CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`21-770
`
`MEDICAL REVIEW
`
`Slayback Exhibit 1063, Page 1 of 70
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`

`

`Medical Officer's Review of NOA 21-770
`Labeling Review # 3
`
`NDA21-770
`Medical Officer's Review
`
`Submission:
`Submission:
`Review Completed:
`
`8/03/05
`8/18/05
`8/18/05
`
`Proposed Tradename:
`
`Alphagan P
`
`Established Name:
`
`Chemical Structure:
`
`brimonidine tartrate ophthalmic solution, 0.1 %
`
`t \
`HNYNH .
`I
`
`Br NU)
`
`COOH
`I
`H-C-OH
`I
`HO-C-H
`I
`COOH
`
`Sponsor:
`
`Allergan, Inc.
`2525 Dupont Drive
`P.O. Box 19534
`Irvine, CA 92623-9534
`
`Pharmacologic Category:
`
`Alpha 2-agonist
`
`Proposed Indication:
`
`, Reduction of intraocular pressure (IOP)
`
`Dosage Form and
`Route of Administration:
`
`Submitted:
`
`Ophthalmic solution for topical ocular
`administration
`
`The following comments are from the DMETS review signed August 12, 2005:
`
`A.
`
`GENERAL COMMENTS
`
`Slayback Exhibit 1063, Page 2 of 70
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`

`

`1.
`
`We note that the preservative for this product bears the tradename
`"Purite®". We ask that you define Purite® in terms of its ingredients
`where it appears throughout your labels and labeling.
`
`Reviewer's comments:
`
`Purite® is a "stabilized oxychloro complex. " Defining Purite® within the labeling will
`provide no additional beneficial information.
`
`2.
`
`DMETS is aware ofpostmarketing reports of inadvertent oral
`administration of Alphagan resulting in hospitalization of pediatric
`patients. DMETS recommends the addition of a prominent statement on
`container labels and carton labeling of "Alphagan" products that these
`product are for use only in the eye. Alternatively ( or additionally),
`DMETS recommends that an eye pictorial appear on those labels and
`labeling.
`
`Reviewer's comments:
`
`The cases referenced are children who accidentally ingested the medication not cases in
`which drug was mis-administered; it is unlikely that an eye pictorial or label statement would
`prevent accidental ingestion.
`
`3.
`
`DMETS recommends that the statement, "New Product Strength" appears
`on product labels and labeling for a period of time not to exceed six
`months.
`Reviewer's comments:
`The proposed drug product is bioequivalent to the currently marketed product. There is no
`safety or efficacy issue related to substitution of these products.
`
`4.
`
`When preparing product labeling, please ensure that the expression of
`strength is well differentiated from the expression of strength of the
`existing Alphagan P product. DMETS recommends the use of contrasting
`colors, boxing, or some other means to differentiate the product strengths.
`
`Reviewer's comments:
`The boxes for these products do differ in color. The Alphagan P 0.15% box top is in purple,
`while the Alphagan P 0.1 % box top is in green. Even if one drug was inadvertently
`substituted for the other, these drugs are bioequivalent and have the same safety and efficacy
`profile.
`
`5.
`
`According to the Division's Project Manager, the sponsor has proposed a
`separate package insert for the lower strength product. DMETS does not
`
`2
`
`Slayback Exhibit 1063, Page 3 of 70
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`
`

`

`recommend two separate package inserts for the two different strengths as
`this may cause confusion and error. For example, practitioners may not be
`aware of the two different strengths if only one strength is listed and/or
`they may think that the products are not indicated or dosed similarly.
`Traditionally, a combined package insert is used for different strengths of
`the same active ingredient.
`
`Reviewer's comments:
`A combined package insert will be used for both products (Alphagan P 0.15% and
`Alphagan P 0.1%).
`
`Appears This Way
`On Original
`
`3
`
`Slayback Exhibit 1063, Page 4 of 70
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`
`

`

`IO Page(s) Withheld
`
`- - Trade Secret / Confidential
`
`✓ Draft Labeling
`
`- -
`
`Deliberative Process
`
`Withheld Track Number: Medical-
`
`I
`
`Slayback Exhibit 1063, Page 5 of 70
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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/
`
`Martin Nevitt
`8/18/2005 01:22:11 PM
`MEDICAL OFFICER
`
`William Boyd
`8/18/2005 01:45:11 PM
`MEDICAL OFFICER
`
`Wiley Chambers
`8/18/2005 03:15:33 PM
`MEDICAL OFFICER
`
`Lillian Gavrilovich
`8/19/2005 09:00:15 AM
`MEDICAL OFFICER
`Sigbning for Dr. Soreth.
`
`Slayback Exhibit 1063, Page 6 of 70
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`
`

`

`Labeling Review - July 18, 2005
`Martin P. Nevitt, M.D., M.P.H.
`NDA 21-770; N-000
`Alphagan P; Brimonidine Tartrate Ophthalmic Solution, 0.1 %
`
`LABELING REVIEW
`
`Application Type NDA 21-770
`Label Review
`Class 1 Resubmission
`Letter Date 6/27 /05
`PDUFA Goal Date 8/28/05
`
`Reviewer Name Martin P. Nevitt, M.D., M.P.H.
`Review Completion Date 7 /18/05
`
`Established Name Brimonidine Tartrate Ophthalmic
`Solution, 0.1 %
`
`(Proposed) Trade Name Alphagan P
`Therapeutic Class Alpha 2 -agonist
`Applicant Allergan, Inc.
`2525 Dupont Drive
`P.O. Box 19534
`Irvine, CA 92623-9534
`714-246-4500
`FAX: 714-246-4272
`
`Lewis Gryziewicz
`714-246-6088
`
`Priority Designation S
`
`1
`
`Slayback Exhibit 1063, Page 7 of 70
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`
`

`

`Labeling Review - July 18, 2005
`Martin P. Nevitt, M.D., M.P.H.
`NDA 21-770; N-000
`Alphagan P; Brimonidine Tartrate Ophthalmic Solution, 0.1 %
`
`Structure
`
`I \
`NH y
`HN
`Br N'CXN)
`~
`I #
`
`N
`
`COOH
`I
`H-C-OH
`I
`HO-C-H
`I
`COOR
`
`Dosing Regimen One drop in the affected eye three
`times daily
`
`Indication Reduction of intraocular pressure
`(IOP)
`
`Intended Population Patients 2 years or older with open
`angle glaucoma or ocular
`hypertension
`
`2
`
`Slayback Exhibit 1063, Page 8 of 70
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`
`

`

`Labeling Review - July 18, 2005
`Martin P. Nevitt, M.D., M.P.H.
`NDA 21-770; N-000
`Alphagan P; Brimonidine Tartrate Ophthalmic Solution, 0.1 %
`
`Submitted:
`
`The applicant has submitted the following labeling based on the April 1, 2005, approvable letter.
`
`Reviewer's comments:
`
`Reviewer's deletions are noted by a and additions by an underline within this review.
`
`- Allergan, Inc.
`ALPHAGANP
`(brimonidine tartrate ophthalmic solution) 0.1 %
`
`Sterile
`
`DESCRIPTION
`
`3
`
`Slayback Exhibit 1063, Page 9 of 70
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`
`

`

`~ - Page(s) Withheld
`
`- - Trade Secret / Confidential
`
`,_/' Draft Labeling
`
`- -
`
`Deliberative Process
`
`Withheld Track Number: Medical- 2-
`
`Slayback Exhibit 1063, Page 10 of 70
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/s/
`
`Martin Nevitt
`7/19/05 02:00:16 PM
`MEDICAL OFFICER
`
`William Boyd
`7/19/05 02:03:45 PM
`MEDICAL OFFICER
`
`Wiley Chambers
`7/19/05 05:19:55 PM
`MEDICAL OFFICER
`
`Janice Soreth
`8/10/05 09:45:42 AM
`MEDICAL OFFICER
`
`Slayback Exhibit 1063, Page 11 of 70
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`
`

`

`Labeling Review Review 1 - March 28, 2005
`Martin P. Nevitt, M.D., M.P.H.
`NDA 21-770; N-000
`Alphagan -.Brimonidine Tartrate Ophthalmic Solution, 0.1 %
`
`LABELING REVIEW
`
`Application Type NDA 21-770
`Label Review 1 - March 28, 2005
`
`PDUFA Goal Date 4/1/05
`
`Reviewer Name Martin P. Nevitt, M.D., M.P.H.
`Review Completion Date 3/28/05
`
`Established Name Brimonidine Tartrate Ophthalmic
`Solution, 0.1 %
`
`(Proposed) Trade Name Alphagan • •
`Therapeutic Class . Alpha 2 -agonist
`Applicant Allergan, Inc.
`2525 Dupont Drive
`P.O. Box 19534
`Irvine, CA 92623-9534
`714-246-4500
`FAX: 714-246-4272
`
`Lewis Gryziewicz
`714-246-6088
`
`Priority Designation S
`
`Slayback Exhibit 1063, Page 12 of 70
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`
`

`

`Labeling Review Review 1 - March 28, 2005
`Martin P. Nevitt, M.D., M.P.H.
`NOA 21-770; N-000
`Alphagan ._Brimonidine Tartrate Ophthalmic Solution, 0.1 %
`
`Structure
`
`t \
`NH y Br
`HN
`I# ~
`
`N ' ( ) :N )
`
`N
`
`COOH
`I
`H-C-OH
`I
`HO-C-H
`I
`COOH
`
`Dosing Regimen One drop in the affected eye three
`times daily
`
`Indication Reduction of intraocular pressure
`(IOP)
`
`Intended Population Patients 2 years or older with open
`angle glaucoma or ocular
`hypertension
`
`2
`
`Slayback Exhibit 1063, Page 13 of 70
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`
`

`

`Labeling Review Review 1 - March 28, 2005
`Martin P. Nevitt, M.D., M.P.H.
`NOA 21-770; N-000
`Alphagan__. Brimonidine Tartrate Ophthalmic Solution, 0.1 %
`
`The original labeling review ( clean copy) has been updated to include the
`recommendations/suggestions from the pharm/tox review and from the chemistry team leader.
`
`Reviewer's comments:
`Reviewer's deletion's are noted by a and additions by an underline within this review.
`
`Allergan, Inc.
`Alphagan ~
`(brimonidine tartr~te ophthalmic solution) 0.1 %
`
`Sterile
`
`DESCRIPTION
`Alphagan LS™ (brimonidine tartrate ophthalmic solution) _., is a relatively selective alpha-2
`adrenergic agonist for ophthalmic use. The chemical name ofbrimonidine tartrate is 5-bromo-6-
`(2-imidazolidinylideneamino) quinoxaline L-tartrate. It is an off-white to pale yellow powder. It
`has a molecular weight of 442.24 as the tartrate salt, and is both soluble in water (0.6 mg/mL)
`and in the product vehicle (1.4 mg/mL) at pH 7.7. The structural formula is:
`
`/7
`HNYNH
`I
`
`Br N'(XN~
`
`I# J
`
`N
`
`COOR
`I
`H-C-OH
`I
`HO-C-H
`I
`COOH
`
`Formula: C11H10BrN5·C4H6O6
`
`CAS Number: 70359-46-5
`In solution, Alphagan ...._ (brimonidine tartrate ophthalmic solution) -
`has a clear,
`greenish-yellow color. It has an osmolality of250-320 mOsmol/kg and a pH of7.4-8.0.
`Each mL of Alphagan _ ~ contains:
`
`Active ingredient: brimonidine tartrate 0.1 % (1.0 mg/mL)
`Inactives: sodium carboxymethylcellulose; sodium borate; boric acid; sodium chloride;
`potassium chloride; calcium chloride; magnesium chloride; (Purite® 0.005% (0.05 mg/ml) as a
`preservative) purified water; with hydrochloric acid and/or sodium hydroxide to adjust pH.
`Reviewer's comments:
`Per discussion with the chemistry team leader, preservative information has been included
`within the "Jnactives" section.
`Mechanism of action:
`
`3
`
`Slayback Exhibit 1063, Page 14 of 70
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`
`

`

`Labeling Review Review 1 - March 28, 2005
`Martin P. Nevitt, M.D., M.P.H.
`NDA 21-770; N-000
`Alphagan. -
`Brimonidine Tartrate Ophthalmic Solution, 0.1 %
`
`Alphagan ..... · is an alpha adrenergic receptor agonist. It has a peak ocular hypotensive effect
`occurring at two hours post-dosing. Fluorophotometric studies in animals and humans suggest
`that brimonidine tartrate has a dual mechanism of action by reducing aqueous humor production
`and increasing uveoscleral outflow.
`
`Pharmacokinetics:
`After ocular administration of either a 0.1 % or 0.2% solution, plasma concentrations peaked
`within 0.5 to 2.5 hours and declined with a systemic half-life of approximately 2 hours.
`In humans, systemic metabolism ofbrimonidine is extensive. It is metabolized primarily by the
`liver. Urinary excretion is the major route of elimination of the drug and its metabolites.
`Approximately 87% of an orally-administered radioactive dose was eliminated within 120 hours,
`with 74% found in the urine.
`
`Reviewer's comments:
`
`Clinical Evaluations:
`Elevated IOP presents a major risk factor in glaucomatous field loss. The higher the level of
`IOP, the greater the likelihood of optic nerve damage and visual field loss. Brimonidine tartrate
`has the action of lowering intraocular pressure with minimal effect on cardiovascular and
`pulmonary parameters.
`
`A clinical study was conducted to evaluate the safety, efficacy, and acceptability of Alphagan
`compared with ALPHA GAN®
`_. '(brimonidine tartrate ophthalmic solution) -
`administered three-times-daily in patients with open-angle glaucoma or ocular hypertension.
`Those results indicated that Alphagan --· (brimonidine tartrate ophthalmic solutionj_...
`is
`equivalent in IOP lowering effect to ALPHAGAN® (brimonidine tartrate ophthalmic solution)
`0.2%, and effectively lowers IOP in patients with open-angle glaucoma or ocular hypertension
`by approximately 2- 6 mmHg.
`INDICATIONS AND USAGE
`Alphagar • .-- · is indicated for the lowering of intraocular pressure in patients with open-angle
`glaucoma or ocular hypertension.
`
`CONTRAINDICATIONS
`Alphagan __._ 'f is contraindicated in patients with hypersensitivity to brimonidine tartrate or
`any component of this medication. It is also contraindicated in patients receiving monoamine
`oxidase (MAO) inhibitor therapy.
`
`4
`
`Slayback Exhibit 1063, Page 15 of 70
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`
`

`

`Labeling Review Review 1 - March 28, 2005
`Martin.P. Nevitt, M.D., M.P.H.
`NDA 21-770; N-000
`Alphagan ._ Brimonidine Tartrate Ophthalmic Solution, 0.1 %
`
`PRECAUTIONS
`General:
`Although brimonidine tartrate ophthalmic solution had minimal effect on the blood pressure of
`patients in clinical studies, caution should be exercised in treating patients with severe
`cardiovascular disease.
`
`Alphagan - - ' has not been studied in patients with hepatic or renal impairment; caution
`should be used in treating such patients.
`
`Alphagan - - t should be used with caution in patients with depression, cerebral or coronary
`insufficiency, Raynaud's phenomenon, orlhostatic hypotension, or thromboangiitis obliterans.
`Patients prescribed !OP-lowering medication should be routinely monitored for IOP.
`Information for Patients:
`As with other drugs in this class, Alphagan .... 'may cause fatigue and /or drowsiness in some
`patients. Patients who engage in hazardous activities should be cautioned of the potential for a
`decrease in mental alertness.
`
`Drug Interactions:
`the
`Although specific drug interaction studies have not been conducted with Alphagan -
`possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates,
`opiates, sedatives, or anesthetics) should be considered. Alpha-agonists, as a class, may reduce
`pulse and blood pressure. Caution in using concomitant drugs such as anti-hypertensives and/or
`cardiac glycosides is advised.
`
`Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic
`clonidine. It is not known whether the concurrent use of these agents with Alphagan __, in
`humans can lead to resulting interference with the IOP lowering effect. No data on the level of
`circulating catecholamines after Alphagan- administration are available. Caution, however,
`is advised in patients taking tricyclic antidepressants which can affect the metabolism and uptake
`of circulating amines.
`
`Carcinogenesis, Mutagenesis, and Impairment of Fertility:
`No compound-related carcinogenic effects were observed in either mice or rats following a 21-
`month and 24-month study, respectively. In these studies, dietary administration ofbrimonidine
`tartrate at doses up to 2.5 mg/kg/day in mice and 1.0 mg/kg/day in rats achieved 150 and 120
`times, respectively, the plasma drug concentration (Cmax) estimated in humans treated with one
`drop of Alphagan -
`1 into both eyes 3 times per day.
`
`Reviewer's comments:
`The pharm/tox reviewer has recommended the changes listed within the Carcinogenesis section.
`The changes are acceptable and have been included within this updated label.
`
`5
`
`Slayback Exhibit 1063, Page 16 of 70
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`

`

`Labeling Review Review I - March 28, 2005
`Martin P. Nevitt, M.D., M.P.H.
`NDA 21-770; N-000
`AlphagaL ._ Brimonidine Tartrate Ophthalmic Solution, 0.1 %
`
`Brimonidine tartrate was not mutagenic or cytogenic in a series of in vitro and in vivo studies
`including the Ames test, chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells,
`a host-mediated assay and cytogenic studies in mice, and dominant lethal assay.
`
`Pregnancy: Teratogenic effects: Pregnancy Category B.
`Reproductive studies performed in rats and rabbits with oral doses of0.66 mg base/kg revealed
`no evidence of impaired fertility or harm to the fetus due to Alphagan - - Dosing at this level
`produced an exposure in rats and rabbits that is 190 and 100 times higher, respectively, than the
`exposure seen in humans following multiple ophthalmic doses.
`
`There are no adequate and well-controlled studies in pregnant women. In animal studies,
`brimonidine crossed the placenta and entered into the fetal circulation to a limited extent.
`Alphagan - - should be used during pregnancy only if the potential benefit to the mother
`justifies the potential risk to the fetus.
`
`Reviewer's comments:
`The pharmltox reviewer has recommended the changes listed within the Pregnancy section. The
`changes are acceptable and have been included within this updated label.
`
`Nursing Mothers:
`It is not known whether this drug is excreted in human milk; although in animal studies
`brimonidine tartrate was excreted in breast milk. A decision should be made whether to
`discontinue nursing or to discontinue the drug, taking into account the importance of the drug to
`the mother.
`
`Pediatric Use:
`In a well-controlled clinical study conducted in pediatric glaucoma patients (ages 2 to 7 years)
`the most commonly observed adverse events with brimonidine tartrate ophthalmic solution 0.2%
`dosed three times daily were somnolence (50% - 83% in patients ages 2 to 6 years) and
`decreased alertness. In pediatric patients 7 years of age or older {>20kg), somnolence appears to
`occur less frequently (25%). Approximately 16% of patients on brimonidine tartrate ophthalmic
`solution discontinued from the study due to somnolence.
`
`The safety and effectiveness of brimonidine tartrate ophthalmic solution have not been studied in
`pediatric patients below the age of 2 years. Brimonidine tartrate ophthalmic solution is not
`recommended for use in pediatric patients under the age of2 years. (Also refer to Adverse
`Reactions section.)
`
`Geriatric Use:
`No overall differences in safety or effectiveness have been observed between elderly and other
`adult patients.
`ADVERSE EVENTS
`Adverse events occurring in approximately 10-20% of the subjects included: allergic
`conjunctivitis, conjunctival_hyperemia, and eye pruritis.
`
`6
`
`Slayback Exhibit 1063, Page 17 of 70
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`

`Labeling Review Review 1 - March 28, 2005
`Martin P. Nevitt, M.D., M.P.H.
`NDA 21-770; N-000
`Alphagan -
`Brimonidine Tartrate Ophthalmic Solution, 0.1 %
`
`Adverse events occurring in approximately 5-9% of the subjects receiving brimonidine
`ophthalmic solution (0.1 -0.2%) included: burning sensation, conjunctiva! folliculosis,
`hypertension, ocular allergic reaction, oral dryness, and visual disturbance.
`
`Events occurring in approximately 1-4% of subjects receiving brimonidine ophthalmic solution
`(0.1 - 0.2%) included: allergic reaction, .
`_
`, , asthenia, blepharitis,
`blepharoconjunctivitis, blurred vision, bronchitis, ..-1!!!11111---.
`conjunctival edema,
`conjunctival hemorrhage, conjunctivitis, cough, dizziness, .
`.
`.
`dyspepsia, dyspnea,
`epiphora, eye discharge, eye dryness, eye irritation, eye pain, eyelid edema, eyelid erythema,
`fatigue, flu syndrome, follicular conjunctivitis, foreign body sensation, gastrointestinal disorder,
`headache, hypercholesterolemia, hypotension, infection, insomnia,. - -~ keratitis, lid
`disorder, . __...
`, pharyngitis, photophobia, rash, rhinitis, sinus infection, sinusitis,
`somnolence, stinging, superficial punctate keratopathy, tearing, visual field defect, vitreous
`detachment, vitreous disorder, vitreous floaters, and worsened visual acuity.
`
`The following events were reported in less than 1 % of subjects: burning sensation, corneal
`erosion, hordeolum, nasal dryness, and taste perversion.
`
`The following events have been identified during post-marketing use ofbrimonidine tartrate
`ophthalmic solutions in clinical practice. Because they are reported voluntarily from a
`population of unknown size, estimates of frequency cannot be made. The events, which have
`been chosen for inclusion due to either their seriousness, frequency ofreporting, possible causal
`connection to brimonidine tartrate ophthalmic solutions, or a combination of these factors,
`include: bradycardia; depression; keratoconjunctivitis sicca; iritis; miosis; nausea; skin reactions
`(including erythema, eyelid pruritis, rash, and vasodilation); and tachycardia. Apnea,
`bradycardia, hypotension, hypothermia, hypotonia, and somnolence have been reported in infants
`receiving brimonidine tartrate ophthalmic solutions.
`
`OVERDOSAGE
`No information is available on overdosage in humans. Treatment of an oral overdose includes
`supportive and symptomatic therapy; a patent airway should be maintained.
`
`DOSAGE AND ADMINISTRATION
`The recommended dose is one drop of Alphagan. -
`approximately 8 hours apart.
`
`in the affected eye(s) three times daily,
`
`Alphagan - · ophthalmic solution may be used concomitantly with other topical ophthalmic
`drug products to lower intraocular pressure. If more than one topical ophthalmic product is
`being used, the products should be administered at least 5 minutes apart.
`
`HOW SUPPLIED:
`
`Alphagan -
`1 is supplied sterile in opaque teal LDPE plastic bottles and droppers with purple
`high impact polystyrene (HIPS) caps as follows:
`
`7
`
`Slayback Exhibit 1063, Page 18 of 70
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`

`

`Labeling Review Review l - March 28, 2005
`Martin P. Nevitt, M.D., M.P.H.
`NDA 21-770: N-000
`Brimoniciine Tartrate Ophthalmic Solution, 0.1 %
`Alphagan -
`
`Reviewer's comments:
`
`Per discussion with the chemistry team leader, the How Supplied section has been revised.
`
`5 mL in 1 0mL bottle
`
`NDC XXXX-XXXX-XX
`
`10 mL in 10 mL bottle
`
`NDC XXXX-XXXX-XX
`
`15 mL in 15 mL bottle
`
`NDC XXXX-XXXX-XX
`
`NOTE: Store at 15°-25°C (59-77°F).
`
`Rx Only
`
`©2004 Allergan, Inc.
`
`Irvine, CA 92612, U.S.A.
`
`9541X
`
`® Marks owned by Allergan
`
`US Pat. 5,424,078; 5,736,165; 6,194,415; 6,248,741
`
`Recommendation:
`
`8
`
`Slayback Exhibit 1063, Page 19 of 70
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`

`

`Labeling Review Review 1 - March 28, 2005
`Martin P. Nevitt, M.D., M.P.H.
`NDA 21-770; N-000
`Alphagan -
`Brimonidine Tartrate Ophthalmic Solution, 0.1 %
`
`It is recommended that NDA 21-770 be approved with the changes to the label noted in this
`review.
`
`Martin P. Nevitt, M.D., M.P.H.
`Medical Officer
`
`Cc:
`NDA21-770
`HFD-5 50/PM/Puglisi
`HFD-550/TL/Ng
`HFD-550/TLNang
`HFD-550/MO/Nevitt
`HFD-550/TL/Boyd
`HFD-550/DepDir/Chambers
`
`9
`
`Slayback Exhibit 1063, Page 20 of 70
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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/
`
`Martin Nevitt
`3/29/05 02:21:11 PM
`MEDICAL OFFICER
`
`William Boyd
`3/29/05 02:33:02 PM
`MEDICAL OFFICER
`
`Wiley Chambers
`3/29/05 03:30:18 PM
`MEDICAL OFFICER
`
`Slayback Exhibit 1063, Page 21 of 70
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Division Director's Review of NDA
`
`Original New Drug Application
`
`Submission Date:
`Review Completed:
`
`May 27, 2004
`March 31, 2005
`
`Deputy Division Director:
`
`Wiley A. Chambers, MD
`
`Trademark:
`Established Name:
`
`Applicant:
`
`Alphagan.-
`brimonidine tartrate ophthalmic solution
`
`Allergan, Inc.
`2525 Dupont Drive
`P.O. Box 19534
`
`Pharmacologic Category:
`
`Alpha-2 agonist
`
`Proposed Indication:
`Dosage Form:
`Route of Administration:
`NDA Drug Classification:
`
`Reduction of intraocular pressure
`Ophthalmic solution
`Topical ocular
`3S
`
`Table of Contents
`I. Recommendations ......................................................................................................................................... 1
`A.
`Recommendation on Approvability ........................................................................................................... 1
`Recommendation on Postmarketing Studies and/or Risk Management Steps .............................................. 1
`B.
`II.
`Summary of Clinical Findings ................................................................................................................ 2
`A.
`Brief Overview of Clinical Program .......................................................................................................... 2
`B.
`Efficacy .................................................................................................................................................... 2
`C.
`Safety ....................................................................................................................................................... 2
`D.
`Dosing, Regimen, and Administration ....................................................................................................... 2
`III.
`Reviews from Chemistry, Animal Pharmacology and Toxicology, and/or Microbiology ..................... 3
`Labeling .................................................................................................................................................. 3
`IV.
`
`I. Recommendations
`A. Recommendation on Approvability
`NDA 21-770 is approvable for lowering intraocular pressure in patients with open-angle
`glaucoma or ocular hypertension following the resolution of the manufacturing
`deficiencies, manufacturing compliance with current Good Manufacturing Practices
`(cGMPs) and submission ofrevised labeling.
`
`B. Recommendation on Postmarketing Studies and/or Risk Management Steps
`No postmarketing studies are recommended. No risk management steps are
`recommended.
`
`Slayback Exhibit 1063, Page 22 of 70
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`· Division Director's Review of ND~
`
`II. Summary of Clinical Findings
`A. Brief Overview of Clinical Program
`Ocular hypertension is defined as high intraocular pressure (IOP) and may lead to optic
`nerve head abnormalities and visual field defects. Currently there is no proven direct
`treatment for optic neuropathy regardless of the initiating cause. Therapy is focused on
`lowering the intraocular pressure. Presently, five classes of drugs are used to reduce IOP:
`adrenergic beta-receptor antagonists; cholinergic agonists; adrenergic agonists, carbonic
`anhydrase inhibitors; and prostaglandin/prostaglandin analogs.
`
`The new drug product proposed in this application is a reformulation ofbrimonidine
`tartrate ophthalmic solution, lowering the concentration to 0.1 %. The application
`included the results of a clinical bioequivalence study (190342-021) in which the
`proposed new drug product demonstrated bioequivalence with Alphagan (brimonidine
`tartrate ophthalmic solution) 0.2%.
`
`B. Efficacy
`Efficacy is based on the applicant's studies supporting NDA 20-613, Alphagan
`(brimonidine tartrate ophthalmic solution), 0.2% and NDA 21-262, Alphagan P
`(brimonidine tartrate ophthalmic solution), 0.15%. Study 190342-021 provides a link to
`Alphagan through clinical bioequivalence. The Division's definition of clinical
`bioequivalence with respect to efficacy (95% confidence interval within lmmHg at the
`majority of time points and within l.5mmHg at all times points in a 3 month study
`evaluating peak and trough time points) has been met.
`
`C. Safety
`Safety is based on the applicant's studies in NDA 20-613, Alphagan (brimonidine tartrate
`ophthalmic solution), 0.2% and NDA 21-262, Alphagan P (brimonidine tartrate
`ophthalmic solution), 0.15%. Study 190342-021 provides a link to Alphagan through
`clinical bioequivalence and no new issues of safety have been identified in the clinical
`bioequivalence study.
`
`D. Dosing, Regimen, and Administration
`In the clinical studies evaluating safety, efficacy and bioequivalence, one drop of
`brimonidine tartrate ophthalmic solution was administered three times daily to the
`affected eye.
`
`2
`
`Slayback Exhibit 1063, Page 23 of 70
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`'<:1;v Division Director's Review of NDAl ..
`
`Ill. Reviews from Chemistry, Animal Pharmacology and Toxicology, and/or Microbiology
`
`Reviews have been completed from Chemistry/Manufacturing, Non-clinical
`Pharmacology/Toxicology, Microbiology (sterility assurance), Clinical Pharmacology, and the
`Division of Drug Marketing, Advertising and Communications (DDMAC). There are several
`unresolved issues with respect to sterility assurance and compliance with current good
`manufacturing practices at the manufacturing facility in Waco, TX. This facility was not found
`to be in compliance with cGMPs and was issued a 483 in January 2005. These issues involved
`in the inspection will need to be satisfactorily resolved prior to approval of the application.
`
`IV. Labeling
`
`Labeling is based on the labeling of Alphagan (brimonidine tartrate ophthalmic solution) 0.2%
`and Alphagan P (brimonidine tartrate ophthalmic solution) 0.15% and includes formulation
`specific changes. Additional proposed claims with respect to the contribution of the drug
`product's increased pH to the bioavailability of the drug substance have not been supported in
`the application and have not been included in the proposed labeling.
`
`Review by the Division of Medication Errors and Technical Support in the Office of Drug
`Safety, does not recommend the use of the name Alphagan ._ The recommendation is based on
`belief that the ... is "not a necessary modification of the proprietary name, Alphagan and may
`be misinterpreted to mean purite free since it does not use the modifier 'P' ." The review
`suggests that the products may be sufficiently differentiated with the prominent labeling of their
`respective strengths. The Division disagrees with this assessment. The products Alphagan,
`have been found to be equivalent to each other with respect to
`Alphagan P and Alphagan. -
`safety and efficacy in spite of their different concentrations ofbrimonidine. Efforts to
`differentiate them with prominent labeling of their respective strengths would be potentially
`misleading. Confusion between the products, even if it is to occur, is not likely to be clinically
`meaningful because of the clinical equivalence. It is not clear that failing to include the letter P
`in the trademark will necessarily be interpreted to mean purite free and the inclusion or exclusion
`ofpurite has never been shown to have a more clinically meaningful effect on the drug product
`compared to any other preservative. To the extent that the letter P has differentiated the
`products in the past, the letters-. should do the same in the future and the Division believes that
`it is an appropriate level of distinction. Additionally, there is no evidence that the modifier -
`has resulted in any clinical harm as it has been applied to another of Allergan's products, -
`
`.,,,,.
`
`3
`
`Slayback Exhibit 1063, Page 24 of 70
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/s/
`
`Wiley Chambers
`4/1/05 08:26:37 AM
`MEDICAL OFFICER
`
`Wiley Chambers
`4/1/05 08:36:04 AM
`MEDICAL OFFICER
`
`Slayback Exhibit 1063, Page 25 of 70
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Clinical Review
`Martin P. Nevitt, M.D., M.P.H.
`NDA 21-770; N-000
`Alphagan _. Brimonidine Tartrate Ophthalmic Solution, 0.1 %
`
`CLINICAL REVIEW
`
`Application Type NDA 21-770
`Submission Number 000
`Submission Code Original
`
`Letter Date 5/27 /04
`Stamp Date 6/1/04
`PDUFA Goal Date 4/1/05
`
`Reviewer Name Martin P. Nevitt, M.D., M.P.H.
`Review Completion Date 3/18/05
`
`Established Name Brimonidine Tartrate Ophthalmic
`Solution, 0.1 %
`
`(Proposed) Trade Name Alphagan ~
`Therapeutic Class Alpha 2 -agonist
`Applicant Allergan, Inc.
`2525 Dupont Drive
`P.O. Box 19534
`Irvine, CA 92623-9534
`714-246-4500
`FAX: 714-246-4272
`
`Lewis Gryziewicz
`714-246-6088
`
`Priority Designation S
`
`1
`
`Slayback Exhibit 1063, Page 26 of 70
`Slayback v. Eye Therapies - IPR2022-00142
`
`

`

`Clinical Review
`Martin P. Nevitt, M.D., M.P.H.
`NDA 21-770; N-000
`Alphagan. Brimonidine Tartrate Ophthalmic Solution, 0.1 %
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`Table of Contents
`EXECUTIVE SUMMARY ............................................................................................................. ; ........... 5
`I.I
`RECOMMENDATION ON REGULATORY ACTION ....................................................................................... 5
`1.2
`RECOMMENDATION ON POSTMARKETING ACTIONS ................................................................................ 5
`1.2.1
`Risk Management Activity ......................................