CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`‘
`
`21-920
`
`MEDICAL REVIEW
`
`

`

`CLINICAL REVIEW
`
`Application Type
`Submission Number
`
`21 -920
`N—OOO
`
`Submission Code BM
`
`Letter Date April 15, 2005
`Stamp Date May 11, 2005
`PDUFA Goal Date February 18, 2005
`
`Reviewer Name Karen B. Feibus, M.D.
`- Review Completion Date December 27, 2005
`
`Established Name Naproxen sodium
`(Proposed) Trade Name
`not known
`Therapeutic Class
`nonsteroidal anti—inflammatory
`Applicant Banner Pharmacaps, Inc.
`
`Priority Designation
`
`S
`
`Formulation Capsules, 220 mg
`Dosing Regimen
`1-2 capsules, then 1 capsule Q 8
`12 hours
`
`Indication
`
`fever reduction, temporary relief
`of minor aches and pains
`Intended Population Ages 12 years and older
`
`

`

`Clinical Review
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`{Insert Reviewer Name}
`{Insert Application and Submission Number}
`
`{Insert Product Trade and Generic Name}
`
`Table of Contents
`
`1
`
`EXECUTIVE SUMMARY ................................................................................................................................ 4
`
`1.1
`1.2
`
`1.3
`
`1.2.1
`1.2.2
`1.2.3
`
`1.3.1
`1.3.2
`1.3.3
`1.3.4
`1.3.5
`1.3.6
`
`RECOMMENDATION ON REGULATORY ACTION ........................................................................................... 4
`RECOMMENDATION ON POSTMARKETING ACTIONS .................................................................................... 4
`
`Risk Management Activity ....................................................................................'................................ 4
`Required Phase 4 Commitments ............................................................................................................ 4
`Other Phase 4 Requests .......................................................................................................................... 4
`SUMMARY OF CLINICAL FINDINGS .............................................................................................................. 4
`
`Brief Overview of Clinical Program ...................................................................................................... 4
`Efficacy .................................................................................................................................................. 4
`Safety ..................................................................................................................................................... 5
`Dosing Regimen and Administration ..................................................................................................... 5
`Drug-Drug Interactions .......................................................................................................................... 5
`Special Populations ................................................................................................................................ 6
`
`INTRODUCTION AND BACKGROUND ...................................................................................................... 6
`
`PRODUCT INFORMATION ............................................................................................................................. 6
`CURRENTLY AVAILABLE TREATMENT FOR INDICATIONS ............................................................................ 6
`AVAILABILITY OF PROPOSED ACTIVE INGREDIENT IN THE UNITED STATES ................................................ 6
`IMPORTANT ISSUES WITH PHARMACOLOGICALLY RELATED PRODUCTS ..................................................... 9
`PRESUBMISSION REGULATORY ACTIVITY ....................................................... -. ........................................... 9
`OTHER RELEVANT BACKGROUND INFORMATION ........................................................................................ 9
`
`SIGNIFICANT FINDINGS FROM OTHER REVIEW DISCIPLINES .................................................... 10
`
`CMC (AND PRODUCT MICROBIOLOGY, IF APPLICABLE) ........................................................................... 10
`ANIMAL PHARMACOLOGY/TOXICOLOGY .................................................................................................. 10
`
`DATA SOURCES, REVIEW STRATEGY, AND DATA INTEGRITY ..................................................... 10
`
`SOURCES OF CLINICAL DATA .................................................................................................................... 10
`TABLES OF CLINICAL STUDIES .................................................................................................................. 10
`REVIEW STRATEGY ................................................................................................................................... 10
`
`DATA QUALITY AND INTEGRITY ............................................................................................................... 10
`COMPLIANCE WITH GOOD CLINICAL PRACTICES ....................................................................................... 1 1
`FINANCIAL DISCLOSURES .......................................................................................................................... l 1
`
`CLINICAL PHARMACOLOGY ................................................................................................................... 11
`
`PHARMACOKINETICS.............................................- .................................................................................... 11
`PHARMACODYNAMICS .........................................................................' ...................................................... 1 3
`EXPOSURE-RESPONSE RELATIONSHIPS ..................................................................................................... 13
`
`INTEGRATED REVIEW OF EFFICACY ................................................................................................... 13
`
`INTEGRATED REVIEW OF SAFETY ........................................................................................................ 13
`
`2.1
`2.2
`2.3
`2.4
`2.5
`2.6
`
`3 .1
`3 .2
`
`4.1
`4.2
`4.3
`
`4.4
`4.5
`4.6
`
`5.1
`5 .2
`5 .3
`
`7.1
`
`METHODS AND FINDINGS .......................................................................................................................... 13
`Deaths .................................................................................................................................................. 16
`Other Serious Adverse Events ............................................................................................................. 16
`
`Dropouts and Other Significant Adverse Events ................................................................................. 16
`Other Search Strategies ........................................................................................................................ 16
`Common Adverse Events ..................................................................................................................... 17
`Less Common Adverse Events ............................................................................................................ 19
`
`Laboratory Findings ............................................................................................................................. 19
`Vital Signs ........................................................................................................................................... 20
`
`7.1.1
`7.1.2
`
`7.1.3
`7.1.4
`7.1.5
`7.1.6
`
`7.1.7
`7.1.8
`
`

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`Clinical Review
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`{Insert Reviewer Name}
`{Insert Application and Submission Number}
`{Insert Product Trade and Generic Name}
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`1 EXECUTIVE SUMMARY
`
`1.1 Recommendation on Regulatory Action
`
`In the opinion of this reviewer, this application should be approved if prior to the PFUFA data,
`the sponsor submits labeling with directions for use that inform consumers to take the drug on an
`empty stomach. This request is based on the results of the relative bioavailability study results in
`the non-fasting state.
`
`1.2 Recommendation on Postmarketing Actions
`
`1.2.1 Risk Management Activity
`
`No risk management activities are required other than compliance with required periodic
`reporting.
`'
`
`1.2.2 Required Phase 4 Commitments
`
`If approved, the sponsor will be required to submit pediatric studies in children ages six months
`to 11 years of age prior to the end of granted deferral period.
`
`1.2.3 Other Phase 4 Requests
`
`None.
`
`1.3 Summary of Clinical Findings
`
`1.3.1 . Brief Overview of Clinical Program
`
`The clinical development program for the proposed naproxen product is based on demonstration
`of the relative bioavailability of the product to the reference listed drug (RLD).
`
`1.3.2 Efficacy
`
`No efficacy data was submitted with this 505(b)(2) application. Efficacy data is referenced from
`the RLD, Aleve® (NDA 20-204).
`
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`1.3.3 Safety
`
`This application primarily relies on safety data referenced in NDA 20-204. Among the 56
`subjects who completed the two submitted biopharmacology studies, no new safety signals were
`detected. No serious adverse events occurred. Only three adverse events occurred following use
`of the proposed drug product, one of which (headache) was considered probably related to drug
`study drug treatment.
`
`No new safety signals were evident from the eleven published studies reviewed by the sponsor.
`The one nested case-control study submitted by the sponsor that addressed cardiovascular or
`cerebrovascular risk with naproxen use did show some increased risk (adjusted R = 1.27) with
`use within three months of the index event; however, data was based on naproxen prescriptions
`in the United Kingdom and use probably does not reflect nonprescription doses or durations of
`use.
`
`1.3.4 Dosing Regimen and Administration
`
`Dosing of the proposed drug product will be identical to the RLD, Aleve®.
`
`1.3 .5 Drug-Drug Interactions
`
`Naproxen is highly protein bound; therefore, there is a theoretical potential for interaction with
`other albumin-bound drugs like coumarin-type anticoagulants, sulphonylureas, hydantoins, other
`NSAIDs, and aspirin. Due to competition at protein binding sites, unbound portions of drug may
`change and dose adjustments may be needed.
`
`Drug—drug interactions may occur between naproxen and aspirin, angiotensin converting enzyme
`inhibitors, anticoagulants and thrombolytic agents, diuretics, lithium, methotrexate, and
`probenecid.
`
`Potential drug-drug interactions are addressed through the class warnings for OTC NSAIDs
`published June 15, 2005. Some of these warnings contain more specific language than others.
`These Drug Facts label warnings instruct consumers to:
`
`Ask a doctor before use if you have:
`
`0
`
`0
`0
`0
`
`0
`
`bleeding problems
`
`high blood pressure
`heart of kidney disease,
`taken a diuretic
`
`reached age 60 or older.
`
`Ask a doctor or pharmacist before use if you are:
`0 Under a doctor’s care for any serious condition
`
`0 Taking a blood thinning (anticoagulant) or steroid drug
`
`

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`0 Taking any other drug.
`
`1.3.6 Special Populations
`
`None
`
`2
`
`INTRODUCTION AND BACKGROUND
`
`2.1 Product Information
`
`Naproxen sodium is a FDA-approved nonsteroidal anti-inflammatory (NSAID) and analgesic
`agent marketed over-the-counter (OTC) in tablet form at a dose of 220 mg. Banner Pharrnacaps,
`Inc. has developed a naproxen sodium 220 mg soft gel capsule and has filed a 5 05b2 new drug
`application for this new dosage form. The NDA contains data on two clinical bioequivalence
`studies comparing the proposed naproxen sodium capsules, 220 mg, to the reference listed drug
`(RLD), Aleve®. The sponsor proposed use of this product by individuals ages 12 years and
`older for the following indications:
`
`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.
`
`If approved, the proposed naproxen product. would need to follow the labeling for the RLD.
`
`2.2 Currently Available Treatment for Indications
`
`Naproxen sodium 220 mg, ibuprofen 200 mg, acetaminophen (APAP) 325 mg and 500 mg,
`ketoprofen 25 mg, and acetyl salicylic acid (ASA) are currently marketed OTC for the same
`indications (temporary fever reduction, temporary relief of minor aches and pains).
`
`2.3 Availability of Proposed Active Ingredient in the United States
`
`In 1976, naproxen sodium (275 mg) was approved by FDA as a prescription analgesic.
`Prescription indications for use include:
`the treatment of rheumatoid arthritis, osteoarthritis,
`ankylosing spondylitis, juvenile arthritis, tendonitis, bursitis, acute gout, and the management of
`pain and primary dysmenorrhea.
`In January 1994, FDA granted OTC approval for naproxen
`sodium 220 mg for:
`
`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.
`
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`{Insert Product Trade and Generic Name}
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`The maximum daily OTC dose is 660 mg. Directions state that consumers should not exceed
`two tablets (440 mg) in any twelve hour period.
`
`Use of naproxen sodium and other NSAIDs is associated with an increased risk of:
`gastrointestinal adverse effects, severe skin reactions, and renal insufficiency in individuals with
`underlying renal compromise.
`
`On April 7, 2005, FDA published a public health advisory and announcement outlining
`requested labeling changes for all COX-2 selective and non-selective prescription NSAIDs and
`OTC NSAIDs. Long—term controlled clinical trial data with cardiovascular endpoints are not
`available for most NSAIDs; however, the available data suggest that chronic use of these drugs
`may increase the risk for cardiovascular and cerebrovascular thromboembolic events. The
`available data do not suggest an increased risk of these events with short-term, low-dose use of
`NSAIDs available over the counter.
`
`Based on previously known potential adverse events and more recent concerns about potential
`thromboembolic adverse events associated with NSAID use, FDA is requiring the following
`label warnings and information on NSAID Drug Facts labels (published 06/ 15/2005):
`
`APPEARS THIS WAY
`
`0N ORIGINAL
`
`

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`Clinical Review
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`I
`{Insert Reviewer Name}
`{Insert Application and Submission Number}
`{Insert Product Trade and Generic Name}
`
`10 APPENDICES
`
`10.1 Line-by-Line Labeling Review
`
`The labeling is reviewed by Michael Koenig, interdisciplinary scientist from the Division of
`Nonprescription Regulatory Development, in a separate document. His review may be found in
`DFS.
`
`10.2 Pediatric Study Waiver Request: Consult response from the Division of
`Over-the-Counter Drug Products
`
`Date: July 12, 2004
`
`From: Karen B. Feibus, MD.
`Medical Officer, Division of Over-the-Counter Drug Products
`
`Through: Andrea Leonard—Segal, MD.
`Medical Team Leader, Division of Over-the-Counter Drug Products
`
`Through: Charles J. Ganley, MD.
`Director, Division of Over-the—Counter DrUg Products (HFD-S 60)
`
`To: Mr. Gary Buehler
`Director, Office of Generic Drugs (HFD-600)
`
`Subject: Request for Pediatric Waiver for Naproxen Sodium Softgel Capsules, 220 mg
`
`Sponsor: Banner Pharmacaps, Inc.
`
`Introduction
`
`This consultation from the Division 'of Over-the-Counter Drug Products evaluates Banner
`Pharmacaps’ pediatric waiver request for their ANDA application for Naproxen Sodium Softgel
`Capsules.
`
`Background
`On October 19, 2002, Banner Pharmacaps, Inc. filed a citizen petition (CP) with FDA requesting
`a change of dosage form for Naproxen Sodium, 220 mg from tablet to soft gelatin capsule. The
`change in dosage form was for submission of an abbreviated new drug application (ANDA)
`referencing the Reference Listed Drug (RLD), Bayer Corporation’s Aleve ® (Naproxen Sodium,
`
`“
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`220 mg tablets). In addition, Banner requested a waiver of the requirement to perform pediatric
`studies, in accordance with 21 CFR 314.55(c)(2), based on the following reasons:
`
`1. The effectiveness of the proposed drug product can be extrapolated from adequate and
`well-controlled studies in adult and pediatric populations;
`2. The dosing and safety data for relevant age groups is well-defined;
`3. The innovatbr product has a 10 year history of use in ages 12 — 17 as an OTC drug
`product.
`- The drug product is not labeled with dosage recommendations in children less than 12
`years old.
`
`4.
`
`HFD-600 reviewed the submission and on February 25, 2002, granted approval of Banner’s
`suitability petition for the change in dosage form under section 5050)(2)(C)(i) of the Food, Drug,
`and Cosmetic Act. The change in dosage form was not found to pose questions of safety or
`effectiveness because the uses, dose, and route of administration of the proposed drug product
`were the same as the RLD. HFD-600 stated that if the proposed product met bioavailability
`requirements, then it could be expected to have the same therapeutic effect as the RLD. In the
`approval letter, FDA informed Banner Pharmacaps that there was no obligation to conduct
`pediatric studies on the proposed Naproxen Sodium product at that time due to the October 17,
`2002, decision by the United States District Court for the District of Columbia, which ruled that
`the FDA did not have the authority to issue the Pediatric Rule and could not enforce it.
`
`On January 7, 2003, the 108th Congress of the United States of America signed the Pediatric
`Research Equity Act of 2003 (PREA) into law. Section 505B is titled: Research into Pediatric
`Uses for Drugs and Biological Products. This amendment to the Food, Drug, and Cosmetic Act
`requires the following for new drug products:
`
`1. A person who submits an application under section 505 for a new active ingredient, new
`indication, new dosage form, new dosing regimen, or new route of administration will
`submit the following assessments:
`
`I The application will contain appropriately gathered data using appropriate formulations
`for each age group. The data will be adequate to assess the safety and effectiveness of
`the drug for the claimed indication with the stated dose and route of administration in
`all relevant pediatric subpopulations.
`. If the course of the disease and the effects of the drug are sufficiently similar in adults
`and pediatric patients, then FDA may conclude that pediatric effectiveness can be
`extrapolated from adequate and well-controlled studies in adults with the provision of
`supplemental information obtained in pediatric subjects, such as pharmacokinetic data.
`I A study may not be needed in each pediatric age group if data from one age group can
`be extrapolated to another age group.
`
`2. At the request of the applicant, the FDA may defer submission of some or all required
`pediatric assessments until a specified date after drug approval if:
`
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`I the drug is ready for approval for use in adults before pediatric studies are complete or
`I if there is another appropriate reason for deferral as determined by FDA.
`
`The applicant’s deferral request will include:
`I certification of the grounds for deferring the assessments;
`I a description of the planned or ongoing studies;
`I evidence that the studies are being conducted or will be conducted with due diligence
`and at the earliest possible time.
`
`3. A full or partial waiver of these requirements will be granted at the request of the
`applicant or on the initiative of the FDA if the applicant certifies and the FDA finds that:
`
`I necessary studies are impossible or highly impractical
`I there is evidence strongly suggesting that the drug would be ineffective or unsafe in all
`pediatric age groups
`I the drug does not represent a meaningful therapeutic benefit over existing therapies for
`pediatric patients
`I the drug is not likely to be used in a substantial number of pediatric patients
`I reasonable attempts to produce a pediatric formulation necessary for a particular age
`group have failed.
`
`If the FDA grants a full or partial waiver due to evidence that a drug product would be
`ineffective or unsafe in pediatric populations, the information will be reflected in
`labeling.
`
`With the passage of PREA, HFD-600 suspended approval of Banner’s suitability petition for
`Naproxen Sodium Capsules, 220 mg, and the sponsor was informed that they could submit a
`request for a waiver of the pediatric study requirement with supporting information and
`documentation as required by PREA. Approval could be reinstated if a full waiver was granted.
`
`Amendment to Suitability Petition for Naproxen Sodium Capsules, 220 mg
`On February 18, 2004, Banner Pharmacaps, Inc. submitted an amendment to the ANDA
`suitability petition for Naproxen Sodium Capsules, 220 mg, requesting a full waiver of the
`pediatric study requirements based on the following claims:
`
`1. Naproxen sodium does not represent a meaningful benefit over existing therapies
`for pediatric patients.
`I Acetaminophen, aspirin, and ibuprofen are available in multiple OTC pediatric
`formulations and labelled for the temporary relief of: fever and minor aches and pains
`due to the common cold, flu, headache, sore throat, and toothaches. Acetaminophen is
`also labelled for the temporary relief of aches and pains due to immunizations, sprains,
`muscle aches, and overexertion. Acetaminophen is labelled for children ages two years
`
`33
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`3 SIGNIFICANT FINDINGS FROM OTHER REVIEW DISCIPLINES
`
`3.1 CMC (and Product Microbiology, if Applicable)
`
`The CMC review is being completed by Rao Puttagunta, chemist from the Office of New Drug
`Quality Assurance
`
`3.2 Animal Pharmacology/Toxicology
`
`There are no animal pharmacology/toxicology data submitted to this application.
`
`4 DATA SOURCES, REVIEW STRATEGY, AND DATA INTEGRITY
`
`4.1 Sources of Clinical Data
`
`The two pharmacokinetic studies submitted with this 505(b)(2) application are the only sources
`of clinical data.
`
`4.2 Tables of Clinical Studies
`
`
`
`
`Study
`Sub'ects
`
`A relative bioavailability study of 220 mg naproxen sodium soft gelatin capsules
`.
`.
`.
`under fasting conditions
`
`28 enmned
`27 completed
`
`
`
`
`
`
`30 enrolled
`A relative bioavailability study of 220 mg naproxen sodium soft gelatin capsules
`
`under non-fasting conditions
`29 completed
`
`
`4.3 Review Strategy
`
`The safety data from the two relative bioavailability studies was reviewed and the adverse events
`were evaluated for association with drug treatment and against the well-established safety profile
`for nonprescription naproxen sodium.
`
`4.4 Data Quality and Integrity
`
`A Division of Scientific Investigation site inspection was requested to evaluate the analytical
`portion of the bioequivalence study conducted under fasting conditions. This report is currently
`pending completion.
`
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`4.5 Compliance with Good Clinical Practices
`
`The two bioavailability studies were conducted in compliance with good clinical practices.
`
`4.6 Financial Disclosures
`
`The applicant has adequately disclosed financial arrangements with clinical investigators and
`there are no questions raised regarding study integrity.
`
`5 CLINICAL PHARMACOLOGY
`
`The biopharmacology review was completed by Lei Zhang, pharmacologist in the Office of
`Clinical Pharmacology and Biopharmaceutics. The test product and reference product, Aleve ®,
`demonstrated dissimilar dissolution profiles with 60%‘0f the test product dissolved at 15 minutes
`compared to > 95 % of the reference product. At 30 minutes, about 77% of the test product was
`dissolved versus 100% of the reference product.
`In both fasting and non-fasting relative
`In the
`bioavailability studies, the test product had a lower Cmax and longer Tmax than the RLD.
`fasting state, the differences in Cmax fell within the equivalence range for relative bioavailability.
`The Tmax for Aleve was 0.99 hours compared to 1.42 hours for the proposed product but this
`difference was felt to be clinically undetectable. Food decreased the rate of absorption (AUC
`unchanged) for both the proposed naproxen capsules and Aleve®. For Aleve, Cmax was 15%
`lower and Tmax was 1.5 hours longer in the fed state compared to the fasting state, but the
`effective naproxen serum level of 15,000 ng/mL was achieved within one hour. For the
`proposed product, Cmax was 20% lower and Tmax was 2.3 hours longer in the fed state. Effective
`serum levels of naproxen were not attained for almost two hours, and this was felt to be a
`clinically significant difference.
`
`'
`
`5.1 Pharmacokinetics
`
`Naproxen is rapidly and completely absorbed from the gastrointestinal tract and has in-vivo
`bioavailability of 95%. Following administration of naproxen sodium tablets, peak plasma levels
`are attained in 1 — 2 hours. The elimination half-life for naproxen sodium ranges from 12 — 17
`hours. Steady-state levels of naproxen are reached in 4 — 5 days of continuous treatment, and the
`degree of naproxen accumulation is consistent with the drug’s half life.3‘ 4
`
`Naproxen is extensively metabolized by the liver to 6-desmcthylnaproxen. Approximately 95%
`of the drug is excreted in the urine in a variety of forms: unchanged drug (< 1%), 6-
`desmethylnaproxen (< 1%), and different conjugated compounds formed from these two
`precursors (66 — 92%). The half-lives of naproxen metabolites are less than 12 hours. Less than
`I 5% of the drug is excreted in the feces.
`
`Table 3 presents potential naproxen—associated drug-drug interactions. 3’ 4
`
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`
`
` '[TI‘able 3: Na - roxen-associated dru_-dru interactions
`
`Drug
`Effect
`‘ll
`
`
`Protein bound
`
`drugs
`
`,
`
`Aspirin
`
`Anti—coagulants
`and thrombolytic
`agents
`
`Furosemide/
`
`Thiazides
`
`Naproxen is highly protein bound; therefore, there is a theoretical potential
`for interaction with other albumin-bound drugs like coumarin-type
`anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin. Due
`to competition at protein binding sites, unbound portions of drug may
`change and dose adjustments ma be needed.
`Concomitant administration of naproxen and aspirin is not recommended.
`Naproxen is displaced from its protein binding sites by aspirin and this leads
`
`to lower plasma concentrations of naroxen and lower peak plasma levels.
`Reports suggest that NSAIDs may diminish the antihypertensive effect of
`ACE inhibitors
`
`ACE inhibitors and may potentiate renal disease states.
`Administration of naproxen with warfarin results in a slight increase in free
`warfarin in serum but does not affect the hypoprothrombinemic effect of
`warfarin. Because naproxen may cause GI bleeding and may inhibit platelet
`aggregation, it should be used with caution inpatients receiving any
`anticoagulant or thrombolytic agent.
`Clinical studies and postmarketing observations suggest that NSAIDs can
`reduce the natiuretic effect of furosemide and thiazides in some patients.
`This effect is attributed to NSAID inhibition of renal prostaglandin synthesis
`NSAID inhibition of renal prostaglandin synthesis may decrease the renal
`clearance of lithium by 20% and increase mean lithium serum
`concentrations by 15%. When NSAIDs and lithium are administered
`concurrently, close monitoring of lithium levels and observation for lithium
`
`toxicity are warranted.
`
`
`
`
` Probenecid
`
`Lithium
`
`Methotrexate
`
`Concomitant administration of a NSAID with methotrexate may increase
`serum methotrexate levels and cause toxicity. This effect may be due to
`NSAID inhibition of renal prostaglandin synthesis.
`Administration of probenecid with naproxen substantially increases the
`plasma half-life of naproxen and plasma naproxen concentrations.
`Probenecid may interfere with plasma clearance through inhibition of
`naproxen glucuronidatiOn and renal clearance.
`
`Results of a study in diabetic patients taking tolbutamide showed that administration of naproxen
`did not effect plasma glucose concentrations.
`
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`5.2 Pharmacodynamics
`
`The sodium salt of naproxen is more rapidly absorbed than free naproxen due its increased
`aqueous solubility. The mechanism of action of the naproxen anion, while not completely
`understood, is related to prostaglandin synthetase inhibition. 3’ 4
`
`For prescription'strengths of naproxen sodium, a reduction in daily dose is recommended for
`individuals with compromised renal or liver function to help prevent unintentional adverse
`events and their sequelae including renal failure. Naproxen-containing products are not
`recommended for use in patients with moderate to severe and severe renal impairment
`(creatinine clearance <30 mL/min). Renal toxicity has been seen with naproxen use in
`individuals with prerenal conditions where renal prostaglandins serve a supportive role in
`maintaining adequate renal perfusion. The administration of a NSAID to these individuals may
`cause a dose-dependent reduction in prostaglandin formation and may precipitate renal failure.
`Individuals at greatest risk include those who: are elderly; have impaired renal function,
`hypovolemia, heart failure, liver dysfunction, or salt depletion; or use diuretics, ACE inhibitors,
`or angiotensin receptor blockers. l
`
`5.3 Exposure-Response Relationships
`
`Not applicable.
`
`6
`
`INTEGRATED REVIEW OF EFFICACY
`
`No efficacy data were submitted with this 505(b)(2) application.
`
`7
`
`INTEGRATED REVIEW OF SAFETY
`
`The sponsor submitted two relative bioavailability studies conducted in a total of 5 9 subjects.
`This portion of the review will present the adverse event data from these studies. The sponsor
`has not submitted a safety update with the application.
`
`7.1 Methods and Findings
`
`The sponsor submitted results from two relative bioavailability studies, one fasting and one non-
`fasting. The protocols were identical except for the subjects’ feeding condition. The protocol
`for the fasting study is described below. Afterwards, protocol differences in the non-fasting
`study. are described.
`'
`
`.
`Objectives
`A Phase III clinical study to evaluate the bioequivalence of Banner Pharmacaps Inc. naproxen
`sodium 220 mg soft gelatin capsules to the reference listed drug (RLD), Bayer’s Aleve® 220 mg
`tablet (NDA 20-204)
`
`Study Design
`
`13
`
`

`

`Clinical Review
`
`{Insert Reviewer Name}
`{Insert Application and Submission Number}
`{Insert Product Trade and Generic Name}
`
`Randomized, single-dose, two-way crossover study under fasting conditions
`Minimum washout period between doses is 14 days.
`
`Informed Consent
`
`Informed consent was obtained prior to the screening process The consent form was submitted
`with the protocol.
`
`Population
`' 26 or 30 healthy volunteers age 18 years or older.
`' Recruitment will be from the community at large including university students.
`I
`Inclusion Criteria:
`
`1.
`
`2.
`
`3.
`
`4.
`
`healthy men and women, 18 years or older
`weight will not exceed 120% for height and body frame according to the Desirable
`Weight for Adults table (1983 Metropolitan Height and Weight Table)
`screening completed within 28 days of dosing
`females of childbearing potential or who are not postmenopausal for one year will use
`an acceptable method of birth control for the duration of the study (condom with
`spermicide, diaphragm with spermicide, intrauterine device, abstinence)
`
`' Exclusion Criteria:
`1.
`
`recent history of drug or alcohol addiction or abuse
`presence of a clinically significant disorder involving the cardiovascular, respiratory,
`renal, gastrointestinal, immunologic, hematologic, endocrine, Or neurologic system(s)
`or psychiatric disease as determined by the investigator
`clinical laboratory test values outside the accepted reference range and on repeat
`testing are deemed clinically significant
`reactive hepatitis B surface antigen screen
`reactive HIV
`positive drug abuse screen
`positive pregnancy test
`breastfeeding
`history of allergy to naproxen sodium or related drugs
`history of clinically significant allergies, including drug allergies
`clinically significant illness during the four weeks prior to Period I dosing
`use of tobacco products
`use of any drug known to induce or inhibit hepatic drug metabolism during the 28
`days prior to Period I dosing
`blood donation