NDA 22-304
`Tapentadol HCL
`Clinical Review
`
`'
`
`7 INTEGRATED REVIEW or SAFETY
`
`Ellen Fields, M.D., M.P.H.
`September 18, 2009
`
`Summary of Safety Results and Conclusions
`
`Exposure
`A total of 3515 subjects were exposed to at least one dose of tapentadol IR during the
`development program, 467 during Phase 1 trials, 870 in Phase 2 single—dose trials, and
`2178 in nine Phase 2/3 multiple-dose, double-blind trials. Phase, 2/3 multiple-dose
`double-blind trials were carried out in the following populations: post-operative dental
`pain, post-operative bunionectomy pain, chronic non—malignant pain, end-stage joint
`disease, osteoarthritis, and chronic low back pain.
`
`In the Phase 2/3 multiple-dose, double-blind trials, 2,034 subjects received 50mg-100mg
`per dose. A total of 449 subjects received flexible dosing of 50mg or 100mg every 4-6
`hours as needed for at least 45 days, and 318 of these subjects received tapentadol IR for
`at least 90 days.
`
`Therefore, in regard to the sought indication, an adequate number of subjects have been
`exposed to tapentadol IR to meet the ICH guidelines for exposure.
`
`Deaths and Serious Adverse Events (SAEsl
`No deaths were reported after treatment with tapentadol IR in any of the completed Phase
`1 through 3 studies. Four deaths were reported in the Phase 3 tapentadol ER ongoing
`studies as of March 15, 2008. Details are located in Section 7.3.1.
`
`There were a total of 21 nonfatal SAEs reported in 17 subjects from all phases of the
`completed studies in the tapentadol IR development program in subjects who received
`tapentadol IR. Serious adverse events occurred in 1% of subjects in the multiple-dose,
`double-blind safety analysis set treated with either tapentadol IR or oxycodone. The rate
`of SAEs in placebo treated patients was <1%.
`
`The most commonly occurring SAEs (by System Organ Class (SOC) included cardiac
`disorders and nervous system disorders. All SOCs or individual preferred terms occurred
`in <1% of treated subjects in the tapentadol IR group. The occurrence of SAEs did not
`appear to be dose related. Details regarding all SAEs are located in Section 7.3.2.
`.
`
`’
`
`_
`Common Adverse Events
`Treatment emergent adverse events (TEAEs) occurred in 76% 0f the “all” tapentadol
`group in the multiple-dose, double-blind safety analysis set, compared to 47% in the
`placebo group and 84% in the “all” oxycodone group. The most common TEAEs in the
`tapentadol
`IR group were nausea, dizziness, vomiting,
`somnolence, headache,
`. constipation and pruritis. These occurred at a greater rate in the tapentadol IR group than
`in the placebo group. TEAEs related to asthenic conditions when combined (fatigue,
`lethargy, asthenia and malaise) were also common. The incidence of TEAEs appeared to
`be dose related.
`1
`
`83
`
`

`

`NDA 22-304
`Tapentadol HCL
`Clinical Review
`
`Ellen Fields, M.D., M.P.H.
`September 18, 2009
`
`There were no meaningfiil differences in adverse events reported with respect to age or
`racial groups. There was, however, an observation of a higher incidence of nausea,
`vomiting and dizziness in women compared to men treated with tapentadol IR or
`oxycodone IR compared to placebo.
`'
`
`A full discussion of TEAEs may be found in Section 7.4.] .
`
`Adverse Events of Interest
`The Division requested that SMQs be performed on the pooled TEAE data for 1) severe
`cutaneous reactions and 2) possible drug-related hepatic disorders.
`In the nine Phase 2/3
`multiple-dose, double-blind studies, the percentage of subjects with TEAEs included in
`the Severe cutaneous reactions SMQ was <1% in the “all” tapentadol group, similar to the
`percentage in the placebo group (<1%). The data do not point to a signal regarding
`severe cutaneous reactions of tapentadol IR. ,
`'
`
`-
`
`The percentage of subjects with adverse events included in the possible drug-related
`hepatic disorders SMQ was 1% in both the “all” tapentadol group and the placebo group.
`The most commonly reported events in the “all” tapentadol group included increased
`GGT (<l%), ALT (<1%), and AST (<l%). In evaluation of laboratory abnormalities, no
`treatment-related laboratory findings were evident for liver fimction tests. Details of the
`SMQ analyses are located in Section 7.5.5, and laboratory evaluations in Section 7.4.2.
`
`trial I-IF5503/10. This subject had a
`There was one report of seizure in the Phase 1
`history of seizures (“grand-ma] epilepsy) which was withheld during screening. He had
`stopped taking his seizure medication (valproic acid) a few months prior to enrollment in
`_ the study.
`'
`
`Laboratory Tests and Vital Signs
`The only laboratory test result or vital sign measurement that showed consistent patterns
`that would indicate a potential for clinically relevant safety concerns in the Phase 1, 2, or
`3 completed studies of tapentadol IR was oxygen saturation as measured by pulse
`oximetry. No consistent changes in cardiac parameters of heart rate or blood pressure
`were observed. In studies that measured oxygen saturation by pulse oximetry, a dose-
`dependent increase in the number of subjects with oxygen desaturation was detected with
`tapentadol IR. Similar findings were observed in with oxycodone IR; these findings
`reflect the mu-opioid agonist properties of tapentadol IR. Laboratory evaluations and
`Vital signs are discussed in Sections 7.4.2 and 7.4.3 respectively.
`
`ECG/QT Interval
`In a thorough QT Phase 1 study, no effect of therapeutic (100 mg) and supratherapeutic
`(150 mg) doses of tapentadol IR on the QT interval was shown. Similarly, tapentadol IR
`had no relevant effect on other ECG parameters of heart rate, PR interval, QRS duration,
`T—wave or U—wave morphology. The assay sensitivity of the study was validated by the
`expected QTc prolongation observed in the moxifloxacin group.
`
`84
`
`

`

`NDA 22-304
`Tapentadol HCL
`Clinical Review
`
`>
`
`Ellen Fields, M.D., M.P.H.
`September 18, 2009
`
`There was no evidence of drug-related ECG abnormalities in the analysis of ECGs
`obtained during the Phase 1, 2, or 3 studies of tapentadol IR.
`
`Evaluation of ECGs and the TQT study are discussed in Sections 7.4.4 and 7.4.5
`respectively.
`
`Drug-Disease Interactions
`The results of the Phase 1 drug—disease interaction studies in subjects with hepatic
`impairment
`(HP5503/16)
`and
`in
`subjects with renal
`impairment
`(HP5503/15)
`demonstrated that, although there were effects on the pharmacokinetics of the parent
`compound or of the major metabolite, tapentadol IR was well tolerated with a safety
`profile similar to that observed in other single-dose tapentadol IR studies in healthy
`subjects. Nevertheless, the Applicant’s dosing recommendations will reflect the results of
`the pharmacokinetic assessment in these populations, considering the potential outcomes
`in multiple-dosing situations
`
`These studies are discussed in Section 7.5.3
`
`Drug-drug interactions
`No clinically relevant interactions were observed in the 4 Phase 1 drug-drug interaction
`studies when tapentadol IR was coadministered with metoclopramide (HP5503/l9),
`probenecid (HP5503/21), naproxen
`and ASA (HP5503/22),
`or
`acetaminophen
`(HP5503/23). There was however approximately twice the percentage of reports of
`vomiting and somnolence in the group that received omeprazole plus tapentadol
`compared to tapentadol alone in Study (HP5503/20). There were not however changes in
`the PK parameters oftapentadol when coadministered with omeprazole.
`
`These studies are discussed in Section 7.5.4.
`
`Abuse liabilifl, overdose, and withdrawal
`Results from a Phase 1 study, conducted in opiate-experienced, nondependent subjects,
`showed that single doses of tapentadol IR (50, 100, and 200 mg) had a similar abuse
`liability profile to that of hydromorphone IR (4, 8, and 16 mg).
`
`No cases of overdose were reported in the completed studies with tapentadol IR.
`
`A small number of patients self-administered more than the intended daily dose of
`tapentadol IR, up to 1200mg/day for one or two days. All subjects had prior opioid
`experience and none reported an adverse event.
`
`Withdrawal was evaluated in one study (KF5503/34). Seventeen percent of subjects in
`the tapentadol treatment group reported at least one withdrawal symptom. One percent
`(9/679) of subjects experienced drug withdrawal syndrome, one of which was coded as a
`serious adverse event (elevated systolic BP, irritability and anxiety).
`
`85
`
`

`

`NDA 22-304
`Tapentadol HCL
`Clinical Review
`
`Ellen Fields, M.D., M.P.H.
`September 18, 2009
`
`is clear that withdrawal can occur following abrupt cessation of tapentadol IR
`It
`administration.
`
`There were no reports of study drug diversion.
`
`Abuse liability, overdose, and withdrawal are discussed in detail in Section 7.6.3.
`
`Comparison ‘with oxycodone
`Throughout the Phase 2/3 multiple-dose double-blind studies, oxycodone was used as an
`active comparator to assess assay sensitivity. Safety data was collected on all subjects in
`the oxycodone treatment groups, and the rates of adverse events for tapentadol IR were
`compared to both placebo and oxycodone. The incidence of gastrointestinal events
`(nausea, vomiting, and constipation) was lower in the “all” tapentadol group compared to
`the “all” oxycodone group. The overall incidence of CNS effects of somnolence and
`dizziness was similar for tapentadol IR and oxycodone treated subjects, however in study
`KF5503/32 (post—operative bunionectomy pain),
`the incidence of somnolence was
`reported approximately tWice as frequently in the tapentadol IR 100mg group (21%) than
`in the oxycodone 15mg IR group (10%).
`
`The findings in the 2 pivotal Phase 3 studies are supported by the results of the Phase 3,
`90-day safety study. In this study, comparisons between tapentadol IR (flexible doses of
`50 mg or 100 mg) and oxycodone HCl IR (flexible doses of 10 mg or 15 mg) showed a
`lower
`likelihood of nausea, vomiting, nausea/vomiting (the composite nausea or
`vomiting), and constipation with tapentadol IR vs. oxycodone IR, and a similar likelihood
`of somnolence or dizziness between the tapentadol IR and oxycodone IR treatments.
`
`.
`Pertinent negatives
`There were no reports of seizures during the development of tapentadol IR. This is
`relevant because of the known risk of seizures associated with Tramadol, and the
`similarity in the mechanisms of action of the two drugs.
`
`Given that tapentadol is structurally related to tramadol whose labeling contains language
`warning about the risks of serotonin syndrome and tapentadol’s selective norepinephrine
`reuptake inhibitor activity, tapentadol carries at least a theoretical risk of precipitating
`serotonin syndrome. Therefore, the following analysis was performed by .Dr. Robert
`Shibuya.
`'
`
`The integrated database for the Phase 2/3 studies, excluding periods when subjects were
`not on study drug (screening, post-treatment), was searched for the following verbatim
`terms:
`serotonin,
`syndrome, myoclonus,
`tremor,
`fever,
`tachycardia, diaphoresis,
`mydriasis, hyperreflexia, hyperthermia, pyrexia, clonus, and hypertension.
`Patients
`treated with morphine or ibuprofen were also excluded due to small numbers. One
`hundred and four adverse events, occurring in 101 subjects were identified. These are
`summarized in Table 32b, below.
`
`Table 32b: Adverse events associated with serotonin syndrome (tapentadol, placebo, and
`oxycodone-treated subjects only)
`
`86
`
`

`

`NDA 22-304
`Tapentadol HCL
`Clinical Review
`
`Ellen Fields, M.D., M.P.H.
`September 18, 2009
`
`111.6
`
`
`
`
`
`
`
`
`
`__—
`—-
`
`—-
`
`
`-—- 2178
`
`t—i
`411.9
`g a
`Z
`_—
`2
`_
`- 1
`r—jC/J
`14 O 6
`otal
`K
`1
`—_
`2
`_
`KHZ
`2 0.3
`.
`otal
`16 07 -.-
`2
`—-—
`3
`_—
`HK
`Tach cardia
`14 0 6
`otal
`.
`10.3
`I-
`_ no —-
`‘-
`5 —
`_ oderate
`_
`evere
`_ _—
`
`
`' _
`———
`
`Fever
`
`_—
`
`_——
`
`HTN
`
`
`
`_-
`
`
`
`
`
`Table 32b shows that the non—specific symptoms and signs associated with serotonin
`syndrome were observed more frequently in subjects treated with tapentadol than with
`the comparators. However, it_should_be noted that serotonin syndrome is a constellation
`of symptoms and signs. Three subjects experienced more than one adverse event
`associated with serotonin syndrome. Details are summarized in Table 320.
`
`
`
`Placebo
`
`Table 320: Adverse events associated with serotonin syndrome reported more than once
`in a sub'ect
`
`
`Sub'ectID
`AB
`A KFSSO4/04-005-5180
`EI!
`KF5504/04-005-5180
`
`Tach cardia
`KF5504/04-005-5232
`
`Unlikel
`Di’ahoresis
`KF5504/04-005—5232
`
`Probable
`KF5503/22-006-600001 - Diahoresis
`
`Possible
`KF5503/22-006-600001
`Diahoresis
`
`*Severity and relationship to study drug administration were both in the investigator’sjudgment
`
`
`
`
`
`
`Table 320 shows that three subjects experienced more than one serotonin syndrome-
`related adverse event. However, each subject only experienced two ABS and one of the
`subjects was treated with placebo. Therefore, it is extremely unlikely that any of these
`cases represented serotonin syndrome.
`
`Overall, there-was no evidence that tapentadol resulted in serotonin syndrome.
`
`Overall conclusions
`
`The safety profile of tapentadol IR was demonstrated in over 3500 subjects treated with
`tapentadol
`IR in the completed Phase I, 2, and 3 studies. Tapentadol IR appears
`reasonably well tolerated across the intended marketed dose range (50mg, 75mg, or
`100mg every 4 to 6 hours as needed) in both inpatient and outpatient settings. The profile
`
`87
`
`

`

`NDA 22-304
`Tapentadol HCL
`Clinical Review
`
`' Ellen Fields, M.D., M.P.H.
`September 18, 2009
`
`of adverse events is consistent with a centrally-acting compound with mu-opioid agonist
`activity. The data provided by the Applicant appears adequate, as does the exposure to
`study drug.
`
`The Applicant has submitted a risk management proposal (Section Q) that includes both
`general pharmacovigilance and product specific activities to mitigate risks associated
`with the use of tapentadol IR. A complete review of this plan has been completed by
`DRISK (June 26, 2008). At this writing, the Eight Factor Analysis for scheduling is
`underway; however the Applicant has requested a Schedule II determination for
`tapentadol IR. As a Schedule II immediate-release opioid product for the treatment of
`acute pain, a pharmacovigilance plan rather than a REMS (Risk Evaluation and
`' Mitigation Strategy) is likely sufficient to manage the risks associated with the use of
`tapentadol IR given the safety profile to date. The risks associated with the use of
`tapentadol IR are similar to the risks of other immediate—release opioids indicated for the
`treatment of pain. If post-marketing safety data reveals additional safety risks, the level of
`risk management will be reevaluated and augmented as needed.
`
`Tapentadol IR has not been studied in subjects 18 years of age or younger. Studies must
`be administered to children prior to general use in this population. The Applicant has
`submitted a Pediatric Plan that is discussed in Section l__..4 A staged deferral has been
`requested, such that older age groups will be studied prior to younger ones. This plan
`will be reviewed by PERC on October 8, 2008.
`
`7.1 Methods
`
`7.1.1 Discussion of Clinical Studies Used to Evaluate Safety
`Thirty-one clinicaltrials have been completed during the development of Tapentadol IR
`(20 Phase 1, and 11 Phase 2/3 double—blind studies). Two additional Phase 3 studies
`(KF5503/38 and KF5503/37) were ongoing at the time of the 4-month safety update, and
`are also included in the safety summary.
`
`The Applicant pooled studies for the safety data as follows:
`0
`Twenty—nine of the 31 completed clinical studies of tapentadol IR are presentedln
`5 separate pooled safety analysis sets.
`0 Two pooled analysis sets (single——dose and multiple-dose studies) of 18
`Phase 1 studies
`
`0
`
`0 Three pooled analysis sets (single-dose, multiple-dose double-blind, and
`open--label extension) of ll Phase 2/3 studies.
`.
`Safety results from 2 completed Phase 1 studies of Tapentadol IR (R331333-PAI—
`1027 in healthy Japanese subjects living in the USA; and HP5503/25, a thorough
`QT study) are presented separately.
`to safety data from other
`0 The Applicant provided references
`formulations (ER, i.v infilsions, and oral solution)m the ISS.
`0 Adverse event data from four completed Phase 2- studies of tapentadol ER were
`integrated and presented in a single pooled analysis set.
`
`tapentadol
`
`88
`
`

`

`NDA 22-304
`
`Tapentadol HCL
`Clinical Review
`
`Ellen Fields, M.D., M.P.H.
`September 18, 2009
`
`The Applicant’s figure below shows the pooling scheme:
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`89
`
`

`

`NDA 22-304
`Tapentadol HCL
`Clinical Review
`
`Ellen Fields, M.D., M.P.H.
`September 18, 2009
`
`
`
`
`
`
`
`Figure 14: Organization of Studies for the Integrated Summary of Safety
`Tapentadol IR
`
`
`
`
`Completed Studies Ongoing Studies
`
`
`Phase 1 Studies
`Phase 2/3 Studies
`Phase 3 Studies
`
`
`Phase 1 Single-Dose
`Phase 2 Single-Dose Double-Blind
`(Reorts o SAEs onl d.-
`
`
`
`
`KFéSles-L
`Safety Analysis Set:
`Safety Analysis Set:
`
`
`
`
`KF5503/35
`HP5503/03 HP5503/20
`KF5503/02
`
`
`
`HP5503/0fl HPSSO3/21
`KF5503/04 (Part 1)
`W
`
`
`
`
`HP5503/05 HPSSO3/22
`KF5503/05
`KF5503/38
`
`
`
`
`HP5503/07 HP5503/23
`KF5503/08 (Part 1)
`KF5503/39“
`
`
`
`
`
`HP5503/09 HP5503/24
`
`- HP5503/ l4 HPSSOS/27
`Phase 2/3 Multiple-Dose Double-Blind
`
`
`
`HP5503/15 HPSSO3/30
`Safety Analysis Set:
`
`
`
`HP5503/16 HPSSO3/34
`Phase 3:
`Phase 2:
`
`
`
`HP5503/19
`KF5503/04 (Part 2) KF5503/3l
`
`
`
`KF5503/08 (Part 2) KF5503/32
`
`
`KF5503/21
`KF5503/33
` Phase 1 Multiple-Dose
`KF5503/22
`KF5503/34
`
`Safety Analysis Set:
`
`
`KF5503/37
`HP5503/13
`
`
`
`Phase 3 Open-Label Extension
`
`
`Phase 1 Studies
`Safety Analysis Set:
`
`
`KF5503/32 -
`(Reported separately):
`KF5503/3]
`
`
`
`HP5503/25
`
`R33 l333-PAI-1027
`
`
`
`Tapentadol ER and
`
`
`Other Formulations
`
`
`Tapentadol ER
`V Other Formulations
`
`(R ' arts 0 SAEs on] r):
`
`
`
`
`Intravenous:
`
`
`
`HP5503/01 (Part 1)
`Ongoing Studies
`
`
`(Reports ofSAEs only):
`I—IP5503/02
`
`
`
`
`HP5503/06
`
`
`
`
`
`
`Phase 1 Studies
`Phase 2 Safety
`Phase I Study
`
`
`
`
`144550391
`SAEs only):
`(Re .
`Analysis Set:
`
`
`
`KF5503/09
`HP5503/07 HP5503/27
`HP5503/36
`
`
`
`
`HPSSOS/ZS
`HP5503/08
`KF5503/10
`Phase 3 Studies
`
`
`
`
`
`
`KF5503/19
`HP5503/10 . HPSSOS/29
`K55503/11
`KF5503/23
`
`
`
`
`
`
`
`HP5503/12 HP5503l32
`KE5503/20
`KFSSOSIIZ
`KF5503/24
`
`
`
`
`
`HP5503/l 7
`HPSSOB/35
`KF5503/15
`KF5503/36
`
`HP5503/l8
`R331333—PAI
`
`
`KF5503/16
`KF5503/39a
`
`
`-1026
`KF5503/18
`
`
`
`
`HPSSO3/ll
`KF5503/01
`Oral Solution
`HP5503/01 (Part 2)
`
`’ KF5503/39 is a Phase 3 ongoing study oftapemadol IR and tapentadol ER.
`
`Source: Tapentadol ISS, 4-month safety update p. 46
`
`A brief description of Phase 1 studies may be found in Section 9.4.
`
`Safety data for‘subjects randomized at site 011006 in KF5503/31 were excluded from
`Phase 2/3. Multiple-dose Double-blind Safety Analysis Set and Open-label Extension
`
`90
`
`

`

`NDA 22-304
`Tapentadol HCL
`Clinical Review
`
`Ellen Fields, M.D., M.P.H.
`September 18, 2009
`
`Safety Analysis Set in the integrated 4-month safety update database by the Applicant
`due to data irregularities discovered during an audit. Data for 35 subjects (1%, 35/3642)
`randomized in the double-blind treatment period and 26 subjects (5%, 26/537) enrolled in
`the open-label extension period at site 011006 in ‘KF5503/31 are presented separately.
`According to the Applicant,
`the exclusion of these data from the main analysis
`populations did not impact the results of the integrated safety analysis. This will be
`assessed in the sections below.
`
`The data irregularities were found as a result of an investigation of a single clinical
`investigator. On October 2-4, 2007, to assess concerns regarding duplicate ECG tracings
`across multiple subjects DSI performed an inspection of the study site. Details regarding
`the results of the investigation may be found in Section 3.2.
`
`7.1.2 Adequacy of Data
`
`In the individual study reports, adverse events were coded to preferred terms using
`various versions of Medical Dictionary of Regulatory Activities (MedDRA). MedDRA
`version 10.0 was used in the original NDA and updated to version 10.1 in the 4-month
`safety update. A review was performed comparing the verbatim terms to the preferred
`terms. The Applicant’s approach to safety coding appeared adequate.
`
`7.1.3 Pooling Data Across Studies to Estimate and Compare Incidence.
`
`The pooled data used in the review of safety is described in Section M. This review of
`safety emphasizes the Phase 2/3 Multiple-Dose Double-Blind, and Phase 3 Open-Label
`Extension safety analysis sets. The double-blind safety analysis set allows for the
`comparison of adverse event rates between those receiving study drug and placebo,
`whichis useful in determining possible causality. The Phase 3 Open-Label extension
`safety analysis set shows adverse events occurring after longer term use of tapentadol IR.
`Any important safety information obtained from the other safety analysis sets (Phase 1,
`Phase 2 single—dose, Phase 3 open-label) are also discussed in this review.
`
`7.2
`
`Adequacy of Safety Assessments
`
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of
`Target Populations
`
`The exposure to Tapentadol IR in terms of numbers of subjects, dose and duration, and
`demographics was adequate. The details are delineated below by safety analysis set
`groupings.
`
`Exposure
`A total of 3515 subjects were exposed to at least one dose of tapentadol IR during the
`development program. The breakdown by study phase is shown below.
`
`91
`
`

`

`NDA 22-304
`Tapentadol HCL
`Clinical Review
`
`Ellen Fields, M.D., M.P.I-I.
`september 18, 2009
`
`Table 33: Exosure to Ta-entadol IR
`
`
`
`
`
`ex nosed to ta . entadol IR
`
`Phase 2/3 multi nle-dose, double-blind
`
`
`
`2178
`3515
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`.
`Phase 1 single and multiple-dose
`In the Phase 1 Single-dose Safety Analysis Set, 439 subjects received a single-dose of
`tapentadol IR (21 to 200 mg).
`‘
`
`In the multiple-dose study (HPSSO3/I3), 2 subjects received 4 doses, 15 subjects received
`6 doses, and 8 subjects received 12 doses of tapentadol IR.
`
`Phase 2 single-dose
`A total of 870 subjects received a single dose of tapentadol IR in the Phase 2 single-dose
`Safety Analysis Set in 1 of the following dose groups: 0-30 mg (n=l38), >30-6O mg
`(n=187), >60-90 mg (n=327), and >120 mg (n=218).
`
`Phase 2/3 multiple-dose double-blind
`subjects with moderate-to-severe pain
`Two-thousand, one-hundred seventy-eight
`received tapentadol IR (21—120mg) in nine clinical studies included in the Phase 2/3
`Multiple-Dose, Double-Blind Safety Analysis Sets; 2034 of these subjects received
`tapentadol IR (50 to 100 mg every 4 to 6 hours as needed) for at least 45 days, and 318
`received tapentadol IR for at least 90 days in study KF5503/34.
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`92
`
`

`

`NDA 22-304
`Tapentadol HCL
`Clinical Review
`Table 34: DUration
`ofExposure: Phase 2/3 Multiple-Dose, DB Analysis Set
`“All”
`{SM1”
`Placebo
`
`Ellen Fields, M.D., M.P.H.
`September 18, 2009
`
`Tapentadol IR
`(n=2178
`
`Oxycodone IR
`n=675)
`
`(n=619
`
`619
`
`4.3 (3.47)
`3.0
`
`(L10)
`
`619
`
`191 (31)
`200 ( 32)
`228 (37)
`
`0 o
`
`619
`
`4.3 (3.48)
`3.0
`
`(1:12)
`
`Treatment duration, days‘
`
`N M
`
`ean (SD)
`Median
`
`Range
`
`Treatment duration category, 11 (%)’I
`
`N 1
`
`day
`22—3 days
`>3-lO days
`>10-45 days
`>45 days
`
`Total duration, daysh
`
`N M
`
`ean (SD)
`Median
`Range
`
`2178
`22.3 (34.35)
`4.0
`
`(1;105)
`
`2178
`481 (22)
`592 (27)
`535 (25)
`121 ( 6)
`449 ( 21)
`
`675
`
`17.8 (30.98)
`4.0
`
`(1;106)
`
`675
`
`142 (21)
`195 (29)
`211 (31)
`25( 4)
`102 ( 15)
`
`2178
`22.7 (34.88)
`4.0
`
`(l;105)
`
`675
`
`18.1 (31.32)
`4.0
`
`(1;111)
`
`675
`141 (21)
`192(28)
`213 (32)
`25 ( 4)
`104(15)
`ICF5503/31 (excluding
`
`.
`
`619
`
`191 (31)
`199 ( 32)
`228 ( 37)
`1 (<1)
`0
`
`Total duration mtegory, n (”/o)"
`
`N 1
`
`day
`22-3 days
`>3-10 days
`>10—45 days
`>45 days
`
`2178
`481 (22)
`586 ( 27)
`534 ( 25)
`123( 6)
`454 ( 21)
`_..,
`Studies included: KF5503/04 (Pan 2), KF5503/08 (Part 2), KF5503/21, KF5503/77
`site 011006), F5503/32, KF5503/33, H5503/34, and KF5503/37.
`calculated based on the acctnnulative number of days on treatment dining the treatment phase.
`" calculated based on the number of days on study.
`Subject R331333-PAI—3004-011002-4100880 entered both KF5503/33 and KF5503/34 studies and was
`treated with tapentadol but was counted once in the “all" tapentadol IR group by using KF5503/34 study
`data with longer treatment duration.
`SD = standard deviation.
`
`Source: Tapentadol 4—Month Safety Update, p. 96
`
`Among subjects in the “all” tapentadol IR pooled analysis treatment group, the mean total
`daily dose based on days on study drug (271.31) and the mean total daily dose while on
`study drug including days on and off study drug (269.42) were similar. The maximum
`mean total daily tapentadol IR dose taken was 800 mg.
`
`The maximum total daily dose of tapentadol IR specified in the Phase 2/3 multiple-dose,
`double-blind protocols was 700 mg on Day 1 and 600 mg thereafter. Seven subjects in
`the Phase 3 study, KF5503/34, took a total daily dose of 1200 mg for 1 or 2 days. Further
`description of these subjects is provided in Section 7.6.4 (Overdose, Drug Abuse
`Potential/ Withdrawal and Rebound).
`
`93
`
`

`

`NDA 22-304
`Tapentadol HCL
`Clinical Review
`
`-
`
`Ellen Fields, M.D., M.P.H.
`September 18, 2009
`
`.
`
`The Applicant’s table below shows the extent ofexposure by mean daily dose during the
`Phase 2/3 Multiple-Dose, Double-Blind Safety Analysis Set. The mean daily dose was
`271 mg in the “all” tapentadol IR group, with a range of 50 to 800 mg.
`
`Table 35: Extent ofExposure-Mean Total Daily Dose: Phase 2/3 Multiple-Dose, Double
`Blind
`
`Placebo
`n=619
`Mean total daily dose (mg) (days on drug only)a
`N
`619
`Mean (SD)
`0.00 (0.000)
`Median
`0.00
`Range
`(0.0;0.0)
`
`“All” Tapentadol 1R
`n=2178)
`
`“All” Oxycodone IR
`n=675)
`
`2178
`271.31 (126.570)
`250.00
`(50.0;800.0)
`
`675
`40.24 (20.872)
`35_oo
`(10.0;95.0)
`
`.
`
`-
`
`Mean total daily dose (mg) (days on/ofl’ drug)"
`675
`2178
`. N
`619
`40.04 (20.920)
`269.42 (126.910)
`Mean (SD)
`0.00 (0.000)
`35.00
`247.39
`Median
`0.00
`(2.5;95.0)
`(15.4;8000)
`Range
`(0.0;0.0)
`Studies included: KF5503/04 (Part 2), KF5503/08 (Part 2), KFSSO3/21, KF5503/22, KF5503/31 (excluding
`site 011006), KF5503/32, KF5503/33, KF5503/34, and KF5503/37.
`“ Mean daily dose calculated based on the accumulative number ofdays on treatment during the treatment
`phase.
`b Mean daily dose calculated based on the number of days on study.
`Subject R331333-PAI—3004-011002-400880 entered both KF5503/33 and KF5503/34 studies and was
`treated with tapentadol [R in each study but was counted once in the “all”_ tapentadol [R group by using
`103550364 study data with higher treatment dose.
`Source: Tapentadol IR 4-Month Safety Update, p. 98
`
`.
`Phase 3 open-label
`A total of 483 subjects received tapentadol IR (flexible dose 50 or 100 mg) during the
`Phase 3 open-label extension studies (KF5503/31 and KF5503/32). The mean duration
`of treatment was seven days, with a range of one to ten days.
`'
`
`The mean daily dose of tapentadol IR was 234.78 mg, with a range of 50 to 600 mg.
`
`Demographics
`
`_
`Phase 1 single and multiple-dose safefl analysis set
`In the Phase 1 Single-dose Safety Analysis Set, demographic and baseline characteristics
`were similar in “all” tapentadol IR and the placebo pooled analysis treatment groups.
`The majority of subjects were female (60% in the “all” tapentadol IR group and 74% in
`the placebo group) and white (82% and 87%, respectively). The mean age was 39.6 years
`in the “all” tapentadol IR group and 32.7 years in the placebo group. Mean BMI was
`24.39 kg/m2 in the “all” tapentadol IR group and 24.01 kg/m2 in the placebo group
`pooled analysis treatment groups. Table 93 in Section 9.4 illustrates the demographic
`characteristics.
`'
`
`and baseline
`study (HP5503/l3), demographic
`1 multiple-dose
`the Phase
`In
`characteristics were similar across the pooled analysis treatment groups. About half of
`subjects in the pooled analysis treatment groups were male (50% in the “all” tapentadol
`1R group and 59 % in the placebo group); the majority of subjects were white (66% and
`71%).
`
`94
`
`

`

`NDA 22~304
`Tapentadol HCL
`Clinical Review
`
`Ellen Fields, M.D., M.P.H.
`September 18, 2009
`
`Phase 2 single-dose
`Demographic and baseline characteristics were similar in “all” tapentadol IR and placebo
`pooled'analysis treatment groups in the Phase 2/ Single-dose Safety Analysis Set. Most
`subjects were White (78% in the “all” tapentadol IR group and 74% in the placebo
`group). The majority of subjects were women (68% and 69%, respectively); the median
`age of subjects was 26 years in the “all” tapentadol IR group and 25.0 years in the
`placebo group. Table 94 in Section 9.4 illustrates the demographic characteristics.
`
`Phase 2/3 multiple-dose, double-blind
`The demographic and baseline characteristics of sex, age, race, and BMI were similar
`across the placebo, “all” tapentadol IR, and “all” oxycodone IR pooled analysis treatment
`groups in the Phase 2/3 Multiple-dose Double-blind Safety Analysis Set. Approximately
`70% of the subjects were women and 75% were Caucasian. The median age was 52 years
`of age with 81% of subjects less than 65‘years of age.
`
`The percentage of subjects who participated in outpatient (non-surgical) pain model
`studies was greater in the “all” tapentadol IR (48%) and “all” oxycodone IR (51%)
`groups than in the placebo group (27%). This is due to the fact that KF5503/08 and
`KF5503/34 were designed as outpatient pain model with no placebo treatment arms. The
`percentage of subjects who participated in studies in which rescue medications were
`allowed during the double-blind period was 30% in the placebo group, 45% in the “all”
`tapentadol IR group and 35% in the “all” oxycodone IR group; not all subjects in these
`studies took rescue medications.
`
`The Applicant’s table below illustrates the demographic characteristics of subjects in the
`Phase 2/3 Multiple-Dose, Double—Blind Safety Analysis Set.
`
`APPEARS THIS WAY
`0N ORlGlNfiI
`
`95
`
`

`

`ND_A 22—304
`Tapentadol HCL
`Clinical Review
`
`‘
`
`Ellen Fields, M.D., M.P.H.
`September 18, 2009
`
`Table 36: Demographic Characteristics: Phase 2/3 Multiple-Dose, Double-Blind Safety
`Analysis Set
`
`Sex, 11 (%)
`N
`Female
`Male
`
`Race/Ethnicity Group, 11 (%)
`N .
`White
`Black
`Hispanic
`Other
`
`Age (years)
`N
`Mean (SD)
`Median
`Range
`Category
`<65
`265 to <75 years
`275 years
`
`Body mass index (kg/m2)
`N
`Mean (SD)
`Median
`Range
`
`Pain model, u (%)
`N
`Preoperativea
`Postoperativeb
`
`Placebo
`n=619
`
`’
`
`“All” Tapentadol IR
`n=2178
`
`'
`
`“All” Oxycodone 1R
`(n=675
`
`-
`
`‘
`
`619
`463 ( 75)
`156 (25)
`
`619
`460 (74)
`61 (”10)
`86 ( 14)
`12(2)
`
`--
`
`619
`49.3 (16.38)
`52.0
`(18;83)
`
`499 ( 81)
`92 ( 15)
`28 ( 5)
`
`.
`
`_
`
`.
`
`618
`29.1 (6.79)
`28.0
`(16;60)
`
`619
`159 ( 27)
`45003)
`
`2178
`1448 ( 66)
`730 ( 34)
`
`2178
`1644 ( 75)
`219( 10)
`259 ( 12)
`56( 3)
`
`2178
`51.0 (14.96)
`52.0
`(18:85)
`
`1759 ( 81)
`316( 15)
`103 ( 5)
`
`2176
`29.8 (6.96)
`28.6
`(16;76)
`
`2178
`1043 ( 43)
`1130(52)
`
`675
`457 (68)
`218 (32)
`
`675
`509 ( 75)
`77 ( 1])
`80( 12)
`9( 1)
`
`675
`52.6 (14.79)
`55.0
`(18;84)
`
`524 ( 78)
`119( 18)
`32 ( 5)
`
`674
`30.3 (6.89)
`29.3
`(16;63)
`
`675
`342 ( 51)
`333(49)
`
`'
`
`Rescue medication allowed, 11 (%)
`675
`2178
`619
`N
`438 ( 65)
`1204 ( 55)
`436 ( 70)
`NO
`237 ( 35)
`974 ( 45)
`183 ( 30)
`Yes
`Studies included: KF5503/04 (Part2), KF5503/08 (Part 2), KF5503/21, KF5503/22, KF5503/31
`a
`(excluding site 011006) KP5503/32 KF5503/33. KF5503/34, and KF5503/37
`bindicates an outpatient pain model.
`'
`bindicates an inpatient pain model
`Subject R331333-PAI—3004~011002-400880 entered both KF5503/33 and KF5503/34 studies and was
`treated with tapentadol IR111 each study but was counted once in the “all” tapentadol IR group.
`source: Tapentadol 4-Month Safety Update, p. 103
`
`Phase 3 open-label
`A total of 483 subjects received tapentadol IR (flexible dose 50 or 100 mg) during the
`open-label studies. The majority of subjects in the Phase 3 open-label studies were female
`(82%), Caucasian (61%), and less than 65 years of age (86%). The average age was 48.8
`years.
`.
`
`96
`
`

`

`NDA 22-304
`Tapentadol HCL
`Clinical Review
`
`7.2.2 Explorations for Dose Response
`
`See Section 7.4.l
`
`Ellen Fields, M.D., M;P.H.
`September 18, 2009
`
`7.2.3 Special Animal and/or In Vitro Testing
`The overall assessment of data fi'om the preclinical development program of tapentadol
`did not
`identify human-relevant safety signals related to teratogenicity,
`fertility,
`genotoxicity or carcinogenicity.
`
`Safety pharmacology studies analyzed potential side effects of tapentadol on vital organ
`systems.
`In general, side effects were consistent with opioid activity. At supra—
`antinociceptive doses,
`there were compound-related relevant effects on the CNS,
`cardiovascular, respiratory and gastrointestinal systems.
`
`The cardiovascular effects were assessed clinically in a thorough QT study, which
`showed that tapentadol is not associated with QTc prolongation.
`
`For details regarding preclinical studies and their results, the reader is referred to Dr.
`Kathleen Young’s pharmacotoxicological review.
`
`7.2.4 Routine Clinical Testing
`
`The routine clinical testing performed during the development of tapentadol IR appears
`adequate.
`
`7.2.5 Metabolic, Clearance, and Interaction Workup.
`The reader is referred to Section fl and the Cli