©©©ò¿®½¸·ª»ò±®¹
`ìïëòëêïòêéêé
`ìïëòèìðóðíçï »óº¿¨
`
`ײ¬»®²»¬ ß®½¸·ª»
`íðð Ú«²­¬±² ߪ»²«»
`Í¿² Ú®¿²½·­½±ô Ýß çìïïè
`ÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁ
`
`ßÚÚ×ÜßÊ×Ì ÑÚ ÒßÌØßÒ×ÛÔ Û ÚÎßÒÕóÉØ×ÌÛ
`
`ïò
`
`× ¿³ ¿ λ½±®¼­ λ¯«»­¬ Ю±½»­­±® ¿¬ ¬¸» ײ¬»®²»¬ ß®½¸·ª»ò × ³¿µ» ¬¸·­ ¼»½´¿®¿¬·±²
`±º ³§ ±©² °»®­±²¿´ µ²±©´»¼¹»ò
`
`îò ̸» ײ¬»®²»¬ ß®½¸·ª» ·­ ¿ ©»¾­·¬» ¬¸¿¬ °®±ª·¼»­ ¿½½»­­ ¬± ¿ ¼·¹·¬¿´ ´·¾®¿®§ ±º ײ¬»®²»¬
`­·¬»­ ¿²¼ ±¬¸»® ½«´¬«®¿´ ¿®¬·º¿½¬­ ·² ¼·¹·¬¿´ º±®³ò Ô·µ» ¿ °¿°»® ´·¾®¿®§ô ©» °®±ª·¼»
`º®»» ¿½½»­­ ¬± ®»­»¿®½¸»®­ô ¸·­¬±®·¿²­ô ­½¸±´¿®­ô ¿²¼ ¬¸» ¹»²»®¿´ °«¾´·½ò ̸» ײ¬»®²»¬
`ß®½¸·ª» ¸¿­ °¿®¬²»®»¼ ©·¬¸ ¿²¼ ®»½»·ª»­ ­«°°±®¬ º®±³ ª¿®·±«­ ·²­¬·¬«¬·±²­ô
`·²½´«¼·²¹ ¬¸» Ô·¾®¿®§ ±º ݱ²¹®»­­ò
`
`íò ̸» ײ¬»®²»¬ ß®½¸·ª» ¸¿­ ½®»¿¬»¼ ¿ ­»®ª·½» µ²±©² ¿­ ¬¸» É¿§¾¿½µ Ó¿½¸·²»ò ̸»
`É¿§¾¿½µ Ó¿½¸·²» ³¿µ»­ ·¬ °±­­·¾´» ¬± ¾®±©­» ³±®» ¬¸¿² ìëð ¾·´´·±² °¿¹»­ ­¬±®»¼
`·² ¬¸» ײ¬»®²»¬ ß®½¸·ª»ù­ ©»¾ ¿®½¸·ª»ò Ê·­·¬±®­ ¬± ¬¸» É¿§¾¿½µ Ó¿½¸·²» ½¿² ­»¿®½¸
`¿®½¸·ª»­ ¾§ ËÎÔ ø·ò»òô ¿ ©»¾­·¬» ¿¼¼®»­­÷ò ׺ ¿®½¸·ª»¼ ®»½±®¼­ º±® ¿ ËÎÔ ¿®»
`¿ª¿·´¿¾´»ô ¬¸» ª·­·¬±® ©·´´ ¾» °®»­»²¬»¼ ©·¬¸ ¿ ¼·­°´¿§ ±º ¿ª¿·´¿¾´» ¼¿¬»­ò ̸» ª·­·¬±®
`³¿§ ­»´»½¬ ±²» ±º ¬¸±­» ¼¿¬»­ô ¿²¼ ¾»¹·² ¾®±©­·²¹ ¿² ¿®½¸·ª»¼ ª»®­·±² ±º ¬¸» É»¾ò
`Ô·²µ­ ±² ¿®½¸·ª»¼ º·´»­ ·² ¬¸» É¿§¾¿½µ Ó¿½¸·²» °±·²¬ ¬± ±¬¸»® ¿®½¸·ª»¼ º·´»­
`ø©¸»¬¸»® ØÌÓÔ °¿¹»­ ±® ±¬¸»® º·´» ¬§°»­÷ô ·º ¿²§ ¿®» º±«²¼ º±® ¬¸» ËÎÔ ·²¼·½¿¬»¼
`¾§ ¿ ¹·ª»² ´·²µò Ú±® ·²­¬¿²½»ô ¬¸» É¿§¾¿½µ Ó¿½¸·²» ·­ ¼»­·¹²»¼ ­«½¸ ¬¸¿¬ ©¸»² ¿
`ª·­·¬±® ½´·½µ­ ±² ¿ ¸§°»®´·²µ ±² ¿² ¿®½¸·ª»¼ °¿¹» ¬¸¿¬ °±·²¬­ ¬± ¿²±¬¸»® ËÎÔô ¬¸»
`
`½´±­»­¬ ¿ª¿·´¿¾´» ¼¿¬» ¬± ¬¸» ·²·¬·¿´ º·´» ½±²¬¿·²·²¹ ¬¸» ¸§°»®´·²µò
`
`ìò ̸» ¿®½¸·ª»¼ ¼¿¬¿ ³¿¼» ª·»©¿¾´» ¿²¼ ¾®±©­»¿¾´» ¾§ ¬¸» É¿§¾¿½µ Ó¿½¸·²» ·­
`±¾¬¿·²»¼ ¾§ «­» ±º ©»¾ ¿®½¸·ª·²¹ ­±º¬©¿®» ¬¸¿¬ ¿«¬±³¿¬·½¿´´§ ­¬±®»­ ½±°·»­ ±º º·´»­
`¿ª¿·´¿¾´» ª·¿ ¬¸» ײ¬»®²»¬ô »¿½¸ º·´» °®»­»®ª»¼ ¿­ ·¬ »¨·­¬»¼ ¿¬ ¿ °¿®¬·½«´¿® °±·²¬ ·²
`¬·³»ò
`
`ëò ̸» ײ¬»®²»¬ ß®½¸·ª» ¿­­·¹²­ ¿ ËÎÔ ±² ·¬­ ­·¬» ¬± ¬¸» ¿®½¸·ª»¼ º·´»­ ·² ¬¸» º±®³¿¬
`¸¬¬°æññ©»¾ò¿®½¸·ª»ò±®¹ñ©»¾ñÅÇ»¿® ·² §§§§ÃÅÓ±²¬¸ ·² ³³ÃÅÜ¿§ ·² ¼¼ÃÅÌ·³» ½±¼» ·²
` ̸«­ô ¬¸» »¨¬»²¼»¼ ËÎÔ
`¸¬¬°æññ©»¾ò¿®½¸·ª»ò±®¹ñ©»¾ñïççéðïîêðìëèîèñ¸¬¬°æññ©©©ò¿®½¸·ª»ò±®¹ñ ©±«´¼ ¾» ¬¸»
`ËÎÔ º±® ¬¸» ®»½±®¼ ±º ¬¸» ײ¬»®²»¬ ß®½¸·ª» ¸±³» °¿¹» ØÌÓÔ º·´»
`ø¸¬¬°æññ©©©ò¿®½¸·ª»ò±®¹ñ÷ ¿®½¸·ª»¼ ±² Ö¿²«¿®§ îêô ïççé ¿¬ ìæëè ¿ò³ò ¿²¼ îè
`­»½±²¼­ øïççéñðïñîê ¿¬ ðìæëèæîè÷ò ̸» ¼¿¬» ·²¼·½¿¬»¼ ¾§ ¿² »¨¬»²¼»¼ ËÎÔ ¿°°´·»­
`¬± ¿ °®»­»®ª»¼ ·²­¬¿²½» ±º ¿ º·´» º±® ¿ ¹·ª»² ËÎÔô ¾«¬ ²±¬ ²»½»­­¿®·´§ ¬± ¿²§ ±¬¸»®
`º·´»­ ´·²µ»¼ ¬¸»®»·²ò ̸«­ô ·² ¬¸» ½¿­» ±º ¿ °¿¹» ½±²­¬·¬«¬»¼ ¾§ ¿ °®·³¿®§ ØÌÓÔ º·´»
`¿²¼ ±¬¸»® ­»°¿®¿¬» º·´»­ ø»ò¹òô º·´»­ ©·¬¸ ·³¿¹»­ô ¿«¼·±ô ³«´¬·³»¼·¿ô ¼»­·¹²
`»´»³»²¬­ô ±® ±¬¸»® »³¾»¼¼»¼ ½±²¬»²¬÷ ´·²µ»¼ ©·¬¸·² ¬¸¿¬ °®·³¿®§ ØÌÓÔ º·´»ô ¬¸»
`°®·³¿®§ ØÌÓÔ º·´» ¿²¼ ¬¸» ±¬¸»® º·´»­ ©·´´ »¿½¸ ¸¿ª» ¬¸»·® ±©² ®»­°»½¬·ª» »¨¬»²¼»¼
`ËÎÔ­ ¿²¼ ³¿§ ²±¬ ¸¿ª» ¾»»² ¿®½¸·ª»¼ ±² ¬¸» ­¿³» ¼¿¬»­ò
`
`êò ߬¬¿½¸»¼ ¸»®»¬± ¿­ Û¨¸·¾·¬ ß ¿®» ¬®«» ¿²¼ ¿½½«®¿¬» ½±°·»­ ±º ­½®»»²­¸±¬­ ±º ¬¸»
`ײ¬»®²»¬ ß®½¸·ª»ù­ ®»½±®¼­ ±º ¬¸» ¿®½¸·ª»¼ º·´»­ º±® ¬¸» ËÎÔ­ ¿²¼ ¬¸» ¼¿¬»­ ­°»½·º·»¼
`·² ¬¸» ¿¬¬¿½¸»¼ ½±ª»®­¸»»¬ ±º »¿½¸ °®·²¬±«¬ò
`
`0001
`
`SYDNEXIS - EXHIBIT 2005
`Eyenovia, Inc. v. Sydnexis, Inc.
`IPR2022-00384, IPR2022-00414, & IPR2022-00415
`
`

`

`it
`
`7.
`Attached hereto as Exhibit B are true and accurate copies of the Internet Archive's
`éò ߬¬¿½¸»¼ ¸»®»¬± ¿­ Û¨¸·¾·¬ Þ ¿®» ¬®«» ¿²¼ ¿½½«®¿¬» ½±°·»­ ±º ¬¸» ײ¬»®²»¬ ß®½¸·ª»ù­
`records of the archived files for the URLs andthe dates specified in the attached
`®»½±®¼­ ±º ¬¸» ¿®½¸·ª»¼ º·´»­ º±® ¬¸» ËÎÔ­ ¿²¼ ¬¸» ¼¿¬»­ ­°»½·º·»¼ ·² ¬¸» ¿¬¬¿½¸»¼
`coversheetof eachfile.
`½±ª»®­¸»»¬ ±º »¿½¸ º·´»ò
`
`èò
`
`I declare under penalty of perjury under the laws of the United States of America
`× ¼»½´¿®» «²¼»® °»²¿´¬§ ±º °»®¶«®§ «²¼»® ¬¸» ´¿©­ ±º ¬¸» ˲·¬»¼ ͬ¿¬»­ ±º ß³»®·½¿
`that the foregoingis true and correct.
`¬¸¿¬ ¬¸» º±®»¹±·²¹ ·­ ¬®«» ¿²¼ ½±®®»½¬ò
`
`
`
`03/09/2022
`ðíñðçñîðîî
`DATE:
`ÜßÌÛæ ÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁ
`
`Wreapliewiel & Weeule-Whape
`ÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁÁ
`Nathaniel E Frank-White
`Ò¿¬¸¿²·»´ Û Ú®¿²µóɸ·¬»
`
`0002
`
`0002
`
`

`

`EXHIBIT A
`ÛÈØ×Þ×Ì ß
`
`0003
`
`0003
`
`

`

`https://web.archive.org/web/20170130222453/https://www.accessdata.fda.gov/scripts/cder/daf/inde
`¸¬¬°­æññ©»¾ò¿®½¸·ª»ò±®¹ñ©»¾ñîðïéðïíðîîîìëíñ¸¬¬°­æññ©©©ò¿½½»­­¼¿¬¿òº¼¿ò¹±ªñ­½®·°¬­ñ½¼»®ñ¼¿ºñ·²¼»
`x.cfm?event=overview.process&App|INo=206289
`¨ò½º³á»ª»²¬ã±ª»®ª·»©ò°®±½»­­úß°°´Ò±ãîðêîèç
`
`0004
`
`0004
`
`

`

`
`
`
`
`
`iT em iNe |[Ga|SF|htlpsi//Www.accessdata, (da.gov/senptsicder/dat/index. cl?avent=overview,process@AppINo=206289 aan APR
`
`WAYDSCHMACHN
`2cseies
`“ha”
`partment of Health and Human Sern
`
` owFDA | EnE
`
`ee
`
`Home|Food|Orugs|Medical Devices|Radiation-Emitting Products|Vaccines, Blood & Biologics|Animal & Veterinary|Cosmetics|Tobacco Products
`
`Home * Drug Databases » Drugs@FDA
`
`Drugs@FDA: FDA Approved Drug Products
`in UNKEDIN =@ PINIT 3 EMAIL|& PRINT
`
`
`
`Home | Previous Page
`
`New Drug Application (NDA): 206289
`Company: AKORN
`Drug Name(s):
`- ATROPINE SULFATE (ATROPINE SULFATE)
`
`Products on NDA 206289
`
`Approval Date(s) and History, Letters, Labels, Reviews for NDA 206289
`
`Labels for NDA 206289
`
`EMAIL
`
`w
`
`I
`
`Note: If you need help accessing information in differantfila formals, see Instructions for Downloading Viewers and Playars,
`LanguageAssistance Available: Espafiol| $486 | Tiéng Viet | ©1431 | Tagalog | Pycckwa | 44!| Kreydl Ayisyen| Frangais | Polski| Portugués| Italiano | Deutsch | 35 | —4
`| English
`
`Website Policies
`
`U.S, Food and Drug Administration
`70903 New Hampshire Avenue
`Silver Spring, MD 20993
`1-888-INFO-FDA (1-888-463-6332)
`
`Q FDAArchive
`
`A Emergency Preparedness
`
`@ Federal, State & Local Officials
`
`+ Combination Products
`
`@ Intemational Programs
`
`i Consumers
`
`Accessibility
`
`Lee]t-1bd
`
`OPWble)
`
`ae)
`
`No FEAR Act Tey
`
`Preterea UTE
`
`fetea aay.)
`
`$B Advisory Committees
`
`fit) News & Events
`
`=
`oOG8oS
`
`4, Regulatory Information
`@ Salety
`
`#&Training & Continuing Education
`© Inspections & Compliance
`
`© Health Professionals
`
`4 Science & Research
`# Industry
`
`0005
`
`0005
`
`

`

`EXHIBIT B
`ÛÈØ×Þ×Ì Þ
`
`0006
`
`0006
`
`

`

`https://web.archive.org/web/20170228021220/http://www.accessdata.fda.gov/drugsatfda_docs/label
`¸¬¬°­æññ©»¾ò¿®½¸·ª»ò±®¹ñ©»¾ñîðïéðîîèðîïîîðñ¸¬¬°æññ©©©ò¿½½»­­¼¿¬¿òº¼¿ò¹±ªñ¼®«¹­¿¬º¼¿Á¼±½­ñ´¿¾»´
`/2014/206289s000lbl.pdf
`ñîðïìñîðêîèç­ððð´¾´ò°¼º
`
`0007
`
`0007
`
`

`

`NDA 206289
`Page 5
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`-------------------WARNINGS AND PRECAUTIONS-———————-
`
`These highlights do not include all the information needed to use
`Atropine Sulfate Ophthalmic Solution, USP 1% safely and
`effectively. See full prescribing information for Atropine Sulfate
`Ophthalmic Solution, USP 1%.
`
`Atropine Sulfate Ophthalmic Solution, USP 1%
`for topical application to the eye.
`Initial U.S. Approval: 1960
`
`e
`
`e
`
`Photophobia and blurred vision due to pupil unresponsiveness
`and cycloplegia may last up to 2 weeks. (5.1)
`Risk of blood pressure increase from systemic absorption (5.2)
`
`soneeneneenennonnne==----ADVERSE REACTIONS-------------------------
`
`Most common adverse reactions that have been reported are eye pain
`and stinging on administration, blurred vision, photophobia, decreased.
`lacrimation, increased heart rate and blood pressure (6)
`
`a—-----------------------INDICATIONS AND USAGE---------------------
`
`To report SUSPECTED ADVERSE REACTIONS, contact
`Akorn, Inc. at 1-800-932-5676 or FDA at 1-800-FDA-1088 or
`Atropine is an anti-muscarinic agentindicatedfor:
`www.fda.gov/medwatch
`e=.Cycloplegia (1.1)
`e
`=©Mydriasis (1.2)
`eaeneeeenenenennnnnneeeDRUG INTERACTIONS------------2----0-+-+
`e=Penalization of the healthy eye in the treatment of amblyopia
`The use of atropine and monoamine oxidase inhibitors (MAOI) is
`(1.3)
`generally not recommended because of the potential to precipitate
`hypertensive crisis.(7)
`
`mannannnannannnDOSAGE AND ADMINISTRATION----------------
`
`e
`
`e
`
`1 drop
`In individuals from three(3) months of age or greater,
`topically to the cul-de-sac of the conjunctiva, forty minutes prior
`to the intended maximal dilation time (2.1)
`In individuals 3 years of age or greater, doses may be repeated up
`to twice daily as needed.(2.2)
`
`wonemeteennnennenenDOSAGE FORMS AND STRENGTHS---------------
`
`1% ophthalmic solution (3)
`
`wnannnnnnCONTRAINDICATIONS-------------------------
`
`Hypersensitivity or allergic reaction to any ingredient in formulation
`(4.1)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1 INDICATIONS AND USAGE
`
`1.1 Cycloplegia
`1.2 Mydriasis
`1.3 Penalization of the healthy eye in the treatment of amblyopia
`2 DOSAGE AND ADMINISTRATION
`3 DOSAGE FORMSAND STRENGTHS
`4 CONTRAINDICATIONS
`
`4.1 Hypersensitivity to any Componentof this Medication
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Photophobia and Blurred Vision
`5.2 Elevation of Blood Pressure
`6 ADVERSE REACTIONS
`6.1 Ocular Adverse Reactions
`
`6.2 Systemic Adverse Reactions
`
`wareeeenencnnenenenUSE IN SPECIFIC POPULATIONS-----------------
`
`Should only be used in pregnant womenif clearly needed (8)
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`Revised: 07/2014
`
`7 DRUG INTERACTIONS
`
`7.1 Monoamineoxidase inhibitors (MAOT)
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, ImpairmentofFertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information
`are notlisted.
`
`Reference ID: 3595294
`λº»®»²½» ×Üæ íëçëîçì
`
`0008
`
`0008
`
`

`

`NDA 206289
`Page 6
`
`FULL PRESCRIBING INFORMATION
`1. INDICATIONS AND USAGE
`
`Atropine Sulfate Ophthalmic Solution, USP 1% is indicatedfor:
`1.1
` Cycloplegia
`1.2
`Mydriasis
`1.3.
`Penalization of the healthy eye in the treatment of amblyopia
`
`2. DOSAGE AND ADMINISTRATION
`
`2.1
`
`2.2
`
`In individuals from three (3) monthsof age or greater, 1 drop topically to the cul-de-sac of the conjunctiva, forty minutes
`prior to the intended maximal dilation time.
`In individuals 3 years of age or greater, doses may be repeated up to twice daily as needed.
`
`3. DOSAGE FORMS AND STRENGTHS
`
`Atropine Sulfate Ophthalmic Solution, USP 1%: each mL contains 10 mgofatropine sulfate equivalent to 8.3 mg of atropine
`
`4. CONTRAINDICATIONS
`
`Hypersensitivity to any Componentof this Medication
`4.1
`Atropine sulfate ophthalmic solution should not be used in anyone who has demonstrated a previous hypersensitivity or known
`allergic reaction to any ingredient of the formulation because it may recur.
`
`5. WARNINGS AND PRECAUTIONS
`
`Photophobia and Blurred Vision
`5.1.
`Photophobia and blurred vision due to pupil unresponsiveness and cycloplegia may last up to 2 weeks.
`5.2__Elevation of Blood Pressure
`
`Elevation in blood pressure from systemic absorption has been reported following conjunctival instillation of recommended
`doses of atropine sulfate ophthalmic solution, 1%.
`
`6. ADVERSE REACTIONS
`
`The following serious adverse reactions are described below and elsewherein the labeling:
`e
`Photophobia and Blurred Vision [See Warnings and Precautions (5.1)]
`°
`Elevation in Blood Pressure [See Warnings and Precautions (5.2)]
`
`The following adverse reactions have been identified following use of atropine sulfate ophthalmic solution. Because these
`reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency
`or establish a causal relationship to drug exposure.
`
`6.1
`
`Ocular Adverse Reactions
`
`Eye pain and stinging occurs uponinstillation of atropine sulfate ophthalmic solution. Other commonly occurring adverse
`reactions include, blurred vision, photophobia, superficial keratitis and decreased lacrimation. Allergic reactions such as papillary
`conjunctivitis, contact dermatitis, and lid edema mayalso occur less commonly.
`
`Systemic Adverse Reactions
`6.2
`Systemic effects of atropine are related to its anti-muscarinic activity. Systemic adverse events reported include drynessofskin,
`mouth, and throat from decreased secretions from mucus membranes;restlessness, irritability or delirium from stimulation of the
`central nervous system; tachycardia; flushed skin of the face and neck.
`
`7. DRUG INTERACTIONS
`7.1|Monamine oxidase inhibitors
`
`The use of atropine and monoamine oxidase inhibitors (MAOJ)is generally not recommended because ofthe potential to
`precipitate hypertensivecrisis.
`
`8. USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`8.1
`Pregnancy Category C:
`There are no adequate and well-controlled studies of atropine sulfate in pregnant women. Animal development and reproduction
`studies have not been conducted with atropine sulfate. Since it is not known whethertopically administered atropine sulfate can
`
`Reference ID: 3595294
`λº»®»²½» ×Üæ íëçëîçì
`
`0009
`
`0009
`
`

`

`NDA 206289
`Page 7
`
`cause fetal harm, atropine sulfate ophthalmic solution, 1% should only be used during pregnancyif the potential benefit justifies
`the potential risk to the fetus.
`
`Nursing Mothers
`8.3
`Traces of atropine have been found in human milk following administration of atropine solution for injection. Because some
`systemic absorption occurs from topical administration, caution should be exercised when Atropine Sulfate Ophthalmic Solution
`USP, 1% is administered to a nursing woman.
`
`8.4
`
`Pediatric Use
`
`Dueto the potential for systemic absorption of atropine sulfate ophthalmic solution, the use of atropine sulfate ophthalmic
`solution, 1% in children under the age of 3 months is not recommendedandthe use in children under 3 years of age should be
`limited to no more than one drop per eye per day.
`
`8.5
`
`Geriatric Use
`
`No overall differences in safety and effectiveness have been observed between elderly and youngeradult patients.
`
`10. OVERDOSAGE
`
`In the event of accidental ingestion or toxic overdosage with atropine sulfate ophthalmic solution supportive care may include a
`short acting barbiturate or diazepam as needed to control marked excitement and convulsions. Large doses for sedation should be
`avoided because central depressant action may coincide with the depression occurring late in atropine poisoning. Central
`stimulants are not recommended.
`
`Physostigmine, given by slow intravenousinjection of 1 to 4 mg (0.5 to 1 mgin pediatric populations), rapidly abolishes delirium
`and coma caused by large doses of atropine. Since physostigmineis rapidly destroyed, the patient may again lapse into coma
`after one to two hours, and repeated doses may be required.
`
`Artificial respiration with oxygen may be necessary. Cooling measures may be neededto help to reduce fever, especially in
`pediatric populations.
`
`Thefatal adult dose of atropine is not known.In pediatric populations, 10 mg or less may be fatal.
`
`11. DESCRIPTION
`
`Atropine Sulfate Ophthalmic Solution, USP 1% is a sterile topical anticholinergic for ophthalmic use. The active ingredientis
`represented by the chemical structure
`
`3
`Gis
`
`ip:
`
`O geO) ,
`oc—ox)
`
`» H,SOs
`
`+ HO
`
`
`Chemical Name: Benzeneacetic acid, a-(hydroxymethyl)-, 8-methyl-8-azabicyclo[3.2.1.]oct-3-yl ester, endo {+)-, sulfate (2:1)
`(salt), monohydrate.
`
`Molecular Formula: (C,7H23NO 3). © H,SO, ®H,O
`
`Molecular Weight: 694.83 g/mol
`
`Each mL of Atropine Sulfate Ophthalmic Solution USP, 1% contains: Active: atropine sulfate 10 mg equivalent to 8.3 mg of
`atropine. Inactives: benzalkonium chloride 0.1 mg (0.01%), dibasic sodium phosphate, edetate disodium, hypromellose (2910),
`monobasic sodium phosphate, hydrochloric acid and/or sodium hydroxide may be addedto adjust pH (3.5 to 6. 0), and water for
`injection USP.
`
`Reference ID: 3595294
`λº»®»²½» ×Üæ íëçëîçì
`
`0010
`
`0010
`
`

`

`NDA 206289
`Page 8
`
`12. CLINICAL PHARMACOLOGY
`12.1
`Mechanism of Action
`
`Atropine is a reversible antagonist of muscarine-like actions of acetyl-choline andis therefore classified as an antimuscarinic
`agent. Atropine is relatively selective for muscarinic receptors. Its potency at nicotinic receptors is much lower, and actions at
`non-muscarinic receptors are generally undetectable clinically. Atropine does not distinguish among the M1, M2, and M3
`subgroups of muscarinic receptors.
`
`The pupillary constrictor muscle depends on muscarinic cholinoceptor activation. This activation is blocked by topical atropine
`resulting in unopposed sympathetic dilator activity and mydriasis. Atropine also weakens the contraction of the ciliary muscle, or
`cycloplegia. Cycloplegia results in loss ofthe ability to accommodate such that the eye cannot focus for near vision.
`
`Pharmacodynamics
`12.2
`The onset of action after administration of atropine sulfate ophthalmic solution, USP 1%,is usually within 40 minutes with
`maximaleffect being reached in about 2 hours. The effect can last for up to 2 weeks in a normaleye.
`
`12.3
`
`Pharmacokinetics
`
`The bioavailability of atropine sulfate ophthalmic solution, 1% wasassessed in six healthy subjects, 24 to 29 years of age.
`Subjects received either 0.3 mg atropine sulfate administered as bolus intravenousinjection or 0.3 mg administered as 30 pl
`instilled unilaterally in the cul-de-sac of the eye. Plasma l-hyoscyamine concentrations were determined overselected intervals
`up to eight hours after dose administration.
`
`
`The mean bioavailability of topically applied atropine was 63.5 + 29% (range 19 to 95%) with large inter-individual differences.
`Mean maximum observed plasma concentration for the ophthalmic solution was 288 + 73 pg/mL. Maximum concentration was
`reached in 28 + 27 min after administration. Terminal half-life of |-hyoscamine wasnot affected by route of administration and
`wascalculated to be 3 + 1.2 hours (intravenous) and 2.5 + 0.8 hours (topical ophthalmic).
`
`In another placebo-controlled study, the systemic exposure to 1-hyoscyamine, and the anti-cholinergic effects of atropine were
`investigated in eight ocular surgery patients 56 to 66 years of age, following single topical ocular 0.4 mg atropine dose (given as
`40 microliters of atropine sulfate ophthalmic solution, 1%). The mean (+ standard deviation (SD)) C,,,. of -hyoscyamine in these
`patients was 860 + 402 pg/mL, achieved within 8 minutes of eyedropinstillation.
`
`Following intravenous administration, the mean (+ SD) elimination half-life (t,.) of atropine was reported to be longerin
`
`pediatric subjects under 2 years (6.9 + 3.3 hours) and in geriatric patients 65 to 75 years (10.0 + 7.3 hours), comparedto in
`children over 2 years (2.5 + 1.2 hours) and in adults 16 to 58 years (3.0 + 0.9 hours). (see 8.4 Pediatric Use).
`
`Atropine is destroyed by enzymatic hydrolysis, particularly in the liver; from 13 to 50% is excreted unchanged in the urine.
`Traces are foundin various secretions, including milk. The major metabolites of atropine are noratropine, atropin-n-oxide,
`tropine, and tropic acid. Atropine readily crosses the placental barrier and enters the fetal circulation, but is not found in amniotic
`fluid.
`
`Atropine binds poorly (about 44%) to plasmaprotein, mainly to alpha-1 acid glycoprotein; age has no effect on the serum protein
`binding of atropine. Atropine binding to a-1 acid glycoprotein was concentration dependent(2 to 20 mcg/mL) and nonlinear in
`vitro and in vivo. There is no gender effect on the pharmacokinetics of atropine administered by injection.
`
`13. NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, ImpairmentofFertility
`Atropine sulfate was negative in the Salmonella/microsome mutagenicity test. Studies to evaluate carcinogenicity and
`impairmentoffertility have not been conducted.
`
`14, CLINICAL STUDIES
`
`Topical administration of atropine sulfate ophthalmic solution, 1% results in cycloplegia and mydriasis which has been
`demonstrated in several controlled clinical studies in adults and pediatric patients. Maximal mydriasis usually occurs in about 40
`minutes and maximal cycloplegia is usually achieved in about 60 to 90 minutes after single administration. Full recovery usually
`occurs in approximately one week, but maylast a couple of weeks.
`
`Reference ID: 3595294
`λº»®»²½» ×Üæ íëçëîçì
`
`0011
`
`0011
`
`

`

`

`

`https://web.archive.org/web/20170217113254/http://www.accessdata.fda.gov/drugsatfda_docs/nda/
`¸¬¬°­æññ©»¾ò¿®½¸·ª»ò±®¹ñ©»¾ñîðïéðîïéïïíîëìñ¸¬¬°æññ©©©ò¿½½»­­¼¿¬¿òº¼¿ò¹±ªñ¼®«¹­¿¬º¼¿Á¼±½­ñ²¼¿ñ
`2014/2062890rig1sO00SumR.pdf
`îðïìñîðêîèçÑ®·¹ï­ðððÍ«³Îò°¼º
`
`0013
`
`0013
`
`

`

`CENTER FOR DRUG EVALUATION AND
`ÝÛÒÌÛÎ ÚÑÎ ÜÎËÙ ÛÊßÔËßÌ×ÑÒ ßÒÜ
`RESEARCH
`ÎÛÍÛßÎÝØ
`
`APPLICATION NUMBER:
`ßÐÐÔ×ÝßÌ×ÑÒ ÒËÓÞÛÎæ
`
`2062890rig1s000
`îðêîèçÑ®·¹ï­ððð
`
`SUMMARY REVIEW
`ÍËÓÓßÎÇ ÎÛÊ×ÛÉ
`
`0014
`
`0014
`
`

`

`NDA 206289, Atropine Sulfate Ophthalmic Solution, USP 1%
`Cycloplegia. Mydriasis, Penalization of the healthy eye in the treatment of amblyopia
`Division Director Review
`
`Summary Review for Regulatory Action
`
`
`Date
`(electronic stamp)
`
`From
`Renata Albrecht, MD
`Subject
`Division Director Summary Review
`NDA/BLA #
`NDA206289
`Supplement #
`N/A
`
`Related IND
`pIND 118218
`
`Applicant Name
`Akorn Inc.
`Application Type
`505(b)(2)
`
`Date of Submission
`10/22/2013
`
`None
`Proprietary Name/
`Established (USAN) Name
`atropine sulfate ophthalmic solution
`
`
`Dosage Forms/ Strength
`solution /eye drops 1%
`Preservative
`benzalkonium chloride, 0.01% (0.1 mg/mL)
`Route of Administration
`
`
`
`Therapeutic Class
`Indication(s)
`
`Dosage Regimen
`How Supplied
`
`Action/Recommended
`
`Cycloplegia
`Mydriasis
`Amblyopia
`
`in plastic dropperbottle with red cap in the following
`sizes: 2mL fill in 6cc bottle: 5 mL fill in 6cc bottle;
`15mL fill in 1Scc bottle
`approval
`
`Page 1 of 20
`
`Reference ID: 3596015
`
`0015
`
`0015
`
`

`

`NDA 206289, Atropine Sulfate Ophthalmic Solution, USP 1%
`Cycloplegia, Mydriasis, Penalization of the healthy eye in the treatment of amblyopia
`Division Director Review
`
`
`
`
`
`
`
`
`
`Pharmacokinetic parameters of atropine (measured as |-hyoscyamine) following
`
`topical ocular administration of 1% atropine sulfate ophthalmic solution
`in
`
`
`
`
`
`
`Subjects
`Study Objective
`Treatment
`Pharmacokinetic Parameters
`(Mean + SD) for l-hyoscyamine
`(Dose/Dosage
`(No.(M/F),
`Cmax
`Tmax AUC.) AUCo-nn
`t%
`CL
`
`
`
`
`
`Form/Route)
`Type, Age
`
`
`(pg/mL)|(min) (h)|(mL/min/kg)|(h.ng/mL)| (h.ng/mL)
`
`
`
`
`
`
`
`Kailaet al.
`Determine
`Open label,
`0.3 mg, single
`(1999) 1.794|2.974]absolute randomized, dose, IV 6 (1M/5F), NA NA NA 23E-5+4
`
`
`
`
`
`
`
`
`bioavailability of]
`crossover, with
`solution
`Healthy,
`0.64
`1.22
`6.5E6
`
`topical ocular|2-week washout|0.3 mg,single 2429 y
`
`
`
`
`
`
`dose, ophthalmic 288.3 +|27.67+ 102+|245+NA 4E-5 +
`
`
`solution
`72.91
`26.85
`0.33
`0.76
`3.1E-5
`
`
`0.4 mg,
`Determine
`Open label,
`8 (7M/LF),
`
`
`|pharmacokinetics}|
`randomized,
`ophthalmic
`ocular surgery}
`al. (1988)
`of ophthalmic
`.
`solution
`patients,
`
`administration
`56-66
`
`
`‘converted to h*ng/mL from AUC of 43.25 + 24.1 min*ng/mL
`Source: Clinical Pharmacology Review
`
`
`
`
`
`
`NA
`
`860+
`402
`
`0.72+
`0.40?
`
`NA
`
`NA
`
`Ocular Pharmacodynamics (PD):
`With 1% atropine sulfate ophthalmic solution, full mydriasis is achievable with 1 drop;
`multiple eyedrops are needed to achieve full cycloplegia. Full recovery from these effects
`could take up to 18 days.
`
`Mydriasis
`Based onthe study conducted Wolf and Hodge (1946)’ in healthy subjects 16 to 37 yearsold,
`1 drop of 1% atropine sulfate ophthalmic solution into the eye produced a maximum pupil
`diameter of 8.3 mm (2.5-fold greater than normalsize) within 40 minutes of eye drop
`instillation. Recovery started at 6 hoursafter instillation of the eye drop, and it took up to 12
`days for the pupil diameter to fully return to its normal size.
`
`Cycloplegia
`Based on the study conducted by Marron (1940)!° in subjects 15 to 40 yearsold, 1 drop of 1%
`atropine sulfate ophthalmic solution instilled in the eye three times daily for 3 days with an
`additional 1 drop on the morning of the day of the ocular examination produceda residual
`accommodation (RA) of 1.9 D (17% of baseline); maximum effect was observed after the 4th
`of 10 drops. The average patient was able to read newsprint by the third day after the last
`instillation, and it took up to 18 days for the range of accommodation to fully return to normal.
`(In this study, the maximum extent of pupil dilation or mydriasis was achievedafterthe first
`drop anddid not increase further with the instillation of additional eyedrops.)
`
`The clinical pharmacology reviewer concludes that: Based onliterature data, 65% (on
`average) and up to 95% (on an individual basis) of the administered topical ocular dose of
`atropine is absorbed. One drop (actual drop volume ~ 40 mcL) of 1% atropine sulfate
`ophthalmic solution contains 0.4 mg atropine sulfate. No dosage adjustmentis needed for
`
`° Wolf AV, Hodge HC.Effects of atropine sulfate, methylatropinenitrate (metropine) and homatropine
`hydrobromide on adult human eyes. Arch Ophthal 1946; 36: 293-301.
`'° Marron J. Cycloplegia and mydriasis by use of atropine, scopolamine, and homatropine-paradrine. Arch
`Ophthalmol 1940; 23: 340-50.
`
`Page 9 of 20
`
`Reference ID: 3596015
`λº»®»²½» ×Üæ íëçêðïë
`
`0016
`
`0016
`
`

`

`NDA 206289, Atropine Sulfate Ophthalmic Solution, USP 1%
`Cycloplegia, Mydriasis, Penalization of the healthy eye in the treatment of amblyopia
`Division Director Review
`
`patients with dark irides for adequate pupil dilation (mydriasis) and complete and uniform
`cycloplegia. No dose adjustment is needed based on genderor race. No dosage adjustmentis
`neededfor elderly patients, patients with renal impairmentor patients with hepatic
`impairment; these patients should be monitored for systemic adverse reactions such as change
`in blood pressure and heart rate given they may have impairmentin elimination ofatropine.
`No dosage adjustmentis needed for pediatric patients > 4 years in age. The clinical
`pharmacology reviewer notes that the medicalliterature prior to 1951 reports four pediatric
`deaths in patients between 10 months and 3 years in age whoreceived atropine 1%;the total
`estimated doses were between 1.6 to 18 mg given as over 1 to 2 days. No pediatric deaths
`associated with atropine 1% are reported since the 1950’s. Therefore patients 3 monthsto 3
`years should receive only single doses (0.4 mg) and children under the age of 3 months should
`not receive atropine eyedrops.
`
`Labeling will reflect that: Atropine is a reversible antagonist of muscarine-like actions of
`acetyl-choline andis therefore classified as an antimuscarinic agent. Atropineis relatively
`selective for muscarinic receptors. Its potency at nicotinic receptors is much lower, and actions
`at non-muscarinic receptors are generally undetectable clinically. Atropine does not
`distinguish among the M1, M2, and M3 subgroupsof muscarinic receptors.
`
`The pupillary constrictor muscle depends on muscarinic cholinoceptor activation. This
`activation is blocked by topical atropine resulting in unopposed sympathetic dilator activity
`and mydriasis. Atropine also weakensthe contraction ofthe ciliary muscle, or cycloplegia.
`Cycloplegia results in loss of the ability to accommodate such that the eye cannot focus for
`near vision.
`
`Pharmacodynamics
`12.2.
`The onset of action after administration of atropine ophthalmic solution, USP 1%,is usually
`within 40 minutes with maximal effect being reached in about 2 hours. The effect can last for
`up to 2 weeks in a normaleye.
`
`Pharmacokinetics
`12.3.
`The bioavailability of atropine ophthalmic solution, 1% wasassessed in six healthy subjects,
`24 to 29 years of age. Subjects received either 0.3 mg atropine sulfate administered as bolus
`intravenousinjection or 0.3 mg administered as 30 ul instilled unilaterally in the cul-de-sac of
`the eye. Plasma l-hyoscyamine concentrations were determined over selected intervals up to
`eight hours after dose administration.
`
`The mean bioavailability of topically applied atropine was 63.5 + 29% (range 19 to 95%) with
`large inter-individual differences. Mean maximum observed plasma concentration for the
`ophthalmic solution was 288 + 73 pg/mL. Maximum concentration was reached in 28 + 27
`min after administration. Terminal half-life of l-hyoscamine wasnot affected by route of
`administration and wascalculated to be 3 + 1.2 hours (intravenous) and 2.5 + 0.8 hours
`(topical ophthalmic).
`
`In another placebo-controlled study, the systemic exposure to l-hyoscyamine, and the anti-
`cholinergic effects of atropine were investigated in eight ocular surgery patients 56 to 66 years
`
`Page 10 of 20
`
`Reference ID: 3596015
`λº»®»²½» ×Üæ íëçêðïë
`
`0017
`
`0017
`
`

`

`NDA 206289, Atropine Sulfate Ophthalmic Solution, USP 1%
`Cycloplegia, Mydriasis, Penalization of the healthy eye in the treatment of amblyopia
`Division Director Review
`
`of age, following single topical ocular 0.4 mg atropine dose (given as 40 microliters of
`atropine ophthalmic solution, 1%). The mean (+ standard deviation (SD)) Cmax of1-
`hyoscyaminein these patients was 860 + 402 pg/mL, achieved within 8 minutes of eye drop
`instillation.
`
`Following intravenous administration, the mean (+ SD)elimination half-life (t1/2) of atropine
`wasreported to be longer in pediatric subjects under 2 years (6.9 + 3.3 hours) and in geriatric
`
`patients 65 to 75 years (10.0 + 7.3 hours), compared to in children over 2 years (2.5 + 1.2
`hours) and in adults 16 to 58 years (3.0 + 0.9 hours).
`
`Atropine is destroyed by enzymatic hydrolysis, particularly in the liver; from 13 to 50% is
`excreted unchangedin the urine. Traces are found in various secretions, including milk. The
`major metabolites of atropine are noratropine, atropin-n-oxide, tropine, andtropic acid.
`Atropine readily crosses the placental barrier and enters the fetal circulation, but is not found
`in amniotic fluid.
`
`Atropine binds poorly (about 44%) to plasmaprotein, mainly to alpha-1 acid glycoprotein; age
`has no effect on the serum protein binding of atropine. Atropine binding to a-1 acid
`glycoprotein was concentration dependent (2-20 pg/mL) and nonlinear in vitro and in vivo.
`There is no gender effect on the pharmacokinetics of atropine administered by injection.
`
`Comment:
`I concur with the conclusions reachedby the clinical pharmacology reviewers to recommend
`approval. Labeling revisions to this section have been completed. There are no outstanding
`clinical pharmacology issues that preclude approval.
`
`6. Clinical Microbiology
`Notapplicable
`
`7. Clinical/Statistical-Efficacy
`
`For details, see the Clinical and Statistical reviews. A brief summary is provided below.
`
`The applicant identified several hundred publications based on their literature search and
`selected six publications to support efficacy of atropine for their 505(b)(2) application. The
`medical officer identified and reviewed fifty-seven studies published between 1931 and 2013
`evaluating atropine in the proposed indications. Eight representative studies were reviewed and
`summarized in the primary reviews. These studies evaluated atropine, including the atropine
`1% solution. The studies included subjects from 2 months to 92 years in age. The Chia’’ study
`of
`©”did not evaluate 1% atropine and was conducted over 2 years and did not provide 5
`year data considered necessary from the ophthalmology perspective. The remaining seven
`trials are summarized below.
`
`ø¾÷ øì÷
`
`1 Chia A, Chua WH, Cheung YB, Wong WL, Lingham A,Fong A, Tan D. Atropine for the treatment of
`childhood ©: safety and efficacy of 0.5%, 0.1%, and 0.01% doses. Ophthalmology 2012;119(2):347-54
`
`ø¾÷ øì÷
`
`Page 11 of 20
`
`Reference ID: 3596015
`λº»®»²½» ×Üæ íëçêðïë
`
`0018
`
`0018
`
`

`

`NDA 206289, Atropine Sulfate Ophthalmic Solution, USP 1%
`Cycloplegia, Mydriasis, Penalization of the healthy eye in the treatment of amblyopia
`Division Director Review
`
`Mydriasis and Cycloplegia
`Six selected representative studies in support of the indications of mydriasis and cycloplegia
`are listed in the table below:
`
`Mydriasis and/or cycloplegia results for studies of atropine 1% ophthalmic solution
`Mydriasis (dilation) is measured by pupil diameter and cycloplegia iis measured by accommodation (A)or
`residual accommodation
`(RA
`Dilation Results for
`Dilation Results for
`Cycloplegia Results
`Cycloplegia Results
`Control or other arm
`for
`for
`Atropine 1%
`Control or other arm
`Atropine 1%
`All other active
`Mean baseline ~4mm|All7other agents had|Change in pupilsize
`1957
`mean dilation greater
`(A) close to zero (Fig
`agents had values
`Mean posttrt ~6.5 mm
`than 6 mm. One
`No difference among
`2 bottom)
`>atropine (thereby the
`A after treatment<0.1
`other agentsare less
`races and eye colors.
`agent, scopolamine,
`mm
`had a mean
`(Fig 1)
`effective)
`value>atropine
`Forcyclopentolate,
`53% haddilation
`> 6mm
`For cyclopentolate
`+0.5%Tropicamide,
`94% haddilation
`> 6mm
`Forscopolamine,
`average full dilation
`of 8 mm
`For Homatropine,
`average full dilation
`of 8 mm
`
`100% had RA
`0-0.5 D
`Mean RA 0.04 D Sign.
`Lower RA than other
`agents p<0.0001
`
`Average minimum A
`of 1.9D
`(ratio RA ~0.16 from
`Fig 3)
`Full effect after 4
`drops/fell within 30’
`Mean RA of
`0.21 (ratio)
`
`Mean refraction
`<6yrs +3.55D
`
`>Tyrs +2.60 D
`
`For cylcopentolate,
`54%