CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`200533Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`
`

`

`NDA: 200-533
`Submission Type;
`Brand/Code Name:
`Generic Name:
`Primary Reviewer:
`Team Leader:
`OCP Division:
`OND Division:
`
`Sponsor:
`
`Relevant NDA(s)
`Relevant IND(s):
`Formulation; Strength(s):
`Proposed Indication:
`Proposed Dosage
` Regimen:
`
`CLINICAL PHARMACOLOGY REVIEW
`Submission Date:
`02/28/11
`Complete Response Resubmission;
`Nucynta™ ER
`Tapentadol HCl Extended Release tablet
`David Lee, Ph.D.
`Yun Xu, Ph.D. (acting)
`DCP 2
`Division of Anesthesia, Analgesia and Addiction
`Products
`J&J Pharmaceutical Research and Development, L.L.C.,
`On behalf of Ortho-McNeil-Janssen Pharmaceuticals,
`Inc.
`22-304
`61,345
`Tablet; 50, 100, 150, 200 and 250 mg
`Management of moderate to severe chronic pain
`As with many centrally acting analgesic medications, the dosing
`regimen of NUCYNTA™ ER should be individualized according to
`the severity of pain being treated, the previous experience with
`similar drugs and the ability to follow-up and provide oversight of
`treatment.
`The recommended NUCYNTA™ ER total daily dose is 100 mg to
`250 mg twice daily approximately every 12 hours with or without
`food. Patients currently not taking opioid analgesics should begin
`NUCYNTA™ ER therapy with 50 mg twice a day.
`Patients receiving NUCYNTA™ (immediate-release formulation)
`may be converted to NUCYNTA™ ER by administering the same
`total daily dose. Administer half the total daily dose of
`NUCYNTA™ ER approximately every 12 hours. Daily doses
`greater than 500 mg of NUCYNTA™ ER have not been studied
`and, therefore, are not recommended.
`
`
`Table of Contents
`1 EXECUTIVE SUMMARY .................................................................................................................. 2
`1.1
`RECOMMENDATIONS ..................................................................................................................... 2
`1.2
`PHASE IV COMMITMENTS............................................................................................................. 5
`1.3
`SUMMARY OF CLINICAL PHARMACOLOGY FINDINGS.................................................................. 5
`2 QBR ....................................................................................................................................................... 8
`2.1 GENERAL ATTRIBUTES OF THE DRUG AND DRUG PRODUCT....................................................... 8
`2.1.1 What are the highlights of the pharmaceutical development of tapentadol ER tablet
`formulation? .......................................................................................................................................... 8
`2.1.2 What is tapentadol to-be-marketed formulation?................................................................. 8
`2.1.3 What are the proposed dosage and route of administration?............................................. 10
`
`
`
`Reference ID: 2981210
`
`1
`
`

`

`2.2 GENERAL CLINICAL PHARMACOLOGY – NOT APPLICABLE....................................................... 13
`2.3
`INTRINSIC FACTORS – NOT APPLICABLE..................................................................................... 13
`2.4
`EXTRINSIC FACTORS – NOT APPLICABLE.................................................................................... 13
`2.5 GENERAL BIOPHARMACEUTICS .................................................................................................. 13
`2.5.1
`Are PR2 and To-be-marketed TRF formulations bioequivalent?...................................... 13
`2.5.2
`Are there any comparability or interchangeability issues if smaller-dose unit is
`administered as multiple units to achieve a particular dose?............................................................. 21
`2.6
`ANALYTICAL SECTION ................................................................................................................ 28
`2.6.1 What are the accuracy, precision and selectivity parameters? What is the sample stability
`under the conditions used in the study?.............................................................................................. 28
`2.7 OFFICE OF SCIENTIFIC INVESTIGATION INSPECTION FOR THE 250 MG BIOEQUIVALENCE STUDY
`28
`
`3 DETAILED LABELING RECOMMENDATIONS........................................................................ 29
`4 APPENDICES..................................................................................................................................... 31
`4.1
`PROPOSED PACKAGE INSERT ...................................................................................................... 31
`4.2
`INDIVIDUAL STUDY REVIEW ........................................................................................................ 53
`4.3
`CONSULT REVIEW (INCLUDING PHARMACOMETRIC REVIEWS)................................................ 53
`4.4
`COVER SHEET AND OCPB FILING/REVIEW FORM .................................................................... 53
` Executive Summary
`
` 1
`
`1.1 Recommendations
`
`The Office of Clinical Pharmacology / Division of Clinical Pharmacology II (OCP/DCP-
`II) has reviewed the information submitted in the current Complete Response application.
`The Applicant submitted bioequivalence information bridging the PR2 Phase 3 clinical
`and tamper-resistant-formulation (TRF) to-be-marketed (TBM) tapentadol extended-
`release (ER) formulations.
`
`information
`the clinical pharmacology
`From clinical pharmacology perspective,
`submitted in the Complete Response is acceptable provided a mutual agreement on the
`labeling language is reached between the Applicant and the Agency, and, the results from
`the Office of Scientific Investigation (OSI) inspection are acceptable In order to provide
`adequate information to address the issues stated in the Complete Response respect to
`clinical pharmacology, the Applicant needed to submit bioequivalence information from
`two doses, 50 and 250 mg strengths, comparing PR2 and TRF TBM formulations along
`with in vitro dissolution data in support of the biowaiver request for the intermediate
`strengths. The Applicant submitted bioequivalence information from all available
`strengths to address the concerns in the current complete response submission.
`
`With respect to Labeling, there are minor changes recommended for the Clinical
`Pharmacology section of the label. The recommended changes to the package insert are
`made by striking out the existing texts and adding new texts, in RED fonts, where
`appropriate (see section 3: Detailed Labeling Recommendations).
`
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`
`
`Reference ID: 2981210
`
`2
`
`

`

`
`'
`'
`.
`The exact
`is a centrally—acting
`Tapentadol
`mechanism of action is unknown;
`
`
`
`12.2 Pharmacod amics
`
`Tapentadolis_ 18 times less potent than
`
`morphine in binding to the human mu-opioid receptor and is 2-3 times less potent
`in producing analgesia in animal models. Tapentadol has been shown to inhibit
`norepinephrine reuptake in the brains of rats resulting in increased norepinephrine
`concentrations. In preclinical models, the analgesic activity due to the mu-opioid
`receptor agonist activity of tapentadol can be antagonized by selective mu—opioid
`antagonists (e.g., naloxone), whereas the norepinephrine reuptake inhibition is
`sensitive to norepinephrine modulators. Tapentadol exerts its analgesic efi'ects
`without a pharmacologically active metabolite.
`
`Effects on the cardiovascular system: There was no effect of therapeutic and
`supratherapeutic doses of tapentadol on the QT interval. In a randomized, double-
`blind, placebo— and positive-controlled crossover study, healthy subjects were
`administered five consecutive immediate-release formulation doses of tapentadol
`100 mg every 6 hours,_ tapentadol 150 mg every 6
`hours, placebo and a single oral dose of moxifloxacin. Similarly, the immediate-
`release formulation tapentadol_ had no relevant effect on other
`ECG parameters (heart rate, PR interval, QRS duration, T-wave or U-wave
`morphology).
`
`
`
`12.3 Pharmacokinetics
`
`Absorption
`
`The mMean absolute bioavailability after single-dose administration (fasting) of
`
`* NUCYNTA ER is approximately 32% due to extensive first-pass
`
`sm. Maximum semm concentrations of tapentadol are observed between
`meta
`3 and 6 hours after administration ofNUCYNTA” ER.
`
`Dose proportional increases for AUC have been observed after administration of
`NUCYNTA1M ER over the therapeutic dose range.
`
`
`
`Reference ID: 2981210
`
`

`

`
`
`Food Effect
`
`The AUC and Cmax increased b 6% and 17%, respectively, when NUCYNTA
`ER
`table
`was administered after a hi —fat hi
`-
`
`
`
`calorie breakfast.
`_NUCYNTATM ER may be given with or without food.
`
`Metabolism and Elimination
`
`In humans,_ about 97% of the parent
`compound is metabolized. Tapentadol
`is mainly metabolized via Phase 2
`pathways, and only a small amount is metabolized by Phase 1 oxidative pathways.
`The major pathway of tapentadol metabolism is conjugation with glucuronic acid
`to produce glucuronides. Afler oral administration approximately 70% (55% O—
`glucuronide and 15% sulfate of tapentadol) of the dose is excreted in urine in the
`conjugated form. A total of 3% of drug was excreted in urine as unchanged drug.
`Tapentadol
`is additionally metabolized to N—desmethyl tapentadol (13%) by
`CYP2C9 and CYP2C19 and to hydroxy tapentadol (2%) by CYP2D6, which are
`finther metabolized by conjugation. Therefore, drug metabolism mediated by
`cytochrome P450 system is of less importance than phase 2 conjugation.
`
`None of the metabolites contributes to the analgesic activity.
`
`Tapentadol and its metabolites are excreted almost exclusively (99%) via the
`kidneys. The terminal half-life is on average 5 'hours after oral administration.
`The total clearance of tapentadol is- 1603 +/- 227 I mllmin.
`
`In Vivo NUCYNTATM ER Formulation-Alcohol Interaction
`
`Tapentadol may be expected to have additive effects when used in conjunction
`with alcohol, other opioids, or illicit drugs that cause central nervous system
`depression because respiratory depression, hypotension, and profound sedation or
`coma may result.
`
`An in vivo study examined the effect of alcohol (240 mL of 40%) on the
`bioavailability of a single dose of 100
`and 250 mg ofNUCYNTATM ER tablet
`in healthy, fasted volunteers. After
`co—administration of 100 n -_
`NUCYNTATM ER tablet and alcohol,
`
`fie me
`an Cmax value
` increase 0
`
`. 48%
`
`Reference ID: 2981210
`
`

`

`
`with a rang
`
`of 0.99-fold to 4.38-fol
`The mean tapentadol AUCl
`an AUCinf were increased by 17%;
`e Tmax and W2 were unchanged. Afler
`-co-administration of a 250 u ; NUCYNTATM ER tablet and alcohol,
`
`
`
`
`the mean Cmax value increased b
`to control.
`
`=
`
`-0.90-fold to 2.67—fold.
`
`
`e mean tapentao AUC ast an
`. . by 16%; the Tmax and
`t'/: were unchanged.
`
`1.2 Phase IV Commitments
`
`Not applicable.
`
`1.3 Summary of Clinical Pharmacology Findings
`
`the Applicant did not submit bioequivalence
`In the original NDA submission,
`information bridging the PR2 Phase 3 clinical and tamper-resistant—formulation (TRF) to-
`be-marketed (TBM)
`tapentadol extended-release (ER)
`formulations.
`Instead,
`the
`Applicant utilized in vitro—in vivo correlation (IVIVC) data to bridge the two
`formulations. This information was reviewed by Dr. Sandra Suarez (Biopharmaceutics
`Reviewer, Oflice of New Drug Quality Assessment (ONDQA)). During the assessment
`of the IVIVC information, there were several deficiencies related to the proposed IVIVC
`models and the findings were conveyed to the Applicant on April 21, 2010, during a
`teleconference. The Applicant was asked to ‘reconstruct the model using individual
`plasma concentration values and to eliminate a mathematical term bein used in the
`
`modelm In
`
`g app cation on May 13, 2010
`ent to pen
`an amen
`e App cant su mitt
`response,
`proposing to perform new fasted bioequivalence trials between the PR2 Phase 3 clinical
`and TRF TBM on the 150 mg and 200 mg strengths and proposing to submit the
`information prior to the end of the 10-month review cycle (See Biopharmaceutics Review
`dated June 14, 2010). Thus, from clinical pharmacology perspective, since the proposed
`IVIVC modeling data was not suflicient to adequately bridge the PR2 and TRF TBM
`formulations, the clinical pharmacology section of the original NDA was not acceptable.
`In order to provide adequate information,
`the Applicant was informed to submit
`bioequivalence information from two doses, 50 and 250 mg strengths, comparing PR2
`and TRF TBM formulations along with in vitro dissolution data in support of the
`biowaiver request for the intermediate strengths. This approach was discussed in a
`teleconference between the Applicant and the Agency on November 9, 2010. The
`Agency agreed with the proposed approach in general,
`i.e., conducting new
`bioequivalence studies, pending on the review of the study results.
`
`so
`
`Reference ID: 2981210
`
`

`

`In this current Complete Response submission, the Applicant conducted bioequivalence
`studies for all strengths, 50, 100, 150, 200 and 250 mg. The results indicated that the
`TRF TBM tablets (100, 150, 200 and 250 mg) were bioequivalent to the PR2 tablets. The
`50 mg strength met the bioequivalence criteria in terms of AUC, but the TRF formulation
`showed slightly higher (about 29%) Cmax compared to the PR2 formulation. However,
`50 mg dose will be strictly used for a titration purpose. Therefore,
`the result is
`considered acceptable afier discussion with the clinical team.
`
`Analytical Methodology
`
`An LC—MS/MS method was used for the quantification of tapentadol and its 0-
`glucuronide and the O-sulfate metabolites in plasma. The method had a validated range
`of 0.2 to 200 ng/mL, 5 to 400 ng/mL and 10.0 to 5,000 ng/mL for tapentadol, tapentadol—
`O-sulfate and tapentadol—O-glucuronide, respectively. Similarly an LC-MS/MS method
`was used for the quantification of tapentadol and its O-glucuronide in urine. The method
`had a validated range of 10 to 10,000 ng/mL and 500 to 100,000 ng/mL for tapentadol
`and tapentadol—O-glucuronide, respectively.
`
`Additional information submitted by the Applicant
`
`The Applicant submitted completed clinical studies in the current Complete Response.
`The following table contains clinical studies which may contain tapentadol exposure
`information. These studies were not reviewed due to the fact majority of the studies were
`conducted with other formulations, e.g., i.v., oral solution, IR, PR2, etc., which are not
`the proposed TRF extended release formulation. An exception was that a cursory review
`was conducted for Study HP5503/51, a food effect study (with a ‘standard Japanese meal
`- total calories are approximately 700 - 800 kcal; percentages of energy of contents of
`meal are: carbohydrate 50—70%, protein less than 20%, lipid 20-30%) with 100 mg TRF
`ER formulation Japanese healthy men (n=12).
`m“)
`This
`
`study was reviewed briefly since TRF ER formulation was utilized. The results indicated
`that the geometric means for Cmax and AUC of tapentadol under fed conditions were
`approximately 54 and 12% higher compared to under fasted conditions (see table below).
`The observed arithmetic mean Cmax and AUC values for fed and fasted conditions were
`
`65.7 and 42.8 ng/mL, and, 585 and 520 ng-h/mL, respectively. The provided information
`was considered not to be critical for this application simply because this study utilized a
`‘standard Japanese meal’, not an Agency’s recommended high—fat meal, and, the fact that
`the studied population does not represent the population majority in the US. Additionally,
`the high-fat food effect information was assessed in the original NDA submission, and,
`that study was considered as a pivotal food effect study; in that assessment, the AUC and
`Cmax increased by 6% and 17%, respectively, when TRF ER tablets were administered
`after a high-fat meal. The tmax was prolonged by about 1 hour with a median tmax of
`6.00 hours (range: 2.98-12.0 hours) in the fed state and 5 hours (range: 200-120 hours)
`in the fasted state.
`In Phase 3 studies, tapentadol ER tablets were also administered
`without restriction to food. Therefore, we recommend that tapentadol ER tablets may be
`taken without restriction to food.
`
`Reference ID: 2981210
`
`

`

`Summary of Analysis on the Pharmacokjnetic Parameters of Tapentadol — Food Efl'ect
`Assessment in Japanese Healthy Men (Study R331333-PAI-1052; HP5503/51-: Pharmacokinetic
`
`Analysis Set
`
`Tapentadol
`Tapentadol TRF
`TRF (fed)
`(fasted)
`Ratio
`100 mg
`100 mg
`Test.‘
`(Test)
`(Reference)
`Reference .
`(Geometric mean)
`(Geometric mean)
`90°- 0 (‘I o o('\'
`(11:12}
`0-0
`(n=1 2)
`63.45
`41.06
`154.52
`16.3
`Cm“. ng’mL
`559.96
`498.23
`113.39
`8.8
`AUG“.
`ngh‘mL
`562.57
`501.96
`10193—11971
`AUG”. neh‘niL
`‘? oCV:° o Coefficient of Variation: TRF:mmper resistant formulation: CI:confidence interval.
`N=number of subjects included in the mfeiential statistical analysis
`
`112.07 136379717453
`
`
`
`10526—12001
`
`8.8
`
`Additional clinical studies submitted in the Com n lete Res u onse submission:
`
`Stud NumberM
`HP5503/65
`i.v. formulation —
`Single-center, sequential S-
`Single dose on Day 1 and
`not reviewed
`and M-dose administration.
`multiple doses Q4h on Days
`3 and 4 for a total of 7 doses.
`DB. R. To evaluate the PK5
`of S— and M—doses of
`
`HP5503/69
`
`HP5503/59
`
`HP5503/51
`R331333-PAI-
`
`1052: US
`
`HP5503/64
`
`(GRT):
`R331333-PAI-
`1053
`
`tapentadol administered by
`i.v. infusion in healthy
`subjects
`
`Single-center, S—dose. 0L. R.
`2—period crossover. To
`assess BE of 2 tapentadol ER
`(PR) 25-mg tablets and a
`tapentadol ER (PR25mall)
`50-mg tablet in healthy
`subjects under fasted
`conditions.
`
`Single-center, S-dose, 0L, R,
`2—period crossover. To
`compare the BA of
`tapentadol 100-mg oral
`solution (OS) and tapentadol
`100-m IR tablet.
`
`Single-center, SD, 0L. R 2-
`period crossover. To
`evaluate the effect of food
`
`(standard Japanese meal) on
`the PK5 of
`
`tapentadol TRF in healthy
`Ja anese men.
`
`Single-center. S-dose, OL, R,
`2-period crossover. Evaluate
`the relative BA of the
`
`tapentadol TRF tablet
`formulation to the tapentadol
`PR1 tablet formulation in
`
`Japanese healthy subjects
`under fasted conditions.
`
`Reference ID: 2981210
`
`— not reviewed
`
`-Tapentadol iv 5 mg, 15
`and 25 mg
`Day 1 and Days 3/4
`separated by a 48-h washout
`i.v. infiision over 2 minutes
`
`PR formulation —
`not reviewed
`
`IR and oral
`solution
`formulations —
`not reviewed
`
`Conducted in
`
`Japanese subjects
`0) (4)
`
`cursory review
`
`Comparison to
`PR1 formulation
`
`Single dose per period
`-Tapentadol PR 25 mg x 2
`-Tapentadol PR25mall 50 mg
`Two l-day periods with 7-14
`days washout between
`Oral
`
`Single dose per period
`-Tapentadol IR 100 mg
`-Tapentadol OS 100 mg
`Two 1 day periods with 7-14
`days washout between.
`
`Single dose per period
`-Tapentadol TRF 100 mg
`(fed)
`-Tapentadol TRF 100 mg
`(fasted)
`Two l-day periods with 7-14
`da 5 washout between
`
`Single dose per period
`-Tapentadol TRF 100 mg
`-Tapentadol PR1 100 mg
`Two l-day periods with 7-14
`days washout between
`Oral
`
`

`

`2 QBR
`
`2.1 General Attributes of the Drug and Drug Product
`
`2.1.1 What are the highlights of the pharmaceutical development of tapentadol
`ER tablet formulation?
`
`Several difi'erent formulations were developed: PR1 fommlation was mostly used in
`Phase I and 2 clinical trials; PR2fommlation was mostly used in Phase 3 clinical trials;
`the tamper-resistant formulation (TRF) was subsequently developed to ofler tamper-
`resistant properties with similar dissolution profile to PR2 fommlation.
`The TRF
`tapentadol ERformulation is designated as commercialformulation.
`
`Overall tablet formulation development
`
`Phase 1
`
`l and 2 clinical trials were conducted with
`
`formulations of the tapentadol ER tablets, designated PR1. Phase 3
`(P3) clinical trials, as well as additional Pl studies during that period, were conducted
`with the PR2 formulations. The PR2 tablets were similar in ingredients and dissolution
`to the PR1 tablets. The Applicant stated that the PR2 formulations were developed to
`accommodate the higher doses required for P3 clinical trials.
`
`The tamper-resistant formulations (TRF) were subsequently developed to ofi'er tamper-
`resistant properties with similar dissolution profile to the P3 PR2 formulations. The TRF
`tapentadol ER formulation is designated as commercial formulation. There are three
`TRF formulations, namely, pilot, registration and to-be-marketed (IBM) formulations.
`Registration stability batches of TRF tapentadol ER tablets were manufactured by
`J&JPRD (Beerse, Belgium). To-be—marketed stability batches of TRF tapentadol ER
`tablets were manufactured at the
`r0 sed commercial site Janssen Ortho L.L.C.
`
`
`
`discussion on formulations.
`
`ee original new drug application review dated 8/9/10 for further
`
`2.1.2 What is tapentadol to-be-marketed formulation?
`
`Tamper-resistantformulation is the to-be-marketedformulation.
`
`Major excipients used in the TRF formulation
`
`The excipients contained in tapentadol ER tablets are listed below. The excipients used
`in the core tablet are GRAS (generally regarded as safe) and are of compendial grade.
`
`Reference ID: 2981210
`
`

`

`Excipients
`
`Function
`
`Polyethylene Oxide
`
`Hypromellose
`
`Polyethylene Glycol
`
`Reference to
`Standard
`
`NF
`
`Compositions of the clinical, registration stability, commercial site stability and proposed
`commercial TRF tapentadol extended-release tablets are provided in the table below.
`Composition of tapentadol TRF tablets: Pilot, Registration stability and to-be-marketed
`
`TF5. 63235F
`50
`
`Pilot batches
`TF4. 6322$F
`100
`
`TF3. GJIGSF
`250
`
`F029
`50
`
`ch'smtion subiliyx batches and Io-be-cmrlmed Melts '
`F030
`F031
`F032
`100
`150
`200
`
`F033
`250
`
`Tapemadol h)drochlonde. In;
`Polyethylene oxide. mg
`1% Mr oft-arr
`ram-m—
`1% Mr o/com
`Polmhwene glycol-
`I°/. m.- afcom
`Vitamin E. nu
`1% Wm" or rare!
`Table! core mi hl
`
`
`
`Component
`
`Reference
`
`Tapemadol HCl
`(R33 I 333 )
`Polyethylene
`Oxide
`
`Himmellose
`
`Polyeth lenc
`Glycol
`
`USP
`Vitamin E
`Polycth lene NF
`Glycol
`Total Core Tablet Weight
`
`- = Not a licable
`
`Reference ID: 2981210
`
`

`

`Co m. sition coa -'
`
`l
`
`- of the .
`
`r
`
`- Itadol TRF tablets: re 'stration and TBM batches onl
`
`Film Coal
`
`Quality Reference
`
`Function
`
`m
`
`50mg
`'/o \\'/\\r
`
`loo-mg
`% w/w
`
`m
`
`Dose Strength
`ISO-mg
`m
`% \v/w
`
`ZOO-mg
`% w/w
`
`m
`
`250mg
`
`m
`
`96 WW Noncompendial
`
`Noncompendial
`Noncompendial
`Noncompendial
`Noncompendial
`USP
`
`Noncompendial
`
`Noncompendial
`
` Propylene Glycol”
`
`-- = Not applicable
`
`2.1.3 What are the proposed dosage and route of administration?
`
`Tapentadol HCl tablet is taken orally. As per the proposed package insert, the proposed
`tapentadol dosage and administration is as follows:
`
`the dosing regimen should be
`As with many centrally acting analgesic medications,
`individualized according to the severity of pain being treated, the previous experience with opioid
`analgesics and the ability to follow-up and provide oversight of treatment
`
`The NUCYNTAm ER tablet formulation is designed to increase mechanical resistance to
`breakage and crushing. NUCYNTATM ER tablets are to be swallowed whole with the aid of
`liquids, and must not be broken, chewed, dissolved, or crushed. Taking broken, chewed,
`dissolved, or crushed NUCYNTAm ER Tablets could lead to rapid release and absorption of a
`potentially fatal dose of tapentadol.
`
`The recommended NUCYNTAT“ ER daily dose is 100 mg to 250 mg twice daily, taken
`approximately every 12 hours, with or without food
`
`Patients Currently Not Taking Opioid Analgesics
`Patients currently not taking opioid analgesics should begin NUCYNTATM ER therapy with 50
`mg twice a day (approximately every 12 hours) and then be individually titrated to adjust to an
`optimal dose within the therapeutic range of 100 mg to 250 mg twice daily.
`
`Patients Currently Taking Opioid Analgesics
`When switching from opioids to NUCYNTAT“ ER and choosing the initial dose, the nature of
`the previous medication, administration and the mean total daily dose should be taken into
`account
`
`Conversion from NUCYNTAT“, the immediate—release formulation, to NUCYNTATM ER
`NUCYNTATM can be converted to approximately equivalent total daily dose of NUCYNTATM
`ER, and vice-versa, with equivalent eflicacy and comparable tolerability. The total daily dose of
`
`Reference ID: 2981210
`
`10
`
`

`

`NUCYNTA™ ER should be divided into two equal administrations per day separated by
`approximately 12-hour intervals. As an example, a patient receiving 200 mg/day immediate-
`release formulation NUCYNTA™ may take 100 mg NUCYNTA™ ER twice a day
`(approximately every 12 hours). Although the total daily maintenance dose of immediate-release
`formulation NUCYNTA™ may be as high as 600 mg per day, total daily doses greater than 500
`mg of NUCYNTA™ ER have not been studied and, therefore, are not recommended.
`
`
`
`Individualization of Dose
`
`NUCYNTA™ (the immediate release formulation) can be converted to approximately equivalent
`total daily dose of NUCYNTA™ ER, and vice-versa, with equivalent efficacy and comparable
`tolerability. Therefore, the dose recommendations in special population for NUCYNTA™ ER
`will be consistent with those in NUCYNTA™ label.
`
`Pain relief and other opioid effects should be frequently assessed. In clinical practice, titration of
`the total daily dose of NUCYNTA™ ER should be based upon the amount of supplemental
`opioid utilization, severity of the patient’s pain, and the patient’s ability to tolerate NUCYNTA™
`ER. Patients should be titrated to a dose providing a meaningful improvement of pain with
`acceptable tolerability.
`
`Experience from clinical studies has shown that a titration regimen in increments of 50 mg
`NUCYNTA™ ER twice daily every 3 days was appropriate to achieve adequate pain control in
`most patients. Total daily doses greater than 500 mg of NUCYNTA™ ER have not been studied
`and, therefore, are not recommended [see Clinical Studies (14)].
`
`
`
`Reference ID: 2981210
`
`11
`
`(b) (4)
`
`

`

`
`If signs of excessive opioid-related adverse experiences are observed, the dose can be reduced
`depending on patient status and medical
`judgment. Adverse events can be
`treated
`symptomatically, as well. Once adverse events are under control, upward titration can continue to
`an acceptable level of pain control. During periods of changing analgesic requirement, including
`initial titration, frequent contact is recommended between physician and or health care provider
`and the patient.
`
`Cessation of Therapy
`
`Tapering NUCYNTA™ ER therapy was not required in the clinical studies; however, potential
`withdrawal symptoms may be reduced by tapering NUCYNTA™ ER [see Withdrawal].
`
`Renal Impairment
`
`No dosage adjustment is recommended in patients with mild or moderate renal impairment [see
`Clinical Pharmacology].
`
`NUCYNTA™ ER has not been studied in patients with severe renal impairment. The use in this
`population is not recommended.
`
`Hepatic Impairment
`
`No dosage adjustment is recommended in patients with mild hepatic impairment [see Clinical
`Pharmacology].
`
`NUCYNTA™ ER should be used with caution in patients with moderate hepatic impairment.
`Treatment in these patients should be initiated at 50 mg NUCYNTA™ ER and not be
`administered more frequently than once every 24 hours. Further treatment should reflect
`maintenance of analgesia with acceptable tolerability [see Clinical Pharmacology].
`
`NUCYNTA™ ER has not been studied in patients with severe hepatic impairment and use in this
`population is not recommended [see Warnings and Precautions].
`
`Elderly Patients
`
`In general, recommended dosing for elderly patients with normal renal and hepatic function is the
`same as for younger adult patients with normal renal and hepatic function. Because elderly
`patients are more likely to have decreased renal and hepatic function, consideration should be
`given to starting elderly patients with the lower range of recommended doses.
`
`There is no dosage and administration for pediatric patients and nursing mothers.
`
`
`
`Reference ID: 2981210
`
`12
`
`

`

`2.2 General Clinical Pharmacology – not applicable
`
`2.3
`
`Intrinsic Factors – not applicable
`
`2.4 Extrinsic Factors – not applicable
`
`2.5 General Biopharmaceutics
`
`2.5.1 Are PR2 and To-be-marketed TRF formulations bioequivalent?
`
`
`Summary: Tapentadol TRF and PR2 tablets are bioequivalent based on serum Cmax,
`AUClast, and AUCinf at the therapeutic doses of 100, 150, 200, and 250 mg when
`administered to healthy subjects in the fasted state.
`
`Tapentadol TRF and PR2 tablets are bioequivalent for the 50-mg tapentadol titration
`dose based on the estimates of serum AUClast and AUCinf. Bioequivalence was not
`demonstrated based on serum Cmax. However, 50 mg dose will be strictly used for a
`titration purpose.
`
`Based on cross-study comparisons, the systemic exposures of tapentadol are linear for
`the TRF and the PR2 tablets.
`
`Bioequivalence study design
`
`The bioequivalence studies compared the to-be-marketed tapentadol TRF tablets,
`produced at the commercial manufacturing site at Gurabo, Puerto Rico, US, to the current
`tapentadol PR2 tablets manufactured in Springhouse, PA, US used in pivotal Phase 3
`efficacy studies in healthy subjects under fasted conditions.
`
`All of the bioequivalence studies had the following study design: Study was an open-
`label, single-center, in-house, randomized, 2-way crossover study of a single dose of
`tapentadol to evaluate the bioequivalence, safety, and tolerability of the to-be-marketed
`tapentadol TRF tablet with the currently used tapentadol PR2 tablet in healthy men and
`women under fasted conditions. Subjects were included in the analyses if they did not
`vomit after first 6 hours post dosing and during at least 1 treatment period. Subjects
`fasted for at least 10 hours overnight prior to dosing. Study drug was administered with
`240 mL of noncarbonated water. Subjects consumed food no earlier than 4 hours after
`study drug administration. Subjects received standardized meals given at the same time
`in each treatment period. Subjects had a standard diet. Water was allowed ad libitum,
`except for 2 hours before and after study drug administration. Study drug administration
`was separated by a washout period of at least 7 and no more than 14 days. Blood
`samples were collected at predose, 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48 hours post
`dose.
`
`For each treatment, descriptive statistics, including arithmetic mean, standard deviation,
`coefficient of variation, geometric mean (PK parameters only), median, minimum, and
`
`
`
`Reference ID: 2981210
`
`13
`
`

`

`maximum were calculated for tapentadol serum concentrations at each sampling time and
`for all PK parameters of tapentadol. The primary parameters of interest for the statistical
`analysis were AUClast, AUC∞, and Cmax of tapentadol. The analysis was performed on
`log-transformed estimated PK parameters A mixed-effect model that included treatment,
`period, and treatment sequence as fixed effects, and subject as random effect was used to
`estimate the least squares means and intrasubject variance. Using these estimated least
`squares means and intrasubject variance, the point estimate and 90% confidence intervals
`(CI) for the difference in means on a log scale between Treatment A and Treatment B
`were constructed. The limits of the CI were retransformed using antilogarithms to obtain
`90% CI for the ratios of the mean values for AUC and Cmax of the test to reference
`formulation. Tapentadol TRF and tapentadol PR2 doses were considered bioequivalent if
`the 90% CI for the ratio of the means (TRF/PR2) fell within 80% to 125%.
`
`50 mg titration dose
`
`Study HP5503/82 evaluated tapentadol 50 mg tablets. Sixty-four subjects (32 men and
`32 women) were enrolled for the study. The batch numbers for test (TRF 50-mg tablet)
`and reference (PR2 50-mg tablet) products were 9EG9279-X and PD3137, respectively.
`Subjects were excluded from bioequivalence analyses if they did not complete both
`treatments and vomited anytime during the treatments.
`
`The mean serum concentration-time profiles were somewhat dissimilar between two
`formulations.
`
`The mean serum concentration-time profiles for 50 mg tablets
`
`
`
`
`
`
`The tapentadol pharmacokinetic parameters and a summary of statistical results are
`presented below.
`
`
`
`
`
`
`
`
`Reference ID: 2981210
`
`14
`
`

`

`Mean (±SD) Serum Pharmacokinetic Parameters of Tapentadol
`(Study HP5503/82: Pharmacokinetic Data Analysis Set)
`
`
`Note: Four subjects (Subjects 105911, 105913, 105943, and 105951) discontinued from the study. Subject
`105911 tested positive for alcohol prior to dosing in Period 2. Subjects 105913, 105943 and 105951
`withdrew consent from the study after completion of Period 1.
`
`
`Summary Statistics on the Ph