Ranbaxy Ex. 1005
`IPR Petition - USP 9,050,302
`
`

`
`PHYSlCiANS’ DESK REFEREN
`
`rious adverse events to the manufacturer. (SeeWAR.N-
`JNGS).
`
`-
`
`DESCRIPTION
`Xyi-em (sodium oxybate) is a central nervous system de-
`pressant that reduces excessive daytime slccpincss and
`cataplexy in patients with nnrcolcpsy. Sodium oxybate ia
`intended for oral administration. The chemical name for
`sodium oxybate is sodium 4-hydroxybutyrato. The molecu-
`lar formula is C,,H-,Na0;.f and the molecular weight is
`‘ 126.09 grams/mole. The chemical structure is:
`
`1688/JANSSEN
`
`Risperdal Consta—Cont. '
`
`HOW SUPPLIED
`RISPERDALP c0NsT/ii’ (rispcridone) is available indes-
`age strengths of 25, 37.5, or 50 mg risperidone. It is "pro-
`vided as a dose pack, consisting of a vial containing the
`rispeiidone microsphcrcs, a prc—filled e
`’ ge containing
`2 mL of ' diluent
`for RISPERDAL ._ CONSTA®,
`a
`SmurtSite® Nccdlc-Free Vial Access Device, and one
`Needle-Pro® safety needle for intramuscular injection
`(20 G TW needle with needle protection device).
`26-mg via]/kit (NDC 60458-306-ll): 25 mg ofa white to ofl"-
`whitc powder provided in a vial with a pink flip-o£f.cap
`(NDC 50458-306-01)..
`_
`-
`‘
`.
`37.5-mg vial/kit (NDC 50458-307-1,1 37.5 mg ofa white to
`off-white powder provided in a vial with a green flip-oft‘cap
`(NDC 50458-307-01).
`«
`,
`5U-mg vial/kit (NDC 60458-308-11): 50 mg ofawhite tu off-‘
`White powder provided in,a vial with a blue {lip-oil‘ cap
`(NDC 50468-308-01).
`‘
`.
`Storage and Handling
`The entire dose pack should be stored in the refrigerator
`(36'—4G°F; 2°—8"C) and protected from light.
`'
`If refrigeration is unavailable, RISPERDAL® CONSTA°-°
`can be stored at temperatures not exceeding 77°F (25°c)£m'
`no more than 7 days prior to adrninistration. Do not expose
`u_n1'ef1_'igerated product to temperatures above 77”F (25°C).
`Kespout of reach oi children.
`,
`-
`7519605 .
`,
`US Patent 4,804,663
`Revised March 2006
`©Janssen 2003
`2
`Risperidone is manufactured by:
`Janssen Pbarmaceutical Ltd.
`Waiiingstnwn, Little Island, County Cork, Ireland
`Microspheres are manufactured by:
`Alkermes Controlled Therapeutics II ,'
`-.
`Wilmington, Ohio
`"
`Diluent is manufactured by:
`Vetter Pharma Fertigung GmbH & Co. KG
`Iiavensburg, Germany
`RlSI‘ERDA.L.® c0NsrA® is distributed by:
`Janssen, L.P.
`Tiizusville, NJ 08560
`_
`I
`Shown in Product Identification Guide, page 318
`4
`
`_
`
`Jazz i;’harmace_uti_cals, Inc.
`3130 PORTER DRIVE
`.
`PALO ALTO, CA 94304
`
`Direct inquiries to:
`Phone: (650) 496-3777
`Fax: (650) 496-3781 '
`E-mail: contact@jazzpharms.com
`For medical information:
`E-mail: jazzpharma@medcomsol.com
`For media information:
`-
`E-mail: Inediainfo@jazzpha1‘1:na.cL>In
`
`xvaeme ,-.
`(sodium oxybate) oral solution
`Rx only
`
`changed drug appearsin human urinewithin 6“
`after dosing. Fecal excretion is negligible.
`Special Populations
`.'
`-~
`-
`'
`Geriatric
`-
`=
`The pharmocokinetics of" sodium‘= oxybate in D3;
`greater than the age of 65 years have not been stud“,
`Pediatric
`- - ‘
`..-
`.:
`‘w
`The pharmaccikinetics of sodium oxybate in patien
`the age of 18 years have not been studied; —
`Gender
`,.
`.:
`,
`,
`In a study of 18 female and 18 male healthy adu
`teers, no gender differences were detected in the-ph
`cokinetics of sodium oxybate following a single um}
`4.5 g.
`'
`Race
`--"
`.
`-
`-'
`w
`T
`<3
`There are insufficient data to evaluate any pl mg
`netic differences among races.
`'
`1
`'
`'
`7
`'Na*‘Q—C-CH2-CH2—Ci-lg-AC5—H
`\
`Renal Disease
`J -
`"
`Sodium oxybate is a white to oft‘-white, crystalline powder
`Because the kidney does not have a significantfro a
`that is very soluble in aqueous solutions. Xyrem oral solu-
`excretion of sodium oxybute, no phormacokinei.-ic snug
`tion contains 500 mg of sodium oxybate per'mi1}l1lter of
`patients with renal dysfunction has been .condu '
`USP Purified Water, neutralized to pH 7.5 with malic acid.
`effect of renal function on sodium oxybatc phat-nmc
`ics would be expected.
`-
`.
`-
`-
`'
`'
`‘- 2
`CLINICAL PH.AR'M.ACOL0GY
`Hepatic Disease
`Mechanism of Action
`Sodium oxybate undergoes significant prcsystemic(i
`The precise mechanism by which sodium oxybate produces
`fil'El'/‘pDS5) metabolism: Therlcineiics of sodium oxyba
`an eiTect on cataplexy isunknown.
`16 cirrhotic patients, halfwithout ascitea, (Child’s 0p
`Pharmacokinetics ‘
`and half with ascites (Child’s Class C) were comp]:
`the kinetics in 8 healthy adults after a single oral lie
`Sodium oxybate is rapidly but incompletely absorbed after
`oral admiiiistrution; absorption is delayed and decreased
`25 mg/kg. AUC values were double in the cirrhotic
`by a high fat rneal. It is eiiminnted mainly by metabolism
`with apparent oral clearance reduced from 9:1 in ‘h
`with is hall‘-life of 0.5 to 1 lloui‘. Pbrn-macolcinetics are non-
`adultsto 4.5 and 411 mL/min/kg in Class A ai1d.Cl
`linear with bloodllevels increasing 3,7-fold as dose is dou-
`ticnts,- respectively. Elimination half-life was sign;
`bled from 4.5 to 9 grams (g). The pliarmacokinetics are not
`longer in Class C and Class A patients than in contrgl
`altered with repeat dosing.
`.
`-
`-
`~
`'
`-
`jects (rnean t1,z_of 59 and 32 versus 22 minutes),
`Absorption
`dent to reduce the starting dose of sodium miyh
`Sodium oxybate is absorbed rapidly following oral admin-
`one-halfin patients with liver dysfunction (see‘Do ‘ge
`Administration).
`‘
`'
`-
`‘
`'
`istration with an absolute bioavallability ofabout. 25%.Tl1n
`Drug-Drug interaction
`--
`average peak plasma concentrafions (1“ and 2"“ peak) fol-
`lowing administration of a 9 g daily dose divided into two
`Drug interaction studies in healthy adults demon
`equivalent doses given four hours apart were 78 and
`no pharmacokinetic interactions between sorlid‘"’
`142 mic1‘og1'a.ms/milliliter (mcg/mL), respectively. The av-
`and protriplzyline hydrochloride, zolpidem itarlzra
`erage time to peak plasma concentration (Tnm) ranged
`modafinil.‘ However, pharmacodynamic interaciri
`from 0.5 to 1.25 hours in eight pharrnacokinetic studies.
`these drugs ‘cannot be ruled out‘. Alteration ofg
`with omcprazolc ‘produced no significant cha '
`Following oral administ'ration,'_the plasma levelsnofsodium
`oxybate increase more than p'r'opoi-tionally with increasing
`oxybate kinetics.
`»
`-
`dose. Single doses greater than 4.5 g have not been studied:
`CLINICAL TRIALS
`Administration of sodium oxybate immediately after a high
`.
`V
`-
`Cataplexy
`fat meal resulted in delayed absorption (average Tm, in-
`The effectiveness ofsodium oxybate iii the t-reatmeubo
`creased from 0.75 hr to 2.0 hr) and a reduction in peak
`plasma level (C,,,,,,) by a mean of 58% and of systemic ex-
`aplexy was established in Lwo"randomized, doubt A
`posure (AUC) by 37%.
`placebo-controlled trials (Trials 1 and 2) in patien
`Distribution
`’
`narcolepsy, 85% and 80%, respectively; of wbomvr
`Sodium oxybnt/3 is a hydrophilic compound with an appar-
`being treated with CNS sthnulants. The high pare’
`of concomitant stimulant use make it impossible to
`ent volume of distribution averaging 190-384 ml./kg. At so-
`dium oxyhatc
`concentrations
`ranging from 3
`to
`9
`the efficacy and safety of Xyrem independent ct
`use. In each trial, the treatment period was 4 \veek‘
`300 nrcg/mL, less tha.n.l% is bound to plasmaiproteins.
`' Metabolism :— r
`-
`the total daily doses ranged from 3 to 9 g, with fl_
`dose divided into two equal doses. The first dose car;
`Animal studies indicate thatmetabolism is the major elim-
`was taken at bedtime and the second dose was ta]:
`ination pathway for sodium-oxybatc, producing carbon
`dioxide and water via the tricarboxylic ucid (Krebs) cycle_
`4 hours later. There were no restrictions on the
`tween food consumption and dosing.
`»
`*7’
`'~
`7
`‘
`and secondarily by betn—oxidntion. The primary pathway
`involves a cytosolic NADP‘—]inlrcd cnzyn-ro, GI-IB dchydro-'
`Trial
`.1 was
`a multi-center, double-bli'nd,“ 0;
`controlled, parallel-group trial that enrolled 136 ‘n
`genase, that catalyses the conversion of sodium oxybutc to
`tic patients with moderate to severe cataplexy (In
`succinlc semiald_ehyde. which is then biotransformed to
`succinic acid by,the enzyme succinic semiuldehydo dehy-
`21 cata'plexy~attacks per week) at baseline:
`'
`drogenase. Succinic acid enters the Krebs cycle where it is
`domization, medications’ with possible effects 0
`metabolized to carbon dioxide and water. A second mito-
`,1,
`we're‘ withdrawn, but stimulants were continu
`chondrial oxidoreductase enzyme. a transhydrogcnusc,
`doses; .Patien‘t‘s were randomized to receive plat h
`also catalyses the conversion to succinic semialdehyde in
`dium oxybpte 3 g/night, sodium oigybate 6 g/nigh,
`the presence of or-ketoglutarate. An alternate pathway of
`dium oxybate 9 g/night.’
`'
`'
`_
`‘
`"
`.
`_
`liiotransformation
`involves
`ll-oxidation
`via
`’I‘ri_al' 2' ‘was. a‘ 'nu'1li:i—c:enter,
`' double-blind, pin
`3,4--dihydmxybutyrate to carbon dioxide-and water. No
`controllcd, parallel-group, randomized withdraw
`active metabolites have been identified.
`that enrolled 55' narcolcptic patients who had beeilyrt
`Studies in uifm with pooled human liver microsomes‘indi-
`open-label sodiiim oxybatc for 7 to 44 months. ’ib"b
`cate that sodiu_m oxybate does not significantly inhibit the
`eluded, paticntswerc required to haife a history of ii?‘
`activities of the human isoenzyines: CYP1A2, CYPZCB,
`5 cataplcxy attacks pervyeek prior to any trcatme
`CYPZC19, CYPZDG, CY_P2E1, or CYPSA up to the concen-
`aplexy. Patients were randomized tocontinlied
`tration of 3 mM (378 nicg/mL).' These levels are consider-
`with sodium‘o2"cyb_ate at their stabledose or to place
`ably higher than levels achieved with therapeutic doses.
`2 was designed specifically to evaluate the can't
`Elimination
`cac’y'ofsodium oxybate after long-tenn use.
`The primary etiicacy measure in Trials 1 and 2 w
`The clearance of sodium nxybate is almost entirely by
`biutransfonnntlon to carbon dioxide, which is then elimi-
`quency ofcataplexy attacks.
`'
`nated by expiration. On’ average,
`less than 5% of un-
`[See table 1 below]
`--
`.
`Table 1
`'
`Sum marv of Outcomes in clinical Trials Supportin
`the Eliicacy of Sodium Oxybnte
`Baseline
`Nledian
`Change From _
`Baseline
`
`1
`
`A
`
`V
`
`.
`
`g
`
`V
`
`Comparison ,
`to Placebou II-
`p-value
`
`(median attacks/week)
`-4
`.
`-10
`-16
`
`'
`
`-
`
`"'
`
`(median attacksltwo weeks)
`2 1.0
`0
`
`-010151
`0.0016 0
`
`_
`
`central nervous system depressantwilh .
`-.
`,.
`abuse potential.
`,
`-
`Should not be used with alcohol or other CNS
`depressants.
`_Sodium oxybate Is GHB, a known_drug of abuse. Abuse
`has been associated with some important central
`nervous system (CNS) adverseevents (including death).
`Even at recommended doses, use has been associated
`with confusion, depression and other neuropsychiatric
`events. Reports of respiratory depression occurred in
`clinical trials.
`ost all of the patients who received so-
`dium oxyhateyduring clinical trials were receiving CNS
`stimulants.
`._
`'
`,,
`Important CNS adverse events associated with abuse of
`GHB include seizure, respiratory depression and pro-
`found decreases in level of consciousness. with in-
`stances of coma and death. For events that occurred
`outside of clinical trials. in people taking GHB for recre-
`ational purposes, the circumstances surrounding the
`events are often unclear ($9.. dose of GHB taken. the
`nature and amount of alcohol or any concomitant
`drugs).
`'
`'
`‘
`-'
`Xyrem is availablethrough thexyrem Success Program.
`_using_ a ‘ ‘centralized
`pharmacy
`1-E66-XVREM88®
`ii’-866-997-3688). The Success Program provides educa-
`tional materials to the prescriber and the patient ex-
`plaining the risks and proper use of sodium oxybnte,and
`the required prescription form. Once it is documented
`that the patient has read andlor understood the mate-
`rials, the drug will be shipped to the patient. The Xyrem
`Placebo (29)
`Success Program also recommends patient follow-up
`Sodium oxybate (26)
`every 3 months. Physicians are expected to reportali se-
`Information will be superseded by supplements and subsequent editions
`
`CATAPLEXY ATTACKS
`Trial 1
`
`Placebo (33)
`6.0 g/night (31)
`9.0 g/night(83)
`Trial 2
`
`Trial/Dosage Group in)
`
`

`
`DUCT INFORMATION
`
`. _.
`,
`Tablo2
`,
`Daytlme sleepiness in Trlal 3
`
`:.+:l-.son.,n.e
`
`Epworth Sloeplness Scale (Flange 0-24)
`Nledlsn‘
`Change from -
`Baseline
`
`_o,s ,
`
`Changefronr ,
`;Euseline Compared
`to Placebo
`lp~valuc)
`
`.
`
`..
`.-
`__
`. Tabled
`.I
`Daytlmesleeplnessas EvaluatedlnTrlal-1 -
`,- . MalntenanceoiWakefulnessTest(minutes]
`Dose Group Baseline Endpolnt
`' Mean
`Endpoint
`(pl
`.
`__
`.
`,
`‘
`Change
`Compared,
`-
`from
`,to.
`.-
`fl,.
`Baseline
`“Placebo
`.
`
`.'
`
`,
`
`,
`
`.
`
`,,
`
`-
`~
`
`.
`
`.
`
`‘
`
`’
`
`no
`
`1, bollrtlge 6 / lg it and 9 g/night doses gave sta-
`y significant.
`luctions, in the fiiequgncy _of_ cata-,
`ttscks. The
`g/night dose had littleveffeot. I,_n Trial
`‘mg the discontinuation pflong-terru open-label sp-
`kybats thé,rapy,,patients randomized to placebo ex_-
`aced a significant increase in cataplexy (p 59.091),
`ding evidence of long-term efficacy of sorlium__oxybate.
`rm 2, the responsew‘as’nui-oe1ic_zilly similar for pa-,
`eated with doses of 6 to 9 g/night, _but',there, was no
`u in pationtsfltreated with doses less, than
`suggesting little effect,at these doses.’
`'
`V’
`ve Daytime sleepiness’
`'
`‘
`V
`.
`*
`__
`A
`iveness of_sodiu'rri'o'xyb>ate in__ the trca, r_nen_t ofex-’
`ytlme s1‘sa‘pines‘é'in narcolepsy was cstdblishediri
`andomized, double-blind, ‘placebo-eontrdllcd trials
`;,-—‘3 and 4) i.n patienlfs with ‘narcolepsy Seventyveight
`nt of patients in Trial 3_ were also being treated with
`Lnulnnts.
`“‘
`’
`" '
`'
`'
`'
`,
`' enter, rnhdorriizéd,"double-blind,
`controlled, parallel-arm trial that evaluated 228
`ts with moderate to severe symptomsat entry into
`y i1icl_i‘iding‘a ‘median Epworth Sleepiness Scale
`elow) score of 13,- and Maintenance of Wakefulness
`cc below)‘score' of8.25 minutes. ’l‘hes'e-"patients were
`mixed to one of 4 treatment groups; placebo;-sodium
`baits 4.6 g/night; sodium oxybate 6 g/night; and sodium
`'afe '9 glnight. The period of double-blind-treatment in
`ialwas 8.weeks. Antidepressants ‘were withdrawn
`o randomization; stimulants were continued at sta-
`-unary eiT1cacy.msasures in Trial 3 were the Epworth
`.53 Scale and the. Clinical Global Impression of
`e. The Epworth Sleepiness Scale is intended to eval-
`the extent ofsleepiness in everyday situations by ask-
`patient a seriespfquestions. In,these questions, pa-
`ts are asked to rate their chancash ozing duiingeach
`ctivities on a scale from 0-3 (0—Vnsve1'; =slight;
`odsratc; 3=high). .Higher, total scores iudicate a
`ter tendency to sleepiness. The Clinical Global Impres-
`9§‘Change is a 7-point scale, centered at No Clzdrigs,
`iahging from Very Much Worse to Very Much Ilnp-failed.
`ml 3, patients were rated by evaluato
`'
`eats on the severity ofnarcolep
`_
`.
`'
`multi-center randomized, double-blind,
`may placebo-controlled,'pardll;cl-arm trial that
`ted 222 patients with moderatc‘to scvcrc sy'mpto'm_s
`try into the study including a raedi:i'i1'Epworth Sleep-
`s‘—S_chle score of 15, and Maintenance‘ of Wakefulnoss
`(s’ee‘below) score oi‘ 10.25 minutes. At entry, patients
`obe taking niodafirril for 21 mouth and at stable doses
`20 , 400, or 600 mg daily for at least 1 month prior to
`domization. The patients enrolled in the study were
`fll'1d0_mizc'(l to one oi'4 treatment groups: placebo; sodium
`‘bate; modafinil; . and sodium oxybats plus. modafinil.
`dium oxybotc wasadministered in a dose offi g/night for
`s s, followed by 9 glnight for 4 weeks. Modafinil was
`ed at tlieprior close, Patients taking antidepres-
`could continue these medications at stable doses.
`,
`only primary efficacy measure in 'l‘r1'al 4 was the
`tenance of Wakefulness Test. The Maintenance of
`efulness Test measures latency (in minutes) to sleep
`set averaged over 4 sessions at 2 hour intervals following
`rnal polysomnography. For each test session, the sub-
`sked to remain awake without using cxtraordinary
`or 3: Each test session is terminated after 20 minutes
`cep occurs, or‘ after 10 minutes, ifsleep occurs. The
`era_ll score is the mean sleep latency fur the 4 sessions.
`{ill 3’, statistically significant irnprovemsnts were seen
`
`_
`.
`. Table 3
`-V
`‘
`cal Global lmpresslon of Change ln Day and Nighttime
`Symptoms (Responder Analysis) in Trial 3
`Ԥ_~
`Group
`Percent Responders Significance Compared
`ht lnll
`(Very Much lmproved
`to Placebo _
`or Much Improved)
`lp-value)
`'
`’
`‘
`I
`Change from Baseline
`
`9!
`
`'
`
`[Ulric] 4, a statistically sigiiificant improvement on the
`Wficnance ofWal(efulness Test score was seen in the so-
`Uloxybate and sodium oxyhate plus modafinil groups. _
`
`reatineiit I
`:l, rloubl
`
`.-dstory of
`treal.m_G}1l«
`
`lmparison
`3 Placebo
`p-value ;
`
`Placebo(55)
`
`917,
`
`'
`
`,‘”c.9f
`
`',—2.7’_’_f
`
`'
`
`Modaflnil
`.‘.5‘%.’ .
`
`‘This trial was not capable by design oflcom ar “g the
`effects ofsodium oxybate to rnodalinil, because" patients re-
`ceiving modafinil were not titrated to a uiazdmallyefieetive
`d9ag_-.
`-.
`-'
`.
`-«
`= .,o
`..
`*
`.
`0-‘.
`
`,,.
`,
`,
`_
`]NDI_CATl0NS A1$1n‘Us_Aq_E
`the
`Xyrem (sodium oxyhate) oral solution is indicated
`treatment ofexcessive daytime sleepiness and cataploxy in
`patients withnarcolcpsy. .
`5'‘
`.~
`,
`.
`.
`.
`~-
`.
`In lbrram clinical trials, approximately 80% of patients
`maintained concomitant stimulant use (see BLACK BOX
`WARNINGS).
`.-
`;
`-4 f
`.
`.
`
`,
`
`,
`_
`_ ,
`V
`,
`_
`'coNTRe_.mInoATI_oNs'
`Sodium oxybate is ‘contraindicated in patients being
`treated with sedative hypnotic agents.
`-
`‘C ,
`.-
`V,
`Sodium oxybate is contraindicated in patients with succinic
`sernialdehyde dehydrogenasc deficiency. This rarqdisor‘der
`is an inborn error of metabolismyariably characterized by
`~;
`mental retardation, hypotonia, and ataxia.
`-
`'1-.:-.
`J
`: -'
`WARl\1NG-S,
`‘
`7
`,
`V,
`sea BOXED WARNING '
`effects, so-
`Due to the rapid onset of its C‘N_S glepre
`V
`4
`, a'nd
`dium oxybatc_ should only be ingested ,
`while in_ bed. For iil: least t_l__hou'r,sV fter>ing_esti'ng sod.ium
`oxybate, patients must not ‘engage in haznrdolis occupa-_
`tions or activities rfcquiring complete mental_aler;tnes‘s or
`motor c'oordina'tion, such as operating machinery, drivinga
`motor vehicle, or flying‘ an airplane. When, patients first
`start taking Xyrem or any other sleep medicine, until they
`know whether the medicine will still have some carryover
`effect on them the ne7it'_(l_ay, they should use extreme care
`while performing any tasli that couldbe dangerousor re-
`quires full mental alertness.
`The combined use of alcohol (ethanol) vvlth sodiiini oxybate
`mayjesult in potsntiation of the,central nervous system-
`depressant effects of sodium oxybate and alcohol. There-
`tore, patients should be warned strongly against the use of
`any alcoholic beverages In conjunction with sodium
`oxybato. Sodium oxybate should not be used in combina-
`tion wlth sedative hypnotics or other CNS depressants.
`Central Nervous System Depressionlfiespiratory Depres-
`sion
`-
`‘
`‘
`‘
`'
`‘
`»
`Sodium oxybate is a CNS depressant with the ‘potential to
`impair respiratory drive, especially in patients with
`already-compromised respiratory function. In ‘overdoses,
`lifc-threatening respiratory depression has he
`reported
`(sec OVERDOSAGEJ. In clinical ‘trials two spbjécts had
`profound GNS_dsprsssion. A 39 year-old woman, zi healthy
`volunteer received a single 4.5 g dose of sodium oxybate af-
`ter fasting for 10 hours. An hour later, while asleep, she
`developed decreased respiration and was treated with an
`oxygen mask. An hour later, this event recurred. She also
`vomited and had fecal inoontiru-.-ni:'e. In another case, a 64
`year-old ‘narcoleptic man was fou.nd 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 later the same day. Two other pa-
`tients discontinued sodium oxybate because ofsevsre diffi-
`culty breathing and an increase in obstructive sleep apnea.
`The respiratory depressant effects of Xyrcm, at recom-
`mended doses, were assessed in 21 patients with narco-
`lepsy, and no dose-related changes in oxygen saturation
`were demonstrated in the group as a whole. One of these
`patients had significant concomitant pulmonary illness,
`and 4 of the 21 had moderate-to-severe sleep apnea. One of
`
`.JAZZ/1689?s
`
`tho 4 patients with sleep apnea had significant worsening
`of the apnea/hypopnea index during treatment, bu‘t\vcirs-
`ening did not increase at higher doses. Another patient dis-
`continued treatment because of ,a perceived increase in
`clinical apnea events. In the r'.anLl_oniized controlled 'll'ials[jl
`and.,4, a totalxoi‘ 40 narcolepsy patients were included wi ‘
`a baseline apneelhypopnea index of 16 to ,6_7 events per
`hour indicdtive of mild to severe sleep di_sord
`ed breath-
`ing. None of thc,,40 patients had a clinically significant
`worsening of their respiratory function as ,measur,ed.‘byl
`apnea/hypopnea inde;E and pulse oximetry while receiving
`sodium oxybate at dosages of4.5 to 9 g/nightin divided dos-
`ages. Nevertheless, caution should be observed ifXyreni is
`prescribed to patients with compromised respiratory func-
`tion. ,Prescrib
`should, be aware that sleep apnea has
`been reportodwi h a high in‘cid,ence‘(even 50%) in some co-
`he1'ts,ofnarcolepti,p patients. _.
`,
`H
`,
`5
`ConfuslonlNeuropsvchiatrie Adverse Events '
`_
`During clinical trials, 2.6% ofpatients treated wt
`'ts
`oxybate experienced confusion. Fewerthan 1% of pati
`discontinued the drug becauseof confusion. Confusion was
`reported at all recpmmcnrled doses from G-to 9 g/night. In a
`controlled trial where patients were randomized to liked
`total daily doses of 3, 6, and 9,g/night or placebo, in dose-
`response relationship for c9_nfusio_ri__was demonstraterlwith
`17% of patients at 9 g/night experiencing confusion. In all
`cases in.that controlled trial, the. confusion resolved soon
`afier termination of treatment. In ‘Trial 3 where sodium
`oxybate was titrated from an initial 4.5 g/night dose, there
`was a single event of confusion in one patient at
`the
`9 g/night dose. In the majority of cases in all clinical trials,
`confusion resolved either soon after terminatioh of dosing
`or with continued treatment: However, ‘patients treated
`with Xy-reni who become confused should be ‘Evaluated
`fully, ‘and "appropriate int‘eryention'considered on an indi-
`Yitlualbssiss.
`.
`.
`.
`.
`.
`_..
`Other neuropsychiatrlc events included psychosis, para:
`noia, hallucinations, and agitation.,,.The emergencc,of
`thought disorders and/or behavior abnormalities when pa-
`tients are treatedwith sodium oxybate requires careful and
`imm'ediate'evaluation.- *
`.
`».,_.
`i
`Depression’
`-
`_,.
`'.
`‘
`--
`,
`_
`._
`,
`_
`In clinical trials, 8.2% of patients. treated with so rum
`oxybate reported depressive ‘symptoms, In the majority of
`cases,-no change in sodium oxybate treatment was re-
`quired. Four patients (<l%) discontinued because of de-
`pressive symptoms. In the controlled clinical trial where
`patients were randomized to fixed doses of3-, 6, 9 g/night or
`ploccbo,--there-.was_,a single event of depression at the
`3_g/night dose. In ’l'rial 3, where. patients were titratedfrom
`aninitial 4.5 g/night starting dose, the incidence of depres-
`sion was 1 (1.7%), 1 (1.5%), 2 (3.2%), and 2- (3.6%) for the
`placebo, 4.5 g, 6 ggand 9 g/night dnfi,Ps,respectiVely._
`,
`In the 717 patient dataset, there weretwo suicides and one
`attempted suicide rccorded in patients with a previous his-
`tory ofideprsssivo psychiatric disorder. Of‘the two suicides,
`one’ patient used sodium oxyb_ate in conjunctiouwitli other
`drugs. Sodium oxybatq. was not involved in the second sui-
`cid0.=Sodium.'oxybute. was the only drug involved in the
`attempted-suicidc. A fourth patient without a previous his-
`tory of depression attempted suicidebytakiug an overdose
`ofa drug other than sodium oxybate;
`'
`'
`.
`»
`~
`.
`-’
`The emergence of depression when patients are treated
`with Xyrem requires careful and immediate evaluation.
`Patients with a previous history ofa depressive illness and/
`or suicide attempt should be monitored especially careI'ully'
`for the emergence ‘of depressive symptoms‘ while taking
`Xyrem.
`2.:
`,
`'-
`.
`'~
`-
`- ‘
`v
`'
`Usage ln the Elderly‘
`’r.'
`.2 -.
`7-
`.
`There is very limited expei'ience"with sodium oxybate in
`the elderly. Therefore, elderly patients should be monitored
`closely for impaired motor andlor cognitive fiuiction when
`taking sodium oxybate.
`~
`-
`l‘
`'
`'
`-'
`'
`_
`PRECAUTIONS‘
`-
`:7
`1- hi . ,.
`..
`..
`Incontinence. _,
`During clinical trials, -7%_ of narcolsptic patients treated
`with sodium oxybate experienced either a single episode or
`sporadic nocturnal urinary incontinence and <l% experi-
`enced a single episode ofnoctumal fecal incontinence. Less
`than 1% of patients discontinued as a -result of inconti-
`nence. Incontinence has been reported at all doses tested.
`In a controlled trial where. paticnts were randomized to
`fixed total daily doses‘of.3.,6, and E glnight or placebo, a
`dose-response relationship for urinary incontinence was
`demonstrated with 14% of patients initiated at 9 g/night
`experiencing urinary incontinence. In the some trial, one
`patient axperiencedfccal inconti.nsn_ce when initiated at a
`dose of 9 g/night and discontinued treatment as a result.
`If a patient experiences _’uri.nary or fecal incontinence dur-
`ing Xyremzthcrupy, the prescribe!‘ should consider pursu-
`ing investigations.. to_ rule out .u.nclerly'ing etiologies,
`including worsening sleep opnea.or nocturnal seizures, al-
`though there. is no_evidence -to suggest that incontinence
`has bccnassociated with seizures in patients being treated
`with Xyrem.
`V
`>
`—
`-
`"
`Slsepwalking
`-~ —.
`..
`.~
`.
`~
`_ -:
`_
`.
`The term “sleep\valking"’ ingthis section refers to confilsed
`behavior occurring at night and, at times, associated with
`wandering. It is unclear if someor all ofthese episodes cor-
`respond to true»somnarnbulis1n,‘whlch is :1 parasomnia oc-
`curring during non-REM sleep, or ‘to any: other specific
`medical disorder. Slsepwalking was reported in /1% of 717
`.
`.
`_
`..
`»,
`_.y ,.-
`-
`.
`.
`. -Cnnffnunri nn nnvr rmrm
`
`

`
`1690/JAZZ
`. .__:
`
`PHYSICIANS’ DESK REFERENCE
`
`Xyrem—Cont.
`
`patients treated in clinical trials with sodium oxybate. In
`sodium oxyhate-treated patients <1”/a discontinued due to
`sleepwalldng. In controlled trials ofup to /1 weeks duration,
`the incidence of sleepwalking was 1% in both placebo and
`sodium oxybate-treated patients. Sleepwallring was "re-
`purtedby 32% of patients treated with sodium ‘oxybate for
`periods up to 16 years in one independent uncontrolled
`trial. Fewer than 1% ofthe patients in that trial discontin-
`ued due to sleepwalking. Five instances of significant in-
`jury or potential injury were associated with sleepwalking
`during a chnieal trial of sodium oxybate including a fall,
`clothing set on fire while attempting to smoke, attempted
`ingestion of nail polish remover, and overdose of oxybate.
`Therefore, episodes of sleepwalking should be fully evalu-
`ated and appropriate interventions considered.
`Sodium Intake
`‘
`'
`'
`Daily sodium intake in patients taking sodium oxybate is
`provided below ‘and should be considered in patients with
`heart failure, hypertension or compromised renal function.
`Table 5
`'
`'
`’
` «—__?—
`Sodium Content per '_l'ola| Nightly Dose
`'
`'
`Xyrsm Dose lg)
`Xyrem (mL)
`Sodium Contonil
`
`
`
`
`
`
`
`' . ‘ 1- --»., Dose
`
`
`3 '
`,
`6
`545 mg
`
`. 9,, 4.5 are mg
`
`_,12_._‘__6"’ 1092mg ‘ g
`
`
`
`
`7.5 l
`V 15'
`A
`1365 mg
`__.:_____:__m_._..__._'_.
`'9
`18
`1638 mg‘ 7
`'
`'*
`
`gastric pH with omeprazole produced no significant change
`in the oxybate kinetics.
`Carcinogenicity, Mutagenicity, Impairment ofFertiIl1y
`Sodium oxybate was not ea.rci.nogenic in rats administered’
`oral doses ofup to 1000 mg/lryday (2 times the exposursin
`humans receiving‘ the maximum recommended dose
`(MRHD) of'9 g/day, on an AUG basis) for 83 weeks in the
`male rats and for 104 weeks in female rats. The results of
`2-year carcinogenicity studies in mouse and rat with
`gamma-butyrolactone, a compound that is metabolized to
`sodium oxybate in. nine, showed no clear evidence ofcarcin-
`ogenic activity. The plasma AUCs of sodium oxybate
`achieved at the high doses in these studies were 1/2 (mice
`and female rats) and 1/10 (male rats) the plasma AUCS at
`the MRHD.
`,
`'
`Sodium oxybate was negative in the Ames microhidl nil1ta-
`gen test, an in uitrc chromosomal aberration assay in CHO
`cells, and an in viva rat midronuclaus assay.
`.1
`Sodium oxybate did not impair fertility in rats at doses up
`to 1000 mg/kg (approximately equal to ‘the'n1aXin'lum rec-
`ommended human daily dose on a mg/in’ basis).
`Pregnancy
`'-'
`‘-
`Pregnancy Category B: Reproduction studies conducted
`in pregnant rats at doses up to 1000 mg/kg (approximately
`equal to the maximum recommended human daily dose on
`a mg/m’ basis) and in pregnant rabbits at doses‘ up ‘to
`1200 mg/kg (approximately 3 times the maximum recom-
`menrlerl human daily dose "on a "mg/mz basis) revealed no
`evitleniza of teratogenicity. In a study in whic_h.'rats were
`given sodium oxybate from Day 6 ofgestation through Day
`2] post-pa'rtu‘m,' slight decreases in pup and maternal
`weight gains were seen at 1000 mg/kg; there were no drug
`effects on other developmental parameters. There are,
`however, no adequate and well-controlled studies in preg-
`nant women. Because animal reproduction studies are not
`alwayspredictive of human response, this drug sh_ould_be
`used during pregnancy only ifclearly needed.
`Labor and Delivery.
`;
`'
`,
`‘
`-
`»
`Sodium oxybate has not been studied in labor or delivery.
`Inobstetric anesthesia using an injectable formulationof
`-
`.
`Hepatic Insufficiency
`sodium oxybate newborns had stable cardiovascular and
`Patients with compromised liver function will have an in-
`creased elimination half-life and systemic exposure to so-
`respiratory measures but wereveiy sleepy, causing a slight
`decrease in Apgar scores. There" was‘ a fall in the rate of
`dium oxybats (see Pharmacokinetics). The starting dose
`uterine contractions 20 minutes after injection. Placental
`should therefore be decreased by one-halfin such patients,
`transfer‘ is - rapid, but umbilical -vein —levels of sodium
`and response to dose increments monitored closely (see
`oxybate were no more than 25% of the maternal concentras
`Dosage and Administration).
`' -'
`5
`'
`'
`I
`'-
`tion. No sodium oxybate was detected in the infant’s blood
`Rsnal Insufficiency
`'
`'
`'
`I
`" ~..
`30 minutes after delivery. Elimination curves of sodium
`No studies have been conducted in patients with renal fail-
`oxyhatc between a 2-day old infant and a 15-year old
`ure. Because less than 6‘7n’ofsodium oxybate is eiicretedvia
`patient were similar. Subsequent effects ofsodium oxybate
`the kidney, no dose adjustment should be necessary in pa-
`on later growth, development and maturation in humans
`tients with renal vimpairment. The sodium load associated
`areunknownC'
`" “
`‘
`-'
`with administration of sodium oxybate should be consid-
`Nursing Mothers
`-
`-
`ered in patients with renal insufficiency.
`.'
`r ».
`'
`-
`" i
`‘
`Information for Patients‘ '—
`=1 .'
`~
`".
`-.
`i
`It is ‘not known whether sodium oxybate is excreted in
`human milk Because many drugs are excreted in human
`The Xyrem Patient Success Program® includes detailedin-
`formation about the safe and proper use‘ ofsodium oxybate;
`milk, cautioffsllould be exercised when sodium oxybate is
`administered to a"n'u'.i-sing woman.‘
`—
`' 1‘
`'
`"
`’
`as well as information to helpithe patient prevent acciden-
`Pediatric Use
`-
`-,
`.. .
`tal use or aliifse ofsodium oxybate by others. Patients must
`Safety and effectiveness in patients under _16 years, of age
`read anrl/or understand the materials before initiating
`have not been established.
`"
`‘ "'
`therapy. Prescribers will dlscussdosing (including thc'pro-
`Race arid Gender Effects
`’
`V
`cedure-for preparing the dose tdbe administered) prior to
`the initiation of treatment. Patients should also be in-
`There‘were too few non‘-Caucasian patients to permit eval-
`formed that they should be seen by the prescribcr fre-
`uation ofiiaclal laffects bn safety or elIicacy.'More than 90%
`of the subjects in clinical trials were Caucasian,”
`‘
`‘
`_
`quently during the coureeof their treatment to review dose
`The database was 58% female. No"importar_\t differences
`titration, symptom response and adverse reactions. Food
`significantly-‘ decreases
`the bioavailability of sodium
`safetyyorr efficacyiuf Xyrein were noted betwleei-1' men and
`women. The‘overall'pe1‘c'entage ofpatients with at least one
`oxybate (see Pharmacokinctics). Whether sodium oxybate
`is taken in the fed or fasted state may affect both the effl-
`adverse event was slightly higher_ in women (80%) than in
`men (69%). The incidence ofserious ‘adverse events and dis-
`cacy and safety of sodium oxybate for a given patient. Pa-
`tients should be made aware ofthis and try to take the flrst
`cohtinuations t_lue‘to‘adv_erse events were similar in both '
`men and vvomell”.
`i‘
`‘
`dose several hours after a meal. Patients--should be in-
`formed that.sodium oxybateis associated with urinaryand,
`ADVERSEREACTIONS .
`~
`.
`-
`,
`. ,
`.
`less frequently, fecal incontinence. As a‘ safety precaution,
`Atotal of 717 narcoleptic p