received rosiglitazone\noccurred in the upper arm, hand, and foot. These sites of fracture\nare different from those usually associated with postmenopausal osteoporosis\n(e.g., hip or spine). No increase in fracture rates was observed in\nmen treated with rosiglitazone. The risk of fracture should be considered\nin the care of patients, especially female patients, treated with\nrosiglitazone, and attention given to assessing and maintaining bone\nhealth according to current standards of care.
Weight Gain: Dose-related weight gain was seen with AVANDARYL,\nrosiglitazone alone, and rosiglitazone together with other hypoglycemic\nagents (see Table 5). The mechanism of weight gain is unclear but\nprobably involves a combination of fluid retention and fat accumulation. In postmarketing experience with rosiglitazone\nalone or in combination with other hypoglycemic agents, there have\nbeen rare reports of unusually rapid increases in weight and increases\nin excess of that generally observed in clinical trials. Patients\nwho experience such increases should be assessed for fluid accumulation\nand volume-related events such as excessive edema and congestive heart\nfailure (see BOXED WARNING).
Hematologic: Across all controlled clinical studies, decreases\nin hemoglobin and hematocrit (mean decreases in individual studies���1.0 gram/dL and���3.3%, respectively) were observed\nfor rosiglitazone alone and in combination with other hypoglycemic\nagents. The changes occurred primarily during the first 3 months\nfollowing initiation of therapy with rosiglitazone or following a\ndose increase in rosiglitazone. White blood cell counts also decreased\nslightly in patients treated with rosiglitazone. The observed changes\nmay be related to the increased plasma volume observed with treatment\nwith rosiglitazone and may be dose related.
Ovulation: Therapy with rosiglitazone, like other thiazolidinediones,\nmay result in ovulation in some premenopausal anovulatory women. As\na result, these patients may be at an increased risk for pregnancy\nwhile taking rosiglitazone (see PRECAUTIONS, Pregnancy, Pregnancy\nCategory C). Thus, adequate contraception in premenopausal women should\nbe recommended. This possible effect has not been specifically investigated\nin clinical studies so the frequency of this occurrence is not known. Although hormonal imbalance has been seen in preclinical\nstudies (see PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment\nof Fertility), the clinical significance of this finding is not known.\nIf unexpected menstrual dysfunction occurs, the benefits of continued\ntherapy with AVANDARYL should be reviewed.
Hepatic Effects: Another drug of the thiazolidinedione class, troglitazone,\nwas associated with idiosyncratic hepatotoxicity, and very rare cases\nof liver failure, liver transplants, and death were reported during\nclinical use. In pre-approval controlled clinical trials in patients\nwith type 2 diabetes, troglitazone was more frequently associated\nwith clinically significant elevations in liver enzymes (ALT>3X upper\nlimit of normal) compared to placebo. Very rare cases of reversible\njaundice were also reported. In pre-approval\nclinical studies in 4,598 patients treated with rosiglitazone, encompassing\napproximately 3,600 patient years of exposure, there was no signal\nof drug-induced hepatotoxicity or elevation of ALT levels. In the\npre-approval controlled trials, 0.2% of patients treated with rosiglitazone\nhad elevations in ALT>3X the upper limit of normal compared to 0.2%\non placebo and 0.5% on active comparators. The ALT elevations in patients\ntreated with rosiglitazone were reversible and were not clearly causally\nrelated to therapy with rosiglitazone. In postmarketing\nexperience with rosiglitazone, reports of hepatitis and of hepatic\nenzyme elevations to 3 or more times the upper limit of normal have\nbeen received. Very rarely, these reports have involved hepatic failure\nwith and without fatal outcome, although causality has not been established.\nRosiglitazone is structurally related to troglitazone, a thiazolidinedione\nno longer marketed in the United States, which was associated with\nidiosyncratic hepatotoxicity and rare cases of liver failure, liver\ntransplants, and death during clinical use. Pending the availability\nof the results of additional large, long-term controlled clinical\ntrials and additional postmarketing safety data, it is recommended\nthat patients treated with AVANDARYL undergo periodic monitoring of\nliver enzymes. With sulfonylureas, including\nglimepiride, there may be an elevation of liver enzyme levels in rare\ncases. In isolated instances, impairment of liver function (e.g.,\nwith cholestasis and jaundice), as well as hepatitis (which may also\nlead to liver failure) have been reported. Liver\nenzymes should be checked prior to the initiation of therapy with\nAVANDARYL in all patients and periodically thereafter per the clinical\njudgement of the healthcare professional. Therapy with AVANDARYL should\nnot be initiated in patients with increased baseline liver enzyme\nlevels (ALT>2.5X upper limit of normal). Patients with mildly elevated\nliver enzymes (ALT levels���2.5X upper limit of normal) at baseline\nor during therapy with AVANDARYL should be evaluated to determine\nthe cause of the liver enzyme elevation. Initiation of, or continuation\nof, therapy with AVANDARYL in patients with mild liver enzyme elevations\nshould proceed with caution and include close clinical follow-up,\nincluding more frequent liver enzyme monitoring, to determine if the\nliver enzyme elevations resolve or worsen. If at any time ALT levels\nincrease to>3X the upper limit of normal in patients on therapy with\nAVANDARYL, liver enzyme levels should be rechecked as soon as possible.\nIf ALT levels remain>3X the upper limit of normal, therapy with AVANDARYL\nshould be discontinued. If any patient develops\nsymptoms suggesting hepatic dysfunction, which may include unexplained\nnausea, vomiting, abdominal pain, fatigue, anorexia, and/or dark urine,\nliver enzymes should be checked. The decision whether to continue\nthe patient on therapy with AVANDARYL should be guided by clinical\njudgement pending laboratory evaluations. If jaundice is observed,\ndrug therapy should be discontinued. There are\nno data available from clinical trials to evaluate the safety of AVANDARYL\nin patients who experienced liver abnormalities, hepatic dysfunction,\nor jaundice while on troglitazone. AVANDARYL should not be used in\npatients who experienced jaundice while taking troglitazone.
Laboratory Tests: Periodic fasting\nglucose and HbA1c measurements should be performed to monitor therapeutic\nresponse. Liver enzyme monitoring is recommended\nprior to initiation of therapy with AVANDARYL in all patients and\nperiodically thereafter (see PRECAUTIONS, Hepatic Effects).
Information for Patients: Patients should\nbe informed of the potential risks and advantages of AVANDARYL and\nof alternative modes of therapy. They should also be informed about\nthe importance of adherence to dietary instructions, weight loss,\nand a regular exercise program because these methods help improve\ninsulin sensitivity. The importance of regular testing of blood glucose\nand glycosylated hemoglobin (HbA1c) should be emphasized. Patients\nshould be advised that the sulfonylurea effect of AVANDARYL can begin\nto takeeffect within days after initiation, however it can take 2\nto 3 months to see the full effect of glycemic improvement. The risks of hypoglycemia, its symptoms and treatment,\nand conditions that predispose to its development should be explained\nto patients and their family members. Patients\nshould be informed that blood will be drawn to check their liver function\nprior to the start of therapy and periodically thereafter per the\nclinical judgement of the healthcare professional. Patients with unexplained\nsymptoms of nausea, vomiting, abdominal pain, fatigue, anorexia, or\ndark urine should immediately report these symptoms to their physician.\nPatients who experience an unusually rapid increase in weight or edema\nor who develop shortness of breath or other symptoms of heart failure\nwhile on AVANDARYL should immediately report these symptoms to their\nphysician. AVANDARYL should be taken with the\nfirst meal of the day. Therapy with rosiglitazone,\nlike other thiazolidinediones, may result in ovulation in some premenopausal\nanovulatory women. As a result, these patients may be at an increased\nrisk for pregnancy while taking AVANDARYL (see PRECAUTIONS, Pregnancy,\nPregnancy Category C). Thus, adequate contraception in premenopausal\nwomen should be recommended. This possible effect has not been specifically\ninvestigated in clinical studies so the frequency of this occurrence\nis not known.
Drug Interactions:
Rosiglitazone: Drugs Metabolized by\nCytochrome P450 An inhibitor of CYP2C8 (such as gemfibrozil) may increase\nthe AUC of rosiglitazone and an inducer of CYP2C8 (such as rifampin)\nmay decrease the AUC of rosiglitazone. Therefore, if an inhibitor\nor an inducer of CYP2C8 is started or stopped during treatment with\nrosiglitazone, changes in diabetes treatment may be needed based upon\nclinical response. (See CLINICAL PHARMACOLOGY, Drug Interactions, Rosiglitazone.)
Glimepiride: Certain\ndrugs tend to produce hyperglycemia and may lead to loss of control.\nThese drugs include the thiazides and other diuretics, corticosteroids,\nphenothiazines, thyroid products, estrogens, oral contraceptives,\nphenytoin, nicotinic acid, sympathomimetics, and isoniazid. When these\ndrugs are administered to a patient receiving glimepiride, the patient\nshould be closely observed for loss of control. When these drugs are\nwithdrawn from a patient receiving glimepiride, the patient should\nbe observed closely for hypoglycemia. A potential\ninteraction between oral miconazole and oral hypoglycemic agents leading\nto severe hypoglycemia has been reported. Whether this interaction\nalso occurs with the IV, topical, or vaginal preparations of miconazole\nis not known. Potential interactions of glimepiride with other drugs\nmetabolized by cytochrome P450 2C9 also include phenytoin, diclofenac,\nibuprofen, naproxen, and mefenamic acid. (See CLINICAL PHARMACOLOGY,\nDrug Interactions, Glimepiride.)
Carcinogenesis, Mutagenesis,\nImpairment of Fertility: No animal\nstudies have been conducted with AVANDARYL. The following data are\nbased on findings in studies performed with rosiglitazone or glimepiride\nalone.
Rosiglitazone:
Glimepiride:
Animal Toxicology:
Rosiglitazone: Heart\nweights were increased in mice (3 mg/kg/day), rats (5 mg/kg/day),\nand dogs (2 mg/kg/day) with rosiglitazone treatments (approximately\n5, 22, and 2 times human AUC at the maximum recommended human\ndaily dose, respectively). Effects in juvenile rats were consistent\nwith those seen in adults. Morphometric measurement indicated that\nthere was hypertrophy in cardiac ventricular tissues, which may be\ndue to increased heart work as a result of plasma volume expansion.
Glimepiride: Reduced\nserum glucose values and degranulation of the pancreatic beta cells\nwere observed in beagle dogs exposed to glimepiride 320 mg/kg/day\nfor 12 months (approximately 1,000 times the recommended\nhuman dose based on surface area). No evidence of tumor formation\nwas observed in any organ. One female and one male dog developed bilateral\nsubcapsular cataracts. Non-GLP studies indicated that glimepiride\nwas unlikely to exacerbate cataract formation. Evaluation of the co-cataractogenic\npotential of glimepiride in several diabetic and cataract rat models\nwas negative and there was no adverse effect of glimepiride on bovine\nocular lens metabolism in organ culture (see ADVERSE EVENTS, Human Ophthalmology Data).
Pregnancy: Pregnancy Category\nC. Because current information\nstrongly suggests that abnormal blood glucose levels during pregnancy\nare associated with a higher incidence of congenital anomalies as\nwell as increased neonatal morbidity and mortality, most experts recommend\nthat insulin monotherapy be used during pregnancy to maintain blood\nglucose levels as close to normal as possible. AVANDARYL should not\nbe used during pregnancy. There are no adequate\nand well-controlled studies with AVANDARYL or its individual components\nin pregnant women. No animal studies have been conducted with AVANDARYL.\nThe following data are based on findings in studies performed with\nrosiglitazone or glimepiride individually.
Rosiglitazone: Rosiglitazone has been reported to cross the human\nplacenta and be detectable in fetal tissue. The clinical significance\nof these findings is unknown. There was no effect on implantation\nor the embryo with rosiglitazone treatment during early pregnancy\nin rats, but treatment during mid-late gestation was associated with\nfetal death and growth retardation in both rats and rabbits. Teratogenicity\nwas not observed at doses up to 3 mg/kg in rats and 100 mg/kg\nin rabbits (approximately 20 and 75 times human AUC at the maximum\nrecommended human daily dose, respectively). Rosiglitazone caused\nplacental pathology in rats (3 mg/kg/day). Treatment of rats\nduring gestation through lactation reduced litter size, neonatal viability,\nand postnatal growth, with growth retardation reversible after puberty.\nFor effects on the placenta, embryo/fetus, and offspring, the no-effect\ndose was 0.2 mg/kg/day in rats and 15 mg/kg/day in rabbits.\nThese no-effect levels are approximately 4 times human AUC at\nthe maximum recommended human daily dose. Rosiglitazone reduced the\nnumber of uterine implantations and live offspring when juvenile female\nrats were treated at 40 mg/kg/day from 27 days of age through\nto sexual maturity (approximately 68 times human AUC at the maximum\nrecommended daily dose). The no-effect level was 2 mg/kg/day\n(approximately 4 times human AUC at the maximum recommended daily\ndose). There was no effect on pre- or post-natal survival or growth.
Glimepiride: Glimepiride\ndid not produce teratogenic effects in rats exposed orally up to 4,000\nmg/kg body weight (approximately 4,000 times the maximum recommended\nhuman dose based on surface area) or in rabbits exposed up to 32 mg/kg\nbody weight (approximately 60 times the maximum recommended human\ndose based on surface area). Glimepiride has been shown to be associated\nwith intrauterine fetal death in rats when given in doses as lowas\n50 times the human dose based on surface area and in rabbits\nwhen given in doses as low as 0.1 times the human dose based\non surface area. This fetotoxicity, observed only at doses inducing\nmaternal hypoglycemia, has been similarly noted with other sulfonylureas,\nand is believed to be directly related to the pharmacologic (hypoglycemic)\naction of glimepiride. In some studies in rats,\noffspring of dams exposed to high levels of glimepiride during pregnancy\nand lactation developed skeletal deformities consisting of shortening,\nthickening, and bending of the humerus during the postnatal period.\nSignificant concentrations of glimepiride were observed in the serum\nand breast milk of the dams as well as in the serum of the pups. These\nskeletal deformations were determined to be the result of nursing\nfrom mothers exposed to glimepiride. Prolonged severe hypoglycemia\n(4 to 10 days) has been reported in neonates born to mothers who were\nreceiving a sulfonylurea drug at the time of delivery. This has been\nreported more frequently with the use of agents with prolonged half-lives.
Labor and Delivery: The effect of\nAVANDARYL or its components on labor and delivery in humans is unknown.
Nursing Mothers: No studies have\nbeen conducted with AVANDARYL. It is not known whether rosiglitazone\nand/or glimepiride is excreted in human milk. Because many drugs are\nexcreted in human milk, AVANDARYL should not be administered to a\nnursing woman. If AVANDARYL is discontinued, and if diet alone is\ninadequate for controlling blood glucose, insulin therapy should be\nconsidered (see PRECAUTIONS, Pregnancy, Pregnancy Category C).
Rosiglitazone: Drug-related\nmaterial was detected in milk from lactating rats.
Glimepiride: In rat reproduction studies, significant concentrations\nof glimepiride were observed in the serum and breast milk of the dams,\nas well as in the serum of the pups. Although it is not known whether\nglimepiride is excreted in human milk, other sulfonylureas are excreted\nin human milk.
Pediatric Use: Safety and effectiveness of AVANDARYL in pediatric\npatients have not been established. AVANDARYL and its components,\nrosiglitazone and glimepiride, are not indicated for use in pediatric\npatients.
Geriatric Use:
Rosiglitazone: Results of the population pharmacokinetic analysis\nshowed that age does not significantly affect the pharmacokinetics\nof rosiglitazone (see CLINICAL PHARMACOLOGY, Special Populations, Geriatric ). Therefore, no dosage adjustments\nare required for the elderly. In controlled clinical trials, no overall\ndifferences in safety and effectiveness between older (���65\nyears) and younger (<65 years) patients were observed.
Glimepiride: In US clinical\nstudies of glimepiride, 608 of 1,986 patients were 65 and older. No\noverall differences in safety or effectiveness were observed between\nthese subjects and younger subjects, but greater sensitivity of some\nolder individuals cannot be ruled out. Comparison\nof glimepiride pharmacokinetics in type 2 diabetes patients���65\nyears (n = 49) and those>65 years (n = 42) was\nperformed in a study using a dosing regimen of 6 mg daily. There were\nno significant differences in glimepiride pharmacokinetics between\nthe 2 age groups (see CLINICAL PHARMACOLOGY, Special Populations, Geriatric). The\ndrug is known to be substantially excreted by the kidney, and the\nrisk of toxic reactions to this drug may be greater in patients with\nimpaired renal function. Because elderly patients are more likely\nto have decreased renal function, care should be taken in dose selection,\nand it may be useful to monitor renal function. Elderly patients are particularly susceptible to hypoglycemic action\nof glucose-lowering drugs. In elderly, debilitated, or malnourished\npatients, or in patients with renal, hepatic or adrenal insufficiency,\nthe starting dose, dose increments, and maintenance dosage should\nbe conservative based upon blood glucose levels prior to and after\ninitiation of treatment to avoid hypoglycemic reactions. Hypoglycemia\nmay be difficult to recognize in the elderly and in people who are\ntaking beta-adrenergic blocking drugs or other sympatholytic agents\n(see CLINICAL PHARMACOLOGY, Special Populations,Renal Impairment; PRECAUTIONS, General;and DOSING AND ADMINISTRATION, Special Populations).",
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"value" : "AVANDARYL (rosiglitazone maleate and glimepiride)\ntablets contain 2 oral antidiabetic drugs used in the management of\ntype 2 diabetes: Rosiglitazone maleate and glimepiride. Rosiglitazone maleate is an oral antidiabetic agent of\nthe thiazolidinedione class which acts primarily by increasing insulin\nsensitivity. Rosiglitazone maleate is not chemically or functionally\nrelated to the sulfonylureas, the biguanides, or the alpha-glucosidase\ninhibitors. Chemically, rosiglitazone maleate is (��)-5-[[4-[2-(methyl-2-pyridinylamino)\nethoxy]phenyl] methyl]-2,4-thiazolidinedione, (Z)-2-butenedioate (1:1) with a molecular\nweight of 473.52 (357.44 free base). The molecule has a single chiral\ncenter and is present as a racemate. Due to rapid interconversion,\nthe enantiomers are functionally indistinguishable. The molecular\nformula is CHNOS���CHO. Rosiglitazone maleate is a white\nto off-white solid with a melting point range of 122��to 123��C.\nThe pKvalues of rosiglitazone maleate are 6.8 and 6.1.\nIt is readily soluble in ethanol and a buffered aqueous solution with\npH of 2.3; solubility decreases with increasing pH in the physiological\nrange. The structural formula of rosiglitazone maleate is: Glimepiride is an oral antidiabetic drug of the sulfonylurea\nclass. Glimepiride is a white to yellowish-white, crystalline, odorless\nto 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\nwith a molecular weight of 490.62. The molecular formula for glimepiride\nis CHNOS. Glimepiride\nis practically insoluble in water. The structural formula of glimepiride\nis: AVANDARYL is available for oral administration\nas tablets containing rosiglitazone maleate and glimepiride, respectively,\nin the following strengths (expressed as rosiglitazone maleate/glimepiride):\n4 mg/1 mg, 4 mg/2 mg, 4 mg/4 mg, 8 mg/2 mg, and 8 mg/4 mg. Each tablet\ncontains the following inactive ingredients: Hypromellose 2910, lactose\nmonohydrate, macrogol (polyethylene glycol), magnesium stearate, microcrystalline\ncellulose, sodium starch glycolate, titanium dioxide, and 1 or more\nof the following: Yellow, red, or black iron oxides.",
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"value" : "Rosiglitazone: Limited data\nare available with regard to overdosage in humans. In clinical studies\nin volunteers, rosiglitazone has been administered at single oral\ndoses of up to 20 mg and was well tolerated. In the event of\nan overdose, appropriate supportive treatment should be initiated\nas dictated by the patient's clinical status.
Glimepiride: Overdosage of\nsulfonylureas, including glimepiride, can produce hypoglycemia. Mild\nhypoglycemic symptoms without loss of consciousness or neurologic\nfindings should be treated aggressively with oral glucose and adjustments\nin drug dosage and/or meal patterns. Close monitoring should continue\nuntil the physician is assured that the patient is out of danger.\nSevere hypoglycemic reactions with coma, seizure, or other neurological\nimpairmentoccur infrequently, but constitute medical emergencies\nrequiring immediate hospitalization. If hypoglycemic coma is diagnosed\nor suspected, the patient should be given a rapid IV injection of\nconcentrated (50%) glucose solution. This should be followed by a\ncontinuous infusion of a more dilute (10%) glucose solution at a rate\nthat will maintain the blood glucose level above 100 mg/dL. Patients\nshould be closely monitored for a minimum of 24 to 48 hours, because\nhypoglycemia may recur after apparent clinical recovery.",
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