Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/4038
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Glucotrol XL (Tablet, Extended Release)
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There is no fixed dosage regimen for the management of diabetes mellitus with GLUCOTROL XL Extended Release Tablet or any other hypoglycemic agent. Glycemic control should be monitored with hemoglobin Aand/or blood-glucose levels to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate blood-glucose-lowering response after an initial period of effectiveness. Home blood-glucose monitoring may also provide useful information to the patient and physician. Short-term administration of GLUCOTROL XL Extended Release Tablet may be sufficient during periods of transient loss of control in patients usually controlled on diet. In general, GLUCOTROL XL should be given with breakfast.<br/>Recommended Dosing: The usual starting dose of GLUCOTROL XL as initial therapy is 5 mg per day, given with breakfast. Those patients who may be more sensitive to hypoglycemic drugs may be started at a lower dose. Dosage adjustment should be based on laboratory measures of glycemic control. While fasting blood-glucose levels generally reach steady-state following initiation or change in GLUCOTROL XL dosage, a single fasting glucose determination may not accurately reflect the response to therapy. In most cases, hemoglobin Alevel measured at three month intervals is the preferred means of monitoring response to therapy. Hemoglobin Ashould be measured as GLUCOTROL XL therapy is initiated and repeated approximately three months later. If the result of this test suggests that glycemic control over the preceding three months was inadequate, the GLUCOTROL XL dose may be increased. Subsequent dosage adjustments should be made on the basis of hemoglobin Alevels measured at three month intervals. If no improvement is seen after three months of therapy with a higher dose, the previous dose should be resumed. Decisions which utilize fasting blood glucose to adjust GLUCOTROL XL therapy should be based on at least two or more similar, consecutive values obtained seven days or more after the previous dose adjustment. Most patients will be controlled with 5 mg to 10 mg taken once daily. However, some patients may require up to the maximum recommended daily dose of 20 mg. While the glycemic control of selected patients may improve with doses which exceed 10 mg, clinical studies conducted to date have not demonstrated an additional group average reduction of hemoglobin Abeyond what was achieved with the 10 mg dose. Based on the results of a randomized crossover study, patients receiving immediate release glipizide may be switched safely to GLUCOTROL XL Extended Release Tablets once-a-day at the nearest equivalent total daily dose. Patients receiving immediate release Glucotrol also may be titrated to the appropriate dose of GLUCOTROL XL starting with 5 mg once daily. The decision to switch to the nearest equivalent dose or to titrate should be based on clinical judgment. In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions .<br/>Combination Use: When adding other blood-glucose-lowering agents to GLUCOTROL XL for combination therapy, the agent should be initiated at the lowest recommended dose, and patients should be observed carefully for hypoglycemia. Refer to the product information supplied with the oral agent for additional information. When adding GLUCOTROL XL to other blood-glucose-lowering agents, GLUCOTROL XL can be initiated at 5 mg. Those patients who may be more sensitive to hypoglycemic drugs may be started at a lower dose. Titration should be based on clinical judgment.<br/>Patients Receiving Insulin: As with other sulfonylurea-class hypoglycemics, many patients with stable type 2 diabetes receiving insulin may be transferred safely to treatment with GLUCOTROL XL Extended Release Tablets. When transferring patients from insulin to GLUCOTROL XL, the following general guidelines should be considered: For patients whose daily insulin requirement is 20 units or less, insulin may be discontinued and GLUCOTROL XL therapy may begin at usual dosages. Several days should elapse between titration steps. For patients whose daily insulin requirement is greater than 20 units, the insulin dose should be reduced by 50% and GLUCOTROL XL therapy may begin at usual dosages. Subsequent reductions in insulin dosage should depend on individual patient response. Several days should elapse between titration steps. During the insulin withdrawal period, the patient should test urine samples for sugar and ketone bodies at least three times daily. Patients should be instructed to contact the prescriber immediately if these tests are abnormal. In some cases, especially when the patient has been receiving greater than 40 units of insulin daily, it may be advisable to consider hospitalization during the transition period.<br/>Patients Receiving Other Oral Hypoglycemic Agents: As with other sulfonylurea-class hypoglycemics, no transition period is necessary when transferring patients to GLUCOTROL XL Extended Release Tablets. Patients should be observed carefully (1���2 weeks) for hypoglycemia when being transferred from longer half-life sulfonylureas (e.g., chlorpropamide) to GLUCOTROL XL due to potential overlapping of drug effect.
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Glipizide is an oral blood-glucose-lowering drug of the sulfonylurea class. The Chemical Abstracts name of glipizide is 1-cyclohexyl-3-[[p-[2-(5-methylpyrazinecarboxamido)ethyl] phenyl]sulfonyl]urea. The molecular formula is CHNOS; the molecular weight is 445.55; the structural formula is shown below: Glipizide is a whitish, odorless powder with a pKa of 5.9. It is insoluble in water and alcohols, but soluble in 0.1 N NaOH; it is freely soluble in dimethylformamide. GLUCOTROL XL' is a registered trademark for glipizide GITS. Glipizide GITS (Gastrointestinal Therapeutic System) is formulated as a once-a-day controlled release tablet for oral use and is designed to deliver 2.5, 5, or 10 mg of glipizide. Inert ingredients in the 2.5 mg, 5 mg and 10 mg formulations are: polyethylene oxide, hypromellose, magnesium stearate, sodium chloride, red ferric oxide, cellulose acetate, polyethylene glycol, Opadry blue (OY-LS-20921)(2.5 mg tablets), Opadry white (YS-2-7063)(5 mg and 10 mg tablet) and black ink (S-1-8106).<br/>System Components and Performance: GLUCOTROL XL Extended Release Tablet is similar in appearance to a conventional tablet. It consists, however, of an osmotically active drug core surrounded by a semipermeable membrane. The core itself is divided into two layers: an "active" layer containing the drug, and a "push" layer containing pharmacologically inert (but osmotically active) components. The membrane surrounding the tablet is permeable to water but not to drug or osmotic excipients. As water from the gastrointestinal tract enters the tablet, pressure increases in the osmotic layer and "pushes" against the drug layer, resulting in the release of drug through a small, laser-drilled orifice in the membrane on the drug side of the tablet. The GLUCOTROL XL Extended Release Tablet is designed to provide a controlled rate of delivery of glipizide into the gastrointestinal lumen which is independent of pH or gastrointestinal motility. The function of the GLUCOTROL XL Extended Release Tablet depends upon the existence of an osmotic gradient between the contents of the bi-layer core and fluid in the GI tract. Drug delivery is essentially constant as long as the osmotic gradient remains constant, and then gradually falls to zero. The biologically inert components of the tablet remain intactduring GI transit and are eliminated in the feces as an insoluble shell.
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Mechanism of Action: Glipizide appears to lower blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. Extrapancreatic effects also may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs. Two extrapancreatic effects shown to be important in the action of glipizide are an increase in insulin sensitivity and a decrease in hepatic glucose production. However, the mechanism by which glipizide lowers blood glucose during long-term administration has not been clearly established. Stimulation of insulin secretion by glipizide in response to a meal is of major importance. The insulinotropic response to a meal is enhanced with GLUCOTROL XL administration in diabetic patients. The postprandial insulin and C-peptide responses continue to be enhanced after at least 6 months of treatment. In 2 randomized, double-blind, dose-response studies comprising a total of 347 patients, there was no significant increase in fasting insulin in all GLUCOTROL XL-treated patients combined compared to placebo, although minor elevations were observed at some doses. There was no increase in fasting insulin over the long term. Some patients fail to respond initially, or gradually lose their responsiveness to sulfonylurea drugs, including glipizide. Alternatively, glipizide may be effective in some patients who have not responded or have ceased to respond to other sulfonylureas.<br/>Effects on Blood Glucose: The effectiveness of GLUCOTROL XL Extended Release Tablets in type 2 diabetes at doses from 5���60 mg once daily has been evaluated in 4 therapeutic clinical trials each with long-term open extensions involving a total of 598 patients. Once daily administration of 5, 10 and 20 mg produced statistically significant reductions from placebo in hemoglobin A, fasting plasma glucose and postprandial glucose in patients with mild to severe type 2 diabetes. In a pooled analysis of the patients treated with 5 mg and 20 mg, the relationship between dose and GLUCOTROL XL's effect of reducing hemoglobin Awas not established. However, in the case of fasting plasma glucose patients treated with 20 mg had a statistically significant reduction of fasting plasma glucose compared to the 5 mg-treated group. The reductions in hemoglobin Aand fasting plasma glucose were similar in younger and older patients. Efficacy of GLUCOTROL XL was not affected by gender, race or weight (as assessed by body mass index). In long term extension trials, efficacy of GLUCOTROL XL was maintained in 81% of patients for up to 12 months. In an open, two-way crossover study 132 patients were randomly assigned to either GLUCOTROL XL or Glucotrol' for 8 weeks and then crossed over to the other drug for an additional 8 weeks. GLUCOTROL XL administration resulted in significantly lower fasting plasma glucose levels and equivalent hemoglobin Alevels, as compared to Glucotrol.<br/>Other Effects: It has been shown that GLUCOTROL XL therapy is effective in controlling blood glucose without deleterious changes in the plasma lipoprotein profiles of patients treated for type 2 diabetes. In a placebo-controlled, crossover study in normal volunteers, glipizide had no antidiuretic activity, and, in fact, led to a slight increase in free water clearance.<br/>Pharmacokinetics and Metabolism: Glipizide is rapidly and completely absorbed following oral administration in an immediate release dosage form. The absolute bioavailability of glipizide was 100% after single oral doses in patients with type 2 diabetes. Beginning 2 to 3 hours after administration of GLUCOTROL XL Extended Release Tablets, plasma drug concentrations gradually rise reaching maximum concentrations within 6 to 12 hours after dosing. With subsequent once daily dosing of GLUCOTROL XL Extended Release Tablets, effective plasma glipizide concentrations are maintained throughout the 24 hour dosing interval with less peak to trough fluctuation than that observed with twice daily dosing of immediate release glipizide. The mean relative bioavailability of glipizide in 21 males with type 2 diabetesafter administration of 20 mg GLUCOTROL XL Extended Release Tablets, compared to immediate release Glucotrol (10 mg given twice daily), was 90% at steady-state. Steady-state plasma concentrations were achieved by at least the fifth day of dosing with GLUCOTROL XL Extended Release Tablets in 21 males with type 2 diabetes and patients younger than 65 years. Approximately 1 to 2 days longer were required to reach steady-state in 24 elderly (���65 years) males and females with type 2 diabetes. No accumulation of drug was observed in patients with type 2 diabetes during chronic dosing with GLUCOTROL XL Extended Release Tablets. Administration of GLUCOTROL XL with food has no effect on the 2 to 3 hour lag time in drug absorption. In a single dose, food effect study in 21 healthy male subjects, the administration of GLUCOTROL XL immediately before a high fat breakfast resulted in a 40% increase in the glipizide mean Cmax value, which was significant, but the effect on the AUC was not significant. There was no change in glucose response between the fed and fasting state. Markedly reduced GI retention times of the GLUCOTROL XL tablets over prolonged periods (e.g., short bowel syndrome) may influence the pharmacokinetic profile of the drug and potentially result in lower plasma concentrations. In a multiple dose study in 26 males with type 2 diabetes, the pharmacokinetics of glipizide were linear over the dose range of 5 to 60 mg of GLUCOTROL XL in that the plasma drug concentrations increased proportionately with dose. In a single dose study in 24 healthy subjects, four 5 mg, two 10 mg, and one 20 mg GLUCOTROL XL Extended Release Tablets were bioequivalent. In a separate single dose study in 36 healthy subjects, four 2.5-mg GLUCOTROL XL Extended Release Tablets were bioequivalent to one 10-mg GLUCOTROL XL Extended Release Tablet. Glipizide is eliminated primarily by hepatic biotransformation: less than 10% of a dose is excreted as unchanged drug in urine and feces; approximately 90% of a dose is excreted as biotransformation products in urine (80%) and feces (10%). The major metabolites of glipizide are products of aromatic hydroxylation and have no hypoglycemic activity. A minor metabolite which accounts for less than 2% of a dose, an acetylamino-ethyl benzene derivative, is reported to have 1/10 to 1/3 as much hypoglycemic activity as the parent compound. The mean total body clearance of glipizide was approximately 3 liters per hour after single intravenous doses in patients with type 2 diabetes. The mean apparent volume of distribution was approximately 10 liters. Glipizide is 98���99% bound to serum proteins, primarily to albumin. The mean terminal elimination half-life of glipizide ranged from 2 to 5 hours after single or multiple doses in patients with type 2 diabetes. There were no significant differences in the pharmacokinetics of glipizide after single dose administration to older diabetic subjects compared to younger healthy subjects. There is only limited information regarding the effects of renal impairment on the disposition of glipizide, and no information regarding the effects of hepatic disease. However, since glipizide is highly protein bound and hepatic biotransformation is the predominant route of elimination, the pharmacokinetics and/or pharmacodynamics of glipizide may be altered in patients with renal or hepatic impairment. In mice no glipizide or metabolites were detectable autoradiographically in the brain or spinal cord of males or females, nor in the fetuses of pregnant females. In another study, however, very small amounts of radioactivity were detected in the fetuses of rats given labelled drug.
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Glipizide is contraindicated in patients with:
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GLUCOTROL XL (glipizide) Extended Release Tablets are supplied as 2.5 mg, 5 mg, and 10 mg round, biconvex tablets and imprinted with black ink as follows: 2.5 mg tablets are blue and imprinted with "GLUCOTROL XL 2.5" on one side.Bottles of 30: NDC 0049-1620-30 5 mg tablets are white and imprinted with "GLUCOTROL XL 5" on one side.Bottles of 100: NDC 0049-1550-66Bottles of 500: NDC 0049-1550-73 10 mg tablets are white and imprinted with "GLUCOTROL XL 10" on one side.Bottles of 100: NDC 0049-1560-66Bottles of 500: NDC 0049-1560-73<br/>Recommended Storage: The tablets should be protected from moisture and humidity and stored at controlled room temperature, 59��to 86��F (15��to 30��C).
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dailymed-ingredient:Opadry_blue_(OY-LS-20921),
dailymed-ingredient:black_ink_(S_1_8106),
dailymed-ingredient:cellulose_acetate,
dailymed-ingredient:hypromellose,
dailymed-ingredient:magnesium_stearate,
dailymed-ingredient:polyethylene_glycol,
dailymed-ingredient:polyethylene_oxide,
dailymed-ingredient:red_ferric_oxide,
dailymed-ingredient:sodium_chloride
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glipizide
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Glucotrol XL (Tablet, Extended Release)
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In U.S. controlled studies the frequency of serious adverse experiences reported was very low and causal relationship has not been established. The 580 patients from 31 to 87 years of age who received GLUCOTROL XL Extended Release Tablets in doses from 5 mg to 60 mg in both controlled and open trials were included in the evaluation of adverse experiences. All adverse experiences reported were tabulated independently of their possible causal relation to medication.<br/>Hypoglycemia: See PRECAUTIONS and OVERDOSAGE sections. Only 3.4% of patients receiving GLUCOTROL XL Extended Release Tablets had hypoglycemia documented by a blood-glucose measurement<60 mg/dL and/or symptoms believed to be associated with hypoglycemia. In a comparative efficacy study of GLUCOTROL XL and Glucotrol, hypoglycemia occurred rarely with an incidence of less than 1% with both drugs. In double-blind, placebo-controlled studies the adverse experiences reported with an incidence of 3% or more in GLUCOTROL XL-treated patients include: The following adverse experiences occurred with an incidence of less than 3% in GLUCOTROL XL-treated patients: Other adverse experiences occurred with an incidence of less than 1% in GLUCOTROL XL-treated patients: Although these adverse experiences occurred in patients treated with GLUCOTROL XL, a causal relationship to the medication has not been established in all cases. There have been rare reports of gastrointestinal irritation and gastrointestinal bleeding with use of another drug in this non-deformable sustained release formulation, although causal relationship to the drug is uncertain. In post-marketing experience of GLUCOTROL XL, the additional adverse reaction of abdominal pain has been reported. The following are adverse experiences reported with immediate release glipizide and other sulfonylureas, but have not been observed with GLUCOTROL XL:<br/>Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, and pancytopenia have been reported with sulfonylureas.<br/>Metabolic: Hepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas. In the mouse, glipizide pretreatment did not cause an accumulation of acetaldehyde after ethanol administration. Clinical experience to date has shown that glipizide has an extremely low incidence of disulfiram-like alcohol reactions.<br/>Endocrine Reactions: Cases of hyponatremia and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion have been reported with glipizide and other sulfonylureas.<br/>Laboratory Tests: The pattern of laboratory test abnormalities observed with glipizide was similar to that for other sulfonylureas. Occasional mild to moderate elevations of SGOT, LDH, alkaline phosphatase, BUN and creatinine were noted. One case of jaundice was reported. The relationship of these abnormalities to glipizide is uncertain, and they have rarely been associated with clinical symptoms.
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SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY: The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study 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 type 2 diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups (Diabetes, 19, SUPP. 2:747���830, 1970). 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��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 study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of glipizide and of alternative modes of therapy. Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, 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. As with any other non-deformable material, caution should be used when administering GLUCOTROL XL Extended Release Tablets in patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of another drug in this non-deformable sustained release formulation.
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GLUCOTROL XL is indicated as an adjunct to diet for the control of hyperglycemia and its associated symptomatology in patients with type 2 diabetes formerly known as non-insulin-dependent diabetes mellitus (NIDDM) or maturity-onset diabetes, after an adequate trial of dietary therapy has proved unsatisfactory. GLUCOTROL XL is indicated when diet alone has been unsuccessful in correcting hyperglycemia, but even after the introduction of the drug in the patient's regimen, dietary measures should continue to be considered as important.In 12 week, well-controlled studies there was a maximal average net reduction in hemoglobin Aof 1.7% in absolute units between placebo-treated and GLUCOTROL XL-treated patients. In initiating treatment for type 2 diabetes, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling blood glucose and symptoms of hyperglycemia. The importance of regular physical activity should also be stressed, cardiovascular risk factors should be identified, and corrective measures taken where possible. If this treatment program fails to reduce symptoms and/or blood glucose, the use of an oral sulfonylurea should be considered. If additional reduction of symptoms and/or blood glucose is required, the addition of insulin to the treatment regimen should be considered. Use of GLUCOTROL XL must be viewed by both the physician andpatient as a treatment in addition to diet, and not as a substitute for diet or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood-glucose control on diet alone also may be transient, thus requiring only short-term administration of glipizide. Some patients fail to respond initially or gradually lose their responsiveness to sulfonylurea drugs, including GLUCOTROL XL. In these cases, concomitant use of GLUCOTROL XL with other oral blood-glucose-lowering agents can be considered. Other approaches that can be considered include substitution of GLUCOTROL XL therapy with that of another oral blood-glucose-lowering agent or insulin. GLUCOTROL XL should be discontinued if it no longer contributes to glucose lowering. Judgment of response to therapy should be based on regular clinical and laboratory evaluations. In considering the use of GLUCOTROL XL in asymptomatic patients, it should be recognized that controlling blood glucose in type 2 diabetes has not been definitely established to be effective in preventing the long-term cardiovascular or neural complications of diabetes. However, in insulin-dependent diabetes mellitus controlling blood glucose has been effective in slowing the progression of diabetic retinopathy, nephropathy, and neuropathy.
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Glucotrol XL
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