CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-304
`
`SUMMARY REVIEW
`
`

`

`“IZOIO‘B
`
`11(4)
`
`Summary Basis for Regulatory Action _
`
`3 November 20, 2008
`Curtis J'Rosebraugh, MD, MPH ,
`
`Director, Office of Drug Evaluation II
`Surmnary_Review
`Subject
`
`NDA/BLA #
`IV C
`j
`.
`Supp #
`
`A licant Name
`. Johnson & Johnson Pharmaceutical Research & Develo ment
`Proprietary /
`TBD
`Established
`Tapentadol
`SA E 1 Names
`Dosage Forms /
`Strength
`Proposed
`Indicatimgs)
`Action:
`
`
`
`Tablet
`50 m , 75 mg,_100 mg
`1. Relief of moderate to severe acute pain
`
`1.
`
`Introduction and Discussion
`
`This review will be a brief summary of the basis for the regulatory action regarding tapentadol
`and the reader should refer to the reviews in the action package for a more detailed discussion.
`Tapentadol is a mu opioid agonist and also has norepinephrine'reuptake inhibitor activity.
`Tapentadol is structurally related to tramadol and has similar pharmacological actions,
`however tapentadol has demonstrated abuse liability similar to hydrornorphone. This will
`require scheduling for tapentadol (schedule 11) unlike tramadol which is not scheduled.
`
`As detailed in Drs. Shibuya, Fields, Rappaport and Norton’s reviews, tapentadol has
`demonstrated efficacy in replicated adequate clinical trials. The safety profile appears typical
`for an opioid agent and also similar to tramadol in certain aSpects.’ As such, if agreements can
`be made regarding labeling, I will recommend an approval action.
`
`Efficacy
`
`This has been thoroughly covered in Drs. Shibuya, Fields and Norton’s reviews and I will not
`elaborate on their reviews. The evaluation for efficacy was demonstrated in two studies, 32
`and 33. Study 32 was conducted in bunionectomy subjects evaluated with a Summed Pain
`Intensity Difference over 48 hours (SPID48). This study demonstrated clear efficacy, dose
`response and was supported by secondary endpoints.
`
`Study 33 was conducted in subjects with degenerative joint disease of the hip or knee with
`efficacy evaluated by a SPID-S days. Efficacy was again demonstrated and supported by
`secondary endpoints, although there was not demonstration of a dose response.
`
`

`

`am
`
`The safety profile for tapentadol is similar to other opioids and to tramadol. The most
`common AEs as stated in Dr. Shibuya’s review are those typical of an opioid and were nausea,
`dizziness, vomiting, somnolence, constipation and pruritus.
`
`There are other safety concerns to be considered and the product should have labeling to
`reflect these concerns and uncertainties. Seizures were observed in rats at high doses and in
`dogs at clinically relevant doses. During clinical trials, there was one case in which a Phase I
`study participant had a seizure, but this was confounded as discussed in Dr. Shibuya’s review.
`I note that subjects at risk for seizures were excluded from the trials and labeling should reflect
`this concern and uncertainty regarding how subjects at risk may react if given tapentadol.
`
`Another safety concern is in regard to the norepinephrine reuptake activity of this NME as this
`activity poses a concern of possible serotonin syndrome if used concomitantly with MAOIs,
`SSRIs etc.
`I also note that drug combinations which may pose an interaction problem were
`prohibited in the clinical trials and this should also be reflected in labeling.
`
`Finally, abuse liability studies demonstrated liability similar to hydromorphone. This has
`sparked interest in requiring a medication guide. This probably has merit as it should be
`instructed that, even though this is similar to tramadol, it has much greater abuse liability
`issues.
`.
`
`Conclusions and Recommendations
`
`Tapentadol has demonstrated efficacy for the relief of moderate to severe pain. It also has a
`safety profile that has both the characteristics of a typical opioid and tramadol. Tapentadol has
`the risks briefly outlined above, and labeling should reflect these concems. Tapentadol was
`not taken to an Advisory Committee meeting as there are several previously approved agents
`in the opioid class of drugs and evaluation ofthe safety data did not reveal particular safety
`issues unexpected for this class or of tramadol—like agents. Additionally, design and results of
`the efficacy trials did not pose particular concerns. I agree that a medication guide is probably
`appropriate for tapentadol.
`
`I.believe, that with proper labeling, the risk: benefit considerations of tapentadol would allow
`marketing. As such, I recommend an Approval action if proper labeling can be negotiated
`with the sponsor.
`~
`
`APPEARS THlS WAY
`
`ON ORlGlNAL
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Curtis Rosebraugh
`11/20/2008 04:20:21 PM
`MEDICAL OFFICER
`
`

`

`anoi°8
`
`o"
`
`.D‘P'i
`
`j‘ 4
`
`(“EH
`”"3"
`
`.
`FDA CENTER FOR DRUG EVALUATION AND RESEARCH
`DIVISION OF ANESTHESIA, ANALGESIA, AND RHEUMATOLOGY PRODUCTS
`
`
`Summary Review for Regulatory Action
`
`
`November 16, 2008
`Bob A. Rappaport, M.D.
`_ Director
`Division of Anesthesia, Analgesia and Rheumatology
`
`Products
`
`
`
`Division Director Summa Review
`
`
`
`Johnson & Johnson Pharmaceutical Research &
`Develoment, L.L.C.
`'
`
`January 22, 2008
`Date of Submission
`
`PDUFA Goal Date
`November 23, 2008
`Proprietary Name /
`N/A
`
`Established
`SAN Name
`Tagnadol hydrochloride
`
`and 100 m_
`Dosage Forms / Strength
`Immediate-release tablets, 50 m ,
`Pro nosed Indication
`For the relief of moderate to severe acutgpain
`Recommended Action:
`A roval
`
`Applicant Name
`
`‘
`
`

`

`Ellen Fields, M.D.
`Jonathan Norton, Ph.D.; Dionne Price, Ph.D.; Thomas
`Permutt, Ph.D.
`Kathleen Youn, Ph.D.; Adam Wasserman, Ph.D.
`John C Hill, Ph.D.; Ali Al-Hakim, Ph.D.; Blair Fraser,
`Ph.D.
`'
`N/A
`
`David Lee, Ph.D.; Suresh Doddaaneni, Ph.D.
`Michelle Safarik, PA-C
`Antoine El-Hae, Ph.D.; Constance Lewin, MD.
`Robert B. Shibu a, MD.
`Laura Pincock, Pharm.D.; Kellie Taylor, Pharm.D.,
`M.P.H.; Carole Holuist, R.Ph.
`
`Gita Akhavan-Toyserkani, Pharm.D.; Mary Dempsey;
`Claudia Karwoski, PharmD.
`
`Material Reviewed/Consulted
`0ND Action Packae, includin_:
`Medical Officer Review
`Statistical Review
`
`
`
`Pharmacolo Toxicolo_ Review
`CMC Review
`
`Microbiolo Review
`
`.
`
`Clinical Pharmacolog Review
`DDMAC .
`DSI
`.
`CDTL Review
`
`OSE/DMEPA
`
`OSE/DAEA
`
`OSE/DRISK ~
`
`'
`OSE/DEPI
`.
`OND=Offrce ofNew Drugs
`_ DDMAC=Division of Drug Marketing, Advertising and Communication
`OSE= Office, of Surveillance and Epidemiology
`DMEPA=Division ofMedication Error Prevention and Analysis
`DSI=Division of Scientific Investigations
`DRISK= Division of Risk Management
`DAEA=Division of Adverse Event Analysis
`CDTL=Cross-Discipline Team Leader
`DEPI= Division of Epidemiology
`
`,
`
`
`
`
`
`
`
`
`
`1. Introduction
`
`Tapentadol HCl is a weak u—opioid agonist and norepinephrine reuptake inhibitor developed
`for the treatment of acute, moderate to severe pain. Tapentadol is structurally similar to
`tramadol and has similar pharmacological properties. This product is an immediate-release
`fg_rr_nulation of tapentadol. C _
`l:
`
`j
`
`J
`
`M4)
`
`Tapentadol
`Division Director Review and Summary Basis for Approval Action Recommendation
`November 16, 2008
`
`N 22-304
`
`2
`
`

`

`2. Background
`
`The sponsors had numerous interactions with the Agency during development. Agreement
`was reached on study design, study length, the statistical analysis plan, and the level of risk
`mitigation necessary for this novel opioid. Some of the efficacy studies included oxycodone
`as an active comparator. This was done primarily
`_
`
`The sponsor has asked that the product be controlled underj
`1::
`Schedule H ofthe Controlled ubstances Act and that routine pharmacovigilance be the only
`additional risk mitigation strategy employed to address abuse liability. Based on the relatively
`low potency of the product and the fact that it is an immediate—release formulation, extensive '
`risk management strategies to address abuse have not been required. However, a REMS was
`required due to the need for a MedGuide to inform patients of the risks associated with the use
`of this product.
`
`3. CMC
`
`jThe synthetic
`The formulation consists offilm-coated tabletsl/
`and manufacturing processes were determined tfi’be robust by Dr. Hill. The different strengthbM)
`are g:
`:1 The release specifications have been determined to be
`acceptable by the CMC review team. The stability data support an expiration dating of 18
`months. The sponsor has agreed to continue stability testing to more firmly establish their
`proposed shelf life.
`
`4. Nonclinical Pharmacology/Toxicology
`
`The nonclinical studies of tapentadol demonstrated notable toxicities including:
`
`o
`0
`
`o
`
`convulsions in both rats and dogs,
`dose-related elevations in transaminases, alkaline phophatase and liver weights, with
`heptocellular hypertrophy and one instance of hepatic necrosis, and
`hERG channel inhibition at concentrations far greater than the maximum human dose,
`but with QT prolongation in both in vivo and in vitro pharmacology studies in dogs
`also at high doses.
`
`Subjects at risk for the development of seizures were excluded from the clinical studies based
`on the findings in the animal studies.
`
`Tapentadol did not demonstrate mutagenicity or clastogenicity in the Ames and mouse
`micronucleus tests, but the results of a CHO assay were equivocal. A two-year carcinogenicity
`study was, however, negative. While some fetal malformations were noted in the Segment II
`(Embryofetal Development) Study, Drs. Young and Wasserman concur with the sponsor that
`these abnormalities were due to maternal toxicity and not to a direct teratogenic effect of
`
`N 22-304
`
`3
`
`Tapentadol
`Division Director Review and Summary Basis for Approval Action Recommendation
`November 16, 2008
`
`

`

`tapentadol. No other significant abnormalities were documented in the reproductive
`toxicology studies.
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`The proposed dosing regimen is 50 mg, 75 mg or 100 mg every 4 to 6 hours, with a single ,
`extra dose one hour following the first dose (a “reload” dose per the protocol). The sponsor
`submitted nine biopharmaceutics and twenty-two clinical pharmacology studies. The Clinical
`Pharmacology review team has determined that this product is BCS Class I. The product is .
`dose linear for all doses and the oral bioavailability is 32% fasted and 42% fed. The t1/2 is ~4.3
`hours. Approximately 97% of the drug is metabolized in Phase 2 conjugation and excreted in
`the urine within 24 hours. The metabolites are not pharmacologiCally active and no relevant
`CYP interactions were demonstrated. Nor were there any clinically relevant
`pharmacodynamic interactions foimd in studies of tapentadol administered concomitantly with
`metoclopramide, omeprazole, probenecid, naproxen, ASA and APAP.
`
`\
`
`A Thorough QT Study demonstrated no QT prolongation. Pharmacokinetic parameters were
`similar between elderly and young adults, and there were no differences between Japanese and
`non-Japanese subjects. Cmax and AUC values were ~20% higher in women than men, but this
`difference was no longer apparent after normalization for body weight. The Cmax and AUC of
`tapentadol increased to a moderate degree with mild to moderate hepatic impairment, as did
`the tug. Renal impairment did not affect the pharmacokinetics of tapentadol. While increasing
`renal impairment did result in increases in the Cmax and AUC of the tapentadol-O-glucuronide
`metabolite, this metabolite is pharmacologically inactive.
`
`6. Clinical Microbiology
`
`No clinical microbiology data were necessary for this application.
`
`7. ClinicallStatistical-Efficacy
`
`The sponsor has submitted two studies to provide evidence of the efficacy of tapentadol, Study
`32 and Study 33. Both studies were randomized, double-blind, active— and placebo-controlled,
`parallel-group trials comparing various doses of tapentadol to oxycodone and placebo. Study
`32 was performed in patients with at least moderate pain following bunionectomy. If
`sufficient pain was reported within 9 hours post-surgery, the subjects were randomized and
`treated for 72 hours as inpatients with tapentadol 50 mg, 75 mg or 100 mg every 4 to 6 hours,
`or to oxycodone 15 mg or placebo every 4 to 6 hours. A single “reload” dose was allowed one
`hour after the first dose, but no rescue medication was permitted. The primary outcome
`analysis was the Summed Pain Intensity Difference over 48 hours (SPID48), based on the
`results of pain assessments employing an 11-point numerical rating scale. Missing data were
`imputed using an LOCF methodology. The, results of the primary outcome analysis are
`summarized in the following table reproduced from page 36 of Dr. Field’s review:
`
`N 22-304
`Tapentadol
`Division Director Review and Summary Basis for Approval Action Recommendation
`November 16, 2008
`'
`
`‘
`
`4
`
`

`

`Table 12: Descriptive Statistics and Pairwise Comparison of SPID48 Using Hochberg
`
`\
`ProcedurejPrimary Analysis, LOCF
`,
`Tapentadol 1R
`Tapentadol 1R
`Tapentadol IR Oxycodone HCl IR
`Placebo
`50 mg
`75 mg
`100 mg
`15 mg
`
`(N=120)
`(N=119)
`'
`(N=l20)
`(N=118)
`(N=125)
`0—48 Hours
`
`Mean (SD)
`Median
`(Range)
`
`24.5 (120.93)
`43 .4
`(-278;274)
`
`119.1 (125.86)
`127.6
`.
`(433402)
`
`139.1 (118.93)
`131.3
`(—199;462)
`
`167.2 (98.99)
`158.5
`(-94;408)
`
`172.3 (110.86)
`170.6
`(-190:431)
`
`LS Means (ditf
`fi'om placebo)
`95% CI
`
`--
`
`--
`
`88.2
`
`113.5
`
`141.4
`
`142.4
`
`60.71 to 115.59
`
`86.1210 140.81
`
`113.98 to 168.90
`
`115.2810 169.47
`
`--
`
`<0.001
`
`Adjusted p-valne
`vs. placebo8
`Based on analysrs of covariance model With factors of treatment, center, and baseline pain mtensny as a
`covariate. Adjusted p-values using Hocliberg procedure. Oxycodone group is not included.
`CSR R331333-PAI-3003 (KF5503/32), p. 86
`
`<0.001 '
`
`<0.001
`
`All of the secondary analyses of the primary endpoint, including use of a BOCF imputation
`strategy, were supportive of the primary outcome. The secondary outcome measures were also
`supportive. The cumulative response curve below has been reproduced from page 40 of Dr.
`Field’s review;
`
`Figure '4: Cumulative Distribution of Responders at 48 Hours
`:00 ~
`
`
`aqua-0:; vamp, mama m
`cusses soumu 1mm":
`
`
`
`
`Cumulatiw%ofSubj.Mmpanse
`
`no ~
`
`ms .
`
`(.0 1
`
`:80
`
`40 ,.
`
`1m ~
`
`:20 ‘
`
`m .
`
`oxymmmw I 3' mg
`
`I
`‘
`
`.
`
`
`
`tar—on
`-
`.
`M» reduction In pain intcvsxity From baseline at 48 hours
`
`:smu
`
`Source: . CSR R33l333-PAI-3003 (KF5503/32), p. 90
`Source: . CSR R331333-PAI-3003 (KFSSO3/32), p. 90
`
`Tapentadol
`Division Director Review and Summary Basis for Approval Action Recommendation
`November 16, 2008
`
`N 22—304
`
`5
`
`

`

`In Study 33, patients with end-stage osteoarthritis of the hip or knee, who were candidates for
`replacement of the affected joint and who were currently at Step 2 or higher of the WHO Pain
`Ladder (combination opioid/non-opioid analgesic or opioid analgesic), were randomized to 10
`days of treatment with either tapentadol 50 mg or 75 mg (titrated from 50 mg for the first two
`days), or oxycodone 10 mg or placebo, each on an every 4 to 6 hour regimen. No rescue or
`“reload” was permitted. The primary outcome analysis was a 5-Day SPID, based on the
`results of pain assessments employing an 11-point numerical rating scale. Double blind
`dosing was continued, however, for up to ten days to collect more accurate safety data over a
`time period that OA patients may well continue to take this type of product in the
`postmarketing period. The results of the primary outcome analysis are summarized in the
`following table reproduced from page 61 of Dr. Field’s review:
`
`Table 23: Descriptive Statistics and Pairwise Comparison of SPID at Day 5 (LOCF)
`Tapentadol IR Tapentadol IR
`Oxycodone
`5.0 mg
`75 mg
`1101 IR 10 mg .
`(N=153)
`(N=166)
`(N=l71)
`n %)
`n (%)
`n (%)
`
`Placebo
`(N=169)
`n (‘56)
`
`Day 1-5
`N
`Mean (SD)
`Median
`(Range)
`
`166
`153
`169
`130.6 (182.77) 229.2 (228.92) 223.8 (217.76)
`86.6
`164.1
`210.2
`(-3 58;695)
`(-480;881)
`(-308;823)
`
`171
`236.5 (222.82)
`206.7
`(-268;884)
`
`LS Means (diff from placebo)
`95% CI
`Raw p-vnlue
`Adjusted p-value using
`Hochberg
`Source: Clinical sway Report R331333-PA1-3002 (KF5503/33), p. '85
`
`—-
`—-
`--
`—-
`
`111.9
`'
`97.5
`101.2
`54581014789 51.81 to 143.26 66.49 to 157.38
`<0.001
`<0.001
`<0.001
`<0.001
`<0.001
`~-
`
`Again, all of the secondary analyses of the primary endpoint, including use of a BOCF
`imputation scheme, were supportive ofthe primary outcome. However, no dose—response was
`seen between the 50 mg and 75 mg doses in this study.. The secondary outcome measures
`were also supportive. The cumulative response curve below has been reproduced from page
`64 of Dr. Field’s review:
`
`APPEARS THlS WAY
`0N ORIGINAL
`
`N 22-304
`
`6
`
`Tapentadol
`Division Director Review and Summary Basis for Approval Action Recommendation .
`November 16, 2008
`
`

`

`Figure 7: Cumulative Distribution of Responder rates Based on Percent Change from Baseline
`in Pain Intensity at Day 5
`
`Placebo
`' "“ ’ (265503 50ng Base 11?.
`“" “ 605503 75mg Basel IR
`
`""""’“ Oxycodone 10 mg
`
`
`
`Cumulative%ol‘Subj.VV/lfCSpOI‘ISC
`
`"k. 3
`
`‘
`
`9.....11
`
`
` 1;. ~__ "\,""< ,,
`
`
`fi‘ ‘2: L.
`EH “DALE-G
`“a:
`EL.
`“-{IE— -*--—.
`_
`"1
`“ML
`~+=
`1:
`-——.
`_
`at“
`-
`4‘1? x".
`,,,,,,“"—~1_."_‘:£“C2;Z..1:3_~_
`a.“ Lh-‘A-LsN‘
`H
`m‘x
`"1.2.:
`
`ham”:— ————.
`1
`moo
`ease
`mo
`
`Mao
`
`1
`
`_ _fi
`.mao
`
`% reduction in pain intensity from baseline at’Day 5
`
`Source: Clinical Study Report R331333-PAI-3002 (KF5503/33), p. 89
`
`DSI conducted routine inspections and found data irregularities at two clinical sites. However,
`Dr. Norton assessed the data from these two sites and found that they were similar to the data
`from the other sites.
`
`5(4)
`
`A
`
`l
`
`a-
`
`,
`
`--
`
`8. Safety
`
`The safety database for this application consisted of 3,515 subjects treated with one or more
`doses of tapentadol. Most of the subjects were treated for 10 days or less, but 454 patients in
`
`Tapentadol
`Division Director Review and Summary Basis for Approval Action Recommendation
`November 16, 2008
`
`N 22-304
`
`7
`
`

`

`the Phase 2/3 studies were treated for greater than 45 days. There was one death reported in a
`subject treated in an ongoing study of immediate-release tapentadol. Treatment assignment
`- remains blinded for this study; however, this death did not appear to be causally related to the
`study drug. There have been four deaths reported from ongoing studies of the extended-
`release tapentadol product. None of these deaths occurred during treatment and three ofthe
`deaths did not appear to be causally related to study drug. The fourth death, due to cardiac
`arrest, is being further evaluated by the sponsor at this time and the treatment assignment
`remains blinded.
`
`I concur with the following statements from page 13 of Dr. Shibuya’s review:
`
`Dr. Fields reviewed each death, non-fatal serious adverse event, and adverse event
`leading to discontinuation in detail. While some of these events could be reasonably
`attributed to treatment with tapentadol such as ileus, lethargy, etc., none of the deaths,
`serious adverse events, or adverse events leading to discontinuation were [sic]
`unexpected for an opioid agonist used in an acute setting.
`
`With regard to the common AEs, generally, the safety profile is consistent ofthat of an
`opioid agonist with the most common AEs being nausea, dizziness, vomiting,
`somnolence, constipation, and pruritis.
`
`There was one seizure reported in a subject in a Phase 1 study. This subject failed to report a
`history of epilepsy at screening and experienced a generalized tonic—clonic seizure three days
`after a single ISO-mg dose of tapentadol. He later acknowledged having discontinued his
`anticonvulsant medication a few months before entering the study. While there were a small
`number of subjects treated with tapentadol with elevated liver enzymes, the rates of enzyme
`elevation were not above those seen with oxycodone or placebo, and there were no cases of
`enzyme elevations concurrent with clinically relevant bilirubin elevations.
`
`An abuse liability study demonstrated a liability similar to hydromorphone. In a study in
`which subjects were discontinued from treatment without a tapering of dose, a modest
`percentage of the subjects experienced symptoms consistent with withdrawal. There were no
`overdoses and there was no evidence of abuse or diversion during the clinical studies. I concur
`with the clinical review team and the DRISK review team that the abuse risk for tapentadol
`appears to be high and that a Schedule 11 classification is appropriate.
`
`9. Advisory Committee Meeting
`
`This application was not taken before an advisory committee as tapentadol is not a “first—in-
`class” drug and there were no concerning safety signals; nor was there any concern regarding
`the data provided to support evidence of the product’s efficacy.
`
`10.
`
`Pediatrics
`
`The sponsor has requested deferral of pediatric studies until a reasonable safety experience in
`adults has occurred post-marketing. I concur with the review team that this is appropriate.
`
`Tapentadol
`Division Director Review and Summary Basis for Approval Action Recommendation
`November 16, 2008
`
`N 22-304
`
`8
`
`

`

`11.
`
`Other Relevant Regulatory Issues
`
`The initial choice of trade name was rejected by the DMEPA review team due to possible
`name confusion concerns. The product may be approved under the generic name until an
`acceptable trade name has been determined. There are no other unresolved regulatory issues.
`
`12.-
`
`Labefing
`
`The review team proposed a number of labeling changes to the package insert and to the carton
`and container labeling which will need to be resolved prior to approval.
`
`13.
`
`Decision/ActionIRisk Benefit Assessment -
`
`Recommended Regulatory Action
`
`I recommend approval, pending agreement on product labeling.
`
`Risk Benefit Assessment
`
`The sponsor has provided adequate evidence to support the efficacy, safety and
`quality of their product. There appear to be no unusual concerns for this
`product compared to other similar analgesics. The risk of abuse has been
`appropriately addressed as discussed below. The pro-convulsive activity of
`tapentadol does support limitation of the product’s use in at risk patients. I
`concur with Dr. Shibuya that consideration should be given to raising
`“predisposition to seizure” to a Contraindication.
`
`Recommendation for Postmarketing Risk Management Activities
`
`Standard phannacovigilance and a Schedule 11 classification should be adequate
`to mitigate the risk of abuse for this product. Should signals of abuse be found
`postmarketing, more extensive risk management strategies may need to be
`implemented. A REMS has been required due to the need for a MedGuide to
`inform patients of the risks associated with the use of tapentadol.
`
`Recommendation for other Postmarketing Study Commitments
`
`No postmarketing study commitments are required for this application other
`than the pediatric program which will be deferred until a reasonable safety
`profile has been established in adults in the postmarketing period.
`
`'
`
`Tapentadol
`Division Director Review and Summary Basis for Approval Action Recommendation
`November 16, 2008
`
`N 22-3 04
`
`9
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Bob Rappaport
`11/16/2008 06:50:41 PM
`MEDICAL OFFICER
`
`