CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`202514Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`

`

`NDA 202514 ZioptanTM (tafluprost ophthalmic solution) 0.0015%
`Proposed indication: reduction of elevated intraocular pressure in open-angle glaucoma or ocular hypertension
`
`Summary Review for Regulatory Action #2
`
`
`Date
`See electronic stamp date
`From
`Renata Albrecht, MD
`Division of Transplant and Ophthalmology Productsl
`
`Division Director Summary Review
`Subject
`NDA Number
`NDA 202514
`
`IND 62,690 (MK-2452)
`Related IND
`
`Applicant Name
`Merck Sharpe & Dohme Corp. (Merck)
`AmplicationTe
`505 n
`1
`Date of Ori_ ' : a1 Submission
`Jan .
`
`7, 2011 standard review
`
`Com n lete Res I onse Letter
`
`November 7, 2011
`
`Janumy 13, 2012
`
`January 23, 2012
`Amendment - labelin_
`
`PDUFA Goal Date
`March hid 2012
`Proprietary Name /
`Zioptan
`Established
`S .
`Taflu rost o hthahnic solution
`
`Name
`
`Dosage Form
`Dosage Strength
`Preservative
`
`Sterile ophthahnic solution
`0.0015% (15 micrograms/mL)
`Preservative free
`
`Route of Administration
`Dose
`
`Topical
`One drop in affected eye or eyes once daily in the
`
`reduction of elevated intraocular pressure in open—angle
`. laucoma or ocular h pertension
`
`How Supplied
`
`
`
`Foil pouch containing strip of 10 single-use LDPE_ ampoule, containing0.3 mLclearsolution
`
`Recommended Action
`
`Approval
`
`this resubmission
`
`U 0 date Review
`
`CDTL Review
`
`Product Quality Microbiology
`Review
`
`Bill Boyd, Wiley Chambers 2/ 1/2012
`Wile Chambers, 2/1/2021
`
`Jessica Cole, John Metcalfe 1/18/2012
`
`Product 0 uali 0ND 0A Review Maotan Zhou, Ra ti Madurawe 1/31/2012
`
`DMEPA — Pro n.riet Name
`
`Jun Lee, Carol Holtuist 2/9/2012
`
`l The Office ofAntimicrobial Products was reorganized efl‘ective May 2011: specifically the Division of Special
`Pathogen and Transplant Products (DSPTP) and Difision of Anti-Infective and Ophthahnology Products
`(DAIOP) were reorganized into the Division of Transplant and Ophthalmology Products (DTOP) and the
`Division of Anti-Infective Products (DAIP).
`
`Reference ID: 3085836
`
`

`

`NDA 202514 ZioptanTM (tafluprost ophthalmic solution) 0.0015%
`Proposed indication: reduction of elevated intraocular pressure in open-angle glaucoma or ocular hypertension
`
`Table of Contents:
`Table of Contents: ................................................................................................... 2
`1. Summary and Recommendations .................................................................... 3
`1.1 Deficiencies: ..................................................................................................................... 3
`1.2 Post-Marketing Studies: .................................................................................................... 3
`1.3 Other Issues ........................................................................................................................ 3
`2. Background ...................................................................................................... 3
`3. CMC/Product Quality Microbiology ............................................................... 4
`3.1 Product Quality Microbiology Sterility Deficiencies: ....................................................... 4
`4. Nonclinical Pharmacology/Toxicology ........................................................... 5
`5. Clinical Pharmacology/Biopharmaceutics ....................................................... 5
`6. Clinical Microbiology/Immunology ................................................................ 5
`7. Clinical/Statistical-Efficacy ............................................................................. 5
`8. Safety ............................................................................................................... 5
`9. Advisory Committee Meeting ......................................................................... 6
`10.
`Pediatrics ...................................................................................................... 7
`11. Other Relevant Regulatory Issues ................................................................ 7
`12. Labeling ........................................................................................................ 7
`13. Decision/Action/Risk Benefit Assessment ................................................... 8
`13.1 Regulatory Action ........................................................................................................... 8
`13.2 Risk Benefit Assessment................................................................................................. 8
`13.3 Recommendation for Postmarketing Requirements (PMR) and Commitments (PMC) 8
`
`
`Reference ID: 3085836
`
`2
`
`

`

`NDA 202514 ZioptanTM (tafluprost ophthalmic solution) 0.0015%
`Proposed indication: reduction of elevated intraocular pressure in open-angle glaucoma or ocular hypertension
`
`1. Summary and Recommendations
`Based on the review of the January 13, 2012, resubmission of NDA 202514, the applicant has
`addressed the manufacturing deficiencies outlined in the Complete Response letter dated
`November 7, 2011, submitted a safety update and resubmitted labeling including a new
`statement in the package insert that the date when the foil package is opened should be written
`on the package. Therefore, I agree with the reviewers that the application should be issued an
`Approval letter.
`
`For a complete summary of the findings during the previous review cycle and this review
`cycle, the Action package, including primary, secondary and tertiary reviews should be
`consulted.
`
`This review briefly summarizes the information in the January 13, 2012, resubmission and
`review team recommendations.
`
`1.1 Deficiencies:
`None
`(m4) deficiency resolved in this resubmission)
`
`1.2 Post-Marketing Studies:
`None
`
`1.3 Other Issues
`
`None
`
`2. Background
`Zioptan (tafluprost ophthahnic solution) 0.0015% is a prostaglandin F2a analogue indicated
`for the reduction of elevated intraocular pressure GOP) in open-angle glaucoma or ocular
`hypertension in adult patients. The dosing regimen is 1 drop of tafluprost solution in the
`conjunctiva] sac given once daily in the evening in the affected eye or eyes. The product to-
`be—marketed is a preservative free (PF 1, sterile, clear solution supplied in single-dose ampules.
`Phase 3 clinical trials included both the PF and preservative-containing (PC) formulations; the
`preservative is benzalkonium chloride. The efficacy of this new molecular entity was
`demonstrated in two Phase 3 clinical trials (Study 15-003 and 001) conducted in the US and
`Europe comparing tafluprost to timolol, along with a bridging trial (Study 77550) comparing
`the PF and preservative—containing formulations. Other Phase 1, 2 and 3 studies conducted
`during development were also included in the application.
`
`A Complete Response letter was issued November 7, 2011, because the application did not
`provide adequate assurance of sterility of the final drug product. To address this deficiency, the
`applicant has performed three consecutive
`(m4) runs consistent with the
`recommendations in the
`
`m"
`
`Reference ID: 3085836
`
`

`

`NDA 202514 ZioptanTM (tafluprost ophthalmic solution) 0.0015%
`Proposed indication: reduction of elevated intraocular pressure in open-angle glaucoma or ocular hypertension
`
`
`
`The applicant conducted this testing in collaborationwith_ and submitted
`results of the testing on January 13, 2012. A class 1 resubm1ss10n was requested and granted.
`
`3. CMCIProduct Quality Microbiology
`
`3.1 Product Quality Microbiology Sterility Deficiencies:
`
`The November 7, 2012, Complete Response letter stated that the “NDA does not provide
`assurance of the sterility of the final drug product,” and further noted that although Merck had
`revised the
`rocessin validation rotocol in the NDA submission of October 27, 2011,
`
`filling procedures using this revised
`
`
`results, FDA cannot determine that the product is
`validation protocol. Without the
`sterile and safe for use.
`
`To address this deficiency, Merck was asked to rovide a report describing three consecutive
`
`successful- processing simulationsi that will be used to manufacture
`the product using the inspection and accounting procedures provided in the revised-
`processing validation protocol submitted in the October 27, 2011, amendment.
`
`The January 13, 2012, resubmission included the results of the 3- simulating
`processing, batches 10019, 10020 and 10021, which are summarized in the table below from
`Dr Cole’s review. The acce tance criteria
`
`
`umts teste were negatlve. Dr. Cole
`
`concluded that the results are acceptable
`
`Batch
`Number
`
`Mfg.
`Dale
`
`
`
`l0019
`10020
`l002l
`
`20Nov20l I
`22Nov201 l
`24Nov20| |
`
`In his Deputy Director Review, Dr. Chambers writes that he disagreed with the requirement
`for the company to conduct the three- requested because it does not appear to be one
`
`Reference ID: 3085836
`
`

`

`NDA 202514 ZioptanTM (tafluprost ophthalmic solution) 0.0015%
`Proposed indication: reduction of elevated intraocular pressure in open-angle glaucoma or ocular hypertension
`
`of the reasons to not approve an application listed in 21 CFR 314.125. However Dr. Hussong,
`Associate Director for New Drug Nlicrobiology, our experts in the area of Product Quality
`Microbiology and Sterility in OPS, wrote in his review that complete validation of the
`(m4)
`processing is critical to sterility assurance. Per 21 CFR 200.50, ophthalmic products are
`required to be sterile. Therefore the applicant was asked to address the outstanding deficiency
`of inadequate assurance of sterility of the final drug product in the November 7, 2011,
`Complete Response letter. This issue was discussed in detail prior to the final action and is
`also discussed in the Division Director’s Review and the Office Director’s Memorandum.
`
`Comment:
`(but) are necessarv to
`Given that ophthalmic products are required to be sterile,
`validate the
`(m4) processing to ensure sterility ofthe drugproduct, I agree with Dr.
`Hussong ’s recommendation
`(we) be available before approvalfor
`tafluprost, which is incidentally a preservative-free product. Merck has conducted and
`submitted the 3
`a”). This information provides adequate assurance ofsterilityfor the
`final drugproduct. Tthe application is now recommendedfor approvalfrom the Product
`Quality, including Quality Microbiologv, perspective.
`
`4. Nonclinical Pharmacology/Toxicology
`No new information submitted
`
`5. Clinical Pharmacology/Biopharmaceutics
`No new information submitted
`
`6. Clinical Microbiology/Immunology
`Not applicable.
`
`7. ClinicallStatistical-Efficacy
`No new information submitted
`
`8. Safety
`
`The November 7, 2011, Complete Response letter requested that Merck submit a Safety
`Update as described at 21 CFR 314.50(d)(5)(vi)(b). The safety update should include data
`from all non-clinical and clinical studies/trials of the drug under consideration regardless of
`indication, dosage form, or dose level.
`
`In response to the request for a safety update, Merck noted that :
`
`There are no ongoing or completed studies that were sponsored by Merck during the
`reporting period for this SUR (March 2, 2011 to November 7, 2011).
`
`Safety data from a total of 6 new studies sponsored by our development partner,
`
`(we)
`
`safety data from 2 ongoing post-marketing safety surveillance studies sponsored by
`
`In addition,
`
`Reference ID: 3085836
`
`

`

`NDA 202514 ZioptanTM (tafluprost ophthalmic solution) 0.0015%
`Proposed indication: reduction of elevated intraocular pressure in open-angle glaucoma or ocular hypertension
`
`Santen for preservative containing tafluprost in Japan and Korea are also included.
`Lastly, the final Clinical Study Report for the
` study for tafluprost
`that was not available for submission in the previous SUR in May 2011 is being
`submitted in this SUR. It should be noted that the safety data from this study were
`previously discussed in detail and submitted in the May 2011 SUR. The Safety Update
`Report (SUR) is being submitted in accordance with Merck’s SUR proposal submitted
`to the FDA on December 7, 2011. There were no non-clinical studies that were either
`ongoing or completed during the reporting period for this SUR.”
`
`Merck further notes that of the nine studies, five studies are ongoing double masked
`studies
` of tafluprost and timolol. Two of the remaining studies
`are ongoing open labeled, observational, post marketing, safety surveillance studies for
`tafluprost, while one is an open labeled long term safety study
`
` with approximately 42 patients exposed to tafluprost monotherapy for 4
`weeks during the open labeled randomization phase. The remaining study
`
` study for tafluprost) was previously discussed in detail in the May 2011
`SUR and the safety data were previously submitted to the FDA. Only the final Clinical
`Study Report for the
` study that was not available for submission in
`May 2011 is being submitted in this SUR.
`
`
`The information in the Safety Update Report (SUR) was reviewed by Dr. Boyd whose review
`includes a tabular presentation of the studies mentioned above as well as brief summaries of the
`available information from these ongoing studies. Based on his assessment of the information
`provided from the studies, he agrees that the findings are comparable to those seen in the original
`NDA and first safety update. No further labeling recommendations are needed based on the
`information included in the safety update.
`
`Comment:
`The adverse events reported in the safety update for this resubmission do not identify new
`safety signals and the no labeling revisions are needed based on the information from the
`safety update. The application is recommended for approval.
`9. Advisory Committee Meeting
`ZIOPTAN was not referred to an FDA advisory committee because it is a member of the class
`of ophthalmic prostaglandin analogs with similar potential risks and benefits as other members
`in this class. The benefits and risks of using prostaglandin analogs to treat elevated intraocular
`pressure have been previously discussed at a meeting of the Dermatologic and Ophthalmic
`Drugs Advisory Committee on December 8, 1995, and the safety profile of tafluprost did not
`raise any new significant safety issues. The clinical design including endpoints of the adequate
`and well-controlled studies was similar to other approved drugs in this class and we are not
`aware of any controversial issues that would benefit from further advisory committee
`discussion.
`
`
`Reference ID: 3085836
`
`6
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 202514 ZioptanTM (tafluprost ophthalmic solution) 0.0015%
`Proposed indication: reduction of elevated intraocular pressure in open-angle glaucoma or ocular hypertension
`10. Pediatrics
`A waiver was granted during previous review cycle for this indication, because necessary
`studies are impossible or highly impracticable to conduct as there are too few children with
`this disease/condition to study.
`11. Other Relevant Regulatory Issues
`No new information submitted
`12. Labeling
`The package insert, patient package insert, and carton and container labeling were reviewed as
`applicable by the Division, DMEPA, DDMAC and the patient labeling group (now part of the
`Office of Medical Policy). The carton and container labels sent November 4, 2011, and the
`package insert and patient package insert sent January 23, 2012, incorporate all the requested
`revisions and are acceptable for approval.
`
` •
`
` Package insert (PI): The PI is written in PLR format and has been reviewed by all
`groups, and includes the recommendations made by these groups. DMEPA recommended
`deleting language that the single-use ampoule is sufficient to treat both eyes to avoid
`inappropriate use and saving the opened ampoule for future doses and risking bacterial
`contamination. A statement “discard unused portion” is recommended for this product
`containing no preservative. Additional comments regarding formatting and font size,
`bolding, color, and graphics were made. DDMAC’s comments were also incorporated.
`
`Under Section 16 How Supplied/Storage and Handling, the following sentence was
`added, “Write down the date you open the foil pouch in the space provided on the
`pouch. Discard any unused containers 28 days after first opening the pouch.”
`
`Comment:
`This language is acceptable and needed in the PI because Merck and OMP agreed that
`language telling patients to write the date they open the package is appropriate and
`should be in the patient package insert. Therefore, this information also needs to be
`included in the PI, which includes the statement, “Write down the date you open the
`foil pouch in the space provided on the pouch” under Instructions for Use to the
`patient and “Write down the date the pouch is opened here: ___________” on the
`pouch itself. Of note, similar language was included by Merck for Cosopt PF, a
`dorzolamide/timolol fixed combination product, for reduction of IOP approved on
`February 1, 2012.
`
`
`
` •
`
` •
`
`
`
` Patient package Insert (PPI): The PI is submitted with the original application was
`revised to remove promotional, incorrect and misleading language, reviewed by OMP
`patient package labeling group and DDMAC.
`
` Carton and Container Labels: The labels were reviewed by CMC and DMEPA.
`
`
`Reference ID: 3085836
`
`7
`
`

`

`NDA 202514 ZioptanTM (tafluprost ophthalmic solution) 0.0015%
`Proposed indication: reduction of elevated intraocular pressure in open-angle glaucoma or ocular hypertension
`
`Merck submitted carton and container labels on November 4, 2011, for the commercial
`presentation for 30 single-use containers (packaged as 3 pouches x 10 single-use
`containers), and a commercial presentation for 90 single-use containers (packaged as 9
`pouches x 10 single-use containers), as well as a professional sample containing one
`pouch x 10 single-use containers.
`
` •
`
` Proprietary Name: The applicant’s initial proposed proprietary name of Saflutan was
`unacceptable because of its similarity to Xalatan and the applicant was sent a letter on
`April 15, 2011. The subsequent proposed proprietary name Zioptan was reviewed and
`found acceptable from the safety and promotional perspective by DMEPA on August 31,
`2011, and a letter stating that the name is acceptable was issued by Dr. Holquist of
`DMEPA on October 31, 2011. The proposed proprietary name was re-reviewed following
`this re-submission and found to be acceptable on February 9, 2012.
`13. Decision/Action/Risk Benefit Assessment
`13.1 Regulatory Action
`The application is recommended for Approval as the deficiency from the Complete Response
`letter of November 7, 2011 have been addressed.
`
`13.2 Risk Benefit Assessment
`As noted in prior reviews from the original review cycle, two Phase 3 studies demonstrated
`that Zioptan is effective in the reduction of IOP in patients with open-angle glaucoma and
`ocular hypertension, by meeting their pre-specified NI margin, and a bridging study
`demonstrated that the PC and PF formulations had similar efficacy.
`
`The safety profile of tafluoprost is consistent with the adverse reactions previously identified
`for this class including pigmentary changes and some ocular irritation and toxicity; these
`findings are addressed in labeling and are similar to other products in the class.
`
`The product is preservative free, however, no specific benefits were included as endpoints in
`the study, nor were any particular compliance, efficacy, or safety differences in terms of
`advantages noted for the PF versus the PC product. Because there is not preservative included,
`the instructions will state that the product is for single use and any unused portion should be
`discarded.
`
`The patient package insert has been reviewed by the Office of Medical Policy and provides
`information on the product and its use in patient-friendly language and includes pictorial
`directions on how the product should be used.
`
`13.3 Recommendation for Postmarketing Requirements (PMR) and Commitments
`(PMC)
`None
`
`
`
`Reference ID: 3085836
`
`8
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`02/10/2012
`
`EDWARD M COX
`02/10/2012
`
`Reference ID: 3085836
`
`

`

`Deputy Division Director Review of NDA 202-514
`(Amended Application after Complete Response Letter)
`
`Review Date
`1, 2012
`Feb
`From
`Wiley A. Chambers, M.D.
`202514
`NDA #
`
`Merck Sh o & Dohme Co .
`A licant
`
`Date of Original Submission
`January 7, 2011
`Date of Amendment
`Jan .
`13, 2012
`
`Recommended:
`
`TpueofAlication
`Name
`
`Dosa _e forms / Stren_ h
`Proposed Indication(s)
`
`1
`505 0
`Zio tan taflurost o hthalmic solution 0.0015%
`
`To u ical o hthahnic solution
`Reduction of elevated intraocular pressure in patients with
`o o en—an 1e ‘laucoma or ocular h ‘0 efiension
`Recommended for A. oroval
`
`l. Introduction/Background
`
`Tafluprost (AFP-l68, MK—2452) is a new chemical entity drug product proposed for the reduction of
`elevated intraocular pressure GOP) in open—angle glaucoma or ocular hypertension. It is an ester
`prodrug of a synthetic prostaglandin F201 (PGFZu) analog that is converted in vivo into the
`pharmacologically active tafluprost acid. Tafluprost 0.0015% preservative free (PF) and preservative
`containing (PC) have been approved for reducing of elevated IOP in open angle glaucoma and ocular
`hypertension in a number of countries including Austria, Germany, Czech Rep, Denmark, Finland,
`Norway, Poland, Sweden, Iceland, Italy, Spain, Portugal, the Netherlands, Romania, Bulgaria, Estonia,
`Latvia, Lithuania, Slovak Rep, United Kingdom, Russia, Ukraine, Armenia, Georgia, Kazakhstan,
`Kyrgyzstan, Moldova, Uzbekistan, Japan, Korea, Hong Kong, and Indonesia. Tafluprost has not been
`marketed in the United States.
`
`2. CMC
`
`HQ
`
`-
`HO
`
`0
`\ MW 7/
`/
`0
`F F//L\
`V'
`
`The drug substance, tafluprost, is a colorless to light yellow viscous liquid, with a molecular formula
`of C25H34F205 and a molecular weight of 453.53 Daltons. Tafluprost is manufactured, packaged, and
`stability-tested at
`a”). The information on manufacturing processes and
`controls for tafluprost is described in
`(I'm DMF
`(5)“). All chemistry issues have been resolved.
`
`The drug product, tafluprost 0.0015% ophthahnic solution is a sterile aqueous isotonic solution that
`contains tafluprost, sodium dihydrogen phosphate dihydrate, polysorbate 80, disodium edetate,
`glycerol, sodium hydroxide and/or hydrochloric acid to adjust to pH 5.5—6.7, and water for injection.
`
`Reference ID: 3081063
`
`

`

`Deputy Division Director Summary Review
`Wiley A. Chambers. M.D.
`NDA 202514 Zioptan (tafluprost ophthalmic solution) 0.0015%
`
`Page: 2
`
`Glycerol is used
`
`(m4) of the drug product. The drug product solution is manufactured,
`(m4) by Laboratoire Unither, France.
`M0
`
`(hm) pouches, 10
`The ampoules are packed
`ampoules per pouch. Commercial cartons are either 30-count (3 pouches) or 90-count (9 pouches) and
`sample cartons are 10-count (1 pouch).
`
`COMPOSITION OF THE DRUG PRODUCT (mg per mL)
`Tafluprost
`0.0015
`Glycerol
`Sodium dihydrogen phosphate dehydrate
`Disodium edentate
`
`(b) (4)
`
`Adjust pH
`q.s.
`
`Clear. colorless solution. Practically free from visible particles
`Match reference standard
`
`5.5-6.7
`
`260-300 mOsm/kg
`
`Polysorbate 80
`NaOH/HCl
`Water for injection
`
`Re ato Secifications:
`
`A earance
`
`Taflu rost identification/HPLC , UV
`H
`
`Osmolali
`
`Impurities
`
`Taflu rost Assa
`
`Sterili
`
`Endotoxin
`
`Particulate Matter (light
`obscuration/microscopy)
`
`(we)
`Ophthalmic drug product specifications normally include a limit on unspecified impurities at
`. The exceptions in recent years have been with products in which the
`concentration of the active ingredient is less than
`«our These exception products have had
`specifications for unspecified impurities listed as
`(hm instead of a percent of the active
`ingredient. While it would have been preferable to list this specification
`M0, the
`current proposed specification is acceptable because the concentration of the active ingredient is less
`than
`(5)(4)
`
`(I!) (4)
`
`While it would be preferable to use the entire specification, the failure to include the full specification
`is not a sufficient reason by itself to not approve the product.
`
`FACILITIES INSPECTIONS:
`
`The overall recommendation from the Office of Compliance is “Acceptable” in EES.
`
`Reference ID: 3081063
`
`

`

`Deputy Division Director Summary Review
`Wiley A. Chambers, M.D.
`NDA 202514 Zioptan (tafluprost ophthalmic solution) 0.0015%
`
`3. Nonclinical Pharmacology/Toxicology
`
`
`
`Page: 3
`
`
`The active metabolite, tafluprost acid (AFP-172) is the pharmacologically active agent. In primary
`pharmacology studies, tafluprost acid (AFP-172) was shown to bind to the FP prostanoid receptor with
`subnanomolar affinity, and binding was shown to be substantially selective for this receptor.
`
`The primary safety signals in safety pharmacology studies were a low incidence of central nervous
`effects in mice and a dose-dependent increase in blood pressure, heart rate, and Qtc intervals in
`anesthetized dogs. However, the cardiovascular effects occurred only minimally in repeated-
`intravenous dose toxicology studies in dogs, and did not occur in repeated-ocular dose studies in
`monkeys. Because clinical exposures are expected to be on the order of 100 fold lower than the
`exposures associated with the high ocular doses in the monkey studies, cardiovascular toxicity is not
`expected to be a clinical concern.
`
`Ocular changes included iridial darkening, sunken eyelids, and blue-gray discoloration of the lower
`eyelid. However, all of the tafluprost-related ocular changes are consistent with ocular changes
`observed with other marketed PGF2α analogs. These effects are considered to be mainly cosmetic, not
`associated with loss of function, and not toxicologically significant. Other, more serious ocular
`toxicities including pronounced inflammation or alterations in electroretinography were not observed
`with topical ocular administration of tafluprost at any of the administered doses.
`
`Topical ocular administration of 3H-tafluprost in rats and monkeys resulted in widespread ocular
`distribution. Repeated dosing produced a similar ocular distribution pattern, and accumulation did not
`occur in any tissue other than the lens where concentrations increased approximately 50% after 21
`days of dosing.
`
`Tafluprost acid was >90% bound to serum albumin from rat, rabbit, dog and humans. Tafluprost
`demonstrated extensive tissue distribution consistent with renal and hepatobiliary excretion and limited
`CNS distribution. Tissue distribution following repeated ocular dosing was similar to that following a
`single dose indicating an absence of systemic tissue accumulation. Tafluprost administered topically to
`the eye or intravenously was excreted primarily in urine and through hepatobiliary excretion with final
`deposition in feces.
`
`3H-Tafluprost or its metabolites transferred into milk in lactating rats, and crossed the placental barrier
`in pregnant rats. Milk Cmax radioactivity levels were similar to those in plasma, and fetal exposure
`was approximately two thirds that of plasma exposure.
`
`Tafluprost was shown to be negative for genotoxicity in an in vitro bacterial reverse mutation assay, an
`in vitro chromosome aberration assay in Chinese Hamster lung cells, and an in vivo mouse bone
`marrow micronucleus assay.
`
`In both a 24-month rat carcinogenicity study and a 78-week mouse carcinogenicity study where
`tafluprost was administered subcutaneously, no unusual tumors or significantly increased tumor
`incidence suggestive of tafluprost-related carcinogenicity was observed.
`
`
`
`
`Reference ID: 3081063
`
`

`

`Deputy Division Director Summary Review
`Wiley A. Chambers, M.D.
`NDA 202514 Zioptan (tafluprost ophthalmic solution) 0.0015%
`
`4. Clinical Pharmacology/Biopharmaceutics
`
`
`
`Page: 4
`
`
`In four Phase 1 dose-escalation studies (74450, 74451, 74452, and 74453), neither tafluprost nor
`tafluprost acid could be detected when using a bioanalytical method (HPLC/MS/MS) with LLOQ at
`0.2 ng/mL (tafluprost) and 0.1 ng/mL (tafluprost acid). One confounding factor is that the plasma
`samples may have not been stored properly in some of these studies to ensure adequate sample
`stability. In a subsequent Study 15005, systemic exposure following topical ocular administration of
`0.0015% tafluprost ophthalmic solution was successfully assessed using an improved analytical
`method (HPLC/MS/MS)with LLOQ at 10 pg/mL (tafluprost acid). Furthermore, Study 77551 was
`conducted to verify if the systemic bioavailability of tafluprost in humans after topical ocular q.d.
`administration of either tafluprost (0.0015%) PF or PC ophthalmic solution is similar.
`
`
`5. Sterility Assurance
`
`
`This is a non-preserved aqueous solution that is sterile
`containers
`.
`
`
` filled into single-use
`
` prior to approval because it does
`I disagreed with requirement to conduct three additional
`not appear to be one of the reasons to not approve an application listed in 21 CFR 314.125. The
`
`
`
`Reference ID: 3081063
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Deputy Division Director Summary Review
`WileyA. Chambers, M.D.
`NDA 202514 Zioptan (tafluprost ophthalmic solution) 0.0015%
`
`Page: 5
`
`applicant had amended their procedures to provide an acceptable procedure. The application received
`
`letter with a request for data fiom 3 consecutive- processing sirm11ations I
`
`using the revised validation protocol submitted to the agency on October 27, 2011.
`
`batches 10019, 10020, and 10021 were manufactured
`tel and batch 10019 had a
`
`
`
`The revised- procedures were summarized in Module 3.5.5.2 and were consistent with data
`
`reviewed for the Product
`' Microbiolo Reviews #1 and #2.
`ules were filled
`
`Wltll
`
`Reference ID: 3081063
`
`

`

`Deputy Division Director Summary Review
`Wiley A. Chambers, M.D.
`NDA 202514 Zioptan (tafluprost ophthalmic solution) 0.0015%
`
`Page: 6
`
`6. Clinical/Statistical - Efficacy
`
`Analyses of Endpoints
`The primary efficacy variable utilized in the review of this NDA is mean IOP at each time point
`measured.
`
`Mean IOP (Studies 001,15-003 and 74458)
`
`27.0
`
`25.0
`
`23.0
`
`21.0
`
`19.0
`
`17.0
`
`mmHg
`
`
`
`-m
`
`m-I-m-Im-mmmm-mmmm-m-mm
`
`
`
`I-nm-I-mmmm-Imm-m-mmm-m-
`
`Ian-Ia:--m--m-mmmm-mmmm-m-mmm
`
`
`mm-E-mm-“m-m-------------
`
`—--EEIEfl-EE-IIEIIEmmmmm--------------
`
`Visit
`
`As noted in the graph above, tafluprost ophthalmic solution (preserved and non-preserved) is
`equivalent to timolol ophthalmic solution (preserved and non-preserved) in its ability to lower
`intraocular pressure. The 95% confidence intervals for IOP reduction is within the equivalence
`margins of 1.5mmHg at all timepoints and within 1 mmHg for the majority of timepoints. Tafluprost
`ophthalmic solution was not demonstrated to be equivalent to latanoprost ophthalmic solution. The
`data support Zioptan (tafluprost ophthalmic solution) 0.0015% administered once daily in the evening
`for reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular
`hypertension.
`
`Reference ID: 3081063
`
`

`

`Deputy Division Director Summary Review
`Wiley A. Chambers. M.D.
`NDA 202514 Zioptan (tafluprost ophthalmic solution) 0.0015%
`
`Page: 7
`
`7. Safety
`
`Five studies are used to support the safety and efficacy of tafluprost. The patient exposure and safety
`assessments were adequate.
`
`Exposure to Study Drug by Protocol
`
`___“mifl-
`
`——-_—-_
`___“—
`74458 ___—
`___——
`
`Serious Adverse Events occurring in more than 1 patient
`
`(Studies 001, 15-002, 15-003, 74457, 74458)
`
`n=905
`
`n=543
`
`n=311
`
`"___——
`
`___—
`___
`___—
`___—
`___—
`___—
`___—
`
`Reference ID: 3081063
`
`

`

`Deputy Division Director Summary Review
`Wiley A. Chambers. M.D.
`NDA 202514 Zioptan (tafluprost ophthalmic solution) 0.0015%
`
`Page: 8
`
`The most common ocular adverse events (pooled) were conjunctiva] hyperemia (10.7%) and ocular
`stinging/irritation (7.2%). The most common nonocular adverse event was headache (5.6%).
`
`Adverse Events reported by 22% of patients from Studies 001, 15—002, 15-003, 74457, and 74458
`
`n=905
`
`n=543
`
`n=3l l
`
`
`
`Ocular nuitis
`
`44 5%
`
`11 2%
`
`5
`
`2%
`
`_m—
`
`——-._--_
`
`_mfi—z-I-
`_—n_—n-
`
`—-._-.-_
`
`_II-m
`_fll—----_
`
`Safety Update
`Merck submitted a Safety Update Report (SUR) in the response for the reporting period of March 2,
`2011, to November 7, 2011. The safety data was reported to be consistent with information submitted
`in the original NDA. Merck reported that there were no ongoing clinical studies for t