`
`Q”
`60
`
`EDITION
`
`2006
`
`one9W5 BremenLu-
`
`DEC 012005
`
`RECEIVED
`
`
`
`PHYSICIANS
`DESK
`REFERENCE
`
`Senior Vice President. FDR Sales and Marketing leran N. Bersamian
`Vioe Pruidont. Product Management: William T. Hicks
`Vice President. Rearletory Allolro: Mukeeh Mehta. RFh
`Vice President, PDii Servioee: Brian Holland
`Senior Directoro, Pinnnaceutical Solutions Sales: Chantal Comes,
`Anthony Sorce
`Notional Solutions Managers: Frank Kamowsky. Marlon Reid. RPh
`Senior Solutions Managua: Debra Goldman. Elaine Musco.
`Warner Stuart. Suzanne E. Yarrow, RN
`Solutions Mm: Eileen Bruno. Cory Coleman. Marjorie A. Jaxel.
`Kevin McGlynn. Lois Smith. Richard Zwlckel
`Sales Coordlnetcro: Arlene Phayre. Janet Wallendal
`Senior Director, Brand and Product Management: Valerie E. Berger
`Associate Product Managua: Michael Caeale. Andrea Colavecchlo
`Senior Director, Publishing Solo. and Marketing: Michael Bennett
`Director, Trade Salas: Bill Gaffney
`Aeeoclate Director. Marketing: Jennifer M. Fronzaglla
`Senior Marketing Manager: Kim Marlch
`Direct Mail Manager: Lorraine M. Leaning
`Manager. Marketing Anaiyoio: Dina A, Maeder
`Promotion Manager: Linda Levine
`Director oi Operations: Robert Klein
`Director, PDR Operations: Jeffrey D. Schaefer
`Director oi Finance: Mark S. Ritchln
`
`
`Director, Client Services: Stephanie Struble
`Director. clinical content: Thomas Fleming, PharmD
`Director. Editorial em: Bette LaGow
`Drug lniorrnation Specialists: Michael DeLuca, PharrnD, MBA;
`Kaial Solankl. PharrnD; Greg Taiils. RPh
`Project Editors: Nell Chesanow, Harrie Fleming
`Senior Editor: Lori Murray
`Senior Production Editor: Gwynned L. Kelly
`Manager, Production Purchasing: Thomas Westburgh
`FDR Production Manager: Steven Mailer
`Producdon Manager: Gayle Grelzzaro
`Production Specialiet: Christina Klinger
`Senior Won Coordinatora: Glenna Caradonna. Yasmin Hernandez
`Production coordinator: Nick W. Clark
`Senior index Editoro: Noel Deloughery. Shannon Reilly
`Format Editor: Michelle 6. Auffent
`Troilic Aaeietant: Kim Condon
`Production Design Supervisor: Adeline Rich
`Senior Electronic Publishing Designer: leio Udina
`Electronic Publishing Deeignere: Bryan C. Dix, Carrie Faeth.
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`organ Imaging Manager: Christopher Husted
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`
`THOMSON Copyngmczoofl and published by Thurman Fun at Montvaie. NJ 07845-1742. All rights reserved. Nona ol the cement at this publication
`*
`.. may be reproduced. stored in a retrieval system. reeoid. redistribmad. ortranemitted in any lonn or by any means (electronic. mechanical.
`photocopying. recording. or otherwise) without the prior written permission of the publisher. Physicians' Desk Relerence'. PDR‘. Pocket
`PDR
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`Nutrition and Health- are registered trademarks used herein under license PDR‘ tor Ophthalmic Machines. PDR' tor Nonprescription Drugs and Dietary Supplements. PDH‘
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`Nurse's Dictionary. PDR‘ Family Guide Encyclopedia oi Medical Care. PDR' Family Guide to Natural Medicines and Healing Therapies. PDR' Family Guide to Common
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`
`Officers oi Thornton iioalthcare. lnc.: President and Cir/er Executive Officer.- Kevin King; Chief Financial Officer: Paul Huger: cnlef Med/cal Officer: Rich Klaeco. MD. FACEP:
`Executive Vice President. Medsrac Carol Diephuis: Executive Woe President. Mrcromedex. left Reihl; Senior Vice President. Marketing: Timothy Murray; Senior Vice President,
`Technology Michael Karaman; Vrce Pros/dent. finance: Joseph Scarlone, Vice President Human Resources: Pamela M. Biiash
`
`Page 1 of 5
`
`LUPIN EX. 1019
`
`Page 1 of 5
`
`LUPIN EX. 1019
`
`

`

`PRODUCT lNFORMATlON UCYCLYD/3323
`
`
`
`HOW SUPPIJED
`HOW SUPPLIED
`whether to discontinue nursing or to discontinue the drug,
`
`wiring into account the importance of the drug to the
`mother
`
`
`TUSSIONEX Peonklnetit (hydrocndona pollshrax and
`ZAROXOLYN Tablets (motolnzonc tableta. USP) are shal-
`low hiconvex. round tablets, and are available in three
`chlorphemramine polistirea) Extendedifioleaee Suspension
`mogul.-
`is a gold-colored suspension. .
`Pediatric Use: Safety and etfectivenese of tHSSlQNF-X
`
`
`
`
`.
`P-an-ueuc Extendedvkvlaaos Suspension m radiator
`soc maimed-I m mi. bottle.
`2w inn-pink. dehosssd momm- an m min. and
`GSA
`
`in under u: have not been ambushed Cm Shake well. com in a mum-m container. Eton: at
`Pat!
`swan reverse side.
`
`
`
`
`59'588'17 (lfi'oWC).
`NDC 5&016~9’1§-71 Bottled? 100's
`
`
`come Use; Clinical studieg ormssléNEx didnot l9'
`commmm tno.
`.
`NDC sacres'lsoso Bottle of 1000‘s
`
`
`and over tode- Mum NY 14323 USA
`NDC 53014-975312 Barton ni‘ 100's. unit dose
`clude ruflclent numbers ofsulueets aged.
`
`
`when whether they named difiareptiv mew «lb
`0 zoos. Cellioch Woes-u, inc.
`5 mg, blue. duh-sod 'ZAROKOLYN'nn one use and '5' on
`jects. Other reported clinical saperienm has not identified
`ravens aids.
`
`_
`O Celltscir Manufacturing, Inc.
`diderenus in reepopsps between the elderly and younger
`N90 631114460311 Halide of 100'.
`moon-rue PepnkinetinE Extended-Release Suspension:
`
`patients. in general, close selection for an elderly patient
`US Patent No. 4,763,709.:
`N09 6901+fl50-90 Bottle of 1000‘s
`
`
`should he cautious“ usually starting at the low and of the
`Current as of 08/2005
`LRMM
`
`
`NDC 63014—850472 Carton of 100’s. unit dose
`
`dosing range. reflecting the greater frequency of deemed
`Hoe 12m
`10 mg, yellow, dchosssd ‘ZABDXQLYN‘ on one side. and
`
`hepatic. renal, or cardiac Motion. and of concomitant dip-
`l‘iiJ' on reverse side.
`esse or other dnig therapy.
`-
`NDC 5301+835-7l Bottle of [We
`
`Thisdruaisknown mhssuhetnntiallyemtedbythekid-
`NDQ 5801688580 Bottle M10005
`
`nay. and the risk of toxic reactions to this drug may be
`NBC 53014-835413 Carton of 10%. unit dose
`greater in patients with impaired renal flmcfian. Demons
`
`VICONm Ceps'uies
`3
`
`Store at iifi'C (7TB). unusions permitted to more (59'-
`elderly patients are more likely to have demand renal
`[urban {or'tdl
`Ba‘l?) (See USP Gootroilsd Room Temperature). Protect
`Thor
`Vitamins-Minerals
`function. care should be taken in dose selection. and it may
`
`
`from light. Keep out oi‘ths reach ofchildren.
`beuesfidmmonltormnaihmcdoo.
`WHWM
`Eon
`‘
`
`sovcs‘an assmous
`Meme NY 14823 USA
`DESCRIPTION
`Conn-Ii Nervous System: Sedation. drew-ins“, mental
`0 00“” Mmufictuflns. Inc-
`
`Eech black and orange VICON FOR'I'EO capsule for oral
`clouding, lethargy, impairment of mental and physical per-
`0 2003. Oolltcch “3”“qu
`
`
`administration contains:
`furmanos, a'nxiety, fear. dyephoris, euphoria, diulness. psy-
`“1 “Eh“ Wed.
`Vitamin a .....
`chic dependence, mood changes.
`Gun-m u “9W5
`
`Vitamin E ..
`Dammit; Sync-n: Rash. pruritus.
`
`
`Ascorblc acid §
`x' ,
`<
`amusement Systsm: Nausea and vmtina may who.
`.
`,
`'
`t ’
`amh
`to
`'
`t
`
`
`patients. Prolonged administration of TUSSIONEX
`Zinc initiate U l”
`Ucvclyd Pharma. Inc.
`they are more honor:
`in
`ulo ry
`ur mum o
`Magnesium sulfate. USPl'
`.
`
`Niocinamide
`Pennkinstlc Extended-Release Suspension may produce
`8125 N. HAYDEN RD.
`
`
`constipation.
`Thiamine monenltrats ..
`SCOTTSDALE. AZ 86280
`Genitourinary System: Uretarsl spasm. spasm of vesicle
`
`sphincters and urinary retention have been reported with
`
`.
`opiates.
`
`
`Pennkinetic
`Pyridoxins hydrochloride
`Respiratory Depression: Tusslomni
`Folio acid
`..
`._
`..
`Extended-Release Suspension may produce dose-related
`
`Vitamio Bu (Cyanomhalamin)
`respiratory depression by acting directly on brain stain res-
`‘ As 50 my dried zinc sulfate.
`piratory centers (see OVERDOSAGE).
`1‘ As 60 mg dried magnesium sulfate
`Hum System: Dryness of the pharynx. occasional
`
`
`
`tightness ofthe chest.
`Each capsule also contains Edible ink. mac Blue No. l.
`B
`ouum
`W Red No. ‘0. mm Yellow No. 6. gelatin. law. All
`
`
`mum “m m ”Emma”
`magnesium mania. siilmn dioxide. sodium lsuryl sulfate.
`[am-mam!)
`TUSSIONEX Pennhinetic Extended-Release Suspension is
`
`
`and titanl
`dioxide:
`
`lsodluro manna-tags and sedan) Nomi urination
`
`a Schedule ll! narcotic. Psychic dependence, physical de-
`um
`
`lost I was
`.
`,
`.
`
`
`madness and tolerance rosy develop open repeated admin-
`HOW SUPPLIED
`Rx Only
`
`
`_
`intuition of narcotics; therefore, ’l'USSiONEX Pennkinstie
`Orange and black capsules imprlpted Inth ‘uch' and “316'
`
`
`
`
`rn bottles orsb moo snowmen) add 500 mod 60474- ”mama"
`Extended-Release Suspension should is prescribed and ad-
`ministered with caution However. psychic dependence is
` 318—24) and unit—dose who: 100 mm 6047Hit6-27).
`
`unlikely to develop when ’l'USSlONEX Pennkinstic
`
`momma (sodiumphonylacetste and sodium hennate‘l
`Dispense in tight, iiglrbresiitant container with s child-
`Extended-Release Suspension is usedfor a short time for
`moo 10%] 10% is a sterile concentrated, aqueous solu-
`mmgfi oiosiirfi
`'
`the treatment of cough. Physical dsddndcncs. the condition
`
`tion ofsodiui‘n’piienylam'etaia and sodium beacon“, used!"
`theirést‘msot of h
`mo‘nsmis in urea cycle disorders.
`prevent the appearance ate with
`syndrome. assumes
`in which continued administration F15 thhdrugis required tic
`
`Mp}! ofths sol
`unisltetwsen fl and 8. Sodium phony)
`mum:
`lacotata is a crystalline. white to ofl’dwhite powder with a
`clinically significant proportions only ads-r several weeks of
`~
`In,“
`-
`as" B
`strong odirnsi‘ve odor. it is soluble in water: Sodium henu'y
`
`.
`Hobé‘rt. NY 131”
`1): 1m not is'a whitesnd odorless, crystalline powder that ii
`wndnmdgdzguniafigdfipdflbr a to:lld1; atria:
`
`
`readily soluble m we:
`Zillion;
`.
`'
`'
`*-
`Cdrrcnt as ofomoos
`
`OWu. 'znr
`fl .
`’
`
`
`monorail-Gymnasium Serious ovardossgc with hydroce-
`done is characterized by respiratory depression (a decrees
`
`
`in respiratory rate andlon tidalvolnme, Choynsfitohss retr-
`lAROXOLYNO TABLETS
`B
`piration, cyanoais). extreme somnolenoe progressing to stir
`lzar ”ox ’uh-linl
`
`por outcome, skeletal musde. flaccidity. cold) and dammy
`immlsm table” USP)
`
`skim. and snmntimna‘ hradyeandia and hypotcasion. Al-
`B‘ on"
`9:
`.
`.
`i
`rhouglrmiusisis diaractarlstieofnareoflc overdose; mydri-
`oifismtoecurinotsrmioalnareomiirssvezshyponia. in
`eeverrnverdnasgeapnas', circulatory collapse. cardiac so
`06 NOT 4mm: oo nor m-reacnmos
`ownrseim sun omen FORMUMMNS or
`rastonddoadsmnyomm 'l'haiuanifsatauonsiofchlnrphcm
`MEFOLAZONE MTSHAREWSStOWANDINOOMPLETE
`iramins ovardoasge may vary from esntru nervousaystem
`
`depression to stimulation.
`slosvsiutoiun sun as: E mammary
`
`ewwsrsur at me same noses TO mxooxe TAB-
`Treatment. i’rimary attentionshould be given to the rose
`
`LETS. A moss my AVAILABLE mo OOMPLETELV
`
`tobli'shmsnt ofsdequaounspiratoty audience through pro-
`snowman: momma: mower. mum
`vis'tan‘of «patent airway and the institution of assisted or
`
`eiocouwstem T0 moxouu one FORMULATIONS
`
`nontmlledyintilation. 'Dis narcotic antoginlst naloxnoa hm
`BIOEOUWALENTJ'CI mvxaox suouw fl so meo-
`drochloride i- a mono antidote for mail-ml! mm more For) on: women.
`
`DESCBH’HON
`"mm ”with“ ovardoasxeor unusual teammate
`
`when Includms hydmeudanea Therefore. an enumerate
`doseiof‘osloaons hydrochloride should be administered.
`ZAROXOLYN 'ihhlsts (motoionme tablets. USP) for oral ad-
`preferably by. the intravenous routs. simultaneously with
`
`ministration disdain 2K, 5) or 10 mi of motolanooe, USP. a
`
`chin-ts st respiratory resuscitation. Since the duration ofac-
`diuretidsulumfidantihypertensive drug of the quinazoilne
`tion ofhydrnmdona in thisformuiation may exceed that of
`class.
`,
`the antagonist, the patient should he kept under continued
`Mstoissoos has the molecular formula C,,H..CIN,O,S. the
`surveillance and repeated doses ofths antagonist should he
`chemical name 7119hn'04, 2. h. ewmhysmemoiyiaie
`administered as needed to maintain adequate respiration.
`mathylplienyiH-ono—Bquinmlinssalfnnamide. and a mo-
`For further information, see full prescribing information for
`lseulcr weight of366.83. ’lhs structural formula is:
`nolnxone hydmchioi-idn.An antagmist shouid not he admin-
`H
`istered in the absence ofclinically significant respiratory de-
`pression. Oxygen. intravenous fluids. vasepressors and
`other supportivaincssures should he unnloyed as indicahai,
`fists-it emptying may be useful in removing unabsorbed
`DOSAGE AND ADMINISTRATION
`Shake well before using.
`Adults: lienspoonful (5 mL) every 12 hours; do not closed 2
`timopuonfuls in 24 hours.
`Children 6—12: U2 tesspoonful every 12 hours; do not ex-
`cess! t tsespoontul In 16 home.
`Not recommended for children under a years of age [sue
`PRECAUTIONS).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`R6228
`Rev. W03
`
`_
`.
`.
`Rf” Izw‘gggmg
`Failimizl Ems.
`nciee Canto
`'lbi how (am) $5.25”
`313
`
`.
`
`-
`
`J...
`
` W coat-u animu-
`
`swan phenylacetate has a molecular some means and
`the molecular formula C,H7Na0r Sodium ileum): has a
`molecular weight of 144.11 and tho molecular foriguls
`C1HsN-Or
`Each m1. of AMMONULO contains 100 mg of sodium
`phenylalanine and 100 mfi'uf aodlum bonus». and Water
`for injection. Sodium hydroxide andlor hydrochloric acid
`may have been used for pH adjustment
`momma injection is a stefilg,!coacentrotsd solution in
`tended for intravenous administration via a central line
`only afier dilution (see nossoc AND Annamaria.
`'I'ION). AMMONUUD is packaged in single-use vials.
`CLINICAL PHARMACOIDOY
`Sodium phenylaoetnta and sodium benmals are metaboli-
`cally active compounds that can serve as altematlves to
`urea for the excretion of waste nitrogen. Phenyiscetats con-
`jugates with glutamme in the liver and kidneys to form phe
`nylacetylalutamlne. via acetylation. Hienylacetylgiutamine
`is excreted by the kidneys via giomerular filtration and tu-
`bular searches The nitrogen content of phenylaeetyl-
`giutomine per male is identical to that ofures (both contain
`two males of nitrogen). Similarly. preceded by acylation.
`bensoate conjugates'srlth glycine to form hippuric acid.
`which is rapidly excreted by the kidneys by zlomerular fll-
`tration and tubular secretion. One mole of hippuric acid
`contains one mole ofwaste nitrogen. It has been shown that
`phenylncetylgiutaminc and hippuratc can serve as alterna-
`tive vehiclm it) efl‘ectively rediwa waste nitrogen levels in
`patients with deficiencies of one cycle enzymes and. thus.
`attenuate the risk of ammonia and glutamlne-induced
`neurntnncity.
`
`{YouH
`on
`)3cu,
`w»
`Metolnwne is only sparingly soluble in water, but more sol-
`uble in plasma. blood. alkali. and organic solvents
`Inactive ingredients; Magnesium steerate. microcrystal-
`line cellulose and dye 2‘45 mg-D&C Red N0. 33. 5 mg m0
`Blue No 2. 10 mg—DfiC Yellow No. 10 and FDhC Yellow
`No. 6
`
`
`
`
`
`Continuadonnoxrpaga
`mmzoosron-Weunmmmiwmm
`
`Page 2 of 5
`
`LUPIN EX. 1019
`
`Page 2 of 5
`
`LUPIN EX. 1019
`
`

`

`PRODI
`
`were on
`tients wl
`monia
`AMMOh
`high (> 4
`episodes.
`Improve-
`served in
`rated no
`the same
`to treatn
`97% of e)
`ofepisodl
`episodsa)
`INDICA'
`AMMON
`treatmen
`cephalopl
`urea cycl
`moderate
`lopathy,
`.
`to respon-
`modialysi
`moving a
`administi
`re-occumi
`excretion
`CONTRA
`AMMON1
`known by
`bencoats.
`WARNIN
`Any sple-
`should he
`mom of iv
`bemodlsh
`controlled
`damage o
`nary to Ill
`Mansgemt
`mstaholisr
`personnel
`disorder [1’
`with nutn
`multidiscii
`the faciliti-
`Ongoing rn
`status, lab!
`oelvingAM
`treatment.
`excretion
`glutamins
`be careful]
`when nece
`tored and r
`AMMONU
`luted prod
`great care,
`or severe ri
`there is a-
`reaction I
`AMMONUI
`ate therape
`Adminlmm
`tlon ttwoug
`Bolus infus
`infants (ace
`vasation of
`lead to skin
`tinue the in
`necessary. :
`clude ospirz
`ovation, ant
`infusion sit:
`tion during
`luted produ
`Due to aim
`bemoate to
`typically as)
`ventilation :
`to perform l
`and pCO, n
`PRECAUT
`General:
`AMMONU]
`Iuted before
`dium pheny
`in the liver
`and hippun
`caution wha
`hepatic or I
`been ussociz
`may be adm
`Because on
`state in one
`AMMONUlt
`Use ofcortic
`tein and, the
`els in pntien
`Neurotoxlclt
`Neurotoxicit
`(ravenous pl
`
`b_..a-
`ll
`
`
`
`
`
`
`
`
`‘-.5£A'£;aafl-[I‘-"g'r:v“.41-h"
`
`u.ahung.-
`r........-a..a.«.a.ma...-
`
`T—fi
`Drug Interactions:
`rapidly (TM of 1.5 hr at 3.75 g/m") and were undetectable
`at 14 and 26 hours following the 3.75 and 4 glm2 dose,
`Formal drug interaction studies have not been performed
`with AMMONULO.
`respectively.
`Pharrnsoodvnsmlcs
`A difference in the metabolic rates for phanylacetnta and
`Urea cycle disorders can result from decreased activity of
`benzoato was noted. The formation of hippurste from
`any ofthe following enzymes: N-acetylglutamste synthstase
`In patients with hyperammonemia due to deficiencies in ca-
`benwete occurred more rapidly than that of phenylsostyl-
`(NAGS), carbamyl phosphate synthetase (CPS), arginino-
`‘ zymss of the urea cycle, AWOWhu been sho'w'n to
`dam-ease elevated plasma ammonia levels and improve a.
`gluternine from phenylacetate, and the rats of elimination
`succinate synthetess (ASS), ornithino transcarbsmylase
`cephslopsthy and survival outcome compared to historic“;
`for hippurate appeared to be more rapid than that. for phe—
`(UPC), argininosuccinate lyase (ASL). or arginase (AHG).
`nylacetylglutamios.
`controls, These effects are considered to be the result of“.
`The most frequently observed initial presenting symptoms
`in neonates indude lethargy, seizures, poor feeding. neuro-
`dudes in nitrogen overload through glutamins and glycing
`Pharmacohinetic observations have also been reported from
`logic changes, edema, and respiratory distress. Patients
`twelve episodes of hyperammonemic encephalopathy in
`scavenging by AMMONUID in combination with approprl.
`ate dietary and other supportive measures.
`with milder forms of enzyme deficiencies may not present
`seven children diagnosed (age a to 26 months) with urea cy-
`Cllnlcai DIM
`cle disorders who had been administered AMMONUIQ in-
`until late childhood, adolescence, or adulthood. Hyperam—
`monemie crisis with lethargy, delirium, and coma, in these
`‘ The efficacy ofAMMON'UM in improving patient survival
`travenously. These data showed peak plasma levels of phe~
`patients, are often precipitated by viral illness, high protein
`ofacute hyperammonemic episodes was demonstrated in an
`nylaoetate and henzoste at approximately the name times
`diet. stress, or trauma.
`analysis of 316 patients (1045 episodes of hospitalization}
`as were observed in adults. As in adults, the plasma levels
`treated between 1981 and 2003.
`Plasma and urine amino acid analyses are used to diagnose
`of phenylacetats were higher than benzoate and were pres-
`ent for a longer time [i].
`ASS and ASL and to provide a preliminary diagnosis of
`The demographic characteristics and diagnoses of the pa.
`tient population are shown in ’Ihblo 1.
`CPS, OTC, or ARG. Blood citmlhns levels are very low or
`The pharmacolrinetics of intravenous phenylacetata have
`absent in ON and CPS, very high in AS, and normal to
`been reported following administration to adult patients
`Table 1 Baseline Characteristics and Diagnoses of Study
`with advanced solid tumors. The decline in serum
`moderately high in ASL sod ARG. ASL may be distin-
`Population
`guished by the pruence of high levels oftho unusual amino
`phenylaoetata concentrations following a loading infusion of
`acid argininaeuccinic acid (ASA) in the urine. It should be
`150 mg/kg was consistent with saturable enzyme hinefics.
`noted, however, that ASA tends to welute initially with
`Ninety-nine percent of administered phenylncctate was ex-
`other amino adds (such as leucins and isolaucine) in chro-
`creted as phonylacotylglutnmins [23].
`matographs, and may be missed on initial examination.
`Special Populations
`ARC is characterized by high urine levels of arglnine. A de-
`Gender:
`finitive diagnosis of CPS and OTC require a liver biopsy,
`Fharmacokinetic parameters of AMMONUDD were com-
`and red blood cell enzyme analysis is needed to confirm a
`i pared in healthy males and females. Bioavailability of both
`diagnosis ofARG Patients suspected of having a urea cycle
`benzoste and phenylacetate was slightly higher in females
`disorder, based on family history, should have documented
`than in males However. conclusions cannot be drawn due to
`hyporammonamia prior to administration ofAMMOW.
`Mechanism of Action
`the limited number of subjects in this study.
`I
`Hepatic Insutliclancv:
`I"
`'
`'
`'
`tr t‘
`h
`th
`ts f .
`AMMONUDO, phenylocetate and bsnssate, provide an al-
`In” 2 u a schematic In“. I log cm a coman o
`‘ Limited information is available on the metabolism and ex-
`ternative pathway for nitrogen disposal in patients without
`l cretion ofsodium phanylacetate and sodium bennoats in pa-
`'
`tients with impaired hepatic function. However, as the liver
`a fully functioning urea cycle The moles of nitrogen are re-
`is one of the two organs (the other is the kidney) in which
`moved per mole ofphenylooetate when it is conjugated with
`glutamioe, and one mole of nitrogen is removed per mole of
`the metabolic conjugation of sodium phenylacetote and
`sodium benzoata is known to take place, care should be used
`benzoats when it is conjugated with glycine.
`in administering AMMONUID to patients with hepatic
`[See figure 2 below]
`insufficiency.
`Phannscoltlnatica
`Renal Impairment
`intravenously administered
`'l'he pharmacokinetirs of
`For cfl'active AMMONULE drug therapy, renal clearance of
`AMMONUUD were characterized in healthy adult volun-
`the drug metabolites and subsequently ammonia is re
`teers. Both benzoate and phenylacetate exhibited nonlinear
`quired. Therefore, patients with impaired renal function
`kinetics Following 90 minute intravenous infusion mean
`should be closely monitored.
`,
`AUG.m for benzoate was 20.3, 114.9, 584.6, 562.8, and
`1599.1 mog/mL following doses of 1, 2, 3 75, 4, and 5.5 g/m‘,
`, Dialysis:
`)
`Intravenous use ofmonsoon complementary with the
`respectively. The total clearance decreased from 5.19 to
`362 Wm at the 3.75 and 5.5 giro2 doses. respectively.
`, use of dielysislljl. In the non-neonatal study patient pop—
`ulation treated with AMMONUIIE , dialysis (standard he—
`Similarly, phenylacatats exhibited nonlinear kinetics fol-
`lowing the priming dose regimens. AUG.” was 175.6, 713.8,
`i modialysia. peritoneal dialysis, arteriuvenous hemoiiltrn-
`2040.8, 2181.5, and 3829.2 mcg-hlmL following doses of 1,
`tion, or other dialysis) was
`required in 13% of
`2, 3.75, 4, and 5.5 gm“, respectively. The total clearance de-
`hyperommonsmic episodes. Standard hemodialysis was the
`creased frum 1.82 to 0.89 mog'hlmL with increasing dose
`most frequently used dialysis methods High levels of ammo-
`nia can be reduced quickly when AMMONUw is used with
`(375 and 4 pm”, respectively).
`During the sequence of 90 minute priming infusion followed
`i dialysis, as the ammonia-scavenging of AMMONUMI) any
`by a 24 hour maintenance infusion, phenylscetats was de-
`i presses the production of ammonia from cataholism of en-
`tected in the plasma at the end of infusion ('l‘w of 2 hr at
`dogenous protein“) and dialysis eliminates the ammonia
`and ammonia conjugates.
`375 g/m’) whereas, benzoate concentrations declined
`
`nosuccinats synthetase deficiency; CPS = carbamyl p no-
`(YI'C = ornithine transcarbamylase deficiency;ASS = mini-
`'
`| phate synthatase deficiency; ASL = argininosuocinaie lyase
`deficiency: ARG = arginase deficiency; 'I'HN = transient hy-
`perammonemia of the newborn
`‘For the summary at. the patient level, data obtained at first
`: episode used.
`”Diagnosis unknown or pending (33 episodes), acidemia
`(14 episodes), HRH syndrome (6 episodes), oarnitino trans-
`locsse deficiency (4 episodes), liver disease (3 episodes).
`. HMG CoA lyase deficiency (1 episode), non-hetetic hypergly-
`cinsmis (1 episode). suspected fatty acid oxidation dcflA
`* cisncy (1 episode), and valprnic-ocid-Induoed hyper-ammonia
`min (1 episode).
`
`. On admission to the hospital, patients with hyperammons-
`' min or a potential one cycle disorder (UCD) were treated
`with a bolus dose of 0.25 ding (or 55 g/m’) sodium pheny-
`lacetate s 0.25 g/kg (or 5.5 g/m’) sodium henzoats over a
`period of 90 minutes to 6 hours, depending on the specific
`UCD. Infusions also contained arginine; the dose ufarginlne
`depended on the specific UCD. After completion ofthe bolus
`| dose. maintenance infusions of the same dose over 24 hours
`were continued until the patient was no longer hypersm-
`. moncmic or oral therapy could be tolerated. The mean (SD)
`duration of treatment was 4.6 (6.45) days per episode, and
`i
`ranged from 1 to 72 days.
`1 Survival was substantially improved otter AMMONUID
`treatment compared with historical values (estimated [4%
`1-year survival rate with dietary therapy alone) [10) and
`with dialysis (estimated 43% survival of acute hyperemmo-
`nemia) [11].
`I Ninety-four percent (981 of 1045) of hypersmmonemic epl~
`sodas treated with AMMONUID resulted in patients being
`I discharged from the hospital. Eighty percent of patients
`(252 of 316) survived their last episode. of the 64 patient!
`who died, 53 (83%) died during their first hyperammnnemic
`episode. of the 104 neonates (<30d)
`treated with
`AMMONUDD, 34 (33%) died during the first hyperammnne-
`mic episode.
`Ammonia levels decreased from very high levels () 4 times
`the upper limit of normal [ULND to lower levels in 91% of
`episodes after treatment. In patients responding to therapy.
`mean ammonia concentrations decreased significantly
`within four hours of initiation of AMMONUDD therapy and
`
`
`9
`Figure 2
`u—Katngimnrntu
`NH,
`Domain
`
`G cine {———-—) NH“—L>alutamatsA—b Ilutnmlna Phenylscetats
`H00:
`
`Y iiV
`
`Urine excretion
`
`
`
`oaroamyl pompous
`
`Omitiilnc
`
`I’T'l
`....'T.J
`
`Supplemented __..-V
`Arplnlne _.-"
`
`Amlnina
`
`
`
`Fumarate
`
`CPS = carbomyl phosphole \) nthelssc' (Tl'c = ormlhino lmnwnrhomylasc; ASS = urglmnoiumnulc xynllwtox, Ail. =
`nrgininusuainslc lynsc. ARG = urginsse; VAC-S = N acriy:glummslc symhcme
`
`IMonnstion will be Wad by supplements and subsequent editions
`
`Page 3 of 5
`
`LUPIN EX. 1019
`
`3324/UCYCLYD
`
`PHYSICIANS' DESK REFERENCE®
`
`Ammonuk—Cont.
`
`Mean (SD)
`
`CPS
`
`158 (51*)
`150 (49%)
`
`8.2 (8.54)
`
`
`
`
`
`
`
`104 (34%)
`
`
`55 (10%)
`
`
` 30 (10%)
`
`
`31 (10%)
`
`
`148 (48%)
`71 (22%)
`38 (12%)
`
`
` 56 (18%)
`
`Age (years)
`
`
`
`
`
`
`
`
`Enzyme deficiency
`
`
`
`-
`
`
`
`‘
`
`’
`
`E
`
`l ll
`
`Page 3 of 5
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`LUPIN EX. 1019
`
`

`

`
`
`
`
`._-.A..\...,_-._...amt-4m._—-i
`
`
`
`'
`
`I
`
`'
`
`:
`
`AMMONUDE has been used as a treatment for acute hyper-
`ammonemis in pediatric patients including patients in the
`early neonatal period (see DOSAGE ANDADMINISTRA—
`TION).
`ADVERSE REACTIONS
`The safety data were obtained from 316 patients who re-
`ceived AMMONUIE as emergency (rescue) or prospective
`treatment for by-perammonemia as part of an uncontrolled.
`open-label study. The study population inc'uded patients
`between the ages of 0 to 53 years with a mean (SD) of 6 2
`(B 54) years. 51'): were male and 49'? were femaln who had
`the following diagnoses OTI‘ 16%», ASS (22% I, CPS (12%),
`ASL (2‘i), ARC (’ 1%), THN'I
`I'i- ), and other (18%).
`Tabla 2 Adverse Events Occurring in z 3% of Patients
`Treated with AMMONULO
`
`
`
`PRODUCT INFORMATION
`UCYCLYD/3325
`
`
`
`wcrl' maintained Dialysis i4 recommended for those pa-
`
`peated at 4-woi-k .ntirvols. Manifimuitmns were predomi-
`tients who fail to bowl a significant reduction in plasma um-
`
` Infection! 39 (12‘Iv)
`
`nantly somnolencc, fatigue, and Iightheudcdncss, with lens
`monia leles Within 4
`to 8 hours after
`receiving
`l'niqur-nt headaches, dycgi-usia, hypoacusiii, disorientation,
`
`AMMONUIJS. A shift from high E- 4 times ULN) to very
`Urinary tract infection NOS
`9 (3%)
`impaired memory, and exacerbation of a preexisting neurop-
`high (> 4 times ULN) levels was observed in only 4% oftho
`episodes.
`othy. Thesi- adverse events were mainly mi Id. The acute on-
`Injury, poisoning and procedural
`12(4‘b)
`set ofsymptoms upon initiation of treatment and reversibil-
`complications
`Improvements in neurological status endpoints were ob»
`ity of symptoms when the phenylacetaui was discontinued
`suggest a drug ufl'ect [2.3).
`served in most episodes and patients Overall, investigators
`I
`rated neurological status as improved, much improved, or
`in animal studies. subcutaneous administration to rat pups
`the same in 93% of episodes, and overall status in response '
`of 190-474 mg/kg of phenylacetate caused decreased prolif-
`to treatment as improved, much improved, or the same in
`eration and increased loss of neurons, and reduced central
`974 of episodes. Recovery from coma was observed in 97%
`nervous system (CNS) myelin. Cerebral synapse matura-
`of episodes where coma was present at admission (111 of 114
`episodes).
`tion was retarded, and the number of functioning nerve ter-
`minals in the cerebrum was reduced, which resulted in im-
`INDICATIONS AND USAGE
`paired brain growth I15). Pregnant rats were given
`phenylucetate at 3.5 Aumol/g/day subcutaneous from gesta»
`AMMONL‘W is indicated as mljunctive therapy for the
`’reotment of acute hyperammonemia and associated en-
`tion day 7 through normal delivery. Prenatal exposure ofrat
`pups to phenylacetate produced lesions in layer 5 cortical
`cephalopathy in patients with deficiencies in enzymes ofthe
`pyramidal cells; dendritic spines were longer and thinner
`.rea cycle In acute neonatal hyperamniunemic coma, in
`than normal and reduced in number [16].
`uoderate to severe episodes of hyperammonemic encepha-
`Drug Interactions:
`opathy. and in episodes of hyperammonemia which fail
`Some antibiotics such as penicillin may compete with phe-
`to respond to an initial course ofAMMONUW therapy, he-
`modialysis is the most rapid and efi'cctive technique for re-
`nylacetylgiutamine and hippurate for active secretion by re-
`moving ammonia [12.13]. In such cases, the concomitant
`nal tubules. which may affect the overall disposition of the
`infused drug.
`administration of AMMONUW can help prevent
`the
`re-accumulation of ammonia by increasing waste nitrogen
`Probenecid is known In inhibit the renal transport of many
`excretion [4.5.13].
`organic compounds, including aminohippunc acrd, and may
`CONTRAINDICATIONS
`rate I13].
`affect renal excretion of phenylacetylglutamine and hippu-
`AMMONUW should not be administered to patients with
`There have been reports that valproic acid can indum hy-
`known hypersensitivity to sodium phenyleietave or sodium
`benzoate
`peramrnonemia through inhibition of' the synthesis of‘ N-
`acetylglutamate, a co-factar for carbamyl phosphate synthe-
`WARNINGS
`tosa I14]. Therefore, administration of valproic acid to
`patients with urea cycle disorders may exacerbate their con~
`Any episode of acute symptomatic hyperammonamla
`dition rind antagonize the efficacy ofAMMONUIJlD I15].
`should be treated as a lilo-threatening emergency. Treat-
`Carcinogenesis, Mutagoaalla, lmpalrmont of Fertility:
`ment of hyperammonomla may require dialysis, prafarably
`Carcinogenicity, mutagenicity and fertility studies of
`hemodlalysls, to remove a large burden of ammonia. Un-
`sodium phenylacetafe have not been conducted. Sodium
`controllld hyporammonamla can rapidly result In brain
`benzoste has been extensively tested as a food preservative.
`damage or death, and prompt use of all therapies neew
`sary to reduce ammonia levels In anantlal.
`Results indicate that sodium benzoakA is not mutagenie or
`carcinogenic, and does not impair fertility.
`Management of liyperammonemia due to inborn errors of
`Pregnancy:
`metabolism should he done in coordination with medical
`Pregnancy Category C. Animal reproduction studies have
`personnel familiar with these diseases. The severity of the
`not been conducted with AMMONUUE. It is not known
`d sorder may necessitate the use of bemodiaiysis combined
`whether AMMONUW can cause fetal harm when adminis-
`with nutritional management and medical support. The
`tered to a pregnant woman or can affect reproduction capac-
`multidisciplinary nature of the treatment usually requires
`the facilities ofa tertiary or quaternary care center.
`ity. Thus, AMMONUW should be given to a pregnant
`woman only ifclearly needed.
`Ongoing monitoring ofplosms ammonia levels, neurological
`Labor and Dollvory:
`status, laboratory tests. and clinical response in patients re-
`unknown.
`The effects of AMMONUW on labor and delivery are
`ceiving AMMONL‘UD is crucial to assess patient response in
`treatment. Because urine potassium loss is enhanced by the
`Nursing Mothoro:
`excretion of the nonreabsorbsble anions, phenylacetyl-
`glutamine and hippurate, plasma potassium levels should
`[t is not known whether sodium phenylacetate, sodium ben-
`‘ zoate, or their conjugation products are excreted in human
`be carefully monitored and appropriate treatment given
`when necessary. Scrum electrolyte levels should be moni-
`milk. Because many drugs are excreted in human milk. cau-
`tion should be exercised when AMMONUIm is adminis-
`tored and maintained within the normal range.