CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`’
`
`APPLICA TION NUMBER:
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`21-926
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`SUMMARY REVIEW
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`

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`Cross Discipline Team Leader Review
`
`Cross-Discipline Team Leader Review
`
`Aril 15 2007
`
`Eric Bastins, MD
`Cross-Disci line Team Leader Review
`21926
`
`Pozen
`
`October 11, 2007
`
`Aril 15, 2008
`
`Treximet/sumatn'ptan and naproxen sodium
`
`85m_ sumatritan/ 500m_ naroxen sodium
`
`Acute treatment of Mi raine
`A I rroval
`
`
`
`From
`
`Sub'ect
`NDA/BLA #
`Su . lement#
`A ulicant
`Date of Submission
`PDUFA Goal Date
`
`Proprietary Name /
`Established USAN names
`
`Dosa_e forms / Stren h
`Pro . osed Indication s
`Recommended:
`
`1. Introduction
`
`
`
`
`
`This submission is a response to the approvable letter of August 1, 2007 for a combination
`product of sumatn'ptan and naproxen sodium. The remaining issue in this application was
`related to potential carcinogenicity of the combination, which had been inadequately addressed
`by the sponsor. The sponsor was also requested to provide a safety update.
`
`2. Background
`
`I reproduce below the relevant section from the August 1, 2007 approvable letter, which is the
`key issue to be addressed in this submission:
`
`We acknowledge that you have performed, as we had requested in our Approvable letter of
`June 8, 2006, a repeat in vitro chromosomal aberration assay in CHO cells, as well as an in
`vitro mouse lymphoma tk assay (MLA). We further acknowledge that the MLA was negative
`for sumatrz'ptan and naproxen alone and in combination, up to the highest concentrations
`teste. We do note, however, that the results for naproxen alone in this study are at odds with
`the positive findings in the presence ofmetabolic activation, at lower concentrations, obtained
`in an earlier MLA conducted to support -——l— [he reasons for these
`discrepantfindings are not clear, and we ask that you address this issue.
`
`0ffar greater concern, however, is the finding ofa synergistic eflect in the in vitro
`chromosomal aberration assay in CHO cells. Specifically, in this study, sumatriptan and
`naproxen alone were negative, both in the presence and absence ofmetabolic activation;
`however, the combination produced a concentration—related increase in the percentage ofcells
`with aberrations, both with and without metabolic activation.
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`Cytotoxicity was expressed as reductions in mitotic index (% Mitotic inhibition) and cell count
`(% Reduction in Cell Count), as well as in population doubling (% Population Doubling
`Inhibition). Current guidelines (OECD, ICH) indicate that % reduction in cell count is the
`most appropriate measure of cytotoxicityfor this assay. Population doubling has been
`proposed as an alternative measure (Greenwood SK et al. Environ Mole Mutagen 43:36—44,
`2004); however, it has not been accepted as a more valid or more appropriate measure of
`cytotoxicity and should not be used to dismiss the positive responses observed.
`
`In the absence ofmetabolic activation (S9), significant increases in the % ofcells with
`chromosomal aberrations were obtained at concentrations ofnaproxen and sumatriptan in
`combination associated with 50-68% reductions in cell count. This degree of cytotoxicity is
`consistent with that recommendedfor the highest concentrations in this assay (ICH, OECD
`guidelines). In the presence ofS9, increases in the % ofcells with chromosomal aberrations
`were obtained at concentrations associated with only 32- 52% decreases in cell count. It is
`notable that naproxen (at 2500 pg/mL) was negative in the presence ofS9, whereas the
`combination ofnaproxen and sumatriptan (at I 745/1745pg/mL) was positive, at the same
`degree of cytotoxicity (42% reduction in cell count); therefore, the positive response with the
`combination cannot be explained by a greater cytotoxic eflect.
`
`In our view, these findings cannot be dismissed, for the following reasons:
`
`(a) Positive findings in the repeat in vitro CHO assay were not associated with excessive
`cytotoxicity and, as noted above, naproxen alone at a concentration producing a similar
`degree ofcytOtoxicity (as measured by reduction in cell count) was negative.
`
`(b) Although it is true that the other in vitro and the in vivo genetic toxicology assays were
`negative, there is no apparent basis for dismissing a reproducible positive signal in one
`component of the standard battery ofgenetic toxicology assays based solely on negative
`findings in other assays comprising the battery.
`
`(c) We acknowledge that sumatriptan was negative in carcinogenicity studies in mouse (78-
`week) and rat (104-week) and that naproxen was negative in a 2—year carcinogenicity study in
`rats (8- 24 mg/kg/day) and, in combination with metoclopramide, in a 26-week p53 transgenic
`mouse assay (50 mg/kg). However, none of these studies tested the combination ofsumatriptan
`and naproxen. In our opinion, rather than lessening the concern, it is the lack ofa signalfor
`carcinogenicity in these studies that heightens the concern regarding a possible synergistic
`efi‘ect of the combination ofsumatriptan and naproxen. (It is ofnote that, due to the sensitivity
`of the rodent to the gastrointestinal eflects ofNSAIDs, naproxen could not be evaluated in any
`of the carcinogenicity studies at more than a fraction ofclinically relevant doses or plasma
`exposures.)
`
`The results ofthis study raise the possibility that the combination may be carcinogenic. We
`believe that you must adequately address this concern prior to the application being approved.
`We acknowledge that, were the application to be approved, the typical patient would not
`administer the drug daily; however, acute migraine treatments can be administeredfrequently,
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`andfor many years, For this reason, we consideran adequate assessment ofcarcinogenicity
`critical prior to the approval ofany acute migraine treatment. It appears to us unlikely that
`conducting additional in vitro or in vivo genetic toxicology studies would provide data that
`could be used to adequately address our concern about the positive finding in the in vitro
`CHO cell assays. It is also unlikely that lifetime carcinogenicity studies or shorter-term studies
`in transgenic animals (e.g., p53, TgHras2) would provide meaningful data, specifically
`because of the sensitivity ofrodents to naproxen, It might be possible, however, to conduct a
`study in humans to assess the clastogenic potential ofnaproxen alone and in combination with
`sumatriptan. A number ofstudies have been published on the evaluation ofclastogenic and/or
`'mutagenic ejfects in circulating lymphocytes in various populations (e.g., smokers, industrial
`workers, military personnel). Studies have also been conducted in patients on therapeutic
`doses ofvarious medications. For example, Saxena and Ahuja (Saxena R, Ahuja YR. Hum
`Genet 62(3):] 98-200, 1982) reported a significant increase in patients treated with
`thioridazine for 4 weeks. Ahuja et al. (Ahuja YR et al. Arzneimittelforschung 34(6):699~701,
`1984) reported increases in chromosomal aberrations in patients on therapeutic doses of
`haloperidol. More recently, studies have been conducted to assess the ejfects of therapeutic
`doses 0fmethylphenidate on circulating lymphocytes in children (EI—Zein et al, Cancer Lett
`230(2):284-291, 200$; Walitz S et al, Environ Health Perspect [15:936-940, 2007). Although
`we admit that the interpretation ofa positive finding in such a study is not entirely clear, we do
`believe that the results ofsuch a study would provide useful additional information that would
`afi‘ect our decision about the approvability ofthis combination,
`
`In lieu ofconducting such a clinical trial, you could also re-evaluate the. conduct ofthe in vitro
`chromosomal aberration assays to investigate, for example, whether or not the apparent
`synergistic efi‘ect is an artifact ofassay conditions.
`
`As discussed during the first review cycle, the sponsor committed to perform a post-approval
`study evaluating the effects of Trexima on blood pressure. The sponsor was requested to
`submit dates by which they will submit the final study protocol and final study report.
`
`3. CMC/Device
`
`There were no outstanding CMC issues from the previous review cycle.
`
`4. Nonclinical Pharmacology/Toxicology
`
`As noted by Dr. Freed in her supervisory memorandum, the sponsor submitted 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, and data from three in vitro cell cycle analysis studies in CHO cells treated with
`various NSAIDs, or naproxen sodium and sumatriptan succinate. Although Dr. Freed
`concludes that the sponsor did not adequately address all the issues in the Agency’s AE letter
`(see her memorandum for a detailed discussion), she believes that the data from the clinical
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`trial demonstrating n0 genotoxic effects of naproxen either alone or in combination with
`sumatriptan is sufficient to support approval of the application.
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`There were no outstanding Clinical Pharmacology/Biopharmaceutics from the previous review
`cycle. Dr. R. Uppoor reviewed minor labeling changes proposed by the sponsor, and reviewed
`a pharmacokinetic study which provided a comparison of the pharmacokinetic profile of
`sumatriptan when administered as Treximet and when administered as IMITREX 100 mg, in
`support of the labeling changes. Dr. Uppoor essentially agreed to the changes, with minor
`edits, which were incorporated in the label.
`
`6. Clinical Microbiology
`N/A.
`
`'
`
`7. Clinical/Statistical- Efficacy
`
`Efficacy of the combination product was established in earlier cycles. There was no
`outstanding efficacy issue.
`
`8. Safety
`
`The sponsor provided a safety update. The sponsor added two studies to the NDA database:
`Study TRX105850 and Study TRXlOS 852, which were conducted in women with menstrual
`migraine (single attack). As a result of the addition of these two studies, the database
`increased from 2999 subjects to 3302 migraine patients. In addition, there were 117 healthy
`volunteers exposed during the drug development program (number unchanged from the full
`response).
`
`The overall incidence of adverse events in the update was similar to that reported in the NDA
`and the Full Response. There is no new case of significant cardiac adverse event. There is no
`new death, adverse dropout, or treatment emergent serious adverse event. The additional safety
`data led to some minor changes in the adverse event section of labeling, which are acceptable.
`
`The sponsor agreed to set up a pregnancy registry for this product, as recommended by the
`Pediatric and Maternal Health Staff.
`‘
`
`Regarding the post-approval commitment for a chronic blood preSsure study, the sponsor
`proposed that, following NDA approval, the protocol for the blood pressure study will be
`submitted to the Agency within 2 months. The sponsor anticipates that the final study protocol
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`will be submitted and the study will start within approximately 4 months after that, and that the
`final study report will be submitted to the Agency 18 months after initiation. In my opinion,
`this proposal is acceptable.
`
`9. Advisory Committee Meeting
`
`There was no need for an Advisory Committee Meeting, because this product is a combination
`of two currently marketed products, and there is ample experience for the indication being
`sought.
`
`10.
`
`Pediatrics
`
`A written request was sent to the sponsor on 06/29/2007. The request was for a PK study, an
`efficacy study in patients age 12-17, and a long-term safety study. On April 9, 2008, PERC
`recommended that the division grant a waiver for study in children under the age of 6, and a
`deferral for children age 6—17. PERC recommended that the sponsor be required to study the
`population age 6—1 1, if studies in that population are believed to be practicable. In the opinion
`of Dr. V. Elgin, a pediatric neurologist member of PERC, studies in that age group are
`possible. The division will further discuss the issue with outside migraine experts. Based on
`the outcome of these discussions, studies in the age group 6-11 may later be either required, or
`waived if believed not practicable.
`
`11.
`
`Other Relevant Regulatory Issues
`
`There is no other relevant regulatory issue.
`
`12.
`
`LabeHng
`
`In a 12/21/2007 review document, OSE (DMETS) and DDMAC found the names _
`and “Treximet” acceptable. The Treximet name was re-evaluated by OSE (DMEP) in this
`review cycle, and its acceptability was confirmed.
`
`There were only minor changes to the Professional Insert sent with the last approvable letter,
`and labeling negotiations with the sponsor resulted in an agreed upon labeling.
`
`This product has a Medication Guide, as it contains an NSAID, naproxen. The sponsor
`proposed rather extensive changes to the Medication Guide sent with the last approvable letter.
`DNP and OSE (DRISK) reviewed the proposed language, and agreement was reached with the
`sponsor after labeling negotiations.
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`13.
`
`Recommendations/Risk Benefit Assessment
`
`The sponsor has adequately addressed the remaining issue (potential carcinogenicity of the
`combination). I therefore recommend approval of Treximet.
`
`As the combination contains an NSAID, this product must have a medication guide.
`The sponsor has agreed to conduct a post—marketing safety study to assess the effect of the
`chronic intermittent administration of Trexima on blood pressure. The study will be
`randomized, double-blind, active—comparator study in adults with episodic migraine dosed
`with either Treximet, naproxen sodium 500mg or sumatn'ptan 85mg. Both active ingredients
`have the potential to increase blood pressure. We have sufficient short-term data to approve
`Treximet with the current labeling, which includes a contraindication for use in patients with
`uncontrolled hypertension, and a warning that Treximet should be used with caution in
`patients with controlled hypertension. The study is intended to better characterize if the
`chronic intermittent administration of Treximet may lead to new or worsened hypertension,
`which would need to be described in labeling.
`V
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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.
`
`Eric Bastings
`4/15/2008 03:54:02 PM
`MEDICAL OFFICER
`
`