CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-023
`
`CLINICAL PHARMACOLOGY AND
`
`BIOPHARMACEUTICS REVIEW! S 2
`
`
`
`
`
`

`

`
`
`Clinical Pharmacology/Biopharmaceutics Review
`
`
`NDA:
`
`21-023
`
`SUBlVHSSION DATE: 2/25/99, 3/30/99
`
`PRODUCT: RestatisTM 0.05%
`
`(Cyclosporin Ophthalmic Emulsion)
`
`SPONSOR: Allergan, Inc.
`Irvine, CA.
`
`
`REVIEWER: Veneeta Tandon, PhD.
`
`Review ofa NDA
`
`1.
`
`Background
`
`CyCIOSpor-ine ophthalmic emulsion 0.05% is indicated for .WM
`memmmwmw ,. It
`
`acts as an immunomodulator and an anti-inflammatory agent. Cyclosporin helps in
`suppressing the immunekbased inflammation of the ocular surface, allowing for the
`secretion of more normal ocular surface supportive tears and a more stable tear film.
`Tepical use of cycl05porin exerts a local effect only, an action termed
`immunomodulatory, rather than systemic immonosuppresive effect. Although
`cyclosporin is not a classical anti-inflammatory agent and has not been demonstrated to
`inhibit cyclo—oxygenase, it does inhibit inflammation in other ways. Cyclosporine
`prevents the synthesis andfor secretion of several THl pro-inflammatory cytokines, and is
`also known to upregulate secretion of THZ-type anti—inflammatory cytokines.
`Additionally, cyclosporine has been shown to regulate immune-based inflammation
`within ocular surface tissues by inhibiting intercellular adhesion molecule—1
`
`(ICAM-l).
`
`Current treatment options for dry eye are palliative, and provide symptomatic relief only
`without addressing the underlying mechanisms Of the disease. Cyclosporine, as an
`immunomodulating agent, has been shown to break the cycle of the immune reactivity
`underlying the disease both in dry-eye dogs“2 and in dry-eye patients? Cyclosporine
`reduces lacrimal gland lymphocytic infiltrates and improves tear production in KCS dogs
`”'5 and in KCS patients with or without Sjogren’s syndrome “'5”. Power et al
`demonstrated that patients with secondary Sjiigren’s disease are undergoing continued
`
`1 Kaswan et al, Arch ophthalmol, 107:1210—1216, 1989
`2 Stem at al, Cornea, 17:584-589,1998
`a Power at al, Comea,12:507-Sl 1,1993
`4 Kaswan et a], Vet Clin North Am Small Anim prac, 20:583-6 13,1990
`5 Morgan et al, J Am Vet Assoc, 199:1043-1046, 1991
`6 Drosos el al, Ann Rheum Dis, 45:732-735,1986
`’ Laibovitz et al, Cornea, 12:315-323,1993
`
`
`
`

`

`
`
`immune reactivity, indicated by the presence of significantly more CD4 (T-helper) cells
`than age/sex-matched controls. Following treatment with topical cyclosporine, there was
`a significant reduction in the number of CD4 cells in both the conjunctival epithelium and
`substantia propria, indicating immunopathological improvement.
`
`Oral cyclosporin is available for the treatment of rheumatoid arthritis, psoriasis (2.5 to 5
`
`mg/kg/day-NEORAL®) and systemic prophylaxis of organ transplant rejection (7—9
`
`mg/kg/day-NEORAL®). SANDIMMUNE® is also used at higher doses, but has lower
`
`bioavailability as compared to NEORAL®. In contrast tOpical cyclosporin emulsion is to
`be used at the dose of 1 to 2 ugfkg/day.
`
`Dosage and Administration
`
`The recommended dosage is one drop { v-j of RESTASISTM (0.05%) instilled twice a
`day in each eye approximately 12 hours apart.
`Foreign marketing history
`Not yet marketed in any other country.
`
`II.
`
`Recommendation
`
`The cyclosporin concentrations were below the limit of quantitation in most samples.
`Only 9 samples out of 348 samples from the phase 2 and 3 studies had quantifiable
`concentrations, with a highest value of ‘4’“ ng/ml. All these samples were from
`patients receiving 0.1% cyclosriorin emulsion. The Cm“, Cmin and AUCMZwei-e several
`orders of magnitude below than those produced by systemic treatments already approved
`for non—life threatening conditions. All patients treated with 0.05% cyclosporin
`emulsion, were below the detection limit of 0.1 ng/ml with up to 9 months of dosing.
`
`The concentration—time profile of cyclosporin in tears over the course of one 12 hour
`dosing interval and the 12 month data from study 192371-002 has not been submitted yet.
`The application is approvable from the biopharmaceutics standpoint, contingent upon the
`availability of the remaining data and its appropriateness.
`
`
`CONTENTS
`
`I.
`11.
`III.
`
`IV.‘
`V.
`
`*
`Background
`Recommendation
`Formulation
`*
`
`*
`*
`*v
`
`Analytical Validation *
`Pharmacokinetic Studies
`
`. *
`*
`*
`
`*
`*
`
`at
`f
`1:
`
`*
`*
`
`*
`*
`t
`
`*
`*
`
`a:
`*
`a:
`
`=0:
`*
`
`a:
`4:
`1k
`
`*
`at:
`
`at
`xi:
`4:
`
`2k
`at:
`
`1
`2
`3
`
`3
`4
`
`*
`
`*
`
`Study # 192371-001(dose ranging study)
`at:
`II:
`5
`Study # 192371-002 (systemic bioavailability
`1k* 9
`VI.
`Appendix
`*
`*
`*
`*
`*
`*
`
`*
`
`4
`
`
`
`
`
`

`

`
`
`III.
`
`Formulation
`
`Ingredient
`
`(“Aw/w)
`
`Concentration for 0.1 % %
`
`Concentration for 0.05%
`
`
`(”Aw/w)
` N ot-to—be marketed
`
`To—be marketed
`
`
`Cyclosporin USP
`Castor oil PhEur
`
`
`
`Giycerine USP
`Polysorbate 80 NF
`Carbomer 1324 nF
`
`i __, Sodium hydroxide NF
`
`'——-—-———-—--——...._.e_
`
`.
`
`Purified water USP M
`
`IV.
`
`Analytical Validation
`
`Cyclosporin A in human blood was analyzed using I
`JM
`
`,M and
`
`LOQ:
`Linearity:
`
`0.1 ng/ml
`with
`.—__.__..
`The linearity was tested over the concentration range
`
`a coeffidient of correlation of ‘j—w ,__-—---'~ tor
`day 3‘ of the validation, respectively-
`Intra-day Precision and Accuracy. The accuracy of intra-day variability ranged from
`TH" of the nominal concentrations and precision (%CV) ranged
`
`from
`
`Inter-day Precision and Aceuraey: The accuracy ranged from
`
`nominal with a precision between
`*"
`Freeee Thaw Stability. The mean percent differences from nominal were
`
`at‘ -«“'
`__
`respectively after F“ .The precision was --
`and r—" ,at' M _respectively.
`Stability: At room temperature- Mean percentage difference from nominal was "—--
`after 24 hours and M after 48 hours for
`“*7:
`. It was
`-—---’
`after 24 hours and "H after 48 hours for —--'
`'
`
`
`1 of the
`
`K
`
`Precision ranged from
`
`After
`
`- mean percent difference was
`. and _._....:__
`_ respectively. The precision
`_ -
`and "F,“ J for‘
`1, respectively.
`was
`r—‘--——~
`In human blood, unextractedfor 24 hours at room temperature- Mean percent
`difference from nominal was W“—“and
`
`
`Recovery:
`
`respectively.
`precision was
`The percent recovery ofthe overall process which includes f
`‘-"""'j and r .was -—--— whichis unusually high.
`
`

`

`
`
`V.
`
`Pharmacokinetic Studies
`
`The human pharmacokinetics of cyclosporin Ophthalmic emulsion has been evaluatedin
`a phase 11 close ranging study and a phase III safety and efficacy studyfor up to one year
`duration. Blood samples up to 9 months have been evaluated. The 12'h month blood
`cyclosporin concentrations and concentration-time profilein tears up to 12 hours of
`dosing will be submitted later.
`
`Quantitation of cyclosporin A was preferred in whole blood over plasma due to high
`blood-plasma concentrations ratios at very low doses of cyclosporin and even on
`systemic dosing- Cyclosporin has high affinity of blood cells than for plasma proteins.
`Preliminary in vitro experiments evaluating the blood—to—plasma concentration ratio
`suggested that blood concentrations of cyclosporin may be twice those of plasma.
`
`Study # 192371—001 (PK-96-018)
`
`A dose ranging study evaluating the safety, tolerability and efficacy ofcyclosprorin (0. 05,
`0.1, 0. 2, 0.4%) and vein/ole ophthalmic emulsions in the treatment ofmoderate to severe
`keratoconjuctivitis sicc'a.
`
`This study was a randomized, double-masked, parallel-group design in 162 subjects (26M
`and 136F) treated topically with either vehicle, 0.05%, 0.1%, 0.2% or 0.4% cyclosporin
`emulsion twice daily in each eye for 12 weeks.
`
`Blood samples were collected from each subject at baseline, trough samples prior to
`morning dose following 1, 4, and 12 weeks of dosing. To obtain maximum blood
`concentrations for each treatment groups, blood samples were also collected at one of the
`study sites from approximately 3-5 subjects per treatment group at 1, 2 and 4 hours after
`the final dose at the end of 4 weeks of dosing. Peak blood concentrations are reported to
`occur between 1 and 4 hours after oral dosing. Blood samples were also collected at 4
`weeks post treatment (week 16).
`
`Results
`
`Cyclosporin A was neither quantifiable in blood samples collected prestudy from all
`subjects nor in blood samples from vehicle-treated subjects after 1, 4 and 12 weeks of
`dosing. Trough samples after 1, 4 and 12 weeks of dosing with 0.05, 0.1, 0.2, and 0.4%
`cyclosporin twice daily were very low (less than 0.2 ng/ml). Only 5 out of 120 subjects
`(includes all dosing groups) showed detectable trough concentrations with values of
`Wm nglml. The ranges of trough blood concentrations
`for the four treatment groups after 1,4 and 12 week of dosing and maximum blood
`concentration at 1, 2 and 4 hours after the last dose on week 12 are shownin the
`following table.
`
`
`
`

`

`
`
`
`
`
`
`
`
`
`Treatment
`
`
`
`Trough Conc. at weeks 1, 4, 12
`
`<01 am
`
`
`
`
`<01 to ~.ngrm1-
`
`<o.1 tr ,_. tug/mi
`
`
`
`*N=I20 (2833 subjects per group)
`** N=l5 (3-5 subjects per group)
`a= highest value at week I
`b= highest value at week 12
`c:hig_hest value at week 4
`
`Maximum Cone. on week 12‘”
`
`
`
`
`
`Cmaxl-4hr Range
`<01 ng/ml
`<0.l rig/ml
`
`‘
`I ng/ml
`<0.l t'o'p rig/ml
`
`
`
`The week 16 blood samples were not analyzed. The individual subject data is attached in
`the Appendix on pages 10-14.
`
`Conclusions
`
`0 Overall, the results demonstrate that ocular instillation of 0.05 to 0.4% cyclosporin
`emulsion produces low systemic exposure of eyclosporin A. The highest trough
`concentration was —— ng/mL which was at least 600—fold lower than trough
`concentrations of 100-400 ng/mL reported after administration of therapeutic oral
`doses of cyclosporin'A to organ transplant patients (Transplant Proceed 20,Suppl 2;
`382-389,1985).
`‘
`'
`Peak concentration at 1-4 hours post dose on week 12 was A /‘ ng/ml after
`instillation of 0.4% topical cyclosporin emulsion. Peak blood concentrations after
`oral administration of each mg of cyCIOSporin ranged from 1.4 to 2.7 ng/mL at 2 to 4
`hours post dosing (Goodman Gilrnan’s, “Pharmacological Basis of Therapeutics”, 7m
`edition, pg 1299).
`
`0
`
`Reviewer ’s Comment
`
`Ocular pharmacokinetic studies in rabbits after a single drop of 0. 2% cyclosporin
`indicated a 26 to 44 hour halflife in most ocular tissues (Study report PK-95-010, 1995),
`suggesting the possibility ofonce daily dosing. However, the sponsor has chosen a
`twice-daily regimen for the dose ranging study. The sponsor has chosen this regimen to
`minimize difiizrences between peak and trough drug levels and therefore, provide more
`constant drug exposure to ocular tissues over the entire dosing interval.
`
`Study # 192371-002 (PK-98409 and PK-98-112)
`
`A multicenter, double masked, randomized, vehicle conrolled, parallel—group stuafv of
`safety and efi‘icacy ofcyclosporin 0.05% and 0.1% ophthalmic emulsions used twice daily
`for up to 1 year in patients with moderate to severe keratoconjunctivitis sicca.
`
`Patients were administered either vehicle, 0.05% or 0.1% cyclosporin ophthalmic
`emulsion. Patients taking vehicle emulsion were switched to 0.1% cyclosporin emulsion
`
`

`

`at month 6, therefore, during months 9 to 12, all patients were taking either 0.05 or 0.1%
`emulsion. Formulations used and their batch numbers are given in Appendix on page 15.
`
`The cyclosporin doses instilled were 0.0570 and 0.1 14 mg/day during 0.05% and 0.1%
`
`treatment groups, assuming a drop volume of 28.5 pl. Cyclosporin was quantified in
`trough blood samples taken from selected patients before the start of treatment and after
`
`1, 6 and 9 months of treatment. Trough blood concentrations between month 9 and 12
`were analyzed at preselected site at l, 2, 3, 4, 6, 8, 10 and 12 hours after the morning
`dose.
`
`Trough blood concentration at month 12 and concentration-time profile of cyclosporin A
`in tears measured during the course of a 12 hour dosing interval will be submitted later.
`
`Results
`
`Month 1 and Month 6
`
`A total of 338 samples from 131 patients were analyzed up to 6 months, consisting of 131
`prestudy samples, 113 samples at 1 month and 94 samples at month 6. 140 samples were
`from cyclosporin treated patients collected at months 1 or 6, out of these 70 were from
`each 0-05% and 0.1% cYc103porin treatment group.
`
`Mean concentrations in all treatment groups at all sampling times were BLQ. Only 6 out
`of 140 samples collected from cyclosporin treated patients at months 1 and 6 had
`quantifiable cyclOSporin A concentrations. Out of these 6 patients, there were 5 females ‘
`and one male. 3 patients each at month 1 and month 6 had quantifiable levels. The
`concentrations at month 1 were PM and ”- ng/ml. Out of these 3, two were
`BLQ at month 6, and one of them was not analyzed at month 6. The quantifiable
`concentrations at month 6 were M and-
`_“‘".ng/ml All these 3 patients were
`BLQ at month 1. All the concentrations belonged to the 0.1% cyclosporin emulsion
`treatment group. The data for these 6 subjectsIS attached1n the Appendixm Table IV
`and V on page 15.
`
`Month 9
`
`208 post-dose samples were analyzed between 9 and 12 months from 26 patients, 8 on
`0.05% and 18 patients on 0.1% cyclosporin emulsion. Out of the 18 taking 0.1%, 9 had
`taken 0.1% cyclOSpon'n emulsion for 9-12 months and the other 9 were on vehicle till 6
`months and then on 0.1% cyclosporin emulsion for another 3-6 months.
`
`AUG“: was calculated using linear trapezoidal rule. Since most concentrations were
`BLQ, an upper limit to AUCMzwas calculated assuming a mean Cmax equal to the LOQ
`at each sampling time and then expressing the mean AUCM1 as below this upper limit.
`
`
`
`

`

`
`
`Mean Cm was not calculable but was less than 0.1 nglrnl in 0.05 and 0.1% treatment
`groups. Out of the 208 post dose samples from 26 pateints, only 3 samples from 3
`different patients contained quantifiable concentrations. They were: ~11ng at 1 hr,
`’” ng/ml at 2 hrsg-‘W"~ ng/ml at 3 hrs. This is show in Table III on page 16 of the
`Appendix. Concentrations in other 205 samples were below the LOQ of 0.1 ng/ml. The
`AUC was less than 1.2 ng.hr/ml in both treatment groups.
`
`Conclusions
`
`"—7 ng/ml with the 0.1%
`The highest trough blood concentration observed was
`emulsion. All concentration values were below 0.1 ng/ml in the 0.05% emulsion
`
`group.
`
`The cyclosporin doses instilled were 0.0570 and 0.114 rug/day during 0.05% and
`0.1% treatment groups. Assuming a 60 Kg patient, these doses are 0.000950
`
`mg/kg/day and 0.0190 mgfkg/day. The recommended starting dose ofNEORAL®
`for the treatment of rheumatoid arthritis and psoriasis is 2.5 mg/kg/day to 5
`mg/kg/day. The topical doses are 2,630 and 1,320 times lower, than the starting
`NEORAL® doses. The mean trough blood concentrations after topical cyclosporin
`emulsions were less than 0.1 ng/ml. The trough concentrations from systemic use
`ranged from 74.9 to:‘46.7 ng/ml (PDR-NEORAL, 1998). The trough concentrations
`after topical use is at least 750 times lower than mean trough levels seen with
`systemic therapeutic use. The mean Cmax produced by systemic use ranged from
`655i186 to 728fl65 ng/ml and that after ‘topical application of the emulsions were
`less than 0.1 ng/ml,
`therefore, at least 6,550 times lower than that produced with
`systemic use. The blood AUC0_,2produced by topical application was less than 1.2
`nghrl'ml, and therefore, at least 1,940 times lower than that produced after oral use.
`
`These comparisons between the 0.05% and 0.1% cyclosporin emulsion and NEORAL®
`/
`are tabulated below.
`
`Mean parameter
`
`NEURAL“
`
`Startingdose
`
`150
`
`Cyclosporine
`ophthalmic emulsions”
`outlaw: ______
`
`NEORALolophthalmic
`
`
`emulsion ratio
`
`
`
`
`blood cyclosporine mmuations measured during oralml of rheumatoid arthritis or psoriasis with NEORAL'
`
`blood cyclosporin A «imitations measured during ophthalmic mount with q-closp-orine emulsions.
`
`from PDR-NEORAL'. 1998 (for NEURAL“) and study report “(-984 I2 (for cyclosporinc emulsions)
`
`calculated as AUCN2(ng-hrlml}+12 hr
`
`from PDR-NEORAL'. 1998 (for NEORAL') and “(93-109 (for cyclosporine emulsions)
`
`

`

`—_—1
`
`.__, —
`
`0 Comparing to the animal data it was found that blood Cmax in rabbits and dogs were at
`least 14 and 7 times higher, respectively, than the blood Cmax in humans during
`ophthalmic treatment with cyclosporine emulsions. However, concentrations in these
`animals were still more than 440 times lower than the mean blood Cmax produced by
`approved oral treatment with cyclosporine for systemic indications.
`
`Reviewer ’s Comment (not for the sponsor)
`
`With these comparisons it is clear that the systemic exposure fiom 0. 05% cyclosporin
`ophthalmic emulsion is minimal and the applicant has met with the bioavailability
`requirements. However, the sponsor has calculated the dose administered to the patients
`
`in the study 1923 71-002 based on a drop volume of28.5 pl, but the label indicates a drop
`
`size of —-*'* . With very low concentrations with the 0.05% cyclosporin, this increase in
`drop volume will not be show any significant and meaningful increase the blood levels.
`
`,. [5(
`
`g/lfi/‘i‘f
`
`Veneeta Tandem, PhD.
`Pharmacokineticist
`Division of Pharmaceutical Evaluation III
`
`Peer Reviewer: E. Dennis Bashaw, Pharm. D. P l
`
`CC: NDA 21-023(OR1G)
`HFD-SSOfDiv File
`
`HFD—SSO/CSO/Gorski
`
`HFD—880(Bashaw/Tandon)
`LIED—880(Lazor)
`HFD-870(attn:CDR.B.Murphy)
`HFD—344(Viswanathan)
`
`AB
`
`
`
`'
`
`
`
`

`

`
`
`APPENDIX
`
`NDA 21—023
`
`

`

`
`
`Study 192371-001 (Report 96-018)
`
`Table IV. Trough bloodcyclosporinA concentration": mks L4 and 121:: dry eye human
`subject; tmamd twice daily in'cach cyl: with 0.05% cydosporinc crmkion for 12 weeks.
`
`0.05%
`
`-. - urine Grou-
`
`Tmugb Blood Cyclosporin A Contamination (ngiml)
`
`wm
`
`
`
`
`
`
`
`
`
`
`
`
`
`<99“0'._l
`'
`[or0.05M49!: groups
`10“.;39541,19%95552;him
`
`10
`
`

`

`Table V. Trough blood cyclpspofin A conccmnuons at Weeks 1. 4 and 12 in dryeya human
`subjects treated mica dain'111 mh eye with 01% cyclospofinc emulsion for 12 :rymks.
`0.1% '
`III neGI-I
`
`‘Trough Blood Cyclospofin A Coucmtrnlkm (nglml)
`M4
`Week 12
`
`
`
`forO.0$9&10;4‘igrqu
`(03:1
`Bleclowhmltofquznfimfioflvnlmsm wad
`Rcfmnce: Ll”6‘3953: [r1996-B954; L-l
`3955: ”95414-199643!”
`
`

`

`'13th]. Trough blood cs'dospofinAoomtrafiouatwocks 1.4 andth dxycychum
`subjects awed twlc: daily in each eye with 0.2% cydospodnc emulsion for 12 weeks.
`
`0.2% 'dh nurinaGI-on
`
`Trough Blood Cyde A Commutation (nglml)
`Week 1
`
`
`
`BLQCbelow£ilmholqmflmion) “lustre upheed by (0.1 aymliorOHOS‘Ko-Ofififim
`NA15 sample no! Ivallabk. 14-1996-3953: L-l996-3954: LIME-3955'. L—I996—4352:Whim-4300
`
`12
`
`

`

`
`
`TnbleVILTrough'blooglcydnsporinAconccnflafionatwceks 1,4md mindqcychuman
`scrbjecmmmdmiecdailyincachcyc with 0.4% cyclosporinc emulsion for 112\I.ro<:k:.~
`
`
`
`__ <o-no
`BLQMowlimhofqmafiufion valucsm lacodby «:oa ng/gl.m1f01005%-0A% groups
`Wm: magma-1 3954; “$395),1A996-4352; “9954300
`
`13
`
`

`

`
`
`' AmmficusmzlmuinhloodmxptgoolmmL2m4
`TahieVIII.
`«0.0595. 0.1%, 0.2% «0.4%
`‘
`emulsion was instilled in
`'
`ham am: uu:
`each eye of dry eye human subjects (mated topically for 2 wet-ks.
`
`_
`
`WA.W_W
`0.05%
`u-nrlneGmu-
`'ucm
`'
`»-u
`_
`'= ..
`MEIEHE m
`< I
`< I.
`<0!
`<0 I
`.
`<0.1
`
`
`
`
`' ucnt
`013
`I.
`(0.1
`
`
`
`
`
`
` '77
`
`samples orcachsupct
`NA means sample not available .
`BLQ (balm: [knit of quantitation) value-s an uplaocd by < 0.1 lag/ml for 0.059604% groups
`Mm L-l996-3953;b1996-3954;Lr1996-3955;b1996—4352: DIM-4300
`
`APPEARS nus WA
`0N ORIGINAL Y
`
`14
`
`

`

`
`
`Study 192371-002 (Report PK 98-109)
`
`Formulations used in the study:
`
`-
`
`-
`
`0
`
`Cyclosporim 0.05% ophthalmic emulsion (9654K, lot #1 1143)
`
`Cg-olosporino 0.1% ophthalmic mnulsioo (8735K. lot #11101)
`
`Vehicle ofcyclospodnc ophthalmic emulsion (8m [01 #11102)
`
`Fomulafions mam packaged in unit dose oontaincts that dispensed amcan drop volume of28.5 pl.
`
`Table IV.
`
`Trough blood cydospotiu A concentrations at all 3 sampling times In
`patlcnis who possessed at least 1 quintifinble blood ooncentmflon
`after 1 or 6 111th ol'topical administration of 0.05% or 0.1%
`cyclosporine Ophthalmic emulsions to both eyes twice-daily.
`
`
`
`mwmmmmmnumc
`
`15
`
`Highst Individual trough blood qdosporln A oonccnmllonn
`mason-ad m l and 6 months of topical ndmhxktmtlon or vehlcle,
`0.05% or 0.1% cydospodne ophthalmic cum-Lions to both eyes twice--
`daily.
`.
`
`‘
`
`Table V.
`
`

`

`Report PK 98-112
`
`Table III.
`
`admins-[n A mnemhfiuns in all blood samples containlng a
`quanflflable ambition orcydosporlu A.
`
`0I92: (vehicle):
`
`modmnymunmmmmmummmwummmums
`
`
`
`16
`
`