CENTER FOR DRUG EVALUATION AND
`
`’
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-304
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW! S l
`
`

`

`CLINICAL PHARMACOLOGY REVIEW
`
`Submission Date:
`
`1/23/08, 9/16/08
`
`% N
`
`DA: 22-304
`
`Submission Type; Code:
`
`Original; 1S
`
`Brand/Code Name:
`
`To—be-deterrninedTM
`
`Generic Name:
`Primary Reviewer:
`
`Team Leader:
`
`OCP Division:
`
`0ND Division:
`
`Tapentadol HCl Immediate Release tablet
`David Lee, Ph.D.
`
`Suresh Doddapaneni, Ph.D.
`
`DCP 2
`
`Division of Anesthesia, Analgesia, and Rheumatology
`' Products
`
`Sponsor:
`' Relevant IND(s):
`
`J&J Pharmaceutical Research and Development, L.L.C.
`61,345
`_
`
`Formulation; Strength(s):
`
`Tablet; 50, 75 and 100 mg
`
`Proposed Indication:
`Proposed Dosage
`Regimen:
`
`For the relief of moderate to severe acute pain
`-
`Individualize according to the severity of pain being
`treated, the previous experience with similar drugs
`and the ability to monitor the patient
`0 Tapentadol can be administered with or without food
`at a dose of 50 mg, 75 mg, or 100 mg Q4-6H
`depending upon pain intensity
`0 On the first day of dosing, the second dose may be
`administered as soon as one 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 Q4—6H and should be adjusted to maintain
`adequate analgesia with acceptable tolerability.
`0 Daily doses greater than 700 mg on the first day of
`therapy and 600 mg on subsequent days have not
`been studied and are, therefore, not recommended.
`
`“UM
`
`Table of Contents
`
`1 EXECUTIVE SUMIVIARY.................................................................................................... 3
`
`1.1 Recommendations
`
`......................................................3
`
`1.2
`
`1.3
`
`Phase IV Commitments";..............................................................................................................................3
`
`Summary of CPB Findings .............................................................................................................................3
`
`

`

`2 QBR 10
`
`.....................................................................10
`General Attributes of the Drug and Drug Product...........
`2.1
`What are the highlights of the chemistry and physical-chemical properties of tapentadol? .......... 10
`2.1.1
`2.1.2 What are the highlights of the pharmaceutical development of tapentadol tablet formulation? ...11
`2.1.2.1 What is tapentadol to-be-marketed formulation? .......................................................................... l 1
`
`12
` 2.1.2.2 How was the tapentadol IR Formulation developed?
`2.1.3 What is the proposed mechanism of action? .....................................
`...16
`2.1.4 What are the proposed dosage and route of administration? ............................................................ 17
`
`General Clinical Pharmacology...................................................................................... 18
`2.2
`2.2.1 What are the design features of the pivotal clinical trials? ................................................
`l 8
`
`2.2.2
`What biomarkers and how are they measured in clinical pharmacology and clinical studies?...
`...25
`2.2.3
`Are the active moieties in the serum and urine appropriately identified and measured to assess
`pharmacokinetic parameters and exposure response relationships? ................................................................27
`Exposure-response ........L.............................................................................................
`...27
`2.2.4.
`
`2.2.4.1 What are the characteristics ofthe exposure-response relationships (dose-response, concentrati
`1
`_
`response) for efficacy?......................................................................................................................................... 27 '
`2.2.4.2 What are the characteristics of the exposure-response relationships (dose-response, concentration~
`response) from PhaSe 3 efficacy studies? ............................................................................................................29
`2.2.4.3 What are the characteristics of the exposure-response relationships (dose-response, concentration-
`response) for safety? ............................................................................................................................................30
`...31
`2.2.4.4 What other exposure-response relationship information were presented in the NDA?
`
`2.2.4.5 Does tapentadol prolong the QT interval? ...........................................................................................40
`2.2.5 What are the PK characteristics of the drug and its major metabolite? .......................................... 43
`’
`...44
`2.2.5.1 Absorption .......................................................................................................
`
`Protein binding, metabolism, enzyme induction/inhibition and mass balance .................
`...45
`2.2.5.2
`2.2.5.3 What are the single dose and multiple dose PK parameters?............................................................... 48
`2.2.5.4 What is the inter- and intra-subject variability ofPK parameters in volunteers and patients, and what
`are the major causes of variability? ..................................................................................................................... 51
`
`.....................................52
`Intrinsic Factors ....................................................................................................
`2.3
`2.3.1 What intrinsic factors (age, gender, race, weight, height, disease, genetic polymorphism,
`pregnancy, and organ dysfunction) influence exposure and/or response and what is the impact of any
`differences in exposure on the pharmacodynamics? .......................................................................................... 52
`2.3.2
`ls dosage adjustments needed in the following populations? ............................................................. 52
`......52
`2.3.2.1 What is the status of pediatric studies and/or any pediatric plan for study? .
`
`2.3.2.2 Gender differences ............................................................................................................
`.....54
`
`2.3.2.3 Race ........................................................................................ 56
`
`Elderly .................................. 56
`2.3.2.4
`
`.............................................................. 59
`2.3.2.5
`Renal impairment...
`2.3.2.6 Hepatic impairment ................................................................................61
`
`2.4
`2.4.1
`2.4.1.1
`
`Extrinsic Factors ..................................................................................................................64
`
`Drug-Drug Interactions ............................................64
`Effects of Other Drugs on Tapentadol .................................................................................................64
`
`................................................70
`General Biopharmaceutics........‘................................................................
`2.5
`2.5.1 What is the in vivo relationship of the proposed to-be—marketed formulation to the pivotal clinical
`trial formulation in terms of comparative exposure? ......................................................................................... 70
`2.5.2.
`Based on BCS principles, in what class is this drug and formulation? What solubility,
`permeability and dissolution data support this classification? What data support a waiver of in vivo BE
`data?
`7]
`
`What is the effect of food on the bioavailability (BA) of tablets? What dosing recommendation
`2.5.3
`should be made, if any, regarding administration of tablets in relation to meals or meal types? ..................78
`
`

`

`How do the dissolution conditions and specifications assure in vivo performance and quality of
`2.5.4
`the product? ........................................................................................................................................................... 79
`
`Analytical Section ....................................................._.....................................................................................79
`2.6
`‘ How are tapentadol and its metabolites measured in the serum and urine? .................................... 79
`2.6.1
`2.6.1.1 What are the accuracy, precision and selectivity parameters? What is the sample stability under the
`conditions used in the study? ............................................................................................................................... 79
`
`3 DETAILED LABELING RECOMNIENDATIONS
`
`........
`
`.........
`
`.........
`
`........
`
`...... 81
`
`4 APPENDICES ..........................................................
`
`..........
`
`............. ....................... 84
`
`4.1
`
`4.2
`
`4.3
`
`4.4
`
`Proposed Package Insert ...............................................................................................................................84
`
`Individual study review — Population PK/PD study report ...................................................................... 101
`
`Consult Review (including Pharmacometric Reviews)...................................'..........................................145
`
`Cover Sheet and OCPB Filing/Review Form ............................................................................................ 145'
`
`
`1 ~ Executive Summary
`
`1.1 Recommendations
`
`From the viewpoint of the Office of Clinical Pharmacology and Biopharmaceutics / Division of
`Pharmaceutical Evaluation 11
`(OCPB/DPE-II),
`the information contained in the NDA is
`acceptable, provided that a mutually satisfactory agreement can be reached between the
`Applicant and the Agency with respect to the language in the package insert (see section 3:
`Detailed Labeling Recommendations).
`
`1.2
`
`Phase IV Commitments
`
`Not applicable.
`
`1.3
`
`Summary of CPB Findings
`
`Johnson & Johnson Pharmaceutical Research and Development, L.L.C. (J&JPRD), on behalf of
`Ortho—McNeil—Janssen-Pharmaceuticals,
`Inc.
`(OMJPI),
`submitted on 1/23/08,
`the New Drug
`Application 22—304, tapentadol hydrochloride Immediate Release Tablets for the relief of moderate
`to severe acute pain with 50-, 75- and lOO—mg doses every 4 to 6 h as needed in all patients at
`least 18 years of age. Throughout the submission the following notations were also used for
`tapentadol HCl: CG5503 and R33l333.
`It is noted that many of the studies were conducted by
`Grfinenthal GmbH, Aachen Germany (GRT).
`
`The NDA contained extensive Clinical Pharmacology and Biopharmaceutics program. There
`were 6 Phase 2 studies to gather preliminary efficacy and safety information.
`The phase 2
`
`

`

`studies included 2 single- and/or multiple-dose, studies of acute pain following third molar
`extraction (KF5503/02 and KF5503/04), a single- and multiple-dose study in subjects with
`chronic non-malignant pain (KF5503/08), a single-dose study in subjects with acute pain
`following bunionectomy (KF5503/05), and 2 multiple-dose studies in subjects with acute pain
`following bunionectomy (KF5503/21 and KF5503/22). There were 2 pivotal Phase 3 studies in
`inpatient
`(KF5503/32;
`bunionectomy)
`and
`outpatient
`settings
`(KF5503/33;
`end-stage
`degenerative joint disease of the hip or knee) supporting the proposed indication. Both studies
`used fixed dose with flexible dosing regimen of Q4 to 6h. Additionally, there was 1 Phase 3 -
`safety study to assess the safety of tapentadol dosed as flexible'doses of 50 mg or 100mg every
`4 to 6 hours, 'as needed, over a 9C9lmday period in subjects with low back pain or pain from
`osteoarthritis of the hip or knee.
`no
`_
`:i
`3
`If
`.
`Tapentadol is a centrally active antinociceptive drug for the relief of moderate to severe acute
`pain. Tapentadol is both a u-opioid receptor (MOR) agonist and an inhibitor of norepinephrine
`(NE) (re)uptake. Both mechanisms are likely to contribute to the analgesic effects of the
`compound. Tapentadol is a pure enantiomer and has no clinically-relevant active metabolites.
`No enantiomeric interconversion has been observed. Tapentadol is the only active moiety and
`tapentadol was measured appropriately in serum and urine. Since the metabolites (inactive) are
`excreted in the urine, glucuronide metabolites were measured in hepatic and renal studies.
`
`l1(4)
`
`Tapentadol HCl is freely soluble in water, 0.1 N HCl and simulated intestinal fluid (34 and 35
`2/100 mL, respectively).
`Its solubility decreases at higher pH. The hydrochloride salt was used
`C;
`
`We)
`
`Phase 3 studies
`
`In Study KF5503/32, a bunionectomy study, there was a trend of increasing efficacy (SPID48)
`with increasing tapentadol dose (50mg, 75mg, and 100 mg).
`In Study KF5503/33, an end-stage
`degenerative joint disease of the hip or knee study, it appears that there was no dose related
`increase in efficacy (SPID at Day 5) from 50mg to 75mg. Nevertheless, both tapentadol doses
`were found to be efficacious.
`
`The observed treatment emergent adverse events (TEAEs) appear to be dose-related. Common
`adverse events appear to increase with increase in tapentadol doses.
`'
`
`Population Pharmacokinetics and exposure-response information
`
`The overall information from the population PK model supported the pharmacokinetic findings
`from the Phase 1 and 2 studies. Additionally,
`the overall
`information obtained from the
`exposure-response model exercise also supported the findings fiom the Phase 3 studies.
`It is
`noted that each of the Phase 2/3 studies used in the modeling had a different study design and
`duration,
`inconsistent dosing regimens including flexible dosing schemes,
`inconsistent rules
`regarding the supplemental rescue usage, as well as different primary efficacy variables, and,
`these studies are not pooled and separate analysis was performed for each of the studies.
`
`Thorough QT study
`
`

`

`(Dr. Christine Garnett;
`No significant QT prolongation effect of tapentadol was detected.
`Interdisciplinary Review Team for QT Studies Consultation: Thorough QT Study Review,
`7/1/08)
`
`Inter- and intra—subject variability
`
`For the Cmax of tapentadol dos'e-nOrmalized to 100 mg, the inter subject CV was estimated at
`39% and the intra—subject CV was estimated at 20%.
`For the AUC of tapentadol dose-
`normalized to 100 mg, the inter-subject CV was estimated at 34%, whereas the intra-subject CV
`was estimated at around 13%.
`
`Pediatric
`
`Pediatric data has not been submitted seeking approval of pediatric indications at this stage.
`Instead,
`the package insert will state 'safety and effectiveness has not been established in
`pediatric patients less than 18 years of age'. The Applicant requested a ‘staged’ deferral of the
`requirement 'to conduct pain studies in the pediatric populatiOn. The Applicant proposed that
`trials be conducted in a step-wise manner to gather adequate pharmacokinetic, safety and
`efficacy information in the older children before exposing younger age groups. Adequacy ofthis
`plan is currently ongoing discussion in the review team.
`
`Gender
`
`Men and women showed that women in general had about 20% higher Cmax and AUC values.
`After bodyweight correction in this pooled analysis (men had about 20% higher body weight),
`the mean oral clearance was very similar between men and women. No dose adjustment is
`recommended due to gender differences.
`L
`
`Race
`
`No separate studies were conducted to evaluate the effects of race on the PK of tapentadol.
`However, comparison of PK data obtained in Japanese subjects in study R331333-PAI—1027 to
`historical data shows that PK is similar in Japanese subjects as compared to non—Japanese
`subjects. Additionally, the Cmax and AUC values increased with an increase in tapentadol doses
`(10, 20, 40 mg) in Japanese subjects. No dose adjustment
`is recommended due to race
`differences.
`
`Elderly
`
`PK characteristics for tapentadol were similar in elderly (65 to 78 years of age) and healthy
`subjects, suggesting that age hasno impact on the PK oftapentadol. No specific dose adjustment
`for elderly is needed; however, due to the fact that elderly patients are more likely to have
`decreased renal and hepatic function, care should be taken in dose selection.
`
`Hepatic
`
`

`

`The tapentadol Cmax values increased 1.4---and 2.54—fold in subjects with mild or moderate
`hepatic impairment, respectively, versus subjects with normal hepatic function. The AUC of
`tapentadol was increased 1.7- and 42-fold in subjects with mild and moderate hepatic
`impairment, respectively, versus subjects with normal hepatic function. Severe impairment
`subjects were not tested. The terminal elimination half-life of tapentadol was increased 1.4-fold
`in subjects with moderate hepatic impairment, compared to healthy subjects. The mean CL/F of
`tapentadol decreased 3.6-fold (ratio of arithmetic means) in subjects with moderate hepatic
`impairment, compared to healthy subjects, but the amount excreted over 48 hours remained
`below 5% of the total dose.
`
`The serum tapentadol-O-glucuronide AUC values were comparable for all subjects.
`
`the
`is needed in mild impairment subjects. In moderate impairment,
`No dose adjustment
`tapentadol should be used with caution and should be initiated at 50 mg. every 8 hours followed
`by either shortening or lengthening the dosing interval for fiirther treatment. Tapentadol has not
`been studied in patients with severe hepatic impairment and, therefore, use in this population is
`not recommended.
`-
`
`Renal
`
`Total exposure to tapentadol was not different between normal and subjects with renal
`impairment, indicating that a reduced renal functioning does not influence the single-dose PK of
`orally administered tapentadol.
`'
`
`Data for tapentadol-O-glucuronide demonstrate that Cmax increased 1.2-, 1.3-, and 1.4-fold for
`mild, moderate, and severe renal
`impairment subjects, respectively, compared with healthy
`subjects. The AUC data showed a 1.5-, 2.5—, and 55—fold increase for mild, moderate, and
`severe renal
`impairment subjects, respectively, compared with healthy subjects. The mean
`terminal half-life of tapentadol-O—glucuronide increased 33-fold in subjects with severe renal
`impairment compared to subjects with normal renal fimction.
`
`Because of the significant accumulation potential of tapentadol-O-glucuronide in severe renal
`impairment group, the Applicant proposed that tapentadol use is not recommended in this group.
`However, this metabolite is inactive and not recommending the use of tapentadol based on
`accumulation potential of an inactive metabolite is not justified. Therefore, it is recommended
`
`W
`
`[1(5)
`
`Drug-Drug interaction
`
`Metoclopramide, omeprazole, naproxen, acetylsalicylic acid and acetaminophen did not affect
`tapentadol pharmacokinetics. However, the serum Cmax and AUC levels of tapentadol were
`elevated in the presence of probenecid, approximately 30% and 57%, respectively, as compared
`with the control. The elimination half-life of tapentadol in the control was 4.1 hours and was 4.4
`hours when tapentadol IR was co-administered with probenecid. The tapentadol-O-glucuronide
`Cmax and AUC values were reduced in the presence of probenecid.
`
`

`

`Metoclopramide - Tapentadol 80 mg was either administered alone or one hour after the 5m dose
`of metoclopramide (6 doses of. 20 mg, Q6h). The Cmax and AUCs were comparable
`between the two treatments for both tapentadol and tapentadol-O-glucuronide.
`
`Omeprazole - Tapentadol IR (80 mg) was administered either alone or 2 hours afier the
`last administration of omeprazole once daily for 4 days.
`Serum PK parameters of
`tapentadol
`and tapentadol-O—glucuronide were similar when tapentadol
`[R was
`administered either alone or with omeprazole.
`
`Probenecid - Tapentadol [R (80 mg) was administered either alone or together with the
`third administration of probenecid 500 mg b.i.d. for 2 days. The serum Cmax and AUC
`levels of tapentadol were elevated in the presence of probenecid, approximately 30% and
`57%, respectively, as compared with the control. The tapentadol-O-glucuronide Cmax
`and AUC values were reduced in the presence of probenecid.
`
`Naproxen and acetylsalicylic acid (ASA) - Subjects received a single oral dose of
`tapentadol 80 mg alone or in combination with naproxen (together with the third dose of
`500 mg b.i.d. for 2 days) and in combination with ASA (together with the second dose of
`325 mg ASA once daily for 2 days). Cmax and exposure of tapentadol was similar in all
`treatment groups, indicating that co-administration of either naproxen or ASA has no
`influence on the oral PK of tapentadol.
`
`Acetaminophen — Subjects received a single oral dose oftapentadol IR 80 mg alone or in
`combination with acetaminophen (together with the fifih dose of 1000 mg acetaminophen
`Q6h for 2 days). Concentrations of tapentadol were similar after administration of
`tapentadol IR alone and after co-administration with acetaminophen.
`
`Bioequivalence
`
`jfilm-coated tablet
`80-mg Q ., gcapsule formula and the 80-m C
`. manufactured 1::
`fiwere bioequivalent (Study PAI-1016).
`Absolute Bioavailability
`
`b(4)
`
`The absolute oral bioavailability oftapentadol capsules (using 86 mg dose) was 32.0%. I
`
`Protein Binding
`
`Tapentadol protein binding is approximately 20%, mainly to albumin, and protein binding is
`independent of drug and protein concentration.
`
`Mass balance, Metabolism, Induction, and Inhibition Potential
`
`More than 95% of the dose was excreted within 24 hours after intake and an average of 99.9% of
`the dose was recovered after approximately 5 days. Total urinary excretion amounted to 99% of
`the dose. Only a few percent (mean: 3%) was excreted as unchanged CG5503 base, 69% was
`
`

`

`excreted as conjugates. Approx. 27% should be excreted as other metabolites. Fecal excretion
`amounted to approximately 1%, and excretion in C02 was negligible.
`
`The main metabolic pathways for the elimination of tapentadol
`glucuronidation and sulphatation.
`
`in all species are direct
`
`Tapentadol is not an inhibitor of CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYPZEl
`and CYP3A4 in vitro.
`
`Tapentadol is not an inducer of CYP1A2, CYP2C9 and CYP3A4 in vitro.
`
`Single dose linearity
`
`AUC or Cmax values increased linearly with increase in doses from 50 7 150 mg.
`
`Multiple dose linearity
`
`StudyI-[P5503/13 showed that, at 75, 100, 125, 150 and 175 mg, AUC or Cmaxvvalues increased
`linearly with increases in doses.
`
`Food effect
`
`Cmax and AUC increased by 16% and 25% with food, respectively. The tmax was prolonged by
`about 1.5 hours with a median tmax of 3.00 hours (range: 1.02-6.00 hours) in the fed ‘state'and
`1.50 hours (range: 1.00-4.00 hours) in the fasted state. The Applicant discussed the food effect
`during the drug development program and, with Agency's concurrence; the Applicant did not
`restrict the use of tapentadol with respect to meal consumption.
`
`In Phase 3 studies, all doses of study treatment were administered with approximately 120 mL of
`water, with or without food. Study treatment was swallowed whole and not chewed, divided,
`dissolved, or crushed.
`
`BCS class I assessment
`
`The Applicant requested a biowaiver from conducting an in vivo bioequivalence study
`comparing the TBM 100 mg IR tapentadol tablet and the 100 mg IR capsule formulation used in
`Clinical development; the bioequivalence study between IR capsules and tablets was performed
`at the 80-mg dose strength. In support of the request, the Applicant presented the information
`regarding the physicochemical properties, the composition, formulation, and pharmacokinetic
`characteristics of the drug product, the dissolution test results, and the manufacturing method and
`scale. During the review, additional information regarding the stability oftapentadol in .
`simulated gastric fluid (SGF), USP, and simulated intestinal fluid (SIF) was requested. Overall,
`adequate data showing that tapentadol is highly soluble, highly permeable, and that the tablet
`formulation is rapidly dissolving has been submitted. This information was forwarded to the
`BCS Committee and the BCS Committee concurred on the Class I designation for tapentadol.
`
`

`

`Analytical Methodology
`
`An LC-MS/MS method was used for the quantification of tapentadol and its O-glucuronide and
`the O-sulfate metabolites in plasma. The method had a validated range of 0.2 to 200 ng/mL,
`5.00 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 thequantification 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 and tapentadol-O-glucuronide, respectively.
`
`Population pharmacokinetic analysis
`
`Six Phase 1 studies and six Phase 2/3 studies were used in the Nonlinear mixed effects modeling
`(NONMEMo). A two-compartment PK model with zero-order release followed by first-order
`absorption and first-order elimination described the individual tapentadol PK profiles. The CL/F
`and V2/F parameters were identified as parameters which may be affected by various covariates.
`As body weight increased, both CL/F and V2/F increased almost linearly. However, the body
`weight effect may not be clinically important due to minimal significance. The model predicted
`CL/F values for men were about 16% higher than that for women. Total bilirubin (TB) and total
`protein (TP) the majority of the subjects were healthy'subjects, were identified as statistically
`significant covariates on CL/F. Overall, where applicable the findings from these analyses were
`in agreement with findings from standalone PK studies.
`
`Renal impairment population PK analysis
`
`The database for the population PK analysis of tapentadol and its metabolite tapentadol-o-
`glucuronide consisted of 40 subjects with varying degree of renal impairment from a single
`Phase 1 study. A three-compartment model with 1st order elimination best described the PK of
`tapentadol following oral administration. The most important covariate was CRCL on the
`clearance of the metabolite. Simulations indicate dosing to subjects with mild renal impairment,
`moderate or severe renal impairment resulted in up to 1.5, 2.5 and 8.7 fold higher exposure to
`tapentadol-O—glucuronide compared to subjects with normal renal function, while the exposures
`to tapentadol was not affected. However, it should benoted that tapentadol-o-glucuronide is an
`inactive metabolite and its accumulation in renal impairment subjects is not expected to be a
`significant safety issue.
`
`Exposure-response analysis
`
`Data from two Phase 3 studies (PAI-3002/KF5503/33 and PAI-3003/KF5503/32) and 2 Phase
`2B studies (PAl—2004/KF5503/21 and PAI-2003/KF5503/22) were used. Each of these studies
`had a different study design and duration, inconsistent dosing regimens including flexible dosing
`schemes, inconsistent rules regarding the supplemental rescue usage, as well as different primary
`efficacy variables. The models built were either linear models (Yi = [30+ B1 ° DOSez' + [32 ' Bpaz'm
`+ 81') or simple Emax models:
`
`Y: = E0 + Emax* Exposurei + 5r
`ECSO + Exposure,
`
`

`

`Clear exposure-efficacy response relationships were observed for all efficacy variables (e.g.
`SPID 5D for PAI-3002/KF5503/33). Among the selected demOgraphic variables examined (age,
`body weight, baseline pain, sex, and race), only baseline pain intensity significantly affected the
`analgesic response profile of tapentadol IR. Subjects with higher baseline pain intensity had
`higher pain reductions.
`
`Exposure-adverse event analysis
`
`There are 6 main adverse events (nausea, vomiting, constipation, dizziness, somnolence, and
`pruritus) that can occur from taking opioids. These AEs have also been observed in the Phase 2
`and 3 studies for tapentadol IR. The objectives of this analysis were (1) to assess the potential
`relationships between the occurrence of selected adverse events after oral administration of
`tapentadol IR and the extent of drug exposure, and (2) to identify potential risk factors that
`influence the occurrence of ABS following tapentadol IR administration. Nausea, vomiting,
`constipation, dizziness, somnolence, and pruritus were selected for analysis. Constipation and
`pruritus appeared to be associated with average exposure measures (average concentration,
`average daily dose, and average daily AUC). Dizziness and somnolence tended to'be associated
`with peak exposure (Cmax). Onset of somnolence was reported to be rapid, and after 10h very
`few subjects reported new occurrences. The occurrence of the first incidences of nausea and
`vomiting was associated with exposure (randomized dose or AUCss calculated from randomized
`dose) following the first dose of tapentadol IR.
`
`Overall, adequate data characterizing the Clinical Pharmacology and Biopharmaceutics aspects
`oftapentadol IR tablets was provided.
`'
`
`_
`
`2 QBR
`
`2.1 General Attributes of the Drug and Drug Product
`
`2.1.1 What are the highlights of the chemistry and physical-chemical properties of
`tapentadol?
`-
`
`Tapentadol HCZ isfreely soluble in water, 0.1 N HCl and simulated intestinalfluid (34 g/IOO mL
`and 35 g/1_0 mL,... respectively).
`Its solubility decreases at higher pH. The hydrochlori e salt
`
`was used r. -_
`
`b(4)
`
`3-[(1R,2R)-3-(dimethylarnino)—1-ethyl-2—methylpropyljphenol
`is
`HCl
`Tapentadol
`Its molecular formula is C14HZ3NO.HCI and its has a molecular weight of
`monohydrochloride.
`257.80 g/mol for the hydrochloride salt and 221.34 g/mol for the free base. Tapentadol
`hydrochloride has 2 chiral centers leading to 4 possible stereoisomers. However, the proposed
`product is a pure stereoisomer with the absolute configuration (1R, 2R). The pKal and pKa2 are
`9.34 (phenolic OH) and 10.45 (HN(CH3)2 +), respectively. The n-octanol/water partition
`coefficient (logP) is 2.87. Tapentadol HCl is freely soluble in water, 0.1 N HCl and simulated
`intestinal fluid (34 and 35 g/100 mL, respectively).
`Its solubility decreases at higher pH (to 5.8
`g/IOO mL at pH=7.63 and 3.4 g/ 100 mL at pH=12.48), which is likely due to the conversion
`from HCl salt to free base form. This decrease in pH dependent solubility does not affect its
`
`10
`
`

`

`overall high solubility at the highest proposed strength of 100 mg tablet. The hydrochloride salt
`was usedC
`7
`.
`,
`3
`Chemical Structure of tapentadol HCI
`
`I3(4)
`
`
`
`2.1.2 What are the highlights of the pharmaceutical development of tapentadol tablet
`formulation?
`
`2.1.2.1 What is tapentadol to-be—marketed formulation?
`
`Film coated immediate release Tablets (50-, 75-, and ZOO-mg) are proposedfor marketing.
`
`IhevTarget Formulation Composition for Tapentadol Tablets,(50—. 75- and lOO-rng) is shown below;
`
`V
`
`M4)
`
`11
`
`

`

`The three strengths are
`a;
`
`,
`_
`
` «mm..
`W.m“,“film‘ ura- W.'51.,
`-
`-
`~ --
`7
`
`.
`3
`
`31(4)
`
`2.1.2.2 How was the tapentadol IR Formulation developed?
`
`m
`
`i
`
`M4)
`
`.3
`
`Intravenous Formulations
`
`Tapentadol hydrochloride was formulated either as a 1% (w/v) solution for injection (10 mg/mL)
`or as a solution for infusion (10-80 mg per 50 mL).
`
`Quantitative Com osition of Ta entadol Hydrochloride Solution for Injection
`
`Dosage Strength
`10 ngl mL
`100 mg!10 m1.
`(tapentadol hydrochloride)
`
`2439B
`6082 SF
`Formulatioifi
`
`Quantity
`Ingredient
`
`
`
`
`
`
`f (m
`
`13(4)
`
`12
`
`

`

`Quantitative Com osition of Ta entadol Hydrochloride Solution for Infusion
`
`
`
`Dosage Strength
`10 rag/50 mL 20 mg/SD mL 40 rug/50 mL 80 mg/SO mL
`
`
`(tapentadol hydrochloride)
`
`
`Formulationa
`Ingredient
`
`
`
`6039SF
`603881"
`Quantity
`("‘6‘
`
`6040$F
`
`6037SF
`
`r
`
`‘
`
`'
`
`MA)
`
`__l
`
`Capsule Formulations
`
`The Phase 1 and 2 clinical trial capsule batches were manufactured in doses ranging from 25 to
`200 mg. The Phase 1 and 2 clinical trial capsule batches were manufactured in doses ranging
`from 25 to 200 mg by both Grilnenthal GmbH and J&IPRD.
`
`Quantitative Compositions of Griinenthal GmbH Capsule Batches Employed in
`
`Phase land 2 Clinical Studies
`" 25- to 75-mg (Tapentadol Hydrochloride)
`
`61128]?
`25
`
`2476}:
`
`6073.517
`
`607ISF/1
`
`607ZSF
`
`no
`
`Quantity Per Dosage Unit
`(mg)
`
`Bl
`
`Quantitative Compositions of Grfinenthal GmbH Capsule Batches Employed in
`Phase land 2 Clinical Studies (I W" 100- to ZOO-mg (Tapentadol
`
`
`H drochloride) per Ca sulea .
`
`
`
`
`
`Formulation
`6073517
`60735F/1
`607451:
`6075 SF
`
`
`Dosage Strenggh (tafltadol hydrochloride}
`100
`11 6
`150
`200
`Ingredient
`Function
`Quantity Per Dosage Unit
`
`__££g)
`
`
`
`
`
`‘
`
`
`
`__/
`
`‘ hm
`
`l3
`
`

`

`Quantitative Compositions of Tapentadol Capsule Batches Employed in Phase 1 and 2 Clinical
`Studies . N :25— to 100,-m2 (fi'ee baseequivalent) per Cm‘
` s“
`WW
`
`
` W3
`w:
`
`
`
`
`.
`_'
`_______
`QuanfiwPerDmgeUniumz)
`‘./
`
`m4)
`
`Film-Coated Tablets 1
`
`r
`
`Batch Formula for Tapentadol Tablets fiom Formulation DOE *
`m
`
`Ingredient
`Function
`Quantity”
`.
`,
`Alamo—
`
`_
`
`BioequivalenCe of Film-Coated Tablet to Capsule Formulation
`
`It is noted that a bioequivalence study ( M _ demonstrated equivalence