DEPARTMENT
`
`SERVICES
`
`OF HEALTH AND HUMAN
`PUBLIC
`HEALTH
`SERVICE
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`CENTER
`FOR BIOLOGICS
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`TRANSMHTAL
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`unless
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`Federal
`Food, Drug,
`and Cosmetic
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`this completed
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`2. CHECK
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`ONE
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`Draft
`
`$1
`received
`form has been
`submittal
`(U.S. Public Health Se&m
`of Federal Regulatiotw, Part 600).
`502: and Title 21 U.S. Code
`
`OMB No. 0910-0315.
`Form Approved:
`Date: August 31. 2003
`Expiration
`s88 ohf6
`St8t8fll8nt
`On r8Vem8.
`1. LABEL REVIEW NO. AND REVISION
`/03/7q45~U
`
`3.
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`6.
`
`7.
`
`MANUFAC-
`TURER NAME
`AND RETURN
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`PRODUCT
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`LABELING
`DETAILS
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`I;CdLCl,
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`ffv
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`In/r)/
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`J,A
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`&
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`: r/a55
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`(A/$A‘3c)
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`lo48
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`q New Scientific
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`Format
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`(select only one)
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`0
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`Dosage
`
`Change
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`64. ~~M&~cgtionss
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`PCKR
`SHIP
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`
`in
`(Spec/w
`Comments)
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`Additive
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`0
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`Comments)
`
`CIRC
`CONT
`PACK
`
`Circular
`Container
`Package
`
`DILT
`BLST
`CRTN
`
`Dlluent
`Blister
`Carton
`
`1.
`
`9.
`
`THE BOX(es)
`CHECK
`THIS SUBMISSION
`
`OF
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`INDICATING
`(More
`than one maybe
`checked).
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`IF THIS LABELING
`OF:
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`11. COMMENTS
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`q Appllcatton
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`description
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`g
`
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`$I
`Associated
`BLAI PtA No.
`q Part of an Annual
`/03/ 7Z/fW
`,I3 Supplement
`Report
`or revision no. oflabel being repla&. IF FFM. p~bU..l7, p~vide LOT ~0. & DATE of
`
`12.
`AUTHORIZED
`OFFICIAL
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`
`DATE
`
`:OMMENTS
`
`THE SPACES
`(See attached
`
`BELOW ARE FOR USE BY CENTER FOR BIOLOGIC
`q ) metie awlt
`final printed labeling S Ul
`comments
`-y.
`ofd3e grid include implementation
`$xmation on Form 2567. Please provide 8
`PDF-format electronic copy and Original
`,.
`paper copies (10 for circulars and5 for OthS
`. .
`aabeb.~
`
`-+tlr,rrr,:r~,.(:,c,‘irili~~r’r.n ,
`. . . . . --_
`
`LUATION AND RESEARCH
`
`REVIEWED BY
`
`RETURNED
`
`BY
`
`SIGNATURE
`
`45Ld&ye
`SIGNATURE
`
`v-
`
`.\
`
`DATE
`5/3/d
`
`2.
`
`.
`
`Ex. 1028 - Page 1 of 32
`
`AMGEN INC.
`Exhibit 1028
`
`

`

`DEPARTMENT
`
`SERVICES
`
`OF HEALTH AND HUMAN
`PUBLIC
`HEALTH
`SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER
`FOR BIOLOGICS
`EVALUATION
`AND RESEARCH
`TRANSMHTAL
`OF LABELS AND CIRCULARS
`
`NOTE:
`
`unless
`No license may be granted
`Federal
`Food, Drug,
`and Cosmetic
`
`this completed
`Act, Section
`
`2. CHECK
`
`ONE
`
`Draft
`
`$1
`received
`form has been
`submittal
`(U.S. Public Health Se&m
`of Federal Regulatiotw, Part 600).
`502: and Title 21 U.S. Code
`
`OMB No. 0910-0315.
`Form Approved:
`Date: August 31. 2003
`Expiration
`s88 ohf6
`St8t8fll8nt
`On r8Vem8.
`1. LABEL REVIEW NO. AND REVISION
`/03/7q45~U
`
`3.
`
`6.
`
`7.
`
`MANUFAC-
`TURER NAME
`AND RETURN
`ADDRESS
`
`PRODUCT
`NAME
`
`LABELING
`DETAILS
`
`I;CdLCl,
`
`ffv
`
`*
`
`/ DNA
`
`In/r)/
`
`J,A
`
`&
`
`frmG:ILU,
`
`CA Wo8~-4esa
`
`A4 c
`
`: r/a55
`
`(A/$A‘3c)
`
`LABEL TYPE CODE
`(see below)
`
`PREVIOUS
`REPLACES
`REVIEW & REVISION
`NO.
`
`LABEL
`DATE
`
`6. SUBMISSION
`
`REASONS
`
`(Check
`
`all that app/y)
`
`cz4
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`c
`
`I
`
`0
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`New Product
`
`[7 New
`
`Indication
`
`0
`
`Final
`
`(in distribution)
`
`Act, Section
`
`351;
`
`the
`
`4. LICENSE
`
`NO.
`
`lo48
`5. REGISTRATION
`
`NO
`
`I
`
`q New Scientific
`lnfoimatton
`c]‘ Editorial,
`
`Format
`
`LABEL TYPE CODES
`(select only one)
`
`0
`
`Dosage
`
`Change
`
`64. ~~M&~cgtionss
`
`PCKR
`SHIP
`BULK
`OTHR
`
`Packer
`Shipping
`Bulk
`Other
`
`in
`(Spec/w
`Comments)
`
`IJ
`
`.Manufacturing
`.Method
`Change
`
`I
`Cl Anticoagulant
`Additive
`Change
`
`Precautions
`
`’
`
`0
`New Formulation
`0 Other (Sped@ in
`Comments)
`
`CIRC
`CONT
`PACK
`
`Circular
`Container
`Package
`
`DILT
`BLST
`CRTN
`
`Dlluent
`Blister
`Carton
`
`1.
`
`9.
`
`THE BOX(es)
`CHECK
`THIS SUBMISSION
`
`OF
`FORMAT
`INDICATING
`(More
`than one maybe
`checked).
`
`BOX
`10. CHECK
`IS IN SUPPORT
`
`IF THIS LABELING
`OF:
`
`11. COMMENTS
`FIRST USE.)
`
`(Include
`
`any Man&
`
`q Appllcatton
`ID number,
`description
`
`Electronic
`
`g
`
`Paper
`
`$I
`Associated
`BLAI PtA No.
`q Part of an Annual
`/03/ 7Z/fW
`,I3 Supplement
`Report
`or revision no. oflabel being repla&. IF FFM. p~bU..l7, p~vide LOT ~0. & DATE of
`
`12.
`AUTHORIZED
`OFFICIAL
`
`SIGNATURE
`
`DATE
`
`:OMMENTS
`
`THE SPACES
`(See attached
`
`BELOW ARE FOR USE BY CENTER FOR BIOLOGIC
`q ) metie awlt
`final printed labeling S Ul
`comments
`-y.
`ofd3e grid include implementation
`$xmation on Form 2567. Please provide 8
`PDF-format electronic copy and Original
`,.
`paper copies (10 for circulars and5 for OthS
`. .
`aabeb.~
`
`-+tlr,rrr,:r~,.(:,c,‘irili~~r’r.n ,
`. . . . . --_
`
`LUATION AND RESEARCH
`
`REVIEWED BY
`
`RETURNED
`
`BY
`
`SIGNATURE
`
`45Ld&ye
`SIGNATURE
`
`v-
`
`.\
`
`DATE
`5/3/d
`
`2.
`
`.
`
`Ex. 1028 - Page 2 of 32
`
`

`

`I
`
`f
`
`ACTIVASE@
`Alteplase
`recombinant
`DESCRIPTION:
`is a tissue plasminogen activator produced by recombinant DNA
`Activase, Alteplase,
`technology.
`It is a sterile, purified glycoprotein of 527 amino acids.
`It is synthesized
`using the complementary DNA (cDNA) for natural human
`tissue-type plasminogen
`activator obtained
`from a human melanoma cell line. The manufacturing
`process
`involves
`the secretion of the enzyme alteplase
`into the culture medium by an
`established mammalian
`cell line (Chinese Hamster Ovary cells) into which the cDNA
`for’alteplase
`has been genetically
`inserted. Fermentation
`is carried out in a nutrient
`medium containing
`the antibiotic gentamicin, 100 mg/L. However,
`the presence of
`the antibiotic
`is not detectable
`in the final product.
`
`)
`
`Phosphoric acid and/or sodium hydroxide may be used prior to lyophilization
`adjustment.
`
`for pH
`
`for intravenous
`lyophilized powder
`is a sterile, white to off-white,
`Activase
`administration
`after reconstitution with Sterile Water for Injection, USP.
`
`I
`
`Quantitative Composition of the Lyophilized Product
`_
`l-
`100 mg Vial
`50 mg Vial
`100 mg (58 million IU)
`50 mg (29 million IU)
`3.5 g
`1.7 g
`0.5 g
`54 mg
`Yes
`
`lg
`111 mg
`No
`
`is determined by an in vitro clot lysis assay and is expressed
`Biological potency
`International Units as tested against the WHO standard. The specific activity of
`Activase
`is 580,000
`IU/mg.
`
`in
`
`CLINICAL PHARMACOLOGY:
`Activase
`is an enzyme (serine protease) which has the property of fibrin-enhanced
`conversion of plasminogen
`to plasmin.
`It produces
`limited conversion of
`plasminogen
`in the absence of fibrin. When introduced
`into the systemic circulation
`
`recombinant)-Genentech,
`(Alteplase,
`1048: Activase@
`U.S. License
`l/Revision 4800511 angioedema clean RI 2 032102
`
`Inc.
`
`MAR2002
`
`Ex. 1028 - Page 3 of 32
`
`

`

`in a thrombus and converts
`concentration, Activase binds to fibrin
`at pharmacologic
`the entrapped plasminogen
`to plasmin. This initiates local fibrinolysis with limited
`systemic proteolysis. Following administration of 100 mg Activase,
`there
`is a
`decrease
`(16%-36%)
`in circulating
`fibrinogen.“*
`In a controlled
`trial, 8 of 73 patients
`(11%) receiving Activase
`(1.25 mglkg body weight over 3 hours) experienced a
`decrease
`in fibrinogen
`to below 100 mg/dL.*
`
`from
`that it is rapidly cleared
`in AMI patients has shown
`The clearance of Alteplase
`in
`the plasma with an initial half-life of less than 5 minutes. There
`is no difference
`the dominant
`initial plasma half-life between
`the 3-Hour and accelerated
`regimens
`for AMI. The plasma clearance of Alteplase
`is 380-570 mUmin.3’4 The clearance
`mediated primarily by the liver. The initial volume of distribution approximates
`plasma volume.
`
`is
`
`(AMI) Patients
`Infarction
`( Acute Myocardial
`coronary
`in the infarct-related
`Coronary occlusion due to a thrombus
`is present
`artery
`in approximately
`80% of patients experiencing a transmural myocardial
`infarction evaluated within 4 hours of onset of symptoms. 595
`
`in patients experiencing
`Two Activase dose regimens have been studied
`myocardial
`infarction.
`(Please see DOSAGE AND ADMINISTRATION.)
`comparative
`efficacy of these two regimens has not been evaluated.
`
`acute
`The
`
`in AMI Patients
`Infusion
`Accelerated
`trial
`in an international, multi-center
`infusion of Activase was studied
`Accelerated
`to four
`(GUSTO)
`that randomized 41,021 patients with acute myocardial
`infarction
`thrombolytic
`regimens. Entry criteria
`included onset of chest pain within 6 hours of
`treatment and ST-segment elevation of ECG. The regimens
`included accelerated
`infusion of Activase
`(I 100 mg over 90 minutes, see DOSAGE AND
`ADMINISTRATION)
`plus intravenous
`(IV) heparin
`(accelerated
`infusion of Alteplase,
`n =10,396), or the Kabikinase brand of Streptokinase
`(1.5 million units over 60
`minutes) plus IV heparin
`(SK [Iv], n=l0,410),
`or Streptokinase
`(as above) plus
`subcutaneous
`(SQ) heparin
`(SK [SQ], n =9841). A fourth
`regimen combined
`Alteplase and Streptokinase. Aspirin and heparin use was directed by the GUSTO
`
`U.S. License 1048: Activase”
`2/Revision4800511angioedemaclean
`
`(Alteplase, recombinant)-Genentech,
`R12032102
`
`Inc.
`
`MAR2002
`
`Ex. 1028 - Page 4 of 32
`
`

`

`study protocol as follows: All patients were to receive 160 mg chewable
`aspirin
`administered as soon as possible,
`followed by 160-325 mg daily.
`IV heparin was
`directed
`to be a 5000 U IV bolus initiated as soon as possible,
`followed by a
`1000 U/hour continuous
`IV infusion
`for at least 48 hours; subsequent heparin
`therapy was at the discretion of the attending physician. SQ heparin was directed
`be 12,500 U administered 4 hours after initiation of SK therapy,
`followed by 12,500
`came first. Many of the
`U twice daily for 7 days or until discharge, whichever
`patients
`randomized
`to receive SQ heparin
`received some
`IV heparin, usually in
`response
`to recurrent chest pain and/or the need for a medical procedure. Some
`received
`IV heparin on arrival
`to the emergency
`room prior to enrollment and
`randomization.
`
`to
`
`1
`
`in Table 1.
`Results for the primary endpoint of the study, 30-day mortality, are shown
`The incidence of 30-day mortality for accelerated
`infusion of Alteplase was 1 .O%
`lower than for SK (IV) and I .O% lower than for SK (SQ). The secondary endpoints
`of combined 30-day mortality or nonfatal stroke, and 24-hour mortality, as well as the
`safety endpoints of total stroke and intracerebral hemorrhage are also shown
`in
`Table 1. The incidence of combined 30-day mortality or nonfatal stroke for the
`Alteplase accelerated
`infusion was 1 .O% lower than for SK (IV) and 0.8% lower than
`for SK (SQ).
`
`I
`
`I
`
`Ex. 1028 - Page 5 of 32
`
`

`

`.
`
`Table 1
`
`Accelerated
`Activase
`
`6.3%
`
`SK (IV)
`
`p-Value’
`
`7.3%
`
`0.003
`
`SK (SQ)
`
`7.3%
`
`p-value’
`
`0.007
`
`7.2%
`
`2.4%
`
`1.6%
`
`8.2%
`
`2.9%
`
`1.4%
`
`0.006
`
`0.009
`
`0.32
`
`8.0%
`
`2.8%
`
`1.2%
`
`0.036
`
`0.029
`
`0.03
`
`0.7%
`
`0.6%
`
`0.22
`
`0.5%
`
`. 0.02
`
`is for comparison
`
`of Accelerated Activase
`
`to the respective SK control
`
`Event
`
`30-Day Mortality
`
`30-Day Mortality
`or Nonfatal Stroke
`
`24-Hour Mortality
`
`Any Stroke
`
`lntracerebral
`Hemorrhage
`
`’ Two-tailed p-value
`arm.
`
`time from symptom onset to
`Subgroup analysis of patients by age, infarct location,
`thrombolytic
`treatment, and treatment
`in the U.S. or elsewhere
`showed consistently
`lower 30-day mortality
`for the Alteplase accelerated
`infusion group. For patients
`who were over 75 years of age, a predefined subgroup consisting of 12% of patients
`enrolled,
`the incidence of stroke was 4.0% for the Alteplase accelerated
`infusion
`group, 2.8% for SK (IV), and 3.2% for SK (SQ); the incidence of combined 30-day
`mortality or nonfatal stroke was 20.6% for accelerated’infusion
`of Alteplase, 21.5%
`for SK (IV), and 22.0% for SK (SQ).
`
`artery
`trial provided data on infarct-related
`substudy of the GUSTO
`An angiographic
`patency. Table 2 presents go-minute, 180-minute, 24-hour, and 5-7 day patency
`values by TIMI
`flow grade for the three treatment
`regimens. Reocclusion
`rates were
`similar for all three treatment
`regimens.
`
`1048: Activase”
`U.S. License
`4/Revision 4800511 angioedema
`
`recombinant)-Genentech,
`(Alteplase,
`clean RI2 032102
`
`Inc.
`
`MAR2002
`
`Ex. 1028 - Page 6 of 32
`
`

`

`Patency
`(TIMI 2 or 3)
`
`Accelerated
`Activase
`
`go-Minute
`
`180-Minute
`
`24 Hour
`
`S-7 Day
`
`n=272
`
`81.3%
`
`n=80
`
`76.3%
`
`n=81
`88.9%
`
`n=72
`
`83.3%
`
`Table 2
`
`SK (IV)
`
`n=261
`
`59.0%
`
`n=76
`
`72.4%
`
`n=72
`
`87.5%
`
`n=77
`
`90.9%
`
`p-Value
`
`<0.0001
`
`0.58
`
`0.24
`
`0.47
`
`SK (SQ)
`
`n=260
`
`53.5%
`
`n=95
`
`71.6%
`
`n=67
`82.1%
`
`n=75
`
`78.7%
`
`p-Value
`
`<0.0001
`
`0.48
`
`0.79
`
`.0.17
`
`The exact relationship between coronary artery patency and clinical activity has not
`been established.
`
`infusion of Alteplase have not been
`The safety and efficacy of the accelerated
`evaluated using antithrombotic or antiplatelet
`regimens other than those used in the
`GUSTO
`trial.
`
`in AMI Patients
`~-HOW Infusion
`at 90 and
`trial with coronary angiography
`In patients studied
`in a controlled
`in
`120 minutes
`following
`infusion of Activase,
`infarct artery patency was observed
`In a second study, where patients
`71% and 85% of patients
`(n =85), respectively.*
`received coronary angiography prior to and following
`infusion of Activase within
`6 hours of the onset of symptoms,
`reperfusion of the obstructed vessel occurred
`within 90 minutes after the commencement of therapy
`in 71% of 83 patients.’
`
`The exact relationship between coronary artery patency and clinical activity has not
`been established.
`
`to placebo,
`trial (138 patients) comparing Activase
`randomized
`In a double-blind,
`patients
`infused with Activase within 4 hours of onset of symptoms experienced
`improved
`left ventricular
`function at Day IO compared
`to the placebo group, when
`ejection
`fraction was measured by gated blood pool scan (53.2% vs 46.4%,
`
`1048: Activase@
`U.S. License
`5/Revision 4800511 angioedema
`
`recombinant)-Genentech,
`(Alteplase,
`clean RI 2 032102
`
`Inc.
`
`MAR2002
`
`I
`
`I
`
`-
`
`Ex. 1028 - Page 7 of 32
`
`

`

`the net changes
`(Day 1) values,
`to baseline
`p=O.O18). Relative
`were +3.6% and -4.7%
`for the treated and placebo
`groups,
`respectively
`(p=O.OOOl). Also documented was a reduced
`incidence of clinical congestive heart
`failure
`in the treated group
`(14%) compared
`to the placebo group (33%) (p=O.OOg).’
`
`in ejection
`
`fraction
`
`to placebo,
`trial (145 patients) comparing Activase
`randomized
`In a double-blind,
`patients
`infused with Activase within 2.5 hours of onset of symptoms experienced
`improved
`left ventricular
`function at a mean of 21 days compared
`to the placebo
`group, when ejection
`fraction was measured by gated blood pool scan (52% vs 48%,
`p=O.O8) and by contrast ventriculogram
`(61% vs 54%, p=O.O06). Although
`the
`contribution of Activase alone is unclear,
`the incidence of nonischemic
`cardiac
`complications when
`taken as a group (i.e., congestive heart failure, pericarditis, atrial
`fibrillation, and conduction disturbance) was reduced
`\4vhen compared
`to those
`patients
`treated with placebo
`(p cO.OI).~
`
`to placebo
`trial (5013 patients) comparing Activase
`randomized
`In a double-blind,
`(ASSET study), patients
`infused with Activase within 5 hours of the onset of
`symptoms of acute myocardial
`infarction experienced
`improved 30-day survival
`compared
`to those treated with placebo. At 1 month, the overall mortality
`rates were
`7.2% for the Activase-treated
`group and 9.8% for the placebo-treated
`group
`(p=o.ool).g~lo
`This benefit was maintained at 6 months
`for Activase-treated
`(10.4%) compared
`to those treated with placebo
`(13.1%, p=0.008).10
`
`patients
`
`to placebo,
`trial (721 patients) comparing Activase
`randomized
`In a double-blind,
`patients
`infused with Activase within 5 hours of the onset of symptoms experienced
`improved ventricular
`function 1 O-22 days after treatment compared
`to the placebo
`group, when global ejection
`fraction was measured by contrast ventriculography
`(50.7% vs 48.5%, p=O.Ol). Patients treated with Activase had a 19% reduction
`infarct size, as measured by cumulative
`release of HBD (a-hydroxybutyrate
`dehydrogenase)
`activity compared
`to placebo-treated
`patients
`(p=O.OOl). Patients
`treated with Activase had significantly
`fewer episodes of cardiogenic
`shock
`to
`(p=O.O2), ventricular
`fibrillation
`(p ~0.04) and pericarditis
`(p=O.Ol) compared
`patients
`treated with placebo. Mortality at 21 days in Activase-treated
`patients was
`reduced
`to 3.7% compared
`to 6.3%
`in placebo-treated
`patients
`(l-sided p=O.O5).”
`
`in
`
`recombinant)-Genentech,
`(Alteplase,
`1048: Activase@
`U.S. License
`6/Revision 4800511 angioedema clean R12 032102
`
`Inc.
`
`MAR2002
`
`~
`
`Ex. 1028 - Page 8 of 32
`
`

`

`in
`reduction
`a significant
`these data do not demonstrate unequivocally
`Although
`for this study, they do indicate a trend that is supported by the results of the
`mortality
`ASSET study.
`
`lschemic Stroke Patients
`Acute
`t-PA Stroke Trial, Part 1 and
`trials (The NINDS
`Two placebo-controlled,
`double-blind
`Part 2) have been conducted
`in patients with acute ischemic stroke.‘* Both studies
`enrolled patients with measurable neurological deficit who could complete screening
`and begin study treatment within 3 hours from symptom onset. A cranial
`computerized
`tomography
`(CT) scan was performed prior to treatment
`to rule out the
`presence of intracranial hemorrhage
`(ICH). Patients were also excluded
`for the
`presence of conditions
`related to risks of bleeding
`(see CONTRAINDICATIONS),
`minor neurological deficit, for rapidly improving symptoms prior to initiating study
`treatment, or for blood glucose of ~50 mg/dL or >406 mg/dL.
`
`for
`
`(maximum of 90 mg),
`to receive either 0.9 mg/kg Activase
`Patients were randomized
`or placebo. Activase was administered as a 10% initial bolus over 1 minute followed
`by continuous
`intravenous
`infusion of the remainder over 60 minutes
`(see DOSAGE
`AND ADMINISTRATION).
`In patients without
`recent use of oral anticoagulants
`or
`heparin, study treatment was initiated prior to the availability of coagulation
`study
`results. However,
`the infusion was discontinued
`if either a pretreatment
`prothrombin
`time (PT) > 15 seconds or an elevated activated partial thromboplastin
`time (aPlT)
`was identified. Although patients with or without prior aspirin use were enrolled,
`administration
`of anticoagulants and antiplatelet agents was prohibited
`for the first
`24 hours following symptom onset.
`
`at
`improvement
`1, n=291) evaluated neurological
`The initial study (NINDS-Part
`24 hours after stroke onset. The primary endpoint,
`the proportion of patients with a
`4 or more point improvement
`in the National
`Institutes of Health Stroke Scale
`(NIHSS) score or complete
`recovery
`(NIHSS score = 0), was not significantly
`different between
`treatment groups. A secondary analysis suggested
`improved
`3-month outcome associated with Activase
`treatment using the following stroke
`assessment
`scales: Barthel
`Index, Modified Rankin Scale, Glasgow Outcome
`Scale, and the NIHSS.
`
`1048: Activase@
`U.S. License
`-//Revision 4800511 angioedema
`
`recombinant)-Genentech,
`(Alteplase,
`clean R12 032102
`
`Inc.
`
`MAR2002
`
`Ex. 1028 - Page 9 of 32
`
`

`

`2, n=333) assessed clinical outcome at 3 months as
`A second study (NINDS-Part
`the primary outcome. A favorable outcome was defined as minimal or no disability
`using the four stroke assessment scales: Barthel
`Index (score 295), Modified
`Rankin Scale (score >I), Glasgow Outcome Scale (score =I), and NIHSS
`(score
`II).
`The results comparing Activase- and placebo-treated
`patients for the
`four outcome scales together
`(Generalized Estimating Equations) and individually
`are presented
`in Table 3. In this study, depending upon the scale, the favorable
`outcome of minimal or no disability occurred
`in at least 11 per 100 more patients
`treated with Activase
`than those receiving placebo. Secondary analyses
`demonstrated
`consistent
`functional and neurological
`improvement within all four
`stroke scales as indicated by median scores. These
`results were highly consistent
`with the 3-month outcome
`treatment effects observed
`in the Part 1 study.
`
`’
`Table 3
`t-PA Stroke Trial, Part 2
`The NINDS
`3-Month Efficacy Outcomes
`
`1
`
`Frequency of Favorable Outcome
`Absolute
`Relative 2
`Difference
`Frequency
`(95% Cl)
`(95% Cl)
`
`Activase
`(n= 168)
`
`Placebo
`(n= 165)
`
`-
`
`-
`
`-
`
`(1.0:,3?.72)
`
`Analysis
`Generalized Estimating
`Equations
`(Multivariate)
`
`Barthel
`
`Index
`
`37.6%
`
`50.0%
`
`Modified Rankin Scale
`
`26.1%
`
`38.7%
`
`Glasgow Outcome Scale
`
`31.5%
`
`44.0%
`
`12.4%
`(3.0, 21.9)
`
`1.33
`(1.04,1.71)
`
`12.6%
`(3.7, 21.6)
`
`1.48
`(1.08, 2.04)
`
`12.5%
`(3.3,21.8)
`
`1.40
`(1.05, 1.85)
`
`p-Value3
`0.02
`
`0.02
`
`0.02
`
`0.02
`
`20.0%
`
`31 .O%
`
`0.02
`
`NIHSS
`
`1.55
`11.0%
`(1.06, 2.26)
`(2.6, 19.3)
`is defined as recovery with minimal or no disability.
`’ Favorable Outcome
`frequency of recovery
`in favor of Activase
`treatment.
`* Value > 1 indicates
`3 p-Value
`for Relative Frequency
`is from Generalized Estimating Equations with log link.
`
`ICH, and new ischemic stroke following
`The incidences of all-cause go-day mortality,
`Activase
`treatment compared
`to placebo are presented
`in Table 4 as a combined
`
`1048: Activase@
`U.S. License
`8IRevision 4800511 angioedema
`
`recombinant)-Genentech,
`(Alteplase,
`clean R12 032102
`
`Inc.
`
`MAR2002
`
`Ex. 1028 - Page 10 of 32
`
`

`

`for Parts 1 and 2. These data indicated a significant
`(n=624)
`safety analysis
`increase
`in ICH following Activase
`treatment, particularly symptomatic
`ICH within
`36 hours.
`In Activase-treated
`patients,
`there were no increases compared
`to
`placebo
`in the incidences of go-day mortality or severe disability.
`
`Table 4
`t-PA Stroke Trial
`The NINDS
`Safety Outcome
`
`Part 1 and Part 2 Combined
`
`Placebo
`
`Activase
`
`WCause
`
`go-day Mortality
`
`Total ICH’
`
`Symptomatic
`
`Asymptomatic
`
`(n=312)
`64 (20.5%)
`
`20 (6.4%)
`4 (1.3%)
`16 (5.1%)
`
`(n=312)
`54 (17.3%)
`
`48 (15.4%)
`25 (8.0%)
`23 (7.4%)
`
`Symptomatic
`
`ICH within 38 hours
`
`2 (0.6%)
`
`20 (6.4%)
`
`p-Value2
`0.36
`
`<O.Ol
`< 0.01
`0.32
`
`<O.Ol
`
`17 (5.4%)
`
`18 (5.8%)
`
`New
`lschemic Stroke
`(3-months)
`ICH was defined as the occurrence of sudden
`’ Within
`trial follow-up period. Symptomatic
`clinical worsening
`followed by subsequent verification of ICH on CT scan. Asymptomatic
`ICH was defined as ICH detected on a routine repeat CT scan without preceding clinical
`worsening.
`* Fisher’s Exact Test
`
`1 .oo
`
`In a prespecified
`stroke symptoms,
`patients.
`
`in patients receiving aspirin prior to onset of
`subgroup analysis
`there was preserved
`favorable outcome
`for Activase-treated
`
`to investigate
`(n=624)
`Exploratory, multivariate analyses of both studies combined
`potential predictors of ICH and treatment effect modifiers were performed.
`In
`Activase-treated
`patients presenting with severe neurological deficit (e.g., NIHSS
`>22) or of advanced age (e.g., >77 years of age), the trends
`toward
`increased
`risk
`for symptomatic
`ICH within the first 36 hours were more prominent. Similar
`trends
`were also seen for total ICH and for all-cause go-day mortality
`in these patients.
`When risk was assessed by the combination of death and severe disability
`in these
`patients,
`there was no difference between placebo and Activase groups. Analyses
`
`1048: Activase@
`U.S. License
`S/Revision 4800511 angioedema
`
`recombinant)-Genentech,
`(Alteplase,
`clean R12 032102
`
`Inc.
`
`MAR2002
`
`Ex. 1028 - Page 11 of 32
`
`

`

`for
`clinical outcome
`for efficacy suggested a reduced but still favorable
`Activase-treated
`patients with severe neurological deficit or advanced age at
`presentation.
`
`Embolism Patients
`Pulmonary
`treated with
`(n=22)
`In a comparative
`randomized
`trial (n=45),13 59% of patients
`Activase
`(100 mg over 2 hours) experienced moderate or marked
`lysis of pulmonary
`emboli when assessed by pulmonary angiography 2 hours after treatment
`initiation.
`Activase-treated
`patients also experienced a significant
`reduction
`in pulmonary
`embolism-induced
`pulmonary hypertension within 2 hours of treatment
`(p=O.O03).
`Pulmonary perfusion at 24 hours, as assessed by radionuclide
`scan, was
`significantly
`improved
`(p=O.O02).
`
`!
`
`AND USAGE:
`INDICATIONS
`,. Acute Myocardial
`Infarction
`in
`infarction
`Activase
`is indicated
`for use in the management of acute myocardial
`adults for the improvement
`of ventricular
`function
`following AMI, the reduction of the
`incidence of congestive heart failure, and the reduction of mortality associated with
`AMI. Treatment
`should be initiated as soon as possible after the onset of AMI
`symptoms
`(see CLINICAL PHARMACOLOGY).
`
`lschemic Stroke
`Acute
`Activase
`is indicated
`for the management of acute ischemic stroke in adults for
`improving neurological
`recovery and reducing
`the incidence of disability. Treatment
`should only be initiated within 3 hours after
`the onset of stroke symptoms,
`and after exclusion
`of intracranial
`hemorrhage
`by a cranial computerized
`tomography
`(CT) scan or other diagnostic
`imaging method
`sensitive
`for the
`presence
`of hemorrhage
`(see CONTRAINDICATIONS).
`
`Embolism
`Pulmonary
`Activase
`is indicated
`in the management of acute massive pulmonary embolism
`in adults:
`
`(PE)
`
`the lysis of acute pulmonary emboli, defined as obstruction of blood flow
`-For
`to a lobe or multiple segments of the lungs.
`
`recombinant)--Genentech,
`(Alteplase,
`1048: Activase@
`U.S. License
`1 O/Revision 4800511 angioedema
`clean RI 2 032102
`
`Inc.
`
`MAR2002
`
`Ex. 1028 - Page 12 of 32
`
`

`

`the lysis of pulmonary emboli accompanied by unstable hemodynamics,
`-For
`e.g., failure
`to maintain blood pressure without supportive measures.
`
`The diagnosis should be confirmed by objective means, such as pulmonary
`angiography
`or noninvasive
`procedures such as lung scanning.
`
`CONTRAINDICATIONS:
`or Pulmonary Embolism
`Acute Myocardial
`Infarction
`or pulmonary
`infarction
`Activase
`therapy
`in patients with acute myocardial
`embolism
`is contraindicated
`in the foll,owing
`situations
`because of an
`increased
`risk of bleeding:
`
`l
`
`l
`
`l
`
`Active
`
`internal bleeding
`
`History of cerebrovascular
`
`accident
`
`.
`
`Recent
`
`intracranial
`
`or intraspinal
`
`surgery or trauma
`
`(see WARNINGS)
`
`I
`
`0
`
`Intracranial
`
`neoplasm,
`
`arteriovenous
`
`malformation,
`
`or aneurysm
`
`l
`
`l
`
`Known bleeding
`
`diathesis
`
`Severe uncontrolled
`
`hypertension
`
`lschemic Stroke
`Acute
`ischemic
`Activase
`therapy
`in patients with acute
`the following
`situations
`because of an increased
`result
`in significant
`disability or death:
`
`in
`is contraindicated
`stroke
`risk of bleeding, which could
`
`l
`
`l
`
`l
`
`l
`
`l
`
`l
`
`l
`
`Evidence
`
`of intracranial
`
`hemorrhage
`
`on pretreatment
`
`evaluation
`
`Suspicion
`
`of subarachnoid
`
`hemorrhage
`
`on pretreatment
`
`evaluation
`
`intracranial
`(within 3 months)
`Recent
`trauma, or previous
`stroke
`
`History of intracranial
`
`hemorrhage
`
`or intraspinal
`
`surgery,
`
`serious head
`
`hypertension
`Uncontrolled
`or >I10 mm Hg diastolic)
`
`at time of treatment
`
`(e.g., >I85 mm Hg systolic
`
`Seizure at the onset of stroke
`
`Active
`
`internal bleeding
`
`0
`
`Intracranial
`
`neoplasm, arteriovenous
`
`malformation,
`
`or aneurysm
`
`U.S. License
`1 l/Revision
`
`recombinant)-Genentech,
`(Alteplase,
`1048: Activase@
`4800511 angioedema
`clean R12 032102
`
`Inc.
`
`MAR2002
`
`Ex. 1028 - Page 13 of 32
`
`

`

`l
`
`Known bleeding
`
`diathesis
`
`including
`
`but not limited
`
`to:
`
`sodium) or an
`(e.g., warfarin
`use of oral anticoagulants
`-Current
`International
`Normalized Ratio (INR) >I.7 or a prothrombin
`time (PT)
`> 15 seconds
`
`of heparin within 48 hours preceding
`-Administration
`and have an elevated activated
`partial
`thromboplastin
`presentation
`
`the onset of stroke
`time (aPT.T) at
`
`- Platelet count < 100,000/mm3
`
`WARNINGS:
`Bleeding
`is bleeding.
`therapy
`The most common complication encountered during Activase
`The type of bleeding associated with thrombolytic
`therapy can be divided
`into two
`\
`broad categories:
`
`,
`
`l
`
`l
`
`Internal bleeding,
`gastrointestinal,
`
`intracranial and retroperitoneal
`involving
`genitourinary, or respiratory
`tracts.
`
`sites, or the
`
`Superficial or surface bleeding, observed mainly at invaded or disturbed sites
`(e.g., venous cutdowns, arterial punctures, sites of recent surgical
`intervention).
`
`to bleeding. Some
`The concomitant use of heparin anticoagulation may contribute
`of the hemorrhage
`episodes occurred 1 or more days after the effects of Activase
`had dissipated, but while heparin
`therapy was continuing.
`
`from recent puncture sites may
`therapy, bleeding
`As fibrin is lysed during Activase
`occur. Therefore,
`thrombolytic
`therapy
`requires careful attention
`to all potential
`bleeding sites (including catheter
`insertion sites, arterial and venous puncture sites,
`cutdown sites, and needle puncture sites).
`
`injections and nonessential handling of the patient should be avoided
`Intramuscular
`during
`treatment with Activase. Venipunctures
`should be performed
`carefully and
`only as required.
`
`Should an arterial puncture be necessary during an infusion of Activase,
`preferable
`to use an upper extremity vessel
`that is accessible
`to manual
`
`it is
`
`recombinant)-Genentech,
`(Alteplase,
`1048: Activase@
`U.S. License
`12/Revision4800511angioedemaclean
`RI2032102
`
`Inc.
`
`MAR2002
`
`Ex. 1028 - Page 14 of 32
`
`

`

`for at least 30 minutes, a pressure
`Pressure should be applied
`compression.
`dressing applied, and the puncture site checked
`frequently
`for evidence of bleeding.
`
`(not controllable by local pressure) occur, the infusion of
`Should serious bleeding
`Activase and any concomitant heparin should be terminated
`immediately.
`
`for therapy with Activase should be carefully
`Each patient being considered
`evaluated and anticipated benefits weighed against potential
`risks associated with
`therapy.
`
`indications
`for all approved
`therapy
`the risks of Activase
`In the following conditions,
`may be increased and should be weighed against the anticipated benef,it,s:
`
`Recent major surgery, e.g., coronary artery bypass graft, obstetrical delivery,
`organ biopsy, previous puncture of noncompressible
`vessels
`
`Cerebrovascular
`
`disease
`
`Recent gastrointestinal
`
`or genitourinary bleeding
`
`Recent
`
`trauma
`
`Hypertension:
`
`systolic BP 2175 mm Hg and/or diastolic BP 2 110 mm Hg
`
`High likelihood of left heart thrombus, e.g., mitral stenosis with atrial fibrillation
`
`Acute pericarditis
`
`Subacute bacterial endocarditis
`
`Hemostatic defects
`
`including
`
`those secondary
`
`to severe hepatic or renal disease
`
`Significant hepatic dysfunction
`
`Pregnancy
`
`Diabetic hemorrhagic
`
`retinopathy, or other hemorrhagic ophthalmic conditions
`
`Septic thrombophlebitis
`
`or occluded AV cannula at seriously
`
`infected site
`
`Advanced age (e.g., over 75 years old)
`
`Patients currently
`
`receiving oral anticoagulants,
`
`e.g., warfarin sodium
`
`in which bleeding constitutes a significant hazard or would
`Any other condition
`be particularly difficult
`to manage because of its location
`
`recombinant)-Genentech,
`(Alteplase,
`1048: Activase@
`U.S. License
`13/Revision 4800511 angioedema
`clean RI 2 032102
`
`Inc.
`
`MAR2002
`
`Ex. 1028 - Page 15 of 32
`
`

`

`j
`
`Embolization
`Cholesterol
`treated with all types of
`rarely in patients
`Cholesterol embolism has been reported
`thrombolytic agents;
`the true incidence
`is unknown. This serious condition, which
`can be lethal, is also associated with invasive vascular procedures
`(e.g., cardiac
`catheterization,
`angiography,
`vascular surgery) and/or anticoagulant
`therapy.
`Clinical
`features of cholesterol embolism may,include
`livedo
`reticularis,
`“purple
`syndrome, acute renal failure, gangrenous digits, hypertension, pancreatitis,
`myocardial
`infarction, cerebral
`infarction, spinal cord infarction,
`retinal artery
`occlusion, bowel
`infarction, and rhabdomyolysis.
`
`toe”
`
`Infarction
`Use in Acute Myocardial
`In a small subgroup of AMI patients who are at low risk for death from cardiac
`causes (i.e., no previous myocardial
`infarction, Killip class I) and who have high
`blood pressure at the time of presentation,
`the risk for’stroke may offset the survival
`benef