`
`Officers of Thomeon Healthcare, Inc.: President and Chief Executive Officer: Kevin King; Chief Financial Officer: Pau! Hilger; Chief Medical Officer: Rich Klasco, MD, FACEP;
`Executive Vice President, Medstat: Carol Diephuis; Executive Vice President, Micromedex:Jeff Reih!; Senior Vice President, Marketing: Timothy Murray; Senior Vice President,
`Technofogy: Michael Karaman; Vice President, Finance: Joseph Scartone, Vice President. Human Resources: Pamela M. Bilash
`COOREMNEBRSEO
`XCHANGEBy ac
`BOSTON, MA 02109
`
`Page 1 of 5
`
`LUPIN EX. 1019
`
`ageSWIM PROGTERLLP
`DEC 01 2005
`
`RECEIVED
`
`PDR’
`60
`
`EDITION
`
`2006
`
`
`
`PHYSICIANS
`DESK
`KEFEIKENCE
`
`Senior Vice President, PDR Sales and Marketing: Dikran N. Barsamian
`Vice President, Product Management: William T. Hicks
`Vice President, Regulatory Affalra: Mukesh Mehta, RPh
`Vice President, PDR Services: Brian Holland
`Senlor Directors, Pharmaceutical Solutions Sales: Chantal Corcos,
`Anthony Sorce
`National Solutions Managers: Frank Karkowsky, Marion Reid, RPh
`Senior Solutions Managers: Debra Goldman, Elaine Musco,
`WamerStuart, Suzanne E. Yarrow, RN
`Solutfons Managers: Eileen Bruno, Cory Coleman, Marjorie A. Jaxel,
`Kevin McGlynn, Lols Smith, Richard Zwickel
`Sales Coordinators: Arlene Phayre, Janet Wallendal
`Senior Director, Grand and Product Management: Valerie E. Berger
`Associate Product Managers: Michael Casale, Andrea Colavecchio
`Senior Director, Publishing Seles and Marketing: Michael Bennett
`Director, Trade Sales: iii Gaffney
`Associate Director, Marketing: Jennifer M. Fronzaglia
`Senior Marketing Manager: Kim Marich
`Direct Mail Manager: Lorraine M. Loening
`Manager, Marketing Anatysts: Dine A. Maeder
`Promotion Manager: Linda Levine
`Director of Operations: Robert Klein
`Director, PDR Operations:Jeffrey 0. Schaefer
`Director of Finance: Mark S, Ritchin
`
`
`Director, Client Services: Stephanie Strubie
`Director, Clinica! Content: Thomas Fleming, PharmD
`Director, Editortal Services: Bette LaGow
`Drug information Specialists: Michael DeLuca, PharmD, MBA;
`Kajal Solanki, PharmD; Greg Tallis, RPh
`Project Editors: Neil Chesanow, Harris Fleming
`Senior Editor: Lori Murray
`Senior Production Editor: Gwynned L. Kelly
`Manager, Production Purchasing: Thomas Westburgh
`POR Production Manager: Steven Maher
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`Production Specialist: Christina Klinger
`Senlor Production Coordinators: Gianna Caradonna, Yasmin Hemandez
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`
`THOMSON Copyright © 2006 and published by Thomson PDR at Montvale, NJ 07646-1742. All rights reserved. None of the content of thig publication
`=» May be reproduced,stored in a retrieval system, resold, redistributed, or transmitted in any form or by any means (electronic, mechanical,
`Ing, recording, or otherwise) without the prior written permission of the publisher. Physicians’ Desk Reference, PDR®, Pocket
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`
`Page 1 of 5
`
`LUPIN EX. 1019
`
`

`

` PRODUCT INFORMATION
`
`
`
`
`
`UCYCLYD/3323
`
`
`HOW SUPPLIED
`HOW SUPPLIED
`whether to discantinue nursing or to discontinye the drug,
`
`taking. into account the importance of the drug to the
`mother,
`
`TUSSIONEX Pennkinetie (hydrocodone polishrex and
`ZAROXOLYN Tablets (metolazonetablets, USP) are shal-
`
`chlorpheniramine polistirex) Extended-Release Suspension
`
`Pediatric Use: Safety and offectivenese of THSSIQNEX|ig q goid-colored suspension,- atrerigths:
`low biconvex, round tablets, and are available in three
`
`
`
`
`Pennkinetic Extonded-Releage Suspension in pedigtri¢|NDC 5014-46-67|473 ml bottle . : 2% mb,pink, deboasad “ZAROXOLYN’on one side, and
`
`
`
`patignts nier sin have, not bapa established (gee|Shake well. Disponge in a wallyelosed container. Store at "214" gn reverse side.
`
`§9°-86"F (16%90°C),
`NDC 69014-975-71 Bottleof 100's
`
`Gorigtric Use: Clinical studies ofTUSSIONEX didnot in-|Calttech Pharmateuticals, ine. ¢ NDC 68014-976-60 Bottle of 1000's
`
`
`
`
`
`clude sufficient nymbersofaubjects agpd,pi over tnde-|Rochester, NY 14923 USA NDC 59014-876-72|Sarton of 100’s, unit dose.
`
`
`
`
`termine whetherthey reapand differentlyfromyounger sul|© 3002, Celltegh Pharmaceuticals, Inc, 5 mg, blue, debossed “ZAROXOLYN"on one side, and “6” on
`
`
`jects. Otherreported clinical experienre has notidentified .|reverse side.® Celltech Manufactyring, Inc.
`
`
`
`differences in responags between the elderly end younger|‘Tussionex® Pennkinetico® Extended-Release Suspension; NDC 63014-850-71 Bottle of 100's
`
`
`
`
`
`patients. In general, dose selection for an eldariy patient|(J§ Patent Na. 4,762,109.2 NDC 63014-850-80 Bottle of 1000
`
`
`
`should bo cautious, upually starting gt the low end of the
`Currentas af 06/2005
`LR242A
`NDC 63014-850-72 Carton of 100's, unit dose
`
` 10 mg, yellaw, deboesed “ZAROXQLYN™ un one side, and
`dosing range,reflecting the greater frequency of decreased
`Rev. 12/99
`hepatic, renal, or cardiac function, and of concomitant dig-
`“10” on reverse side.
`eage or other drug therapy.
`..
`
`NDC 63014-845-71 Bottle of 100'a
`
`This drug is known to be substantially excreted by the kid-
`NDC 68014-886-90 Bottle of 1000's
`ney, and the risk of toxic reactions to this drug may be
`NDC 63034-836-72., Carton of 100, unit dose
`
`
`
`greaterin patients with impaired renal fimetion. Because|VICON FORTE® Capsules B|Store et 96°C (77°F); excursions permitted to 15°-30°C (69"-
`
`elderly patients are more likply.ta have decreased renal|[vt'hon for'td] 86°F) (See USP Controlled Room Temperature). Protect
`
`
`function, care should be taken in dose selection, and it may Repent Vitamine-Minerals
`from light, Keep out ofthe reach ofchildren.
`———
`be useful to monitor renal function.
`B an
`;
`Celttech Pharmacsuticeis, Ino.
`
`
`ADVERSE REACTIONS
`Rochester, NY 14623 USA
`
`
`Central Nervous System: Sedation, drowsiness, mantal|DESCRIPTION @ Celitech Manufacturing, Inc. R622B
`
`clouding, lethargy, impairment of meatal and physica! per-|Fach black and orange VICON FORTE® capsule for oral|© 2003, Celitech Pharmaceuticals, Inc. Rev. 108
`
`
`
`
`formance, énxiety, fear, dyephorta, euphoria, dieziness, pay-|administration contains: All righsoservedi
`chic dependence, mood changes.
`
`Dermatologic System: Rash, pruritus.
`
`Geatrointestinal System: Nausea and vomiting may occur;
`
`they are mare frequent in ambulatory than in recumbent
`patients. Prolonged administration of TUSSIONEX
`Ucyclyd Pharma,Inc.
`
`
`Pennkinetic Extended-Release Suepension may produce|Niacinamide Tee astane 8125 N. HAYDEN RD.
`
`
`SCOTTSDALE, AZ 85258
`Thiamine monenitrate ..
`constipation.
`
`
`Genitourinary System: Ureteral spasm, apasm of vesicle|d-Calclum fantothenate
`
`sphincters and urinary retention have been reported with|Riboflavin’ 00
`;
`opiates,
`Direct Inquiries to:
`Respiratory Depression: TUSSJONEX Pennkinetic
`
`Telephone: 800-900-6889
`
`
`respiratorydepression by astingdirectlyon brainstem ros-|Vitamin By,(Cyanocobalamin) FoMailtngCana i
`
`Extended-Release Suspension may produce dose-related|Folic atid... matte : .
`
`
`piratory centers (see OVERDOSAGE).
`* As 60 mg dried tine sulfate.
`
`Respiratory System: Dryness of the pharynx, occasional
`t As 50 mg dried magnesium sulfate.
`tightness of the chest.
`
`
`Each capsule also contains Edible ink, FD&C Blue No.*1,
`
`
`
`DRUG ABUSE AND DEPENDENCE:
`FD&C Rod No. 40, FD&O Yollow No. 6, golatin, lactose,
`B
`;
`AMMONUL®
`
`[4m-mén-al]
`magnesium stearate, siliron dioxide, eodium lauryl sulfate,
`TUSSIONEX Pennkinetic Extended-Release Suspension ig
`and titanium dioxide
`.
`
`
`{aodium phenylacatate and sodium benzoate) injection
`a Schedule II narcotic. Paychic dependence, physical de-
`10% / 10%
`j
`aii
`HOW SUPPLIED
`
`
`Rx Onty
`pendence-and tolerance may develop upon repeated admin-
`
`
`.
`Orange and black capsulea imprinted with “ucb” and “316”
`istration of narcotics; therefore, TUSSIONEX Pennkinetic
`
`Extended-Release Suspension should be prescribed and ad-|in bottles of 60 (NDC 60474-316-22) arid 600 INDC@ 50474- DESCRIPTION
`
`
`ministered with caution. However, psychic dependence is
`316-24) and unit-dose packs of 100 (NDC 60474-816-27).
`
`
`unlikely!
`to develop when TUSSIONEK Pennkinetia
`
`
`Dispense in tight, light-residtant container with a child-
`AMMONUL® (eodiumphenylacetate and sodium benzoate)
`Extended-Retease Suspension is used-for a short time for
`realataht closing|'
`Injectioh 10%/ 10% ia a sterile, concentrated, aqueous solu-
`
`
`{Manufhctured for
`the treatment ofcough. Physical dependence, the condition
`and
`sod
`A
`i
`ee
`:
`ton ofsodiuin’pllenylacsthte and ¢odium benzoate, used for
`in whichcontinued adtainistratinn ¢fthedragisrequired to
`UCB Pharma, ine.
`thetréatment ofhyperammenemia in ae
`preventthe appearanceofa with
`syndrome, assumes
`90080
`The’pH ofthe solation ia between 6 and 8. Sodium pheny!
`Stiyrt,
`clinicallysignificantproportionsonly
`afterseveral weekaof
`byMal ee tne.
`lacetate is a aanialline, white to off-white powder witha
`continued dral nareotic use, although’ come mild degree of
`Hobart, NY 19768
`strong, offensive odor. It is soluble in water. Bodiuri bened-
`Cirrént as of08/2008
`robemerge
`ii
`¥
`readily eoluble in water:
`dependence may develop after a: fow days of nar 1£ 10/2003|9t@ ts « white and odorless, crystalline powder that is; 4
`
`
`
`
`
`OVERDOSAGB:, a5. 14
`
`Signa:end Symptoms: Serious overdosage with hydroca-
`a
`
`done is characterized by respiratory depression (a decrease
`
`
`in respiratory rate and/or tidal volume, Cheyne-Stokes re-
`B
` ZAROXOLYN® TABLETS
`
`piration, cyanosis), extrema somnolence progressing to stu:
`lzar "ox 'uh-lin]
`por or:coma, skeletal. muscle. flaccidity, cold) aid clammy
`
`
`{metolazone,
`tablets, USP)
`skin;. and sometimes: bradycardia and hypotension. Al-
`Be Only
`9,
`te
`"
`
`
`though’ miosis is characteristic of narcatic overdose; mydri-
`asis may. occur in:terminal nareosin or severe hypoxit’ In
`DO_NOT INTERCHANGE’ DO NOT INTERCHANGE
`severeoverdosage. apnea, circulatory collapse, cardiac ar
`GLYN TABLETS AND OTHER FORMULATIONS OF
`rest aad death may occur, The manifestatians.ofchlorphen,
`Sodiém phshylacetate has a molécular weight of 168.19 and
`
`
`METOLAZONE THAT SHARE ITS SLOW AND INCOMPLETE
`the molecular formula C.H,NaO,, Sodium Venzoate has a
`iramine overdosage may vary from central nervous.aystem
`depression to stimulation.
`BIOAVAILABILITY AND ARE NOT THERAPEUTICALLY
`molecular weight of 144.11 and the molecular formule
`EQUIVALENT AT THE GAME DOSES TO MYKROX® TAB-
`C,HNaQ,.
`Treptment:. Primary. attention ehould be giyen to the reqs-
`
`
`LETS, A MORE RAPIDLY AVAILABLE AND COMPLETELY
`
`
`Each mL of AMMONUL® contains 100 mg of sodium
`tablishmentof adequate,respiratory exchange through pro-
`BIOAVAILABLE METOLAZONE PRODUCT. FORMULATIONS
`vision-of apatent airway and the institutiga of assisted or
`
`
`phenylacetate and 100 mg-of sodium benzoate, and Water
`SIDEQUIVALENT TO ZAROXOLYN AND FORMULATIONS
`for Injection. Sodium hydroxide and/or hydrochloric acid
`
`
`controlledventilation. The narcotic antagonist naloxang hy-
`BIOEQUIVALENT TO MYKROX SHOULD NOT BE INTER-
`may have been used for pH adjustment.
`
`Grochlorids is a specific antidote for respiratory depression|CHANGED FOR ONE ANOTHER. AMMONULZ injectionis a sterita,concentrated solution in-
`
`
`which may result from overdosage or unusual sensitivity to
`DESCRIPTION
`tended for intravenous administration via a central line
`
`
`narcotics including hydrocodone, Therefore, an apprapriate
`only after dilution (see DOSAGE AND ADMINISTRA-
`dose :of- naloxone hydrpchisride should be administered,
`ZAROKOLYN Tablets (metolazone tablets, USP) for oral ad-
`
`
`TION). AMMONUL® ia packaged in single-use viala.
`preferably by. the intravenous route, simultansously with
`ministration contain 24, 6, or 10 mg of metolazone, USP. a
`
`efforts at respiratory resuscitation. Since the duration ofac-
`CLINICAL PHARMACOLOGY
`
`
`diuretic/aoluretic/antihypertensive drug of the quinazoline
`tion of hydrocodone in this.formulation may exceed that of
`class.
`‘
`Sodium phenylacetate and sodium benzoate are metaboli-
`the antagonist, the patient should be kept under continued
`Metolazone has the molecular formula CgH,¢CIN,O,8, the
`cally active compounds that can serve as alternatives to
`
`
`surveillance and repeated doses of the antagonist should be
`chemical name ?-chloro-1, 2, 3, 4-tetrahydro-2-methyl-3-(2-
`urea for the excretion of waste nitrogen. Phenylacetate con-
`adminiatered as needed to maintain adequate respiration
`methyiphenyl)-4-oxo-6-quinagolinesulfonamide, and a mo-
`jugates with glutaminein the liver and kidneys to form phe-
`For further information,see full prescribing information for
`lecular weight of365.83. The structural formula is:
`nylacetylglutamine,via ecetylation, Phenylacetylgtutamine
`naloxone hydrochloride, An antagonist should not be admin-
`is excreted by the kidneys via glomerular filtration and tu-
`istered in the absence ofclinically significant respiratory de-
`bular secretion. The nitrogen content of phenylacetyl-
`preagion. Oxygen, intravenous fluids, vasopressora and
`glutamine per mole is identicalto that ofures (both contain
`other supportive,measures should be employed aa indicated.
`two moles of nitrogen). Similarly, preceded by acylation,
`Gaatric emptying may be useful in removing unabsorbed
`benzoate conjugates with glycine to form hippuric acid,
`which is rapidly excreted by the kidneys by glomerular fil-
`DOSAGE AND ADMINISTRATION
`tration and tubular secretion. One mole of hippuric acid
`containa one mole of waste nitrogen. It has been shown that
`Shake well before using,
`phenylacatyiglutamine and hippurate can serve as alterna-
`Adults: 1 teaspoonful (5 mL) every 12 hours; do not exceed 2
`teaspoonfuls in 24 hours.
`tive vehicles tp effectively reduce waste nitrogen levels in
`patients with deficiencies af urea cycle enzymes and, thus,
`Children 6-12: 1/2 teaspoonful every 12 hours; do not ex-
`attenuate the risk of ammonia and glutamine-induced
`ceed 1 teespoonful in 24 hours.
`neurotoxicity,
`Not recommended for children under @ years of age (sce
`PRECAUTIONS).
`
` i
`
`ct
`
`me
`
`AL Cte
`y'
`10CHy
`
`Phenyteodiate
`
`Sodium Bonzoate
`
`Continued on next page
`Consult 2006 POR* supplements and future editions for revisions
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Metolazone is only sparingly soluble in water. but more sal-
`uble in plasma, blood, alkali, ond organic salventa
`Inactive Ingredients: Magnesium stearate, microcrystal-
`line cellulose and dya: 244 mg-D&C Red No, 33:5 mg-FD&C
`Blue No. 2; 10 mg-D&C Yellow No. 10 and FD&C Yellow
`No. 6.
`
`Page 2 of 5
`
`LUPIN EX. 1019
`
`Page 2 of 5
`
`LUPIN EX. 1019
`
`

`

`Age groups
`
`Ca
`fs
`
`nosuccinate synthetase deficiency, CPS = carbamyl phos-
`phate synthetase deficiency, ASL = argininosuceinate lyasé
`deficiency; ARG = arginase deficiency; THN = transient hy-
`perammonemia of the newborn
`*For the summary at the patient level, data obtained atfirst
`| episode used,
`**Diagnosis unknown or pending (23 episodes), acidemia
`(14 episodes), HHH syndrome(6 episodeg), carnitine trans-
`locase deficiency (4 episodes), liver disease (3 episodes),
`HMGCoA lyase deficiency {1 episode), non-ketotic hypergly-
`cinemia (1 episode), suspected fatty acid oxidation defi-
`ciency (1 episode), and valproic-acid-induced hyperammone-
`mia (1 episode).
`
`|
`
` than in males. However, conclusions cannot be drawn due to
`
`|
`
`| ||
`
`£3gtd3
`
`eneene>Tortecwececenmmecnercenenete
`
`
`+
`Figure 2
`o-Ketoglutarate
`NHt,
`Banzoate
`Gtycine <-———~—p> nut,—\> aiutamateAss» Glutamine Phenylacetete
`HCOs:
`¥
`
`70, * Carbamyl phosphate
`
`Gq
`ty,
`
`o
`é
`
`PRODI
`3324/UCYCLYD
`PHYSICIANS’ DESK REFERENCE®
`=aaseeaeenamaiammammeaas
`were mt
`DrugInteractions:
`rapidly (T,,., of 1.5 hr at 3.75 g/m?) and were undetectable
`Ammonul:—Cont.
`tients wl
`at 14 and 26 hours following the 3.75 and 4 g/m” dose,
`Formal drug interaction studiea have not been performed
`with AMMONUL®,
`monia
`respectively.
`AMMON
`Pharmacodynamics
`A difference in the metabolic rates for phenylacetate and
`Urea cycle disorders can result from decreased activity of
`benzoate wae noted. The formation of hippurate from
`any ofthe following enzymes: N-acetylglutamate synthetase
`In patients with hyperammonemiadueto deficiencies in en-
`high (> 4
`benzoate occurred more rapidly than that of phenylacetyl-
`(NAGS), carbamy! phosphate synthetase (CPS), arginino-
`zymes of the urea cycle, AMMONUL®has been shown to
`episodes.
`decrease elevated plasma ammonia levels and improve ey.
`Improve
`glutamine from phenylacetate, and the rate of elimination
`succinate synthetase (ASS), ornithine transcarbamylase
`served in
`cephalopathy and survival outcome compared to hiastoricaj
`for hippurate appeared to be more rapid than that for phe-
`(OTC), argininosuccinate lyase (ASL), or arginase (ARG).
`rated ne
`nylacetylglutamine.
`controls. These effects are considered to be the result of re.
`The most frequently observed initial presenting symptoms
`the same
`in neonates include iethargy, seizures, poor feeding, neuro-
`duction in nitrogen overload through glutamine end glycing
`Pharmacokinetic observations have also been reported from
`to treaty
`logic changea, edema, and respiratory distress. Patienta
`twelve episodes of hyperammonemic encephalopathy in
`scavenging by AMMONUL® in combination with appropri-
`ata dietary and other supportive measures.
`with milder forms of enzyme deficiencies may not present
`97% of ej
`seven children diagnosed (age 3 to 26 months) with urea cy-
`Clinical Data
`cle disorders who had been administered AMMONUL® in-
`until late childhood, adolescence, or adulthood. Hyperam-
`ofepisod:
`monemie crisis with lethargy, delirium, and coma, in these
`| Theefficacy ofAMMONUL® in improving patient surviva)
`travenously, These data ehowed peak plasma levels of phe-
`episodes)
`patients, are often precipitated by viral ilnees, high protein
`ofacute hyperammonemic episodes was demonstrated in an
`nylacetate and benzoate at approximately the same times
`INDICA
`diet, stress, or trauma.
`analysis of 316 patienta (1045 episodes of hospitalization)
`as were observed in adults. As in adults, the plasma levels
`AMMON
`treated between 1981 and 2003,
`Plasma and urine amino acid analyses are used to diagnose
`of phenylacetate were higher than benzoate and were pres-
`treatmen
`ent for a longer time[1].
`ASS and ASL and to provide a preliminary diagnosis of
`The demographic characteristics and diagnoses of the pa-
`cephalopi
`tient. population are shown in Table1.
`CPS, OTC, or ARG. Blood citrulline levels are very low or
`The pharmacokinetics of intravenous phenylacetate have
`urea cycl
`absent in OTC and CPS, very high in ASS, and norma! to
`been reported following administration to adult patients
`moderate
`Table 1 Bassiine Characteristics and Diagnoses of Study
`with advanced solid tumors, The decline in serum
`moderately high in ASL and ARG. ASL may be distin-
`Population
`lopathy,
`:
`guished by the presence of high levels ofthe unusual amino
`phenylacetate concentrations following a loading infusion of
`to respon:
`acid argininosuccinic acid (ASA) in the urine. It should be
`160 m
`was consistent with saturable enzyme kinetics.
`modialysi
`ed
`noted, however, that ASA tends to co-elute initially with |
`Ninety-nine percent of administered phenylacetate was ex-
`Moving a
`other amino acids (such as leucine and isoleucine) in chro-
`creted as phenylacetylglutamine {2,3}.
`administr
`matographs, and may be missed on initial examination.
`re-accumt
`Special Populstions
`158 (61%)
`ARGis characterized by high urine levels of arginine, A de-
`Gender;
`excretion
`finitive diagnosis of CPS and OTC requirealiver biupsy,
`150 (49%)
`| Pharmacokinetic parameters of AMMONUL® were com-
`CONTRA
`and red blood cell enzyme analysis is needed to confirm a
`| pared in healthy males and females. Bicavailability of both
`diagnosis ofARG. Patients suspected of having a urea cycle
`AMMONT
`benzoate and phenylacetate was slightly higher in females
`disorder, based on family history, should have documented
`known hy
`hyperammonemiaprior to administration ofAMMONUL®.
`benzoate.
`Mechanism of Action
`the limited numberof subjects in thie study.
`WARNIN
`Hepatic insufficiency:
`Figure 2 is a schematic illustrating how the components of
`|
`
`Any opis:
`| Limited informationis available on the metabolism and ex-
`AMMONUL®, phenylacetate and benzoate, provide an al-
`
`should ba
`104 (34%)
`ternative pathway for nitrogen disposal in patiente without
`| cretion ofsodium phenylacetate and sodium benzoate in pa-
`ment of h
`
`|
`tients with impaired hepatic function. However,as the liver
`a fully functioning urea cycle. Two moles of nitrogen are re-
`
`is one of the two organa (the other is the kidney) in which
`hamodiah
`55 (18%)
`moved per mole ofphenylacetate when it is conjugated with
`controlled
`the metabolic conjugation of sodium phenylacetate and
`glutamine, and one mole of nitrogen is removed per moleof
`
`damage o
`benzoate when it ia conjugated with glycine.
`sodium benzoate is known to take place, care should be used |
`sary to rec
`in administering AMMONUL® to patients with hepatic
`[See figure 2 below)
` 30 (10%)
`insufficiency,
`Pharmacokinetics
`Managem
`
`metabolisi
`Renal impsirmant:
`intravenously administered
`The pharmacokinetica of
`
`personnel
`31 (10%)
`For effective AMMONUL® drug tharapy, renal clearance of
`
`|
`AMMONUL® were characterized in healthy adult volun-
`disorder ¢
`the drug metabolites and subsequently ammonia is re-
`
`teers. Both benzoate and phenylacetate exhibited nonlinear
`with nutn
`146 (46%)
`quired. Therefore, patients with impaired renal function
`kinetics. Following 90 minute intravenous infusion mean |
`multidisciy
`
`should be clasely monitored.
`AUC,,,, for benzoate waa 20.3, 114.9, 564.6, 662.8, and |
`71 (22%)
`the faciliti:
`
`1599.1 meg/mL following dosesof }, 2, 3.75, 4, and 6.6 g/m?,
`| Dialysis:
`Ongoing m
`|
`Intravenous use ofAMMONUL@ is complementary with the
`38 (12%)
`statua, lab
`reapectively. The total clearance decreased from 5.19 to
`
`3,62 L/h/m* at the 3.75 and 5.5 g/m? doses, respectively.
`| use of dialysis[4,5]. In the non-neonatal study patient pop-
`ceivingAM
`ulation treated with AMMONUL®,dialysis (standard he-
`Similarly, phenylacetate exhibjted nonlinear kinetics fol-
`treatment,
` 7 (2%)
`
`lowing the priming dose regimens. AUC,,,, was 175.6, 713.8,
`excretion
`| modialysis, peritoneal dialysis, arteriovenous hemofiltra-
`2040.6, 2181.6, and 3829.2 megeh/mLfollowing doses of 1,
`2(< 1%)
`tion, or other dialysis) was
`required in 13% of
`glutamine
`2, 3.75, 4, and 5.5 g/m”, reapectively. The total clearance de-
`hyperammonemicepisodes. Standard hemodialysis was the
`be carefull
`creased from 1.82 to 0.89 meg*h/mL with increasing dose
`2(< 1%)
`mostfrequently used dialysis method. High levels of ammo-
`when nece:
`
`nia can be reduced quickly when AMMONUL® is used with
`(3.76 and 4 g/m’, respectively).
`tored and 1
` 66 (18%)
`During the sequence of 90 minute priming infusion followed
`| dialysis, as the ammonia-scavenging of AMMONUL® aup-
`AMMONU
`by a 24 hour maintenance infusion, phenylacetate was de-
`presses the production of ammonia from catabolism of en-
`luted prod
`tected in the plasma at the endof infusion (T,,,, of 2 hr at
`dogenous protein[6} and dialysis eliminates the ammonia
`great cure,
`and ammonia conjugates.
`or severe 1
`3.75 g/m”) whereas, benzoate concentrations declined
`there is &
`reaction ¢
`AMMONUI
`ate therape
`Administts:
`tlen throug
`Bolus infus
`infants (see
`vasation of
`lead to skin
`tinue the in
`necessary. !
`clude aspire
`| On admission to the hospital, patients with hyperammone-
`evation, anc
`infusion site
`| mia or a potential urea cyclo disorder (UCD) were treated
`with a bolus dose of 0.25 g/kg (or 5.6 g/m?) sodium pheny-
`tion during
`lacetate + 0.25 g/kg (or 5.6 g/m?) sodium benzoate over a
`luted produ
`Due to stru
`period of 90 minutes to 6 hours, depending on the specific
`benzoate to
`UCD.Infusions also contained arginine;the dose ofarginine
`depended on the specific UCD. After completion ofthe bolus
`typically as:
`ventilation ;
`dose, maintenance infusions of the same dose over 24 hours
`were continued until the patient was no longer hyperam-
`to perform |
`monemicor oral therapy could be tolerated. The mean (SD)
`and pCO, n
`duration of treatment was 4.6 (6.45) days per apisode, and
`PRECAUT
`ranged from 1 to 72 days.
`General:
`Survival was substantially improved after AMMONUL®
`AMMONU}I
`treatment compared with historical values (estimated 14%
`luted before
`1-year survival rate with dietary therapy alona) [10) and
`dium pheny
`with dialyais (estimated 43% survival of acute hyperammo-
`in the liver
`nemia) (111.
`and hippun
`Argininosuccinate|.--’
`caution whe
`Ninety-four percent (981 of 1045) of hyperammonemiceepi-
`aodes treated with AMMONUL® resulted in patients being
`hepatic or t
`D asBOcie
`| discharged from the hospital, Eighty percent of patients
`(262 of 316) survived their laat episode. Of the 64 patients
`may be adm
`who died, 53 (83%) died duringtheir first hyperammonemic
`Because of ;
`episode, OF the 104 neonates (<30d)
`treated with
`atate in pha
`AMMONULC
`AMMONUL®,34 (33%) died during thefirst hyperammone-
`mnie episode.
`Une ofcortic
`Ammonia levels decreased from very high levels (> 4 times
`tein and, the
`the upper limit of normal [ULN]) to lower levela in 91% of
`els in putien
`episodes after treatment. In patienta responding to therapy,
`Neurotoxicit
`Neurotoxicit
`mean ammonia concentrations decreased significantly
`within four houra ofinitiation of AMMONUL® therapy and
`travenous pt
`
`Da,rr
`
`a
`
`a m
`
`hAalaleBe
`Laiisaioe
`a
`
` | OTC =ornithine tranacarbamylase deficiency;ASS = mpl
`
`Age(years)
`
`6.2 (8.54)
`
`
`
`
`
` Mean (SD)
`
`
`Enzymedeficiency
`
`Arginine
`
`Supplemented ay
`Arginine
`..--"
`
`
`
`Fumarate
`
`CPS = carbamyt phosphaie synthetase: OTC = ornithine transcarbamylase; ASS = argininosuccsnute sy athetase, AST, =
`arginingsuctinate lyase, ARG = urginase, NAGS = N-acety|ghutamate synthetase
`
`Information will be superseded by supplements and subsequent editiona
`
`Page 3 of 5
`
`LUPIN EX. 1019
`
`Page 3 of 5
`
`LUPIN EX. 1019
`
`

`

` PRODUCT INFORMATION
`
`Investigations
`Metabolism and nutrition disorders
`Acidosis NOS
`Hyperammonemia
`Hyperglycemia NOS
`Hypocaleemia
`Hypokalemia
`Metabolic acidosis NOS
`Nervous system disorders
`Brain edema
`Coma
`Convulsions NOS
`Mental impairment NOS
`Psychiatric disorders
`Agitation
`Renal and urinary disorders
`Respiratory, thoracic and mediastinal
`disorders
`
`Respiratory distresa
`Skin and subcutaneous tissue disorders
`Vascular disorders
`Hypotension NOS
`
`32 (10%)
`67 (21%)
`8 (3%)
`17 (5%)
`22 (7%)
`8 (3%)
`23 (7%)
`13 (4%)
`71 (22%)
`17 (6%)
`10 (3%)
`19 (6%)
`18 (6')
`16 (5%)
`8 (3%)
`14 (4%)
`47 (15%)
`
`9 (3%)
`19 (6%)
`19 (6%)
`14 (40%)
`
`UCYCLYD/3325
`
`
`
`
`
`were maintained, Ditlysia is recommended for those pa-
` peated at 4-week intervals. Manifestations were predomi-
`tents whofail to havea significant reduction in plasma am-
`
`Infections
`39 (126)
`nantly somnolence, fatigue, and lighthendedauss, with leas
`
`monia levels within 4
`to 8 hours after
`receiving
`frequent headaches, dysgeusia, hypoacusia, disorientation,
`AMMONUL®.A shift from high (- 4 times ULN)to very
`Unnary tract infection NOS
`9 (3%)
`impaired memory, and exncerbation ofa preoxisting nevrop-
`high (> 4 times ULN)levels was observed in only 4% of the
`episodes,
`athy. Theseadverse events were mainly mild. The acute on-
`Injury, poisoning and procedural
`12 (4%)
`set ofsymptomsuponinitiation of treatment and reversibil-
`complications
`Improvements in neurological statua endpoints were ob-
`ity of symptoms when the phenylacetate was discontinued
`suggest a drug offect [2,3].
`served in moat episodes and patients. Overall, investigators
`rated neurological status as improved, much improved, or
`Tn animalstudies, subcutaneous administration to rat pups
`the same in 93of 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
`97S of episodes. Recovery from coma wasobserved in 97%
`nervous system (CNS) myelin. Cerebral aynapse matura-
`of episodes where comawaspresent at admission (112 of 114
`episodes),
`tion wasretarded, and the numberof functioning nerveter-
`minals in the cerebrum was reduced, which resulted in im-
`INDICATIONS AND USAGE
`paired brain growth [15]. Pregnant rate were jiven
`phenylacetate at 3.6 Apmol/g/day subcutaneousfrom gesta-
`AMMONUL® is indicated as adjunctive therapy for the
`‘reatment of acute hyperammonemia and associated en-
`tion day 7 through norma) delivery. Prenatal exposure ofrat
`Pups to phenylacetate produced lesions in layer 5 cortical
`cephalopathyin patients with deficiencies in enzymes of the
`pyramidal cells; dendrilic spines were longer and thinner
`urea cycle.
`In acute neonatal hyperammonemic coma, in
`than normal and reduced in number [16].
`noderate to severe episodes of hyperammonemic encepha-
`Orug Interactions:
`opathy, and in episcdes of hyperammonemia which fail
`Some antibiotica such as penicillin may compete with phe-
`to respondto an initia! course ofAMMONUL® therapy, he-
`modialysis is the most rapid and effective technique for re-
`nylacetyiglutamine and hippurate for active secretion by re-
`moving ammonia [12,13]. In such cases, the concomitant
`nal tubules, which mayaffect the overall disposition of the
`infused drug.
`administration of AMMONUL® can help prevent
`the
`Probenecid is known to inhibit the renal transport of many
`re-accumulation of ammonia by increasing waste nitrogen
`excretion (4,5,13).
`organic compounds,including aminohippuric acid, and may
`CONTRAINDICATIONS
`rate [13],
`affect renal excretion of phenylacetylglutamine and hippu-
`AMMONUL® should not be administered to patients with
`There have beenreports that valproic acid can induce hy-
`known hypersensitivity to eudium phenylacetate or sodium
`benzoate
`Perammonemia through inhibition of the synthesis of N-
`acetylglutamate, a co-factor for carbamy! phosphate synthe-
`WARNINGS
`tase [14]. Therefore, administration of valproic acid to
`patients with urea cycle disorders may exacerbate their con-
`Any episode of acute symptomatic hyperammonemia
`dition and antagonize the efficacy of AMMONUL® [15].
`should be treated as p life-threatening emergency. Treat-
`Carcinogenesis, Mutagenesis, Impairment of Fertility:
`ment of hyperammanemia mayrequire dialysis, prefarably
`Carcinogenicity, mutagenicity and fertility studies of
`hemodialysis, to remove a large burden of ammonia. Un-
`sodium phenylacetate have not been conducted. Sodium
`controlled hyperammonemie can rapidly result in brain
`benzoate has been extensively tested as a food preservative.
`damage or death, and prompt use of all tharaples neces-
`sary to reduce ammonia fevelsis essential,
`Results indicate that sodium benzoate is not mutagenic or
`carcinogenic, and does not impair fertility.
`Management of hyperammonemia due to inhorn errors of
`Pregnancy:
`metaboliam should be 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 AMMONUL®.It is not known
`disorder may necessitate the use of hemodialysis combined
`whether AMMONUL® can causefetal harm when adminia-
`with nutritional management and medical support. The
`tered to a pregnant womanorcan affect reproduction capac-
`multidisciplinary nature of the treatment usually requires
`the facilities of a tertiary or quaternary care center,
`ity. Thus, AMMONUL® should be given to a pregnant
`womanonly if clearly needed.
`Ong