CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-304
`
`PHARMACOLOGY REVIEW} S!
`
`

`

`Tertiary Pharmacology Review
`
`By:
`
`Paul C. Brown, Ph.D., ODE Associate Director for Pharmacology and Toxicology
`0ND 10
`
`NBA: 227304
`Submission date: January 23, 2007
`Drug: tapentadol
`Sponsor: Ortho-McNeil Pharmaceuticals
`Indication: moderate to severe pain
`
`Reviewing Division: Division of Anesthesia, Analgesia, and Rheumatology Drug
`Products
`
`Introductory Comments:
`The pharm/tox reviewer and supervisor found the nonclinical information submitted for
`tapentadol to be sufficient to support its use for the proposed indication.
`
`Reproductive and developmental toxicity:
`The reviewer and supervisor agreed with the sponsor’s proposed pregnancy category of
`C. Studies in rats and rabbits showed that tapentadol was not teratogenic in the rat but it
`did induce some malformations at high maternally-toxic doses in the rabbit. The reviewer
`and supervisor recommended that information LA
`”HA be deleted from the labeling since toxicokinetic data from these
`studies were not available, whereas toxicokinetic data were available fiom subcutaneous
`studies and since the subcutaneous study in rabbits did show some effects at high doses.
`The reviewer has expressed the margin of exposures for the various studies based on a
`
`comparison of AUC in the human and animals rather than on
`7
`_
`-
`as
`originally proposed by the sponsor. I agree that it is preferable to use AUC comparisons.
`
`Carcinogenicity:
`The executive carcinogenicity assessment committee found no drug-related tumors in
`either the rat or mouse study conducted with tapentadol. Therefore, I agree that the
`, labeling can state that no increase in tumor incidence was observed in either species.
`
`Animal Toxicology and/or Pharmacology:
`The wording proposed by the sponsor for this section of the labeling included a
`description of a variety Of CNS effects observed1n toxicology studies. The reviewer and
`supervisor recommend that this section be edited to emphasize the occurrence of
`convulsions, particularly since these were observed1n dogs at plasma levelsin the range
`of those achieved in humans at the maximum recommended human dose. I agree that it is
`acceptable to include this information in the labeling since this is a significant adverse
`effect that may be caused directly by the drug, and a description of this finding may be
`useful information should someone experience such an adverse effect.
`
`Conclusions:
`
`I concur with the Division pharm/tox conclusion that the nonclinical data support
`approval of this NDA. I concur with the labeling recommended by the supervisor.
`
`

`

`
`
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`
`/S/
`
`Paul Brown
`11/19/2008 05:38:19 PM >
`PHARMACOLOGI ST
`
`

`

`)l/ZD, 0%
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Supervisory Pharmacologist Memorandum (#3)
`
`NDA NUMBER:
`
`SERIAL NUMBER:
`
`00—000
`
`000
`
`DATE RECEIVED BY CENTER:
`
`23-JAN-2008
`
`PRODUCT:
`
`V
`
`(Proposed) Trade Name:
`
`Not Finalized
`
`Established Name:
`
`Tapentadol HCl
`
`INDICATION:
`
`SPONSOR:
`
`Relief of Moderate to Severe Acute Pain
`
`., Ortho-McNeil-Janssen Pharmaceuticals, Inc
`
`DOCUMENTS REVIEWED:
`
`‘ N/A
`
`REVIEW DIVISION:
`
`PHARM/TOX REVIEWER:
`
`PHARM/TOX SUPERVISOR:
`
`DIVISION DIRECTOR:
`PROJECT MANAGER:
`
`Division of Anesthesia, Analgesia and
`
`Rheumatology Products (HFD-l70)
`
`.
`
`Kathleen A. Young, Ph.D.
`
`Adam Wasserman, PILD.
`
`Bob Rappaport, M.D.
`Matthew Sullivan
`
`Page 1 of 2
`
`NDA 22-304 Tapentadol HCl
`Ortho-McNeil-Janssen Pharm.
`
`

`

`Background/Purpose
`
`This addendum to the NDA serves to correct an error in human AUC value at the
`maximum recommended human dose (MRHD) which was used to calculate safety
`margins in the nonclinical NDA review and Supervisory memo. The exposure value used
`to calculate safety margins in the original review was based on an AUCo_t (area under the
`plasma concentration-time curve for a dosing interval) which was estimated to be 500
`ng*h/mL at the MRHD. However, this exposure value is representative of only a single
`dosing period within the day. As tapentadol is administered up to 6 times per day, the
`AUC0_24 h, is therefore approximately 6X higher '(i.e. ~ 3000 ng*h/mL). Cmax, however,
`remains roughly the same (~30% increase) with multiple dosing during the day.
`
`The impact .of this change does not alter the recommendation for approval from the
`nonclinical standpoint though an approximately
`1—"
`reduction in safety margins as
`expressed in the previously recommended nonclinical sections of the label (from Memo
`#2) were subsequently necessary. These margins have been negotiated with the
`Applicant and agreement reached in the final label.
`
`“(4)
`'
`
`General toxicology studies of chronic duration in the rat and dog identified NOAELs
`which are below the daily AUC exposure associated with the MRHD. The principal
`target organs identified include the liver in the rat and the CNS in the dog. For the dog
`the principal toxicity is convulsion, therefore the toxicokinetic parameter of importance is
`likely Cm;x which is not greatly affected by the change to the AUC0_24 hr. The original
`review and Supervisory memo indicated that the human exposure was not supported by
`the nonclinical NOAEL; however, in both species the adverse findings were reversible
`and clinical data has been provided to address these findings.
`
`Reproductive toxicology sections of the label now indicate exposures associated with the,
`NOAEL in the studies are generally below the exposures associated with the MRHD.
`Studies were conducted up to maximum tolerated maternal dose and were negative for
`direct toxicity to the fetus though findings were observed 'at frank maternally toxic doses
`and are described in the label.
`'
`
`Carcinogenicity studies, which were negative for drug-related tumor development in both
`mouse and rat, were conducted up to the maximum tolerated dose as agreed through
`evaluation by the Executive Carcinogenicity Assessment Committee. The re-analysis
`using the correct AUC comparison does not provide safety margins for exposure at the
`MRHD, however. This is described in the negotiated labels
`
`Page 2 of 2
`
`NDA 22-3 04 Tapentadol HCl
`Ortho—McNeil-Janssen Pharm.
`
`

`

`This'Is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Adam Wasserman
`11/20/2008 11:33 :08 AM
`PHARMACOLOGIST
`
`

`

`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Supervisory Pharmacologist Memorandum (#2)
`
`NDA NUMBER:
`
`SERIAL NUMBER:
`
`DATE RECEIVED BY CENTER:
`PRODUCT:
`
`22-304
`
`000
`
`23-JAN-2008
`
`(Proposed) Trade Name:
`
`Established Name:
`
`Not Ffinalized
`
`Tapentadol HCI
`
`INDICATION:
`
`SPONSOR:
`
`'
`
`Relief of moderate to severe acute pain
`
`Ortho-McNeiI-Janssen Pharmaceuticals, Inc;
`Johnson & Johnson
`
`DOCUMENTS REVIEWED:
`
`Proposed package insert and addendum to Dr.
`
`REVIEW DIVISION:
`
`PHARM/TOX REVIEWER:
`PHARM/TOX SUPERVISORE
`DIVISION DIRECTOR:
`PROJECT MANAGER:
`
`Young’s review
`
`Division of Anesthesia, Analgesia and
`
`Rheumatology Products (HFD—170)
`
`Kathleen A. Young, PILD.
`Adam Wasserman, Ph.D.
`Bob Rappaport, M.D.
`Matthew Sullivan
`
`

`

`EM6'”I'll/5'SUM/111M]
`
`I.
`
`BACKGROUND
`
`This memo serves to document the rationale underlying the recommendations made by
`the nonclinical team to the proposed package insert for Tapentadol HCl.
`
`Page 2 of 8
`NDA 22-304 (Memo #2)
`Tapentadol HCl
`Ortho-McNeil—Janssen/Johnson & Johnson
`
`

`

`é
`
`Page(s) Withheld
`
`_Trade Secret / Confidential (b4)
`/ Draft Labeling (b4)
`
`Draft Labeling (b5)
`
`Deliberative Process (b5)
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Adam Was serman
`10/23/2008 03:32:22 PM
`PHARMACOLOGIST
`
`

`

`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Supervisory Pharmacologist Memorandum
`
`NDA NUMBER:
`
`SERIAL NUMBER:
`
`22-304
`
`000
`
`DATE RECEIVED BY CENTER:
`
`1/23/2008
`
`PRODUCT:
`
`(Proposed) Trade Name:
`
`N/A
`
`Established Name:
`
`Tapentadol HCI
`
`INDICATION:
`
`SPONSOR:
`
`Moderate to Severe Pain
`
`Ortho-McNeil—Janssen-Pharmaceuticals,
`
`Inc; Johnson & Johnson
`
`DOCUMENTS REVIEWED:
`
`Primary NDA review of Dr. Kathleen
`
`REVIEW DIVISION:
`
`Young; electronic NDA submission
`
`Division of Anesthesia, Analgesia and
`Rheumatology Products (HFD—l70)
`
`PHARM/TOX REVIEWER:
`PHARM/TOX SUPERVISOR:
`
`Kathleen A. Young, Ph.D.
`Adam Wasserman, Ph.D.
`
`I
`
`DIVISION DIRECTOR:
`
`Bob Rappaport, M.D.
`
`PROJECT MANAGER:-
`
`Matthew Sullivan
`
`

`

`AZXZRZDTY12?JZZh0hQLEQ7
`
`I. BACKGROUND
`
`The present NDA has been submitted by Johnson & Johnson Pharmaceutical Research
`and Development on behalf of Ortho—McNeil-Janssen Pharmaceuticals, Inc. for
`marketing authorization of Tapentadol HCl, a centrally active u—opioid agonist possessing
`norepinephrine reuptake (NET) inhibition properties, which has been developed for the
`treatment of moderate to severe acute pain. Tapentadol HCl is fomiulated as immediate
`release (IR) tablets of 50, 75, and 100 mg and proposed dosing will allow for Q4h dosing
`Ee. 600 mg/day with 700 mg/day allowed on the first day ofuse) C
`=1 3
`L-
`] TapentadolIS in a similar pharmacologic class asTramadol (Ultram®),
`which shares the same u—opioid—NET inhibition pharmacologic profile. Although
`Tramadol isunscheduled with the Drug Enforcement Agency, Tapentadol HCl13 being
`proposed to be a C-11 scheduled drug due to concerns of abuse potential.
`
`, 3(4)
`
`A. Regulatory Summary (Pharmacology/Toxicology)
`Regulatory issues which required interaction and agreements with the Applicant during
`tapentadol development primarily centered on the evaluation of the major human
`metabolite, tapentadol- O-glucuronide, which due to high first pass metabolism with the
`oral route circulates at levels substantially higher (20—30X) than the parent at the
`maximum recommended human dose (MRHD). The Applicant was advised that
`nonclinical models would need to provide support for the safety of metabolite levels and
`several safety evaluations were recommended.
`
`II. MAJOR NONCLINICAL ISSUES IDENTIFIED IN PRIMARY REVIEW
`
`A. General Toxicology Findings
`CNS (rat and dog)
`The primary target organ identified in all nonclinical species was the central nervous
`system (CNS). Observational signs were typical of a u-opioid agonist and/or NET
`inhibitor and included evidence of CNS depression (recumbency, decreased/irregular
`respiratory rate, and decreased activity) as well as paradoxical evidence of CNS
`stimulation including hyperactivity, increased sensitivity to touch/noise and enhanced
`escape responses, tremors and convulsions.
`In general, CNS observations reduced in
`intensity/incidence with repeated dosing indicative of tolerance —— a common aspect of 11-
`opioid pharrnacodynamics though some effects did not show tolerance, including
`,
`convulsions which may indicate a NET inhibition effect._ Convulsive activity was most
`prominent in the dog in both short-term repeat-dose studies through the subcutaneous
`(SC) and oral (PO) route as well as in longer studies up to 52 weeks duration with P0
`dosing. Of concern, convulsions observed in the dog were associated with exposure
`levels that do not support human exposures. Convulsions were not seen in the rat with
`
`Page 2 of 9
`
`NDA 22-304
`Tapentadol HCI
`Ortho-McNeil/Johnson & Johnson
`
`

`

`PO administration; however, convulsions were observed in rat studies of CNS safety in
`which tapentadol was administered intravenously at high doses, and in one study
`demonstrated a late—developing convulsion component to the CNS safety profile. Dr.
`Young indicated that the levels of parent and glucuronide metabolite were below the
`limits of detection in both plasma and CSF at this time—point (12 hrs post—administration)
`and therefore the mechanism for this toxicity was unclear from the study. The
`Applicant’s hypothesis that this could be caused by an unidentified metabolite in “deeper
`CNS compartments” was not investigated. A direct pro-convulsant effect for the parent
`or primary glucuronide metabolite was also continued with demonstration that tapentadol
`lowered seizure-threshold (as measured by increased incidence) when administered
`intravenously prior to injection of the convulSant pentylenetetrazole. Although one study
`in rat indicated these convulsions were not prevented by pre-treatment with the broad-
`spectrum opioid receptor antagonist naloxone administered intraperitoneally (lP) (but
`were inhibited by diazepam and phenobarbital), a second study reported that these
`observations (and other clinical signs) were blocked dose-dependently by IP or IV
`naloxone. This distinction is important in that attribution of convulsions to a u—opioid
`effect places the risk within the known profile of opioids and not a direct effect of
`secondary pharmacology of the molecule for which the human relevance is less clear by
`prior clinical experience. Upon examination of the two studies, it appears that the
`inconsistency may be due to the different routes of administration and resulting naloxone
`exposures; this is supported by re-testing of the dose/1P route used in the initial
`exploratory study which was previously only moderately effective. In contrast, IV
`naloxone clearly inhibited the convulsive effect (as well as with most of the other clinical
`signs) associated with high dose IV tapentadol in the rat, supporting the Applicant’s
`contention that this is predominantly a u—opioid-mediated effect. Dr. Young’s review
`notes that convulsions observed in the 52—week chronic toxicity study in dog were
`reversible with naloxone administration, strengthening a opioid-mechanism argument.
`That evidence of tolerance did not occur in both species is of some concern and may
`indicate that some aspect of this toxicity is mediated by NET inhibition. Nevertheless, a
`similar drug — tramadol — which also has a NET inhibitory component in addition to the
`u—opioid activity has a known clinical adverse event (AE) profile which includes seizures,
`especially with overdose. Although it might have been best to have a head-to-head
`comparison of the 'pro-convulsant activities of tapentadol relative to tramadol, I agree
`with Dr. Young that the clinical safety database of~3500 patients without demonstration
`of seizure activity is somewhat reassuring. Nevertheless, seizures were not reported in
`clinical studies of tramadol and tramadol ER (500+ and 3000+ exposures) clinical trials
`but seizures were detected through post-marketing reports and as the propensity of this
`class (both u-opioid as well as the p-opoioid/NET inhibition) are well known and can be
`addressed in the product label as it is clearly communicated in the Ultram® (tramadol)
`label. Intriguingly, it is noted that the label for tramadol states that convulsions in animals
`was ameliorated by barbiturates and benzodiazepines but, in contrast to tapentadol, was
`worsened by administration of naloxone. This latter finding may be expected if
`convulsions were primarily or exclusively driven by NET inhibition and opioid—induced
`
`Page 3 of 9
`
`NBA 22-304
`Tapentadol HCl
`Ortho-McNeil/Johnson & Johnson
`
`

`

`CNS depression is blocked with an antagonist. It is possible the pharmacologic
`foundation of the convulsions observed with tapentadol is slightly different, however.
`
`Liver (rodent)
`Liver findings described in Dr. Young’s review of the rodent (mouse and rat) toxicology
`data appears to most likely be explained by hepatic enzyme induction, likely of Phase 2
`rather than Phase 1 metabolizing enzymes. Evidence of increased liver weight and
`centrilobular hepatocellular hypertrophy was noted in the mouse 13-week study and rat
`l3- and 26-week studies with correlative increased LFTs. Hepatic necrosis was not
`generally observed in rodent toxicology studies with the exception of a 4-week high—dose
`IV study in the rat and with very high PO doses in the mouse (2500 mg/kg/day). Fatty
`deposits in the liver was noted at all dose levels - including controls - in the chronic rat
`study though the elevated incidence in the high dose group may reflect increased lipid
`transport from periphery to liver to satisfy energy requirements as this was coincident
`with significant reduction of body weight and early reduction in food consumption. It is
`worth noting that hepatic necrosis was not observed in the treatment group receiving the
`highest dose (450 mg/kg/day) which demonstrated large increases in LFTs and this group
`was terminated early at study week (SW)13 due to mortality in the face of severe CNS
`signs. The 300 mg/kg/day level which provide a significant margin of exposure over
`human clinical dose, while not well tolerated due to CNS effects, also showed no
`evidence of necrotic changes or significant hepatic pathology at the end of 26 weeks of
`dosing. All hepatic changes were considered reversible upon examination after 8-week
`treatment-free recovery period. Hepatic effects were not an observed toxicity in the dog
`studies through the SC or PO route, including the pivotal 52-week chronic oral study.
`It
`must be noted that due to poor CNS tolerability that the maximum tolerated dose
`provides limited assurance of safety as this dose was associated with an AUC that is
`slightly below or at best roughly equivalent to the human AUC; therefore, no safety
`margins could be developed to support safety.
`
`Cardiovascular system (dog)
`Nonclinical safety studies provided an equivocal signal for cardiovascular toxicity. In
`vitro evaluation of hERG channel blockade identified a potential for blockade as well as
`prolongation of the action potential in isolated cardiac tissue though this was reached at
`high concentrations (28 pg/mL; 270-fold above human Cmax at MRHD). No
`prolongation was noted in other isolated or more intact in vitro/ex vivo preparations such
`as in guinea pig papillary muscles or isolated, spontaneously beating rabbit hearts. The
`Applicant also examined the glucuronide metabolite ~ critical as the circulating levels are
`far in excess of the parent - and determined that this species does not block the hERG
`channel or prolong action potential duration (APD) in vitro. In vivo the cardiovascular
`profile was mixed but appeared to depend on the state of consciousness: Hypotension
`and decreased cardiac output was observed in anesthetized preparations while in
`.
`conscious animals (rat and dog) increased HR and BP was observed.
`In a 13—week and in
`the 52—week chronic dog study there was mild QT prolongation noted at the highest dose
`evaluated (+7—10% by Van de Water’s or Fridericia’s correction associated with a Cmax 1-
`
`Page 4 of 9
`
`.
`
`NDA 22-304
`Tapentadol HCl
`Ortho-McNeil/Johnson & Johnson
`
`

`

`2X human levels; glucuronide Cmax 16X human levels). No significant effect on ECG
`was apparent at the mid-doses though Cmax at this level does not provide support for
`human use (.25 - .40X human maximal concentrations). Nevertheless, this concern has
`been largely addressed in clinical trials, and a thorough QT study at supra-therapeutic
`levels was negative according to the clinical review of Dr. Ellen Fields.
`
`Gastrointestinal system (rat and dog)
`GI toxicity noted by Dr. Young primarily involved typical alterations in food
`consumption and slowed transit associated with u—opioid agonist drugs but also was
`suggested by local toxicity in which dogs administered tapentadol by the oral route at
`high dose displayed activated lymphocytes in Peyer’s patches ofthe intestines and gastric
`mucosa. The significance of these findings is not clear: they did not appear in all oral
`studies and the findings reversed in studies in which a recovery group was included. A
`general local intolerance was observed with parenteral dosing, particularly SC. However,
`administration oftapentadol did appear to generate GI hemorrhage in a 13-week study
`and this would not be expected to be a result of local intolerability.
`
`Adrenal gland
`. Adrenocortical hypertrophy was observed in a 13-week dog study by the PO route.
`Findings were only observed in males, were noted at lower incidence and severity in
`controls, but was not associated with any overall changes in adrenal weight and
`histological abnormalities were absent in recovery group animals. Thymic atrophy was
`also noted and theApplicant proposed a stress response as the principal underlying
`explanation for both findings. Neither effect was observed in the 52-week chronic dog
`study which suggests these findings have limited relevance.
`
`.
`3. G’e/zetlk’ betZ’o/qu fi'lm’ilzgs
`The Applicant conducted the standard battery ofgenotoxicity tests and due to a positive
`finding in an initial chromosomal aberration assay, this assay was repeated, found to be
`negative, and argued that the negative follow-up study in combination with a negative in
`Vivo micronuclcus assay in rat as well as a negative Unscheduled DNA Synthesis (UDS)
`assay argued that the weight-of-evidence suggests tapentadol is not genotoxic. Dr.
`Young notes that the positive finding in the chromosomal aberration assay occurred only
`in the condition in which the target cells (V79 hamster fibroblasts) were exposed to
`tapentadol in the presence of a rat liver (S9) metabolizing system. She suggests that this
`indicates a genotoxic potential by an unidentified metabolite under the conditions ofthe
`assay and fiirther that the potential for clastogenicity by tapentadol in humans cannot be
`ruled out. While it is perhaps likely that the clastogenic finding is associated with a
`metabolite (as conditions without the S9 system were negative), it is noted that this initial
`study did not use current methodologies — in particular the incubation duration with S9
`was far in excess of that used in current protocols (l8 and 28 hr vs. 3-6 hr, respectively)
`and long exposure to this preparation has been associated with false positive results
`(Kirkland et al., 1989). When current study protocols were used there was no evidence of
`
`Page 5 of 9
`
`'
`
`'
`
`NBA 22-304
`Tapentadol l~lCl
`Ortho-McNeil/Johnson & Johnson
`
`

`

`clastogenicity. While this is reassuring, it is also important to note that the rat liver S9
`preparation may produce metabolites “quite different from those produced by normal
`human liver metabolism” (Kirkland et al., 2007) and fiirthermore‘the relative levels of
`CYPIA and CYPZB compared to other CYP isoforms are greater than in standard liver
`tissue which may lead to the non-representative profile of metabolite exposure. Most
`important for the evaluation of tapentadol, however, is that in the rat liver S9 preparation
`there is practically no activity of Phase 2 hepatic enzymes. Therefore, it would be
`expected that in this condition there is virtually no exposure to the primary metabolite
`tapentadol-O-glucuronide (and therefore any positive finding is unlikely to be due to this
`metabolite, even if not an artifact of an outdated protocol). This does of course raise the
`point that the in vitro evaluations of genotoxicity (Ames assay, chromosomal aberration
`assay) did not evaluate the glucuronide metabolite; however, this would have been
`evaluated in the in vivo micronucleus assay and UDS assay, both of which were negative.
`Therefore, I agree with the Applicant that the findings suggest tapentado]15 not genotoxic
`under current accepted assay conditions.
`I agree with Dr. Young that the negative
`carcinogenicity data adds fiirther reassurance
`
`CI Carthage/1127'” findings
`Tapentadol administration was not associated with tumor development in 2-year rat and
`mouse bioassays1n the evaluation by Dr. Young; an assessment to which the Executive
`Carcinogenicity Assessment Committee concurred.
`
`D. Iqlrodflctiue Toxicology filmy/(gs
`Fertility and Early Embryonic Development (Segment 1)
`No statistically significant effects were noted on fertility or reproductive performance
`following IV administration oftapentadol (0, 3, 6, or 12 mg/kg) prior to mating in both
`male and female rats through the early part of gestation in females according to Dr.
`YOung’s review. These study endpoints (fertility, reproductive performance) are not
`especially sensitive measures in highly multiparous species like rodents, however. As
`noted by Dr. Young, statistically significant and dose—related pre-implantation loss was
`observed in the study at 2 MD level as was significantly increased pest-implantation loss
`(deaths) during the embryonic or fetal stage which resulted in a statistically significant
`decrease in the number of living fetuses in the HD group. Dr. Young concurred with the
`Applicant that embryofetal toxicity was likely explained by the significant maternal
`toxicity present in pregnant dams in the MD and HD treatment groups. There was
`significantly reduced body weight gain and decreased food consumption in these treated
`groups compared with controls and this may be a partial explanation. However, the
`effects do not appear to be dramatic (+1 vs. 2.9% body weight gain in treated vs. control
`animals; -3 to -9% food consumption vs. controls; with most observed of the decline
`prior to mating); opioids have known effects on fertility through actions on the
`hypothalamic-pituitary—gonadal axis and it would seem possible or perhaps likely that
`this route may also be involved. No evaluation of pituitary hormones or sex steroids was
`provided to examine this possibility directly, however. Regarding effects on male
`reproductive capacity, treatment-related pathology was not noted in male reproductive
`
`Page 6 of 9
`
`NDA 22-304
`Tapentadol HCl
`Ortho-McNeil/Johnson & Johnson
`
`

`

`organs though the most sensitive measure of effects involving the male reproductive
`system require evaluating the complete stages of the spermatogenic cycle which was not
`undertaken. As effects observed do not suggest a strong male-associated component this
`is not necessary for study validity. Toxicokinetic evaluation was not performed for the
`study or in a dose-range finding study, therefore a comparison to human exposure at the
`.MRHD is not straightforward. Dr. Young notes a 4-week IV study with similar dosing
`(0, 3, 7, or 15 mg/kg) which she indicates would only provide a safety margin of~0.4X
`MRHD by AUC comparison. The label will indicate this lack of a safety/exposure
`margin.
`
`Overall, the results of these studies suggest that tapentadol does not present a significant
`risk for fertility at the admittedly low exposure levels achieved though embryofetal
`toxicity should be described in the label as part of this discussion. It should be noted that
`these findings are generally in line with other opioids and appear to be very similar to
`findings described in the package insert for the pharmacologically— and structurally-
`related tramadol.
`
`Emé/yofem/a’eve/qwrzeflt flag/22612! 2/
`Studies to evaluate embryofetal development were conducted by both the SC and IV
`route in rats and rabbits. Tapentadol was not associated with embryofetal malformations
`in the rat with either route when administered at dose levels (up to 15 mg/kg/day IV or 20
`mg BID SC) which produce significant maternal toxicity including lethality. These
`studies indicate the absence of teratogenicity in the rat with maternal dose levels
`producing 3-fold the AUC exposure observed at the MRHD. Evidence of embryofetal
`toxicity included delays in skeletal maturation (i.e. reduced ossification).
`I concur with
`both Dr. Young’s review and the Applicant that these probably reflect a secondary
`outcome of maternally toxic doses. Evaluation of tapentadol in the rabbit, however,
`revealed teratogenicity though this occurred only in the setting of very significant
`maternal toxicity. An IV study conducted with doses up to 9 mg/kg/day IV (once daily)
`did not detect malformations even at the high dose which was associated with moderate
`to severe CNS sings such as tremors and opisthotonus. The examination conducted did
`not appear to evaluate visceral tissues (only skeletal and external structures were
`evaluated). A follow-up study with dosing up to 12 mg/kg/BID (Le. 24 mg/kg/day) by
`the SC route produced runts at the MD and HD and identified multiple internal visceral
`malformations in runts and non-runt fetuses. In addition to evidence of skeletal delays
`and other variations, malformations such as gastroschisis/thoracogastroschisis,
`amelia/phocomelia, and cleft palate was observed at Z 10 mg/kg/day; albepharia,
`encephalopathy, and spina bifida in the 24 mg/kg/day fetuses. Overall, fetal viability was
`also compromised. Findings were observed at dose levels which were associated with
`significant maternal toxicity as indicated by transiently decreased food consumption (-49,
`-77, and -92% vs. controls over dosing period of Gestation days 6-20), body weight loss
`(-11 to -18%), and abdominal position afier dosing. The Applicant appears to make two
`arguments at the same time: 1) Malformations are likely due to severe maternal toxicity;
`and/or 2) Malformations are within the historical control data for the laboratory and
`species. Dr. Young indicates that either may be true, and the Applicant has provided
`
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`literature and'historical control data to support both arguments. Despite the findings
`being largely within the HCD of the laboratory/species, I do not agree that the findings
`are likely to represent incidental background findings. Data clearly indicates that a dose-
`effect is observed for malformations (incidence of 0, 0, 2, and 6 fetuses from control, LD,
`MD and HD litters). I do agree that the findings are likely caused by nutritional deficits
`observed in dams at these doses and that tapentadol does not appear to be a direct
`reproductive teratogen. These findings will be described in the package insert along with
`the information on maternal toxicity. Toxicokinetic evaluation indicates that the NOAEL
`dose is associated with an exposure that is roughly equivalent to that observed in the
`human at the MRHD. The package insert for Ultram® does not describe malformations
`though it is unclear if the doses explored produced a similar degree of maternal toxicity.
`
`Pre— (MdPyramid!Develop/”emailDevelop/72612! (fag/”exit )7
`Oral administration oftapentadol up to 150 mg BID to pregnant rats through parturition
`and lactation resulted in significant maternal toxicity with doses of2 75 mg BID. Pup
`body weight was significantly reduced in the (maternal) high dose treatment group and
`increased pup mortality over the first 4 days post-birth was noted at 2 25 mg BID. No
`significant postnatal developmental effects on neurobehavioral or reproductive
`parameters were noted in surviving progeny. These findings are described in the
`Applicant’s proposed labelA
`
`
`
`and provide a false safety margin which is actually absent
`when using toxicokinetic comparison. Dr. Young has appropriately noted this issue.
`Again, it is usefiil to note that the package insert for Ultram® describes similar results
`though safety margins are based on BSA.
`
`Otfierlrsues
`
`The Applicant conducted a pharmacologic screen of major and minor metabolites and
`found that the major metabolite tapentadol- aglucuronide did not bind to opioid
`receptors or any other screened receptor or enzyme. Supporting this apparent lack of
`pharmacology, tapentadol- O-glucuronide was without effect in a nonclinical pain model
`for which opioids, including the tapentadol parent, is active. Further evaluation of the
`major metabolite in cardiovascular safety pharmacology studies demonstrated an absence _
`of effect 1'17 Vllro on hERG channel as well as in an Action Potential Duration evaluation
`in isolated cardiac tissue. The applicant furthermore provided toxicokinetic data that
`established that nonclinical models used in toxicology studies efficiently produced the
`metabolite tapentadol-aglucuronide at levels which exceed the human exposure.
`
`Tapentadol is a u—opioid agonist and therefore is considered to have significant abuse
`liability. The proposed scheduling of tapentadol as a 011 substance is perhaps merited
`(see review by Controlled Substance Staff) though it is worth noting that the very similar
`u—opioid agonist/NET inhibitor tramadol is currently unscheduled.
`
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`III.ADVISORY COMMITTEE ISSUES
`N/A
`
`IV. RECOMMENDATIONS
`
`A. Recommendation on approvability
`I concur with the recommendation made by Dr. Kathleen Young that the
`application may be approved from the nonclinical perspective.
`
`B. Recommendation for nonclinical studies
`
`I am in agreement with Dr. Young that no fithher nonclinical studies a