4600800
`
`ENTOCORT® EC
`(budesonide)
`Capsules
`
`'
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`wetter ence eens WARNINGS AND PRECAUTIONS ---------------
`
`
`
`*
`
`the information needed to use
`include all
`These highlights do not
`ENTOCOAT®EC safely and effectively. See full prescribing information for
`° Hypercorticismandadrenalsuppression: Since ENTOCORT EC is a
`ENTOCORTEC.
`glucocorticosteroid,
`general warnings
`concerning
`glucocorticoids
`ENTOCOAT®EG (budesonide) capsules, for oral use
`should be followed. (5.1)
`» GareIs
`initial US Approval: 1997
`|
`i
`needed in patients who aré transferred from glucocorticosteroid
`wre atccrrer scenes INDICATIONS AND USAGE +++ ----++reerere>
`treatment with high systemic effects to corticosteroids with lower
`systemic availability, such.as ENTOCORT EC. (5.2)
`ENTOCORTECis a glucocorticosteroid indicated for:
`°
`«—|mmunosuppression: Potential worsening of infections (¢.g., existing
`Treatment of mild to maderate active Crohin’s disease involving the ileum
`tuberculosis, fungal, bacterial, viral, or parasitic infection). Use with
`and/or the ascending colon. (1.1)
`caution in patients with these infections. More serious or even fatal
`Maintenance of clinical remission of mild to moderate Crohn's disease
`course of chickenpox or measles can occurin susceptible patients. (5.3)
`involving the ileum and/or the ascending colon for up to 3 months. (1.2)
`vette ene eee ee eeee ADVERSE REACTIONS ---------+----++7>>
`wet c eee e eens DOSAGE AND ADMINISTRATION-----------++--
`Most common adverse reactions (2 5%) are headache, respiratory infection,
`Mild to moderate active Crohn’s disease: 9 mq oncedaily in the morning
`nausea, back pain, dyspepsia, dizziness, abdominal pain, flatulence, vomiting,
`for up to 8 weeks. Repeated 8 week courses of ENTOCORT EC can be
`fatigue, pain. (6.1)
`given for recurring episodes ofactive disease. (2.1}
`To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at
`Maintenance ofclinical remission of mild to moderate Crohn's disease:
`1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwateh.
`6 mg once daily for up to 3 months. Continued treatment with
`ENTOCORT EC 6 mg for more than 3 months has not been shownto
`provide substantial clinical benefit. (2.2)
`weer ee eeeee DOSAGE FORMS AND STRENGTHS --+--+-++++--
`
`voce ee teeter ewer eee DRUG INTERACTIONS«=~ <--+2+++--ee 820+
`®
`Cytochrome P450 3Ad inhibitors (e.9., ketoconazole, grapefruit juice)
`should be avoided. May cause increased systemic corticosteroid effects.
`(2.8, 7, 12.3)
`Capsules: 3 mg (3)
`weet een nent ees USE IN SPECIFIC POPULATIONS- «+++ ---+-++-++
`weet eee eeeeeeeee CONTRAINDICATIONS- «+ +--+ ++-++2220-5+
`+—Hepatic Insufficiency: Monitor patients for signs and/or symptoms of
`Hypersensitivity to any of the ingredients in ENTOCORTEC.(4)
`hypercorticism. (5.4, 8.6)
`See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient
`labeling
`
`Revised: December2011
`
`1
`
`2
`
`4
`
`INDICATIONS AND USAGE
`1.1 Mild to Moderate Active Cronn’s
`Disease
`4.2 Maintenanceof Clinical Remission
`of Mild to Moderate Crohn’s Disease
`DOSAGE AND ADMINISTRATION
`2.1 Mild to Moderate Active Crohn’s
`Disease
`2.2 Maintenance of Clinical Remission
`of Mild to Moderate Grohn’s Disease
`2.3 CYP3A4 inhibitors
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1 Hypercorticism and Adrenal
`Suppression
`5.2 Transferring Patients from Systemic
`Glucocorticosteroid Therapy
`Immunosuppression
`
`5.3
`
`6
`
`7
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`54 increasedSystemic
`.
`Glucocorticosteroid Suscepiibility
`5.5 Other Glucocorticosteroid Effects
`ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`6.2
`Postmarketing Experience
`DRUG INTERACTIONS
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.3 Nursing Mothers
`Pediatric Use
`8.4
`8.5 Geriatric Use
`8.6 Hepatic Insufficiency
`10 OVERDOSAGE
`11
`DESCRIPTION
`
`12.3 Pharmacokinetics
`13. NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis,
`impairmentof Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND
`HANDLING
`PATIENT COUNSELING INFORMATION
`17.1 Hypercorticism and Adrenal
`We ee .
`Immunosuppression
`.2
`17.3 How to Take ENTOCORT EC Capsules
`
`17
`
`2. CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`$2.2 Pharmacodynamics
`
`* Sections or subsections omitted from the Ill prescribing information
`are not fisted.
`
`
`
`000001
`
`Exhibit 1032
`Exhibit 1032
`ARGENTUM
`ARGENTUM
`IPR2018-00080
`IPR2018-00080
`
`000001
`
`

`

`2
`
`+
`*
`
`ENTOCORT® EC (budesonide) Capsules
`FULL PRESCRIBINGINFORMATION
`5.4 Increased Systemic Glucocorticosteroid Susceptibility
`Reducedliver functicn affects the elimination of glucocorticosteroids, and increased systemic
`INDICATIONS AND USAGE
`1
`availability of oral budesonide has been demonstrated in patients with liver cirrhosis [see Use
`1.1 Mild to Moderate Active Crohn‘s Disease
`in Specific Populations (8.6)).
`ENTOCORT ECis indicated for the treatment of mild to moderate active Crohn's disease
`5.5 Other Glucocorticosteroid Effects
`involving the ileum and/or the ascending colon.
`Caution should betaken in patients with hypertension, diabetes mellitus, osteoporosis, peptic
`1.2 Maintenance of Clinical Remission of Mild to Moderate Crohn’s Disease
`ulcer, glaucoma orcataracts, or with a family history of diabetes or glaucoma, or with any
`ENTOCORT ECis indicated forthe maintenance of clinical remission of mild to moderate
`other condition where glucocorticostercids may have unwantedeffects.
`Crohn’s. disease involvingthe ileum and/orthe ascending. colon far up to 3 months.
`&
`ADVERSE REACTIONS
`2
`DOSAGE AND ADMINISTRATION
`Systemic glucocorticosteroid use may result in the following:
`2.1 Mild to Moderate Active Crohn’s Disease
`* Hypercorticism and Adrenal Suppression [see Warnings and Precautions (6.1))
`The recommended adult.dosagefor the treatmentof mild to moderate active Crohn's disease
`+ Symptoms of steroid withdrawal
`in those patients transferring from Systemic Gluco-
`involving the ileum and/or the ascending colon is 9 mgorally taken once daily in the morning
`corticosteroid Therany [see Warnings and Precautions (5.2)]
`for up to 8 weeks. Repeated 8 week courses of ENTOCORTEC can be given for recurring
`Immunosuppression [see Warnings and Precautions (5.3)}
`episodesofactive disease.
`Increased Systemic Glucocorticostercid Susceptibility [see Warnings and Precautions
`2.2 Maintenance of Clinical Remission of Mild to Moderate Crohn’s Disease
`(5.4)]
`Following an 8 week course(s) of treatment for active disease and once: the patient's
`» Other Glucocorticosteroid Effects [see Warnings and Precautions (5.5)|
`symptomsare controlled (GDAI less than 150}, ENTOCORT EC 6 mgorally is recommended
`6.1 ClinicalTrials Experience
`once daily for maintenanceof clinical remission up to 3 months, If symptom controlis stili
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`maintained at 3 months an attempt
`to taper to complete cessation is recommended.
`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical
`Continued treatment with ENTOCORT EC 6 mg for more than 3 months has not been shown
`trials of another drug and maynot reflect the rates observed in practice
`to provide substantial clinical benetit.
`The safety of ENTOCORT EC was evaluated in 651 patients. in five short-term, active disease
`Patients with mild to moderate active Crohn's diseaseinvolving the ileum and/or ascending
`state studies, They ranged in age from 17 to 74 (mean 35), 40% were male and 97% were
`colon have been switchedfrom oral prednisolone to ENTOCORTEC with no reported episodes
`white, 2.6% were greater than or equal to 65 years of age. Five hundred and twenty patients
`of adrenal insufficiency. Since prednisolone should not be stopped abruptly, tapering should
`were treated with ENTOCORT EC 9 mg (total dally dose). The most common adverse
`begin-concomitantly with initiating ENTOGORT EC treatment.
`reactions reported were headache, respiratory infection, nausea, and symptomsof hyper-
`corticism. Clinical studies have shown that the frequency of glucocorticosteroid-associated
`2.3 CYP3A4 inhibitors
`adverse reactions was substantially reduced with ENTOCORT EC capsules compared with
`lf concomitant administration with ketoconazole, or any other CYP3A4inhibitor, is indicated,
`prednisoloneat therapeutically equivalent doses. Adverse reactions occurring in greater than
`patients should be closely monitored forincreased signs and/or symptomsof hypercorticism.
`or equa! 10.5%ofthe patients are listed in Table 1:
`Grapefruit juice, which is known to inhibit CYP3A4, should also be avoided when taking
`ENTOCORT EC.In these cases, reduction in the dose of ENTOCORT EC capsules should be
`Table 1
`Adverse Reactions Occurring in greater than or equal to 5%
`
`of the Patients in any treated group
`considered [see Drug Interactions (7) and Clinical Pharmacology (12.3).
`ENTOCORT EC Prednisolone©Comparator*Placeba
`
`
`3
`DOSAGE FORMS AND STRENGTHS
`9 my
`40 mg
`ENTOCORT EC 3 mg capsules are hard gelatin capsules with an opaquelight grey body and
`n=520
`n=145
`an opaque pink cap, coded with ENTOCORTEC 3 mg on the capsule.
`Adverse
`
`4—CONTRAINDICATIONS
`Reaction
`Number (%)
`Number(%)
` Number(%)
`Number(%)
`ENTOCORTECis contraindicatedin patients with hypersensitivity to budesonide or any of the
`Headache
`107(21)
`19(18)
`31(21)
`14(13)
`ingredients of ENTOCORT EC. Anaphylactic reactions have occurred (see Adverse Reactions
`Respiratory
`(6.2).
`20(14)
`7(7)
`56 (11)
`Infection
`WARNINGS AND PRECAUTIONS
`5
`18(42)
`10(9}
`57(11)
`Nausea
`5.1 Hypercorticism and Adrenal Suppression
`17(12)
`10(9}
`36(7)
`Back Pain
`When glucocorticosteroids are used chronically, systemic effects such as hypercorticism
`and adrenal suppression may occur. Glucccorticosteroids can reduce the response of the
`17(12)
`(4)
`31(6)
`Dyspepsia
`hypothalamus-pituitary-adrenal (HPA)axis to stress.In situations wherepatients are subject
`18(12)
`5(8)
`38(7)
`Dizziness
`to surgery-orotherstress situations, supplementation with a systemic glucocorticosteroid is
`6(4)
`18(17)
`32(8)
`Abdominal Pain
`recommended, Since ENTOCORT ECis.a glucocorticosteroid, general warnings concerning
`12(8)
`6(6)
`30(6)
`Flatulence
`glucocorticoids should be followed.
`6(4)
`6(6)
`29(8}
`Vomiting
`5,2 Transferring Patients from Systemic Glucocorticosteroid Therapy
`Careis neededin patients who are transferred: from glucocorticosteroid treatmentwith high
`11{8)
`8(7)
`25(5)
`Fatigue
`systemic effects to corticosteroids with lower systemic availability, such as ENTOCORT EC,
`17(12)_
`8(7)
`24(5)
`Pain
`since symptomsattributed to. withdrawal of steroid therapy, including those of acute adrenal
`* This drug.is not approvedforthe treatment.of Crohn's discase in the United States.
`Suppression or benign intracranial hypertension, may develop. Adrenocortical:
`function
`monitoring may be required in these patients and the dose of glucccorticosteroid treatment
`The safety of ENTOCORT EC was evaluated in 233 patients in four long-term clinical trials
`with high systemic effects should he reduced cautiously.
`(52 weeks). A total of 145 patients were treated with ENTOCORT EC 6 mg.Atotal of 8% of
`ENTOCORTEC patients discontinued treatment due to adverse reactions compared with 10%
`5.3 Immunosuppression
`in the placebo group. The adverse reaction profile in long-term treatmentof Crohn's disease
`Patients whoare on drugsthat suppressthe immune system are more Susceptible to infection
`was similar to that of short-term treatment with ENTOGORT EC 9 mgin active Crohn's
`than healthy individuals. Chicken pox and measles,for example, can have a more serious or
`disease.
`even fatal course in susceptible patients or patients on immunosuppressant doses. of gluco-
`In the long-term clinical trials, the following adverse reactions occurred in greater than or
`corticosteroids. In patients who have not had these diseases, particular care should be taken
`equalto 5%of the 6 mg ENTOCORTEC patients and are notlisted in (Table 1) or by bedy
`to avoid exposure.
`system below: diarrhea (10%); sinusitis (8%); infection viral (6%); and arthralgia (5%).
`How the dose, route and duration of glucocorticosteroid administration affect the risk of
`Adverse reactions, occurting in patients treated with ENTOCORTEC 9 mg(total daily dase) in
`developing a disseminatedinfection is not known. The contribution of the underlying disease
`short-term active disease state studies and/or ENTOGORT EC 6 mg(total daily dose) long-
`and/or prior glucocorticosteroid treatment to therisk is also not known.If exposed, therapy
`term, with an incidenceless than 5% and greater than placebo are listed below by system
`with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG),
`organ class:
`as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramus-
`Blood and lymphatic system disorders:leukocytosis
`cular immunoglobulin (IG) may be indicated. (See prescribing information for VZIG and IG.)
`Cardiac disorders;palpitation, tachycardia,
`If chicken pox develops, treatment with antiviral agents may be considered.
`Eye disorders: eye abnormality, vision abnormal
`Glucocorticostercids should be used with caution, if at all, in patients with active or quiescent
`General disorders and administrationsite conditions: asthenia, chest pain, dependent edema.
`tuberculosis infection, untreated fungal, bacterial, systemicviral or parasitic infections.
`face edema, flu-like disorder, malaise, fever
`Replacement of systemic glucocorticosteroids with ENTOCORT EC capsules may unmask
`Gastrointestinal disorders: anus disorder, Crohn's disease aggravated, enteritis, epigastric
`allergies(e.g., rhinitis and eczema), which were previously controlledby the systemic drug.
`
`2(2)
`
`n=107
`
`i=88
`
`5(6)
`7(8)
`5(6)
`3(3)
`5(6)
`10(11)
`5(6)
`6(7)
`0(0)
`
`000002
`
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`
`

`

`ENTOCORT® EC (budesonide) Capsules
`immune System Disorders: Anaphylactic reactions
`pain, gastrointestinal fistula, glossitis, hemorrhoids, intestinal obstruction, tongue edema,
`tooth disorder
`Nervous System Disorders: Benign intracranial hypertension
`Infections and infestations: Ear infection-not otherwise specified, bronchitis, abscess,rhinitis,
`Psychiatrie Disorders: Mood swings
`urinary tract infection, thrush
`7
`DRUG INTERACTIONS
`Investigations: c-reactive protein increased, weight increased
`‘Concomitantoral administration of ketoconazole-(a knowninhibitor of CYP3A4 activity in the
`Metabolism and nutrition disorders: appetite increased, hypokalemia
`liver and in the intestinal mucosa) caused an eight-fold inerease of the systemic exposure to
`Muscutoskeletal and connective tissue disorders: arthritis, cramps, myalgia
`oral budesonide.
`If treatment with inhibitors of CYP3A4 activity (such as ketoconazole,
`itraconazole,ritonavir, indinavir, saquinavir, erythromycin, etc.) is indicated, reduction of the
`Nervous system disorders: hyperkinesia, parasthesia, tremor, vertigo,dizziness, somnclence,
`amnesia
`budesonide. dose should be considered. After extensive intake of grapefruit juice (which
`inhibits CYP3A4 activity predominantly in the intestinal mucosa), the systemic exposure for
`oral budesonide increased abouttwo times.Ingestion of grapefruit or grapefruit juice should
`be avoidedin connection with budesonide administration [see Clinical Pharmacology (12.3)).
`8
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`Taratogenie Effects: Pregnancy Category C: Budesonide was teratogenic and. embryocidal in
`tabbits and rats. Budesonide produced fetal
`loss, decreased pup weights, and skeletal
`abnormalities at subcutansous doses of 25 meg/kgin rabbits (approximately 0,05 times the
`maximum recommended human dose on a body surface area basis) and 500 meg/kgin rats
`(approximately 0.5 times the maximum recommended human dose on a body surface area
`basis).
`There are no adequate and well-controlled studies in pregnant women, Budesonide should be
`used during pregnancy only if the potential benefit justifies the potential risk.to the fetus.
`Nonteratogenic Effects: Hypoadrenalism may occurin infants born of mothers receiving corti-
`costeroids during pregnancy. Such infants should be carefully observed.
`8.3 Nursing Mothers
`The disposition of budesonide when delivered by inhalation from a dry powderinhaler at
`doses of 200 or 400 meg twice daily for at least 3 months was studied in eight lactating
`women with asthma from 1 te 6 months postpartum. Systemic exposure to budesonidein
`these women appears to be comparable to that in non-lactating women with asthma from
`other studies, Breast milk obtained over eight hours post-dose revealed that the maximum
`budesonide concentration for the 400 and 800 mcg total daily doses was 0.39 and
`0.78 nmol/L, respectively, and occurred within 45 minutes after inhalation. The estimated
`oral daily dose of budesonide trom breast milk to the infant is approximately 0.007 and
`0.014 meg/kg per day for the two dose regimens used in this study, which represents
`approximately 0.3%to 1% of the dose inhaled by the mother. Budesonide plasma concentra-
`tions obtained from five infants at about 90 minutes after breast feeding (and about
`140 minutes after drug administration to the mother) were belowquantifiable levels (less than
`0.02 nmol/L in four infants andless than 0.04 nmol/L in oneinfant).
`The recommended daily dose of ENTOCORT EC capsules is higher (up to 9 mg daily)
`compared with inhaled budesonide (up to 800 mqdaily) given to mothers in the abovestudy.
`The maximum budesonide plasmacoficentration following a 9 mgdaily dose (in both single-
`and repeated-dose pharmacokinetic studies) of oral budesonide is approximately 5-10 nmol/L
`which is up to 10 times higher than ‘the 1-2 nmol/L for a 800 mg daily dose of inhaled budes-
`onide at steady state in the above inhalation study.
`Since there are no data from controlledtrials on the use of ENTOGORTEC by nursing mothers
`or their infants, and becauseof the potential for serious adverse reactionsin nursinginfants
`from ENTOCORTEC,a decision should be made-whetherto discontinue nursing or to discon-
`tinue ENTOCORT EG,taking into account the clinical importance of ENTOCORTEC to the
`mother.
`Budesonideis secreted in human milk. Data from budesonidedelivered via dry powderinhaler
`indicates that the total daily oral dose of budesonide available In breast milk to the infant
`is approximately 0.3% to 1% of the dese inhaled by the mother. Assuming the coefficient
`of extrapolation between the inhaled and oral doses is constant across all dose levels, at
`therapeutic doses of ENTOCORT EC, budesonide exposure to the nursing child may be up to
`10-times higherthan that by budesonide inhalation.
`8.4 Pediatric Use
`Safety andeffectiveness in pediatric patients have not been established. Systemic and inhaled
`corticosteroids,
`including ENTOCORT EC, may cause a reduction of growth velocity in
`pediatric patients.
`8.5 Geriatric Use
`Clinical studies of ENTOCORT EC did not include sufficient numbers of subjects aged 65 and
`over to determine whether they respond differently from younger subjects. Other reported
`clinical experience has not
`identified differences in responses between the elderly and
`younger patients. In general, dose selection for an elderly patient should be cautious, usually
`starting: at the low end of the dosing range, reflecting the greater frequency of decreased
`hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
`8.6 Hepatic Insufficiency
`Patients with moderate to severe liver disease should be monitored for increased signs and/or
`symptoms of hypercorticism. Reducing the dese of ENTOCORT EC capsules should be
`considered in these patients [see Warnings and Precautions (5.4).
`10
`OVERDOSAGE
`Reportsof acute toxicity and/or death following overdosageof glucocorticosteroids are rare.
`Treatment consists of immediate gastric lavage or emesis followed by supportive and
`symptomatictherapy.
`
`Psychiatric disorders,agitation, confusion, insomnia, nervousness, sleep disorder
`Renal and urinary disorders: dysuria, micturition frequency, nocturia
`Reproductive system and breastdisorders: intermenstrualbleeding, menstrual disorder
`Respiratory, thoracic and mediastinal disorders: dyspnea, pharynx disorder
`Skin and subcutaneous tissue disorders: acne, alopecia, dermatitis, eczema, skin disorder,
`sweating increased, purpura
`Vascular disorders: flushing, hypertension
`Table 2 displays the frequency and incidence of signs/symptomsof hypercorticism by active
`questioning of patients in short-term clinical trials.
`Table 2
`Summary and Incidence of Signs/Symptoms of Hypercarticism
`
`in Short-Term Studies
`Prednisolone
`ENTOCORT EC
`omg
`Taper 40 mg
`n=427
`n=i07
`n=46
`
`Signs/Symptom
`Humber (%)
`Number (%)
`Number(%)
`Acne
`63(15)
`14(13)
`33(23}*
`Bruising Easily
`63(15)
`12(11)
`13(9)
`Moon Face
`46(11)
`(4)
`53(37)*
`Swollen Ankles
`32{7)
`6(6)
`13(8)
`Hirsutism
`22(5)
`2(2)
`5(3)
`Buffalo Hump
`6(1)
`2(2)
`5(3)
`
`__Skin Striae
`4(i)
`2(2)
`0(0)
`* Statistically significantly different from ENTOCORT EC 9 mg
`tT Adverse reaction dictionary included lerm hair growth increased, focal and hair growthincreased, general,
`Table 3 displaysthe frequencyand incidence of signs/symptomsof hypercorticism. byactive
`questioning of patients in long-term clinical trials.
`Table3
`Summary and Incidence of Symptems of Hypercorticism
`
`in Long-Term Studies
`ENTOCORT EC
`ENTOCORT EC
`3 mg
`6 mg
`n=88
`n=145
`n=143
`
`Signs/Symptom
`Number(%)
`Number (%) Number(%)
`Bruising easily
`4(5)
`15{10)
`5(4}
`Acne
`4(5)
`14(10)
`3(2)
`Moonface
`3 (3)
`6(4)
`0
`Hirsutism
`2 (2)
`§(3)
`A(t)
`Swollen ankles
`2 (2)
`3(2)
`3(2)
`Buffalo hump
`1(1)
`1 (1)
`0
`Skin striae
`2(2)
`0
`heincidence of signs/symptoms of hypercorticism as described abovein long-term clinical
`trlals was similarto that seen in the short-term clinicaltrials.
`A randomized, open, parallel-group multicenter safety study specifically compared theeffect
`of ENTOCORTEC(less than 9 mg per day) and predrisolone (less than 40 mg per day) on
`bone mineral density over 2 years when used at doses adjusted to disease severity, Bone
`mineral density decreased significantly less with ENTOCORT EC than with prednisolone in
`steroid-naive patients, whereas no difference could be detected between treatment groupsfor
`steroid-dependent patients and previous steroid users. The
`incidence of symptoms
`associated with hypercorticism wassignificantly higher with prednisolone treatment.
`Clinical Laboratory Test Fladings
`Thefollowing potentially clinically significant laboratory changes in clinical trials, irrespective
`of relationship to ENTOCORT EC, were reported in greater than or equal to 1% of patients:
`hypokalemia,
`leukocytosis, anemia, hematuria, pyuria, erythrocyte sedimentation rate
`increased, alkaline phosphatase increased, atypical neutrophils, C-reactive protein increased,
`and adrenal insufficiency.
`6.2 Postmarketing Experience
`Thefollowing adverse reactions have been reported during post-approval use of ENTOCORT
`EC. Because these reactions are reported voluntarily from a population of uncertain size,itis
`not always possible to reliably estimate their frequency or establish a causal relationship to
`drug exposure.
`
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`ENTOCORT® EC (budesonide) Capsules
`tye, after administration of intravenous doses ranges
`The plasma elimination half-life,
`if glucocorticosteroids are used at excessive doses for prolonged periods, systemic gluco-
`between 2 and 3.6 hours, and doesnotdiffer between healthy adults and patients with Crohn's
`corticosteroid effects such as hypercorticism and adrenalsuppression may occur. For chronic
`disease.
`overdosage. in the face of severe disease requiring continuous steroid therapy, the dosage
`Excretion
`maybe reduced temporarily,
`Budesonide is excreted in urine and feces in the form of metabolites. After oral as well
`Single oral doses of 200 and-400 mg/kg werelethalin female and male mice, respectively, The
`as intravenous administration of micronized [#H]-budesonide, approximately 60%of the
`signs of acute toxicity were decreased motoractivity, piloerection and generalized edema.
`recovered radioactivity is found in urine. The major metabolites,
`including 6(-hydroxy
`11
`DESCRIPTION
`budesonide and 16cc-hydroxy prednisolone, are mainly renally excreted, intact or in conju-
`Budesonide,the active ingredient of ENTOCORT EC capsules,is a synthetic corticostercid.
`gated forms. No unchanged budesonideis detected in urine.
`Budesonide is designated chemically as (RS)-118, 18c, 17,21-tetrahydroxypregna-1,4-
`Special Populations
`diene-3,20-dionecyclic 16,17-acetal with butyraldehyde. Budesonideis provided as a mixture
`Gender
`of two epimers (22R and 225). The empirical formula of budesonide is CostgqQg andits
`Nosignificant pharmacokinetic differences have beenidentified due to gender.
`molecular weight Is 430.5. Its structural formula is:
`SH,OH
`Hepatic Insufficiency
`H
`CH, gro2 ~o
`
`In patients with liver cirrhosis, systemic availability of orally administered budesonide
`OOSyCH)~CH,
`correlates with disease. severity and is, on average, 2.5-fold higher. compared with healthy
`controls. Patients with mild liver disease are minimally affected, Patients with severe liver
`dysfunction were not studied. Absorption parameters are notaltered, and for theintravenous
`dose, no significantdifferences in CL or Vsg are observed.
`RenalInsufficiency
`The pharmacokinetics of budesonide in patients with renal impairment has not been studied.
`Intact budesonide is not renally excreted, but metabolites are to a large extent, and might
`therefore reach higherlevels in patients with impaired renal function. However, these metabo-
`Epimer 228 of budesonide
`}
`o
`lites have negligible-corticasterold activity as compared with budesonide (less than 1/100).
`Budesonideis a white to off-white,tasteless, odorless powderthat is practically insoluble in
`Drug-Drug Interactions
`water and heptane, sparingly soluble in ethanol,and freely soluble in chloroform.lis partition
`Budesonideis metabalized via.CYP3Ad.Potent inhibitors of CYP3A4 can increase the plasma
`coefficient between octanol and waterat pH 5 is 1.6 x 10% ionic strength 0.01.
`levels of budesonide several-fold. Co-administration of ketoconazole results in an eight-fotd
`Each capsule for oral administration contains 3 mg. of micronized budesonide with the
`increase in AUC of budesonide, compared to budesonide alone. Grapefruit juice, an inhibitor
`following inactive
`ingredients:
`ethylcellulose,
`acetyltributy!
`citrate, methacrylic
`acid
`of gut mucosal CYPSA, approximately doubles the systemic exposure of oral budesonide.
`copolymertype C, triethy! citrate, antifoam M, polysorbate 80; tale, and sugar spheres. The
`Conversely, induction af CYP3A4 can result in the lowering of budesonide plasmalevels.
`capsule shells have the following inactive ingredients: gelatin,
`iron oxide, and titanium
`Oral. contraceptives containing ethinyl estradiol, which are also metabolized by CYP3A4, do
`dioxide.
`not affect the pharmacokinetics of budesonide. Budesonide does notaffect the plasmalevels
`12
`CLINICAL PHARMACOLOGY
`oforal contraceptives (ie, ethinyl estradiol} [see Drug Inieractions (7}].
`12.1 Mechanism of Action
`Since the dissolution of the coating of ENTOCORT EC is pH dependent (dissolves at pH
`Budesonide has a high topical glucacorticosteroid (GCS) activity and a substantial first pass
`greater than 5.5), the release properties and uptake of the compound may be altered after
`elimination. The formulation contains granules which are coated to protect dissolution in
`treatment with drugs that change the gastrointestinal pH. However, the gastric acid inhibitory
`gastric juice, but which dissolve at pH greater than 5.5, ie, normally when the granules reach
`drug omeprazole, 20 mg once daily does not affect the absorption or pharmacokinetics of
`ENTOGORTEC. When an uncoated oral formulation of budesonide is co-administered with a
`the duodenum. Thereafter, a matrix of ethylcellulose with budesonide controls the release of
`the drug into the intestinal lumen in a time-dependent manner.
`daily dose of cimetidine 1 g, a slight increase in the budesonide peak plasma concentration
`andrate of absorption occurs, resulting in significant cortisol suppression.
`12.2 Pharmacodynamics
`Food Effects
`Budesonide has a high glucocorticoid etfect and a weak mineralocorticoid effect, and the
`affinity of budesonide to. GCS receptors, which reflects the intrinsic potency of the drug,is
`A meandelay in time to peak concentrationof 2.5 hours is observed with the intake of a high-
`about 200-fold that of cortisol and 15-fold that of prednisolone.
`‘
`fat meal, with no-significant differences in AUC.
`13.
`NONCLINICAL TOXICOLOGY
`Treatment with systemically active GCS is associated with a suppression of endogenous
`costisol concentrations and an impairment of the hypothalamus-pituitary-adrenal (HPA) axis
`13.1 Carcinogenesis, Mutagenesis, Impairmentof Fertility
`function. Markers, indirect and direct, of this are cortisol
`levels in plasma or urine and
`Carcinogenicity studies with budesonide were conducted in rats and mice. In a two-year study
`response fo ACTH stimulation.
`in Sprague-Dawleyrats, budesonide causedastatistically significantincrease in the incidence
`Plasmacortisol suppression was compared followingfive days’ administration of ENTOCORT
`of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum
`EC capsules and prednisolone in a crossover studyin healthy volunteers. The mean decrease
`recommended human dase on a body surface area basis). in addition, there were increased
`in the integrated 0-24 hour plasma cortisol concentration was greater
`(78%) with
`incidences of primary hepatocellular tumors in male rats at 25 meg/kg (approximately
`prednisolone 20 mg per day.compared to 45% with ENTOCORT EC 9 mg perday.
`0.023 times the maximum recommended human dose on a body. surface. area basis)
`12.3 Pharmacokinetics
`and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg
`(approximately 0.05 times the maximum recommended human dese-on a body surface area
`Absorption
`basis). In an additional two-year study in mate Sprague-Dawleyrats, budesonide caused no
`The absorption of ENTOCORT EC seemsto be complete,although Cra, ahd Tray are variable.
`gliomasat an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended
`Time to peak concentration varies in individual patients behveen 30 and 600 minutes.
`human dose ona body surface area basis). However,
`it caused a statistically significant
`Following oral administration of 9 mg of budesonide in healthy subjects,.a peak plasma
`increase in the incidence of hepatoceliular
`tumors at an oral dose of 50 mg/kg
`concentration of approximately 5 nmol/L is observed and the area underthe plasma concen-
`(approximately 0.05 times the maximum recommended human dose on a body surface area
`tration time curve is approximately 30 nmol‘hr/L. The systemicavailability after a single dose
`basis). The concurrent reference corticosteroids (prednisolane and triamcinolone acetonide)
`is higherin patients with Crohn's disease compared to healthy volunteers, (21% vs 9%) but
`showed similar findings,ina 91-weekstudy in mice, budesonide caused no treatment-related
`approachesthat in healthy volunteers after repeated dosing.
`.
`carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.1 times the maximum
`Distribution
`recommended human dose ona body surface area basis}.
`The mean volume of distribution (V..) of budesonide varies between 2.2 and 3.9 U/kg in
`Budesonide was not genotoxic in the Amestest, the mouse lymphoma cell forward gene
`healthy subjects and in patients. Plasma protein binding is estimated to be 85 to 90% in
`mutation (TK**) test, the human lymphocyte chromosome aberration test, the Drosophila
`the concentration range 1 to 230 nmol/L, independent of gender. The erythrocyte/plasma
`melanogaster sex-linked recessivelethality test, the rat hepatocyte UDS test and the mouse
`partition ratio at clinically relevant concentrations is about0.8.
`micronucleus test.
`Metabolism
`In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 meg/kg
`Following absorption, budesonide is subject to high first pass metabolism (80-90%), in vitro
`(approximately 0.07 times the maximum recommended human dose on a bodysurface area
`experiments in humanliver microsomes demonstrate that budesonideis rapidly and exten-
`basis). However, it caused a decrease in prenatal viability and viability in pupsat birth and
`sively biotransformed, mainly by GYP3A4, tc its 2 major metabolites, 6B-hydroxy budesonide
`during lactation, along with a decrease in maternal body-weightgain, at subcutaneous doses
`and 16cx-hydroxy prednisolone. The glucocorticoid activity of these metabolites is negligible
`of 20 meg/kg (approximately 0.02 times the maximum recommended human dose ona body
`(les