Clinical Review
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`events were musculoskeletal system and general disorders. There were no differences
`between males and females in reporting events in cardiac disorders.”
`
`Age
`No meaningful difference in adverse events were identified by comparing the older half of
`patients to the younger half in the controlled studies:
`
`“The effect of age was examined above and below the median age of 41 years. Younger
`subjects reported slightly more adverse events with Trexima than older subjects (3 0%
`versus 23% respectively), however the other treatment groups did not show an age
`differential. The increased reports in subjects <41 years were primary classified as
`nervous system disorders (dizziness and somnolence) and musculoskeletal disorders.
`Importantly, there were no differences in the reported incidences of cardiac disorders
`between the two age groups.”
`
`Few subjects were over the age of 55 (about 60-80 subjects/group in pivotal studies). No
`significant difference in adverse events was found in this ‘oldest 1/3’ compared to each younger
`1/3 of subjects:
`
`“Further examination of age compared three groups of subjects, those 18-35 years, those
`36 to 55 years, and those over 55 years. This examination needs to be interpreted with
`caution due to the lower numbers of subjects in the over 55 years age group. The general
`trend of adverse event reporting was again inversely related to, age. The same trends in
`System Organ Classification reports were repeated. No differences were noted in the
`number of events in cardiac disorders among the age groups, however the oldest subjects
`reported more cardiac events following treatment with sumatriptan (6%; chest
`discomfort, cardiac flutter, chest pain and palpitations) than following treatment with
`Trexima (1%; chest discomfort)”
`
`Race '
`
`About 70- to 80 subjects/arm were African American in the pivotal studies, with very few other
`races represented. No important differences in adverse event rates were found in African
`Americans.
`
`7.2.4 Adequacy of Special Animal and/or In Vitro Testing
`
`Dog studies designed to asses possible additive cardiovascular effects of sumatriptan and
`naproxen in Trexima were performed (discussed in detail in Section 3.2, Animal
`Pharmacology/Toxicology).
`I find these studies suggest a possible increase in both
`vasoconstriction and blood pressure from Trexima that is greater than that from sumatriptan
`alone. Given the critical nature of these questions, the number of animals studied, 6 or fewer per
`arm, was not adequate. High experimental variability suggests that the studies might not have
`been conducted with adequately rigorous methodology or technique, and my review of the raw
`blood pressure datasets supports this.
`
`101
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`7.2.5 Adequacy of Routine Clinical Testing
`
`Monitoring of blood pressure, ECGS, and other vital signs was not carried out adequately at
`times when drug would be expected to be present in the body, or over the long-term safety study
`(see Sections 1.1, 7.1, 7.1.8.1, 7.1.9.1).
`
`7.2.6 Adequacy of Metabolic, Clearance, and Interaction Workup
`
`Since both components of Trexima are currently approved, no studies were conducted examining
`metabolism, clearance, or drug interaction (other than preclinical studies examining
`cardiovascular effects in dog).
`'
`
`Mamba/131115 411d (Yea/alive
`
`Sumatriptan:
`Sumatriptan is rapidly but incompletely absorbed when given orally, and undergoes first-
`pass metabolism. Sumatriptan is extensively metabolised in the liver, predominantly by
`monoamine oxidase type A, and is excreted mainly in the urine as the inactive indole
`acetic acid derivative and its glucuronide. Sumatriptan and its metabolites also appear in
`the feces.
`
`Naproxen
`Naproxen is reported to be nearly 100% absorbed from the GI tract. About 95% of a
`dose is excreted in urine as naproxen and 6- adesmethylnaproxen and their conjugates.
`Less than 5% of a dose appears in the feces.
`
`[/zteractl'wz
`
`The Division, in pre-submission meetings, indicated that new studies would not be necessary
`examining the PK interaction of naproxen and sumatriptan. The effect of naproxen on
`'
`sumatriptan pharmacokinetics had been examined by Srinivasu et al. (“Lack of Pharrnacokinetic
`Interaction between Sumaptriptan and Naproxen,” Clin. Pharmacol 2000;40:99-104). Twelve
`healthy volunteers were treated with 100 mg sumatriptan succinate either alone or with 500 mg
`naproxen orally. Naproxen had no statistically significant (p > 0.05) effect on any
`pharrnacokinetic parameters of sumatriptan. The authors concluded that no alteration in
`sumatriptan dosage was necessary for migraine patients taking naproxen prophylactic therapy.
`
`7.2.7 Adequacy of Evaluation for Potential Adverse Events for Any New Drug
`and Particularly for Drugs in the Class Represented by the New Drug;
`Recommendations for Further Study
`
`Cardiovascular safety of Trexima was not adequately addressed. See in particular sections 1.1
`and 1.3.3
`
`102
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`7.2.8 Assessment of Quality and Completeness of Data
`
`The Trexima trials were either single-dose (controlled studies) or chronic intermittent dose
`(extension study) in migraine patients that were otherwise generally healthy. Most adverse
`effects were mild and reversible, and derived mainly from patient reported symptoms.
`Importantly, however, the trials provided insufficient evidence of cardiovascular safety.
`
`7.2.9 Additional Submissions, Including Safety Update
`
`The results of the l-year open-label extension study were submitted with the 120-day safety
`update, and are integrated in the overall safety review.
`
`7.3 Summary of Selected Drug-Related Adverse Events, Important Limitations of
`Data, and Conclusions
`
`Common Adverse Events
`
`Common adverse events from Trexima generally reflect those encountered with sumatriptan.
`These common events could affect ability to drive or operate machinery, and I find this should
`be added to the Trexima label.
`
`0 Dizziness:
`
`0 Generally of mild or moderate intensity, but sometimes severe
`0 Brief duration (few hours), reverses spontaneously
`Somnolence:
`
`0 Generally of mild or moderate intensity.
`0 Brief duration (few hours), reverses spontaneously
`Paresthesia:
`
`o
`
`o
`
`0 Generally mild intensity
`0 Brief duration, reverses spontaneously.
`o Nausea
`
`0 Generally mild or moderate intensity, but can be severe.
`0 Also a major symptom of the underlying migraine
`0 Dry Mouth
`0 Generally mild intensity
`0 Brief duration, reverses spontaneously
`
`o Dyspepsia
`0 Generally mild or moderate intensity, but less often severe
`0 Brief duration, reverses spontaneously
`
`.
`0 Chest pain
`0 Generally mild or moderate, but can be severe
`
`o
`
`throat pain/tightness
`0 Generally mild or moderate, but can be severe
`0 Brief duration, reverses spontaneously
`
`103
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`less ewe/12011 éutserz'wts adverse Eve/Ms
`
`Trexima is dosed intermittently, and is generally not present in the body between doses.
`Therefore, adverse events in close proximity to dosing could suggest causality.
`
`Logically, adverse events in Trexima studies similar to those caused by sumatriptan or naproxen
`were likely caused by Trexima.
`
`Many of the adverse effects of NSAIDs are similar or identical to those of sumatriptan, including
`heart attack, stroke, hypertension, and dizziness.
`
`. Due to the size and design of the Trexima database, it. is not possible to determine if the risk from
`Trexima is greater than that from sumatriptan or naproxen alone.
`
`I conclude that Trexima can cause serious cardiovascular adverse events, including acute
`coronary syndrome (two subjects in the safety study, one definite, one ‘possible’).
`
`There were 2 cases of elevated liver enzymes in the long-term Trexima study, a known adverse
`event associated with naproxen (described fully in section 7.1.3, Dropouts and Other Significant
`Adverse Events).
`
`7.4 General Methodology
`
`7.4.1 Pooling Data Across Studies to Estimate and Compare Incidence
`
`7.4.1.1 Pooled data vs. individual study data
`
`The safety database for Trexima was relatively small. Adverse events data was examined for
`each study individually, and for pooled data from controlled trials.
`
`7.4.1.2 Combining data
`
`Not applicable
`
`104
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`7.4.2 Explorations for Predictive Factors
`
`7.4.2.1 Explorations for dose dependency for adverse findings
`
`See Section 8.], Dosing Regimen and Administration.
`
`7.4.2.2 Explorations for time dependency for adverse findings
`
`The reported incidenCe of adverse events declined between the first and last treated migraine
`attack regardless of the use of one or two tablets of Trexima to treat the migraine. This might
`represent an actual decrease of adverse events with time, or a lower reporting rate for adverse
`events with time.
`
`7.4.2.3 Explorations for drug-demographic interactions
`
`Like sumatriptan, Trexima appears most likely to induce adverse cardiac events in demographic
`groups with the highest cardiovascular risk. Although the safety population for Trexima is small,
`obesity and a history of hypertension appear to be risk factors for adverse cardiac events
`proximate to Trexima dosing.
`
`7.4.2.4 Explorations for drug—disease interactions
`
`The migraine syndrome studied in this NDA was fairly narrowly defined, such that differences in
`efficacy or safety across subgroups were not found.
`
`7.4.2.5 Explorations for drug-drug interactions .
`
`See Section 8.2, Drug-Drug Interactions
`
`7.4.3 Causality Determination
`
`See section 7.3, Summary of Selected Drug-Related Adverse Events
`
`8 ADDITIONAL CLINICAL ISSUES
`
`8.1 Dosing Regimen and Administration
`
`Appropriateness ofdose
`Study MT400-204 evaluated the combination of Imitrex 50 mg non-RT and naproxen 500 mg,
`co-administered as separate pills. This represents about half the dose of sumatriptan in the final
`formulation ofTrexima. Estimating dose/response by comparing separate studies is not usually
`productive, but I believe study MT400-204 can be cautiously compared to studies of Trexima.
`Table 67 and Table 68 show 2-hour and sustained pain efficacy results for studies MT100~204
`
`105
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21 -926
`MT400/Trexima
`
`and MT100-301/302, respectively. The response rates for placebo and naproxen are very similar
`across studies. In addition, sumatriptan 85 mg appeared more efficacious than 50 mg, as might
`be expected. Trexima, however, did not have any efficacy advantage over the lower dose
`combination used in study 204.
`
`Table 67: Study MT400-204, 'Low' Dose Efficacy
`
`50 mg Sumatriptan +
`500 mg naproxen
`‘MT—400’ (%)
`65
`
`2—hour -ain relief
`Sustained ain free
`
`25
`
`50 mg Sumatriptan
`
`500 mg Naproxen
`
`Placebo
`
`'
`
`(%
`
`(%
`
`Table 68: MT400-301/302, 'High‘ Dose Efficacy
`
`85mg Sumatriptan +
`500 mg naproxen
`‘Trexima’ (%)
`301/302
`57/65
`23/25
`
`2-hour nain relief
`
`
`
`85 mg Sumatriptan
`
`500 mg Naproxen
`
`Placebo
`
`(%)
`301/302
`50/55
`
`(%)
`301 /302
`43/44
`10/10
`
`(%)
`301/302
`29/28
`7/8
`
`Regardless of the strength of the above comparison, for many migraine patients 50 mg is an
`appropriate dose of sumatriptan based on the balance of safety and efficacy. Sumatriptan is
`known to have a dose-related increase in adverse events in the clinically prescribed dose range
`(from Imitrex label). Trexima would clearly ”vibe an appropriate choice for most patients
`starting triptan therapy. For the subset of patients failing 50 mg sumatriptan, the next
`appropriate clinical step might be a combination of 50 mg sumatriptan and 500 mg naproxen, as
`was used in the proof-of—concept study for Trexima and shown to be effective. Thus, only for
`those patients failing the combination of 50 mg sumatriptan and 500 mg naproxen might an
`increase of sumatriptan to 85 mg, as in Trexima, be appropriate.
`
`Ragga! dwizzg a: flex/777m with}: 24’flay/y
`Pozen proposes the following labeling for repeat dosing:
`
`_
`
`-—'-
`,
`tablets in 24 hours.
`
`'
`
`'
`
`’
`
`'
`
`Do not take more than 2
`
`The safety study did not suggest increased adverse events within 24 hours after a second dose of
`Trexima versus a single dose (Table 69). In fact, a lower rate of adverse events was reported in
`patients taking a second dose compared to those taking only 1 tablet.
`I reviewed the MedDRA
`terms (not shown) and found no evidence for excess adverse events in the second-dose group.
`
`106
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`[Comment the population that took a second tablet for the first attack might have been different
`from the population that took only one tablet. For example, patients with more experience using
`triptans might have been more likely to take a second tablet, and also more likely not to report
`adverse events that were familiar. This effect of decreased reporting with patient experience is
`similarly likely responsible for the decreased reporting rate of adverse events between first and
`last migraine attacks during the study (Table 69), although a biological explanation is also
`possible].
`
`Table 69: Adverse Events, 1 vs. 2 tabs, first vs. last headache, MT400-303
`
`
`
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`
`8.2 Drug-Drug Interactions
`
`Nagroxen and antihzgertensives
`
`I discuss the
`The interaction of naproxen on the action of antihypertensives is discussed here.
`effect of naproxen on blood pressure in normotensives in Section 8.6, Literature Review.
`
`Sumatriptan is contraindicated in patients with uncontrolled hypertension. Trexima might lead to
`poorer control of blood pressure in treated hypertensives. NSAIDs are thought to attenuate the
`antihypertensive effects of several common classes of antihypertensives, including diuretics,
`beta-blockers, and vasodilators (but probably not calcium channel blockers). For diuretics and
`beta-blockers, this is reflected in current naproxen labeling:
`
`“Reports suggest that NSAIDS may diminish the antihypertensive effect of ACE—inhibitors.
`The use of NSAIDs in patients who are receiving ACE-inhibitors may potentiate renal
`disease.”
`
`“Naproxen and other nonsteroidal anti-inflammatory drugs can reduce the antihypertensive
`effect of propranalol and other beta-blockers.”
`
`Walgroxe/zflu/Imtflg'tall lhteracfl'o/zy
`The effect of naproxen on sumatriptan pharrnacokinetics was examined by Srinivasu et al.
`(“Lack of Pharmacokinetic Interaction between Sumaptriptan and Naproxen,” Clin. Pharmacol
`
`107
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`2000;40:99-104). Twelve healthy volunteers were treated with 100 mg sumatriptan succinate
`either alone or with 500 mg naproxen orally. Naproxen had no statistically significant (p > 0.05)
`effect on any pharmacokinetic parameters of sumatriptan. The authors concluded that no
`alteration in sumatriptan dosage was necessary for migraine patients taking naproxen
`prophylactic therapy.
`
`Irllfll—V/l firllg-fl/wg[lite/actl'wzy 0g flail/m Cameo/zelzzr
`
`Prescribing information for Trexima will include those interactions currently listed in the
`individual prescribing information for naproxen and sumatriptan. Additional modifications
`include:
`
`o Co-administration of valproic acid and naproxen appears to affect the clearance of both
`drugs. A small (20%) but significant displacement of valproic acid from plasma proteins
`results in increased overall metabolic flux. A small decrease (10%) in plasma clearance
`of naproxen also occurred. Accordingly, Trexima should be used with caution in patients
`receiving valproic acid therapy.
`'
`
`8.3 Special Populations
`
`Renal Failure
`
`Naproxen pharrnacokinetics has not been determined in subjects with renal insufficiency. Given
`that naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential
`exists for naproxen metabolites to accumulate in the presence of renal insufficiency. Elimination
`of naproxen is decreased in patients with severe renal impairment. Naproxen-containing products
`are not recommended for use in patients with moderate to severe and severe renal impairment
`(creatinine < 30 ml/min).
`
`While the effect of renal impairmenton the, PK of sumatriptan has not been examined, little
`\
`clinical effect is expected because sumatriptan is metabolized to an inactive substance.
`
`Haw/2’ fizflzffl'a’ency
`
`From lmitrex label:
`
`“The liver plays an important role in the presystemic clearance of orally administered
`sumatriptan. Accordingly, the bioavailability of sumatriptan following oral administration
`may be markedly increased in patients with liver disease. In 1 small study of hepatically
`impaired patients (n = 8) matched for sex, age, and weight with healthy subjects, the
`hepatically impaired patients had an approximately 70% increase in AUC and Cmax and a
`tmax 40 minutes earlier compared to the healthy subjects.”
`
`108
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21—926
`MT400/Trexima
`
`In chronic hepatic insufficiency, the clearance of naproxen is reduced and the dose should likely
`be reduced.
`
`8.4 Pediatrics
`
`See Section 1.2, Recommendation on Postmarketing Actions.
`
`8.5 Advisory Committee Meeting
`
`In February 2005, FDA held a joint meeting of the Arthritis Advisory Committee and the Drug
`Safety and Risk Management Advisory Committee to address risk of COX-2 selective NSAIDs
`and related agents, including naproxen. The meeting transcript can be accessed through FDA
`Dockets Management: http://www.fda.gov/ohrms/dockets/default.htm
`
`From the discussions, I conclude that the cardiovascular risk of naproxen has not been
`established.
`
`0 The ADAPT study data that was influential in specifically implicating naproxen in
`increased cardiovascular risk appears weak, and remains not publicly released or peer-
`reviewed.
`
`. Meta-analysis of about a dozen studies using naproxen generally fails to find an increased
`cardiovascular risk from naproxen, although importantly the studies are methodologically
`weak. The studies can more confidently be interpreted to indicate that naproxen is
`unlikely to have a cardioprotective effect.
`0 Many of the advisory committee members thought that the cardiovascular risk posed by
`naproxen was probably less than that of other NSAIDs. However, the data is not strong
`enough to justify indicating this in labeling.
`
`8.6 Literature Review
`
`Hypertensive Effect 0fNSAIDs
`NSAIDs appear to have small but significant effects on blood pressure (Frishman, Am J. Cardiol.
`2002;89:18D-25D). This effect is largest in hypertensive patients on antihypertensive
`medication, but NSAIDs might also increase blood pressure to a lesser degree in normotensive
`subjects. For Trexima, a major safety concern is that the combination of NSAID—induced
`hypertension with sumatriptan-induced vasoconstriction could result in additive cardiovascular
`adverse effects.
`
`I have included below brief summaries of selected publications examining the relationship
`between naproxen/NSAIDS and blood pressure in non-hypertensive subjects. Some studies have
`positive findings, and others negative.
`I conclude that the chance of an effect is high enough,
`and the risk great enough, that the effect should be considered in Trexima approval and labeling.
`
`109
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`Artie/em [waif/7g a}? increased/”1157c og&ger/elzyz'0/z (r0172 flagroxe/z exgoyzzre
`
`0 Curh an et al., Freyue/zcy offal/raga]? are 4120’1731' offlyper/e/zyz'o/z 1'11you/Iggy” 14/0/726/7,
`Arch Intern Med. 2002 Oct 28;162(l9):2204-8.
`Prospective study of 80,020 women aged 31 to 50 years who participated in the
`Nurses'Health Study II and had no previous history of hypertension.
`NSAIDs and acetaminophen (P<.001 for trend for both) were significantly
`associated with risk of hypertension. Compared with nonusers, the relative risk of
`hypertension for women taking NSAIDs 22 d/mo or more was 1.86 (95%
`confidence interval, 1.51-2.28) and for those taking acetaminophen 22 d/mo or
`more was 2.00 (95% confidence interval, 1.52-2.62).
`
`O O
`
`0
`
`0
`
`John son et al., Do ”any/eroz'da/dizlzlz'Ide/IZ/fla/wy (2’ng affect b/oodpreyyure?1 mela—
`a/za/yyzlr. Ann Intern Med 1994;121(4):289—300.
`0
`When pooled, NSAIDs elevated supine mean blood pressure by 5.0 mm Hg (95%
`CI, 1.2 to 8.7 mm Hg) but had no effect on variables other than blood pressure.
`Nonsteroidal anti-inflammatory drugs antagonized the antihypertensive effect of
`beta-blockers (blood pressure elevation, 6.2 mm Hg; CI, 1.1 to 11.4 mm Hg) more
`than did vasodilators and diuretics.
`
`Pope et al ., ,4 meta-4124525137 oflfle effec/J aflzwzy/ero/a’a/alzl/lfiflammam/y (fie/gs 017
`é/ooa’premzmz Arch Intern Med. 1993 Feb 22;153(4):477-84.
`O
`Fifty-four studies with 123 NSAID treatment arms met inclusion criteria. The
`mean age of subjects was 46 years. Of the 1324 participants, 1213 subjects (92%)
`were hypertensive. The effects of NSAIDs on blood pressure were found solely in
`hypertensive subjects.
`The increase in mean arterial pressure (MAP) was 3.59 mm Hg for indomethacin
`(57 treatment arms), 3.74 mm Hg for naproxen (four arms), and 0.49 mm Hg for
`piroxicam (four arms). The MAP decreased by 2.59 mm Hg for placebo (10
`arms), 0.83 mm Hg for ibuprofen (six arms), 1.76 mm Hg for aspirin (four arms),
`and 0.16 mm Hg for sulindac (23 arms).
`
`Arab/es [waif/2g 120 increased17.3% of fl%€l’/€lflflbll[f‘0/fl
`
`flag/”oxen exgmwre
`
`0 Kurth et a1., Aim/gent use and17.3% 0fJZ/éyegue/z/ éyper/e/zyz'o/z 1'17 apde’flZZ/j/ keg/[fly
`1723/2. Arch Intern Med. 2005 Sep 12;165(16):1903-9.
`Prospective cohort study of 8229 participants in the Physicians' Health Study who
`were free of hypertension and completed detailed analgesic questionnaires.
`Apparently healthy male physicians who self—selected for analgesic use had no
`significantly increased risk of subsequent hypertension
`
`O O
`
`110
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21 -926
`MT400/Trexima
`
`o
`
`sewers et al., 726 W615 figc/ooyzgeflaye-Z [hail/013’ dfld/M/zy/erofa’a/a/z/zl
`[Maw/770130 lflerapy 012 24-40211” é/oodpreyyzxre 1'17Ina/1191715 14/12/17 flyper/e/zrz'ofl,
`asleoar/érl'lzig 4/26/0506 2 afaée/ey ”id/12%". Arch Intern Med. 2005 Jan 24;165(2):161-8.
`o Double-blind, randomized trial to evaluate the effects of celecoxib, rofecoxib, and
`
`naproxen on 24—hour blood pressure (BP) in patients with type 2 diabetes,
`hypertension, and osteoarthritis.
`0 BP following 6 weeks of therapy was increased significantly by rofecoxib (from
`130.3 +/- 1.2 to 134.5 +/- 1.4 mm Hg; P < .001) but not by celecoxib (132.0 +/-
`1.3 to 131.9 +/-1.3 mm Hg; P = .54) or naproxen (133.7 +/- 1.5 to 133.0 +/— 1.4
`mm Hg; P = .74).
`
`Myocardial/Izfircflblz andNSA/fls
`No agreement exists in the literature about the degree naproxen might increase the risk of
`myocardial infarction. Risk from naproxen might be less than the risk from some other
`commonly used NSAIDs.
`I find that the chance of increased risk is great enough that it should
`be considered in Naproxen approval and labeling. A selection of informative papers are
`described below:
`
`flr/z'c/ey [waif/2g [kc/”easedr1396 oilfizocara’lfa/[Marc/1'0}: [r0172 flag/”axe” argon/re
`
`o Hippisley—Cox and Coupland, Rik/r ofmyocamflz/z’zz/arc/z’o/z 1'17palz'e/z/y [4/ng cyclo—
`aryge/zaye-Z [haw/0115' 0r 60/7Ve/z/z'o/za/”alt-steroidalafllzlz'iflam/iZd/wy drugs
`papa/aim” flayed/2651647came-calzlrola/mé/fllfl BMJ 2005 ;3 30: 13 66
`o Nested case—control study
`0
`9218 cases with a first myoCardial infarction ‘
`0
`Increased risks 'were associated with naproxen at < 0.05 rather than < 0.01 for
`current use but significant at < 0.01 in the tests for trend.
`0 No evidence was found to support a reduction in risk of myocardial infarction
`associated with current use of naproxen.
`
`o
`
`Johnsen et al ., ilk/r offlwpz'la/z'za/fafl/Zr myocaraf’a/z’zyflrc/z’o/z amoflg use/25' afrofécoxzé
`66/660,172, afldotfle‘r/VLSk/[Dx' apquz/a/zwz-ém’edcam-0012170!3/1/de Arch Intern Med
`2005;165:978-84.
`_
`
`o Nested case-control study.
`0
`10,280 cases of first-time hospitalization for MI
`0 Current users of rofecoxib had an elevated risk estimate for hospitalization for M1
`compared with nonusers of any category of nonaspirin NSAIDs (adjusted relative
`risk [ARR], 1.80; 95% confidence interval [CI], 1.47-2.21). Increased risk
`estimates were also found among current users of celecoxib (ARR, 1.25; 95% CI,
`0.97—1.62), other cyclooxygenase-Z selective inhibitors (ARR, 1.45; 95% CI,
`1.09-1.93), naproxen (ARR, 1.50; 95% CI, 0.99-2.29), and other conventional
`nonaspirin NSAIDS (ARR, 1.68; 95% CI, 1.52-1.85). The highest ARRs were
`found among new users of all examined drug categories.
`
`111
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`0 Graham et al., 117119? ofaczzz‘e myocarfla/z'zy’arc/m/z 412dIll/dell cardiac dad/é 1'17pd/z'eiz/J
`[red/ed wz'z‘é g/c/o-myge/zdye Z Je/ec/z'I/e 017dKali-Je/eclzi/e ”on-J/eroz'a’d/mz/zl
`[Wain/7241017 aka/gs: Izzy/edcayé-cofllro/J/zmjz Lancet 2005 ;3 65 :475 — 8 1 .
`o Nested case-control study.
`0
`8143 cases of serious coronary heart disease
`0 Multivariate adjusted odds ratios versus celecoxib were: for rofecoxib (all doses),
`1.59 (95% CI 1.10-2.32, p=0.015); for rofecoxib 25 mg/day or less, 1.47 (0.99—
`2.17, p=0.054); and for rofecoxib greater than 25 mg/day, 3.58 (1.27-10.11,
`p=0.016). For naproxen versus remote NSAID use the adjusted odds ratio was
`1.14 (1.00-1.30, p=0.05).
`
`A’r/zb/ar [waif/2g 120 [bereaved171% ozmzocamfa/[flaw/1'01: [mm ”gamma/z 6.120.571}?
`
`0
`
`Fischer et al., Cur/€171 21.519 oflzwzytemz'c/d/diztfl'lflammwa/y drug; 417dlfle 173% ofacu/e
`myocamfiz/f/r/fim/z'wz Pharmacotherapy. 2005 Apr;25(4):503-10.
`o Retrospective case—control analysis of 8688 case patients with a first-time acute
`myocardial infarction and 33,923 matched control subjects.
`0 The relative risk (expressed as odds ratio [OR]) of acute myocardial infarction
`was 1.07 (95% confidence interval [CI] 0.96-1.19) for subjects with current
`NSAID exposure compared with those not taking NSAIDs. The adjusted OR for
`current diclofenac use was 1.23 (95% CI 1.00-1.51), for current ibuprofen use
`1.16 (95% CI 0.92-1.46), and for current naproxen use 0.96 (95% CI 0.66-1.38)
`compared with those not taking NSAIDs. Current aspirin use combined with
`current NSAID use was associated with a‘ statistically significant risk reduction
`(adjusted OR 0.74, 95% CI 0.57—0.97), compared with nonuse of NSAIDs and
`aspirin.
`
`o Garcia Rodriguez et al., XVom/emz‘a’a/dfl/12'7y7fl/77/72d/0/j/ drags and/£3 rzk/r ofmyocamfa/
`IWrc/zb/z 1'17 tflegeflera/popu/g/z'o/z. Circulation. 2004 Jun 22; 1 09(24):3000-6.
`o Nested case-control analysis.
`0 4975 cases of acute myocardial infarction (MI) and death from coronary heart
`disease (CHD) were identified.
`'
`o The multivariate—adjusted OR for current NSAID use compared with nonuse was
`1.07 (95% CI, 0.95 to 1.20). Treatment duration or daily dose did not change the
`results. The effect was similar among patients free of CHD history (1.04; 95% CI,
`0.90 to 1.20) and patients with previous history (1.12; 95% CI, 0.91 to 1.38).
`Estimates for individual NSAIDs were all comparable, with no major effect on
`the risk of acute MI. Naproxen was associated with an OR of 0.89 (95% CI, 0.64
`
`to 1.24).
`
`112
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21—926
`MT400/Trexima
`
`o Levesque et a1., fie riff/01’ myocarfla/z’zyfirc/z’o/z MM cyc/omyge/mye-Z z'zzflzZ/lom' a
`papa/4712b}: .r/zzafi/ ofe/a’eré/ daft/[1.9. Ann Intern Med 2005 ; 1 42 :48 1 ~9.
`o Nested case-control approach.
`0 NSAID exposure and occurrence of MI assessed by using Quebec's administrative
`health databases.
`
`0 Compared with no use of NSAIDs in the year preceding the event, current use of
`rofecoxib was associated with an increased risk for an acute MI (rate ratio [R],
`1.24 [95% CI, 1.05 to 1.46]) that was more pronounced at higher doses (RR, 1.73
`[CI, 1.09 to, 2.76]). The concomitant use of aspirin appears to decrease the risk
`' associated with low-dose rofecoxib (RR, 1.00 [C1, 0.77 to 1.28]) but not with
`high-dose rofecoxib (RR, 2.36 [C1, 1.27 to 439]). No increased risks were
`observed with celecoxib (RR, 0.99 [C1, 0.85 to 1.16]) or the other NSAIDs.
`
`0 Rahme et a1 ., Ayyocz’aZJ'o/z flatware/z Imp/axe}? are afldpralec/fa/z again.” dazzle myocardz’a/
`[Wm/1'0”. Arch Intern Med 2002;162:1111-5.
`o Nested case—control study
`0 4163 cases
`
`0 Determinants (adjusted odds ratios [95% confidence intervals]) of AMI included
`use in the prior year of anticoagulants (0.76 [0.64-0.90]), nitrates (2.01 [1 .86-
`2.17]), antidiabetic agents (1.72 [1.56-1.90]), antihypertensive agents (1.36 [1.28—
`1.45]), and lipid—lowering agents (0.83 [0.75-0.91]), as well as concurrent
`exposure to naproxen vs other NSAIDs (0.79 [0.63-0.99]).
`0 Compared with other NSAIDs, concurrent exposure to naproxen has a protective
`effect against AMI.
`
`0 Mamdani M et al., 237/651 ofse/ecz‘z'ue qxc/omyge/zaye 2 [aha/0115' a/zd/mpmxe/z 012 .rflort-
`[6/772 173% ofacz/te myocard‘a/zkfarc/fofl 1'12 Me e/a’eréz Arch Intern Med. 2003 Feb
`24;]63(4):481-6.
`o Retrospective cohort study using administrative health care data from Ontario,
`Canada
`
`0 No significant differences in AMI risk for new users of celecoxib (adjusted rate
`ratio [aRR], 0.9; 95% confidence interval [CI], 0.7-1.2), rofecoxib (aRR, 1.0; 95%
`CI, 0.8-1.4), naproxen (aRR, 1.0; 95% CI, 0.6—1.7), or nonnaproxen nonselective
`NSAIDs (aRR, 1.2; 95% CI, 0.9-1.4).
`o No increase in the short-term risk of AMI among users of selective
`cyclooxygenase 2 inhibitors as commonly used in clinical practice. Furthermore,
`the findings do not support a short-term reduced risk of AMI with naproxen.
`
`Other articles finding no increased risk of first-time myocardial infarction from naproxen:
`0
`Fischer et a1 ., 2005 , Car/”emf 2156 ojrflaflyterofdd/dlzllk'lflammg/wy drug; 412d[fie 1731’ of"
`acme myocardial[Wm/1’0”. Pharmacotherapy. 2005 Apr;25 (4)25 03-1 0.
`
`113
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21 -926
`MT400/Trexima
`
`Corolla/y Arte/y Coast/1211b}: and/V5110!
`
`Evidence is conflicting regarding the effect of COX inhibitors on coronary artery constriction.
`Studies examining the effect of naproxen specifically have apparently not been conducted.
`
`A summary of current knowledge is provided by Duffy SJ et al.( Cozz/rzéz/tz'o/z ofMiro/217751101”
`pray/afloz'afs’ and171';er oxide [0 rem/122gflow, ma/aéO/z'c 1252504974170”, 4125/flowaited/bled4274/1'0/2
`1'72 ham/12 corona/y arm/aim”. Circulation. 1999;100:1951~7):
`
`“Previous studies have shown that cyclooxygenase inhibition with indomethacin reduces
`resting CBF in patients with coronary artery disease. Although it has been confirmed by
`others, some have speculated thatthe effects of indomethacin are not due to PG inhibition.
`However, experimental studies have suggested that PGs are not essential for coronary
`metabolic vasodilation. In humans, there has been conflicting evidence regarding the effect
`of cyclooxygenase inhibition on metabolic vasodilation. Although experimental studies have
`not demonstrated a reduction of resting CBF after cyclooxygenase inhibition, in models of
`c0ronary artery disease, PG inhibition significantly decreased coronary diameter and CBF. In
`humans with atherosclerosis, indomethacin has been shown to reduce resting CBF and
`increase CVR; these effects are associated with increased MABP, estimated myocardial
`oxygen demand, and arteriovenous oxygen extraction. Although estimated myocardial
`workload did not increase in the present study, our findings are otherwise consistent with
`these previous investigations.”
`
`I find that this increases concern regarding the cardiovascular safety of Trexima.
`
`8.7 Postmarketing Risk Management Plan
`
`None recommended
`
`8.8 Other Relevant Materials
`
`None
`
`9 OVERALL ASSESSMENT
`
`9.1 Conclusions
`
`See Section 1.1
`
`9.2 Recommendation on Regulatory Action
`
`See Section 1.1
`
`114
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`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`
`9.3 Recommendation on Postmarketing Actions
`
`See Section 1.2 and subheadings.
`
`9.3.1 Risk Management Activity
`
`None
`
`9.3.2 Required Phase 4 Commitments
`
`None
`
`9.3.3 Other Phase 4 Requests
`
`See Section 1.2.3
`
`9.4 Labeling Review
`
`The nonclinical dog study of possible cardiovascular interactions between sumatriptan and
`naproxen is not adequately conclusive —
`
`Adverse events related to chest pain should be combined and added to common adverse events.
`
`The adverse events ‘neck/throat/jaw—pain/tightness/pressure’ should be combined and added to
`common adverse events.
`'
`'
`
`9.5 Comments to Applicant
`
`See DNP letter to sponsor.
`
`10 APPENDICES
`
`10.1 Review of Individual Study Reports
`
`Reviews of all studies are contained in main review sections.
`
`10.2 Line-by-Line Labeling Review
`
`115
`
`

`