CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-304
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S) ,
`
`

`

`
`
`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`Date:
`
`To:
`
`Through:
`
`From:
`
`'
`
`November 20, 2008
`
`Bob A. Rappaport, M.D., Director
`Division of Anesthesia, Analgesia, and Rheumatology Products
`
`Claudia Karwoski, PharmD, Director (Acting)
`Division of Risk Management (DRISK)
`
`Jodi Duckhorn, 'M.A., Team Leader
`Patient Labeling and Education Team
`Division of Risk Management (DRISK)
`
`Sharon R. Mills, BSN, RN, CCRP
`Patient Product Information Specialist
`Patient Labeling and Education Team
`Division of Risk Management (DRISK)
`
`Subject:
`'
`
`'
`
`Review of Patient Labeling (Medication Guide) and
`Proposed REMS
`
`Drug Name(s):
`
`Application
`Type/Number:
`
`TRADENAME (tapentadol) immediate release oral tablets
`(CII)
`
`NDA 22-304
`
`Applicant/sponsor:
`
`Johnson & Johnson
`
`OSE RCM #:
`
`2008—1808
`
`

`

`1
`
`INTRODUCTION
`
`This review is written in response to a request from the Division of Anesthesia, Analgesia, and
`Rheumatology (DAARP) for the Patient Labeling and Education Team to review the sponsor’s
`proposed RiskEvaluation and Mitigation Strategy (REMS), which includes the draft Medication
`Guide (MG) prepared by the DAARP and the sponsor’s Timetable for Submission of
`Assessments of the effectiveness of the REMS.
`
`FDA has determined that tapentadol poses a serious and significant public health concern
`requiring the distribution of a Medication Guide. The Medication Guide is necessary for patients’
`safe and effective use of tapentadol. FDA has determined that tapentadol meets two of the three
`triggering criteria for a Medication Guide as set forth in 21 CFR 208.1. Tapentadol is a product
`that has serious risks (relative to benefits) of which patients should be made aware because
`information concerning the risks could affect patients’ decision to use, or continue to use,
`tapentadol. FDA has also determined that tapentadol is a product for which patient labeling could
`help prevent serious adverse events.
`
`2 MATERIAL REVIEWED
`
`0 DRAFT TRADENAME (tapentadol) Professional Information (PI) as revised by the sponsor
`and review division throughout the review cycle, most recently versions dated November 17,
`2008 and November 18, 2008
`
`0 DRAFT TRADENAME (tapentadol) Medication Guide (MG) prepared by the review
`division and including CSS comments, version provided to OSE on November 12, 2008.
`
`0
`
`Proposed REMS, submitted on November 11, 2008 and the Amendment to the Proposed
`REMS, submitted on November 18, 2008.
`
`3 BACKGROUND
`
`Johnson & Johnson submitted an original New Drug Application, NDA 22-304 for
`TRADENAME (tapentadol) immediate-release tablets, on January 22, 2008. TRADENAME
`(tapentadol) is indicated for the relief of moderate to severe acute pain in patients 18 years of age
`or older.
`
`During the review of NDA 22—3 04 it became evident that tapentadol exhibits distinctive
`properties indicating high potential for abuse.
`
`After consultations between the Office of New Drugs and the Controlled Substance Staff, the
`DAARP determined that a REMS is necessary to ensure that the benefits of tapentadol outweigh
`its risks. In reaching this determination the DAARP considered the following:
`
`0 The indication proposed for the formulation in NDA 22-304, treatment of acute moderate
`to severe pain, could result. in millions of prescriptions each year.
`
`0 Moderate to severe pain is considered serious in that untreated pain can lead to physical
`and emotional disability, job loss and suicide.
`
`0
`
`The potential benefit of tapentadol is that it represents the first novel analgesic with mu
`agonist activity in over a decade. Patients often do not respond to or tolerate some
`opioids. Having a novel option could offer pain relief to many patients unable to be
`treated successfully with existing therapies.
`
`

`

`O The duration of treatment is days to months.
`
`0 This product carries all of the risks of an opioid including CNS depression, respiratory
`depression, nausea, vomiting, constipation, along with the possibility of an abuse
`potential that could be comparable or possibly exceed currently available opioid
`analgesics. In a human abuse liability pharmacology study, tapentadol displays an abuse
`potential comparable to that of hydromorphone. However, the duration of the euphoria
`from tapentadol lasted'longer than hydromorphone. For this reason, it stands out in
`comparison to other immediate-release opioids and warrants a Medication Guide to
`ensure that patients are informedon the proper use of this product.
`
`Title IX, Subtitle A, Section 901 of the Food and Drug Administration Amendments Act of 2007
`(FDAAA) amends the Federal Food, Drug, and Cosmetic Act (FDCA) to provide FDA with new
`authorities to require sponsors of approved drugs to develop and comply with Risk Evaluation
`and Mitigation Strategies (REMS) section 505-1 of the FDCA if FDA finds that a REMS is
`necessary to ensure that the benefits of the drug outweigh the risks. These provisions took effect
`on March 25, 2008.
`V
`
`A teleconference took place on November 3, 2008 in which the DAARP informed the sponsor
`that a REMS is necessary for tapentadol. The only elements of the REMS will be a Medication
`Guide (MG) and a timetable of submission of assessments of the REMS.
`The sponsor submitted a proposed REMS for NDA 22-304 on November 11, 2008, and following
`feedback from the Agency submitted an amendment to the proposed REMS on November 18,
`2008.
`
`4 DISCUSSION
`
`4.1 MEDICATION GUIDE
`
`The purpose ofpatient directed labeling is to facilitate and enhance appropriate use and provide
`important risk information about medications. Our recommended changes are consistent with
`current research to improve risk communication to a broad audience, including those with lower
`literacy.
`‘
`'
`
`The drafi MG drafted by the DAARP has a Flesch Kinkaid grade level of 8.1. To enhance patient
`comprehension, materials should be written at a 6th to 8" grade reading level, and have a reading
`ease score of at least 60% (60% corresponds to an 8‘” grade reading level). The reading scores as
`submitted by the sponsor are acceptable. In our review of the MG, we have:
`0
`simplified wording and clarified concepts where possible,
`ensured that the MG is consistent with the PI,
`rearranged information due to PLR labeling format
`removed unnecessary or redundant information
`ensured that the Medication Guide meets the Regulations as specified in 21 CFR
`208.20.
`'
`
`0
`
`ensured that the MG meets the criteria as specified in FDA’s Guidance for Useful
`Written Consumer Medication Information (published July 2006).
`
`In 2008, The American Society of Consultant Pharmacists Foundation in collaboration with The
`American Foundation for the Blind published Guidelinesfor Prescription Labeling and
`. Consumer Medication Informationfor People with Vision Loss. They recommend using fonts
`such as Arial, Verdana, or APHont to make medical information more accessible for patients with
`
`

`

`low vision. We have reformatted the MG document using the font APHont, which was
`developed by the American Printing House for the Blind specifically for low vision readers.
`See the attached document for our recommended revisions to the MG. Comments to the review ‘
`
`division are bolded, underlined and italicized.
`
`We are providing the review division a marked—up and clean copy of the revised MG. We
`recommend using the clean copy as the working document.
`
`All future relevant changes to the PI should also be reflected in the MG.
`
`4.2
`
`PROPOSED REMS
`
`The proposed REMS states that the Sponsor will include a supply of MG 3 to the wholesaler with
`. each shipment of tapentadol in accordance with 21 CFR 208.24. The Sponsor will additionally
`supply copies of the MG to all retail and hospital pharmacies at least biannually.
`
`The Timetable for Submission of Assessments is as follows:
`
`'
`'
`I
`
`1st assessment: 18 months afier approval
`2nd assessment: 3 years after approval
`3rd assessment: 7 years afier approval
`
`The original proposed REMS included a section entitlef _
`At this time, the Agency does not consider this information to be included in the REMS
`document; this was appropriately removed in the amended REMS based on Agency feedback.
`
`5 CONCLUSIONS AND RECONIMENDATIONS
`
`DRISK believes that the Sponsor’s proposed REMS for tapentadol meets the statutory
`requirements outlined under ZICFR 208 and in accordance with 505-1. We have the following
`comments and recommendations:
`
`a?»
`
`j
`
`hi4)
`
`1. The sponsor’s proposed timetable for assessments (18 months, 3 years, and 7 years)
`is acceptable. The Sponsor should submit for review a detailed plan to evaluate the
`patient’s understanding about the safe use of tapentadoh The submission should
`include:
`'
`
`0 All methodology and instruments that will be used to evaluate the patient’s
`understanding about the safe use of tapentadol. This should include, but not be
`limited to:
`_
`0
`Sample size and confidence associated with that sample size
`How the sample will be determined (selection criteria)
`The expected number of patients surveyed
`How the participants will be recruited
`How and how often the Surveys will be administered
`Explain controls used to minimize bias
`Explain controls used to compensate for the limitations associated with
`their methodology
`The survey instruments (questionnaires and/or moderator's guide).
`Any background information on testing survey questions and the correlation to
`the messages in the Medication Guide.
`
`

`

`2. Tapentadol is supplied in bottles of 100 and hospital unit dose blister packs of 10.
`Since tapentadol is not supplied in unit of use packaging, there is concern that the
`larger size bottles may be repackaged prior to dispensing and flius there would not be
`sufficient numbers of Medication Guides if bottles are repackaged and dispensed to
`multiple patients. Under 21CFR208.24 (b) (1) sufficient numbers of Medication
`Guides must be provided.
`'
`
`

`

`10.‘
`
`,
`
`Please let us know if you have any questions.
`
`31(4)
`
`I]
`
`APPEARS THSS WAY
`
`0N ORIGWM
`
`

`

`__l_ Page(s) Withheld
`
`Trade Secret / Confidential (b4)
`
`/ Draft Labeling (b4)
`
`Draft Labeling (b5)
`
`Deliberative Process (b5)
`
`

`

`
`
`
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`
`
`Mary Dempsey
`11/20/2008 12:43:42 PM
`DRUG SAFETY OFFICE REVIEWER
`
`Claudia Karwoski
`11/20/2008 01:47:42 PM
`DRUG SAFETY OFFICE REVIEWER
`
`

`

`
`
`Date:
`
`To:
`
`Through:
`
`From:
`
`~
`
`Department of Health and Human Services
`Public Health Service
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`June 26, 2008
`
`Bob Rappaport, M.D., Director
`Division of Anesthesia, Analgesia and Rheumatology Products
`
`Claudia Karwoski, Pharm.D., Acting Director
`Division of Risk Management (DRISK)
`
`Gita Akhavan—Toyserkani, Pharm.D., MBA, Senior Drug Risk
`Management Analyst (DRISK)
`Mary Dempsey, Risk Management Coordinator (DRISK)
`
`Subject:
`
`Review of proposed Risk Management Plan (RMP)
`
`Drug Name(s):
`Submission Number:
`
`Tapentadol hydrochloride immediate-release (IR) tablets
`000
`
`Application Type/Number: NDA 22-304
`
`Applicant/sponsor:
`OSE RCM #:
`
`Johnson & Johnson Pharmaceutical Research & Development, LLC
`2008-283
`
`'
`
`

`

`1
`
`INTRODUCTION AND BACKGROUND
`
`This review follows the February 12, 2008 request from the Division of Anesthesia, Analgesia
`and Rheumatology Products (DAARP) for the Office of Surveillance and Epidemiology (0813) to
`review Johnson & Johnson’s (J&JPRD) January 23, 2008 proposed risk management plan.
`
`Tapentadol hydrochloride immediate-release (IR) is a centrally acting analgesic agent.
`Tapentadol is both a mu—opioid receptor agonist and an inhibitor of norepinephrine uptake. The
`proposed indication for tapentadol IR isthe relief of moderate to severe acute pain. The
`recommended starting dose is 50 mg, 75 mg, or 100 mg every 4 to 6 hours depending upon pain -
`intensity. Daily doses greater than 700 mg for the first day of therapy and 600 mg on subsequent
`days have not been studied and are, therefore, not recommended. The Sponsor proposes labeling
`and routine pharmacovigilance to manage the risks of this Schedule [1 controlled product.
`
`1.1 REGULATORY HISTORY
`
`Tapentadol HCl is a New Molecular Entity (NME) that has not been previously marketed or
`' approved in the US or abroad. Tapentadol is an analog of tramadol and therefore not a first in
`class NME. The application is filed as a 505(b)(l), non-priority NDA with 10-month review
`clock.
`
`During a pre-NDA meeting, on June 5, 2007, J&JPRD discussed the requirements for a Risk
`Minimization Action Plan (RiskMAP) with the Agency. The Sponsor stated thagthey plan on
`conducting a pharmacovigilance program for the IR formulation Li
`L
`,
`,, ME The Reviewing Division informed
`J&JPRD that the IR formulation would not require aflRiskMAP unless there was something
`unusual (e.g. particularly vulnerable population, a more highly abusable dosage form, etc.);
`2“”
`'
`’
`'
`,l
`
`":2
`
`A
`
`l1(4)
`
`2 MATERIAL REVIEWED
`
`The following materials were reviewed:
`
`0
`
`0
`
`“Tapentadol IR Safety Surveillance plan” submitted January 23, 2008 by Johnson &
`Johnson Benefit Risk Management, LLC.
`
`Tapentadol HCL immediate-release tablets pre-NDA (IND 61,345) Meeting Minutes,
`dated June 5, 2007.
`,
`
`3 REVIEW
`
`3.1
`
`SPONSOR’S SAFETY CONCERNS
`
`Tapentadol HCL is a Scheduled II controlled substance. J&JPRD states that, to date, the adverse
`events experienced with tapentadol IR throughout the clinical program have revealed a profile
`consistent with a centrally acting compound with mgr—opioid agonist activity. The following
`important identified and potential risks determined by J&JPRD are listed in Table l:
`
`
`
`‘ Guidance for industry: Development and Use of Risk Minimization Action Plans:
`http://www.tdigov/cder/gfl:lancel6358nt.pdf, dated March 2005
`
`

`

`
`Table 1: Summary of Safety Concerns
`
`Safety Concerns
`Important identified risks:
`Potential for abuse
`
`Seizure
`
`Important potential risks:
`Overdose
`
`Off-label use, incl. pediatric patients
`Potential for medication errors (inappropriate
`prescribing, inappropriate dosing, inappropriate
`use) and patient misuse
`Accidental exposure
`
`Diversion
`
`Important missing information:
`Use in pediatrics
`
`The potential for abuse was regarded as an important identified risk due to known class effects for
`substances with mgr-opioid activity. In addition, results of a Phase I abuse liability trial suggest
`that single doses of tapentadol IR had a similar abuse liability profile to that of calculated
`equianalgesic single doses of hydromorphone IR.2 Seizure was included as well, due to known
`class effects for substances with mp-opioid activity. One case of seizure was observed in a Phase
`1 trial; however, the patient had a history of seizure which had been denied during screening for
`study. Subjects with history of seizures were excluded from Phase 2 and 3 clinical studies.
`
`During the preclinical development of tapentadol IR, subjects below 18 years of age were not
`studied. Therefore, knowledge of exposure in the pediatric population does not exist and the use
`of tapentadol IR in this population is not recommended.
`
`3.2 , SPONSOR’S RISK MANAGEMENT PROPOSAL
`
`F
`
`53(4)
`
`4 DISCUSSION
`
`1&IPRD states that, to date, the adverse events experienced with tapentadol IR throughout the
`clinical program have revealed a profile consistent with a centrally acting compound with mp-
`opioid agonist activity. Specific adverse events of interest for tapentadol IR include identified
`risks (drug abuse, and seizures) and potential risks based on adverse events seen with product in
`the mu—opioid receptor class (overdose, addiction, diversion, intentional misuse, medication
`
`
`2 Clinical Study Report (Mod 5.3.4.1): A Single-Center, Single-Dose, Double-Blind, Double-Dummy,
`Placebo~Controlled, Randomized Cross—Over Study to Evaluate the Abuse Potential of Three Doses of
`CGSSO3 Compared to Immediate Release Hydromorphone in Opiate-Experienced Non-Dependent
`Subjects.
`’
`
`

`

`errors, and accidental exposure). The sponsor states that while the drug possesses norepinephrine
`reuptake inhibitory activity, no specific safety issues arising from this mechanism has become
`evident during the clinical trials.
`
`Based on the clinical experience, tapentadol IR (50 mg to 100 mg) provides analgesia similar to
`oxycodone IR at doses of 10 mg and 15 mg. 'We note that other immediate-release opioids
`indicated for the treatment of pain, with potency similar to morphine or oxycodone, do not have
`RiskMAPs in place. We fin‘ther note that tapentadol is an analog of tramadol. Unlike tramadol,
`which is not scheduled under the Controlled Substances Act in the U.S., tapentadol will be a
`schedule II controlled product and therefore subject to inherent restrictions on supply and
`distribution.
`’
`
`The Sponsor’s proposal is consistent with a routine pharmacovigilance program. The Sponsor
`states that all the safety risks can be adequately monitored and addressed by the planned
`surveillance activities and label. The Sponsor states that they agree with the recommendation of
`the Agency in that a RiskMAP is not needed for tapentadol IR.
`
`5 CONCLUSION
`
`We agree with the Sponsor and the Reviewing Division. The risks associated with the use of
`tapentadol HCL IR are similar to the risks of other immediate-release Opiate products indicated
`for the treatment of pain with potency similar to morphine IR and oxycodone IR. It is appropriate
`to manage the risks of tapentadol HCL IR with labeling and routine pharmacovigilance. At this
`time, we do not recommend establishing a risk evaluation and mitigation strategy (REMS) for
`this product.
`
`Should the safety data in the NDA show unanticipated risks associated with the use of tapentadol
`HCL IR, we ask that you consult OSE again to reconsider the risk management plan.
`'
`
`Y
`PPEARS nus WA
`A UN omcmm
`
`

`

`-----.--------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`' fé/""""""-'
`‘
`" " W" "_'""""""""""_
`
`'
`
`Mary Dempsey
`6/26/2008 01:01:02 PM
`DRUG SAFETY OFFICE REVIEWER
`
`Claudia Karwoski
`6/26/2008 01:35:41 PM
`DRUG SAFETY OFFICE REVIEWER
`
`

`

`"W
`
`FDA CENTER FOR DRUG EVALUATION AND RESEARCH
`DIVISION OF ANESTHESIA, ANALGESIA, AND RHEUMATOLOGY PRODUCTS
`
`
`
`DATE:
`
`November 6, 2008
`
`TO:
`
`From:
`
`Through:
`
`File, NDA 22—304, Tapentadol
`
`Ellen Fields, M.D., M.P.H
`Clinical Team Leader
`
`Curtis Rosebraugh, MD.
`Director, Office of Drug Evaluation 11
`Office of New Drugs
`Center for Drug Evaluation and Research
`
`RE:
`
`Risk Evaluation and Mitigation Strategy (REMS) Requirements
`
`M T
`
`itle IX, Subtitle A, Section 901 of the Food and Drug Administration Amendments Act
`of 2007 (FDAAA) amends the Federal Food, Drug, and Cosmetic Act (FDCA) to
`authorize FDA to require the submission of a Risk Evaluation and Mitigation Strategy
`(REMS) if FDA makes a determination that such a strategy is necessary to ensure that the
`benefits of the drug outweigh the risks (section 505-1(a)( 1)). Section 505-1(a)(l)
`provides the following factors:
`
`(A) The estimated size of the population likely to use the drug involved;
`
`(B) The seriousness of the disease or condition that is to be treated with the drug;
`
`(C) The expected benefit of the drug with respect to such disease or condition;
`
`(D) The expected or actual duration of treatment with the drug;
`(E) The seriousness of any known or potential adverse events that may be related to
`the drug and the background incidence of such events in the population likely to
`use the drug;
`
`(F) Whether the drug is a new molecular entity.
`
`

`

`NDA 22-304
`
`After consultations between the Office of New Drugs and the Controlled Substance Staff,
`we have determined that a REMS is necessary to ensure that the benefits of tapentadol
`outweigh its risk of high potential for abuse due to distinctive properties that became
`evident during the application review. In reaching this determination we considered the
`following:
`
`A. The indication proposed for the formulation in NDA 22-304, treatment of acute
`moderate to severe pain, could result in millions of prescriptions each year.
`
`- B. Moderate to severe pain is considered serious in that untreated pain can lead to
`physical and emotional disability, job loss and suicide.
`
`C. The potential benefit of tapentadol is that it represents the first novel analgesic with
`mu agonist activity in over a decade. Patients often do not respond to or tolerate
`some opioids. Having a novel option could offer pain relief to many patients unable
`to be treated successfiilly with existing therapies.
`
`D. The potential duration of treatment is days to months.
`P1 This product carries all of the risks of an opioid including CNS depression,
`respiratory depression, nausea, vomiting, constipation, along with the possibility of an
`abuse potential that could be comparable or possibly exceed currently available
`opioid analgesics. In a human abuse liability pharmacology study, tapentadol
`displays an abuse potential comparable to that of hydromorphone. However, the
`duration of the euphoria from tapentadol lasted longer than hydromorphone. For this
`reason, it stands out in comparison to otherimmediate—release opioids and warrants a
`Medication Guide to ensure that patients are informed on the proper use of this
`product.
`p
`
`F. Tapentadol is a new molecular entity.
`
`In accordance with section 505-1 of the FDCA, as one element of a REMS, FDA may
`require the development of a Medication Guide as provided for under 21 CFR Part 208.
`Pursuant to 21 CFR Part 208, FDA has determined that tapentadol poses a serious and
`significant public health concern requiring the distribution of a Medication Guide. The
`Medication Guide is necessary for patients’ safe and effective use of tapentadol. FDA
`has determined that tapentadol is a product that has serious risks (relative to benefits) of
`which patients should be made aware because information concerning the risks could
`affect patients’ decision to use, or continue to use, tapentadol. FDA has also determined
`that tapentadol is a product for which patient labeling could help prevent serious adverse
`events.
`'
`
`The only elements. of the REMS will be a Medication Guide and a timetable for
`submission of assessments of the REMS.
`
`

`

`
`his is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`‘
` mun. .
`
`
`
`Sharon Hertz
`11/21/2008 02:38:07 PM
`MEDICAL OFFICER
`signing for Curtis Rosebraugh
`
`