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(11) EP 2 961 399 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/19 (2006.01) A61K 31/196 (2006.01) 15.11.2017 Bulletin 2017/46 A61P 11/00 (2006.01) A61P 25/20 (2006.01) A61P 43/00 (2006.01) A61K 31/20 (2006.01) (2006.01) (2006.01) (21) Application number: 14709858.6 A61K 31/33 A61K 31/505 A61K 31/55 (2006.01) A61K 31/616 (2006.01) (22) Date of filing: 28.02.2014 (86) International application number: PCT/US2014/019217

(87) International publication number: WO 2014/134380 (04.09.2014 Gazette 2014/36)

(54) ADMINISTRATION OF GAMMA HYDROXYBUTYRATE WITH MONOCARBOXYLATE TRANSPORTERS VERABREICHUNG VON GAMMA-HYDROXYBUTYRAT MIT MONOCARBOXYLAT-TRANSPORTERN ADMINISTRATION D’ACIDE 4-HYDROXYBUTANOÏQUE ET DE TRANSPORTEURS MONOCARBOXYLATE

(84) Designated Contracting States: (56) References cited: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB • Fuller D ET AL: "From Club Drug to Orphan Drug: GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Sodium Oxybate (Xyrem) for the Treatment of PL PT RO RS SE SI SK SM TR Cataplexy", , 1 September 2003 (2003-09-01), XP055123175, Retrieved from the Internet: (30) Priority: 01.03.2013 US 201361771557 P URL:http://onlinelibrary.wiley.com/store/1 12.03.2013 US 201361777873 P 0.1592/phco.23.10.1205.32756/asset/phco.23 .10 15.03.2013 US 201313837714 .1205.32756.pdf?v=1&t=hwd6sj5s&s=83f56b 29.04.2013 US 201313873000 e5dea98a39c083d39d2396ab75a192f4ac 29.04.2013 US 201313872997 [retrieved on 2014-06-13] • Viviane Hechler ET AL: (43) Date of publication of application: "gamma-Hydroxybutyrate Conversion into 06.01.2016 Bulletin 2016/01 GABA Induces Displacement of GABA B Binding that is Blocked by Valproate and Ethosuximide (73) Proprietor: Jazz Pharmaceuticals Ireland Limited 1", , 30 January 1997 (1997-01-30), XP055123267, Dublin 4 (IE) Retrieved from the Internet: URL:http://jpet.aspetjournals.org/content/ (72) Inventor: ELLER, Mark 281/2/753.full.pdf#page=1&view=FitH [retrieved Redwood City, CA 94061 (US) on 2014-06-13] • BHATTACHARYA I ET AL: "GHB (74) Representative: Jones Day (GAMMA-HYDROXYBUTYRATE) Rechtsanwälte,Attorneys-at-Law, Patentanwälte CARRIER-MEDIATED TRANSPORT ACROSS Prinzregentenstrasse 11 THE BLOOD-BRAIN BARRIER", JOURNAL OF 80538 München (DE) PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, AMERICAN SOCIETY FOR PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, US, vol. 311, no. 1, 1 October 2004 (2004-10-01), pages 92-98, XP009049440, ISSN: 0022-3565, DOI: 10.1124/JPET.104.069682

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 961 399 B1

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• PETRINE WELLENDORPH ET AL: "Phenylacetic acids and the structurally related non-steroidal anti-inflammatory drug diclofenac bind to specific [gamma]-hydroxybutyric acid sites in rat brain", FUNDAMENTAL & CLINICAL PHARMACOLOGY, vol. 23, no. 2, 1 April 2009 (2009-04-01), pages207-213, XP055123069, ISSN: 0767-3981, DOI: 10.1111/j.1472-8206.2008.00664.x

2 1 EP 2 961 399 B1 2

Description (Mg•(GHB)2), and a calcium salt of gamma-hydroxybu- tyrate (Ca•(GHB)2). 1. CROSS REFERENCE [0011] The methods of treatment disclosed herein are to be construed as referring to the compounds of the [0001] This application claims priority from U.S. Provi- 5 invention for use in those methods. sional Application No. 61/771,557, filed March 1, 2013, [0012] Herein disclosed is a method for treating a pa- and U.S. Provisional Application No. 61/777,873, filed tient who is suffering from excessive daytime sleepiness, March 12, 2013. cataplexy, sleep paralysis, apnea, narcolepsy sleep time disturbances, hypnagogic hallucinations, sleep arousal, 2. BACKGROUND 10 insomnia, and nocturnal myoclonus with gamma-hy- droxybutyrate (GHB) or a salt thereof, comprising: orally [0002] This application relates to methods for safely administering to the patient in need of treatment, an ad- administering gamma hydroxybutyrate (GHB) together justed dosage amount of the salt of GHB when the patient with one or more other monocarboxylate transporter is receiving a concomitant administration of valproate. In (MCT) inhibitors for therapeutic purposes. Example15 certain cases the adjusted amount is reduced at least transporter inhibitors are valproate, diclofenac, and ibu- about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, profen and combinations thereof. Fuller et al., "From Club 45%, or 50% of the normal dose of the salt of GHB nor- Drug to Orphan Drug: Sodium Oxibate (Xyrem) for the mally given to the patient. In certain cases the amount treatment of Cataplexy," Pharmacotherapy,of GHB is reduced at least about 10% and about 30% of 23(9):1205-9, 2003 discloses the use gamma-hydroxy- 20 the normal administration and the daily administration of butyrate to treat cataplexy in patients with narcolepsy. the GHB salt is between 1 gram and 10 grams. In certain cases the adjusted amount is reduced between the rang- 3. SUMMARY OF THE INVENTION es of about 1% to 5%, about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% [0003] In one aspect, the invention provides gamma- 25 to 30%, about 30% to 35%, about 35% to 40%, about hydroxybutyrate (GHB) or a salt thereof for use in a meth- 40% to 45%, or about 45% or 50%, relative to the normal od of treating narcolepsy in a patient, wherein said patient dose of the salt of GHB normally given to the patient. In is also taking or will be taking divalproex sodium, the certain cases the adjusted amount is reduced between method comprising administering GHB or a salt thereof the range of about 1% to 50%, about 1% to 45%, about to the patient in a dose that is reduced by 10% to 40% 30 1% to 40%, about 1% to 35%, about 1% to 30%, about to compensate for the effect caused by the divalproex 1% to 25%, about 1% to 20%, about 1% to 15%, about sodium, wherein the dose of GHB or salt thereof when 1% to 10%, about 1% to 5%, about 5% to 50%, about the patient is not taking the divalproex sodium is between 5% to 45%, about 5% to 40%, about 5% to 35%, about 4.5 g to 9.0 g/day. 5% to 30%, about 5% to 25%, about 5% to 20%, about [0004] In one embodiment, the GHB or salt thereof is 35 5% to 15%, about 5% to 10%, about 10% to 50%, about administered in a dose that is reduced by 15% to 25% 10% to 45%, about 10% to 40%, about 10% to 35%, to compensate for the effect caused by the divalproex about 10% to 30%, about 10% to 25%, about 10% to sodium. 20%, about 10% to 15%, about 15% to 50%, about 15% [0005] In a further embodiment the GHB or salt thereof to 45%, about 15% to 40%, about 15% to 35%, about is administered in a dose that is reduced by 20% to com- 40 15% to 30%, about 15% to 25%, about 15% to 20%, pensate for the effect caused by the divalproex sodium. about 15% to 15%, about 15% to 10%, about 20% to [0006] In certain embodiments, the GHB or salt thereof 50%, about 20% to 45%, about 20% to 40%, about 20% is prepared as a formulation which has a concentration to 35%, about 20% to 30%, about 20% to 25%, about of between 350 - 750 mg/ml. 25% to 50%, about 25% to 45%, about 25% to 40%, [0007] In further embodiments, the GHB or salt thereof 45 about 25% to 35%, about 25% to 30%, about 30% to is prepared as a formulation which has a concentration 50%, about 30% to 45%, about 30% to 40%, about 30% of between 450 - 550 mg/ml. to 35%, about 35% to 50%, about 35% to 45%, about [0008] In another embodiment, the GHB or salt thereof 35% to 40%, about 40% to 50%, relative to the normal is prepared as a formulation which has a pH between 6 dose of the salt of GHB normally given to the patient. - 10. 50 [0013] Further disclosed herein is a method of safely [0009] In a further embodiment, the GHB or salt thereof administering GHB a salt thereof for excessive daytime is prepared as a formulation which has a pH between 6.5 sleepiness, cataplexy, sleep paralysis, apnea, narcolep- - 8. sy, sleep time disturbances, hypnagogic hallucinations, [0010] In yet another embodiment, the salt comprises sleep arousal, insomnia, and nocturnal myoclonus in a a single salt or a mixture of salts of GHB selected from 55 human patient, comprising: determining if the patient is a sodium salt of gamma-hydroxybutyrate (Na•GHB), a has taken, or will take a concomitant dose of valproate; potassium salt of gamma-hydroxybutyrate (K•GHB), a orally administering a reduced amount of the GHB or magnesium salt of gamma-hydroxybutyrateGHB salt to the patient compared to the normal dose so

3 3 EP 2 961 399 B1 4 as to diminish the additive effects of the GHB or GHB sleep arousal, insomnia, and nocturnal myoclonus in a salt when administered with valproate. The amount of human patient, comprising: determining if the patient has GHB is reduced at least 10% to 30%, or at least + 15% taken, or will take a concomitant dose of diclofenac; orally of the normal administration. administering an increased amount of a GHB salt to the [0014] Disclosed herein is a method for treating a pa- 5 patient so as to compensate for the effects of diclofenac tient who is suffering from excessive daytime sleepiness, on the GHB salt when concomitantly administered. cataplexy, sleep paralysis, apnea, narcolepsy sleep time [0016] Disclosed herein is a method for treating a pa- disturbances, hypnagogic hallucinations, sleep arousal, tient who is suffering from narcolepsy wherein said pa- insomnia, and nocturnal myoclonus with GHB or a salt tient is currently taking or has been prescribed GHB or thereof, comprising: orally administering to the patient in 10 a salt thereof, comprising determining if the patient is need of treatment, an adjusted dosage amount of the salt taking or has also been prescribed valproate or di- of GHB when the patient is receiving a concomitant ad- clofenac; and adjusting the dose of the GHB or GHB salt ministration of diclofenac. In certain cases the adjusted to compensate for the effect caused by valproate or di- amount is at least about 1%, 5%, 10%, 15%, 20%, 25%, clofenac. In certain cases the method additionally com- 30%, 35%, 40%, 45%, or 50% higher than the normal 15 prises administering the adjusted dose to the patient. dose of the salt of GHB normally given to the patient. In [0017] Disclosed herein is a method for treating a pa- certain cases the increased amount of GHB is at least tient who is suffering from excessive daytime sleepiness, about 15% more than the normal administration and the cataplexy, sleep paralysis,apnea, narcolepsy, sleep time daily administration of the GHB salt is between 1 gram disturbances, hypnagogic hallucinations, sleep arousal, and 10 grams. In certain cases the adjusted amount is 20 insomnia, and nocturnal myoclonus with a salt of gamma increased between the range of about 1% to 5%, about GHB, wherein said patient is also being treated with val- 5% to 10%, about 10% to 15%, about 15% to 20%, about proate or diclofenac, comprising: administering to the pa- 20% to 25%, about 25% to 30%, about 30% to 35%, tient a daily dose of a GHB salt wherein said daily dose about 35% to 40%, about 40% to 45%, or about 45% or is administered at an amount sufficient to reduce or elim- 50%, relative to the normal dose of the salt of GHB nor- 25 inate additive effects. mally given to the patient. In certain cases the adjusted [0018] Disclosed herein the GHB can be admnistered amount is increased between the range of about 1% to at a level of between 1 and 4.5 grams/day or between 6 50%, about 1% to 45%, about 1% to 40%, about 1% to and 10 grams/day. The concentration of the formulation 35%, about 1% to 30%, about 1% to 25%, about 1% to can be between 350-750 mg/ml or 450-550 mg/ml and 20%, about 1% to 15%, about 1% to 10%, about 1% to 30 a pH between 6-10 or 6.5-8. 5%, about 5% to 50%, about 5% to 45%, about 5% to [0019] Disclosed herein is a method for treating a pa- 40%, about 5% to 35%, about 5% to 30%, about 5% to tient who is suffering from narcolepsy, comprising: ad- 25%, about 5% to 20%, about 5% to 15%, about 5% to ministering a salt of GHB or a salt thereof to a patient or 10%, about 10% to 50%, about 10% to 45%, about 10% determining whether the patient is currently on a GHB to 40%, about 10% to 35%, about 10% to 30%, about 35 drug regimen; determining if the patient is also being ad- 10% to 25%, about 10% to 20%, about 10% to 15%, ministered ibuprofen; and advising a patient to cease or about 15% to 50%, about 15% to 45%, about 15% to ceasing the administration of ibuprofen. In some cases 40%, about 15% to 35%, about 15% to 30%, about 15% patients benefitting from this directive when the patient to 25%, about 15% to 20%, about 15% to 15%, about has will have a renal impairment. 15% to 10%, about 20% to 50%, about 20% to 45%,40 [0020] Disclosed herein is a method for treating a pa- about 20% to 40%, about 20% to 35%, about 20% to tient who is suffering from narcolepsy, comprising: ad- 30%, about 20% to 25%, about 25% to 50%, about 25% ministering a therapeutically effective amount of a formu- to 45%, about 25% to 40%, about 25% to 35%, about lation containing GHB or a salt thereof to a patient at a 25% to 30%, about 30% to 50%, about 30% to 45%, concentration of between 450 and 550 mg/ml and a pH about 30% to 40%, about 30% to 35%, about 35% to45 between 6 and 8, said formulation being administered 50%, about 35% to 45%, about 35% to 40%, about 40% before bed and 1-2 hours thereafter; determining if the to 50 %, relative to the normal dose of the salt of GHB patient is also being administered valproate; warning of normally given to the patient. See the product insert for a potential drug/drug interaction due to the combination normal dose ranges of GHB as sold by Jazz Pharmaceu- of valproate and GHB; and reducing the dose of the GHB ticals (Jazz Pharmaceuticals, Inc., "XYREM® (sodium 50 or GHB salt at least 15% to compensate for the effect oxybate) oral solution Prescribing Information,"caused by valproate. Disclosed herein is a method for XYREM® US Package Insert available at treating ht- a patient who is suffering from narcolepsy, com- tp://www.xyrem.com/xyrem-pi.pdf). GHB is commercial- prising: administering a therapeutically effective amount ly known as Xyrem®. of a formulation containing GHB or a salt thereof to a [0015] Further disclosed herein is a method of safely 55 patient at a concentration of between 450 and 550 mg/ml administering a GHB salt for excessive daytime sleepi- and a pH between 6 and 8, said formulation being ad- ness, cataplexy, sleep paralysis, apnea, narcolepsy, ministered before bed and 1-2 hours thereafter; deter- sleep time disturbances, hypnagogic hallucinations, mining if the patient is also being administered di-

4 5 EP 2 961 399 B1 6 clofenac; warning of a potential drug/drug interaction due a daily dosage of between 6g and 10g GHB per day while to the combination of diclofenac and the GHB salt; and avoiding valproate concomitant administration, and any increasing the dose of the GHB salt at least 15% to com- one or more of the following: (a) advising the patient that pensate for the effect caused by diclofenac. valproate should be avoided or discontinued, (b) advising [0021] The method includes administering GHB at be- 5 the patient that concomitant administration of GHB with tween 1 and 4.5 grams/day or between 6 and 10 drugs that are MCT inhibitors can alter the therapeutic grams/day and at a concentration of between 350-750 effect or adverse reaction profile of GHB, (c) advising the or 450-550 mg/ml, and a pH between 6-10 or between patient that concomitant administration of GHB with val- 6.5-8. In further instances the valproate or diclofenac is proate can alter the therapeutic effect or adverse reaction administered within three days, one or two weeks (before 10 profile of GHB, (d) advising the patient that use of GHB or after) of GHB administration. In another instance the in patients being treated with valproate is contraindicat- present invention is a method wherein aspirin is also ad- ed, (e) advising the patient that concomitant administra- ministered to the patient, especially with valproate. tion of GHB and valproate resulted in an increase in ex- [0022] In some embodiments the method can include posure to GHB, or (f) advising the patient that MCT in- administering GHB as a single salt or a mixture of salts 15 hibitors should be used with caution in patients receiving of GHB selected from the group consisting of a sodium GHB due to the potential for increased GHB clearance. salt of hydroxybutyrate (Na•GHB), a potassium salt of [0028] Disclosed herein is a method for distributing a gamma-hydroxybutyrate (K•GHB), a magnesium salt of drug containing GHB or a salt thereof to an approved gamma-hydroxybutyrate (Mg•(GHB)2), and a calcium pharmacy, the method comprising: identifying an ap- 20 salt of gamma-hydroxybutyrate (Ca•(GHB)2). proved pharmacy that has an established management [0023] In a certain cases the method can include ad- system to dispense information concerning the risks as- ministering GHB to a patient suffering from excessive sociated with ingesting a MCT inhibitor concomitantly to daytime sleepiness, comprising: administering a thera- said drug to patients that are prescribed said drug; pro- peutically effective amount of GHB to the patient; deter- viding said pharmacy with said information related to the mining if the patient has concomitant administration of 25 risks; and authorizing distribution of said drug to said an MCT inhibitor; and adjusting the GHB dose or ceasing pharmacy, wherein said pharmacy dispenses the drug administering of the MCT inhibitor to maintain the effect with said information when filling a prescription for said of the GHB. drug. The method may also comprise including an elec- [0024] In certain cases, the methods optionally further tronic or written alert, which can explain the risks, to em- include administering aspirin to the patient. 30 ployees to dispense said information with said drug when [0025] In some cases the method of administering prescriptions are filled. Also, the information can be dis- GHB to a patient in need thereof comprises administering pensed when a subject refills said prescription. The warn- to the patient a therapeutically effective amount of GHB ings would be as recited above. while avoiding concomitant administration of a diclofenac [0029] The methods disclosed herein may include a or valproate. 35 warning for patients not to operate hazardous machinery, [0026] Disclosed herein is a method of administering including automobiles or airplanes, until they are reason- GHB or a salt thereof (GHB) to a patient with narcolepsy, ably certain that GHB does not affect them adversely and wherein said patient is also in need of diclofenac, com- not to engage in hazardous occupations or activities re- prising administering to the patient a daily dosage of be- quiring complete mental alertness or motor coordination, tween 6g and 10g GHB or a GHB salt per day while avoid- 40 such as operating machinery or a motor vehicle or flying ing diclofenac concomitant administration, and any one an airplane, for at least 6, 7, 8 or 9 hours after taking the or more of the following: (a) advising the patient that di- second nightly dose of GHB. Any information dispensed clofenac should be avoided or discontinued, (b) advising with said drug advises patients of the potential for en- the patient that concomitant administration of GHB with hanced potency of said drug if said patients also take drugs that are MCT inhibitors can alter the therapeutic 45 valproate or advises patients of the potential for de- effect or adverse reaction profile of GHB, (c) advising the creased potency of said drug if said patients also take patient that concomitant administration of GHB with di- diclofenac. clofenac can alter the therapeutic effect or adverse re- [0030] Disclosed herein is a method of administering action profile of GHB, (d) advising the patient that use of GHB to a patient in need thereof, comprising administer- GHB in patients being treated with diclofenac is contrain- 50 ing to the patient a therapeutically effective amount of dicated, (e) advising the patient that concomitant admin- GHB while avoiding concomitant administration of di- istration of GHB and diclofenac resulted in an decrease clofenac or valproate. in exposure to GHB, or (f) advising the patient MCT in- [0031] Disclosed herein is a method for reducing the hibitors should be used with caution in patients receiving effects of GHB toxicity in a patient in need thereof, com- GHB due to the potential for increased GHB clearance. 55 prising administering to said patient an effective amount [0027] Some cases comprise administering GHB to a of diclofenac such that the toxic effects of GHB are re- patient with narcolepsy, wherein said patient is also in duced. It may also comprise a method for potentiating need ofvalproate, comprising administering to thepatient the beneficial effects of GHB in a patient in need thereof

5 7 EP 2 961 399 B1 8 comprising concomitantly administering to said patient Arena et al., "Absorption of Sodiumγ -Hydroxybu- an effective amount of valproate such that the beneficial tyrate and Its Prodrug γ-Butyrolactone: Relationship effects of GHB are increased. between In Vitro Transport and In Vivo Absorption," J. Pharmaceutical Sciences, 69(3): 356-358, 1980 4. BRIEF DESCRIPTION OF THE DRAWINGS 5 ("Arena et al., 1980").

[0032] Banerjee et al., "Presynaptic Gamma-Hydroxybutyr- ic Acid (GHB) and Gamma-Aminobutyric AcidB Figure 1 shows change from baseline figure (LS- (GABAB) Receptor-Mediated Release of GABA and mean with 95% CI) for Power of Attention (ms) (PD 10 glutamate (GLU) in Rat Thalamic Ventrobasal Nu- Completer Population). Treatment A= diclofenac cleus (VB): A Possible Mechanism for the Genera- placebo + Xyrem®. Treatment B= diclofenac + tion of Absence-Like Seizures Induced by GHB," J. Xyrem®. Treatment C= diclofenac + Xyrem® place- Pharmacol. Exp. Ther., 273 (3): 1534-1543, 1995 bo. ("Banerjee et al., 1995"). 15 Figure 2 shows change from baseline figure (LS- Bédard et al., "Nocturnal γ-Hydroxybutyrate. Effect mean with 95% CI) for Digit Vigilance Accuracy (%) on Periodic Leg Movements and Sleep Organization (PD Completer Population). of Narcoleptic Patients," Clin. Neuropharmacol., 12(1): 29-36, 1989 ("Bédard et al., 1989"). Figure 3 shows change from baseline figure (LS- 20 mean with 95% CI) for Digit Vigilance Mean Reaction Broughton et al., "The Treatment of Narcolepsy-Cat- Time (ms) (PD Completer Population). aplexy with Nocturnal Gamma-Hydroxybutyrate," Le Journal Canadien Des Sciences Neurologiques, Figure 4 shows change from baseline figure (LS- 6(1): 1-6, 1979 ("Broughton et al., 1979"). mean with 95% CI) for Choice Reaction Time Mean 25 (ms) (PD Completer Population). Cash et al., "γ-Hydroxybutyrate Receptor Function Studied by the Modulation of Nitric Oxide Synthase Figure 5 shows change from baseline figure (LS- Activity in Rat Frontal Cortex Punches," Biochemical mean with 95% CI) for Continuity of Attention (#) (PD Pharmacology, 58 (11): 1815-1819, 1999 ("Cash et Population). Treatment A= Xyrem®. Treatment B= 30 al., 1999"). Xyrem® placebo. Treatment C=valproate. Dimitrijevic et al., "Drosophila GABAB Receptors are Figure 6 shows change from baseline figure (LS- Involved in Behavioral Effects ofγ -Hydroxybutyric mean with 95% CI) for Simple Reaction Time Mean Acid (GHB)," Eur. J. Pharmacol., 519 (3): 246-252, (ms) (PD Population). 35 2005 ("Dimitrijevic et al., 2005").

Figure 7 shows change from baseline figure (LS- Gallimberti et al., "Gamma-Hydroxybutyric Acid for mean with 95% CI) for Digit Vigilance Accuracy (%) Treatment of Alcohol Withdrawal Syndrome," The (PD Population). Lancet, September 30: 787-789, 1989 ("Gallimberti 40 et al., 1989"). Figure 8 shows change from baseline figure (LS- mean with 95% CI) for Tracking Distance from Target Gallimberti et al., "Gamma-Hydroxybutyric Acid in (mm) (PD Population). the Treatment of Alcohol Dependence: A Double- Blind Study," Alcoholism: Clinical and Experimental Figure 9 shows change from baseline figure (LS- 45 Research, 16(4): 673-676, 1992 ("Gallimberti et al., mean with 95% CI) for Numeric Working Memory 1992"). Sensitivity Index (#) (PD Population). Gallimberti et al., "Gamma-Hydroxybutyric Acid for Figure 10 shows change from baseline figure (LS- Treatment of Opiate Withdrawal Syndrome," Neu- mean with 95% CI) for Numeric Working Memory 50 ropsychopharmacology, 9(1): 77-81, 1993 ("Gallim- Mean Reaction Time (ms) (PD Population). berti et al., 1993").

5. DETAILED DESCRIPTION OF THE INVENTION Gallimberti et al., "Clinical Efficacy of Gamma-Hy- droxybutyric Acid in Treatment of Opiate Withdraw- [0033] The following references provide exemplary55 al," Eur Arch Psychiatry Clin Neurosci, 244: 113-114, procedural or other details supplementary to those set 1994 ("Gallimberti et al., 1994"). forth herein, Gessa et al., "Gamma-Hydroxybutyric Acid in the

6 9 EP 2 961 399 B1 10

Treatment of Alcohol Dependence," Clin. Neurop- ("Lettieri et al., 1978"). harm.--Supplement, 15 (Suppl. 1, Pt. A): 303A- 304A, 1992 ("Gessa et al., 1992"). Maitre et al., "A Specific γ-Hydroxybutyrate Receptor Ligand Possesses both Antagonistic and Anticon- Gerra et al., "Flumazenil Effects on Growth Hormone 5 vulsant Properties," J. Pharmacol. Exp. Ther., 255 Response to Gamma-Hydroxybutyric Acid," Inter- (2): 657-663, 1990 ("Maitre et al., 1990"). nat. Clin. Psychopharm., 9: 211-215, 1994 ("Gerra et al., 1994"). Maitre etal., "Mécanismesd’action d’un medicament détourné: le γ-hydroxybutyrate" (’A mechanism for Hasenbos et al., "Anaesthesia for bullectomy," An- 10 gamma-hydroxybutyrate (GHB) as a drug and a sub- aesthesia, 40: 977-980, 1985 ("Hasenboset al., stance of abuse’) (in French), Med Sci (Paris), 21 1985"). (3): 284-9, 2005 ("Maitre et al., 2005").

Hechler et al., "Extracellular Events Induced byγ - Mamelak et al., "Sleep-Inducing Effects of Gam- Hydroxybutyrate in Striatum: A Microdialysis Study," 15 mahydroxybutyrate," The Lancet, 302 (7824): J. Neurochem., 56 (3): 938-944, 1991 ("Hechler et 328-329, 1973 ("Mamelak et al., 1973"). al., 1991"). Mamelak et al., "The Effects ofγ -Hydroxybutyrate Kuriyama et al., "Blood-Brain Barrier to H3-γ-Ami- on Sleep," Biol. Psychiatry, 12(2): 273-288, 1977 nobutyric Acid in Normal and Amino Oxyacetic Acid- 20 ("Mamelak et al., 1977"). Treated Animals," Neuropharmacology, 10: 103-108, 1971 ("Kuriyama et al., 1971"). Mamelak et al., "Treatment of Narcolepsy and Sleep Apnea with Gammahydroxybutyrate: A Clinical and Laborit, H., "Gamma-Hydroxybutyrate, Succinic Polysomnographic Case Study," Sleep, 4(1): Semialdehyde and Sleep," Laboratoire d’Eutonolo- 25 105-111, 1981 ("Mamelak et al., 1981"). gie, Hopital Boucicaut, Paris 15, France, pp. 257-274, 1973 ("Laborit, 1973"). Mamelak, "Gammahydroxybutyrate: An Endog- enous Regulator of Energy Metabolism," Neuro- Ladinsky et al., "Mode of Action of Gamma-Butyro- science and Biobehav. Reviews, 13: 187-198, 1989 lactone on the Central Cholinergic System, Naunyn- 30 ("Mamelak, 1989"). Schmiedeberg’s Arch.Pharmacal., 322: 42-48,1983 ("Ladinsky et al., 1983"). Nema et al., "Excipients and Their Use in Injectable Products," PDA J. Pharm. Sci. Technol., 51(4): Lammers et al., "Gammahydroxybutyrate and Nar- 166-171, 1997 ("Nema et al., 1997"). colepsy: A Double-Blind Placebo-Controlled Study," 35 Sleep, 16(3); 216-220, 1993 ("Lammerset al., Palatini et al., "Dose-Dependent Absorption and 1993"). Elimination of Gamma-Hydroxybutyric Acid in Healthy Volunteers," Eur. J. Clin. Pharmacol., 45: Lapierre et al., "The Effect of Gamma-Hydroxybu- 353-356, 1993 ("Palatini et al., 1993"). tyrate: A Double-Blind Study of Normal Subjects," 40 Sleep Research, 17: 99, 1988 ("Lapierreet al., Roth et al., "γ-Butyrolactone and γ-Hydroxybutyric 1988"). Acid-I Distribution and Metabolism," Biochemical Pharmacology, 15: 1333-1348, 1966 ("Roth et al., Lapierre et al., "The Effect of Gamma-Hydroxybu- 1966a"). tyrate on Nocturnal and Diurnal Sleep of Normal45 Subjects: Further Considerations on REM Sleep- ROTH et al., " γ-Butyrolactone and γ-Hydroxybutyric Triggering Mechanisms," Sleep, 13(1): 24-30, 1990 Acid-II The Pharmacologically Active Form," Int. J. ("Lapierre et al., 1990"). Neropharmacol., 5: 421-428, 1966 ("Rothet al., 1966b"). Lee, C.R., "Evidence for theβ -Oxidation of Orally 50 Administered 4-Hydroxybutyrate in Humans," Bio- Scharf et al., "The Effects and Effectiveness ofγ- chem. Med., 17, 284-291: 1977 ("Lee, 1977"). Hydroxybutyrate in Patients with Narcolepsy," J. Clin. Psychiatry, 46(6): 222-225, 1985 ("Scharfet Lettieri et al., "Improved Pharmacological Activity via al., 1985"). Pro-Drug Modification: Comparative Pharmacoki- 55 netics of Sodium γ-Hydroxybutyrate and γ-Butyrol- Scrima et al., "Gamma-Hydroxybutyrate Effects on actone," Research Communications In Chemical Cataplexy and Sleep Attacks in Narcoleptics," Sleep Pathology and Pharmacology, 22(1): 107-118, 1978 Res., 16: 134, 1987 ("Scrima et al., 1987").

7 11 EP 2 961 399 B1 12

Scrima et al., "Efficacy of Gamma-Hydroxybutyrate herein refer to the administration of at least two drugs to versus Placebo in Treating Narcolepsy-Cataplexy: a patient either subsequently, simultaneously, or conse- Double-Blind Subjective Measured," Biol. Psychia- quently within a time period during which the effects of try, 26: 331-343, 1989 ("Scrima et al., 1989"). thefirst administered drug are stilloperative in thepatient. 5 Thus, if the first drug is, e.g., Xyrem®, or GHB, and the Scrima et al., "The Effects of γ-Hydroxybutyrate on second drug is valproate, the concomitant administration the Sleep of Narcolepsy Patients: A Double-Blind of the second drug occurs within two weeks, preferably Study," Sleep, 13(6): 479-490, 1990 ("Scrima et al., within one week or even three days, before or after the 1990"). administration of the first drug. 10 [0037] "Dosage amount" means an amount of a drug Sériès et al., "Effects of Enhancing Slow-Wave suitable to be taken during a fixed period, usually during Sleep by Gamma-Hydroxybutyrate on Obstructive one day (i.e., daily). Sleep Apnea," Am. Rev. Respir. Dis., 1378-1383, [0038] "Dosage amount adapted for oral administra- 1992 ("Sériès et al., 1992"). tion" means a dosage amount that is of an amount 15 deemed safe and effective for the particular patient under Smolders et al., "Tonic GABA-ergic Modulation of theconditions specified.As used hereinand inthe claims, Striatal Dopamine Release Studied by In Vivo Micro- this dosage amount is determined by following the rec- dialysis in the Freely Moving Rat," Eur. J. Pharma- ommendations of the drug manufacturer’s Prescribing col., 284 (1-2): 83-91, 1995 ("Smolders et al., 1995"). Information as approved by the US Food and Drug Ad- 20 ministration. Strong, γ "-Hydroxybutyric Acid and Intracranial [0039] "Dosing regimen" means the dose of a drug tak- Pressure," The Lancet, Vol. 1: No. 8389, 1984 en at a first time by a patient and the interval (time or ("Strong, 1984"). symptomatic) and dosage amounts at which any subse- quent doses of the drug are taken by the patient. Each Van Den Bogert et al., "Placentatransfer of 4-Hy- 25 dose may be of the same or a different dosage amount. droxybutyric Acid in Man," Anesthesiology and In- [0040] A "dose"means themeasured quantity of adrug tensive Care Medicine, 110: 55-64, 1978 ("Van Den to be taken at one time by a patient. Bogert et al., 1978"). [0041] A "patient" means a human in need of medical treatment. In one embodiment medical treatment can in- Vickers, M.D., "Gammahydroxybutyric Acid," Int. An- 30 clude treatment of an existing condition, such as a dis- esth. Clinic, 7: 75-89, 1969 ("Vickers, 1969"). ease or disorder, prophylactic or preventative treatment, or diagnostic treatment. In another embodiment, medical Waszkielewicz et al., γ "-Hydrobutyric Acid (GHB) treatment also includes administration to treat excessive and its Chemical Modifications: A Review of the GH- daytime sleepiness, cataplexy, sleep paralysis, apnea, Bergic System," Pol J Pharmacol., 56 (1): 43-49, 35 narcolepsy, sleep time disturbances, hypnagogic hallu- 2004 ("Waszkielewicz et al., 2004"). cinations, sleep arousal, insomnia, and nocturnal myo- clonus. Wu et al., "γ-Hydroxybutyric acid (GHB) and γ-ami- [0042] "Providing" means giving, administering, sell- nobutyric acidB receptor (GABABR) binding sites ing, distributing, transferring (for profit or not), manufac- are distinctive from one another: molecular evi-40 turing, compounding, or dispensing. dence," Neuropharmacology, 47 (8): 1146-56, 2004 [0043] The terms "therapeutically effective amount," ("Wu et al., 2004"). as used herein, refer to an amount of a compound suffi- cientto treat, ameliorate, or prevent theidentified disease Yamada et al., "Effect of Butyrolactone and Gamma- or condition, or to exhibit a detectable therapeutic, pro- Hydroxybutyrate on the EEG and Sleep Cycle in45 phylactic, or inhibitory effect. The effect can be detected Man," Electroenceph. Clin. Neurophysiol., 22: by, for example, an improvement in clinical condition, or 558-562, 1967 ("Yamada et al., 1967"). reduction in symptoms. The precise effective amount for a subject will depend upon the subject’s body weight, [0034] In the specification and claims that follow, ref- size, and health; the nature and extent of the condition; erences will be made to a number of terms which shall 50 and the therapeutic or combination of therapeutics se- be defined to have the following meaning. lected for administration. Where a drug has been ap- [0035] The terms "a" and "an" do not denote a limitation proved by the U.S. Food and Drug Administration (FDA), of quantity, but rather denote the presence of at least one a "therapeutically effective amount" refers to the dosage of the referenced item. The term "or" means "and/or". approved by the FDA or its counterpart foreign agency The terms "comprising", "having", "including", and "con- 55 for treatment of the identified disease or condition. taining" are to be construed as open-ended terms (i.e., [0044] "Side effect" means a secondary effect resulting meaning "including, but not limited to"). from taking a drug. The secondary effect can be a neg- [0036] "Concomitant" and "concomitantly" as used ative (unfavorable) effect (i.e., an adverse side effect) or

8 13 EP 2 961 399 B1 14 a positive (favorable) effect. thorizing distribution of said drug to said pharmacy, [0045] Pharmacokinetic parameters referred to herein wherein said pharmacy dispenses the drug with said in- describe the in vivo characteristics of drug (or a metab- formation when filling a prescription for said drug. The olite or a surrogate marker for the drug) over time. These established management system may include an elec- 5 include plasma concentration (C), as well as Cmax, Cn, tronic alert to employees to dispense said information C24, Tmax, and AUC. The term "Tmax" refers to the time with said drug when prescriptions are filled. Such infor- from drug administration until Cmax is reached. "AUC" is mation may be dispensed in written form, for example in the area under the curve of a graph of the measured a brochure explaining the risks of concomitant ingestion plasma concentration of an active agent vs. time, meas- of GHB and an MCT inhibitor such as diclofenac, val- ured from one time point to another time point. For ex- 10 proate, or ibuprofen or combinations thereof. For exam- ample AUC0-t is the area under the curve of plasma con- ple, the information dispensed with GHB may advise a centration versus time from time 0 to time t, where time patient of the potential for enhanced potency of GHB if 0 is the time of initial administration of the drug. Time t the patient also takes valproate. Alternatively, or in ad- can be the last time point with measurable plasma con- dition thereto, the information dispensed with GHB may 15 centration for an individual formulation. The AUC0-.infin. advise a patient of the potential for decreased potency or AUC0-INF is the calculated area under the curve of of GHB if the patient also takes diclofenac. Such infor- plasma concentration versus time from time 0 to time mation may also be dispensed in verbal form. Distributors infinity. In steady-state studies, AUC 0-.tau. is the area un- may maintain a directory of approved pharmacies, for der the curve of plasma concentration over the dosing example in a computer readable storage medium, to fur- interval (i.e., from time 0 to time .tau. (tau), where tau is 20 ther ensure that GHB is dispensed only to patients who the length of the dosing interval. are advised of the additive effects. [0046] It may be advantageous to incorporate a phar- [0048] In addition, the system can prevent the dispens- macymanagement system into themethod of the present ing of GHB or salt thereof until proper testing or confir- invention. Pharmacy management systems are compu- mation is obtained that the patient is not taking or going ter-based systems that are used by commercial pharma- 25 to take valproate or diclofenac concomitantly with GHB. cies to manage prescriptions and to provide pharmacy Alternatively, the patient can be warned of the adverse and medical personnel with warnings and guidance re- effect and instructed to modify the dose of GHB to ac- garding drugs being administered to patients. Such sys- commodate the increased or reduced effects of GHB due tems typically provide alerts warning either or both of to valproate or diclofenac. health care providers and patients when a drug that may 30 [0049] A pharmacy management system can be a be harmful to the particular patient is prescribed. For ex- REMS system as shown in U.S. Patent Nos. 7,895,059, ample, such systems can provide alerts warning that a 7,797,171, and 7,668,730, and also include monitoring patient has an allergy to a prescribed drug, or is receiving for concomitant use of diclofenac, valproate, or ibupro- concomitant administration of a drug that can have a dan- fen, or combinations thereof. Warnings may be adminis- gerous interaction with a prescribed drug. U.S. Patent 35 tered through the existing pharmacy management sys- Nos. 7,895,059,7,797,171, 7,668,730, 7,765,106, tem as described in the patents above. 7,765,107, 5,758,095, 5,833,599, 5,845,255, 6,014,631, [0050] One embodiment of the present invention, with- 6,067,524, 6,112,182, 6,317,719, 6,356,873, and out being limited by theory, is the discovery of drug in- 7,072,840, disclose various pharmacy management sys- teractions that change either, or both, the efficacy or safe- tems and aspects thereof. Example pharmacy manage- 40 ty profile of GHB. The three compounds are valproate, ment systems are now commercially available, e.g., diclofenac, and ibuprophen or combinations thereof. To CENTRICITY Pharmacy from BDM Information Systems achieve the above benefits, GHB of the present invention Ltd., General Electric Healthcare, Waukesha, Wis., Rx30 can be administered in a reduced amount when a second Pharmacy Systems from Transaction Data Systems, compound, such as valproate, is concomitantly adminis- Inc., Ocoee, Fla., SPEED SCRIPT from Digital Simplis- 45 tered with GHB. It can also be administered in an in- tics, Inc., Lenexa, Kans., and various pharmacy manage- creased amount to overcome any effects of diclofenac. ment systems from OPUS-ISM, Hauppauge, N.Y. The compounds can also be avoided or discontinued to [0047] In some cases a pharmacy management sys- prevent unsafe concomitant administration. tem may be required or preferred as part of a drug dis- [0051] In one embodiment of the present invention, tribution program. For example, the discloded methods 50 concomitant administration of GHB with other agents is may include a method for distributing a drug containing monitored and potential changes to the doses of GHB GHB ora salt thereof to an approvedpharmacy, the meth- are made, or changes in the administration of other com- od comprising: (1) Identifying an approved pharmacy that pounds are made. In certain instances, when GHB was has an established management system to dispense in- concomitantly administered with ibuprofen, there were formation concerning the risks associated with ingesting 55 pharmacokinetic (PK) changes consistent with monocar- a MCT inhibitors concomitantly to said drug to patients boxylic transporter (MCT) inhibition and renal excretion that are prescribed said drug; (2) Providing said pharma- of GHB doubled (statistically significant). Plasma levels cy with said information related to the risks; and (3) Au- wereabout ∼ 5% lower, which was statistically significant.

9 15 EP 2 961 399 B1 16

In another case, when GHB and Diclofenac are concom- sleepapnea ( see,e.g., Scrima et al.,1987), and improves itantly administered, PD effects were significantly re- general anesthesia (see, e.g., Hasenbos et al., 1985). duced. In another case, when GHB and divalproate were [0056] GHB has several clinical applications other than concomitantly administered, PK showed both MCT and narcolepsy and sleep disorders. GHB has been reported GHB dehydrogenase inhibition, with the latter predomi- 5 to reduce alcohol craving, the number of daily drinks con- nating. MCT inhibition caused renal clearance to be in- sumed, and the symptoms of alcohol withdrawal in pa- creased 30% (statistically significant). GHB dehydroge- tients (see, e.g., Gallimberti et al., 1989; Gallimberti et nase inhibition caused systemic exposure (plasma AUC) al., 1992; Gessa et al., 1992). GHB has been used to to be increased 26%. Both measures are statistically sig- decrease the symptoms of opiate withdrawal, including nificant and outside FDA "equivalence window". PD10 both heroin and methadone withdrawal (see, e.g., Gal- shows more pronounced effects with concomitant admin- limberti et al., 1993; Gallimberti et al., 1994). It has an- istration. algesic effects that make it suitable as a pain reliever [0052] Disclosed herein is a method of administering (see, e.g., U.S. Patent No. 4,393,236). Intravenous ad- a therapeutically effective amount of GHB to a patient in ministration of GHB has been reported to reduce intrac- need of treatment, such as with narcolepsy, the invention 15 ranial pressure in patients ( see, e.g., Strong, 1984). Also, provides an improvement that comprises avoiding or dis- administration of GHB was reported to increase growth continuing administration of a compound that affects hormone levels in patients ( see, e.g., Gerra et al., 1994). GHB potency and administering a therapeutically effec- [0057] A good safety profile for GHB consumption, tive amount of GHB. The compound can be diclofenac when used long term for treatment of narcolepsy has or valproate and they can alter the therapeutic effect or 20 been reported. Patients have been safely treated for adverse reaction profile of GHB. many years with GHB without development of tolerance (see, e.g., Scharf et al., 1985). Clinical laboratory tests Gamma hydroxybutyrate (GHB) carried out periodically on many patients have not indi- cated organ or other toxicities ( see, e.g., Lammers et al., [0053] GHB (also called oxysorbate or oxybate) is ap- 25 1993; Scrima et al., 1990; Scharf et al., 1985; Mamelak proved in the United States (US) for the treatment of ex- et al., 1977; Mamelak et al., 1979; Gessa et al., 1992). cessive daytime sleepiness (EDS) and for the treatment The side effects of GHB treatment have been minimal in of cataplexy, both in patients with narcolepsy. GHB is incidence and degree of severity, though they include commercially sold as Xyrem® sodium oxybate by Jazz sleepwalking, enuresis, headache, nausea and dizzi- Pharmaceuticals. Sodium oxybate is the sodium salt of 30 ness (see, e.g., Mamelak et al., 1979; Mamelak et al., the endogenous neurotransmitter gamma hydroxybu- 1981; Mamelak et al., 1977; Scrima et al., 1989; Scrima tyrate (GHB), which is found in many tissues of the body. et al., 1990; Scharf et al., 1985). Therefore, it is critical "GHB", oxybate, a GHB salt or Xyrem® will be used to to identify adverse drug-drug interactions to maintain the refer to these active forms. It can be used as a sodium, positive safety profile for GHB. calcium, potassium, or magnesium salt. See U.S. Patent 35 Application No. 13/739,886. GHB Pharmacology [0054] GHB is present, for example, in the mammalian brain and other tissues. In the brain, the highest GHB [0058] GHB has at least two distinct binding sites ( see, concentration is found in the hypothalamus and basal e.g., Wu, et al., 2004) in the central nervous system. GHB ganglia and GHB is postulated to function as a neuro- 40 is an agonist at the GHB receptor, which is excitatory, transmitter. The neuropharmacologic effects of GHB in- (see, e.g., Cash et al., 1999) and it is a weak agonist at clude increases in brain acetylcholine, increases in brain the GABAB receptor, which is inhibitory. GHB acts in a dopamine, inhibition of GABA-ketoglutarate transami- similar fashion to some neurotransmitters in the mam- nase and depression of glucose utilization but not oxygen malian brain and is probably synthesized from GABA in consumption in the brain. GHB is converted to succinate 45 GABAergic neurons, and released when the neurons fire. and then metabolized via the Krebs cycle. Clinical trials If taken orally, GABA itself does not effectively cross the have shown that GHB increases delta sleep and im- blood-brain-barrier (see, e.g., Kuriyama et al., 1971). proves the continuity of sleep (see, e.g., Laborit, 1973; [0059] GHB induces the accumulation of either a de- Lapierre et al., 1988; Lapierre et al., 1990; Yamada et rivative of tryptophan or tryptophan itself in the extracel- al., 1967; Scharf et al., 1985). 50 lular space, possibly by increasing tryptophan transport [0055] GHB treatment substantially reduces the signs across the blood-brain barrier. The blood content of cer- and symptoms of narcolepsy, i.e. excessive daytime tain neutral amino-acids, including tryptophan, is also in- sleepiness, cataplexy, sleep paralysis, apnea, narcolep- creasedby peripheral GHBadministration. GHB-induced sy, sleep time disturbances, hypnagogic hallucinations, stimulation of tissue serotonin turnover may be due to an sleep arousal, insomnia, and nocturnal myoclonus. In ad- 55 increase in tryptophan transport to the brain and in its dition, GHB increases total sleep time and REM sleep, uptake by serotonergic cells. As the serotonergic system and it decreases REM latency ( see, e.g., Mamelak et al., may be involved in the regulation of sleep, mood, and 1973; Yamada et al., 1967; Bédard et al., 1989), reduces anxiety, the stimulation of this system by high doses of

10 17 EP 2 961 399 B1 18

GHB may be involved in certain neuropharmacological to what is shown here to produce endogenous GHB. events induced by GHB administration. However, when GHB is consumed for recreational or [0060] However, at therapeutic doses, GHB reaches health promotion purposes, its concentration in the body much higher concentrations in the brain and activates is much higher than normal, which changes the enzyme GABAB receptors, which are primarily responsible for its 5 kinetics so that these pathways operate to metabolize sedative effects. see, ( e.g., Dimitrijevic et al., 2005). GHB rather than produce it. GHB’s sedative effects are blocked by GABAB antago- [0065] The pharmacokinetics of GHB have been in- nists. vestigated in alcohol dependent patients (Ferrara et al., [0061] The role of the GHB receptor in the behavioral "Pharmacokinetics of Gamma-hydroxybutyric Acid in Al- effects induced by GHB is more complex. GHB receptors 10 cohol Dependent Patients after Single and Repeated are densely expressed in many areas of the brain, in- Oral Doses," Br. J. Clin. Pharmacol., 34(3): 231-5, 1992 cluding the cortex and hippocampus, and these are the ("Ferrara et al., 1992") and in normal healthy males (Pal- receptors that GHB displays the highest affinity for. There atini et al., "Dose-Dependent Absorption and Elimination has been somewhat limited research into the GHB re- of Gamma-Hydroxybutyric Acid in Healthy Volunteers," ceptor; however, there is evidence that activation of the 15 Eur. J. Clin. Pharmacol., 45: 353-356, 1993 ("Palatini et GHB receptor in some brain areas results in the release al., 1993")) after oral administration. GHB possesses a of glutamate, the principal excitatory neurotransmitter. rapid onset and short pharmacological effect (Ferrara et Drugs that selectively activate the GHB receptor cause al., 1992; Palatini et al., 1993; Lettieri et al., 1978; Arena absence seizures in high doses, as do GHB andet al.,1980; Roth et al.,1966a; Roth etal., 1966b; Vickers, GABA(B) agonists (see, e.g., Banerjee et al., 1995.) 20 1969; Lee, 1977). In alcohol dependent patients, GHB [0062] Activation of both the GHB receptor and absorption into and elimination from the systemic circu- GABA(B) is responsible for the addictive profile of GHB. lation were fast processes. Virtually no unchanged drug GHB’s effect on dopamine release is biphasic ( see, e.g., could be recovered in the urine. There were preliminary Hechler et al., 1991). Low concentrations stimulate indications that the pharmacokinetics of GHB might be dopamine release via the GHB receptor ( see, e.g., Maitre 25 non-linear or dose-dependent (Ferrara et al., 1992). In et al., 1990). Higher concentrations inhibit dopamine re- the healthy volunteers study, the pharmacokinetics of lease via GABA(B) receptors as do other GABA(B) ag- three rising GHB doses (12.5, 25, and 50 mg/kg) were onists such as baclofen and phenibutsee, ( e.g., investigated. These findings indicate that both the oral Smolders et al., 1995). After an initial phase of inhibition, absorption and elimination processes of GHB were ca- dopamine release is then increased via the GHB recep- 30 pacity-limited though the degree of dose dependency tor. Both the inhibition and increase of dopamine release was moderate (Palatini et al., 1993). by GHB are inhibited by opioid antagonists such as [0066] Methods of making GHB salts are described, naloxone and naltrexone. Dynorphin may play a role in for example, in U.S. Patent No. 4,393,236, and U.S. Pat- the inhibition of dopamine release via kappa opioid re- ent Application No. 13/739,886. ceptors (see, e.g., Mamelak, 1989). 35 [0067] It has been discovered that there are unexpect- [0063] This may explain the paradoxical mix of seda- ed drug-drug interactions (DDI) between GHB and com- tive and stimulatory properties of GHB, as well as the so- mon drugs frequently prescribed for other ailments. It is called "rebound" effect, experienced by individuals using one goal of the present disclosure to warn when those GHB as a sleeping agent, wherein they awake suddenly interactions may affect the safety profile of GHB. Drugs after several hours of GHB-induced deep sleep. That is 40 that may affect GHB administration include valproate, to say that, over time, the concentration of GHB in the diclofenac, and ibuprofen and combinations thereof. system decreases below the threshold for significant [0068] GHB is a central nervous system (CNS) depres- GABAB receptor activation and activates predominantly sant. Alcohol and sedative hypnotics are contraindicated the GHB receptor, leading to wakefulness. However, one in patients who are using GHB. The concurrent use of embodiment of the present invention is the unexpected 45 GHB with other CNS depressants, including but not lim- discovery that drugs change the PD profile of GHB to ited to opioid analgesics, benzodiazepines, sedating alter its effects and its safety profile. Example drugs are antidepressants or antipsychotics, general anesthetics, include valproate and diclofenac. It is important for effi- muscle relaxants, and/or illicit CNS depressants, may cacy safety purposes that the effect of GHB be main- increase the risk of respiratory depression, hypotension, tained consistently and not subject to variation due to the 50 profound sedation, syncope, and death. If use of these effects of other drugs. CNS depressants in combination with GHB is required, [0064] Both of the metabolic breakdown pathways dose reduction or discontinuation of one or more CNS shown for GHB can run in either direction, depending on depressants (including GHB) should be considered. In the concentrations of the substances involved, so the addition, if short-term use of an opioid (e.g. post- or peri- body can make its own GHB either from GABA or from 55 operative) is required, interruption of treatment with GHB succinic semialdehyde. Under normal physiological con- should be considered.See the package insert for ditions, the concentration of GHB in the body is rather Xyrem®. low, and the pathways would run in the reverse direction [0069] GHB may impair respiratory drive, especially

11 19 EP 2 961 399 B1 20 with overdoses associated with interactions with other is an acid selected from the group of: acetic, acetylsali- drugs and alcohol. Since valproate may potentiate the cylic, barbital, barbituric, benzoic, benzyl penicillin, boric, effect of GHB, a warning should accompany any use of caffeine, carbonic, citric, dichloroacetic, ethylenediami- valproate and GHB as stated herein. The warning should netetra-acetic acid (EDTA), formic, glycerophosphoric, address the use of additional drugs that may further en- 5 glycine, lactic, malic, mandelic, monochloroacetic, oxal- hance the effect of GHB, such as alcohol or aspirin, for ic, phenobarbital, phenol, picric, propionic, saccharin, example. salicylic, sodium dihydrogen phosphate, succinic, sul- [0070] Healthcare providers should caution patients fadiazine, sulfamerazine, sulfapyridine, sulfathiazole, about operating hazardous machinery, including auto- tartaric, trichloroacetic, and the like, or inorganic acids mobiles or airplanes, until they are reasonably certain 10 such as hydrochloric, nitric, phosphoric or sulfuric, and that GHB does not affect them adversely (e.g., impair the like. judgment, thinking, or motor skills). Patients should not [0075] GHB is commercially available as a sodium salt, engage in hazardous occupations or activities requiring however, it can also be formulated as a mixture of salts complete mental alertness or motor coordination, such as shown in U.S. Patent Application No. 13/739,886. For as operating machinery or a motor vehicle or flying an 15 example, the mixture comprises one, two, or three or airplane, for at least 6, 7, 8 or 9 hours after taking the more salts selected from the group consisting of a sodium second nightly dose of GHB. Patients should be queried salt of hydroxybutyrate (Na•GHB), a potassium salt of about potential adverse events, such as excessive day- gamma-hydroxybutyrate (K•GHB), a magnesium salt of time sleepiness, CNS depression related events, etc. up- gamma-hydroxybutyrate (Mg•(GHB)2), and a calcium 20 on initiation of GHB therapy and periodically thereafter. salt of gamma-hydroxybutyrate (Ca•(GHB) 2). The differ- These queries should include info regarding additional ent salts may be present in different percentages. For medication such as diclofenac and valproate for exam- example, in certain embodiments, the pharmaceutical ple. See the Xyrem® package insert. composition comprises Na•GHB, K•GHB, and

[0071] In certain cases, patients are warned that com- Ca•(GHB)2. In certain embodiments, the Na•GHB salt is bination of GHB with valproate can increase plasma lev- 25 present in a wt/wt% of about 5% to about 40%, the K•GHB els and potentiate the activity of GHB and exacerbate all salt is present in a wt/wt% of about 10% to about 40%, the effects and adverse event associated with GHB. and the Ca•(GHB)2 salt is present in a wt/wt% of about These effects include the intended effects of drowsiness, 20% to about 80%. In certain embodiments, the Na•GHB, sedation, and sleep and typically unintended events such K•GHB, and Ca•(GHB)2 salts are present in a wt/wt% as depressed respiration, CNS depression, excessive 30 ratio of about 11% : 39% : 50%, respectively. drowsiness, hepatic impairment, and depression, among other things. Valproic acid [0072] Diclofenac mitigates and protects against the pharmcodynamic effects the effects of GHB. However, [0076] Valproic acid (VPA, also called valproate or di- the mixture of GHB and diclofenac does not affect sleep- 35 valproex), an acidic chemical compound, has found clin- iness and does not make a patient more attentive. With- ical use as an anticonvulsant and mood-stabilizing drug, out wishing to be bound by theory, the effects may be primarily in the treatment of epilepsy, bipolar disorder, due to the interaction between diclofenac and the GHB and, less commonly, major depression. See,e.g., Rosen- receptor in lieu of the MCT inhibitor activity. berg, G., "The Mechanisms of Action of Valproate in Neu- [0073] Typical concentrations of GHB formulations are 40 ropsychiatric Disorders: Can We See the Forest for the shown in U.S. Patent Nos. 8,263,650 and 8,324,275, for Trees?" Cel. Mol. Life Sci., 64 (16): 2090-2103, 2007 example. They include minimum concentrations starting ("Rosenberg, 2007"). It is also used to treat migraine from 150 mg/ml to 450 mg/ml (at 10 mg/ml increments) headaches and schizophrenia. A typical dose of val- and increasing to 600 mg/ml to 750 mg/ml (at 10 mg/ml proate varies by indication. Dosages for seizures are be- increments) as a maximum. So, a broad range would 45 tween 10 to 15 mg/kg/day, with potential increases of 5 include 150-750 mg/ml and any range within the broad to 10 mg/kg/day. VPA is a liquid at room temperature, range using 10 mg/ml increments. One embodiment of but it can be reacted with a base such as sodium hydrox- the invention is a range of 350-750 mg/ml and another ide to form the salt sodium valproate, which is a solid. is 450-550 mg/ml GHB. One embodiment of the present The acid, salt, or a mixture of the two (valproate semiso- invention uses a GHB formulation with a pH range of50 dium, divalproate) are marketed under the various brand 6-10, another uses a pH range of between 6.5-8. For names Depakote, Depakote ER, Depakene, Depakene example, a minimum concentration includes 350, 360, Crono (extended release in Spain), Depacon, Depakine, 370, 380 mg/ml, and so on up to at least 730, 740, and Valparin and Stavzor. 750 mg/ml and all concentrations (measured in 10 mg/ml [0077] Valproate is believed to affect the function of increments in between). 55 the neurotransmitter GABA in the human brain, making [0074] pH adjusting agents can include acids, bases it an alternative to lithium salts in treatment of bipolar and many of the compounds found in U.S. Patent No. disorder. Its mechanism of action includes enhanced 8,263,650. In some embodiments the pH adjusting agent neurotransmission of GABA (by inhibiting GABA

12 21 EP 2 961 399 B1 22 transaminase, which breaks down GABA). However, elling in Cardiac Patients Submitted to Cardiopulmonary several other mechanisms of action in neuropsychiatric Bypass," Braz. J. Med. Bio. Res., 30: 369-374, 1997, and disorders have been proposed for valproic acid in recent Hasan et al., "Pharmacokinetics of Diclofenac Sodium in years (see, e.g., Rosenberg, 2007). Normal Man," Pakistan Jour. Pharmaceutical Sciences, [0078] Valproic acid also blocks the voltage-gated so- 5 18(1): 18-24, 2005. dium channels and T-type calcium channels. These [0084] The name is derived from its chemical name: mechanisms make valproic acid a broad-spectrum anti- 2-(2,6-dichloranilino) phenylacetic acid, it may be sup- convulsant drug. Valproic acid is an inhibitor of the en- plied as either the sodium or potassium salt. Diclofenac zyme histone deacetylase 1 (HDAC1), hence it is a his- is available as a generic drug in a number of formulations; tonedeacetylase inhibitor. Valproic acid may interactwith 10 including Dichlofenacdiethylammonium applied topically carbamazepine, as valproates inhibit microsomal epox- to joints. Over-the-counter (OTC) use is approved in ide hydrolase (mEH), the enzyme responsible for the some countries for minor aches and pains and fever as- breakdown of carbamazepine-10,11 epoxide (the main sociated with common infections. active metabolite of carbamazepine) into inactive metab- [0085] Diclofenac is typically absorbed readily, but ab- olites. (See, e.g., Gonzalez et al., "Drug Metabolism," in 15 sorption is delayed upon administration with food. Its half- Goodman & Gilman’s The Pharmacological Basis of life varies from 1 to 3 hours with mean peak plasma levels Therapeutics (11th ed.), Brunton et al. (eds.), New York: of about 0.5 ug/ml to 1.0 ug/ml after 2 hours of a single McGraw-Hill. pp. 71-91, 2006.) By inhibiting mEH, valp- dose of 25 mg. Diclofenac binds to human serum pro- roic acid causes a buildup of the active metabolite, pro- teins, specifically albumin. ( See,e.g., Hasan et al., "Phar- longing the effects of carbamazepine and delaying its 20 macokinetics of Diclofenac Sodium in Normal Man," Pa- excretion. Valproic acid also decreases the clearance of kistan Jour. Pharmaceutical Sciences, 18(1): 18-24, amitriptyline and nortriptyline. 2005.) [0079] Aspirin may decrease the clearance of valproic acid, leading to higher-than-intended serum levels of the Ibuprofen anticonvulsant. Also, combining valproic acid with the 25 benzodiazepine clonazepam can lead to profound seda- [0086] Ibuprofen (from iso-butyl-propanoic-phenolic tion and increases the risk of absence seizures in patients acid) is a nonsteroidal anti-inflammatory drug (NSAID) susceptible to them. widely prescribed for pain relief, fever reduction, and [0080] Valproic acid and sodium valproate reduce the swelling. Ibuprofen was derived from propanoic acid. apparent clearance of lamotrigine (lamictal). In most pa- 30 Originally marketed as Brufen, ibuprofen is available un- tients, the lamotrigine dosage for coadministration with der a variety of popular trademarks, including Motrin, valproate must be reduced to half the monotherapy dos- Nurofen, Advil, and Nuprin. Ibuprofen is used primarily age. for fever, pain, dysmenorrhea and inflammatory diseases [0081] Valproic acid is contraindicated in pregnancy, such as rheumatoid arthritis. It is also used for pericarditis as it decreases the intestinal reabsorption of folate (folic 35 and patent ductus arteriosus. It is a commonly used drug acid), which leads to neural tube defects. Because of a commercially available over the counter. decreasein folate, megaloblastic anemia may also result. [0087] Nonsteroidal anti-inflammatory drugs such as Phenytoin also decreases folate absorption, which may ibuprofen work by inhibiting the enzyme cyclooxygenase lead to the same adverse effects as valproic acid. (COX), which converts arachidonic acid to prostaglandin [0082] Valproic acid, 2-propylvaleric acid, is synthe- 40 H2 (PGH2).PGH2, in turn, isconverted byother enzymes sized by the alkylation of cyanoacetic ester with two to several other prostaglandins (which are mediators of moles of propylbromide, to give dipropylcyanoacetic es- pain, inflammation, and fever) and to thromboxane A2 ter. Hydrolysis and decarboxylation of the carboethoxy (which stimulates platelet aggregation, leading to the for- group gives dipropylacetonitrile, which is hydrolyzed into mation of blood clots). valproic acid. See U.S. Patent Nos. 3,325,361 and45 [0088] Like aspirin and indomethacin, ibuprofen is a 4,155,929 and GB Patent Nos. 980279 and 1522450. nonselective COX inhibitor, in that it inhibits two isoforms See also, Henry, T.R., "The History of Divalproex in Clin- of cyclooxygenase, COX-1 and COX-2. The analgesic, ical Neuroscience," Psychopharmacology Bulletin, 37 antipyretic, and anti-inflammatory activity of NSAIDs ap- (Suppl 2): 5-16, 2003. pears to operate mainly through inhibition of COX-2, 50 whereas inhibition of COX-1 would be responsible for Diclofenac unwanted effects on the gastrointestinal tract. However, the role of the individual COX isoforms in the analgesic, [0083] Diclofenac is a nonsteroidal anti-inflammatory anti-inflammatory, and gastric damage effects of NSAIDs drug (NSAID) taken to reduce inflammation and as an is uncertain and different compounds cause different de- analgesic reducing pain in certain conditions. Diclofenac 55 grees of analgesia and gastric damage. is used to treat pain, inflammatory disorders, and dys- [0089] The synthesis of this compound consisted of six menorrhea and is a commonly used NSAID. See Auler steps, started with the Friedel-Crafts acetylation of iso- et al., "Diclofenac Plasma Protein Binding: PK-PD Mod- butylbenzene. Reaction with ethyl chloroacetate

13 23 EP 2 961 399 B1 24

(Darzens reaction) gave the α,β-epoxy ester, which was effects of GHB by altering its blood levels or otherwise. hydrolyzed and decarboxylated to the aldehyde. Reac- Reduction in the GHB level may also provide an unsafe tion with hydroxylamine gave the oxime, which was con- condition due to excessive daytime sleepiness. In each verted to the nitrile, then hydrolyzed to the desired acid. situation, where GHB is increased, decreased or exces- See U.S. Patent No. 3,385,886. 5 sively cleared, those drug-drug interactions need to be [0090] An improved synthesis by BHC required only identified to a health care worker to adjust the dose of three steps. After a similar acetylation, hydrogenation GHB or discontinue the use of the other compound. with Raney nickel gave the alcohol, which underwent pal- [0096] As recited on the product insert for Xyrem®, ladium-catalyzed carbonylation. healthcare providers should caution patients about op- [0091] Valproate, diclofenac, and ibruprofen are10 erating hazardous machinery, including automobiles or monocarboxylate transporter inhibitors. One embodi- airplanes, until they are reasonably certain that GHB ment of the present application is a method to improve does not affect them adversely (e.g., impair judgment, safety by monitoring the combination of these com- thinking, or motor skills). Patients should not engage in pounds with GHB. hazardous occupations or activities requiring complete 15 mental alertness or motor coordination, such as operat- Monocarboxylate transporters ing machinery or a motor vehicle or flying an airplane, for at least 6, 7, 8 or 9 hours after taking the second [0092] Monocarboxylate transporters, or MCTs, con- nightly dose of GHB. stitute a family of proton-linked plasma membrane trans- [0097] In some cases in which diclofenac or valproate porters that carry molecules having one carboxylate20 is discontinued to avoid an adverse drug interaction, they group (monocarboxylates), such as lactate and pyruvate, are discontinued within at least 3 days prior to or after across biological membranes. See, e.g., Halestrap et al., starting GHB therapy. In various cases diclofenac or val- "TheSLC16 Gene Family-FromMonocarboxylate Trans- proate is discontinued within at least 4 days, or at least porters (MCTs) to Aromatic Amino Acid Transporters and 5 days, or at least 6 days, or at least 7 days (or one week), Beyond," Pflugers Arch., 447 (5): 619-628, 2004. 25 or at least 8 days, or at least 9 days, or at least 10 days, [0093] MCTs are a series of transporters which move or at least 11 days, or at least 12 days, or at least 13 chemicals in body tissues, such as kidneys, blood/brain days, or at least 14 days (or two weeks), or at least 15 barrier, intestines, etc. They can transport chemical com- days, or at least 16 days, or at least 17 days, or at least pounds back from urine to create a higher concentration 18 days, or at least 19 days, or at least 20 days, or at in the blood than the urine. They can be used to treat an 30 least 21 days (or three weeks) prior to or after starting overdose or to prevent excretion of a compound. They GHB therapy. In some cases, the diclofenac or valproate can also be used to prevent absorption or transport into is discontinued no later than 2 weeks or 1 week before the brain or gut, or excretion via the urine. Exemplary starting GHB therapy. MCT inhibitors include valproate, diclofenac, and ibubro- [0098] In some embodiments, a method of optimizing fen. 35 GHB therapy when valproate is provided comprises ti- trating the dosage of GHB administered to a patient Concomitant Administration of GHB and Drug-Drug In- downward relative to a previously administered dosage teractions in the patient, so the dose does not result in an increased exposure to GHB. In some cases, a method of optimizing [0094] The concomitant administration of MCT inhibi- 40 GHB therapy when diclofenac is provided comprises ti- tors, such as either valproate, diclofenac, or ibuprofen trating the dosage of GHB administered to a patient up- with GHB can affect GHB levels or activity and alter the ward relative to a previously administered dosage in the GHB safety and efficacy profile to create an unsafe con- patient, so the dose results in an effective exposure to dition. For example, valproate can increase or prolong GHB. Thus, the present invention includes a salt of gam- GHB effects and diclofenac can reduce or shorten GHB 45 ma-hydroxybutyrate (GBH) for use in a method for treat- effects. For example, if the effects are increased, then ing a patient who is suffering from narcolepsy, wherein there could be an increase of adverse events associated said patient is also being treated with valproate, compris- with too much GHB. Also, the effect of GHB may be pro- ing: administering to the patient a daily dose of a GHB longed to cause side effects, such as excessive daytime salt wherein said daily dose is administered at an amount sleepiness (EDS), to last into the daytime. Prolongation 50 sufficient to reduce or eliminate such of the effect would counter the purpose for providing the [0099] Further disclosed herein is a method for treating GHB and could create an unsafe situation for patients a patient who is suffering from excessive daytime sleep- who wish to be alert and who may be engaged in other- iness, cataplexy, sleep paralysis, apnea, narcolepsy, wise dangerous activity. This concomitant administration sleep time disturbances, hypnagogic hallucinations, can transform an otherwise safe dose of GHB into one 55 sleep arousal, insomnia, and nocturnal myoclonus with with safety concerns. It is a health risk to patients and a a salt of gamma-hydroxybutyrate (GHB), wherein said medical challenge to health care workers. patient is also being treated with valproate or diclofenac, [0095] The drug-drug interaction could also reduce the comprising: administering to the patient a daily dose of

14 25 EP 2 961 399 B1 26 a GHB salt wherein said daily dose is administered at an percentages, or both. Furthermore, the absolute amount amount sufficient to reduce or eliminate such additive of GHB per dose or per day may be increased at least effects. 0.5g, 1g, 1.5g, 2.0g, 2.5g, 3.0g, 3.5g, or 4g. An exemplary [0100] In one embodiment of the present invention, a decrease in an adult dose would be to increase the min- reduced amountof GHB isadministered toa patient when 5 imum dose to 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5g/day and so concomitantly administered with valproate. In certain on. An increase in the maximum dose would be at least cases, an increased amount of GHB is administered to 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14g/day and a patient when concomitantly administered with di- so on. clofenac. [0103] Disclosed herein is, a package or kit comprising [0101] When valproate is concomitantly administered 10 GHB, optionally in a container, and a package insert, with GHB, The amount of GHB can be reduced at least package label, instructions or other labelling including 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, any one, two, three or more of the following information or 50% of the normal dose of GHB. For example, if the or recommendations: (a) use of diclofenac or valproate normal dose is 9g/day, then a dose that is adjusted to should be avoided or discontinued, (b) concomitant ad- reduce the normal dose by 15% is 7.65g/day. The GHB 15 ministration of GHB with drugs that are MCT inhibitors, dose reduction may be taken for one or multiple GHB such as diclofenac or valproate can alter the therapeutic dosings. For example, GHB may be administered in two effect or adverse reaction profile of GHB, (c) concomitant doses per night for narcolepsy. A typical adult range of administration of GHB and valproate resulted in an in- doses for GHB are between 4.5 or 6g as a minimum and crease in exposure to GHB, (d) concomitant administra- 8 or 10g/day as a maximum divided into two doses. The 20 tion of GHB and diclofenac resulted in a decrease in ex- dose recommended on the package insert and approved posure to GHB, and/or (e) MCT inhibitors should be used by the FDA is between 4.5 and 9.0 g/day. Typical exem- with caution inpatients receiving GHB due to thepotential plary paediatric daily doses of GHB are between 1g and for increased GHB clearance. 6g/day for pediatric patients aged 0-6 years. Typical ex- [0104] Alternatively, diclofenac can be administered to emplary paediatric daily doses of GHB are between 1g 25 counteract the effects of GHB toxicity using a reverse of and 9g/day for pediatric patients aged 7-17 years. How- the numerical relationships above. Similarly, valproate ever, these ranges are not absolute and can be increased can be used to increase the effects of GHB in patients or decreased by 1-2 grams in either direction. One dose that cannot take higher amounts of GHB. In this regard, is typically administered prior to bed (night time sleep) the present disclosure includes methods for reducing the and another dose administered 1-2 hours later. See the 30 effects of GHB toxicity in a patient in need thereof, com- Xyrem® package insert (Xyrem® is a registered trade- prising administering to said patient an effective amount mark of Jazz Pharmaceuticals plc or its subsidiaries.). of diclofenac such that potential toxic effects of GHB are Either or both of the multiple doses may be reduced to reduced. The present invention also includes methods present a safer administration profile. For example, the for potentiating the beneficial effects of GHB in a patient first dose may be reduced by the numbers referred to 35 in need thereof comprising concomitantly administering above or the second may be reduced by the same per- to said patient an effective amount of valproate such that centages, or both. Furthermore, the absolute amount of the beneficial effects of GHB are increased. GHB per dose or per day may be reduced at least 0.5g, [0105] The examples below, which show drug interac- 1g, 1.5g, 2.0g, 2.5g, 3.0g, 3.5g, or 4g. An exemplary de- tion studies in healthy adults, demonstrated those in- crease in an adult dose would be to reduce the maximum 40 stances, test conditions or metrics which showed a dis- dose to less than 8.5, 8, 7.5, 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, tinction between GHB and either of the test compounds, 3 g/day and so on. The minimum dose will be reduced diclofenac, valproate, or ibuprofen. Additionally, drug in- accordingly to 4, 3.5, 3, 2.5, 2, and so on. teraction studies in healthy adults demonstrated phar- [0102] Diclofenac may dampen or delay the effect of macokinetic or clinically significant pharmacodynamic in- GHB upon a patient during concomitant administration. 45 teractions between GHB and diclofenac or valproate. In some cases, it may be useful to increase the amount of GHB that is administered to the patient. For example, REFERENCE EXAMPLE 1 GHB may be increased at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% of the normal dose [0106] This study was designed to compare Pharma- of GHB. For example, if the normal dose is 10g/day, then 50 cokinetic (PK) and Pharmacodynamic (PD) endpoints of a dose that is adjusted to increase the normal dose by Xyrem® sodium oxysorbate (GHB) with and without con- 15% is 11.5g/day. The GHB dose increase may be taken comitant administration of diclofenac. A crossover design for one or multiple GHB dosings. For example, GHB may was employed to allow within-subject comparisons of the be administered in two doses per night for narcolepsy. PK and PD of Xyrem® dosed alone and in combination Either, or both, of the multiple doses may be increased 55 with diclofenac. The PK and PD effects of Xyrem® upon to present a safer administration profile. For example, those of diclofenac were also studied. the first dose may be increased by the numbers referred [0107] The PD parameters included a selection of au- to above or the second may be increased by the same tomated tests of attention, information processing, work-

15 27 EP 2 961 399 B1 28 ing memory and skilled coordination from the CDR Sys- Results tem. (Rapeport et al, 1996ab; Williams et al, 1996). (Wesnes et al, 1997). (Wesnes et al, 2000) (Modi et al, [0113] Power of attention-On this measure of focussed 2007). attention and information processing Xyrem® when co- 5 dosed with diclofenac produced significantly less impair- Methods ment than Xyrem® alone at 0.5 h; while the smaller im- pairments with the combination narrowly missed signifi- [0108] This was a Phase 1, randomized, double-blind, cance at 1 and 4.5 h. Xyrem® when co-dosed with di- placebo-controlled, three-period, crossover study in clofenac also resulted in impairments at two timepoints healthy subjects. 24 subjects were recruited to ensure 10 compared to diclofenac alone which at 6.5 h was signif- that 18 completed the study. Following Screening and icant and a trend at 8 h.See Figure 1 which shows Baseline procedures, eligible subjects were entered into Change from Baseline Figure (LSmean with 95% CI) for the study and received one of the following treatments Power of Attention (ms) (PD Completer Population). per period, in randomized order: [0114] Digit Vigilance Accuracy-On this measure of fo- [0109] Diclofenac placebo administered as one cap- 15 cussed attention Xyrem® when co-dosed with diclofenac sule qid (doses separated by 4 hours during the day, eg, produced significantly less impairment than Xyrem® approximately 8 am, 12 pm, 4 pm, and 8 pm) for 2 days alone at 1 and 2.5 h. See Figure 2 which shows Change before concomitant administration day. On concomitant from Baseline Figure (LSmean with 95% CI) for Digit Vig- administration day, one diclofenac placebo capsule ad- ilance Accuracy (%) (PD Completer Population). ministered at -1 h and 3 h, and 3 g of Xyrem® adminis- 20 [0115] Digit Vigilance Mean Reaction Time- On this tered at 0 h and 4 h. measure of focussed attention Xyrem® when co-dosed [0110] Diclofenac administered as 50 mg immediate- with diclofenac produced significantly less impairment release (IR) tablet (overencapsulated) qid (doses sepa- than Xyrem® alone at 1 and 2.5 h. See Figure 3 which rated by 4 hours during the day, eg, approximately 8 am, shows Change from Baseline Figure (LSmean with 95% 12 pm, 4 pm, and 8 pm) for 2 days before concomitant 25 CI) for Digit Vigilance Mean Reaction Time (ms) (PD administration day. On concomitant administration day, Completer Population). 50 mg diclofenac administered at -1 h and 3 h and 3 g [0116] Choice Reaction Time Mean-Impairments to of Xyrem® administered at 0 h and 4 h. this measure of attention and information processing [0111] Diclofenac administered as 50 mg IR tablet (ov- were significantly smaller than with Xyrem® alone when erencapsulated) qid (doses separated by 4 hours during 30 co-dosed with diclofenac during the hour following the the day, eg, approximately 8 am, 12 pm, 4 pm, and 8 pm) first dose of Xyrem®. See Figure 4 which shows Change for 2 days before concomitant administration day. On from Baseline Figure (LSmean with 95% CI) for Choice concomitantadministration day,50 mg diclofenac admin- Reaction Time Mean (ms) (PD Completer Population). istered at -1 h and 3 h and Xyrem® placebo (volume [0117] While diclofenac alone had no effect on sleep- equivalent to 3 g of Xyrem® oral solution) administered 35 iness or cognitive function, when co-dosed with Xyrem® at 0 h and 4 h. it significantly reduced the effects of the compound on [0112] Subjects were randomized to one of the above Power of Attention and two of the contributing scores, treatments on Day 1, crossed over to another treatment simple and choice reaction time; these effects being seen on Day 6, and crossed over again to the remaining treat- during the hour after the first dose of Xyrem®. On the ment on Day 11 (Table 1). Subjects were dosed in groups 40 other hand, there was no evidence on any measure of of up to 12. A 2-day washout period followed each of the greater cognitive impairment or sleepiness when the two treatment periods. The treatments were as follows: A = compounds were co-dosed. Diclofenac placebo (qid 4 h apart on the 1st and 2nd day [0118] The extent of the reductions in the impairments and 2 doses on the 3rd day of the period) + Xyrem® two to the ability to focus attention and efficiently process 3 g doses 4 h apart on the 3rd day of the period. B =45 information were quite notable, and likely to be of clinical Diclofenac (50 mg qid 4 h apart on the 1st and 2nd day relevance. It is interesting that protective effect of di- and 2 doses on the 3rd day of the period) + Xyrem® two clofenac was not seen on the subjects ratings of alert- 3 g doses 4 h apart on the 3rd day of the period. C = ness, such a dissociation having been seen previously Diclofenac (50 mg qid 4 h apart on the 1st and 2nd day with haloperidol in healthy elderly volunteers (Beuzan et and 2 doses on the 3rd day of the period) + Xyrem®50 al., 1991). placebo two doses 4 h apart on the 3rd day of the period. [0119] In conclusion, evidence of an interaction was PD parameters include the following: Cognitive Drug Re- seen in this study over the hour following the first dose search (CDR) System tasks: Karolinska Sleepiness of Xyrem® on the study days, the impairments being no- Scale (KSS), Simple Reaction Time (SRT), Digit Vigi- tably smaller when diclofenac was co-dosed with lance (DV), Choice Reaction Time (CRT), Tracking and 55 Xyrem®. There was no interaction however on the feel- Numeric Working Memory (NWM). ings of sleepiness in the subjects.

16 29 EP 2 961 399 B1 30

EXAMPLE 2 acid concentrations were collected before the divalproex sodium dose (to determine trough concentration for as- [0120] This study is designed to compare the pharma- sessment of steady state) on Days 13 and 14. Safety cokinetic (PK) and pharmacodynamic (PD) endpoints of was monitored at specified timepoints as well as through- Xyrem® with and without co-administration of divalproex 5 out the period. sodium extended-release tablets. The crossover design allows within-subject comparisons of the PK and PD of Periods 4 and 5: Xyrem® dosed alone and in combination with divalproex sodium extended-release tablets. PD parameters in- [0126] Subjects continued taking 1250 mg divalproex clude the following: Cognitive Drug Research (CDR) Sys- 10 sodium extended-release tablets at approximately 8 AM tem tasks: Karolinska Sleepiness Scale (KSS), Simple on Days 15 through 18. Subjects were also randomized Reaction Time (SRT), Digit Vigilance (DV), Choice Re- to receive two 3 g doses of Xyrem® or Xyrem® placebo action Time (CRT), Tracking and Numeric Working Mem- in a crossover fashion at approximately 9 am (first dose) ory (NWM). and 1 pm (second dose) on Days 15 and 18. The first [0121] The objectives of this study were to evaluate 15 dose of Xyrem® or Xyrem® placebo was taken approx- the PK and PD of Xyrem® co-administered with dival- imately 1 hour after dosing with divalproex sodium ex- proex sodium extended-release tablets and to evaluate tended-release tablets, and the second dose of Xyrem® and compare the safety and tolerability of Xyrem® with or Xyrem® placebo was taken 4 hours after the first and without co-administration of divalproex sodium ex- Xyrem®/Xyrem® placebo dose. tended-release tablets. 20 [0127] Blood samples (4 mL) to measure plasma so- [0122] This was a Phase 1, randomized, double-blind, dium oxybate concentrations were collected at pre placebo-controlled, five-period, crossover study in Xyrem®/Xyrem® placebo dose and at specified time- healthy male subjects. The study was conducted in ap- points after the first Xyrem®or Xyrem® placebo dose on proximately 24 healthy subjects to ensure completion of Days 15 and 18. Blood samples (4 mL) to measure plas- 16 subjects. Following Screening and Baseline proce- 25 ma valproic acid concentrations were collected pre dival- dures, eligible subjects were randomized to receive proex sodium dose and at specified timepoints after the Xyrem® and Xyrem® placebo in a crossover fashion in dose of divalproex sodium extended-release tablets on Periods 1 and 2; were dosed with divalproex sodium ex- Day 15 and 18. tended-release tablets for 10 consecutive days in Period [0128] The PD battery was administered on Day 15 3; and while continuing to take divalproex sodium extend- 30 and 18, and safety was monitored at specified times on ed-release tablets, were randomized to receive Xyrem® Days 15 and 18 as well as throughout the periods. and Xyrem® placebo in a crossover fashion in Periods [0129] The treatments were as follows: A = Xyrem®, 4 and 5 (Table 1). two 3 g doses, 4 hours apart at approximately 9 AM (1 st dose) and 1 PM (2nd dose); B = Xyrem® placebo, two Periods 1 and 2: 35 doses, 4 hours apart; and C = Divalproex sodium 1250 mg, once a day at approximately 8 AM. [0123] Subjects were randomized to receive two 3 g doses of Xyrem® or Xyrem® placebo 4 hours apart in a Results crossover fashion at approximately 9 AM (first dose) and 1 PM (second dose) on Days 1 and 3. PK and PD pa- 40 [0130] The results below show the tests in which GHB rameters were evaluated during the 24 hours postdose. administration was affected by concomitant administra- [0124] Blood samples (4 mL) for sodium oxybate con- tion of any of three MCT inhibitors, such as valproate, centrations were collected at predose and at specified diclofenac, and ibubrofen. time-points up to 12 hours after the first dose of Xyrem® or Xyrem® placebo on Days 1 and 3. A PD Battery in- 45 Continuity of attention cluding the Karolinska Sleepiness Scale, Simple Reac- tion Time task, Digit Vigilance task, Choice Reaction [0131] Xyrem® and divalproex sodium together (A+C) Time task, Tracking task, and Numeric Working Memory when compared to Xyrem® alone (A) showed a slightly task was administered at planned timepoints up to X delayed recovery for the combination at 4 hours and 8 hours after first dose (X hours after second dose), and 50 hours. See Figure 5 which shows Change from Baseline safety were monitored at specified timepoints on Days 1 Figure (LSmean with 95% CI) for Continuity of Attention and 3 as well as throughout the periods. (#) (PD Population).

Period 3: Simple Reaction Time Mean 55 [0125] All subjects received divalproex sodium extend- [0132] At 1 hour and 4 hours, Xyrem® and divalproex ed-release tablets 1250 mg at approximately 8 AM on sodium together produced statistically reliably greater Days 5 through 14. Blood samples (4 mL) for valproic impairments than Xyrem® alone. See Figure 6, which

17 31 EP 2 961 399 B1 32 shows Change from Baseline Figure (LSmean with 95% sleepiness. There were occasions when co-administra- CI)for SimpleReaction TimeMean (ms) (PD Population). tion of Xyrem® and divalproex sodium produced greater deficits than Xyrem® alone. Further the combination also Digit Vigilance Accuracy produced more consistent impairments when compared 5 with divalproex sodium alone, than did Xyrem® when [0133] At 2.5 and 4 hours Xyrem® and divalproex so- compared to its placebo. Thus this study has found evi- dium together were statistically reliably different greater dence that co-administration of Xyrem® and divalproex impairment to Xyrem® alone. See Figure 7, which shows produces greater impairments to cognitive function and Change from Baseline Figure (LSmean with 95% CI) for sleepiness than were seen with Xyrem® alone. Digit Vigilance Accuracy (%) (PD Population). 10 REFERENCE EXAMPLE 3 Tracking Distance from Target [0141] The effects of Ibuprofen were evaluated when [0134] Xyrem® and divalproex sodium together (A+C) combined with Xyrem® in a manner similar to the above. when compared to Xyrem® alone (A) showed a statisti- 15 No differences were seen using the metrics above for cally significant difference by a slightly delayed recovery Karolinska Sleepiness Scale (KSS), and the following for the combination at 4 and 8 hours. See Figure 8 which CDR System tasks: Simple Reaction Time, Digit Vigi- shows the Change from Baseline Figure (LSmean with lance, Choice Reaction Time, Tracking and Numeric 95% CI) for Tracking Distance from Target (mm) (PD Working Memory. However, it was observed that renal Population). 20 excretion of Xyrem® doubled upon concomitant admin- istration of Ibuprofen and Xyrem®. Numeric Working Memory Sensitivity Index

[0135] Xyrem® and divalproex sodium together (A+C) Claims when compared to Xyrem® alone (A) showed a differ- 25 ence at 4.5 through 8 hours. See Figure 9, which shows 1. Gamma-hydroxybutyrate (GHB) or a salt thereof for the Change from Baseline Figure (LSmean with 95% CI) use in a method of treating narcolepsy in a patient, for Numeric Working Memory Sensitivity Index (#) (PD wherein said patient is also taking or will be taking Population). divalproex sodium, 30 the method comprising administering GHB or a salt Numeric Working Memory Mean Reaction Time thereof to the patient in a dose that is reduced by 10% to 40% to compensate for the effect caused by [0136] Xyrem® and divalproex sodium together (A+C) the divalproex sodium, when compared to Xyrem® alone (A) showed statistically wherein the dose of GHB or salt thereof when the significant differences at 2.5, 5 and 8 hours when the35 patient is not taking the divalproex sodium is be- combination produced greater impairment. See Figure tween 4.5 g to 9.0 g/day. 10, which shows the Change from Baseline Figure (LS- mean with 95% CI) for Numeric Working Memory Mean 2. The GHB or salt thereof for use of claim 1, wherein Reaction Time (ms) (PD Population). the GHB or salt thereof is administered in a dose that [0137] In addition, it was observed that renal excretion 40 is reduced by 15% to 25% to compensate for the of GHB increase 30% upon co-administration of Val- effect caused by the divalproex sodium. proate. [0138] We also found PK changes which were consist- 3. The GHB or salt thereof for use of claim 1, wherein ent with the inhibition of GHB dehydrogenase. This effect the GHB or salt thereof is administered in a dose that will increase the exposure of GHB to the subject and45 is reduced by 20% to compensate for the effect increase Cmax and AUC about 15%. caused by the divalproex sodium. [0139] The combination of Xyrem® dosed with dival- proex sodium was compared to divalproex sodium alone, 4. The GHB or salt thereof for use of any one of claims more consistent statistically significant impairments over 1-3 wherein the GHB or salt thereof is prepared as time were seen with the combination, than when Xyrem® 50 a formulation which has a concentration of between was compared to its placebo, indicating that the effects 350 - 750 mg/ml. of co-administration, when they appeared, were in the direction of increased impairments. 5. The GHB or salt thereof for use of any one of claims [0140] As has been seen previously, Xyrem® induces 1-3 wherein the GHB or salt thereof is prepared as sleepiness and produces impairments to attention, work- 55 a formulation which has a concentration of between ing memory and performance on a tracking task in 450 - 550 mg/ml. healthy volunteers. Divalproex sodium alone showed no consistent or notable effects on cognitive function or 6. The GHB or salt thereof for use of any one of claims

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1-5 wherein the GHB or salt thereof is prepared as zwischen 6 - 10 aufweist. a formulation which has a pH between 6 - 10. 7. GHB oder Salz davon zur Verwendung nach einem 7. The GHB or salt thereof for use of any one of claims der Ansprüche 1-5, wobei das GHB oder Salz davon 1-5 wherein the GHB or salt thereof is prepared as 5 als eine Formulierung zubereitet wird, die einen pH a formulation which has a pH between 6.5 - 8. zwischen 6,5 - 8 aufweist.

8. The GHB or salt thereof for use of any one of claims 8. GHB oder Salz davon zur Verwendung nach einem 1-7 wherein the salt comprises a single salt or a mix- der Ansprüche 1-7, wobei das Salz ein einzelnes ture of salts of GHB selected from a sodium salt of 10 Salz oder ein Gemisch von Salzen von GHB um- gamma-hydroxybutyrate (Na•GHB), a potassium fasst, ausgewählt aus einem Natriumsalz von Gam- salt of gamma-hydroxybutyrate (K•GHB), a magne- ma-Hydroxybutyrat (Na•GHB), einem Kaliumsalz

sium salt of gamma-hydroxybutyrate (Mg•(GHB)2), von Gamma-Hydroxybutyrat (K•GHB), einem Mag- and a calcium salt of gamma-hydroxybutyrate nesiumsalz von Gamma-Hydroxybutyrat 15 (Ca•(GHB)2). (Mg•(GHB)2) und einem Calciumsalz von Gamma- Hydroxybutyrat (Ca•(GHB)2).

Patentansprüche Revendications 1. Gamma-Hydroxybutyrat (GHB) oder ein Salz davon 20 zur Verwendung in einem Verfahren zum Behandeln 1. Gamma-hydroxybutyrate (GHB) ou un sel de celui- von Narkolepsie bei einem Patienten, wobei der Pa- ci pour une utilisation dans un procédé de traitement tient auch Divalproexnatrium einnimmt oder einneh- de la narcolepsie chez un patient, dans lequel ledit men wird, patientprend égalementou va prendre du divalproex wobei das Verfahren Verabreichen von GHB oder 25 sodique, einem Salz davon an den Patienten in einer Dosis le procédé comprenant l’administration de GHB ou umfasst, die zum Kompensieren der durch das Di- un sel de celui-ci au patient en une dose qui est ré- valproexnatrium verursachten Wirkung um 10% bis duite de 10 % à 40 % pour compenser l’effet causé 40% vermindert ist, par le divalproex sodique, wobei die Dosis von GHB oder dem Salz davon,30 dans lequel la dose de GHB ou de sel de celui-ci wenn der Patient das Divalproexnatrium nicht ein- lorsque le patient ne prend pas le divalproex sodique nimmt, zwischen 4,5 g bis 9,0 g/Tag liegt. se situe entre 4,5 g et 9,0 g/jour.

2. GHB oder Salz davon zur Verwendung nach An- 2. GHB ou un sel de celui-ci pour l’utilisation selon la spruch 1, wobei das GHB oder Salz davon in einer 35 revendication 1, dans lequel le GHB ou un sel de Dosis verabreicht wird, die zum Kompensieren der celui-ci est administré en une dose qui est réduite durch das Divalproexnatrium verursachten Wirkung de 15 % à 25 % pour compenser l’effet provoqué par um 15% bis 25% vermindert ist. le divalproex sodique.

3. GHB oder Salz davon zur Verwendung nach An- 40 3. GHB ou un sel de celui-ci pour l’utilisation selon la spruch 1, wobei das GHB oder Salz davon in einer revendication 1, dans lequel le GHB ou un sel de Dosis verabreicht wird, die zum Kompensieren der celui-ci est administré en une dose qui est réduite durch das Divalproexnatrium verursachten Wirkung de 20 % pour compenser l’effet provoqué par le di- um 20% vermindert ist. valproex sodique. 45 4. GHB oder Salz davon zur Verwendung nach einem 4. GHB ou un sel de celui-ci pour l’utilisation selon l’une der Ansprüche 1-3, wobei das GHB oder Salz davon quelconque des revendications 1 à 3, dans lequel le als eine Formulierung zubereitet wird, die eine Kon- GHB ou un sel de celui-ci est préparé en une formu- zentration von zwischen 350 - 750 mg/ml aufweist. lation ayant une concentration comprise entre 350 50 et 750 mg/ml. 5. GHB oder Salz davon zur Verwendung nach einem der Ansprüche 1-3, wobei das GHB oder Salz davon 5. GHB ou un sel de celui-ci pour l’utilisation selon l’une als eine Formulierung zubereitet wird, die eine Kon- quelconque des revendications 1 à 3 dans lequel le zentration von zwischen 450 - 550 mg/ml aufweist. GHB ou un sel de celui-ci est préparé en une formu- 55 lation ayant une concentration comprise entre 450 6. GHB oder Salz davon zur Verwendung nach einem et 550 mg/ml. der Ansprüche 1-5, wobei das GHB oder Salz davon als eine Formulierung zubereitet wird, die einen pH 6. GHB ou un sel de celui-ci pour l’utilisation selon l’une

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quelconque des revendications 1 à 5, dans lequel le GHB ou un sel de celui-ci est préparé en une formu- lation qui a un pH compris entre 6 et 10.

7. GHB ou un sel de celui-ci pour l’utilisation selon l’une 5 quelconque des revendications 1 à 5, dans lequel le GHB ou un sel de celui-ci est préparé en une formu- lation qui a un pH compris entre 6,5 et 8.

8. GHB ou un sel de celui-ci pour l’utilisation selon l’une 10 quelconque des revendications 1 à 7, dans lequel le sel comprend un sel unique ou un mélange de sels de GHB choisi(s) parmi un sel de sodium de gamma- hydroxybutyrate (Na•GHB), un sel de potassium de gamma-hydroxybutyrate(K•GHB), un selde magné- 15 sium de gamma-hydroxybutyrate (Mg•(GHB) 2) et un sel de calcium de gamma-hydroxybutyrate

(Ca•(GHB)2).

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

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