MAR 1 5 2007
`("S'-Jo·o8"
`fj
`
`EDITION
`
`2007
`
`PHYSCANS'
`DESK
`REFERENCE
`
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`ISBN: 1·56363-568-2
`
`Ranbaxy Ex. 1005
`IPR Petition - USP 8, 772,306
`
`

`
`1688/JANSSEN
`
`Risperdal Consta-Cont.
`
`rio us adverse events to tile manufacturer. (See WARN(cid:173)
`INGS).
`
`HOW SUPPLIED
`RISPERDAL® OONSTA ® (risperidone) is available in dos(cid:173)
`age strengths· of 25, 37 ,6, or 50 mg rispmidone. It is pro(cid:173)
`vided as a dose pack, consisting of a vial containing the
`~sp~~~do~}e- -:m~:~fh~~:s, ;1§~~~~~~~~~~~~n!
`SmartSit.e® Needle-Freo Vial Access Device, and one
`Needle-Pro® safety needle for intramuscular injection
`(20 G TW needle with needle protection device).
`25-mg vial/kit CNDC 50458-306-11); 25 mg of a white to off(cid:173)
`white powder provided in a vial with a pink ilip-off.cnp
`• :.
`·
`.
`(NDC 50458-306-on.
`37.5-mg viallkit(NDC 50458-307-1~): 37.5 mgofa white to
`off-white powder provided in a vial with a gresn flip-ofT cap
`.
`(NDC 50458-307-01).
`50-rog vial/kit (NDC 50458-308-11): 50 mg of a white to off_:
`white powder provided-in.a vial with a blue flip-off cap
`·
`(NDC 50458-308·01).
`Storage and Handling
`The entire dose pack -should be stored in the refrigerator
`· _
`(36°-46"J:I'; 2°-8°0) and protected from light.
`If refrigeration is unavailable, RISPERDAL® CONSTA ®.
`can be stored at temperahu·es not exceeding 77°F (25°C) for
`no more than 7 days prioi· to administration. Do not expose
`u~~·efrig~ratcd proc{uct._to_ tAmperatures above 77°F (25"C).
`-
`Keep_~ut of reac!l of chil~ren.
`. .
`7MB506
`US Patent 1-,~04,663
`Revised March 2006
`©Janssen 2003
`Risperidone is manufactured by:
`Janssen Pharmaceutical Ltd.
`Wallingsto\Vn, Little Island, County Cork1 Ireland
`Microspheres are munufnctured by:
`AlkerineS ContrOlled Therapeutics II;
`·
`Wihnington 1 OhiO·
`Diluent is manufactured by:
`Vetter P11armF1 FertigUllgGmbH & CO. KG
`RnvensLurg 1 Germany
`R!SPERDAL® CONSTA ®is distributed by:
`Janssen, L.P.
`.
`.
`Titusville, NJ 08560
`Shown in Product Identification Guide, page 318
`
`J~zz J>harmaceuticals, Inc.
`3180 PORTER DRIVE
`PALO ALTO, CA 94304
`
`Direct Inquiries to:
`Phone: (650) 496-3777
`Fax: (650) 496-3781 '
`E-mail: contact@jazzpharmn.com
`For medical information:
`E.:.mail: jazZpharma®medco_mso1.com
`For media information: •
`E-1U:~l: ,mc_diain~o@j~z~vharroa.coni
`
`XYREM® .•
`!sodium oxybate) oral solution
`Rx only
`
`WARNING: Central nervous system depressant with.
`abuse potential.
`·
`·.
`_,
`Should not be used with alcohol or other CNS
`depressants.
`Sodium oxybate I~ GHB, a known.F~rug of a.b~s.e. Abuse
`"has·. h,ee.n associated with soma Important central
`nerVoUs System !CNS) adverse-events (including death).
`Even ~t_ recommended do~es, use has been associated
`with confusion, depreS~io.n and other neuropsychiatric
`ev~nts. Reports_ of respiratory depressTon occurred in
`clinical trialS: A!inost all of the patients who received so(cid:173)
`dium oxybate,d~rlng clln~cal trials were receiving CNS
`·
`.
`· ., ·
`stimulahts.
`Important CNS adv9rse events associated with abuse of
`GHB include seizure, respiratory depression and pro(cid:173)
`found decreases In level of consciousness, with in(cid:173)
`stances of coma and death, For events that occurred
`ocutSide ot.Ciirilcal trialS, in people tolting GHB for re_cre(cid:173)
`a.tiorial purp'oses, the Circumstances surrounding tho
`events are aftOn unclear (~.g., dose of GH~ taken, the
`riatUrC ··and amoUnt of alcohol or any cOnComitant
`drugs).
`Xyrem is availablethro·uyh theXyrem Success PrOgram,
`using· a- -centralized pharmacy 1-866~XYREM88®
`· (1"-866-991-3688). The Success Program provides educa(cid:173)
`tional materials to the "prescriber and the patient ex(cid:173)
`plaining the risks and proper use of sodium oxybate,and
`the required prescription form. Once it Is documented
`that the patient has read and( or understood the mate~
`rials, the drug will be shipped to the patient. The Xyrem
`Success Program also recommends patient follow-up
`every 3 months. Physicians are expected to report all se-
`
`Information will be superseded by supplements and subsequent editions
`
`DESCIUPTION
`Xy1·em (sodiuin oxybate) is a centra] nervous system de~
`pressflnt that. reduces excessiv:~ ~a.ytime sleepiness and
`cataplexy in patients with n~rcolepsy. Sodium oxybate is
`intended for oral adminiF;tration. The chemical nnme for
`sodium oxybatc is sodium 4-hydroxybutyrate. The molecu(cid:173)
`lar funnula- is C4H 7Na03 '- and the molecular weight ia
`i26.09 grumshnolc. The chemical structure is:
`
`0
`II
`'Na• ·o-C-CH2·CH2 -CHa-,0-H
`
`Sodium ox.ybate is a whlte. to on:. white, crystalline powder
`that is very soluble in aqueous solutions. Xyrem oral solu-.
`Lion contains 500 mg of sodium oxybate per· milliliter of
`USP Purified Water1 neutralized to pH 7.5 with malic acid,
`CLINICAL PHARMACOLOGY
`Mechanism of Action
`The precif>B mechanism by which sodium oxybate product:s
`an effect on cataplexy is_unknovm.
`PharmacOkiileHcs
`Sodium oxybfl.t~ i~> rapidly but incompletely absorbed after
`o"ral adminis"t.rati'onj abSorptiOn is delayed ancl decreased
`by a high fat m,Eial. It is eliminated mainly by metabolism
`wfth !i half-life Of_O.f)_ to 1-houi· .. Pharmacokinetics are non~
`linear with b1ood'levels increaSfng 3.7-±0ld as dose 1s dou~
`bled from 4Jl to 9 grams (g), The pharmacokinetics are not
`·
`altcrorl with repeat dosing,
`AbSorption
`Sodium oxyhate is absorbed rapidly following oral admin~
`istration with an ahsolute bioavailabilityofabout25%. The
`average peak plasma concentrations (1st and 2nd peak) fol(cid:173)
`lowing administration of a 9 g daily pose divided into two
`equivalent doses given four homs · apart were 78 and
`142 micrograms/milliliter (mcg/mL), respectively. The av(cid:173)
`erage Lime to peak plasma concentr~t.ion (T mmJ ranged
`from 0.5 to 1.25 hours in eight pharmacokinetic studies.
`Following otal adnlinisti-ation,"the plflsrria lev9ls-ofsodium
`oxybitte inCreAse mol-e thEln 'plioportionally with iJ!creasing
`dose. Singh~ doses greater thEm 4.5 g have not beeri. studied:
`Adlninis'tration of sodiuril oxybil'te inu;nediate]y after a high
`fat meal resulted in delayed aDsorption (average Trr.n]( in(cid:173)
`creased from 0.75 hr to 2.0 hr) and a reduction in peak
`plasma level (C ... ux) by n mean of 58% and of systemic ex(cid:173)
`posure (AUC) by 37%.
`Distribution
`Sodium oxyba.te is a hydrophilic compound ¥.ith un uppar(cid:173)
`en,t Vt?~WD~·of di~tribution averaging 190-384 mL/kg, At so(cid:173)
`to
`from 3
`ranging
`dium oxYbat~.. concentrations
`300 m_cg/mL, less than.l% is l;)Qund to plasma:proteina.
`,
`Metabolism
`Animal studies indicate thatlnetabolism is the major elim(cid:173)
`inaf.io~ pat]lway for sodi'Wl··Dxybate, producing carbon
`dioxide and water via the tricarboxylic acid UU:ebs) cycle.
`and secondarily by beta-oxidation. The primary pathway
`involves n cytosolic NADP+-Hnked enzyme 1 GIIll dehydro·:
`genaso, that catalyses t.he conversion of sodium oxybate to
`sucd.Illc scmiald_ehyde,. which js· then biotransfonned to
`succinic o.cid by-the enzyme succinic semialdehyde dehy(cid:173)
`drogenase. Succinic acid ent13rs tPe I{rebs cycle where it is
`metabolized to carbon dioxide rmd wat9r. A second mito(cid:173)
`chondrial oxidoreductase enzyme, a trnnshydmgenaRe,
`also catalyses the conversion to succinic scmialrlehyde ln
`the presence of ex-ketoglutarate. An nltcrnute pathwAy of_
`via
`(3-oxidaUun
`involves
`biotransformation
`3,4~dihydroxybutyrate to carbon dioxide. awl water. No
`active metabolites have belm identified.
`Studies in vitro with pooled human liver microsomeS "indi(cid:173)
`cat~ that sodium oXybate does not significantly inhibit tho
`activities of the human isoeniymes: CYP1A2, CYP2C9,
`CYP2C19, CYP2D6, CYP2E1, or CYP3A up to the concen~
`tration of 3 mM (378 mCg/mL); 'I'hese levels are consider(cid:173)
`ably higher than levels achieved with therapeutic doses.
`.
`Elimination
`The clearance of sodium oxybEi.te is almost entirely by
`biotransformation to carbon dioxide, which is then elimi(cid:173)
`nated by expiration. On average, less than 5% of un-
`
`'
`changed drug appears·in human urine
`after dosing. Fecal excri!tiOil is negligible.
`Special P.opulations
`·--t: ,, .-,
`_r
`.: :·
`Geriatric
`The- pharmacokinetics of sodium·:- oxybate
`greater than the age of 65 years have not been
`Pediatric
`The pharmacOkinetics of sodium
`the age of 18 years have not been
`Gender
`In a study of 18 female and 18 male
`teers, no gender differences were
`cokinetics ofsodiuin oxybnto followinJ{H
`4.6g.
`Race
`There are- insufficient data to evaluate
`netic differences among races.
`Renal Disease
`Becnuse the kidney does not have n
`excretion ·or·sodiwn oxybato, tio pham'""'ki•oe
`patients with renal dysfunction has
`effect ofrenal fnnclion on sodium
`ics would be expected,
`Hopatic Disease
`Sodium oxybal.P.undergoes significanLt plCOSJI'Le.rr
`first-pass) met.abolism:-The
`16 cirrhotic patient31 halfwilhdut '"cites.
`and half with ascites (Child'S
`the kinetics in 8 healthy adults after
`25 mg/kg. AUCvalues were double in
`with apparent oral clearance reduced
`adults to 4,5 and 4".1 mLimin!kgin Clnss
`tients,- respectively, Elimi:llation half-life
`longer. in Class C and ClasB A patients
`jects (niean t 112 of 69 alld 32 versus 22
`dent to reduce' the starting "dose of
`one-half in patients with liver dysfunction
`Administration).
`Drug~Drug InteractiOn
`Drug interaction studies in healthy adults
`no- phanmicokinetic interactions 'between
`and protriptyline hydrochloride 1
`mtidaflnil: Hov.,"i.wer, ·· F Lhmcm<wmlynnirricint
`thesri drugs ·cannot
`with omeprazole ·Produced no
`oxybate kinetiCS.
`
`•
`
`open-label _soditim
`cluqcd, patients '"-;_ere
`5 cataplexy attacks per
`aplcxy. Pat.i.euts were randomized to
`wlttt SodiuuluX.yLate at their stable- dOse
`2 was desigri-ed specificnlly to ovalu.ale ~he
`caCY'ofS.Odiwn oxybate oftcrlong-t~rm use.
`The prim~ry effica~y measure in 'l)ia1s 1
`quBn!_!y of 'cataplexy attacks.
`[See table 1 belo~ l
`
`Table 1
`..
`.
`Summary of Outcomes in Clinical Trials Supporting
`the Efficacy of SOdium Oxybate
`
`Trial/Dosage Group (n)
`
`Baseline
`
`Tria11
`
`Placebo (33)
`6.0 g/night (31)
`9.0 g/night (33)
`
`Trial2
`
`Placebo (29)
`Sodium oxybate (26)
`
`(median attacks/week)
`.
`-4
`-10
`-16
`
`,·
`(median attacks/two weeks)
`21.0
`0
`
`4.0
`1.9
`
`

`
`.JAZZ/1689
`
`the 4 patients with sleep apnea ho,d signifi~ant W!?l'Bt?~ng
`of the apnealhypopnea index rluxing treatment, bU:t. ·wor·s(cid:173)
`ening did not incn:m.se at higher dosos. Another patient disw
`c_ontinued, tr_eatment because. of a perceivE;!d increas_e in
`clinical a_pn_e_a events. In the randoinb:ed contrullecl '~11als .3.
`and/1_1.a to_t~I __ of ~o narcolepsy p·atientS were in'cluded. __ \Vitl~
`a Qaseli.J:le apnea/hypopnea index of 16 to 6,7 events per
`hoUl' indimitive of mild tO severe sleep di_soi-dSre"d bran th(cid:173)
`ing. None of th~ .~0 J?atiep.tS had a clinioUUy sf_gnific~nt
`worsening of their l'esph·atory function qs .meaSur~d. bY
`apnea!hypopf.Lea. indo* and {mise. oximetry while ,recei~ng
`aqdium oxybate at. dosage~ of 4.5 to 9 g/nightin divided dps(cid:173)
`ages. rf.evel;'theleRs, caution should lJB observed if:Xyrem is
`prescribed to patientS with compromiserl rcspirat"oryfuric(cid:173)
`tion . .,PreScribe.i·s ahould. be aware that. sleep -~pnea . haS
`be~ i-eportei(Wi'~ ~ h,igh illcidence.'(eVe!l50%) in Sonie cO·
`horts pfnarc9lept!r.Patients, _,
`, ___ ,_ .... ,
`Confusion/NeuropsychiatricAdver$e Events-,.,_._.-_- __ '
`During clinical tdals, 2.6% of patients treate.q_}V~~~o4-~uni
`oxybate exp~rienced confusi.on:. Fewer. than 1% of pntle_rit::J
`discontim,1ed the dt'Ug because of confuSion. Confusion ·was
`reported, at all rec_onun~nded do-ses. fl:om s·to ~ glnfglit. ~1o9,
`controlled trial where patients were randomized to fixed
`total daily doses of 3, 6, anc\·_P,glnight or placebo, a dose(cid:173)
`response relationship fo1· CO!J-f}l~ion_was ct~monsb:ated with
`17% of patients at 9 girlight cXperiencini contUsion, In all
`cases in. that controlled trial; the_.confusion reaolved ~oon
`after termination of treatment. In T.rinl 3 where sodium
`oxybate was titrated ft•om an initial4.5 g)night dose, there
`was a single event of confusion in one po.tient at the
`9 g/night dose. In the majority of cases in-all clinical trials,
`confusion reRolved either soon after terminatiOn of dosing
`or with conti~ued- treatment; However, ·patien,ts treated
`with Xyreni Who become confused should be' evaluated
`fully, ·and B.p-pfopriate intm:ventiori·considei8d .on ~n indi(cid:173)
`vidual basis.
`Other nem:OpsychiatriC··eve~~ts- iD.CiUd9d. PsYchosiS; Para~
`noia, hallucinations, and agitution_._ .. The emerg_ence;_Qf
`thought dism•ders and/or behaviot' abnormalities when paw
`ticnts are treated with sodium oxybo.te rl:lquire_s careful and
`immediate-evaluation;
`·
`'
`,-,-:·~
`Depression.
`. ;,
`-
`-- ·, .,, '·
`-._
`.,_" :-.-, ·.-.:--.
`In. olini.t::al trial~, 3.~%- of_patienta, treated with sodium
`oxybate reported·dopt:_essive ·symptoms. In the majoriLy of
`cases,' no_ chang~ in sodium oxybate treatment was. re·
`quired. Four patients (<1%) discontinued bP.causa-ofdew
`pressive symptoms, In the controlled clinical trial where
`patients were randomized l;o fixed dosesof3-, _6, 9 g/nightor
`plaCebo,:·there .. was.,a .sirigle event of depression at tho
`8. g/night dose~ In 'Iii.a13,-whore-patients were titrated from
`im.initial4.5 g/night starting dose1 the incidence'ofdepJ:es(cid:173)
`sion was 1 (1,7%), 1 (1.5%), 2. (3.2%), and 2· (3.8%) for,tho
`placebo, 4.5 g, 6 g,-and 9 glnight dos~s respectiw:ly,
`In the 717 patient dataset, there w.ere.two suicides-and one
`attempted suicide reCorded in patientS with a :Pteviouli his(cid:173)
`tory .of;depl'essiv'e psychiatric disorder. Of the two suicides,
`one· patient use4 sodium oxybd.te in conjunction. with other
`drugs. Sodium oxyb_ate. \vas nOt involVed in the second sui(cid:173)
`ci~e,,Sodium;·oxybate,.wf?-s. the oilly-drug inVolved ·in the
`attempted· suicide. A four.th patieutwithouta previoushis-;(cid:173)
`tory of dEipression attempte_d suicid_e_by, taking an overdose
`of a drug ather than sodium oxybate:
`The emergence of depression when pa.tierits al'e treated
`with Xyrcm requires careful and immediate evaluation,
`Patients with a previous history of a depressive illness and/
`or sulcide attempt should be monitored especially carefully'
`for tl].e emergence ·of depressive symptom·sr while taking
`Xyrem.
`·
`Us·age in the Elderly·
`-~;-
`There is very limited experionce-·\\<ith sodium oxybahl in
`the elderly. Therefore; elderly patierits should be monitored
`closely .for imj:lah·ed moto1· und/or cognitive function when
`:_,,_ . __ , ..
`taklng sodium oxybato.
`•<··. · ·
`•
`PUJiJCAUTIONS:
`·.
`:··
`,..
`Incontinence .... .-
`.
`___ /,
`During clinical trials, 7%_ of narcoleptic patients tl'cntcd
`with sodium oxybote.experienced either a sihgle epi.':!odc or
`sporndic nocr.urnal urinary incontinenCe and <1% experi(cid:173)
`enced a sing] e episode of nocturnal fecal incontinence, Less
`than 1 o/0 of pationt::J discontinued as .a -result of inconti(cid:173)
`nence. Incontinence has been reported ai. all dOses tested.
`In a controlled trial where. patients _were randomized to
`fix~d total daily dose_s·ofa,_.6, aud 9 g/night or placebo, a
`dose-response relationship for urinary incontinence was
`demonstrated witJl 14% of p.aticJlts·initi~ted at 9 g/night
`experiencing minar,Y incontin~nce, In tha same trial,.one
`patient experienced.fecal_incont_ihen_ce whe.n initiated at a
`dose of9 g/night and discontinued treatment as a re:s.ult.
`If a patient expel'iences .'u.l'inary or fecal incontinence dur(cid:173)
`ing Xyrem· _ther!\py, the_ prsscribor. should consider pursu~
`ing investigations.,-to~ rul~ out .underlying_ .etiologies,
`including Worsening slc.op i:l.pnea.or noc_turnal seizures, ul~
`though there. is nq.evidcnce,to :suggest that incontinence
`has been· associated w_ith seizures· in patients being treated
`withXyrem.
`Sleepwalking
`· ,
`_ ·!
`The term "sleepwalking'' in~this.section refers tq confused
`behavior occuxring at night and, at-times, associut.ed with
`wandering. It is. undear ifsome.or all_ of these episodes cor(cid:173)
`respond tO true·SOillnambulism,'which iR fi pUl'USOIDUia OC-,
`curdng during non-REM sleep, or ·to any, other specifiC
`medical dil:;order, Sleepwalking was reported in 4% of717
`'·' .,:
`.-:
`:.-
`· Gnntlmuul nn nP.rl nnnP.
`
`.
`
`E~Qp~i-nt
`Compamd
`to.
`_Pla-CebO
`
`11.3
`
`lOA
`
`Sodiulli
`Oxyhate (r;'OJ
`SOdium'
`Oxjbate
`:plus·
`Modafinil
`(5t).
`
`1!\;nrcATit:iNSMw UsAGE
`. . . .
`......
`,
`Xyrem (sodium c\xybate) oral A6lution is indicat:d for-the
`treatment of excessiVe daytime sleepiness and cataplexy in
`patients with-narcolepsy.
`In Xyrem clinical trialB, approximately 80% of patients
`mairitainell concomitant .stimulant use (sec BLACK BOX
`WARNINGS),
`
`Socii~~ ~x;b~~e ·-'is ~contra~di~ated in ·patients b~_ing
`treated with sedative hypnotic agents.
`..,, .•· -,.
`Sodiun"). oxyba te is contr::j.~ndicated in patie;nts 'With ~ucclnic
`sernial~ehyde dehydrogenase deficiency. Ttii!' ra}'e,disordcr
`is· an inborn erro·r of+;n~tal:JOlism._variably characterized by
`mental retard~iion, hypotcinia1 and at:;cria. ·-l
`.
`WARNINGS
`SEE B6X:En 'wAR'NrNQ.
`~
`·!;;-_- _,
`.
`,
`Due to the rapid onset of iL., CNS _depre.ss~t i3ffects, s~·
`dium o~ybate_ shm~ld only_ }Je irig~s~~d -~t be~tir\1-e, · aild
`while in bed. Fm· ij.t Tea'st ~ ho~r~ __ after)ngestfug sodium
`oxybate, patieil.ts inust_ not '8ngage 1D; hilza.rdOus occupa·
`tions or apti'0ties rflQuir:ing _ci:J~p~ete ¥teri£~l_alertneSS_ci1:
`motor Coordinatiori, such ~s operating m~chinery, driving a
`:iri~tor vehicle, 1?1'. :flying'_ an uirplan_e_, Wheit_~atientf:! first
`stEirt taking Xyrem or a_ny_ other sleep mediCiri_e, until they
`knm\· ~hf!the:t;' the nledicine ·mn stil~ have so,me._CarJ.yqYer
`effe~t on them the neXf!la_y, thCy ~?ol.Ud Use ~Xtren:-_e Care
`while performing any tiisic that cullld'be dangerop.s or re(cid:173)
`quires full mental alertness.
`The combined use of alcohol (ethanol) With sodiimfOxybate
`m~y __ resul~ in-potentiation of the,central nervous ~ystem·
`depressant effects of sodi4m oxybate and alco~ol. There(cid:173)
`fore, patients should be warn·ed strongly against the use of
`any alcoholic beverages In conjunction with sodium
`oxybate. Sodium oxybate should not be used in comblna:
`tlon with sedative hypnotics or other GNS depressants.
`Central Nervous System Depression(ResPiratory Dapres·
`Siori
`· ·
`·
`··
`··
`·
`Sodium oxybatc is a C}:[S depressant With the potential to
`impair 'respiratory "drive, especially 'in patients with
`already-c'omprOinised 'respiratory function, In' overdoses,
`life-threatening respiratory depreasion has been reported
`(see 0\i"RRDOSAGE). In cliniCal trials two sUbjects had
`profound CNS depression. A 39 year-old womai-i, ri hea1thy
`v6lunLeor receiVed a single 4.5 g dose of sodium oxybate af(cid:173)
`t6r fH.<~ting for 10 hours. An hoUT later, \'vhile asleep, she
`developed decreased respiration and was treated with an
`Oxygen mask. An hour latei·, this Bvent recurred. She also
`voulitell alld h8.d tecal incontinence. In nnuther·case, a 64
`yefi.r-uld-·narcoleptic man was found unresponsive on the
`floor on Day 1-70 of treatment·with sodium oxybate at a
`total daily· dose· of -4.5 g/night. He was· taken to an
`emergency room where he was intubated. He improved and
`was able to return home lat.er the same day. 'I\vo other pa(cid:173)
`tients discontinued sodium oxybo.le because of severe difli(cid:173)
`culty breathing and anincreaso in obstructive sleep apriea.
`The respiratory depressant effects of Xyrem, at recom(cid:173)
`mended doses, wem assesBed in 21 patients with narco(cid:173)
`lepsy, and no dose-related changes in oxygen saturation
`were demonstrated in the group as a whole, One of these
`patients had significant concomitant puimonary illness,
`and 1 of the 21 had m9deratewto-severe sleen annea. One of
`
`0.0151
`0.0016
`
`<0.001
`
`

`
`urinary incontinence (6%)1 and nasopharyngitis
`These itlcidenccs are based oD. combined data
`'I'rial2, Tdal3, and two smaller randomized,
`placebo-conirollod, cross~over trials (n = 655),
`·
`Because clinical trials are conducted under
`conditions, adverse reaclion rates observed '
`trials of a drug cannot be directly compared to ·
`clinical trials of another drug and may not
`observed in practice. The odverse reacti
`from· ~liuical trials does, however, provide a ba~is
`ti:fying the adverse events that appear to be rellite
`· ·
`ltse and for approximating incidence ratos.
`The. data pre;;ente<J. be1ow come from
`controlled clir~ical trials, Triall and TrialS.
`Tables 6 and 7list. the incidence oft,rea,tment·ernce>
`verse events in Trials 1 and 3,
`was an incidence of :::::::.5% aiid the
`dosage group ·on sodium oxybate waS
`The nUmber Of pation~. in each
`at
`the totlu nmnber- of paUents ·
`~·~~C~t was iilltiate_d at a~sigD.ed doses of 3, 6,
`
`[Soc table 6 at top of next page]
`[Sec tabl.i 7 at bottom of page 16921
`·
`Dose ResponSe lnfOrrTIBtion
`Discontinuatf6ns nfl'""''tmoni
`most common "at
`dose-response
`iting, pir~thesia, dt' ~~;~;;~t!~.~~~';'J;~~b~~~~~
`iri Eit'ten{irm, feeling C
`ii;lcidcnce of all these
`Dizziness was most common at 3 and 9
`Less Common Adverse Events
`During clinical .trials sodium oxybate.was
`717.. patients Wi.tl)natw"!lepsy, ~d 182
`A total of283 patients and 26l;o,,mvvnlnnt: .... ,
`9·gfnighL, lhe .. maxi~mm recqptmeQ.de
`one
`patients recCivcd .sodi.um,.oxyba:te for at
`establish the rate; of adverse events, 4ata from all
`receiving. any doso.ofsoclium.oxybate were
`verse events reported by at least two
`except for those- a1Ieady listed elsewhere
`terms too general to be informative, or
`drug induced. Events HI'O classified by
`listed under the following definitions:
`eVents (those occurring in nt lco.sll/100
`events (those occurring in 11100 to
`events are notnecessarilyrelated to sodiurrl m<vhat
`·
`ment.
`I
`
`1690/JAZZ
`
`Xyrem-Cont.
`
`patients treated in clinical trial!'\ with sodium oxybatei. In
`sodiuni oxybateMtreated patients <1% discontinued due to
`slGepwalklng. In controlled trials ofup to·4 weeks duration,
`thG incidence· of sleepwalking waS 1% in both placebo and
`sodium oxybuteMtreated patients. Sleepwalking Wa;J. re(cid:173)
`ported-by ·sz% of patients_ treated With sodium 'oxybatc fo!
`peliods up to 1G years in one independent uncontrolled
`trial. Fewer thai~ 1% of the patients in that trial discont:in(cid:173)
`ueCl due to sleepwalking. Five ii1Stances of significant in(cid:173)
`jury or potential ii1jury were asSoc)ated \vith sleepwalltin~
`during a clinical t-rial· of sodh,nit oxybate including a foil,
`clothing set on :fb_.e while attempting'-to smoke, attempted
`ingestiori of nail polish remover, and ovel-dose of Oxybate.
`'l'herefure, episor1es of sleepwalking shouid be-fUlly evalu~
`a ted und_npproJniate interVentions cOnsidered.
`'
`-
`Sodium Intake
`DB.ily sodiuni int~e in patients taking sodium oxybata is
`provided b<:low and should be considered in patients with
`heart failure, hypertension or compromised rcnHl function.
`
`Table 6
`Sodium Content Per'"'fotal Nightly Dose
`
`Xyrem Dose (g)
`
`Xyrem(mL)
`
`Sodium Content}
`Dose
`
`'4.5.
`.6
`7.5
`
`'9
`
`,,12
`15.
`
`18
`
`51Gmg
`
`819mg
`
`1092mg
`
`1365 mg
`
`lfl3~_ing
`
`Hepatic Insufficiency
`Patients with compromised liver function will have an-in(cid:173)
`creased elimination half-life and systemic exposure Lo so(cid:173)
`diuril. oxybate (see Pharmacoldnetics),- The starting dose
`should therefore be decreased by one-half in such patients,
`and response to dose increments monitored closely (see
`- ·
`Dosage and Administration),
`Renal Insufficiency
`No studies have been conducted in patients wlth renal fail·
`ure. Be~ause less than 6% ·of sodium oxybate-is eXcreted via
`the kidney, ri.o dose adjusttnenl shOuld l:il'l ·neoossary in pa(cid:173)
`tients 'With retial-impairment. The sodium load associated
`with administration of sodium oxybntc o;hould be consid~
`·
`ered in patients with renal insufficiency, .
`'
`. -
`Information for Patients·
`The Xyrem Patieri.t Success Program® includes detailed in·
`formation about the safe o.nd propei~us·e· ofsodium oxybate;
`as well as information to help. the patient prevent accidenw
`t.al use or abii~e of sodium oxybate by others. Patients must
`1~ead and/or ·understand· the'- mfltcrials before •inltlating
`therapy. Prescri~erS:\vi~ discuss.dosing (indudhl.g the·pro(cid:173)
`cedure-for- pr.eparing the doss t.o.be administered) prior to
`the initiation of treatment .. Patients should ·also be in(cid:173)
`formed that they should be seen by the prescriber fre(cid:173)
`quently during Lhe-Course·oftheir treatment to revie"wdose
`titration, sytrtiJt.om respOnse arid adverse reflctions. Food
`the· bioavailability of-: sodium
`significantlY-' decreases
`oxjrbate (sec Pharmacokinetics). Whether ·sodium oxybate
`is taken in the fP.d or fasted state may affect both the effi(cid:173)
`cacy and safety of sodium oxybate for a given patient, Pa(cid:173)
`tients should bB madG aware oftllis and try to take the first
`dose several hours after a meaL Patients···should bo in(cid:173)
`forr'ned that.sodium oxybateis associated with urinary and,
`less frequently, fecal incontinence. As a· safety .precaution,
`patients should be. instructed to lie dowp n_~d .sleep after
`each dose of sodium oxybnte, and nut to tt8.ke sodiuni
`oxyhate at any time qther than al night, immediately be(cid:173)
`fore bedtime and again 2.5 to 4 hours later. Patients 8hould
`be instructed that-they should not take alcohol or other Sed·
`·
`ative hypnotics with sOdlumoxybate.
`For additional.- inforinaLion, pa'li~nLE •should · sec. the
`Medication Guide fOr Xyre:n1, · ._.._,,· .. -.
`laboratory TeSts
`· I!'· ·
`Laboratory tests are not 11;eqtl:ired to nionitor patient·re(cid:173)
`sponse or adverse events -reSultihg from sodium oxybate
`]
`·
`administration. .
`In .an open-label:trti:Jl- 'of long terin- expOsure to sodium
`oxybate, which extended -a:s 'long as 16: years for some pa~
`tients, 30% (26187) of patients tEisted had at least one posi~
`tive -UnLi-nuclear antibody "'(ANA) test. Of the 26, 17
`patientS had multiple positive ANA t.Bsts over time. The
`clinical cOurse of these patients was not alwayR cleal']yre(cid:173)
`corded, but one patient was clearly diagrto~eil .:v-.1th rheu(cid:173)
`matoid arthritis nt the.t.ime of the flrst'tecorded .positive
`ANA test. No .j.nstunces of syStemic lupu,s erythematosus
`have been reported in patients taking sOdium oxylmte.
`·
`Drug Interactions
`Interactions between sodium oxybate and three di·ugs com~
`manly used in Patients with narcolepSy (zolpidem tartrate·,
`pl'Otriptyline HC1, and modafinil) have been evaluated-in
`formal studies. Sodium oxybate, in combination with these
`drugs, produced no· sigllili.cunt pharmucoltinetic changes
`for either drug (see Pharmacokinetics), However; pharma(cid:173)
`codynamic interactions cannot be ruled out. Nonetheless,
`sodium oxybate should not be used in combination with
`sedative hypnotiCs or other- CNS depressants. Alteration of
`
`Information will ·bG superseded by supplements and subsequent editions
`
`gastric pH with omcpro.mle produced no significant change
`in the ox.ybate kinetics.
`Carcinogenicity, Mutagenicity, Impairment of Fertility
`Sodium oxybate was not carcinogenic in rats administered
`oral doses of up Lo 1000 mgfkgfday (2 times the exposure in
`humans receiving .. the maximum recommended dose
`(MRHD) of-9 g/day~·on an AUC basis) for 83 we"eks in the
`male rats and for 104 weeks in female rats. The results of
`2·year cru·cinog'enicity sludies in mouse and rat with
`gamma-buiyrolactonc, a compound that is metabolized to
`sodium-oxybate in vivo, showed no clear evidence of carcin(cid:173)
`ogenic activity. The plasma AUCs of sodium oxybate
`achieved at th8 Wgh doses in these studies were 1/2 (mice
`and female rats) and 1/10 (:rilrile rats) the plasma AUCs at
`..
`"
`.
`.
`.
`.
`theMRHD..
`Sodium oxybate was negative in the Ames microbial muta~
`gen test, an in vr:tro chromosomal aberration a~;say in CHO
`cells, and-an in vivo rat miCronucleus assay.-.'
`Sodium oxybate did not impair fertility in rats at doses up
`to 1000 mglkg (ap'proximately·equa1 to'the·mrudrrium rec(cid:173)
`Oiumended human daily dose on a mg/m2 basis).
`·
`·'
`· ·
`PregnanCy
`Pregnancy Category 8: Reproduction studies conducted
`in pre·gnant rats at doses up to 1000 mglkg (approximately
`equ"al to the maximum recommended human daily dose on
`a mgfm2 basis) and in pregnant rabbits· at dtisCS up to
`1200 m~fkg (approximately 3 limes the maximum ·recom(cid:173)
`mended human daily dose ·on a··uig/m2 basis) tevcaled no
`eyidani:e of teratogenicity, In a atudy in whic