CENTER FOR DRUG EVALUATION AND
`
`RESEARCH .
`
`APPLICA TION NUMBER:
`
`2 1 -92 0
`
`CLINICAL PHARMACOLOGY AND
`
`BIOPHARMACEUTICS REVIEW; S 2
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS
`REVIEW
`
`NDA
`
`21—920
`
`Submission Dates
`
`4/18/2005; 7/28/2005
`
`Brand Name
`
`N/A (OTC product)
`
`Generic Name
`
`Naproxen Sodium
`
`Reviewer
`
`.
`
`.
`
`Lei Zhang, Ph.D.
`
`Team Leader
`
`Suresh Doddapaneni, PhD.
`
`OCPB Division
`
`. DCPB2
`
`0ND Division
`
`Office of Non-Prescription Products/Division of Non-Prescription
`Clinical Evaluation
`
`Applicant
`
`Banner Pharmacaps, Inc.
`
`Relevant IND
`
`IND 71,161
`
`Type of Submission; Code
`
`505 (b)(2); 3S
`
`Formulation; Strength(S)
`
`Liquid-filled Soft Gelatin Capsules, 220 mg
`
`Indication
`
`OTC use for— Temporarily relieves minor aches and pains due to:
`
`headache, muscular aches, minor pain of arthritis, toothache,
`
`backache, the common cold, menstrual cramps, and temporarily
`
`reduces fever
`
`TABLE OF CONTENTS
`
`1
`
`EXECUTIVE SUMMARY ..................................................................................................... 2
`1.1 Recommendations ........................................................................................................................................ 3
`1.2 Phase 4 Commitments ................................................................................................................................. 3
`
`1.3 Summary of Important Clinical Pharmacology and Biopharmaceutics (CPB) Findings ..................... 3
`2 QUESTION BASED REVIEW....... ....................................................................................... 6
`2.1 General Attributes ....................................................................................................................................... 6
`
`2.2 General Clinical Pharmacology .................................................................................................................. 8
`2.3
`Intrinsic Factors ......................................................................................................................................... 10
`2.4 Extrinsic Factors ........................................................................................................................................ 10
`
`2.5 General Biopharmaceutics ........................................................................................................................ 10
`2.6 Analytical .................................................................................................................................................... 13
`3 LABELING RECOMMENDATIONS ................................................................................ l4
`
`4 APPENDICES ....................................................................................................................... 15
`4.1 Proposed Package Inserts from the Sponsor ........................................................................................... 15
`4.2
`Individual Study Review ........................................................................................................................... 17
`4.2.1
`PRACS Protocol N0. R03- 725: A Relative Bioavailabi/ily Study of220 mg Naproxen Sodium Soft
`Gelatin Capsules under Fasting Conditions ........................................................................................ 17
`
`NDA 21-920
`
`Naproxen Sodium (220 mg)
`Liquid filled soft gelatin capsules
`Original NDA Review
`
`1
`
`

`

`4.2.2
`
`PRACS Protocol No. R03—739: A Relative Bioavailability Stu'aj} of220 mg Naproxen Sodium Soft
`Gelatin Capsules under Non-Fasting Conditions ................................................................................ 23
`Dissolution Profile Testing Study ........................................................................................................ 29
`4.2.3
`4.3 OCPB Filing and Review Form ................................................................................................................ 32
`
`1 EXECUTIVE SUMMARY
`
`It
`Naproxen sodium belongs to the nonsteroidal anti-inflammatory class of drugs (N SAIDs).
`inhibits the synthesis of prostaglandins in body tissues by inhibiting cyclooxygenases (COX).
`Naproxen inhibits both COX-1 and COX-2. Naproxen sodium was approved in 1976 for
`prescription use (275 mg and 550 mg). The prescription indications include — treatment of
`rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, juvenile arthritis, tendonitis, bursitis,
`acute gout, and the management of pain and primary dysmenorrheal.
`In 1994, FDA granted
`over-the-counter (OTC) approval for naproxen sodium 220 mg for the indication of the
`temporary relief of minor aches and pains due to headache, muscular aches, minor pain or
`arthritis, toothache, backache, common cold, and menstrual cramps; the temporary reduction of
`fever. The maximum daily OTC dose is 660 mg. Consumers should not exceed tWo tablets (440
`mg) in any twelve hour period.
`
`In this 505 (b)(2) NDA application, the sponsor is seeking approval for naproxen sodium liquid-
`filled soft gelatin capsules, 220 mg, a new dosage form for the OTC indication. The listed
`reference compound is ALEVE® tablets, 220 mg, manufactured by Bayer Healthcare (NDA 20—
`204).
`
`The applicant is relying on the Agency’s findings of the safety and efficacy of the approved
`ALEVE product (including preclinical, toxicology and clinical data) to support the safety and
`clinical portion of this application.
`
`The Labeling, Chemistry and Manufacturing Controls (CMC), and Human Pharmacokinetics and
`Bioavailability Sections of this application are based on the new formulation.
`In terms of clinical
`pharmacology and biopharmaceutics aspects, this application is supported by two
`_
`pharmacokinetic studies (PRACS R03—725 and PRACS R03-73 9) and a comparative dissolution
`study " J4—264A). Studies PRACS R03-725 and; PRACS R03—739 assessed for the proposed
`product relative to ALEVE, the relative bioavailability under fasting conditions and effect of a
`high fat meal.
`
`Naproxen sodium liquid—filled soft gelatin capsules 220 mg (test) was bioequivalent to ALEVE
`tablets 220 mg (reference) under fasting conditions based on Cmax and AUC. A delayvin Tmax
`was observed with the liquid-filled soft gelatin capsules (Tmax was approximately 25 min later
`compared to ALEVE). However, this delay may not be clinically detectable because the
`effective concentration was reached by about 30 min for both the test and the reference products.
`
`Food decreases the rate of absorption of naproxen but not the extent of absorption for'both the
`test and reference compounds. For the test compound, naproxen sodium 220 mg soft gelatin
`capsules, Cmax was 20% lower and Tmax was 2.3 hr longer under fed conditions. This delay may
`
`NDA 21-920
`
`Naproxen Sodium (220 mg)
`Liquid filled soft gelatin capsules
`Original NDA Review
`
`l\)
`
`

`

`not be cliniCally desirable because the effective concentration would not be reached until about
`1.5 to 2 hours based on mean plasma—concentrations time profile. NSAIDs are generally taken
`with food to minimize potential GI side effects. However, in this case, taking the product with
`food may delay the onset of analgesic effect. This finding would be brought to the attention of
`the Clinical Reviewer for labeling considerations.
`
`The ALEVE tablet was approved for patients 12 years and above. The Sponsor requested a
`pediatric study waiver for this new naproxen sodium drug product. The Clinical Division
`decided that for this new product, a waiver was granted for patients younger than 6 months old.
`However, the sponsor should conduct clinical studies in pediatric patients 6 months to 12 years
`old. The submission of the pediatric studies is deferred until February 18, 2009. When a
`pediatric program in the age group is undertaken, PK studies in pediatric patients are warranted
`to determine the appropriate dose recommendations for this patient population. Further, an age
`appropriate pediatric dosage form may need to be developed for the younger age group patients.
`
`1.1 Recommendations
`
`From a Clinical Pharmacology and Biopharmaceutics perspective, this application is acceptable.
`
`1.2 Phase 4 Commitments
`
`None
`
`1.3 Summary of Important Clinical Pharmacology and Biopharmaceutics (CPB) Findings
`In terms of clinical pharmacology and biopharmaceutics aspects, this application is supported by
`two pharmacokinetic studies (PRACS ROS-725 and PRACS R03-73 9) and a comparative
`dissolution study {~w04—264A). Individual study reviews are presented as appendices in Section
`4 of this review.
`
`Study PRACS R03—725 evaluated the bioequivalence of the test product with that of ALEVE
`tablets in healthy adults under fasting conditions. The data demonstrated that the estimated 90%
`confidence intervals (Cls) for log transformed Cmax and AUC for the test product versus
`reference products in the fasting state were within the recommended limits (SO-125%) (Table
`2.5.1.1, Section 2.5). Therefore, the test product is bioequivalent to the reference product in
`adults under fasting conditions. The test product appeared to have slower absorption rate than
`the reference product (Tmax of 1.42 hour vs. 0.99 hr). The analytical portion of this study was
`inspected by the Division of Scientific Investigation (DSI) and it was found that the data from
`the study are acceptable for Agency review.
`
`Study PRACS R03—739 evaluated the bioequivalence of the test product and ALEVE tablets (the
`reference product) in healthy adults under fed state. The data from this study demonstrated that
`the estimated 90% confidence intervals for log transformed AUC for the test product versus the
`reference product was within the recommended limits (SO—125%), but not for Cmax (90% CI,
`78.75, 94.16) (Table 2.5.1.2, Section 2.5). Similar to results from StudyPRACS R03—725, the
`
`_ NDA 21—920
`Naproxen Sodium (220 mg)
`Liquid filled soft gelatin capsules
`Original NDA Review
`
`.
`
`3
`
`

`

`test product had slower absorption rate than the reference product under fed conditions (Tmx of
`3.7 hr vs. 2.5 hr).
`
`Food EZZect
`Food delayed the rate of absorption for both the test and the reference products, with a decrease
`in Cmx and an increase in Tmax. Overall extent of exposure, as indicated by AUCinf, was similar
`between fasting and fed conditions (Tables 2.5.2.1 and 2.5.2.2, Section 2.5).
`
`For the test product, naproxen sodium 220 mg soft gelatin capsules, Cmax was 20% lower and
`Tnm was 2.3 hr longer under fed conditions (Table 2.5.2.1, Section 2.5). AUC values of
`naproxen when administered with food were within 80—125% limits when compared to fasted
`conditions for the test product (Table 2.5.2.1, Section 2.5).
`
`Similar food effect-was also observed for the reference compound, ALEVE 220 mg tablets.
`Food decreases the rate of absorption of naproxen but not the extent of absorption for the
`reference compound. Cmax was 15% lower and Tm.X was 1.5 hr longer under fed conditions
`(Table 2.5.2.2, Section 2.5). AUC values of naproxen when administered with food were within
`80—125% limit when compared to fasted conditions for the reference compound (Table 2.5.2.2,
`Section 2.5).
`
`Assessment at Delay in TLax 07_‘ the Test Product
`
`A delay in TmX for the test product relative to the reference product is observed under both
`fasting and fed conditions. In addition, food delays Tmax for both the test and reference products.
`Whether the difference observed in mean Tmax clinically meaningful is not clear. To relate
`plasma levels to potential clinical efficacy, the results from a dental pain model in the original
`ALEVE approval package (NDA 20-204) were used.
`In that model, the effective concentration
`for naproxen to achieve a meaningful pain reduction was 15,000 ng/mL.
`
`Because a 440 mg dose of naproxen was used in Study PRACS R03—725 (fasting condition) and
`a 220 m g dose of naproxen was used in Study PRACS R03—739 (fed condition), and PK of
`naproxen was linear up to 500 mg, the plasma concentrations from Study PRACS R03—725 were
`divided by 2 to fit all data (fasting and fed) on the same plot (Figure 1). This PK profile also
`reflects the mean plasma levels for naproxen when one capsule is taken.
`
`Under fasting conditions, both the test and reference products reached 15,000 naproxen plasma
`level before 30 min from the mean plasma—concentration profile (Figure 1). ' Therefore, the
`slightly—delayed absorption of naproxen from the test product to the reference product under
`fasting conditions (mean Tmax of 1.42 hr vs. 0.99 hr) is most likely undetectable clinically.
`
`Under fed conditions, it was found that the reference product reached level of 15 ,000 ng/mL
`beforel hour from the mean plasma—concentration profile (Figure 1). However, the test product
`did not reach this level until close to 1.5 to 2 hours (Figure 1). Compared to the fasting
`condition, the delayed absorption of naproxen from the test product under the fed condition may
`translate to delay of onset of analgesic effect which is not desirable clinically (mean Tmax of3.7
`hour). In general, NSAID would be recommended to be taken with food due to G1 effect.
`
`NDA 21—920
`Naproxen Sodium (220 mg)
`Liquid filled soft gelatin capsules
`Original NDA Review.
`
`4
`
`

`

`However, in this case, food may delay the onset of analgesic effect. This finding would be
`brought to the attention of the Clinical Reviewer for labeling considerations.
`
`
`30000
`
`Figure 1. The mean plasma concentration-
`time profile (linear scale) for Test (0) and
`Reference (a) products under fed and
`fasting conditions (0-4 hr).
`
`EE
`
`: 25000
`5C
`a 20000
`g
`3 15000
`5
`10000
`
`U(
`
`BE(
`
`I!
`En.
`
`5000
`
`_____a
`5
`
`
`
`
`\ +Test—Fast
`--e--- Test—Fed
`m-»+—-Ref—Fast
`Ref-Fed
`
`
`
`
`
`
`
`Dissolution
`The dissolution was performed and the samples were analyzed as per method ”433—202 (see
`Table below). The lots of the test and reference products studied in bioequivalence studies were
`used in the dissolution study. Samples from 12 individual capsules or tablets from each lot were
`pulled and tested at 15, 30, 45, and 60 min. The dissolution profiles were compared with the
`similarity factor (f2) calculations.
`
`‘ -
`
`_,__..____....
`
`Mm N...
`l
`
`
`A paratus
`
`Number of units
`“W“
`
`
`Sam ling times {minutes)
`
`
`WW:- ind m
`
`Media
`‘
`, gm...
`
`
`Anal tical Method
`HPLCngmjwrmg.;......._WW...mmM. rww‘mme‘mtwm |
`
`Proposed Specification l Not less thar N‘*(Q)IS dissolved1n 45 min
`
`
`
`Temperature
`
`
`The test product has a slower dissolution rate than the reference product. On average, about “W
`of the test product was dissolved at 30 min while the reference product showed an almost
`complete dissolution at 30 min. The in vitro dissolution results were consistent with the results
`from the in vivo bioequivalence study that showed the test product had a slower absorption rate
`than the reference product.
`
`A specification of ”x”?:Q) at 45 min as proposed by the Sponsor for the test product is
`acceptable.
`
`
`
`Lei Zhang, PhD.
`
`NDA 21-920
`
`Naproxen Sodium.(220 mg)
`Liquid filled soft gelatin capsules
`Original NDA Review
`
`5
`
`.
`
`

`

`Clinical Pharmacology Reviewer
`Division of Clinical Pharmacology and Biopharmaceutics II
`Office of Clinical Pharmacology and Biopharmaceutics
`
`Concurrence:
`
`
`
`Suresh Doddapaneni, Ph.D.
`Clinical Pharmacology Team Leader
`Division of Clinical Pharmacology and Biopharmaceutics 11
`Office of Clinical Pharmacology and Biopharmaceutics
`
`OCPB briefing (Optional Intra—Division) Date: January 27, 2006
`
`2 QUESTION BASED REVIEW
`
`2.1 General Attributes
`
`
`2.1.] What are the highlights ofthe chemistry and physico—chemical properties of the drug
`substance, and the formulation ofthe drug product?
`
`Table 2.1.1.1. Physical-chemical Pro erties of Na roxen Sodium.
`
`Drug Name
`Naproxen SodiUm
`Chemical Name
`(—)~6—methoxy—alpha—methyl—Z—napthaleneacetic acid, sodium
`salt
`
`CH3
`
`Structure
`
`Molecular Formula
`Molecular Weight
`Melting Point
`Appearance
`Solubility
`
`f‘T‘IJ/{T/ \COOR
`
`H3C\O/ \\&£(/
`
`“\\:;:r/
`
`R = H (Naproxen); R =» Na (Naproxen sodium)
`
`C 14H13 NaO3
`252.23
`225°C with decomposition
`White to creamy crystalline powder
`Soluble in water at neutral pH, soluble in methyl alcohol,
`sparingly soluble in alcohol, very slightly soluble in acetone, and
`practically insoluble in chloroform
`
`The composition of the drug product (220 mg hard gelatin capsule) is listed in Table 2.1.1.2.
`
`’
`NDA 21-920
`Naproxen Sodium (220 mg)
`Liquid filled soft gelatin capsules
`Original NDA Review
`
`'
`
`6
`
`

`

`Table 2.1.1.2. Naproxen Sodium Liquid-filled Soft Gelatin Capsule Composition.
`
`
`
`1 Component
`img/capsule
`Capsule Fill
`‘
`
`LacticAcid,USP
`7
`
`
`
`Naproxen Sodium, USP
`
`220
`
`
`“‘3
`
`
`
`
`J
`t...
`
`"Capsule Shell
`I
`Gelatin, NF
`
`FD&C Yellow #6
`
`Purified Water, USP
`
`Total Shell Weight . \
`
`
`
`
`
`
`
`2. 1. 2- What is the proposed mechanism ofdrug action and therapeutic indications?
`
`Naproxen sodium is a nonsteroidal anti-inflammatory drug (NSAID). It inhibits the synthesis of
`propstaglandins in body tissues by inhibiting cyclooxygenases. At least 2 isoenzymes,
`cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX—2), have been identified that catalyze
`the formation of postglandins in the arachidonic acid pathway. Naproxen inhibits both COX—1
`and COX-2. Although the exact mechanisms have not been clearly established, NSAIDs appear
`to exert anti—inflammatory, analgesic, and antipyretic activity principally through inhibition of
`the COX—2 isoenzyme; COX—1 inhibition presumably is responsible for the drugs’ unwanted
`effects on GI mucosa and platelet aggregation.
`
`This is a 505 (b)(2) application. The proposed indication is the same as the reference product,
`ALEVE tablets, i.e., fever reduction and temporary relief from aches and pains for the common
`cold, headache, toothace, muscle ache, backache, minor arthritis pain and menstrual cramps for
`adults and children 12 years and older.
`
`
`2.1.3 What is the proposed dosage and route ofadministration ofnaproxen sodium?
`
`Naproxen sodium capsules are taken orally. The following is extracted from the proposed
`labeling:
`
`NDA 21-920
`
`Naproxen Sodium (220 mg)
`Liquid filled soft gelatin capsules
`Original NDA Review
`
`'
`
`7
`
`

`

`2.2 , General Clinical Pharmacology
`
`
`
`
`
`2. 2.] What is known about the PK characteristicsfor naproxen in general?
`
`Naproxen sodium is completely absorbed from the GI tract. Oral bioavailability of naproxen is
`approximately 95%. The peak plasma concentrations occur in 1—2 hours following oral
`absorption of naproxen sodium. The volume of distribution is 0.16 L/kg. Plasma half—life ranges
`from 10—20 hours (mean of 13hr). At therapeutic doses, naproxen is more than 99% bound to
`plasma proteins.
`
`2.2.2 Were the active moieties in the plasma appropriately identified and measured to assess
`
`pharmacokinetic parameters?
`
`Yes, total naproxen concentrations were measured in human plasma. Please refer to Section 2.6
`Analysis for analytical details.
`
`2.2.3 What are the PK characteristics ofthe drug? How do they compare to those ofthe RLD
`
`(ALEVE tablets, 220 mg)?
`
`Fasting conditions (Study PRACS R03-725 ):
`The PK parameters for Test and Reference products under fasting conditions were summarized
`in Table 2.2.3.1.
`
`NDA 21—920
`
`Naproxen Sodium (220 mg)
`Liquid filled soft gelatin capsules
`Original NDA Review
`
`8
`
`

`

`Table 2.2.3.1. Summary of PK Parameters for Test and Reference Products under Fasting ‘
`
`Conditions
`=24, Dose=440 mg).
`
`
`
`Reference
`I
`Test
`Parameters
`
`
`
`Mean
`CV
`CV
` AUCN
`
`
`(ng'hr/mL)
`
`
`
`
`
`AUCinf
`
`830462
`
`830822
`
`
`Mean
`
`782232
`
`15.4
`
`773444
`
`
`18.5
`
`
`57210
`
`
`
`
`0.99
`
`0.039
`
`The median Tmax was 1.33 hr for the Test (range 0.33—3 hr, 1.42 :1: 0.79, mean 3: SD, N=24) and
`0.67 hr for the Reference (range 0.33—2 hr, 0.99 i 0.47, mean i SD, N=24) products, respectively
`under fasting conditions.
`
`
`Fed conditions (Study PRACS R03-739_L
`The PK parameters for Test and Reference products under fed (non—fasting) conditions were
`summarized in Table 2.2.3.2.
`
`
`
`Table 2.2.3.2. Summary of PK Parameters for Test and Reference Products under Fed
`
`Conditions (N=27, Dose=220 mg).
`
`Parameters
`Test
`Reference
`—I
`
`
`Mean
`CV
`
`Mean
`
`
`
`Cm“
`21719
`28.6
`24499
`i
`18.1
`
`AUCM
`
`(ng'hr/mL)
`
`19.5
`
`' CV
`
`
`407136
`415316
`
`
`AUCinf
`444744
`19.8
`451526
`19.9
`
`(ng'hr/mL)
`
`
`
`
`
`
`
`(ng/mL)
`Tmax
`3.7
`78.7
`2.5
`63.2
`
`(hr)
`
`Kenn,
`an")
`Tm
`
`(hr)
`
`0.039
`
`18.6
`
`22.8
`
`21
`
`0.038
`
`19.1
`
`22
`
`24.2
`
`l__
`
`NDA 21-920
`
`Naproxen Sodium (220 mg)
`Liquid filled soft gelatin capsules
`Original NDA Review
`
`9
`
`

`

`The median Tmax was 3 hr for the Test (range 1-12 hr, 3.7 i 2.9, mean i SD, N=27) and 2 hr for
`theReference (range 0.67-8 hr, 2.5 i 1.6, mean :1: SD, N=27) products, respectively under non-
`fasting conditions.
`
`2.3
`
`Intrinsic Factors
`
`Not applicable.
`
`2.4 Extrinsic Factors
`
`Not applicable.
`
`2.5 General Biopharmaceutics ‘
`
`
`2. 5. 1
`Is naproxen sodium liquidjfilled soft gelatin capsules (220 mg) bioequivalent t0 the RLD
`(ALE VE tablets, 220 mg)) under fasting andfed conditions in healthy adults?
`
`Study PRACS R03-725 evaluated the bioequivalence of the test product with that of ALEVE
`tablets in healthy adults under fasting conditions. The data demonstrated that the estimated 90%
`confidence intervals (Cls) for log transformed Cmm and AUC for the test product versus
`reference products in the fasting state were within the acceptable limits (80-125%) (Table
`2.5.1.1). Therefore, the test product is bioequivalent to the reference product in adults under
`fasting conditions. The test product appeared to have slower absorption rate than the reference
`product (Tmax of 1.42 hour vs. 0.99 hr). The analytical portion of this study was inspected by the
`Division of Scientific Investigation (DSI) and it was found that the data from the study are
`acceptable for Agency review.
`
`Table 2.5.1.1. Comparison of Geometric Least Squares Means of Cmax, AUC0_2, AUC0_4,
`AUCM, and AUCinf for Test and Reference Products under Fasting Conditions.
`
`Na ' roxen
`AUCinf
`AUCM
`AUCM
`AUC0_2
`773412
`743099
`1590499
`819861
`
`
`
`Test Product
`
`Geometric
`
`
`Mean
`
` Reference
`56739
`
`Product
`
`867389
`
`1698359
`
`758909
`
`814286
`
`
`
`(78.30, 93.73) (98.09, 105.88) (97.99, 103.45)
`
`
`
`
`
`
`
`
`Mean
`
`0/0 Ratio
`
`
`
`90 %
`
`(87.79, 9797)
`
`92.74
`
`
`
`Geometric
`
`
`
`93.65 100.68 101.91
`85.67
`
`
`
`
`
`(90.06, 97.38)
`
`Confidence
`
`
`
`Interval
`
`
`
`Study PRACS R03-739 evaluated the bioequivalence of the test product and ALEVE tablets (the
`reference product) in healthy adults under fed states. The data from this study demonstrated that
`the estimated 90% confidence intervals for log transformed AUC for the test product versus the
`
`NDA 21-920
`
`Naproxen Sodium (220 mg)
`Liquid filled soft gelatin capsules
`Original NDA Review
`
`10
`
`

`

`reference product was within the acceptable limits (80-125%), but not for Cmax (90% CI, 78.75,
`94.16) (Table 2.5.1.2). Similarlto results from Study R03-725,'the test product had slower
`absorption rate than reference product underfed conditions (Tmax of 3.7 hr vs. 2.5 hr). Partial
`AUC values of early timepoints (e. g., 0-2 hr and 0-4 hr) were not bioequivalent between the test
`and the reference products with the test product being lower.
`
`Table 2.5.1.2. Comparison of Geometric Least Squares Means of Cm“, AUCM, AUCM,
`
`AUC“, and AUCinf for Test and Reference Products under Fed Conditions.
`
`Na 1 roxen
`AUC0-2
`AUC0_4
`AUCinf
`AUC0_t
`443781
`4039491
`441040
`110791
`
`Test Product
`
`20821
`
`Geometric
`
`Mean
`
`Reference
`
`Product
`
`Geometric
`
`630951
`
`411049
`
`446755
`
`
`
`
`
`% Ratio 22211
`(34.45, 72.23) (56.69, 87.27)
`
`
`Mean
`70.34 98.72
`49.88
`98.27
`
` Interval
`
`90%
`
`Confidence
`
`(78.75, 94.16)
`
`(96.23, 100.36)
`
`(96.39,101.11)
`
`7
`
`
`
`2.5.2 What is the effect offood on the bioavailability 0fthe drugfrom the dosageform?
`
`Food delayed the rate of absorption for both the test and the reference products, with a decrease
`in Cmax and an increase in Tmax. Overall extent of exposure, as indicated by AUCinf, was
`bioequivalent between fasting and fed conditions.
`
`26295
`
`79.02 .
`
`69.50
`
`89.85
`
`Tmax
`(hr) 2
`* Data for fasted conditions were divided by 2 assuming linear PK between 220 mg and 440 mg.
`11
`
`
`
`NDA 21—920
`
`Naproxen Sodium (220 mg)
`Liquid filled soft gelatin capsules
`Original NDA Review
`
`For the test product, naproxen sodium 220 mg soft gelatin capsules, Cmax was 20% lower and
`Tmax was 2.3 hr longer under fed conditions (Table 2.5.2.1). AUC values of naproxen when
`administered with food were within 80—125% limit when compared to fasted conditions for the
`test product (Table 2.5.2.1).
`Table 2.5.2.1. Comparisons of Naproxen Results for 220 mg Naproxen Sodium Soft
`Gelatin Capsules WhengAdministered as a Single Dose after a Standard High-Fat
`
`Breakfast (Test-Fed) and When Administered After an Overniaght Fast (Test-Fasted)*.
`
`90% Confidence Interval
` Geometric Least Squares Means
`
`
`
`Parameter
`Test—Fasted
`Ratio 1
`Lower
`Upper
`
`
`
`AUC0_t
`399393
`385764
`103.53
`94.84
`[T1302
`
`
`
`(ng-hr/mL)
`
`
`AUCinf
`435708
`409107
`106.50
`97.18
`116.72
`
`
`
`(ng-hr/mL)
`
`
`
`20779
`
`
`
`
`
`3 -
`
`
`
`
`
`
`
`
`
`'
`
`'
`
`'
`
`

`

`1 Ratio calculated as Fed to Fasted.
`2 Arithmetic mean
`
`Similar food effect was also observed for the reference compound, ALEVE 220 mg tablets.
`Food decreases the rate of absorption of naproxen but not the extent of absorption for the
`reference compound. Cmax was 15% lower and Tmax was 1.5 hr longer under fed conditions
`(Table 2.5.2.2). AUC values of naproxen when administered with food were within 80-125%
`limit when compared to fasted conditions for the reference product (Table 2.5.2.2).
`
`Table 2.5.2.2. Comparisons of Naproxen Results for 220 mg ALEVE Tablets When
`Administered as a Single Dose after a Standard High-Fat Breakfast (Ref-Fed) and When '
`
`Administered After an Overnight Fast (Ref-Fasted)*.
`
`
`Geometric Least Squares Means
`90% Confidence Interval
`
`
`Ref—Fed
`Parameter
`Ref—Fasted
`Ratio 1
`Lower
`Upper
`
`
`
`
`
`407318
`AUCM
`379455
`107.34
`97.62
`118.03
`
`(ng-hr/mL)
`
`
`
`AUCinf
`442461
`407143
`
`
`(ng-hr/mL)
`-
`
`
`
`
`
`
`
`
`
`24063
`
`2.5
`
`28369
`
`0.99
`
`
`
`
`
`
`108.67
`98.61
`119.77
`
`
`84.82
`
`78.20
`
`92.00
`
`—
`
`—
`
`* Data for fasted conditions were divided by 2 assuming linear PK between 220 mg and 440 mg.
`1 Ratio calculated as Fed to Fasted.
`2 Arithmetic mean
`
`
`
`
`2. 5.3 How do the dissolution profiles ofthe test product compared to the reference prouduct?
`How do the dissolution conditions and specifications ensure in vivo performance and
`
`quality of the product?
`
`The dissolution was performed and the samples were analyzed as per method /.«'03-202 (see
`Table below). The lots of the test and reference products studied in bioequivalence studies were
`used in the dissolution study. Samples from 12 individual capsules or tablets from each lot were '
`pulled and tested at 15, 30, 45, and 60 min.
`
`
`
`
`———......ww-«me‘Nuflwm
`Apparatus
`
`Speed
`~——»~
`
`Number of units
`L»—
`
`
`Sampling times (minutes)
`‘
`
`Media
`’i wwwmwwmmm
`
`Temperature
`’ Wm»
`,
`1 Analytical Method
`HPLC vn—m_.,2.__- -2 .,
`
`l Proposed Specification (Q) is dissolved in 45 min Not less than L...»~'
`
`
`
`
`
`The test product has a slower dissolution rate than the reference product (Figure 2.5.3.1). On
`average, about v—of the test product was dissolved at 30 min while the reference product
`NDA 21-920
`Naproxen Sodium (220 mg)
`Liquid filled soft gelatin capsules
`Original NDA Review
`
`12
`
`

`

`showed a complete dissolution at 30 min. The in vitro dissolution results were consistent with
`the results from the1n Vivo bioequivalence study that showed the test product had a slower
`absorption rate than the reference product
`
`r
`
`36?>1-
`B»-
`we.2:
`DE
`.\°§
`
`Capsule (Test) vs Tablet (Reference)
`
`
`- Test
`
`—< Reference
`
`
`
`_J
`
`Time (min)
`
`
`Figure 2.5.3.1. Comparative Dissolution Profiles between the Test and Reference Products.
`
`Based on the dissolution profile of the test product, a specification of1“" (Q) at 45 min as
`proposed by the Sponsor for the test product is acceptable.
`
`2.6 Analytical
`
`
`2. 6.] Were the analytical methods used to determine naproxen in biologicalfluids adequately
`validated?
`
`
`Yes. Plasma samples were analyzed by a validated HPLC method (\)~—
`by the PRACS Institute Ltd., Bioanalytical Laboratory as summarized1n Table 2 6.1.1 The
`standard naproxen (Lot O72K1806) and internal standard (IS) "'F"f"“* (Lot 043K0684) were
`supplied bywww:M as
`performed on naproxen to IS peak 1esponse ratio versus \— The lower limit of
`quantitation (LOQ) was Mng/mL.
`
`
`Table 2.6.1.1. Analytical Assay Used for Naproxen.
`
`|Assay Method
`I
`,
`,_
`Analytical Site
`
`
`W
` Precision (CV%)
`
`llnternal Standard
`
`Matrix
`
`'
`
`“Wm“
`
`__)
`
`Accuracy (% Bias)
`Within—batch
`'
`wwegm
`W
`
`Within—batch
`
`m
`Accuracy (% Bias)
`I[getweerI-batcli
`
`J
`
`NDA 21-920
`Naproxen Sodium (220 mg)
`Liquid filled soft gelatin capsules
`Original NDA Review
`
`13
`
`

`

`W '“Hfixlil‘zt‘i‘nux -
`
`recision (CV%)
`etween-batch
`
`
`
`
`
`
`M .ig/mL (R >_
`,)
`Standard Curve Ran e
`
`QCs
`\w _
`ng/mL and one blind QC 1 I ng/mL)
`
`
`w, ng/mL
`
`
`Selectivity
`0 significant baseline interference was detected at the retention 7
`ime of Naproxen or internal standard.
`
`
`Stability
`Freeze/thraw
`’—
`'
`Long term‘ "-3—”
`
`Eensitivity (LOQ)
`
`
`
`ecovery
`aproxen:
`.__...,
`'
`
`
`
`3 LABELING RECOMMENDATIONS
`The label for an OTC product does not contain PK information. Please refer to the appropriate
`reviews from ONP/DNCE for details of labeling review comments.
`
`Appears This Way
`On Original.
`
`NDA 21-920
`
`Naproxen Sodium (220 mg)
`Liquid filled soft gelatin capsules
`Original NDA Review
`
`14
`
`

`

`APPENDICES
`
`3.1
`
`Proposed Package Inserts from the Sponsor
`
`grogosed (’amm Labgj Text
`
`F
`
`n l:\r‘
`
`NDA 21—920
`
`Naproxen Sodium (220 mg)
`Liquid filled soft gelatin capsules
`Original NDA Review
`
`15
`
`

`

`
`
`NDA 21-920
`
`Naproxen Sodium (220 mg)
`' Liquid filled soft gelatin capsules
`Original NDA Review
`
`16
`
`

`

`3.2 Individual Study Review
`
`3.2.1 PRA CS Protocol No. R03-725: A Relative Bioavailability Study of 220 mg Naproxen
`Sodium Soft Gelatin Capsules under Fasting Conditions
`
`
`
`Objective: To evaluate the relative bioavailability (rate and extent of absorption) of the test
`Naproxen Sodium Capsules 220 mg (liquid-filled soft gelatin capsules) compared to the
`reference ALEVE Tablets 220 mg after a single oral dose administration of 440 mg (2 X 220
`mg) under fasting conditions in healthy adults.
`
`(Reviewer ’s Comment: Although the 440 mg dose is included in the OTC label, Agency
`generallyprefers the use ofa 220 mg dose (a single tablet/liquid-filled capsule) to assess in vivo
`bioequivalence. Because multiple dose units may result in multiple peaking which could
`translate into a peak plasma level value that does not support bioequivalence with the reference
`list drug. This comment was conveyed to the Sponsor during the [ND phase but the Sponsor had
`initiated the protocol already.)
`'
`
`Study Site:
`
`PRACS Institute, Ltd., Fargo, North Dakota 58104
`
`Principle Investigator: James D. Carlson, PharmD.
`
`Study Periods: Period I: December 4 to December 7, 2004
`Period II: December 18 to December 21, 2004
`
`Analytical Site: PRACS Institute, Ltd., 4801 Amber Valley Parkway, Fargo, North Dakota
`58104
`'
`
`Analysis Dates: December 22, 2004 to January 2, 2005
`
`Study Design: This was a randomized, single dose, two—way crossover study in 28 healthy
`subjects (9 males and 19 females) under fasting conditions (Table 1 and Table A1, Appendix).
`Twenty—seven subjects finished the study. Subject 14 was dropped from the study prior to Period
`II dose administration due to a positive pregnancy screen. Subject 21 failed to return for the
`Period II ambulatory blood sample collections.
`
`Subjects received the two treatments separated by a 14-day washout period. Treatment A (test
`product) was Naproxen Sodium Capsules 220 mg (liquid—filled soft gelatin capsules) and
`Treatment B (reference product) was ALEVE® Tablets 220 mg (Bayer). A single dose of 440
`mg (2 X 220 mg) was administered with 240 mL of room temperature water after an overnight
`fast.
`
`1NDA21-920
`
`Naproxen Sodium (220 mg)
`Liquid filled soft gelatin capsules
`Original NDA Review
`
`17
`
`

`

`Table 2. Summary of PK Parameters for Test and” Reference Products under Fasting
`Conditions (N=24).
`
`_l
`Parameters
`1—
`Test
`1
`Reference
`
`
`1
`Mean _l
`CV
`Mean
`CV
`
`782232
`15.4
`773444
`20.0
`
`,
`
`AUCM
`(ng'hr/mL)
`
`
`
`
`AUCin;
`
`830462
`
`16.4
`
`
`n 'hr/mL)
`l..—
`.
`53625
`19.1
`,
`57210
`12.6
`
`! g/mL)
`L
`,
`.
`1.42
`55.5
`0.99
`47.1
`
`
`
`
`
`830822
`
`+
`
`20.8
`
`
`
`0.038
`12.4
`0.039
`16.7
`
`
`18.5
`
`13.9
`
`18.5
`
`18.6
`
`The 90% confidence interval (CI) of the relative geometric mean of the Test to the Reference
`product for Cmax, AUC0-41AUC0_t, and AUCinf were all within the acceptance range of 80—125%
`under the fasting conditions (Table 3). However, when partial AUC of 0—2 hours were compared
`between the Test and the Reference compound, the lower boundary of 90% CI was slightly
`below 80 (78.3).
`
`Table 3. Compa