CENTER FOR DRUG EVALUATION AND _
`' RESEARCH
`
`APPLICATION NUMBER:
`
`21-926
`
`PHARMACOLOGY REVIEW(S)
`
`

`

`MEMORANDUM
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`Public Health Service
`
`Food and Drug Administration
`
`Division of Neurology Products (HFD-120)
`Center for Drug Evaluation and Research
`
`Date: April 15, 2008
`
`From: Lois M. Freed, Ph.D.
`Supervisory Pharmacologist
`
`Subject: NDA 21-926 (Treximet; sumatriptan/naproxen, Submissions 11 OCT 2007
`(Amendment 025) and 1 1 JAN 2008 (Amendment 026)
`
`The submission dated October 11, 2007 represents the sponsor’s Complete Response to
`the Agency’s Approvable letter (August 1, 2007). Briefly, the nonclinical issues were as
`follows:
`
`0
`
`Inconsistency between the negative results for naproxen in an in vitro mouse
`lymphoma tk assay submitted for Treximet and the positive results for naproxen
`in in vitro mouse lymphoma tk assays submitted for: — 7
`o The apparent synergistic genotoxicity finding in the in vitro chromosomal
`aberration assay in CHO cells when naproxen and sumatriptan were tested in
`combination; neither was positive when tested alone.
`
`Regarding the latter issue, the sponsor was asked to either demonstrate that the in vitro
`findings were not relevant to the in vivo situation or to assess the genotoxic potential of
`the combination (and naproxen alone) in vivo in humans.
`
`Four new study reports are included in this submission. These consist of (1) in vitro cell
`cycle analysis in CHO cells treated with various NSAIDs and Indoles (not including
`either naproxen or sumatriptan), (2) in vitro cell cycle analyses in CHO cells treated with
`naproxen sodium and sumatriptan succinate (2 studies) and (3) an open-label, placebo-
`controlled, parallel group study in healthy volunteers to assess the effects of MT 400
`tablets or naproxen sodium on the frequency of chromosomal aberrations in peripheral
`lymphocytes. These data have been reviewed by David Hawver, Ph.D.
`(Pharmacology/Toxicology Review, 4/15/08) and the in vivo study in humans has also
`been reviewed by David Jacobson-Kram, Ph.D. (Associate Director of
`Pharmacology/Toxicology, IO).
`
`

`

`Based on his review, Dr. Hawver has concluded that the sponsor has addressed the
`nonclinical issues stated in the Agency’s AE letter and that the nonclinical package for
`Treximet is sufficient to support approval.
`
`Nonclinical AE issues
`
`1. Regarding the apparently discrepant findings for naproxen, ie., the negative results
`obtainedIn the1n vitro mouse lymphoma tk assay conducted (by GSK) for Treximet and
`the positive responses in the same assaym
`——n
`the sponsor provided the following explanations:
`
`(a) Different concentrations of naproxen were used in the studies. “Thus, in the
`NAP arm of the repeated study (with S9 activation) the highest concentration
`tested only reduced RTG to 59% and was not excessively cytotoxic. In
`contrast, the positive findings with NAP in the earlier study (at concentrations
`of 150 & 300 ug/mL) reduced total growth to 32% and 12%, respectively,
`indicating significant toxicity, albeit at concentrations which were much lower
`than those used in the GSK study (1700 ug/mL)”.
`(b) “At GSK, a 3 hr treatment arm (with and without S9 activation) is the
`standard study design, whereas ’ _ used a 4 hr treatment arm (with
`S9 activation) in the earlier study.”
`(0) “As L5178Y mouse lymphoma cells have relatively short cycling times (~8-
`10 hrs), the 25% increase in treatment duration and increased NAP exposure
`likely contributes to the increased cytotoxicity and associated positive
`findings in the earlier — study. Moreover, since the repeated GSK
`mouse lymphoma TK+/- assay. . .was designed to investigate the genotoxic
`potentiation of the NAP/SS combination, the assessment of NAP alone was
`not a primary objective. The repeated GSK mouse lymphoma TK +/- assay
`was GLP/OECD compliant for the combination (i.e., the primary objective)
`and the positive controls induced the expected increase in mutant colonies,
`confirming the validity of this assay. The contribution of inter-laboratory
`variation, based on cell phenotype, passage number, compound batches, etc.,
`on’ the contradictory outcome of the two studies also cannot be excluded.”
`(d) “Finally, false positive in vitro findings in general are not uncommon in
`standard in vitro mammalian genotoxicity assays, especially at highly toxic
`exposure levels, and are considered by many to be unacceptably high...”
`
`0 Dr. Hawver concluded that “The sponsor’s points are valid, and adequately address this
`issue”. The sponsor has addressed this issue by suggesting potential differences in study
`conduct that might be responsible for the discrepant results. However, the only specific
`suggestion provided is that the 25% increase in duration of the short treatment arm and,
`therefore, exposure to NAP, “likely” contributed to the increased cytotoxicity and
`positive finding in the a! ; study. It is not intuitive that simply a 25% longer
`duration of exposure at <0. 1 times the concentration (i.e., 150 vs. 1700 ug/mL) would
`have resulted1n greater cytotoxicity. (Although a 3—hr treatment duration may be
`standard for GSK, the 4-hr duration used by — is acceptable. The OECD
`
`

`

`guidelines state that the duration of exposure “should be for a suitable period of time
`(usually three to six hours is effective).”) And, NAP was positive at a concentration
`associated with a RTG of 32%, which is not excessively cytotoxic in this assay. The
`sponsor provided no data to support this possibility, nor any of the other potential reasons
`suggested as explanations for the discrepant findings. Therefore, in my opinion the
`sponsor did not adequately address this issue.
`
`2. Regarding the apparently synergistic genotoxic effect when naproxen and sumatriptan
`were tested in combination in the in vitro chromosomal aberration assay in CHO cells,
`the sponsor conducted studies to address both of the recommendations of the Agency: (a)
`demonstrate that the in vitro result were not clinically relevant or (b) conduct a clinical
`trial to assess effects of naproxen alone and in combination with sumatriptan on
`peripheral lymphocytes.
`
`(a) It is the sponsor’s position that the reproducible synergistic effect observed in
`the in vitro chromosomal aberration assay in CHO cells with the combination of
`naproxen and sumatriptan was due to a synergistic inhibition of DNA synthesis,
`resulting in induction of chromosomal aberrations at high (i.e., not clinically
`relevant), excessively cytotoxic concentrations of the combination. To address the
`relevance of the in vitro data, the sponsor conducted 3 in vitro studies (all non-
`GLP), reviewed in detail by Dr. Hawver.
`
`In Study No. V27824, selected NSAIDs (e.g., diclofenac, ibuprofen) and indoles
`(tryptamine, serotonin) were tested in CHO cells for their effects on the cell cycle.
`All NSAIDs tested decreased the % of cells in S phase, while increasing the % of
`cells in G1 and Go phases. Serotonin and tryptamine tended to have the opposite
`effect. The sponsor stated that the combination of diclofenac and tryptamine
`resulted in potentiation of DNA synthesis arrest (i.e., increase in % of cells in S
`phase) and an associated synergistic effect on cytotoxicity.
`
`- Dr. Hawver agreed that the combination of diclofenac and tryptamine resulted
`in potentiation of DNA synthesis arrest, but not of cytotoxicity. Of note was that
`neither naproxen nor sumatriptan was tested, and no genotoxicity assessment was
`conducted. Therefore, in this study it was not possible to correlate effects on cell
`cycle with effects on chromosomal aberrations. The sponsor did provide a copy of
`a published study by Reddy et al. (Reddy MV et al. Environ Mole Mutagen 40: l -
`17, 2002) that demonstrated that inhibition of DNA synthesis may result in
`induction of chromosomal aberrations. This study, however, also reported no
`increase in the chromosomal aberrations in cultured CHO cells treated with
`tryptamine, even though, at the concentrations tested, tryptamine induced “a
`strong, dose—dependent inhibition of DNA synthesis. ..” Therefore, these data
`would suggest that a “strong” inhibition of DNA synthesis (i.e., cell cycle delay)
`does not invariably lead to an increase in chromosomal aberrations in this system.
`
`Study No. V27836 assessed in cultured CHO cells the effects of naproxen and
`sumatriptan alone and in combination on cell cycle; CHO cells were exposed to
`
`

`

`test articles for 24 hr treatment duration. Only effects on cell cycle and
`cytotoxicity were assessed; genotoxicity was not measured. The data indicate that
`the combination of naproxen and sumatriptan produced a concentration-dependent
`decrease in the % of cells in S phase, greater than either compound alone.
`
`0 Dr. Hawver concluded that the data suggested an additive effect of the
`combination. Unfortunately, assessment of genotoxicity was not conducted in this
`study and combinations associated with genotoxicity in the in vitro CHO cell
`assays previously submitted to NDA 21-926 are not similar to those tested in this
`study. Therefore, the results of this study do not adequately support the sponsor’s
`proposed mechanism.
`
`Study No. V27862 also assessed in cultured CHO cellsthe effects of naproxen
`and sumatriptan alone and in combination on cell cycle; CHO cells were exposed
`to test articles for 3 and/or 24 hrs as in Study No. V27836. The results of this
`'
`study were inconclusive since none of the experiments tested naproxen alone,
`sumatriptan alone, and the combination of naproxen and sumatriptan.
`
`0 Dr. Hawver concluded that naproxen, sumatriptan, and the combination reduced
`the % of cells in S phase, but that the magnitude of the effect of each cannot be
`compared since they were not all tested in any one experiment. Also, since
`genotoxicity data were not collected, effects on cell cycle, cytotoxicity, and
`chromosomal aberrations could not be correlated.
`
`(b) The sponsor conducted an “Open-Label, Placebo-Controlled, Parallel Group
`Study in Healthy Volunteers...” in order to assess the potential for a synergistic
`genotoxicity effect of the combination of naproxen and sumatriptan directly in
`humans. The study (MT400-108) was conducted in a total of 42 non-smoking
`healthy volunteers. According to Dr. Hawver, potential subjects were screened at
`baseline for “abnormal cell cycle proliferation, stable chromosomal
`rearrangements or abnormally high background chromosomal aberration
`frequencies”. MT 400, naproxen sodium (550 mg), or placebo were administered
`to 5/sex/grp bid. for 7 consecutive days. Blood samples were collected on Day 1
`and 24 and 48 hr after the final dose (Day 7); only the 24,—hr samples were used
`for analysis of chromosomal aberrations in peripheral lymphocytes.
`
`No increase in number of cells containing chromosomal aberrations was detected
`with either MT 400 or naproxen sodium.
`
`0 This study report was reviewed by Drs. Hawver and Jacobson—Kram. There is
`agreement that the study was adequately conducted and negative.
`
`

`

`Conclusion
`
`In my opinion, the sponsor did not adequately address the inconsistencies in the in vitro
`mouse lymphoma assay results for naproxen. Although a number of possible reasons
`were proposed, no data or other information was provided to demonstrate that any or all
`of the suggested differences in the conduct of the GSK and the —— ; assays
`actually accounted for the discrepant results.
`'
`
`It is also my opiniOn that, while the sponsor did provide data suggesting that delays in
`cell cycling may be contributory, the synergistic genotoxic effect of the combination of
`naproxen and sumatriptan in the in vitro chromosomal aberration assay in CHO cells
`cannot be completely dismissed based on the data provided by the sponsor. Reasons for
`this are as following:
`
`None of the new in vitro studies was designed to demonstrate a correlation
`between effects on cell cycle and on induction of chromosomal aberrations. The
`variability between studies is sufficiently large to preclude definitive assessment
`when each effect is tested in separate studies, particularly when the studies are
`conducted years apart.
`The data provided by the sponsor in this submission did not demonstrate a clear
`synergistic effect of naproxen and sumatriptan on cell cycle or a relationship
`between inhibition of the cell cycle and induction of chromosomal aberrations for
`these compounds. The sponsor did provide published literature that demonstrated
`this relationship for some compounds; however, tryptamine was a notable
`exception.
`The sponsor attempted to demonstrate that the synergistic effect of naproxen and
`sumatriptan on chromosomal aberrations occurred only at excessively cytotoxic
`concentrations based on inhibition of population doubling. It is the sponsor’s
`position that for compounds that inhibit the cell cycle, population doubling is a
`more appropriate parameters for assessing cytotoxicity than, e.g., relative cell
`growth. The sponsor provided several published articles that support this position.
`However, it is not clear to me that there is consensus among experts on this issue.
`In addition, it is unclear from the sponsor’s data and discussion what the
`quantitative relationship is between decreases in population doubling and
`induction of chromosomal aberrations, i.e., what is the magnitude of the effect on
`population doubling that would be reasonably expected to result in a clastogenic
`effect. It is also important to note that the population doubling data were quite
`variable. For example, in Study No. V27862, inhibition of population doubling
`(PD) was markedly inconsistent and non-concentration related at combinations of
`naproxen and sumatriptan ranging from 500/500 to 2000/2000 ug/mL; inhibition
`of PD was 0% at 1675/1675 and 1745/1745 ug/mL, but 100% at 1710/1710
`
`ug/mL.
`
`There does not appear to be a way to further assess the clinical relevance of the
`synergistic in vitro genotoxicity results in nonclinical studies, and in vivo measurement
`of test article effects on circulating lymphocytes is a recognized strategy for assessing
`
`

`

`potential clastogenicity in humans. Although the sponsor did not adequately address all
`the issues in the Agency’s AE letter, I believe that the data from the clinical trial
`demonstrating no genotoxic effects of naproxen either alone or in combination with
`sumatriptan is sufficient to support approval of the application.
`
`Recommended labeling
`
`I would recommend retaining the labeling conveyed to the sponsor in the AE letter, with
`the following changes (designed by bold and strikethroughs):
`
`

`

`r
`
`w
`
`The combination of sumatriptan and naproxen sodium was negative in an in vitro
`mouse lymphoma tk assay in the presence and absence of metabolic activation. However,
`in separate in vitro mouse lymphoma tk assays, naproxen sodium alone was reproducibly
`positive in the presence of metabolic activation.
`Naproxen sodium alone and in combination with sumatriptan was positive in
`an in vitro clastogenicity assay in mammalian cells in the presence and absence of
`metabolic activation. The clastogenic effect for the combination was reproducible
`within this assay and was greater than observed with naproxen sodium alone.
`Sumatriptan alone was negative in this assay.
`Chromosomal aberrations were not induced in peripheral blood lymphocytes
`following 7 days of twice daily dosing with Treximet in human volunteers.
`In previous studies, sumatriptan alone was not mutagenic in two gene mutation
`assays (the Ames test and the in vitro Chinese Hamster V79/HGPRT assay) and was not
`clastogenic in two cytogenetics assays (the in vitro human lymphocyte assay and the in
`vivo rat micronucleus assay).
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Lois Freed
`
`4/15/2008 03 :48 : 08 PM
`PHARMACOLOGI ST
`
`

`

`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`-
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION
`
`NDA NUMBER:
`
`SERIAL NUMBER:
`
`21-926
`
`025 & 026
`
`DATE RECEIVED BY CENTER:
`PRODUCT:
`
`11 OCT 2007 (025) & 11 JAN 2008 (026)
`Treximet
`
`INTENDED CLINICAL POPULATION:
`
`Migraine patients
`
`Sumatriptan/Naproxen combination tablet
`
`SPONSOR:
`DOCUMENTS REVIEWED:
`
`REVIEW DIVISION:
`PHARM/TOX REVIEWER:
`
`PHARM/TOX SUPERVISOR:
`
`DIVISION DIRECTOR:
`PROJECT MANAGER:
`
`POZEN Inc., Chapel Hill, NC
`eNDA
`
`Division of Neurology Products
`David B. Hawver, Ph.D.
`
`Lois M. Freed, PILD.
`
`Russell Katz, M.D.
`Lana Chen
`
`Date of review submission to Division File System (DFS): 15 APR 2008
`
`

`

`TABLE OF CONTENTS
`
`Executive Summary .............................................................................................. 3
`
`2.6 PHARMACOLOGY/TOXICOLOGY REVIEW................................................. 5
`
`INTRODUCTION AND DRUG HISTORY.................................................................... 5
`
`2.6.1
`
`2.6.2
`2.6.2.1
`2.6.2.2
`2.6.2.3
`2.6.2.4
`2.6.2.5
`
`PHARMACOLOGY .................................................................................................................... s
`
`Brief summary ......
`8
`
`Primary pharmacodynamics
`.. 8
`Secondary pharmacodynamics ..
`.. 8
`
`Safety pharmacology .................................................................................................................. 8
`Pharmacodynamic drug interactions ........................................................................................... 8
`
`2.6.3
`
`PHARMACOLOGY TABULATED SUMMARY..................................................................... 8
`
`2.6.4
`2.6.4.1
`
`PHARMACOKINETICS/TOXICOKINETICS ........................................................................ 9
`Brief summary ............................................................................................................................ 9
`
`2.6.5
`
`PHARMACOKINETICS TABULATEd SUMMARY.............................................................. 9
`
`10
`2.6.6
`TOXICOLOGY ...................................................................................
`10
`2.6.6.1 Overall toxicology summary ..
`
`10
`2.6.6.2 Single-dose toxicity ................
`
`2.6.6.3 Repeat-dose toxicity .......................................................................................'.............................. 10
`2.6.6.4 Genetic toxicology .................................................................................................................... 10
`Cell Cycle Analysis in CHO Cells Treated with Various NSAIDs and Indoles, Individually and in
`Combination (Study No. V27824) .................................................................................................... 1 1
`Investigative Study: Cell Cycle Analysis Using Chinese Hamster Ovary Cells Treated with a 1:1
`Combination of Naproxen Sodium and Sumatriptan Succinate (NON-MONITORED STUDY)
`(Study No. V27862) ......................................................................................................................... 22
`Investigative Study: Cell Cycle Analysis Using Chinese Hamster Ovary Cells Treated with
`Naproxen Sodium and Sumatriptan Succinate Individually and in Combination (NON-
`MONITORED STUDY) (Study No. V27836) ................................................................................. 28
`Open-Label, Placebo-Controlled, Parallel Group Study in Healthy Volunteers to Evaluate the
`Effects of MT 400 Tablets or Naproxen Sodium Tablets on Chromosomal Aberrations in Peripheral
`Blood Lymphocytes (Study MT400-108)......................................................................................... 33
`
`2.6.6.5
`Carcinogenicity ............................................
`37
`
`2.6.6.6
`Reproductive and developmental toxicology.............
`37
`
`2.6.6.7
`Local tolerance ..........................................................
`37
`
`2.6.6.8
`Special toxicology studies ......
`37
`
`2.6.6.9 Discussion and Conclusions ..................................................................................................... 37
`2.6.6.10
`Tables and Figures ................................................................................................................ 37
`
`Sponsor’s response to issues in 01 AUG 2007 approvable letter ............................................................ 38
`
`OVERALL Summary and recommendations:......................................................................................... 48
`
`Reviewer’s Conclusions: ............................... 50
`Recommendations: .....
`51
`
`Suggested Labeling: ................................................................................................................................. 52
`
`

`

`
`
`Reviewer: David B. Hawver Ph.D. NDA No. 21-926
`
`EXECUTIVE SUMMARY
`
`1.
`
`Recommendations
`
`A. Recommendation on approvability
`
`The nonclinical package is adequate to support an approval action for NDA
`21-926 TREXIMET (sumatriptan succinate/naproxen sodium) Tablets for the
`acute treatment of migraine.
`
`B. Recommendation for nonclinical studies: None
`
`C. Recommendations on labeling
`
`/'
`
`

`

`
`
`Reviewer: David B. Hawver Ph.D. NDA No. 21-926
`
`II.
`
`Summary of nonclinical findings
`
`A. Brief overview of nonclinical findings
`
`The current Complete Response to Approvable Letter (submitted October 11,
`2007 at Amendment #025) contained the following items:
`0
`a detailed explanation of the factors that might account for the discrepancy in
`the mouse lymphoma assay results with naproxen sodium
`three nonclinical studies evaluating the effects of NAP and SS (2 studies) or
`other NSAIDs and indoles (tryptamine and serotonin) on the cell cycle in
`CHO cell cultures
`
`0
`
`0
`
`a study of the clastogenic potential of naproxen alone and in combination with
`sumatriptan in humans (submitted as Amendment #026 on January 11, 2008)
`
`The sponsor has adequately addressed the issues raised in the Approvable Letter
`of August 1, 2007. The explanation for the discrepancy in the findings for
`naproxen sodium in the two mouse lymphoma assays included several factors
`(e.g., treatment period of 4 vs. 3 hrs, higher levels of cytotoxicity) that could
`reasonably account for the positive results in the earlier study. The nonclinical
`studies presented a compelling case that the combination of NAP and SS can
`profoundly disrupt the cell cycle at concentrations well below those inducing
`cytotoxicity and clastogenicity. This reviewer considers it reasonable to conclude
`that the profound inhibition of DNA synthesis induced by NAP/SS may
`contribute to the clastogenicity observed at very high concentrations (2 7.6 mM
`NAP; 2 5.9 mM SS) of this combination in CHO cells (though it is not clear how
`widely accepted this proposed link is). If the clastogenicity induced by NAP/SS
`was caused by indirect effects on DNA, then it is reasonable to consider the large
`safety margins (~30-fold for NAP, ~30,000-fold for SS) between the clastogenic
`in Vitro concentrations and the maximum clinical plasma concentrations in
`evaluating the risk to patients. The lack of significant increases in the frequency
`of cells with chromosomal aberrations in peripheral lymphocytes collected from
`humans treated for 7 days with the maximum recommended daily dose of
`Treximet (compared to placebo) provides additional assurance that the risk of
`genotoxicity in humans is reasonable.
`
`B. Pharrnacologic activity: No new pharrnacologic activity studies were
`conducted.
`
`C. Nonclinical safety issues relevant to clinical use: None.
`
`

`

`
`
`Reviewer: David B. Hawver Ph.D. NDA No. 21-926
`
`2. 6 PHARMACOLOGY/TOXICOLOGY REVIEW
`
`2.6.1
`
`INTRODUCTION AND DRUG HISTORY
`
`NDA number: 21-926
`Review number: 3
`
`Sequence number: 025 & 026
`Date of submission: 11 OCT 2007 (025) & 11 JAN 2008 (026)
`Type of submission: NDA 505 (b)(2) Resubmission—Complete Response to 01 AUG
`2007 Approvable Letter (025); Amendment containing Final Study Report MT400- 108
`Information to sponsor: Yes (X) No ()
`Sponsor and/or agent: POZEN Inc., Chapel Hill, NC
`Manufacturer for drug substance:
`Sumatriptan Succinate (SS): Glaxo Wellcome Manufacturing Pte Limited, Singapore
`Naproxen Sodium (NAP): ‘
`
`Reviewer name: David B. Hawver, Ph.D.
`Division name: Division of Neurology Products
`HFD #:
`120
`
`Review completion date:
`
`15 APR 2007
`
`Drug:
`
`Trade name: Treximet
`
`Generic name: sumatriptan succinate/naproxen sodium
`Code name: MT400
`Chemical name:
`SS: 3-[2-(dimethylamino)ethyl]-N-methyl-indole-5-methanesulfonamide succinate (1:1)
`NAP: (S)-6-methoxy-(alpha)—methyl-2-naphthaleneacetic acid, sodium salt
`CAS registry number:
`103628-48-4 (sumatriptan succinate)
`26159-34-2 (naproxen sodium)
`Molecular formula/molecular weight:
`sumatriptan succinate: C14H21N3028-C4H604 MW 413.5
`naproxen sodium: C14H13 NaO3 MW 252.25
`Structure:
`
`I“
`meow-
`
`P‘bCO
`
`(Eli
`Kc":
`com
`
`C02H
`
`- E
`
`lH
`
`meme
`
`sumatriptan succinate
`
`naproxen sodium
`
`

`

`
`
`Reviewer: David B. Hawver Ph.D. NDA No. 21-926
`
`Relevant INDs/NDAs/DMFs:
`
`IND 68,435 MT 400 for migraine, POZEN’s current IND for sumatriptan/naproxen
`combined in one ~ tablet; submitted 18 DEC 2003
`IND 60,669 MT 400 for migraine, POZEN’s initial IND for sumatriptan/naproxen using
`marketed products in combination; submitted 26 JUL 2000
`NDA 20-132 IMITREX® Tablets, sumatriptan succinate for migraine; Glaxo Inc.;
`approved 01 JUN 1995
`NDA 17-581 NAPROSYN® Tablets, naproxen for rheumatoid arthritis, now also for
`acute pain, ankylosing spondylitis, tendonitis, bursitis, and acute gout; Roche
`(originally Syntex, Inc.); approved 11 MAR 1976
`NDA 18-164 ANAPROX® Tablets, naproxen sodium for rheumatoid arthritis,
`osteoarthritis, ankylosing spondylitis, and juvenile arthritis; Roche/Syntex; approved
`04 SEP 1980
`
`‘
`
`Drug class:
`Sumatriptan succinate is a selective 5-HTID receptor agonist.
`Naproxen sodium is a nonsteroidal anti-inflammatory drug (NSAID).
`
`Intended clinical population:
`The proposed indication for Treximet Tablets is for the treatment of acute migraine
`headache with or without aura in adults.
`
`Clinical formulation:
`
`Each Treximet Tablet contains 119 mg sumatriptan succinate (equivalent to 85 mg
`sumatriptan) and 500 mg naproxen sodium. Inactive ingredients (which are all GRAS for
`use in oral pharmaceuticals) include: m (microcrystalline cellulose),
`croscarmellose sodium, dibasic calcium phosphate, magnesium stearate, microcrystalline
`cellulose, a , sodium bicarbonate and talc; the aqueous film coat contains sodium
`carboxymethyl-cellulose, maltodextrin, dextrose monohydrate, titanium dioxide, lecithin
`and FD&C Blue No. 2.
`
`Route of administration: Oral tablet
`
`Disclaimer:
`
`.
`
`Tabular and graphical information are constructed by the reviewer unless cited otherwise.
`
`

`

`Reviewer: David B. Hawvcra Ph.D.
`
`NDA No. 21-926
`
`Data reliance:
`
`Except as specifically identified below, all data and information discussed below and
`necessary for approval of NDA 21-926 are owned by POZEN Inc. or are data for which
`POZEN Inc. has obtained a written right of reference. Any information or data necessary
`for approval of NDA 21-926 that POZEN Inc. 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 fi'om a previously
`approved application that POZEN Inc. 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 21-926.
`
`Studies reviewed within this submission:
`
`0
`
`0 Cell Cycle Analysis in CHO Cells Treated with Various NSAIDs and Indoles,
`Individually and in Combination (Study No. V27824)
`Investigative Study: Cell Cycle Analysis Using Chinese Hamster Ovary Cells Treated
`with Naproxen Sodium and Sumatriptan Succinate Individually and in Combination
`(NON-MONITORED STUDY) (Study No. V27862)
`Investigative Study: Cell Cycle Analysis Using Chinese Hamster Ovary Cells Treated
`with a 1:1 Combination of Naproxen Sodium and Sumatriptan Succinate (NON-
`MONITORED STUDY) (Study No. V27836)
`0 Open-Label, Placebo-Controlled, Parallel Group Study in Healthy Volunteers to
`Evaluate the Effects of MT 400 Tablets or Naproxen Sodium Tablets on
`Chromosomal Aberrations in Peripheral Blood Lymphocytes (Study MT400-108)
`
`0
`
`Studies not reviewed within this submission: None.
`
`

`

`
`
`Reviewer: David B. Hawver Ph.D. NDA No. 21-926
`
`2.6.2 PHARMACOLOGY
`
`2.6.2.1 Brief summary
`
`No Pharmacology studies were included in this submission.
`
`2.6.2.2 Primary pharmacodynamics
`
`2.6.2.3 Secondary pharmacodynamics
`
`2.6.2.4 Safety pharmacology
`
`2.6.2.5 Pharmacodynamic drug interactions
`
`2.6.3 PHARMACOLOGY TABULATED SUMNIARY
`
`2.6.3.2 Primary Pharmacodynamics
`
`2.6.3.3 Secondary Pharmacodynamics
`
`2.6.3.4. Safety Pharmacology
`
`

`

`Reviewer: David B. Hawver Ph.D.
`
`NDA No. 21-926
`
`2.6.4 PHARMACOKINETICS/TOXICOKINETICS
`
`2.6.4.1 Brief summary
`
`No Pharmacokinetics/Toxicokinetics studies were included in this submission.
`
`2.6.5 PHARMACOKINETICS TABULATED SUMNIARY
`
`on ofiginO‘
`
`

`

`
`
`Reviewer: David B. Hawver Ph.D. NDA No. 21-926
`
`2.6.6 TOXICOLOGY
`
`2.6.6.1 Overall toxicology summary
`
`2.6.6.2 Single-dose toxicity
`No single-dose toxicity studies were included in this submission.
`
`2.6.6.3 Repeat-dose toxicity
`
`No repeat-dose toxicity studies were included in this submission.
`
`2.6.6.4 Genetic toxicology
`
`The following genetic toxicology studies were submitted and are reviewed in this section:
`
`0
`
`0 Cell Cycle Analysis in CHO Cells Treated with Various NSAIDs and Indoles,
`Individually and in Combination (Study No. V27824)
`Investigative Study: Cell Cycle Analysis Using Chinese Hamster Ovary Cells Treated
`with a 1:1 Combination of Naproxen Sodium and Sumatriptan Succinate (NON-
`MONITORED STUDY) (Study No. V27862)
`Investigative Study: Cell Cycle Analysis Using Chinese Hamster Ovary Cells Treated
`with Naproxen Sodium and Sumatriptan Succinate Individually and in Combination
`(NON-MONITORED STUDY) (Study No. V27836)
`0 Open-Label, Placebo-Controlled, Parallel Group Study in Healthy Volunteers to
`Evaluate the Effects of MT 400 Tablets or Naproxen Sodium Tablets on
`Chromosomal Aberrations in Peripheral Blood Lymphocytes (Study MT400-108)
`
`0
`
`10
`
`

`

`Reviewer: David B. Hawver, PhD.
`
`NDA No. 21-926
`
`Cell Cycle Analysis in CHO Cells Treated with Various NSAIDs and Indoles,
`Individually and in Combination (Study No. V27824)
`
`(GSK Study #WD2007/01420-01; Initiated 13 SEP 2006, Completed 11 OCT 2007;
`conducted by GSK in the United Kingdom; no GLP or QA statement)
`
`The effect of 6 and 24 hour treatments of CHO cells with marketed non-steroidal anti-
`
`inflammatory drugs (NSAIDs: diclofenac, ibuprofen, indomethacin, piroxicam, and
`sulindac) and indoles (tryptamine and serotonin) were evaluated using flow cytometry to
`assess the % of cells in S phase, G1 phase, and G2/M phase. Additional studies were
`conducted with diclofenac and tryptamine, alone and in combination, assessing the % of
`cells in each phase of the cell cycle after 24-hr treatments. Evaluation of genotoxicity by
`counting micronucleated cells in each culture was planned, but results were not available
`due to a technical error. Vehicle controls and positive controls (hydroxyurea) were
`reported to have performed as expected in all assays. (Note: Data tables were not
`submitted, so results ofcontrols could not be verified.)
`
`As shown in the figures below, all of the NSAIDs dose-dependently reduced the
`percentage of cells in S phase and increased the % of cells in G1 and/or G2/M phase after
`6 and/or 24 hrs of treatment. In contrast, treatment with tryptamine induced increases in
`the % of cells in S phase and decreases in the % of cells in G1 and G2/M phase, and
`serotonin had very little effect on these parameters.
`
`Figure 15 below was very difficult to interpret, due to incomplete labeling and the lack of
`supporting data tables. However, this reviewer believes that Figure 15 shows that, in the
`presence of 100 ug/mL tryptamine (upper panels), 50 ug/mL diclofenac treatment for 24
`hrs induced an increase to ~90% cells in S phase, while higher concentrations of
`diclofenac shifted cells away from S phase, and back toward G1 and G2/M phases. At
`200 ug/mL diclofenac + 100 ug/mL tryptamine, only ~5% of cells were lefi in S phase,
`down from 60% in controls. In contrast, the presence of 300 ug/mL tryptamine (lower
`panels in Figure 15) altered the effect of diclofenac such that virtually all cells were
`“blocked” in S phase at 50, 100, and 200 ug/mL diclofenac.
`
`The sponsor concluded that treatment with the combination of diclofenac and tryptamine
`for 24 hrs induced a concentration-dependent potentiation of DNA synthesis arrest
`compared with each component alone, associated with “a synergistic in