`
`PHYSICIANS
`See
`RsrareNe=
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`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1024, p. 001
`
`

`

`2000
`
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`
`
` PDR
`eh
`
`EDITION
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`
`PHYSICIANS
`OK
`REFERENCE
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`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1024, p. 002
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`PHYSICIANS’ DESK REFERENCE®
`
`2. Diabetic ketoacidosis, with or without coma. This condi-
`tion should be treated with insulin.
`:
`3. Type I diabetes mellitus, as sole therapy.
`SPECIAL WARNING ON INCREASED RISK OF CAR-
`DIOVASCULAR 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 ef-
`fectiveness of glucose-lowering drugs in preventing or de-
`laying vascular complications 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).
`UGDPreported 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'/,
`timesthat of patients treated with diet alone. A significant
`increasein total mortality was not observed, but the use of
`tolbutamide wasdiscontinued basedontheincreasein car-
`diovascular mortality, thus limiting the opportunity for the
`study to show anincrease in overall mortality. Despite con-
`troversy regarding the interpretation of these results, the
`findings of the UGDPstudy provide an adequatebasis for
`this warning. The patient should be informed of the poten-
`tial risks and advantages of MICRONASEandofalternative
`modesof therapy.
`Althoughonly one drugin the sulfonylurea class (tolbuta-
`mide) wasincludedin this study,it is prudent from a safety
`standpoint to consider that this warning mayalso apply to
`other oral hypoglycemic drugsin this class, in view of their
`close similarities in mode of action and chemical structure.
`PRECAUTIONS
`General
`Hypoglycemia: All sulfonylureas are capable of producing
`severe hypoglycemia. Proper patient selection and dosage
`and instructions are important to avoid hypoglycemic epi-
`sodes. Renal or hepatic insufficiency may cause elevated
`drug levels of glyburide and the latter may also diminish
`gluconeogenic capacity, both of which increasetherisk of se-
`rious. hypoglycemic reactions. Elderly, debilitated or mal-
`nourished patients, and those with adrenalor pituitary in-
`sufficiency, are particularly susceptible to the hypoglycemic
`action of glucose-lowering drugs. Hypoglycemia maybedif-
`ficult to recognize in the elderly and in people whoare tak-
`ing beta-adrenergic blocking drugs. Hypoglycemia’ is more
`likely to occur when caloric intake is deficient, after severe
`or prolonged exercise, when alcohol is ingested, or when
`more than one glucose lowering drug is used. The risk of
`hypoglycemia may be increased with combination therapy.
`Loss of Control of Blood Glucose: When a patient stabi-
`lized on any diabetic regimen is exposed to stress such as
`fever, trauma, infection or surgery, a loss of control may oc-
`cur. At such times it may be necessary to discontinue
`MICRONASEandadministerinsulin.
`including
`The effectiveness of any hypoglycemic drug,
`MICRONASE,in lowering blood glucose to a desired level
`decreases in manypatients over a period of time which may
`be dueto progression of the severity of diabetes or to dimin-
`ished responsiveness to the drug. This phenomenon is
`knownassecondary failure, to distinguish it from primary
`failure in which the drug is ineffective in an individual pa-
`tient when MICRONASEisfirst given. Adequate adjust-
`ment of dose and adherenceto diet should be assessed be-
`fore classifying a patient as a secondary failure.
`Information for Patients: Patients should be informed of
`the potential risks and advantages of MICRONASEandof
`alternative modes of therapy. They also should be informed
`about the importance of adherence to dietary instructions,
`of a regular exercise program, and of regular testing of
`urine and/or blood glucose.
`The risks of hypoglycemia, its symptoms and treatment,
`and conditions that predispose to its development should be
`explained to patients and responsible family members. Pri-
`mary and secondary failure also should be explained.
`Laboratory Tests
`Therapeutic response to MICRONASETablets should be
`monitored by frequent urine glucosetests and periodic blood
`glucose tests. Measurementof glycosylated —— lev-
`els may be helpful in somepatients.
`DrugInteractions
`The hypoglycemic action of sulfonylureas may be potenti-
`ated by certain drugs including nonsteroidal anti-inflamma-
`tory agents and other drugs that are highly protein bound,
`salicylates, sulfonamides, chloramphenicol, probenecid, cou-
`marins, monoamine oxidase inhibitors, and beta adrenergic
`blocking agents. When such drugs are administered to a pa-
`tient receiving MICRONASE, the patient should be ob-
`served closely for hypoglycemia. When such drugs are with-
`drawn 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, phenothiazines, thyroid
`products, estrogens, oral contraceptives, phenytoin, nico-
`tinic acid, sympathomimetics, 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 pa-
`tient should be observed closely for hypoglycemia.
`
`fect dependent upon functioning betacells in the pancreatic
`islets. The mechanism by which glyburide lowersblood glu-
`cose during long-term administration has not been clearly
`established. With chronic administration in TypeII diabetic
`patients, the blood glucose loweringeffect persists despite a
`gradual decline in the insulin secretory response to the
`drug. Extrapancreatic effects may be involved in the mech-
`anism of action of oral sulfonylurea hypoglycemic drugs.
`The combination of glyburide and metformin may have a
`synergistic effect, since both agents act to improve glucose
`tolerance by different but complementary mechansims.
`Some patients whoareinitially responsive to oral hypolgy-
`cemic drugs, including MICRONASE, may become unre-
`sponsive or poorly responsive over time. Alternatively,
`MICRONASETablets maybeeffective in some patients who
`have become unresponsive to one or more other sulfonyl-
`urea drugs.
`In addition to its blood glucose lowering actions, glyburide
`produces a mild diuresis by enhancementof renal free wa-
`ter clearance. Disulfiram-like reactions have very rarely
`been reported in patients treated with MICRONASE Tab-
`lets.
`:
`Pharmacokinetics
`Single dose studies with MICRONASETablets in normal
`subjects demonstrate significant absorption of glyburide
`within one hour, peak drug levels at about four hours, and
`low but detectable levels at twenty-four hours. Mean.serum
`levels of glyburide, as reflected by areas under the serum
`concentration-time curve, increase in proportion to corre-
`sponding increases in dose. Multiple dose studies with
`MICRONASEin diabetic patients demonstrate drug level
`concentration-time curves similar to single dose studies, in-
`dicating no buildupof drugin tissue depots. The decrease of
`glyburide in the serum of normal healthy individuals is bi-
`phasic; the terminal half-life is about 10 hours. In single
`dose studies in fasting normal subjects, the degree and du-
`ration of blood glucose lowering is proportional to the dose
`administered and to the area under the drug level concen-
`tration-time curve. The blood glucose lowering effect per-
`sists for 24 hours following single morning dosesin nonfast-
`ing diabetic patients. Under conditions of repeated admin-
`istration in diabetic patients, however, there is no reliable
`correlation between blood druglevels and fasting blood glu-
`cose levels. A.one year study of diabetic patients treated
`with MICRONASEshowednoreliable correlation between
`administered dose and serum druglevel.
`The major metabolite of glyburide is the 4-trans-hydroxy
`derivative. A second metabolite, the 3-cis-hydroxy deriva-
`tive, also occurs. These metabolites probably contribute no
`significant hypoglycemic action in humans since they are
`only weakly active (1/400th and 1/40th as active, respec-
`tively, as glyburide) in rabbits.
`Glyburide is excreted as metabolites in the bile and urine,
`approximately 50% by each route. This-dual excretory path-
`way is qualitatively different from that of other sulfonylu-
`reas, which are excreted primarily in.the urine.
`Sulfonylurea drugs are extensively bound to serum pro-
`teins. Displacement from protein binding sites by other
`drugs may lead to enhanced hypoglycemic action:In vitro,
`the protein binding exhibited by glyburide is predominantly
`non-ionic, whereas that of other sulfonylureas (chlorpropa-
`mide, tolbutamide, tolazamide) is predominantly ionic.
`Acidic drugs such as phenylbutazone, warfarin, andsalicyl-
`ates displace the ionic-binding sulfonylureas from serum .
`proteins to a far greater extent than the non-ionic binding
`glyburide. It has not been shownthatthis difference in pro-
`tein bindingwill result in fewer drug-drug interactions with
`MICRONASETabletsin clinical use.
`INDICATIONS AND USAGE
`MICRONASETablets are indicated as an adjunct to diet to
`lowerthe blood glucose in patients with non-insulin-depen-
`dent diabetes mellitus (Type II) whose hyperglycemia can-
`not be satisfactorily controlled by diet alone.
`Glyburide may be used concomitantly with metformin when
`diet and glyburide or diet and metformin alonedo 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 treat-
`ment. Caloric restriction and weightloss are essential in the
`obese diabetic patient. Proper dietary management alone
`maybeeffective in controlling the blood glucose and symp-
`toms of hyperglycemia. 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 useof an oral sulfonyl-
`urea or insulin should be considered. Use of MICRONASE
`must be viewed by both the physician and patient as a treat-
`mentin addition to diet and not as a substitution or as a
`convenient mechanism for avoiding dietary restraint. Fur-
`thermore,loss of blood glucose control on diet alone may be
`transient, thus requiring only short-term administration of
`MICRONASE.
`During maintenance programs, MICRONASEshould be
`discontinued if satisfactory lowering of blood glucose is no
`longer achieved. Judgment should be based on regular clin-
`ical and laboratory evaluations.
`In considering the use of MICRONASEin asymptomatic pa-
`tients, it should be recognized that controlling blood glucose
`in non-insulin-dependent diabetes has not been definitely
`established to be effective in preventing the long-term car-
`diovascular or neural complications of diabetes.
`CONTRAINDICATIONS
`MICRONASETablets are contraindicated in patients with:
`1. Known hypersensitivity or allergy to the drug.
`
`2466/PHARMACIA & UPJOHN
`
`Medrol—Cont.
`
`The chemical name for methylprednisolone is pregna- 1,4 -
`diene- 3,20-dione, 11, 17, 21-trihydroxy-6-methy]-, (6a,118)-
`and the molecular weight is 374.48. The structural formula
`is represented below:
`
`CH,OH
`|co
`
`
`
`CHs
`Each MEDROLTablet 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
`FD & C Yellow No. 6
`Lactose
`Mineral Oil
`Sorbic Acid
`Sucrose
`
`24 mg
`Calcium Stearate
`Corn Starch
`FD & C Yellow No. 5
`Lactose
`Mineral Oil
`Sorbic Acid
`Sucrose
`
`HOW SUPPLIED
`MEDROLTablets are available in the following strengths
`and packagessizes:
`2 mg(pink,elliptical, scored, imprinted MEDROL2)
`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
`DOSEPAK™Unit of Use (21 tablets) NDC 0009-0056-04
`8 mg(peach,elliptical, scored, imprinted MEDROL8)
`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 roomfierpeesbire 20° to 25°C (68° to
`77°F) [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
`1.25, 2.5, and 5 mg
`
`BR
`
`DESCRIPTION
`MICRONASETablets contain glyburide, which is an oral
`blood-glucose-lowering drug of the sulfonylurea class. Gly-
`buride is a white, crystalline compound, formulated as
`MICRONASETablets 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 mgcontains aluminum oxide and FD&C
`Blue No. 1. The chemical namefor glyburide is 1-[[p-[2-(5-
`chloro-o-anisamido)-ethyl]pheny!]-sulfony]|-3-cyclohexy-
`lurea and the molecular weight is 493.99. The structural
`formula is represented below:
`
`StgpSoren)
`
`0
`
`OCH3
`
`CLINICAL PHARMACOLOGY
`Actions
`Glyburide appears to lower the blood glucose acutely by
`stimulating the release of insulin from the pancreas, an ef-
`
`information will be superseded by supplements and supseaueTSCON PHARMA LTD (IPR2020-0 1 263) Ex. 1 024, p. 003
`
`
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1024, p. 003
`
`

`

`PRODUCT INFORMATION
`PHARMACIA & UPJOHN/2467
`
`EEE
`
` OVERDOSAGE
`
`A possible interaction between glyburide and ciprofloxacin,
`a fluoroquinoloneantibiotic, 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. Whetherthis 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 C,,,, were ob-
`served, but were highly variable. The single-dose nature of
`this study and the lack of correlation between glyburide
`blood levels and pharmacodynamiceffects, makestheclini-
`cal significance ofthis interaction uncertain. Coadministra-
`tion of glyburide and metformin did not result in any
`changesin either metformin pharmacokinetics or pharma-
`codynamics.
`Carcinogenesis, Mutagenesis, and ImpairmentofFertility
`Studies in rats at doses up to 300 mg/kg/day for 18 months
`showedno carcinogenic effects. Glyburide is nonmutagenic
`whenstudied in the Salmonella microsometest (Amestest)
`and in the DNA damage/alkaline elution assay. No drug re-
`lated effects were noted in any ofthe 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 andhavere-
`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 normalaspossible.
`Nonteratogenic Effects:
`Prolonged severe hypoglycemia
`(4 to 10 days) has been reported in neonates born to mothers
`whowerereceiving a sulfonylurea drugat the timeof deliv-
`ery. This has been reported more frequently with the use of
`agents with prolonged half-lives. If MICRONASEis 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 knownto 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, andif 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; MICRONASETablets should be dis-
`continuedif 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 commonreactions, 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
`MICRONASEand 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 syndromeof 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
`ADHand/orincrease release of ADH.
`Other Reactions: Changes in accommodation and/or
`blurred vision have been reported with glyburide and other
`sulfonylureas. These are throweh to.be related to fluctuation
`in glucoselevels.
`z
`In addition to dermatalaies reactions; allergic reactions
`such as angioedema, arthralgia. myalgia and vasculitis
`have been reported.
`
`|
`
`
`
`
`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 te
`identify the optimal dose of each drug neededto achieve this
`goal. With concomitant glyburide and metformin therapy.
`the risk of hypoglycemia associated with sulfonylurea ther-
`apy continues and maybe increased. Appropriate precau-
`tions should be taken (see PRECAUTIONSsection).
`Maximum Dose
`Daily doses of more than 20 mg are not recommended.
`DosageInterval
`Once-a-day therapy is usually satisfactory. Some patients,
`particularly those receiving more than 10 mg daily, may
`have a moresatisfactory response with twice-a-day dosage.
`Specific Patient Populations
`MICRONASEis 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 te
`avoid hypolgycemic reactions. (See PRECAUTIONSsec-
`tion.)
`HOW SUPPLIED
`MICRONASETablets are supplied as follows:
`MICRONASETablets 1.25 mg (White, Round, Scored, im-
`printed MICRONASE1.25)
`NDC 0009-0131-01
`Bottles of 100
`MICRONASETablets 2.5 mg (Dark Pink, Round, Scored. im-
`printed MICRONASE2.5)
`NDC 0009-0141-01
`Bottles of 100
`NDC 0009-1041-03
`Bottles of 1000
`NDC 0009-0141-02
`Unit Dose Pkg of 100
`MICRONASETablets 5 mg (Blue, Round, Scored imprinted
`MICRONASE5)
`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
`NDC 0009-0171-03
`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
`Revised February 1999
`
`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 impairmentoccurinfre-
`quently, but constitute medical emergencies requiring im-
`mediate hospitalization. If hypoglycemic coma is diagnosed
`or suspected, the patient should be given a rapid intrave-
`nousinjection of concentrated (50%) glucose solution. This
`should be followed by a continuousinfusion of a more dilute
`(10%) glucose solution at a rate which will maintain the
`blood glucoseat a level above 100 mg/dL. Patients should be
`closely monitored for a minimum of 24 to 48 hours, since
`hypoglycemia mayrecur after apparentclinical recovery.
`DOSAGE AND ADMINISTRATION
`There is nofixed dosage regimen for the managementof di-
`abetes mellitus with MICRONASETablets or any other hy-
`poglycemic agent. In addition to the usual monitoringof uri-
`nary glucose, the patient’s blood glucose must also be mon-
`itored periodically to determine the minimumeffective dose
`for the patient; to detect primary failure, ie, inadequate low-
`ering of blood glucose at the maximum recommended dose
`of medication; and to detect secondary failure,ie, lose of ad-
`equate blood glucose lowering response after an initial pe-
`riod of effectiveness. Glycosylated hemoglobin levels may
`also be ofvalue in monitoring the patient’s responseto ther-
`apy:
`Short-term administration of MICRONASE maybesuffi-
`cient during periods of transient loss of control in patients
`usually controlled well on diet.
`Usual Starting Dose
`The usual starting dose of MICRONASETablets is 2.5 to 5
`mg daily, administered with breakfast or the first main
`meal. Those patients who maybe moresensitive to hypogly-
`cemic drugs should be started at 1.25 mg daily. (See PRE-
`CAUTIONSsection for patients at increased risk.) Failure
`to follow an appropriate dosage regimen mayprecipitate hy-
`poglycemia. Patients who do not adhereto their prescribed
`dietary and drug regimen are more proneto 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 andtheinitial
`daily dose should be 2.5 to 5 mg. Whentransferring patients
`from oral hypoglycemic agents other than
`to MICRONASE, notransition period andno initial or prim-
`
`ing does are necessary. When tra
`chlorpropamide, particular care sho
`
`the first two weeks because the prolonged re
`propamide in the body and subsequentover!
`fects may provoke Cue“ac,Some TypeI diabetic patients
`| Patients ReceivingInsulin:
`being treated with insulin may respond satisfactorily to
`MICRONASE,if the insulin doseis less than 20 unitsdaily,
`substitution of MICRONASETablets 2.5 to 5 mg as a single
`daily dose may betried. If the insulin dose is between 20
`and 40 units daily, the patient may be placed directly on
`MICRONASETablets 5 mg daily as a single dose.If thein-
`sulin dose is more than 40 units daily, a transition period is
`required for conversion to MICRONASE.In thesepatients,
`insulin dosage is decreased by 50% and MICRONASETab-
`lets 5 mg daily is started. Pleaserefer to Titration to Main-
`tenance Dose for further explanation.
`Titration to Maintenance Dose
`The usual maintenancedoseis 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.
`ag
`No exact dosage relationship exists between MICRONASE
`and the other oral hypoglycemic agents. Although patients
`maybe transferred from the maximum doseof other sulfo-
`nylureas, the maximum starting dose of 5 mg of MICRON-
`ASE Tablets should be observed. A maintenance dose of 5
`mg of MICRONASETablets provides approximately the
`same degreeof blood glucose control as 250 to 375 mgchlor-
`propamide, 250 to 375 mg tolazamide, 500 to 750 mg aceto-
`hexamide, or 1000 to 15 00 mg tolbutamide,
`Whentransferring patients receiving more than 40 units of
`insulin daily,
`they may be started on a daily dose of
`MICRONASETablets 5 mg concomitantly with a 50% re-
`duction in insulin dose. Progressive withdrawal of insulin
`and increase of MICRONASEin 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 MICRONASEare be-
`ing used, hypoglycemia may rarely occur. During insulin
`withdrawal, patients should test their urine for glucose and
`acetoneat least three times daily and report results to their
`physician. The appearance of persistent acetonuria with
`glycosuria indicates that the patient is a Type I diabetic who
`requires insulin therapy.
`Concomitant Glyburide and Metformin Therapy
`MICRONASETablets should be added gradually to the dos-
`ing regimen of patients who have not responded to the max-
`imum dose of metformin monotherapyafter four weeks (see
`Usual Starting Dose and Titration to Maintenance Dose).
`Refer to metformin packageinsert.
`BIOCON PHARMALTD(IPR2020-01263)Ex?"1024>p:004°""
`
`811 985 722
`692166
`
`jeaér-d-pex)
`Dem
`diryorocnence ames
`
`DESCRIPTION
`wees SICA Ce Ee
`
`¢ tresoment of de seme en? eemgmee of
`
`
`N
`oh
`
`The structural formula is:
`
`Hn—C |
`‘s
`
`wt 2 HCl+H:0
`H
`“Se
`
`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, about
`0.5% in ethanol, and practically insoluble in dichle-
`romethane.
`MIRAPEX Tablets, for eal administration, contain 0.125
`mg, 0.25 mg, 0.5-mg, 1.0 mg; or 1.5 mg of pramipexole d-
`hydrochloride monohydrate. Inactive ingredients consist
`of
`
`mannitol, corn starch, colloidal silicon dioxide, pow
`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 dopaminereceptors, binding with higher affin-
`ity to D3 than to D, or D, receptor subtypes. The relevance
`of Dz receptor binding in Parkinson’s disease is unknown.
`The precise mechanism of action of pramipexole as a treat-
`ment for Parkinson’s disease is unknown, althoughit 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 & Upjohn products is based
`on labeling in effect June 1, 1999. Further information
`concerning these and other Pharmacia & Upjohn products
`may beobtained by direct inquiry to Medical Information,
`Pharmacia & Upjohn, Kalamazoo, Mi 49001.
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1024, p. 004
`
`