CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203214Orig1s000
`
`PHARMACOLOGY REVIEW(S)
`
`
`
`
`
`
`

`

`Tertiary Pharmacology Review
`
`By: Paul C. Brown, Ph.D., ODE Associate Director for Pharmacology and
`Toxicology, OND IO
`NDA: 203214
`Submission date: 10/21/2011
`Drug: tofacitinib
`Sponsor: Pfizer Inc.
`Indication: Treatment of Adult Patients with Moderately to Severely Active
`Rheumatoid Arthritis (RA) and Inadequate Response to One or More Disease-
`Modifying-Anti-Rheumatic Drugs (DMARDs)
`
`Reviewing Division: Division of Pulmonary, Allergy and Rheumatology Products
`
`Background Comments:
`The pharmacology/toxicology reviewer and team leader in the Division of
`Pulmonary, Allergy and Rheumatology Products reviewed the nonclinical
`information for tofacitinib and found it adequate to support approval from a
`pharmacology/toxicology perspective for the indication listed above.
`
`Discussion:
`
`Genotoxicity
`Tofacitinib was assessed in five genotoxicity studies. All of these studies were
`negative except for an in vitro cytogenetic study in peripheral human
`lymphocytes. The study was positive for chromosomal aberrations with a 3-hour
`incubation in the presence of metabolic activation.
`
`Carcinogenicity
`The applicant conducted two carcinogenicity studies: a 2-year study in rats and a
`6-month study in Tg.rasH2 mice. These studies were reviewed by the division
`and the Executive Carcinogenicity Assessment Committee. The Committee
`found that the studies were acceptable and that there were no drug-related
`neoplasms in mice. The Committee concurred that the following were drug
`related neoplasms in rats: interstitial cell tumors in the testis of males; benign
`thymomas in the thymus of females; and malignant hibernomas in females (a
`rare tumor not meeting statistical significance, but seen at a higher than usual
`incidence). The Committee noted that the mechanism of action studies support
`the hibernomas as being pharmacologically plausible.
`
`In addition to the neoplasms noted in the rodent studies, lymphoma was
`observed in 3 high dose (10 mg/kg/day) animals in the 39 week monkey study.
`All three animals were also positive for lymphocryptovirus. Immune suppression
`was the predominant toxicity finding in all repeated-dose animal studies as would
`be expected from the pharmacologic activity of tofacitinib. The occurrence of
`
`
`
`Reference ID: 3205502
`
`1
`
`

`

`lymphoma in monkeys is likely related to immune suppression and viral re-
`emergence.
`
`Developmental and Reproductive Toxicity
`The primary and secondary reviewers initially recommended that the male rat
`fertility study be repeated because they considered the design of the study
`inadequate, albeit, for different reasons. After further assessment of the study, it
`was determined that the study was adequate and no further assessment of male
`fertility is considered necessary at this time.
`
`Tofacitinib produced external, skeletal and visceral malformations in rabbits and
`external and skeletal malformations in rats. The NOAEL for these findings
`occurred at exposures in rats that are substantially higher (50-100 times) than
`those achieved in humans; however, the NOAEL for these findings in rabbits
`occurred at exposures that are within 10 times the maximum human exposure.
`
` A
`
` pre/postnatal study in rats showed reduced pup viability and weight gain with a
`NOAEL substantially greater than the maximum human exposure. Given these
`findings, the applicant and the primary and secondary pharm/tox reviews
`recommend pregnancy category C with appropriate wording describing the
`potential risk to the fetus.
`
`Established Pharmacologic Class
`Tofacitinib is an inhibitor of the Janus-associated kinases. One possible
`appropriate Established Pharmacologic Class term would be "kinase inhibitor".
`This term has been used for several other moieties that target a variety of
`kinases. Other more specific terms may also be appropriate such as "Janus-
`associated kinase inhibitor". This term has not been used previously as an
`Established Pharmacologic Class.
`
`Conclusions:
`I concur with the Division pharmacology/toxicology recommendation that this
`NDA can be approved. No additional nonclinical studies are recommended.
`The overall risk of genotoxicity may be relatively low considering the results of all
`the studies; however, description of the results of the chromosomal aberration
`assay in labeling seems appropriate. The results of the carcinogenicity studies as
`described by the Executive Carcinogenicity Assessment Committee should be
`conveyed in labeling. Including a description of the lymphomas observed in
`monkeys also seems appropriate. Use of a pregnancy category of C seems
`warranted.
`
`
`
`Reference ID: 3205502
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`2
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`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`PAUL C BROWN
`10/18/2012
`
`Reference ID: 3205502
`
`

`

`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA/BLA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`Indication:
`Applicant:
`Review Division:
`
`203214
`SD-000
`Oct 21, 2011
`Oct 21, 2011
`Xeljanz (tofacitinib)
`Rheumatoid Arthritis
`Pfizer Labs
`Division of Pulmonary, Allergy, and
`Rheumatology Products (DPARP)
`Molly E. Shea, Ph.D.
`Reviewer:
`Molly E. Shea., Ph.D.
`Supervisor/Team Leader:
`Badrul Chowdhury, M.D., Ph.D.
`Division Director:
`Philantha Bowen
`Project Manager:
`Template Version: September 1, 2010
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 203214 are owned by Pfizer or are data for which Pfizer
`has obtained a written right of reference. Any information or data necessary for approval
`of NDA 203214 that Pfizer does not own or have a written right to reference constitutes
`one of the following: (1) published literature, or (2) a prior FDA finding of safety or
`effectiveness for a listed drug, as reflected in the drug’s approved labeling. Any data or
`information described or referenced below from reviews or publicly available summaries
`of a previously approved application is for descriptive purposes only and is not relied
`upon for approval of NDA 203214.
`
`Reference ID: 3193040
`
`1
`
`

`

`NDA # 203214
`
`
`1
`
`Executive Summary
`
`
`
`Reviewer: Molly E. Shea, Ph.D.
`
`Introduction
`1.1
`This review is a secondary labeling review of NDA 203214 for tofacitinib, a Janus
`associated kinase inhibitor. Reference is made to Dr. Lawrence (Steve) Leshin’s
`primary review dated July 3, 2012 that provides recommendations for changes to
`Pfizer’s proposed labeling for sections 8.1, 8.3, 8.4, 12.1, and 13.1. Dr. Leshin’s
`recommended changes to the labeling for sections 8.3, 8.4, 12.1 and 13.1 are
`inconsistent with 21 CFR § 201.00, 201.56, 201.57, and 314 recommendations.
`Additionally, the Established Pharmaceutical Class for Sections 11 and 12.1 was not
`determined. Therefore, a secondary review of the label is being conducted herein. This
`review supersedes Dr. Leshin’s labeling recommendations.
`
`The Established Pharmaceutical Class of tofacitinib is Janus-associated Kinase inhibitor
`(JAK inhibitor).
`
`With the assumption that the clinical 5 mg BID oral dose of tofacitinib is supported by
`the clinical safety and efficacy data, the 5 mg BID dose is being used to determine
`exposure ratios in the relevant nonclinical sections of the label. Clinical AUC data were
`provided for the 5 mg BID dose by the Clinical Pharmacology reviewer (see below).
`
`Clinical Human Pharmacokinetic
`Cmax, ng/mL
`AUC0-12, ng/mL*hr
`Day 1 Day 14
`Day 1
`Day 14
`48.3
`50.9
`161
`154
`
`
`
`5 mg BID
`
`
`These data were provided as AUC values from 0-12 hours. Therefore, the AUC0-24
`hours is 308 ng*h/mL.
`
`Based on the doses at which toxicities were observed and the No Observed Adverse
`Effect Levels (NOAELs) identified in the reproductive toxicity assays (fertility, EFD in rat
`and rabbit, and PPND in rat), in the 39-week monkey general toxicity study, and the
`two-year rat carcinogenicity study, the following exposure ratios were determined using
`the animal: human values based on the AUC0-24 h observed at 5 mg BID.
`
`
`Study
`
`Fertility
`Females
`
`Males
`
`EFD
`
`Animal:Human Exposure Ratios
`Toxic Dose and NOAEL Dose
`AUC0-24 h
`(ng*h/mL)
`
`5620
`412
`-
`67500
`
`
`
`Toxic: 10 mg/kg/day
`NOAEL: 1 mg/kg/day
`Toxic: None
`NOAEL: 100 mg/kg/day
`
`
`Exposure
`Ratio
`
`18
`1
`-
`220
`
`
`Reference ID: 3193040
`
`2
`
`

`

`NDA # 203214
`
`Reviewer: Molly E. Shea, Ph.D.
`
`
`
`Study
`
`Toxic Dose and NOAEL Dose
`
`AUCo.24..
`no*hImL
`
`Exposure
`Ratio
`
`NOAEL. 30 moulklda
`
`29400
`
`95
`
`Rabbit
`
`Toxic: 30 mg/kg/day
`NOAEL: 10 moo/k/da
`
`NOAEL: 10 moo/k/da
`
`36900
`7380
`
`120
`24
`
`Toxic Dose for lymphoma: 5 mg/kg
`twice daily
`NOAEL: 1 moo/k twice dail
`
`2890
`
`524
`
`1470 Toxic: 50 mg/kg/day
`
`40
`12600
`Toxic: 30 mg/kglday
`2-yr Rat
`
`NOAEL: 10 mg/kg/day
`3880
`13
`*- No toxicokinetic data from study. Data were extrapolated from rat EFD.
`
`Using these calculated exposure ratios, the Nonclinical sections of the label were
`updated.
`
`Section 8.1 was revised to include CFR recommended label structure and to provide
`more detailed descriptions of the rat and rabbit teratogenic findings
`
`M"
`
`Section 8.3 was revised to include CFR recommended language.
`
`Changes recommended in Section 8.3 and 8.3 by Dr. Leshin are not recommended.
`
`No animal data were included in Section 10, which is in agreement with CFR
`recommendations.
`
`Section 12.1 Mechanism of Action was revised by Clinical Pharmacology with support
`from nonclinical reviewers, Dr. Luqi Pei and Dr. Leshin. This reviewer agrees with these
`recommendations. This section has not yet been added to the review team label but it
`should read as follows:
`
`(5) (4)
`
`Reference ID: 31 93040
`
`

`

`NDA # 203214
`
`Reviewer: Molly E. Shea, Ph.D.
`
`
`
`Section 13.1 was revised tom include more
`
`, mu geneSIs an ertility impairment.
`
`detailed information regarding
`
`e carcrnogenl
`
`These changes are captured in the track-changes version below.
`
`1.3.3 Labeling
`
`
`
`Reference ID: 3193040
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MOLLY E SHEA
`09/21/2012
`I concur.
`
`Reference ID: 3193040
`
`

`

`INTEROFFICE MEMO
`
`
`
`
`NDA 203214 Original submission
`Xeljanz (Tofacitinib)
`
`
`TO:
`
`
`FROM:
`
`
`
`
`
`DATE:
`
`
`Addendum to Nonclinical Supervisory Review July 21, 2012
`
`The July 21, 2012 nonclinical supervisory secondary review recommended that
`Pfizer conduct a properly designed and analyzed fertility assessment in adult
`male rats as recommended in ICH5(R2) to be completed as a post-marketing
`requirement (PMR). The sponsor was informed of this PMR request.
`
`The basis for the male fertility PMR request included the primary reviewers (Dr.
`Leshin primary review dated July 3, 2012) identification that the study was
`deficient and the Supervisor’s misinterpretation of the primary reviewers
`summary of the completed male fertility study design. On July 26, 2012, the
`Nonclinical Supervisor reviewed study 05GR051 Oral fertility and embryonic
`development study of CP-690-550-10 (tofacitinib) in male and female rats. Upon
`review, the Nonclinical Supervisor concluded that the study design and
`methodology were in line with the recommended ICH-S5A Guideline and the
`study results were in agreement with the sponsor’s conclusion that tofacitinib had
`no adverse effect on male rat fertility up to oral doses of 100 mg/kg/day.
`Therefore, the male rat fertility study is adequate and the PMR request is
`unfounded and is rescinded. The label should accurately reflect the completed
`reproductive battery outcomes.
`
`There are no outstanding nonclinical issues for NDA 230214 that require
`additional studies prior to or post-approval.
`
`_____________________________
`Molly E. Shea, Ph.D.
`Pharmacology/Toxicology Supervisor
`
`Molly E. Shea, Ph.D.
`Pharmacology/Toxicology Supervisor
`Division of Pulmonary, Allergy and Rheumatology Products
`
`July 27, 2012
`
`
`
`Reference ID: 3165529
`
`1
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MOLLY E SHEA
`07/27/2012
`
`Reference ID: 3165529
`
`

`

`
`
`INTEROFFICE MEMO
`
`
`
`
`NDA 203214 Original submission
`Xeljanz (Tofacitinib)
`
`Molly E. Shea, Ph.D.
`Pharmacology/Toxicology Supervisor
`Division of Pulmonary, Allergy and Rheumatology Products
`
`July 21, 2012
`
`
`TO:
`
`
`FROM:
`
`
`
`
`
`DATE:
`
`
`Nonclinical Supervisory Recommendation:
`
`NDA 203214 is recommended for approval from the nonclinical perspective
`pending labeling revisions.
`
`Nonclinical Supervisory Post-Marketing Requirement Recommendation:
`
`Conduct a properly designed and analyzed fertility assessment in adult male rats
`as recommended in ICH5(R2).
`
`Basis of PMR Recommendation:
`
`Based on the overall nonclinical NDA evaluation, Dr. Leshin concluded that
`characterization of the nonclinical toxicity profile of tofacitinib was complete with
`the exception of having an adequate male fertility reproductive toxicology study
`(see Dr. Leshin’s review submitted into DARRTS on July 3, 2012). Dr Leshin
`recommended approval of the NDA from the nonclinical perspective. Dr. Leshin
`recommended 2 post-marketing requirement (PMR) nonclinical studies as
`follows:
`
`
`1) Conduct a properly designed and analyzed fertility assessment in adult
`male rats as recommended in ICH5(R2).
`2) Conduct a properly designed and analyzed fertility assessment in juvenile
`male and female rats as recommended in ICH5(R2).
`
` A
`
` secondary review for the necessity of these studies was completed. From the
`nonclinical supervisory perspective, one PMR is needed to address the deficient
`male reproductive fertility study. The sponsor completed a male fertility study in
`rats that were dosed for 63 days but were not mated until 1 month post-dosing.
`Tofacitinib has a short half-life (ranges from 0.6 to 2.8 hours) and clearance of
`the drug from the system is rapid. Therefore, Male rats were not sufficiently
`exposed to drug one month post-dose, potentially allowing recovery from any
`adverse consequences of tofacitinib on male fertility. A valid male reproductive
`toxicity study is needed and the study results are recommended to be included in
`
`
`
`Reference ID: 3162524
`
`1
`
`

`

`
`
`the label. The lack of a valid study was determined to not be critical for approval
`of tofacinitib from the nonclinical perspective. This was determined based on the
`following: 1. labeling can state that male fertility has not adequately been
`evaluated and 2. the potential benefit of the drug outweighs the risk when
`physicians and patients are made aware of this deficiency via proper labeling.
`
`Dr. Leshin’s recommendation for a second PMR to conduct a fertility assessment
`in juvenile male and female rats is not supported by the Nonclinical Supervisor.
`Reproductive toxicology studies including fertility, embryo-fetal development, and
`peri-post natal studies, should all be conducted in sexually mature animals.
`Further, the peri- post-natal study assesses development including sexual
`maturation. Although toxicity studies conducted in juvenile animals studies may
`reveal an impact on fertility (delayed sexual maturation or direct toxicities on
`developing reproductive organs), the intent of the male fertility assessment in
`sexually mature animals is to identify a change in fertility when adults are
`exposed to drug. Therefore, the second recommended PMR is unfounded.
`
`General Nonclinical Supervisory Review:
`
`Pfizer Incorporated (Pfizer) submitted their New Drug Application (NDA) 203214
`on October 21, 2011 for Xeljanz (tofacitinib tablets) as a chronic treatment of
`adult patients with moderately to severely active rheumatoid arthritis (RA) who
`have had an inadequate response to one or more disease-modifying anti-
`rheumatic drugs (DMARDs). The proposed clinical daily oral treatment for RA is
`5 mg BID
`
` Tofacitinib is proposed as monotherapy or in combination with
`methotrexate or other nonbiologic DMARDs treatment.
`
`The nonclinical program for tofacitinib included pharmacology, safety
`pharmacology, pharmacokinetic studies, toxicology studies with durations up to 6
`months in rats and 9 months in monkeys, reproductive toxicology, genetic
`toxicology, carcinogenicity assays in mice and rats, and a photosafety study. Dr.
`Lawrence Leshin completed the primary review for this package. The following
`summarizes tofacitinib’s toxicological profile and the Nonclinical Supervisory
`conclusions and recommendations, some of which differ from Dr. Leshin’s review.
`
`Tofacitinib is a first-in-class Janus associated kinase (JAK) inhibitor. Tofacitinib’s
`mechanism of action includes inhibition of JAK1, JAK2 and JAK3 with less
`inhibitory activity against TyK2, all members of the JAK family. Inhibition of these
`kinases decreases inflammatory cytokine release which in turn decreases
`lymphocyte activation and proliferation.
`
`Tofacinitib had no adverse effect on cardiovascular, respiratory, renal or
`gastrointestinal systems in stand alone safety pharmacology studies. Mice orally
`administered tofacitinib showed a reduction in spontaneous activity at high (100
`mg/kg) doses suggesting potential neurotoxicity. However, this observation
`
`
`
`Reference ID: 3162524
`
`2
`
`(b) (4)
`
`

`

`
`
`coincided with general toxicity observations and no promotion or inhibition of
`seizures was observed.
`
`Pharmacokinetic assessments of tofacitinib in rat, rabbit, dog and monkeys
`demonstrated rapid oral absorption with a short half-life (ranged from 0.6 to 2.8 h
`for all species). Tofacitinib was minimally to moderately protein bound in mice
`(67%), rats (85%), dogs (80%), monkeys (65%) and humans (62%). After oral
`administration to rats, tofacitinib was observed to be both renally (~50%) and
`fecally (~50%) excreted. In rabbits and monkeys, tofacitinib was mainly excreted
`in the urine (~56%) with less fecal excretion (~30%) after oral administration.
`Cytochrome P450 isoforms CYP3A4/3A5 and CYP2C19 were the main enzymes
`metabolizing tofacitinib in an in vitro human liver microsome assay.
`
`General toxicology studies were completed in Sprague-Dawley rats (single-dose,
`2- week, 6-week and 6-month oral toxicology studies) and Cynomolgus monkeys
`(single-dose, 2-week, 1-month, and 39-week oral toxicology studies). In the 6-
`month oral rat toxicity study where animals were dosed with 0, 1, 10 or 100
`mg/kg/day, the target organs of toxicity included: lymph nodes (lymphocyte
`depletion and atrophy), thymus (lymphocyte depletion and atrophy), spleen
`(lymphocyte depletion and atrophy), bone marrow (cellular decrease), changes in
`hematology (decreased white blood cells and red blood cells), adrenal gland
`(cortical vacuolation), gastrointestinal tract (stomach, duodenum, jejunum), liver
`(increased liver enzymes and hypertrophy), and lung (histiocytosis thought to be
`a result of immunosuppression). In general, the longer the duration of the toxicity
`study in rats the more severe the toxicities were (e.g., shorter term studies
`showed lymphoid depletion but the chronic study resulted in atrophy of the lymph
`organs). Based on the 6-month oral toxicity study in rats with atrophy of lymph
`organs, GI effects and lung histiocytosis, the NOAEL was identified as the low-
`dose (1 mg/kg/day) that has an associated AUC0-24 h of 765 and 742 ng*h/mL for
`males and females, respectively.
`
`In the 39-week oral monkey toxicity study where animals were treated with 0,
`0.25, 1, and 5 mg/kg BID (for a total daily dose of 0.5, 2, and 10 mg/kg), the
`toxicities included: severe immunosuppression resulting in infections and a
`decrease in immunosurveillance resulting in lymphomas in 3 animals orally
`treated with 10 mg/kg/day (5 mg/kg BID) and hematological changes (decreased
`white blood cells, lymphocytes, red blood cell, hematocrit and hemoglobin). The
`target organs of toxicity included: spleen (viral inclusions and lymphocyte
`hyperplasia), thymus (lymphocyte hyperplasia), lymph nodes (lymphocyte
`hyperplasia), bone marrow (erythroid hyperplasia), and stomach (viral inclusions,
`inflammation-secondary infections). Shorter duration studies in the monkey
`resulted in general lymphocyte depletion of the lymph organs, where longer
`duration of treatment resulted in lymphocyte hyperplasia in these organs. The
`lymphomas were positive for Epstein-Barr virus encoded small RNA 1 and
`EBNA-2 which indicates that these lymphomas are associated with
`lymphocryptovirus infection. The Nonclinical Supervisor identified the NOAEL as
`
`
`
`Reference ID: 3162524
`
`3
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`

`

`
`
`the mid-dose (2 mg/kg/day or 1 mg/kg BID), which differed from the primary
`reviewers recommendation of no NOAEL. The Supervisory conclusion was
`based on the observed hematology and lymph related findings were expected
`pharmacological effects. These findings were observed at the low-dose and mid-
`dose but were not considered dose-limiting. The dose-limiting toxicities were
`considered severe immunosuppression resulting in lymphomas in monkeys at
`the high-dose 10 mg/kg/day (5 mg/kg BID). The 2 mg/kg/day (1 mg/kg BID)
`NOAEL dose is associated with an AUC0-24 h of 397 and 652 ng*h/mL for males
`and females, respectively.
`
`Juvenile oral toxicology studies were completed in Sprague-Dawley rats (1-
`month) and Cynomolgus monkeys (39-week study). In the rat doses of 0, 1, 10
`and 100 mg/kg/day were orally administered. Only the immune system and
`related organs were examined for toxicities. No new findings or more severe
`toxicities were observed in juvenile animals compared to those observed in adult
`rat toxicity studies. The target organs were changes in hematology (decreased
`WBCs, RBCs, and lymphocytes), thymus (lymphoid depletion), spleen (decrease
`in lymphocytes), and lymph nodes (lymphoid depletion). No toxicokinetic
`evaluation was completed for this study.
`
`In the 39-week juvenile monkey study, animals were orally dosed with 0, 0.5, 2
`and 10 mg/kg/day delivered as 0.25, 1, and 5 mg/kg BID (the same doses as the
`adult chronic monkey study). The major organ systems were evaluated in this
`study but a standard histopathology was not completed. This is considered
`acceptable for the purposes of this study. There were no lymphomas observed in
`this study, no premature deaths and no drug-related effects on the
`cardiovascular system (no changes in ECG). Compared to the adult chronic
`monkey study, the potential new finding in the juvenile monkey study was an
`increase in inflammatory cell foci in the heart at the high-dose. The target organs
`were the hematologic system (decreased WBC, RBCs and lymphocytes), spleen
`(lymphocyte hyperplasia), bone marrow (lymphoid follicle), lymph node
`(lymphocyte hyperplasia), and heart (inflammatory cell foci). As these findings
`were similar to those observed in the adult chronic toxicity study and these
`findings (hematological and lymph system) are the expected pharmacological
`mechanism that are not considered dose-limiting, the dose limiting toxicity was
`determined to be the inflammatory cell foci of the heart. Therefore, the
`Nonclinical Supervisor identified the NOAEL as 2 mg/kg/day (1 mg/kg BID) which
`is associated with an AUC0-24 h of 424 ng*h/mL.
`
` standard genetic toxicology battery was completed for tofacitinib (bacterial
`reverse mutation assay, an in vitro chromosome aberration assay with human
`lymphocytes, and an in vivo rat micronucleus assay). Tofacitinib was negative for
`genetic toxicology in the bacterial reverse mutation assay and the in vivo rat
`micronucleus assay. However, tofacitinib showed a statistically significant
`increase in chromosome aberrations in cultured human lymphocytes in the 3-
`hour test with metabolic activation, but not in the absence of the addition of
`
` A
`
`
`
`Reference ID: 3162524
`
`4
`
`

`

`
`
`induced liver enzymes. The concentration at which the positive response
`occurred, ≥1700 µg/mL, corresponded to 48% mitotic suppression. Additional
`follow-up assays were conducted, in vitro CHO/HGPRT assay to assess for
`mammalian gene mutations and an in vivo rat hepatocyte unscheduled DNA
`synthesis assay which were both negative. Based on the weight of evidence
`approach, tofacitinib is considered negative for genotoxic potential. However,
`labeling is recommended to relay the outcomes of each of these studies.
`
`The carcinogenic potential of tofacitiniib was assessed in a 2-year study in rats
`and in a 6-month study in rasH2 transgenic mouse. In the rat study, the findings
`were sex specific and included interstitial cell adenomas in testis in males,
`benign thymomas in females and malignant hibernomas in females. Tofacitinib
`was not carcinogenic in rasH2 transgenic mice. Concurrence was obtained from
`the Executive Carcinogencity Assessment Committee on these studies on March
`6, 2012. Lymphomas were observed in the 39-week general toxicology study in
`adult cynomolgus monkeys (see above). These findings are recommended to be
`included in the label.
`
`Pfizer submitted a reproductive toxicology battery (male and female rat fertility
`studies, embryofetal development rat and rabbit studies and a peri/post-natal rat
`reproductive toxicology study). In the female fertility assay, tofacitinib increased
`post-implantation loss and a reduced pregnancy rate due to reduced numbers of
`corpora lutea, implantation sites, early resorptions and pre- and post-implantation
`loss.
`
`The fertility assessment for males was not adequate (see above for
`recommended PMR). Males were administered tofacitinib for a 63 days, dosing
`was stopped and males were without exposure to drug for 1 month. Due to the
`short half-life of the drug (0.6 to 2.8 hours), all drug is systemically cleared
`quickly. Males were allowed to mate 1 month post-dose, therefore, no drug is
`present in males. No adverse effects on mating or pregnancy rate were observed
`in untreated females. The duration of treatment at the time of mating was
`insufficient for drug exposure for a complete spermatogenic cycle. Adult male
`rats should be exposed to drug for an adequate assessment of potential effects
`of drug on male fertility. Therefore, the sponsor is requested to conduct a valid
`male fertility assessment as a post-marketing requirement.
`
`Tofacitinib was teratogenic in both rats and rabbits. Therefore, Pregnancy
`Category C is recommended. In rats, postimplantation loss, consisting of early
`and late resorptions and consequently a reduced number of viable fetuses, and
`decreased uterine weight was observed. Teratogenic effects included anasarca
`and membraneous ventricular septal defect and numerous skeletal
`malformations. In rabbits, teratologic findings included thoracogastroschisis,
`omphalocele, microstomia, microphthalmia, membranous ventricular septal
`defects, absent gallbladder, and multiple skeletal malformations.
`
`
`
`
`Reference ID: 3162524
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`5
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`

`

`
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`Tofacitinib had no effect on pup delivery, standard landmarks of development,
`growth, sexual, or behavioral development in the peri-post-natal rat reproductive
`toxicology study. Tofacitinib was found in breast milk of lactating rats.
`
`Tofacitinib was not phototoxic nor was it a skin sensitizerDr. Leshin reviewed the
`nonclinically relevant sections of the sponsor’s proposed labeling.
`Recommendations to the labeling were made in the primary review dated July 3,
`2012 in DARRTS. The labeling will require revisions with completion of an
`addendum to the primary and secondary reviews. There are no outstanding
`nonclinical issues that would affect tofacitinib’s approval. Therefore, from the
`nonclinical perspective NDA 203214 for tofacitinib is recommended for approval
`pending labeling revisions to the nonclinical sections of the label.
`
`_____________________________
`Molly E. Shea, Ph.D.
`Pharmacology/Toxicology Supervisor
`
`
`
`Reference ID: 3162524
`
`6
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MOLLY E SHEA
`07/21/2012
`
`Reference ID: 3162524
`
`

`

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`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA/BLA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`Indication:
`Applicant:
`Review Division:
`
`Reviewer:
`Supervisor/Team Leader:
`Division Director:
`Project Manager:
`
`203214
`SD-000, SD-9
`Oct 21 2011, Feb 16 2012
`Oct 21 2011, Feb 16 2012
`Xeljanz (Tofacitinib)
`Rheumatoid Arthritis
`Pfizer Inc.
`Division of Pulmonary, Allergy and
`Rheumatology Products
`L. Steven Leshin, D.V.M., Ph.D.
`Molly Shea, Ph.D.
`Badrul Chowdhury, M.D., Ph.D.
`Philantha Bowen
`
`
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 203214 are owned by Pfizer or are data for which Pfizer
`has obtained a written right of reference. Any information or data necessary for approval
`of NDA 203214 that Pfizer does not own or have a written right to reference constitutes
`one of the following: (1) published literature, or (2) a prior FDA finding of safety or
`effectiveness for a listed drug, as described in the drug’s approved labeling. Any data
`or information described or referenced below from a previously approved application
`that Pfizer does not own (or from FDA reviews or summaries of a previously approved
`application) is for descriptive purposes only and is not relied upon for approval of NDA
`203214.
`
`
`Reference ID: 3154116
`
`1
`
`

`

`NDA 203214
`
`
`
`
`Reviewer: L.S. Leshin, DVM, PhD
`
`TABLE OF CONTENTS
`
` 1
`
` Executive Summary..................................................................................................... 9
`1.1
`INTRODUCTION.................................................................................................... 9
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 9
`1.3 RECOMMENDATIONS.......................................................................................... 20
`2 Drug Information........................................................................................................ 28
`2.1 DRUG............................................................................................................... 28
`2.2 RELEVANT INDS, NDAS, BLAS AND DMFS......................................................... 28
`2.3 DRUG FORMULATION ......................................................................................... 29
`2.4 COMMENTS ON NOVEL EXCIPIENTS..................................................................... 29
`2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ....................................... 29
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN .................................... 30
`2.7 REGULATORY BACKGROUND .............................................................................. 30
`3 Studies Submitted...................................................................................................... 32
`3.1
`STUDIES REVIEWED................................................................................