PDR°
`
`so
`
`EDITION
`
`G69°“".5’a'i'ili9.-}°*‘"“’
`use 01 2005
`
`We
`
`PHYSICIANS’
`DESK
`REFERENCE
`
`Senior Vice President. FDR Sales and Msliletina Dlkren N. Barsamlan
`Vios Prsoidsnt. Product Mmuernent: William T. Hicks
`Vice President. Regulatory Arielle: Mullesli Mehia. RFh
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`Anthony Sorce
`National Solutions Managers: Frank Karkowsky. Marlon Reid. RPh
`E'°'"°
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`5°"'°' °"°°‘°'- 9'3"“ 3"‘ "WW MFWIWWN‘ V3'°”° 5- 593°’
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`Director. Trade Salas: Bill Gaffney
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`mm“ Ma“ Manage" Lemme M_ Loemng
`"mag." uaflwflng Numb: Dina A’ Meade’
`Promotion Mama": “ma Levine
`Director or operations: Robert Klein
`Director, FDR operations: Jeffrey D. Schaefer
`Director or Finance: Mark S. Ritchln
`
`Director, client services: Stephanie Stmbie
`Director. clinical content: ‘l1'lomas flaming. PharrnD
`Director. Editorial Oollillrll: Bette LBGOW
`.
`M N am 1
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`3;‘; 's°,a"H_ ,h;m’°°"'D;G,”eg”'T§fl',:"‘;°,lh°°L“°“' P"°""°' MBA’
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`H
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`:.'°n?;'EEamnmmi°:°L‘uc:::a"w'
`ems Fleming
`W r~««=~~» mm med L «iv
`M"'33°'v "°‘“““"" P“""”"‘3‘ "‘°”“’5 W°5“’“'3“
`PW P'°¢“°“°" "W59" SW9" MW’
`:'°¢"°“°" :Gg:':sg":'l;fi"‘°ger
`senior Production coordinators: Gianna caradonna. Yasmin Hernandez
`hung” gmmmmn Nick w_ cram
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`narnc figglgfgfgt; Kim condo"
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`copyrighlozooe and published by Thomson Pun at Monivaie. NJ areas-1742. All rights reserved. None oi the content or this publication
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`photocopying. recording. or otherwise) without the prior written permission of the publisher. Physicians‘ Desk Reference‘. FDR‘. Pocket
`PDFF, FDR Family Guide in Prescription Drugs‘. PDR Family Guide in Women's Health and Prescription Drugs‘. and PDR Family Guide in
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`Companion Guide. FDR‘ Phanriaoopoeia. PDFI‘ lor Herbal Medicines. PDQ‘ ior Nutritional Supplements. FDR’ Medical Dictionary. PDFI‘ Nurse’: Drug Handbook. PDFP
`Nurse's Dictionary. FDR‘ Family Guide Encyclopedia oi Medical Care. FDR‘ Family Guide to Natural Medicines and Healing Therapies, FDR‘ Family Guide in Common
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`llosnse.
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`Oirieers or Thornton iiesltllcare. ine.: President and Chief Executive Ofilcer: Kevin King; Chief Financial officer: Paul Hllger: Chief Medical Orlicer: Rich Klasco. MD. FACEP:
`Executive Vice President. Medsiac Carol Diephuis: Executive was President, Mrcromedex. Jefi Reihi; Senior Vice President. Marketing: Timothy Murray; Senior vice President,
`Tecirnoiogic Michael Karaman; Vice President. finance: Joseph Scarrone. Vice President, Human Resources: Pamela M. Biiash
`
`LUPIN EX. 1021
`
`1 of 5
`
`

`
`PRODUCT INFORMATION
`
`whether to discontinue nursing or to discontinue the dung,
`uniting into account the importance of the drug to the
`mother.
`.
`Pediatric Use: Safety and eii'ect.iveni.-so of TIJSSIONEX
`Psonkrnotic Extended-Release Suspspsion in pediatric
`pati
`to under sis have not been established
`Gsh
`Geriatric Use: Clinical studies orrqssiounx didnot in-
`cludn suflclent numbers ofsuluects agpd.
`and over toda-
`Ienriine whether they respond difiaraitlv
`in-mew ui-lr
`191:“. Other reported
`egparienm has not identified
`diliorenees in responsps behvcco the elderly and younger
`patients. in general, dose selection for an eldgrly patient
`should be cautious, upually starting at the low and of the
`dosing range. reilecting the greater frequency of decreased
`hepatic. renal, or cardiac function. and of concomitant dis-
`ease or other dnig therapy
`-
`Thisdrugisknown tohs_sohetantis,llyssci'etadbythskid-
`nsy. and the risk of toxic reactions to this drug may be
`greater in patients with impaired renal iimi.-flan. Bemuaa
`elderly patients are more lihly to have decreased renal
`function. are should be taken in dose selection. and it may
`be useful to monitor renal function.
`ADVEKSE REACTIONS
`Central Nervous System: Sedation, drowsiness, mental
`clouding. lethargy. impairment oi‘ mental and physical per-
`formance, a'nxisty, fear, dyephor-ls, euphoria, diulness. psy-
`chic dependence, mood changes.
`Dsnnstologlg Bynomz Bash, pruritus.
`Gastrointestinal sysum: Nausea and vomiting may occur;
`they are more frequent in ambulatory than in recumbent
`patients. Prolonged administration of TUSSIONEX
`Pennkiaslic Extended-Release Suspension may produce
`constipation.
`Genitourinary Syatam: Ureteral spasm. spaam of vesicle
`sphincters and urinary retention have been reported with
`opiates.
`Respiratory Depression: TUBSIONDK Pennkinetic
`Extended-Release Suspension may produce dose-related
`respiratory depression by acting directly on brain stem ros-
`pirstory centers (see OVERDOSAGED.
`Ruplramrv System: Drynesa oi‘ the pharynx. occasional
`tightness of the chest.
`DRUG ABUSE AND DEPENDENCE"
`TUSSIONEX Pennkinetic Extended-Release Suspension is
`a Schedule ll! narcotic. Psychic dependence, physical de-
`pendence and tolerance may develop npon repeated admin-
`istration of narcotics; therefore, TUSSIONBX Pennkinstic
`Extended-Release Suspension should be prescribed and ad-
`ministered with caution However, psychic dependence is
`unlikely to develop when TUSSIONEX Pennlrlnstie
`Extended-Release Suspension is
`a slum time tor
`the treatment of cough. Physical dsdéndenoa. the condition
`in which continued sdinlnlstretlnn ii thtadrug is required In
`preeeni: the appearance coin with
`syndrome. aasumss
`clinically significant pmpérlioria only
`r several weeks of
`continued oral narcotic use, slthoiiglh some mild degree of
`“mi
`.
`..
`..
`Llxinl-deperideadsmaydsvelopatliersfswdaysofnar
`0 :a 1:1:
`st .
`’
`Signs.-amt-aymsrtoniai Serious overdossgo with hydroca-
`done is characterized by respiratory depression (a decrease
`in respiratory rate andlon tidalvolume, Chsyns-Stokes retr-
`piration, cyanaais). extreme somnolence progressing to stu-
`por or.-coma; skeletal musde. flaocidity. onldi and clammy
`skim. and sornntimnt hredycandls and hypoteasion. Al-
`rhouglrmiuslsis charaeterlsticofaarooflc overdose: mydrl-
`arfismay.oa:urlnutsrrni.oalnarcomorsevenrl:ypo:ria. in
`sevorn4nverd.oaage.apnsa', circulatory collapse. cardiac an
`reatonddoaflamayoanm Ilmmsnifsatsunnsrnfdrlnrpheni
`ir-amina ovardoesge may vary from central nervous-system
`depression to stimulation.
`'I’nstmsm:. Primary susntionshould be given to the rose-
`labliahment. ofsdequaiemspiratory onchansa through pro-
`visi'ton~ot' gpatent. airway and the institution of assisted or
`nontrolledientiiation. ‘Dis narcotic antayinlst naloxnns hp
`drochlorids is a specific antidote for respiratory depression
`whichmay resultnonroverdossgearuoususl sanaitiviuto
`narcotics including lrydrocodonca 'l'hcrei'orc. an appropriate
`dossiofnalasnns hysiroohlorlds should be administered.
`preferably by. the intravenous routs. simultaneously with
`cflln-ts at respiratory resuscitation. Since the duration ciao-
`tiaa oflwdromdone in thiaiormuiation may exceed that of
`the antagonist, the patient should be kept wider amtlnued
`surveillance and repeated doses ntrhe antagonist should its
`administered as needed to maintain adequate respiration.
`For further information, see full prescribing information for
`nalnxone hydrochlorida,An aatapnist. should not he admin-
`istered in the absence ofclinically sigriiiicant respiratory de-
`pression. Oxygen, intravenous iluids, vasopressors and
`other Iupportivsanaasuras should be employed as indicated.
`gxgtric emptying may be useful in removing unabsorbed
`DOSAGE AND ADMINISTRATION
`Shalre well before using,
`Adults: iieaspoonful (5 ml.) every 12 hours; do not edtcsod 2
`tenspoonfula in 24 hours.
`Children 6-12: 112 tiesspooaful every 12 hours. do not as-
`and 1 usspooniul In 26 hours.
`Not. recommended for children under 6 years of age was
`PRECAUTIONS).
`
`HOW SUPPIJED
`TUSSIONEX Punnklnetic (hydrouidona pollshral and
`chlorphenirainina polistirest Extended-Release Suspension
`is s gold-colored suspension. I
`NDC 58014-648-67
`A78 mL bottle .
`.
`shake well. Dispense in a weilyclnssd container. Eton: at
`5D'58Ii'l' (16'ali0'.C).
`
`0 2002.
`_ Pltarutanputiosls,
`.
`In
`USA
`_
`0 Colltaclj , lac.
`'i\sssi_onea0 Pepnkinctiofl Extended-Release Suspension:
`US Patent No. 4,763,709}
`Current as of 08/2005
`LRMZA
`liar. 13195!
`
`.
`
`vicou FOITEO capéuiu
`lurkon [:or'tdl
`Ttiar
`Vtramlns-Minerals
`R on
`‘
`DESCRIPTION
`Each block and orange VICON FORTEO capsule for oral
`adrninistrstioa contains:
`Vitamin A
`..
`Wtamin E ..
`Ascorbic acid ..
`Zine sullhts. USP’ .
`Magnesium sulfats. USPl'
`Niacinaniids
`_
`Thiainine mononitrats ..
`
`.
`
`Fynldoxins hydrochloride
`..
`Folio acid ..... ..
`..
`Vitamin B“ (Gyanomlsalamln)
`‘ As 50 nigdrled zinc sulfate.
`1‘ Al 50 mg dried magnesium sulfate
`Eaolr capsule also contains Edible ink. F080 Blue No. 1.
`F‘D&0 Red No. 00. F030 Yellow No. 6. gelatin. lactose.
`magnesium sizeai-sis. sillmn dioxide. sodium lsuryl sulfate.
`and titanium dioxide;
`-
`now surrnnm
`d "316"
`with “ur.‘b'
`’ prl
`‘
`l
`0panga_ andlrlack
`rn bottles orsb <ui37b”s'i4‘3i'§1e’i§i5"lrir soo iuiildn som-
`318-24) and uoitdosc pa5lrs_of100iN'DC M1474-316-27).
`Dispense in tight, lightpresiitant container with a child-
`,
`.
`mmafi uosioi’.
`'
`
`eooao
`V
`Hobart. NY raise
`.
`,
`Ciirrént as of omoos
`
`IE ioooiis
`
`IAROXOLYNO TABLETS
`lzar “ox 'uh-linl
`lmetolasono,t_ablc3g USP)
`It only
`,
`'
`no not -.|Nl'E : oo nor in-rsncumas
`omnaiusrs mo omen FORMULATIONS or
`MEFOLAZONE TNAT8HAREl'l’SSI.0WANDlNOOMPl.ETE
`Bl0AVAll.ABl|.l‘l'.Y sun an: E TIIERAPEUTICALLV
`eouwaisur of are same noses ro Mvioioxo TAB-
`Lsrs. A Mass MPIDLV AVAILABLE mo DOMPLETELV
`cioavaiusis uarouzon: mooucr. roioviuurious
`BIOEOUIVALENI ro ZAROXOLVN mo FORMULATIONS
`BIOEOUIVALEQIT ‘TO MVKROX SHOULD NOT BE INTER-
`DESCRIPHON
`ZAROXOLYN 'l\Ihlets (mstnlaxorre tablets, USP) for oral ad-
`minisu-au'on contain 2%, 5; or 10 mg‘ oi’ mstolanooe, USP. e
`diuretic/soluretidantihypertensive drug oi’ the quiriszollne
`class.
`,
`Metoluone has the molecular formula C.,l-l,.ClN,0,S. the
`chemical name ‘I-chlnro-l. 2. 3). I-tatrshydro-2-methyl4H2-
`metliylphenyl)-4-oso-fiquiaasolinasolinnamids. and a mo-
`lecular weight ai'366.83. ’l1ia stnicturnl formula is:
`H
`
`on
`ll
`X)
`rauso.
`en,
`Metoliiwne is only sparingly soluble in water, but more sol-
`uble in plasma, blood. alkali. and organic solvents
`Inactive ingredients: Magnesium stearete. microcrystal-
`line cellulose and dye 2-«5 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 Yelloiv
`No. 6
`
`UCYCLYD/3323
`
`HOW SUPPLIED
`ZAROXOLYN Thhlets (motnlazonc tablets. USPl are shal-
`low biconvex. round tablets, and are available in three
`
`2% rag,-pink-.. dehosgd -?ZAll0XOLYN' on one lll‘ll4 and
`'-'25?’ on reverse side.
`NDC 5.51016-975-71 Bottleot‘ 100's
`NDC 58014-975790 Bottle of 1000's
`NDC 53014-976-72 Barton oi‘ 100's. unit dose
`6 mg, blue. dsliosaed 'ZAROKOLYN'an one side, and '6' on
`revesu sida.
`NDO 63014-B50-71 Bottle of 100':
`NDC 690l4~fl50-90 Bottle of 1llll0‘a
`NDC 5SiJl4—B50-72 Carton of WW5. unit dose
`10 mg. yellow, deboassd “ZAIiDXOLYN“ on one side. and
`‘ill’ on reverse side.
`NDC 53014-835-71 Bottle of wife
`NDQ 5801988580 Bottle M10005
`NDC 53014-835-73 Carton of 1003. unit dose
`Stars at il5'C i77'Ft. exnirsions permitted to I5‘-30'C (ii?-
`B6‘l?) (Bee USP Gnotrollad Room Temperature]. Protect
`from light. Keep out ofths reach ofcliiidren.
`
`Inc.
`utiolllsglnc.
`
`allrlzhtstgoarved.
`Curremasocntllmos
`
`Ucyolyd Pharma. Inc.
`8125 N. HAYDEN RD.
`SCOTTSDALE. AZ 86280
`
`,
`Direct Inquiries to:
`For
`ical Emergencies Coats
`filemro 800-9Qi)-6889
`Telephone (893) 829-2593
`
`'
`
`1}
`.
`AHHOIIULD
`[am-mlivi-all
`lsodluro ptianyisostata and sodium bonaostsl lnlsotlon
`I095 I 10%
`,
`.
`-
`Rx0I1lV
`
`DEUBIPTION ‘
`AMIMONUUD isodlurnphsnylacstato and sodium licnsoatis‘)
`Injcctioil 10%! 10% is s
`concentrated, aqueous solu-
`tion oi'sodiin"a’ptienyIsm:tate and sodium bensoete, uaedjor
`tlretréetmsnt of Ii
`mdnemia in area cycle disorders.
`'llié’pl'loftlie sol onishelwaenlianlllsodium phenyl
`laeetata is a crystalline. white to oflfiwhlts powder with a
`strong. oltrnsrve odor. it is soluble in water. Sodium beau’:-
`aoi is a white and odorless, crystalline powder that ii
`readily soluble in water.
`
`J...
`
`iimnyaciacs
`
`soon-i asnzws
`
`Bodifii phenylaoetate has a molecular weight of 158.13 and
`the molecular formula C,l~l,Na0,
`licnsoate has a
`molecular weight of 144.11 and the molecular forigiila
`C1HoN-0:-
`Each mL of AMMONULO contains 100 mg of sodium
`phcaylacetate and 100 mg-of sodium beams“. and Water
`for injection. Sodium hydroxide andlor hydrochloric acid
`may have been used for pH adjustment.
`AMMONULO injection is a star-ilggconiaentrnted solution in-
`tended for intravenous administration via a central line
`only afler dilution (see DOSAGE AND ADhIl'N18TllA-
`TION). AMMONUUD is packaged in single-use vials.
`CLINICAL PHAEMACOIDOY
`Sodium phenylaoetata and sodium benznele are metaboli-
`cally ective compounds that can serve as altsmatives to
`area for the excretion of waste nitrogen. Plieaylacetaoe con-
`jugates with giutamme ill the liver and kidneys to form pbe
`nylaoetylglutamlnc. via aoetyiation. Phenylaoetylglutaraiae
`is excreted by the kidneys via glomerular filtration and to-
`bular secretion The nitrogen content of phenylacetyl-
`gluuimrnc per male is identical to that ofures (bath contain
`two males of nitrogen). Similarly. preceded by acyletion,
`bonsoate corijugat.es'srlth glycine to form hippuric acid.
`which is rapidly excreted by the kidneys by glonierular lil-
`tration and tubular reaction. One mole of hippurlc acid
`contains one mole ofwaste nitrogen. It has been shown that
`pheaylacetylgiutnmine and hippurats can serve as alumna-
`tive vehlclra to eflectiveiy reduce waste nitrogen levels in
`patients with deficiencies of one cycle enzymes and. thus.
`attenuate the risk oi’ ammonia and glutamine-induced
`neurutnncity.
`
`continued on next page
`consollzonafloilhiippismsataarrdiritiussdlrloirslorrsvlsirsu
`
`2 of 5
`
`

`
`PROD!
`
`were mi
`lients wl
`mnnis
`AMM0l~
`high (> 4
`opisodes.
`Improve‘
`served in
`rated no
`the same
`to treatn
`97% of e_\
`ofepisndu
`episod)
`INDlCA'
`AMMON
`treatmen
`oephalopl
`urea cycl
`moderate
`lopsthy,
`.
`to respon-
`modialysi
`moving a
`odministi
`re-accumi
`excretion
`CONTRA
`AMMONI
`known hy
`henmate.
`WARNIN
`Any spla-
`should be
`mom of ir
`bomodlah
`controlled
`damage it
`sary to red
`Managem:
`metaholisi
`personnel
`disorder a’
`with nutrl
`ruultidisci]
`the faciliti-
`Ongoing in
`status, lab:
`oelvingAM
`treatment.
`excretion
`glutamios
`be careful]
`when nece
`tored and l
`AMMONU
`luted prod
`great care,
`or severe ri
`there is as
`reaction 1
`AMMON'Ul
`ate therape
`Administr-
`tlon throng
`Bolus infus
`infants (ace
`vasation of
`lead to skin
`tinue the in
`necessary. :
`clude aspir:
`ovation, an:
`infusion sit:
`tion during
`luted produ
`Due to aim
`bensaste to
`typically as:
`ventilation :
`to perform l
`and pCO, n
`PRECAUT
`Gsnsrsl:
`AMMONUI
`luted before
`dium pheny
`in the liver
`and hippurz
`caution who
`hepatic or I
`been ussocil
`may be adm
`Because on
`state in phs
`AMMONUl.(
`Use ofcortic
`tein and, the
`cls in putien
`Nsurotoxlcit
`Neurotoxicil
`(ravenous pl
`
`""3
`2
`
`PHYSICIANS’ DESK REFERENCE®
`
`‘
`
`Drug Interactions:
`Formal drug interaction studies have not been performed
`with AMMONULD.
`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.)
`controls. These effects are mnsidersd to be the result Dfn.
`ducfion in nitrogen overload through glutamins and glyeing
`scavenging by AMMONUIID in oombinstion with appmprl.
`ate dietary and other supportive measures.
`Clinical Data
`‘ The aficacy ofAMMON'Ulfl in improving patient survival
`ofacute hyperammonemlc 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 Baseline characteristics and Diagnoses of Study
`Population
`
`158 (61%)
`
`104 (34%)
`55 (18%)
`
`146 (48%)
`
`38 (12%)
`
`£§
`
`Enzyme deficiency
`
`noauccinats synthetaae deficiency; CPS = oarbamyl p os-
`' CYFC = omithine transcarbamylase deficienry;ASS = mini-
`I phats synthatass deficiency; ASL = argininosuocinafe lyase
`deficiency: ARG = arginase deficiency; 'l'HN = transient hy-
`persmmoncmia 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-lnduned 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 ding (or 5.5 g/ml) sodium pheny-
`lscetaw 4 0.25 g/kg (or 6.5 g/m’) sodium benzosts 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 H9:
`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 epi~
`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 l) 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
`
`
`
`
`
`Lpuos-or-<£'~¢.gnn(.‘-..&‘i:IIo\n.l§.".-‘a-is'.fi..r,..;.,g-,...,,-at":-a=.a,.i..g...-.-L.‘__“‘.h,F-‘
`
`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
`heowale occurred more rapidly than that of phenylaoetyl-
`glutamina from phenylacetafe, 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 benzosto 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 phenylacetato have
`been reported following administration to adult patients
`with advanced solid tumors. The decline in serum
`phenylaoetata concentrations following a loading infusion of
`150 mg/kg was consistent with saturable enzyme lrincfics.
`Ninsty-nine percent of administered phenylacetate was ex-
`creted as phonylacetylglutamino (2.31.
`Special Populations
`Gender:
`Fharrnacokinetic parameters of AMMONUDE were com-
`pared in healthy males and females. Binavailshility 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 insufllcisncyt
`: unwed information in avaihbh on um maubouam and “-
`cretion ofsodium phanylacetate 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 benzoste is known to take place, care should be used
`in administering AMMONUID to patients with hepatic
`insulliciency.
`Renal Impslnnant:
`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 hs1nnfiltra-
`tion, or other dialysis) was
`required in 13% of
`hyperammonomic episodes. Standard hemodislysis was the
`most frequently used dialysis method‘ High levels of ammo-
`nia can be reduced quickly when AMMONUID is used with .
`‘ dialysis, as the ammonia-scavenging of AMMONUIE sup— i
`i presses the production of ammonia from catsbolism of en-
`dogenous profeinldl and dialysis eliminates the ammonia
`and ammonia conjugates.
`
`E
`
`l l1
`
`AMMONUID, phanylacerate and benate, 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 ofpheoylaoetate 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}
`Phsrrnsooltlnotica
`intravenously administered
`The phsrmacokinetics of
`AMMONUID were characterized in healthy adult volun-
`tears. Both benzoatc and phcnylaoctate exhibited nonlinear
`kinetics. Following 90 minute intravenous infusion mean
`AUC.,,, for benzoate 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, phenylacatate 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 gm’, respectively).
`During the sequence of 90 minute priming infusion followed
`by a 24 hour maintenance infusion, phenylacetate was de-
`tected in the plasma at the end of infusion ('l‘,,,_ of 2 hr at
`3.75 glm’) whereas, benzosts concentrations declined
`
`u-Kntnplmnrnfu
`
`9
`NH,
`
`G cine (———-) NH“—L>G|utarnaleAT) Iutnmlns Phenylacoteta
`
`Y iiV
`
`Urine ssorotion
`
`Figure 2
`Benznsh
`
`carbanlyl pllosphals
`
`Arglnlna
`
`CPS = carbsmyl phosphaue sy nl.hela.~e- (Tfl: = urmlhi-in lmmcnrhamyl-.L<e; ASS = urglninosurunuic .»yn|lm,,,,,_ As|, =
`argininnsuainslc lynsc. ARG = urginssc; ‘(AGE = N ac:-Iy:glummslc symhclase
`
`Information will be superseded by supplements and subsequent editions
`
`3324/UCYCLYD
`
`Ammonul=—cont.
`
`-
`
`Urea cycle disorders can result from decruised activity of
`any ofthe following enzymes: N-aeetylglutsmate synthstesa
`(NAGS), carbamyl phosphate synthetase (CPS). arginino-
`succinate synthetese (ASS). ornithioe tranacarbamylase
`(UPC). argininosuacinate lyasc (ASL). or orgioase (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. Hypersm-
`moncmlc crisis with lethargy, delirium, and coma, in these
`patients, are ofhan 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-
`malngraphs, and may be missed on initial examination.
`ARC is characterized by high urine levels of srginina. A de-
`finitivs diagnosis of CPS and OTC require a liver biopsy,
`and red blood cell enzyme analysis is needed to confirm s
`diagnosis ofARG Patients suspected of having a urea cycle
`disorder, based on family history, should have documented
`hypsrammonamis prior to administration of'AMMONUI£.
`Mechanism of Action
`
`.
`
`3 of 5
`
`

`
`PRODUCT INFORMATION
`
`UCYCLYD/3325
`
`were maintained Di:ily.~ii.~s i4 i‘l'l‘i|i'llllil'X'li'IPi'I for those pn-
`ui-ntsi who fail to have a significant reduction in plaiimzi um-
`monin levels within 4
`to 8 hours
`.ifti-r
`rccciving
`AMMONUIJE. A shift from high I‘ 4 times ULN) to very
`high (> 4 times ULN) levels was observed in only 4% ofthe
`episodes.
`improvements in neurological status endpoints were ob-
`served in most episodes and patients Overall, investigators
`l
`rated neurological status as improved, much improved, or
`the some in 9371- of episodes, and overall status in response '
`to treatment as improved, much improved, or the same in
`974 of episodes. Recovery from coma was observed in 97% l
`of episodes where coma was present at admission (111 of 114
`episodes).
`INDICATIONS AND USAGE
`.\.\ri.\lIONI.'I@ is indicated as mijunetive therapy for the
`'reatment of acute byperammonemia and associated en-
`cephalopathy in patients with deficiencies in enzymes ofthe
`.rea cycle In acute neonatal hyperamnionemic coma, in
`iioderate to severe episodes of hyperammonemic encepha-
`opathy, and in episodes of hyperammonemia which fail
`to respond to an initial course ofAl\IMONUlD therapy, he-
`modialysis is the most rapid and efi'er:tive technique for re-
`moving ammonia [12,13]. In such cases. the concomitant
`administration of AMMONUL® can help prevent
`the
`rc--accumulation of ammonia by increasing waste nitrogen
`excretion I-1.5.13].
`CONTRAINDICATIONS
`AMMONUIE should not be administered to patients with
`known hypersensitivity to sodium plienylau.-tube or sodium
`benzoate
`WARNINGS
`Any episode of acute symptomatic hypararrimonemla
`should be treated as a lilo-threatening emergency. Treat-
`ment of hyperammonomia may require dialysis, pratarably
`liemodlalyais, to remove a large burden at ammonia. Un-
`controliad iiypararnmonornla can rapidly result in brain
`damage or death, and prompt uaa oi all therapies neces-
`sary to reduce ammonia levels is essential.
`.\Ianageinent of liyperammonemia due to inborn errors of
`metabolism should he done in coordination with medical
`personnel familiar with these diseases. The severity of the
`d sorder may necessitate the use of he-modialysis combined
`with nutritional management and medical support. The
`multidisciplinary nature of the treatment usually requires
`the facilities ofo tertiary or quaternary care center.
`Ongoing monitoring ofplosms ammonia levels, neurological
`status, laboratory tests, and clinical response in patients re-
`ceiving AMMONIJIQ is crucial to assess patient response in
`treatment. Because urine potassium loss is enhanced by the
`excretion of the nonreabsorbable anions, phenylacetyl-
`glutamine and hippurate, plasma potassium levels should
`be carefully monitored and appropriate treatment given
`when necessary. Scrum electrolyte levels should be moni-
`tored and maintained within the normal range.
`AMMONIil.w contains 305 mg of sodium per mL of undr-
`'=:ted product Thus, AMMONUU8) should be used with
`great care, if at all. in patients with congestive heart failure
`or severe renal insuiliciency, 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'- therapi-iitic crrintermcasures
`Administration must be through a central line. Administra-
`tion through a peripheral line may cause burns.
`Bolus infusion ilaw nites are relatively high, especially for
`infants (see DOSAGE AND ADMINISHIATION). Extra-
`vrisation of AMMOi‘\'UIJE into the perivcrious tissues may
`feed to skin necrosis. If extravssatiun is suspected, dismo-
`tinue the infusion and resume at a different infusion site, if
`necessary. Standard treatment for extrav.-isntian can in
`c ode aspiration of residual dnig from the catheter, limb el-
`evation, and intermittent cooling using cold packs [14]. The
`infusion site must be monitored closely for possible infiltra-
`tion during drug administration. Do not administer undi-
`.-iiterl product
`Due to structure.’ similarities between phenylacetste and
`bcnzoate to srilicylate, AM)/l0NUl£l may cause side eifects
`typically associated with salicylate overdose, such as hyper-
`H:lii.Iltll.i01l and metabolic aiidosis. The clinician is ndvised
`to perform blood chemistry profiles, and frequent blood pH
`and pC0, monitoring.
`PRECAU'l‘IONS
`General:
`AM.VIONUIJ® is a concentrated solution and must be di-
`luted before administration via a central line Because so-
`dium phenylacetate and sodium benzoate are meliibolized
`in the liver and kidney, and since phenylacetylglutamine
`and hippurate are primarily excreted by the kidney, use
`caution when odministerii-5; AM.\I()I\'Ul)® to patients with
`hepatic or renal insufficir.-ncy AMMONUMD infusion has
`been associated with nausea and vomiting An anticmetic
`may be administered during A.\lMONUL® infusion.
`Because of prolonged plasma Iavaia achieved by pirany|ai:-
`state in pharrnacoitinatlr: studies, repeat loading dose: oi
`AMMONULO should not be administered.
`Use of corticosteroids may cause the breakdown ofbody pro-
`tein and, thereby, potentially increase plasma ammonia let-
`izis in patients with impaired .ibility in form urea.
`lilourotoaiclty oi Phanyiacatata:
`N:-uriitoxieity ‘v\
`is I'l[i(lI'i.(‘d ii
`I.‘-tii('L‘f p'clIit:‘ili.5 rn-ciiving .n-
`5i‘{lVk'nlrllS phcnylacct.-itc, Ail)-.'iOI) mg/kojdsy for 14 days, re-
`
`No. patients with any adverse event
`Blood and lymphatic system disorders
`Anemia NOS
`
`Disseminated intravasculai
`coagulatioii
`..:_.____._j_
`Cardiac disorders
`Gastrointestinal disorders
`DilIi'i'l]t‘a NOS
`Nausea
`
`Vomiting, .\'i)S
`
`Giiieriii disorders rird
`administratinii-site conditions
`,_;_____:_
`ii-_'ection-site ri-action NOS
`Py rl"K a
`__.___.__:___j__
`
`I63 (52%)
`{I5 (li'i)
`
`ll(3'7t)
`
`-i.’i(i4'i)
`
`peated at 4-week .ntirv.ils. M.inifimtritmn.s wi-re predomi-
`nontly somnolenci-, fatigue, and lightheiidednt-ss, with IL‘i|lI
`fniqui-nt hi-ridaches, dysgi-usin, hypoacuriiii, disorientation,
`impaired memory, and exacerbation of a preexisting neurop-
`othy. Thr-no adverse events were mainly mild. The acute on-
`set ofsymptoms upon initiation of treatment and reversibil-
`ity of symptoms when the phenylacetaw was discontinued
`suggest a drug ufl'ect [2,3].
`In animal studies, subcutaneous administration to rat pups
`of 190-474 mg/kg of phenylacetate caused decreased prolif-
`eration snd increased loss of neurons, and reduced central
`nervous system (CNS) myelin. Cerebral synapse matura-
`Linn was retarded, and the number of functioning nerve ter-
`minals in the cerebrum was reduced, which resulted in im-
`paired brain growth i15l. Pregnant rats were given
`phenyiucetate at 3.6 Aumol/g/day subcutaneous from gesta-
`tion day 7 through normal delivery. Prenatal exposure ofrat
`pups to phenylacetate produced lesions in layer 5 cortical
`pyramidal cells: dendritic spines were longer and thinner
`than norrnnl an