Reviewer: Kathleen Young, PhD.
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`NDA No. 22-304 1
`
`toxicity was reversible at the doses, routes and durations studied, based on absence of
`hepatotoxic findings afier treatment-free recovery periods.
`
`Dog:
`
`Repeated dose toxicology studies were conducted in Beagle dogs, with dosing durations
`of 10 and 28 days by the IV route, 9 days and 13-weeks by the SC route, and 2, 13, and
`52 weeks by oral gavage. The main target organs of toxicity in the dog were the CNS,
`and gastrointestinal (GI) and cardiovascular (CV) systems.
`
`Intravenous toxicity was assessed in M and F dogs given tapentadol for up to 10
`consecutive days (1-7.5 mg/kg/day for 4 consecutive days with sacrifice 12 days afier the
`last dose in the first dose-escalation phase dogs, and 7.5 mg/kg/day for 10 consecutive
`days with sacrifice 24 hours after the last dose in the maintenance treatment (second
`study phase) dogs. The results showed transient, treatment-related salivation (M),
`restlessness and whimpering (F, 25 mg/kg/day), and rhinorrhea, panting, labored
`breathing, decreased activity and uncoordinated movements at 7.5 mg/kg/day, with
`lateral recumbency in the HD M and limb buckling in the HD F. The clinical signs were
`evident during or immediately after injection, and lasted approximately 1-3 hours after
`. the injections. There were slight decreases in food consumption in the M and F at 25
`mg/kg/day, and slight body weight loss in the HDF after treatment Day 2.. Moderate
`body weight loss was found in most HD animals at the end ofthe 10-day treatment
`period. There were observations at the HD cf increased glutamate dehydrogenase, total
`lipids, cholesterol, triglyceride, phospholipid, iron concentration and protein at the end of
`the study. Histopathology was not conducted in this Study, but the macroscopic
`examination showed red foci at the injection sites in HD dogs.
`
`A subsequent 4-week study on intravenous tapentadol toxicity in dogs (1-7.5 mg/kg/day)
`showed treatment-related clinical signs consistent with those observed in the 10-day
`study, with dose-related increases in incidence and severity of excessive salivation,
`decreased activity, hind-leg buckling uncoordinated movements, vomiting, urination,
`ventral recumbency and rhinorrhea beginning during or immediately after injection and
`lasting for 1-2 hours. Tachypnea, panting, retching, and defecation were seen with less
`frequency than were the other signs. Food consumption (F at 23 mg/kg/day and HD M)
`and body weights (HD F) were reduced in the F (23 mg/kg/day). There were no
`treatment-related effects on any other parameter, including ophthalmologic examinations,
`electrocardiograms (including QT interval), and inspection of the injection sites. Special
`assessments of microsomal drug metabolizing enzymes in the livers at necroscopy
`showed no inhibition or induction of P450 enzymes, and no effects on phase II
`aminophenol glucuronyl transferase activity.
`
`Subcutaneous tapentadol toxicity was tested in Beagle dogs dosed for a 7-9—day period
`(10 mg/kg b.i.d. followed by 7.5 mg/kg bid). The treatment-related findings were
`similar to those in the IV toxicology studies in dogs, and included CNS behavioral signs
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`NDA No. 22-304
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`known to be associated with opioid receptor agonist activity. The observations were
`dose—related increases in incidence and severity of decreased activity, recumbency,
`tremor, salivation, somnolence, forelimb and hindlimb buckling, uncoordinated
`movements and occasional whimpering. The male dogs also showed vomiting, and
`occasional pale or loose feces and fecal mucus. Several dogs showed injection site
`swelling. Food intake and body weights were reduced in the first dosing week in both
`treatment periods, and resolved after increasing the duration of the feeding period over
`the remainder of the study period. The reversibility of reduced food consumption and
`body weights, and observed decreases in the severity of the behavioral effects may have
`also been related to development of partial tolerance to tapentadol effects.
`
`Two 3-month SC tapentadol toxicity studies were conducted in Beagle dogs (20-160
`mg/kg/day dose escalation phase for 13 days followed by 40 mg/kg/day treatment phase
`on Days 14-91 in the first study, and 4-16 mg/kg/day in the second study). One F dog
`given 16 mg/kg/day died on dosing day 17 in the second study. The treatment-related
`clinical signs were similar to those observed in the IV toxicity studies in dogs, and
`included dose related restlessness, decreased activity, drowsiness, fearfulness,
`vocalization, unsteady gait, hindlimb weakness, ventral recumbency, spontaneous
`urination and defecation, vomiting and salivation, with increased respiratory frequency
`and forced respiration in several animals beginning around 30 minutes after dosing and
`lasting for up to 5 hours. The higher doses administered (240 mg/kg/day SC) produced
`defense behavior, tremor, twitches, and convulsions in 1 dog. A potential relationship of
`the tremors to possible seizure activity was not addressed. Acute tolerance was
`suggested by observed decreases in severity and duration of the behavioral signs after the
`second than after the first daily doses. Also, the clinical signs were progressively reduced
`in severity over the course of the treatment duration, further suggesting the development
`of partial tolerance to tapentadol CNS effects.
`Injection site inspections indicated that
`the dogs scratched the sites throughout the study. Reduced body weights, body
`temperature and heart rate observed early in the studies showed gradual, slight recovery
`throughout the dosing periods, but body weights remained below control levels at the end
`of the second study. Food consumption, greatly reduced during the first weeks of
`treatment, was also only partially reversed by extension of the feeding periods. The
`results of the ECG measurements showed treatment-related absolute and corrected QT
`prolongation at 30 minutes after dosing compared to baseline values in the dogs given 24
`mg/kg b.i.d during Week 1, and trends toward increased absolute QT values in Weeks 4
`and 13.
`
`’ The necroscopic examination in the 3-month SC toxicity studies in dogs showed local
`toxicity at the injection sites in both studies. The main injection site findings were
`subcutaneous ecchymoses with hemorrhages, edema and gelatinous consistency of
`. underlying tissues, that indicated scratching by the dogs throughout the first study.
`There was considerable local injection site toxicity in the second study that was
`qualitatively similar to the findings in the first SC study, with dark red discoloration,
`hemorrhages, acute and subacute inflammatory infiltrates, fibrosis, phlebitis and
`thrombophlebitis, and at the HD (16 mg/kg/day) chronic focal or multifocal
`perivasculitis. The injection site effects were only partially reversible during the 4—week
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`NDA No. 22—304
`
`recovery period, and suggested that the SC route is likely not suitable for evaluation of
`chronic tapentadol toxicity in dogs. Tapentadol-related GI toxicity was evident in the
`necropsy in the second study, by findings of hemorrhage in the mesentery, and dark red
`discolorations in the stomach, and small and large intestines. Toxicokinetic analyses
`showed consistent exposure to .the test article and the metabolite tapentadol-O-
`glucuronide, with dose-proportional increases in concentrations, peak plasma
`concentrations at approximately 0.5 h, and considerably higher exposure to the
`metabolite (t1/2 = 4h) than to the parent drug (t1/2 = 1.77 h). Parent drug exposure (AUC)
`was higher in the dog that convulsed than in the other dogs, but there were no differences
`in peak plasma tapentadol concentration (Cmax).
`
`Oral (gavage) tapentadol toxicity was tested in two 2-week, and in 13- and 52-week
`studies in dog. The 2-week studies evaluated doses of 50 and 150 mg/kg/day in the first,
`and in the second study there was a 13-day dose escalation period (10-350 mg/kg/day)
`followed by a dose de-escalation period from 320 down to 200 mg/kg/day for 14 days.
`The clinical signs of tapentadol toxicity were generally similar to those observed in the
`IV and SC assays in the dogs (salivation, vomiting, irregular respiration, and
`recumbency), with observations of whimpering (2220 mg/kg/day), somnolence (2280
`mg/kg/day), dyspnea , tachypnea 0r panting (280 mg/kg/day) and tremors (2160
`' mg/kg/day) beginning approximately 15 minutes after oral dosing and persisting for up to
`8 hours at the higher doses in the second assay. Convulsions were observed in several
`dogs in the first (1 M and 1 F at 50 mg/kg/day, and l M and 1 F at 150 mg/kg/day) and
`second (1F at 350, 320, 280, and occasionally at 200 mg/kg/day) study. ECG and
`hearing measurements were normal in both studies. Liver weights were increased in all
`treated dogs in the second but not in the first study, in the dogs given the dose escalations
`up to 350 mg/kg/day and then de-escalation from 350 to 200 mg/kg/day. Observed
`treatment-related increases in liver weights were without clinical laboratory, and
`macroscopic and microscopic correlates. Treatment-related GI toxicity revealed in the
`necropsies was manifest by activation of the enteric lymphatic system (Peyer’s patches)
`in the small and large intestines with activated lymphoid follicles in the gastric mucosa
`and proximal small intestine suggesting hyperplasia in the germinal centers characteristic
`of gastrointestinal immune response.
`
`The results of 13-week oral tapentadol toxicity observations in Beagle dogs (10-80
`mg/kg/day) were comparable to those in the shorter term (2-week) oral studies and to the
`toxicity found by the IV and SC routes.
`Initial HD administration at 120 mg/kg/day
`produced severe CNS toxicity, beginning 15-30 minutes after dosing and lasting for up to
`5 hours. The signs included tachypnea, apathy and convulsions with paddling
`movements, twitching and tremors, and mortality in 2 M dogs, prompting loWering the
`dose to 80 mg/kg/day on treatment Day 23 until the end of the study. The convulsions
`were observed at 30-60 minutes after tapentadol administration, except for a convulsion
`immediately after dosing in one of the F. Food consumption was reduced .in the M (HD)
`and F (235 mg/kg/day), predominantly during the first several weeks of dosing. Body
`weight gain was reduced at the HD. The treatment-related effects on clinical signs and
`body weights were reversible after the 4-week recovery period.
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`
`‘
`
`NDA No. 22-304
`
`ECG assessments in the 13-week oral toxicity study in dogs showed QT prolongation,
`with similar results after correction for heart rate (QTc), at 35 mg/kg/day in Week 13, and
`in the high-dose groups in Weeks 1 (120 mg/kg/day) and 13 (80 mg/kg/day). Treatment—
`related decreased gamma glutamyltransferase and increased serum sodium were found.
`Macroscopic and microscopic examinations during necropsy showed thymic atrophy and
`prostate gland inflammation (235 mg/kg/day) and adrenal cortical hypertrophy in the M
`235 mg/kg/day). Hepatic microsomal enzyme activity analysis in liver samples
`recovered during the necropsy in the HD and control dogs showed a statistically
`significant treatment-related induction of aminopyrine N—demethylase activity in the M
`and F, and inhibition of glucuronyltransferase activity in the M. The NOAEL in this
`study (10 mg/kg/day) represented systemic exposure to the parent drug of approximately
`0.04 times the-clinical exposure at the MRHD of 600 mg/kg/day on an AUC basis, and on
`a Cmax basis, relevant to the CNS and cardiovascular effects noted during the study.
`Plasma O-glucuronide metabolite was not assessed.
`
`The chronic (52-week) oral (gavage) study in M and F Beagle dogs given tapentadol once
`daily (10-80 mg/kg/day) confirmed the target organs toxicity seen in the shorter term oral
`and injection (IV and SC) studies in dog, in the CNS and cardiovascular system. One HD
`F was euthanized in extremis on dosing Day 12 due to convulsions on several days
`observed within 30 minutes after dosing. There were no necroscopic abnormalities in
`this dog. Convulsions were also seen in another HD F on multiple days throughout the
`dosing period up to Day 358, starting at 20-30 minutes after dosing and lasting for up to 5
`hours. The convulsions were associated with paddling movements, muscle twitching,
`recumbency, tremor, labored breathing, and decreased activity, and were reversed with
`naloxone. ,No convulsions were observed during the recovery period. There were also
`treatment-related clinical signs consistent with tapentadol mu—opioid receptor agonist
`effects in the dog studies, including salivation, decreased activity, recumbency, vomiting,
`tremor, and occasional whimpering, and fearfulness, beginning at 15-30 minutes after
`dosing, and lasting for up to 5 hours. Reductions in food consumption (F at 230
`mg/kg/day) and body weights (BB) were observed during the first several weeks of
`dosing.
`
`ECG assessments in the chronic dog study revealed slight but statistically significant
`prolongation of the QT and corrected QT (Van de Water’s and Fridericia’s corrections)
`intervals in the 1 hour post—dose recordings in most of the HD dogs compared to baseline
`and control values throughout the treatment period. There were no other treatment—
`related ECG effects during the dosing period, and no ECG findings during the recovery
`period. Slight, minimal, treatment-related decreased partial thromboplastin time (PTT)
`values were found in the HD dogs, which-were not reversible during the 4-week recovery
`period. The necropsy results were negative in the standard evaluations. However,
`special examination of brain showed minimal to slight focal gliosis with perivascular
`mononuclear cell infiltration in the medulla oblongata and/or pons in 2 M and F at 30
`mg/kg/day, and in 1 HD F, with no correlation to seizure incidence, and are considered to
`be spontaneous, in agreement with the Sponsor. In the liver enzyme activity analysis, no
`tapentadol effects on cytochrome P450 content were found, but there were dose-related
`increases in O-deethylase activity in the F, and dose-related increases in N-demethylase‘
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`NDA No. 22-304
`
`activity in the M and F. Also, 2-aminophenol glucuronyltransferase activity was
`decreased in the M and F dogs. The NOAEL in the 52-week toxicity study in dogs (10
`mg/kg/day) represented systemic exposure to the parent drug that of approximately 0.05
`times the exposure at the clinical maximum recommended human dose (MRI-ID) of 600
`mg/day in a 70 kg patient, on an AUC basis, and 0.06 times on a Cmax basis, relevant to
`CNS and CV observations. The systemic exposure to the O-glucuronide metabolite at the
`NOAEL (10 mg/kg/day) in this study represented approximately 1.7X the clinical
`exposure at the MRHD. The exposure to the parent drug and metabolite at the NOEL for
`convulsions in this study represented approximately 0.4 and 5.2 times the clinical
`exposures to the parent drug and metabolite, respectively, at the MRI-ID on an AUC
`basis.
`.
`
`In summary, the main target organs of tapentadol toxicity in the repeated dose studies in
`dogs, most of which were commonly observed using several routes and durations of
`treatment, were the central nervous system (CNS), cardiovascular system (CV),
`gastrointestinal system (GI) and local toxicity in the intravenous and subcutaneous
`toxicity studies. The CNS clinical signs were similar in all of the studies across dose
`ranges given, and included salivation, restlessness, recumbency, decreased activity,
`rhinorrhea, panting, labored breathing, and tachypnea. In the bid. study in the dogs
`given twice daily subcutaneous (SC) tapentadol injections for 3 months, the signs were
`more severe after the first than after the second daily dose, suggesting development of
`short term tolerance, a know/n phenomena with mu-opioid receptor agonist treatment.
`Also, the severity of the clinical signs decreased with increasing duration of treatment
`within several of the studies, further suggesting tolerance to opioid-induced behavioral
`effects. Most notable of the clinical signs were convulsions, observed in M and/or F dogs
`treated by SC injection for 3 months at 240 mg/kg/day (NOEL = 20 mg/kg/day SC), and
`by oral gavage at 250 mg/kg/day (NOEL = not determined) and 2200 mg/kg/day (NOEL
`= 160 mg/kg) for 2 weeks, at 120 mg/kg/day for 13 weeks (NOEL = 80 mg/kg/day), and
`at 80 mg/kg/day for 52 weeks (NOEL = 30 mg/kg/day). No convulsions were observed
`in IV treated dogs at up to 7.5 mg/kg/day for up to 4 weeks duration. The convulsions
`were accompanied by paddling movements, tremors, and twitching. A possible
`relationship of the tremors observed in several studies in dogs to seizure activity was not
`investigated. There was no tolerance development to the treatment—related convulsant
`'
`1 effect in the dogs. Although mOSt of the dogs that convulsed either were sacrificed in
`extremis or received dose reductions following the seizures, a F given 80 mg/kg/day by
`oral gavage for 52 weeks showed convulsions on multiple days up to day 358 of dosing.
`
`Tapentadol-related cardiovascular effects in the Beagle dog were indicated by QT
`prolongation in the ECG measurements across studies, at 28 mg/kg/day SC for 3 months
`(NOEL 4 mg/kg/day) particularly during the first week of treatment, at 235 mg/kg/day
`(Week 13) and 120 mg/kg/day (Week 1) in the 13-week gavage study (NOEL 10
`mg/kg/day) and at 80 mg/kg/day in the 52-week oral gavage study (NOEL 30
`mg/kg/day). No other ECG effects were found in the studies in dog. QT prolongation is
`probably associated with norepinephrine reuptake inhibition by tapentadol.
`
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`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`Treatment-related GI toxicity was observed in dogs given tapentadol by several routes.
`Dogs administered SC tapentadol injections in the 3-month study showed reversible
`hemorrhage in the mesentery, and dark red discolorations in the stomach, small and large
`intestines at all doses (24 mg/kg/day). The necroscopic examinations in several oral
`gavage studies revealed activated lymphoid follicles in the gastric mucosa and small
`intestines in the 2-week oral gavage study (250 mg/kg/day), that were attributed to GI
`immune response by the examining pathologist. Local tissue toxicity was found in dogs
`given IV and SC injections, and included red foci at the highest dose of 7.5 mg/kg/day in
`the 4-week IV study, and injection site hemorrhage and fibrosis, with scratching of the
`site by the dogs throughout the dosing periods in both 3-month SC studies (220
`mg/kg/day in one and 24 mg/kg/day in the second study).
`
`Monkey:
`
`Two-week pilot studies were conducted in Cynomolgus monkeys to evaluate
`toxicokinetics and compare toxicity of tapentadol given by repeated IV (5 mg/kg/day)
`and oral (15 mg/kg/day) administration. No necroscopic examinations were performed
`in this study. There was occasional, slight sedation noted after the intravenous infusions,
`but no other clinical signs, no effects on body weights and food consumption, and no
`local toxicity was found upon examination of the injection sites. The results of the
`toxicokinetic evaluation showed extremely low oral bioavailability (<l%) suggesting
`extensive first-pass metabolism, and a short half life (1h by IV), with no accumulation
`using either route over the 14-day period.
`
`Overall Repeated Dose Toxicology Summary:
`
`There were interspecies differences and similarities in target organ toxicity between the
`mouse, rat and dog. In the rat, the predominant treatment-related effect, after CNS
`clinical signs, was in the liver, evident by increased liver enzymes (e.g., ALAT, ASAT,
`ALP, etc) and increased liver weights, hepatocellular hypertrophy with fatty change at
`higher doses and longer durations, and hepatocellular necrosis. Hepatotoxicity was also a
`main treatment effect in mice, which showed increased liver enzymes in the clinical
`laboratory analyses and increased liver weights in the 2- and 13-week dietary studies and
`in the 13-week gavage study, and hepatocellular hypertrophy with group cell necrosis in
`the 13-week dietary study at high doses of 500 and 1000 mg/kg/day, in the males and
`females. In the dog, there were more severe CNS toxicity that included convulsions, and
`CV toxicity with treatment-related QT‘ prolongation. Clinical signs were not evident in
`the dietary and gavage studies in mice, at up to high doses of 1000 mg/kg/day dietary for
`13 weeks and 200 mg/kg/day by gavage for 13 weeks. Target organ similarities between
`rat and dog were in the CNS clinical signs, such as sedation, decreased body weights and
`food consumption in both species with tolerance development to these signs. Also, GI
`'_
`toxicity was found in rat and dog, but not in the mouse, and included red foci in stomach .
`in the 4-week IV study in rat, and duodenal dilation at the highest dietary dose of 1000
`mg/kg/day in rat. In the dog, gastrointestinal hemorrhages and activated lymphoid
`follicles in the gastric mucosa and small intestine were predominant. Local injection site
`toxicity was found in both rat and dog. These effects included infusion site swelling,
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`
`NDA No. 22-304
`
`particularly by the SC route in rat, and red foci after IV infusion, and hemorrhage and
`fibrosis after SC injections in the dog. The results in both species snowed greater local.
`toxicity by SC than by IV dosing.
`
`Most of the treatment-related toxicity, the clinical signs including convulsions, QT
`prolongation, and toxicity in the gastrointestinal system were reversible in the studies that
`used recovery period evaluations. However, injection site findings, such as hemorrhages,
`inflammatory infiltrates, fibrosis, phlebitis and thrombophlebitis afier SC dosing in the 3-
`month study were only partially reversible at 4-weeks following drug withdrawal.
`
`The results of the nonclinical toxicology studies suggest potential adverse effects in
`clinical treatment by mu—opioid receptor binding and norepinephrine reuptake inhibition.
`The main treatment-related target organs of toxicity, including the liver in rat, CNS in rat
`and dog, and cardiovascular system (QT prolongation) in dog, suggest careful screening a
`and monitoring patients with existing hepatic disease, seizure disorders and
`cardiovascular conditions. Most of the treatment-related toxicity observed in the
`nonclinical studies, such as CNS depression and hepatic changes reversible after
`withdrawal of treatment. These adverse effects are also monitorable to some extent, such.
`as by periodic clinical laboratory assessments during clinical treatment. However,
`unexpected or severe CNS and cardiovascular toxicity may not be as easily monitored in
`an outpatient setting. Therefore, aW
`M. discussed with the patients during treatment.
`
`Genetic Toxicology
`
`Tapentadol HCl was evaluated by the Sponsor in a standard, battery of genetic toxicity
`studies. The studies included in vitro assays in Salmonella typhimurium and Escherichia
`coli (Ames Test, Reverse Mutation Assay, using both the plate incorporation test in
`Experiment I and pre-‘incubation test in Experiment II), and two independent
`Chromosome Aberrations Assays in Chinese Hamster V79 cells. Additionally,
`tapentadol was tested in the Chromosome Aberration Assay in rat bone marrow cells in
`vivo, and the Unscheduled DNA Synthesis assay in rat hepatocytes ex vivo.
`
`Tapentadol was clastogenic in the first of two independent in vitro Chromosome
`Aberration studies in Chinese hamster V79 cells, resulting in a statistically significant
`increase in the incidence of structural chromosome aberrations at concentrations greater
`than 1000 meg/ml in the presence of S9 mix. A second study, conducted to further
`explore the results of the positive findings in the Chromosome Aberration assay in V79
`cells, revealed no increases in the frequencies of cells with aberrations at concentrations
`of up to the maximum concentration tested (1500 meg/ml for 4 hours without metabolic
`activation with S9, and up to 1000 mcg/ml for 4 hours and 300 mcg/ml for 18 and 28
`hours exposure with S9 mix).
`
`No evidence was found of mutagenic potential‘by tapentadol in Salmonella typhimurium
`strains TA1537, TA 98, TA 1535, and TAlOO, and in Escherichia coli strain WP2: trp;
`uvrA in the Ames test using the plate incorporation and pre-incubation methods at
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`

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`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`concentrations of up to 5000 meg/plate. Tapentadol was also negative in the in vivo
`assay for clastogenicity in male and female Wistar rat bone marrow cells at doses of up to
`the maximum tolerated dose (MTD) of 40 mg/kg IV evaluated at 24 and 48 hours.
`Evaluation of potential mutagenicity in the hepatocytes of rats given up to 35 mg/kg IV
`and 350 mg/kg PO (gavage) tapentadol in the Unscheduled DNA Synthesis assay
`revealed no increased DNA repair synthesis induced indicative of treatment-related DNA
`damage and subsequent repair.
`
`In conclusion, tapentadol was equivocal in the in vitro Chromosome Aberrations assay in
`Chinese hamster V79 cells, in the presence of metabolic activation with S9. The findings
`, suggest potential clastogenicity by a metabolite of tapentadol HCl in the rat, from which
`the metabolic activating system ($9 mix) was obtained. The identity and production by
`human metabolism of the potentially genotoxic metabolite is not known.
`
`Carcinogenicity
`
`Tapentadol was negative for carcinogenicity in 104-week studies in male and female
`mice and rats. Male and female CD-1 mice were administered tapentadol by oral gavage
`at doses of 50—200 mg/kg/day for 2 years. The Sponsor reported a statistically
`significant treatment-related increase in hepatocellular carcinomas in the HD male mice
`that was found not statistically significant by Agency statistical analyses for this common
`tumor type in mice. Agency analyses found positive trends toward increased
`hepatocellular adenomas in the female mice, and a statistically significant dose response
`for liver adenoma + carcinoma in the male mice without statistically significant
`differences in the pairwise comparisons with controls. There were statistically significant
`trends for subcutis sarcoma in male mice, and ovarian benign granulosa cell and luteoma
`tumors in the female mice, also without statistically significant treatment-related
`increases in the pairwise comparisons. Historical control data suggested that the tumor
`incidences are within the background for the strain in this laboratory. The NOEL for
`carcinogenicity by tapentadol at the highest dose tested in mice represents approximately
`1.4 times the clinical exposure to the parent drug at the maximum recommended human
`dose (MRHD), and approximately 8.4 times the exposure to the glucuronide metabolite at
`the MRHD, on an AUC basis.
`-
`
`Male and female Wistar rats were administered oral tapentadol by admixture in the diet,
`at daily doses of 10-250 mg/kg/day for 104 weeks. The results of the histopathology
`evaluation showed slight non—statistically significant (compared to controls) increases in
`the incidence of hepatocellular adenomas in the high dose females and one additional
`hepatocellular carcinoma in the high dose male rats. Agency statistical analyses detected
`positive trends in the incidence in female rats in liver hepatocellular adenoma. There was
`a statistically significant dose response for increased liver adenomas + carcinomas in the
`female rats, but no statistically significant increases over controls in any treated group.
`There was a positive trend for increased incidence of thymic lymphoma, but not for
`lymphomas at all sites, combined. Historical control data suggested that the tumor
`incidences in the rats are within the background for the strain in this laboratory.
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`
`NDA No. 22-304
`
`Evaluation of non-neoplastic lesions in the rats showed a minimal but statistically
`significant treatment-related increase in centrilobular hepatocellular hypertrophy in the
`male and female rats. The histopathology findings in the liver are likely related to
`chronic, adaptive response associated with treatment-related increased metabolic enzyme
`activities. Increased follicular cell hypertrophy and focal follicular hyperplasia in the
`thyroid was observed in the HD females, probably resulting from chronic, enhanced liver
`enzyme activities and hypertrophy, in agreement with the Sponsor. The changes in
`thyroid in the females is probably not due to induction of thyroxine UDP
`glucuronosyltransferase activity by tapentadol, because assessments of hepatic
`microsomal enzyme induction and inhibition studies in liver microsomes isolated during
`necropsy in several studies in rats and dogs were negative for this effect. Thyroxine '
`UDP glucuronosyltransferase may be involved in thyroid tumor formation by non-
`‘genotoxic CYP enzyme induction, via stimulation of thyroxine glucuronidation and
`biliary excretion, resulting in decreased serum thyroxine and triiodothyronine, with
`increased serum thyroid stimulating hormone, which during chronic stimulation results in
`thyroid follicular cell hyperplasia that may progress to follicular cell tumors. The NOEL
`values for carcinogenicity produced by tapentadol at the highest dose tested in rats are
`approximately 0.7 times in the males and 2.7 times in the females the clinical exposure to
`the parent drug at the maximum recommended human dose (MRHD, 600 mg/day) and
`approximately 27 times in the male and female rats the clinical exposure to the
`glucuronide metabolite at the MRHD, on an AUC basis.
`
`Reproductive and developmental toxicology
`
`Tapentadol reproductive and developmental effects were investigated in rats and rabbits.
`Dose selection for the main studies was based on maximum tolerated dese (MTD) levels
`in the preliminary range-finding toxicity studies in pregnant and non-pregnant animals
`using oral gavage, and injections by the IV and SC routes. The animals were dosed by
`IV and SC injections in the main reproductive toxicology studies to maximize systemic
`exposure to the parent drug, due to the rapid and extensive first-pass metabolism by the
`oral route in these species.
`'
`
`Tapentadol was negative for adverse effects on mating and fertility at intravenous (IV)
`doses of up to the MTD in male and female Wistar rats. There were embryonic
`developmental abnormalities (pre—implantation and post-implantation losses), considered
`to be secondary to maternal toxicity, in agreement with the Sponsor. The NOEL values
`were 3 mg/kg/d for maternal toxicity, and 12 mg/kg/d for adverse effects on fertility in
`the male and female rats. The systemic exposure at the NOEL for adverse fertility effects
`represented approximately 0.41 times in the male and 0.35 times in the female rats the
`MRHD, on an AUC basis, based on plasma sampling in another IV study in rats.
`
`Embryo-fetal development toxicity by tapentadol was studied in rats and rabbits.
`Tapentadol was negative for teratogenicity in the rats at up to maternally toxic
`intravenous and subcutaneous doses. However, there was a treatment-related increase the
`incidence and severity of fetal variations and malformations in rabbits given
`subcutaneous tapentadol, but not when dosed by the intravenous route.
`
`~
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`315
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`

`

`Reviewer: Kathleen Young, Ph.D.
`
`NDA No. 22-304
`
`In an IV study on developmental toxicity, pregnant Sprague Dawley rats were
`administered tapentadol a doses of 3—1 5 mg/kg/day (gestation days 6-17, inclusive).
`There were 2 maternal deaths each at 7 and 15 mg/kg/day, within 2-45 minutes of the
`first injection, preceded by convulsions, exophthalmus, flaccid position and hemorrhagic
`snout. Although there were reduced numbers of fetuses and implantation sites and
`increased late resorptions, correlating with the observed maternal toxicity (decreased
`maternal body Weights and severe maternal clinical signs), there were no treatment-
`related effects on sex distribution, placenta weight, fetal weight, fetal deaths, incidence of
`runts, and no external, skeletal and soft tissue malformations, variations and retardations.
`Subsequent investigation of adverse effects on embryofetal development by SC
`tapentadol (10-40 mg/kg/day on Gestation days 6-17, inclusive) showed maternal toxicity
`at all dose levels, with dose—related increases in severity and duration of reduced body
`weight gain, abdominal position lasting 1—2 hours, and'local toxicity (eschar formation
`and hemorrhagic foci) at 220 mg/kg/day. No treatment-related malformations or
`variations were observed in this study. However, tapentadol was embryotoxic at the HD
`(approximately 3 times the systemic clinical exposure at the MRI-ID on an AUC basis),
`produc