`
` Reviewer: Mamata De Ph.D. NDA No. 21-897
`
`sites appeared clinically normal. Injection site reactions, after subsequent doses at
`intervals of 30 or 60 days, were similar to those noted after the first dose. The reactions
`at sites receiving multiple injections also gradually diminished and the sites were
`essentially normal in appearance by 2 to 4 months after the last dosing.
`
`For all sacrifices up to Day 134 (2 to 6 weeks after the most recent treatment), residual
`test material was grossly visible at the local injection sites within the muscle and in some
`cases in small raised areas on the adjacent superficial muscle surface. The residual
`material within some injection sites was firm and well—defined while in others it was
`more diffuse and viscous. As the study progressed, less residual material was present.
`Adhesions were present in the subcutaneous region between the skin and superficial
`muscle surface at the injection sites in some animals (261/0). Tissue adhesion was rarely
`evident at the 6-month post—dose sacrifices (Days 210, 240 and 301).
`
`Microscopically, residual test material was readily identified in injection site sections as
`retractile material. The residual material was progressively degraded, in that, by the 6-
`month post—dose sacrifices, significantly less foreign material was present compared to
`sites from earlier sacrifices.
`
`The predominant histopathological findings consisted of an inflammatory reaction with
`fibrosis. For most sites evaluated approximately 2 weeks after dosing, chronic active
`inflammation (moderate to severe) was observed and was characterized predominantly by
`macrophages and multinucleated giant cells as well as neutrophils, eosinophils and
`lymphoplasmacytic cells. A component of granulomatous inflammation (minimal to
`severe) was also present in occasional sites at 2 weeks post-dose but this change was
`more obvious in sites examined at longer intervals after dosing. At the Day 44 sacrifice
`for Group 1 animals, chronic active inflammation was observed at sites from the left leg
`(2 weeks post-dose), whereas granulomatous inflammation was seen in the right leg sites
`(6 weeks post—dose).
`In Group 4 animals sacrificed at Day 134, 2 of 4 animals presented
`with primarily granulomatous inflammation, whereas the remaining exhibited chronic
`active inflammation. Minimal to moderate degeneration/regeneration of skeletal muscle
`was also observed at some injection sites primarily at earlier sacrifices. Minimal to
`moderate edema was noted in some, but not all injection sites at the 2-week post—dose
`sacrifices (Days 18, 44, 74 and 134) and was slightly more prominent with multiple
`dosings. Occasional minimal injection site hemorrhage observed in a few animals was
`attributed to the dosing procedure.
`
`The recovery sacrifices conducted 6 months after the last dosing and up to 10 months
`after the first dosing (Group 1), demonstrated that polymer degradation was progressive
`and that it was accompanied by evidence of reversal of local inflammation and fibrosis.
`At the recovery time points, chronic active inflammation was no longer present and a
`lower incidence and/or severity of granutomatous inflammation was observed. Similarly,
`minimal to moderately severe fibrosis, most apparent at earlier sacrifices had diminished
`significantly by the time ofthe recovery sacrifices.
`
`7l
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`

`

`Reviewer: Mamata De, Ph.D.
`
`NDA No. 21-897
`
`Study title: Investigative Local Tolerance Study of Medisorb® Naltrexone in
`Dogs Following Intramuscular Administration I :5 6403—123 Sponsor
`Reference No: AT-21—06)
`\
`
`In a previous study with beagle dogs (Alkermes Reference AT-21-05), an injection site
`reaction (a localized swelling) was clinically evident following intramuscular
`administration of Medisorb Naltrexone. In other species (rabbits, monkeys and humans),
`Medisorb Naltrexone did not produce similar reactions following intramuscular
`administration. The purpose of this investigative study was to further assess the injection
`site response following intramuscular administration of Medisorb Naltrexone in dogs.
`The study was designed to assess the following: 1) the effect of dose on the severity of
`injection site reactions to Medisorb Naltrexone, and 2) the effect of using a different lot
`of Medisorb Naltrexone to that used in study AT-21-05 on the severity of injection site
`reactions.
`
`Four male and four female purebred beagle dogs approximately 7 to 10 months of age
`and 6.2 to 1 1.5 kg at study initiation, were utilized in the study. Medisorb Naltrexone
`was suspended in 1.2 mL of Medisorb Diluentjust prior to administration (within
`approximately 5 to 10 minutes). The nominal microsphere concentration was
`approximately 280 mg/mL. For Group 3 (4 mL dose volume), three vials were pooled to
`deliver each microsphere dose. For Groups 1 and 2 (1 mL dose volume), one via] was
`used for each dose. '
`
`All animals survived to the scheduled necropsy. There were no adverse body weight
`changes during the study. Clinical effects were limited to injection site reactions, as
`described below. Following intramuscular injection of Medisorb Naltrexone, a clinically
`evident injection site reaction (a localized swelling) developed. This reaction was similar
`to that observed in the AT—21—05 dog study. The injection site reactions were dose
`related in that the onset of the reaction was earlier, the size of the swelling was larger and
`the reaction was more persistent in animals that received 4 mL compared to those that
`received a 1 mL dose. Swelling was noted in both Group 3 animals, beginning on Days 2
`or 4 and was still observed on Day 15. Serosanguineous discharge was also present for
`one Group 3 animal (#H3 8505) on Day 10. Swelling was present in most animals in
`Groups 1 and 2 ranging between Days 7 and 15. Reddened skin was noted at a saline
`control injection site for one Group 3 animal on Day 7. No other findings were apparent
`for saline control injection sites.
`
`At necropsy, residual test material was observed at most injection sites, either within the
`muscle and/or as a raised area in the adjacent subcutaneous region. Some injection sites
`exhibited a pale fluid filled pocket surrounding the test material within the muscle.
`In
`addition, tissue adhesion was present in the subcutaneous region between the skin and
`just above the muscle at the injection sites of some animals. Macroscopically, a greater
`amount of residual test material was observed for sites which received 4 mL compared to
`those that received 1 mL. No macroscopic findings were noted for saline control sites.
`
`Study title: Investigative Local Tolerance Study of Medisorb® Naltrexone in
`
`72
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`

`Reviewer: Mamata De, Ph.D.
`
`NDA No. 21-897
`
`Rabbits Following Intramuscular Administratio
`Reference No: AT-21-07)
`-'
`
`9'”
`
`‘7'"
`
`. 6403-122 Sponsor
`
`:
`
`In a previous study with beagle dogs (Alkermes Reference AT-21-05), an injection site
`reaction (a localized swelling) was clinically evident following intramuscular
`administration of Medisorb Naltrexone. In other species (rabbits, monkeys and humans),
`Medisorb Naltrexone did not produce similar reactions following intramuscular
`administration. The purpose of this investigative study was to assess the local tolerance
`for Medisorb® Naltrexone when administered intramuscularly as a single dose or as two
`consecutive doses to rabbits. Three male and three female Hra:(NZW)SPF Rabbits,
`approximately 18 to 20 weeks of age and 2.5 to 3.0 kg at study initiation, were utilized in
`the study.. Medisorb Naltrexone was suspended in 1.2 mL of Medisorb Diluentjust prior
`to administration (within approximately 5 minutes). The nominal microsphere
`concentration was approximately
`ng/mL and the target dose volume for each
`intramuscular injection was approximately 3.0 mL (a maximum intramuscular volume in
`rabbits). Two vials were pooled to deliver a single dose. The nominal dose per injection
`for Medisorb Naltrexone was approximately
`ng (approximately 294 mg of
`naltrexone). All animals were clinically normal throughout the study and survived to the
`scheduled necropsy. There were no adverse effects on body weights during the study.
`Intramuscular injection of Medisorb Naltrexone or Medisorb Diluent did not result in any
`adverse reactions at the local injection sites. A slight raised area was noted one hour after
`dosing for one animal each from Group 2 on Day 1 and Group 3 on Day 8. The raised
`areas in both animals did not persist and injection sites were clinically normal one day
`after dosing. No other test or vehicle control related injection site findings were noted
`clinically. The macroscopic findings were limited to the intramuscular injection sites. At
`necropsy, a light focus interpreted as residual test materials was observed at all
`intramuscular Medisorb Naltrexone dose sites. Findings for all injection sites consisted
`of a single, firm and tan area within the muscle. One or two distinct firm tan areas were
`observed within the muscle. A small light focus area of residual material on the surface
`of the muscle was also observed. There were no macroscopic findings for any of the
`vehicle control treated sites. There were no other macroscopic findings reported.
`
`Genetic toxicology:
`
`The Sponsor is referencing the genetic toxicology data that was evaluated for the Revia
`NDA and described in the approved label. The Sponsor also submitted their evaluation
`of the genetic testing results and copies of the published literature that served as the basis
`of the Revia genetic toxicology submission. Of the genetic toxicity studies conducted
`with naltrexone, only the Drosophila sex linked recessive lethal assay was positive.
`Specifically, a concentration of 10 mg/ml naltrexone was found to consistently increase
`recessive lethal frequency of the experimental groups 2-3x over their controls.
`Naltrexone was administered at 7.0 x 10.0 mg to the flies either by feeding (6 tests) in
`10% sucrose or by injection (2 tests) in saline. Up to four broods, were examined
`covering several stages of spermatogenesis; sperm (Brood 1)), spermatids (Brood ll),
`spermatocytes (Brood 111), and spermatogonid (Brood IV). The results showed a
`
`73
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`

`

`Reviewer: Mamata De, Ph.D.
`
`-
`
`NDA No. 21-897
`
`consistent positive response at 10 mg/ml in the post meiotic cells. Both injection and
`feeding studies produced similar responses at this concentration.
`
`Naltrexone was also tested in in vivo chromosome alteration studies with both somatic
`
`cell and germinal cell risk assessments completed. Doses of 90, 300, and 900 mg/kg
`were administered by gavage to rats. Animals were killed at 6, 24, and 48 hrs, and after
`an acute exposure and at 6 hrs after a 5 day subchronic exposure. No evidence for either
`clastogenicity or mitotic inhibition was obtained.
`
`Naltrexone was evaluated for its ability to induce reciprocal translocations in mouse
`sperm cells using the Heritable Translocation Assay (HTA). Male mice were treated by
`oral gavage with 103, 343, and 1030 mg/kg/day for seven weeks. One hundred F1 male
`progeny from crosses of the exposed males to unexposed females were mated
`sequentially to three sets of females and the embryos scored for evidence of semisterility.
`All semisterile and sterile males were examined cytologically. No confirmed
`translocation carriers were found in the control or treatment groups with the exception of
`TEM, the positive control. No non-disjunction in the experimental animals was found.
`Inconsistency was seen in the in vitro cytogentic evaluations, in the metaphase analysis.
`One study reported positive results in lymphoblast cells but a second study reported
`negative results in CHO cells. Similar inconsistency was observed in the Sister
`Chromatid Exchange assay, positive results in long-term human lymphoblast cells but
`negative results were reported in CHO cells. Anaphase analysis in vitro was the only
`consistent observation ofa positive nature.
`
`Secondary DNA repair tests with E. coli and Wl-38 cells indicated weak non specific
`DNA damage. Urine analysis, which is not generally considered to be directly applicable
`to genetic risk evaluation, was found to be positive.
`
` / /
`
`/
`
`Carcinogenicity: No carcinogenicity study is done with the current formulation.
`Available carcinogenicity data fot the Naltrexone and PLG polymer is discussed later in
`this section.
`
`Reproductive toxicology: The Revia NDA contains Segment 1 fertility and general
`reproductive toxicity study of naltrexone administered via gavage to CrzRats. The doses
`tested were 0, 20, 60, and 200 mg/kg/day. One female rat died (1/30) after 12 days of
`drug administration (high dose). The dam was described as thin in appearance.
`Necropsy findings indicated hemorrhage/brown color in the lungs, pitted surface in the
`
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`

`

`
`
`Reviewer: Mamata De Ph.D. NDA No. 21—897
`
`In addition a
`heart, and enlargements in thymus, mediastinal lymph nodes, and caecum.
`membrane—encased mass of soft, co animalsagulated white opaque material was found to
`fill the thoracic cavity and encase the lungs and heart and/or ungroomed coat, and
`vocalization was seen both in male and female.
`In males, dose related increase in
`
`excreted seminal plugs and hyperactivity/hypersensitivity, and in females
`chromorhinorrhea, were observed. Postmortem findings obtained at scheduled necropsy
`for both male and female rats indicated no drug related lesions. For F0 generation female
`rats, the incidence of pseudopregnancy was significantly increased at high dose animals
`(7-20%) compared with the vehicle. The incidence for rats with any resorptions were 3
`(27.3%), 3 (21.4%), 8 (66.7%), and 8 (80%) for vehicle, low, mid, high dose of
`naltrexone, respectively. This corresponds to average resorptions per liter of 0.3, 0.2,
`1.2, and 2.6. All resorptions were early. No change in the average of corpora lutea,
`implantations litter sizes (live and dead), live fetuses, and the incidence of fetal gross
`external malformations was seen after naltrexone administration. Likewise, there were
`
`no alterations in fetal sex ratio or average fetal weights evident.
`
`Natural delivery data showed one low dose dam and one mid dose dam (mated with
`vehicle control) each had no surviving litter beyond day 2 post parturition. This finding
`may have been either a drug—mediated effect on maternal behavior (poor maternal care,
`e.g. failing to remove placentas and umbilical cords from live born pups) or one
`secondary to pup mortality. Administration of naltrexone to dams mated with vehicle
`control males significantly increased the absolute incidence of stillborn pups. Although
`not significant, the average number of stillborn pups per litter and the incidence of
`,
`delivering stillborn pups were increased in treated dams mated either with treated or
`vehicle control males. The incidence of dams delivering stillborn pups in vehicle control
`(both males and females untreated), and 0, low, mid and high dose naltrexone groups was
`2 (14.3%), 1 (8.3%), 1 (7.7%), and 3 (27.3%), respectively with an average of 0.1, 02, 0.1
`and 0.3 stillborn pups per litter.
`In these same respective groups, the incidence of
`stillbirth was 2 (1.4%), 2 (1.4%), 1 (0.6%), and 3 (2.0%). One (1 1.1%) ofthe vehicle
`control dams (mated with treated? males) and three (42.9%) of the treated dams (mated
`with vehicle control males) delivered stillborn pups; with averages 0.l and 0.9 stillbirths
`per litter, respectively; the incidence of stillborn pups in these same respective groups
`was 1 (0.8%) and 6 (6.2%). Necropsy of F. generation rats showed no abnormalities in
`pups that either died during the first 21 days postpartum or on scheduled sacrifice at day
`21 postpartum. Possible drug related behavioral signs were seen in F1 generation pups,
`such as weak appearance, coldness to touch, and absence of nursing.
`
`At weaning, average body weights of the pups born to high dose dams were significantly
`lower than the vehicle control rats; however, during the post weaning to cohabitation
`period average body weights were similar for all groups. A significant increase in
`average body weights of F1 generation male rats was observed at scheduled sacrifice. No
`changes in average body weights ofF, generation female rats were found throughout the
`gestation period. No drug related postmortem findings were disclosed for F1 generation
`males or females either at scheduled sacrifice or at caesarean sectioning. The
`reproductive capacity of F1 generation rats (including mating, fertility, caesarean
`
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`

`

`
`
`Reviewer: Mamata De Ph.D. NDA No. 21—897
`
`observations [both parenteral (F1) and litter (F2)] was not affected by naltrexone
`administration to the F1 generation.
`
`Teratology studies in rats and rabbits administered naltrexone (up to 200 mg/kg, oral)
`produced essentially no teratogenicity in F1 generation rats and rabbits. In the rat study,
`naltrexone administration produced the expected behavioral signs and caused a transient,
`reversible dose related inhibition of maternal body weight gains. At the doses employed,
`naltrexone neither affected pregnancy rate nor any caesarean sectioning observations
`(both maternal and litter parameters). Fetal variations including gross external, soft tissue
`and skeletal variations and fetal ossification site averages were generally not affected.
`In
`the rabbit study, no teratogenic effects of naltrexone were demonstrated. However, dose
`related trends toward increased resorptions and average percentage of dead or resorbed
`implants/litter were observed. No other reproductive parameters, maternal or litter, were
`affected.
`
`A perinatal and postnatal reproduction study in rats showed that naltrexone, up to 100
`mg/kg, affected neither maternal (pregnancy and delivery) parameters in rats receiving
`naltrexone from day 13 of gestation to day 21 postpartum, nor litter parameters including
`pup mortality, litter size, live pups/litters pup survival, pup body weight, and pup sex
`ratio. At the doses employed, naltrexone produced the expected behavioral changes and
`caused a dose related inhibition of maternal body weight gain which persisted to day 1 of
`lactation.
`
`Segment III perinatal and postnatal reproductive toxicity study with naltrexone
`administered orally via gavage were done in
`,SD) female rats with 0, 10, 30, and 100
`mg/kg/day. The animals were dosed from day 15 of gestation to day 21 post parturition.
`Necropsy was done at day 21 post parturition. Maternal observations include drug
`related slight to marked excess salivation seen in the high dosage group. Other minor
`clinical changes were noted, such as swollen axilla and/or chest. No drug related gross
`lesions were noted at necropsy. The lesions observed included moderate to marked
`dilatation ofthe pelvis of one or both kidneys in all dose group and a perforated
`esophagus and left axillary region engorged with a red—brown material in one high dose
`dam, and a tiny fluid filled area) in the left uterine born in another high dose dam. A
`significant, dose related inhibition of average maternal body weight gain was evident
`three days after drug administration (day 18 of gestation) and continued through day 20
`of gestation. Maternal body weight change decreased with increased dose (averaged
`+34.6, +31.3*, +25.3** and +20.C** grams for days 15 t018 of gestation and +59.6,
`+56.2, *52.4** and 45.4** grams for days 15 to 20 of gestation in the vehicle, low mid
`and high dose groups respectively (*=significant).
`
`The dose-related decrease in average maternal body weight persisted to day 1 of lactation
`for dams administered nltrexone (283.7, 279.9, and 275.3 gms for vehicle, low, mid., and
`high dose respectively), thereafter dose-dependent increases in average maternal body
`weight gain from day 1 to 4 of lactation occurred (+6.5, +1 1.0, +12.0, and 13.2 gms,
`respectively). Neither effect, however, was significant. Subsequent average maternal
`
`76
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`

`

`Reviewer: Mamata De, Ph.D.
`
`NDA No. 21-897
`
`body weight gain during the remainder of the lactation period was similar for all dosage
`groups.
`
`Administration of naltrexone did not affect the incidences of pregnancy, of dams
`surviving parturition, dams delivering pups, averages for implantation length of gestation,
`duration of parturition, or incidences of dams with stillborn or with one or more live
`pups, and of dams with no pups surviving to day 21 post parturition. Thin appearance,
`not nursing, cold to touch, decreased maternal care, weak appearance and lesion occurred
`in a non dose related fashion. No post mortem physical signs were observed in stillborn
`pups, or in pups which died during the 21-day post parturition period or pups that were
`sacrificed on day 21-post parturition were related to naltrexone administration to the F0
`generation dams.
`
`The evaluation of the safety for PLG polymer in terms of potential reproductive-toxicity
`reference the teratology data from '. ___,M
`
`
`
`///
`
`V However, the Sponsor did not
`submit patent certification to these NDAs, nor do they have right of reference to the data.
`Therefore, in the absence of the PLG data for Segment 1 and III reproductive toxicity
`study, it is recommended that the data for the above mentioned toxicity studies should be
`provided for labeling purposes.
`I do not believe that the lack of Segment I and Ill
`reproductive toxicology data should block approval ofthe NDA.
`It is my opinion that the
`studies may be completed as part of a phase 4 strategy.
`
`Special toxicology: None
`
`2.6.6.2 Single-dose toxicity
`
`Study title: Oral Toxicity Screen with Glycolide‘
`Administration in Rabbits.
`
`Lactide Copolymer by Capsule
`
`Key study Findings:
`
`0 Under the conditions of this study, the ALO for Glycolide’
`was greater than 648 mg/kg of body weight.
`
`cactide copolymer
`
`77
`
`

`

`Reviewer: Mamata De, Ph.D.
`
`NDA No. 21-897
`
`Study Number:
`
`./"'"
`
`Sponsor Reference No: AT-09~01
`
`Conducting Laboratory: w
`
`
`
`The purpose of this test was to estimate the potential oral toxicity of glycolide/
`Lactide Copolymer by determining if the ‘Approximate Lethal Dose’ (ALD) is greater or
`less than approximately 500 mg/kg body weight. The ALD was defined as the lowest
`dose administered which caused death either on the day of dosing or within 14 days post
`exposure. Approximately 0.55 to 0.59 grams of test material per gelatin capsule was
`used. Three female rabbits ranging in weight from 2220 to 2360 grams were each dosed
`with l to 3 capsules. The dosing day was test day one; postexposure day 14 was test day
`15. Rabbits were weighed on the day of dosing and during the recovery period of 14
`days (excluding postexpcsure days 1
`l and 12). Rabbits were observed for clinical signs
`of toxicity and mortality on the day of dosing and twice daily on most days throughout
`the recovery period. The feces were also observed routinely, for any evidence of
`elimination of the test material through the gastrointestinal tract.
`
`Due to an apparent obstruction of the trachea during dosing attempts, one rabbit was
`killed in extremis.
`In this study two rabbits were treated with approximately 500 or 648
`mg/kg of the test material and observed for 14 days. The test rabbits were dosed with 2
`and approximately 2 2/3 capsules, respectively. Both treated rabbits showed evidence of
`anorexia and one rabbit lost approximately 1% of its initial body weight one day after
`dosing. These responses were slight and were probably due to irritation off the throat
`incurred during balling gun dosing or were generalized reactions to stress. They are not
`considered to be toxicologically significant. Generally, rabbits continued to gain body
`weight throughout the recovery period. They showed no adverse clinical signs of toxicity
`and there was no mortality. On test day 6 the feces of one rabbit was white—coated and
`contained crystal appearing specks. From this observation, a small amount of test
`material was thought to be eliminated through the gastrointestinal tract
`
`2.6.6.3 Repeat—dose toxicity
`
`l-Month Toxicokinetic Study of Medisorb® Naltrexone in Rhesus
`Study title:
`Monkeys with a l-Month Recovery.
`
`Key study findings:
`
`0 Under the conditions ofthis study, a single subcutaneous administration at doses
`upto 200 mg/kg and intramuscular administration at a dose of50 mg/kg
`Medisorb® Naltrexone to male rhesus monkeys was well—tolerated.
`
`78
`
`

`

`
`
`Reviewer: Mamata De Ph.D. NDA No. 21—897
`
`o
`
`Subcutaneous and intramuscular administration of Medisorb® Naltrexone
`
`provided an initial release phase (during the first week) followed by a sustained—
`release phase. Dose proportional increases in Cmax and AUC were observed
`after subcutaneous administration of Medisorb® Naltrexone. Compared to the
`subcutaneous dose, intramuscular administration of Medisorb® Naltrexone
`
`resulted in a similar plasma profile, although the initial naltrexone levels were
`slightly higher.
`- Microscopically, at the .terminal sacrifice, the subcutaneous injection sites with
`the test material (Medisorb® Naltrexone with 20, 50, or 200 mg naltrexone/kg)
`and the injection sites with the control material (Medisorb® Naltrexone Placebo
`microspheres) were essentially similar, except for the inflammatory response and
`fragmentation of the microspheres. Compared to the placebo sites, the test,
`material sites had an increased incidence and severity of inflammatory response
`and more fragmentation of the microspheres. All subcutaneous injection sites
`(control and test material) had a minimal to moderately severe fibrous response
`enveloping the material. A granulomatous response (macrophages and foreign
`body multinucleated giant cells) was also present in all groups and varied in
`severity from minimal to moderately severe.
`
`o The intramuscular sites (Medisorb® Naltrexone with 50 mg naltrexone/kg) had an
`inflammatory response of similar incidence and severity to that noted in the
`subcutaneous test material injection sites. The intramuscular injection sites also
`had minimal to slight lymphoplasmacytic inflammatory response and microsphere
`fragmentation. All ofthe animals treated by intramuscular injection had minimal
`skeletal muscle regeneration in one or more of the dose sites. Two of the
`intramuscular injection sites exhibited a minimal fibrous response enveloping the
`injected material where the material was between muscle bundles. All injection
`sites had residual material at the time of evaluation.
`
`Study no.2
`
`r—‘i 6403-1 17
`
`Sponsor Reference No: AT—21-02
`
`Volume # and page #: 1, 1—489
`Conducting laboratory and location:
`.Date of study initiation: March 23, 2000
`GLP compliance: Yes
`QA report: Yes
`Drug, lot #, and % purity: 190-0292B, Vehiclezplacebo Medisorb microspheres, lot no:
`191-273 8B
`
`____.
`
`Methods
`
`Doses: 20, 50,200 mg/kg SC and 50 mg/kg lM
`Species/strain: Monkeys Macca mulatta
`Number/sex/group or time point (main study): 3/sex/group
`
`79
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`

`Reviewer: Mamata De, Ph.D.
`
`NDA No. 21-897
`
`Route, formulation, volume, and infusion rate: SC; Medisorb—Naltrexone
`Satellite groups used for toxicokinetics or recovery: 2/sex/group at high dose
`were used for recovery
`Age:
`1.5—3 years old
`Weight: 2.4-4.1 kg
`Sampling times: Blood (approximately 1 mL) was collected predose;
`approximately 2, 8, 24, 36, and 48 hours after each animal’s last injection on Day
`1; once on Days 5, 8, 11, 15, 18, 22, 26, and 30; and once on Days 34, 38, 45, 53,
`and 60 for recovery animals.
`Unique study design or methodology (if any): Doses were selected, by the
`Sponsor, based on naltrexone exposure level in monkeys compared to humans.
`The highest dose (200 mg/kg naltrexone) in monkeys was estimated to provide
`naltrexone level of approximately 25X human AUC. The high dose was 4- and
`10-fold higher than the selected mid- and low-dose levels (50 and 20 mg/kg
`naltrexone, respectively). On Day 1, Medisorb® Naltrexone and Medisorb®
`Naltrexone placebo microspheres were reconstituted with 1.5 ml L—
`Diluent (approximate total suspension volume of 1.75 mL) and were administered
`within approximately 5 minutes of reconstitution. Approximate suspension
`concentrations were 140 mg/mL Medisorb® Naltrexone microspheres (50 mg/mL
`naltrexone) and 145 mg/mL placebo microspheres. Both subcutaneous and
`intramuscular injections were used because the intended route of administration in
`humans was not determined at the time ofthe study and would either be
`subcutaneous or intramuscular. Each animal was anesthetized with ketamine
`(approximately 10 to 15 mg/kg) for dose administration.
`
`Experimental Design:
`
`
`Dose
`Nominal Naltrexone
`Dose VolumeE
`
`Group
`Routea
`No. of Animals
`Dose Levflmg/kg)
`(mL/kg)
`l (Control)c
`SC
`3
`0
`3.77
`2 (Low)
`SC
`4
`20
`0.38
`3 (Mid)
`SC
`4
`50
`0.94
`4 (High)d
`sc
`6
`200
`3.77
`5 Mid
`1M
`4
`50
`0.94
`a Animals in Groups 1 through 4 were dosed via subcutaneous injection (SC) and
`animals in Group 5 were dosed via intramuscular injection (1M).
`b Medisorb® Naltrexone contained ._— of active drug in micrOSpheres. Each vial
`ofMedisorb® Naltrexone was suspended at approximately 50 mg naltrexone/mL.
`Multiple injections were administered as required based on the dose and body
`weight (up to 1.5 mL/site).
`c The control animals received the Medisorb® Naltrexone placebo microspheres
`(approximately 145 mg/mL) at a microsphere dose equivalent to the high dose.
`d Two animals in the high—dose group were placed on recovery for an additional
`30 days.
`
`
`
`Observations and-times and Results:
`
`Mortality: The animals were observed twice daily (am. and pm.) for
`mortality and morbidity. All animals survived to the end ofthe study.
`
`80
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`

`Reviewer: Mamata De, Ph.D.
`
`NDA No. 21-897
`
`Clinical signs: Each animal was observed daily for clinical signs and abnormal findings
`were recorded. Once weekly, detailed observations were made for each animal;
`abnormal findings or an indication of normal was recorded. There were no test material-
`related clinical observations during either the treatment (Days 1 through 31) or recovery
`periods (Days 32 through 61). Vomiting, abnormal feces, or low food consumption were
`observed for some treated animals; however, these findings were noted infrequently,
`were not observed in a dose-dependent manner, and were, therefore, not considered to be
`related to administration of the test material.
`
`Injection Site Observations. The injection sites of each animal were examined for
`possible irritation two times/week (on nonconsecutive days). Any remarkable
`observations were identified and the dose deposition sites were measured (length x
`width). Subcutaneous and intramuscular dosing of Medisorb® Naltrexone and
`subcutaneous administration of Medisorb® Naltrexone Placebo microspheres were well-
`tolerated in monkeys. Intramuscular injection sites were not visible. Subcutaneous
`injection sites showed a localized firm enlargement attributed to the presence oftest
`material depot (0.4 mL to 1.6 mL dose volume). When measured, these enlargements
`varied in size among sites. The sizes of injection sites on Day 1 (length X width) ranged
`from 28 x 27 mm to 15 x 14 mm. Generally, these sites were largest immediately
`following dosing on Day 1 and gradually became smaller during the 1—month period; the
`greatest decrease in size occurred during Days 1 through 4. Clinically, Medisorb®
`Naltrexone sites were similar to the placebo microsphere sites. However, placebo
`microsphere sites were slightly smaller in size on Day 29 compared to Medisorb®
`Naltrexone sites. The subcutaneous injection site of one animal given 20 mg/kg and
`three of three subcutaneous injection sites of one animal given 50 mg/kg were softer and
`swollen in appearance compared to other sites during the third and fourth weeks (to Day
`29). One subcutaneous injection site of one animal given 200 mg naltrexone/kg was
`softer on Day 25 compared with the other sites. Microscopically, the injection sites that
`had clinical softness and swelling were not remarkably different from the other dose sites.
`There was little change in the size of the Medisorb® Naltrexone subcutaneous injection
`sites during recovery compared with the Day 29 observations. The injection site sizes at
`the end ofrecovery ranged from 18 x 14 mm to 15 x 11 mm.
`
`Body weights: Individual body weight data were recorded before initiation oftreatmeht,
`on the first day of treatment, and weekly thereafter. There were no test in arterial—related
`effects on body weights.
`
`Food consumption: Food consumption was assessed qualitatively, once daily. There
`were no test material-related effects on food consumption.
`
`Ophthalmoscopy: Not done.
`
`EKG: Not done.
`
`81
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`

`

`Reviewer: Mamata De, Ph.D.
`
`NDA No. 21-897
`
`Hematology: Blood samples for hematology, and coagulation (approximately 2, 1.8, and
`1.5 mL, respectively) were collected twice before initiation of treatment and on Days 4,
`31, and 61. The following hematological parameters were analyzed:
`Red blood cell (erythrocyte) count; Wh