CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`
`APPLICATION NUMBER:
`22-272
`22-272
`
`
`
`APPLICA TION NUMBER:
`
`OTHER REVIEW(S)
`OTHER REVIEW! S!
`
`
`
`
`
`

`

`MEMORANDUM: DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC
`HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`DATE:
`
`TO:
`
`
`
`08-MAR-2010
`
`N 22272 File for OxyContin® (oxycodone
`hydrochloride controlled-release) Tablets
`
`
`FROM:
`
`Craig M. Bertha, Ph.D.
`Chemistry Reviewer
`ONDQA, Division I, Branch II
`
`THROUGH: Prasad Peri, Ph.D.
`
`
`Acting Branch Chief
`
`
`ONDQA, Division I, Branch II
`
`SUBJECT: Review of CMC-related labeling revisions in the 24-FEB-2010, amendment of
`N22272
`
`
`BACKGROUND: After review of the 04-FEB-2010, labeling amendment to N22272, the CMC
`team sent two comments to the applicant regarding the labeling. The 24-FEB-2010, amendment
`is a response to these comments and is the subject of this review.
`
`EVALUATION:
`
`Agency Comment 1
`Revise the DESCRIPTION section of the labeling to state that the new OxyContin
`formulations
`
`
`
`
`
`.
`
`
`Summary of Applicant Response
`The applicant has chosen the alternative and has removed the statement from the DESCRIPTION
`section altogether.
`
`Evaluation: Adequate.
`
`Agency Comment 2
`For each strength of the drug product, revise and resubmit the mock-ups of the bottle
`labels such that it is clear where the lot number and expiration date will be located.
`Although the location had been clear in earlier versions of the bottle labels, it is not clear in
`the latest version supplied with the February 4, 2010, amendment.
`
`(b) (4)
`
`

`

`NDA 22272
`
`
`Review of Labeling Revisions
`
`p. 2
`
`
`
`Summary of Applicant Response
`The location of the lot number and the expiration date are now clear on the labels. The label for
`the 10 mg strength is reproduced below as an example to illustrate the placement.
`
`
`
`
`Evaluation: Adequate.
`
`Recommendation
`NAI. The CMC team has no further comments on the labels/labeling.
`
`
`
`
`________________________
`Craig M. Bertha, Ph.D.
`Chemistry Reviewer
`
`
`
`
`cc:
`Orig. NDA 22-272
`C.Bertha/ONDQA//Reviewer/3/8/10
`PPeri/ONDQA/Acting Branch Chief________________
`DChristodoulou/ONDQA/PAL
`LBasham/DAARP/Regulatory PM
`
`
`

`

`Application
`Type/Number
`--------------------
`NDA-22272
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`PURDUE PHARMA
`INC
`
`------------------------------------------
`OXYCONTIN
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`CRAIG M BERTHA
`03/08/2010
`
`PRASAD PERI
`03/08/2010
`I concur
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`
`
`September 29, 2009
`Bob Rappaport, MD, Director
`Division of Anesthesia, Analgesia and Rheumatology Products
`Kristina C. Arnwine, PharmD, Team Leader
`Denise P. Toyer, PharmD, Deputy Director
`Division of Medication Error Prevention and Analysis (DMEPA)
`Loretta Holmes, BSN, PharmD, Safety Evaluator
`Division of Medication Error Prevention and Analysis (DMEPA)
`Container Label Review
`OxyContin (Oxycodone Hydrochloride Controlled-Release) Tablets
`10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, and 80 mg
`NDA 22-272
`Purdue Pharma L.P.
`2009-717
`
`Date:
`To:
`
`Through:
`
`From:
`
`Subject:
`Drug Name:
`
`Application Type/Number:
`Applicant:
`OSE RCM #:
`
`
`
`
`
`

`

` 1
`
`
`INTRODUCTION
`This review is written in response to a request from the Division of Anesthesia, Analgesia and
`Rheumatology Products for assessment of the container labels for OxyContin (Oxycodone
`Hydrochloride Controlled-Release Tablets).
`OxyContin (NDA 20-553) was approved on December 12, 1995. Due to abuse liability similar to
`morphine, the Applicant has submitted a new NDA. With this new NDA (NDA 22-272), the
`Applicant proposes a reformulated product that is bioequivalent to the currently marketed product
`but more resistant to manipulations that could damage or destroy the control of Oxycodone
`release as compared to the currently marketed product. The reformulated tablets will replace the
`currently marketed OxyContin tablets. Additionally, the new product will have a REMS and
`Medication Guide.
`
`2 METHODS AND MATERIALS
`
`2.1 LABEL AND LABELING RISK ASSESSMENT
`DMEPA used Failure Mode and Effects Analysis (FMEA) in our evaluation of the container
`labels submitted as part of the November 30, 2007 and March 29, 2009 submissions
`(see Appendix B).
`• Container Labels
`o 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 100-count bottles, (submitted on November
`30, 2007)
`o 60 mg and 80 mg, 100-count bottles, (submitted on March 29, 2009)
`
`2.2 AERS SELECTION OF MEDICATION ERROR CASES
`Since OxyContin is a currently marketed product in the U.S., DMEPA conducted a search of the
`FDA Adverse Event Reporting System (AERS) for medication errors associated with its use.
`Errors associated with the use of OxyContin should be taken into consideration when reviewing
`the labels and labeling for this new NDA in order to prevent such errors from occurring with
`these proposed labels after they are introduced into the marketplace. DMEPA searched AERS
`using the High Level Terms “Maladministration” and “Medication Errors”, and the trade name
`“OxyContin” (the active ingredient name “Oxycodone” was not included in the search). The
`search was conducted on August 19, 2009 and retrieved a total of 485 AERS cases. Our search
`was further narrowed by electronically searching these cases for narratives that contained one or
`more of the following terms: wrong strength, look-alike, similar, labels, container, confused, or
`instead.
`The cases identified through this narrowed search were manually reviewed to determine if
`medication errors occurred involving the labels/labeling of OxyContin. Those cases that did not
`describe a medication error were excluded from further analysis. See Appendix A for the results
`of the AERS search.
`
`
`
`
`2
`
`

`

`3 RESULTS
`DMEPA identified twenty-nine (n=29) medication error cases involving wrong drug (n=16),
`wrong strength (n=8), and wrong technique (n=5). See Appendix A.
`
`3.1 WRONG DRUG
`The sixteen wrong drug cases involved confusion with OxyContin and the following products
`Oxycodone (n=9), MS Contin (n=2), Roxicodone (n=1), Percocet (1), Lexapro (n=1),
`Cyclobenzaprine (n=1), and Oxytocin (n=1). The wrong drug medication error cases appear to be
`due primarily to name confusion, overlapping product characteristics and/or similarities between
`the physical appearance and/or the labels and labeling of OxyContin and some of the
`aforementioned products. The three cases involving Lexapro, Cyclobenzaprine and Oxytocin
`involved reports of potential confusion (Lexapro and Cyclobenzaprine) and selection errors when
`using a computerized physician order entry system where the physician chose Oxytocin instead of
`OxyContin. Thus these three cases will not be discussed further.
`Eleven of the OxyContin wrong drug cases involve confusion with immediate-release Oxycodone
`products while two cases involved confusion between OxyContin and the extended-release
`morphine product MS Contin. Some cases did not report causality, however, in some cases
`reporters indicated that name similarity contributed to the wrong drug errors. These names all
`share the letters ‘oxy,’ ‘codone’ or ‘contin’ in their proprietary names and the established name
`“oxycodone” (except for MS Contin which contains morphine). Additionally, all of these
`products are indicated for the treatment of pain and have overlapping strengths and doses which
`compound the potential to confuse the names.
`Although not stated as a contributing factor, Purdue Pharma markets both OxyContin and
`MS Contin and uses a similar trade dress for both product lines. However, the proposed container
`labels for the reformulated OxyContin product look different from those of the currently
`marketed OxyContin product which may decrease the potential for selection errors between these
`two products.
`No regulatory action is indicated at this time. However, DMEPA will continue to monitor the
`wrong drug cases between OxyContin and the aforementioned drugs.
`
`3.2 WRONG STRENGTH
`We identified eight wrong strength cases involving confusion within the OxyContin product line.
`Our review of the container labels and tablet appearance indicate that the strength on the
`OxyContin labels is color-coded to match the color of the corresponding tablet strength. All of
`the colors are different. Although some of the colors may appear similar, the differences are
`more apparent when compared side-by-side. Additionally, the tablet strength is embossed on the
`tablet. However, one case indicated that the font size of the strength presentation is small and this
`was a contributing factor to the medication error. Thus, we will evaluate the prominence of the
`strength presentation on the container labels for the reformulated OxyContin product.
`
`3.3 WRONG TECHNIQUE
`The five wrong technique cases identified involved knowledge deficits with patients, healthcare
`providers, and family members. These cases involved circumstances where the tablets were
`crushed, chewed, or cut to improve administration (e.g., via PEG tube, inability to swallow) of
`the drug. It appears that the providers or patients were unaware that the product should be taken
`whole. The current insert labeling and container labels contain the appropriate warning
`
`
`
`
`
`3
`
`

`

`statements on this issue. However, we will evaluate the prominence of the statement on the
`container labels for the reformulated OxyContin product.
`
`4 RECOMMENDATIONS
`We note that the Applicant did not submit for review the unit dose packaging. We recommend
`that those labels and labeling be submitted for review. Our evaluation of the bulk bottles noted
`areas where information on the container labels can be improved to minimize the potential for
`medication errors. We provide our recommendations for the container labels in Section 4.1
`Comments to the Applicant. We request the recommendations in Section 4.1 be communicated to
`the Applicant prior to approval.
`We would be willing to meet with the Division for further discussion, if needed. Please copy the
`Division of Medication Error Prevention and Analysis on any communication to the Applicant
`with regard to this review. If you have further questions or need clarifications, please contact
`OSE Regulatory Project Manager, Abolade Adeolu, at 301-796-4264.
`
`4.1 COMMENTS TO THE APPLICANT
`1. The 10 mg, 15 mg, 20 mg, 30 mg, and 40 mg statements of strength are presented in a
`pastel color that matches the color of the respective tablet strength. Although the strength
`is outlined in black, the pastel colors are not prominent and make it difficult to clearly
`distinguish the differences between the colors. Make the colors bolder/deeper so that
`they are more easily distinguished from one another. Additionally, increase the size of
`the strength presentation.
`2. Increase the prominence of the “Swallow tablets whole. Do not cut, .....” statement on the
`side panel of the container label.
`3. The labels do not have a Medication Guide statement. We recommend the following
`language dependent upon whether the Medication Guide accompanies the product or is
`enclosed in the bottle/carton:
`a. “Dispense the enclosed Medication Guide to each patient.” or
`b. “Dispense the accompanying Medication Guide to each patient.”
`4. Container Label 60 mg Strength Only
` color is also
`. This
`Both the 60 mg strength and the tablet picture are presented in
` color prominently on
`used in the triangular box on the 80 mg label. Using the same
`the labels for both strengths minimizes the differentiation between the two strengths. We
`recommend you use a different color for the triangular box on the 80 mg label. Ensure
`that this color is not used on any of the other container labels in order to better
`differentiate all of the strengths.
`
`
`
`
`
`
`
`
`
`4
`
`(b)
`(4)
`
`(b)
`(4)
`
`(b)
`(4)
`
`

`

`APPENDICES
`Appendix A: AERS Search Results
`
`Wrong Drug Cases
`DMEPA identified sixteen (n=16) wrong drug cases. These cases are summarized in the chart
`below:
`# of cases Date Report
`Received
`09/21/2007
`
`2
`
`Drug Prescribed Drug Dispensed or
`Administered
`Oxycodone
`
`OxyContin
`
`Causality
`
`Disorganized medication cabinet;
`lack of double check by the
`pharmacist
`Not stated
`Not stated
`Not stated
`Not stated
`Sound-alike names
`Similar names, same strength
`Similar names, packaging, pill size
`and color
`Not stated
`Causality
`
`Not stated
`Not stated
`(3 errors reported). The first five
`letters of the sustained release brand
`(Oxyco) are identical to the first five
`letters of the generic name for both
`products.
`Similarity of the names. The dosage
`form is rarely specified in an order
`and the drug is ordered by its
`generic name.
`Similar appearance, the imprint “10”
`to represent the strength of 10 mg.
`Name similarity
`
`Both used for pain management,
`sometimes prescribed together for
`treatment; similar size, shape, color
`
`02/26/2008
`05/23/2003
`12/20/2004
`02/25/1999
`10/03/2002
`10/09/2008
`03/19/2003
`
`2
`
`1
`1
`1
`1
`
`11/07/2003
`1
`# of cases Date Report
`Received
`06/07/2001
`05/12/2003
`05/12/2003
`
`4
`
`08/14/2003
`
`08/06/2003
`
`02/22/2006
`
`08/20/2008
`
`1
`
`1
`
`1
`
`Oxycodone
`
`OxyContin
`
`MS Contin
`OxyContin
`Oxycodone IR
`Roxicodone
`
`OxyContin
`MS Contin
`OxyContin
`OxyContin
`
`OxyContin
`Percocet
`General or Potential Confusion
`
`General confusion between Oxycodone
`immediate-release and long-acting products
`
`Potential confusion between Lexapro 10 mg
`tablets and OxyContin 10 mg tablets
`Physician meant to select OxyContin from
`the CPOE program but mistakenly selected
`Oxytocin
`Potential confusion between OxyContin
`40 mg and cyclobenzaprine 10 mg (Casdista
`brand)
`
`
`
`
`
`5
`
`

`

`Wrong Strength Cases
`DMEPA identified eight (n=8) cases in which the wrong strength of OxyContin was dispensed.
`These cases are summarized in the chart below:
`
`Strength
`Prescribed
`
`Strength
`Dispensed or
`Administered
`OxyContin 10 mg OxyContin 20 mg
`
`Causality
`
`Not stated
`“Not familiar with product color of tablet or
`label on stock bottle”
`Not stated
`Same size, white color
`
`OxyContin 10 mg and 20 mg tablets
`confused
`OxyContin 10 mg OxyContin 40 mg Not stated
`OxyContin 10 mg OxyContin 80 mg
`Identical except for strength which is in a
`small font
`OxyContin 20 mg OxyContin 80 mg Not stated
`OxyContin 40 mg OxyContin 80 mg Not stated
`
`Date Report
`Received
`
` #
`
` of
`cases
`
`12/31/2001
`06/12/2002
`
`05/25/2004
`03/26/2001
`
`06/12/2001
`03/19/2003
`
`01/06/2004
`01/03/2006
`
`3
`
`1
`
`1
`1
`
`1
`1
`
`
`Wrong Technique Cases
`DMEPA identified five (n=5) cases in which OxyContin was administered by the wrong
`technique. These cases are summarized in the chart below:
`
`Date Report
`Received
`04/19/2000
`
`11/18/2004
`
`04/22/2003
`10/29/2003
`
`Technique Used
`
`Causality
`
`OxyContin crushed
`
`
`OxyContin chewed
`
`OxyContin was ordered. Patient had a PEG tube. No suffix
`like XR, SR, CD etc. in the name to identify the product as a
`controlled-release product.
`Patient’s sister crushed the OxyContin and mixed with
`applesauce because of the patient’s declining ability to
`swallow.
`Confusion due to disease state.
`Accidental. Patient thought he was chewing a different
`tablet.
`Patient cut tablets in order to make the medication last
`longer.
`
`02/22/2006
`
`OxyContin cut
`
`
`
`6
`
` #
`
` of
`cases
`2
`
`2
`
`1
`
`
`
`
`
`
`
`
`
`

`

`
`Appendix B Container Labels
`
`
`
`
`
`
`
`
`
`
`
`
`7
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`LORETTA HOLMES
`09/29/2009
`
`KRISTINA C ARNWINE
`09/29/2009
`
`DENISE P TOYER
`09/29/2009
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`
`
`August 31, 2009
`Bob A. Rappaport, MD, Division Director
`Division of Anesthesia, Analgesia, and Rheumatology
`Products
`Jodi Duckhorn, MA, Team Leader
`Division of Risk Management
`Sharon R. Mills, BSN, RN, CCRP
`Patient Labeling Reviewer
`Division of Risk Management
`DRISK Review of Patient Labeling (Medication Guide)
`OxyContin (oxycodone hydrochloride controlled-release)
`Tablets
`NDA 22-272
`
`Purdue Pharma L.P.
`2009-788
`
`
`
`Date:
`To:
`
`Through:
`
`From:
`
`Subject:
`Drug Name(s):
`
`Application
`Type/Number:
`Applicant/sponsor:
`OSE RCM #:
`
`
`

`

`1
`
`INTRODUCTION
`This review is written in response to a request by the Division of Anesthesia,
`Analgesia, and Rheumatology Products (DAARP) for the Division of Risk
`Management (DRISK) to review the Applicant’s proposed Medication Guide (MG)
`for OxyContin (oxycodone hydrochloride controlled-release). Please let us know if
`DAARP would like a meeting to discuss this review or any of our changes prior to
`sending to the Applicant. The proposed REMS is being reviewed by DRISK and will
`be provided to DAARP under separate cover.
`
` MATERIAL REVIEWED
`(cid:131) Draft OxyContin (oxycodone hyrdrochloride controlled-release) Tablets
`Prescribing Information (PI) submitted March 30, 2009, revised by the Review
`Division throughout the current review cycle, and provided to DRISK on August
`7, 2009.
`(cid:131) Draft OxyContin (oxycodone hyrdrochloride controlled-release) Tablets
`Medication Guide (MG) submitted on July 27, 2009.
`
` RESULTS OF REVIEW
`In our review of the MG, we have:
`simplified wording and clarified concepts where possible
`•
`•
`ensured that the MG is consistent with the PI
`•
`rearranged information due to PLR formatting
`•
`removed unnecessary or redundant information
`•
`ensured that the MG meets the Regulations as specified in 21 CFR 208.20
`•
`ensured that the MG meets the criteria as specified in FDA’s Guidance for
`Useful Written Consumer Medication Information (published July 2006)
`Our annotated MG is appended to this memo. Any additional revisions to the PI
`should be reflected in the MG.
`
` 2
`
` 3
`
`
`Please let us know if you have any questions.
`
`
`
`
`
`
`1
`
`23 pp withheld in full immed. after this page as (b)(4) Draft Labeling.
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SHARON R MILLS
`09/01/2009
`
`JODI M DUCKHORN
`09/02/2009
`
`

`

`
`
`SEALD LABELING REVIEW
`
`
`
`APPLICATION NUMBER
`APPLICANT
`DRUG NAME
`
`SUBMISSION DATE
`SEALD REVIEW DATE
`SEALD REVIEWER(S)
`
`
`NDA 22-272
`Purdue Pharma
`
`OxyContin (oxycodone hydrochloride controlled-release)
`March 31, 2009
`August 13, 2009
`Jeanne M. Delasko, RN, MS
`
`36 pp withheld in full immed. after this page as (b)(4) Draft Labeling.
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JEANNE M DELASKO
`08/14/2009
`SEALD comments sent to DARRP 8/13/09
`
`LAURIE B BURKE
`08/17/2009
`
`

`

`DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service
`
`
`Pediatric and Maternal Health Staff
`Office of New Drugs
`Center for Drug Evaluation and Research
`Food and Drug Administration
`Silver Spring, MD 20993
`Tel 301-796-0700
`FAX 301-796-9744
`
`
`Maternal Health Team (MHT) Review
`
`
`
`
`
`Date:
`
`From:
`
`June 18, 2008
`
`Date Consulted: March 27, 2008
`
`Richardae Araojo, Pharm.D.
`Regulatory Reviewer, Pediatric and Maternal Health Staff
`
`Karen Feibus, MD
`Medical Team Leader, Pediatric and Maternal Health Staff
`
`
`Through:
`
`
`
`
`
`
`To: Division of Analgesia, Anesthesia, and Rheumatology Products (DAARP)
`
`Drug: OxyContin (oxycodone) Controlled-Release Tablets (NDA 22-272)
`
`Subject:
`
`Materials
`Reviewed: Relevant data submitted in NDA 22-272, Pharmacology/Toxicology Review for
`NDA 22-272, Reprotox, TERIS-The Teratogen Information System, Shepard’s
`Catalog of Teratogenic Agents, and the National Library of Medicine’s Drug and
`Lactation Database on oxycodone. Other published reports and references as
`cited.
`
`
`
`
`Lisa Mathis, MD
`Associate Director, Pediatric and Maternal Health Staff
`
`Pregnancy and Lactation Human Data for Oxycodone
`
`
`Consult Questions:
`1. Review of nonclinical data with oxycodone suggests that there are no clear signals for
`embryo-lethal or teratogenic effects supporting the current classification as Pregnancy
`Category B. All other opioids are designated Pregnancy Category C due to either lack of
`any data and/or evidence of embryo-lethal and/or teratogenic effects. Are there any data
`in the clinical realm that would suggest that oxycodone is safer to use during pregnancy
`than other opioids?
`
`
`
`

`

`DAARP Oxycodone Consult
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`2. Are there any new clinical data for oxycodone or opioids in general that should be
`included in the Labor and Delivery, Nursing Mothers, or Pregnancy sections of the
`current oxycodone label?
`
`3. Major malformations involving the heart or lungs have been observed in one study in a
`few offspring of rats treated with oxycodone during gestation. It is not clear whether
`these malformations are spontaneous background occurrences or if they are treatment-
`related. Are there any clinical data that would shed light on whether these findings in the
`rat are biologically relevant?
`
`
`
`
`
`
`EXECUTIVE SUMMARY
`The Division of Anesthesia, Analgesia, and Rheumatology Products (DAARP) is reviewing a
`New Drug Application for reformulated OxyContin (oxycodone hydrochloride) Controlled-
`Release Tablets (NDA 22-272). Oxycodone is a pure μ opioid receptor agonist and is indicated
`for the management of moderate to severe pain when a continuous, around-the clock analgesic is
`needed for an extended period of time. The new OxyContin formulation was developed by
`Purdue Pharma, L.P. to provide improved resistance to physical and chemical alterations
`(crushing and chemical extraction) of OxyContin that are considered common forms of non-
`medical use and abuse of the current formulation.
`
`As part of NDA 22-272, the sponsor submitted final study reports from Segment I and Segment
`III reproductive toxicology studies. Data from the Segment III study revealed an unusual finding
`of visceral malformations involving the heart and lungs in rat offspring exposed to oxycodone
`during gestation. The sponsor attributed these findings to maternal toxicity and spontaneous
`events. Following review of these data, the DAARP Pharm/Tox review team concurred with the
`sponsor’s conclusions that the Segment I and III studies conducted by the sponsor did not reveal
`an increased risk of teratogenicity or developmental abnormalities. Based on these animal
`findings, DAARP consulted the MHT to determine if there are human data on the fetal effects of
`oxycodone exposure during pregnancy and lactation.
`
`To determine if new clinical data exists on the fetal effects of oxycodone exposure during
`pregnancy or nursing, the MHT performed a literature search and found that there are limited
`human data on the fetal effects of oxycodone exposure during pregnancy. However, based on
`available human data, oxycodone does not appear to be associated with an increased risk of
`congenital anomalies. In addition, animal reproduction and developmental toxicology studies
`have revealed no evidence of harm to a developing fetus. Therefore, OxyContin is labeled as a
`pregnancy category B due to lack of adequate and well controlled studies in pregnant women
`and negative animal studies.
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`It is important to note that while OxyContin is labeled as pregnancy category B, we cannot
`conclude that it is safer than all other opioids when used during pregnancy. Some opioids are
`labeled as pregnancy category C simply because they lack both human and animal data.
`However, current human data on oxycodone exposure during pregnancy do not suggest an
`increased risk of congenital anomalies and animal data findings do not support a category
`change.
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`In addition, there are limited data on the effects of oxycodone exposure during breastfeeding.
`Based on available data, oxycodone is secreted into human milk. Infants exposed to oxycodone
`during pregnancy and breastfeeding may experience neonatal abstinence syndrome and should
`be monitored closely. Infants should also be monitored for excess sedation and respiratory
`depression.
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`Published data are important to include in product labeling to facilitate well informed
`risk/benefit decision making by patients and their healthcare practitioners when medicine is
`needed during pregnancy and lactation. Available data on drug use during pregnancy and
`lactation is limited to post-marketing experience since pregnant and lactating women are usually
`excluded from pre-marketing clinical trials. Label revisions suggested by MHT are intended to
`enable well informed and judicious use of oxycodone during pregnancy and lactation and are not
`intended to support approval of this application.
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`RECOMMENDATIONS
`1. OxyContin should remain pregnancy category B. The MHT recommended revisions to
`the sponsors proposed labeling are provided on pages 19-22 of this review.
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`BACKGROUND
`The Division of Anesthesia, Analgesia, and Rheumatology Products (DAARP) is reviewing a
`New Drug Application for reformulated OxyContin (oxycodone hydrochloride) Controlled-
`Release Tablets (NDA 22-272). Oxycodone is a pure μ opioid receptor agonist and is indicated
`for the management of moderate to severe pain when a continuous, around-the clock analgesic is
`needed for an extended period of time. The new OxyContin formulation was developed by
`Purdue Pharma, L.P. to provide improved resistance to physical and chemical alterations
`(crushing and chemical extraction) of OxyContin that are considered common forms of non-
`medical use and abuse of the current formulation.
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`There is limited human data on the effects of oxycodone in pregnancy and animal reproduction
`studies revealed no evidence of teratogenicity. Therefore, the current formulation of OxyContin
`is labeled as pregnancy category B. However, as part of NDA 22-272, the sponsor submitted
`final study reports from Segment I and Segment III reproductive toxicology studies. Data from
`the Segment III study revealed an unusual finding of visceral malformations involving the heart
`and lungs in rat offspring exposed to oxycodone during gestation. The sponsor attributed these
`findings to maternal toxicity and spontaneous events.
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`Based on the animal findings described above, DAARP consulted the MHT to determine if there
`are human data on the fetal effects of oxycodone exposure during pregnancy. In addition,
`DAARP would like MHT to provide any relevant new clinical data for the Labor and Delivery
`and Nursing Mothers subsections of labeling.
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`REVIEW OF DATA
`This review responds to specific consult questions from DAARP and discusses relevant data
`included in the pharmacology/toxicology review for NDA 22-272. In addition, this review
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`provides revisions to the sponsor’s proposed Pregnancy, Labor and Delivery, and Nursing
`Mothers subsections of labeling.
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`Animal Data
`In support of this application, the sponsor submitted final study reports from Segment I and
`Segment III reproductive and developmental toxicology studies. Data from the Segment III
`study revealed an unusual finding of visceral malformations involving the heart and lungs in two
`male high dose pups from different rat litters treated with oxycodone. The heart defects were
`described as, “major vessels: aorta descends to the right side of the heart and intraventricular
`septal defect, cranial ¼.” The lung malformations were described as, “accessory lung lobe
`absent and lung lobes fused on the right side.” The incidence of these malformations were above
`historical controls. The sponsor attributed these findings to maternal toxicity and spontaneous
`events. A similar heart and lung malformation was observed in one F2 generation female pup
`from the low dose group. The sponsor concluded that these findings were not dose dependent
`and not related to treatment. Following review of these data, the DAARP Pharm/Tox review
`team concurred with the sponsor’s conclusions that the Segment I and III studies conducted by
`the sponsor did not reveal an increased risk of teratogenicity or developmental abnormalities.
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`Reviewer comment:
`Please see the pharmacology/toxicology review by Dr. Elizabeth Bolan for a detailed analysis of
`the reproductive and developmental toxicity studies submitted in support of this application.
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`Response to Consult Questions
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`1. Review of nonclinical data with oxycodone suggests that there are no clear signals for
`embryo-lethal or teratogenic effects supporting the current classification as Pregnancy
`Category B. All other opioids are designated Pregnancy Category C due to either lack
`of any data and/or evidence of embryolethal and/or teratogenic effects. Are there any
`data in the clinical realm that would suggest that oxycodone is safer to use during
`pregnancy than other opioids?
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`Response: Many opioids are labeled as pregnancy category C because they lack adequate
`and well controlled studies in pregnant women, and animal reproduction studies have not
`been conducted or animal reproduction studies revealed adverse fetal effects. Examples of
`category C drugs that lack human data and have positive animal data include methadone,
`codeine, morphine, hydrocodone, and hydromorphone.
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`There are limited human data on the fetal effects of oxycodone exposure during pregnancy.
`However, based on available human data, oxycodone does not appear to be associated with
`an increased risk of congenital malformations. As stated in product labels, infants exposed to
`opioids in utero may experience neonatal abstinence syndrome (NAS) or drug withdrawal
`depending on the timing of maternal opiate use and amount of drug used during pregnancy.
`Clinical features of NAS include neurologic excitability, gastrointestinal dysfunction,
`increased sweating, fever, nasal stuffiness, mottling, and temperature instability.1
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`1 American Academy of Pediatrics, Committee on Drugs. Neonatal Drug Withdrawal. Pediatrics. June 1998: 101
`(6); 1079-1088.
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`To determine if new clinical data exists on the fetal effects of oxycodone exposure during
`pregnancy, a PubMed search of the literature was performed using the following search
`terms:
`• Oxycodone and pregnancy
`• Oxycodone and fetus
`• Oxycodone and neonate
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`In addition, the following sources were used to gather information on oxycodone exposure
`during pregnancy:
`• TERIS-The Teratogen Information System
`• Reprotox
`• Shepard’s Catalog of Teratogenic Agents
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