Micronase Warnings and Precautions

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Micronase
Diabetes and Foot Problems Slideshow Warnings & Precautions
(glyburide) Tablets, USP 1.25, 2.5, and 5 mg

DRUG DESCRIPTION
MICRONASE Tablets contain glyburide, which is an oral blood-glucose-lowering drug of the sulfonyl- urea class. Glyburide is a white, crystalline com- pound, formulated as MICRONASE Tablets of 1.25, 2.5, and 5 mg strengths for oral administration. Inactive ingredients: colloidal silicon dioxide, dibasic calcium phosphate, magnesium stearate, microcrys- talline cellulose, sodium alginate, talc. In addition, the 2.5 mg contains aluminum oxide and FD&C Red No. 40 and the 5 mg contains aluminum oxide and FD&C Blue No. 1. The chemical name for glyburide is 1-[ [p-[2-(5-chloro-o-anisamido)-ethyl]phenyl]-sulfo- nyl]-3-cyclohexylurea and the molecular weight is 493.99. The structural formula is represented below.

MICRONASE Tablets are indicated as an adjunct to diet to lower the blood glucose in patients with non-insulin-dependent diabetes mellitus (Type II) whose hyperglycemia cannot be satisfactorily con- trolled by diet alone.

Glyburide may be used concomitantly with met- formin when diet and glyburide or diet and metformin alone do not result in adequate glycemic control (see metformin insert).

In initiating treatment for non-insulin-dependent 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 con- trolling the blood glucose and symptoms of hyper- glycemia. The importance of regular physical activity should also be stressed, and cardiovascular risk fac- tors 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 or insulin should be considered. Use of MICRONASE must be viewed by both the physician and patient as a treatment in addition to diet and not as a substitution or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone may be transient, thus requiring only short- term administration of MICRONASE.

During maintenance programs, MICRONASE should be discontinued if satisfactory lowering of blood glucose is no longer achieved. Judgment should be based on regular clinical and laboratory evaluations.

In considering the use of MICRONASE in asymp- tomatic patients, it should be recognized that control- ling blood glucose in non-insulin-dependent diabetes has not been definitely established to be effective in preventing the long-term cardiovascular or neural complications of diabetes.

DOSAGE AND ADMINISTRATION
There is no fixed dosage regimen for the manage- ment of diabetes mellitus with MICRONASE Tablets or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patient's blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, ie, inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, ie, loss of adequate blood glucose lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient's response to therapy.

Short-term administration of MICRONASE may be sufficient during periods of transient loss of control in patients usually controlled well on diet.

Usual Starting Dose
The usual starting dose of MICRONASE Tablets is 2.5 to 5 mg daily, administered with breakfast or the first main meal. Those patients who may be more sensitive to hypoglycemic drugs should be started at 1.25 mg daily. (See PRECAUTIONS section for patients at increased risk.) Failure to follow an appropriate dosage regimen may precipitate hypo- glycemia. Patients who do not adhere to their pre- scribed dietary and drug regimen are more prone to exhibit unsatisfactory response to therapy.

Transfer From Other Hypoglycemic Therapy Patients Receiving Other Oral Antidiabetic Therapy: Transfer of patients from other oral antidia- betic regimens to MICRONASE should be done conservatively and the initial daily dose should be 2.5 to 5 mg. When transferring patients from oral hypo- glycemic agents other than chlorpropamide to MICRONASE, no transition period and no initial or priming dose are necessary. When transferring patients from chlorpropamide, particular care should be exercised during the first two weeks because the prolonged retention of chlorpropamide in the body and subsequent overlapping drug effects may pro- voke hypoglycemia.

Patients Receiving Insulin: Some Type II diabetic patients being treated with insulin may respond satis- factorily to MICRONASE. If the insulin dose is less than 20 units daily, substitution of MICRONASE Tablets 2.5 to 5 mg as a single daily dose may be tried. If the insulin dose is between 20 and 40 units daily, the patient may be placed directly on MICRONASE Tablets 5 mg daily as a single dose. If the insulin dose is more than 40 units daily, a tran- sition period is required for conversion to MICRONASE. In these patients, insulin dosage is decreased by 50% and MICRONASE Tablets 5 mg daily is started. Please refer to Titration to Maintenance Dose for further explanation.

Titration to Maintenance Dose
The usual maintenance dose is in the range of 1.25 to 20 mg daily, which may be given as a single dose or in divided doses (See Dosage Interval section). Dosage increases should be made in increments of no more than 2.5 mg at weekly intervals based upon the patient's blood glucose response.

No exact dosage relationship exists between MICRONASE and the other oral hypoglycemic agents. Although patients may be transferred from the maximum dose of other sulfonylureas, the maxi- mum starting dose of 5 mg of MICRONASE Tablets should be observed. A maintenance dose of 5 mg of MICRONASE Tablets provides approximately the same degree of blood glucose control as 250 to 375 mg chlorpropamide, 250 to 375 mg tolazamide, 500 to 750 mg acetohexamide, or 1000 to 1500 mg tolbutamide.

When transferring patients receiving more than 40 units of insulin daily, they may be started on a daily dose of MICRONASE Tablets 5 mg concomitantly with a 50% reduction in insulin dose. Progressive withdrawal of insulin and increase of MICRONASE in increments of 1.25 to 2.5 mg every 2 to 10 days is then carried out. During this conversion period when both insulin and MICRONASE are being used, hypo- glycemia may rarely occur. During insulin withdrawal, patients should test their urine for glucose and ace- tone at least three times daily and report results to their physician. The appearance of persistent ace- tonuria with glycosuria indicates that the patient is a Type I diabetic who requires insulin therapy.

Concomitant Glyburide and Metformin Therapy
MICRONASE Tablets should be added gradually to the dosing regimen of patients who have not responded to the maximum dose of metformin monotherapy after four weeks (see Usual Starting Dose and Titration to Maintenance Dose). Refer to metformin package insert.

With concomitant glyburide and metformin therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. However, attempts should be made to identify the optimal dose of each drug needed to achieve this goal. With concomitant glyburide and metformin therapy, the risk of hypo- glycemia associated with sulfonylurea therapy contin- ues and may be increased. Appropriate precautions should be taken (see PRECAUTIONS section).

Maximum Dose
Daily doses of more than 20 mg are not recommended.

Dosage Interval
Once-a-day therapy is usually satisfactory. Some patients, particularly those receiving more than 10 mg daily, may have a more satisfactory response with twice-a-day dosage.

Specific Patient Populations
MICRONASE is not recommended for use in preg- nancy or for use in pediatric patients.

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. (See PRECAUTIONS section.)

HOW SUPPLIED
MICRONASE Tablets are supplied as follows:

MICRONASE Tablets 1.25 mg (White, Round, Scored, imprinted MICRONASE 1.25)

Bottles of 100..............................NDC 0009-0131-01

MICRONASE Tablets 2.5 mg (Dark Pink, Round, Scored, imprinted MICRONASE 2.5)

Bottles of 100..............................NDC 0009-0141-01
Bottles of 1000............................NDC 0009-0141-03
Unit Dose Pkg of 100.................NDC 0009-0141-02

MICRONASE Tablets 5 mg (Blue, Round, Scored imprinted MICRONASE 5)

Bottles of 30..............................NDC 0009-0171-11
Bottles of 60..............................NDC 0009-0171-12
Bottles of 100............................NDC 0009-0171-05
Bottles of 500............................NDC 0009-0171-06
Bottles of 1000..........................NDC 0009-0171-07
Unit Dose Pkg of 100...............NDC 0009-0171-03

Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP]. Dispensed in well closed containers with safety closures. Keep container tightly closed.

Pharmacia & Upjohn Company. A subsidiary of Pharmacia Corporation, Kalamazoo, MI 49001, USA. Revised March 2002. FDA Rev date: 11/30/1999


SIDE EFFECTS
Hypoglycemia: See PRECAUTIONS and OVERDOSAGE Sections.

Gastrointestinal Reactions: Cholestatic jaundice and hepatitis may occur rarely; MICRONASE Tablets should be discontinued if this occurs.

Liver function abnormalities, including isolated transaminase elevations, have been reported.

Gastrointestinal disturbances, eg, nausea, epigas- tric fullness, and heartburn are the most common reactions, having occurred in 1.8% of treated patients during clinical trials. They tend to be dose related and may disappear when dosage is reduced.

Dermatologic Reactions: Allergic skin reactions, eg, pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions occurred in 1.5% of treated patients during clinical trials. These may be transient and may disappear despite continued use of MICRONASE; if skin reactions persist, the drug should be discontinued.

Porphyria cutanea tarda and photosensitivity reac- tions have been reported with sulfonylureas.

Hematologic Reactions: Leukopenia, agranulocyto- sis, thrombocytopenia, hemolytic anemia, aplastic anemia, and pancytopenia have been reported with sulfonylureas.

Metabolic Reactions: Hepatic porphyria and disulfi- ram-like reactions have been reported with sulfonyl- ureas; however, hepatic porphyria has not been reported with MICRONASE and disulfiram-like reac- tions have been reported very rarely.

Cases of hyponatremia have been reported with glyburide and all other sulfonylureas, most often in patients who are on other medications or have medi- cal conditions known to cause hyponatremia or increase release of antidiuretic hormone. The syn- drome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with certain other sul- fonylureas, and it has been suggested that these sul- fonylureas may augment the peripheral (antidiuretic) action of ADH and/or increase release of ADH.

Other Reactions: Changes in accommodation and/or blurred vision have been reported with glyburide and other sulfonylureas. These are thought to be related to fluctuation in glucose levels.

In addition to dermatologic reactions, allergic reac- tions such as angioedema, arthralgia, myalgia and vasculitis have been reported.

DRUG INTERACTIONS
The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta adrenergic blocking agents. When such drugs are administered to a patient receiving MICRONASE, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving MICRONASE, the patient should be observed closely for loss of control.

Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phe- nothiazines, thyroid products, estrogens, oral contra- ceptives, phenytoin, nicotinic acid, sympathomimet- ics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving MICRONASE, the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving MICRONASE, the patient should be observed closely for hypoglycemia.

A possible interaction between glyburide and ciprofloxacin, a fluoroquinolone antibiotic, has been reported, resulting in a potentiation of the hypo- glycemic action of glyburide. The mechanism for this interaction is not known.

A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this inter- action also occurs with the intravenous, topical or vaginal preparations of miconazole is not known.

Metformin: In a single-dose interaction study in NIDDM subjects, decreases in glyburide AUC and Cmax were observed, but were highly variable. The single-dose nature of this study and the lack of corre- lation between glyburide blood levels and pharmaco- dynamic effects, makes the clinical significance of this interaction uncertain. Coadministration of gly- buride and metformin did not result in any changes in either metformin pharmacokinetics or pharmaco- dynamics.


WARNINGS
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 compli- cations in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups (Diabetes, 19 (Suppl. 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 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regard- ing the interpretation of these results, the find- ings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of MICRONASE 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.

PRECAUTIONS
General
Hypoglycemia: All sulfonylureas are capable of pro- ducing severe hypoglycemia. Proper patient selection and dosage and instructions are important to avoid hypoglycemic episodes. Renal or hepatic insuffi- ciency may cause elevated drug levels of glyburide and the latter may also diminish gluconeogenic capacity, both of which increase the risk of serious hypoglycemic reactions. Elderly, debilitated or mal- nourished patients, and those with adrenal or pitu- itary insufficiency, are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or pro- longed exercise, when alcohol is ingested, or when more than one glucose lowering drug is used. The risk of hypoglycemia may be increased with combina- tion therapy.

Loss of Control of Blood Glucose: When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection or surgery, a loss of control may occur. At such times it may be necessary to discontinue MICRONASE and administer insulin.

The effectiveness of any hypoglycemic drug, including MICRONASE, in lowering blood glucose to a desired level decreases in many patients over a period of time which may be due to progression of the severity of diabetes or to diminished responsive- ness to the drug. This phenomenon is known as sec- ondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual patient when MICRONASE is first given. Adequate adjustment of dose and adherence to diet should be assessed before classifying a patient as a secondary failure.

Laboratory Tests
Therapeutic response to MICRONASE Tablets should be monitored by frequent urine glucose tests and periodic blood glucose tests. Measurement of glycosylated hemoglobin levels may be helpful in some patients.

Carcinogenesis, Mutagenesis, and Impairment of Fertility
Studies in rats at doses up to 300 mg/kg/day for 18 months showed no carcinogenic effects. Glyburide is nonmutagenic when studied in the Salmonella microsome test (Ames test) and in the DNA damage/ alkaline elution assay. No drug related effects were noted in any of the criteria evaluated in the two year oncogenicity study of glyburide in mice.

Pregnancy
Teratogenic Effects: Pregnancy Category B

Reproduction studies have been performed in rats and rabbits at doses up to 500 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to glyburide. There are, how- ever, no adequate and well controlled studies in pregnant women. Because animal reproduction stud- ies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Because recent information suggests that abnormal blood glucose levels during pregnancy are associ- ated with a higher incidence of congenital abnormali- ties, many experts recommend that insulin be used during pregnancy to maintain blood glucose as close to normal as possible.

Nonteratogenic Effects: Prolonged severe hypo- glycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sul- fonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. If MICRONASE is used during pregnancy, it should be discontinued at least two weeks before the expected delivery date.

Nursing Mothers
Although it is not known whether glyburide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discon- tinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If the drug is discontinued, and if diet alone is inade- quate for controlling blood glucose, insulin therapy should be considered.

Pediatric Use
Safety and effectiveness in pediatric patients have not been established.

Geriatric Use
Elderly patients are particularly susceptible to the hypoglycemic action of glucose lowering drugs. Hypoglycemia may be difficult to recognize in the elderly (see PRECAUTIONS). The initial and mainte- nance dosing should be conservative to avoid hypo- glycemic reactions (see DOSAGE AND ADMINISTRATION).

Elderly patients are prone to develop renal insuffi- ciency, which may put them at risk of hypoglycemia. Dose selection should include assessment of renal function.