CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`75-434
`
`BIOEQUIVALENCE
`
`AMN1037
`IPR of Patent No. 7,919,499
`
`

`

`Naltrexone Hydrochloride Tablets
`50mg
`ANDA #75434
`Reviewer: Carol Y. Kim
`x:\new\firmsam~~m\ltrs&rev\75434SD.898.doc
`
`Eon Labs Manufacturing, Inc.
`Laurelton, NY
`Submission Date:
`August 1, 1998
`November 6, 1998
`
`Review of a Bioequivalence Study and Dissolution Data ·
`
`I.
`
`Introduction
`
`Class:
`
`RLD:
`
`Opioate antagonist
`
`ReviaR Tablets, 50 mg, Du Pont Pharma (Previously known as Du
`Pont Merck)
`
`Recommended Dose: Initial dose- 25 mg/day, Target dose- 50 mg/day
`
`II.
`
`Objectives
`
`Review of:
`
`• Two-way crossover in vivo bioequivalence study comparing Eon Labs
`Manufacuring Inc.'s Naltrexone Hydrochloride Tablets 50 mg strength, to Du Pont
`Pharma's ReviaR Tablets, 50 mg strength.
`• Dissolution data for 50 mg tablets.
`
`III. Background
`
`Naltrexone is indicated in the treatment of alcohol dependence and for the blockade of the
`effects of exogenously administered opiods.
`
`Naltrexone is rapidly and almost completely (about 96%) absorbed following an oral
`administration, but the drug undergoes extensive first-pass metabolism in the liver. The
`major metabolite is 6-13-naltrexol. Like naltrexone, 6-13-naltrexol has opiate antagonist
`activity. Peak plasma concentrations of naltrexone and 6-13-naltrexol usually occur
`within 1 hour following oral administration of tablets. Plasma concentration of 6-13-
`naltrexol generally range 1.5-10 times greate.r than those of naltrexone. Naltrexone is 21-
`28% protein bound. Naltrexone and its metabolites (unconjugated and conjugated) are
`excreted principally in urine via glomerular filtration.
`
`AMN1037
`IPR of Patent No. 7,919,499
`
`

`

`IV. Protocol No. 970983: A single-dose, open-label, 2-way crossover randomized
`study under fasting conditions:
`
`A. Study information
`.-..
`Study facility information:
`Clinical Site:·
`
`Investigator:
`Analytical Site:
`
`Analytical Director:
`Study Dates:
`
`Analysis Dates:
`Storage Period:
`
`Study design:
`Protocol No.:
`Design Type:
`Randomized:
`Single or Multiple dose:
`No. of Treatment:
`No. of Periods:
`No. of Sequences:
`Washout Period:
`
`Subjects:
`Normal Healthy Volunteers:
`IRB Approval:
`Informed Consent
`No. of Subjects Enrolled:
`
`Age:
`Inclusion/Exclusion Criteria:
`Housing:
`
`Treatment information:
`Treatment:
`Test or Reference:
`Product Name:
`Strength:
`Manufacturer:
`
`Phoenix International Life Sciences Inc.
`St-Laurent, Quebec
`Samuel Serfaty, M.D.
`Phoenix International Life Sciences, Inc.,
`St-Laurent, Quebec
`
`Period #1: May 1, 1998
`Period #2: May 15, 1998
`May 25, 1998 to July 10, 1998
`no> 69 days at -22°C
`
`970983
`two-way crossover
`y
`single
`2
`2
`2
`14 days
`
`y
`y
`y
`Entered: 40 males
`Completed: 39 males
`Excluded from analysis: 3 males
`18-45 years
`listed in vol: 1.2, pages 2035-2036
`Evening prior to each drug administration until
`After 36 hour blood sample.
`
`B
`A
`Reference
`Test
`ReviaR Tablet
`Naltrexone Tablet
`50mg
`50mg
`Eon Labs Manufacturing Inc. Du Pont Pharma
`
`2
`
`AMN1037
`IPR of Patent No. 7,919,499
`
`

`

`Lot No.:
`Batch Size (ANDA/Full):
`Expiration Date:
`Content Uniformity
`Assay:.
`Dose Administered:
`Length of Fasting:
`
`J..
`
`#971001
`
`TBE
`99.8%
`97.2%
`50mg
`overnight
`
`#LDI58A
`
`4/99
`100.9%
`98.2%
`50mg
`overnight
`
`Dosing:
`Subjects fasted overnight before dosing and for at least 4 hours after dosing. Each oral dose
`was administered with 240 ml of water. Standard meals were provided at 4 and
`approximately 9 hours after dosing.
`
`Blood Sampling:
`Blood sample volume
`No. of time points
`Time points:
`
`5 ml
`22
`0.167, 0.33, 0.5, 0.67, 0.83, 1, 1.25, 1.5, 2, 3, 4, 6, 8,
`10, 12, 16, 24, 36, 48, 60, 72, and 96 hours post dose
`
`The plasma blood samples were stored at -22°C until analysis
`
`8. Study Results
`
`1. Clinical
`
`Drop-outs:
`
`Subject #30 was discontinued during period I in treatment group B due to
`medical events (nausea, vomiting, trembling left and right hand and sore
`stomach) requiring treatment. The medical Designate diagnosed that the
`subject was having gastritis with a remote association with the study
`drug.
`
`Adverse events: From a total of 32 adverse events reported in association to the study
`drug, four adverse events (3 subjects) were possibly or probably drug
`related to the treatment group A and ten adverse events (6 subjects) for
`treatment group B. The remaining events were reported as remote
`association with the study drug. (vol. 1.2, pp.2292-2304) The common
`adverse events were headache, dizziness, nausea, and vomiting.
`
`2. Analytical Analysis (The following section is not to be released under FOi)
`
`3
`
`AMN1037
`IPR of Patent No. 7,919,499
`
`

`

`Method:
`
`Internal Standard:
`..,._
`Specificity:
`
`Linearity:
`
`Sensitivity:
`
`No interfering peaks noted in blank chromatograms (see vol. 1.5,
`p.3078)
`0.2 -20.00 ng/ml for naltrexone and 2.00-200.00 ng/ml for 6-0-
`naltrexol, R2 ranged from 0.9852 to 0.9993 for naltrexone and
`0.9813 to 0.9997 for 6-(3-naltrexol.
`LOQ=0.2 ng/ml (naltrexone), 2.00 ng/ml (6-(3-naltrexol)
`
`Quality Control (QC) Samples:
`High:
`Mid:
`Low:
`
`Naltrexone
`16.10 ng/ml
`7.04 ng/ml
`0.60 ng/ml
`
`6-B-naltrexol
`160.63 ng/ml
`70.28 ng/ml
`6.02 ng/ml
`
`Precision of QC Samples:
`
`Accuracy of QC Samples:
`
`4.9-12.6 % CV within run
`5. 6-16 .4 % CV between run
`91.5-101.1 % within run
`96.3-105.4 % between run
`
`Stability in Plasma:
`Freeze-thaw: 4 cycles
`Short-term (bench top) at 20°c: 7.5 hours
`Long term at -22°C: 169 days
`Recovery:
`Naltrexone
`High (16.10 ng/ml): 60.4%
`Mid (7.04 ng/ml): 58.6%
`Low (0.60 ng/ml): 84.2%
`
`6-B-naltrexol
`160.63 ng/ml: 67.0%
`70.28 ng/ml: 67.1%
`6.02 ng/ml: 87.3
`
`4.2-13.9 % CV within run
`8.6-13.8 % CV between run
`90.3-104.0 % CV within run.
`91.5-103.4 % CV between.run
`
`Internal standard: 57.1%
`
`Dilution Integrity:
`
`Prepared concentration in human plasma: 70.490 ng/ml (Naltrexon),
`702.75 ng/ml (6-13-naltrexol)
`Naltrexon:
`I: 5 dilution (6 replicates)- %CV=5.7, accuracy=96.8%
`1: 10 dilution (6 replicates)- %CV=6.9, accuracy=96.2%
`6-(3-naltrexol: I: 5 dilution (6 replicates)- %CV=6.2, accuracy=92.5%
`1: 10 dilution (6 replicates)- %CV=5.2, accuracy=87.4%
`
`Reassays:
`
`There were at least 79 repeat assays (57 for naltrexone vs. 22 for 6-13-
`naltrexol) and 2 reasons for reassays: 1) anomalous sample value, 2)
`highest and/or lowest standards missing from the regression (vol 1.5, pp.
`3021-3027 (T5J, T52))
`
`Protocal Deviations:
`Conclusion:
`
`Y (see vol 1.2, p. 2287)
`Analytical method is acceptable
`
`4
`
`AMN1037
`IPR of Patent No. 7,919,499
`
`

`

`3. Pharmacokinetic/Statistical Analysis
`
`As per study protocol, data were analyzed from only 36 subjects. Since subject #30
`withdrew, subject #38 was substituted.
`
`Mean Naltrexone and 6-~-naltrexol plasma levels of 36 subjects are summarized in
`Table I.
`
`Table 1: Mean Naltrexone and 6-~-naltrexol Plasma Concentrations following an oral
`dose of 50 mg for test and reference products (N=36)
`
`Naltrexone: Reference
`Naltrexone : Test
`Lot# 971001
`Lot# LD158A
`Mean (ng/ml) CV% Mean (ng/ml) CV%
`0.000
`0.0
`0.000
`0.0
`0.0
`0.084
`0.000
`382.3
`1.137
`102.4
`1.05 I
`86.8
`3.043
`3.971
`78.3
`66.8
`62.3
`5.423
`60.2
`5.322
`52.4
`6.210
`64.5
`5.938
`48.2
`62.4
`5.731
`6.323
`47.7
`6.054
`5.081
`63.2
`4.537
`48.2
`5.331
`59.7
`54.7
`4.117
`3.686
`55.6
`2.593
`55.4
`2.942
`57.4
`1.974
`60.8
`2.072
`64.1
`1.144
`1.045
`57.5
`59.7
`0.690
`63.8
`0.663
`60.2
`0.469
`85.7
`0.463
`78.4
`0.444
`82.3
`0.445
`77.6
`97.7
`0.288
`0.258
`138.0
`0.029
`294.2
`0.033
`301.2
`0.006
`600.0
`0.007
`600.0
`0.0
`600.0 ·
`0.000
`0.009
`0.000
`0.0
`0.000
`0.0
`0.000
`0.0
`0.000
`0.0
`0.0
`0.0
`0.000
`0.000
`
`Ratio
`
`T/R
`0
`0
`1.08
`1.30
`1.02
`0.96
`0.91
`0.84
`0.85
`0.89
`0.88
`0.95
`0.91
`1.04
`1.01
`0.99
`I.II
`0.88
`0.86
`0
`0
`0
`0
`
`Time (hour)
`0.00
`0.167
`0.33
`0.5
`0.67
`0.83
`I
`1.25
`1.5
`2
`3
`4
`6
`8
`IO
`12
`16
`24
`36
`48
`60
`72
`96
`
`6-13-naltrexol: Test
`Lot# 971001
`Man (ng/ml) CV%
`0.000
`0.0
`0.125
`600.0
`15.122
`77.8
`70.8
`59.368
`76.220
`44.5
`76.247
`37.9
`75.270
`33.4
`66.144
`28.6
`61.200
`22.2
`51.650
`27.8
`41.750
`23.3
`23.8
`34.888
`28.401
`24.1
`23.509
`26.5
`18.574
`26.4
`24.5
`16.789
`13.847
`27.9
`9.449
`27.8
`4.182
`39.4
`1.933
`90.9
`0.438
`222.4
`0.000
`0.0
`0.000
`0.0
`
`6-13-naltrexol: Reference
`Lot# LD158A
`Mean (ng/ml) CV%
`0.000
`0.0
`0.797
`200.3
`13.997
`90.1
`38.042
`59.5
`63.816
`46.2
`72.858
`39.7
`74.435
`35.8
`71.044
`29.7
`63.667
`28.3
`53.809
`22.0
`42.571
`24.4
`35.461
`25.1
`28.714
`24.3
`22.647
`26.3
`18.831
`27.4
`16.851
`24.5
`24.3
`13.848
`9.426
`26.1
`4.299
`36.9
`2.158
`89.9
`0.211
`329.6
`0.063
`600.0
`0.000
`0.0
`
`Ratio
`
`T/R
`0
`0.16
`1.08
`1.56
`1.19
`I.OS
`1.01 --
`0.93.
`0.96 •
`0.96 ·
`0.98
`0.98
`0.99
`1.04
`0.99
`0.99
`1.0
`1.0
`0.97
`0.89
`2.07
`0
`0
`
`Analysis of variance was performed on each pharrnacok.inetic parameter using SAS
`GLM procedure. Mean reported pharrnacok.inetic parameters for Naltrexone are
`shown in Table 2. The LS means of the log-transformed pharrnacokinetic parameters,
`means, and the 90% confidence intervals of test product versus reference product are
`presented in Table 3.
`
`5
`
`AMN1037
`IPR of Patent No. 7,919,499
`
`

`

`Table 2: Test mean/Reference mean ratios ofNaltrexone and 6-(3-naltrexol
`pharmcokinetic parameters
`
`Test Meart
`
`Naltrexone
`Parameter• Test Mean CV% Ref Mean CV% Ratio
`,.:._
`(T/R) 1
`719.5
`1.05
`55.1
`23.113
`54.9
`24.229
`653.7
`0.94
`64.1
`23.199
`57.4
`21.773
`89.84.
`0.93
`62.5
`7.339
`45.8
`6.812
`0.053
`0.93
`43.3
`0.21714
`41.5
`0.20091
`13.688
`1.09
`35.1
`3.644
`37.4
`3.989
`0.87
`27.7
`0.910
`1.077
`38.0
`0.941
`• AUCT=ng*hr/ml, AUCI=Ng*hr/ml, TMAX=hr, CMAX=ng/ml
`'Calculated by reviewer
`
`AUCI
`AUCT
`CMAX
`KE
`T½
`TMAX
`
`CV%
`
`6-0-naltrexol
`Ref Mean
`
`CV%
`
`22.0
`24.1
`36.5
`21.9
`29.0
`37.4
`
`717.3
`654.4
`85.62
`0.05386
`13.674
`1.046
`
`21.8
`23.6
`33.4
`23.5
`26.8
`27.9
`
`Ratio
`(T/R) 1
`1.00
`0.99
`1.05
`0.98
`1.00
`0.87
`
`Table 3: Geometric LSMeans and 90% confidence intervals for Naltrexone and 6-13-
`naltrexol Tablet
`
`--
`
`Naltrexone
`Low CI
`(%)••
`88.5
`90.1
`88.8
`
`Upper CI
`(%)**
`103.6
`103.1
`109.6
`
`6-0-naltrexol
`Low CI
`(%?*
`96.2
`97.1
`96.5
`
`Upper CI
`(%)••
`103.3
`102.3
`112.9
`
`Parameter•
`
`LAUCI
`LAUCT
`LCMAX
`
`6-(3-naltrexol
`Naltrexone
`LS Means
`LS Means LS Means LS Means
`(ref)
`(ref)
`(test)
`(test)
`699
`19.49
`699
`18.92
`632
`21.54
`632
`20.70
`80.6
`6.23
`83.9
`6.11
`**Used natural log transformed parameter
`
`Comments
`
`1. Plasma concentration levels for 6-(3-naltrexol are approximately 10 times higher
`than the parent drug_.
`
`2. Values of CMAX, AUCT, and AUCI mean ratios ofNaltrexone and 6-(3-naltrexol
`for the test product versus reference product administered under fasting conditions
`(ratio NB) are within the acceptable range of 0.8-1.2.
`
`3. There were no statistically significant period or sequence effects for any of the
`above parameters. (p>0.05) The pharmacokinetic parameters and 90% confidence
`intervals ofNaltrexone and 6-(3-naltrexol re-calculated by the reviewer were in
`good agreement with the values determined by the firm.
`
`4. The mean (¾CV) AUC/AUC1 ratios ofNaltrexone were 91.30 (3.55), range 83.0
`to 96.9, and 91.73 (3.76), range 82.8 to 96.8, for test and reference, respectively.
`The mean (¾CV) AUC/AUC1 ratios of 6-~-naltrexol were 90.56 (5.22), range
`68.7 to 96.6, and 90.43 (3.98), range 81.7 to 95.7, for test and reference,
`respectively.
`
`5. AUCI could not be calculated for subject# 3,4,6,14,17,23,24,28, and #32 _because
`subject Kel could not be determined. The reviewer concurs with this decision.
`
`6
`
`AMN1037
`IPR of Patent No. 7,919,499
`
`

`

`6. The 90% confidence intervals of log-transformed AUCT, AUCI, and CMAX
`ratios for Naltrexone and 6-13-naltrexol are all within 80-125% range.
`
`V.
`
`Dissolutfon
`
`Method of dissolution
`Speed
`No. of Units Tested
`Medium
`Temperature
`Volume
`Specifications
`Assay Methodology
`Reference Product
`
`USP 23, Apparatus II (paddles)
`50 rpm
`12
`Water
`31°c
`900 ml
`NLT
`
`; dissolved in 60 minutes
`
`Du Pont Phanna's ReviaR Tablet, 50 mg
`
`Result of In Vitro Dissolution Profile Summary for Naltrexone 50 mg
`
`Sampling
`Times
`(minutes)
`
`Eon Manufacturing, Inc.
`Lot# 11971001
`Strength: 50 mg
`Mean¾
`
`... 1 ~0ange
`
`10
`20
`30
`60
`70
`
`29.9
`64.0
`86.5
`98.1
`98.9
`
`..
`
`¾CV
`
`15.0
`7.2
`4.4
`2.6
`2.2
`
`ReviaK
`Lot##LDl58A
`Strength: 50 mg
`Mean¾
`
`37.0
`66.2
`85.9
`100.6
`100.8
`
`I Range
`% -·
`
`.
`
`¾CV
`
`12.4
`5.7
`3.5
`1.4
`1.8
`
`Composition of Eon's Naltrexone 50 mg Tablet (Not to Be Released Under FOi)
`
`Components
`
`Naltrexone Hydrochloride
`Colloidal Silicon Dioxide
`Lactose Monohydrate
`Crospovidone,
`Microcrystalline Cellulose,
`Magnesium Stearate,
`
`I Mg/tablet
`Core
`I 5o.o
`. -
`--
`-+-···
`
`I
`
`Coatrd Tableb
`
`Total
`
`I 308
`
`Comment
`
`I ¾w/w
`
`I 16.2
`
`...
`
`I Removed
`
`I 100
`
`-
`-
`
`-
`
`The firm conducted dissolution according to the procedure described in the OGD
`guidance. The dissolution data are acceptable.
`
`AMN1037
`IPR of Patent No. 7,919,499
`
`

`

`VI. Recommendations
`
`I. The single-dose bioequivalence study #970983 under fasting conditions, conducted
`by Eon Manufacturing Inc. on its Naltrexone Hydrochloride Tablet, 50 mg, lot
`#971001, cow.paring it to ReviaR 50 mg, lot #LD158A, manufactured by Du Pont
`Pharma, has been found acceptable by the Division of Bioequivalence. The study
`demonstrates that Eon Manufacturing Inc.'s Naltrexon Hydrochloride Tablet, 50 mg
`is bioequivalent to Du Pont Pharma's ReviaR Tablet, 50 mg.
`
`2. The dissolution method conducted by Eon Manufacturing Inc. on its Naltrexone
`Tablets, 50 mg, lot #971001, is acceptable.
`
`3. The dissolution testing should be incorporated into the firm's manufacturing controls
`and stability program. Dissolution testing should be conducted in 900 ml of water at
`37°C using USP 23 Apparatus II (paddles) at 50 rpm. The test should meet the
`following specification:
`
`of the labeled amount of the drug in the dosage
`Not less than - ·
`form is dissolved in 60 minutes.
`
`The firm should be informed of the recommendations.
`
`Division of Bioequivalence
`Review Branch III
`
`\ i
`{iµ \I\ CD\ 0...
`. I C\
`RD INITIALLED BY BDA VIT\p
`FT INITIALLED BY BO.A VIT ~ .L)a,u.bL' Date: (,
`
`l \
`tO \qi
`
`Con e~~
`aleP.Ccmner, Pharrn.D.
`Director
`Division of Bioequivalence
`
`8
`
`AMN1037
`IPR of Patent No. 7,919,499
`
`