reoosoo
`
`ENTOCORT® ac
`
`‘
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`(budesonid
`
`6)
`
`CopsuIes
`
`the information needed to use
`include all
`These highlights do not
`ENTDCDHT® EC safely and effectively. See lull prescribing information for
`ENTDCDHT EC.
`
`ENTITCOITT® EC (budesonide) capsules, for oral use
`Initial US Approval: 1997
`----------------- INDICATIONSANDUSAGE
`
`ENTOCORT EC is a glucocorticosteroid indicated for:
`'
`Treatment of mild to moderate active Crohn’s disease involving the IIeum
`and/or the ascending colon. (1.1)
`Maintenance of clinical remission of mild to moderate Crohn's disease
`involving the ileum and/or the ascending colon for up to 3 months. (1.2)
`--------------- DOSAGE AND ADMINISTRATION - - - - - - - - - - - - - --
`
`.
`
`o
`
`‘
`
`Mild to moderate active Crohn’s disease: 9 mg once daily in the morning
`for up to 8 weeks. Repeated 8 week courses of ENTOCORT EC can be
`given for recurring episodes of active disease. (2.1)
`
`Maintenance of clinical remission of mild to moderate Crohn‘s disease:
`6 mg once daily for up to 3 months. Continued treatment with
`ENTOCORT EC 6 mg for more than 3 months has not been shown to
`provide substantial clinical benefit. (2.2)
`-------------- DOSAGE FORMS AND STRENGTHS -- -
`
`- - - - - - - - - --
`
`Capsules: 3 mg (3)
`------------------ CONTRAINDICATIONS--------—-------v--
`
`Hypersensitivity to any of the ingredients in ENTOCORT EC. (4)
`
`............... WARNINGS AND PRECAUTIONS ...............
`,
`WWW Since ENTOCORT EC is a
`glucocorticosteroid,
`general warnings
`concerning
`glucocorticoids
`should be followed. (5.1)
`
`'Care is
`
`r
`
`needed In patients who are transferred from giucccorticosteroid
`treatment with high systemic effects to corticosteroids with lower
`systemic availability, such as ENTOCORT EC. (5.2)
`Immtiuosuonmsiou; Potential worsening of infections (e.g., existing
`tuberculosis, fungal, bacterial, viral, or parasitic infection). Use with
`caution In patients with these infections. More serious or even fatal
`course of chickenpox or measles can occur in susceptible patients. (5.3)
`--------------- ADVERSEREACTIONS---------------~---
`
`Most
`common adverse reactions (2 5%) are headache, respiratory infection,
`nausea, back pain, dyspepsia, dizziness, abdominal pain, flatulence, vomiting,
`fatigue, pain. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at
`1-800-236-9933 or FDA at l-BtIfl-FDA-ttiltlt or www.fda.gov/medwatch.
`--------------- DRUGINTERACTIONS---«---------------
`
`. . __
`
`Cytochrome P450 3A4 inhibitors (e.g., ketooonazole, grapefruit juice)
`should be avoided. May cause increased systemic corticosteroid effects.
`(2.3, 7, 12.3)
`------------ use IN SPECIFIC POPULATIONS- - - - -- - - - - -- - - --
`
`Hepatic Insufficiency: Monitor patients for signs and/or symptoms of
`hyperccrticism. (5.4, 8.6)
`See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient
`labeling
`
`Revised: December 2011
`
`I
`
`2
`
`4
`
`INDICATIONS AND USAGE
`1.1 Mild to Moderate Active Crohn‘s
`Disease
`1.2 Maintenance of Clinical Remission
`of Mild to Moderate Grohn 3 Disease
`DOSAGE AND ADMINISTRATION
`2.1 Mild to Moderate ACIIVB Crohn‘s
`Disease
`22 Maintenance of Clinical Remission
`of Mild to Moderate Crohn’s Disease
`2,3 CYP3A4 inhibitors
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`51 Hypercorticism and Adrenal
`Suppression
`5.2 Transferring Patients from Systemic
`Glucocorticosteroid Therapy
`.
`Immunosuppressmn
`
`5.3
`
`FULL PRESCNIDIING INFORMATION: CONTENTS‘
`
`5.4
`
`IncreasedSystemic
`’
`..
`SIECO§H'C°SI:IW {Suscderégbrhtty
`t er
`ucocor Icos eroI
`ecs
`5'5
`ADVERSE REACTIONS
`51
`Clinical was Experience
`6.2
`Postmarketing Experience
`DRUG INTERACTIONS
`
`6
`
`7
`
`12.3 Pharmacokinetics
`13 NQNCUNICAL TOXICOLOGY
`13.1 Carcinogenesis,Mutagenesis,
`Impairment of Fertility
`14 CLINICAL STUDIES
`I 6 HOW SUPPLIED/5TORAGE AND
`HANDLING
`
`USE IN SPECIFIC POPULATIONS
`3-1
`Pregnancy
`8.3 Nursing Mothers
`8.4
`Pediatric Use
`3,5 Geriatric use
`8.6 Hepatic Insufficiency
`l0 OVERDOSAGE
`
`DESCRIPTION
`i I
`'2 CLINICAL PHARMACOLOGY
`121 Mechanism of Action
`.
`12.2 Pharmacodynamics
`
`I7 PATIENT COUN3ELING INFORMATION
`17.1 Hypercortimsm and Adrenal
`W 2 'Suooresswn
`.
`. mmunosuppressron
`17.3 How to Take ENTOCORT EC Capsules
`
`' Sections or subsections omitted item the lull prescribing Information
`are nolilsled.
`
`
`
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`
`MYLAN Ex 1032, Page 1
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`

`

`ENTOCCHT® ED (budesonide) Capsules
`5.4 Increased Systemic Glucocorticosteroid Susceptibility
`Reduced liver function alfects the elimination of glucocorticosteroids, and increased systemic
`availability of oral budesunide has been demonstrated in patients with liver cirrhosis (see Use
`in Specific Populations (8.6)].
`5.5 Other Glucocorticosteroicl Effects
`Caution should be taken in patients with hypertension, diabetes mellitus, osteoporosis. peptic
`ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any
`other condition vrbere glucocorticosteroids may have unwanted efiects.
`6
`ADVERSE REACTIONS
`Systemic glucocorticostcroid use may result in the following:
`~ Hyperconicism and Adrenal Suppression [see Warnings and Precautions (5.1)]
`' Symptoms oi steroid withdrawal
`in those patients transferring from Systemic Gluco-
`corticosferoid Therapy (sea Wamlngs and Precautions (5.2)]
`lmmunosuppression [see Warnings and Precautions (5.3)]
`increased Systemic Glucocorticosteroid Susceptibiilty [see Warnings and Precautions
`l5‘ 4)]
`- Other Glucocorticosteroid Effects [see Warnings and Precautions (55))
`6.1 Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical
`trials of another drug and may not reflect the rates observed in practice
`The safety of ENTOCORT EC was evaluated in 651 patients in five short~term, active disease
`state studies. They ranged in age from 17 to 74 (mean 35), 40% were male and 97% were
`white, 2.6% were greater than or equal to 65 years of age. Five hundred and twenty patients
`were treated with ENTOCORT EC 9 mg (total daily dose). The most common adverse
`reactions reported were headache, respiratory infection, nausea, and symptoms of hyper.
`cortlcism. Clinical studies have shown that the frequency of glucocorticosteroid-associated
`adverse reactions was substantially reduced with ENTOCORT EC capsules compared with
`prednisolone at therapeutically equivalent doses. Adverse reactions occurring in greater than
`or equal to 5% of the patients are listed in Table i:
`Table 1
`Adverse Reactions Occurring in greater than or equal to 5%
`
`of the Patients in any treated group
`ENTDCOBT EC
`Placebo
`9 mg
`n=520
`
`2
`
`Comparator‘
`
`n=88
`
`Prednisolone
`40 mg
`n=145
`
`n=107
`
`FULL Pnescnieiili/owiiirorthnON
`INDICATIONS AND USAGE
`i
`Ll Mild to Moderate Active Crohn’s Disease
`ENTOCORT EC is indicated for the treatment of mild to moderate active Crohn‘s disease
`involving the ileum and/or the ascending colon.
`'l.2 Maintenance of Clinical Remission at Mild to Moderate Crohn’s Disease
`ENTUCORT EC is indicated for the maintenance of clinical remission of mild to moderate
`Crohn's disease involving the ileum and/or the ascending colon for up to 3 months.
`2
`DOSAGE AND ADMINISTRATION
`2.1 Mild to Moderate Active Crohn's Disease
`The recommended adult dosage for the treatment oi mild to moderate active Crohn‘s disease
`involving the ileum and/or the ascending colon is 9 mg orally taken once daily in the morning
`for up to 8 weeks. Repeated 8 week courses of ENTOCORT EC can be given for recurring
`episodes of active disease.
`2.2 Maintenance of Clinical Remission at Mild to Moderate Crahn’s Disease
`Following an 8 week course(s) of treatment tor active disease and once the patient’s
`symptoms are controlled (CDAl less than 150), ENTOCORT EC 6 mg orally is recommended
`once daily for maintenance of clinical remission up to 3 months. If symptom control is stlli
`maintained at 3 months an attempt
`to taper to complete cessation is recommended
`Continued treatment with ENTOCORT ECG mg for more than 3 months has not been shown
`to provide substantial clinical benefit.
`Patients with mild to moderate active Crobn’s disease involving the ileum and/or ascending
`colon have been switched from oral prednisolone to ENTOCORT EC with no reported episodes
`of adrenal insutficiency. Since prednisolone should not be stopped abruptly. tapering should
`beginconcomitantly with initiating ENTOCORT E0 treatment.
`2.3 CYP3A4 inhibitors
`Ii concomitant administration with ketoconazole, or any other CYP3A4 inhibitor, is indicated,
`patients should be closely monitored torincreased signs and/orsymptoms of hypercorticism,
`Grapefruit luice, 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
`considered [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
`3
`DOSAGE FORMS AND STRENGTHS
`ENTOCORT EC 3 mg capsules are hard gelatin capsules with an opaque light grey body and
`an opaque pink cap, coded with ENTOCORT EC 3 mg on the capsule
`4
`CONTRAINDICATIONS
`ENTOCORT EC is contraindicated in patients with hypersensitivity to budesonide or any of the
`ingredients of ENTOCORT EC. Anaphyiactic reactions have occurred (see Adverse Reactions
`(6.2)).
`WARNINGS AND PRECAUTIONS
`5
`5.1 Hypercorticism and Adrenal Suppression
`When glucocorticosteroids are used chronically, systemic effects such as hypercorticism
`and adrenal suppression may occur. Glucocorticosferoids can reduce the response oi the
`hypothalamuspituitary-adrenal (HPA) axis to stress. In situations where patients are subject
`to surgery or other stress situations, supplementation With a systemic glucocorticosteroid is
`recommended. Since ENTOCORT EC is a glucocorticosteroid, general warnings concerning
`glucocorticolds should be followed.
`5.2 Transferring Patients from Systemic Glucocorticosteroicl Therapy
`Care is needed in patients who are transferred lrom glucocorticosterold treatment with high
`systemic effects to corticosteroids with lower systemic availability, such as ENTOCORT EC,
`since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal
`suppression or benign intracranial hypertension, may develop. Adrenocortical
`function
`monitoring may be required in these patients and the dose of glucocorticoslerold treatment
`with high systemic effects should be reduced cautiously.
`5.3 lmmunosuppression
`Patients who are on drugs that suppress the immune system are more susceptible to infection
`than healthy individuals. Chicken pox and measles, for example, can have a more serious or
`even fatal course in susceptible patients or patients on immunosupprcssant doses of gluco-
`corticosteroids. in patients who have not had these diseases, particular care should be taken
`to avoid exposure.
`How the dose, route and duration of glucocorticosteroid administration affect the risk of
`developing a disseminated infection is not known. The contribution oi the underlying disease
`and/or prior glucocorticosteroid treatment to the risk is also not known. It exposed, therapy
`with variceiia zostcr immune globulin (VZIG) or pooled intravenous immunoglobulin (MS),
`as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramus-
`cular immunoglobulin (iG) may be indicated. (See prescribing information for VZIG and IG.)
`lf chicken pox develops, treatment with antiviral agents maybe considered.
`Glucocorticosteroids should be used with caution, if at all, in patients with active or quiescent
`tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections.
`Replacement cl systemic glucocortlcosteroids with ENTOCORT EC capsules may unmask
`allergies (eg, rhinitis and eczema), which were previously controlled by the systemic drug.
`
`-
`-
`
`Adverse
`
`Reaction
`Numbarfik)
`Number(°_n)
`Numberfl/EL
`Numbcrflu)
`Headache
`107(21)
`19(18)
`31(21)
`ii 13)
`Respiratory
`20(14)
`7(7)
`55(11)
`infection
`18(12)
`10(9)
`57(11)
`Nausea
`17(12)
`10(9)
`36(7)
`Back Pain
`17(12)
`4(4)
`31 6)
`Dyspepsia
`18(12)
`5(5)
`38(7)
`Dizziness
`6(4)
`18(17)
`32(6)
`Abdominal Pain
`12(8)
`6(6)
`30(6)
`Flatulencc
`6(4)
`6(6)
`29(6)
`Vomiting
`11(8)
`8(7)
`25(5)
`Fatigue
`17(12)
`8(7)
`24(5)
`Pain
`' This drug is not approved to! the treatment of Crohn's disease in the United States.
`
`
`
`5 6)
`7 8)
`5 6)
`33)
`5 6)
`10(11)
`5 6)
`6(7)
`0(0)
`2 2)
`
`The safety of ENTOCORT EC was evaluated in 233 patients in four long-term clinical trials
`(52 weeks). A total of 145 patients were treated with ENTOCOBT EC 6 mg. A total of 8% of
`ENTOCORT EC patients discontinued treatment due to adverse reactions compared with 10%
`in the placebo group. The adverse reaction profile in long-term treatment of Crohn’s disease
`was similar to that of short—term treatment with ENTDCORT EC 9 mg in active Crohn’s
`disease.
`in the longsterm clinical trials, the following adverse reactions occurred in greater than or
`equal to 5% of the6 mg ENTOCORT EC patients and are not listed in (Table i) or by body
`system below: diarrhea (10%): sinusitis (6%); infection viral (6%); and arthraigia (5%).
`Adverse reactions, occurring in patients treated with ENTOCORT EC 9 mg (total daily dose) in
`short-term active disease state studies and/or ENTOCORT EC 6 mg (total daily dose) long-
`tcrm, with an incidence less than 5% and greater than placebo are listed below by system
`organ class:
`Blood and lymphatic system disorders: ieukocytosis
`Cardiac disorders: paipitation, tachycardia,
`Eye disorders: eye abnormality. vision abnormal
`General disorders and administration site conditions: asthenla, chest pain. dependent edema,
`lace edema, fiuiike disorder, malaise. lever
`Gastrointestinal disorders: anus disorder. Crohn’s disease aggravated, enteritis, epigastric
`
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`

`ENTOCOHT® 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,
`Psychiatric Disorders: Mood swings
`urinary tract infection, thrush
`7
`DRUG INTERACTIONS
`Investigations: c-reaotive protein increased, weight increased
`Concomitant oral administration of ketoconazoie (a known inhibitor of CYP3A4 activity in the
`Metabolism and nutrition disorders: appetite increased, hypokalemia
`liver and in the intestinal mucosa) caused an eight-fold increase of the systemic exposure to
`Muscuiosirelefaland connective tissue disorders: adhritis, cramps, myalgia
`oral budesonide,
`lt 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, somnolence,
`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 about two times. Ingestion of grapefruit or grapefruit juice should
`be avoided in connection with budesonide administration [sea Clinical Pharmacology (72.3)].
`8
`USE IN SPECIFIC POPULATlONS
`8.I
`Pregnancy
`Teratogenic Effects: Pregnancy Category C: Budesonide was teratogenic and embryocidal in
`rabbits and rats. Budesonide produced fetal
`loss, decreased pup weights, and skeletal
`abnormalities at subcutaneous doses of 25 meg/kg in rabbits (approximately 005 times the
`maximum recommended human dose on a body surface area basis) and 500 meg/kg in 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,
`Nonterafogenic Effects: Hypoadrenalism may occur in 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 powder inhaler at
`doses of 200 or 400 mcg twice daily for at least 3 months was studied in eight lactating
`women with asthma from t to 6 months postpartuml. Systemic exposure to budesonide in
`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 039 and
`0,78 nmollL, respectively, and occurred within 45 minutes after inhalation. The estimated
`oral daily dose of budesonide from breast milk to the infant is approximately 0,007 and
`0.014 mcglkg per day for the the 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
`t40 minutes after drug administration to the mother) were below quantifiable levels (less than
`002 nmollL in four infants and less than 0.04 nmollL in one infant).
`The recommended daily dose of ENTOCORT EC capsules is higher (up to 9 mg daily)
`compared with inhaled budesonide (up to 800 mg daily) given to mothers in the above study,
`The maximum budesonide plasma concentration following a9 mg daily dose (in both single-
`and repeated-dose pharmacokinetic studies) of oral budesonide is approximately 5-10 nmoliL
`which is up to 10 times higher than the 12 nmollL for a 800 mg daily dose of inhaled budes-
`onide at steady state in the above inhalation study,
`Since there are no data from controlled trials on the use of ENTOCORT EC by nursing mothers
`or their infants, and because of the potential for serious adverse reactions in nursing infants
`from ENTOCORT EC, a decision should be made whether to discontinue nursing orto discon-
`tinue ENTOCDRT EC, taking into account the clinical impedance at ENTOCORT EC to the
`mother.
`Budesonide is secreted in human milk. Data from budesonide delivered via dry powder inhaler
`indicates that the total daily oral dose of budesonide available to breast milk to the infant
`is approximately 0.3% to 1% of the dose 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 higher than that by budesonide inhalation.
`8,4 Pediatric Use
`Safety and effectiveness 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 foran 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 hypercurticism. Reducing the dose of ENTOCORT EC capsules should be
`considered in these patients [see Warnings and Precautions (5, 4)),
`lO OVERDOSAGE
`Reports of acute toxicity and/or death following overdosage of glucocorticosteroids are rare.
`Treatment consists of immediate gastric lavage or emesis followed by supportive and
`symptomatic therapy.
`
`Psychiatric disorders: agitation. contusion, insomnia, nervousness, steep disorder
`Renal and urinary disorders: dysuria, mlcturition frequency, nocturia
`Reproductive system and breast disorders: intermenstrual bleeding, menstrual disorder
`Respiratory, thoracic and mediastinai 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/symptoms of hypercorticism by active
`questioning of patients in short-term clinical trials.
`Table 2
`Summary and incidence ot Signs/Symptoms of Hypersorticism
`
`in Short—Term Studies
`Prednisolone
`ENTOCCRT EC
`9 mg
`Taper 40 mg
`n=427
`n=107
`n=145
`
`Signs/Symptom
`Number (%)
`Number 13/2).
`Number (it/g)
`Acne
`53(t5)
`i4(l3)
`33(23)’
`Bruising Easily
`63(15)
`12(11)
`13(9)
`Moon Face
`46(11)
`4(4)
`53(37)‘
`Swollen Ankles
`32(7)
`6(6)
`13(9)
`Hirsutismt
`22(5)
`2(2)
`5(3)
`Buffalo Hump
`6(1)
`2(2)
`5(3)
`
`Skin Striae
`4(1)
`2(2)
`0(0)
`‘ Statistically significantly different from ENTOCORT EC 9 mg
`T Adverse reaction dictionary included term hair growth increased, local and hair growth increased. general.
`Table 3 displays the frequency and incidence of slgnsisymptoms of hypercorticism by active
`questioning of patients in longierm clinical trials.
`Table 3
`Summary and Incidence of Symptoms of Hypercorticism
`
`in Long-Term Studies
`ENTOCORT EC
`ENTDCORT EC
`3 mg
`6 mg
`[1:38
`[1:145
`11:14.3
`
`Signs/Symptom
`Number (at)
`Number (“/3)
`VVVVV Number (“/o)
`Bruislng easily
`4(5)
`15(10)
`5(4)
`Acne
`4(5)
`14(10)
`3(2)
`Moon face
`3 (3)
`6(4)
`0
`Hirsutism
`2 (2)
`5(3)
`1(1)
`Swollen ankles
`2 (2)
`3(2)
`3(2)
`Buffalo hump
`i (l)
`l (t)
`0
`Skin striae
`2(2)
`0
`he incidence of signs/symptoms of hypercorticism as described above in long~term clinical
`trials was similar to that seen in the shortierm clinical trials.
`A randomized, open, parallelgroup multicenter safety study specifically compared the effect
`of ENTOCORT EC (less than 9 mg per day) and prednisolone (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 groups for
`steroid-dependent patients and prevlous steroid users. The
`incidence of symptoms
`associated with hypercorticism was significantly higher with prednisolone treatment.
`Clinical Laboratory Test Findings
`The following potentially clinically significant laboratory changes in clinical trials, irrespective
`of relationship to ENTOCOHT EC, were reported in greater than or equal to 1% of patients:
`hypokalemia,
`leukocytosis, anemia, hematuria, pyirria, erythrocyte sedimentation rate
`increased, alkaline phosphatase increased. atypical neutrophils, C-reactive protein increased,
`and adrenal insufficiency,
`6.2 Postmarkefing Experience
`The following adverse reactions have been reported during post-approval use of ENTOCORT
`EC. Because these reactions are reported voluntarily from a population of uncertain size, it is
`not always possible to reliably estimate their frequency or establish a causal relationship to
`drug exposure.
`
`3
`
`MYLAN Ex 1032, Page 3
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`Placebo
`
`Placebo
`
`0 T
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`HO
`cw,
`
`.
`
`o
`
`Epimeri’ER olhudesonidc
`
`4
`ENTOCORT® E0 (budesonide) Capsules
`The plasma elimination half-life, rm. alter administration of intravenous doses ranges
`if glucocorticosteroids are used afrexcessive doses for prolonged periods, systemic gluco-
`between Zand 3.6 hours, and does not differ between healthy adults and patients with Crohn's
`corticosteroid effects such as hypercorticlsm and adrenal suppression may occur. Forchronic
`disease.
`overdosage in the face of severe disease requiring continuous steroid therapy. the dosage
`Excretion
`maybe reduced temporarily.
`Budesonide is excreted in urine and faces in the form of metabolites. After oral as well
`Single oral doses of 200 and 400 mg/kg were lethal in female and male mice, respectively. The
`as intravenous administration of micronized (am-budesonide, approximately 60% of the
`signs of acute toxicity were decreased motor activity, piloerection and generalized edema.
`recovered radioactivity is found in urine. The major metabolites,
`including tilt-hydroxy
`II
`DESCRIPTION
`budesonide and iGa—hydroxy prednisolone, are mainly renally excreted, intact or in conic-
`Budesonide, the active ingredient of ENTOCORT EC capsules, is a synthetic corticosteroid.
`gated forms. No unchanged budesonide is detected in urine.
`Budesonide is designated chemically as (RSHTB, I60t, 17,21-tetrahydroxypregna-1,4-
`Specioi Populations
`dlene-3,20-dione cyclic 16,17-acetal with butyraldehyde. Budesonide is provided as a mixture
`Gender
`of two epimers (220 and 223). The empirical formula of budesonide is 025I‘I3405 and its
`No significant pharmacokinetic differences have been identified due to gender.
`molecular weight is 430.5. its structural formula is:
`omen
`Hepatic Insufficiency
`H
`5
`”‘0
`CH (3:0
`in patients with liver cirrhosis, systemic availability of orally administered budesonide
`<J>C<crr,—-cro~cn3
`correlates with disease severity and is, on average, 2.5ofold higher compared with healthy
`controls. Patients with mild liver disease are minimally affected. Patients with severe liver
`dysfunction were not studied. Absorption parameters are not altered, and for the intravenous
`dose. on significant differences in ct or V55 are observed.
`Renoi Insufficiency
`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 higher levels in patients with impaired renal function. However, these metabo-
`lites have negligible corticosteroid activity as compared with budesonide (less than 1/1 00).
`Drug-Drug Interactions
`Budesonide is metabolized via CYP3A4. Potent inhibitors of CYP3A4 can increase the plasma
`levels of budesonide several-told. [to-administration of ketoconazole results in an eight~fold
`increase in AUC of budesonide, compared to budesonide alone. Grapefruit juice, an inhibitor
`of gut mucosa! CYPSA, approximately doubles the systemic exposure of oral budesonide.
`Conversely, induction of CYP3A4 can result in the lowering of budesonide plasma levels.
`Oral contraceptives containing ethinyl estradiol, which are also metabolized by CYP3A4, do
`not affect the pharmacokinetics of budesonide. Budesonide does not affect the plasma levels
`of oral contraceptives (ie. ethinyl estradlol) [see Drug Interactions (7)).
`Since the dissolution of the coating of ENTOCORT EC is pH dependent (dissolves at pH
`greater than 5.5), the release properties and uptake of the compound may be altered after
`treatment with drugs that change the gastrointestinal pH. However, the gastric acid inhibitory
`drug omeprazoie. 20 mg once daily does not affect the absorption or pharmacokinetics of
`ENTOCORT EC. When an uncoated oral formulation of budesonide is co-administered with a
`daily dose of cimetidine 1 g, a slight increase in the budesonide peak plasma concentration
`and rate of absorption occurs, resulting in significant cortisol suppression.
`Food EiIects
`A mean delay in lime to peak concentration of 2.5 hours is observed with the intake of a high
`fat meal, with no significant differences in AUG,
`13
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutogenesis, Impairment of Fertility
`Carcinogenicity studies with budesonide were conducted in rats and mice. in a two-year study
`in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence
`of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum
`recommended human dose on a body surface area basis). in addition, there were increased
`incidences of primary hepatocellular tumors in male rats at 25 meg/kg (approximately
`0.023 times the maximum recommended human dose on a body surface area basis)
`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 dose on a body surface area
`basis). in an additional hvoyear study in male Sprague-Dawley rats. budesonide caused no
`gliomas at an oral dose of 50 meg/kg (approximately 0.05 times the maximum recommended
`human dose on a body surface area basis). However,
`it caused a statistically significant
`increase in the incidence of hepatocellular
`tumors at an oral dose of 50 mag/kg
`(approximately 005 times the maximum recommended human dose on a body surface area
`basis). The concurrent reference corticosteroids (prednisolone and triamcinolone acetonide)
`showed similar findings. in a 91 week study in mice, budesonide caused no treatment-related
`carcinogenicity at oral doses up to 200 meg/kg (approximately 0.1 times the maximum
`recommended human dose on a body surface area basis).
`Budesonide was not genotoxic in the Ames test, the mouse lymphoma cell forward gene
`mutation (TK‘I') test, the human lymphocyte chromosome aberration test, the Drosaphi/a
`melanogasiersex—linked recessive lethality test. the rat hepatocyte U03 test and the mouse
`micronucleus test.
`In rats. budesonide had no effect on fertility at subcutaneous doses up to 80 meg/kg
`(approximately 0.07 times the maximum recommended human dose on a body surface area
`basis). However, it caused a decrease in prenatal viability and viability in pups at birth and
`during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses
`of 20 rncg/kg (approximately 0.02 times the maximum recommended human dose on a body
`surface area basis) and above. No such effects were noted at 5 mcgikg (approximately
`0.005 times the maximum recommended human dose on a body surface area basis).
`14
`CLINICAL STUDIES
`The safety and efficacy of ENTOCORT E0 were evaluated in 994 patients with mild to moderate
`active Crohn‘s disease of the ileum and/or ascending colon in 5 randomized and double-blind
`
`EprmerIQS otbudesonida
`‘
`0
`Budesonide is a white to offvwhite, tasteless. odorless powder that is practically insoluble in
`water and heptane, sparingly soluble in ethanol, and freely soluble in chloroform. its partition
`coefficient betwaen octancl and water at pH 5 is 1.6 x 103 ionic strength 0.01.
`Each capsule for oral administration contains 3 mg of micronized budesonide with the
`following inactive
`ingredients:
`ethylcellulose,
`acetyltributyl
`citrate. methacrylic
`acid
`copolymertype C, triethyl citrate, antitoam M, polysorbate 80, talc, and sugarspheres. The
`capsule shells have the following inactive ingredients: gelatin,
`iron oxide, and titanium
`dioxide
`12
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`Budesonide has a high topical glucocorticosteroid (GCS) activity and a substantial first pass
`elimination The formulation contains granules which are coated to protect dissolution in
`gastric juice, but which dissolve at pH greater than 5.5, is, normally when the granules reach
`the duodenum. Thereafter, a matrix of ethylcellulose with budesonide controls the release of
`the drug into the intestinal lumen in a time-dependent manner.
`12.2 Pharmacodynamics
`Budesonide has a high glucocorticoid effect and a weak mineralocorticoid effect. and the
`affinity of budesonide to 008 receptors, which reflects the intrinsic potency of the drug, is
`about ZOO-fold that of cortisol and 15-fold that of prednisolone.
`'
`Treatment with systemically active (305 is associated with a suppression of endogenous
`cortisol concentrations and an impairment of the hypothalamuspituitaryadrenal (HPA) axis
`function. Markers, indirect and direct, of this are cortisol
`levels in plasma or urine and
`response to ACTH stimulation
`Plasma cortisol suppression was compared following five days’ administration of ENTOCORT
`EC capsules and prednisolone in a crossover study in healthy volunteers. The mean decrease
`in the integrated 0-24 hour plasma cortisol concentration was greater
`(78%) with
`prednisolone 20 mg per day compared to 45% with ENTOCORT EC 9 mg per day.
`12.3 Pharmacokinetics
`Absorption
`The absorption of ENTOCORT EC seems to be complete, although CW and Tm are variable.
`Time to peak concentration varies in individual patients between 30 and 600 minutes.
`Following oral administration of 9 mg of budesonide in healthy subjects, a peak plasma
`concentration of approximately 5 nmol/L is observed and the area under the plasma concen-
`tration time curve is approximately 30 nmol'hr/L. The systemic availability after a single dose
`is higher in patients with Crohn's disease compared to healthy volunteers, (21% vs 9%) but
`approaches that in healthy volunteers after repeated dosing.
`'
`Distribution
`The mean volume of distribution (V55) of budesonide varies between 2.2 and 3.9 ng in
`healthy subieots and in patients. Plasma protein binding is estimated to be 85 to 90% in
`the concentration range 1 t