Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`Tingling/numbness
`
`Site 339 / Subject 2324/ increased tingling all extremities
`Site 367 / Subject 2640/ numbness of hip, numbness of shoulder
`
`Site 025 / Subject 2387/ bilateral heaviness of arms, jittery feeling
`Site 197 / Subject 2007/ diabetes type 2 ,
`
`7.1.3.3 Other significant adverse events
`
`
`Other
`
`None
`
`7.1.4 Other Search Strategies
`
`There is an extensive literature on the safety of sumatriptan and naproxen. See Section 8.6
`
`7.1.5 Common Adverse Events
`
`7.1.5.1 Eliciting adverse events data in the development program
`
`At each visit, the subject spontaneously mentioned problems then the investigator inquired about
`adverse events:-
`
`0
`
`0
`
`"Have you had any (other) medical problems since your last visit/assessment?"
`
`"Have you taken any new medicines, other than those given to you in this study, since
`your last visit/assessment?"
`
`Subjects in the MT400—204 study and the three Phase 3 studies (MT400-301, MT400-302 and
`MT400—3 03) were instructed to record adverse events on diary cards.
`
`Since migraine headaches are typically accompanied by pain, nausea, vomiting, phonophobia
`and photophobia, these specific signs and symptoms were not recorded as adverse events, unless
`the condition worsened.
`
`Investigators were not obligated to actively seek adverse events in former study
`participants, but were instructed to notify Pozen if they became aware of any deaths or SAEs in
`any subject after sign-out from a clinical trial, when the event could have reasonably been related
`to study drug.
`
`7.1.5.2 Appropriateness of adverse event categorization and preferred terms
`
`I examined adverse events as categorized by preferred terms and combination of preferred terms
`(for example, ‘chest pain’ and ‘neck pain’ categories were assembled from several preferred
`
`72
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`terms, see section 7.1.6). Adverse effects were generally not serious and reversible, and derived
`mainly from patient reported symptoms. Adverse events data was generally straightforward
`given the healthy patient population and relative tolerability of Trexima.
`
`7.1.5.3 Incidence of common adverse events
`
`Studies MT400—204, MT400-301 and MT400—302 were single dose efficacy studies of Trexima
`in an outpatient setting. Therefore, objective safety assessments followed treatment with study
`medication by several days, making the measures less useful for safety determinations. Subjects
`recorded subjective adverse events during dosing of study medication.
`
`Phase I studies
`
`MT400-101, 102, 103, 105 (N = 13 to 31 for each)
`Common adverse events reported by healthy volunteers were dizziness, somnolence, nausea, and
`headache. All events were mild except for one case of moderate nausea and vomiting.
`
`Phase II studies
`
`MT400-204, (single-dose outpatient ‘proof of concept’ study)
`Importantly, the dose of sumatriptan in study MT400-204 was 50 mg non—RT, instead of the 85
`mg RT ( _ "
`in the final Trexima formulation. The
`incidences of adverse events were similar in subjects treated with MT400 and sumatriptan (23%
`and 24%, respectively), and higher than the incidences of adverse events with naproxen sodium
`(17%) and placebo (15%). Events occurring in 2% or more of subjects are listed in Table 51
`
`Appears This Way
`On Orlglnal
`
`73
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`Table 51: Adverse Events in 2 2% of subjects, MT400-204
`
`v
`
`Treatment Groups
`
`Body System
`Adverse event
`
`(preferred term)
`
`MT 400
`
`Sumatriptan
`
`50 mg
`
`(non-RT)
`N=229
`
`(sumatriptan
`
`50 mg non—RT +
`naproxen
`sodium
`
`500 mg)
`N=251
`
`Naproxen v
`Sodium
`
`500 mg
`N=250
`
`
`
`Subjects with at least one
`
`58 (23)
`
`adverse event — n (%)
`
`Nervous System Disorders
`
`18 (7)
`
`Dizziness
`
`Somnolence
`
`Paresthesia
`
`General Disorders
`
`Chest tightness
`
`Fatigue
`
`Gastrointestinal Disorders
`
`Dry mouth
`
`Nausea aggravated
`
`Diarrhoea
`
`9 (4)
`
`3(1)
`
`2 (1)
`
`18 (7)
`
`5 (2)
`
`5 (2)
`
`14 (6)
`
`4(2)
`
`1 (<1)
`
`Bar and Labyrinth Disorders
`
`8 (3)
`
`2(1)
`-—
`
`37(15)
`
`11 (5)
`
`8 (3)
`
`1 (<1)
`
`5 (2)
`
`3(1)
`
`18(7)
`
`1(<1)
`
`4(2)
`
`3(1)
`
`2(1)
`
`Tinnitus
`
`6 (2)
`
`2(1)
`
`74
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`Phase III studies
`
`The most Common Treatment-Emergent Adverse Events in >2% of Subjects in the Primary
`Safety Population (MT400-301 and MT400-302) are shown in Table 52, while the same data
`with a >1% cutoff is shown in Table 53 . Adverse events are increased in Trexima and
`
`sumatriptan arms versus the other two arms. No clear distinction can be made between Trexima
`and sumatriptan, however. ‘
`I
`
`Table 52: Common Adverse Events, >2%, MT400-301, MT400-302
`
`From Table 2.7.61
`
`Treatment Group
`
`
`
`Trexima
`(sumatriptan 85 mg
`(RT) / naproxen
`
`sodium 500 mg)
`N=737
`
`197 (27)
`
`89 (12)
`
`28 (4)
`
`24 (3)
`
`18(2)
`
`69 (9)
`
`24 (3)
`
`15 (2)
`
`15 (2)
`
`23 (3),
`
`13(2)
`
`'
`
`Any Adverse
`Event
`
`Nervous System
`
`Any Event
`Dizziness
`
`Somnolence
`
`Paresthesia
`
`Gastrointestinal
`
`Any Event
`Nausea
`
`Dry mouth
`
`Dyspepsia
`Cardiac
`
`Any Event
`Chest discomfort
`
`Sumatriptan Naproxen
`85 mg (RT)
`Sodium 500 mg
`
`N=735
`
`N=732
`
`N=752
`
`194 (26)
`
`100(14)
`
`84(11)
`
`63 (9)
`
`16 (2)
`
`17 (2)
`
`17 (2)
`
`71 (10)
`
`21(3)
`
`15(2)
`
`14(2)
`
`26(4)
`
`10(1)
`
`37 (5)
`
`11 (2)
`
`12(2)
`
`2 (<1)
`
`32(4)
`
`5 (<1)
`
`1 (<1)
`
`6 (1)
`
`7 (1)
`
`3 (<1)
`
`35(5)
`
`16(2)
`
`15(2)
`
`3 (<1)
`
`33(4)
`
`10(1)
`
`8(1)
`
`5(1)
`
`6(1)
`
`1(<1)
`
`75
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`Table 53:Common Adverse Events, >1%, MT400—30l, MT400-302
`
`'
`Treatment Group
`Placebo
`Trexima
`Sumatriptan
`Naproxen
`N = 752
`(sumatriptan 85 mg
`85 mg (RT)
`SOdmm
`(RT) / naproxen
`N = 735
`500 mg
`sodium 500 mg)
`N = 732
`
`N=737 0/0)-
`
`An Adverse Eveng
`
`Nervous System
`disorders
`
`197 (27)
`
`89 (12)
`
`194 (26)
`
`63 (9)
`
`100 (14)
`
`37 (5)
`
`Dizziness
`
`Somnouence
`
`Paraesthesaa
`
`disorders
`
`a mouth
`
`osuesaa
`
`Vommn
`
`connectlve tlssue
`
`
`A
`
`84 (11)
`
`35 (5)
`
`16(2)
`
`15(2)
`
`3<<1>
`
`mm
`
`80>
`
`5<<1>
`
`90>
`
`3<<1>
`
`90>
`
`1<<1>
`
`6<<9
`
`1<<1>
`
`5<<1>
`
`3(<1)
`
`
`
`Muscleumness—--
`Neck am
`
`Genera: disorders
`
`Asmema
`
`cardiacaisomer
`
`cheswiscomron
`
`Pantauons
`
`and medrastlnal
`
`ThrO‘attihtness __“
`Vasculardisorders
`
`Homush
`
`‘ Total number of subjects with at least one adverse event
`Source: Section 2.7.4.722
`
`76
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21—926
`MT400/Trexima
`
`Moderate/severe ratings were reported by 8 (3%) of subjects in the Trexima treatment
`group, by 7 (2%) subjects in the sumatriptan group, 4 (1%) subjects in the naproxen
`sodium group and 3 (1%) of subjects in the placebo group.
`
`Common adverse events in the long-term safety study (MT400-303) are shown in Table 54.
`find the common adverse events to be similar to those in current sumatriptan and naproxen
`labeling.
`
`I
`
`77
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21 -926
`MT400/Trexima
`
`Table 54: Common Adverse Events, MT400-303
`
`(Table 2.7.4, Safety Update)
`
`Type of Event:
`.
`v
`
`'
`
`Oxeral! Safety
`Popuiatiou
`N= 565
`11(.%)
`
`V
`
`6-M0nth
`Completers
`N=414
`n(%)
`
`/
`
`IZ-Month
`Completers .
`N=362
`n(%)-
`
`V
`
`sfu,bjf¢h£§lWithAtLeastOxie 5.
`‘dL-v’erseiflvent
`.
`
`374(66.2)j_7.'i2.:'
`*
`*
`'
`I
`'3
`
`31, 228(35.1)-1
`,
`
`y :'246f(6:sgojf§gzz f
`.
`
`1'00 (242)
`
`«
`
`5
`
`1,80“(3.11:9333,»
`' 50 (838133"
`>
`v
`'W”3VE.EI4.6 (.8313)
`321:7":2125 (4L4)
`
`1
`
`'
`
`.
`
`a:
`
`(nféctien‘sfind Infestations
`..
`Nasophamyngitls
`,
`_
`
`f
`
`'
`
`L
`
`i
`.1
`; 7
`
`infection
`i1 -.
`influenza
`'
`,
`{\‘Bronehitis
`”fsvtrdifitjesfinal Disorders \
`“Anyi'Ei/em,
`,.
`»
`
`~
`
`‘
`
`_,
`
`2085)
`
`_
`
`_
`
`,
`
`..
`131(2335
`
`, .
`
`23 (56)
`13(33.)
`
`:
`
`. "
`‘Dyspepsia
`~ Abdominal} pain upper
`
`V
`
`5 ”
`
`i
`'
`20 (3S)
`
`»
`
`' d5“6)
`
`EMuscquskeletaISz
`.ConnectiVe{PissneDisordersv
`
`,5:
`
`»
`
`..
`f:
`
`:
`
`.
`
`4
`
`v
`
`,
`
`‘
`
`,
`
`_
`'Muscie‘tighmessr 1.2-:
`
`iiiii21 (37)
`
`'1
`
`*
`
`2*1407(381713222
`" 47 (1,39)
`34 (94)
`23 (64)
`
`'
`
`17(47)
`l1(3Q)
`-
`
`(
`
`‘
`
`*
`
`‘1
`
`-'
`
`.
`
`.
`
`V
`
`"if .
`
`;
`
`‘
`
`Arthralgia-
`NeCkpain
`'Backpain ,3
`
`,3
`
`E‘NervousSystemDisorders
`
`AnyEvent
`'
`Dizziness
`"insomnia
`
`1
`
`9;
`
`" ' 5'
`
`,
`
`» 94'Ci..i6.6)335231a
`26146)“
`=
`'
`,
`
`,:v,;,16(2.8)
`{15.(27).
`
`~.
`' ,
`1 M
`1
`
`'V ——
`
`'5
`
`78
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`(qgntinuecl)
`
`1 media‘stinalr“
`‘4
`'
`‘ Any event?
`' Pliamgoiarynge
`
` : Respiratory”,
`
`79
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21 -926
`MT400/Trexima
`
`Twenty-seven percent of subjects within the overall safety population reported an event judged
`related to Trexima by the investigator. These events were primarily from the gastrointestinal or
`nervous system (Table 55).
`
`Table 55: Common Adverse Events Judged Drug-Related by Investigator, MT400-303
`
`(from table 2:7?63, Safety Update)
`
`p
`
`.
`
`.
`
`'“ ‘VN=555»;
`
`.,
`,
`st
`"ne Adverse Event.
`" gGa rein ~,stxnalDlsorders ’
`
`'
`
`naectl‘ve 1 ,
`
`80
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`7.1.5.4 Common adverse event tables
`
`(see under heading 7.1.5.3)
`
`7.1.5.5
`
`Identifying common and drug-related adverse events
`
`(see under main heading 7.1.5)
`
`7.1.5.6 Additional analyses and explorations
`
`None
`
`7.1.6 Less Common Adverse Events
`
`I examined the table of all treatment emergent adverse events for rare (<2%) but possibly
`significant events (Table 56).
`'
`
`“Cardiac disorders” (listed as ‘chest discomfort, palpitations, chest pain, cardiac flutter’) were
`more common, about equally, for Trexima and sumatriptan versus naproxen and placebo. These
`symptoms are expected given previous adverse events documented for sumatriptan alone.
`
`0 Chest discomfort
`
`0
`
`Palpitations
`
`0 Chest pain
`
`Trexima(%)
`1.8
`
`Sumatriptan(%)
`1.4
`
`1 .1
`
`0.8
`
`1.4
`
`0.8
`
`Similarly, muscle tightness, particularly throat and neck tightness and discomfort, occurred more
`commonly for Trexima and sumatriptan:
`
`0 Muscle tightness
`
`0 Neck pain
`
`o Throat tightness
`
`o
`
`Pharyngolaryngeal pain
`
`Trexima(%)
`1.4
`
`Sumatriptan(%)
`1.2
`
`1.1
`
`1.4
`
`0.7
`
`0.5
`
`1.2
`
`0.8
`
`[Comment neck/throat pain should be included in labeling as a single adverse event]
`
`81
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`Table 56: Adverse Events, Controlled Trials
`
`
`T.ab1e2'7..4722
`'E'reatmen: Emergent: Advez;
`e_ EvTents
`.
`By MedDRA System Organ Class '
`eterredTerm
`
`. Safety Population from Studie
`and 302
`
`
`Treyima
`Sumeriptan
`(14633?)
`{143735}
`
`
`
`fiagroxen
`032732)
`
`-
`
`Placebo.
`(14:75.?)
`
`Subject Had at Least Ema Adverse Event
`' N9
`_.Yes
`
`.
`;
`
`'Ii_ 1
`
`'
`
`_
`. 543} (?3.3%)
`137.
`(253.73.)
`
`.
`
`.
`
`541 {73.6%}
`194 (25.42)
`
`:
`
`'
`
`'532‘(8§.3§s)
`210.043.3324;
`
`,
`658‘ (88.8%)
`simian
`
`
`
`g ‘_
`
`3
`
`-
`
`,
`
`V,
`
`,
`
`"
`
`'
`
`.
`
`-
`
`I 0.1%)
`
`( 0.1%)
`
`I 6.5%}
`
`-
`
`.
`
`'
`
`( 0.14;)
`
`’
`
`g
`‘
`
`,
`
`>
`
`'
`
`,
`
`.
`
`‘
`
`,
`
`*
`
`'
`
`'
`
`; 35 ("4.7311
`371,5.14} -
`63 ( 8.43%)f :3
`39, (32.1%)
`'
`'VNétvous system disoxders
`.«16 { 2.1%);
`_ 11 «'4 1.5%)
`16 ( 2. 2%}
`. ~ 28’
`( 3.8%}
`Dizziness
`V
`"12] {1.6%} " ~15 ( 24.0%);
`17 (2 3%)
`‘
`.- 2'4 ( 3.3%)
`:Somnolence
`‘17 f 2. 3%}
`. _.
`2 i 0.3%}
`3 ( 0.4%).
`18 l 2.33%)
`=Pa‘raesthesia
`4 i 0. 5%):
`’
`2 (9.3%) ‘
`O
`‘
`’7 (/ 9.9%)
`”Frame:
`,
`3 {0.4%}
`3 ( 0.4%),
`0
`’
`4
`(' 0.5%)
`Earning sensation
`3
`( 0.1%)
`l ( 0.1%)
`2 ( 0.3%)
`4 ,( 0.5%)
`Headache
`i
`l 0.1%)
`0
`0
`3 ( 0.4%)
`Hyparaesthesia
`3.
`( 0.1%)
`:4
`2 ( 0.3%)
`3 (10.4%)
`Vertigo
`5
`g 0.7%}
`0
`0
`2 l 0.3%)
`Hypoaeathesia
`0
`0
`0
`2 ( 0.3%)
`Mental impairment
`0
`O
`1
`2.
`l 0.3%)
`Migraine
`2
`0
`0
`2 ( 0.3%)
`Sensoxy distuxbance
`O
`0
`0
`1_
`‘( 0.192).
`Cognitive disorder
`3 l 0.1%)
`0
`0
`l
`( 0.1%)
`Fertilisation
`_ l
`l 0.1%)
`2 ( 0.3%)
`O
`1
`( 0.1%)
`Insomnia
`> 0
`0
`.
`0
`1
`( 0.1%)
`Restlessness
`,1 i 0.1%)
`l l 0.1%)
`0
`1
`( 0.1%)
`Tension headache
`:1
`' 2 {0.3%}
`0
`{ 0.1%)
`l '( 0.1%)
`Vision blurred
`I
`(3.1%}
`O
`'
`0
`0
`v
`Eyelid ytosis
`. 2 ( 0.3%)
`‘ 0
`0
`0
`_ Hypoaesthesia oral
`i
`( 0.1%)
`0-
`0
`0
`xncranasal paraeschesia
`3.
`( 0.1%}
`0
`1
`0
`.Paxzaesthesia oral
`1 ( 0.1%)
`0
`0
`0
`.E’arosmia
`63 L 8.fi%l
`37 i 5.1%}
`35 ( 4.7%)
`89 (32.1%)
`Nexvcus system disorders wont.)
`0
`1
`{ 0.1%}
`O
`O
`Psychometor hyperactivity
`.
`'70
`1
`i 0.1%}
`O
`0
`Psychometor skilis impaired
`I t 9.1%) ’
`0 .
`0
`0
`Sedation
`1.
`(
`IO..1%)
`0
`0
`O
`Skin burning sensation
`_
`0
`,1 { 0.1%)
`0
`O
`Tinnitus
`'71 ( 9.7%}
`32 E 4.4%)
`33 ( 4.4%)
`69 ( 9.4%)
`Gastrointestinal disorders
`23 (' 2.9%)
`5
`l 0.7%)
`10 l 1.3%).
`24 ( 3.3%) ‘
`Nausea
`15 ( 2.0%)
`1 E 0.1%}
`8 ( 1.3%)
`15 l 2.0%)
`Dry mouth
`14 t 1.9%)
`6 { 0.8%}
`5 i 6.7%)
`15 (2.03s)
`Dyspepsia
`i
`( 0.1%)
`7 i 1.9%
`2 ( 0.3%}
`5 ( 0.7%)
`Abdominal pain upper
`6 (0.8%)
`5
`{ 0.7%)
`5 { 0.7%)
`5 £ 0.73)
`Diarrhoea
`0
`2 E 0.3%)
`0
`_3
`i 9.4%)
`‘Dysgemsia
`6 (0.8%)
`3 t 0.4%)
`9 ( 1.2%)
`3 (10.4%)
`Vomiting
`0
`0
`0
`2 .( 0.3%)
`Eructacion
`2
`( 0.3%)
`l t 0.1%)
`0
`.2 (0.3%)
`flatulence
`8
`I)
`0
`1 ( 0.1%)
`Abdominal distension
`4
`1 i 0.1%)
`0
`1
`( 0.1%}
`Abdominal pain
`0»
`l
`( 0.1%}
`0
`1 ( 0.1%)
`Dysphagia
`1
`0
`0
`1
`( 0.1%)
`Gastric irritation
`:3:
`{5
`0
`1 ( 0.1%)
`Gastrooesophageal reflux disease
`.0
`0
`0
`1
`( 0.1%)
`Lip dry
`0
`1 ( 0.1%)
`0
`0
`Abdominal tenderness
`.
`i)
`i
`f 0.1%}
`0
`O
`Abnormal faeces
`(3.1%)
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`
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`
`
`
`82
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`Gastrointestinal disordezs (Cont.)
`Gastritis
`Gastrointestinal pain
`Hiccups
`Loose stools
`salivary hypersscretion
`Sensitivity of teeth
`Stomach discomfort
`Throat irritation
`
`Musculoskéletal and connective tissue
`Muscle tightness
`Neck’pain
`Akthralgia
`Musculoskeletal stiffness
`Myalgia
`‘Pain in jaw
`Muscular weakness
`g Sensatios cf heaviness
`V Back paih
`Limb discomfort
`Muscle rigidity
`.Musculoskeletal discomfort
`‘Pain in extremity
`'
`Arthropathy
`'Chest,wall pain
`jFacia;gpaifi
`'Joint stiffness
`Musculoskaletal and connective tissue (Cont.}
`‘Jointiswelling
`Muscle twitching
`Trigmus
`General diSorders
`‘ Aschenia
`ffgbigue
`'Eeeling hot
`‘Lethargy
`' Feeling abnexmal
`Thirst
`Cold sweat.
`'Faeling cold
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`Malaise
`.
`Sensation of pressure
`“Energy increased >
`illnfilvenza like illness
`Qédema,pexiphéral
`. Pain
`Pyrexia
`, Rigazs
`Sensation of foreign body
`sluggishness
`Suprapubic pain
`
`83
`
` A
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`
`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT4OO/Trex1ma
`
`
`
`Cardiac disorders
`',Ches€ discomfart
`V Palpitations
`*Chést pain
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`-
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`. Productive cough =-
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`
`-
`
`23 l 3.1%)
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`-,.,
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`Infections and infestations
`7
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`
`84
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21—926
`MT400/Trexima
`
`GO
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`Vascular disoréers
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`Labile blood pressure
`
`Metabolism and nutrition disorders
`- Thirst
`Anorexia‘
`Dehydraticn
`Fluid retention
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`Decreased appetite
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`Eye disorders
`Abnormal sensation in eye
`Asthenopia
`Visual disturbance
`Eye disoréer
`Eye pain
`Eya pruxitus
`Lacrimation increased
`
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`Investigations
`Body temperature decreased
`Fundoscopy abnormal
`fleart rate increased
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`
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`
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`Ear pain
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`
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`Renal ané urinary disardezs (Cont 3
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`.
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`Breast pain 3
`- Election increased
`
`Injury, poisoning, procedural ccmplications
`Animal scratch
`Cantusion
`Joint sprain
`
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`Ectopi6»pregnancy
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`85
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`7.1.7 Laboratory Findings
`
`7.1.7.1 Overview of laboratory testing in the development program
`
`Laboratory testing was carried out for subjects in the controlled trials, but these were essentially
`all single dose studies, such that drug exposure was very low, and it would be unlikely for most .
`drug effects to be detected.
`
`The open-label study Of Trexima did not have a comparator group, greatly limiting power to
`identify anything but very rare events.
`
`For all studies, laboratory testing was conducted at times remote from Trexima dosing (baseline
`and follow-up visits), increasing the difficulty of associating changes to drug effects.
`
`7.1.7.2 Selection of studies and analyses for drug—control comparisons of laboratory
`values
`
`All studies submitted were used for analysis of laboratory values.
`
`7.1.7.3 Standard analyses and explorations of laboratory data
`
`Primary Safefl Population
`
`Table 57 lists selected markedly abnormal laboratory values in study 301 and 302 (Table 58
`shows cutoffs for defining values as markedly abnormal). There was no increase in abnormal
`values for Trexima versus the three other study arms.
`
`I reviewed the individual hematology data for the subjects with markedly abnormal values and
`believe that none were serious.
`
`Blood chemistry showed one Trexima-treated patient with hyperkalemia (baseline 5.4 mEq/L,
`increased to 6.6, then 1 day later decreased to 5.4) a known adverse effect of NSAIDS.
`
`Modest elevations in certain enzymes (e.g. CPK, AST) were seen in a small number of subjects
`in all groups, but without apparent relationship to pre- or post—dosing, or treatment arm.
`
`86
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`Table 57: Selected Markedly Abnormal Laboratory Abnormalities,vPrimary Safety Population
`
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`
`87
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21—926
`MT400/Trexima
`
`Table 58: Cutoff Definition of Markedly Abnormal Laboratory Values
`
`,
`{Table 1,412.20, MT400-303 final) ,
`
`
`
`
`
`
`
`MT400-303, Open Label Safefl Study
`
`This study included the collection of clinical laboratory test data at the time of the screening
`visit, at the 6 month visit, and at the 12 month visit. Routine hematology and
`chemistry tests were performed.
`
`Z Z Z .2 / Alzdé/Jarfocwedon 172652521135" green/falle/m’e/zcy
`
`' Pozen reports, and I agree, that:
`“There was no evidence of a relationship between episodic treatment with Trexima over
`the period of this study and the results of any specific clinical laboratory tests.”
`
`“Because of the possible effects of NSAIDs on hepatic and renal function, hepatic
`enzymes (ALT and AST) and renal function parameters (creatinine and BUN) were
`examined specifically and no suggestion of a safety signal was present.”
`
`88
`
`

`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`1421-926
`MT400fI‘rexima
`
`Z l. 7.]. 2 14/74/1256,)"floured0/2 pal/1'6” alryéfiyfmm 170/7724/10 dé/mmm/
`
`Little change occurred for most of the hematology and blood chemistry values in the long term
`study. For MCHC (mean corpuscular hemoglobin concentration)(Table 1), 23% of subjects
`shifted from ‘high or normal to low.’ However, MCHC was a highly volatile measure, with
`12% of subjects showing ‘change to normal,’ while other hematology values showed 2-4% shift
`to normal. Also, decreased MCHC was not accompanied by other laboratory signs of anemia,
`suggesting it is not indicative of a true adverse effect.
`
`Table 59: Hematology shift values, MT400-303
`
`
`
`
`Low or Normal w) Sign
`H
`_
`
`\High or Normal —> Low: :,;§
`
`iNo Change
`'
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`
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`
` dNe Change
`
`
`
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`
`
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`
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`
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`
`
`
`
`
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`
`
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`,«to Normal
`
`
`
`
`89
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21—926
`MT400/Trexima
`
`7. /. Z3. 3 fl/m‘l’ed01/1/1911)" 4174’d/QflOZ/llflr laéora/aly dé/zorma/z'lz'es
`There were two subjects with increased liver enzymes likely'due to Trexima (see section 7.1.3,
`Dropouts and Other Significant Averse Events). Otherwise, only a small number of marked
`laboratory value outliers were identified, and no patterns of abnormalities were found.
`
`7.1.7.4 Additional analyses and explorations
`
`None
`
`None
`
`7.1.7.5 Special assessments
`
`7.1.8 Vital Signs
`
`7.1.8.1 Overview of Vital signs testing in the development program
`
`Both sumatriptan and naproxen are known to increase blood pressure, but insufficient blood
`pressure data was collected in the Trexima studies. Clinical pharmacology studies did not record
`vital signs during medication administration. The controlled trials measured blood pressure only
`days before, or days after single doses. The safety study measured blood pressure only at
`baseline.
`
`7.1.8.2 Selection of studies and analyses for overall drug-control comparisons
`
`(see 7.1.8.1)
`
`7.1.8.3 Standard analyses and explorations of vital signs data
`
`7. /. 0°. 33 / 1120445195flawed0/2 mean/res ofcem‘ra/[glide/26129;
`
`Table 60 lists Vital signs change from the single-dose studies 301 and 302. Vital signs
`differences were calculated between screening and follow-up visits, distant from drug dosing.
`Vital sings, including blood pressure, showed no meaningful change.
`
`90
`
`

`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`Table 60: Vital Signs Change, Studies 301 and 302
`
`2mm, Inc.
`
`Table 2.?.1;.‘}f.-1'4-.3
`.
`Vital Signs (mange from Scseeninq to Fellow—up
`Safety yopulati-oe from .Sfiudi‘es 3&1 and .362
`
`Study Number made-433.
`
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`141
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`Z l. 6’. 3. 2 14/744473;foamed0/2 out/[em or Jéfirflom 120mm]10 aélzor/im/
`
`No patients on Trexima in the single dose trials MT400-301 and MT400—302 (combined N=737)
`experienced the adverse event of ‘blood pressure increased’ as determined by blood pressure
`measurement at follow-up visit.
`
`7. 1 cf 3’. 3 Mrka/owl/1191’s aflddmpou/Jfar VIM/51g}; aé/zor/Im/zlzley
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`None
`
`None
`
`7.1.8.4 Additional analyses and explorations
`
`7.1.9 Electrocardiograms (ECGs)
`
`7.1.9.1 Overview of ECG testing in the development program, including brief review of
`preclinical results
`
`No ECG testing was conducted at the time of Trexima exposure in any study. Controlled trials
`and the safety trial examined ECGs only at baseline.
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`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`7.1.9.2 Selection of studies and analyses for overall drug-control comparisons
`
`No data available (see Section 7.1 .91)
`
`7.1.9.3 Standard analyses and explorations of ECG data
`
`No data available (see Section 7.1.9.1)
`
`7. /. ,0. f. / 1412052165flea/Jed0/7 measures g’ce/z/ra/te/m’e/zcy
`
`Not data available (see Section 7.1.9.1)
`
`Z Z ,0. J”. 2 Afldé/JeJ/oczuedwz owl/129m or Jflflyfloflz normalto 45/20/7720/
`
`No data available (see Section 7.1.9.1)
`
`Z l. 2 53 3 Jig/”fedout/fem 41752799015024.5721” ECG aé/mr/Im/M'ey
`
`No data available (see Section 7.1.9.1)
`
`7.1.9.4 Additional analyses and explorations
`
`No data available (see Section 7.1.9.1)
`
`7.1.10 Immunogenicity
`
`The components of Trexima are not considered immunogenic.
`
`7.1.11 Human Carcinogenicity
`
`No carcinogenicity studies were conducted with the combination of sumatriptan and naproxen.
`
`Neither sumatriptan alone, nor naproxen alone, were found to be carcinogenic after lifetime, oral
`administration studies in rodents (from prescribing information for Imitrex and Naprosyn).
`
`7.1.12 Special Safety Studies
`
`None
`
`7.1.13 Withdrawal Phenomena and/0r Abuse Potential
`
`While triptans and NSAIDs are not subject to abuse in the classic sense, migraine headache
`medication is frequently overused. Overuse is defined by the IHS as intake more than 15 times a
`
`92
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`

`Clinical Review
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`month for a minimum of three months. Frequent use of sumatriptan or naproxen can cause
`‘medication overuse headache (MOH).’ MOH his treated by medication withdrawal.
`Withdrawal of headache medication itself often causes a ‘withdrawal headache’ lasting about 5-
`10 days.
`
`The Imitrex label states: “One clinical study with IMITREX (sumatriptan succinate) Injection
`enrolling 12 patients with a history of substance abuse failed to induce subjective behavior
`and/or physiologic response ordinarily associated with drugs that have an established potential
`for abuse.”
`
`7.1.14 Human Reproduction and Pregnancy Data
`
`Sumatriptan:
`Pregnancy category C
`No evidence suggests that sumatriptan increases human fetal abnormalities. Weak and
`contradictory data suggests that sumatriptan might increase the rate of preterm delivery
`(reviewed in TERIS, The Teratogen Information System).
`
`.
`Distribution in breast milk (from Martindale)
`“The distribution of sumatriptan into breast milk following a 6-mg subcutaneous dose has been
`studied in 5 lactating mothers. The mean total recovery of sumatriptan in breast milk was
`estimated to be 14.4 micrograms or 0.24% of the dose. It was calculated that on a weight
`adjusted basis an infant could receive a maximum of 3.5% of the maternal dose.”
`
`.
`Naproxen:
`Pregnancy category C
`The risk of congenital anomalies from naproxen is not likely to be great. Persistent pulmonary
`hypertension and premature closure of the ductus arteriosus have been reported in infants whose
`mothers took naproxen just before delivery (from TERIS).'
`
`Distribution in breast milk (from Martindale)
`“In a study of a breast-fed infant only 0.26% of the mother's dose was recovered from the infant
`
`7.1.15 Assessment of Effect on Growth
`
`Sumatriptan:
`Safety and effectiveness of sumatriptan in pediatric patients has not been established.
`Sumatriptan increases the release of growth hormone
`
`Naproxen:
`Experience injuvenile arthritis and other use experience have established that single doses of 2.5
`to 5 mg/kg, with total daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric
`patients over 2 years of age (from prescription naproxen label).
`
`93
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`

`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`7.1.16 Overdose Experience
`
`No cases of Trexima overdose are reported. Overdose experience with the individual drugs, as
`reflected in labeling, is presented below.
`
`Sumatriptan overdosage:
`“Patients (n=670) have received single oral doses of 140 to 300 mg without significant adverse
`effects. Volunteers (n=174) have received single oral doses of 140 to 400 mg without serious
`adverse events.”
`
`“It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of
`sumatriptan.”
`
`Naproxen overdosage:
`“Significant naproxen overdosage may be characterized by lethargy, dizziness, drowsiness,
`epigastric pain, abdominal discomfort, heartburn, indigestion, nausea, transient alterations in
`liver function, hypoprothrombinemia, renal dysfunction, metabolic acidosis, apnea,
`disorientation or vomiting. Gastrointestinal bleeding can occur. Hypertension, acute renal
`failure, respiratory depression, and coma may occur, but are rare. Anaphylactoid reactions have
`been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose.
`Because naproxen sodium may be rapidly absorbed, high and early blood levels should be
`anticipated. A few patients have experienced convulsions, but it is not clear whether or not these
`were drug—related. It is not known what dose of the drug would be life threatening.”
`
`“Patients should be managed by symptomatic and supportive care following a NSAID overdose.
`There are no specific antidotes. Hemodialysis does not decrease the plasma concentration of
`naproxen because of the high degree of its protein binding. Emesis and/or activated charcoal (60
`to 100 g in adults, I to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients
`seen within 4 hours of ingestion with symptoms or following a large overdose. Forced diuresis,
`alkalinization of urine or hemoperfusion may not be useful due to high protein binding.”
`
`7.1.17 Postmarketing Experience
`
`Trexima is not marketed in any other country. No other combination of triptan/NSAID is
`marketed.
`'
`
`Extensive postmarketing experience exists for both sumatriptan and naproxen.
`
`Naproxen:
`Major recognized adverse effects of NSAIDs, including naproxen, are listed in Table 61.
`
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`Clinical Review
`
`Ronald Farkas, MD, PhD
`N21-926
`MT400/Trexima
`
`Table 61
`
`: Major adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs)
`Serious side effects include:
`
`-heart attack
`
`~stroke
`
`°high blood pressure
`-heart failure from body swelling (fluid retention)
`
`~kidney problems including kidney failure
`'bleeding and ulcers in the stomach and intestine
`-low