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`PHYSIOANS’
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`# DESK
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`5.3
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`2466/PHARMACIA & UPJOHN
`
`PHYSICIANS’ DESK REFERENCE®
`
`The chemical name for methylprednisolone is pregna - 1,4 -
`diene - 3,20—dione, 11, 17, 21-trihydroxy-6-methyl-, (601,116)-
`and the molecular weight is 374.48. The structural formula
`is represented below:
`
`CHQOH
`|CO
`
` .
`
`
`Medrol—Cont.
`2. Diabetic ketoacidosis, with or without coma. This condi-
`fect dependent upon functioning beta cells in the pancreatic
`tion should be treated with insulin.
`.
`islets. The mechanism by which glyburide lowers blood glu-
`cose during long-term administration has not been clearly
`3. Type I diabetes mellitus, as sole therapy.
`established. With chronic administration in Type II diabetic
`SPECIAL WARNING 0N INCREASED RISK OF CAR-
`patients, the blood glucose lowering eflect persists despite a
`DIOVASCULAR MORTALITY
`gradual decline in the insulin secretory response to the
`drug. Extrapancreatic effects may be involved in the mech-
`The administration of oral hypoglycemic drugs has been
`anism of action of oral sulfonylurea hypoglycemic drugs.
`reported to be associated with increased cardiovascular
`The combination of glyburide and metformin may have a
`mortality as compared to treatment with diet alone or diet
`synergistic effect, since both agents act to improve glucose
`plus insulin. This warning is based on the study conducted
`tolerance by different but complementary mechansims.
`by the University Group Diabetes Program (UGDP), a long-
`Some patients who are initially responsive to oral hypolgy-
`term prospective clinical trial designed to evaluate the ef-
`cemic drugs, including MICRONASE, may become unre-
`fectiveness of glucose-lowering drugs in preventing or de-
`sponsive or poorly responsive over time. Alternatively,
`laying vascular complications in patients with non-insulin-
`MICRONASE Tablets may be effective in some patients who
`dependent diabetes. The study involved 823 patients who
`have become unresponsive to one or more other sulfonyl-
`were randomly assigned to one of four treatment groups
`urea drugs.
`(Diabetes, 19 (Suppl. 2):747-830, 1970).
`In addition to its blood glucose lowering actions, glyburide
`UGDP reported that patients treated for 5 to 8 years with
`produces a mild diuresis by enhancement of renal free wa-
`diet plus a fixed dose of tolbutamide (1.5 grams per day)
`ter clearance. Disulflramdike reactions have very rarely
`been reported in patients treated with MICRONASE Tab-
`had a rate of cardiovascular mortality approximately Z‘l2
`lets.
`times that of patients treated with diet alone. A significant
`increase in total mortality was not observed, but the use of
`,
`Pharmacokinetics
`tolbutamide was discontinued based on the increase in car-
`Single dose studies with MICRONASE Tablets in normal
`diovascular mortality, thus limiting the opportunity for the
`subjects demonstrate significant absorption of glyburide
`study to show an increase in overall mortality. Despite con-
`within one hour, peak drug levels at about four hours, and
`troversy regarding the interpretation of these results, the
`low but detectable levels at twenty-four hours. Meanserum
`findings of the UGDP study provide an adequate basis for
`levels of glyburide, as reflected by areas under the serum
`this warning. The patient should be informed of the poten-
`concentration-time curve, increase in proportion to corre-
`tial risks and advantages of MICRONASE and of alternative
`sponding increases in dose. Multiple dose studies with
`modes of therapy.
`MICRONASE in diabetic patients demonstrate drug level
`concentration-time curves similar to single dose studies, in-
`Although only one drug in the sulfonylurea class (tolbuta-
`dicating no buildup of drug in tissue depots. The decrease of
`mide) was included in this study, it is prudent from a safety
`standpoint to consider that this warning may also apply to
`glyburide in the serum of normal healthy individuals is bi-
`phasic; the terminal half-life is about 10 hours. In single
`other oral hypoglycemic drugs in this class, in view of their
`close similarities in mode of action and chemical structure.
`dose studies in fasting normal subjects, the degree and du-
`ration of blood glucose lowering is proportional to the dose
`PRECAUTIONS
`administered and to the area under the drug level concen—
`General
`tration-time curve. The blood glucose lowering efl'ect per-
`Hypoglycemia: All sulfonylureas are capable of producing
`sists for 24 hours following single morning doses in nonfast-
`severe hypoglycemia. Proper patient selection and dosage
`ing diabetic patients. Under conditions of repeated admin-
`and instructions are important to avoid hypoglycemic epi-
`istration in diabetic patients, however, there is no reliable
`correlation between blood drug levels and fasting blood glu-
`sodes. Renal or hepatic insufficiency may cause elevated
`drug levels of glyburide and the latter may also diminish
`cose levels. Anne year study of diabetic patients treated
`with MICRONASE showed no reliable correlation between
`gluconeogenic capacity, both of which increase the risk of se-
`rious hypoglycemic reactions. Elderly, debilitated or mal-
`administered dose and serum drug level.
`nourished patients, and those with adrenal or pituitary in-
`The major metabolite of glyburide is the 4—trans—hydroxy
`sufficiency, are particularly susceptible to the hypoglycemic
`derivative. A second metabolite, the 3-cis-hydroxy deriva-
`action of glucose-lowering drugs. Hypoglycemia may be dif»
`tive, also occurs. These metabolites probably contribute no
`ficult to recognize in the elderly and in people who are tak-
`significant hypoglycemic action in humans since they are
`ing beta-adrenergic blocking drugs. Hypoglycemia is more
`only weakly active (1/400th and 1/40th as active, respec-
`likely to occur when caloric intake is deficient, after severe
`tively, as glyburide) in rabbits.
`or prolonged exercise, when alcohol is ingested, or when
`Glyburide is excreted as metabolites in the bile and urine,
`approximately 50% by each route. This dual excretory path-
`more than one glucose lowering drug is used. The risk of
`hypoglycemia may be increased with combination therapy.
`way is qualitatively difi‘erent from that of other sulfonylu-
`Loss of Control of Blood Glucose: When a patient stabi-
`reas, which are excreted primarily in the urine.
`lized on any diabetic regimen is exposed to stress such as
`Sulfonylurea drugs are extensively bound to serum pro—
`fever, trauma, infection or surgery, a loss of control may oc-
`teins. Displacement from protein binding sites by other
`cur. At such times it may be necessary to discontinue
`drugs may lead to enhanced hypoglycemic action. In vitro,
`MICRONASE and administer insulin.
`the protein binding exhibited by glyburide is predominantly
`including
`The effectiveness of any hypoglycemic drug,
`non-ionic, whereas that of other sulfonylureas (chlorpropa-
`MICRONASE, in lowering blood glucose to a desired level
`mide, tolbutamide, tolazamide) is predominantly ionic.
`decreases in many patients over a period of time which may
`Acidic drugs such as phenylbutazone, warfarin, and salicyl-
`be due to progression of the severity of diabetes or to dimin-
`ates displace the ionic-binding sulfonylureas from serum _
`ished responsiveness to the drug. This phenomenon is
`proteins to a far greater extent than the non~ionic binding
`known as secondary failure, to distinguish it from primary
`glyburide. It has not been shown that this difference in pro-
`failure in which the drug is ineffective in an individual pa-
`tein binding will result in fewer drug-drug interactions with
`MICRONASE Tablets in clinical use.
`tient when MICRONASE is first given. Adequate adjust—
`ment of dose and adherence to diet should be assessed be—
`INDICATIONS AND USAGE
`fore classifying a patient as a secondary failure.
`Information for Patients: Patients should be informed of
`MICRONASE Tablets are indicated as an adjunct to diet to
`lower the blood glucose in patients with non-insulin-depem
`the potential risks and advantages of MICRONASE and of
`dent diabetes mellitus (Type II) whose hyperglycemia can—
`alternative modes of therapy. They also should be informed
`not be satisfactorily controlled by diet alone.
`about the importance of adherence to dietary instructions,
`Glyburide may be used concomitantly with metformin when
`of a regular exercise program, and of regular testing of
`diet and glyburide or diet and metformin alone do not result
`urine and/or blood glucose.
`in adequate glycemic control (see metformin insert).
`The risks of hypoglycemia, its symptoms and treatment,
`In initiating treatment for non-insulin-dependent diabetes,
`and conditions that predispose to its development should be
`diet should be emphasized as the primary form of treat—
`explained to patients and responsible family members. Pri~
`ment. Caloric restriction and weight loss are essential in the
`mary and secondary failure also should be explained.
`obese diabetic patient. Proper dietary management alone
`Laboratory Tests
`may be efi‘ective in controlling the blood glucose and symp—
`Therapeutic response to MICRONASE Tablets should be
`toms of hyperglycemia. The importance of regular physical
`monitored by frequent urine glucose tests and periodic blood
`activity should also be stressed, and cardiovascular risk fac-
`glucose tests. Measurement of glycosylated hemoglobin lev-
`tors should be identified and corrective measures taken
`els may be helpful in some patients.
`,
`where possible. If this treatment program fails to reduce
`Drug interactions
`symptoms and/or blood glucose, the use of an oral sulfonyl-
`urea or insulin should be considered. Use of MICRONASE
`The hypoglycemic action of sulfonylureas may be potenti-
`ated by certain drugs including nonsteroidal anti—inflamma-
`must be viewed by both the physician and patient as a treat-
`tory agents and other drugs that are highly protein bound,
`ment in addition to diet and not as a substitution or as a
`salicylates, sulfonamides, chloramphenicol, probenecid, cou-
`convenient mechanism for avoiding dietary restraint. Fur-
`marins, monoamine oxidase inhibitors, and beta adrenergic
`thermore, loss of blood glucose control on diet alone may be
`blocking agents. When such drugs are administered to ‘a pa‘
`transient, thus requiring only short-term administration of
`tient receiving MICRONASE, the patient should be ob-
`MICRONASE.
`served closely for hypoglycemia. When such drugs are with-
`During maintenance programs, MICRONASE should be
`drawn from a patient receiving MICRONASE, the patient
`discontinued if satisfactory lowering of blood glucose is no
`should be observed closely for loss of control.
`longer achieved. Judgment should be based on regular clin-
`Certain drugs tend to produce hyperglycemia and may lead
`ical and laboratory evaluations.
`to loss of control. These drugs include the thiazides and
`In considering the use of MICRONASE in asymptomatic pa-
`other diuretics, corticosteroids, phenothiazines, thyroid
`tients, it should be recognized that controlling blood glucose
`products, estrogens, oral contraceptives, phenytoin, nico-
`in non-insulin~dependent diabetes has not been definitely
`tinic acid, sympathomimetics, calcium channel blocking
`established to be effective in preventing the long—term car—
`drugs, and isoniazid. When such drugs are administered to
`diovascular or neural complications of diabetes.
`a patient receiving MICRONASE, the patient should be
`CONTRAINDICATIONS
`closely observed for loss of control. When such drugs are
`MICRONASE Tablets are contraindicated in patients with:
`withdrawn from a patient receiving MICRONASE, the pa-
`1. Known hypersensitivity or allergy to the drug.
`tient should be observed closely for hypoglycemia.
`
`
`
`
`
`
`
`H
`CH3
`Each MEDROL Tablet for oral administration contains 2
`mg, 4 mg, 8 mg, 16 mg, 24 mg or 32 mg of methylpredniso-
`lone.
`Inactive ingredients:
`2 mg
`Calcium Stearate
`Corn Starch
`Erythosine Sodium
`Lactose
`Mineral Oil
`Sorbic Acid
`Sucrose
`
`4 and 16 mg
`Calcium Stearate
`Corn Starch
`Lactose
`Mineral Oil
`Sorbic Acid
`Sucrose
`
`8 and 32 mg
`Calcium Stearate
`Corn Starch
`F D & C Yellow No. 6
`Lactose
`Mineral Oil
`Sorbic Acid
`Sucrose
`
`24 mg
`Calcium Stearate
`Corn Starch
`F D & C Yellow No. 5
`Lactose
`Mineral Oil
`Sorbic Acid
`Sucrose
`
`HOW SUPPLIED
`MEDROL Tablets are available in the following strengths
`and packages sizes:
`2 mg (pink, elliptical, scored, imprinted MEDROL 2)
`Bottles of 100
`NDC 0009-0049—02
`4 mg (white, elliptical, scored, imprinted MEDROL 4)
`Bottles of 100
`NDC 0009-0056-02
`Bottles of 500
`NDC 0009-0056-03
`Unit dose packages of 100
`NDC 0009-0056-05
`DOSEPAKTM Unit of Use (21 tablets) NDC 0009-0056-04
`8 mg (peach, elliptical, scored, imprinted MEDROL 8)
`Bottles of 25
`NDC 0009-0022—01
`16 mg (white, elliptical, scored, imprinted MEDROL 16)
`Bottles of 50
`NDC 0009—0073-01
`24 mg (yellow, elliptical, scored, imprinted MEDROL 24)
`Bottles of 25
`NDC 0009—0155-01
`32 mg (peach, elliptical, scored, imprinted MEDROL 32)
`Bottles of 25
`.
`NDC 0009-0176-01
`Store at controlled room temperature 20° to 25“C (68° to
`WT) [see USP].
`Caution: Federal law prohibits dispensing without pre-
`scription.
`Pharmacia & Upjohn Company
`Kalamazoo, Michigan 49001, USA
`Revised September 1997
`
`810 487 722
`692166
`
`MICRONASE®
`[mik-run-aze]
`glyburide tablets, USP
`125, 2.5, and 5 mg
`
`Bv
`
`DESCRIPTION
`MICRONASE Tablets contain glyburide, which is an oral
`blood-glucose-lowering drug of the sulfonylurea class. Gly-
`buride is a white, crystalline compound, 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,
`microcrystalline cellulose, sodium alginate, talc. In addi-
`tion, 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-anisarnido)-ethyl]phenyl]-sulfonyl]-3-cyclohexy-
`lurea and the molecular weight is 493.99. The structural
`formula is represented below:
`
`Cl
`
`9
`G—NH—CHz—CHz—
`OCHa
`
`.
`
`SOg—NH—ICl—NHO
`
`CLINICAL PHARMACOLOGY
`Actions
`Glyburide appears to lower the blood glucose acutely by
`stimulating the release of insulin from the pancreas, an ef-
`
`“m”w“”’°‘“"°"°“°"“"“””“""'°“‘°""“M“HTBCON PHARMA LTD (IPR2020-01263) Ex. 1024, p. 003
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1024, p. 003
`
`

`

`PRODUCT INFORMATION
`PHARMACIA 81 UPJOHN/246‘l
`
`A possible interaction between glyburide and ciprofloxacin,
`a fluoroquinolone antibiotic, has been reported, resulting in
`a potentiation of the hypoglycemic 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 interaction also occurs with the
`intravenous, topical or vaginal preparations of miconazole
`is not known.
`In a single-dose interaction study in NIDDM
`Metformin:
`subjects, decreases in glyburide AUC and Cmax were ob-
`served, but were highly variable. The single-dose nature of
`this study and the lack of correlation between glyburide
`blood levels and pharmacodynamic effects, makes the clini-
`cal significance of this interaction uncertain. Coadministra»
`tion of glyburide and metformin did not result in any
`changes in either metformin pharmacokinetics or pharma-
`codynamics.
`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 re-
`lated 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 rab-
`bits at doses up to 500 times the human dose and have re-
`vealed no evidence of impaired fertility or harm to the fetus
`due to glyburide. There are, however, no adequate and well
`controlled studies in pregnant women. Because animal re-
`production studies are not always predictive of human re-
`sponse, this drug should be used during pregnancy only if
`clearly needed.
`Because recent information suggests that abnormal blood
`glucose levels during pregnancy are associated with a
`higher incidence of congenital abnormalities, many experts
`recommend that insulin be used during pregnancy to main-
`tain blood glucose as close to normal as possible.
`Nonteratogenic Effects:
`Prolonged severe hypoglycemia
`(4 to 10 days) has been reported in neonates born to mothers
`who were receiving a sulfonylurea chug at the time of deliv-
`ery. 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 ex-
`creted in human milk. Because the potential for hypoglyce-
`mia in nursing infants may exist, a decision should be made
`whether to discontinue 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 in-
`adequate for controlling blood glucose, insulin therapy
`should be considered.
`Pediatric Use
`Safety and effectiveness in pediatric patients have not been
`established.
`ADVERSE REACTIONS
`Hypoglycemia: See Precautions and Overdosage Sections.
`Gastrointestinal Reactions: Cholestatic jaundice and hep-
`atitis may occur rarely; MICRONASE Tablets should be dis-
`continued if this occurs.
`Liver function abnormalities, including isolated transami-
`nase elevations, have been reported.
`Gastrointestinal disturbances, eg, nausea, epigastric full-
`ness, 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 dos-
`age is reduced.
`Dermatologic Reactions: Allergic skin reactions, eg, pruri-
`tus, erythema, urticaria, and morbilliform or maculopap-
`ular 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 reactions
`have been reported with sulfonylureas.
`Hematologic Reactions:
`Leukopenia, agranulocytosis,
`thrombocytopenia, hemolytic anemia, aplastic anemia, and
`pancytopenia have been reported with sulfonylureas.
`Metabolic Reactions: Hepatic porphyria and disulfiram-
`like reactions have been reported with sulfonylureas;
`however, hepatic porphyria has not been reported with
`MICRONASE and disulfiram-like reactions have been re-
`ported 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 medical conditions known to
`cause hyponatremia or increase release of antidiuretic hor-
`mone. The syndrome of inappropriate antidiuretic hormone
`(SIADH) secretion has been reported with certain other sul-
`fonylureas, and it has been suggested'that these sulfonylu-
`reas 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 through to be related to fluctuation
`in glucose levels.
`-
`.
`In addition to dermatologic reactions, allergic reactions
`such as angioedema. arthralg'n. mm and vasculitis
`have been reported.
`
`OVERDOSAGE
`Overdosage of sulfonylureas, including MICRONASE Tab-
`lets, can produce hypoglycemia. Mild hypoglycemic symp-
`toms, without loss of consciousness or neurological findings,
`should be treated aggressively with oral glucose and adjust-
`ments in drug dosage and/or meal patterns. Close monitor-
`ing should continue until the physician is assured that the
`patient is out of danger. Severe hypoglycemic reactions with
`coma, seizure, or other neurological impairment occur infre-
`quently, but constitute medical emergencies requiring im-
`mediate hospitalization. If hypoglycemic coma is diagnosed
`or suspected, the patient should be given a rapid intrave-
`nous injection of concentrated (50%) glucose solution. This
`should be followed by a continuous infusion of a more dilute
`(10%) glucose solution at a rate which will maintain the
`blood glucose at a level above 100 mg/dL. Patients should be
`closely monitored for a minimum of 24 to 48 hours, since
`hypoglycemia may recur after apparent clinical recovery.
`DOSAGE AND ADMINISTRATION
`There is no fixed dosage regimen for the management of di-
`abetes mellitus with MICRONASE Tablets or any other hy-
`poglycemic agent. In addition to the usual monitoring of uri-
`nary glucose, the patient's blood glucose must also be mon-
`itored periodically to determine the minimum effective dose
`for the patient; to detect primary failure, is, inadequate low-
`ering of blood glucose at the maximum recommended dose
`of medication; and to detect secondary failure, ie, lose of ads
`equate blood glucose lowering response after an initial pe-
`riod of effectiveness. Glycosylated hemoglobin levels may
`also be ofvalue in monitoring the patient’s response to ther-
`apy-
`Short-term administration of MICRONASE may be suffi—
`cient 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 hypogly-
`cemic drugs should be started at 1.25 mg daily. (See PRE-
`CAUTIONS section for patients at increased risk.) Failure
`to follow an appropriate dosage regimen may precipitate hy-
`poglycemia. Patients who do not adhere to their prescribed
`dietary and drug regimen are more prone to exhibit unsat—
`isfactory response to therapy.
`Transfer From Other Hypoglycemic Therapy Patients Re-
`ceiving Other Oral Antidiabetic Therapy: Transfer of pa-
`tients
`from other
`oral
`antidiabetic
`regimens
`to
`MICRONASE'should be done conservatively and the initial
`daily dose should be 2.5 to 5 mg. When transferring patients
`from oral hypoglycemic agents other than drlorpropamide
`toMICRONASE, notransitionperiodandnoinixialarm
`
`ingdoesareneeessaryWhentr-a
`~32:
`
`chlorproparnide. particular care she
`"
`-
`the first two weeks because Lire prolonged rs
`
`propamide in the body and su sequent over
`fects may provoke h§poglycem1a
`Some Type II diabetic panes-.5
`‘ Patients Receiving Insulin:
`being treated with insulin may respond satisfactorili
`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 in-
`sulin dose is more than 40 units daily, a transition period is
`required for conversion to MICRONASE. In these patients,
`insulin dosage is decreased by 50% and MICRONASE Tab—
`lets 5 mg daily is started. PleaSe refer to Titration to Main-
`tenance Dose for further explanation.
`Tltration 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 re-
`sponse.
`_
`'
`No exact dosage relationship exists between MICRONASE
`and the other oral hypoglycemic agents. Although patients
`may be transferred from the maximum dose of other sulfo-
`nylureas, the maximum starting dose of 5 mg of MICRON-
`ASE 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 chlor-
`propamide, 250 to 375 mg tolazamide, 500 to 750 mg aceto-
`hexamide, or 1000 to 15 00 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% re-
`duction 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 con-
`version period when both insulin and MICRONASE are be-
`ing used, hypoglycemia may rarely occur. During insulin
`withdrawal, patients should test their urine for glucose and
`acetone at least three times daily and report results to their
`physician. The appearance of persistent acetonuria with
`glycosuria indicates that the patient is a ’lype I diabetic who
`requires insulin therapy.
`Concomitant Glyburide and Metformin Therapy
`MICRONASE Tablets should be added gradually to the dos-
`ing regimen of patients who have not responded to the max-
`imum dose of metforrnin 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 de
`sired 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 hypoglycemia associated with sulfonylurea ther-
`apy continues and may be increased. Appropriate precau-
`tions 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 pregnancy 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 hypolgycemic reactions. (See PRECAUTIONS sec—
`tion.)
`HOW SUPPLIED
`MICRONASE Tablets are supplied as follows:
`MICRONASE Tablets 1.25 mg (White, Round, Scored. im-
`printed MICRONASE 1.25)
`NDC 0009-0131431
`Bottles of 100
`MICRONASE Tablets 2.5 mg (Dark Pink, Round, Scored. im—
`printed MICRONASE 2.5)
`NDC 0009-0141-01
`Bottles of 100
`NDC 0009-1041413
`Bottles of 1000
`NDC 0009-0141-4317.
`Unit Dose Pkg of 100
`MICRONASE Tablets 5 mg (Blue, Round, Scored imprinted
`MICRONASE 5)
`Bottles of 30
`NDC 0009-0171-1‘.
`Bottles of 60
`NDC 0009-0171-12
`Bottles of 100
`NDC 0009-0171435
`Bottles of 500
`NDC 0009—0171436
`Bottles of 1000
`NDC 0009—0171-07
`NDC 0009-0171413
`Unit Dose Pkg of 100
`Rx only
`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
`Kalamazoo, MI 49001, USA
`3 Revised February 1999
`
`611 955 :22
`692166
`
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`
`dro-6-4 propylaizi.
`- drate. Its empirica
`and its molecular we
`
`The structural formula is:
`
`I
`
`- 2 HCI - H20
`
`N
`
`HzN—</
`3
`
`/
`....u\N
`\HH
`Pramipexole dihydrochloride is a white to off-white powder
`substance. Melting occurs in the range of 296° C to 301‘ C.
`with decomposition. Pramipexole dihydrochloride is more
`than 20% soluble in water, about 8% in methanol, aboul
`0.5% in ethanol, and practically insoluble in dichlo—
`romethane.
`MIRAPEX Tablets, for oral administration, contain 0.15
`mg, 0.25 mg, 0.5 mg, 1.0 mg, or 1.5 mg of pramipexcm' (r.-
`hydrochloride monohydrate. Inactive ingredients comn '~"
`mannitol, corn starch, colloidal silicon dioxide. post
`
`and magnesium stearate.
`CLINICAL PHARMACOLOGY
`Pramipexole is a nonergot dopamine agonist with high rel-
`ative in vitro specificity and full intrinsic activity at the D;
`subfamily of dopamine receptors, binding with higher afiin-
`ity to D3 than to D2 or D4 receptor subtypes. The relevance
`of D3 receptor binding in Parkinson’s disease is unknown.
`The precise mechanism of action of pramipexole as a treaI-
`ment for Parkinson’s disease is unknown, although it is be
`lieved to be related to its ability to stimulate dopamine re-
`ceptors in the striatum. This conclusion'is supported by
`electrophysiologic studies in animals that have demon-
`
`Continued on next page
`
`Information on these Pharmacia & Upiohn products is based
`on labeling in effect June 1, 1999. Further information
`concerning these and other Pharmacia & Upjohn produds
`may be obtained by direct inquiry to Medical Information.
`Pharmacia 81 Upjohn, Kalamazoo, MI 49001.
`
`BIOCON PHARMA LTD (1Pm020-01mzfikfimmflhm
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1024, p. 004
`
`