foi
`
`5243139
`
`A
`
`* 5 2 4 3 1 3 9 *
`
`* A *
`
`{Part of Complete Approval Document 5226341 A} Fragmin
`(Pharmacia and Upjohn) 03/30/1999 Supplemental Approval
`[Prophylaxis of Deep Vein Thrombosis]: S8 Approval Letter; Final
`Labeling
`
`This document was provided by: FOI Services, Inc
`704 Quince Orchard Road • Suite 275
`Gaithersburg MD 20878-1751 USA
`Phone:
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`any of the information in these documents; the documents will be faithful copies of the information supplied to FOI Services, Inc.
`
`0001
`
`MYLAN - EXHIBIT 1027
`
`

`

`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`
`food and Omg Administration
`fiockvtlle MD 20857
`
`m 30 1339
`
`• / ' 2
`
`ki
`
`NDA20-287/S-008
`
`f
`
`- .
`Pharmacia & Upjohn
`Attention: James H. Chambers
`7Q0t) Portage Road
`Kalamazoo, Michigan 49001-0199
`
`Dear Mr. Chambers:
`
`Please refer to your supplemental new drug application dated April 16* 1997, received
`April 17,1997, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for
`Fragmin® (daltepans sodium injection).
`
`We acknowledge receipt of your submissions dated May 9, June 11 and 12, August 13,
`November 21,1997, and February 25, March 19, September 8, and November 6,1998.
`Your submission of November 6,1998 constituted a complete response to our April 15,1998
`-
`action letter.
`
`This supplemental new drug application provides for the use of Fragmin® for prophylaxis of deep
`vein thrombosis (DVT), which may lead to pulmonary embolism, in patients undergoing hip
`replacement surgeiy.
`
`We have completed the review of this supplemental application, as amended, and have concluded
`that adequate information has been presented to demonstrate that the drug product is safe and
`effective for use as recommended in the enclosed labeling text Accordingly, the~supplemental
`application is approved effective on the date of this letter.
`
`The final printed labeling (FPL) must be identical to the enclosed labeling (text for the package
`insert).
`
`Please submit 20 copies of the FPL as soon as it is available, in no case more than 30 days after it is
`printed. Please individually mount ten of the copies on heavy-weight paper or similar material. For
`administrative purposes, this submission should be designated "FPL for approved supplement NDA
`20*287/8-008." Approval of this submission by FDA is not required before the labeling is used
`
`c
`
`0002
`
`

`

`NDA 20-287/8-008
`Page 2
`
`In addition, please submit three copies of the introductoiy promotional materials that you propose to
`use for this product. All proposed materials should be submitted in draft or mock-up form, not final
`print Please submit one copy to this Division and two copies of both the promotional materials and
`the package insert directly to:
`
`Division of Drug Marketing, Advertising, and Communications, HFD-40
`Food and Drug Administration
`5600 Fishers Lane
`Ro&viUe, Maryland 20857
`
`If a letter communicating important information about this drug product (i.e., a "Dear Health Care
`P^actItioner,, letter) is issued to physicians and others responsible for patient care, we request that
`you submit a copy of the letter to this NDA and a copy to the following address:
`
`MEDWATCH, HF-2
`FDA
`5600 Fishers Lane
`Rockville, MD 20857
`
`Please submit one market package of the drug product when it is available.
`
`We remind you that you must comply with the requirements for an approved NDA set forth under
`21 CFR 314.80 and 314.81.
`
`If you have any questions, contact Karen Oliver, Regulatoiy Health Project Manager,
`at (301) 827-7310.
`
`r ^
`
`Lilia Talanco, M D.
`Director
`Division of Gastrointestmal and Coagulation Drug
`Products
`Office of Drug Evaluation Qt
`Center for Drug Evaluation and Research
`
`Enclosure: Package Insert Text
`
`('
`
`r
`
`0003
`
`

`

`rV-NTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICATION NUMBER; O2O287/S0OS
`
`PRINTED LABELING
`
`0004
`
`

`

`FRAGMIN-Supplement for uie itt htp replacement
`proposed insert - 10/28^98 B (underiine and smkeout based on version dated 3'! B/98
`
`FRAGMIN®
`dalteparin sodium injection
`
`for Subcutaneous Use Only
`
`SPINAL/EPIDURAL HEMATOMAS
`When neuraxjal anesthesia (epidural/spina! anesthesia) or spinal puncture is employed, patients
`anticoagulated or scheduled to be anticoagulated with low molecular weight heparins or
`heparmoids for prevention of thromboembolic complications are at nsk of developing an
`epidural or spinal hematoma which can result in long-term or permanent paralysis
`
`The nsk of these events is increased by the use of mdwellmg epidural catheters for
`administration of analgesia or by the concomitant use of drugs affecting hemostasis such as
`non steroidal anti-inflammatory drugs (NSAlDs), platelet inhibitors, or other anticoagulants
`The nsk also appears to be increased by traumatic or repeated epidural or spinal puncture
`
`Patients should be irequently monitored for signs and symptoms of neurological impaument
`if neurological compromise is noted, urgent treatment is necessary
`
`The physician should consider the potential benefit versus nsk before neuraxial intervention in
`patients anticoagulated or to be anticoagulated for thromboprophylaxis (also see
`WARNINGS, Hemorrhage and PRECAUTIONS, Drug Interactions)
`
`DESCRIPTION
`FRAGMIN Injection (daltepann sodium injection) is a stenle, low molecular weight heparin
`It is available m single-dose, prefilled synnges and a multiple-dose vial With reference to the
`WHO First International Low Molecular Weight Heparin Reference Standard, each synnge
`contains 2500 (16 mg daltepann sodium) or 5000 (32 mg daltepann sodium) anti-Factor Xa
`international units (IU) m 0 2 mJL Bach 9 5 mL vial contains 10,000 (64 mg daltepann
`sodium) anti-Factor XalU per 1 mL, for a total of95,000 anti-Factor XalU per vial
`
`Each prefilled synnge also contains Water for injection and sodium chlonde, when required,
`to maintain physiologic ionic strength The prefilled synnges are preservative free Each
`multiple-dose via! also contains Water for Injection and 14 mg of benzyl alcohol per mL as a
`preservative The pH of both formulations is 5 0 to, 7 5
`
`Daltepann sodium is produced through controlled nitrous acid depolymenzation of sodium
`hepann from porcine intestinal mucosa followed by a chromatographic purification process it
`is composed of strongly acidic sulphated polysacchande chains (ohgosacchande, containing
`2,5-anhydro-D-mannitol residues as end groups) with an average molecular weight of 5000
`and about 90% of the matenal within the range 2000-9000 The molecular weight distnbution
`is
`
`1
`
`0005
`
`

`

`FRAGMIN - Supplement TOT -use m hip repbcemerrt
`Proposed msen - IC/28/98 B (underline and stakeout based 01 version dated 3/I8/98
`
`< 3000 daltons
`3000-to-8000 daltons
`> 8000 daJtons
`
`Structural formula
`
`3 0-15 0%
`65 0-78 0%
`14 0-260%
`
`o R ,
`
`C K f l l *
`
`n ?
`
`tY"l\ h
`Jv7 ^v-AoV^
`
`OH on
`
`Oil NHR
`
`OH OR
`
`ij^.on
`
`&
`
`t
`
`IICTJ
`
`HO
`
`R-WorSO^Ki
`it sWJCMjW tsO,Na
`R -M Rj-COON*
`
`n •» 3-20
`
`CLINICAL PHARMACOLOGY
`Dalteparm is a low molecular weight hepann with antithrombotic properties It acts by
`enhancing the inhibition of Factor Xa and thrombin by antithrombm in man, dalteparm
`potentiates preferentially the inhibition of coagulation Factor Xa, while,only slightly affecting
`clotting time, e g, activated partial thromboplastin time (APTT)
`
`Pharmacodynamics:
`Doses of FRAGMIN Injection of up to 10,000 anti-Factor Xa IU administered
`subcutaneously as a single dose or two 5000 IU doses 12 hours apart to healthy subjects do
`not produce a significant change m platelet aggregation, fibrinolysis, or global clotting tests
`such as prothrombin tune (PT), thrombin time (TT) or APTT Subcutaneous admimstration of
`doses of5000 IU bid of FRAGMIN for seven consecutive days to patients undergoing
`abdominal surgery did not markedly affect APTT, Platelet Factor 4 (PF4), or lipoprotein
`lipase
`
`Pharmacokinetics:
`Mean peak levels of plasma anti-Factor Xa activity following single subcutaneous (s c) doses
`of 2500,5000 and 10,000 IU were 0 19 ± 0 04, 0 41 ± 0 07 and 0 82 ± 0 10 lU/mL,
`respectively, and were attained in about 4 hours in most subjects Absolute bioavailability in
`healthy volunteers, measured as the anti-Factor Xa activity, was 87 ± 6% Increasing the dose
`from 2500 to 10,000 iU.resulted m an overall increase in anti-Factor Xa AUC that was
`greater than proportional by about one-third
`
`Peak anti-Factor Xa activity increased more or less linearly with dose over the same dose
`range There appeared to be no appreciable accumulation of anti-Factor Xa activity with
`twice-daily dosing of 100 lU/kg s c for up to 7 days
`
`2
`
`SJ
`
`0006
`
`

`

`FRAGMtN - Supplement for use in hip rcplacmem
`Proposedinsm' 10/28/988 (underline titdsmkcou based on verston dated VWH
`
`The volume of distribution for daltepann anti-Factor Xa activity was 40 to 60mL/ kg The
`mean-pfesma clearances of daltepann anti-Factor Xa activity m normal volunteers foilowng
`single intravenous bolus doses of 30 and 120 anti-Factor Xa lU/kg were 24 6 ± 5 4 and 15 6 ±
`2 4 mUhr/kgt respecuvely The corresponding mean disposition half-lives are 147 ± 0 3 and
`2 5 ± 0 3 h r
`
`Following intravenous doses of 40 and 60 lU/kg, mean terminal half-lives were 2 1 ±03 and
`23±04 hrs, respectively Longer apparent terminal half-lives (3 to 5 his) are observed
`following s c dosing, possibly due to delayed absoiptton In patients with chronic renal
`insufficiency requiring hemodialysis, the mean temunal half-life of anti-Factor Xa activity
`following a single intravenous dose of50001U FRAGMIN was 5 7±20 hrs, i e considerably
`longer than values observed in healthy volunteers, therefore, greater accumulation can be
`expected in these patients
`
`CLBVICAt TRIALS
`Abdominal Surgery:
`FRAGMIN Injection, administered once daily beginning pnor to surgery and continuing for 5
`to 10 days after surgery, has been shown to prevent deep vein thrombosis (DVT) m patients at
`nsk for thromboembolic complications (see INDICATIONS AND USAGE and DOSAGE
`AND ADMINISTRATION) Data from two double-bhnd randomized controlled clinical trials
`performed m paoents undergoing major abdominal surgery, summarized in the following
`tables, show that FRAGMIN 2500IU was superior to placebo and similar to hepann in
`preventing DVT (see Tables 1 and 2)
`
`Table 1
`Efficacy of FRAGMIN in Abdominal Surgery
`Posing Regimen
`
`I
`
`Placebo
`qdsc
`102
`
`16/91 (176%)
`5/91 (5 5%)
`. n/91 (12 1%>
`2/91 (2 2%)3
`
`Indication
`
`AH Treated Abdominal Surgery Paltcnts
`Treatment Failures m Evaluable Patients
`Total Tbromboembolic Events
`Proximal DVT
`Distal DVT
`PE
`
`FRAGMIN
`2500 IU qdsc
`102
`
`4/91 (44%)'
`0
`4/91(44%)
`0
`
`p-value versus placebo=0 008
`i
`. 2 Both patients also had DVT, I proximal and I distal
`
`3
`
`0007
`
`

`

`FRAGMIN-Supplement for use in hip replacement
`Proposed insert* I0/2&/98 B {underiine mid stnkeoitt baled on version dated 3/I8/9S
`
`Table 2
`EfTTcacy of FRAGMIN in Abdommal Surgery
`Posing Regimen
`
`Indication
`
`All Treated Abdormnal Surgery Patients
`Treatment Failures in Evaluable Patients
`Total Thromboembolic Events
`Proximal DVT
`Distal DVT
`PE
`
`i
`
`p-value versus heparin = 0 74
`
`FRAGMIN
`25CQIUqdsc
`195.
`
`7/178 (39%)'
`3/178(1 7%)
`3/178(1 7%)
`1/178 (06%
`
`Heparin
`5000 U bid sc
`196
`
`7/174(40%)
`4/174(2 3%>
`3/174(1 7%)
`0
`
`Data from a double-blind randomized controlled tnal show that FRAGMIN 5000IU once
`daily is more effective than FRAGMIN 2500 IU once daily in preventing DVT in patients
`undergoing abdominal surgery with malignancy (see Table 3)
`Tabic y
`Efficacy of FRAGMIN in Abdominal Surgery Pahcnts with Malignancy
`Posing Regimen
`
`Indication
`
`All Treated Abdommal Surgery Pautnts.
`Treatment Failures tn Evaluable Patients
`Total Thromboembolic Events
`Proximal DVT
`Distal DVT
`PE
`
`Fatal
`Non-fatal
`
`i
`
`p-value = 0001*
`
`FRAGMIN
`2500 IU qd s c
`696
`
`99/656 f 15 1%)'
`18/657 (2 7%)
`80/657(122%)
`
`1/674(01%)
`2
`
`FRAGMIN
`5000 lUqdsc
`679
`
`60/645(93%)
`14/646 (2 2%)
`41/646(63%)
`
`1/669(0 1%)
`4
`
`Hip Replacement Surgery:
`In an open-label randomized study, FRAGMIN 5000 IU administered once daily
`subcutaneously (s c ) was compared to warfann sodium, administered orally, in patients
`undergoing hip replacement surgery Treatment with FRAGMIN was initiated with a 2500 IU
`dose s c within 2 hours before surgeiy, followed by a 2500 IU s c dose the evening of the
`day of surgery Then, a dosing regimen of FRAGMIN 5000 IU s c once daily was initiated
`on the first postoperative day The first dose of warfann sodium was given the evening before
`surgery, then continued daily at a dose adjusted for INR 20-3 0 Treatment in both groups
`was then continued for 5 to 9 days postoperatively The incidence of total DVT, as
`determined by evaluable venography, was significantly lower for the group treated with
`FRAGMIN compared to patients treated with warfann sodium (28/192 vs 49/190, p=0 006)
`[see Table 4]
`
`4
`
`0008
`
`

`

`FRAGMlN-SuppttnKMfor usevnhipreplBccsncni
`Proposed cnstn- 10/28/98 B (underiineond stnkeout based on version dated 3/18/98
`
`Table 4
`Efficacy of FRAGMIN m Htp Replacement Surgery
`Dosing Regimen
`Warfarin Sodium
`qd" oral
`
`FRACMIN
`5000 !U qd^sc
`
`Indication
`
`All Treated Hip Replacement Surgery
`Patienls
`___
`Treatment Failures m Evaluable Patients
`DVT, Total
`
`Proximal DVT
`PE
`
`271
`
`28/192 (14 6%)J
`10/192 rs 2%)4
`2/271 (07%)
`
`279
`
`49/190(25 8%)
`
`16/190(84%)
`2/279 (07%)
`
`1 The daily dose on the day of surgery was divided 2500 III was given two hours before surgeiy and again
`m the evening of the day of surgery
`2 Warfann dosage was adjusted to mamtam a prothrombin time index of I 4 to 1 5, corresponding to an
`International Normalized Ratio (1NR) of approximately 2 5
`3 p-va!ue=0006
`4 p-values0l85 .
`
`In a second study (single-center, doubte-blmd) of 136 patterns undergoing hip replacement
`surgery, FRAGMIN 5000IU once daily s c starting the evening before surgery, was
`compared to heparin 5000 Use tid, starting the morning of surgery Treatment in both
`groups was continued for up to 9 days postoperatively In the intent-to-treat analysis, the
`incidence of proximal DVT was significantly lower for patients treated with FRAGMIN
`compared to patients treated with hepann {6/67 vs 18/69, p=D 010) Further, the incidence of
`pulmonary embolism detected by lung scan was also significantly lower in the group treated
`with FRAGMIN (9/67 vs 19/69, p=0 032)
`
`INDICATIONS AND USAGE
`FRAGMJN injection is'indicated for prophylaxis of deep vein thrombosis (DVT), which may
`lead to pulmonary embolism
`*
`In patients undergoing hip replacement surgery,
`®
`In patients undergoing abdominal surgery who are at nsk for thromboembolic
`complications Patients at nsk include those who are over 40 years of age, obese,
`undergoing surgery under general anesthesia lasting longer than 30 minutes, or who have
`additional risk factors such as malignancy, or a history of deep venous thrombosis or
`pulmonary embolism
`
`CONTRAINDICATIONS
`FRAGMIN Injection is contramdicated in patients with known hypersensitivity to the drug,
`active major bleeding, or thrombocytopenia associated with positive in vitro tests for anti­
`platelet antibody m the presence of FRAGMIN
`
`Patients with known hypersensitivity to hepann or pork products should not be treated with
`FRAGMIN
`
`5
`
`0009
`
`

`

`FRAGMIN - Supplement far use in hip rcplocement
`Proposed msen- I0/2A/9S B (underline and stnkcout bued on venion dated 3/18/98
`
`WARNINGS
`FRAGMIN Injection is not intended for intramuscular administration
`
`FRAGMIN cannot be used interchangeably (unit for unit) with unfractionated hepann or other
`low molecular weight hepanns
`.
`
`FRAGMIN should be used with extreme caution in patients with history of heparin-
`induced thrombocytopenia.
`
`.
`Hemorrhage:
`FRAGMIN, Idee other anticoagulants, should be used with extreme caution in patients who
`have an increased nsk of hemorrhage, such as those with severe uncontrolled hypertension,
`bacterial endocarditis, congenital or acquired bleeding disorders, active ulceration and
`angvodysplastic gasttomtestmal disease, hemorrhagic stroke or shortly after brain, spinal or
`ophthalmological surgery
`
`Spinal or epidural hematomas can occur with the associated use of low molecular
`weight heparins or heparinoids and neuraxia! (spinal/epidura!) anesthesia or spinal
`puncture, which can result m long-term or permanent paralysis. The risk of these
`events is higher with the use of indwelling epidural catheters or concomitant use of
`additional drugs affecting hemostasis such as NSAIDs (see boxed WARNING and
`ADVERSE REACTIONS, Ongoing Safety SurveiHance.
`
`4
`
`As with other anticoagulants, bleeding can occur at any site during therapy with FRAGMIN
`An unexpected drop in hematocrit or blood pressure should lead to a search for a bleeding
`site
`
`Thrombocytopenia:
`In clinical trials, thrombocytopenia with platelet counts of < 50,000/mm3 and <f00)000/mm3
`occurred in <1% and <1%, respectively, of patients undergoing abdominal surgery or hip
`replacement surgery In clinical practice, rare cases of thrombocytopenia with thrombosis have
`also been observed
`
`Thrombocytopenia of any degree should be monitored closely Hepann-induced
`thrombocytopenia can occur with the administration of FRAGMIN The incidence of this
`complication is unknown at present
`
`.
`Miscellaneous:
`The multiple-dose vial of FRAGMIN contains benzyl alcohol as a preservative Benzyl alcohol
`has been reported to be associated with a fatal "Gasping Syndrome" in premature infants
`Because benzyl alcohol may cross the placenta, FRAGMIN preserved with benzyl alcohol
`should not be used in pregnant women (See PRECAUTIONS, Pregnancy Category B,
`Nonteratogenic Effects )
`
`PRECAUTIONS
`
`6
`
`0010
`
`

`

`FRAGMtN • Supplement for use in hip reptacctnent
`Proposed nsen - 10/28/99 B (urtderlme and nnkeout based on version dfited 3/16/98
`
`General:
`.
`FRAGMIN injection should cot be mixed with other injections or infusions unless specific
`compatibility data are available that support such mixing
`
`FRAGMIN should be used with caution m patients with bleeding diathesis, thrombocytopenia
`or platelet defects, severe liver or kidney insufficiency, hypertensive or diabetic retinopathy,
`and recent gastrointestinal bleeding
`'
`
`If a thromboembolic event should occur despite daltepann prophylaxis, FRAGMIN should be
`discontinued and appropnate therapy initiated
`
`Drug Interactions:
`FRAGMIN should be used with care in patients receiving oral anticoagulants and/or platelet
`inhibitors because of increased risk of bleeding
`.
`.
`
`Laboratory Tests:
`Penodic routine complete blood counts, including platelet count, and stool occult blood tests
`are recommended dunng the course of treatment with FRAGMIN No special monitoring of
`blood clotting times (e g, APTT) is needed
`
`When administered at recommended prophylaxis doses, routine coagulation tests such as
`Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT) are relatively
`insensitive measures of FRAGMIN activity and, therefore, unsuitable for monitoring
`
`Drug/Laboratory Test Interactions:
`Elevations of Serum Transaminases:
`Asymptomatic increases in transaminase levels (SGOT/AST and SGPT/ALT) greater than
`three times the upper limit of normal of the laboratory reference range have been reported in
`I 7 and 4 3%, respectively, of patients dunng treatment with FRAGMIN Similar significant
`increases in transaminase levels have also been observed in patients treated with hepann and
`other low molecular weight heparins Such elevations are folly reversible and are rarely
`associated with increases in bilirubin Since transaminase determinations are important in the
`differential diagnosis of myocardial infarction, liver disease and pulmonary emboli, elevations
`that might be caused by drugs like FRAGMIN should be interpreted with caution
`
`Carcinogenicity, Mutagenesis, Impairment of Fertility:
`Daltepann sodium has not been tested for its carcmogenic potential in long-term animal
`studies It was not mutagenic in the in vitro Ames Test, mouse lymphoma cell forward
`mutation test and human lymphocyte chromosomal aberration test and m the in vivo mouse
`imcronucleus test Daltepann sodium at subcutaneous doses up to 1200 Ill/kg {7080 IU/m2)
`did not affect the fertility or reproductive performance of male and female rats
`.
`
`7
`
`0011
`
`

`

`FRAGMIN - Sopplcmeni for use in hip rtplacement
`Proposed imert- 10/28/98 8 (undefline aid stnkeoul based oa vtrsiondaied 3/18/58
`
`Pregnancy: Pregnancy Category B.
`Teratogenic Effects:
`Reproduction studies with daltepann sodium at intravenous doses up to 2400 IU/kg (14,160
`lU/m2) m pregnant rats and 4800 IU/kg (40,800 lU/m2) in pregnant rabbits did not produce
`any evidence of impaired fertility or ham to the fetuses There are, however, no adequate and
`well-controlled studies m pregnant women Because animal reproduction studies are not
`always predictive of human response, this drug should be used dunng pregnancy only if
`clearly needed
`
`Nonteratogenic Effects:
`Cases of "Gasping Syndrome" have occurred when large amounts of benzyl afcohoi have been
`administered (99 - 404 mg/kg/day) The 9 5 mL multi-dose vial of FRAGMIN contains 14
`mg/mL of benzyl alcohol
`
`Nursing Mothers:
`It is not known whether daltepann sodium is excreted m human milk Because many drugs are
`excreted m human milk, caution should be exercised when FRAGMIN is administered to a
`.
`nursing mother
`
`Pediatric Use:
`Safety and effectiveness in pediatric patients have not been established
`
`ADVERSE REACTIONS
`Hemorrhage:
`The incidence of hemorrhagic complications dunng treatment with FRAGMIN Injectron has
`been low The most commonly reported side effect is hematoma at the injection site The
`incidence of bleeding may increase with higher doses, however, in abdominal surgery patients
`with malignancy, no significant increase in bleeding was observed when comparing
`FRAGMIN 5000 (U to either FRAGMIN 2500IU or low dose hepann
`
`In a study comparing FRAGMIN 5000 IU once daily to FRAGMIN 2500 IU once daily in
`patients undergoing surgery for tna/jgnancy, the incidence of Weeding events was 4 6% and
`3 6%, respectively (n s) In a study comparing FRAGMIN 5000 IU once daily to hepann
`5000 IU twice daily, the incidence of bleeding events was 3 2% and 2 7%, respectively (n s)
`.
`m the malignancy subgroup
`
`Abdominal Surgery:
`
`Table 5 summarizes bleeding events that occurred m chmcal trials which studied FRAGMIN
`2500 and 5000 IU administered once daily to abdominal surgery patients
`
`8
`
`0012
`
`

`

`FfcACMtN - Supplement for us« m hip repJactmeM
`Proposed iRjm- 10/28/93 B (underimeandstnkeoal buedai vemondaied 3/(S/96
`
`TableS
`Bleeding Events in Abdominal Surgery
`PRAGMIN n Plactbo
`FRAGMIN vi Hepana
`Dtmng Rtgimcn
`Doong Rcgtitirn
`Placebo
`FRAGMIN
`Hepann
`qdsc
`SMOIU
`SOOOUbid
`ads^
`sc
`81/508
`36/454
`(159%)
`(79%)
`
`Hepann
`fRAGMIN
`2500(U
`5000 U
`. ^5C
`M s c
`14/(82
`63/498 '
`(77%)
`(127%)
`
`13/182
`01%)
`
`FRACMllVvtFRAGMfN
`Denflg Rrgiraen
`FRAOMIN
`FRAOMIN
`2500 {U
`5000 Rl
`qdsc
`qdsc
`
`89/1025
`(87%)
`
`125/1033
`(12 m
`
`fBdicatwn
`AbdomiMlSureenr
`Poftopeiative
`TnnsJustofls
`
`FRAGMIN
`2500lU
`qdsc
`26/459
`(57%)
`
`Wound Htoutonta
`
`Reoperation due to
`Bleeding
`
`Injection Sue
`Hematoma
`
`16/467
`(3 4%)
`
`2/392
`(05%)
`
`1/466
`(02%)
`
`(8/467
`
`P 9%;
`
`3/392
`(08%)
`
`5/464
`(11%)
`
`(2/508
`(24%)
`
`4/508
`(08%)
`
`4/498
`(12%)
`
`2/498
`(04%)
`
`36/506
`a m
`
`47/493
`(93%)
`
`209
`(2 5%)
`
`1/79
`(13%)
`
`8/172
`(47%)
`
`znr
`(26%)
`
`1/78
`(I 3%)
`
`2/174
`(I 1%)
`
`1/1930
`(01%)
`
`2/1030
`(02%)
`
`4/1039
`(04%)
`
`13/1038
`(13%)
`
`36/1026
`(3 5%)
`
`57/1035
`(5 5%)
`
`Htp Replacement Surgery:
`
`Table 6 sununanzes 1) alt major bleeding events and, 2) other bleeding events possibly or
`probably related to treatment with FRAGMIN, warfarin, or hepann in clinical tnafs of hip
`replacement surgeiy
`
`9
`
`i
`
`0013
`
`

`

`FRAGM1N - Supplement Tor use in iup rtp[accnn.nl
`Proposed irisen - l(V2&/98 B (undethne and strikeout based on venion dated 3/18/98
`
`Table 6
`Bleeding Event? in HIP Replacement Surgery
`FRAGMIN vs Heparin
`FRACM1N vs Warfarin Sodium
`Dosing Rcgtmcn
`Dosing Regimen
`FRAGMIN
`Hepann
`Warfann Sodmro1
`FRAGMIN
`oral *
`50001U q d s c
`5000 U ltd sc
`5000IU q d s c
`(n^eg4)
`(n = 27&)
`(n = 2741)
`In'69)
`7/274(26%
`0
`3/69(43%)
`1/279(04%)
`
`Indication
`Hfp Replacement
`Surgery
`
`•
`
`Mator Bleeding Events^
`Other Bleeding Events3
`Hematuna
`
`8/274 (2 9%)
`
`5/279(18%)
`
`Wound Hematoma
`
`6/274(22%)
`
`Injection Site Hematoma
`
`3/274(11%)
`
`O
`
`NA
`
`0
`
`0
`
`0
`
`0
`
`2/69(29%)
`
`7/69 (fO 1%)
`
`1 Warfann sodmm dosage was adjusted to maintain a prothrombin time index of 1 4 to 15,
`corresponding to an Intemational Normalized Ratto (fNR) of approximately 2 5
`Includes three treated patients who did not undergo a surgical procedure
`2
`3 A bleeding event was considered major if 1) hemorrhage caused a significant climcal event, 2) it
`was associated with a hemoglobin decrease of £2 g/dL or transfusion of 2 or more units of blood
`products, 3) it resulted m reoperation due to bleeding, or 4) it involved retroperitoneal or intracranial
`hemorrhage
`Includes two treated patients who did not undergo a surgical procedure
`4
`5 Occurred at a rate of at least 2% in the group treated with FRAGMIN 50001U once daily
`
`SJX of the patients treated with FRAGMIN experienced seven major bleeding events Two of
`the events were wound hematonia (one requiring reoperation), three were bleeding from the
`operative site, one was mtraoperattve breeding due to vessel damage, and one was
`gastrointestinal bleeding None of the patients expenenced retroperitoneal or tntracrania!
`hemorrhage nor died of bleeding complications
`
`Thrombocytopenia: See WARNINGS: Thrombocytopenia.
`
`Other:
`Alter sic Reactions:
`Allergic reactions (t e, pruritus, rash, fever, injection site reaction, bullous eruption) and skin
`necrosis have occurred rarely A few cases of anaphylactoid reactions have been reported
`
`10
`
`0014
`
`

`

`FRAGMIN - Supplement for use in hrp replacement
`Proposed insert- 10/28/98 B (underline and smkeouibuedon version dued 3/18/98
`
`Local Reactions:
`Pain at injection site, the only non-bleeding event determined to be possibly or probably
`related to treatment with FRAGMIN and reported at a rate of at least 2% m the group treated
`with FRAGMIN, was reported m 4 5% of patients treated with FRAGMIN 5Q00IL/ qd vs
`11 8% of patients treated with heparin. 5000 U bid in the abdominal surgery tnals In the hip
`replacement trials, pain at injection site was reported in 12% of patients treated with
`FRAGMIN 5000IU qd vs 13% of patients treated with heparin 5000 U tid
`
`OneoWB Safety Surveillance;
`Since first international market introduction m 1985, there have been 5 reports of epidural or
`spinal hematoma formation with concurrent use of daltepann sodium and spinal/epidural
`anethesia or spmal puncture No cases have been reported in the United States since approval
`in 1994 Four of the 5 patients had post-operative indwelling epidural catheters placed for
`analgesia or received additional drugs affecting hemostasis The hematomas caused
`long-term or permanent paralysis m four of the cases (one complete, three partial paralyses)
`The fifth patient expenenced temporary paraplegia but made a full recovery Because these
`events were reported voluntarily from a population of unknown size, estimates of frequency
`cannot be made
`
`OVERDOSAGE
`Symptoms/Treatment:
`An excessive dosage of FRAGMIN Injection may lead to hemorrhagic complications These
`may generally be stopped by the slow intravenous injection of protamine sulfate (1%
`solution), at a dose of i mg protamine for every 100 anti-Xa IU of FRAGMIN given A
`.
`second infusion of 0 5 mg protamine sulfate per 100 anti-Xa IU of FRAGMIN may be
`administered if the APTT measured 2 to 4 hours after the first infusion remains prolonged
`Even'with these additional doses of protamine, the APTT may remain more prolonged than
`would usually be found following administration of conventional heparin In all cases, the anti-
`Factor Xa activity is never completely neutralized (maximum about 60 to 75%)
`
`Particular care should be taken to avoid overdosage with protamine sulfate Administration of
`protamine sulfate can cause severe hypotensive and anaphylactoid reactions Because fatal
`1 reactions, often resembling anaphylaxis, have been reported with protamine sulfate, it should
`be given only when resuscitation techniques and treatment of anaphylactic shock are readily
`available For additional information, consult the labeling of Protamine Sulfate Injection, USP,
`products A single subcutaneous dose of 100,000 lU/kg of FRAGMIN to mice caused a
`mortality of 8% (1/12) whereas 50,000 lU/kg was a non-lethal dose The observed sign was
`hematoma at the site of injection
`
`11
`
`0015
`
`

`

`FRAGM1N - Supplement for use tn hip rtplacement
`Proposed ms«n - 10/28/98 B (underiine and snkeoui based on verston daied 3/18/98
`
`DOSAGE AND ADMINISTRATION
`Abdominal Surgery:
`In patients und&rgomg abdominal surgery with a nsk of thromboembolic complications, the
`recommended dose of FRAGM1N Injection is 2500IU administered by subcutaneous {s c)
`injection once daily, starting 1 to 2'hours pnorto surgery and repeated once daily forSto 10
`days postoperatively (See INDICATIONS AND LJSAGE)
`
`In patients undergoing abdominal surgery associated with a high nsk of thromboembolic
`complications, such as malignant disorder, the recommended dose of FRAGMIN is 5000 IU
`s c the evening before surgeiy, then once daily for 5 to 10 days postoperatively Alternatively,
`m patients with malignancy, 2500 IU of FRAGMIN can be administered s c
`I to 2 hours before surgery foilowed by 2500 IU s c J 2 hours later, and tben 5000 IU once
`daily for 5 to 10 days postoperatively
`
`Hip fleplacement Surgeo'.*
`In patients undergoing hip replacement surgery, the recommended first dose of FRAGMIN is
`2500 IU administered by s c injection within 2 hows before surgery and the second dose of
`2500 IU s c in the evening of the day of surgery (at least 6 hours alter the first dose) If
`surgery is performed m the evening, omit the second dose on the day of surgery Starting on
`the first postoperative day, the recommended dose of FRAGMIN is 5000 IU administered by
`s c injection once daily Alternatively, 5000 IU of FRAGMIN can be administered the
`evening before surgery, followed by 5000 IU once daily, starting m the evening of the day of
`surgeiy Up to 14 days of treatment was well tolerated in controlled clinical trials, where the
`•
`average duration of treatment was 5 to 10 days postoperatively
`
`Dosage adjustment and routine monitoring of coagulation parameters are not required if the
`dosage and administration recommendations specified above are followed
`
`Administration:
`FRAGMIN is administered by subcutaneous injection It must not be administered by
`intramuscular injection
`
`Subcutaneous injection technique Patients should be sitting or lying down aid FRAGMIN
`administered by deep subcutaneous injection FRAGMIN may be injected m a U-shape area
`around the navel, the upper outer side of the thigh or the upper outer quadrangle of the
`buttock The injection site should be varied daily When the area around the navel or the thigh
`is used, using the thumb and forefinger, you must lift up a fold of skin while giving the
`injection The entire length of the needle should be inserted at a 45 to 90 degree angle
`
`Parenteral drug products should be inspected visually for particulate matter and discoloration
`pnor to administration, whenever solution and container permit
`
`12
`
`0016
`
`

`

`FRAGMIN-Supplememfor useinhrpreplaccmenl
`Proposed insert- 10/28/98 B (endextine and sinkeout based on venton daied 3/18/98
`
`HOW SUPPLIED
`FRAGMIN Injection is available in the following strengths and package sizes
`
`0 2 mL single-dose prefilled synnge, affixed with a 27-gauge x 1/2 inch