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`CENTER FOR DRUG EVALUATION AND RESEARCH
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`Approval Package for:
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`APPLICATION NUMBER:
`NDA 206276/S-001
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`PAZEO
`Trade Name:
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`olopatadine hydrochloride ophthalmic solution
`Generic Name:
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`Sponsor:
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`Approval Date:
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`Indication:
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`Alcon Research, Ltd.
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`11/27/2015
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`PAZEO is a mast cell stabilizer indicated for the
`treatment of ocular itching associated with allergic
`conjunctivitis.
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`

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`CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`NDA 206276/S-001
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`
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`CONTENTS
`Reviews / Information Included in this NDA Review.
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`
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`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
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`x
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`x
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`x
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`x
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`x
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`CENTER FOR DRUG EVALUATION AND
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`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
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`APPLICATION NUMBER:
`NDA 206276/S-001
`NDA 206276/8-001
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`APPLICA TION NUMBER:
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`APPROVAL LETTER
`APPROVAL LETTER
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`”flu-sane,”I
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`%:{DEPARTMENTOFHEALTHANDH1MANSERVICES
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`Food and Drug Administration
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`Silver Spring MD 20993
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`APPROVAL LETTER
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`NDA 206276IS-001
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`Aicon Research, Ltd.
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`Attention: Teresa McElvaney, Technical (CMC) Regulatory Affairs, Fort Worth
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`6201 South Freeway, R3-50
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`Fort Worth, TX 76134-2099
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`Dear Ms. McElvaney:
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`Please refer to your Supplemental New Drug Application (sNDA) dated July 29, 2015, submitted
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`under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Pazeo®
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`(olopatadine hydrochloride) Ophthalmic Solution, 0.7%.
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`This “Prior Approval” supplemental new drug application provides for addition ofan additional
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`fill size (3.5 mL) for the drug product and changes to the package insert and carton label.
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`We have completed our review ofthis supplemental new drug application. This supplement is
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`approved.
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`We remind you that you must comply with the requirements for an approved NDA set forth
`under 21 CFR 314.80 and 314.81.
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`If you have any questions, call Erin Andrews, Regulatory Business Process Manager, at (240)
`402-8578.
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`Sincerely,
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`DO rota M.
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`Matecka S
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`gfigifl’mfiszm
`33%.?“
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`(Signed on behavofl
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`Balajee Shanmugam, PhD.
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`Acting Branch Chief, Branch 111
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`Division ofNew Drug Product 1
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`Office of New Drug Products
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`Center for Drug Evaluation and Research Branch
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`Enclosures:
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`Carton and Container Image
`Prescriber In formation
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`CENTER FOR DRUG EVALUATION AND
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`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
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`APPLICATION NUMBER:
`NDA 206276/S-001
`NDA 206276/8-001
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`APPLICA TION NUMBER:
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`LABELING
`LABELING
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`HIGHLIGHTS OF PRESCRIBING INFORMATION
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`These highlights do not include all the information needed to use
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`PAZEO safely and ell‘eetively. See full prescribing information
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`for PAZEO.
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`PAZEO (olopatadine hydrochloride ophthalmic solution) 0.7%
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`For topical ophthalmic administration.
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`Initial [1.8. Approval: I996
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`----------------- INDICATIONS AN D USAGE-------—----—
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`PAZEO * is a mast Cell stabilizer indicated for the treatment of
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`ocular itching associated with allergic conjunctivitis. (l).
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`--------------DOSAGE AND ADMINISTRATION-----——--—--
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`The recommended dose is one drop in each affected eye once a day. {2)
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`--—---—--DOSAGE FORMS AND STRENGTHS-----------
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`Ophthalmic solution: 7.?6 mg of olopatadinc hydrochloride in one
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`ml. ot'solution (0.7%) in a four m1. bottle. (3)
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`—---------------CONTRAINDICATIONS------------------
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`None.
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`“Wm—WARNINGS AND PRECAUTIONS——-------
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`Contamination of Tip and Solution. To prevent contaminating the
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`dropper tip and solution, do not touch the eyelids or surrounding
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`areas with the dropper tip ol'the bottle. (5.1)
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`----------------ADVERSE REACTIONS-mmm-uw—n
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`The most common adverse reactions (26%) were blurred vision,
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`superficial punctate keratitis, dry eye, abnormal sensation in eye. and
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`dysgeusia. (6)
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`To report SUSPECTED ADVERSE REACTIONS, contact Alcon
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`Laboratories, Inc. at 1—800-757-9195 or FDA at
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`l-SOO-FDA-IIISS or www.fda.gow‘medwatch.
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`See I? for PATIENT COUNSELING INFORMATION and FDA
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`approved patient labeling.
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`Revised: 732015
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`FULL PRESCRIBING INFORMATION: CONTENTS“
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`“@111wa—
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`INDICATIONS AND USAGE
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`DOSAGE AND ADM INIS’I‘RATION
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`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
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`WARNINGS AND PRECAUTIONS
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`ADVERSE REACTIONS
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`USE IN SPECIFIC POPULATIONS
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`Pregnancy
`81
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`Nursing Mothers
`8.3
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`Pediatric Use
`8.4
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`Geriatric Use
`8.5
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`11
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`DESCRIPTION
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`CLINICAL PHARMACOLOGY
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`12.1 Mechanism of Action
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`12.3
`Phannacokinetics
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`NONCLINICAL TOXICOLOGY
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`Carcinogenesis, Mutagenesis, Impairment oflieitility
`13.1
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`CLINICAL STUDIES
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`HOW SIJPPIEDISTORAGE AND HANDLING
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`PATIENT COUNSELING I N'FORIVIATION
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`*Sections or subsections omitted from the full prescribing
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`information are not listed.
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`FULL PRESCRIBING INFORMATION
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`1
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`INDICATIONS AND USAGE
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`PAZEO ‘ is indicated for the treatment of ocular itching associated with allergic conjunctivitis.
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`2
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`DOSAGE AND ADMINISTRATION
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`The recommended dosage of PAZEO is to instill one drop in each affected eye once a day.
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`3
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`DOSAGE FORMS AND STRENGTHS
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`Ophthalmic solution: 7.76 mg of olopatadine hydrochloride in one mL solution (0.7%) in a 4
`ml. bottle.
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`CONTRAINDICATIONS
`4
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`None.
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`5 WARNINGS AND PRECAUTIONS
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`5.1 Contamination of Tip and Solution
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`As with any eye drop, care should be taken not to touch the eyelids or surrounding areas with the
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`dropper tip of the bottle to prevent contaminating the tip and solution. Keep bottle tightly closed
`when not in use.
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`5.2 Contact Lens Use
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`Patients should not wear a contact lens if their eye is red.
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`The preservative in PAZEO solution, benzalkonium chloride, may be absorbed by soft contact
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`lenses. Patients who wear soft contact lenses and whose eyes are not red, should be instructed to
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`wait at least five minutes after instilling PAZEO before they insert their contact lenses.
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`6 ADVERSE REACTIONS
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`6.1 Clinical Trials Experience
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`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
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`observed in the clinical trials ofa drug cannot be directly compared to rates in the clinical trials
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`of another drug and may not reflect the rates observed in practice.
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`In a randomized, double-masked, vehicle-controlled trial, patients at risk for developing allergic
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`conjunctivitis received one drop of either PAZEO (N=330) or vehicle (N=l 69) in both eyes for 6
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`weeks. The mean age of the population was 32 years (range 2 to 74 years). Thirty-five percent
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`were male. Fifty-three percent had brown iris color and 23% had blue iris color. The most
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`commonly reported adverse reactions occurred in 2-5% of patients treated with either PAZEO or
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`vehicle. These events were blurred vision, dry eye, superficial punctate keratitis, dysgeusia and
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`abnormal sensation in eye.
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`8
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`USE IN SPECIFIC PO PULATIONS
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`8.]
`Pregnancy
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`Risk Summary
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`There are no adequate or well-controlled studies with PAZEO in pregnant women. 010patadine
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`caused maternal toxicity and embryofetal toxicity in rats at levels 1,080 to 14,400 times the
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`maximum recommended human Ophthalmic dose (MRHOD). There was no toxicity in rat
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`offspring at exposures estimated to be 45 to 150 times that at MRHOD. 010patadine should be
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`used during pregnancy only if the potential benefitjustifies the potential risk to the fetus.
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`Anima! Data
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`In a rabbit embryofetal Study, rabbits treated orally at 400 rnnggfday during organogenesis
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`showed a decrease in live fetuses. This dose is 14,400 times the MRHOD, on a mgt'rn2 basis.
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`An oral dose of 600 mg/kg/day 010patadine (10,800 times the MRHOD) was shown to be
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`maternally toxic in rats, producing death and reduced maternal body weight gain. When
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`administered to rats throughout organogenesis, olopatadine produced cleft paiate at 60
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`mg/kgfday (1080 times the MRHOD) and decreased embryofetal viability and reduced fetal
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`weight in rats at 600 mg/kg/day. When administered to rats during late gestation and throughout
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`the lactation period, 010patadine produced decreased neonatal survival at 60 mg/kg/day and
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`reduced body weight gain in offSpring at 4 mg/kg/day. A dose of 2 m g/kgi’day 010patadine
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`produced no toxicity in rat offspring. An oral dose of 1 mg/kg olopatadine in rats resulted in a
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`range of systemic plasma area under the curve (AUC) levels that were 45 to 150 times higher
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`than the observed human exposure [9.7 ng'hri’m L] following administration of the recommended
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`8.3 Nursing Mothers
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`010patadine has been identified in the milk of nursing rats following oral administration. Oral
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`administration of olopatadine doses at or above 4 mg/kg/day throughout the lactation period
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`produced decreased body weight gain in rat offspring; a dose of 2 mg/kgi’day olopatadine
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`produced no toxicity. An oral dose of] mg/kg 010patadine in rats resulted in a range of systemic
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`plasma area under the curve (AUC) levels that were 45 to 150 times higher than the observed
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`human exposure {9.7 ng-hrt’mL] following administration of the recommended human
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`Ophthalmic dose. It is not known whether topical ocular administration could result in sufficient
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`systemic absorption to produce detectable quantities in the human breast milk. Nevertheless,
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`caution should be exercised when PAZEO is administered to a nursing mother.
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`8.4 Pediatric Use
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`The safety and effectiveness of PAZEO have been established in pediatric patients two years of
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`age and older. Use of PAZEO in these pediatric patients is supported by evidence from adequate
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`and well-controlled studies of PAZEO in adults and an adequate and well controlled study
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`evaluating the safety of PAZEO in pediatric and adult patients.
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`8.5
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`Geriatric Use
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`No overall differences in safety and effectiveness have been observed between elderly and
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`11 DESCRIPTION
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`PAZEO is a sterile ophthalmic solution containing 010patadine, which is a mast cell stabilizer,
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`for topical administration to the eyes. 010patadine hydrochloride is a white, crystalline,
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`water-soluble powder with a molecular weight of 373.88 and a molecular formula of
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`C21H23NO3-HC1.
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`The chemical structure is presented below:
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`\N/
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`ac:
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`O O ..
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`0
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`Chemical Name: I l-[(Z)-3(dimethylarnino) propylidene]—6-1 1dihydrodibenz[b,e] oxepin~2-
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`acetic acid, hydrochloride
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`Each mL of PAZEO solution contains an active ingredient [176 mg of olopatadine
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`hydrochloride ( 3" mg olopatadine)] and the following inactive ingredients: povidone;
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`hydroxypropyl-garnma-cyclodextrin; polyethylene glycol 400; hydroxypropyl methylceilulose;
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`boric acid; mannitol; benzalkonium chloride 0.015% (preservative); hydrochloric acidx’sodium
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`hydroxide (to adjust pH); and purified water.
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`PAZEO solution has a pH of approximately 2.2 and an osmolality of approximately 300
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`mOsmz’kg.
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`12 CLINICAL PHARMACOLOGY
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`12.1 Mechanism of Action
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`Olopatadine is a mast cell stabilizer and a histamine ll. antagonist. Decreased chemotaxis and
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`inhibition of eosinophil activation has also been demonstrated.
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`12.3 Pharmacokinetics
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`In healthy subjects, tepical ocular dosing of 1 drop of PAZEO once daily for 7' days into both
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`eyes resulted in mean i SD (range) steady state plasma olopatadine Cmax and AUCau of 1.6 a:
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`0.9 ng/mL (0.6 to 4.5 ng/m L) and 9.7 :I: 4.4 ngl‘hx'mL (3.7 to 21.2 ng*hz’mL), respectively. The
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`olopatadine Cmax and AUCmg alter the first dose were similar to those measured on day 7 in
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`these subjects, suggesting that there was no systemic accumulation of olopatadine after repeated
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`topical ocular closing with PAZEO. The median (range) time to achieve peak olopatadine
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`concentrations (Tmax) was 2.0 hours (0.25 to 4 hours). The mean i SD (range) elimination
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`half-life of olopatadine was 3.4 i 1.2 hours (2 to 8 hours). N—oxide olopatadine (M3) was
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`detected during the first 4 hours after bilateral topical ocular dosing of PAZEO in approximately
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`half of the subjects and in less than 10% of the total plasma samples collected, at concentrations
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`not exceeding 0.12] ng/mL on day l and 0.174 ng/mL on day '2’. None ofthe plasma samples
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`from these subjects had mono-desmethyl olopatadine (Ml) concentrations that were above the
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`lower limit of quantitation (0.05 ng/mL) of the PK assay.
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`13 NONCLINICAL TOXICOLOGY
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`Carcinogenicity
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`Olopatadine administered orally was not carcinogenic in mice and rats in doses up to 500
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`mg/kgi’day and 200 mg/kg/day, respectively. Based on a 35 {L drop size and a 60 kg person,
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`these doses are approximately 4,500 and 3,600 times the MRHOD, on a mga‘m2 basis.
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`Mutagenesis
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`No mutagenic potential was observed when olopatadine was tested in an in vitro bacterial reverse
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`mutation (Ames) test, an in vitro mammalian chromosome aberration assay or an in vivo mouse
`micronucleus test.
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`Impairment qfferfility
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`Olopatadine administered at an oral dose of 400 mg/kg/day (approximately 7,200 times the
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`MRHOD) produced toxicity in male and female rats, and resulted in a decrease in the fertility
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`index and reduced implantation rate. No effects on reproductive function were observed at 50
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`mgikgfday (approximately 900 times the MRHOD).
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`l4 CLINICAL STUDIES
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`The efficacy of PAZEO was established in two randomized, double-masked, placebo-controlled,
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`conjunctiva] allergen challenge (CAC) clinical studies in patients with a history of allergic
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`conjunctivitis (Studies 1 and 2).
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`In Study 1, patients were randomized to receive one of the following study treatments: PAZEO,
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`PATADAY, or vehicle ophthalmic solutions.
`In Study 2, patients were randomized to receive
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`one of the following study treatments: PAZEO, PATADAY, PA’I‘ANOL, or vehicle ophthalmic
`solutions.
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`Patients were evaluated with an ocular itching severity score ranging from 0 (no itching) to 4
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`(incapacitating itch) at several time points after CAC administration. Table 1 displays the mean
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`ocular itching severity scores after ocular administration of a specific antigen using the CAC
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`model in Studies 1 and 2, respectively. A one unit difference compared to vehicle is considered
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`a clinically meaningful change in the ocular itching severity score.
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`PAZEO demonstrated statistically significantly improved relief of ocular itching compared to
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`vehicle at 30—34 minutes, 16 hours, and 24 hours after study treatment. PAZEO demonstrated
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`statistically significantly improved relief of ocular itching compared to PATADAY at 24 hours
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`afier study treatment, but not at 30-34 minutes afier study treatment.
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`Table 1 Itchin_ Scores b Treatment Grou and Treatment Difference* in Mean Itchin
`
`PAZEO
`PATADAY
`Vehicle
`
`
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`(Olopatadine, 0. 7%!
`(Olopatadine, 0.2%)
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`N = 68
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`Difference 95% C1
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`-U.02
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`-0.31,0.26
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`(N: 68
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`Difference 95% Cl
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`-1. 54
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`v]. 82, -1. 25
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`- -'53
`-1. B4 -1. 22
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`-—(180-1. 18)
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`-l. 50
`
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`(-1.7? ‘.123)
`
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`-l. 48
`
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`-1. 79 1.16)
`
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`. -_.
`
`( 1.69, 4.0?)
`.
`
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`- -~0.?6,-0.20)
`
`(-1 88, ~I. 33]
`
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`-1. 51
`.
`
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`
`
`
`
`(0.72.012)
`(-1.8l, 4.21
`
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`4.41
`-0.4I
`.
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`'
`{-1.?2,-l.il)
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`(N =49}4.53
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`(-1.?6, -1.30)
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`-1.46
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`(-1.71. -1.22)
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`(0 IS_ 0.26)
`(-1.43,~0.90)
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`-(-0 57, —0.06
`
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`(—1.60, 09?
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`-0. 26
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`(0510.01)
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`-0.16
`
`41.42. 0.1 I
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`*Mean score estimates. treatment differences and corresponding 95% confidence intermis (CL?) were based on analysis ofrepeated measures
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`using a mixed mode! with itching scoresfrom each eye (12}? or right) as the dependent variabie andfixed wee: rennsfor investigator. treatment.
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`eye-0:09 flefl or right), time. and treatment—by—time imemcn‘on.:
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`The ocuiar itching score range is 0—4. where 0 is none and 4 is incomeimting itch.
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`16 HOW SUPPLIEDISTORAGE AN D HANDLING
`
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`PAZEO (oloparadine hydrochloride ophthalmic solution) 0.7% is supplied in a white, oval, low
`
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`density polyethylene DROP-TAJNER' diSpenser with a natural low density polyethylene
`
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`dispensing plug and a White polypropylene cap. Tamper evidence is provided with a shrink band
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`around the closure and neck area of the package. PAZEO is supplied in a 4 mL bottle that
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`contains olopatadine hydrochloride ophthalmic solution [7.76 mg of olopatadine hydrochloride
`
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`in one mL of solution (0.7%)] in the following sizes:
`
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`2.5 mL in a 4 mL bottle
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`3.5 mL in a 4 mL bottle
`
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`NDC 0065-4273-25
`
`
`NDC 0065-4273-32
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`Storage: Store at 2°C to 25°C (36°F to 27°F). Keep bottle tightly closed when not in use.
`
`17
`
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`PATIENT COUNSELING INFORMATION
`
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`oRisk of Contamination: Advise patients to not touch dropper tip to eyelids or surrounding
`
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`
`areas, as this may contaminate the dropper tip and ophthalmic solution.
`
`
`
`

`

`oConcomitant Use of Contact Lenses: Advise patients not to wear contact lenses if their eyes
`are red. Advise patients that PAZEO should not be used to treat contact lens-related irritation.
`Advise patients to remove contact lenses prior to instillation of PAZEO. The preservative in
`PAZEO solution, benzalkonium chloride, may be absorbed by sofi contact lenses. Lenses may be
`reinserted 5 minutes following administration of PAZEO.
`
`Patents: 8,791,154
`
`ALCON®
`
`ALCON LABORATORIES, INC.
`Fort Worth, Texas 76134 USA
`© 2015 Novartis.
`
`‘ is a Trademark of Novanis
`
`

`

`
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`
`
`SZEELZ‘IS900200(L0)
`
`1
`
`Hx Only Each mL contains
`Active: 7.76 mg olopaladine
`hydrochloride equivalent
`to 7 mg olopatadine
`‘ a Trademark of Novanis
`MOON LABORATORIES. INC.
`Fort Worth.TX 76134 USA
`
`
`
`‘
`
`i2°-25:°C
`_
`ne hydrochloride (aw-77°F).
`solution) 0.7% Usuaiflosaae:
`Read Insert
`.
`
`ophthalmic
`solution) 0.
`
`'
`
`Rx Only
`FOR TOPICAL
`OPHTHALMIC USE
`
`Usual Dosage: Instill one
`drop in the affected eye
`- 7 f
`.
`my
`once daily.
`V
`STORAGE: Store at
`‘
`“Patadl'
`2°-25°c (sir-77°F)
`hydrochlori = "
`‘ a Trademark of Novarfikf ophthalmic
`sillution)0.
`
`,.
`
`'
`
`; Each mL contains:
`Active: 7.76 mg
`: olopatadine hydrochloride
`equivalent to 7 mg
`: olopatadine.
`lnaciives:
`
`I Povidone; hydroxypropyl-
`gamma-cyclodextrin;
`? polyethylene glycol 400;
`hydroxypropyl
`I methylceilulose; boric
`acid; mannitol;
`1 benzaikonium chloride
`0,015% (preservative);
`hydrochloric acid / sodium
`hydroxide (to adjust pH);
`
`‘
`
`:
`
`and purified water.
`
`,
`
`Alcori ..
`Alc
`Laboraiories‘ inc,
`{
`For! Wmih is
`
`aimn m
`
`NMMI
`
`xN \
`
`1’
`In
`‘0
`
`DO
`
`7116317741715
`
`3 Hamill:
`
`Alcori
`.: Nrwnrris v’nmparw
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`APPLICATION NUMBER:
`NDA 206276/S-001
`NDA 206276/8-001
`
`
`APPLICA TION NUMBER:
`
`CHEMISTRY REVIEW(S)
`CHEMISTRY REVIEW! S!
`
`
`
`
`
`

`

`
`
`
`
`
`
`“EI—
`CEHIST’S REVIEW #1
`—i.0RGANIz10N_DANUMBE
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`—N206276
`RESUBMISSION [I
`i
`
`
`
`4. SUPPLEMENT(S)
`
`
`'
`NUMBER 5
`TYPE
`
`
`
`
`
`PAS
`SAUDI
`
`
`
`
`
`
`i Company Name: Alcon Research, Ltd.
`
`
`
`
`
`5. DATE S
`
`
`
`
`
`
`
`_ Street Address:
`6201 South Freeway, R3-50
`
`
`
`
`
`
`
`
`
`
`
`Fort Worth
`July 29, 2015
`Submit Date
`- City:
`
`
`
`
`
`
`
`
`
`
`5 State:
`Texas
`July 29, 2015
`F DA Receipt Date
`
`
`
`
`
`
`
`
`
`
`
`76134-2099
`. Zip Code:
`November 29, 2015
`Goal Date
`
`
`
`
`
`
`
`
`
`
`
`July 31,2015
`Chemist Receipt Date
`USA
`
`
`Amendments
`NOne
`
`
`
`
`
`
`
`
`
`
`Date Completed
`November 4, 2015
`_
`
`
`
`
`
`
`
`
`
`' 6. PROPRIETARY NAME
`7. NAME OF THE DRUG
`i
`
`
`
`Oloatadine H drochloride Ohthalmic Solution, 0.77%
`
`
`
`
`
`
`
`
`8. SUPPLEMENT PROVIDES FOR:
`
`
`
`
`
`
`addition of an additional fill size 3.5 mL for the dru roduct
`
`
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`
`
`9. INDICATION
`10. HOW DISPENSED
`I]. RELATED IND, NDA, DMF
`
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`I
`reatment of ocular itching associated with RX E OTC I]
`
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`
`: alleric con'unctivitis
`
`
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`
`.
`_ 12. DOSAGE FORM
`13. POTENCY
`
`'
`Solution
`0.77 %
`
`
`
`
`
`15. RECORDS AND REPORTS l4. CHEMICAL NAME AND STRUCTURE
`
`
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`
`
`
`
`
`
`
`
`
`
`l l—[(Z)-3(dimethylamino)
`
`
`
`
`
`
`acid,
`propylidene]-6«l ldihydrodibenz[b,e]
`oxepin-Z-acetic
`
`
`
`hydrochloride
`
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`
`3. NAME AND ADDRESS OF APPLICANT
`
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`
`HCI
`
`
`\N
`
`M...
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`
` Chemical Formula: CEIH24CIN03
`
`
`
`
`
`
`
`
`
`Molecular Weight: 373.8?
`
`
` 16. COMMENTS
`
`
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`In support of the proposed change, the applicant provided batch data, stability data and revised labeling. The applicant indicated
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`that no changes to the manufacturing process (except fill volume), composition, specifications, analytical methods, container
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`closure, or indication. The batch data and stability data were evaluated and no 008 data are reported. No major trends were
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`; observed in 13 week (3 months) stability data. The changes made to the carton container, container label, and PI to reflect the
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`increased volume are acceptable from the CMC perspective. The labeling was also found to be acceptable from the DMEPA
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`perspective (Review dated October 20, 2015 by Michelle Rutledge, PharmD).
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`; EES Status: N. A.
`. 17. CONCLUSION AND RECOMMENDATION
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`5 This submission is recommended for a. roval from the stand oint of chemist
`, manufacturin_ and controls.
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`18. REVIEWERS SIGNATURE
`REVIEWER
`BRANCH CHIEF
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`See a -__enedd_ electronic si_nature sheet
`Anamirto Hanen‘eefihD.
`_Bala'!ee Shanmugam, Ph.D.I .
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`

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`Review Notes
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`NDA Number: N 206276
`8-00 1
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`Pazeo was approved on January 30, 20 l 5 for the treatment of ocular itching associated with allergic
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`conjunctivitis.
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`Proposed changes
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`Additional fill trade size of 3.5 mL in 4 mL bottles.
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`Rationale: Larger productfill size will provide patients with additional medication for an extended
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`duration ofuse through the majority ofallergy season and reduce the needfor multiple refills. Additional
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`amount will also allow for inadvertent wastage and enable patients to completefull course oftherapy (up to
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`45 days of use).
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`Summary
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`In support of the proposed change, the applicant provided:
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`1. Drafi labeling text
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`2. Description and composition —)same as approved in original NDA. No changes proposed.
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`3. Batch data
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`4. Stability data, summary and post approval stability protocol and commitment.
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`The applicant indicated that the packaging configuration (4 mL oval, white LDPE bottle, LDPE
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`dispensing plug, white polypropylene closure, and- tamper evidence feature) remains same as currently
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`approved for the 2.5 mL fill.
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`The clinical division (Dr. William Boyd, via email) has indicated no concerns for the proposed change.
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`3.2.P.5.4 Batch Data
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`The applicant provided batch data for several batches of—
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`— batches of the proposed 3.5 mL fill product. The batch data for the 3.5 mL fill batches are
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`comparable to the currently approved 2.5 mL fill batches. No 008 result is reported. The batch data for
`3.5 mL fill bathes are listed in the Table 3.2.P.5.4 below. The proposed 3.5 mL fill sizes do not have-
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`

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`Table 3.2.P.5.4 Batch Data Olopatadine HCl Solution 0.77% (3.5 mL/4 mL Trade Size)
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`Manufacmring lot numberWWW
`8qu Lot Number
`246998F
`247000F
`246997F
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`NDA Number: N 206276
`S-OOl
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`Feb 12, 2015
`Feb 1], 2015
`Feb 11, 2015
`A...........s.,..m.......—_—
`98 98,97
`98,98 98
`100 100 100
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`Olo-atadine Assa
`010 atadine Identi
`OIo atadine Identi
`010 . atadme Im a urities
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`TLC
`PLC
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`Total Im -uritiee
`Benzalkonium Chloride Assa
`Benzalkonium Chloride ldenti
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`None
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`0.0, 0.0, 0.0
`0.0, 0.0, 0.0
`0.0, 0.0, 0.0
`0.0, 0.0, 0.0
`0.0, 0.0, 0.0
`0.0, 0.0, 0.0
`0.0 0.0, 0.0
`100, 100
`Conforms
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`0.0, 0.0, 0.0
`0.0, 0.0, 0.0
`0.0, 0.0, 0.0
`0.0, 0.0, 0.0
`0.0, 0.0, 0.0
`0.0, 0.0, 0.0
`0.0, 0.0, 0.0
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`.2
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`0.0, 0.0, 0.0
`0.0, 0.0, 0.0
`0.0, 0.0, 0.0
`0.0, 0.0, 0.0
`0.0, 0.0, 0.0
`0.0, 0.0, 0.0
`0.0, 0.0 0.0
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`Conforms
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`7.2
`316
`29
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`_ 7.2
`Osmolali mOSm/k;
`316
`34
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`Appearance
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`Color
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`Clarity
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`Preci - itate
`Particulate Matter b I-IIAC
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`Bacterial Endotoxins
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`Pale Yellow
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`Colorless
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`Colorless
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`NMT EP 1,
`Clear
`None
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`NMT EP 1,
`Clear
`None
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`NMT EP 1,
`Clear
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`Fill Size / Bottle Size
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`3.5 mL/ 4 mL
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`Reviewer Evaluation
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`Acceptable
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`The batch data provided by the applicant for the proposed configuration is comparable to the currently
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`approved 2.5 mL configuration. No 008 data is reported.
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`3.2.P.8 Stability Data
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`The applicant provided stability data for eight primary stability lots of 2.5 mL trade size, five primary
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`stability lots of 0.5 mL sample size, and three primary stability lots of 3.5 mL trade size. Thirteen week (3
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`months) of stability data provided in this submission for the three lots of 3.5 mL trade size in 4 mL oval
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`

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`LDPE bottles manufactured at the Alcon ASPEX, Fort Worth facility is evaluated here (Table 3.2.P.8). In
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`the table, the data from accelerated storage conditions (40°C/<25%RH) is indicated in red font, intermediate
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`condition (30°C/75%RH) is in black fonts and long term conditions (25°C/40%RH) are indicated in blue
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`fonts. Any trends noted (or not observed) in the Table 3.2.P.8 is preliminary as only 3 data points are
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`reported for each condition.
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`NDA Number: N 206276
`S-001
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`Table 3.2.P.8 Summary of Stability Data Olopatadine HCI Solution 0.77% (3.5 mL/4 mL Trade Size)
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`Acceptance
`S . ecit'ications
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`250433F
`(Stability Lot 19059-01)
`101 (No change)
`Range: 100 — 101 (no trends)
`Ranre: 100— 101 no trends)
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`250434F
`(Stability Lot 19059-02)
`Range; 100 -— 101 (no trends)
`Range: 99 - 100 (no trends)
`Ran e: 99 - 100 (no trends
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`25043SF
`(Stability Lot 19059-03)
`Range; 101 — 102 (no trends)
`Range: 101 - 102 (no trends)
`101 No change
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`Olopatadine Assay
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`Olopatadine Impurities (% of
`active)
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`Range: 0 — <0.l (no trends)
`Not observed
`Not observed
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`Range: 0 - <0. 1 (no trends)
`Not observed
`Not observed
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`Range: 0 — <0. 1 (no trends)
`Not observed
`Nor observed
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`Not observed under any
`conditions
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`Not observed under any
`conditions
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`Not observed under any
`conditions
`Not observed under any
`conditions
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`Not observed under any
`conditions
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`Not observed under any
`conditions
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`None observed under any
`conditions
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`None observed under any
`conditions
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`None observed under any
`conditions
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`None observed under any
`conditions
`Range: 95 — 104 (no trends)
`Range: 100 -— 103 (no trends)
`Rune: 96 - 102 (no trends
`Range: 102 — 106 (no trends)
`Range: 99 — 104 (no trends)
`Rar , e: 96 — 102 no trends)
`Range: 7 .09 — 7.17 (no trends)
`Range: 7.1 1 — 7.18 (no trends)
`R e: 7.11 —7.20(no trends
`Range: 309 — 315 (increase)
`Range: 309 — 318 (increase)
`Rana: 308 — 310 (no trends
`Range: 30.5 - 31.6 (no trends)
`Range: 30.3 - 33.2 (no trends)
`Rane: 30.5 - 31.7 no trends)
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`None observed under any
`conditions
`Range: 95 — 104 (no trends)
`Range: 94 - 102 (no trends)
`Ran e: 93 — 101 (no trends
`Range: 96 - 104 (no trends)
`Range: 96 — 102 (no trends)
`Rarre: 96 —- 107 no trends
`Range: 7.08 — 7.15 (no trends)
`Range: 7.09 — 7.15 (no trends)
`Rana: 7.10 — 7.16 no trends
`Range: 307 - 315 (increase)
`Range: 307 - 31 1 (increase)
`Ra: c e: 302 — 307 (no trends
`Range: 25.4 — 27.6 (no trends)
`Range: 25.4 — 26.6 (no trends)
`Ra e: 25.4 — 27.8 (no trends)
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`None observed under any
`conditions
`Range: 97 - 103 (no trends)
`Range: 95 - 101 (no trends)
`Ran e: .96 - 101 no trends)
`Range: 99 — 105 (no trends)
`Range: 99 — 103 (no trends)
`Ran_ e: 99 — 105 no trends)
`Range: 7.09 - 7.16 (no trends)
`Range: 7.13 — 7.17 (no trends)
`Rune: 7.12 — 7. | 8 no trends
`Range: 310 — 322 (increase)
`Range: 310 - 316 (increase)
`Ran (I: 310 — 315 (no trends)
`Range: 268 - 28.6 (no trends)
`Range: 26.7 - 28.1 (no trends)
`: 27.8 -29.2 no trends
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`Conforms for all conditions
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`Conforms for all conditions
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`Conforms for all conditions
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`Conforms for all conditions
`Conforms for all conditions
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`Conforms for all conditions
`Conforms for all conditions
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`Conforms for all conditions
`Conforms for all conditions
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`Conforms for all conditions
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`