CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-926
`
`MEDICAL REVIEW! S!
`
`

`

`M E M O R A N D U M
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`
`FOOD AND DRUG ADMINISTRATION
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DATE:
`
`June 6, 2008
`
`FROM:
`
`Eric Bastings, M.D.
`Acting Deputy Director, Division of Neurology Products
`HFD-120
`
`TROUGH: Russell Katz, MD.
`Director, Division of Neurology Products
`HFD-120
`
`SUBJECT:
`
`Satisfaction of REMS requirement for approval action for Treximet for migraine
`
`TO:
`
`File NDA 21-926
`
`Risk Evaluation and Mitigation Strategy (REMS) Requirements — TREXIMET (sumatriptan and
`naproxen sodium)
`
`Title IX, Subtitle A, Section 901 of FDAAA amends the FDCA to authorize FDA to require the
`submission of a Risk Evaluation and Mitigation Strategy (REMS) if the Secretary determines that
`such a strategy is necessary to ensure that the benefits of the drug outweigh the risks (section
`505-1(a)(1)). Section 505-1(a)(1) provides the following factors:
`
`(A) The estimated size of the population likely to use the drug involved;
`(B) The seriousness of the disease or condition that is to be treated with the drug;
`(C) The expected benefit of the drug with respect to such disease or condition;
`(D) The expected or actual duration of treatment with the drug;
`(E) The seriousness of any known or potential adverse events that may be related to the drug
`and the background incidence of such events in the population likely to use the drug
`(F) Whether the drug is a new molecular entity.
`
`We have determined that a REMS is necessary to ensure that the benefits of TREXIMET
`outweigh its risks. In reaching this determination, we considered the following:
`
`In accordance with section 505-1 of FDCA, as one element of a REMS, FDA may require the
`development of a Medication Guide as provided for under 21 CFR Part 208. Pursuant to 21 CFR
`Part 208, FDA has determined that TreximetTM poses a serious and significant public health
`concern requiring the distribution of a Medication Guide. The Medication Guide is necessary for
`
`

`

`patients’ safe and effective use of TreximetTM. FDA has determined that TreximetTM is a product
`that has serious risks of which patients should be made aware because information concerning
`the risks could affect patients’ decisions to use TreximetTM. Specifically, nonsteroidal anti-
`inflammatory drugs (NSAIDs), including naproxen sodium, are associated with numerous safety
`risks, including an increased risk of cardiovascular events and gastrointestinal toxicity. For this
`reason, the Agency has determined that all prescription NSAIDs, including combination products
`in which an NSAID is a component (as is Treximet), must have Medication Guides.
`
`Information needed for assessment of the REMS should include but may not be limited to:
`a. Survey of patients’ understanding of the serious risks of TreximetTM
`b. Report on periodic assessments of the distribution and dispensing of the Medication
`Guide in accordance with 21 CFR 208.24
`
`c. Report on failures to adhere to distribution and dispensing requirements, and corrective
`actions taken to address noncompliance
`
`cc:
`
`Orig NDA 21 -926
`HFD-120/RKatz/EBastings/RFarkas/LChen
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Russell Katz
`
`7/1/2008 04:46:44 PM
`MEDICAL OFFICER
`
`

`

`Page 1 of 5
`Memorandum
`Eric P. Bastings, MD, HFD-1 20
`
`
`MEMORANDUM
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`Public Health Service
`
`Food and Drug Administration
`
`June 15, 2007
`Date:
`Eric Bastings, MD.
`From:
`File
`To:
`NDA 21-926 response to approvable letter
`Subject:
`
`
`Pozen submitted a response to the approvable letter for Trexima issued June 8, 2006. Of
`note, the tradename Trexima was not found acceptable by FDA, but in the absence of an
`alternate name yet submitted to the Agency, I will use it in my memorandum to describe
`this new drug combination product.
`
`In the approvable letter, the division agreed that Trexima is effective as an acute
`treatment for migraine headaches, but raised several safety issues which needed to be
`addressed before Trexima could be approved.
`
`Issue 1: Serious cardiac adverse events
`The division noted in the Trexima safety database the occurrence of a case of “acute
`coronary syndrome (AC8)” in a 47 year old woman with several risk factors for coronary
`artery disease and demonstrated narrowing (70%) of the left main coronary artery. This
`patient had chest discomfort and some shortness of breath two hours after taking
`Trexima, with ECG changes suggestive of ischemia in the lateral precordium, but no
`enzyme elevation during the acute event.
`
`Cases of cardiac ischemia have been reported with triptans, and all triptans carry of
`prominent labeling regarding the risk for serious cardiac events, but the rate of these
`events is believed to be very low, and well justified by the efficacy of drugs of this class.
`
`In the first review cycle, the division estimated that 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 the size of the original Trexima NDA, and that the
`incidence of serious cardiac events with Trexima may be considerably greater than that
`believed to be associated with sumatriptan.
`
`Because GSK is now involved in this NDA, Pozen was able to provide a detailed
`comparative analysis of the Imitrex and Trexima NDA safety databases. The Trexima
`safety database also considerably increased since the original NDA, up to a total of 2999
`patients treated with Trexima, most for short-term administration of the product. As noted
`by Dr. Farkas, no additional cardiac SAEs were reported in the additional 1679 subjects
`exposed since the original NDA.
`
`The sponsor identified nine subjects who received sumatriptan 100 mg in the sumatriptan
`clinical database who experienced a cardiac SAE, out of a total of about 16,000 subjects
`
`

`

`Page 2 of 5
`Memorandum
`Eric P. Bastings, MD, HFD-120
`
`
`exposed. Dr. Farkas notes that only three of these cases are comparable to the cardiac
`SAE in the Trexima database. One of them in particular (SZCSOl/2202) shares a similar
`temporal relationship, with ECG changes [plus mild enzyme elevation], and was
`. attributed by a cardiologist to possible acute coronary ischemia. The other case with close
`temporal relationship (SZBT27/3018) was not reported to have any ECG or laboratory
`associated abnormality, and it is impossible to conclude that there was clearly cardiac
`ischemia involved. The seven other cases are not relevant, in my opinion, because of the
`long delay (2 weeks or more) between drug intake and the event.
`
`The sponsor also provided comparative data based on labeling of all approved triptans:
`
`Table 2.5.24 Estimated Incidence of Clinically Significant Cardiovascular Adverse
`Events among Triptans
`
`
`
`
`
`
`Product
`
`Estimated Incidence
`
`
`
`(%)
`
`0.00 (00000)
`0.11 4/3500
`
`
`0.00. 0.14
`0.00, 0.11
`
`
`
`0.00, 0.12
`
`0.03, 0.29
`
`
`
`0.00, 0.15
`
`
`
`0.00, 0.11
`003 (2/6348)
`Sumatritan tablets
`
`
`
`
`0.00, 0.14
`0.00 (0/2500)
`Zolmitri
`tan tablets
`
`
`0.00, 0.18
`"7
`0.03 (1/2999)
`'
`Trexima tablets
`
`
`
`
`Source: Warnings Sections of current Prescribing Information for marketed Triptans
`
`95% CI
`
`
`
`
`I reviewed the individual cases in labeling. For eletriptan, one of the cases was “atrial
`fibrillation”, which is not clearly directly related to CAD. The other case occurred during
`a coronary angiographic study, and is not clearly similar to these of interest for the
`comparison. For naratriptan, three of the cases were for asymptomatic ECG changes. The
`fourth one was thought to be likely due to coronary vasospasm, but occurred after a dose
`three times higher than the highest recommended approved dose. I obtained the narrative
`from the original NDA review:
`
`
`
`u
`
`
`s
`'33.
`safari:
`=4
`:l:
`2'1-"1
`t.
`..l
`.
`'vr'
`
`
`.” {ID-88904) 60 yo symptomfcss female had ECG showing variable T~waveiflancning (Lead II)
`at 130 minutes afier nararriptan 1mm: and baa-denim ST segment sagging (Lateral Leads) with
`increased been me :0 100 bpm at about 240 minutes post-treatment; pwu‘eaunent ECG showed T-wave
`lave-mien (Lead III): hospitalized for immigration and for unxesolved migraine; ECG was still abnormal
`the following morning and in the afternoon 2 days post treatmenz; cardiac enzymes remained nounal;
`follow-up stress test normal; evaluation of ECG results by independent cardiologist considered L553;
`changes related to drug will: a likcty cause ofcomnary spasm (Case: 89064738).
`
`For rizatriptan, the case is reported in labeling as “chest pain with possible ischemic ECG
`changes”. I obtained the narrative from Dr. Oliva’s NDA review of rizatriptan:
`
`

`

`Page 3 of 5
`Memorandum
`Eric P. Bastings, MD, HFD-120
`
`
`Sims! Pain: A 40 via Fv’ (622-026) taking rizatriptan 10m in the extension phase was hospitalized
`for chest pain. which cccurrad during treatment in ms smergency mom for a warsen‘mg migraine
`6 hours sitar" a dose at diatriptan 10mg. She had pravicusty treatsd M migraine attacks with
`nzatriptan 10mg aver a 4 month period. While in the mmancy room. she swamped non-
`ptcuritic chast pain which was aaraiieved by nitrcgtycarin. She had experienced simitar episodes
`of exertions: and nan-exertions? chest pain at the prior .2 months. not associated with any
`medication use. She was admitted and serial 506’s showed sinus bmdycardia {considsmd
`normal tor the patient}. ctcckwise axis rotation and nonspecific 31W wave changes. but no acute
`changes. Cardtsc enzymes were normai. A stress test to days later was unremarkabie. “the
`investigator felt that the headache and chest pain wars unrelated to n'zatdman. I think a
`relationship between fizakiptan and the chest. gain is possible.
`
`The main difference betWeen this case and the case of acute coronary syndrome on
`Trexima is the absence of demonstrated ECG changes with rizatriptan, and the
`occurrence of similar symptoms off drug prior to the event. The pain was not relieved by
`nitroglycerin, which also argues against a cardiac origin.
`
`Overall, it appears that the cases described in the above table are not qualitatively similar
`(i.e. clearly of cardiac origin) to the case of acute coronary syndrome seen with Trexima,
`except for one of the two cases reported for sumatriptan.
`
`.
`Issue 2: Severe chest pain
`The division also noted in the original NDA review four cases of severe chest pain in
`patients treated with Trexima in short term efficacy studies, compared to none in the
`other treatment groups (including sumatriptan), again suggesting possible important
`differences in the tolerability of Trexima compared to sumatriptan alone. The division
`also noted that a dog study suggested increased coronary constriction with the
`combination compared to sumatriptan given alone, although that study had
`methodological limitations.
`
`As noted by Dr. Farkas, there were no new reports of “severe” chest pain or chest
`discomfort associated with Trexima in additional 1679 patients treated with Trexima
`since the original NDA submission. Thus, the incidence of severe chest pain in the entire
`Trexima database is 0.15% (4/2628), versus 0.11% (2/1785) reported by subjects on
`placebo. In sumatriptan studies, the incidence of severe chest pain ranged between 0.07% .
`and 0.27% for the doses tested (50-100 mg).
`
`Overall, I agree that the incidence of severe chest pain appears similar for Trexima and
`sumatriptan. This may have no relationship to the incidence of coronary vasospasm
`induced by the drugs, but it nevertheless provides some reassurance. The sponsor also
`provided data supporting that the number or type of withdrawals for cardiac adverse
`events were not different between Trexima and sumatriptan studies.
`
`Issue 3: Hypertensive effects of Trexima
`The division noted the complete absence of any blood pressure monitoring appropriately
`timed to dosing with the combination, or with chronic intermittent dosing, and the lack of
`reliable information about the maximal effects of Trexima on blood pressure either
`acutely or chronically.
`
`

`

`Page 4 of 5
`Memorandum
`Eric P. Bastings, MD. HFD-120
`
`
`As noted by Dr. Farkas, the sponsor conducted an inpatient, open-label, 2-way (Trexima
`and sumatriptan) cross-over study in 32 healthy adult volunteers to address this
`deficiency. The study did not show any acute hypertensive effect for either drug. The
`study, however, does not address the possible hypertensive effect of the chronic
`intermittent administration of the drug.
`
`Issue 4: Tradename
`The division rejected the proposed tradename, Trexima. Pozen however submitted
`additional arguments to support the name Trexima, which the division, in concurrence
`with DMETS, also rejected. The sponsor submitted a new proposed tradename, ’
`at the end of June 2007, and this is under review.
`
`Issue 5: Non clinical issues
`The division also raised non clinical issues, and requested a repeat in vitro chromosomal
`aberration assay in CHO cells testing concentrations between those exhibiting minimal or
`no cytotoxicity and those resulting in substantial cytotoxicity, and an in vitro mouse
`lymphoma tk assay (with colony sizing) testing naproxen and sumatriptan alone and in
`combination. I refer to the non clinical reviews for a discussion of these issues.
`
`Conclusions and Recommendation
`
`1.
`
`In this response to approvable letter, the sponsor has provided additional
`information (i.e. larger Trexima database, data from Imitrex database) that
`provide sufficient reassurance regarding the cardiovascular risk of Trexima. My
`observation is that there were two cases suggestive of coronary ischemia in a
`database of about 16,000 patients treated with Imitrex, versus one case suggestive
`of coronary ischemia in about 3,000 patients treated with Trexima. Also, the
`single case reported in the Trexima database had a significant structural coronary
`lesion present, which makes it less relevant. Given the various differences
`between the databases (e.g. increased weight of patients in the Trexima database,
`which is more recent), this does not appear to represent a truly higher rate. In
`addition, the numbers of patients with severe chest pain or discomfort were
`similar for both drugs. There is also a possibility that the increased sustained relief
`provided by Trexima will lead to less use of rescue medication, which could
`lower the risk.
`
`2. Considering the reassuring data obtained from the study looking at the acute
`hypertensive effect of Trexima, I agree with Dr. Farkas that the effect of chronic
`intermittent administration of Trexima on blood pressure could be characterized
`in phase IV. The sponsor is already proposing to conduct a randomized, double-
`blind, active-comparator study in adults with episodic migraine dosed with either
`Trexima, naproxen sodium 500mg or sumatriptan 85mg to further assess the
`hypertensive effect of Trexima. That study should be part of phase IV
`commitments.
`
`

`

`Page 5 of 5
`Memorandum
`Eric P. Bastings, MD, HFD-120
`——__——_.—____—___—————_———-—
`
`3.
`
`If the non clinical issues have been adequately addressed, I recommend approval.
`
`
`
`Eric P. Bastings, M.D.
`Team Leader, Neurology
`
`epb
`cc:
`
`HFD~120
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Eric Bastings
`7/20/2007 05:42:54 PM
`MEDICAL OFFICER
`
`

`

`Review and Evaluation of Clinical Data
`
`
`N21-926
`NDA (Serial Number)
`Pozen
`Sponsor:
`Trexima
`Drug:
`Acute Migraine
`Proposed Indication:
`Approvable action Full Response
`Material Submitted:
`January 31, 2007
`Correspondence Date:
`Ronald Farkas, MD, PhD.
`Reviewer:
`Medical Reviewer, DNP, ODE I
`
`1. Introduction
`
`This submission is a Full Response to the Approvable Letter for Trexima issued June 8, 2006
`(NBA 21946). The Approvable Letter noted Agency concern about the occurrence of a case of
`“acute coronary syndrome” in a subject in the chronic Trexima treatment study (MT400-303),
`and stated “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.” The sponsor and Division in a meeting on July 26, 2006, agreed that a comparison
`of cardiac safety findings in the Trexima development program to cardiac safety findings in the
`original Imitrex development program could contribute to addressing if the cardiac safety of
`Trexima was different from that of sumatriptan alone.
`
`The sponsor’s first Full Response submission, in which a comparison of cardiac safety was made
`between Trexima and Imitrex was considered an Incomplete Response. The following
`deficiencies were noted in the Divisions Incomplete Response letter of December 8, 2006:
`
`1. Comparison of Trexima and sumatriptan adverse events was presented without sufficient
`data and analysis. In particular, incidence calculation of adverse events did not adequately
`consider drug exposure.
`2. Adverse events fiom the sumatriptan program were not described in sufficient detail to make
`comparisons with adverse events in the Trexima program.
`Inadequate data and analysis was presented on the comparability of the sumatriptan and
`Trexima data, for example addressing differences in patient populations and methods of
`collecting adverse events.
`
`3.
`
`Additionally, the Division noted that the tabulation of cardiac adverse events in the submission’s
`summary tables appeared to be incorrect.
`
`A teleconference was held with the sponsor January 4, 2007 to clarify deficiencies in the
`November 6, 2006 Full Response. —————_—
`~
`'
`
`6/22/2007 3:11 PM
`
`

`

`Page 2 of 50
`Ronald Farkas, HFD-120 Medical Review
`NBA 21-926
`
`2. Reviewer Conclusions
`
`The major issues of concern in the Approvable Letter and previous Full Response have been
`adequately addressed by the sponsor. The new safety information supports the assertion that
`Trexima has a similar cardiac safety profile to sumatriptan alone. Approval of Trexima is
`recoMended.
`
`0 Cardiac adverse events in the Trexima and sumatriptan databases were compared using
`adequately transparent and reasonable methods.
`0 Cardiac SAEs rarely (1 in several thousand patients) occurred in both Trexima and
`sumatriptan development. The relationship between drug and cardiac ischemia remained
`uncertain for events in both programs.
`The incidence of severe (non-serious) chest pain was similar for both programs.
`Dropouts due to cardiac adverse events were similar for both programs.
`Acute effects of both drugs on blood pressure were similar.
`An acceptable plan was submitted for gaining chronic blood pressure data post-apprOval.
`
`Proposed labeling for Trexima adequately reflects cardiovascular risks of the combination of
`sumatriptan and naproxen.
`
`3. Organization of Review
`
`In the Approvable Letter, the Division found that Trexima was effective for acute migraine, but
`that the safety of Trexima had not been adequately demonstrated. Data addressing the cardiac
`safety of Trexima is discussed in the following sections:
`
`The incidence of serious cardiac events associated with Trexima versus sumatriptan alone is
`addressed in Section 4, Serious Cardiac Adverse Events.
`
`The Approvable letter also expressed concern at four cases of severe (non-serious) chest pain in
`the Trexima treated patients in studies 301 and 302, compared to none in the other treatment
`groups. Comparison of severe chest pain associated with Trexima versus sumatriptan alone is
`addressed in this review in Section 5, Severe Chest Pain. [Dropouts due to cardiac adverse
`events, while not specifically mentioned in the Approvable letter, are also addressed in this
`section].
`
`A discussion of the methodology of the sponsor’s comparison of the Trexima and sumatriptan
`databases is addressed in this review in Section 6, Comparability of Trexima and Sumatriptan
`Databases.
`
`The Approvable letter also noted a study in dogs designed to assess the effects of the
`.
`combination on coronary artery constriction that showed in five of the six dogs increased
`constriction with the combination compared to sumatriptan given alone. This is addressed in this
`review in Section 8 Drug Combination Study: Dog Coronary Artery Constriction.
`
`

`

`Page 3 of 50
`Ronald Farkas, HFD-120 Medical Review
`NDA 21-926
`
`The Approvable letter noted the absence of blood pressure monitoring during acute or chronic
`dosing with Trexima, with the result that no reliable information was presented about the
`maximal effects of Trexima on blood pressure either acutely or chronically. Acute blood
`pressure changes fiom Trexima are addressed in this review in Section 9, Acute Blood Pressure
`Effects of Trexima. The sponsor proposes a post-approval study to examine chronic effects of
`Trexima on blood pressure. This study proposal is discussed in Section 10 , Proposed Post-
`Approval Chronic Blood Pressure Study
`
`This submission also includes a Safety Update, discussed in Section 11, Full Response Safety
`Update.
`
`4. Serious Cardiac Adverse Events
`
`The sponsor argues that the absence of any additional cardiac SAEs in studies of Trexima since
`the NDA submission suggests Trexima does not pose a cardiac risk. The sponsor states the
`following:
`
`“No serious cardiac adverse events were reported in any of the completed GSK Trexima
`studies [note: the new Trexima studies]. The single SAE reported in the NDA remains the
`only occurrence of a cardiac SAE considered related to Trexima in 2999 migraineurs
`dosed with Trexima.” '
`
`Since the NDA submission, safety data from 5 additional controlled studies with Trexima has
`become available, more than doubling the number of subjects exposed to Trexima (Table 1).
`
`Table I: Trexima Safety Population
`
`(from Table 2.5.1, Adverse Events Analysis Populations for the NDA Trexima Database
`and the GSK Trexima Database: Migraine Subjects Only)
`
`'
`
`Database,
`
`Database
`
`Trexima
`Full
`Response.
`Datab‘a’Se
`
`Population
`Used‘for
`Comparison
`
`All
`migraineurs
`exposed to
`single‘and
`multiple doses
`
`Migraineurs
`Who} took a
`single'dose of
`Tratima to
`treat thefirst
`
`attack
`
`

`

`Ronald Farkas, HFD-120 Medical Review
`NBA 21 -926
`
`Page 4 of 50
`
`No additional cardiac SAEs were reported in the additional 1679 subjects exposed. The
`additional exposures to Trexima are from studies with up to 4 doses.
`
`[Comment The lack of cardiac SAEs, while reassuring, must be interpreted in the context of the
`relatively low power of this exposure to detect rare events]
`
`As discussed in the review of the original Trexima NDA, three subjects experienced cardiac
`SAEs in the Trexima long-term study.
`
`One of these subjects was of particular concern to the Division, and was noted in the Approvable
`Letter (Study MT400-303, subject #2143).
`
`° Subject 2143 / Site 030 / acute coronary syndrome
`
`The patient is a 47-year old female. During the course of her study participation, the
`subject treated 39 migraine headaches (54% with 2 tablets of study drug); an average of
`six headaches per month. Concurrently, she received, Excedrin migraine, ranitidine,
`Elavil, vitamins and a sleep—aid (OTC). Imitrex is listed as a concomitant medication in
`the ISS narrative, but in the CRF is noted as a medication the patient used for migraine
`before the study. During the study, .Ultracet and Tylenol were used asmigraine rescue
`medications. The subject received the first dose of open—label study drug on
`August 2, 2004 and the last dose on —-
`Approximately two hours after
`taking study drug on —_— the subject experienced chest discomfort and
`some shortness of breath. She presented to the emergency department and was given
`nitroglycerin, which provided some relief. An electrocardiogram showed ST-T wave
`changes in the lateral precordium. Troponin and CK levels were normal in the emergency
`room. Based on the subject’s age and family history, the subject was admitted to the
`hospital for further evaluation. A cardiac catheterization, performed -
`showed a moderate dilation of the left ventricle with moderate mitral regurgitation,
`severe hypokinesis of the antero-apical wall of the left ventricle and a calculated ejection
`fraction of 27 percent. The left anterior descending coronary artery had a concentric
`discrete 70% narrowing of the ostium as it arose from the left main coronary artery.
`There was a post-stenotic filling defect suggestive of a thrombus. No significant disease
`was present in either the left main coronary artery or the right coronary artery. On
`7 § the subject underwent coronary artery bypass grafting surgery
`including the left internal mammary artery to left anterior descending artery. The subject
`was discharged from the hospital on — and treated with carvedilol,
`furosernide, and lisinopril for hypertension, aspirin for cardiac prophylaxis, potassium,
`Zocor for hypercholesterolemia and Percocet for postoperative pain.
`
`Medical History:
`The subject was a nonsmoker and reported that her father died of a myocardial infarction
`in his 505. She had a history of tubal ligation, tension headaches, sinus headaches,
`seasonal allergies, obesity, mild rosacea, mild depression, insomnia, acid reflux, and two
`cesarean sections, BMI 35.7. At screening, her physical examination and
`
`

`

`Page 5 of 50
`Ronald Farkas, HFD-120 Medical Review
`
`NDA 21 -926 -
`
`electrocardiogram were normal. Screening laboratory results revealed cholesterol of
`200mg/dL and triglycerides of 386 mg/dL.
`
`In the other two subjects, Trexirna was unlikely related to the serious cardiac adverse events.
`Subject 2129, a 44 year old women, experienced chest pain and increased blood pressure (182/95
`in the emergency room) more than 24 hours after her last dose of Trexima. ECG and cardiac lab
`tests were normal. The other case, subject 2709, was a 27 year old woman who presented to an
`emergency room with chest pain 5 days after her last dose of Trexima. She gave a history of
`chronic recurrent chest pain with radiation of pain to her left arm.
`
`Thus, including all three of the above cases, with the additional Trexirna exposure reported in ‘
`this Full Response, there remain a total of 3 serious cardiac AEs in about 3000 total patients
`exposed to Trexima, including both single-dose and long-term studies.
`
`The sponsor identified nine subjects who received sumatriptan 100mg in the sumatriptan clinical
`database who experienced a cardiac SAE (Table 2), out of a total of about 16,000 subjects
`exposed. The sponsor argues that the rate of cardiac SAEs is therefore similar for Trexima and
`sumatriptan.
`
`Table 2: Sumatriptan Subjects with Cardiac SAES
`
`2.5.8.4.!
`
`Narratives of All Sumatriptan Subjects, with a “Ghost and Cardiac” SOI’iOIlS‘ Adverse Events,
`
`V“um-Ir
`
`11 days TM
`
`F
`
`I.
`
`Yes
`
`Unrelated
`
`"
`
`6mg (so).
`100019
`
`$28370I100
`6009mm
`
`$231.21”; WW"
`
`

`

`Ronald Farkas, HFD-120 Medical Review
`NDA 21-926
`
`.
`
`Page 6 of 50
`
`82812773018
`
`SZCSO1I-1599
`
`
`
`$20501I1885
`
`Only 3 of these cases, discussed below, appear to be possibly comparable to the cardiac SAE in
`the Trexima database:
`
`SZB3 08E/5 0 1
`
`On 12/04/92 the subject was given a 6mg sumatriptan injection at 10:15 am, followed with a
`100mg sumatriptan tablet at 12:35 pm. On - the subject reported the development of arm
`and chest pain which became severe, and was sent to the hospital where an ECG was reportedly
`consistent with M1 and the subject was admitted for emergency angioplasty and was
`subsequently noted to have 2 vessel CAD. Subject was withdrawn from the study and the
`investigator judged the event as probably related to underlying disease and unlikely to be related
`to study drug.
`
`[Comment The interval between dosing and onset of symptoms was more than 24 hours,
`arguing against an effect of sumatn'ptan in the event]
`
`SZCSO l/ 1 5 99
`
`Narrative: This 37-year-old female patient received oral GR43175C to treat migraine. She
`experienced chest tightness 15 minutes after her first and only dose of study medication. She
`likened the pressure to a tight band squeezing across her chest and she could not breathe deeply.
`The symptoms lasted for 45 minutes to one hour. An attending physician described signs of blue
`lips, pallor and dilated pupils. The patient's migraine attack disappeared at the same time as the
`onset of the adverse event. An ECG trace was taken one day later. The investigator commented
`that there were no differences between post and pre—treatment ECG traces. The event was
`considered to be incapacitating to the patient and almost certainly related to the study drug, and
`the patient was withdrawn.
`
`

`

`Page 7 of 50
`Ronald Farkas, HFD-120 Medical Review
`NBA 21-926
`
`[Comment This event might reflect the type of chest pain that, in varying severity, affects 1%
`or more of triptan users. Adverse events in the sumatriptan database were coded as SAEs on the
`basis of criteria different than used in the Trexima studies. This event was originally coded as .
`“disabling or incapacitating” and was, for purposes of the current analysis, reclassified as a
`serious adverse event].
`
`,
`SZCSO 1/2202
`This 33-year-old male patient had no previous cardiac history and no significant family history
`of coronary disease. His baseline ECG showed an RST pattern in lead V1 consistent with right
`bundle branch block, sinus bradycardia and normal left axis deviation. Thirty minutes after
`treating his first migraine attack with study medication (oral sumatriptan 100mg), he developed
`severe throat tightness and central chest pain which was described as feeling like a weight on his
`chest. The pain extended to the jaw and, about an hour after study treatment, there was severe
`pain in both arms. The patient also felt nauseated but there was no sweating. At two hours, the
`patient had difficulty expanding his chest, had pain in the fingertips and felt lightheaded. The
`arm pain and throat tightness resolved in seven hours and the chest pain in ten hours; all were
`reported as disabling or incapacitating. An ECG carried out later that day showed an RSR pattern
`which was similar to the pre-trial ECG but more prominent, particularly in leads V1 and V2. On
`the following day CK was elevated from 94IU/L at approximately eight hours after the event, to
`292TU/L at approximately 20 hours after the event (normal range 23—
`2351U/L), but CK-MB and LDH were within the normal range. The patient was withdrawn from
`the study. Twenty-four days later, he saw a cardiologist and underwent an exercise treadmill test
`without any chest pain or significant ECG changes and an echocardiogram was normal.
`Furthermore, a resting ECG trace at this time was identical to that recorded pre-treatment. The
`cardiologist reported that, although not "Absolutely definitive", the chest pain may have been
`due to acute coronary ischaemia caused by coronary artery spasm triggered by the study
`medication. He further commented that stress may also have been a contributory factor and that
`there was no residual damage to the myocardium or any ongoing coronary ischaemia. The
`investigator considered that the events were almost certainly related to the study medication.
`
`[Comment This event might reflect the type of chest pain that, in varying severity, affects 1% or
`more of triptan users. Adverse events in the sumatriptan database were coded as SAEs on the
`basis of criteria different than used in the Trexima studies. This event was originally coded as
`“disabling or incapacitating” and was, for purposes of the current analysis, reclassified as a
`serious adverse event.
`
`Reviewer Discussion: The sponsor’s reanalysis of cardiac SAEs in the sumatriptan database
`revealed 2 cases that may represent serious cardiovascular adverse events related to sumatriptan
`(in the subject with myocardial infarction, the interval between sumatriptan dosing and the event
`was >24 hours, seemingly excluding the possibility of drug causation). Evidence is insufficient
`to determine if these two cases represent cardiac ischemic events, versus the apparently non-
`ischemic type of chest pain (albeit severe) of unknown origin that can occur in about 1/1000 of
`triptan users. The rarity of serious cardiac adverse events in both the Trexima and sumatriptan
`development programs precludes any convincing conclusions about relative incidence (and type)
`of severe cardiac adverse events in the two development programs.
`
`

`

`Page 8 of 50
`Ronald Farkas, HFD—120 Medical Review
`
`NBA 21-926 .
`
`5. Severe Chest Pain
`
`The sponsor asserts that the additional data from Trexima studies demonstrates a lower incidence
`of severe chest pain then was found in the original Trexima NDA, arguing for the cardiovascular
`safety of Trexima:
`
`“There were no new reports of “severe” chest pain or chest discomfort associated with
`Trexima in the completed GSK Trexima studies. Thus, the three cases of “severe” chest
`d