Cr E>
`Wiia}iie
`
`SLAYBACK EXHIBIT 1008
`
`|i
`
`U
`
`|
`
`i}
`
`Page 1 of 3
`
`
`
`i.
`
`omen ee
`
`
`
`Page 1 of 3
`
`SLAYBACK EXHIBIT 1008
`
`

`

`lAY 1 2 2004
`
`EDIT I ON
`
`1998
`PHVSCANS'
`DESK
`/ REFERENCE®
`
`I ,.
`
`-•
`
`r r
`
`'"#'
`
`..
`
`Medical Consultant
`Ronald Arky, MD, Charles S. Davidson Professor of Medicine and Master, Francis Weld Peabody Society, Harvard Medical School
`
`Vice President of Directory Services: Stephen B. Greenberg
`
`Product Manager: Mark A. Friedman
`National Sales Manager: Dikran N. Barsamian
`National Account Manager, Customized Projects: Anthony Sorce
`Senior Account Manager: Donald V. Bruccoleri
`Account Managers:
`Marion Gray, RPh
`Lawrence C. Keary
`Jeffrey F. Pfoh I
`Stephen M. Silverberg
`Suzanne E. Yarrow
`Director of Trade and Direct Marketing Sales: Robin B. Bartlett
`National Sales Manager, Trade Group: Bill Gaffney
`Promotion Manager: Donna R. Lynn
`Director, Professional Support Services: Mukesh Mehta, RPh
`Senior Drug Information Specialist: Thomas Fleming, RPh
`Drug Information Specialist: Maria Deutsch, MS, RPh, CDE
`Editor, Special Projects: David W. Sitton
`
`Vice President of Production: David A. Pitler
`Director of Print Purchasing: Marjorie A. Duffy
`Director of Database Services: Lynne Handler
`Director of Production: Carrie Williams
`Manager of Production: Kimberly Hiller-Vivas
`Senior Production Coordinators: Amy B. Brooks, Dawn B. McCall
`Production Coordinator: Mary Ellen R. Breun
`Index/Format Manager: Jeffrey D. Schaefer
`Senior Format Editor: Gregory J. Westley
`Assistant Index Editor: Johanna M. Mazur
`Art Associate: Joan K. Akerlind
`Electronic Publishing Coordinator: Joanne M. Pearson
`Senior Digital Imaging Coordinator: Shawn W. Cahill
`Digital Imaging Coordinator: Frank J. McElroy, Ill
`Electronic Publishing Designer: Robert K. Grossman
`Fulfillment Managers: Stephanie DeNardi, Stephen Schweikhart
`
`!!l!-.!!!!! Copyright© 1998 and published by Medical Economics Company, Inc. at Montvale, NJ 07645-1742. All rights reserved. None of the content of this pub(cid:173)
`• • ilcat1on may be reproduced, stored m a retneval system, resold, red1stnbuted, or transmitted in any form or by any means (electromc, mechanical, pho-
`tocopying, recording, or otherwise) without the prior written permission of the publisher. PHYSICIANS' DESK REFERENCE®, PDR®, PDR For Nonprescription
`Drugs®, PDR For Ophthalmology®, Pocket PDR®, and The PDR® Family Guide to Prescription Drugs® are registered trademarks used herein under license. PDR
`Companion Guide'M, PDR® Generics'M, PDR® Medical Dictionary"'· PDR® Nurse's Handbook'M, PDR® Nurse's Dictionary"'. The PDR® Family Guide to Women's
`Health and Prescription DrugsrM, The PDR® Family Guide to Nutrition and Health'M, The PDR® Family Guide Encyclopedia of Medical Care'M, PDR® Electronic
`LibraryTM, and PDR® Drug Interactions, Side Effects, Indications, Contraindications Disk~ttes'M are trademarks used herein under license.
`
`Officers of Medical Economics Company: President and Chief Executive Officer: Curtis B. Allen; Vice President, Human Resources: Pamela M. Bilash; Vice
`President and Chief Information Officer: Steven M. Bressler; Vice President Finance and Chief Financial Officer: Thomas W. Ehardt; Executive Vice President and
`Chief Operating Officer: Rick Noble; Executive Vice President, Magazine Publishing: Thomas F. Rice; Senior Vice President, Operations: John R. Ware
`
`® Printed on recycled Paper
`
`ISBN: 1-56363-251-9
`
`Page 2 of 3
`
`SLAYBACK EXHIBIT 1008
`
`

`

`temperature 15-30'C (59-86'F)
`at controlled r~omht CAUTION: Federal (U.S.A.) law
`lltOJ1'
`. n from hg
`.
`.
`. t'
`. without prescr~p wn.
`'tb protect•o
`~;bits dispens!D~89 969. 4 454,151; 5,110,493
`U"".s'=' patent Nos. ~·
`d' t a' d~mark of Syntex (U.SA) Inc.,
`msterer
`·
`I
`d
`.
`,ACULAR®, a re.,. nd distributed by Allergan, nc. un er
`Ia 111anufnctu.red/ Ioper Syntex (U.S.A.) Inc., Palo Alto,
`'
`Jictnse from •ts eve
`eaJifornia, U.S.A.
`
`jLLERGAN
`01997 A)Jergan, Inc.
`fr9ine, CA 92612 -------
`ALPHAGA~®rtrate ophthalmic so.lutionl 0.2%
`lbrimonldlne a
`
`.
`.
`DESCJUPTION
`AN® (brimonidine tartrate ophthali!'IC solutiO~)
`ALP~G 1 t' ely selective alpha-2 adrene~g~c agomst for
`0.2'l•• a ~:.;~The chemical name of bri?tonidin~ tartr~te
`~phtbalmlc0_6.(Z-imidazolidinylideneammo) qm?oxahne
`II 5-brom It is an off-white pale yellow to pale pmk pow(cid:173)
`J.,..tartra~. t' n ALPHAGAN® has a clear, greenish-yellow
`der. I~ ~ u ~0m'olecular weight of 442.24 as the tartrate salt
`color: t 88
`r soluble (34 mg/mL). The molecular formula is
`and 1s wa e
`1
`C H .,BrN5·C•HsOs.
`.
`.
`Afp~GAN® (brimonidine ta;trate o~hthalm1c solution)
`2'1 is a sterile ophthal~1c solutwn. Each mL of
`0
`.Ai.PHAGAN® Solution contams:
`.
`ACTIVE: brimonidine tartrate 2 mg (eqmvalent to 1.32 mg
`·
`88 brimonidine free base).
`PRESERVATIVE: benzalkonium chlo~de (0.05 !"g)
`.
`INACTIVES: polyvinyl alco.hol; sodmm ch)or1de; s.odm~
`citrate· citric acid; and pur~fied water. Hydrochlonc ac1d
`and/or' sodium hydroxide may be added to adjust pH (6.3-
`6.5).
`C~CALPHAJUKACOLOGY
`MH/Ianism of Action
`ALPHAGAN® is an alpha adrenergic receptor !lgonist. 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 duaJ·mech(cid:173)
`anism of action by reducing aqueous humor production and
`increasing uveoscleral outflow.
`l'llamracokinetics
`After ocular administration of a 0.2% solution, plasma con(cid:173)
`centrations peaked within 1 to 4 hours and declined with a
`systemic half-life of approximately 3 hours.
`.
`In humans, systemic metabolism of brimonidine is exten(cid:173)
`sive. It is metabolized primarily by the liver. Urinary excre(cid:173)
`tion is the major route of elimination of the drug and its
`metabolites. Approximately 87% of an orally-administered
`radioactive dose was eliminated with 120 hours, with 74%
`found in the urine.
`CllniCIJI Studies
`Elevated lOP presents a major risk factor in glaucomatous
`~eld loss. The higher the level of lOP, the greater the like(cid:173)
`hhood of optic nerve damage and visual field
`loss.
`ALPHAGAN® has the action of lowering intraocular pres(cid:173)
`sure with minimal effect on cardiovascular and pulmonary
`parameters.
`In comparative clinical studies with timolol 0.5%, lasting up
`to one .Year, the lOP lowering effect of ALPHAGAN® was
`apprmomately <Hi mm Hg compared with approximately 6
`mm Hg for timolol. In these studies, both patient groups
`wereAL dosed BID, however, due to the duration of action of
`PHAGAN®, it is recommended that ALPHAGAN® be
`~sed TID: Eight percent of the subjects were discontinued
`m stud1es due to inadequately controlled intraocular
`~ressure, which in 30% of these patienta occurred during
`U: first month of therapy. Approximately 20% were discon-
`
`ued due to adverse experiences.
`INDICATIONS AND USAGE
`!!!':'AGAN® is indicated for lowering intraocular pres(cid:173)
`te
`. m patients with open-angle glaucoma or ocular hyper(cid:173)
`thn~10?· The ~OP lowering efficacy of ALPHAGAN® Oph(cid:173)
`Th~ ~lc Solutwn diminishes over time in some patients.
`ea:h os:. of effect appears with a variable time of onset in
`pa lent and should be closely monitored.
`CON1'RAINDICATIONS
`~~?AN~ is c?n.traindicated in patients with hypersen(cid:173)
`medi \ 0 brm~omdme tartrate or any component of this
`moo:: •on. It _'S also contraindicated in patients receiving
`mme ox•dase (MAO) inhibitor therapy . .
`p
`RECAUTIONS
`.
`General· Alth
`blOOd
`·
`ough ALPHAGAN® had minimal effect on
`be exir~~ss~~e of patients in clinical studies, caution should
`disease ISe m treating patients with severe cardiovascular
`ALP
`.
`.
`or .. :~AN® .has not been studied in patients with hepatic
`•ueb Pat'unpaJrment; caution should be used in treating
`Ients.
`
`ALPHAGAN® should be used with caution in patients with
`depression, cerebral or coronary insufficiency, Raynaud's
`phenomenon, orthostatic hypotension or thromboangitis
`obliterans.
`During the studies there was a loss of effect in some
`patients. The
`lOP-lowering efficacy observed with
`ALPHAGAN® Ophthalmic Solution during the first month
`of therapy may not always reflect the long-term level ofiOP
`reduction. Patients prescribed lOP-lowering medication be
`routinely monitored for lOP.
`in
`preservative
`for Patients: The
`Information
`ALPHAGAN®, benzalkonium chloride, may be absorbed by
`soft contact lenses. Patients wearing soft contact lenses
`should be instructed to wait at least 15 minutes after instill(cid:173)
`ing ALPHAGAN® to insert soft contact'lenses.
`Aa 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: Although specific drug interaction stud(cid:173)
`ies have not been conducted. with ALPHAGAN®, the
`possibility of ap additive or potentiating effect with CNS
`depressants (alcohol, barbituates, opiates, sedatives, or an(cid:173)
`esthetics) should be considered. ALPHAGAN® did not have
`significant effects on_ pulse and blood pressure in clinical
`studies. However, , since alpha-agonists, as a class,
`may reduce pulse and blood pressure, caution in using con(cid:173)
`comitant drugs such as beta-blockers (ophthahnic and sys(cid:173)
`temic), antihypertensives and/or cardiac glycosides Is
`advised.
`'J'r!icyclic 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® can lead to an interference in lOP lowering
`effect. No data on the level of circulating catecholamines
`after ALPHAGAN® is instilled are available. Caution, how(cid:173)
`ever, is advised in patients taking tricyclic antidepressants
`which can . affect the metabolism and uptake of circulating
`amines.
`Carcinogenesis, mutagenesis, impairment of fertility: No
`compound-related carcinogenic effects were observed in 21
`month and 2 year. studies in mice and rate given oral doses
`of 2.5 mg/kg/day (as the free base) and 1.0 mg/kg/day,
`respectively (~7.7 and 118 times, respectively. the human·
`plasma drug concentration following the recommended oph(cid:173)
`thalmic dose).
`ALPHAGAN®.was not mutagenic or cytogenic in a series of
`in uitro and in uiuo studies including the Ames test, host(cid:173)
`mediated assay, chromosomal .aberration assay in Chinese
`Hamster· Ovary (CHO) cells, cytogenic studies in mice and
`dominant lethal assay.
`Pregnancy: Teratogenic Effects: Pregnancy Category B.
`Reproduction studies performed in rats with oral doses of
`0.66 mg base/kg revealed no evidence of impaired fertility or
`harm to the fetus due to ALPHAGAN®, Dosing at this level
`produced 100 times the plasma drug concentration level
`seen in humans following multiple ophthalmic doses.
`There are no studies of ALPHAGAN® in pregnant women;
`however in animal studies, brimonidine crossed. the pla(cid:173)
`centa and entered into the fetal circulation to a limited ex(cid:173)
`tent. ALPHAGAN® should be used during pregnancy only if
`the potential benefit to the mother justifies the potential
`risk to the fetus.
`Nursing Mothers: It is not known whether ALPHAGAN® is
`excreted in.human milk,. although in animal studies, bri-·
`monidine tartrate has been shown to be 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: Safety and effectiveness in pediatric patients
`have not been established.
`ADVERSE REACTIONS
`Adverse events occurring in approximately 10-30% of the
`subjects,.in descending order of incidence, included oral dry(cid:173)
`ness, ocular hyperemia, burning and stinging, headache,
`blurring, foreign body sel)Sation, fatigue/drowsiness, con(cid:173)
`junctival follicles, ocular allergic reactions, and ocular pru(cid:173)
`ritus.
`Events occurring in approximately 3-9% of the subjects, in
`descending order included corneal staining/erosion, photo(cid:173)
`phobia, eyelid erythema, ocular ache/pain, ocular drytiess,
`tearing, upper respiratory symptoms, eyelid edema, con(cid:173)
`junctiva) edema, dizziness, blepharitis, ocular irritation,
`gastrointestinal symptoms, asthenia, conjunctival blanch(cid:173)
`ing, abnormal vision and muscular pain.
`'l)le following adverse reactions were reported in less than
`3% of the patients: lid crusting, conjunctival hemorrhage,
`abnoflnl!i taste, insomnia, conjunctival. discharge, depres(cid:173)
`sion, hypertension, anxiety, palpitations, nasal dryness and
`syncope.
`OVERDOSAGE
`No information is available on ,overdosage in humans.
`Treatment of an oral overdose includes supportive and
`symptomatic therapy; a patent airway should be main(cid:173)
`tained.
`
`ALLERGAN, INC./487
`
`DOSAGE AND ADMINISTRATION
`The recommended dose is one drop of ALPHAGAN® in the
`affected eye(s) three times daily, approximately 8 hour~
`apart.
`HOW SUPPLIED
`ALPHAGAN® (brimonidine tartrate ophthalmic solution)
`0.2% is supplied sterile in white opaque plastic dropper
`bottles as follows:
`5 mL NDC 0023-8665-05
`10 mL NDC 0023-8665-10
`15 mL NDC 0023-8665-15
`NOTE: Store at or below 25' C (77' F).
`CAUTION: Federal (U.S.A.) law prohobits dispensing with(cid:173)
`out prescription.
`ALLERGAN
`©January 1997 Allergan, Inc., Irvine, CA 92612
`70830/UC
`
`AZELEX®
`(azelaic acid cream) 20%
`For Dermatologlc Use Only
`Not for Ophthalmic Use
`
`DESCRIPTION
`AZELEX® (azelaic acid cream) 20% contains azelaic acid, a
`naturally occurring saturated dicarboxylic acid.
`Structural Formula: HOOC-(CH2h-COOH. Chemical
`Name: 1,7-heptanedicarboxylic acid. Empirical .Formula:
`C9H160 4• Molecular Weight: 188.22.
`Active Ingredient: 'Each gram· of AZELEX® contains aze-
`laic acid ............. .................. .. ........... 0.2 gm (20% w/w).
`Inactive Ingredients: cetearyl octanoate, glycerin, glyceryl
`stearate and cetearyl alcohol and cetyl palmitate and
`cocoglycerides, PEG-5 glyceryl stearate, propylene glycol
`and purified water. Benzoic acid is present as a preserva(cid:173)
`tive.
`
`CL~CALPHARMACOLOGY
`The exact mechanism of action of azelaic acid is not known.
`The following in uitro data are available, but their clinical
`significance is unknown. Azelaic acid has been shown to
`possess antimicrobial activity against Propionibacterium
`acnes and Staphylococcus epidermidis. The antimicrobial
`action may be attributable to inhibition of microbial cellular
`protein synthesis.
`A noflnalization of keratinization leading . to an anticome(cid:173)
`donal effect of azelaic acid may also contribute to its clinical
`activity. Electron microscopic and immunohistochemical
`evaluation of skin biopsies from human subjecte treated
`with AZELEX® demonstrated a reduction in the thickness
`of the stratum corneum, a reduction in number a:nd size of
`keratohyalin granules, and a reduction in the amount and
`distribution offilaggrin (a protein component of keratohya(cid:173)
`lin) in epide=al layers. This is suggestive of the ability to
`·
`decrease microcomedo fo=ation.
`Pharmacokinetics: Following a single application of
`AZELEX® to human skin in uitro, azelaic acid penetrates
`into the stratum corneum (approximately 3 to 5% of the
`applied dose) and other viable skin layers (up to 10% of the
`dose is found in the epidermis and de=is). Negligible cuta(cid:173)
`neous metabolism occurs after topical applkation. Approxi(cid:173)
`mately 4% of the ·topically applied azelaic acid is systemi(cid:173)
`cally absorbed. Azelaic acid is mainly excreted unchanged in
`the urine but undergoes some !3-oxidation to shorter chain
`dicarboxylic acids. The observed half-lives in healthy sub(cid:173)
`jects are approximately 45 minutes after oral dosing and 12
`hours after topical dosing, indicating percutaneous absorp(cid:173)
`tion rate-limited kinetics.
`Azelaic acid is a dietary ·constituent (whole grain cereals
`and animal products), and can be formed endogenously from
`longer-chain dicarboxylic acids, metabolism of oleic acid,
`and w-oxidation of monocarboxylic acids. Endogenous
`plasma concentration (20 to 80 ng/mL) and daily urinary
`excretion (4 to 28 mg) of.azelaic acid are highly dependent
`on dietary intake. After topical treatment with AZELEX® in
`humans, plasma concentration and urinary excretion of
`azelaic acid are not significantly different from baseline lev(cid:173)
`els.
`INDICATIONS AND USAGE
`AZELEX® is indicated for the topical treatment of mild-to(cid:173)
`moderate inflammatory acne vulgaris.
`
`CONTRAINDICATIONS
`AZELEX® is contraindic'ated in individuals who have
`shown hypersensitivity to .any of its components.
`WARNINGS
`AZELEX® is for dermatologic use only and· not for ophthal(cid:173)
`mic use.
`
`Consult 1 9 9 8 PDR~ supplements and future editions for revisions
`
`Continued on next page
`
`Page 3 of 3
`
`SLAYBACK EXHIBIT 1008
`
`