CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-450
`
`PHARMACOLOGY REVIEW
`
`

`

`NDA 21-450
`
`Linda H. Fossom, Pharmacologist
`
`PHARMACOLOGY/TOXICOLOGY C0 VER SHEET
`
`NDA 21-450.
`Review number:
`
`Sequence number/date/type of submission: N-OOO / stamp date 2-27-02 / New Drug
`Application, Original.
`Information to sponsor: Yes () No (X).
`Sponsor and/or agent: IPR Pharmaceuticals Inc., Carolina, Puerto Rico; Authorized US
`Agent: AstraZeneca Pharmaceuticals LP, 1800 Concord Pike, Wilmington, DE 19803.
`Manufacturer for drug substance: same as for already marketed oral products.
`
`Reviewer name: Linda H. Fossom, Ph.D.
`Division name: Neuropharmacological Drug Products.
`HFD #: 120.
`
`Review completion date: 12/18/02.
`
`Drug:
`
`Trade name: Zomig Nasal Spray.
`Generic name (list alphabetically): zolmitriptan.
`Code names: 311C90 (Wellcome); ZD8250 (AstraZeneca).
`Chemical name: 2-Oxazolidinone, 4—((3~(2-(dimethylamino)ethyl)-1H—indol—S—
`yl)methyl)—, (S)-.
`CAS registry number: 139264-17-8.
`Mole file number: unknown.
`
`Molecular formula/molecular weight: Cm-HZI—Ng-Oz; 28'1—-g/mol.
`Structure:
`
`Relevant INDs/NDAs/DMFS: NDA 20-768 (2.5 and 5 mg oral tablets for acute treatment
`of migraine attacks with or without aura; approved 11-25-97); NDA 21-231 (orally
`disintegrating tablets; approved 2-13-01); IND 45,147 (tablets); IND 53,8848 (nasal
`Spray); IND 55,960 (fast-melt tablets).
`
`Drug class: Agonist at serotonin receptor subtypes 5—HT1 B/D.
`
`Indication: Acute treatment of migraine with or without aura in adults.
`
`Clinical formulation: aqueous solution, buffered to pH 5 using citrate phosphate buffer;
`preservative-free. Provided as a unit dose nasal spray, designed to deliver
`—'_—‘
`r 5
`mg zolmitriptan in a dose volume of 100 u], to the nasal cavity.
`
`

`

`NDA 21—450
`
`Linda H. Fossom, Pharmacologist
`
`Route of administration: intranasal, as spray.
`
`Disclaimer: Tabular and graphical information is excerpted directly from Sponsor’s
`submission where ever feasible and noted as such.
`
`ii
`
`

`

`NDA 21-450
`
`Linda H. Fossom, Pharmacologist
`
`I.
`
`RECOMMENDATIONS
`
`Executive Summary
`
`A. Recommendation on Approvability:
`
`Approval.
`
`B. Recommendation for Nonclinical Studies:
`
`No additional phannacology/toxicology studies are recommended.
`
`C. Recommendations on Labeling:
`
`[These labeling recommendations are compared with the Sponsor’s proposed labeling
`and justified in the body of this review]
`
`CLINICAL PHARMACOLOGYlMechanism of Action: Accept Sponsor’s labeling,
`which is the same as the existing labeling for oral formulations.
`
`Clinical Phamacokinetics and BioavailabilityMetabolism: ' (”i—”7“
`
`
`WARNINGS/Local Adverse Reactions '—————-—-—-————~————-——~——.
`
`u
`«J
`W’"’""’ ‘-
`
`PRECAUTIONSIBinding to Melanin-containing Tissues: Accept Sponsor’s labeling
`including insertion of lack of effect on retina in intranasal animal studies; existing
`labeling for oral formulations includes this information for oral animal studies.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility! Carcinogenesisr
`
`Jim;
`
`_.__._.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility! Mutagenesis:
`
`___,__._.
`
`4:W3
`
`iii
`
`

`

`
`
`NDA 21—450
`
`Linda H. Fossom, Pharmacologist
`
`Mutagenesis: Zolmitliptan was mutagenic in an Ames test, in 2 of 5 strains of S.
`typhimurium tested, in the presence of, but not in the absence of, metabolic activation. It
`was not mutagenic in an in vitro mammalian gene cell mutation (CHO/HGPRT) assay.
`Zolmitriptan was clastogenic in an in vitro human lymphocyte assay both in the absence
`of and the presence of metabolic activation. Zolmitriptan was not clastogenic in in vivo
`mouse and rat micronucleus assays. Zolmitriptan was not genotoxic in an unscheduled
`DNA synthesis study.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility/ Impairment of
`Fertility:Accept Sponsor’s labeling, which is the same as the existing labeling for the
`oral formulations.
`'
`
`Pregnancy: Pregnancy Category C:W
`..__,————-——-———————-——-—___.____ Recommended labeling (existing labeling
`for oral formulations) below.
`
`Pregnancy: Pregnancy Category C: There are no adequate and well controlled
`studies in pregnant women; therefore, zolmitriptan should be used during pregnancy only
`if the potential benefit justifies the potential risk to the fetus.
`
`In reproductive toxicity studies in rats and rabbits, oral administration of zolmitriptan to
`pregnant animals was associated with embryolethality and fetal abnormalities. When
`pregnant rats were administered oral zolmitriptan during the period of organogenesis at
`doses of 100, 400, and 1,200 mg/kg/day, there was a dose—related increase in
`embryolethality which became statistically significant at the high dose. The maternal
`' plasma exposures at these doses were approximately 280, 1,100, and 5,000 times the
`exposure in humans receiving the maximum recommended total daily dose of 10 mg.
`The high dose was maternally toxic, as evidenced by a decreased maternal body weight
`gain during gestation. In a similar study in rabbits, embryolethality was increased at the
`maternally toxic doses of 10 and 30 mg/kg/day (maternal plasma exposures equivalent to
`11 and 42 times exposure in humans receiving the maximum recommended total daily
`dose of 10 mg), and increased incidences of fetal malformations (fused stemebrae, rib
`anomalies) and variations (major blood vessel variations, irregular ossification pattern of
`ribs) were observed at 30 mg/kg/day. Three mg/kg/day was a no effect dose (equivalent
`to human exposure at a dose of 10 mg). When female rats were given zolmitriptan during
`gestation, parturition, and lactation, an increased incidence of hydronephrosis was found
`in the offspring at the maternally toxic dose of 400 mg/kg/day (.1 ,100 times human
`exposure).
`
`iv
`
`

`

`
`
`NDA 21-450
`
`Linda H. Fossom, Pharmacologist
`
`11.
`
`SUMMARY OF NONCLINICAL FINDINGS
`
`A. Brief Overview of Nonclinieal Findings:
`
`This NDA relies upon the preclinical studies that supported the approval of the oral
`formulations. Additionally, new preclinical studies were submitted that are adequate to
`
`support the change in route and qualification of 2 new impurities (
`and
`“— whose specifications for the to-be-marketed nasal spray formulation are
`above threshold. These new studies did not indicate any new concerns for the nasal route
`of administration or attributable to the presence of the new degradants. (See “Overall
`Summary and Conclusions” in section IX. DETAILED CONCLUSIONS AND
`RECOMMENDATIONS, at the end of this review.)
`
`B. Pharmacologic Activity:
`
`Zolmitriptan is a high affinity agonist at 5-HT1D serotonin receptors, but also has
`reasonably high affinity for the 5-HT1A receptor, which is thought to mediate CNS side
`effects, among others.
`
`C. Nonclinical Safety Issues Relevant to Clinical Use:
`
`There are no new preclinical concerns related to the nasal route of administration or
`attributable to the presence of the 2 new degradants ’
`---——-——H.__l_;‘_that
`required qualification.
`
`III.
`
`ADMINISTRATIVE
`
`A. Reviewer signature:
`
`Linda H. Fossom, Pharmacoiogist
`{see appended electronic signature page}
`
`B. Supervisor signature:
`
`Concurrence - Barry Rosloff, Team Leader
`{see appended electronic signature page}
`
`C. cc: list:
`
`Chen, Lana
`Oiiva, Armando
`
`
`
`

`

`NDA 21-450
`
`Linda H. Fossom, Pharmacologist
`
`TABLE OF CONTENTS - PHARMACOLOGY/TOXICOLOGY RE VIEW
`
`1.
`
`PHARMACOLOGY: ............................................................................................... 3
`
`II. SAFETY PHARMACOLOGY: ............................................................................... 4
`
`III. PHARMACOKINETICS/TOXICOKINETICS: ................................................... 5
`
`IV. GENERAL TOXICOLOGY: ................................................................................. 1 2
`
`'V. GENETIC TOXICOLOGY: .................................................................................. 30
`
`VI. CARCINOGENICITY: .......................................................................................... 40
`
`VII.
`
`REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY: ............. 42
`
`VIII.
`
`SPECIAL TOXICOLOGY STUDIES: ......................................................... 51
`
`IX. DETAILED CONCLUSIONS AND RECOMMENDATIONS: ......................... 53
`
`X. APPENDIXIATTACHMENTS: ............................................................................ S9
`
`APPEM‘S 'ME‘S‘W‘S‘!
`0N §F:EE%{"E:?%L
`
`vi
`
`

`

`
`
`NDA 21-450
`
`'
`
`Linda H. Fossom, Pharmacologist
`
`PHARMA COLOGY/TOXICOLOGY RE VIEW
`
`IntroductionlBackground: This NDA is for an intranasal routelformulation of
`zolmitriptan, a drug that is already approved as oral tablets (under NDA 20-768) and
`orally disintegrating tablets (under NDA 21-231). Normally, this NDA would only
`require preclinical testing in local toxicity studies and metabolism studies (if human
`studies indicated changes in-systemic exposures or new metabolites), related to the
`change in route of administration.
`
`However, the Sponsor has set specifications that require qualification for 2 degradants in
`the to—be-marketed Zomig Nasal Spray formulation. Although the maximum
`recommended single dose is 5 mg, the maximum recommended human daily dose is 10
`mg. For maximum recommended human daily doses of 10- —- mg, ICH Guidance (Q33
`Impurities in New Drug Products, November 1996) recommends qualification of
`
`
`
`which ever is smaller; in this case.
`impurities present at
`‘r‘i’s smaller and is the threshold for qualification. The specifications for impurities
`(degradation products) in the drug product are less than ,————, except for ' L.————
`-———--——-, specification set at 2-, and _ fl
`/.—-— , Specification set at
`
`“ " " (see structures, below). Qualification of these impurities requires: 1) a repeated—
`dose toxicology in one animal species of at least 2 weeks duration, 2) a minimal screen
`for genotoxicity, including in vitro tests for both mutations (Ames test) and chromosomal
`aberrations; and 3) because this drug will be used in women of child-bearing potential,
`our Division requests a Segment II reproductive toxicity study in one animal species.
`
`
`
`In this NDA submission, the Sponsor has provided preclinical studies that satisfy the
`requirements for both the change in formulation and the qualification of the 2 degradants
`that exceed threshold. Local toxicity was determined with degraded formulation in l-rno
`studies in rats and monkeys and in a 6—mo study in rats. Although several
`pharmacokinetic studies comparing exposures and metabolism by intranasal and oral
`routes in animals were provided, studies in humans did not indicate pharmacokinetic
`concerns; consequently, the animal studies were not reviewed in support of this
`submission. In terms of degradant qualification, the local toxicity studies using the
`degraded formulation satisfy the requirement for repeated-dose toxicity testing, because
`systemic exposures were adequate, maximum feasible doses were used, and general
`toxicity analysis was performed, including fill] histopathology- The Sponsor also
`submitted the required minimal screen of in vitro genotoxicity tests using the degraded
`
`
`
`

`

`NDA 21-450
`
`Linda H. Fossom, Pharmacologist
`
`formulation, including the Ames test and a test for in vitro chromosomal aberrations
`(specifically, a human lymphocyte assay). [The Sponsor also submitted several in vivo
`chromosomal aberration studies using the degraded formulation; however, these would
`not have been required for qualification of degradants. These studies are discussed in
`Section V. Genetic Toxicology and in Appendix A.] Finally, the Sponsor submitted a
`Segment II reproductive toxicity test of degraded formulation administered orally to
`pregnant rats. These pivotal studies are reviewed in support of the application, below.
`
`APPEARS Tl-llS WA?
`OR GfilGii’ii’iL
`
`

`

`NDA 21-450
`
`Linda H. Fossom, Pharmacologist
`
`I.
`
`PHARMACOLOGY:
`
`Pharmacology summary: The pharmacology studies for zohnitriptan were reviewed
`under NDA 20-768; no new pharmacology studies were submitted in the current NDA.
`Based upon the Review of NBA 20-768, zolmitriptan is a high affinity agonist at 5—
`HTlD serotonin receptors (pKi ~9), but also has
`. .reasonably high affinity for the 5—
`HTlA receptor (pKi 7.0), which is thought to mediate CNS side effects, among others.”
`
`Clinical Pharmacolognyechanism of Action Labeling: No changes; same as labeling
`for Zomig® tablets and Zomig ZMTTM orally disintegrating tablets (see proposed
`labeling, excerpted below).
`
`CLINICAL PHARMACOLOGY
`
`Mechanism of Action
`Zohnitriptaa binds with high affinity to human recombimm 5-»
`HT“) and 5-HTta receptozs. Zolmitriptan exhibits modest
`afinity for 5~HTm receptors, but has no significam affinity (as
`measured by mdioligaul binding assays) or phannacolcgieal
`activity at 5-HT? 5-HT}, 5-HT” alpha” 1511131132" or beta,»
`adrenergic; H1, H3, histaminie; macaritfie; dopaminep or
`dopamine, receptors. The N-desmethyl metabolite also has high
`afiinity for 5-HT 1mm and modest affinity for 5-HTu. receptors-
`
`Currem theories proposed to exphin the etiology of migraine
`Mariachi: suggest tint symptoms are due to local cumial
`modilatafion earlier to the release of screwy neuropeptides
`(vasoactive intestinal peptide, substance P and caicilmlin gene-
`related peptide) through nerve endings in the trigeminal system
`The tlwapeutic activity of zolmitriptan for the treatment of
`migraine headache can most likely be attributed to the agonist
`agents at the 5-Hsz1n receptors on intracmnial blood vessels
`(excluding the Menu—venous anestomeses) and sensory nerves
`of the uigemiml
`system which result
`in. cranial vessel-
`constriction and inhibition of pro-inflammatory neuropeptide
`release
`3,
`
`Comments: Acceptable.
`
`

`

`NDA 21—450
`
`Linda H. Fossom, Pharmacologist
`
`II.
`
`SAFETY PHARMACOLOGY:
`
`Safety pharmacology summary: The safety pharmacology studies for zolmitriptan were
`reviewed under NDA 20—768; no new pharmacology studies were submitted in the
`current NDA. In brief, preclinical studies indicated that zolmitriptan had a potential for
`cardiovascular side effects. It increased blood pressure and heart rate in conscious dogs.
`It also resulted in a concentration-related contraction of human coronary artery in vitro;
`“this may be of some concern, as coronary vasospasm is one of the undesirable side
`effects of sumatriptan.” The active human metabolite 183 C91 was considered to be
`adequately examined for pharmacology and safety pharmacology.
`
`APPEi-"M'ES THIS 2%"le
`0N ORlGii’iAl
`
`
`
`

`

`NDA 21—450
`
`Linda H_ Fossom, Pharmacologist
`
`III.
`
`PHARMACOKINETICSITOXICOKINETICS:
`
`Summary of human findings comparing intranasal to oral formulations/routes: The
`Sponsor submitted reports on 5 clinical pharmacology studies (conducted in Europe) that
`investigated phannacokinetics of zolmitriptan nasal spray: Trials 0032, 0041, 0079, 0104,
`and 01 02.
`
`
`
`the original developer
`- Trial 0032: The results of this study, conducted by
`of zolmitriptan, using a formulation with pH 7.4, are presented in the tables, below.
`From this data it is apparent that intranasal zolmitriptan does not achieve higher
`levels or AUCs for zolmitriptan or its major, active metabolite (183C91) than are
`produced by oral administration. {Subsequently, a formulation at pH 5.0 was used to
`improve stability at room temperature and avoid the need for keeping the formulation
`refn'gerated]
`
`APPEi‘iRS THlS WAY
`0N ORiGiili‘iL
`
`

`

`
`
`NDA 21—450
`
`Linda H. Fossom, Phannacologist
`
`Sponsor’s figures comparing plasma levels of zolmitriptan (upper panel)
`and its major, active metabolite (183091; lower panel) following
`administration of 10 mg doses by oral and intranasal routes. [T rial 0032;
`excerpted directly from the electronic version of this submission,
`clinstatlclin nharmsum. odf
`- es 37 8. 39.
`
`5
`«momma-mm 13mg
`WTil-MVM H
`mwmmymmumyurmmmm 5
`
`Midfield:
`
`" BEST POSSIBLE COPY
`
`

`

`NDA 21-450
`
`Linda H. Fossom, Pharmacologist
`
`‘
`
`«mmwmwummm
`
`
`
`APPEMS THESE 359M
`0N 0?§§3?‘i§fl.
`
`wet pncclm F mp“
`
`

`

`NDA 21-450
`
`Linda H. Fossom, Pharmacologist
`
`Sponsor’s figures comparing PK parameters for zolmitriptan (upper panel)
`and its major, active metabolite (183691; lower panel) following
`administration of 10 mg doses by oral and intranasal routes. [Trial 0032;
`excerpted directly from the electronic version of this submission,
`
`_ clflmnstatlcliltarmsum. - df,am-I- es 38 & 40.
`
`' We form amt pharmcalngicnfiy active
`”the“: INC”,m We 10 mg in!!! finfniltrred iniflnlfifly or
`
`a
`
`l2
`
`km!
`Man
`
`13m
`
`6,... ML)
`
`him or
`an {amp
`
`um rumor-mi
`11
`12 mu
`
`MD“
`
`Chi mm
`was
`
`mes;
`
`3-60 ((156 be 5.09}
`mafia
`
`:3:
`
`12
`
`12
`12
`
`tmm in
`mm... Wk} I!
`3% is
`«g, m
`It
`5091256
`H
`mm;
`n
`“can:
`1:
`6mm)
`It
`will
`it
`Wit!
`IE
`Chat“)
`I! m it
`M 1% dose]
`12
`llfiéfi
`[2
`1m]
`
`name
`1913355
`393mm
`cameras
`6103.115
`Ziflifia
`”323.4
`
`:1
`
`I2
`
`I 2
`I:
`
`l 1
`:1
`:1
`I:
`ll
`ll
`I:
`
`(in! solution
`Mm
`
`tsetse
`
`am (0.75 no am;
`362145.}
`
`meme;
`2.3mm
`4mm
`warm:
`53:22:03?
`2393:254-
`33136.2
`
`f
`
`i
`i
`
`:
`
` Tm my
`
`CmW}
`“tin-gent)"
`mtuhfilu
`at};
`WW}
`All
`it“
`
`I:
`:2
`i2
`5
`5
`12
`
`£911.46
`5m (3&9:le
`23mm
`3.255119
`[51112
`31111.2
`
`I2;
`5.632”?
`l2
`I2 my {0352 to 6.0m 12
`12
`names
`I:
`4
`3313154
`8
`4
`139215
`3
`12
`1921.1
`12.
`
`3.23:1?
`1316 (I175 so 6.00)
`33.33.?
`17010.84
`[631:5l
`3:11:33
`
`I mm
`
`mmmmmhmmmmmmmm mm
`flMWMWfimflufiIHMMdM!; 8%....“ mm
`“WWWMflwmmmmhmmwmmgm,
`
`means was WAY
`an DRiGiiii‘xL
`
`BEST POSSlBlE COPY
`
`
`
`

`

`W
`
`imam
`
`Inland!
`Nat:
`
`Cm {apt-1L}
`yummy} (It?
`WIQMIL)
`MSW
`
`C.- W‘)
`
`[1
`I!
`Ii
`
`11
`
`ant:
`3.0! {am a «as;
`34.92:},6
`
`9.14.3555
`
`“may I! WGMw8Mj
`WW} [2
`58.63545
`a
`mum
`9m-
`
`Tm' w
`WW
`(in! tanks
`fiat:
`
`3,821.3
`4150:1335 lo we;
`333:1]
`
`Emma
`
`0M meter;
`$212
`
`t2
`:2
`l2
`
`:2
`
`5.4mm
`1.50 4 I an in one)
`21143219
`
`isms
`
`iwtljfiiotmm t2
`61.11%”
`:2
`3.5mm
`n
`
`latttléfimfiflm
`mama
`13411115
`
`I2
`11
`I]
`
`:2
`
`12
`I2
`9
`
`
`
`
`
`NDA 21-450
`
`Linda H. Fossom, Pharmacologist
`
`2m
`
`“Hm___._. ' ' 'mm _—vm,
`
`ifiwéamdm'ipuu umlwy,tnhfl,warflm
`
`
`
`13mm
`MWWMWmeWMW;AflC¢$m mm
`hphnlomfllhlfiumfimflmlhmmadmwm sfiweutwmimim-fifir
`
`- Trial 0041 verified that absorption of zolmitriptan was not affected by the change in
`pH from 7.4 to 5.0.
`
`0 Trial 0079 determined that with 3 days of dosing and 2 doses separated by 2 hr each
`day there was no accumulation of zolrnitriptan measured on day 4.
`
`0 Trial 0104 used PET methodology to assess the distribution of llC-labeled
`zolmitriptan (esp nasopharynx and upper abdomen and plasma) after intranasal
`administration.
`
`I Trial 0102 determined that a sympathomimetic (vasoconstricting) nasal decongestant
`(xylometazoline —— wfv solution) administered intranasally 30 min before
`intranasal zolmitriptan (5 mg) did not alter PK parameters (AUC or Cmax) of
`zolmitriptan or 183091.
`
`PKITK conclusions: The pharmacokinetic data from human studies comparing the
`intranasal and oral routes demonstrated that there was no increase in systemic exposures —
`to zolmitriptan or its major metabolites; and no new metabolites were identified.
`
`Consequently, although the Sponsor submitted several studies investigating the PKJTK of
`intranasal zolmitriptan in animals, these studies were not considered necessary to support
`the current NDA submission and have not been reviewed here; however, PK data was
`
`reviewed with toxicology studies, below, where relevant.
`
`BEST POSSIBLE COPY
`
`9
`
`

`

`NDA 21-450
`
`7
`
`Linda H. Fossom, Pharmacologist
`
`CLINICAL PHARMACOLOGY [Metabolism Labeling: Retained from labeling for
`Zomig tablets and Zomig ZMT" orally disintegrating tablets:
`
`active
`an
`to
`converted
`is
`Metabolism: Zahnih‘ipmn
`N-dusmethyl Maholite such that the metabolite mmemrations
`am sham two-«thirds that; ofmhflfiptan- Beam the 51mm
`potency of the mabufitc is 2 to 5 firms that of the patent
`comm the mbolits tnay comm: a substamial portion
`ofthc overall effect after mlmitriptan admnistration-
`)3
`
`The following was added to labeling for Zornig tablets and Zomig ZMTM orally
`disintegrating tablets:
`
`r
`
`'
`
`“1
`
`er—fl-
`’!
`
`Comments: 4.
`
`--—————-———-—-——“—'_———-~--—-
`
`I’________’______..___——————————___.___._______________
`
`APPEARS WES HAY
`
`0N OfiiGiHAL
`
`BEST POSSIBLE copv
`
`‘°
`
`

`

`
`
`NDA 21-450
`
`Linda H. Fossom, Pharmacologist
`
`PRECAUTIONS/Binding to Melanin-containing Tissues Labeling: Expanded from
`labeling for Zomig tablets and Zomig ZMTM orally disintegrating tablets:
`
`Binding to Melanin-Containing Tissues: Menpi‘gumted
`rate were given a single oral dose of 10 mfkg afradiolabelefi
`zonaitriptan, the radioaetivitym the eye alter 7 dam. the latest
`time perm examined was still 75% ofthe valuemamd after
`4 hours This suggests that mtmitriptan atelier its metabolites
`maybindm the malaria ofthe eye. Because there could he
`accumulation‘in melaninrich flames over time. this raises the
`possibflnythatmhniuiptanmzfldeansetoxieityinthesem
`aflerenendeduae Hm. no efi‘ects amine refinamlated to
`Wm mhniniptanrwere notedin any ofthe toxicity
`“”3ms Hannahno“systematic monitoring ofophthalinoiogie
`function wasmmm olinieal trials, and no specific
`recommendations fi)!’ ophthalmologic minimizing are offered,
`pmscfibers should be am affine powibifity of long-term
`Ophthalmohgic efi‘eetst
`
`
`
`Comments: This addition of information regarding the intranasal route is acceptable.
`
`APPESKRS THEE ‘Hi’tY
`
`0N URifiiNAL
`
`BEST POSSIBLE COPY
`
`11
`
`

`

`NDA 21-450
`
`Linda H. Fossom, Pharmacologist
`
`1v.
`
`GENERAL TOXICOLOGY:
`
`Zolmitriptan has been approved under NDA 20-768 for clinical use as an oral tablet;
`general toxicology studies for oral zolmitriptan were reviewed under that NDA (John
`.Jessop, Reviewer; review stamp-dated ~9/16/97).
`
`For the new route of administration (intranasal) in the current application, additional
`general toxicology studies were/are required to determine local toxicity due to the
`intranasal route.
`
`Additionally, the intranasal formulation contains 2 degradants whose specifications in the
`to-be—marketed product have been set above the threshold for qualification.
`
`The Sponsor has submitted several repeated-dose toxicology studies in rats and monkeys:
`
`gram ammouwrmmu
`
`Weflmhhm. M10313
`
`The following 2 studies are of particular interest for this application and are reviewed
`below:
`
`0
`
`Study TPR/2920, a 6-mo intranasal study in rats using a degraded formulation of
`zolmitriptan and looking at general, as well as local, toxicity;
`0 - Study TAP/97 (TKP/ 129 gives additional histopathology), a 28-day intranasal study
`in monkeys using a degraded formulation of zolmitriptan and looking at general, as
`well as local, toxicity [Study TAP/97 was reviewed in detail under IND 53,848, N-
`0061
`
`The following studies are of lesser interest and are not reviewed in detail here:
`
`0
`Study E95376 (in 1996, by
`,fi-afor W
`
`_
`y is a 2-week oral study of degraded and non-degraded zolmitriptan
`
`solutions (batch no ,
`‘15764, pH 5.0;
`in rats; no description of
`degradation procedure nor certificates of analysis (“Data relating to the identity,
`purity and stability of the test or control materials are ‘the responsibility of the Study
`Sponsor.”);
`
`
`
`0
`
`, for Zeneca Pharmaceuticals) is a 28—day
`Study TAR/2735 (in 1997, by
`nasal study of non-degraded zolrnitriptan (powder, batch no Q12 42960) in rats. This
`study was reviewed in detail under IND 53,848, N—006; doses of 18, 36, and 72
`
`BEST POSSIBLE COPY
`
`12
`
`
`
`

`

`NDA 21-450
`
`_
`
`Linda H. Fossom, Pharmacologist
`
`0
`
`-
`
`mglkg non-degraded zolmitriptan to Sprague-Dawley rats resulted in dose- and
`time-related behavioral responses including paddling, squinting, and salivation;
`decreased weight gain and food consumption in HDM; and minimal to slight
`rhinitis in MDM and HD males and females; and minimal nasopharyngitis in HD
`males and females;
`
`
`
`, for Zeneca Pharmaceuticals) is a 28-day
`Study TAR/2813 (in 1998, by
`nasal study of degraded and non-degraded zolmitriptan solutions {batch no
`PH/10828/26; C of A's estimated average amounts of "_—'—--——-————-——-.., as
`
`in rats. This study was reviewed
`in detail under IND 53,848, N—006; nominally 72 mglkg non—degraded vs degraded
`formulations to Wistar Hanover rats, resultedin durationrelated behavioral
`
`responses including paddling, squinting, and salivation, that persisted throughout
`the 28—day treatment, as well as minimal to slight rhinitis;
`Study E95375 (in 1996, bv“
`--——-—"‘f‘ ,forwfi'F‘" "‘3
`
`but Zeneca was ondthe distribution list for the report)18 a 28——day nasal
`study of degraded (15 mgfkg) and non-degraded (batch no F'— ’5764, pH 5.0;
`30 mg/kg/day; 3 times daily bilateral impulsion of ~100ul into each nostril, with ~1 hr
`between administrations) zolmitriptan in monkeys; no description of degradation
`procedure
`..______.___._——_—-—-———-——~*-———-—-—-_____
`
`
`
`
`‘ nor certificates of analysis (“Data relating to the identity, purity
`and stability of the test or control materials are the responsibility of the Study
`Sponsor.”).
`
`APPEl‘..33 “H3 ‘i-il‘i‘l
`0N flRiGi ilAL
`
`13
`
`

`

`NDA 21-450
`
`Linda H. Fossom, Pharmacologist
`
`A. Study TPR/2920, a 6-mo intranasal study in rats using a degraded formulation
`of zolmitriptan and looking at general, as well as local, toxicity.
`
`Study title: Zolmitriptan: 26 week nasal administration toxicity study in the rat.
`
`Key study findings:
`0 No local or general toxicities in rats given maximally feasible intranasal doses up to
`HD of ~72 mgfkg/d for 6 mo;
`Systemic exposures were ~ half those achieved in the 2-yr rat (oral) carcinogenicity
`that supported the approval of the oral formulations.
`
`0
`
`Study no: 9*" study 110. 88/249; AstraZeneca reference no. TPR/2920.
`Volume #, and page #: electronic submission 2/27/02: pharmtox\tox\dose\TPR2920.pdf;
`668 pages.
`'
`Conducting laboratory and location: ———--¢—— —-—_-——-———-—-—-—-"-—‘—"-——"
`Date of study initiation: 1/19/99 (initial dose); until 9/15/99 (last necropSY); amended
`final report issued 8/00.
`GLP compliance: yes, see page 11.
`QA report: yes, see page 14.
`identified
`____.——————————-—-
`Drug, lot #, and % purity __ test article
`as Zomig Nasal Spray 50 mg/ml degraded (batch no. P/2569/I 8; in 10 m1 vials);
`
`Certificate of Analysis (dated 12/9/98) noted pH as 5.0, assay as ‘ ‘
`., with total
`
`degradants of ~--—--., and”
`at ‘2 “-H-land
`' at HEP—(by
`'
`‘
`
`HPLC). The lot of drug substance was Q12, a blended sample of
`
`'
`, and ‘
`-—————--'—"'
`
`Formulation/vehicle: Control article (a clear colorless solution), identified as Placebo
`Zomig Nasal Spray (batch no. P/2569/l7; in 12 m1 vials); Certificate of Analysis (dated
`12/9/98) noted pH as 5.0. The Sponsor indicated that the control article was .5: w/v
`citric acid (anhydrous), — sodium phosphate dodecahydrate, to pHS in water for
`injection. [The Chemist, M. Heiman, informed me that this solution is hyper-osmotic; the
`to-be-marketed HD of 5 mg, 50 mg/ml is 420-470 mosmol/kg .
`m
`
`Methods (unique aspects):
`Dosing:
`Species/strain: male and female Sprague—Dawley rats (HsdBrI:WH strain,
`
`
`
`
`#lsex/gr-oyp (main study): 20/sex at LD and MD and control-ll; 30/sex at HD and
`control-I (but 10/sex in these groups were used for 8-week recovery phase).
`Satellite groups used for toxicokinetics or recovery: 6/sex at Ll), MD, and HD for
`day 1 TK (discarded Without necropsy); 9 main study rats/sex/dose were used for
`subsequent TK; 10 /sex in HD and control-l groups were used for 8-week
`recovery phase.
`
`14
`
`

`

`NDA 21-450
`
`Linda H. Fossom, Pharmacologist
`
`Age; ~ weeks at start of dosing.
`Weight: males, 161-205 g, females, 129—158 g, at start of dosing.
`Housing: in groups of 5 (main study) or 3 (satellites), in stainless steel mesh
`cages, food and water ad Iibitum, 12-hr light (0600—1800)/dark cycle,
`Doses in administered-units: nominally, O, 6, 18, and 72 mg/kg/d (see Sponsor’s
`table, below); HD “. . .considered to be the maximum practical level within the
`routine working day, based on the volume delivered and the use of [a degraded
`sample of] the clinical formulation of the test article.” (see page 16.)
`
`Sponsor’s table showing number of instillations given to different
`dose groups. (Excerpted directly from this submission, electronic
`smssubiion 21271112:
`- banntox\tox\dose\TPR2920.
`
`
`
`MW!!!
`
`
`
`
`
`
`
` f ulhhmfiflhmq 1:13”:memummm
`“tumult: fifimmmhmmmuflm
`
`flWWMumm
`
`
`'0“ “HWWWFWHHMW
`s. militant-Mathew
`
`
`
`
`
`
`it “HWthMmdlsm
`
`
`
`
`
`+ wwwuwmmhwmwmmpmm
`M3“ '
`' “
`
`Because a fixed dose (mg/d) was administered to each rat, the Sponsor calculated
`systemic doses (mg/kg) as the rats grew during the study (see table, below). Based
`upon the average mg/kg/day dose across the study and a conversion factor for
`nasal epithelium surface area compared with body weight (i.e., 10.4 cm2/0.25 kg
`rat), the Sponsor calculated the average local dose, mg/ cmzlday (see table,
`below). The HD produced average local doses of 1.3 and 2.0 mg/ cmzlday in
`males and females, respectively.
`
`.
`
`BEST POSSIBLE cor-w
`
`15
`
`
`
`

`

`
`
`NDA 21-450
`
`Linda H. Fossom, Pharmacologist
`
`Sponsor’s table showing actual doses of zolmitriptan administered
`to rats, based upon increasing body weights. [Excerpted directly
`from this submission, electronic submission, 2127102:
`
`
`
`
`uharrnxkltox‘ltooselTPRZQZO. df,
`“m3 'mmmm swmmu-wm
`
`mining!)
`
`
`
`(hip M 0“
`0"
`thhufitwfihfi
`
`
`“I War ”In “in this
`am
`
`his-nil:
`lad-Ellis
`39'
`‘3
`‘
`i
`as.
`33
`4
`*
`“WI {ms
`
`
`
`m a
`e
`a
`a
`o
`a
`a
`S
`a
`s
`
`
`
`
`tin-um
`a
`s
`o
`a
`a
`e
`a
`o
`a
`a
`
`
`
`
`
`
`
`I 2 3 i 3
`
`In
`
`an!» m as
`
`:3
`
`an
`
`as
`
`9.1
`
`7.:
`
`as m
`
`as m m m is:
`its
`hud- new A?” m :54
`tun
`mum am}
`in m m on ms w m m
`
`
`
`sa—ww-u-
`__““W*”‘mdfi'm‘mtm
`
`'
`
`
`Route form volume: nasal instillation, up to 2/session and up to 6 sessions per
`day, depending upon dose (see Sponsor’s table, above).
`
`Observations and times:
`
`Clinical signs: daily, for overt toxicity or ill health; immediately and 5 min post-
`dosing, daily for first week, then 1 day per week to end of study; detailed physical
`exam weekly.
`Body weights: before treatment on first day of study; then at weekly intervals;
`before necropsy.
`Food consumption: weekly, per cage; calculated as g/rat/week. (Water
`consumption was measured daily in weeks 15 and 16, to investigate possible
`dehydration as explanation for anomalous results in several clinical chemistry
`parameters in week 13.)
`Qphthalmoscopy: all main study rats pro-treatment; controls (I and II) and HD at
`weeks 13 and 25.
`
`EKG: not performed.
`Hematology and Clinical Chemisgy: blood (3 x 0.5 ml; from caudal vein after
`overnight fast) from main study rats, lO/sexfgroup, in weeks 13 and 26; repeated
`in week 15 because of anomalous results in week 13.
`
`Urinalysis: overnight, without food and water, from lO/sexfgroup main study rats
`(not the same ones that were used for hematology and clinical chemistry), in
`weeks 12 and 25.
`
`Gross pathology, Organs weighed, and Histopathology: See histopathology table.
`Nasal cavity and pharynx were examined on all main study rats; other
`histopathology was on controls and HD, only. [NB included is a statement signed
`
`by a DR.
`_
`'7
`_
`7
`_
`‘ confirming “. . .that the
`hist0pathological examination of tissues in this study included assessment of nasal
`
`BEST POSSIBLE copv
`
`16
`
`

`

`
`
`NDA 21-450
`
`Linda H. Fossom, Phannacologist
`
`and respiratory passages in representative tissue sections, and that the
`examination was adequate to assess toxicity to all tissues of the respiratory
`system.” Signed 6/16/02; see page 13.]
`
`The nasal turbinates were ekarnined at 4 levels (excerpted directly from this
`submission, page 28; page 13 of study report):
`'mammmmwwmmmzmmamemw
`timid;
`minim
`mums»
`Immune mm ’firfl
`we W mm man
`age
`gum
`mummmmdmmmwmmwmmm
`
`Toxicokinetics: blood (0.4 ml; caudal vein) from satellite rats on day 1 and from
`9/sex/dosed group of main study rats in week 26; at 0 (or immediately before
`dosing), and 30 min, 2, 4, 8, and 1 hr after dosing.
`
`Results:
`
`Mortality: 1 HDF (#215) died in week 23; cause of death: (slight) hemorrhage in the
`thoracic cavity (especially in tissue adjacent to aorta bifurcation noted in histopathology;
`approximately 2 ml red fluid in thoracic cavity noted on gross exam) of unknown causes,
`considered not to be related to Specific toxicity of zolmitriptan.
`
`Clinical signs: At weekly physical exams, there was increased incidence of fur staining at
`HD; and from week 7 onward, increased incidence of protruding eyes in females in HD
`and HD vehicle control-I group.
`
`Post-dosing in drug-treated rats only, paddling, salivation and sniffing were noted
`immediately alter dosing, but subsided within minutes of being returned to home cages.
`All 3 signs/behaviors were observed in several HD rats on day 1, and essentially all HD
`rats after 1 week through the end of the study.
`
`Body weights: slightly (~10%) decreased body weight gain for HD males only during
`weeks 1—4.
`
`Food consumption: slightly decreased during weeks 1-4 in HD males; dosed females
`tended to eat more than controls throughout the study.
`
`Water consumption: Although water consumption tended to be increased (~6%) in dosed
`rats compared with control-II rats during the 2 weeks that were measured (weeks