`
`Reviewer: David B. Hawver Ph.D. NDA No. 21-926
`
`Left Ventricular -dP/dT:
`
`The mean increase in -dP/dT induced by SS was not statistically significantly affected by
`coadministration of 20 mg/kg IV NAP on Day 1 (p=0.43 86), Day 2 (p=0.9855), or Day 3
`(p=0.1455).
`
`Percent Increase in Ventricular -dPIdT
`
` Group Means
`
`(N=4—5 Dogs)
`
`Day 1
`SS
`214
`nglmL
`
`Day 2
`33
`19.6
`nglmL
`
`Day 3
`SS
`18.4
`nglmL
`
`Day 1
`SS
`19.0
`nglmL
`NAP
`79.2
`nglm L
`
`Day 2
`88
`18.8
`nglmL
`NAP
`40.9
`nglmL
`
`Day 3
`SS
`18.9
`nglmL
`NAP
`26.4
`nglmL
`
`Increase in Ventricular -dPIdT Induced by SS +l- NAP in Dog
`
`50.00%
`
`C
`
`.1102 61104
`
`40.00%
`
`40.00%
`
`Day 1 SS
`
`Day 2 SS
`
`Day 3 SS
`
`Day 1 SSINAP Day 2 SSINAP Day 3 SSINAP
`
`59
`
`

`

`NDA No. 21-926
`Reviewer: David B. Hawver Ph.D.
`
`In Phase III, the mean increase in -dP/dT induced by 200 ug/kg IV SS was not
`statistically significantly different with coadministration of 20 mg/kg IV NAP
`(p=0.3097).
`
`PHASE III
`
`Study 003" 106
`Table 20
`Maxlnul Increases in
`-dP/dT (mung/sec)
`
`200 yg/kg sunatrlptan
`
`20 mg/Kg Naproxen + 200 yg/kg Sumatriptan
`
`Dog
`10
`
`Baseline [a]
`
`Maximum
`-dP/dT [D]
`
`Change
`From
`Baseline
`
`[c]
`
`Baseline [a]
`
`Maximum
`-dP/dT [D]
`
`Change
`From
`Baseline [c]
`
`(Nap+Suna)
`- Suna
`
`1101(01
`1102
`1104
`1105[a]
`1107(01
`1100
`
`5464.8
`2683.8
`.
`
`2510.2
`
`6531.0
`4130.0
`
`2657.0
`
`1066.2
`1446.2
`
`5034.6
`2893.0
`
`6019.0
`3749.0
`
`984.4
`856.0
`
`—B1.B
`.5go,2
`
`46.8
`
`2874.4
`
`2879.0
`
`4.6
`
`-42.2
`
`Mean
`STD
`95% CI
`p-value
`
`
`-236.1
`305.6
`( —997.2.
`521.1)
`0.3097
`
`[3] The baseline values were obtained by taking the mean of the data collected during the 5 minute interval
`immediately proceeding sunatriptan (sunatriptan only) or naproxen (naproxen + sumatriptan).
`[b] Maxi-um -dP/dT during the first hour after sunatriptan administration.
`[c] Maximum -dPIdT - Baseline -dPIdT.
`[d] Period (.) denotes a missing value.
`
`Appears This Way
`On Original
`
`60
`
`

`

`
`
`Reviewer: David B. Hawver Ph.D. NDA No. 21-926
`
`Mean Change in -dP/dT Induced by SS +I- NAP
`
`140.00%
`
`120.00%
`
`100.00%
`
`20.00%
`
`80.00%
`
`60.00%
`
`40.00%
`
`0.00%
`
`Baseline 1
`
`200 uglkg SS
`
`Baseline 2
`
`200 uglkg SS
`+ 20 mglkg NAP
`
`Change in -dPIdT Induced by SS +/- NAP
`
`160.00%
`
`140.00%
`
`120.00%
`
`100.00%
`
`20.00% 0.00%
`
`80.00%
`
`60.00%
`
`40.00%
`
`
`
`
`IDog #1101
`
`IDog #1102
`
`DDog #1104
`
`DDog #1105
`IDog #1107
`
`IDog #1108
`
`
`
`
`Baseline 1
`
`200 uglkg SS
`
`Baseline 2
`
`200 uglkg SS
`+ 20 mg/kg NAP
`
`61
`
`

`

`
`Reviewer: David B. Hawver Ph.D. ,
`-
`NDA No. 21-926
`
`Deviations from Protocol:
`
`0 The LCX flow probe malfunctioned for Dog #1107 preventing collection of data on
`blood flow and other parameters dependent upon blood flow during all 3 phases.
`0 The carotid flow probe malfunctioned for Dog #1104 preventing collection of data on
`blood flow and other parameters dependent upon blood flow during Phase III only.
`Signal was lost from both LCX and carotid flow probes and " ' catheters, and
`from the LCX crystals (measuring diameter) in Dog #1105, so no assessments were
`made in Phase III for this animal.
`
`0
`
`Sponsor’s Conclusions:
`
`0
`
`0
`
`o
`
`“There were no statistically significant changes to the SS-induced response of the
`coronary and carotid arteries observed during Phase I as a result of combined
`administration of naproxen sodium (NAP) with SS during Phase II.”
`“There were no statistically significant, biologically relevant changes to the responses
`of the coronary and carotid arteries as a result of combined administration of NAP
`with SS,” during Phase III (200 ug/kg IV SS + 20 mg/kg IV NAP).
`“In conclusion, co-administration of NAP with SS did not alter the vasoconstrictive
`effect of SS on the coronary arteries of conscious, chronically instrumented female
`beagle dogs, nor did it alter any of the other cardiovascular parameters measured in
`this study.”
`
`Reviewer’s Conclusions:
`
`The Sponsor’s conclusion that Phases I and 11 showed no statistically significant changes
`is technically accurate, based on the paired t-test analyses of the differences between the
`SS-induced reductions in coronary and carotid artery diameter in the presence and
`absence of NAP. However, review of the group mean and individual animal data from
`Day 1 treatments revealed apparent trends toward NAP-related enhancement of SS-
`induced effects on coronary artery diameter, carotid artery diameter, mean arterial blood
`pressure (MAP), and coronary artery resistance. The importance of such trends is
`questionable, though, in the context of the wide inter-individual and intra—individual
`variation observed and the design flaws noted several paragraphs below.
`
`Four out of six dogs showed substantially (2- to 7-fold) greater SS-induced reductions in
`LCX coronary artery diameter in the presence (7-10%) vs. the absence (1-4%) of NAP on
`Day 1. The group average difference (~2-fold) did not reach statistical significance
`because one dog showed only a small change (~5.0% SS—> ~5.5% SS/NAP) and one
`(#1107) showed a change in the opposite direction (~8% SS—> ~3.5% SS/NAP).
`However, it is difficult to argue that these data demonstrate a consistent NAP effect when
`both the intra-individual (day to day) and inter-individual variation are so great.
`
`62
`
`

`

`
`
`Reviewer: David B. Hawver Ph.D. NDA No. 21-926
`
`The mean SS-induced reduction in LCX coronary artery resistance was ~4-fold greater
`with NAP than without on Day 1, yet this difference was not statistically significant, due
`to the high inter—individual variability in the SS alone group (from T10% to 123%). In
`this case, a hint of a possible NAP effect comes from the much lower variability among
`individuals in the Day 1 SS/NAP group (l17—26% in all 5 dogs).
`
`I
`
`The mean SS-induced reduction in carotid artery diameter was 2-fold greater with NAP
`than without on Day 1, yet, again, this difference was not statistically significant, due to
`the wide variability among individuals in the SS group (12-24%) and in the SS/NAP
`group (17-34%). Variation was also quite wide from day to day within each individual,
`arguing against the reliability of these data.
`
`The mean SS-induced increase in MAP was ~1.5-fold greater with NAP than without on
`Day 1, but this difference was not statistically significant, due to variability. One
`anomalous dog showed an increase in MAP of 29% with SS and -1% with SS/NAP, and
`two others showed little or no extra increase in MAP with NAP. The two dogs showing
`the greatest increase in SS-induced MAP increase with NAP (~3-fold), showed similar
`large increases on Day 3, when NAP levels had decreased 3-fold, and no increases on
`Day 2. These data suggest that the increases in MAP were due to technical problems, or
`unknown factors, rather than to the presence of SS/NAP.
`
`The Sponsor’s conclusions regarding Phase III are invalidated by the design flaws
`described in the third paragraph below.
`
`Study MT400-T15 was inappropriately designed. The N of 6 dogs was chosen to provide
`a power of > 80% to detect the mean reduction in external coronary arterial diameter
`(eCAD) of 1.37 um i' 21 (15.3% from baseline) induced by 100 ug/kg IV SS in
`conscious dogs {Cardet a/., 200/, BrJPflar/flac'o/liz1071-1083). However, the
`present study was intended to detect a Mange in that level of reduction (by NAP), not
`just the SS-induced reduction itself. Therefore a larger N would have been needed to
`provide a power of > 80% to detect an effect of NAP on SS-induced coronary artery
`vasoconstriction.
`
`It is not clear to this reviewer that the data derived from Days 2 and 3 of Phase II are
`informative, since having plasma levels of NAP still on‘board from an injection 24 or 48
`hrs before the fresh injection of SS is quite different pharrnacologically from the clinical
`condition of having rapidly rising plasma concentrations of both SS and NAP in the
`absence of recent prior exposure. Compensatory responses to the prolonged NAP
`exposure may even interfere with the SS-induced vasoconstriction. If lower doses of
`NAP are considered desirable to evaluate, they should be administered to a separate
`group of animals, or to the same animals after a sufficient washout period (at least 5 days,
`since the half-life of NAP in dogs is ~35—40 hrs). Also, given the variability observed,
`repeated measures at each dose, with appropriate washout intervals, would improve the
`reliability of the results.
`
`63
`
`

`

`Reviewer: David B. Hawver, Ph.D.
`
`NDA No. 21-926
`
`Most importantly, this study was inappropriately controlled. The changes attributed to SS A
`alone in Phase 1 were collected by recording the minimum or maximum (depending on
`whether that parameter had increased or decreased with IV SS treatment in Care] et al.
`[2001, BrJP/Eammco/ 132: 1071—1083]) change from baseline achieved during the one
`hour period after SS injection. Given the natural variation in these parameters over time,
`and the lack of a vehicle control for the SS injection, the “SS-induced” changes may not,
`in fact, be induced by SS at all. A vehicle control for the SS-injection is essential in this
`sort of min/max change from baseline within 1 hr paradigm. Carel et al. (2001) did not
`include a vehicle control injection, but they cited previous articlesflow Mei/grow
`demonstrating that “saline administration was devoid of any effect in this experimental
`setting. Even better, Carel et al. (2001) studied the entire range of the SS dose-response
`curve, including a dose (0.1 ug/kg) that induced no significant changes in any of the
`parameters tested. Inclusion of representative traces from the recordings of coronary and
`carotid artery diameter before and after injection of sumatriptan or frovatriptan also
`added credibility to the findings of Care] et al. (2001).
`
`Finally, since the half-life of SS in dogs is ~2 hrs, Phase 111 should have included a
`washout period of at least 10 hrs (rather than 1 hr) to allow for clearance of the first
`injection of SS before administration of the second dose of SS (+ NAP).
`Significant levels of SS were still on board, so the second “baseline” was not a true
`baseline, and the SS plasma levels were 65% higher than those after the first dose of SS.
`Therefore, any differences (or lack of differences) seen between the first SS treatment
`without NAP and the second with NAP may be due to the higher SS plasma levels rather
`than to the presence of NAP, so no conclusions can be reached. Also, NAP levels were
`apparently not measured in Phase III, and appropriate vehicle controls for SS and NAP
`were omitted.
`
`SS (ng/mL)
`
`40.5 (1.9 hrs)
`
`50.2 (6.2 hrs)
`
`26.5
`
`32.7
`
`79.2
`
` Comparison of Plasma Drug Levels Between Humans and Dogs
`
` NAP (ug/mL)
`
` Migraineurs: Cmax after one Trexima Tablet
`
`
` Migraineurs: 4 hrs after one Trexima Tablet
`
`
`
`
`19
`Dog Cmax at 80 ug/kg IV SS + 20 mg/kg NAP
`l l
`‘
`l
`
`
`
`(Reviwer’s Table)
`
`S
`
`The comparisons above illustrate that there is no clear margin of safety between plasma
`levels of SS in dogs exhibiting putatively SS-induced coronary artery vasoconstriction
`and those in human migraineurs 2-4 hrs after administration of one Trexima tablet.
`However, as discussed above, the lack of a vehicle control for IV SS in these experiments
`makes it impossible to know whether the reductions in coronary artery diameter observed
`were due to SS, the vehicle, the injection procedure, or natural variation.
`
`64
`
`

`

`
`
`Reviewer: David B. Hawver Ph.D. NDA No. 21—926
`
`In regard to NAP plasma levels, even if the Day 1 NAP Cmax values were to be
`considered a NOEL in dog for exacerbation of SS-induced coronary artery
`vasoconstriction, this study has established, at best, a ~2-fold margin of safety above
`mean human NAP plasma levels four hours after one Trexima tablet. In retrospect, the
`choice of 20 mg/kg IV NAP, based on published dog studies showing that 10-30 mg/kg
`IV NAP blocked prostaglandin synthesis almost immediately after single IV
`administration, seems arbitrarily low. A pilot tolerability and TK study would have
`facilitated a more informed decision.
`
`In summary, wide inter-individual and intra-individual variation observed in most
`parameters measured in this study made it impossible to draw reliable conclusions from
`these data regarding the potential of NAP to exacerbate the cardiovascular effects of SS.
`In addition, numerous serious design flaws, such as the lack of an appropriate control for
`the IV SS injection, call into question the validity of the study.
`
`Therefore, this reviewer does not concur with the Sponsor’s overall conclusion that “co-
`administration of NAP with SS did not alter the vasoconstrictive effect of SS on the
`
`coronary arteries of conscious, chronically instrumented female beagle dogs, nor did it
`alter any of the other cardiovascular parameters measured in this study.”
`
`This study should be considered invalid.
`
`65
`
`

`

`Reviewer: David B. Hawver, Ph.D.
`
`NDA No. 21-926
`
`An Investigational Range-Finding Study to Determine Coronary Blood Flow and
`Resistance Following Intravenous Administration of Sumatriptan Succinate to
`Anesthetized Beagle Dogs
`
`(POZEN Study #MT400-T17, -—_ ; Study # QCBW—0104,
`Abbreviated Report, Issued 29 JAN 2003; Study initiated 27 SEP 2002; Not GLP, Not
`QA)
`
`This pilot dog cardiovascular safety study was originally submitted to IND 60,669 #010
`20 AUG 2003, and was reviewed by this Reviewer (see Review in DFS).
`
`The intent of this pilot study in 5 anesthetized beagle dogs (1 F, 4 M) was to explore the
`effects of IV sumatriptan succinate (SS) on coronary arterial blood flow and coronary
`arterial resistance in preparation for a subsequent study examining the potential for
`naproxen sodium (NAP) to exacerbate the known vasoconstrictive effects of SS.
`However, the procedures used in this study failed to result in a reproducible dose-
`dependent reduction in coronary flow as a function of increasing IV doses of SS, up to
`1434 ug/kg, even after sensitizing two dogs with coronary artery stenosis and one dog
`with beta blocker pre-treatment.
`
`The sponsor was advised to make further attempts to assess the vasoconstrictive potential
`of the combination of sumatriptan and naproxen in an 1’12 Viz/0 model by adapting the
`protocol to include the coronary artery diameter measurement methodology successfully
`employed in the following publications: Gupta et al., (1995) BrJPfla/macol
`116(5):2385-2390; Gupta et al., (2000) Ez/r/Péarmam/398fl3-81; and Carel et al.,
`(2001) Br/Pflamzaco/132: 1071-1083. The publications by Gupta et al., described dose-
`dependent reduction in coronary artery diameter with sumatriptan i.v. 1-300 ug/kg in
`anesthetized dog preparations. Similarly, Carel et al. demonstrated a significant
`prolonged and dose-dependent decrease in mean external coronary artery diameter (after
`a transient fire/”ewe in diameter) with sumatriptan i.v. 0.1-100 ug/kg in a conscious dog
`preparation.
`
`66
`
`

`

`
`
`Reviewer: David B. Hawver Ph.D. NDA No. 21-926
`
`Pulmonafl effects:
`No Safety Pharmacology studies examining pulmonary effects were submitted.
`
`Renal effects:
`
`No Safety Pharmacology studies examining renal effects were submitted.
`
`Gastrointestinal effects:
`
`No Safety Pharmacology studies examining gastrointestinal effects were submitted.
`
`Abuse liability:
`No Safety Pharmacology studies examining the potential abuse liability were submitted.
`
`
`Other:
`
`No Safety Pharmacology studies examining other effects were submitted.
`
`Appears This WOV'
`0n Original
`
`67
`
`

`

`
`
` Reviewer: David B. Hawver Ph.D. NDA No. 21-926
`
`2.6.2.5 Pharmacodynamic drug interactions
`
`“No nonclinical drug interaction studies were conducted with the combination of
`sumatriptan succinate and naproxen sodium.” {afiec/ézflmz e/VDA 21-926 J/adzz/‘e 2,
`Sec/1'01! 2. of Page 12/
`
`2.6.3 PHARMACOLOGY TABULATED SUMMARY
`
`2.6.3.2 Primary Pharmacodynamics
`“No primary pharmacodynamic studies were conducted with the combination of
`sumatriptan succinate and naproxen sodium as the individual components have already
`been well characterized.” {airflow/flaw e/VDA 21-926, film/21k 2, Sec/1'01: 2 of Page 49
`
`2.6.3.3 Secondary Pharmacodynamics
`“No secondary pharmacodynamic studies were conducted with the combination of
`sumatriptan succinate and naproxen sodium as the individual components have already
`been well characterized.” fla’z’recz‘é/flom e/VDA/ 21—925, fl/ozz’z/le 2, Sec/1'0” 2. of Page 49
`
`2.6.3.4. Safety Pharmacology
`
`Toot Article: Sumatriptln Succlnm (SSP Alone or in Combination with Naproxon Sodium (NAP)I
`
`Macaw [Shin
`
`No. par
`
`Escalating 88;
`0.7, 71- 72,712-
`717 1424-1434
`Moment»)
`
`Biolog'edly meaningful Sfirelatod changes
`hoormaryaterflbloodflowmdealaflad
`mnmyartanalvasulmresmmmnot
`mmwmmfimdss.
`
`MT400-T17‘
`
`MT400-T15*
`
`1;0.1.1,10,100, '
`
`Co-adnidshafimofNAPwimSdemt
`siwifiemtiyaltorthevasooonstridive
`(decreaseddarnetar)eflectot883|oneon
`lheoormaryandcarotidaneriesof
`omsdws unanimity instrunented ferrule
`boastedooslhmwerealsonosufiedty
`www-nemmmm
`MotNAPonSSformm
`WWMW. blood
`prawnWlammpm.
`ooronarylcuofidbloodflowandmistanoo)
`evahlatedinlhissmdy.
`
`'Smniptansmdnatedosamcalcnlamdasflnbm Naproxmsodimndosawereulculated‘asfllesah
`bPluseI(wavavehicle£ollawodbyss)andthseH(NAP£oflmvedbySS)wexe“pumedbya1--weekwashwtpaiod.
`‘Phasemwascomhcwdinasingleday widldzoméombawemnosel(SSonly)andDoseZ(NAPfoflawedbySS).
`Wmmysramdinmzmu
`'WxihensrmnuyisfinmdinSecfimZ.6.242.
`
`.
`
`II and Ill
`
`.
`
`2)Phaselll°
`
`(directlyfrom eNDA 21 -926, Module 2, Section 2.6, Page 13)
`
`68
`
`

`

`Reviewer: David B. Hawvera Ph.D.
`
`NDA No. 21-926
`
`2.6.4 PHARMACOKINETICS/TOXICOKINETICS
`
`2.6.4.1 Brief summary
`
`“Nonclinical pharmacokinetic studies were not conducted for the sumatriptan succinate
`and naproxen sodium combination, as the pharmacokinetic profiles of the individual
`components have already been well characterized.” {at‘mc/ézflom e/VDA/ 21-926, film/ale
`2, Sec/1'0” 2. 07 Page 16/
`
`Toxicokinetic information and tables are included within the reviews of each individual
`
`study in the Safety Pharmacology and Toxicology sections. APPENDIX 1 contains
`human PK data.
`
`2.6.5 PHARMACOKINETICS TABULATED SUMNIARY
`
`“Nonclinical pharmacokinetic studies were not conducted for the sumatriptan succinate
`and naproxen sodium combination, as the pharmacokinetic profiles of the individual
`components have already been well characterized.” {drag/flow 6/1101 21-926 Module
`2, Sec/1'01: 2. o: Page [7/
`
`Appears This Way
`On Original
`
`69
`
`

`

`
`
`Reviewer: David B. Hawver Ph.D. NDA No. 21-926
`
`2.6.6 TOXICOLOGY
`
`2.6.6.1 Overall toxicology summary
`
`General toxicology:
`General toxicology studies included two 90-day mouse studies (MT400-T05 and MT400-
`T19), one 28-day mouse study (MT400-T02), two 28-day rat studies (MT400-T01 and
`'
`MT400-T04, both without histopathology evaluation), and one 28-day minipig study
`(MT400-T03, with inaccuracies in dosing solutions of i 15-26%). In all of these studies,
`groups administered high doses of naproxen sodium (NAP), with or without sumatriptan
`succinate (SS), demonstrated changes consistent with the known toxicities of non-
`steroidal anti-inflammatory drugs (NSAIDs): GI inflammation, erosion, ulcer, peritonitis,
`and/or reactive hyperplasia; changes secondary to the GI changes (mild increases in
`WBC count, neutrophils, reticulocytes and platelets; increased absolute and relative
`weights of spleen and/or liver; increased erythroid extramedullary hematopoiesis in
`spleen and/or liver; mild reductions in RBC count, HGB, and HCT; and/or decreased
`serum total protein and albumin); and/or renal toxicity (tubular dilatation and/or
`regeneration). No toxicities were attributed to SS.
`
`In the pivotal 90-day mouse study (MT400-T19), the high dose female (HDF) SS/NAP
`group (320—)210 mg/kg/day SS + 50 mg/kg/day NAP) showed greater GI toxicity than
`the corresponding HDF NAP alone group (50 mg/kg/day NAP), despite 31% lower NAP
`AUC in the SS/NAP group. In the same study high dose male (HDM) SS/NAP mice
`showed greater GI toxicity than HDM NAP alone mice, but this could be because NAP
`' exposure was 37.5% higher in the SS/NAP group. Hence, it appeared that
`coadministration of SS may have exacerbated the GI toxicity of NAP in the HDF group
`in this study. Data from the 28—day mouse study, however, which tested higher doses of
`both drugs and appeared to be a more reliable study, showed greater GI toxicity in
`females given 75 mg/kg/day NAP alone than when combined with 160, 320, or 500
`mg/kg SS. Males in the 28-day mouse study showed no ulcers or erosions at 75
`mg/kg/day NAP with or without 500 mg/kg/day SS. The extent of NAP-related toxicity
`in the presence and absence of SS was not notably different in the rat and minipig studies.
`
`The incidence of NAP-related GI toxicity and associated changes observed in HDM and
`HDF SS/NAP groups after 90 days of treatment was notably reduced in parallel groups
`allowed to recover for 4 weeks, suggesting reversibility.
`
`NAP plasma exposures (AUCo.m)rat the highest no observed adverse effect (NOAEL)
`dose (110/30 mg/kg/day SS/NAP) in mouse study MT400-T19 were 0.32 times (F) and
`0.13 times (M) those observed in humans after a single dose of TREXIMA during a
`migraine. Thus, there is no margin of safety for NAP-induced GI toxicity based on this
`study.
`
`70
`
`

`

`
`
`Reviewer: David B. Hawver Ph.D. NDA No. 21-926
`
`SS alone was not toxic in mouse study MT400-T19 at 320/(210) mg/kg/day in F, and at
`320 mg/kg/day in M, yielding wide margins of safety: 117—fold and 152-fold,
`respectively, above expected human exposures, based on AUC.
`
`Genetic toxicology:
`SS and NAP, alone and in combination, were negative in an ['12 VIZ/’0 bacterial
`mutagenicity assay and an 1'12 Viz/0 mouse micronucleus assay. High dose NAP i high
`dose SS was positive in the CHO cell chromosomal aberrations assay, in the presence or
`absence of metabolic activation, in association with moderate, but not excessive,
`cytotoxicity. SS was not genotoxic alone, but there was some evidence to suggest that SS
`might exacerbate the genotoxicity of NAP.
`
`Carcinogenicity:
`No carcinogenicity studies were submitted for Trexima, and none were required, since
`the components are currently marketed in the US. for chronic or chronic/intermittent use,
`and since the new non-clinical studies conducted with SS/NAP did not yield any findings
`suggesting increased carcinogenic potential for SS/NAP in combination compared to SS
`or NAP alone.
`
`Reproductive toxicology:
`Reproductive and developmental toxicity studies with SS and NAP included a definitive
`embryo-fetal development study in pregnant rabbits, and dose-ranging embryo-fetal
`development studies in rabbit and rat. In the definitive embryo-fetal development study in
`rabbits, significant reductions in maternal and fetal weights were observed even at the
`lowest combination dose tested, but significant increases in resorption parameters and
`specific malformations and variations were only observed in HD NAP groups i SS. The
`rabbit dose-ranging study showed reductions in maternal body weight gain (BWG) with
`increasing dose of SS in combination with the high dose of NAP, reduction of fetal BW
`at HD SS/NAP, increased resorption parameters at HD NAP i SS, and increased gross
`external malformations at HD NAP + LD and HD SS. The rat dose-ranging study showed
`reduced maternal BWG and fetal BW with increasing SS dose in the presence of HD
`NAP, but no treatment-related changes in resorption parameters or fetal gross external
`malformations or variations.
`
`Taken together, the three embryo—fetal toxicity studies demonstrated that NAP and SS
`toxicities resulting in reduction maternal and fetal body weights appeared to be additive.
`In contrast, increases in resorption parameters and incidence of malformations and
`variations observed in animals treated with HD NAP were not consistently exacerbated
`by coadministration of HD SS. Also, the teratogenic effects attributed to NAP were only
`observed at doses well above those that were maternally toxic.
`
`Special toxicology:
`No special toxicology studies were submitted.
`
`2.6.6.1 Single-dose toxicity
`No single-dose toxicity studies were submitted.
`
`71
`
`

`

`
`Reviewer: David B. .Hawver Ph.D.
`NDA No. 21-926
`
`2.6.6.3 Repeat-dose toxicity
`
`A 28-Day Oral Gavage Dose Range-Finding Toxicity Study in Female Gottingen
`Minipigs with Naproxen Sodium and Sumatriptan Succinate
`
`(POZEN Study #MT400-T03, ‘ Study #02-3499, Final report
`completed 24 FEB 2004, GLP (except for endoscopy), QA; Sumatriptan Succinate (SS)
`Lot #QTO 1004, Purity 99.5%; Naproxen Sodium (NAP) Lot #NPXNAM-l27, L002662,
`Purity 99.2%; SS doses were calculated as sumatriptan base)
`
`Methods:
`
`Female Gottingen minipigs (3/group) were given SS and NAP in the following
`combinations for 28 days via oral gavage using water as the vehicle: 0/0, 10/ 100, 50/ 100,
`100/ 100, 150/100, 100/0, 0/ 100, and 0/ 125 SS/NAP mg/kg/day). Parameters measured
`included: viability, clinical observations, eye exam, ECG, body weight (BW), food
`consumption (FC), toxicokinetics (collected but not performed because the study was
`considered invalid), clinical pathology (pre-dose and at termination), organ weights
`(surviving animals), necropsy (all animals), histopathology (all animals), and gastric
`endoscopy (0/0, 150/ 100, 0/ 100, 0/ 125 SS/NAP in Wks 1 and 3).
`
`Results:
`
`DoSe analysis for NAP and SS were ~15.5% greater and ~26% lower than targeted
`concentrations. Severe gastric ulcers were observed in 13/18 minipigs that received NAP
`(with gastric perforaton in 4 of these), associated with decreased RBC parameters,
`increased neutrophils. Other findings included increased vomiting, increased blood urea
`nitrogen, extramedullary hematopoiesis in liver and/or spleen, in increased reticulocytes
`in NAP treated animals, with or without SS. Early deaths included one 100/ 100 found
`dead, and one 0/125 and two 0/100 SS/NAP animals sacrificed moribund (signs included
`lethargy/decreased activity, pale appearance, loss of appetite, slight/moderate BW loss,
`and severe decreases in RBCs). A114 early death animals had gastric ulcers, and 3/4 had
`pale liver at necropsy.
`
`The incidence and severity of gastric ulcers and/or erosions was equivalent in groups
`150/ 100, 0/ 100, and 0/ 125 (all 3 animals/group, moderate to marked), but lower in groups
`10/ 100, 50/100, and 100/ 100 (see Table 3.12.1 below). Only one gastric ulcers/erosions
`was observed at necropsy in the 100/0 group (SS alone), and this lesion was not
`confirmed by the histopathological evaluation.
`
`Conclusions:
`
`The sponsor concluded that NAP induced GI toxicity consistent with its known effects,
`and coadministration of SS with NAP did not exacerbate this GI toxicity. However, the
`sponsor considered the study to be compromised due to the inhomogeneous and
`inaccurate dosing solutions, survival of only 1-2 animals per group, uninterpretable
`endoscopic results due to feed in the stomach, and poor quality of most bone marrow
`smear slides.
`'
`
`72
`
`

`

`
`
`Reviewer: David B. Hawver Ph.D. NDA No. 21-926
`
`Text-Table 3.12.1. Stomach Ulcers/Erasmus at Necro :
`
`I Hlst . tholc :;
`
`mmH»:L:d De
`II--I-I-
`
`xlo‘l
`
`.4 oration
`
`(7.54-8.33)
`mn—M-—-
`--_—-m-—
`—-—--m-_
`m-mm_—-_
`-———-m-—
`--__——-—
`
`—ln-n-m—-m—
`--__——--
`
`
`
`
`
`
`
`
`
`
`
`W .-
`WI
`
`
`IIgn II-
`5517
`20:61x1
`MM)
`
`2U: 0.59x0.5
`
`
`mum-
`
`-I---II-
`
`-IMI-
`
`
`
`1x1; 2x4
`
`1x15
`
`2 U: 0.2x0.5
`
`2U:lxl
`
`mum--
`_-_mmm-—
`—u_—-mm_
`*zRBCcontmlvahresattermination. (l): Lunczzsebcompmdtoprmsucomlvalm
`'1‘: end of study; U: ulcers; P: perforation; (X): focal: X): multifocal; S: slight: M: moderate; MM: marked ’
`Yes?: adhesions between mesenlery and ulcerated area or between stomach and pancreas at necropsy and
`plant material in peritoneum by light microscopy would suggest stomach perforation
`
`§: Animal 8515 was replaced by Animal 8518.
`
`(reproduced directly from eNDA 21-926, Module 4, Section 4.2, Page 5441)
`
`73
`
`‘
`
`
`
`
`

`

`
`
` Reviewer: David B. Hawver Ph.D. NDA No. 21-926
`
`A 28-Day Oral Range-Finding Toxicity Study in Rats with Sumatriptan Succinate
`Combined with Naproxen Sodium
`
`(POZEN Study #MT400-T01, * Study #907—005, Completed 05 MAY 2004,
`GLP, QA; Sumatriptan Succinate (SS) Lot #QTO 1002, L00271], Purity 99.4%;
`Naproxen Sodium (NAP) Lot #NPXNAM-126, L002662, Purity 99.5%; SS was
`calculated as free base)
`
`Methods:
`Wistar Han (.WI(G1x/BRL/Han) IGS Br rats (10/sex/group main study, 10/sex/group
`TK) were treated via oral gavage (10 mL/kg) for 28 days with SS/NAP at 0/0, 300/20,
`500/20, 750/20, 500/0, and 0/20 mg/kg/day. Evaluations included morbidity, mortality,
`injury, and availability of food and water (2X/day); detailed clinical exam (daily at ~1 hr
`postdose); body weight (BW, weekly); food consumption (FC, weekly); ophthalmology
`exam (predosing and Day 26); hematology, blood chemistry, urinalysis (Day 29); TK
`(Day 28); macroscopic changes and organ weights (at termination). Microscopic
`evaluations were not conducted due to termination of the study by the sponsor.
`
`Results:
`
`No treatment-related changes were observed in mortality, clinical signs, BW, FC,
`ophthalmology, urinalysis, necropsy, or organ weights. All groups dosed with 20
`mg/kg/day NAP (i SS) showed increased reticulocytes and eosinophils. All treated
`groups showed slight decreases in erythrocyte parameters compared to controls. SS did
`not appear to exacerbate the hematology changes seen with NAP alone. ALP was
`decreased (25-28%) in M at 300/20, 500/20, and 750/20. BUN was increased in F at
`300/20 (51%), 500/20 (41%), 750/20 30%), and 0/20 (28%), and in M (26-27%) at
`500/20 and 750/20. Cholesterol was increased in M at 300/20 (25%), 500/20 (43%), and
`0/20 (21%). Total protein, albumin, and globulin were lower (6-10%) in M at 0/20, and
`total protein and albumin were decreased (6-8%) in F at 0/20, 300/20, and 500/20. Blood
`chemistry changes seen with NAP were not exacerbated by SS.
`
`Conclusions:
`Mild changes attributed to NAP included increased reticulocytes and eosinophils,
`decreased erythrocyte parameters, decreased alkaline phosphatase, increased BUN and
`cholesterol, and decreased total protein, albumin, and globulin. These changes are
`consistent with mild regenerative anemia (ofien seen associated with GI toxicity—
`inflammation/ulcers/erosions/hemorrhage) and renal toxicity, both of which are
`characteristic toxicities of NSAIDs. None of these changes appeared to be exacerbated
`with administration of increasing dosages of SS. However, in the absence of
`histopathology results definitive conclusions regarding the toxicity of the combination
`compared to NAP and SS alone cannot be reached.
`
`74
`
`

`

`
`
`Reviewer: David B. Hawver Ph.D. NDA No. 21-926
`
`Table 2.
`
`Day 23 Toflmkinefic Parameters for Sunlhiplln in Rats Following Once
`”lily Oral Adnilimflnn ol'smflpal SEEM all! Napmtn Mull
`1111251111311
`
`
`PM
`_____1n;.___
`11-!
`Am“!
`Cm.
`Group M em in: M91:
`(M (hr-Wm”
`(W)
`115.
`"same
`(11511111.)
`(1111 Miami.)
`4
`.
`53550
`55112
`2
`355130
`71145
`4
`55444
`2
`101532
`13355
`3
`5511211
`12555
`4
`95573
`«1
`755125
`15175
`4
`1111155
`22473
`2
`147519,
`
`5
`551111
`151153
`2
`100431
`15534
`1
`112112
`
`Best Possible Copy
`
`Table 3.
`
`Day 18 Toxicnldnelic Plunder: for Newman in Ru: Foaming Once
`Duty 0n] Adlfinist‘nflu of Slmflptal Satchel: and Napmu Sodium
`fol-2811.3!
`
`
`Gm»
`Ho.
`
`no.“
`SWAP
`In
`I
`
`0.;
`(Wm-i
`
`1"“
`(hr)
`
`CI“
`AUG.“
`(15.5mm Wm)
`
`in Mm
`(hr)
`(15.519151)
`
`315.55
`1
`55.75
`315.54
`2
`33.75
`355.120
`2
`355.31
`1
`35.13
`357.35
`4
`3352
`555120
`3
`525.75
`4
`47117
`33514
`2
`35.52
`7511120
`4
`
`
`
`
`
`
`
`5120 55.21 2 401.33 55.31 15 351.15
`
`(reproduced directly from eNDA 21-926, Module 4, Section 4.2, Page 5141)
`
`Appears This Way
`On Original
`
`75
`
`

`

`
`
`Reviewer: David B. Hawver Ph.D. NDA No. 21-926
`
`A Second 28-Day Oral Range-Finding Toxicity Study in Rats with Sumatriptan
`Succinate Combined with Naproxen Sodium
`
`(POZEN Study #MT400—T04, _ Study #907-008, Completed 12 MAR 2004,
`GLP, not QA; Naproxen Sodium (NAP) Lot #NPXNAM-126, L002662, Purity 99.5%)
`
`Methods:
`
`,
`
`Female Wistar Han (’WI(GLx/BRL/han)IGS Br) rats (N=10 per group, ~7 weeks old
`at start of dosing) were dosed via oral gavage with naproxen sodium (NAP) at 0, 25, 30,
`or 35 mg/kg/day in distilled water at 5 mL/kg once daily for 28 days.
`
`Measurements included observations for mortality and morbidity (twice daily), detailed
`clinical examination (daily 30-90 min postdose), body weight (BW) and food
`consumption (FC, weekly), ophthalmologic exam (pre-dose and at necropsy), clinical
`pathology (hematology, clinical chemistry, urinalysis; prior to necropsy), bone marrow
`smears, macroscopic examination, and organ weights. No micrOSCOpic evaluation of
`tissues was performed.
`
`Phase II of this study was intended to determine the maximum dose of sumatriptan
`succinate (SS) that could be coadministered with a maximum tolerated dose (MTD) of
`NAP. However, Phase II was terminated before it was treatment was initiated, following
`receipt of feedback from the FDA the" rat studies would not be required. The planned
`microscopic analysis and dose solution analysis for Phase I were als