CENTER FOR DRUG EVALUATION AND
`
`RESEARCH.
`
`APPLICATION NUMBER:
`
`21-926
`
`APPROVABLE LETTER
`
`

`

`’0‘ «mun»,(’1
`
`a) ( DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`R‘me
`
`PublicHealthService
`
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA 21—926
`
`.
`Pozen, Inc.
`Attention: Paul Ossi
`
`1414 Raleigh Road
`Suite,400
`
`Chapel Hill, NC 27517
`Dear Mr.‘Ossi:
`
`Please refer to your new drug application (NDA) dated August 5, 2005, received August 8, 2005,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Trexima
`(sumatriptan/naproxen) tablets.
`
`We acknowledge receipt of your submissions dated the following:
`January 31, 2007, March 8, 2007, June 21, 2007, July 2, 2007 and July 16, 2007.
`
`The January 31, 2007 submission constituted a complete response to our June 8, 2006 action letter.
`
`This new drug application provides for the use of Trexima (sumatriptan/naproxen) tablets for the acute
`treatment of migraine headaches.
`
`We have completed our review of this application, as amended, and it is approvable. Before the
`application may be approved, however, it will be necessary for you to adequately address the following
`issue:
`
`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 sumatriptan and
`naproxen alone and in combination, up to the highest concentrations tested. We do note, however, that
`the results for naproxen alone in this study are at odds with the positive findings in the presence of
`metabolic activation, at lower concentrations, obtained in an earlier MLA conducted to support
`-——-—————- The reasons for these discrepant findings are not clear, and we ask that you
`address this issue.
`
`Of far greater concern, however, is the finding of a synergistic effect 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 of metabolic activation; however, the combination
`produced a concentration-related increase in the percentage of cells with aberrations, both with and
`without metabolic activation.
`
`Cytotoxicity was expressed as reductions in mitotic index (% Mitotic Inhibition) and cell count
`
`

`

`NDA 21-926
`
`Page 2
`
`(% 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 cytotoxicity for 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 of metabolic activation (S9), significant increases in the % of cells with chromosomal
`aberrations were obtained at concentrations of naproxen and sumatriptan in combination associated
`with 50-68% reductions in cell count. This degree of cytotoxicity is consistent with that recommended
`for the highest concentrations in this assay (ICH, OECD guidelines). In the presence of S9, increases in
`the % of cells with chromosomal aberrations were obtained at concentrations associated with only 32-
`’ 52% decreases in cell count. It is notable that naproxen (at 2500 ug/mL) was negative in the presence
`of S9, whereas the combination of naproxen and sumatriptan (at 1745/ 1 745 ug/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 effect.
`
`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
`of cytotoxicity (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 of genetic 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 of sumatriptan and
`naproxen. In our opinion, rather than lessening the concern, it is the lack of a signal for
`carcinogenicity in these studies that heightens the concern regarding a possible synergistic
`effect of the combination of sumatriptan and naproxen. (It is of note that, due to the sensitivity
`of the rodent to the gastrointestinal effects of NSAIDs, naproxen could not be evaluated in any
`of the carcinogenicity studies at more than a fraction of clinically relevant doses or plasma
`exposures.)
`
`The results of this 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 administered frequently, and for many years.
`For this reason, we consider an adequate assessment of carcinogenicity critical prior to the approval of
`any acute migraine treatment.
`
`

`

`NDA 21-926
`
`Page 3
`
`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 of rodents to naproxen. It might be possible, however, to conduct a study1n humans to
`assess the elastogenic potential of naproxen alone and1n combination with sumatriptan. A number of
`studies have been published on the evaluation of clastogenic and/or mutagenic effectsin circulating
`lymphocytes in various populations (e.g., smokers, industrial workers, military personnel). Studies
`have also been conducted in patients on therapeutic doses of various medications. For example, Saxena
`and Ahuja (Saxena R, Ahuja YR. Hum Genet 62(3): 1 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 effects of therapeutic doses of
`methylphenidate on circulating lymphocytes in children (El-Zein et al. Cancer Lett 230(2):284-291,
`2005; Walitz S et al. Environ Health Perspect 115:936-940, 2007). Although we admit that the
`interpretation of a positive finding in such a study is not entirely clear, we do believe that the results of
`such a study would provide useful additional information that would affect our decision about the
`. approvability of this combination.
`
`In lieu of conducting such a clinical trial, you could also re—evaluate the conduct of the in vitro
`chromosomal aberration assays to investigate, for example, whether or not the apparent synergistic
`effect is an artifact of assay conditions.
`
`We note your commitment to perform a post-approval study evaluating the effects of Trexima on
`blood pressure as described in your Submission dated January 31, 2007. In your response to this
`approvable letter, please submit dates by which you will submit the final study protocol and final study
`report.
`
`We also note that we are reviewing your current proposed tradenames of— Treximet, as
`submitted on July 16, 2007.
`
`Labeling
`
`We are including draft labeling with this letter. Although we have included language for the
`Carcinogenesis, Mutagenesis, Impairment of Fertility section, the language relating to
`carcinogenicity and mutagenicity should be regarded as a place holder; clearly, the specific language
`ultimately adopted will depend upon your response to the issue discussed above. Indeed, the
`approvability of the application itself will depend upon a satisfactory response to our concerns.
`
`When you respond to the above deficiencies, include a safety update as described at 21 CFR
`314.50(d)(5)(vi)(b). The safety update should include data from all non-clinical and clinical studies of
`the drug under consideration regardless of indication, dosage form, or dose level.
`
`1. Describe in detail any significant changes or findings in the safety profile.
`
`2. When assembling the sections describing discontinuations due to adverse events, serious adverse
`events, and common adverse events, incorporate new safety data as follows.
`
`

`

`NDA 21-926
`
`Page 4
`
`Present new safety data from the studies for the proposed indication using the same format as the
`original NDA submission.
`Present tabulations of the new safety data combined with the original NDA data.
`Include tables that compare frequencies of adverse events in the original NDA with the
`retabulated frequencies described in the bullet above.
`——~——_ provide separate tables for the frequencies of
`adverse events occurring in clinical trials.
`
`Present a retabulation of the reasons for premature study discontinuation by incorporating the drop-
`outs from the newly completed studies. Describe any new trends or patterns identified.
`
`Provide case report forms and narrative summaries for each patient who died during a clinical
`study or who did not complete a study because of an adverse event. In addition, provide narrative
`summaries for serious adverse events.
`
`Describe any information that suggests a substantial change in the incidence of common, but less
`serious, adverse events between the new data and the original NDA data.
`
`Provide a summary of worldwide experience on the safety of this drug. Include an updated
`estimate of use for drug marketed in other countries.
`
`7.
`
`Provide English translations of current approved foreign labeling not previously submitted.
`
`In addition, submit three copies of the introductory promotional materials that you propose to use for
`this product. Submit all proposed materials in draft or mock—up form, not final print. Send one copy to
`this division and two copies of both the promotional materials and the package insert directly to:
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`
`Beltsville, MD 20705-1266
`
`Within 10 days after the date of this letter, you are required to amend this application, notify us of your
`intent to file an amendment, or follow one of your other options under 21 CFR 314.110. If you do not
`follow one of these options, we will consider your lack of response a request to withdraw the
`application under 21 CFR 314.65. Any amendment should respond to all the deficiencies listed. We
`will not process a partial reply as a major amendment nor will the review clock be reactivated until all
`deficiencies have been addressed.
`
`Under 21 CFR 314.102(d), you may request a meeting or telephone conference with this division to
`discuss what steps need to be taken before the application may be approved.
`
`The drug product may not be legally marketed until you have been notified in writing that the
`application is approved.
`
`

`

`NDA 2 1 -926
`
`Page 5
`
`If you have any questions, call Lana Chen, Regulatory Project Manager, at (301) 796-1056.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Russell Katz, MD.
`Director
`
`Division of Neurology Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Russell Katz
`8/1/2007 06:00:41 PM
`
`

`

`Q
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`
`6. DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`PublicHealth Service
`
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA 21-926
`
`Pozen, Inc.
`Attention: Paul Ossi
`
`1414 Raleigh Road
`Suite 400
`
`Chapel Hill, NC 27517
`
`Dear Mr. Ossi:
`
`Please refer to your new drug applications (NDA) dated August 5, 2005, received August 8, 2005 and
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Trexima (sumatriptan
`and naproxen sodium) tablets.
`
`We acknowledge receipt of your submissions to NDA 21-926 dated the following:
`
`. August 5, 2005
`October 27, 2005
`November 16, 2005
`December 5, 2005
`December 8, 2005
`January 27, 2006
`
`February 22, 2006
`April 7, 2006
`April 19, 2006
`April 28, 2006
`May 9, 2006
`May 30, 2006
`
`We have completed our review of this application, as amended, and it is approvable. Before the
`application may be approved, however, it will be necessary for you to address the following issues:
`
`Clinical
`
`Although we have determined that Trexima is effective as an acute treatment for migraine headaches,
`there are several findings that raise serious questions about the safety of this combination.
`
`First, we note the occurrence of a case of “acute coronary syndrome” in a 47 year old woman receiving
`chronic treatment in Study 303 (subject 2143, site 030). This woman experienced documented
`coronary ischemia about 2 hours after a dose of Trexima. Although this woman had several risk
`factors for coronary artery disease (obesity, family history), and was noted to have underlying coronary
`artery disease on angiography, clearly the investigator concluded that she was an appropriate candidate
`for treatment with a triptan. Current triptan labeling recommends that patients with risk factors not be
`treated unless a cardiac evaluation does not reveal underlying disease. A reasonable interpretation of
`such cardiac evaluation can be, as was apparently the case here, a normal EKG at baseline.
`
`

`

`NDA 21-926
`
`Page 2
`
`Although we are aware, of course, of cases of documented cardiac ischemia with triptans, the rate of
`these events is considered to be quite low. If the rate of such events with Trexima was similar to that
`of sumatriptan, it would be extraordinarily unlikely to see even one case in a database of this size. The
`occurrence of this case, then, at least suggests that the incidence of serious cardiac events with Trexima
`may be considerably greater than that believed to be associated with sumatriptan.
`
`In addition, our concerns are increased by the finding of four cases of severe chest pain in the Trexima
`treated patients in Studies 301 and 302, compared to none in the other treatment groups. We
`acknowledge that we do not know if these cases represent cases of cardiac ischemia or not, but the
`disparity in the occurrence among the treatment groups in the incidence of severe chest pain again
`suggests that there may be important differences in the tolerability of the combination compared to the
`tolerability of the components.
`
`Further, although we recognize the limitation of the study in dogs designed to assess the effects of the
`combination on coronary artery constriction, five of the six dogs showed increased constriction with
`the combination compared to sumatriptan given alone. The conclusion that this increased constriction
`was drug related is strengthened by the observation that this increased constriction was dose related,
`because it was not seen on Days 2 and 3, when levels of naproxen were diminishing. We also note
`that, based on its effects on prostaglandins, there is at least some reason to believe that naproxen itself
`can be a vasoconstrictor.
`'
`
`Finally, we note the complete absence in your application of any blood pressure monitoring
`appropriately timed to‘dosing with the combination, or with chronic dosing. For this reason, we have
`no reliable information about the maximal effects of this combination on blood pressure either acutely
`or chronically. Although we expect, were this drug to be approved, that few patients would dose
`themselves daily (when we would expect both the incidence, and the sequelae, of hypertension to be
`greatest), many patients may dose relatively frequently. In these caSes, it is possible that important
`changes in blood pressure might occur. Obviously, chronic hypertension is dangerous in itself, but if
`such changes did occur with chronic dosing with Trexima, this might pose an additional risk if, as
`noted above, treatment with Trexima is associated with an increase in the incidence of coronary
`vasoconstriction.
`
`These observations, taken as a whole, suggest that the cardiovascular risks of Trexima may be greater
`than those with sumatriptan or naproxen alone. If this is true, this would raise questions about the
`approvability of the combination. Therefore, you must address these concerns prior to the approval of
`this application.
`'
`
`Regarding the risk of coronary vasoconstriction, a study comparing the effects of the combination to
`sumatriptan alone might be able to be performed in patients who are undergoing catheterization for
`other reasons, and who might consent to have these compounds administered. An adequate study of
`this sort that documents no important increased constriction of the combination might address our
`concerns. Alternatively, a trial comparing the incidence of adverse events of interest (perhaps severe
`chest pain [as a “surrogate” for ischemia] or actual chest pain accompanied by EKG changes consistent
`with ischemia) between patients treated with the combination and sumatriptan might be acceptable.
`Such a study would likely need to enroll several thousand patients per group followed for a reasonable
`duration (at least 3-6 months). Such a trial would also be an appropriate setting in which to obtain
`adequate blood pressure data. Whether such a large, relatively long trial is necessary to obtain
`
`

`

`NDA 21-926
`
`Page 3
`
`adequate blood pressure data can be a matter of discussion, but we will require that adequate blood
`pressure data be obtained.
`
`Product Name
`
`The Division of Medication Errors and Technical Support (DMETS) has recommended that the
`propriety name Trexima not be used for the following reasons:
`
`
`
`

`

`NDA 21-926
`
`Page 4
`
`
`
`3.
`
`In review of the labels and labeling, DMETS has identified the following areas of possible
`improvement, which might minimize potential user error.
`
`a) 'GENERAL COMMENTS
`‘I
`
`
`
`

`

`NDA 21-926
`
`Page 5
`
`
`
`Product Labeling
`
`We have included draft product labeling with this letter. Of course, the clinical issues described above
`will need to be resolved before this application may be approved. Obviously, then, the label we have
`included must be considered relatively preliminary at this point. We do wish to note two points,
`however.
`
`As you know, we had discussed in a phone conversation on May 25, 2006 the possibility that labeling
`for this product might not be required to include a Boxed Warning, and we acknowledge your
`arguments to support this view. As we noted in that conversation, however, the inclusion of a Boxed
`Warning for all naproxen-containing products was a matter for internal Agency discussion beyond the
`division. Such a discussion has taken place, and the decision was made to require these products to
`include a Boxed Warning in their package insert. Therefore, we have included such a Warning.
`
`Also, all naproxen-containing products are required to include a Medication Guide, the language for
`which can be found at the Website referred to in the attached draft labeling. For this reason, the
`product must be made available in unit of use packaging.
`
`

`

`NDA 21-926
`
`Page 6
`
`Preclinical
`
`1. The results of the in vitro chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells
`(Study MT400/T07, #0735/0736-3110) demonstrated clastogenic effects of naproxen alone and in
`combination with sumatriptan. The magnitude of the clastogenic effect was greater with the
`combination of naproxen and sumatriptan than with naproxen alone, both in the absence and presence
`of metabolic activation. (Sumatriptan was negative in this assay.) These results raise the concern that
`naproxen and sumatriptan in combination may have carcinogenic effects not observed with either drug
`alone. However, since the clastogenic effects were observed only at concentrations producing
`substantial cytotoxicity, the biological significance of these effects is unclear, but cannot be dismissed.
`Therefore, you need to conduct the following additional studies:
`
`a. a repeat in vitro chromosomal aberration assay in CHO cells testing
`concentrations between those exhibiting minimal or no cytotoxicity (i.e., 1250/1250 ug/mL
`naproxen/sumatriptan) and those resulting in substantial cytotoxicity (i.e., 2500/2500 and
`2000/2000 naproxen/sumatriptan in the absence and presence of metabolic activation,
`respectively).
`
`b. an in vitro mouse lymphoma tk assay (with colony sizing) testing naproxen and
`sumatriptan alone and in combination.
`
`The results of these studies will determine the need for additional nonclinical studies.
`
`2. You need to include the results of the in vitro mouse lymphoma tk assays (Studies MT 100 T25,
`MT100 T26) and the carcinogenicity study in p53+/‘ heterozygous mice (Study MT 100 T35) for
`naproxen in product labeling.
`
`Safety Update
`‘ When you respond to the above deficiencies, include a safety update as described at 21 CFR
`314.50(d)(5)(vi)(b). The safety update should include data from all non-clinical and clinical studies of
`the drug under consideration regardless of indication, dosage form, or dose level.
`
`1. Describe in detail any significant changes or findings in the safety profile.
`
`2. When assembling the sections describing discontinuations due to adverse events, serious adverse
`events, and common adverse events, incorporate new safety data as follows:
`
`0. Present new safety data from the studies for the propOsed indication using the same format as the
`'
`original NDA submission.
`0 Present tabulations of the new safety data combined with the original NDA data.
`0
`Include tables that compare frequencies of adverse events in the original NDA with the .
`retabulated frequencies described in the bullet above.
`0 ———-—————-— , provide separate tables for the frequencies of
`adverse events occurring in clinical trials.
`
`3. Present a retabulation of the reasons for premature study discontinuation by incorporating the drop-
`outs from the newly completed studies. Describe any new trends or patterns identified.
`
`

`

`NDA 21-926
`
`Page 7
`
`4. Provide case report forms and narrative summaries for each patient who died during a clinical
`study or who did not complete a study because of an adverse event. In addition, provide narrative
`summaries for serious adverse events.
`
`5. Describe any information that suggests a substantial change in the incidence of common, but less
`serious, adverse events between the new data and the original NDA data.
`
`6. Provide a summary of worldwide experience on the safety of this drug. Include an updated
`estimate of use for drug marketed in other countries.
`
`7. Provide English translations of current approved foreign labeling not previously submitted.
`
`In addition, submit three copies of the introductory promotional materials that you propose to use for
`these products. Submit all proposed materials in draft or mock-up form, not final print. Send one copy
`to this division and two copies of both the promotional materials and the package insert directly to:
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`
`Beltsville, MD 20705-1266
`
`Within 10 days after the date of this letter, you are required to amend these applications, notify us of
`your intent to file amendments, or follow one of your other options under 21 CFR 314.110. If you do
`not follow one of these options, we will consider your lack of response a request to withdraw the
`application under 21 CFR 314.65. Any amendment should respond to all the deficiencies listed. We
`will not process a partial reply as a major amendment nor will the review clock be reactivated until all
`deficiencies have been addressed.
`
`Under 21 CFR 314.102(d), you may request an informal meeting or telephone conference with this
`division to discuss what steps need to be taken before the application may be approved.
`
`The drug products may not be legally marketed until you have been notified in writing that the
`applications are approved.
`'
`
`If you have any questions, call Lana Chen, Regulatory Project Manager, at (301) 796-1056.
`
`Sincerely,
`
`{See appended electronic signature pag ,}
`
`Russell Katz, MD.
`Director
`
`Division of Neurology Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page isthe manifestation of the electronic signature.
`
`Russell Katz
`6/8/2006 04:44:23 PM
`
`