`
`NDA 21-038
`
`Overall Toxicology Summary
`
`Dextromedetomidine, the dextro isomer of medetomidine is a potent and selective az-agonist with
`sedative/hypnotic, hypotensive and analgesic effects. The clinical use is to bein the ICU for
`postoperative sedation and analgesia reducing anesthetic and narcotic analgesic requirements. The
`az-agonist activity reduce adrenergic activation, producing a sympatholytic effect, bradycardia and
`a reduced cardiovascular response to noxious stimuli.
`
`The administration of dexmedetomidine is by intravenous infusion with maximum total daily doses
`of less than 20 11ng and blood concentrations of less than 30 ng/ml. The maximum recommended
`human dose (Ml-IRID)15 about 17. 8 pg/kg/day (0.6919 mg/mgrand the initial recommended
`loading dosc1s--1 jig/kg.
`
`The acute toxicity, after rapid iv bolus injection, mice demonstrated a sex difference and the
`highest non-lethal dose was 5000 ug/kg in females and 1000 ug/kg in males; 20,000 and 10,000
`ug/kg in females and males, respectively, after subcutaneous injections. In rats, the highest non-
`lethal dose after rapid iv bolus was 1000 ,ug/kg in both sexes and after subcutaneous injection it
`was 5000 in males and 1000 lag/kg in females (vol 23/pg 222) Considering 1000 leg/kg was non-
`lethal-in mice and rats after iv injection, the ratio of these‘doses in mg/m2 and the daily MRHID
`(loading dose, 1.0 jig/kg) is 120X and 240x, respectively. In comparison with the MRI-IID of 17.8
`11 g/kg for a-24 hour infusion, these non-lethal dose in the mice and rats were still 5X and 9X the
`human dose on a on mg/m basis. The estimated highest non-lethal dose in dogs was about 1000
`lug/kg following rapid intravenous injection and this15 approximately 30X the MRHID on mg/m2
`basis.
`-
`
`The clinical signs at high non-lethal doses was the same in both rats and mice; sedation,
`piloerection, exophthalmia, salivation, tachypnea and clonic convulsions. The signs at lethal
`doses also included jumping, dyspnea, chromodacyrhea, red urine and red fluid from nose and
`mouth.
`
`5
`
`l a
`
`I
`
`.
`
`.
`
`.
`
`The toxicity of repeatdosing was examined in both rats and dogs in studies 4 weeks in duration
`with im or iv administration. The rats were tested afier sc injection for 4 weeks and after
`intrathecal administration for 2 weeks. The dogs were tested for 2 weeks of intrathecal
`adminstration after a single dose pilot study.
`
`The im administration of 20, 100 and 500 jig/kg to rats produced the pharmacological effects of
`sedation, piloerection and cloudy corneas in a dose related manner. The two high doses also
`produced exopthalmus and glucosuria and some hypertrophy of the adrenal glomerulosa. The
`toxicological effects were seen at 100 and 500 ug/kg decreased body weight gain and thymus
`
`-- -
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`NDA 21-038
`
`weight and dose-related pulmonary perivascular hemosiderin laden macrophages. The high dose
`males also had decreased weight of testes, seminal vesicles and prostate. The NOAEL was the 20
`ug/kg dose. The 4 week so study in rats used the same doses and produced the same effects
`although there was an elevated alkaline phosphatase level at 100 and 500 ug/kg and decreased
`uterine weight at 500. The NOEL was 20 ug/kg in the males and possibly 100 in the females. The
`intravenous dosing in rats was at 10, 40 and 160 ,ug/kg and'there was still the dose-related
`pharmacological sedation, piloerection and exopthalrnos at the high dose. The glucosuria, corneal
`opacities and elevated alkaline phosphatase at 40 and 160 and increased liver weight for females
`the‘high dose. The 10 rig/kg dose was considered the NOEL. All of these NOELs produced a
`ratio of less than 1.0 compared to the MHRID in mym2 the daily dose of 17.8 ug/kg/day.
`
`,In dogs, the iv study used doses of 10, 50 and 250 ug/kg for 4 weeks. The sedation, ataxia, muscle
`twitches, miosis and slowed respiration rate were dose related pharmacological effects at all doses.
`The toxicological signs were seen mainly in the high dose animals, elevated ornithine carbamyl
`transferase, alkaline phophatase and hepatic apototic bodies and serum GGT level were
`significantly elevated in both MD and HD groups. There was some increased liver weight and
`decreased thymus weight in the lower doses but 10 ug/kg could be considered LOAEL and the
`ratio with MHRID was 0.3. The irn study in dogs used the same doses, 10, 50 and 250ug/kg, but
`was run once with males and once with females and no pathology reports were supplied for the
`control and LD animals. The toxicity was similar to the iv study, with elevated alkaline
`phosphatase, ALT, in the HD males and females and in the MD males. The MD and HD females
`had eosinophilic inclusions in the hepatocytes. The ALT was over 8-fold in one I-ID male and the
`creatinine kinase, aspartate aminotransferase and alaninme amionotransferase were all elevated in
`the high dose males. The NOEL was 10 ug/kg in both male and female studies. The 50 rig/kg
`NOEL dose in the iv study provides a ratio of 1.5 with the MI-IRID in mg/m2., bift'the lO lug/kg
`dose has a ratio of less than 1. These ratios were in terms of the maximum recommended human
`dose (MI-RID), 17.8 yg/kyday.
`
`The intrathecal administration of dexmedetomidine in bolus doses of 1.5, 6 and 24 ug/rat for two
`weeks, produced transient dose-related sedation but no histopathology that was difference from
`saline controls. The pilot study in two dogs indicated that 40 ug/dog produced transient hindlimb
`weakness and afler 72 ug and l44ug/dog there was a marked decrease in heart rate and increased
`sedation. The sedation was so profound at 144 ug/dog in 1/2 dogs, that it was not arousable by
`voice or paw pinch for about one-half hour, starting 20 minutes post-dosing. Dexmedetomidine
`was administered intrathecally to dogs at the doses of 2, 12 and 80 ug/dog for 28 consecutive days.
`The 2 ug dose did not produce any observable changes, the 12 ug dose produced some transient
`sedation and incoordination. There was incoordination was evident in all dogs at the 80 ug/dog
`dose and some demonstrated analgesia The was no clinical chemistry, hematology or urinalysis
`changes attributed to dexmedetomidine. The histopathological changes were all attributed to the
`invasive procedures as this was also evident in control animals. The 80 ug/dog dose did slightly
`increase the QT interval in 8/10 dogs and one dog had a 2nd degree AV block. The veternary
`
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`NDA 21-038
`
`cardiologist determined the QT lengthing was minor and not cardiotoxic events.
`
`The acute toxicity studies indicated that the safety ratio of acute toxicity is at least two orders of
`magnitude greater than a human would be expected to encounter, when compared to the loading
`dose of 1.0 ,ug/kg. However, the the subacute studies areinconclusive. It is recognized that the
`ratio values with the MHRID are comparing a dose from a total day of infusion in the ICU with a
`daily bolus dosein the animals. It would be expected that if the study dose had been infused, then
`the daily dose comparisons would be more relevant. Itis not known if the toxicities observed,
`liver damage, reduced testes and thymus growth and adrenal glomerulosa hypertrophy, would be
`reduced if the daily dose were presented in a more gradual fashion, infusion. It is also possible
`that the extended exposure during infusion, even at lower concentrations, would be'more
`damaginmg as the tissues have less time without exposure, for repair. In addition, the toxicities
`observed1n the animals studies are the results of 4 week of administration15 four times the
`
`conceived duration and 14 times the presently proposed duration of treatment.
`
`It is the impression of this reviewer that, although the safety ratios in subacute studies are generally
`less than unity, the extension of the testing to weeks versus the planned 24 hours, greatly
`exacerbates any drug induced toxicity. This impression is based, in part, to the fact that the acute
`toxicities produce safety ratios several orders of magnitude greater than 1. In terms of clinical
`safety; dexmedetomidine, an az-agonist, has the following possibly adverse pharmacological
`actions:
`_'
`- initial hypertension if rapidly injected as an iv bolus.
`,bafir
`- hyperglycemia- seen in transientlyin rats, gerbils and rabbits, but not observedin dog studies
`-
`increased GFR and increased “filtered fraction" - seen transiently1n rats and rabbits producing
`glucouria. In dogs no glucosuria was observed by some increased protemuna‘was observedin 4
`the dog studies.
`w” W ““0“"
`- hypothermia has been observed in animal studies, although this is controlled in the ICU setting.
`_lt/” 1d rJ-rfl ‘
`
`’
`
`The following toxicology effects have all been seen after repeated administration and have not
`been observed acutely:
`- elevated liver enzymes, enlarged livers and eosinophilic inclusionsin hepatocytes and have
`been observedin rats and dogs and after 250 ug/kg/day1n the dog, apototic bodies were also
`observed. This dose is about 7 fold the MRI-DD of a daily 17.8 rag/kg, calculated in units of
`mg/mz.
`- decreased thymus weight have been observedin rats and dogs and decreased testicular and
`seminal vesicle weights were observed1n rats.
`- hypertrophy of the adrenal glomerulsa15 observed in both rats and dogs.
`
`/
`
`\/
`
`/
`
`Although the ratios of the NOEL in repeated dose dog and rat studies and the MRHID have mostly
`been below 1, this reviewer feels this was only the result of prolonged adminstration of high bolus
`doses and do not portend problems at the present recommended duration of treatment. The lack of
`
`,
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`i
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`NDA 21-038
`
`toxicology studies using administration by infusion, the clinical use, significantly hinders this
`evaluation. Another compounding variable is the fact that over 50% of the excreted
`dexmedetomidine is in the form of metabolites that are not produced in rats or dogs, except for trace
`amounts. (Metabolic Pathways: pg. 72 (rats), page 100 (human))
`
`################¢############ - - -
`
`APPEARS nus w
`0N ORIGINAL AY
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`NDA 21-038
`
`_
`
`‘ ‘
`
`REPRODUCTIVE TOXICOLOGY
`
`[56]
`
`Wills:
`‘
`
`_
`
`Fertility study (Segment I study) of Dexmedetomidine in Rats
`by Subcutaneous Administration.
`(#228)
`
`WY: TOX 89-001
`Win:N
`23125: started January 3, 1989, ended August 18,1989
`‘
`W: yes (V01 40/113 183): WYes (Vol 40/ pg 169)
`WW5: Batch 14, series 7.1.88
`WWO“)
`
`Methods:
`
`- Species/strain: Rats / Sprague DawleyW
`— Doses employed: 0,6 18,54 ug/kg/day; control, LD, MD, HD, respectively
`- Route of Administration: daily subcutaneous injection I
`- Study Design: Males were injected for 10 week prior to mating and the mating for 2 weeks prior
`to necropsy. One half of the females were dosed for 2 weeks prior to mating, during mating,
`gestation until Day 20 of lactation and then sacrificed. The other half to the females were dosed
`through gestation and lactation, until day 20 post delivery.
`
`Males: 45 days of age at start, about 210 gm, daily injection for ten weeks prior to mating
`(71 injections).
`Females about 75 days of age at start, mean 215 gm, daily injections for 2 weeks prior to mating,
`~ during mating, gestation and lactation until sacrifice.
`- Number of animals/sex/dosing group: 24 males and 24 females/ dose group
`
`Parameters and endpoints evaluatedz. Body weights weekly, food and water consumption weekly,
`clinical signs and morstality daily.
`-At necropsy, uterine content and corpora lutea on Day 20 of gestation with one-half of dams and
`the remaining halfat Day 20 of lactation. Viability and weight of young on days 1, 4, 14 and 21
`postnatal.
`
`Results: Males
`
`- Clinical signs: sedation and piloerection, dose related
`- Mortality: No mortality during study.
`
`134..
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`NDA 21-038
`
`- Body weight: reduced weight gain. In LD group there was no significant change in
`weight gain, but at MD and HD groups there were significant reductions accumulated
`weight gain, 10% and 15%, respectively.
`- Food consumption: there was a slight, but significant reduction in food intake in the I-ID group.
`This was only dining the first week of the 10 weeks of injections.
`- Water intake: The water intake significantly increased during weeks 2 and 4 in the LD
`group, weeks 2, 3 and 4 in the MD and 8 of last 9 weeks in the HD group. The increase of
`1” 37% was seen during week 10 and as the sponsor indicates this is reflecting the increased
`diuresis with dexrnedetomidine.
`
`E
`'I'
`.1”
`.- In-life observations: No treatment induced changein copulatory or fertility indices. However,
`one control male and 2 LD males showed no evidence of mat1ng by vaginal smears of the female.
`In the LD group, 6/24 males were unsuccessfulin mating and produced no pregnancy, as compared
`to 1/24 in MD and in I-ID groups and 0/24 in controls.
`
`- Terminal and Necropsy evaluations: The terminal absolute weights of the seminal vesicles and
`epididymis was significantly reduced in the MD and ED groups, but this probably reflected the
`reduced weight gain as the relative weights were not reduced and the testes weight as percent body
`weight was significantly increased.
`
`Eemales
`
`- Clinical signs: As with the males, there was dose related sedation and piloerection.
`- Body weight: The significant changes of weight gain in the lvfl) and HD at 2 weeks
`premating In the 20 days of gestation, only the HD had a significant reduction in weight gain and
`this was an 11% reduction. During lactation there was no significant differencesin body weight
`gains.
`‘
`- Food consumption: There was no significant change in food consumption at any dose.
`- Water intake: The females in the HD group drank significantly more water than control animals
`the second week of premating, and day l and day 6 of gestation, 16-18%..
`
`Fertility and Early Embryonic Development in Females
`Terminal and Neeroscopic evaluations:
`F0 Dams: The fertility index did not vary significantly between treatment groups. No differences in
`mean number of corpus lutea, implantations, preimplantation loSses, early or late resorptions, live or
`dead fetuses or malformations at any close. The postimplantation losses were sigifificantly more
`than control in the MD and HD groups (pg231). There were no increases in fetal death were found
`in the teratology stage and the sponsor suggests that the loss occurred in late gestation or during
`delivery before the first observation and the dams had eaten the young. The sponsor suggests that
`the low body weight and delayed development may have caused the deaths (pg 196). Examination
`of the data (Vol 40/pg 231) indicates that although the number of living fetuses is not significantly
`
`.
`
`_
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`

`NDA 21-038
`
`different, the number of implantation sites - number of live births is significantly greater in the MD
`and HD than control, number of postimplantation losses. The number of postpartum deaths is not
`different between treatment groups.
`There was a dose related decrease in uterine weight, but this was not statistically significant.
`However, the post-implantation losses were significantly more in the MD and HD groups than in
`controls and this resultedm a dose relatedincrease in fetal losses between implantation and
`recorded births.
`
`--
`Early Embryonic Development1n Offspring
`Fetal body weights were significantly reducedin MD (-13%) and HD (-28%). The mean litter
`weights were significantly reduced1n the MD group only Day .1. of lactations. The HD groups was
`,significantly lighter than control all days measured, 1, 4, 14 and'21 (-15%). Pg230
`
`The ossification of the fetuses appeared to greatly reduced in the HD animals, ribs, metacarpals,
`metatarsals and caudal and lumbar vertebra (V01 40/Pg 228). The only other parameter of physical
`development measured that may have provided evidence of delayed maturation was the delayed
`appearance of surface righting reflex, number of failures for control, LD, MD, HD; was 3, 9, 7, 16.
`In addition there appeared to be a decreased wire-hanging ability in the HD group. However, both
`tests were during lactation, but this may have been the presence of dexrnedetomidine in the dam’s
`milk: There were no delays in other reflexes or sexual maturity, descent of testicles and vaginal
`opening, pinna opening, opening of the eyes, response to sound.
`
`Prenatal and postnatal development, including maternal function, F, generation.
`In-life observationsi
`In the F, groups of rats scheduled for mating, the statistically significant reduced body weight in the
`HD males lasted through lactation and into week 12(-6.5%), and although insignificant weeks 13-
`15, the body weight was 5% below control groups (p235). In the F, females, the MD was
`statistically lighter than controls through most of the 15 week and at week 15 (-5.5%) and HD
`females were significantly lighter than controls theentire 15 weeks, 12% less on week 15. When
`body weight gain was summed weeks 3-15 or 4-15, there was no significant difference between
`controls and any dose group. It is not possible to make a conclusion of the effects of
`“
`dexmedetomidine in the F, generation to maturity as the subjects represented in the tables were
`preselected and not the complete F, generation.
`
`.
`..
`Fertility in Males:
`There was no difference in fertility between dose groups. Unlike F0 generation, there was no
`difference in seminal vesicles or epididymis weights in the MD and HD groups versus control.
`
`Fertility and Early Embryonic Development in Females
`There was no difference in fertility between dose groups and there were no significant
`differences in post-implantation losses, living offspring, implantation sites, sex ratios or weight of
`
`_
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`NDA 21-038
`
`pups Day 1 or Day 4. The uterine weights and fetal examination of possible teratogenic effects
`were not presented.
`—
`
`Summary
`.
`Dexmedetomidine hydrochloride was injected sc at doses of 6, l8 and 54 ug/kg/day. The study
`included Segment I,'Segrnent II and Segment III portions.
`
`In th'é'Segrrient I portion, 10 treatment weeks prior to mating and 2 weeks of mating in males and 2
`treatment weeks prior to mating and two weeks of mating in the females. The body weight gain
`was significantly reduced in the MD and HD groups males and the HD females. The (food
`consumption was significantly reduced only in 1-D males, butwater intake was significantly
`increased during the?initial weeks of treatment in LD and Ivfl) males and in the I-ID females,
`reflecting a diuretic effect of dexmedetomidine. There were statistically significant reductions in
`absolute weight of seminal vesicles and epididymis in the MD and HD males, but this reflected the
`decrease body weight gain and the relative weights were not affected. There was no significant or
`dose related change in male or female fertility. Therefore 54 ug/kg/day can be regarded as a safe
`dose in terms of Segment I, fertility in males and females.
`
`Segment II portion of the study found no significant changes in number of corpora lutea,
`implantations, preimplantation losses, early or late embryonic deaths, number of males or females
`or sex ratio or living implants. However, the MD and HD young were significantly lighter than
`controls, -13% and -28% respectively. There was significant increase in post implantation losses
`and the sponsor suggests that these were due to late gestational losses or loss at birth when the light
`young with delayed development were eaten by the mothers, prior to examination. There were no
`teratogenic effects seen at any dose and the LD, 6 ug/kg}day, is the dose with no adverse effects on
`fetuses, fetal development and fetal survival.
`
`Segment III
`
`The body weight of the HI) young rats were still significantly 15% below controls on Day 21.
`Although there were no obvious teratogenic effects, there were many skeletal sites which were less
`ossified in the fetuses of the HD group than in the control group, but other signs of maturation, eye
`opening, pinna unfolding, decent of testes, vaginal opening, were not significantly different from
`the control group. There was no difference in pregnancy or fertility between treatment groups. The -,
`litter size, deaths during lactation and sex ratios were not different between groups.
`
`
`
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`

`NDA 21-038
`
`[57]
`
`Wills: Pre- and Post-Natal Study (Segment HI study) of Dexmedetomidine in Rats by .
`Subcutaneous Administration
`(#230)
`-
`Slum: TOX 90-017.
`SiteansLtestingiacilim: A”
`
`- —
`
`WW
`
`: yes 01014143321, 36)
`W: Sept 18,1990 .
`QA-_Renons Yes (X )(Vol 41/ng1)
`W: Batch QT0231
`W: 98.9-1 10.3% of target concentration
`Warm: No
`
`Mam:
`
`- Species/strain: Rat / Sprague Dawley outbred
`- Doses employed: 0, 2, 8 and 32 ug/kyday
`- Route of Administration: subcutaneous injection
`- Study Design: The females were injected daily in the morning from Day 16 of pregnancy to
`weaning,- Day 25 postpartum. ICH guidelines say Day of'implantation, Day 6, is the initiation of
`treatment, but this study was pre-ICH
`- Number of animals/sex/dosing group: 22 pregnant females / dose group
`
`- Parameters and endpoints evaluated:
`F0 = sedation, piloerection, exophthalmos
`sdl = slowly moving, slight sedation
`sd3 = asleep but awake when disturbed
`pl = piloerection slight
`
`F1:
`
`sd2 = awake sedated
`sd4 = asleep cannot be awaken
`p2 = piloerection marked
`
`A.
`
`Physical development was recorded on the day indicated
`
`1) Pinna unfolding (Day 2) - detachment of the edge of the pinna.
`
`2) Hair growth (Days 3 and 4) and fur growth (Days 6,7 and 8) - macroscopic
`observation of hair and fiir growth..
`
`3) Tooth eruption (Days 9, 10, 12) - eruption of upper incisors through the gum.
`4) Eyes Opening (Days 13, 14,16, 17 and 18) - separation of the upper and lower
`
`eyelids. Recorded positive, when both eyes were open.
`
`5) Testes descent (Days 14, 15 and 16).
`
`-
`
`6) Opening day of the vagina - inspected from Day 30 until opening observed.
`
`138"
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`NDA 21-038
`
`B.
`
`Neuromuscular function
`
`1) Surface righting reflex (Days 2, 3 and 4) - ability to turn to prone position from
`supine position.
`2) Air righting test (Day 21) - ability to land in prone position when dropped
`3) Wireiianging Days (l6, l7, l8) - forelimb hanging longer than 5 seconds
`
`. C.
`
`l
`
`D.
`
`Hearing and visual function
`1) Hearing ability (Day 21)- response to a sharp noise.
`2) Visual function (Day 21)- see a solid surface ahead and to move onto it.
`3) Pupillary reflex (Day 21)- direct and indirect
`-
`
`-
`Activity
`Activity- locomotor activity; movements of the litters were recorded for 18 hours.
`Activity measurement of various litters was always performed on the same day after
`weaning.
`
`E.
`
`Learning
`
`'-
`
`7
`
`A water-filled Y-maze was used to evaluate learning ability of the offspring on Day
`33 postpartum. The times taken by each animal to swim through the maze in six
`successive trials was measured. A maximum of 60 seconds was allowed for each
`
`trial. Any animal exceeding this time was removed and was considered to have
`
`failed the test. Maintained improvement in swimming time was taken as an
`indication of learning. Test was repeated;on the fourth day afier first trial and
`maintained improvement was considered as indication of memory.
`
`F.
`
`Reproductive Performance
`
`At five weeks of age, 1 male and 1 female picked at random form each litter. At
`
`week 13-15 animals were paired, avoiding mating of siblings. Vaginal smears
`
`were made every morning and if there was no sign of spermatozoa within one ‘
`
`week, the female was placed with another male for a maximum of another week.
`
`3252115.;
`Fo- Clinical signs:
`
`-‘
`
`‘ —
`
`Slight sedation was observed in the MD group, and occasional piloerection postpartum in the
`nursing phase. The HD group was sedated or sleeping 30 minutes post dosing and occasional
`piloerection was observed.
`
`- Mortality: no maternal deaths occurred during the study.
`
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`NDA 21-038
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`- Body weight: Only the HD females had a significant reduction in bodyweight gain between
`
`initiation at Day 16 and Day 20. The HD females gained significantly less than the controls during
`
`the dosing fiom gestation Day 16 to Day 20, but were never significantly lighter than controls. The
`
`post—partum weights orgweight changes were not different in the HD versus the control.
`- Terminal and Necroscopic evaluations: No treatment related effects were observed at autopsy.
`- Fertility and Early Embryonic Development in Females -
`The’fertilit'y of all groups and the length of gestation were the same. The number of pups per litter
`was slightly (insignificantly) reduced in the HD group (11.0 fi'om 12.4), but so were the number of
`implantation sites (12 to 14). There was no difference between groups in the gestation index,
`viability index or lactation index.
`‘
`:- Embryo-fetal Development: On Day 1 postpartum: The mean ’fetal weights were significantly less
`in the HD group than in controls litters(5.7 vs 6.6 g). The significance remained for both males and
`
`female pup. In the middose group, 8ug/kg/day, the females were significantly lighter on Day 4. On
`Day 4, litters greater than 8 pups were randomly culled to this maximum. The HD pups remained
`significantly lighter through the 25th day and the MD group was also significantly lighter during
`this time. On Day 25, the MD pups weighed 6.6% less than control and the HD pups 12% less.
`
`The testing of developmental endpoints did not show any significant difference between controls
`
`and any dose group in pinna unfolding, eye opening, surface righting, hair or fur growth, testes
`descent in males and vaginal opening in females, tooth eruption, auditor function, visual function,
`pupillary reflex, or air righting reflex. The only significant difference was on wire-hanging on
`postpartum Days 16, 17 and 18. A smaller percentage of the HD males and females were able hang
`on to the wire on the initial day of testing. The body weight in the first 8 weeks afler nursing was
`significantly less in the MD males on weeks 3, 5 and 6. The HD males were significantly lighter
`than controls every week. The HD females were lighter only on week 7 and the lvfl) females did
`not differ significantly fi'om connols.
`
`Reproduction in F. generation:
`
`The mating performance did not differ between treatment groups. This was true of the day of sperm
`in vaginal smear, number not pregnant, males not mating, copulation index and fertility index.
`
`The female body weights and body weight gains during pregnancy did not differ-significantly
`between treatment groups and the fetal body weights and placental weights also did differ between
`
`treatment groups. The number of corpora lutea did not differ significantly, however, the mean
`number of living fetuses were significantly reduced in the HD females (11.5 from 13.9) and the
`
`mean number of early implantation losses was increased (0.4 to 0.9). Examination of the fetuses
`(F2) did not show any macroscopic group differences.
`
`_.
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`NDA 21-038
`
`Summary
`
`Pregnant females received'daily subcutaneous injections with dexmedetomidine hydrochloride at
`doses of 2, 8 and 32 pig/kg from Day 16 to Day 25 postpartum. The 8 ug/kg/day dose slightly
`reduced F, body weight gain during nursing and this decreased bodyweight continued after weaning
`in the males until week 6. The 32 ug/kg/day dose decrease bodyweight gain in the F0 dams during
`pregnancy but not during lactation and the absolute bodyweights never differed significantly from
`contbls. In the F, generation the bodyweights were reduced afier delivery and onlyin the males
`after weaning for every Week measured. There waslittle effect on maturation although the lighter
`HD males and females had significantly more difficulty wire-hanging. There wasno, differencesin
`mating performance. The number of dead fetuses was slightlyybut significantly increased and the
`number of living fetuses slightly, but significantly decreased in the HD group, F2 generation. The 8
`ug/kg/day was a NOAEL as the only significant difference fiom control group rats was reduced
`bodyweight and this was not different by week 8.
`
`The reproductive toxicity of dexmedetomidine at the HD, 32 ug/kg/day, to the F0 during gestation
`may have developmental consequences on the F , generation, as they were lighter at birth, and the
`males continued to be lighter even afier weaning. The only significant developmental difference
`was areduced number of HD animals able to lift hindfoo't or body onto a wire they were hung on by
`their forepaws. The deficit was for only one day, but it was statistically significant with both the
`males and the females on Day 16. Although the F. generation mated successfiilly, the number of
`living implants was significantly decreased and number of early dead implants significantly
`increased above controls.
`
`1 [
`
`53]
`
`Study/4111;: Examination of the Influence of MPV-l440 HCL on the Pregnant Rabbit and the
`Foetus by Intravenous Adminisuation.
`(#231)
`
`Wi‘
`Stuudy No: Pjt. #5139/89
`Six: and IESIng fa:innr:. .~__ /' '“‘*-~~—'————— "‘“"“‘.'~
`Wags:
`July 17, l989-November21, 1989
`William? yes (V0142/pgs-11. 85)
`913—1129121112 Yes (X)
`Lmandhatchnumbm: PE 058 L1, PE 056 L1, PE 055 L1
`Wm Yes ( ) No ( X)
`
`
`
`

`

`NDA 21-038
`
`Methods:
`
`- Species/strain: Rabbit/Himalayan (locally bred)
`- Doses employed: 0, 6, 24 and 96 ug/kg/day, control, LD, MD, HD, respectively.
`- Route of Administration: intravenous, iv
`- Study Design: Daily injections from Day 6 to Day 18 ofpregnancy. Cesarean section on Day 29
`of gestation and examination of uterus and fetuses.
`- Number of animals/sex/dosing group: 12/ treatment group
`
`»
`Resigns:
`- Clinical signs: LD demonstrated slight sedation and very slight meiosis after injection and this
`lasted in several dams for 20 minutes. In the MD group, the dams assumed the abdominal position
`and showed sedation and meiosis for l to 2 hours. The sedation‘and time in the abdominal position
`was increased in the PD group and meiosis lasted in one dam for 6 hours.
`
`The bodyweight gain, graphically( pg 55), appeared to be more in the HD and MD groups than in
`control, but the tables of daily weights did not appear significantly different. The sponsor provided
`no tabulation of weight gain or statistical analysis.
`- Mortality: There were no deaths in any treatment group.
`- Consumption: Graph of daily food consumption did not suggest any treatment effect. (Vol 42/Pg
`56): Water consumption was not affected, according to the sponsor.
`
`Segment II in Rabbit
`- Embryo-fetal Development: There were no drug related fetotoxicity or teratogenicity. The
`number of corpora lutea, implantation sites, total fetuses, percent in left and right, number of
`placenta, number of resorptions and mean number per dim did not vary significantly between
`treatment groups and control dams. Other parameters are in the following table:
`
`
`
`
`
`
`—---mes/k8
`mes/k8
`mes/k8
`mam-
`—m-mm
`_____
`—--_-
`—-mmm
`
`
`-n-mm
`
`
`—--mm
`
`
`—mmmm
`
`
`
`
`
`
`
`
`
`
`_.
`
`142.
`
`
`
`

`

`NDA 21-038
`
`There was no evidence that dexmedetomidine hydrochloride at 6, 24 or 96 mcg/kg/day had any
`adverse effects on the rabbit fetus when administered iv from day 6 to 18 of pregnancy. The
`sponsor contrasts this to: the effects in rats and cites publications of another an; agonist, clonidine,
`which had adverse effects in the rat but not the rabbit ’3.
`
`References:-
`
`.
`
`Pizzi WI, -Ali SF and Holston RR Behavioral evaluation ofrats prenatally exposed
`"
`l)_.
`.to the adrenergic agonists and lofexidine Neurotoxicology 9(3):559-66 (1988)
`2).
`PDR, 1995
`
`
`
`[59]
`
`Abbott-85499 Drug Metabolism Report No.31
`We:
`Lacteal excretion and fetal tissue distribution of radioactivity following a single subcutaneous
`dose of [3H]dexmedetomidine HCl (Abbott-85499. l) in the rat
`'-
`(Study No. Covance 6161-175)
`
`(248)
`
`7
`-,
`.
`Study No: 6161-175: R&D/97/565
`MW:
`WWWL M
`W: September 1997
`
`Methods: 33 female Harlan Sprague Dawley rats were separated into 2 groups. Group 1, 12 timed
`pregnant rats at Day 18 of gestation. Group 2 was 21 lactating females, about 10 days postpartum.
`The rats were 11.5 to 12 weeks of age and 241 to 365 grams.
`
`mug: Subcutaneous dosing with labeled dexmedetomidine at 0.015mg/kg
`WW: Medetomidine HCl, with tritium on the bridge methyl group,
`was synthesized by Ainersharn and the dexmedetomidineisomer was separated at Abbott by chiral
`chromatography. (Lot #5 5 585ST-108; 72.6 mcCi/mmol) Unlabeled dexmedetomidine, Lot
`#295260-0-AX, was added to the labeled dexmedetomidine HCl
`to provide a solution of 75
`mcCi/ml and o015 mg/ml. “M
`W: dexmedetomidine, labeled and unlabeled, was dissolvedin normal saline
`Qbiematmniandnmes: Group 1 received a subcutaneous injection of O.015 mg/kg of labeled
`dexmedetomidine and Brats/time point were sacrificed 1, 8, 24 and 72 hours post administration.
`Group 2 lactating females were injected subcutaneously with 0.015 mg/kg of labeled
`
`143
`
`
`
`

`

`NDA 21-038
`
`dexmedetomidine and milk and blood samples were collected, 3 rats/time point, 0.5, 1, 2, 4, 8, 24
`and 72 ho