CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER(S)
`
`NDA 21-727 '
`
`Trade Name:
`
`OraDisc A
`
`Mucoadhesive Patch, 2 mg
`
`Generic Name(s):
`
`(amlexanox)
`
`Sponsor:
`
`Access Pharmaceuticals, Inc.
`
`Agent:
`
`Approval Date:
`
`September 29, 2004
`
`Indication: Provides for the treatment of aphthous ulcers
`in adults and adolescents 12 years of age and older (not
`indicated for use in children below age 12 or in patients with
`an abnormal immune system)
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICATION NUMBER:
`
`ZI- 792 7
`
`CONTENTS
`
`
`
`
`
`
`
`
`I'J—-'
`_-
`
`
`—_-1-
`Medical Review(s)
`-_
`
`__-I-
`
`—_
`
`
`—'—-1-
`—-I-
`
`
`_-_
`—m—-1-
`
`
`
`
`
`
`
`
`-—-'.-
`——
`__
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`NDA 21-727
`
`Approval Letter(s)
`
`

`

`5‘[VIC
`"-1,,1
`
`9'“
`
`g DEPARTMENTOF HEALTH&HUMANSERVICES
`
`
`Food and Drug Administration
`Rockville, MD 20857
`
`PublicHealthService
`
`NDA 21-727
`
`Access Pharmaceuticals, Inc.
`Attention: David P. Nowotnik, Ph.D.
`Senior VP, Research & Development
`2600 Stemmons Freeway, Suite 176
`Dallas, TX 75207-2107
`
`Dear Dr. Nowotnik:
`
`Please refer to your December 4, 2003, new drug application submitted under section 505(b)
`of the Federal Food, Drug, and Cosmetic Act for, TRADENAME (amlexanox) Mucoadhesive Patch,
`2 mg.
`
`We acknowledge receipt of your submissions dated December 12, 2003, January 8 and 30,
`February 3 and 27, March 15 and 24, June 2 and 8, August 13 and 30, September 20
`and September 24, 2004 (facsimile).
`
`This new drug application provides for the use of TRADENAME (amlexanox) Mucoadhesive Patch,
`2 mg for the treatment of aphthous ulcers in adults and adolescents 12 years of age and older.
`TRADENAME is not indicated for use in children below age 12 or in patients with an abnormal
`immune system.
`
`We completed our review of this application, as amended. It is approved, effective on the date of this
`letter, for use as recommended in the agreed-upon labeling.
`
`The final printed labeling (FPL) must be identical to the enclosed labeling (text for the package insert,
`immediate container and carton labels). Marketing the product with FPL that is not identical to the
`approved labeling text may render the product rnisbranded and an unapproved new drug.
`
`Please submit an electronic version of the FPL according to the guidance for industry titled Providing
`Regulatory Submissions in Electronic Format — NDA. Alternatively, you may submit 20 paper copies
`of the FPL as soon as it is available but no more than 30 days after it is printed. Individually mount 15
`of the copies on heavy—weight paper or similar material. For administrative purposes, designate this
`submission “FPL for approved NDA 21-727.” Approval of this submission by FDA is not required
`before the labeling is used.
`
`If you choose to use a proprietary name for this product, the name and its use in the labels must
`conform to the specifications under 21 CFR 201.10 and 201.15. We recommend that you submit any
`proprietary name to the Agency for our review prior to its implementation.
`
`All applications for new active ingredients, new dosage forms, new indications, new routes of
`administration, and new dosing regimens are required to contain an assessment of the safety and
`
`

`

`NDA 21-727
`
`Page 2
`
`effectiveness of the product in pediatric patients unless this requirement is waived or deferred. We
`note that you have fulfilled the pediatric study requirement for thisapplication.
`
`In addition, submit three copies ‘of the introductory promotional materials that you propose to use for
`this product. Submit all proposed materials in draft or mock-up form, not final print. Send one copy to
`the Division of Dermatologic and Dental Drug Products and two copies of both the promotional
`materials and the package insert directly to:
`
`Division of Drug Marketing, Advertising,
`and Communications, HFD-42
`Food and Drug Administration
`5600 Fishers Lane
`
`Rockville, MD 20857
`
`Please submit one market package of the drug product when it is available.
`
`We remind you that you must comply with reporting requirements for an approved NDA (21 CFR
`314.80 and 314.81).
`
`If you have any questions, call Jacquelyn Smith, Regulatory Project Manager, at (301) 827—2020.
`
`Sincerely,
`
`{See appended electronic Signature page}
`
`Jonathan K. Wilkin, MD.
`Director
`
`Division of Dermatologic & Dental Drug Products
`Office of Drug Evaluation V
`Center for Drug Evaluation and Research
`
`Enclosure
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Stanka Kukich
`
`9/29/04 09:40:51 AM
`Sign off for Dr. Wilkin, Division Director
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`NDA 21-727
`
`Approved Labeling
`
`

`

`NDA 21-727
`
`- Page 3
`
`TRADENAME
`
`(amlexanox) Mucoadhesive Patch, 2 mg
`For Oral Cavity Use Only
`
`Description: TRADENAME is a mucoadhesive patch that contains 2 mg of amlexanox per patch.
`
`Amlexanox is 2-amino-7—isopropyl—5-oxo—5H—[1]benzopyrano [2,3-b]pyridine-3-carboxylic acid. It
`has a molecular formula of C16H14N204 and has a molecular weight of 298.30. Amlexanox is an
`odorless, white to yellowish-white crystalline powder. The structural formula is:
`O
`N
`NHZ
`\
`
`HQC
`H30
`
`H
`
`/
`
`COOH
`
`0
`
`Each patch contains 2 mg of amlexanox as part of a multi—layer patch consisting of ethylcellulose,
`FD&C Blue #1, FD&C Red #40, hydroxyethylcellulose, hypromellose, methylparaben, modified
`starch, polycarbophil, povidone, propylene glycol, propylene glycol monostearate, purified water,
`sodium benzoate, sodium carboxymethylcellulose.
`
`Clinical Pharmacology: The mechanism of action by which amlexanox accelerates healing of
`aphthous ulcers is unknown. In vitro studies have demonstrated amlexanox to be a potent inhibitor of
`the formation and/or release of inflammatory mediators (histamine and leukotrienes) from mast cells,
`neutrophils, and mononuclear cells.
`
`Pharmacokinetics and Metabolism: After oral application of TRADENAME patches, the average
`maximum serum levels are 45.4 ng/ml (N=14), and 168 ng/ml (N=3) after application of one or three
`patches, respectively. The mean total exposure, AUC0_24,
`is 258 ngOhr/ml, and 605 ngOhr/ml after
`application of one, or three patches, respectively.
`
`After 3 full days of oral application of TRADENAME, four times a day, and one dose on Day 4,
`maximum serum levels ranged from BLQ (Below limit of quantification: 5 ng/mL in serum) to 79
`ng/ml (N=24) prior to the first dose on Day 4, and also, had a similar range in the serum samples
`collected 2 hours post-dose. For application of two TRADENAME patches, the pre- and post-dose
`levels were BLQ to 164 ng/mL and BLQ to 117 ng/mL, (N=5) respectively. Post—dose levels are
`similar to or slightly higher than pre-dose levels, with the mean level of 9.8 and 16 ng/mL,
`respectively, for one TRADENAME patch and 44 and 44 ng/mL, respectively, for two TRADENAME
`patches.
`‘
`'
`
`CLINCIAL STUDIES
`
`Study A
`
`The efficacy of TRADENAME was established in one controlled clinical study, Study A, in which
`patients with one, two or three aphthous ulcers applied the patch(s) four times daily for 7 days. The
`study evaluated 303 patients receiving TRADENAME, 301 patients receiving the vehicle patch, and
`97 patients receiving no treatment. Tobacco users and diabetics were excluded from clinical testing.
`
`

`

`NDA 21-727
`
`Page 4
`
`The endpoint agreed upon a priori was complete healing on Day 5. After 4 days of treatment (Day 5)
`there was a significant difference in percentage of patients with complete healing of ulcers (30.4% in
`the active group vs. 21.9% in the vehicle group). In the following table, the percentage of patients
`healed in each group at each day of the study is provided.
`
`
`Number (%) of Patients with Complete Ulcer Healing Over Time — Study A '
`Amlexanox
`No-treatment
`
`
`
`
`(n = 303)
`(n = 97)
`
`
`
`
`
`
`
`
`
`
`) )
`
`The comparison (p—value) of amlexanox vs. vehicle is statistically significant (p<0.05) at Day 5 only.
`
`‘
`
`
`
`
`
`
`
`
`
`The data from the above table is provided graphically as follows:
`Study A: Cumulative % of Patients with Complete Ulcer Healing
`
`
`
`
`
`
` PercentHealed
`
`_._ Active
`~ -- Vehicle
`. No Treatment
`
`
`
`
`
`
`
`
`
`
`
`100
`
`90
`
`80
`70
`60
`
`50
`
`4o
`
`30
`
`7 20
`10
`
`o
`
`Day 1
`
`Day 2
`
`Day 3
`
`Day 4
`
`Day 5
`
`Day 6
`
`Day 7
`
`Days on Treatment
`
`Pain relief occurred in conjunction with healing of the ulcers. TRADENAME, by itself was not shown
`to be an analgesic medication.
`
`Indications and Usage: TRADENAME is indicated for the treatment of aphthous ulcers in adults and
`adolescents 12 years of age and older. TRADENAME is not indicated for use in children below age
`12 or in patients with an abnormal immune system.
`
`Contraindications: TRADENAME, is contra-indicated in patients with known hypersensitivity to
`amlexanox or other ingredients in the formulation.
`
`Precautions:
`General
`
`

`

`NDA 21—727
`
`Page 5
`
`Wash hands immediately after applying TRADENAME directly to the ulcers with the fingertips. In
`the event that a rash or contact dermatitis occurs, discontinue use.
`
`Use of TRADENAME in Smokers
`
`Tobacco users may respond differently to TRADENAME. Smokers are known to have a lower
`incidence of aphthous ulcers than the general population, but were excluded from the clinical trials.
`Therefore, the effect of TRADENAME on smokers is not known.
`
`Risk of Aspiration
`
`There were no reports of accidental aspiration or detrimental swallowing of the patches in patients 12
`and older during clinical trials. Nevertheless, it is recommended to apply TRADENAME at least 80
`minutes prior to bedtime to avoid the possibility of aspiration of soft food-like particles that may come
`loose during erosion of the patch in the mouth. Keep out of the reach of children below the age of 12.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility: Amlexanox was not carcinogenic when
`administered to mice for 18 months at dosages up to 100 mg/kg/day (approximately 12 times the
`maximum human dose when comparing on the basis of body surface area estimates) or to rats for 24
`months at dosages up to 250 mg/kg/day (approximately 60 times the maximum human dose).
`Amlexanox was negative in bacterial mutation assays in Salmonella, E. coli, and B. subtilis, in a
`mouse lymphoma assay, and in a micronucleus assay conducted in mice.
`
`Amlexanox did not affect reproductive performance (fertility) or ability of rats to deliver and rear pups
`(perinatal development) when administered at dosages up to 300 mg/kg/day (approximately 70 times
`the maximum human dose).
`
`Pregnancy Category B:
`Reproduction studies have been performed in rats and rabbits at doses up to 300 mg/kg/day
`(approximately 70 and 145 times the maximum human dose in rats and rabbits, respectively, when
`comparing on the basis of body surface area estimates) and have revealed no evidence of impaired
`fertility or harm to the fetus due to amlexanox. There are, however, no adequate and well~controlled
`studies in pregnant women. Because animal reproduction studies are not always predictive of human
`response, this drug should be used during pregnancy only if clearly needed.
`
`Nursing Mothers: Amlexanox was found in the milk of lactating rats; therefore, caution should be
`exercised in administering TRADENAME to a nursing woman.
`
`Pediatric Use: The safety of TRADENAME in pediatric patients between ages 12 and 17 was
`established in a study in which patients with aphthous ulcers (98 of whom were pediatric) applied the
`patch four times daily for 7 days with no significant topical or systemic adverse effects. In a separate,
`long-term study 106 patients with aphthous ulcers (30 of whom were pediatric) applied the patch four
`times daily for 28 days with no significant topical or systemic adverse effects. Use of TRADENAME
`in patients under 12 is not recommended due to the risk of aspiration.
`
`Geriatric Use:
`established.
`
`Safety and effectiveness of TRADENAME in geriatric patients have not been
`
`Adverse Reactions: In the combined safety database, no single adverse reaction was reported by
`more than 10% of patients. Adverse reactions reported by 9.8% of patients were pain or burning,
`
`

`

`NDA 21-727
`
`Page 6
`
`restricted to the site of application, occurring at the time of application. Adverse reactions reported by
`less than 2% of patients were irritation and paresthesia at the site of application.
`
`Systemic adverse events that occurred during clinical trials, that were reported by less than 2% of
`patients, included headache, sore throat, and nausea. Mouth ulceration (new aphthous ulcers) was also
`reported at a rate of less than 2%.
`
`The safety of TRADENAME was established in a long-term study in which 106 patients with aphthous
`ulcers applied the patch four times daily for 28 days with no significant topical or systemic adverse
`effects.
`'
`
`The following table provides a comparison of the adverse events reported by patients in the clinical
`trials who received TRADENAME, a vehicle patch, and no treatment.
`
`Percenta e of Patients with Adverse Events with an Incidence of > 1% — from All Clinical Trials
`—- Vehicle
`N = 409
`N = 301
`
`
`
`
`
`5 8.3
`
`oxxom AND.) oo
`
`. .
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`4;
`1.3
`>
`
`—— _
`Mouth Ulceration (i.e., new
`5 (1.2)
`.13 (4.3)
`6 (6.2)
`
`
`ahthous ulcers
`-
`LII
`p—\ \]
`U) A h—l O
`Sore Throat NOS
`1 1.0
`
`__ —
`Liver function tests NOS
`2 (2.0)
`Not done
`Not done
`abnormal
`
`
`11>>
`
`
`
`
`
`Nervous S stem Disorders
`
`Headache NOS
`
`
`
`4(1.3
`
`
`
`_
`
`Overdosage: There are no clinical reports of overdosage. Gastrointestinal upset such as nausea,
`vomiting, and diarrhea could result from an overdose.
`
`Dosage and Administration: TRADENAME should be applied as soon as possible after noticing the
`symptoms of an aphthous ulcer and should be used four times daily, preferably following oral hygiene
`after breakfast, lunch, dinner, and 80 minutes before bedtime. Up to three patches may be used at one
`time. Apply one TRADENAME patch to each ulcer. Use of the medication should be continued until
`the ulcer heals but no longer than 10 days. If significant healing or pain reduction has not occurred in
`10 days, consult your dentist or physician.
`
`Information for Patients:
`
`1. Apply TRADENAME as soon as possible after noticing the symptoms of an aphthous ulcer.
`Wash hands before applying TRADENAME. Continue to use TRADENAME four times daily,
`preferably following oral hygiene after breakfast, lunch, dinner, and 80 minutes before bedtime.
`In all cases, ensure that the patch is firmly attached to the ulcer.
`
`

`

`NDA 21 —727
`
`Page 7
`
`2.
`
`3.
`
`LII
`
`In case of multiple ulcers, apply one TRADENAME patch to each ulcer. Up to 3 patches may
`be used at one time.
`
`Using clean dry hands, place the light colored side of the patch against the ulcer in the mouth
`and press gently. The patch will stick to the ulcer in the mouth and remain in place. In rare
`circumstances, patients may find that the patch does not adhere readily. In such cases reapply
`the patch and press gently for several seconds before removing the finger.
`Wash hands immediately after applying TRADENAME.
`Patients should not apply a patch within 80 minutes before bedtime, to ensure it has eroded
`before sleep.
`Patients should avoid eating or drinking for an hour after applying the patch.
`Following application, the patch will slowly erode in the mouth, generally disappearing entirely
`in 20-80 minutes. Depending on the location of the patch in the mouth, and factors such as the
`amount of saliva flow and mechanical action of the mouth, complete disappearance of the patch
`may take more or less time. Patients may feel small particles in the mouth as the patch erodes.
`These particles may safely be swallowed.
`Use TRADENAME until the ulcer heals. If significant healing and pain reduction has not
`occurred in 10 days, consult your dentist or physician.
`Keep out of the reach of children below age 12.
`
`How Supplied: TRADENAME is supplied in bottles of 20 patches. NDC 67404-300-20
`
`TRADENAME should be stored at 25 0c (77 0F)
`[Cautionz Avoid prolonged exposure to temperatures above 30°C (86 9 F)
`
`RX ONLY
`
`Manufactured for:
`
`Access Pharmaceuticals, Inc.
`Dallas, TX 75207
`
`TRADENAME is a trademark of Access Pharmaceuticals, Inc.
`August 2004
`
`

`

`. CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER ‘
`
`NDA 21-727
`
`Medical Review(s)
`
`

`

`Multi—Disciplinary Summary -
`.
`NDA 21-727 TRADENAME (amlexanox 2 mg mucoadhesive oral patch)
`
`Treatment of L
`
`3 of aphthous ulcers in adults and adolescents
`_
`-
`12 years of age and older
`
`September 23, 2004
`
`This new NDA for TRADENAME (amlexanox 2 mg mucoadhesive oral patch) for the
`treatment of C
`3 of aphthous ulcers in adults and adolescents 12
`years of age and older is recommended for approval by the review team.
`
`CMC:
`
`Recommendations by the CMC reviewer were limited to minor, but helpful, labeling
`issues. In particular, the stability data submitted by the sponsor did not support the
`storage conditions, which had to be revised in the label.
`
`Pharm/Tox:
`
`The submission contained no new nonclinical data, and referenced NDA 20—511 for
`Aphthasol®, the approved amlexanox 5% paste formulation approved in 1996. The
`reviewer recommended Pregnancy Category B. The reviewer further concluded that no
`toxicity relevant to the proposed clinical use was observed, and there are no nonclinical
`safety issues relevant to clinical use.
`
`Biopharmaceutics:
`
`The Pharmacokinetics of this product were assessed in a Phase 1 single-dose study, a
`Phase 3 multi-dose study and a Phase 1 study that evaluated the effects of amlexanox on
`the cytochrome P450 system. In addition, clinical safety data is available from the
`Aphthasol® paste formulation and the oral tablet formulation that is approved in Japan.
`
`Amlexanox is absorbed largely through the GI tract. It was determined that absorption
`through the ulcer was insignificant. Amlexanox has a half-life of 3—6 hours and only 17%
`is eliminated through the kidney. There a no significant concerns in using this product in
`people with hepatic or renal limitations.
`
`TRADENAME was demonstrated to have a relatively minor effect on various CYP450'
`isozymes (< 10 % inhibition or stimulation), and is therefore unlikely to have a
`significant effect on drugs and xenobiotics metabolized through the CYP450 pathway.
`
`Clinical Safety:
`
`

`

`Adverse events observed in clinical trials with this product were infrequent and non-
`serious.
`
`Clinical Efficacy and Biostatistics:
`
`This reviewer agrees with Dr. Hyman’s clinical review on all points. HoWever a
`clarification needs to be made about the extent to which approval is based on findings
`from studies using the early formulation. While Dr. Hyman has not specifically referred
`to the data from the early formulation as “supportive,” he does refer to that data at
`various points in his review. In particular, his discussion of the non-inferiority
`comparison between vehicle and no treatment refers to data from the Phase 3 trial using
`the early formulation. He also refers to the data from the same trial in his discussion of
`efficacy in adolescents age 12 — 17. For the record, the Division has concluded that the
`two formulations are different enough that they cannot be considered “the same” absent a
`bioequivalence study to demonstrate that they are the same. No study has been
`conducted; therefore the data from the studies of the early formulation cannot be used to
`support the Agency’s finding of efficacy for this product.
`
`The Division Views this product as a line extension of the approved product Aphthasol®
`(amlexanox oral paste), 5 mg, and consequently agreed to accept a single study to support
`efficacy. The agreed upon criteria for success were that the active had to be statistically
`significantly superior to the vehicle and the vehicle had to be non-inferior to no
`treatment. The pre—specified non—inferiority margin was -8%. These criteria for success
`were based on FDA’s draft guidance document, Chronic Cutaneous Ulcer and Burn
`Wounds — Developing Productsfor Treatment. As was discussed in both Dr. Hyman’s
`clinical review and in the Biostatistics review, the non—inferiority comparison between
`vehicle and no treatment (—9.2%) was close, but fell slightly outside the pre-specified
`non-inferiority margin (-8%). However, it should be noted that the point estimates for the
`vehicle and no treatment arms were very close (21.9% for vehicle v. 21.6% for no
`treatment), which supports the fact that the vehicle is not deleterious. In addition, the
`small number of patients in the no treatment group make it difficult to show a difference
`between groups.
`
`This reviewer feels that the failure to meet this criterion should not result in failure to
`approve this product. I recommend approval for this NDA.
`
`Recommendation:
`
`' In summary, all disciplines have recommended that this new dosage form for amlexanox
`be approved. The sponsor has agreed to the labeling attached to Dr. Hyman’s clinical
`review.
`
`

`

`John V. Kelsey, DDS, MBA
`Lead Dental Officer
`
`Appears This Way
`On Original
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`John Kelsey
`9/24/04 04:10:14 PM
`MEDICAL OFFICER
`
`Jonathan Wilkin
`
`9/24/04 04:39:23 PM
`MEDICAL OFFICER
`
`“I concur with the Dental TL that there-is
`
`no need for reliance on data regarding the
`earlier patch formulation, and that there is sufficient
`information provided that the vehicle is not deleterious.
`
`

`

`CLINICALREVIEW
`
`Application Type
`Submission Number
`
`NDA .
`
`21-727
`
`Submission Code
`
`N-000
`
`Letter Date
`Stamp Date
`PDUFA Goal Date
`
`December 4, 2003
`December 9, 2003
`
`October 9, 2004
`
`. Reviewer Name
`Review Completion Date
`
`Frederick Hyman, DDS MPH
`August 26, 2004
`
`Established Name
`
`Amlexanox
`
`(Proposed) Trade Name
`Therapeutic Class
`Applicant
`
`’ OraDiscTMA
`
`Anti-inflammatory
`Access Pharmaceuticals, Inc.
`
`Priority Designation
`
`S
`
`Formulation
`
`Adhesive Oral Patch
`
`Dosing Regimen
`Indication
`
`Intended Population
`
`One Patch q.i.d.
`'U
`.
`Treatment ofC“.
`H-
`-
`J‘ Aphthous
`Ulcers in Adults and
`
`Adolescents 12 Years of Age
`and Older
`Adults and Adolescents
`
`12 Years of Age and Older
`
`

`

`Table of Contents
`
`1
`
`EXECUTIVE SUMMARY................................................................................................................. 5
`
`1.1
`1.2
`
`1.3
`
`RECOMMENDATION ON REGULATORY ACTION ............................................................................ 5
`RECOMMENDATION ON POSTMARKETING ACTIONS ..................................................................... 5
`Risk Management Activity ...........................'.......................................................................... 5
`Required Phase 4 Commitments ............................................................................................. 5
`Other Phase 4 Requests .......................................................................................................... 5
`SUMMARY OF CLINICAL FINDINGS ............................................................................................... 5
`Brief Overview of Clinical Program ....................................................................................... 5
`
`Efficacy....
`......................................................................................................................... 6
`Safety ...................................................................................................................................... 7
`Dosing Regimen and Administration ..................................................................................... 8
`Drug-Drug Interactions ........................................................................................................... 8
`Special Populations................................................................................................................. 8
`
`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
`
`2
`
`INTRODUCTION AND BACKGROUND ..................................................................................... 10
`
`2.1
`2.2
`
`2.3
`2.4
`2.5
`2.6
`
`PRODUCT INFORMATION ............................................................................................................ 1 l
`CURRENTLY AVAILABLE TREATMENT FOR INDICATIONS ........................................................... 12
`
`AVAILABILITY OF PROPOSED ACTIVE INGREDIENT IN THE UNITED STATES .......... . .................... 13
`
`IMPORTANT ISSUES WITH PHARMACOLOGICALLY RELATED PRODUCTS .......................... 13
`PRESUBMISSION REGULATORY ACTIVITY .................................................................................. 15
`OTHER RELEVANT BACKGROUND INFORMATION....................................................................... 17
`
`SIGNIFICANT FINDINGS FROM OTHER REVIEW DISCIPLINES ..................................... 17
`
`3.1
`3 .2
`
`CMC (AND PRODUCT MICROBIOLOGY, IF APPLICABLE) ............................................................ 17
`ANIMAL PHARMACOLOGY/TOXICOLOGY ................................................................................... 18
`
`DATA SOURCES, REVIEW STRATEGY, AND DATA INTEGRITY ..................................... 19
`
`4.1
`4.2
`43
`4.4
`4.5
`4.6
`
`5. 1
`5.2
`5.3
`
`SOURCES OF CLINICAL DATA ..................................................................................................... 19
`TABLES OF CLINICAL STUDIES ................................................................................................... 20
`REVIEW STRATEGY .................................................................................................................... 20
`DATA QUALITY AND INTEGRITY ................................................................................................ 2 1
`COMPLIANCE WITH GOOD CLINICAL PRACTICES ....................................................................... 21
`FINANCIAL DISCLOSURES ............................................................................................... 22
`
`
`CLINICAL PHARMACOLOGY ......................................................................................... 22
`
`PHARMACOKINETICS .................................................................................................................. 22
`
`PHARMACODYNAMICS ..................................................................................................... 24
`EXPOSURE-RESPONSE RELATIONSHIPS
`............................................................. 25
`
`3
`
`4
`
`5
`
`6
`
`INTEGRATED REVIEW OF EFFICACY .................................................................................... 25
`
`6. 1
`
`6.1.1
`
`6.1.2
`6.1.3
`6.1.4
`6.1.5
`6.1.6
`
`INDICATION 4 APHTHOUS ULCERS ............................................................................................. 25
`
`
`General Discussion of Endpoints ..................................................
`Study Design ...................................................................................... -. ................................. 27
`Efficacy Findings .................................................................................................................. 29
`Clinical Microbiology.......; ................................................................................................... 37
`Efficacy Conclusions ............................................................................................................ 37
`
`7
`
`INTEGRATED REVIEW OF SAFETY ......................................................................................... 38
`
`7.1
`
`7.1.1
`
`METHODS AND FINDINGS ........................................................................................................... 38
`Deaths ................................................................................................................................... 38
`
`
`.
`Clinical Review
`Frederick Hyman, D.D.S., M.P.H.
`NDA 21-727 N-000
`
`2
`
`OraDiscTMA (amlexanox 2 mg mucoadhesive oral patch)
`
`

`

`7.1.2
`
`7.1.3
`7.1.4
`7.1.5
`7.1.6
`
`Other Serious Adverse Events .............................................................................................. 38
`
`Dropouts and Other Signifith Adverse Events .................................................................. 38
`Other Search Strategies......................................................................................................... 40
`Common Adverse Events ..................................................................................................... 41
`Less Common Adverse Events ............................................................................................. 45
`
`7.1.7
`7.1.8
`7.1.9
`7.1.10
`7.1.11
`7.1.12
`7.1.13
`7.1.14
`7.1.15
`
`7.2
`
`Laboratory Findings ................................................ V............................................................. 45
`
`Vital Signs ................................................
`47
`Electrocardiograms (ECGs) ............................................'....................................................... 48
`Immunogenicity ............................................................................................................... 48
`. Human Carcinogenicity ................................................................................................... 49
`Special Safety Studies ...................................................................................................... 49
`Withdrawal Phenomena and/or Abuse, Potential .............................................................. 50
`
`Human Reproduction and Pregnancy Data ......_......................................................... 50
`Assessment of Effect on Growth ......................................................... 50
`
`Overdose Experience ....................................................................................................... 50
`7. 1.16
`Postmarketing Experience ............................................................................................... 50
`7.1.17
`ADEQUACY OF PATIENT EXPOSURE AND SAFETY ASSESSMENTS ............................................... 5 1
`Description of Primary Clinical Data Sources (Populations Exposed and Extent of Exposure)
`7.2.1
`Used to Evaluate Safety ...................................................................................................................... 51
`7.2.2
`Description of Secondary Clinical Data Sources Used to Evaluate Safety ........................... 53
`7.2.3
`Adequacy of Overall Clinical Experience ............................................................................ 53
`7.2.4
`Adequacy of Special Animal and/or In Vitro Testing .......................................................... 54
`7.2.5
`Adequacy of Routine Clinical Testing.................................................................................. 54
`
`Adequacy of Metabolic, Clearance, and Interaction Workup ............................................ 54
`7.2.6
`Adequacy of Evaluation for Potential Adverse Events for Any New Drug and Particularly
`7.2.7
`for Drugs in the Class Represented by the New Drug; Recommendations for Further Study ............ 55
`7.2.8
`Assessment of Quality and Completeness of Data ............................................................... 55
`7.2.9
`Additional Submissions, Including Safety Update ............................................................... 55
`SUMMARY OF SELECTED DRUG-RELATED ADVERSE EVENTS, IMPORTANT LIMITATIONS OF
`7.3
`DATA, AND CONCLUSIONS ....................................................................................................................... 56
`7.4
`GENERAL METHODOLOGY ......................................................................................................... 56
`Pooling Data Across Studies to Estimate and Compare Incidence ....................................... 56
`Explorations for Predictive Factors ...................................................................................... 57
`Causality Determination ....................................................................................................... 57
`
`7.4.1
`7.4.2
`7.4.3
`
`8
`
`ADDITIONAL CLINICAL ISSUES ............................................................................................... 58
`
`8.1
`8.2
`8.3
`8.4
`8.5
`8.6
`8.7
`8.8 '
`
`DOSING REGIMEN AND ADMINISTRATION ......................................... .......................................... 58
`DRUG-DRUG INTERACTIONS ................................................................................................... 58
`SPECIAL POPULATIONS ............................................................................................................... 59
`PEDIATRICS ..................................................................................... L .......................................... 59
`ADVI