`
`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`Approval Package for:
`
`
`
`APPLICATION NUMBER:
`ANDA 200744
`
`Tacrolimus Ointment 0.03%, 0.1%
`
`Fougera Pharmaceuticals Inc
`
`Name:
`
`
`
`
`
`Sponsor:
`
`September 9, 2014
`Approval Date:
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`APPLICATION NUMBER:
`ANDA200744Orig1s000
`CONTENTS
`
`Reviews / Information Included in this Review
`
`
`
`Approval Letter
`Other Action Letter (s)
`
`Labeling
`Labeling Review(s)
`Medical Review(s)
`Chemistry Review(s)
`Pharm/Tox Review
`Statistical Review(s)
`Microbiology Review(s)
`Bioequivalence Review(s)
`Other Review(s)
`Administrative & Correspondence Documents
`
`
`
`
`
`
`X
`
`
`X
`X
`
`X
`
` X
`
`X
`X
`X
`
`
`

`

`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`APPLICATION NUMBER:
`ANDA 200744Orig1s000
`
`
`
`
`
`
`APPROVAL LETTER
`
`
`

`

`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`ANDA 200744
`
`
`
` Food and Drug Administration
` Silver Spring, MD 20993
`
`ANDA APPROVAL
`
`Fougera Pharmaceuticals Inc.
`Attention: Amy M. Byrom
` Director, Regulatory Affairs
`60 Baylis Road, P.O. Box 2006
`Melville, NY 11747
`
`Dear Madam:
`
`This is in reference to your abbreviated new drug application (ANDA) dated April 8, 2010,
`submitted pursuant to section 505(j) of the Federal Food, Drug, and Cosmetic Act (the Act), for
`Tacrolimus Ointment 0.03% and 0.1%.
`
`We acknowledge receipt of your amendments dated September 9, October 15, and
`December 15, 2010; February 17, March 4, August 9, September 16, and December 23, 2011;
`February 24, February 29, March 15, May 4, June 11, July 24, July 25, and December 12, 2012;
`and August 23, November 20, December 6, December 12, and April 24, 2014.
`
`We have completed the review of this ANDA and have concluded that adequate information has
`been presented to demonstrate that the drug is safe and effective for use as recommended in the
`submitted labeling. Accordingly the ANDA is approved, effective on the date of this letter. The
`Division of Bioequivalence has determined your Tacrolimus Ointment 0.03% and 0.1%, to be
`bioequivalent and, therefore, therapeutically equivalent to the reference listed drug product
`(RLD), Protopic Ointment, 0.03% and 0.1%, respectively, of Astellas Pharma US, Inc.
`
`Under section 506A of the Act, certain changes in the conditions described in this ANDA require
`an approved supplemental application before the change may be made.
`
`Please note that if FDA requires a Risk Evaluation & Mitigation Strategy (REMS) for a listed
`drug, an ANDA citing that listed drug also will be required to have a REMS. See section 505-
`1(i) of the Act.
`
`Postmarketing reporting requirements for this ANDA are set forth in 21 CFR 314.80-81 and
`314.98. The Office of Generic Drugs should be advised of any change in the marketing status of
`this drug.
`
`Promotional materials may be submitted to FDA for comment prior to publication or
`dissemination. Please note that these submissions are voluntary. If you desire comments on
`proposed launch promotional materials with respect to compliance with applicable regulatory
`
`Reference ID: 3624006
`
`

`

`requirements, we recommend you submit, in draft or mock-up form, two copies of both the
`promotional materials and package insert directly to:
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`5901-B Ammendale Road
`Beltsville, MD 20705
`
`We call your attention to 21 CFR 314.81(b)(3) which requires that all promotional materials be
`submitted to the Office of Prescription Drug Promotion with a completed Form FDA 2253 at the
`time of their initial use.
`
`The Generic Drug User Fee Amendments of 2012 (GDUFA) (Public Law 112-144, Title III)
`established certain provisions with respect to self-identification of facilities and payment of
`annual facility fees. Your ANDA identifies at least one facility that is subject to the self
`identification requirement and payment of an annual facility fee. Self-identification must occur
`by June 1 of each year for the next fiscal year. Facility fees must be paid each year by the date
`specified in the Federal Register notice announcing facility fee amounts. All finished dosage
`forms (FDFs) or active pharmaceutical ingredients (APIs) manufactured in a facility that has not
`met its obligations to self-identify or to pay fees when they are due will be deemed misbranded.
`This means that it will be a violation of federal law to ship these products in interstate commerce
`or to import them into the United States. Such violations can result in prosecution of those
`responsible, injunctions, or seizures of misbranded products. Products misbranded because of
`failure to self-identify or pay facility fees are subject to being denied entry into the United
`States.
`
`As soon as possible, but no later than 14 days from the date of this letter, submit, using the FDA
`automated drug registration and listing system (eLIST), the content of labeling [21 CFR
`314.50(l)] in structured product labeling (SPL) format, as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm, that is
`identical in content to the approved labeling (including the package insert, and any patient
`package insert and/or Medication Guide that may be required). Information on submitting SPL
`files using eLIST may be found in the guidance for industry titled “SPL Standard for Content of
`Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf. The SPL will be accessible via publicly available labeling repositories.
`
`
`Sincerely yours,
`
`{See appended electronic signature page}
`
`CAPT Jason J.Y. Woo, M.D., M.P.H.
`Acting Director, Office of Regulatory Operations
`Office of Generic Drugs
`Center for Drug Evaluation and Research
`
`Reference ID: 3624006
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ROBERT L WEST
`09/09/2014
`Associate Director for Review Quality, for
`Jason Woo, M.D., M.P.H.
`
`Reference ID: 3624006
`
`

`

`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`APPLICATION NUMBER:
`ANDA 200744Orig1s000
`
`
`
`
`
`
`LABELING
`
`

`

`
`
`NDC 0168-0416-30
`
`fougera”®
`
`TACROLIMUS
`OINTMENT 0.1%
`ATTENTION: DISPENSE WITH
`MEDICATION GUIDE
`
`Dosage: Apply twice daily.
`See package insert for dosage information.
`Storage:
`Store at room temperature 25°C
`excursions permitted to 15°-30°C (59°-86°F).
`
`(77°F);
`
`TO OPEN:Use cap to puncture seal.
`IMPORTANT: Donotuse if seal has been
`unctured oris notvisible.
`ee crimp of tube for Lot No. and Expiration Date.
`E. FOUGERA & CO.
`A division of Fougera Pharmaceuticals Inc.
`Melville, New York 11747
`
`
`
`
`
`
`
`Reference ID: 3424221
`
`

`

`
`
`Aani) 1
`
`
`
`
`TACROLIMUS
`OINTMENT 0.1%
`ATTENTION: DISPENSE WITH
`MEDICATION GUIDE
`
`NDC 0168-0416-60 fougera®
`
`
`
`Dosage:Apply twice daily.
`See package insert for dosageinformation.
`Storage: Store at room temperature 25°C (77°F);
`excursions permitted to 15°-30°C (59°-86°F).
`
`TO OPEN: Use cap to puncture seal.
`IMPORTANT:Donotuse if seal has been
`punctured oris notvisible.
`Seecrimp of tube for Lot No. and Expiration Date.
`
`E. FOUGERA & CO.
`A division of Fougera PharmaceuticalsInc.
`Melville, New York 11747
`
`Reference ID: 3424221
`
`

`

`OuUgeTa °
`
`TACROLIMUS
`OINTMENT 0.1%
`
`ATTENTION: DISPENSE WITH
`MEDICATION GUIDE
`
` NDC 0168-0416-99
`
`TO OPEN: Usecap to puncture seal.
`IMPORTANT:Do notuseif seal has been
`puncturedoris notvisible.
`See crimp of tube for Lot No. and Expiration Date.
`
`Dosage: Apply twice daily.
`See packageinsert for dosage information.
`Storage: Store at room temperature 25°C (77°F);
`excursions permitted to 15°-30°C (59°-86°F).
`
`AchicionofFougora Pharmaceuticals Inc.
`
`Melville, New York 11747
`
`3
`
`|ITIMat Mn
`
`168-0416-9
`
`1
`
`Reference ID: 3424221
`
`

`

`NDC 0168-0417-30
`
`fougera®
`
`Melville, New York 11747
`
`TACROLIMUS
`OINTMENT 0.03%
`ATTENTION: DISPENSE WITH
`MEDICATION GUIDE
`
`Dosage: Apply twice daily.
`See package insert for dosageinformation.
`ge:
`Stora’
`re at room temperature 25°Ci °F);
`excursions permitted to 15°-30°C (59°-86°F).
`TO OPEN:Use cap to puncture seal.
`IMPORTANT: Donotuse if seal has been
`ured oris notvisible.
`ee crimp of tube for Lot No. and Expiration Date.
`E. FOUGERA & CO.
`A division of Fougera Pharmaceuticals Inc.
`
`
`
`
`
`
`
`Reference ID: 3424221
`
`

`

`iWa |
`
`168-0417-6
`
`NDC 0168-041 7-60
`
`fOUGETG ®
`
`
`
`TACROLIMUS
`OINTMENT0.03%
`ATTENTION: DISPENSE WITH
`MEDICATION GUIDE
`
`Dosage:Apply twice daily.
`See package insert for dosageinformation.
`Storage: Store at room temperature 25°C (77°F);
`excursions permitted to 15°-30°C (59°-86°F).
`
`TO OPEN: Use cap to puncture seal.
`IMPORTANT:Do notuse if seal has been
`punctured oris notvisible.
`Seecrimp of tube for Lot No. and Expiration Date.
`
`E. FOUGERA & CO.
`A division of Fougera PharmaceuticalsInc.
`Melville, New York 11747
`
`Reference ID: 3424221
`
`

`

`fougera °
`
`TACROLIMUS
`OINTMENT 0.03%
`
`ATTENTION: DISPENSE WITH
`MEDICATION GUIDE
`
`Dosage: Apply twice daily.
`See packageinsert for dosage information.
`Storage: Store at room temperature 25°C (77°F);
`excursionspermitted to 15°-30°C (59°-86°F).
`
` NDC 0168-0417-99
`
`TO OPEN: Use capto puncture seal.
`IMPORTANT: Do notuseif seal has been
`puncturedoris not visible.
`See crimp of tube for Lot No. and Expiration Date.
`
`E. FOUGERA & CO.
`
`Adivision of Fougera PharmaceuticalsInc.
`
`Melville, New York 11747
`
`|eswant|
`
`0168-0417-998
`
`3
`
`Reference ID: 3424221
`
`

`

`|
`
`168-0416-
`
`NDC 0168-0416-30
`
`
`OINTMENT0.1%
`
`
`TACROLIMUS
`
`fougera °
`NDC0168-0416-30
`
`Ougera”
`
`
`TACROLIMUS
`OINTMENT 0.1%
`
`
`
` Dosage: Apply twicedaily. See package insert for dosage information.
`Storage: Store at room temperature 25°C (77°F);
`excursions permitted to 15°-30°C (59°-86°F).
`IMPORTANT:The opening ofthis productis covered by a metal
`
`
`tamperresistantseal. If this seal has been puncturedor is
`
`not visible, do not use and return productto place of purchase.
`
`E. FOUGERA& CO.
`
`A division of Fougera Pharmaceuticals Inc., Melville, New York 11747
`
`NDC 0168-0416-30
`
`fougerTG °
`
`
`
`
`
`
`
`TACROLIMUS
`OINTMENT 0.1%
`
`Reference ID: 3424221
`
`

`

`
` 168-0416-6
`
`
`OINTMENT0.1%
`TACROLIMUS
`NDC0168-0416-60
`Ougera°
`
` 1
`
`
`
`
`NDC 0168-0416-60
`fOuUgETG ”®
`
`PA only
`
`TACROLIMUS
`OINTMENT 0.1%
`
`
` Dosage: Apply twice daily. See packageinsert for dosage information.
`
`
`
`Storage: Store at room temperature 25°C (77°F);
`excursions permitted to 15°-30°C (59°-86°F).
`
`
`IMPORTANT:Theopeningof this product is covered by a metal
`tamper-resistant seal. If this seal has been punctured or is not
`visible, do not use and return productto place of purchase.
`
`E. FOUGERA & CO.
`
`
` A division of Fougera Pharmaceuticals Inc., Melville, New York 11747
`
`
`NDC 0168-0416-60
`TR only
`
`fOuUgEeTG*
`
`
`
`
`TACROLIMUS
`OINTMENT 0.1%
`
`Reference ID: 3424221
`
`

`

`168-0416-9
`
`
`
`
`
`NDC 0168-0416-99
`DS
`
`MS
`
`fougera”
`: i = :
`TACROLIMUS
`8
`= f
`
`OINTMENT 0.1%
`8 3 <I
`
`
`
`
` Dosage: Apply twice daily. See package insert for dosage information.
`Storage: Store at room temperature 25°C (77°F);
`
`
`excursions permitted to 15°-30°C (59°-86°F).
`
`
`IMPORTANT: The openingofthis product is covered by a metal
`tamper-resistant seal. If this seal has been punctured oris not
`
`visible, do not use and return productto place of purchase.
`
`E. FOUGERA & CO.
`
`A division of Fougera Pharmaceuticals Inc., Melville, New York 11747
`
`
` NDC 0168-0416-99 fougera”®
`
`
`TACROLIMUS
`
`OINTMENT 0.1%
`
`Reference ID: 3424221
`
`

`

`NDC 0168-0417-30
`
`fougera®
`
`TACROLIMUS
`OINTMENT 0.03%
`
`168-0417-
`
`
`OPESamenKye
`
`TACROLIMUS
`
`NDC0168-0417-30
`
`
`OugerG*
`
`
`
`
` Dosage:Apply twice daily. See package insert for dosage information.
`Storage: Store at room temperature 25°C (77°F);
`excursions permitted to 15°-30°C (59°-86°F).
`IMPORTANT:The opening ofthis product is covered by a metal
`tamper-resistant seal. If this seal has been puncturedoris
`
`notvisible, do not use and return product to place of purchase.
`E. FOUGERA & CO.
`A division of Fougera Pharmaceuticals Inc., Melville, New York 11747
`
`
`
`TACROLIMUS
`OINTMENT 0.03%
`
`NDC 0168-0417-30
`
`fougera °
`
`Reference ID: 3424221
`
`

`

`
` 168-0417-6
`
`
`OINTMENT0.03%
`TACROLIMUS
`NDC0168-0417-60
`Ougera°
`
` 8
`
`
`
`
`NDC 0168-0417-60
`fOuUgETG ”®
`
`PA only
`
`TACROLIMUS
`OINTMENT 0.03%
`
`
` Dosage: Apply twice daily. See packageinsert for dosage information.
`
`
`
`Storage: Store at room temperature 25°C (77°F);
`excursions permitted to 15°-30°C (59°-86°F).
`
`
`IMPORTANT:Theopeningof this product is covered by a metal
`tamper-resistant seal. If this seal has been punctured or is not
`visible, do not use and return productto place of purchase.
`
`E. FOUGERA & CO.
`
`
` A division of Fougera Pharmaceuticals Inc., Melville, New York 11747
`
`
`NDC 0168-0417-60
`TR only
`
`fOuUgEeTG*
`
`
`
`
`TACROLIMUS
`OINTMENT 0.03%
`
`Reference ID: 3424221
`
`

`

` 168 -0417-998
`
`
`NDC 0168-0417-99
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`only
`
`
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`TACROLIMUS
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`
`OINTMENT0.03%
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`
`
`
` Dosage: Apply twice daily. See packageinsert for dosage information.
`Storage: Store at room temperature 25°C (77°F);
`
`
`excursions permitted to 15°-30°C (59°-86°F).
`
`
`IMPORTANT: The openingofthis productis covered by a metal
`tamper-resistant seal. If this seal has been punctured oris not
`
`visible, do not use and return product to place of purchase.
`
`
`E. FOUGERA & CO.
`
`A division of Fougera Pharmaceuticals Inc., Melville, New York 11747
`
`
` NDC 0168-0417-99 fOugeTG ”
`
`
`
`
`TACROLIMUS
`OINTMENT 0.03%
`
`Reference ID: 3424221
`
`

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`oneditrepaterAlapelpatecese of improvementin the percent body surface area affected in adult and
`
`Figure 1 - Adult Patients Body Surface Area Over Time
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`TACROLIMUS OINTMENT 0.03%
`TACROLIMUS OINTMENT 0.1%
`FOR DERMATOLOGIC USE ONLY
`NOT FOR OPHTHALMIC USE
`Prescribing
`Information
`.
`,
`she apes
`See boxed WARNINGSconcerning long-term safety of topical calcineurin inhibitors
`DESCRIPTION
`Tacrolimus ointment contains tacrolimus, a macrolide immunosuppressantproduced b Streptomyces tsukubaensis.
`tisfrtopical dermatologic use only, Chemical, tacrolimus is designated as [393A
`11S“.3S '48")],4S",5R",88",
`Undo 12hton Shancetnessinnareeanayrotors
`ihydroxy-3-[2-(4-hydroxy-3-methoxycyclo
`-1-methy
`nyl]-14,
`imethoxy-4,10,12,18-tetramethyl-8-(2-
`propen | "18,19-epoxy-ae-p rido[2,1-c][1,4Joxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, monohydrate.
`t has
`the following structural
`formula:
`
`hyo
`
`H
`
`4
`
`i
`
`The following two graphs depict the time course of improvementin erythemain adult andin pediatric patients as a
`result of treatment.
`=
`A
`Figure 3 - Adult Patients Mean Erythema Over Time
`:
`
`Tacrolimus has an empirical formula of C44HggNO49*H90 and a formula weight of 822.03.
`Each gram zibiartirafiacy ane ae is either 0.03% or 0.1% of tacrolimus in a base of mineral oil, paraffin,
`ropylene carbonate, white petrolatum and
`white wax.
`LINICAL PHARMACOLOG
`Mechanismof Action
`The mechanism ofaction oftacrolimusin atopic dermatitis is not known. While the following have been observed,the
`clinical agelins of these observationsin atopic dermatitis is not known. It has been demonstrated that tacrolimus
`inhibits T-lymphocyte activation byfirst binding
`to an intracellular protein, FKBP-12.
`A complex of tacrolimus-FKBP-12,calcium, calmodulin, andcalcineurin is then formed and the phosphatase activity
`of calcineurin is inhibited. This effect has been shownto alate the dephosphorylation and translocation of nuclear
`factorof activated T-cells (NF-AT), a nuclear ome oughtto initiate
`gene transcription for the formation of
`lymphokines (such as interleukin-2, gamma interferon). Tacrolimusalsoinhibits the transcription for genes which
`encode IL-3,IL-4, IL-5, GM-CSF, and
`TNF-a,all of which are involved in the early
`stages of T-cell activation.
`Additionally, tacrolimus has been showntoinhibit the release of pre-formed mediators from skin mastcells and
`basophils, and to downregulate the expression of FceRI on Langerhanscells.
`PHARMACOKINETICS
`s&s
`¢
`®
`Absorption
`Time froota}
`The pooled results from three pharmacokinetic studies in 88 adult atopic dermatitispatients indicate that tacrolimusis
`son
`Hala! absorbedafterthe topicalapplication of tacrolimus ointment. Peak tacrolimus blood concentrations ranged
`from undetectable to 20 ng/mLafter single or multiple doses of 0.03% and 0.1%tacrolimus ointment, with 85%
`Figure 4 - Pediatric Patients Mean Erythema Over Time
`(75/88) of the patients having peak blood concentrations less than 2 ng/mL.In generalas treatment continued,
`stemic exposure declined as the skin returned to normal. In clinical studies with periodic blood sampling, a similar
`
`istribution of tacrolimus blood levels wasalso observed in adult patients, with90%(1253/1391) of patients having a '
`blood concentrationlessthan 2 ng/mL.
`:
`.
`:
`‘
`ew gy
`:
`The absolute bioavailability of tacrolimus from tacrolimus ointmentin atopic dermatitis piers is approximately 0.5%.
`is
`In adults with an average of 53% BSA treated, exposure (AUC)of tacrolimusfrom tacrolimus ointmentis
`approximately 30-fold less than that seen with oral immunosuppressive dosesin kidney andliver transplant patients.
`5 1
`ean peaktacrolimus blood concentrations following oral administration (0.3 mg/kg/day) in adult kidney transplant
`<
`(n=26)
`andlivertransplant (n=17) patients are 24.2+15.8 ng/mL and 68.5+30.0 ng/mL,respectively. The lowest
`iu
`tacrolimus blood level at which systemic effects (eg. immunosuppression) can be observed is not known. Systemic
`levels of tacrolimus have also been measured in pediatric patients (see Special Populations: Pediatrics).
`Distribution
`ry
`The plasma protein binding of tacrolimus is approximately 99% and is independent of concentration over a range of
`
`albumin and alpha-1-acid glycoprotein, and hasa high levelof association5-50 ng/mL.Tacrolimusis bound mainly to gw=O= an
`
`with erythrocytes. The distribution of tacrolimus between whole blood and plasma dependsonseveral factors, such as
`hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration. In a
`Thetime course of improvementin the remaining secondary efficacy variables wassimilar to that of erythema,with
`US study,the ratio of whole blood concentration toplasma concentration averaged 35 (range 12 to 67). There was no
`improvementin lichenification slightly slower.
`evidence based on blood concentrationsthat tacrolimus accumulates systemically uponintermittent topical oe
`for periods of up to 1 year. As with othertopical calcineurininhibitors,it is not known whethertacrolimusis distributed
`INDICATIONS AND USAGE
`into the
`lymphatic system.
`aa ica ia and eles for adults, and o~ 0.03% for omison 2 to 15 years,is ace as
`Metabolism
`second-line therapy for the
`short-term and non-continuous chronic treatment of moderate to severe atopic dermatitis
`Tacrolimusis extensively metabolized by the mixed-function oxidase system,primarily the cytochrome P-450 system
`in non-immunocompromised adults and children who havefailed to respond adequately to other topicalprescription
`corraN A metabolic pathway leading
`treatments for atopic dermatitis, orwhen those treatments are not advisable.
`to the formation of 8 possible metabolites has been proposed. Demethylation
`and hydroxylation were identived as
`the primary mechanismsof biotransformation in vitro. The major metabolite
`Tacrolimus ointmentis not indicated for children youngerthan 2 years of age (see boxed WARNING, WARNINGS
`identified in incubations with human liver microsomesis 13-demethyltacrolimus.In in vitro studies, a 31-demethyl
`and PRECAUTIONS:Pediatric Use).
`— has been reported to have the sameactivity as tacrolimus.
`CONTRAINDICATIONS
`cretion
`=
`:
`7
`ee
`&
`=
`‘
`oye
`a
`;
`The meanclearancefollowing IV administration of tacrolimus is 0.040, 0.083 and 0.053 L/hr/kg in healthy volunteers,
`favouroewereeoe PS ERROR OFFeRNS TN Ye
`adult kidney transplant patients and adult liver transplantpatients, respectively. In man,less than 1% of
`the dose
`WARNINGS
`.
`administered is excreted unchangedin urine. In a mass balance study of lV administered radiolabeled tacrolimusto
`6 healthy volunteers, the mean recovery of radiolabel was 77.8 + 12.7%. Fecalelimination accounted for 92.4 + 1.0%
`WARNING
`.
`ee
`serge
`.
`and im elimination half-lifeond on ate .As“ 1sPci amet= oeS 11.6 hose based on
`Long-term Safety of Topical Calcineurin Inhibitors Has Not Been Established
`tacrolimus concentrations.
`The mean clearance of
`radio
`was
`0.029
`+ 0:
`t/kg
`and
`clearance of
`tacrolimus
`i
`i
`i
`i
`‘1
`was0.029 + 0.009 L/r/kg, When administered PO,the mean recovery ofthe radiolabel was 94.9 +30.7%, Fecal
`beenperkedinpatinatectedwihtopcalcabineuri nbiow,ncudkyimioaeesokinent
`sermon creastiny for =. at seycca een *2.3 eh meee amination —_
`Therefore:
`,
`
`
`
`
`10.5ased on radioactivity was31.9 + hours whereasitwas 48.4 + 12.3 hours based ontacrolimus concentrations. * Conti long-te f topical calcineurin inhibitors, including tacroli intment. i
`
`
`
`
`
`
`
`
`
`
`
`
`The mean clearanceof radiolabel was 0.226+ 0.116 L/hr/kg andclearance oftacrolimus 0.172+ 0.088 L/hr/kg.
`shouldbewer Sdandapplication lhnined6arans ofinvolvernantwithatopicdermathi. ee
`oeisopulations
`* Tacrolimus ointmentis notindicated for use in children less than 2 years of age. Only 0.03%tacrolimus
`
`j
`
`Ss
`5
`“
`it
`
`° °
`
`2
`
`4
`
`#8
`
`e
`
`ointmentis indicated for use in children 2-15 years of age. In a pharmacokinetic study of 14 pediatric atopic dermatitisoe. betweenthe agesof 2-5ons: peak blood
`
`Prolonged systemic useofcalcineurin inhibitors for sustained immunosuppressionin animalstudies and transplant
`concentrations of tacrolimus ranged from undetectable to 14.8 ng/mLafter single or multiple doses of 0.03%
`patients following systemic administration has been associated with anincreased risk of infections, lymphomas, and
`tacrolimusointment, with 86%(12/14)of patients having peakbloodconcentrations below 2 ng/mL throughoutthe
`skin malignancies. ties risks are associated with the intensity and duration of immunosuppression.
`study. The highest
`peak concentration was observed in one patient with 82% BSA involvementon day 1 following
`Based onthe information above and the mechanismofaction,there is a concern aboutpotentialrisk with the use of
`application of 0.03% tacrolimus ointment. The peak concentrations for this subject were14.8 ng/mL on day 1 and 4.1
`topicalcalcineurin inhibitors,including tacrolimus ointment. While a causalrelationship has not been established,rare
`ng/mL on day 14. Mean peak tacrolimus blood concentrationsfollowingoral administration in pediatric liver transplant
`cases of skin malignancy and lymphoma havebeen reported in patients treated with topicalcalcineurin inhibitors,
`atients (n = 9) were 48.4+ 27.9 ng/mL. In a similar slabfociate with 61 enrolled pediatric patients (ages
`includingtacrolimus ointment. Therefore:
`-12 years) with atopic dermatitis,
`peak tacrolimus
`blood concentrations ranged from undetectable to 5.3 ng/mL
`* Tacrolimus ointment should not be used in immunocompromised adults and children.
`after single or multiple doses of 0.1% tacrolimus ointment, with 91% (52/57)of evaluable patients having peak blood
`* If signs and symptomsofatopic dermatitis do not improve within 6 weeks,
`patients should be re-examined by
`concentrationsbelow 2 ng/mL throughout the study period. When detected, systemic exposure generally
`declined as
`their healthcare provider and their diagnosis be confirmed (see PRECAUTIONS: General).
`treatment continued.In clinical studies with periodic
`blood sampling,a similar distribution of tacrolimus blood levels
`* The safety
`of tacrolimus ointmenthas not been established beyond oneyear of non-continuoususe.
`was also observed, with 98%(509/522)of pediatric patients having a blood concentration below 2 ng/mL.
`(See CLINICAL PHARMACOLOGY,boxed WARNINGS, INDICATIONS AND
`USAGE, and DOSAGE AND
`Renal Insufficien
`ss
`Ss
`3
`sin
`:
`ADMINISTRATION)
`Theeffect of renal insufficiency on the pharmacokineticsof topically administered tacrolimushasnot been evaluated.
`PRECAUTIONS
`:
`The mean clearance of IV administered tacrolimusin patients with renal dysfunction was similar to that of normal
`General
`volunteers. On the basis of this information dose-adjustmentis not expected to be needed.
`
`HepaticInsufficiency : es ; sy ¥ The use of tacrolimus ointment should be avoided on pre-malignant and malignant skin conditions. Some malignant
`
`
`
`
`
`
`Theeffect of hepatic insufficiency on the pharmacokinetics of topically administered tacrolimus has not been evaluated
`skin conditions, such as cutaneousT-cell lymphoma (CTCL), may mimic atopic dermatitis.
`eee ato is not expectedto be needed.
`Theuse oftacrolimus ointmentis not recommended in patients
`having skin conditions with a skin barrier defect where
`thereis the potential for increased systemic absorptionof tacrolimus,including but notlimited to, Netherton's
`Three randomized, double-blind, vehicle-controlled, multi-center, phase 3 studies were conducted to evaluate
`syndrome, lamellarichthyosis, generalized erythrodermaor cutaneous Graft Versus Host Disease. Oralapplication is
`included351 patients2-15ane ofage,andthe othertwo (Adult) studies includedatotalof632 patients 1359years
`The use oftacrolimus ointmentmayeee local symptomssuchasskin burning (burnin aaria. stinging,
`0 not recommended. Post-marketing cases of increased tacrolimusblood level have been reported in these conditions.
`tacrolimusointment for the treatmentof patients with moderate to severe atopic dermatitis. One (Pediatric) study
`of oeay Nea (5 a sspanens ves.Aatfen - Peerene ee oo o the ee soreness) orpruritus. Localized symptoms are most commonduringthefirst few days of tacrolimus ointment
`
`
`
`
`
`severe disease and Over80%of patientsthe mean body surface area (BSA) affected was 46%. ha oe rmatitis application andtypically improveasthe lesions of atopic dermatitis resolve. With tacrolimus ointment 0.1%, 90%of
`
`0,
`affecting the face and/or neck region.In these studies,patients applied either tacrolimusointment0.03%,
`tacrolimus
`the skin burning events had a duration between 2 minutes and 3 hours (median 15 minutes). 90%ofthe pruritus
`ointment 0.1%, or vehicle ointment twice daily to 10% - 100% of
`their BSA for upto 12 weeks.
`:
`events had a duration between 3 minutes and 10 hours (median 20 minutes). (see ADVERS' REACTIONS),
`In the pediatric study, a significantly greater (p < 0.001) percentage of patients achieved atleast 90% improvement
`Bacterial and Viral Skin Infections
`based on the physician's global evaluationof clinical response(the pecan primary efficacy endpoint) in the
`Before commencing treatmentwith tacrolimus ointment, cutaneousbacterialorviral infectionsat treatment sites should
`tacrolimus ointment 0.03% peesteatcee compared to the vehicle
`treatment group, butthere was insufficient
`be resolved. Studies have notevaluated the safety andefficacy of tacrolimus ointmentin the treatment of clinically infected
`are that tacrolimus ointment 0.1% provided moreefficacy than tacrolimus ointment 0.03%.
`atopic dermatitis. While patients with atopic dermatitis are predisposed to superficial skin infections including eczema
`n both adult studies, asignificantly greater {p < 0.001) percentage of patients achieved at least 90%improvement
`herpeticum
`(Kaposi's varicelliform eruption), treatmentwith tacrolimus ointment may be independently associated with an
`based on the physician's global evaluation of clinical responsein the tacrolimus ointment 0.03%and tacrolimus
`increased EAesdanazostervirustector (chicken pox or shingles), herpes simplexvirus infection, oreczema herpeticum.
`ointment 0.1%treatment groups compared to the vehicle treatment group. There wasevidence that tacrolimus
`Patients with Lymphadenopathy
`:
`3
`,
`ointment 0.1% may provide more efficacy thantacrolimus ointment
`0.03%.Thedifferencein efficacy between
`In clinical studies, 112/13494
`(0.8%) cases of lymphadenopathy were reported and were usually related to infections
`tacrolimus ointment 0.1% and 0.03% wasparticularly evident in adult patients with severe disease at baseline, adults
`(particularly of the skin) and noted to resolve upon appropriate antibiotic therapy. Of these 112 cases, the majority had
`with extensive BSA involvement, and black adults. Response rates for each treatment group are shown below by age
`either a clearetiology or were knownto resolve. Transplantpatients receiving immunosuppressive regimens(e.9.,
`groups. Because the two adult studies were identically designed, the results from these studies were pooled in this table.
`systemic tacrolimus) are at increasedrisk for developing
`lymphoma; therefore, patientswhoreceive tacrolimus ointment
`Global Improvementover Baseline at the End-Of-Treatmentin
`and who develop Dmephacenoesy shouldhavethe etiologyoftheir lymphadenopathyinvestigated.In the absence of a
`Three Phase 3 Studies
`clear etiology for
`the
`lymphadenopathy, orin the presenceof acute infectious mononucleosis,tacrolimus ointment should
`be discontinued. Patients who develop
`lymphadenopathy should be monitored to ensure that the lymphadenopathy resolves.
`Pediatric Study
`Adult Studies
`Sun Exposure
`(2-15 Years of Age)
`During the courseof treatment, patients should minimize or avoid naturalorartificial sunlight exposure, even while
`Tacrolimus
`Tacrolimus
`Vehicle
`Vehicle
`Tacrolimus
`tacrolimusis noton the skin. It is not known whether tacrolimus ointmentinterferes with skin response to ultraviolet damage.
`
`
`
`
`
`
`
`(%improvement) Ointment=|Ointment 0.03%|Ointment Ointment 0.03% |Ointment 0.1% Immunocompromised Patients . . / ; ;
`N=116
`N=117
`N=212
`N=211
`N= 209
`ie =ima efficacy of tacrolimus ointment in immunocompromisedpatients have not been studied.
`enal
`Insufficiency
`14
`3 fro
`14 (12%
`2 (1%)
`21 (10%
`20 (10%
`100%
`Rare post-marketing cases of acute renalfailure have been reported in patients treated with tacrolimus ointment.
`8
`(7%
`42 (36%
`i 58 (28%
`77 (37%
`290%
`65 (56%
`30
`275%
`Systemic absorption is morelikely to occur in patients with epidermalbarrier defects especially when tacrolimusis
`42
`85
`3%.
`31 (27%
`2 50%
`20%
`
`97 (46%130 (62%)
`117
`(56
`}
`applied to large body surface areas. Caution should also be exercised in patients predisposedto renal impairment.
`Information for Patientsoues on back page)
`See MEDICATION GUID!
`A statistically significant difference in the percentage of adult patients with > 90% improvementwas achieved by week
`atients using tacrolimus ointment should receive and understand the information in the Medication Guide.
`1 for those treatedwith tacrolimus ointment 0.1%, and by week 3 for thosetreated with tacrolimus ointment 0.03%.
`Please refer to the Medication Guide for providing instruction and information to the patient.
`Astatistically significant difference in the pacers ofpecan patients with > 90% improvement was achieved by
`week2 for those treated with tacrolimus ointment 0.03%.
`Whatis the most important information patients should know about tacrolimus ointment?
`The safety
`of using tacrolimus ointmentfor a long period of time is not known. A very small numberof people who
`In adult patients who had achieved > 90% improvementatthe end oftreatment, 35% of those treated with tacrolimus
`ointment 0.03%and 41% of those treated with tacrolimus ointment ooeoteeeet from this state of improvementat
`have used
`tacrolimus ointment have had cancer(for example, skin or lymphoma). However,a link with tacrolimus
`2 weeksafter end-of-treatment.In pediatric patients who had achieved >
`90% improvement, 54% of those treated with
`ointment has not been shown.
`tacrolimus ointment 0.03%regressed from this state of improvement at 2 weeksafter end-of-treatment. Because
`Becauseofthis concern,instruct patients:
`;
`.
`patients were notfollowed for longer than 2 weeks after end-of-treatment, it is not known how many additionalpatients
`+ Do not use tacrolimus