foi
`
`5243106
`
`A
`
`* 5 2 4 3 1 0 6 *
`
`* A*
`
`{Part of Complete Approval Document 5202438A} Lovenox
`Injection (Aventis) 11/27/2000 Supplemental Approval [New
`Indication - Prevention of Deep Vein Thrombosis in Patients with
`Acute Illness]: S36 Approval Letter; Approvable Letter; Final
`Labeling
`
`This document was provided by: FOI Services, Inc
`704 Quince Orchard Road • Suite 275
`Gaithersburg MD 20878-1751 USA
`Phone:
`301-975-9400
`Fax:
`301-975-0702
`infofoi@foiservices.com
`Email:
`
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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 1025
`
`

`

`s
`I
`
`DKPAMMEWT OT HEALTH * HUMAN SBRVICES
`
`hAficHethb Soviet
`
`Pood nd Drc| AdBtaiftmno
`RocfevflfeMD 20857
`
`NDA 20-164/S^J6
`
`Aveutis Phannaceuticals Products Inc.
`C/OQuintiksbe.
`Attention: MB. Michelle Klrewer
`Mail Slio F3-3026
`P.O. Box 9708
`Kansas City, MO 64123-0708
`
`Dear Ms. Kliewer:
`
`Please refer to your supplemental new drug application dated December 10.1999, received
`December 10,) 999, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for
`
`We acknowledge receipt of your submissions daied February 24, March 6, April 26, May I and 24, July 13, September IS,
`and October 12,2000. Your submission of July 13,2000 constituted a complete response to our June 8,2000 action letter.
`
`This supplemental new drug application provides for the use of Lovenox® (enox aparin sodium) Injection for the
`thromboprophylaxis of deep vein thrombosis, which may lead to pulmonary embolism, in medical patients who are at risk
`for thromboembolic complications due to severely restricted mobility during acute illness.
`
`We have completed the review of this supplemental application, as amended, and have concluded that adequate iaformation
`has been presented to demonstrate that the drug product is safe and effective for use as recommended in the agreed upon
`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 paper copies of the FPL as soon as it is available, in no case more than 30 days after il is printed. Please
`individually mount ten of the copies on heavy-weight paper or similar material. Alternatively, you may submit the FPL
`electronicaUy according to the guidance for industry titled Providing Regulatory Submissions in Electronic Format - NDAs
`(January 1999). For administrative purposes, this submission should be designated "FPL for approved supplement NDA
`20-164/S-036." Approval of this submission by FDA is not required before the labeling is used.
`
`Be advised that, as of April 1, 1999, all applications for new active ingredients, new dosage forms, new indications, new
`routes of administration, and new dosing regimens are required to contain an assessment of the safety and effectiveness of
`the product in pediatric patients unless this requirement is waived or deferred (63 FA 66632). We are waiving the pediatric
`study requirement for this action on this application.
`
`0002
`
`

`

`In addition, please submit three copies of the introductory 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 promoliona] materials and the package insert
`directly to:
`
`Division of Dreg Marketing, Advertising, and Communications, HFD-42
`Food and Drug Administration
`5600 Fishers Lane
`Rockville, Maryland 20857
`
`If a letter communicating important information about this drug product (i.e., a Dear Health Care
`Practilioner" 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 21CFR
`314.60 and314.81.
`
`If you have any questions, call Karen Oliver, Regulatory Project Manager, at (301) 827-7457.
`
`Sincerely,
`
`Lilia Talarico, M.D.
`Direct oi
`Division of Gastrointestinal and Coagulation Drug
`Products
`Office of Drug Evaluation IH
`Cento" for Drug Evaluation and Research
`
`Enclosure: Package Insert Text
`
`0003
`
`

`

`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICATION NUMBER:
`APPLICATION NUMBER:
`NDA 20-164/S-036
`NDA 20-16418-036
`
`APPROVABLE LETTER
`APPROVABLE LETTER
`
`
`
`
`
`
`
`0004
`
`0004
`
`

`

`3 DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`NDA20-164/S-036
`
`Aventis Phannaceuticals Products Inc.
`Attention: Edmond Roland, MD.
`P.O. Box 5096
`S00 Areola Road, H-10
`Collegcville, PA 19426-5299
`
`Dear Dr. Roland:
`
`Food and Drug AdmMmttoo
`Rockvfe MO 20667
`
`JUN -8 2000
`
`Please refer to your suppiemental new drug application dated December 10.1999, received
`December 10,1999, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
`for Lovenox® (enoxparin sodium) Injection.
`
`We acknowledge receipt of your submissions dated February 24, March 6, April 26, and
`May land 24,2000.
`
`This supplemental new drag application proposes for the use of Lovenox® Injection for a new
`indication, stated as follows:
`
`Lovenox Injection is indicated for the thromboprophylaxis of deep vein thrombosis,
`which may lead to pulmonary embolism, in medical patients who are at risk, for
`thromboembotic complications due to severely restricted mobility during acute
`illness.
`
`We have completed the review of this application, as amended, and it is approvable. Before this
`application may be approved, however, it will be necessary for you to submit final printed labeling
`(FPL) for the dug. The labeling should be identical- in content to the enclosed labeling (text for
`package insert). In addition, all previous revisions as reflected in the most recently approved
`labeling must be included. To facilitate review of your submission, please provide a highlighted or
`marked-up copy that shows the changes that are being made.
`
`Please submit 20 copies of the final printed labeling ten of which axe individually mounted on heavy
`weight paper or similar material. The submission should include the appropriate number of copies of
`the package insert from both the Maison-AJfort and the Dagenham printing sites.
`
`If additional information relating to the safety or effectiveness of this drag becomes available,
`revision of the labeling may be required.
`
`0005
`
`

`

`NDA 20-164/5-036
`Page 2
`
`Under 21GFR 314.50(d)(5XvtX^X wc ropiest that you update your NDA by submitting aJI safety
`information you now have regarding your new drug. Please provide updated information as listed
`below. The update should cover all studies and uses of the drug including: (1) those involving
`indications not being sought in the present submission, (2) other dosage forms, and (3) other dose
`levels, etc.
`
`1. Reiabulation of all safety data including results of trials that were still ongoing at the time of
`NDA submission. The tabulation can take the same form as in your initial submission.
`Tables comparing adverse reactions at the time the NDA was submitted versus now will
`certainly facilitate review.
`
`2. Reiabulation of drop-outs with new drop-outs identified. Discuss, if appropriate.
`
`3. Details of any significant changes or findings.
`
`4. Summary of worldwide experience on the safety of this drug.
`
`5. Case report forms for each patient who died during a clinical study or who did not complete a
`study because of an adverse event.
`
`6. English translations of any approved foreign labeling not previously submitted
`
`7. Information suggesting a substantial difference in the rate of occurrence of common, but less
`serious, adverse events.
`
`In addition, please submit three copies of the introductory promotional materials that you propose to
`use for these products. 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 inserts directly to:
`
`Division of Drag Marketing, Advertising, and Communications, HFD-40
`Food and Drug Administration
`5600 Hshers Lane
`Rockville, Maryland 20857
`
`Within 10 days after the date of this letter, you are required to amend the supplemental application,
`notify us of your intent to file an amendment, or follow ooe of your other options under
`21 CFR 314.110. Iri the absence of any such action FDA may proceed to withdraw the application.
`Any amendment should respond to all the deficiencies listed. We will not process a partial reply as a
`major amendment nor will the review clock be reactivated until all deficiencies have been addressed.
`
`0006
`
`

`

`NDA 20-164/S-036
`Page 3
`
`This product may be conadered to be misbnmded under the Federal Food, Drag, and Cosmetic Act if
`it is marketed with these changes prior to approval of these supplemental applications.
`
`If you have my questions, call Karen Oliver, Regulatory Health Regulatory Project Manager,
`at (301) 827-7457.
`v
`
`Sincerely,
`
`LiliaTalarico, M.D.
`Director
`Division of Gastrointestinal and Coagulation Drug
`Products
`Office of Drug Evaluation ID
`Center for Drag Evaluation and Research
`
`Enclosure: Package Insert Labeling entitled Red-Line/Strike-Out Version of the Labeling
`
`0007
`
`

`

`i3S page(s) of revised
`draft labeling has been
`redacted from this portion
`of the review.
`
`0008
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICATION NUMBER:
`APPLICATION NUMBER:
`NDA 20-164/5-036
`NDA 20-16418-036
`
`APPROVED LABELING
`APPROVED LABELING
`
`
`
`
`
`_Agfilwwww—w
`
`0009
`
`0009
`
`

`

`•
`
`NDA 20-164/^036
`Page 1
`
`JQVENOX"
`(enoxaparinsodwmllri'ecfen
`
`.Oi
`
`Rxonly
`Rev. —
`50S539D
`
`SPINAL / EPIDURAL HEMATOMAS
`When ncuraxial anesthesia (epidurBl/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or scheduled
`to be anticoagulated with low molecular weight heparins or heparinoids for prevention of thromboembolic complications
`are at risk of developing an epidural or spina) hematoma which can result in long-term or permanent paralysis.
`The risk of these events is increased by the use of indwelling epidural catheters for administration of analgesia or by the
`concomitant use of drugs affectinghemoslasis such as nonsteroidal anti-inflammatory drugs (NSAlDs). platelet inhibitors,
`or other anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture.
`Patients should be frequently monitored for signs and symptoms of neurological impairment. If neurologic compromise is
`noted, urgent treatment is necessaiy.
`The physician should consider (he potential benefit versus risk before neuraxia) intervention in patients anticoagulated or to
`be anticoagulated for thromboprophylaxis (see also WARNINGS, Hemorrhage, and PRECAUTIONS, Drag
`Interactions).
`
`DESCRIPTION
`Lovenox Injection is a sterile solution containing enoxapario sodium, a low molecular weight heparin.
`
`Lovenox Injection is available in two concentrations:
`1 lOOmg per mL of Water for Injection
`
`30mg/0.3 mL, 40Tng / 0.4 mL
`-Prefilled Syringes
`'Graduated Prtfilled Syringes 60 mg / 0,6 mL, 80 mg/ 0.8 mL, lOOmg/l mL
`30mg/0.3 mL
`•Ampules
`
`Lovenox Injection lOOmg/mL Concentration contains 10 mgenoxaparin sodium (or approximate anti-Factor Xa activity
`of 1000 (U (with reference to the W Ji.O. First International Low Molecular Weight Heparin Reference Standard]) per 0.1
`mL Water for Injection.
`
`2 ISO mg per mL of Water for InJectfoD
`'Graduated Prefilled Syringes 90mg/0.6mL, 120 mg 10.8 mL, 150 mg/1 mL
`
`Lovenox Injection ISO mg/mL Concentration contains 1S mg enoxaparin sodium (or appropriate anti-Factor Xa activity
`of 1500IU [with reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard]) per 0.1
`mL Water for Injection.
`
`The solutions are preservative-free and intended for use only as a single-dose injection. (See DOSAGE AND
`ADMINISTRATION and HOW SUPPLIED for dosage unh descriptions.) The pH of the injection is S.S to 7.5. Nitrogen
`is used in the headspace to inhibit oxidation.
`Enoxaparin is obtained by alkaline degradation of heparin benzyl ester derived from porcine intestinal mucosa. Its structure
`is characterized by a 2-0-sulfo-4-enepyr3nosuronic acid group at the non-reducing end and a 2-N,6-0-disulfo-D-
`gtucosamine at the reducing end of the chain. The substance is the sodium salt. The average molecular weight is about 4500
`daltons. The molecular weight distribution is:
`
`0010
`
`

`

`NDA 20-164/S-036
`Page 2
`
`<2000 daitons
`2000 to 8000 daitons
`>8000 daitons
`
`S20%
`568%
`<18%
`
`STRUCTURAL FORMULA
`
`m
`
`NH-fT
`
`NaOOC
`
`O
`
`fi
`—H or —SO/te
`
`Olor
`V."
`
`O v
`
`#r
`—SO,Na or —C-CH,
`B
`O
`
`iHrOA
`
`i#fyr
`
`ft
`
`n
`3 to 20
`
`CLINICAL PHARMACOLOGY
`Enoxapann is a low molecular weight heparin which has antithrombotic properties. In humans, enoxaparin given at a dose
`of 1.5 mg/kg subcutaneously (SC) is characterized by a higher ratio of anli-Factor Xa to anli-Factor lla activity (mean±SD,
`14.0±3.1) (based on areas under anti-Factor activity versus time curves) compared to the ratios observed for heparin
`(meaniSD, l.22±C.13). Increases of up to 1.8 times the control values were seen in the thrombin lime (TT) and the
`activated partial thromboplastin time (aPTT). Enoxaparin at a t mg/kg dose (100 mg / mL concentration), administered SC
`every 12 hours to patients in a large clinical trial resulted in aPTT values of 45 seconds or less in the majority of patients (n
`= 1607).
`Pharmacodynamics (conducted using tOOmg / mL concentration): Maximum anti-Factor Xa and anti-thrombio (anti-
`Factor lla) activities occur 3 to 5 hours after SC injection of enoxaparin. Mean peak anti-Factor Xa activity was 0.16 ILf/mL
`(1.58 jig/mL) and 0.38 lU/mL (3.83 ng/mL) after the 20 mg and the 40 mg clinically tested SC doses, respectively. Mean
`(n = 46) peak anti-Factor Xa activity was 1.) IU/mL at steady state in patients with unstable angina receiving I mg/kg SC
`every 12 hours for 14 days. Mean absolute bioavailability of enoxaparin, given SC, based on anti-Factor Xa activity is 92%
`in healthy volunteers. The volume of distribution of anti-Factor Xa activity is about 6 L. Following intravenous (i.v.)
`dosing, the total body clearance of enoxaparin is 26 mL/min. After i.v. dosing of enoxaparin labeled with the gamma-
`emitter, "Te, 40% of radioactivity and 8 to 20% of anti-Factor Xa activity were recovered in urine in 24 hours.
`Elimination half-life based on anti-Factor Xa activity was 4.5 hours after SC administration. Following a 40 mg SC once a
`day dose, significant anti-Factor Xa activity persists in plasma for about 12 hours.
`Following SC dosing, the apparent clearance (CL/F) of enoxaparin is approximately 15 mL/min. Apparent clearance and
`Am derived from anti-Factor Xa values following single SC dosing (40 mg and 60 mg) were slightly higher in males than
`in females. The source of the gender difference in these parameters has not been conclusively identified, however, body
`weight may be a contributing factor.
`Apparent clearance and A ^..derived from anti-Factor Xa values following single and multiple SC dosing in elderly
`subjects were close to those observed in young subjects. Following once a day SC dosing of40mg enoxaparin, the Day 10
`mem area under anti-Factor Xa activity versus time curve (AUC) was approximately I S% greater than the mean Day I
`AUC value. In subjects with moderate renal impairment (creatinine clearance 30 to 80 mL/min), anti-Factor Xa CIJT
`values were similar to those in healthy subjects. However, mean CL/F values of subjects with severe renal nnpsirment
`(creatinine clearance <30 mUmin), were approximately 30% lower than the mean CL/F value of control group subjects.
`(See PRECAUTIONS.)
`Although not studied clinically, the ISOtng/mL concentration of enoxaparin sodium is projected to result in anticoagulant
`activities similar to those of 100 mg/mL and 200 mg/mL concentrations at the same enoxaparin dose. When a daily 1.5
`mg/kg SC injection of enoxaparin sodium was given to 25 healthy male and female subjects using a lOOmg/ml or a 200
`mg/mL conccnlration the following pharmacokinetic profiles were obtained (see table below):
`
`0011
`
`

`

`NDA 20-164/S-036
`Page 3
`
`Phanaacoklitetlc Paramelen* After 5 Diyi of i£ mgfrg SC Once Daily Doses of
`Euoiaparin Sodium Using 100 mgftnL or 200 mg/mL Concentrations
`
`Concentration
`
`Anti-Xa
`
`Anti-Oa
`
`Heptest
`
`aPTT
`
`Amax
`(TU/mL or A
`sec)
`
`lmax**(b)
`
`AUC (ss)
`(h*lU/mLof h*
`A sec)
`
`100 mg/mL
`
`137 (±0.23)
`
`0.23 (±0.05)
`
`104.5 (±16.6)
`
`19.3 (±4.7)
`
`200 mg/mL
`90% CI
`
`100 mgfanL
`200 mg/mL
`
`1.45 (±0.22)
`102-110%
`
`0.26 (±0.05)
`
`110.9 (±17.1)
`102-111%
`
`22 (±6.7)
`
`3(2-6)
`3.5 (2-6)
`
`4(2-5)
`4i (Z5-6)
`
`2.5 (2-4.5)
`33(2-5)
`
`3 (2-4.5)
`3(2-5)
`
`100 mg/mL
`
`14.26 (±253)
`
`1.54 (±0.61)
`
`1321 (±219)
`
`200 mg/mL
`90% CI
`
`15.43 (±2.96)
`105-112%
`
`1.77 (±0.67)
`
`1401(±227)
`103-109%
`
`•Means ± SD at Day 5 and 90% Confidence Interval (CI) of the ratio
`** Median (range)
`
`CLINICAL TRIALS
`Prophylaxis of Deep Vein Thrombosb Following Abdominal Surgery In Patients at Risk for ThromboemboUc
`Complications: Abdominal surgery patients at risk 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 vein thrombosis or pulmonary embolism.
`In a double-blind, parallel group study of patients undergoing elective cancer surgery of the gastrointestinal, urological, or
`gynecological tract, a total of 1116 patients were enrolled m the study, and 1115 patients treated. Patients ranged in age
`from 32 to 97 years (mean age 67 years) with 52.7% men and 47.3% women. Patients were 98% Caucasian, 1.1% Black.
`0.4% Oriental, 0.4% others. Lovenox injection 40 mg SC. administered once a day, beginning 2 hours prior to surgery and
`continuing for a maximum of 12 days after surgery, was comparable to heparin 5000 U every S hours SC in reducing the
`risk of deep vein thrombosis (DVT). The efftcacy data are provided below.
`
`0012
`
`

`

`NDA 20-164/S-036
`Page 4
`
`Efficacy of Lovcnoi Injection In tfce Prophylaxis of Deep Vein Tfarombosb Following Abdominal Surgery
`Dosing Regimen
`
`LyvtOM lOl-
`40nigq.d. SC
`n(%)
`555 (100)
`
`Heparin
`5000 Uq8h SC
`o(%)
`560(100)
`
`IndkatioD
`All Treated Abdominal
`Sargeiy Patients
`Treatment Failures
`Total VTE?(%)
`
`DVT Only (%)
`
`63(11.3)
`56(10.1)
`(95% Q: 9 to 14)
`(95% Cf: 8 to 13)
`61(10.9)
`54(9.7)
`(95% a: 8 to 13)
`(95% CI: 7 to 12)
`T VTE= Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic m origin.
`3 CI = Confidence Interval
`
`In a second double-blind, parallel group study, Lovenox Injection 40 mg SC once a day was compared to heparin 5000 U
`every 8 hour; SC in patients undergoing colorectal surgery (one-third with cancer). A total of 1347 patients were
`randomized in the study and al! patients were treated. Patients ranged in age from 18 to 92 years (mean age 50.1 years)
`with 54.2% men and 45.8% women. Treatment was initiated approximately 2 hows prior Jo surgery and continued for
`approximately 7 to 10 days after surgery. The efficacy data are provided below.
`
`Efficacy of Loveooi Injection In the Prophylaxis of Deep Vein Thrombosis Following Colorectal Snrgery
`Dosing Regimen
`Lovenoi Inl.
`40 mg q.d. SC
`n(%)
`673 (100)
`
`Heparin
`5000 U q8b SC
`n(%)
`674 (100)
`
`Indication
`All Treated Colorectal Surgery
`Patients
`Treatment Failures
`Total VTE1 (%)
`
`DVT Only (%)
`
`48(7.1)
`45(6.7)
`(95% Ct: 5 to 9)
`(95% CI: 5 to 9)
`44(6.5)
`47(7.0)
`(95% Q: 5 to 9)
`(95% CI: 5 to 8)
`T VTE - Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin.
`1 CI a Confidence Interval
`Propbylazls of Deep Vein Tfaroioboib Foltotrlflg Hip or Knee Replacement Snrgery: Lovenox Injection has been
`shown to reduce the risk of post-operative deep vein thrombosis (DVT) following hip or knee replacement surgery.
`In a double-blind study, Lovenox Injection 30 mg every 12 hours SC was compared to placebo in patients with hip
`replacement. A total of 100 patients were randomized in the study and all patients were treated. Patients ranged in age from
`41 to 84 years (mean age 67.1 years) with 45 % men and 55 % women. After hemostasis was established, treatment was
`initiated {2 to 24 hours after surgery and was continued for 10 to 14 days after surgery. The efficacy data are provided
`below.
`
`Effkacy of Lovenox Injection In the Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery
`Doilqg Regimen
`Lovgnoi Inl.
`Placebo
`30mgql2h SC
`ql2h SC
`n(%)
`n(%)
`50(100)
`50(100)
`
`Indication
`All Treated Hip Replacement Patients
`Treatment Failures
`
`0013
`
`

`

`NDA 20-164/S-036
`PageS
`
`Total DVT (%)
`Proximal DVT (%)
`T p value versus placebo B 0.0002
`2 p value versus placebo = 0.0134
`
`I
`5(10)
`W
`
`23(46)
`11(22)
`
`A double-blind, imihicenter study compared three dosing regnnens of Lovenox Injection in patients with hip replacement.
`A total of 572 patients were randomized m the study and 568 patients were treated. Patients ranged in age from 31 to 88
`years (mean age 64.7 years) with 63% men and 37% women- Patients were 93% Caucasian, 6% Black, <]% Oriental, 1%
`others. Treatment was initiated within two days after surgery and was continued for 7 to 11 days after surgery. The efficacy
`data are provided below.
`
`0014
`
`

`

`NDA 20-164/S-036
`Page 6
`
`Effkxcy of Lovenoz Injection in the FrophyUib of Deep Vein Thrombosis Following Hip Replacement Surgery
`
`10 mg q.d. SC
`n(%)
`161 (100)
`
`Lovenox Dos leg Regimen
`30 mg ql2b SC
`n(%)
`208 (100)
`
`40 mg q.d. SC
`»(*)
`199(100)
`
`Indkattan
`All Treated Hip
`Replacement Patients
`Treatment Failures
`40(25)
`Total DVT (%)
`17(11)
`Proximal DVT (%)
`T p value versus Loveoox 10 mg once a day - 0.0008
`2 p value versus Loveoox 10 rag once a day - 0.0168
`There was no significant difterence between the 30 mg every 12 hours and 40 mg once a day regimens.
`In a double-blind study, Lovenox Injedton 30 mg every 12 hours SC was compared to placebo in patients undergoing knee
`surgery. A total of 132 petienls were randomized in the study and 131 patients were treated, of which 99 had total knee
`replacement and 32 had either unicompartmental knee replacement or tibia! osteotomy. The 99 patients with total knee
`replacement ranged in age from 42 to SS years (mean age 70.2 years) with 36.4% men and 63.6% women. After
`hemostasis was established, treatment was initiated 12 to 24 hours after surgery and was continued up to IS days after
`surgery. The incidence of proximal and total DVT after surgery was signiftcantly lower for enoxaparin compared to
`placebo. The efficacy data are provided below.
`
`i
`22(11)
`TW
`
`27(14)
`9(5)
`
`Efficacy of Lovenox Injection In the Prophylaxis of Deep Vein Thrombosis Following Total Knee Replacement
`Surgery
`Dosing Regimen
`
`LrfVWl loir
`30mgql2h SC
`n(Vo)
`47(100)
`
`Placebo
`ql2h SC
`n(%)
`52(100)
`
`5(11)'
`(95% CP: 1 to 21)
`0(07
`(95% Upper CL4: 5)
`
`32(62)
`(95% CI: 47 to 76)
`7(13)
`(95% CI: 3 to 24)
`
`Indication
`All Treated Total Knee
`Replacement Patients
`Treatment Failures
`Total DVT (%)
`
`Proximal DVT (%)
`
`T p value versus placebo = 0.0001
`*CI ~ Confidence Interval
`1 p value versus placebo = 0.013
`4 CL = Confidence Limit
`
`Additionally, in an open-label, parallel group, randomized clinical study, Lovenox Injection 30 mg every 12 hours SC in
`patients undergoing elective knee replacemeni surgery was compared to heparin 5000 U every 8 hours SC. A total of 453
`patients were randomized in the study and all were treated. Patients ranged in age from 38 to 90 years (mean age 6S.5
`years) with 43.7% men and 56.3% women. Patients were 92.5% Caucasian, 5.3% Black, 0.2% Oriental, 0.4% others.
`Treatment was initiated after surgery and continued up to 14 days. The incidence of deep vein thrombosis was significantly
`lower for enoxaparin compared lo heparin.
`Extended Prophylaxis ofDeep Vein Thrombosis Following Hip Replacement Surgery: In a study of extended prophylaxis
`for patients undergoing hip replacement surgery, patients were treated, while hospitalized, with enoxaparin 40 mg SC,
`initiated up to 12 hours prior to surgery for the prophylaxis of post-operative DVT. At the end of the peri-operative period,
`ail patients underwent bilateral venography. In a double-blind design, those patients with no venous thromboembolic
`disease were randomized to a post-discharge regimen of either enoxaparin 40 mg (n = 90) once a day SC or to placebo (n 8
`89) for 3 weeks. A total of 179 patients were randomized in the double-blind phase of the study and all patients were
`treated. Patients ranged in age from 47 to 87 yean (mean age 69.4 years) with 57 % men and 43 % women. In this
`
`0015
`
`

`

`NDA20-164/S-036
`Page?
`
`population of patients, the incidence of DVT during extended prophylaxis was significantly lower for enoxaparin compared
`to placebo. The efficacy dan are provided below.
`
`Efficacy of Lovrnoi Injection In (he Extended Prophytaxfi of Deep Vein Thrombosis Following Rip Replacement
`Ssrgery
`PotMHacharge Dosing Regimen
`Lwnw IBIT
`Placebo
`40 mg q.d. SC
`q.d. SC
`n(%)
`n(%)
`90(100}
`89(100)
`
`Indication (Poft-DtMharge)
`Alt Treated Extended
`Prophylaxis Patients
`Treatment Failures
`Total DVT (%)
`
`Proximal DVT (%)
`
`T p value versus placebo = 0.008
`2 CI= Confidence Interval
`3 p value versus placebo = 0.537
`
`6(7)'
`(95% Cf: 3 to 14)
`TW
`(95% CJ: 2 to 13)
`
`18(20)
`(95% Q: 12 to 30)
`n*)
`(95% CI: 3 to 16)
`
`In a second study, patients undergoing hip replacement surgery were treated, while hospitalized, with Lovenox Injection 40
`mg SC, initiated up to 12 hours prior to surgery. All patients were examined for clinical signs and symptoms of venous
`thromboembolic (VTE) disease. In a double-blind design, patients without clinical signs and symptoms of VTE disease
`were randomized to a post-discharge regimen of either Lovenox Injection 40 mg (n = 131) once a day SC or to placebo (n ~
`131) for 3 weeks. A total of262 patients were randomized in the study double-blind phase and all patients were treated.
`Patients ranged in age from 44 to 87 years (mean age 68.5 yeats) with 43.1 % men and 56.9% women. Similar to the first
`study the incidence of DVT during extended prophylaxis was significantly lower for Lovenox Injection compared to
`placebo, with a statistically significant difference in both total DVT (Lovenox Injection 21 [16%) versus placebo 45 [34%];
`p = 0.001) and proximal DVT (I.ovenox Injection 8 [6%] versus placebo 28 [21%]; p 9 <0.001).
`Prophylaxis of Deep Vein Thrombosis (DVT) In Medkal PsUenti with Severely Restricted Mobility During Acote
`Illsess: In B double blind multicenter, parallel group study, Lovenox Injection 20 mg or 40 mg once a day SC was
`compared to placebo m the prophylaxis of DVT in medical patients with severely restricted mobility during acute illness
`(defined as walking distance of <10 meters for £3 days). This study included patients with heart failure (NYHA Class III or
`IV); acute respiratory failure or complicated chronic respiratory insufTIciency (not requiring ventilatory support): acute
`infection (excluding septic shock); or acute rheumatic disorder [acute lumbar or sciatic pain, vertebral compression (due to
`osteoporosis or tumor), acute arthritic episodes of the lower extremities]. A total of 1102 patients were enrolled in the
`study, and 1073 patient treated. Patients ranged in age from 40 to 97 years (mean age 73 years) with equal proportions of
`men and women. Treatment continued for a maximum of 14 day* (median duration 7 days). When given at a dose of 40
`mg once a day SC. Lovenox Injection significantly reduced the incidence of DVT as compared to placebo. The efficacy
`data are provided below.
`
`it
`
`0016
`
`

`

`NDA 2Q-164/S-036
`Page B
`
`Effkacy of Lovenox Injection in the Prophylaxis of Deep Vein Thrombosis in Medical Patients With
`Severely Restricted Mobility During Acute Dlness
`Dosing Regimen
`Lovenox Inj.
`40 tng q.d. SC
`n(%)
`«0(100)
`
`Lovenox Inj.
`20 mg q.d. SC
`n(%)
`351(100)
`
`Placebo
`
`n(%)
`362 (100)
`
`Indication
`All Treated Medical Patients
`During Acute Illness
`I
`Treatment Failure
`Total VTC? (%)
`
`Total DVT (%)
`
`43 (12.3)
`43 (12.3)
`(95% CI5 8.8 to 15.7)
`13(3.7)
`Proximal DVT(%)
`Treatment failures during therapy, between Days 1 and 14.
`3 VTE = Venous thromboembolic events which included DVT, PE, and death considered (o be thromboenibolic in origin.
`3 CI = Confidence Interval
`At approximately 3 months following eruollmenl, the incidence of venous thromboembolism remained significantly lower
`in the Lovenox Injection 40 mg treatment group versus the placebo treatment group.
`
`43(11.9)
`41(11.3)
`(95% Cl' 8.1 to 14 6)
`14(3.9)
`
`16(4.4)
`16(4.4)
`(95% CI3 2.3 to 6.6)
`5(1.4)
`
`Prophylaxis of Ischemic Complications In Unstable Angina and Non-Q»Wave Myocardial Infarction: In a
`multicenter, double-blind, parallel group study, patients who recently experienced unstable angina or non-Q-wave
`myocardial infarction were randomized to either Lovenox Injection 1 mg/kg every 12 hours SC or heparin i v. bolus (5000
`U) followed by a continuous infusion (adjusted to achieve an aPTT of 55 to 85 seconds). A total of 3171 patients were
`enrolled in the study, and 3107 patients were treated. Patients ranged in age from 25-94 years (median age 64 years), with
`33.4% of patients female and 66.6% male. Race was distributed as follows: 89.8% Caucasian, 4.8% Black, 2.0% Oriental,
`and 3.5% other. AH patients were also treated with aspirin 100 to 325 mgper day. Treatment was initiated within 24 hours
`of the event and continued until clinical stabilization, revascularization procedures, or hospital discharge, with a maximal
`duration of 8 days of therapy. The combined incidence of the triple endpoint of death, myocardial infarction, or recurrent
`angina was lower for Lovenox Injection compared with heparin therapy at 14 days after initiation of treatment. The lower
`incidence of the triple endpoint was sustained up to 30 days after initiation of treatment. These results were observed in an
`analysis of both all-randomized and all-treated patients. The efficacy data are provided below.
`
`0017
`
`

`

`NDA 20-164/8-036
`Page 9
`
`Redaction
`(%)
`
`p Value
`
`Efflcftcy of tovenoi Injection ID the Prophytaxb of Ischemic Corapllcationt ID Unstable Angina and Non-Q-Wave
`MyoeardlaJ Infarction
`(Combined End point of Death, Myocardial Infarction, or Recnrrent Angina)
`I>oringReglmtn
`Lovenox Inj.
`Heparin
`I mg/kgq!2hSC
`aPTT Adjusted
`i.v. Therapy
`n(%)
`1529(100)
`
`n(%)
`1578(100)
`
`IndlcaHoo
`All Treated Uostable
`An^na and Non-Q-Wave
`Ml Patients
`I
`Timepoint
`112(7.3)
`96(6.1)
`48 Hours
`303(19.8)
`14 Days
`261 (16.5)
`358 (23.4)
`313(19.8)
`30 Days
`T Alt patients were also treated with aspirin 100 to 325 mg per day.
`2 Evaluation limcpoinls are after initiation of treatment. Therapy continued for up to S.days (median duration of 2.6 days).
`
`1.2
`3.3
`3.6
`
`0.120
`0.017
`0.014
`
`The combined incidence of dealh or myocardial infarction at all time points was lower for Lovenox Injection compared to
`standard heparin therapy, but did not achieve statistical significance. The efficacy data are provided below.
`
`i
`
`0018
`
`

`

`NDA 20-164^8-036
`Page 10
`
`Redaction
`<%)
`
`p Value
`
`Eincacy of Loveuox Injection to tbe ProphyHxb ofltcliemlc Complications In Unstable Angina and Non-Q-Wave
`Myocardial Infarction
`i Combined End point of Death or Myocardial Infarction)
`1
`Doting Regimen
`Loveaoi In).
`Heparin
`) mg