CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`206276Orig1s000
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
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`NDA 206276 Biopharmaceutics Review
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`BIOPHARMACEUTICS REVIEW
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`Office of New Druo Quali Assessment
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`Application NDA 206276
`No.:
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`D'v'
`‘ 15“”
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`A licant'
`PP
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`$223:
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`Generic
`Name:
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`Indication
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`Reviewer: Banu Sizanli Zolnik, Ph.D.
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`DIVISIOH Of
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`Transplant and
`Ophthalmic
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`Products
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`Alcon Research Biopharmaceutics Team Leader (Acting):
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`Elsbeth Chikhale, Ph.D.
`LTD
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`Pazeo
`Acting Biopharmaceutics Supervisor: Paul Seo, Ph.D.
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`Olopatadine
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`Hydrochloride
`Date Assngned. August 1, 2014
`Treatment of
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`December 23, 2014
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`ocular itching
`associated with
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`allergic
`,, con'unctivitis
`0.7%
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`Ophthalmic
`Administration Ophthalmic
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`Solution
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`SUBMISSIONS REVIEWED IN THIS DOCUMENT
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`Date of
`Primary Review due in DARRTS
`Submission Dates
`informal/Formal
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`Consult
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`Original submission
`Dated July 30, 2014
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`of
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`NA
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`01/03/2017
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`SUMMARY OF BIOPHARMACEUTICS FINDINGS:
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`Submission:
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`solution, 0.7% (0.776% Olopatadine
`for Olopatadine Ophthalmic
`NDA 206276
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`hydrochloride is equivalent to 0.7% free base) is a 505 (b)(2) submission. Olopatadine is an
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`antihistamine and mast cell stabilizer and the proposed indication is the treatment of ocular
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`itching associated with allergic conjunctivitis. The listed drug product is Patanol®, NDA
`20-688.
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`Reference ID: 3705748
`Reference ID: 3705748
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`NDA 206276 Biopharmaceutics Review
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`The approved olopatadine HCl products are listed below:
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`Patanol® (olopatadine HCl) ophthalmic solution eq. 0.1% base was approved by FDA
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`under NDA 20-688 on December 18, 1996,
`for the treatment of the signs and
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`symptoms of allergic conjunctivitis.
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`Pataday® (olopatadine HCl) ophthalmic solution eq. 0.2% base was approved by FDA
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`under NDA 21-545 on December 22, 2004,
`for the treatment of ocular itching
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`associated with allergic conjunctivitis.
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`Patanases® is a nasal spray olopatadine HCL formulation indicated for the relief of the
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`symptoms of seasonal allergic rhinitis. This product was approved under NDA 21-
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`of efficacy compared to the marketed products Patanol® and Pataday®.
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`The Applicant conducted two clinical safety and efficacy studies (010-126 and C-12—053)
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`in support of approval of the proposed product. The Applicant also conducted clinical
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`pharmacology study C-11—036, a Phase 1 pharmacokinetic study following single and
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`multiple dose topical ocular administration of olopatadine HCL ophthalmic solution 0.77%
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`in Japanese 24 healthy subjects. Phase 1 PK study is evaluated by Office of Pharmacology
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`reviewer Dr. Gerlie Geiser. Dr. Gieser’s review (dated 10/16/2014) states “In healthy
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`subjects topical ocular dosing of I drop of Pazeo once daily for 7 days into both eyes
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`resulted in mean i SD (range) steady state plasma olopatadine Cm,” and AUC0_1_7 of 1.6 :1:
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`0.9 ng (0.6 to 4.5 ng/mL) and 9. 7d: 4.4 ng*h/mL (3.7 to 21.2 ng*h/mL), respectively. The
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`olopatadine Cmax and A UC 0-12 after the first dose were similar to those measured on day 7
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`suggesting that there was no systemic accumulation of olopatadine after repeated topical
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`ocular dosing with Paze0®”.
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`8610n April 15, 2008. The current proposed product was developed with the intention ef to increase the duration
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`Review:
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`The Biopharmaceutics review is focused on the evaluation of the overall information/data
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`supporting the approvability of the biowaiver request.
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`Per 21 CFR 320.22 (b)(1), the Applicant is requesting a waiver from the requirements for
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`submission of in Vivo bioavailability or bioequivalence data on the basis that the proposed
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`product is an ophthalmic product applied topically in the eye and is intended only for local
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`therapeutic effect. However, the Applicant conducted a PK study (which was reviewed by
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`Dr. Gerlie Gieser) in healthy subjects. Therefore, a biowaiver request is not applicable.
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`RECOMMENDATION:
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`The ONDQA-Biopharmaceutics team has reviewed NDA 206276 submitted on July 30,
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`2014. From the Biopharmaceutics perspective, NDA 206276 Pazeo (olopatadine
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`hydrochloride) ophthalmic solution 0.7% is recommended for APPROVAL.
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`Reference ID: 3705748
`Reference ID: 3705748
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`

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`NDA 206276 Biopharmaceutics Review
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`Banu Sizanli Zolnik, Ph.D.
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`Biopharmaceutics Reviewer
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`Office of New Drug Quality Assessment
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`Elsbeth Chikhale, Ph.D.
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`Biopharmaceutics Team Leader (Acting)
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`Office of New Drug Quality Assessment
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`——i
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`Digitally signed by Elsbeth G.
`Chikhale -S
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`DN: c=US, o=U.S. Government,
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`ou=HHS, ou=FDA, ou=People,
`0.9.2342.19200300.10011:1300
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`136142, canlsbeth G. Chikhale <
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`ate: 2014.12.23 18:56:51 ~05'00'
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`SD
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`Elsbeth G.
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`Chikhale —S
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`Digitally signed by Banu S. Zolnik -S
`DN: c=US, o=UlS. Government, ou=HHS,
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`ou=FDA, ou=People, cn=Banu Sr Zolnik >5,
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`0.9134119200300.100.1.1=1300438310
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`Date: 2014.12.23 16:08:30 «05‘00‘
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`Banu S.
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`Zolnik-S
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`cc: P. 860
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`Risk Mitigation
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`Approach
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`RISK ASSESSMENT TABLE
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`From Initial Quality Assessment
`Review Assessment
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`Lifecycle
`Product
`Factors that
`Risk Evaluation
`Risk
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`Considerations/
`attribute /
`can
`Ranking*
`[Acceptable/
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`CQA
`impact the
`Unacceptable]
`Comments* *
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`CQA
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`NA
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`NA
`Solution NA
`L
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`* Risk ranking applies to product attribute/CQA (L, M, E)
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`NA
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`Reference ID: 3705748
`Reference ID: 3705748
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`CLINICAL PHARMACOLOGY REVIEW
`____________________________________________________________________________
`NDA:
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`206-276 (N-000)
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`Submission Date:
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`30 July 2014
`Drug Product:
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`olapatadine hydrochloride ophthalmic solution, 0.7%
`Trade Name:
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`
`PAZEO®
`Proposed indication:
`for treatment of ocular itching associated with allergic
`conjunctivitis
`Alcon Research, Ltd
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`Sponsor:
`505(b)(1) NDA
`Submission Type:
`Gerlie Gieser, Ph.D.
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`OCP Reviewer:
`Philip M. Colangelo, Pharm.D., Ph.D.
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`Team Leader:
`____________________________________________________________________________
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`I. Executive Summary:
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`Alcon is seeking approval of PAZEO® (olapatadine hydrochloride, 0.7%) ophthalmic solution for the
`treatment of ocular itching associated with allergic conjunctivitis; the proposed dosage is 1 drop into
`each eye once daily. The sponsor reported that in two adequate well-controlled Phase 3 Conjunctival
`Allergen Challenge (CAC) trials, PAZEO® (0.7%) demonstrated superiority to vehicle and the active
`comparator(s) PATADAY® (olapatadine hydrochloride 0.2%; Alcon) and PATANOL® (olapatadine
`hydrochloride 0.1%; Alcon) when 1 drop per eye of the treatments were administered to adult allergic
`conjunctivitis patients at 2 to 3 non-consecutive days over 2 to 3 weeks (i.e., on days 0, 14, 21).
`Additionally, the safety and tolerability of PAZEO® (given as 1 drop per eye once daily for 6 weeks)
`was demonstrated in healthy subjects 2 years and older (Study C-12-028). The sponsor’s subgroup
`analyses of safety data generated in Study C-12-028 did not reveal any clinically significant differences
`in the types and the rates of adverse events with respect to age, gender, race, concomitant disease,
`concomitant medications, and iris color. In Study C-12-028, dysgeusia (taste perversion) was the only
`unique common adverse event reported for PAZEO® 0.7%, although the rate (2.4%) was not higher than
`that reported for PATADAY® 0.2% (i.e., 5% or less, in the US package insert).
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`Summary of Clinical Pharmacology Findings
`The sponsor conducted PK Study C-11-036 to determine the plasma exposures to olapatadine and its two
`(N-oxide and mono-desmethyl) metabolites following single and repeated topical ocular administration
`of the proposed commercial ophthalmic solution in 24 healthy adult subjects; 19 subjects had a complete
`set of PK profiles on Days 1 and 7. The plasma olapatadine (parent drug) concentrations were higher
`with topically applied PAZEO® (olapatadine hydrochloride 0.7%) ophthalmic solution administered as 1
`drop per eye once daily for 7 days, compared to that reported for 0.15% olapatadine ophthalmic solution
`administered as 1 drop per eye twice daily for 2 weeks (see the PATADAY® and PATANOL® US
`package inserts), although no apparent accumulation of olapatadine was observed following repeated
`topical ocular administration of the proposed product. The mean steady state plasma olapatadine Cmax
`and AUC0-12 measured with PAZEO® in this PK study were lower (by 90% to 93%, and by 85% to 88%,
`respectively) than that reported in adult healthy subjects and seasonal allergic rhinitis patients following
`administration of PATANASE® (olapatadine hydrochloride 0.6%; Alcon) Nasal Spray given 2 sprays
`per nostril twice daily for 14 days. The N-oxide metabolite of olapatadine (M3) was detected in less than
`10% of the total plasma samples in approximately half of the study participants; the maximum plasma
`concentration was 0.174 ng/mL measured during the first 4 hours post-dosing. Plasma concentrations of
`desmethyl olapatadine (M1) were below the LLOQ (0.05 ng/mL) of the PK assay.
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`Reference ID: 3644206
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`1
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`_______________________________________________
`Gerlie Gieser, Ph.D.
`Office Clinical Pharmacology
`Division of Clinical Pharmacology 4
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`Recommendations
`From a Clinical Pharmacology perspective, this NDA of olapatadine hydrochloride 0.7% ophthalmic
`solution is recommended for approval. See Section III of this document for the reviewer’s recommended
`edits to the sponsor’s proposed language in Section 12.3 of the proposed package insert.
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`RD/FT signed by Philip M. Colangelo, Pharm.D., Ph.D. (TL) _________________________________
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`Reference ID: 3644206
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`2
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`II. Question-Based Review:
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`A. General Clinical Pharmacology
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`1. What are the PK parameters of the drug and its metabolites after single and multiple dosing?
`The PK of olapatadine and its n-oxide and mono-desmethyl metabolites following single and repeated
`topical ocular dosing of PAZEO® (1 drop once daily for 7 days) were investigated in 24 healthy adult
`subjects (24 to 62 years old, weighing 54 to 99 kg). The time course of plasma olapatadine
`concentrations for 19 subjects with a complete set of PK parameters for the two PK profiling days (Days
`1 and 7) are depicted in Figure 1; the corresponding PK parameters are summarized in Table 1. The mean
`olapatadine Cmax, and AUC0-12 were similar on day 1 and day 7, suggesting the lack of systemic
`accumulation after repeated topical ocular dosing with PAZEO®. The olapatadine Cmax and AUC were
`not significantly influenced by gender, race, age and bodyweight.
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`Figure 1. Plasma olapatadine concentration-time profiles following 1 day and 7 days of topical ocular dosing with
`PAZEO® administered as 1 drop per eye once daily to healthy adult subjects (Study C-11-036)
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`*analysis includes 19 subjects with complete set of PK profiles on Days 1 and 7
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`Table 1. Pharmacokinetic Parameters of Olopatadine after Single and Multiple Once Daily Dosing of PAZEO® in
`Healthy Adult Subjects (Study C-11-036); [Mean ± SD; Median (range)]
`Olapatadine
`Day 1
`Day 7
`PK parameter
`(n=19)
`(n=19)
`1.65 ± 1.07;
`1.86 ± 1.1;
`2 (0.25 - 4.02)
`2 (0.25 - 4)
`1.9 ± 1;
`1.6 ± 0.9;
`1.7 (0.6 - 4.1)
`1.6 (0.6 - 4.5)
`10 ± 4.3;
`9.7 ± 4.4;
`9.1 (4.1 - 18.4)
`9.1 (3.7 - 21.2)
`3.01 ± 1.07;
`3.4 ± 1.2;
`2.56 (2.05 - 5.78)
`3.3 (2.13 - 7.77)
`*analysis includes 19 subjects with complete set of PK profiles on Days 1 and 7
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`AUC0-12 (ng*h/mL)
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`Tmax (hours)
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`Cmax (ng/mL)
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`t1/2 (hours)
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`Reference ID: 3644206
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`3
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`Compared to two approved olapatadine ophthalmic solutions marketed by Alcon Research, Ltd, i.e.,
`PATADAY® 0.2% (given 1 drop per eye once daily) and PATANOL® 0.1% (given 1 drop per eye twice
`daily), the plasma olapatadine (parent drug) concentrations following topical ocular use of PAZEO® at
`the proposed dosage were higher in the healthy adult subjects who participated in the PK study. The
`package inserts of PATADAY® and PATANOL® states: “Following topical ocular administration of
`olopatadine 0.15% ophthalmic solution in man, olopatadine was shown to have a low systemic exposure.
`Two studies in normal volunteers (totaling 24 subjects) dosed bilaterally with olopatadine 0.15%
`ophthalmic solution once every 12 hours for 2 weeks demonstrated plasma concentrations to be generally
`below the quantitation limit of the assay (< 0.5 ng/mL). Samples in which olopatadine was quantifiable
`were typically found within 2 hours of dosing and ranged from 0.5 to 1.3 ng/mL.”
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`Compared to PATANASE® (olapatadine 0.66%) Nasal Spray when given as 2 sprays per nostril twice
`daily, the measured mean steady state Cmax and AUC0-12 were lower (by 90% to 93%, and by 85% to
`88%, respectively) in the healthy subjects of the PK study following topical ocular use of PAZEO® at
`the proposed dosage. The reviewer notes that even if adjusting the observed mean olapatadine Cmax and
`AUC0-12 for the low absolute recoveries (<40%) of the simultaneous PK assay (see Section B.3 of this
`NDA review), the exposures to olapatadine (and its metabolites) would still be significantly lower than
`that previously reported for PATANASE®. The PATANASE US package insert describes the systemic
`exposures to olapatadine in healthy subjects and patients, as follows:
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`“Absorption: Healthy Subjects: Olopatadine was absorbed with individual peak plasma concentrations
`observed between 30 minutes and 1 hour after twice daily intranasal administration of PATANASE
`Nasal Spray. The mean (± SD) steady-state peak plasma concentration (Cmax) of olopatadine was 16.0 ±
`8.99 ng/mL. Systemic exposure as indexed by area under the curve (AUC0-12) averaged 66.0 ± 26.8
`ng·h/mL. The average absolute bioavailability of intranasal olopatadine is 57%. The mean accumulation
`ratio following multiple intranasal administration of PATANASE Nasal Spray was about 1.3.
`Seasonal Allergic Rhinitis (SAR) Patients: Systemic exposure of olopatadine in SAR patients after twice
`daily intranasal administration of PATANASE Nasal Spray was comparable to that observed in healthy
`subjects. Olopatadine was absorbed with peak plasma concentrations observed between 15 minutes and 2
`hours. The mean steady-state Cmax was 23.3 ± 6.2 ng/mL and AUC0-12 averaged 78.0 ± 13.9 ng·h/mL.”
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`Table 2. Mean ± SD (range) Pharmacokinetic Parameters of Olopatadine after Multiple QD or BID Intranasal Doses
`Study
`Dose/Regimen
`Cmax
`Tmax
`AUC0-12
`(ng*h/mL)
`(N)
`(ng/mL)
`(h)
`0.4%/BID x 14 days
`15.9 ± 6.4
`1.00 ± 0.55
`57.3 ± 24.5
`(N=14)
`(3.65-29.0)
`(0.25-2.00)
`(10.4-114)
`0.6%/BID x 14 days
`23.3 ± 6.2
`0.97 ± 0.52
`78.0 ± 13.9
`(N=13)
`(14.4-35.3)
`(0.08 - 1.50)
`(54.4- 103)
`0.1%/QD x 3 days (N=12)
`4.36 ± 2.27
`1.23 ± 0.59
`13.92± 5.90
`(0.41 -7.92)
`(0.50 -2.00)
`(1.40 -20.67)
`3.42 ± 1.31
`1.06 ± 0.42
`12.03 ± 3.66
`(0.97 — 5.05)
`(0.50 - 1.50)
`(4.80 - 16.54)
`8.48 ± 3.12
`1.25 ± 0.38
`28.33 ± 9.88
`(2.77- 15.0)
`(0.75-2.00)
`(11.09- 14.03)
`Source Clinical Pharmacology review of PATANASE® (olapatadine 0.6% intranasal spray) NDA
`SAR (Seasonal Allergic Rhinitis); BID (twice daily); QD (once daily)
`
`That the average elimination half-life of olapatadine (3.5 hours) on Day 1 and at steady state following
`topical ocular administration of PAZEO® is shorter than that reported for intranasally administered
`olapatadine and orally administered olapatadine (8 to 12 hours) could be explained by the possible
`
`Study C-02-10 SAR
`patients
`
`Study C-00-58
`Healthy
`Subjects
`
`0.1%/BID x 3 days (N=12)
`
`0.2%/BID x 3 days (N=12)
`
`t1/2
`(h)
`8.3 ± 4.9
`(2.1-21.3)
`10.4 ± 5.1
`(4.0-21.8)
`6.3 ± 4.1
`(1.96 - 13.5)
`8.3 ± 3.5
`(3.06 - 13.3)
`15.0 ± 9.6
`(3.16-29.9)
`
`
`
`Reference ID: 3644206
`
`4
`
`

`

`dependence of the systemic elimination of this drug on the circulating concentrations. Based on the
`Clinical Pharmacology review of the PATANASE® NDA, there appears to have been a trend of longer
`mean elimination half-life with higher cumulative doses of olapatadine nasal spray (see t1/2, Cmax, and
`AUC0-12 of olapatadine of healthy subjects in Table 2).
`
`The reviewer confirms that desmethyl olapatadine (M1) was not detected in any of the plasma samples
`collected in PK Study C-11-036. On the other hand, N-oxide olapatadine (M3) was detected in 8.9%
`(27/304) of the plasma samples (from 58% or 11 of the 19 subjects with a complete set of olapatadine PK
`parameters on Day 1 and Day 7). In those with detectable levels, the maximum steady state M3
`concentration was 0.174 ng/mL, measured during the first 4 hours post-dose. When considering all
`plasma samples collected in the PK study, i.e., even those obtained from subjects who did not have a
`complete set of olapatadine PK parameters on Day 1 and Day 7, similar proportions of plasma samples
`(8.6%) and patients with detectable M3 levels (58%; 14/24) were observed. The reviewer notes that the
`sponsor reported that only 6 of the 24 subjects had “observable” n-oxide olapatadine in their plasma on
`day 1, and only 1 subject on day 7.
`
`
`B. Analytical Section
`
`1. How are the active moieties identified and measured in the plasma in the clinical pharmacology
`and biopharmaceutics studies?
`
`The samples were processed using a protein-precipitation extraction technique, followed by a
`validated HPLC/MS/MS assay to measure the concentrations of olapatadine, n-oxide olapatadine and
`mon-desmethyl olapatadine in the plasma samples of healthy subjects who participated in PK Study
`C-11-036. AL-25287 was used as the internal standard.
`
`
`2. Which metabolites have been selected for analysis and why?
`
`Two minor active metabolites (N-oxide and mono-desmethyl olapatadine) were measured in the
`plasma samples obtained during the conduct of PK Study C-11-036, as these were the same two
`metabolites that were measured in the plasma samples of PK studies conducted by Alcon during the
`development of PATADAY®, PATANOL® ophthalmic solutions, and PATANASE® Nasal Spray.
`
`3. What are the performance characteristics of the PK assay?
`
`The PK assay used to quantify olapatadine and its n-oxide and mono-desmethyl metabolites was at
`least 10-fold more sensitive than the assay that was used previously by Alcon for the PK study as
`described in the PATADAY®0.2% and PATANOL®0.1% ophthalmic solution US package inserts,
`but was the same as that used for the PK measurements as described in the PATANASE® Nasal
`Spray US package insert. For all three analytes, the LLOQ of the most current PK assay was 0.05
`ng/mL, and the ULOQ was 50 ng/mL. Table 3 summarizes the validation parameters for the PK
`assay. Compared to the assay used for PATANASE®, low absolute recoveries were noted for
`olapatadine, M1 and M3 (88%, 92%, 56% versus 39%, 39%, 35%), however the absolute recovery
`was also low for the internal standard (33.9%). Furthermore, the precision of the analyte and internal
`standard recovery replicates at each QC concentration were <15%, suggesting that the extraction
`process is of acceptable reproducibility. [The 2013 draft FDA Guidance on Bioanalytical Method
`Validation states that the recovery of the analyte need not be 100%, but the extent of recovery of an
`analyte and of the internal standard should be consistent, precise, and reproducible.] The
`bioanalytical report stated that all reported data were from analytical runs that met all applicable
`
`
`
`Reference ID: 3644206
`
`5
`
`

`

`validation acceptance criteria, and that the validation data demonstrate the adequacy of the PK assay
`for routine use in the measurement of plasma concentrations of olapatadine and its metabolites.
`
`
`Table 3. Original Validation Parameters for Olapatadine and its N-oxide and Mono-desmethyl Metabolites in
`Human K2EDTA Plasma by HPLC/MS/MS/MS
`olapatadine
`M1 (N-desmethyl)
`0.05 ng/mL
`0.05 ng/mL
`50 ng/mL
`50 ng/mL
`
`
`-3.10 to 2.40
`-2.30 to 2.00
`-3.40 to 2.00
`-2.33 to 2.00
`
`
`1.62 to 5.75
`1.56 to 7.52
`1.22 to 8.84
`1.85 to 17.15
`
`
`38.9
`38.8
`83.1
`81.6
`
`
`
`
`M3 (N-oxide)
`0.05 ng/mL
`50 ng/mL
`
`-3.56 to 3.00
`-5.50 to 5.40
`
`2.53 to 9.18
`1.83 to 8.69
`
`34.7
`83.6
`
`
`
`
`
`
`
`
`
`-6.67 to 6.67
`-8.67
`0.67
`6.10 to 9.29
`6.33
`8.21
`10 Lots of Blank Matrix: No significant interferences (> % of the mean LLOQ
`response or > % of the mean internal standard response) were found at the retention
`times of the analytes of interest.
`No samples had % hemolysis.
`None was detected at > % of the LLOQ response for all analytes of interest
`
` 5
`
`
`hours
` hours
`
`hour
`
`
`hours
`372 days
`372 days
`
`Validation Parameter
`LLOQ
`ULOQ
`Accuracy (%CV)
`Inter-day
`Intra-day
`Precision (%CV)
`Inter-day
`Intra-day
`Recovery of Analyte (%)
`Absolute
`Relative
`Recovery of IS (%)
`Absolute
`Relative
`Reproducibility of Matrix Effects
`Accuracy (% Bias)
`Precision (%CV)
`Specificity against endogenous
`interferences
`
`Hemolysis Interference
`Injection carry-over
`Stability
`Freeze-Thaw Cycles
`Short-Term, RT
`Reinjection (Autosampler), RT
`Sample Processing, RT
`(after extraction prior to
`reconstitution)
`Post-Preparative, RT
`Long-Term Matrix,-70°C
` Long-Term Matrix,-20°C
`
`RT (room temperature); IS (Internal Standard)
`
`
`III. Detailed Labeling Recommendations
`Below are the reviewer’s recommended labeling edits (added text = underscore; deleted text =
`strikethrough).
`
`12.3 Pharmacokinetics
`In healthy subjects,
`once daily for 7 days into both eyes
`
` topical ocular dosing of 1 drop of
`
` PAZEO®
`
`
` resulted in mean ± SD (range) steady state plasma
` of 1.6 ± 0.9 ng/mL (0.6 to 4.5 ng/mL) and 9.7 ±
`olapatadine Cmax and AUC0-12
`4.4 ng*h/mL (3.7 to 21.2 ng*h/mL), respectively. The olapatadine 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 olapatadine after repeated topical ocular dosing with PAZEO®.
` The median (range) time to achieve peak olapatadine concentrations (Tmax) was
`
`
`
`Reference ID: 3644206
`
`6
`
`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b)
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`(b)
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`(b) (4)
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`(b)
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`(b)
`(4)
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`(b)
`(4)
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`

`

`2.0 hours (0.25 to 4 hours)
`
`
`The mean ± SD (range) elimination half-life of
`olapatadine was 3.4 ± 1.2 hours (2 to 8 hours). N-oxide olapatadine (M3) was 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 olapatadine (M1) concentrations that
` were
`above the lower limit of quantitation (0.05 ng/mL) of the PK assay,
`.
`
`
`
`
`
`Reference ID: 3644206
`
`7
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`GERLIE GIESER
`10/16/2014
`
`PHILIP M COLANGELO
`10/16/2014
`
`Reference ID: 3644206
`
`

`

` Office of Clinical Pharmacology
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`New Drug Application Filing and Review Farm
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`General Information About the Submission
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`cell stabilizer
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`OCP Reviewer
`Gerlie Gieser, PhD
`lndication(s)
`For treatment of ocular itching
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`associated with allergic '
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`0 hthalmic solution 0.77%)
`OCP Team Leader
`Phili Colanoelo, PharmD, PhD
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`one drop in each affected eye
`Pharmacometrics Reviewer
`Dosing Regimen
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`once dail
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`Date of Submission
`Route of Administration
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`Alcon Research Ltd
`Estimated Due Date of OCP Review
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`Medical Division Due Date
`Priori Classification
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`Clin. Pharm. and Biopharm. Information
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`“X” if included
`Number of
`Critical Comments If any
`Number of
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`at filing
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`File name: 5_Clinical Pharmacology and Biopharmaceutics Filing Form/Checklist for
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`NDA_BLA or Supplement 090808
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`Reference ID: 3625772
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`Reference ID: 3705748
`Reference ID: 3705748
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`:
`ethnicit
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`7ender:
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`ediatrics:
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`eriatrics:
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`renal im-airment:
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`he-atic imainnent:
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`Phase 2:
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`Phase 3:
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`PK/PD -
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`Phase 1 and/or 2, roof of concet:
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`Phase 3 clinical trial:
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`Po - ulation Anal ses -
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`Data rich:
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`Data sarse:
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`II. Bio - harmaceutics
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`Absolute bioavailabilit
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`Relative bioavailabili
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`solution as reference:
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`alternate formulation as reference:
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`Bioe- uivalence studies -
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`traditional desi n; sin rle / multi dose:
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`relicate desi n; sin yle/ multi dose:
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`Food-dru interaction studies
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`Bio-waiver re I uest based on BCS —
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`BCS class
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`dose—dum - in_
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`_———
`III. Other CPB Studies
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`Geno He/heno
`-estudies ——_—
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`Chrono - harmacokinetics ————
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`Pediatric development plan
`peds 2 2 years included in
`X
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`safe
`trial
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`—————
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`Total Number ofStudies
`5‘. -- 1 PK study (HVs) + 4 clinical
`trials
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`On initial review of the NDA/BLA application for filing:
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`Criteria for Refusal to File RTF
`_—
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`Has the applicant submitted
`1
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`bioequivalence data comparing to-be-
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`marketed product(s) and those used in the
`ivotal clinical trials?
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`Has the applicant provided metabolism
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`and drug-drug interaction information?
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`Not a NME. Sponsor attempted to
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`quantify metabolites in the completed
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`PK study. For reference, additional
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`ADME info available for API after
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`topical ocular, intranasal, and oral
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`administration (PATADAY®,
`PATANASE® USPIs
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`Systemic PK in HVs after repeated
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`toical ocular admin.
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`Did the sonsor submit data to allow the ---
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`3
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`Has the sponsor submitted bioavailability
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`data satisf in 1 the CFR reuirements?
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`File name: 5_Clinical Pharmacology and Biopharmaceutics Filing Form/Checklist for
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`NDA_BLA or Supplement 090808
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`Reference ID: 3625772
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`Reference ID: 3705748
`Reference ID: 3705748
`
`

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`trials
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`II—I _assa ‘7
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`submitted?
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`Is the clinical pharmacology and
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`biopharmaceutics section of the NDA
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`organized, indexed and paginated in a
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`manner to allow substantive review to
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`Is the clinical pharmacology and
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`biopharmaceutics section of the NDA
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`legible so that a substantive review can
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`Are the data sets, as requested during pre—
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`submission discussions, submitted in the
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`Systemic exposure not relevant to
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`efficacy; relative BA of topical ocular
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`vs oral/intranasal to be considered for
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`s stemic safet assessment
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`Active comparators in two Ph3 trials
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`contain lower strengths (0. 2% and
`attempt to determine reasonable dose
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`individualization strategies for this product
`0.1%) of the API
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`(i.e ,appropriately designed and analyzed
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`dose-rang
`ivotal studies ?
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`Are the appropriate exposure-response (for
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`desired and undesired effects) analyses
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`conducted and submitted as described in
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`the Exosure-Res onse ; idance?
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`Is there an adequate attempt by the
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`applicant to use exposure-response
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`relationships in order to assess the need for
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`dose adjustments for intrinsic/extrinsic
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`factors that might affect the
`harmacokinetic or harmacod namics?
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`Are the pediatric exclusivity studies
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`adequately designed to demonstrate
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`effectiveness, if the drug is indeed
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`effective?
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`16 Did the applicant submit all the pediatric
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`exclusivit data, as described in the WR?
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`Is there adeuate information on the ---_
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`X
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`File name: 5_Clinical Pharmacology and Biopharmaceutics Filing Form/Checklist for
`
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`
`
`NDA_BLA or Supplement 090808
`Reference ID: 3625772
`
`
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`
`
`Reference ID: 3705748
`Reference ID: 3705748
`
`

`

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`pharmacokinetics and exposure-response
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`in the clinical pharmacology section of the
`label?
`'
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`submission?
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`18 Are the clinical pharmacology and
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`biopharrnaceutics studies of appropriate
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`design and breadth of investigation to meet
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`basic requirements for approvability of this
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`Was the translation (of study reports or
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`other study information) from another
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`language needed and provided in this
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`IS THE CLINICAL PHARMACOLOGY SECTION OF THE APPLICATION FILEABLE?
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`YES
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`If the NDA/BLA is not fileable from the clinical pharmacology perspective, state the reasons and provide
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`comments to be sent to the Applicant.
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`Please identify and list any potential review issues to be forwarded to the Applicant for the 74-day letter.
`NONE
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`Gerlie Gieser, PhD
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`Reviewing Clinical Pharmacologist
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`Philip Colangelo, PharmD, PhD
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`Team Leader/Supervisor
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`03 September 2014
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`Date
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`Date
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`File name: 5_Clinical Pharmacology and Biopharmaceutics Filing Form/Checklist for
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`NDA_BLA or Supplement 090808
`Reference ID: 3625772
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`Reference ID: 3705748
`Reference ID: 3705748
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`This is a representation of an electronic reco