E”
`60
`
`EDITION
`
`2006
`
`aceBWEJ BREWERLLP
`
`DEC 01 2005
`
`aecevao
`
`
`
`PHYSICIANS’
`DESK
`REFERENCE
`
`senior Vice President. FDR Sales and Mariretina Dlkran N. Barsamian
`Vida President. Product Management: William T. Hicks
`Vice President. Regulatory Aiialraz Mukeah Manta. RFh
`Vice President. PDR services: Brian Holland
`senior Directors, Phennaceutlcai Solutions Sales: Chantal Corcos,
`Anthony Sorce
`National Solutions Managers: Frank Karkowsky. Marlon Reid. RPh
`senior Solutions Managers: Debra Goldman. Elaine Musco.
`Warner Stuart, Suzanne E. Yarrow. RN
`solutions Managers: Eileen Bruno. Cory Coleman. Marjorie A. Jaxel.
`Kevin McGlynn, Lois smith. Richard Zwickel
`Sales coordinators: Arlene Phayre, Janet Wallendal
`senior Director, Brand and Product Management: Valerie E. Berger
`Associate Product Managers: Michael Casale. Andrea Colavecchio
`senior Director. Publishing sales and Marketing: Michael Bennett
`Director, Trade Salas: Bill Gaffney
`Associate Director. Marketing Jennifer M. Fronzaglla
`senior Marketing Manager: Kirrr Marich
`Direct Mail Manager: Lorraine M. Loening
`Manager, Marketing Analysis: Dina A. Maeder
`Promotion Manager: Linda Levine
`Director of operations: Robert Klein
`Director, PDR operations: Jeffrey D. Schaefer
`Director oi Finance: Mark S. Ritchln
`
`Director, client services: Stephanie Stmble
`Director. clinical content: ‘mamas flaming, PharrnD
`Director. Editorial Services: Bette LaGow
`Drug information Specialists: Michael DeLuca, PharrnD, MBA;
`Kalal Solankl. PharrnD; Greg Talils, RPh
`Project Editors: Nell Chesanaw, Harris Fleming
`senior Editor: Lori Murray
`senior Production Editor: Gwynned L. Kelly
`Manager, Production Purchasing: Thomas Westburgh
`PDR Production Manager: Steven Maher
`Production Manager: Gayle Gralzzaro
`Production specialist: Christina Klinger
`Senior Production coordinators: Glenna caradonna. Yasmin Hernandez
`Production Ooordinator: Nick W. Clark
`Senior index Editors: Noel Deloughery. Shannon Reilly
`Format Editor: Michelle G. Auffant
`Traffic Assistant: Kim Condon
`Production Design Supervisor: Adeline Rich
`senior Electronic Publishing Desigrer: Livio Udina
`Electronic Publishing Designers: Bryan C. Dix, Carrie Faeth,
`Monika Popowitz
`Production Associate: Joan K. Akerlind
`Dlgtal Imaging Manager: Christopher Husted
`Dlatai imaging coordinator: Michael Laoruyere
`
`Copyrigtrtfizoofl and published by Thomson FDR at Monlveie. NJ 07845-1742. All rights reserved. None oi the content at this publication
`TI-l()lV|S()|\]
`T*_____ __ may be reproduced. stored in a retrieval ayalem. resold. redistributed. ortranarnitted in any loan or by any means (electronic. mechanical.
`photocopying. recording. or otherwise) without the prior written permission of the publisher. Physicians‘ Desk Reference‘. FDR‘, Pocket
`PDR
`PDR', FDR Family Guide to Prescription Drugs‘. PDR Family Guide to Women's Health and Prescription Drugs‘. and PDR Family Guide to
`Nutrition and Health‘ are registered trademarks used herein under license PDR' lor Ophthalmic Medicines, PDI-3' lor Nonprescription Drugs and Dietary Supplements. i'-‘DH’
`Companion Guide. PDR‘ Phamracopoela. PDFI‘ lor Herbal Medicines. PDQ‘ lor Nutritional Supplements. FDR’ Medical Dictionary. PDFI‘ Nurse’: Drug Handbook. PDR'
`Nurse's Dictionary. FDR‘ Family Guide Encyclopedia oi Medical Care. FDR‘ Family Guide to Natural Medicines and Healing Therapies, PDR' Family Guide to Common
`Ailments. PDR' Family Guide to Over-thecountar Dnrgs. PDR' Family Guide to Nutritional supplements. and FDR’ Electronic Library are trademarks used herein under
`license.
`
`Otiiosrs oi Thomson iiealthcare. lnc.: President and Chief Executive Ofilcer: Kevin King; Chief Financial officer: Paul Hllger: Chief Medical Oriicer: Rich Klasco. MD. FACEP:
`Executive Vice President. Medstec Carol Diephuis. Executive was President, Mrcromedex. Jefi Relhl: Senior Vice President. Marketing: Timothy Murray; Senior vice President,
`Technology Michael Karaman; Vice President. finance: Joseph Scarlone. Vice President Human Resources: Pamela M. Bilesh
`
`LUPIN EX. 1021
`
`1of5
`
`1 of 5
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`

`

`PRODUCT INFORMATION
`UCYCLYD/3323
`
`
`HOW SUPPIJED
`HOW SUPPLIED
`whether to discontinue nursing or to dlsconnnue the dung,
`
`uniting into account the importance of the drug to the
`mother
`
`
`TUSSIONEX Ponnkinetit (hydrouidona polishrar and
`ZAROXOLYN Thbleta (motolazone tablets. USPl are shal-
`low biconvex. round tablets, and are available in three
`chlorpheniramina polistlrerl Extended-Release Suspension
`
`
`Pediatric uu: Safety and etfectiveui.-_so of 'l'_l-¢IElSl0NEX
`1. . ‘.,i¢.m1.,-.3 gugpengluy,
`.
`
`
`
`
`_
`P-nnk-new: Exlendeilvkvlnnos Sump-inn -n i-nlintrlr
`NDC 58014-648-67
`A78 mL bottle.
`aw mg,-pinii-. dehossed -?ZAll0XOLYN' un nnn side. and
`nail
`in under -u have not been a-tanllsl-ed Cm Shake wall. Dispense in a wsllyclnsed container. am at
`'-'2w'nn reviirse aide.
`
`
`.
`.08).
`59"8§'Fi15".1a9'.a).
`NDC 5.51016-975-71 Bottleof100's
`G-rlrtrlc U-an Clinical studies nl'l'U_S3l0NEX dldnnt P3‘
`Gellindi rmnme-uuna, liie.
`-
`NDC Sallie-975790 Bottle nr 1000':
`
`
`cl-nln -nfllnlent nlilnbers nfwliiew nerd.
`Rochester. NY um use
`and war tn-le
`NDC 53014-975-72 ouwn oi‘ 100's. unit does
`tar-nine whether they respond tlllfnnniltlv
`-Y'"‘"8W' -i-lr
`o 2002. Colltsob Phnrnini-nnnnnin, Inc.
`6 mg, blue. debosaod 'ZAR0l(0liYN'un one sun and or no
`
`
`_
`pun, Other rnpofied
`exnorlvnnn lm not identified
`Ocelltacli
`loo.
`revena aide.
`
`dlfinnnnu in reannznnon between the elderly and ynnnenr
`'l\issi_onerO Pnnnkineooo Extended-Release Suspension:
`NDO 63014-B50-'11
`unto: of 100':
`patients. In eenernl. done selection for an elderlr nnueni
`US Patent No. 4,763,709.:
`Nnc 690i4~&50-90 Bottle of moo‘.
`
`
`should no caution». -mllv mrilne at the low and of the
`canon: es nine/2005
`LRMZA
`NDC 5soi4—e5o-12 Carton nr 100's. unit does
`
`
` l0 mg. yellow, dobossed “ZAIiDXOLYN“ nu one side. and
`dosing range. reilectiug the greater frequency of deemesed
`
`liar. lam}!
`hepatic. renal, or cardiac function. and of concomitant dis-
`‘Ill’ on IUVSTIQ side.
`ease or other dnig therapy
`NDC 53014-835-71 Bottle of wife
`Thisdrugisknowu mhs_subatanti'allyeu:i'otedbythekid-
`NDG 5801988580 Bottle of 1000'!
`nay, and the risk of toxic reactions to this drug may be
`NBC 53014-835-73 Carton of 1003. unit dose
`greater in patients with impaired renal llmrfinn. Deanne
`Store at we m'Br. smusiuns penuioai to I5‘-30'C (sv-
`VICON FQWTEO Capsules
`elderll patients are won llbla MI have decreased renal
`56°F) (See USP Goiitrollsd Room Tbmpsinturel. Protect
`[When (:0? “ll
`function. care should be taken in dose selection. and it may
`5..., "gm, K”, W. 394.. mg, .,{d.,'u...,,
`Thar
`Vltsmlne-Minerals
`beuncfultomuniinrmnninincdon.
`iauughpnunwgnagigug,
`Eon
`_
`V3333‘ 3393-"
`Rochester. NY 11823 USA
`gsnntrsl Nervous
`Sedation, dmw.lnu._ manm DESCRIPTION
`0 Colltoch Manufacturing. Inc.
`
`Each black and orange VICON FORTEO capsule for oral
`clouding, lethargy, impairment of mental and physical per-
`O 2003' odmch Pl“""“"u°°l"J"‘°‘
`
`
`edriilnistration contains:
`fui-nianos, doxiety, fear, dyephoria, euphoria, diulness. pey-
`All “KP” '!°"V°d-
`Vitamin A
`..
`chlc dependence, mood changes.
`C‘-‘"'m 5‘ “maul”
`
`Vitamin E ..
`Dsmietotogie System: Bash, pruritue.
`
`
`Aseorbulfhsddufip’
`" >
`~
`ligstvolmastlrml System: Naua‘i:a‘niui v;=:“ting may oclgir;
`Zines
`ts.
`.
`’
`I yaiemoreliequeutinomb
`tory
`Lnrocum nt
`
`
`patients. Prolonged ndninsmnunn. of TUSSIONEX Magnesium nuirnu. UBH .
`U¢V°lYd l’l|l|’m3- "10-
`
`Niacinamide
`..
`..
`Pennkiustle Extended-Releaae Suspension may produce
`3125 N. HAYDEN RD.
`
`Thiainins niononltrats ____ _.
`constipation.
`GGOTTSDAIE. A1 8628!
`Gaaltoiiiinary Synun:
`llreteral spasm. spasm of vesicle
`sphincter-s and urinary retention have been reported with
`opiates.
`Respiratory Depression: TUBSIONDK Pennkinetii:
`Extended-Release Suspension may produce dose-related
`respiratory depression by sitting directly on brain stem roe
`piratory centers (see OVERDOSAGED.
`Rosplrsuirv System: Dryness of the pharynx. occasional
`tightness of the chest.
`DRUG ABUSE AND DEPENDENCE"
`B
`allslouulo
`[dm-mdti-Ill]
`TUSSIONEX Pennbinetic Extended-Release Suspension is
`lsodlurn ptisiiyleostaxs and sodium bsrizostol lnlsotlen
`ii Schedule ll! narootie. Psychic dependence, physical de-
`I095 I 10%
`,
`-
`
`
`
`
`
`
`my only
`_
`’
`pendsnoe and tolerance may develop upon repeated admin- How BUPPLED
`__
`isrration of narcotics; therefore, TUSSIONEX Pennkinstie
`and black capeulea imprinted with ‘uni: and ‘S16’
`
`
`
`
`Extended-Release Suspension uimmi be prescribed and ni.
`rn bottles oral) (mic 60474-31622) and son mod 5047+ Dmmnlm
`ministered with caution However, psychic dependence is
` 318-24) and unitdose pa5lrs_ot'100iN'DC M1414-318-27).
`
`unlikely to develop when TUSSIONEX Penulrlnetia
`
`AMIMONUUD teodluroplienylaestete and sodium benzoate‘)
`Dlspensa in tight, liglitpmsiitant container with a child-
`Extended-Release Suspension is
`a sham time tor
`znsncnfg unslu-&
`'
`,
`Injection 10%! 10% is a
`concentrated, aqueous solu-
`
`
`the treatment of cough. Physical dedéndeiioe. the condition
`'
`ihr
`tioo ofeodiurapiienylamltala and indium benroule, unearn-
`in which continued sdiiilnletratinii it thbdrug is required to
`tlietréatmeut of Ii
`moheniin in urlsa cycle disorders.
`'flie’pl'loftha sol unisbetweeaflanllfl. Sodium phenyl
`prevent the appearance ofa with
`syndrome. assumes
`Imam“! h I
`.
`—
`.
`8
`_
`30050
`...;.-°.*..=.:.:'.::.:.+::
`mnc«°Inn=lv°°dnr-ltls-«lnbl-lnwnhn~ nu. ma»
`”:.:r.2'..l~=l"°*......':.¢
`.
`—
`-
`crystalline. white to oihvhita powder with a
`'
`
`
`dmndmée my dmhp ‘M H M am Mm,
`aw in a white and odorlssli, crystalline powder that ii
`-
`IE lama,
`*-
`
`clin-inc an afouboos M4“? '°l“N° in “W'-
`.;".§'.l."$.a,.§-.
`'
`'
`
`
`0 :a 1:1: n.
`’
`
` Signs.-and-ayiriptnirisi Serious ovordosago with hydroca-
`_l...
`
`'
`'
`done is characterized by respiratory depression (a decrease
`
`
`In resoirntniw rate andlan tidal volume. Glwyus-stokes res: MROXOLYNO TABLEYS
`piration, cyanosis), extreme somnelerioe progressing to stir
`[gap '9, 'uh.1.',,]
`por or.-oonm; skeletal musde flaocidity. cold; and clammy
`|mQ1g||ggng’[gb|m, us?)
`skim. and llllnntllnlll‘ iiradycaidls and hypoteiision. Al-
`I} only
`‘
`'
`_
`Ihouglrmiuslsisi:haraeter|sticofnarnaflcover\insB1In)'llI1-
`eifismay.oa:urinuterrni.nalnnreomorsavezehypoida. in
`aevere4irverd.osage.apnsa', circulatory collapse. cardiac so
`ruatoiiddoadr may omit. TlIBlllBnlfl3liflH_IIl‘IllI1fdllfl!'|Ih£n9
`ii-amine ovardnsage may vary from central nervous-system
`depression to stimulation.
`Trsstmsmi. Primary auaotionshould be given to the rose-
`labhshment o_fedsquats,i-expiratory onchansa through pro-
`visi'ton~oi' gpatent airway and the institution of assisted or
`nontrolledienlilation. ‘Die narcotic antuyiulst ualoxons hy-
`ll'°°l1ll"l4° ii 0 °P°Fi3° NW0“ ‘'0' "=l'il'='4"1 ¢°I"W"°'i
`"h5“l‘ P” “‘'“l‘ n‘-‘m """l°“3° "" "““‘“‘l ’°“‘“MV l°
`MM“ l"°'“4"'8 WWW“! "‘l°"~“°*°- '1' WWW“
`does,iof‘ualunnne hydrochloride should be administered.
`preferably by. the intravenous routs. simultaneously with
`efllu-ts st respiratory resuscitation. Since the duration oi'ae-
`tina ofhydrumdone in thisiormulatiun may exceed that of
`the antagonist, the patient should be kept wider amtinued
`surveillance and repeated doses ntths antagonist should be
`administered as needed to maintain adequate resplratinni
`For further information, see full prescribing information for
`naloxone hydr'ochlorida,An antapnisl. should not be admin-
`istered in the absence ofcliuically sigriiilcant respiratory de-
`pression. Oxygen, intravenous fluids, vasopressors and
`other supportivomsaeures should bsemnloyedaaindicatcd,
`Gastric emptying may be useful in removing unabsorbed
`drug.
`DOSAGB AND Anmmflunom
`_
`Shh '3“ l’°f°"° “'“‘G-
`Adulta: lieaspoonful (5 mL) every 12 hours; do not erased 2
`teaapoonfula in 24 hours.
`Children 6-12: 112 tesspoouful every 12 hours; do not ex-
`cent! 1 tsaspooniul In zs Iioun.
`Not recommended for children under 6 years of age Isue
`PRECAUTIONS).
`
`Bodifii phanylaoetata has a molecular weight of 158.13 and
`the molecular formula C,l~l,Na0,
`lienaoate has a
`molecular weight of 144.11 and the molecular furigiila
`C1HsN-0:-
`Each ml. of AMMONULO contains 100 mg of sodium
`phenylaosiate and 100 mg-of aodlum benwgfli and Water
`for injection. Sodium hydroxide andlor hydrochloric acid
`may have been used for pH adjustment.
`AMMONULO
`storiiggconiaentrnted
`l
`ti
`'
`-
`tended for intrllblvenoususliministmtion via a czlitllralnlllrlle
`only afler dilution (see noasau AND ADMINISTRA-
`TION). AMMONUUD is packaged in single-use vials.
`CLINICAL PHAEMACOIDOY
`Sodium phenyluoetata and sodium benmale are metaboli-
`aslly active compounds that can serve as altematlves to
`urea for the excretion oi’ waste nitrogen. Plienylscetste eon-
`jugatas with glutamme in the liver and kidneys to form phe
`uylseetylglutamlne, via aoetylatlon. Piisnylaoetylglutaraiue
`is excreted by the kidneys via glomerular fllti-atiori and tu-
`bular secretion The nitrogen oontent of phenylacetyl-
`glutoinins per male is identical to that ofures (both contain
`two moles of nitrogen). Similarly. preceded by ncylatiou.
`bensoate conjugaterrlth glycine in form hippuric acid.
`which is l'fl|‘.|ldl|}”excreted by the kidneys by glomerular fl_l-
`tratiori and tu ular secretion. One mole of hippuric acid
`tains
`leofwasteiutrogenlth
`bee aliowrithat
`:)nlll;l\}'lI£$$"ll|lI)t£l'lIl.l1e and hippuratc oalilluervld as altema-
`tiva vehlclu lb eflectively reduce waste nitrogen levels in
`patients with deficiencies of urea cycle enzymes and. thus.
`attenuate the risk oi’ ammonia and glutainlne-induced
`naurritnncity.
`
`_
`-
`V
`finl':“n[::“§.:&°9t&_68a9
`For mini Ex“. mu ennui
`1“ how (am) 3:25”
`all
`
`
`
`..
`
`
`Fyridoxins hydrochloride
`,_
`[rung ma
`,_ __
`
`Vitamin B“ (Gyanombalamln)
`‘ As 50 mg dried sine sulfate.
`
`
`1‘ As 50 mg dried magnesium sulfate
`
`
`Eauh capsule also contains Edible ink. IVDEC Blue No. 1.
`
`
`
`
`more Red No. do. men Yellow No. 6. gelatin. lactose,
`
`
`magnesium oiieai-sis. nillmii dioxide. sodium lsuryl sulfate.
`and titanium dioxide;
`-
`
`
`
`'
`
`
`
`nmysoiiossoonnauimns
`
`A
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`coritinuadonnsxrnags
`consulizoneflotlhiinpismsatsuidhitiussdltloiistorisvlslrau
`
`2of5
`
`B
`
`or‘: NO!’ -.lNl'E : no nor mreacnmas
`omnsaisrs mo omen roomuuimus or
`MEFOLAZONE TliAT8HAlIEl'l’BSl.0WANDlNOOMPl.E1'E
`Bl0AVAli.ABl|.l‘l'.Y one one Q TNERAPEUTICALLV
`eouivaiaur sf rigs suns noses T0 Mviraoxo TAB-
`Lers. A More iuruxv AVAILABLE mo DOMPLETELV
`BDAVAILASLE uaroinzoa: mooucv. rouiviuurious
`BIOEOUNALENT T0 ZAROXOLYN AND FORMULATIONS
`BIOEOUIVALENT ‘TO MVKROX SHOULD NOT BE INTER-
`cusuoeo roe one monies.
`D35‘:
`0:"
`"1 "
`ZAROXOLYN Tablets (metnlamrne tablets, USP) for oral ad-
`ministration edritain 2%, 5; or 10 mg‘ oi’ metolenoue, USP. a
`diuoetidsaluretidantihypertensive drug of the quuiuzollne
`clasii.
`,
`Metolarons has the molecular formula C,.,H,.ClN,0,S, the
`chemical name ‘I-dilurn-1, 2. 5. I-tet.rahydro-2-methyl4H2-
`metliylphenyi)-4-om-fiquinawlinaeollnnamide. and a mo-
`lecular woigl1toi'366.S3. ’l1ia stnieturul formula is:
`H
`l.
`
`CH:
`Y
`ll
`pguso,
`C",
`Metolnwne is only sparingly soluble in water, but more sol-
`uble in plasma, blood. olkali. and organic solvents
`Inactive liiorsdloms: Magnesium atearate. microcryatal-
`line cellulose and dye To mg-D&C Red No. 33. 5 mg l"D&C
`Blue No 2. 10 mg-D&C Yellow No. 10 and l"D&C Yellniv
`No. 6
`
`on
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`R6228
`3"‘ W03
`
`.
`
`
`
`
`
`
`8
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`2 of 5
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`

`

`PHYSICIANS’ DESK REFERENCE®
`
`W
`
`PROD!
`
`Drug Interactions:
`Formal drug interaction studies have not been performed
`with AMMONULQ.
`Phannsoodvnsmlos
`In patients with hyperammonemia due to deficiencies in 3,.
`zymoa of the urea cycle, AMMONUlD‘has been shown to
`decrease elevated plasma ammonia levels and improve g.
`cephaiopsthy and survival outcome compared to historic.)
`oontrols. These effects are mnsidersd to be the result Dfn.
`ducfion in nitrogen overload through glutamins and glyeing
`scavenging by AMMONUIID in oombination with appmprl.
`ate dietary and other supportive measures.
`Clinical Data
`‘ The aficaoy ofAMMON'Ulfl in improving patient survival
`ofacute hyperammonemic episodes was demonstrated in an
`analysis of 316 patients (1045 episodes of hospitalization}
`treated between 1981 and 2003.
`The demographic characteristics and diagnoses of the pa.
`tient population are shown in Thblo 1.
`Table 1 Bassllns characteristics and Diagnoses of Study
`Population
`
` 158 (61%)
`
`104 (34%)
`55 (18%)
`
`
`
`
`
`
`
`noauccinats synthetaae deficiency; CPS = oarbamyl p os-
`' CYFC = omithine transcarbamylase deficienry;ASS = mini-
`I phats synthstaas deficiency; ASL = argininosuocinate lyaae
`deficiency: ARG = arginase deficiency; 'l'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
`I14 episodes). lilili syndrome (6 episodes), oarnitins trans-
`locase deficiency (4 episodes). liver disease (3 episodes).
`. HMG CoA lyase deficiency (1 episode), ooo-ketotic hypergly-
`cinemia (1 episode). suspected fatty acid oxidation deli-
`’ ciancy (1 episode), and valproic-acid-induced hypernmmone-
`min (1 episode).
`
`. On admission to the hospital, patients with hyperammone-
`' min or a potential urea cycle disorder (UCD) were treated
`with a bolus dose of 0.26 dkg (or 5.5 g/m’) sodium pheny-
`lscetato 4 0.25 g/kg (or 6.5 g/m’) sodium benzoats over a
`period of 90 minutes to 6 hours, depending on the specific
`UCD. infusions also contained arginine; the dose ofarginlne
`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-
`I monemic or oral therapy oould be tolerated. The mean (SD)
`ranged from 1 to 72 days.
`r duration of treatment was 4.6 (6.45) days per episode, and
`i Survival was substantially improved after AMMONUID
`treatment compared with historical values (estimated 14%
`1-year survival rate with dietary therapy alone) [10] and
`with dialysis (estimated 43% survival of acute hypcramrno-
`nemia) [11].
`I Ninety-four percent (981 of 1045) of hypersrnmonemic 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 drst hypsrammnnemic
`episode. Of the 104 neonates (<3Dd)
`treated with
`AMMONUl.m, 34 (33%) died during the first hypsrammone-
`mic episode.
`Ammonia levels decreased from very high levels (> 4 times
`the upper limit of normal [ULN]) 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 AMMONUIID therapy and
`
`were mi
`iients wl
`monis
`AMM0l~
`high (> 4
`opisodes.
`improve‘
`served in
`rated no
`the some
`to treato
`97% of e_\
`ofepisndu
`episod)
`INDlCA'
`AMMON
`treatmen
`oephalopl
`urea cycl
`moderate
`lopathy,
`.
`to respon-
`modialysi
`moving a
`odministi
`re-accumi
`excretion
`CONTRA
`AMMONI
`known hy
`henmate.
`WARNIN
`Any sols-
`should be
`mom of ir
`liomodlah
`controlled
`damage o
`sary to red
`Managem:
`metaholisi
`personnel
`disorder a’
`with nutrl
`ruultidisci]
`the faciliti-
`Ongoing in
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`Enzyme deficiency
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`rapidly ('l‘,,,_,, of 1.5 hr at 3.75 g/mt) and were undetectable
`at 14 and 26 hours following the 3.75 and 4 gm" dose,
`respectively.
`A difference in the metabolic rates for phsnylacetata and
`henzoato was noted. The formation of hippurate from
`heowaie occurred more rapidly than that of phenylaoetyl-
`glutamina from phenylacetate, and the rats of elimination
`for hippurate appeared to be more rapid than that for phe-
`nylacstylglutamine.
`Phannacohinctic observations have also been reported from
`twelve episodes of hyperammonemic encephalopathy in
`seven children diagnosed (age 3 to 26 months) with urea cy-
`cle disorders who had been administered AMMONUIQ in-
`trnvenously. These data showed peak plasma lcvels of phe-
`nylaoetole and benzoato at approximately the same times
`as were observed in adults. As in adults, the plasma levels
`of phcnylacetats were higher than benzoate and were pres-
`ent for a longer time ill.
`The pharmacolrinetics of intravenous phenylacetata have
`been reported following administration to adult patients
`with advanced solid tumors. The decline in serum
`pheoylaoetate concentrations following a loading infusion of
`150 mg/kg was consistent with saturable enzyme kinefics.
`Ninaty-nine percent of administered phenylacotate was ex-
`creted as phonylacetylglutamino (2.31.
`Special Populations
`Gender:
`Fharrnacokinetic parameters of AMMONUDE were com-
`i pared in healthy males and females. Binavailahility of both
`benzoate and phenylacetate was shghtly higher in females
`than in males However. conclusions cannot be drawn due to
`the limited number of subjects in this study.
`Hepatic insufllclsncyt
`: unwed information in avaihbh on um maubouam and “-
`I cretion ofsodium phanylacetata and sodium hennoate in pa-
`‘
`tients with impaired hepatic function. However, as the liver
`is one of the two organs (the other is the kidney) in which
`the metabolic conjugation of sodium phenylacetate and
`sodium benzoate is known to take place, care should be used
`in administering AMMONUID to patients with hepatic
`insuliiciency.
`Renal Impslnnsnt:
`For efisctive AMMONULE drug therapy, renal clearance of
`the drug metabolites and subsequently ammonia is re»
`quired. Therefore, patients with impaired renal function
`should be closely monitored.
`,
`, Dialysis:
`)
`Intravenous use ofAMMONUl.@is complementary with tho
`, use of dielysisl4,5l. In the non-neonatal study patient pop-
`ulation treated with AMMONUIIE , dialysis (standard he-
`i modialysis. peritoneal dialysis, arteriuvenous hsmnliltra-
`tion, or other dialysis) was
`required in 13% of
`hyperammonomic episodes. Standard hemodislysis was the
`most frequently used dialysis methods High levels of ammo-
`nia oan be reduced quickly when AMMONUID is used with
`‘ dialysis, as the ammonia-scavenging of AMMONUIE sup-
`‘ presses the production of ammonia from catabolism of en-
`dogenous proteinldl and dialysis eliminates the ammonia
`and ammonia conjugates.
`
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`
`3324/UCYCLYD
`
`Ammonui=—cont.
`
`Urea cycle disorders can result from decreased activity of
`any ofthe following enzymes: N-aeetylglutamate synthstese
`(NAGS), carbamyl phosphate synthetase (CPS). arginino-
`succinate synthetese (ASS). ornithioe transcarbamylaae
`(UPC). argininosuacinate lyasc (ASL). or argioase (ARG).
`The most frequently observed
`presenting sympfnms
`in neonates indude lethargy. seizures, poor feeding, neuro-
`logic changes, edema, and respiratory distress. Patients
`with milder forms of enzyme deficiencies may not present
`until late childhood, adolescence, or adulthood. l-iyperam-
`monsmlc crisis with lethargy, delirium, and coma, in these
`patients, are often procipilated by viral illness. high protein
`diet. stress, or trauma.
`Plasma and urine amino acid analyses are used to diagnose
`ASS and ASL and to provide a preliminary diagnosis of
`CPS, OTC, or ARG. Blood citrullina levels are very low or
`absent in O’!!! and CPS, very high in AS, and normal to
`moderately high in ASL and ARG. ASL may be distin-
`guished by the pruence of high levels oftho unusual amino
`acid argininoauccinic acid (ASA) in the urine. it should he
`noted, however, that ASA tends to co-elute initially with
`other amino adds (such as leucina and isolaucine) in chro-
`matographs, and may be missed on initial examination.
`ARC is characterized by high urine levels of srginina. A de-
`finitive diagnosis of CPS and OTC require a liver biopsy,
`and red blood cell enzyme analysis is needed to confirm a
`diagnosis ofARG Patients suspected of having a urea cycle
`disorder, based on family history, should have documented
`hypsrammonamia prior to administration ofAMMONUW.
`Mechanism of Action
`
`AMMONUID, phanylacetate and benste, provide an al-
`Figure 2 is a schematic illustrating how the components of
`ternative pathway for nitrogen disposal in patients without
`a fully functioning urea cycle The moles of nitrogen are re-
`moved per mole ofpheoylaoetote when it is conjugated with
`glotamine, and one mole of nitrogen is removed per mole of
`benzoats when it is conjugated with glycine.
`[See figure 2 below}
`Pnsrrnsooltlnstica
`intravenously administered
`The pharmacokinetica of
`AMMONUID were characterized in healthy adult volun-
`tears. Both benzoatc and phcnylaoctate exhibited nonlinear
`kinetics. Following 90 minute intravenous infusion mean
`AUC.,,, for bensoate was 20.3, 114.9, 584.6, 662.8, and
`1599.1 mcg/mL following doses of 1, 2, 3 75, 4, and 5.5 glm‘,
`rcspectivel . The total clearance decreased from 5.19 to
`3.62 Uh/m at the 3.75 and 5.5 giro’ doses. respectively.
`Similarly, phenylacataie exhibited nonlinear kinetics fol-
`lowing the priming dose regimens. AUC,,,,, was l76.ti, 713.8,
`2040.8, 2181.5, and 3829.2 meg-hlmL following doses of 1,
`2, 3.75, 4, and 5.5 gm‘, respectively. 'l‘he total clearance dc-
`crossed from 1.82 to 0.89 mcg~hlmL with increasing dose
`(3.75 and 4 pm’, respectively).
`During the sequence of 90 minute priming infusion followed
`by a 24 hour maintenance infusion, phenylacetste was de-
`tected in the plasma at the end of infusion ('l‘,,,_ of 2 hr at
`3.75 glm’) whereas, benzoats concentrations declined
`
`Figure 2
`Benznsh
`
`u-Kstnplmnrntu
`
`9
`NH,
`
`G cine (———-) NH“—L>G|utsrnaleAT) Iutnmlns Phenylaeoteta
`H00:
`
`Y iiV
`
`Urine ssorotion
`
`
`
`carbanlyl pllospilals
`
`Supplemented __
`Arglnlna
`
`
`
`Fumarate
`
`CPS = corbsmyl phosphaue sy nlhels.~e- (Tfl: =ormli1i-in lmmcnrbamyl-.L<e;ASS = urglninosurunuic .iyn|im,,,,,_ As|, =
`arginirmsuainalc lynsc. ARG = urginsse; ‘(AGE = N ac:-Iy:glummslc synihcuse
`
`Information will be superseded by supplements and subsequent editions
`
`3 of 5
`
`

`

`PRODUCT INFORMATION
` UCYCLYD/3325
`were maintained DI:Ily.‘ll.'s I4 i‘l'l‘i|l'llllil'I'li'IPl'I for those pn-
`peated at 4-wi-i-k .ntirv.ile. M.inifimtritiiina iivi-re predomi-
`ui-ntsi who fail to have a significant reduction in plaiimzi um-
`nnntly somnolenci-, fatigue, and lightheiidedni.-ss, with IBM!
`monin levels within 4
`to 8 hours
`.ifti-r
`ri.-ci-iving
`fniqui-nt hi-adaches, dyi=gi-usin, hypoacuriiir, diflDl'It‘nL’lIIOn,
`AMMONUIJE. A shift from high I‘ 4 times ULN) to very
`impaired memory, and exacerbation of a preexisting neurop-
`high (> 4 times ULN) levels was observed in only 4% ofthc
`episodes.
`athy. Thr-so adverse events were mainly mild. The acute on-
`set ofsymptoms upon initiation of treatment and reversibil-
`improvements in neurological status endpoints were ob-
`ity of symptoms when the phenylacetew was discontinued
`suggest a drug ufl'ect [2,3].
`served in most episodes and patients Overall, investigators
`l
`rated neurological status as improved, much improved, or
`In animal studies, subcutaneous administration to rat pups
`the some in 9371- of episodes, and overall status in response '
`of 190-474 mg/kg of phi.-nylacetate caused decreased prolif-
`to treatment as improved, much improved, or the same in
`eration snd 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 i15l. Pregnant rats were [given
`phenylucetate at 3.6 Aumol/g/day subcutaneous from gesta-
`.\.\ri.\lIONI.'I@ is indicated as mljunetive therapy for the
`'rcatment of acute byperaramonemia and associated en-
`tion day 7 through normal delivery. Prenatal exposure ofrat
`pups to phenylacetste produced lesions in layer 5 cortical
`ccphalopathy in patients with deficiencies in enzymes ofthe
`pyramidal cells: dendritic spines were longer and thinner
`.rea cycle In acute neonatal hyperammonemic coma, in
`than normal and reduced in number [16].
`iioderate to severe episodes of hyperammonemic encepha-
`Drug Interactions:
`opiithy. and in episodes of hyperammonemia which fail
`Some antibiotics such as penicillin may compete with phe-
`to respond to an initial course ofAl\IMONUlD therapy, he-
`modialysis is the most rapid and efi'cr:tive technique for re-
`nylacetyiglutsmine and hippurate for active secretion by re-
`niuving ammonia [12,13]. In such cases. the concomitant
`nal tubulea. which may aifect the overall disposition of the
`infused drug.
`administration of AMMONUL® can help prevent
`the
`rc--accumulation of ammonia by increasing waste nitrogen
`Probenecid is known to inhibit the renal transport of many
`excretion I-1.5.13].
`organic compounds, including iiminohippuric acid, and may
`CONTRAINDICATIONS
`rate I13].
`affect renal excretion of phenylacetylglutamine and hippu-
`AMMONUIE should not be administered to patients with
`There have been reports that valproic acid can indum hy-
`known hypersensitivity to sodium plienylau.-tube or sodium
`benzoate
`|'l(‘l‘lii'il.‘liDnumlfl through inhibition of the synthesis of N-
`acetylglutamnte, a co-factor for carbamyl phosphate synthe-
`WARNINGS
`tasa [14]. Therefore, administration of viilproic acid to
`patients with urea cycle disorders niiiy exacerbate their con-
`Any episode of acute symptomatic hyparammonemln
`dition and antagonize the ellicacy ofAMMONUIJiD [15].
`should be treated as a lilo-threatening emergency. Treat-
`Carcinogenesis. Mutaganaula, impairment of Fertility:
`ment of hyperammonomia may require dialysis, pratarably
`Carcinogenicity, mutagsnicity and fertility studies of
`liemodlalyiiis, to remove a large burden at ammonia. Un-
`sodium phenylacetale have not been conducted. Sodium
`controllad liyparammonornla can rapidly result in brain
`benzoate has been extensively tested as a food preservative.
`damage or death, and prompt uaa oi all therapies neces-
`sary to reduce ammonia levels is essential.
`Results indicate that sodium benzoale is not mutagenii: 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 AMMONUIE. It is not known
`d sorder may necessitate the use of he-modialysis combined
`whether AMMONUIJD can cause fetal harm when adminis-
`with nutritional management and medical support. The
`tered to a pregnant woman or can nficct reproduction capac-
`multidisciplinary nature of the treatment usually requires
`the facilities ofa tertiary or quaternary care center.
`ity. Thus, AMMONUIAJ should be given to a pregnant
`woman only ifclearly needed.
`Ongoing monitoring ofplosms ammonia levels, neurological
`Labor and Delivery:
`status, laboratory tests, and clinical response in patients re-
`unknown.
`The eifects of AMMONUL48) on labor and delivery are
`ceiving AMMONIJIQ is crucial to assess patient response in
`treatment. Because urine potassium loss is enhanced by the
`Nurslng Mothers:
`excretion of the nonreabsorbabie anions, phenylacetyl-
`glutamine and hippurate, plasma potassium levels should
`It is not known whether sodium phenylacetate, sodium ben-
`‘ zoate, or their conjugation products are excreted in human
`lie 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.
`tered to a nursing woman.
`AMMONIll.w contains 305 mg of sodium per mL of undi-
`Pediatric:
`'=:ied product Thus, AMMONUIAD should be used with .
`great care, if at all. in patients with congestive heart failure
`or severe renal insufliciency, and in clinical states in which
`there is sodium retention with edema. If an adverse
`reaction does
`occur, discontinue
`administration of
`AMMONUUD, evaluate the patient. and institute appropri-
`1ti'- therripi-iitic crrintermcasnres
`Administration must be through a central line. A