CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`203794Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`

`

`Summary Review for Regulatory Action
`
`electronic st u u
`
`Sharon Hertz, M.D.
`From
`
`Subject
`Deputy Division Director Summary Review
`NDA/Su lement #
`203794/000
`
`A licant Name
`Date of Submission
`
`PDUFA Goal Date
`
`Janssen Pharmaceuticals, Inc.
`
`October 15, 2012
`
`Nucynta (tapentadol) Oral Solution
`Proprietary Name /
`
`Established (USAN) Name
`Dosa_e Forms / Stren_ h
`
`Oral Solution/ 20 l
`
`'
`
`.er mL
`
`
`
`Moderate to severe acute pain in patients 18 years of
`Proposed Indication(s)
`
`age or older
`A OI'OVfil
`
`Action/Recommended Action:
`
`Material Reviewed/Consulted
`
`0ND Action Packa - e, includin :
`Medical Officer Review
`
`Statistical Review
`
`N/A
`
`N/A
`
`'
`
`——
`
`OSE/DMEPA
`
`Denise V. Baugh, PhannD, BCPS, Lubna Merchant,
`PhaimD, M.S.
`
`0ND=0flice ofNew Drugs
`OPDP=Office ofProfessional Drug Promotion
`05E: Office of Surveillance and Epidemiology
`DMEPA=Division ofMedication ErrorsPrevention
`DSI=Division of Scientific Investigations
`CDTIFCross—Discipline Team Leader
`
`NDA 203-794 Dep Dir Memo Nycynta OS br.doc
`
`Page 1 of 6
`
`Reference ID: 3203469
`
`

`

`
`
`
`
`Signatory Authority Review Template
`
`1. Introduction
`
`
`This application for Nucynta Oral Solution is a 505(b)(1) application. The formulation was
`developed initially for conduct of pediatric studies to fulfill the PREA PMR for Nucynta
`tablets, NDA 22304. No new nonclinical, clinical pharmacology, efficacy or safety data were
`submitted for this NDA as this oral solution is supported by a bioequivalence study with the
`oral tablet.
`2. Background
`
`
`Nucynta (Tapentadol) Tablets (NDA 022304) and Nucynta ER (Tapentadol) Extended-Release
`Tablets (NDA200533) were the first tapentadol products approved in the U.S., on November
`20, 2008 and August 25, 2011, respectively. Tapentadol is an opioid agonist and inhibits the
`reuptake of norepinephrine and serotonin. In addition to adverse events consistent with mu-
`opioid agonist activity, tapentadol was shown to have pro-convulsant activity in rats, and
`induced convulsions in rats, mice, and dogs at high doses. The tapentadol-glucuronide
`metabolite may contribute to this effect. Notably, hallucinations, convulsions and serotonin
`syndrome have been reported in postmarketing experience with Nucynta IR tablets. Both
`seizures and serotonin syndrome risk are described in the approved Nucynta label.
`
`This application cross-references NDA 022304 for clinical, nonclinical toxicology and clinical
`pharmacology information. A biowaiver for clinical pharmacology studies was granted by the
`FDA on June 29, 2009. This NDA contains CMC data and labeling.
`
`
`3. CMC/Device
`
`
`The drug substance used for this product is the same as that used for the immediate-release
`oral tablet formulation (NDA 22304) and the extended-release formulation (NDA 200533).
`
`The following is from Dr. Bertha’s review:
`The drug substance is tapentadol hydrochloride, which is a chiral opioid compound…
`The
` form of the drug substance is inconsequential as it is formulated in
`solution. The aqueous-based solution formulation contains no co-solvents, has a target
`pH of 4.0, and also contains both sucralose and a proprietary flavor mixture, for taste
`purposes. The clear and colorless formulation is simply prepared by
`
` The strength of the formulation, in
`terms of the tapentadol base, is 20 mg/mL (equivalent to 23.3 mg of tapentadol
`hydrochloride), and the formulation is packaged in quantities of 100 and 200 mL
`in high density polyethylene bottles fitted with foil induction seals
`
`
`
`NDA 203-794 Dep Dir Memo Nycynta OS br.doc
`
`
`
`Page 2 of 6
`
`Reference ID: 3203469
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

` A
`
`
`
` 24 month expiration dating period is supported by the stability data that have been
`provided in the application and the product is intended to be stored at room
`temperature.
`
`
`The applicant was able to adequately address initial deficiencies concerning the raspberry
`flavor used in the formulaton. The applicant was also able to provide a method validation
`report for the HPLC method used to for the determination of identity, assay, and degradants.
`
`The oral dosing syringe initially provided was novel in design. Rather than have markings on
`the barrel of the syringe, starting at the tip and increasing along the barrel, there were markings
`on the plunger. An acceptable oral dosing syringe was ultimatrely provided with adeqate
`acceptance testing and criteria for deliverable volume. A syringe adapter will be supplied and
`placed into the bottle neck prior to its first use.
`
` A
`
` microbiology review of the drug product noted that the drug product is a non-sterile oral
`liquid without a specific preservative. However, during product development it was noticed
`that the drug substance (tapendatol HCl) had anti-microbial activity. The product meets the
`acceptance criteria for USP Chapter <51>. The applicant adequately addressed the product
`quality microbiology deficiencies by agreeing to test for microbial limits at release for each
`batch and by adding a specification for the absence of B. cepacia.
`
` I
`
` concur with the conclusions reached by the chemistry reviewer regarding the acceptability of
`the manufacturing of the drug product and drug substance. Manufacturing site inspections
`were acceptable. Stability testing supports an expiry of 24 months. There are no outstanding
`issues.
`
`
`4. Nonclinical Pharmacology/Toxicology
`
`
`No new nonclinical data were submitted with this NDA. I concur with the conclusions
`reached by the pharmacology/toxicology reviewer that there are no outstanding pharm/tox
`issues that preclude approval.
`
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`
`No new clinical pharmacology studies were submitted with this NDA. Under IND 61,345, a
`biowaiver was requested and granted by the Agency on June 29, 2009. In a memo dated
`February 24, 2012, Dr. Christine Moore, Acting Office Director of Office of New Drug
`Quality Assessment (ONDQA), noted that the biowaiver granted was still valid for this NDA.
`I concur with the conclusions reached by the Dr. Lee and Dr. Moore that there are no
`outstanding clinical pharmacology issues that preclude approval.
`
`
`NDA 203-794 Dep Dir Memo Nycynta OS br.doc
`
`
`
`Page 3 of 6
`
`Reference ID: 3203469
`
`

`

`
`
`6. Clinical Microbiology
`N/A
`
`
`7. Clinical/Statistical-Efficacy
`
`
`No new clinical efficacy data were submitted in support of this application. Based on the
`formulation and the prior approval of Nucynta immediate-release tablets, a biowaiver was
`granted and the efficacy of Nucynta tablets can be extrapolated to the oral solution. There are
`no outstanding efficacy issues.
`
`
`8. Safety
`
`
`No new clinical safety data were submitted in support of this application. Oral solution
`formulations of opioids have been dosed in error in the past. Therefore, in contrast to the
`tablets, additional labeled warnings and a medication guide are included for oral solutions.
`This is discussed below. There are no outstanding safety issues.
`
`
`9. Advisory Committee Meeting
`
`
`No Advisory Committee meeting was held for this application.
`
`
`10.
`
`Pediatrics
`
`
`The applicant has submitted a pediatric plan and agreed to study the efficacy, safety and
`pharmacokinetics of Nucynta oral solution in pediatric patients ages 0 to less than 17. The
`proposed dates for study completion are based on the current experience with pediatric
`enrollment.
`
`
`11.
`
`Other Relevant Regulatory Issues
`
`
`There are no other unresolved relevant regulatory issues
`
`
`12.
`
`Labeling
`
`
`The dosing for Nucynta oral solution is 50 mg, 75 mg, or 100 mg every 4 to 6 hours depending
`upon pain intensity. On the first day of dosing the second dose may be given as soon as one
`
`NDA 203-794 Dep Dir Memo Nycynta OS br.doc
`
`
`
`Page 4 of 6
`
`Reference ID: 3203469
`
`

`

`
`
`hour after the first dose, if adequate pain relief is not attained with the first dose. Subsequent
`dosing is 50 mg, 75 mg, or 100 mg every 4 to 6 hours and should be adjusted to maintain
`adequate analgesia with acceptable tolerability. Daily doses greater than 700 mg on the first
`day of treatment and 600 mg on subsequent days are not recommended. This is consistent
`with the dosing for Nucynta immediate-release tablets. In contrast to the tablets, opioid oral
`solutions require additional attention to avoid medication errors. Nucynta oral solution has 20
`mg of active drug in each milliliter of solution. Therefore, it is extremely important that
`prescribers clearly write the mg and mL when they prescribe the drug, e.g. 50 mg (2 mL) every
`6 hours as needed for pain. This is to avoid the risk that either 50 mL or 2 mg are dosed
`improperly, the former resulting in overdose, the latter in inadequate pain management. In
`addition, a medication guide has been developed for oral opioid solutions to ensure that
`patients have adequate instruction for proper dosing.
`
`DMEPA has recommended the following
`The recommended dosage and administration for Nucynta oral solution will be the
`same as Nucynta immediate release tablets. Therefore, we do not anticipate confusion
`will occur with the introduction of this new dosage form. However, the presentation of
`the strength as “20 mg/mL” is problematic given that the recommended volume per
`dose for Nucynta may range from 2.5 mL (50 mg) to 5 mL (100 mg). The manner in
`which the strength is stated is inconsistent with the recommended dosing and may lead
`to calculation errors. Expressing the statement of strength as 100 mg/5 mL may
`minimize the potential for medication errors due to miscalculations. Although this
`presentation would still require calculation for the lower doses, the medical community
`is familiar with this presentation (e.g., XX mg/5 mL) and it is consistent with the
`expression of other oral solutions. See our recommendations in Section 5.
`
`
`While there are still some oral opioid solutions with the concentration expressed per 5 mL, this
`has, in the past, resulted in confusion when there were also products available with more than
`one concentration available. For example, morphine oral solution is available in 20 mg per 5
`mL and 20 mg per one mL concentrations. This has led to medication errors where the higher
`concentration product was mistakenly substituted for the lower concentration product and
`patients were overdosed. Therefore, we have attempted to change the labeling for these
`products to consistently display the mg per one mL. As Nucynta will be labeled for doses of
`50 mg, 75 mg or 100 mg, and only the 100 mg dose will be a 5 mL volume, there is still the
`opportunity for medication errors by displaying the concentration as 100 mg per 5 mL. This
`was discussed with DMEPA who agreed as noted in an email entered into DAARTS on
`October 15, 2012.
`
`OPDP provided comments that were incorporated into the labeling.
`
`
`13.
`
`Decision/Action/Risk Benefit Assessment
`• Regulatory Action - Approval
`
`• Risk Benefit Assessment
`
`
`
`NDA 203-794 Dep Dir Memo Nycynta OS br.doc
`
`
`
`Page 5 of 6
`
`Reference ID: 3203469
`
`

`

`
`
`
`
`
`
`
`
`1937-1
`
`
`
`
`1937-2
`
`
`
`The indication and dosing for Nucynta Oral Solution are the same as for the
`immediate-release tablet. The overall risk and benefit are expected to be similar as
`well, except for a higher risk for medication errors. The labeling and medication
`guide are intended to address this added risk.
`
`• Recommendation for Postmarketing Risk Management Activities
`None beyond routine postmarketing pharmacovigilance
`
`• Recommendation for other Postmarketing Study Commitments
`
`A pharmacokinetic, efficacy, and safety study of Nucynta for the management
`of moderate to severe acute pain in pediatric patients ages 6 to less than 17
`years.
`
`Final Protocol Submission: May 31, 2014
`Study/Trial Completion:
`September 30, 2018
`Final Report Submission: March 31, 2019
`
`A pharmacokinetic, efficacy, and safety study of Nucynta for the management
`of moderate to severe acute pain in pediatric patients ages birth to 5 years.
`
`Final Protocol Submission: March 31, 2017
`Study/Trial Completion:
`July 31, 2021
`Final Report Submission: December 31, 2021
`
`
`
`NDA 203-794 Dep Dir Memo Nycynta OS br.doc
`
`
`
`Page 6 of 6
`
`Reference ID: 3203469
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SHARON H HERTZ
`10/15/2012
`
`Reference ID: 3203469
`
`