` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`206276Orig1s000
`LABELING
`
`
`
`

`

`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`PAZEO safely and effectively. See full prescribing information
`for PAZEO.
`
`PAZEO (olopatadine hydrochloride ophthalmic solution) 0.7%
`For topical ophthalmic administration.
`Initial U.S. Approval: 1996
`
`-------------------INDICATIONS AND USAGE-----------------
`PAZEO is a mast cell stabilizer indicated for the treatment of ocular
`itching associated with allergic conjunctivitis. (1).
`
`--------------DOSAGE AND ADMINISTRATION-------------
`The recommended dose is one drop in each affected eye once a day. (2)
`
`-------------DOSAGE FORMS AND STRENGTHS------------
`Ophthalmic solution: 7.76 mg of olopatadine hydrochloride in one
`mL of solution (0.7%) in a four mL bottle. (3)
`
`---------------------CONTRAINDICATIONS---------------------
`None.
`
`--------------WARNINGS AND PRECAUTIONS--------------
`Contamination of Tip and Solution. To prevent contaminating the
`dropper tip and solution, do not touch the eyelids or surrounding
`areas with the dropper tip of the bottle. (5.1)
`
`---------------------ADVERSE REACTIONS---------------------
`The most common adverse reactions (2-5%) were blurred vision,
`superficial punctate keratitis, dry eye, abnormal sensation in eye, and
`dysgeusia. (6)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Alcon
`Laboratories, Inc. at 1-800-757-9195 or FDA at
`1-800-FDA-1088 or www fda.gov/medwatch.
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA
`approved patient labeling.
`
`Revised: 1/2015
`___________________________________________________________________________________________________________
`
`11
`12
`
`13
`
`14
`16
`17
`
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3
`Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`CLINICAL STUDIES
`HOW SUPPIED/STORAGE AND HANDLING
`PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing
`information are not listed.
`
`INDICATIONS AND USAGE
`DOSAGE AND ADMINISTRATION
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`ADVERSE REACTIONS
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.3
`Nursing Mothers
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`________________________________________________________________________________________________
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1
`2
`3
`4
`5
`6
`8
`
`Reference ID: 3694617
`
`

`

`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`PAZEO is indicated for the treatment of ocular itching associated with allergic conjunctivitis.
`
`DOSAGE AND ADMINISTRATION
`2
`The recommended dosage of PAZEO is to instill one drop in each affected eye once a day.
`
`DOSAGE FORMS AND STRENGTHS
`3
`Ophthalmic solution: 7.76 mg of olopatadine hydrochloride in one mL solution (0.7%) in a 4
`mL bottle.
`
`CONTRAINDICATIONS
`4
`None.
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Contamination of Tip and Solution
`As with any eye drop, care should be taken not to touch the eyelids or surrounding areas with the
`dropper tip of the bottle to prevent contaminating the tip and solution. Keep bottle tightly closed
`when not in use.
`
`5.2 Contact Lens Use
`Patients should not wear a contact lens if their eye is red.
`
`The preservative in PAZEO solution, benzalkonium chloride, may be absorbed by soft contact
`lenses. Patients who wear soft contact lenses and whose eyes are not red, should be instructed to
`wait at least five minutes after instilling PAZEO before they insert their contact lenses.
`
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
`of another drug and may not reflect the rates observed in practice.
`
`In a randomized, double-masked, vehicle-controlled trial, patients at risk for developing allergic
`conjunctivitis received one drop of either PAZEO (N=330) or vehicle (N=169) in both eyes for 6
`weeks. The mean age of the population was 32 years (range 2 to 74 years). Thirty-five percent
`were male. Fifty-three percent had brown iris color and 23% had blue iris color. The most
`commonly reported adverse reactions occurred in 2-5% of patients treated with either PAZEO or
`vehicle. These events were blurred vision, dry eye, superficial punctate keratitis, dysgeusia and
`abnormal sensation in eye.
`
`USE IN SPECIFIC POPULATIONS
`8
`8.1 Pregnancy
`
`Reference ID: 3694617
`
`

`

`Risk Summary
`There are no adequate or well-controlled studies with PAZEO in pregnant women. Olopatadine
`caused maternal toxicity and embryofetal toxicity in rats at levels 1,080 to 14,400 times the
`maximum recommended human ophthalmic dose (MRHOD). There was no toxicity in rat
`offspring at exposures estimated to be 45 to 150 times that at MRHOD. Olopatadine should be
`used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
`
`Animal Data
`In a rabbit embryofetal study, rabbits treated orally at 400 mg/kg/day during organogenesis
`showed a decrease in live fetuses. This dose is 14,400 times the MRHOD, on a mg/m2 basis.
`
`An oral dose of 600 mg/kg/day olopatadine (10,800 times the MRHOD) was shown to be
`maternally toxic in rats, producing death and reduced maternal body weight gain. When
`administered to rats throughout organogenesis, olopatadine produced cleft palate at 60
`mg/kg/day (1080 times the MRHOD) and decreased embryofetal viability and reduced fetal
`weight in rats at 600 mg/kg/day. When administered to rats during late gestation and throughout
`the lactation period, olopatadine produced decreased neonatal survival at 60 mg/kg/day and
`reduced body weight gain in offspring at 4 mg/kg/day. A dose of 2 mg/kg/day olopatadine
`produced no toxicity in rat offspring. An oral dose of 1 mg/kg olopatadine in rats resulted in a
`range of systemic plasma area under the curve (AUC) levels that were 45 to 150 times higher
`than the observed human exposure [9.7 ng∙hr/mL] following administration of the recommended
`human ophthalmic dose.
`
`8.3 Nursing Mothers
`Olopatadine has been identified in the milk of nursing rats following oral administration. Oral
`administration of olopatadine doses at or above 4 mg/kg/day throughout the lactation period
`produced decreased body weight gain in rat offspring; a dose of 2 mg/kg/day olopatadine
`produced no toxicity. An oral dose of 1 mg/kg olopatadine in rats resulted in a range of systemic
`plasma area under the curve (AUC) levels that were 45 to 150 times higher than the observed
`human exposure [9.7 ng∙hr/mL] following administration of the recommended human
`ophthalmic dose. It is not known whether topical ocular administration could result in sufficient
`systemic absorption to produce detectable quantities in the human breast milk. Nevertheless,
`caution should be exercised when PAZEO is administered to a nursing mother.
`
`8.4 Pediatric Use
`The safety and effectiveness of PAZEO have been established in pediatric patients two years of
`age and older. Use of PAZEO in these pediatric patients is supported by evidence from adequate
`and well-controlled studies of PAZEO in adults and an adequate and well controlled study
`evaluating the safety of PAZEO in pediatric and adult patients.
`
`Geriatric Use
`8.5
`No overall differences in safety and effectiveness have been observed between elderly and
`younger patients.
`
`11 DESCRIPTION
`
`Reference ID: 3694617
`
`

`

`PAZEO is a sterile ophthalmic solution containing olopatadine, which is a mast cell stabilizer,
`for topical administration to the eyes. Olopatadine hydrochloride is a white, crystalline,
`water-soluble powder with a molecular weight of 373.88 and a molecular formula of
`C21H23NO3•HCl.
`
`The chemical structure is presented below:
`
`Chemical Name: 11-[(Z)-3(dimethylamino) propylidene]-6-11dihydrodibenz[b,e] oxepin-2-
`acetic acid, hydrochloride
`
`Each mL of PAZEO solution contains an active ingredient [7.76 mg of olopatadine
`hydrochloride ( 7 mg olopatadine)] and the following inactive ingredients: povidone;
`hydroxypropyl-gamma-cyclodextrin; polyethylene glycol 400; hydroxypropyl methylcellulose;
`boric acid; mannitol; benzalkonium chloride 0.015% (preservative); hydrochloric acid/sodium
`hydroxide (to adjust pH); and purified water.
`
`PAZEO solution has a pH of approximately 7.2 and an osmolality of approximately 300
`mOsm/kg.
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`Olopatadine is a mast cell stabilizer and a histamine H1 antagonist. Decreased chemotaxis and
`inhibition of eosinophil activation has also been demonstrated.
`
`12.3 Pharmacokinetics
`In healthy subjects, topical ocular dosing of 1 drop of PAZEO once daily for 7 days into both
`eyes resulted in mean ± SD (range) steady state plasma olopatadine Cmax and AUC0-12 of 1.6 ±
`0.9 ng/mL (0.6 to 4.5 ng/mL) and 9.7 ± 4.4 ng*h/mL (3.7 to 21.2 ng*h/mL), respectively. The
`olopatadine Cmax and AUC0-12 after the first dose were similar to those measured on day 7 in
`these subjects, suggesting that there was no systemic accumulation of olopatadine after repeated
`topical ocular dosing with PAZEO. The median (range) time to achieve peak olopatadine
`concentrations (Tmax) was 2.0 hours (0.25 to 4 hours). The mean ± SD (range) elimination
`half-life of olopatadine was 3.4 ± 1.2 hours (2 to 8 hours). N-oxide olopatadine (M3) was
`
`Reference ID: 3694617
`
`

`

`detected during the first 4 hours after bilateral topical ocular dosing of PAZEO in approximately
`half of the subjects and in less than 10% of the total plasma samples collected, at concentrations
`not exceeding 0.121 ng/mL on day 1 and 0.174 ng/mL on day 7. None of the plasma samples
`from these subjects had mono-desmethyl olopatadine (M1) concentrations that were above the
`lower limit of quantitation (0.05 ng/mL) of the PK assay.
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Carcinogenicity
`Olopatadine administered orally was not carcinogenic in mice and rats in doses up to 500
`mg/kg/day and 200 mg/kg/day, respectively. Based on a 35 μL drop size and a 60 kg person,
`these doses are approximately 4,500 and 3,600 times the MRHOD, on a mg/m2 basis.
`
`Mutagenesis
`No mutagenic potential was observed when olopatadine was tested in an in vitro bacterial reverse
`mutation (Ames) test, an in vitro mammalian chromosome aberration assay or an in vivo mouse
`micronucleus test.
`
`Impairment of fertility
`Olopatadine administered at an oral dose of 400 mg/kg/day (approximately 7,200 times the
`MRHOD) produced toxicity in male and female rats, and resulted in a decrease in the fertility
`index and reduced implantation rate. No effects on reproductive function were observed at 50
`mg/kg/day (approximately 900 times the MRHOD).
`
`14 CLINICAL STUDIES
`The efficacy of PAZEO was established in two randomized, double-masked, placebo-controlled,
`conjunctival allergen challenge (CAC) clinical studies in patients with a history of allergic
`conjunctivitis (Studies 1 and 2).
`
`In Study 1, patients were randomized to receive one of the following study treatments: PAZEO,
`PATADAY, or vehicle ophthalmic solutions. In Study 2, patients were randomized to receive
`one of the following study treatments: PAZEO, PATADAY, PATANOL, or vehicle ophthalmic
`solutions.
`
`Patients were evaluated with an ocular itching severity score ranging from 0 (no itching) to 4
`(incapacitating itch) at several time points after CAC administration. Table 1 displays the mean
`ocular itching severity scores after ocular administration of a specific antigen using the CAC
`model in Studies 1 and 2, respectively. A one unit difference compared to vehicle is considered
`a clinically meaningful change in the ocular itching severity score.
`
`PAZEO demonstrated statistically significantly improved relief of ocular itching compared to
`vehicle at 30-34 minutes, 16 hours, and 24 hours after study treatment. PAZEO demonstrated
`statistically significantly improved relief of ocular itching compared to PATADAY at 24 hours
`after study treatment, but not at 30-34 minutes after study treatment.
`
`Reference ID: 3694617
`
`

`

`Table 1. Itching Scores by Treatment Group and Treatment Difference* in Mean Itching
`Time Point
`PAZEO
`PATADAY
`Vehicle
`(Olopatadine, 0.7%)
`(Olopatadine, 0.2%)
`(N = 66)
`(N = 68)
`Mean
`Difference (95% CI)
`0.36
`-0.02
`(-0.31, 0.26)
`-0.08
`(-0.39, 0.22)
`-0.13
`(-0.44, 0.17)
`-0.17
`(-0.44, 0.11)
`-0.24
`(-0.55, 0.07)
`-0.23
`(-0.54, 0.08)
`-0.48
`(-0.76, -0.20)
`-0.42
`(-0.72, -0.12)
`-0.41
`(-0.72, -0.10)
`
`(N = 68)
`Difference (95% CI)
`-1.54
`(-1.82, -1.25)
`-1.53
`(-1.84, -1.22)
`-1.49
`(-1.80, -1.18)
`-1.50
`(-1.77, -1.23)
`-1.48
`(-1.79, -1.16)
`-1.38
`(-1.69, -1.07)
`-1.61
`(-1.88, -1.33)
`-1.51
`(-1.81, -1.21)
`-1.41
`(-1.72, -1.11)
`
`Study 1
`
`Onset
`
`16h
`
` 3 mins
`
` 5 mins
`
` 7 mins
`
` 3 mins
`
` 5 mins
`
` 7 mins
`
` 24h
`
` 3 mins
`
` 5 mins
`
` 7 mins
`
`Mean
`0.39
`
`0.61
`
`0.61
`
`0.87
`
`1.04
`
`0.98
`
`1.41
`
`1.52
`
`1.50
`
`0.53
`
`0.48
`
`0.70
`
`0.79
`
`0.75
`
`0.93
`
`1.10
`
`1.09
`
`Mean
`1.90
`
`2.06
`
`1.97
`
`2.20
`
`2.27
`
`2.13
`
`2.54
`
`2.62
`
`2.50
`
`Study 2
` Onset
`
`24h
`
` 3 mins
`
` 5 mins
`
` 7 mins
`
` 3 mins
`
` 5 mins
`
` 7 mins
`
`(N = 98)
`0.38
`
`0.53
`
`0.65
`
`1.01
`
`1.22
`
`0.47
`
`0.61
`
`0.61
`
`1.33
`
`1.48
`
`(N = 49)
`(N = 99)
`-1.53
`-0.09
`(-1.76, -1.30)
`(-0.28, 0.09)
`-1.46
`-0.08
`(-1.71, -1.22)
`(-0.29, 0.12)
`-1.17
`0.04
`(-1.45, -0.90)
`(-0.18, 0.26)
`-1.29
`-0.31
`(-1.60, -0.97)
`(-0.57, -0.06)
`-1.15
`-0.26
`(-1.46, -0.84)
`(-0.51, -0.01)
`-0.89
`-0.16
`2.14
`1.41
`1.25
`(-1.22, -0.57)
`(-0.42, 0.11)
`* Mean score estimates, treatment differences and corresponding 95% confidence intervals (CIs) were based on analysis of repeated measures
`using a mixed model with itching scores from each eye (left or right) as the dependent variable and fixed effect terms for investigator, treatment,
`eye-type (left or right), time, and treatment-by-time interaction.;
`The ocular itching score range is 0-4, where 0 is none and 4 is incapacitating itch.
`
`1.91
`
`1.99
`
`1.82
`
`2.30
`
`2.37
`
`Reference ID: 3694617
`
`

`

`16 HOW SUPPLIED/STORAGE AND HANDLING
`PAZEO (olopatadine hydrochloride ophthalmic solution) 0.7% is supplied in a white, oval, low
`density polyethylene DROP-TAINER* dispenser with a natural low density polyethylene
`dispensing plug and a white polypropylene cap. Tamper evidence is provided with a shrink band
`around the closure and neck area of the package. PAZEO is supplied in a 4 mL bottle that
`contains 2.5 mL of olopatadine hydrochloride ophthalmic solution [7.76 mg of olopatadine
`hydrochloride in one mL of solution (0.7%)]:
`
`NDC 0065-4273-25
`
`Storage: Store at 2°C to 25°C (36°F to 77°F). Keep bottle tightly closed when not in use.
`
`PATIENT COUNSELING INFORMATION
`17
`●Risk of Contamination: Advise patients to not touch dropper tip to eyelids or surrounding
`areas, as this may contaminate the dropper tip and ophthalmic solution.
`
`●Concomitant 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 soft 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
`© 201X Novartis.
`
`* is a Trademark of Novartis
`
`Reference ID: 3694617
`
`

`

`in......._....
`
`Active: 7.76 mg
`olopatadine hydrochbride
`equivalent to 7 mg
`olopatadine.
`Inactivcs:
`
`‘
`
`Povidone; hvdmxfoOPW-
`gamma~cyc|odcx1rim
`Momma 9W 400;
`hydroxypropyl
`melhylcellulose; boric
`acid; mmnitnl:
`benzalkonium allows
`0.015% (preservatwe'):
`hydrochloric acid / sodium
`hydroxide (to ad'pst pH);
`and puified later.
`
`CEO I 5 Nnmms Each nL contains:
`
`Rx Only
`FDR TOPICAL
`OPHTHALMIC USE Qn
`Usual Dosage: Insull one
`drop m the affected eye
`once daily.
`‘
`STORAGE: Stow a!
`2°-25°c (36°-77°F)
`
`‘ a Trademark o! Pluvnitu'.
`
`Alum Laboram-ies. Inc." I
`aim Scum Freeway
`Fort Wmth Foxes 76134 L'SA
`1'800-757-“95
`anon majimou akon Ivum
`aned In USA
`
`7
`
`00654|2732
`
`901144441115
`
`
`
`Reference ID: 369461 7
`
`

`

`
`
`
`
`Rx Dnly Each mL contains:
`
`
`a1 2°-25°|3
`ficériveifli'flfi mg qiuggtntldine
`-
`+<-
`0:: an as uwa n
`o-
`o
`'
`
`my? mg oiupatattifine
`.
`E hydrochloride ElaalsuarEuEnge'
`
`* a Trademark of Novartls
`=
`'
`
`ALCUH LMUHflTCHIES, IHB.
`i'l' Sflllfllflfl) 0.7%
`Head insert
`Fort Worth. TI i'fi‘lSd USA
`
`
`--
`
`-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3694617
`Reference ID: 3694617
`
`

`

`
`
`
`
`
`
`
`
`FDR PROFESSIONAL USE -
`
`Ranlv
`Fol! l'm’lflL.
`
`HUT FDR SflLE
`
`
`
`
`
`
`
`
`WHEY-TEN
`
`mm m I“
`5 NM
`
`
`
`
`
`
`
`
`
`Ioiupalame
`hyimlllond
`ophllahk
`swimmer“
`
`Reference ID: 3694617
`Reference ID: 3694617
`
`

`

`0065-4274-2
`
`le Only Each mL contains:
`Active: 7.76 mg otopatadine
`1ydmchtoride equivaient
`In 1" mg olopatadine
`* a Trademark of Nevada's
`ALBDH LABORATORIES, INC.
`
`FurtWOrth.TX 76134 USA wemorasnom.us:-:10ij
`
`smrage: Share
`at 2°-25°C
`[36°-7?°F].
`Usual Dosage
`Head insert
`e 2015 Nwarus
`
`'
`
`SALE
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3694617
`Reference ID: 3694617
`
`

`

`NDC 0065-4273-27
`
`Pazeofi
`
`(olopatadine a
`hydrod1lofide
`ophthalmic
`
`solution) 0.7%
`
`
`FOR PROFESSIONAL USE
`NOT FOR SALE
`
`
`
`9011599-0115
`
`
`
`
`
`
`
`
`
`0.5 mL Alum-ii
`
`STERILE
`
`* a Trademark of Novartis
`
`Reference ID: 3694617
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RENATA ALBRECHT
`01/30/2015
`
`Reference ID: 3694617
`
`