(12) United States Patent
`Aantaa et al.
`
`I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US006716867Bl
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 6, 716,867 Bl
`Apr. 6, 2004
`
`(54) USE OF OEXMEDETOMlDlNE FOR ICU
`SEDATION
`
`(75)
`
`lnveotors: Riku Aantaa, Turku (FI); Romeo
`Bachand, Mu.nde lain, IL (US); Esa
`Heinonen, Turku (FI)
`
`(73) As.5ignee: Orion Corporation, Espoo (FI)
`
`(*) Notice:
`
`Subject to any disclaimer, the term oftbis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.:
`
`09/647,364
`
`(22) PCT Filed:
`
`Mar. 31, 1999
`
`(86) PCT No.:
`
`PC'f/ FI99/00266
`
`§ 371 ( c)(J ),
`(2), ( 4) Date: Dec. 6, 2000
`
`(87) PCr Pub. No.: W099/49854
`
`PCT Pub. Date: Oct. 7, 1999
`
`Related U.S. Application Data
`(60) Provisional application No. 60/080,287, filed on Apr. l ,
`1998, and provisiona l application No. 60/ 110.944, filed on
`Dec. 4, 1998.
`
`Int. C l.7
`. .... . . . ... ...... . ................. .... . . . .... A61K 31/415
`(51)
`(52) U.S. Cl . ....................................................... 514/396
`(58) Field of Search .......................................... 514/396
`
`(56)
`
`References C ited
`
`U.S. P.AJ'ENT DOCUMENTS
`
`4,910,214 A
`
`3/ 1990 Karjalainen ct al.
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`
`0 413 487 Al
`0 424 059 Al
`
`2/ 1991
`4/ 1991
`
`OTHER PUBLICATIONS
`
`CA 130:231765, Caudwell et al, Int. Congr. Symp. Ser.-R.
`Soc. Med. l 998, 221, 73-8 L, abstract.*
`CACA130:246080, Mantz et al, lot. Congr. Symp. Ser.-R.
`Soc. Med. 1009, 221, 23-29, abstract.*
`EMBASE AN 1997328166, Celorrio et al, Actualizaciones
`co Aoestesiologia y Reaoimacioo, 1997, 7/3, 105-125,
`abstract.*
`Bischoff P. et al. : ·'[Alpha2-Agonists in Anaesthesia and
`Intensive-Care Medicine]. Alpba2-Agooisten in Anasthesic
`und
`lntensivmedizin." Anastbesiologie Intens ivmedizia
`Notfallmedizin Scbmerztberapie, (1993) 28/1 (2-12).
`Crippen O. et al.: "Stress, Agitation, and Brain railure in
`Critical Care Medicine. " Critical Care Nursing Quatcrly,
`(1992) 15/2 (52-74).
`V. Hooper et al., "Sedation in the Critically ill Patient,"
`Critical Care Nursing Clinics of North America, vol. 9, pp.
`395-410 (1997).
`M. Pepperman, "Benzodiazepine sedation and the use of
`benzodiazepine antagonists in intensive care," Intensive
`Therapy and Clinical Monitoring, pp. 5iH>2 (Feb. 1989).
`Abstract of Belleville JP et al., "Effects of intravenous
`dexmedetomicline in humans. I. Sedaiion, ventilation, and
`
`Anesthesiology
`
`1992
`
`Dec.,
`
`rate",
`metabolic
`77(6):1125-1133.
`Abstract of Jaakola ML, "Dexmedetornicline premedication
`before intravenous regional anesthesia in minor outpatieot
`hand surgery", J Clin Aoesth 1994 May-Ju.a., 6(3):204-211.
`Abstract of Werner C., "Effects of analgesia and sedation on
`ccrcbrova5cular circulation, cerebra I blood volume, cerebral
`metabolism and inlracranial pressure", Anaesthesisl 1995
`Dec., 44 Suppl 3:S566-572.
`Abstract of VuUicmoz Y., Sbeo H., Virag L., ""Alpha-2
`adreooceptor
`agooists
`decrease
`cyclic
`guanosine
`3',5'-mooophospbate in the mouse brain", Aoestbesiology
`1996 Sep., 85(3):544-550.
`Abstract of Ip Yam PC, Forbes A., Kox WJ., "Clonidine in
`the treatment of alcohol withdrawal in the intensive care
`unit", Br J Anaesth 1992 Jan., 68(1):106-108.
`Jean Mamz and tbe French Dexmedetomidioe Phase Tll
`Study Group, '·Phase m Study On Dexmedetomidine Used
`For Postoperative Sedation Of Patients Requiring Mechani(cid:173)
`cal Ventilation For Less Thao 24 Hours: The French Expe(cid:173)
`rience'', M.E.J. Anesth 16 (6):597-606, 2002.
`Mohamad Said Takrouri et al., ''Dcxmedetomidioe la Inten(cid:173)
`sive Care Unit: A Study OfHemodynamic Changes", M.E.J.
`Aoesth 16 (6): 587-595, 2002.
`R. M. Venn et al., "Pharmacokinetics of dexmedetomidioe
`infusions for sedation of postoperative patients requiring
`intensive
`care", British
`Journal
`of Anacsihesia
`88(5):669-75, 2002.
`Mervyn Maze, "Sedation in the intensive care unit", lnter(cid:173)
`national Congress and Symposium Series No. 221, pp. 3-10,
`1998.
`Elizabeth Caudwell ct al., " Nursing considerations in inten(cid:173)
`sive care uojt sedation and experience with dcxmcdctomi(cid:173)
`dine," Lotemational Congress and Symposium Series No.
`221, pp. 73-81, 1998.
`Celorrio et al Sedacion y relajacion neuromuscular en las
`unidades de cuidados iotensivos, Act. Anest. Reaoim, vol. 7,
`pp. 105- 126 (1997) (witb accompanying translatio n o(
`certain sections).
`Bohrer, ·'Clonidinc as a sedative adj unct in intensive care,"
`Intensive Care Med, vol. 16, pp. 265-266 (1990).
`Doze cl al., ·'Pertussis Toxin and 4-Amioopyridioe Differ(cid:173)
`entially Affect the Hypnotic-Anesthetic Action of Dexme(cid:173)
`detomidine and Peotobarbital," Anesthesiology, vol. 73, pp.
`304-307 (1990).
`C.J. Peden et al., "Editorial II: Dexmedetomidioe-A pow(cid:173)
`erful New Adjunct to Anaesthesia?," Br. J. Anaesth., vol. 68,
`pp. 123-125 (1992).
`M. Tryba el al., "Critical Care Pbarmacotbcrapy," Drugs,
`vol. 45, pp. 338-352 (1993).
`
`* cited by examiner
`
`Primary Examiner-Rebecca Cook
`(74) Auorney, Agent, or Firm-Finnegan, Henderson,
`Farabow, Garrell & Dunner, LLP
`
`(57)
`
`ABSTRACT
`
`Tbc preseot ioveotioo relates to a metbod of sedating a
`patient while in the intensive care unit comprising admin(cid:173)
`istering dexme<letomidine of a pbarmaceutically acceptable
`salt thereof to the patient, wherein tbe patient remains
`arousable and orientated .
`
`12 Claims, 2 Drawing Sheets
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1006 – Page 1
`
`

`

`,....
`to
`......:i
`0-..
`QO
`~O"I
`,....
`......:i
`9'
`~ en
`
`FIG.1
`
`~ -.....
`
`~
`=::'
`'J)
`
`N
`0 .....
`
`~
`~
`N
`~~
`:"'!
`"C
`>
`
`~ = .....
`~ .....
`~
`•
`rJ'J.
`
`e •
`
`ASLEEP, NO RESPONSE
`
`TAP OR LOUD AUDITORY STIMULUS
`ASLEEP, SLUGGISH RESPONSE TO LIGHT GLABELLAR
`
`TAP OR LOUD AUDITORY STIMULUS
`ASLEEP BUT WITH BRISK RESPONSE TO LIGHT GLABELLAR
`
`PATIENT RESPONDS TO COMMANDS
`
`PATIENT CO-OPERATIVE, ORIENTED AND TRANQUIL
`
`PATIENT ANXIOUS, AGITATED OR RESTLESS
`
`6
`
`5
`
`4
`
`3
`
`2
`
`1
`
`LEVEL OF SEDATION ACHIEVED
`
`CLINICAL SCORE
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1006 – Page 2
`
`

`

`U.S. Patent
`
`Apr. 6, 2004
`
`Sheet 2 of 2
`
`US 6,716,867 B1
`
`43S00 SNwYC AGCNLS
`
`0.9
`
`0.8
`
`0.7
`
`Ww
`©
`Oo
`oO
`
`
`,@----@----@----@
`
`
`FIG.2
`
`
`=
`oO
`
`6
`oO
`
`N
`oO
`
`v
`CS
`
`1112
`
`10
`
`AYOOS AVSWVY
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC — Exhibit 1006 — Page 3
`
`

`

`US 6, 716,867 Bl
`
`1
`USE OF DEXMEDETOMIDINE FOR ICU
`SEDATION
`
`This application is a national stage filing of PCT lnler(cid:173)
`national Application No. PCT/F199/00266, fi led on Mar. 31, 5
`1999, which claims priority to U.S. Provisional Application
`Ser. No. 60/080,287, filed on Apr. 1, 1998, and which also
`claims priority to U.S. Provisional Application Ser. No.
`60/ll 0,944, fi led on Dec. 4, I 998.
`
`BACKGROUND OF THE INVENTION
`
`2
`increased infections (propofol), lack of orientation and
`cooperation (midawlam, opioids, and propofol), and poten(cid:173)
`tial abuse (midazolam, opioids, and propofol).
`In addition to the adverse effects of every individual
`sedative agent, tbe combinat ion of these agen ts
`(polypharmacy) may cause adverse effects. For example, the
`agents may act synergistically, which is not predictable; the
`toxicity of the agents may be additive; and the pharmaco(cid:173)
`kinetics of each agent may be altered in an unpredictable
`to fashion. In addi tion, the pos.sibil ity of allergic reactions
`increases with the use of more than one agen t. Furthermore,
`these adverse effe.cts might necessitate tbe use of additional
`agents to trea t tbe adverse effects, and the additional agents
`themselves may bavc adverse effects.
`The preferred level of sedation for critically ill patients
`has changed considerably in recent years. Today, most
`intensive care doctors in the ICU prefer their patients to be
`asleep but easily arousable, and the level of sedation is now
`tailored towards the patient's individual requ irements.
`Muscle relaxan ts arc seldom used duriog intensive care. As
`cardiovascular stability is also desired in this often high-risk
`patieot popu lation, hemodyoamically active agents are ofteo
`needed for adequate hemodynamic control despite suilicieot
`sedation.
`a,.-adreooceptor agooists are being evaluated in general
`anaesthetic practice because of tbeir sympatholy tic,
`sedative, anaesthetic, and hemodynamjc stabilizing effects.
`Tryba et al. discussed the usefulness of e1.z-agonists in
`situations where patients with withdrawal symptoms are
`treated in the ICU (Tryba et al, Drugs 45 (3) (1993),
`338-352). The only etz-agonist mentioned was clonidinc,
`w hich was used in conjunc t io n wi tb opioids,
`benzodiazepines, ketaroioe, and aeuroleptics. Tryba et al.
`35 su<>gest tbat clooidinc may be useful in ICU patients with
`wi7Lidrawal symptoms, but Tryba et al. only briefly mention
`tbe use of clooidine for ICU sedation. Furtbermore, Tryba et
`al. only mention clooidine as a supplement to other sedatives
`for ICU sedation.
`
`According to Tryba et al., clonidine has its limitations in
`sedating critically ill patients mainly because of its unpre(cid:173)
`dictable hemody namic effects, i.e., bradycard ia and
`bypotensioo, so tbat it must be titrated for cacb individual
`45 patient. Long term treatment of critically ill patients wit b
`clooidine bas been reported 10 be associated with such
`rebound effects as tachyca rdia and hypertension.
`
`<l:?-agonists are not presently used by themselves in ICU
`sedation. Further, <l:?-agonists arc not generally used in ICU
`so sedation even in conjunction with other sedative agents.
`Only clonidioe bas been evaluated for use in ICU sedation,
`and tben only in conjunction with opiotds, benzodiazepioes,
`ketamioc, and neuroleptics. Further, administra tion of clooi(cid:173)
`dine as esscotially the sole active agen t or the sole active
`55 agent to a patient in the ICU to achieve sedation has not been
`disclosed lo the best of applicants' knowledge.
`
`An ideal sedative agent for a critically ill patient should
`provide sedation at easily determined doses with ready
`arousability together with hemodynam ic stabilizing effects.
`Further, it should be an anxiolytic and an analgesic, and
`should prevent nausea, vomiting, and shivering. It should
`001 cause respiratory depression. Preferably, an ideal sed.a(cid:173)
`tive agent should be used by itself in ICU sedation to avoid
`the dangers of polypharmacy.
`
`Dexmedetomicline, or ( +)-(S)-4-[l-(2,3-dimelhylphenyl)
`ethyl]-lH-imidazole, has the following formu la:
`
`15
`
`20
`
`25
`
`30
`
`The present invention relates to the use of dexmedetomi(cid:173)
`dine or a pharmaceutically acceptable salt thereof in inten(cid:173)
`sive care unit (ICU) sedation. lo addition to tbe actual
`sedation of a patient in the !CU, the word sedation in the
`ICU context also includes the treatment of conditions that
`affect patient comfort, such as pain and anxiety. Also, the
`word intensive care unit includes any setting that provides
`intensive care. Accordingly, tbe present invention relates to
`a method of sedating a patient while in the ICU by admin(cid:173)
`istering dexruedetom idioe or a pharmaceutically accep table
`salt thereof. Particularly, the present inveotioo relates 10 a
`method of sedating a patient while in the ICU by adminis(cid:173)
`tering dexmedetomidioe or a pharmaceutically acceptable
`salt thereof, wherein dexmedetomidine is essentially the sole
`active agent or the sole active agent administered for this
`purpose. The present invcntioD also relates to the use of
`dexmede tomidine or a pharmaceutically acceptable salt
`thereof in the manufacture of a medicament for intensive
`care unit sedation.
`Patients recovering from an episode of critical illness
`have reported factors they found most distressing during
`their ICU stay (Gibbons, C. R., ct al., Clio. Intensive Care
`4 (1993) 222-225). Tbc mosi consistently unpleasant
`memories are anxiety, pain, fat igue, weakness, th irst, the
`presence of various catheters, and minor procedures sucb as
`physiotherapy. The aim of ICU sedation is to ensure that the
`patient is comfortable, relaxed, and tolerates uncomfortable
`procedures such as placement of iv-lines or other catheters, 40
`but is still arousable.
`Al the moment, there is no universally accepted sedative
`regimen for critically ill patients. Thus, these patients
`receive a variety of drugs during their stay in an !CU, often
`receiving the variety of clnigs concurrently Tbe agents used
`most commonly arc given to achieve patient comfort. Vari(cid:173)
`ous drugs are administered to produce anxiolysis
`(benzodiazepines), amnesia (benzodiazepines), analgesia
`( opioids), antidepression ( antidepressants/benzodiazepines),
`muscle relaxation, sleep (barbiturates, benzodiazepines,
`propofol) and anaesthesia (propofol, barbiturates, vola tile
`anesthetics) for unp leasant procedures. These agents are
`cumulatively called sedatives in tbc context oflCU sedation,
`though sedation also includes the treatment of conditions
`that a[ect patient comfort, such as pain and anxiety, and
`many of the drugs men tioned above are not considered
`sedatives outside the context of ICU sedation.
`The presently available sedative agents are associa ted
`with such adverse effects as prolonged sedation or overse(cid:173)
`dation (propofol and especially poor metabolizers of 60
`midazo!am), prolonged weaning (midazolam), respiratory
`depression (bcozodiazepioes, propofol, and opioids),
`bypoteosion (propofol bolus dosing), bradycardia, ileus or
`decreased gastrointestinal motility (opioids), immunosup(cid:173)
`pression (volat ile anaesthetics and nitrous oxide), renal 65
`function impairment, hepatotoxicity (barbiturates), toler(cid:173)
`ance (midazolam, propofol), byperlipidemia (propofol),
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1006 – Page 4
`
`

`

`US 6, 716,867 Bl
`
`3
`
`4
`In a further aspect, the invention relales to a use of
`dexmedetomidine or a pharmaceutically acceptable salt
`tbereof in ICU sedation.
`A fur1bcr aspect of the invemion relates to a use of
`5 dexmcdetomidi ne or a pharmaceutically acceptable sail
`thereof in tbe manufacture of a medicament for ICU seda(cid:173)
`tion.
`It is to be understood tba t botb tbe foregoing general
`description and the following de tailed description are exem(cid:173)
`lO plary and explana tory only and are aot rcslrictive of the
`invention, as claimed.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 shows the Ramsay Scale that was developed for
`tbe assessment of sedation in experimental subjects. lo tbis
`system, tbe level of wakefulness is scored on a scale of 1-6
`(Ramsey Sedation Score) based on progressive loss of
`responsiveness to sti muli ranging from auditory to deep
`20 painful stimuli.
`FIG. 2 shows the dosing period fro m lhe Phase III
`dexmedctomidine siudy described in Example 3, case No.
`13. Tbe dotted line signifies Ramsay Sedation Score fluc(cid:173)
`tuations and the solid line signifies dexmedetomicliae dose
`25 adjustments.
`
`Dexmedetomidine is described in U.S. Pat. No. 4,910,214
`as an a.2 -rcceptor agonist for general sedation/analgesia and
`the treatment of bypcrlcnsion or anxiety. U.S. Pat. Nos.
`5,344,840 and 5,091,402 discuss dexmede1omidine in perio(cid:173)
`perative and epidural use, respectively. U.S. Pai. No. 5,304,
`569 discusses tbe use of dexmedetomidioe in glaucoma. 15
`U.S. Pat. No. 5,712,301 discusses the use of dexmedetomi(cid:173)
`dioe for preventing neurodegeneration caused by ethanol
`consumption.
`Medetomidine, which is the racemic mixture of dexme(cid:173)
`detomidine and Jevomedetomidine, is known as a selective
`and potent ~-agonist and has been described in U.S. Pat.
`No. 4,544,664 as an antibypertensive agent and in U.S. Pat.
`No. 4,670,455 as a veterinary sedative-analgesic agem.
`In U.S. Pat. Nos. 4,544,664 and 4,910,214, parenteral,
`intravenous, and oral ways of administration are discussed.
`U.S. Pat. No. 4,670,455 describes intramuscular and intra(cid:173)
`venous administration. U.S. Pat. Nos. 5,124,157 and 5,217,
`718 describe a method and device for administering dexmc(cid:173)
`detomidioe through lbe skin. U.S. Pat. No. 5,712,301 states
`that dexmedetomidine can be administered transmucosally. JO
`The U.S. Patents discussed herein are specifically incor(cid:173)
`porated by reference in their entirety.
`
`SUMMARY OF THE INVENTION
`
`35
`
`II has been unexpectedly found that dexmedetomidine or
`a pharmaceutically acceptable salt thereof is an ideal seda(cid:173)
`tive agen t to be admi nistered to a patient in the ICU 10
`achieve patient comfort. Accordingly, an object of the inven(cid:173)
`tion is 10 provide a melbod of sedating a patient while in tbe 40
`ICU that comprises administering dexmedetomidine or a
`pharmaceutically acceptable salt thereof fo r a time sufficien t
`to give the desired therapeutic effect.
`It should be noted thal the met hod fo r sedating a patient
`in the ICU encompasses all of the potential ICU uses of 45
`dexmedelomidine and a pham1aceutically acceptable salt
`thereof, including all potential uses that derive from their
`activ ity as ~-agonists, e.g., tl1cir use as bypotcnsivc agents,
`anxiolytics, analgesics, sedatives, and the like. II should also
`be noted tbat 1bc word intensive care unit encompasses any 50
`setting tbat provides intensive care.
`Additional objects and advantages oft be invemion will be
`set forth in part in tbe description wbich follows, and in part
`will be obviolL'> from the description, or may be learned by
`practice of the invention. The objects and advantages o( tbe 55
`invention will be realized and allaincd by means of the
`elements and combinations particularly pointed out in the
`appended claims.
`lo one aspect, lhe invention relates to a method of
`sedating a patient wbile in tbe ICU by administering dexme- 60
`detomidine or a pbarmaceutically acceptable salt thereof,
`wherein dexmedetomicline is essentially lhe sole active
`agent or the sole active agen t. The method is premised on lbe
`discovery lhal essentially only dexinedetomidine or a phar(cid:173)
`maceutically acceptable salt thereof need to be administered 65
`to a patient in tbe ICU to achieve seda1ion and pa1ient
`comfort. No additional sedative agents are rcqufred.
`
`DETAILED DESCRIPTION OF 11-IE
`INVENTION
`
`Applicants have surprisingly discovered that clexmedeto(cid:173)
`midioe or a pbarmaceuticaUy acceptable salt thereof is an
`ideal agent to be administered to a patient in the ICU for
`achieving sedation and patient comfort. Particularly, it bas
`been found that dexmedetomidiae or a pharmaceutically
`acceptable sail thereof can be essentially the sole active
`agent or tbc sole active agent administered to a patient in tbe
`ICU in order 10 sedate the patient.
`The method for sedating a patient in the ICU encompasses
`all of tbe potential ICU uses of dexmedetomidioe and a
`pharmaceutically acceptable salt thereof, includ ing all
`potential uses 1ha1 derive from their activi ty as ~-agooists,
`e.g., their use as bypotensivc agents, anxioly tics, analgesics,
`sedatives, and the like.
`The word intensive care uni t encompasses any setting tha t
`provides intensive care. Tbe word patient is intended to
`include botb human and animal patients. Preferably, tbe
`animal patient is a mammal, especially a clog, a cat, a horse,
`or a cow.
`The quality of the sedation in the ICU achieved by
`administering dexmedctomidine is unique. Patients sedated
`by dexmeclctomidine or a pbarmaceuticaUy acceptable sal t
`thereof are arousable aod oriented, which makes tbc treat(cid:173)
`ment of tbe patient easier. Tbe patients can be awakened and
`they are able to respond to questions. They are aware, but not
`anxious, and tolerate an endotracheal tube well. Shou Id a
`deeper level of sedation or more sedation be required or
`desired, an increase in dexmede tomidine dose smoothly
`trans its the patient into a deeper level of sedation. Dcxme(cid:173)
`cletomidine does oot have adverse effects associated witb
`other sedative agents, sucb as, respiratory depression,
`nausea, prolonged sedation, ileus or decreased gastrointes-
`tinal motility, or imnmunosuppression. Lack of respiratory
`depression should allow dexmedetomidioe to be used also
`for ooa-veotilated, critically ill patients wbo require
`sedation, anxiolysis, analgesia, and hemoclynamic stability
`yet mus t remain oriented and easily aroused. In addition, it
`is waler soluble and, thus, docs no t increase tbc lipid load in
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1006 – Page 5
`
`

`

`US 6, 716,867 Bl
`
`6
`sedation became evident (approximately within 15 to 30
`minutes) the maintenance rate of infusion could be adjusted
`in increments of 0.1 pg/kg/h or bigber 10 acbieve aod
`maiotain a Ramsey Sedation Score level of 3 or bigber (see
`s FIG. 1).
`Yitai signs, adverse events, and sedation scores were
`recorded duriog tbe study. Tbe patients did oot receive any
`of the following medications du ring t be administration of
`dexmedetomidiae: sedating agents, neu.romuscuJar blocking
`agents except for insertation of the endotracheal tube, and
`epidural or spinal analgesic/anaesthetic agents. Two patieots
`required morphine for pain. One patient had two serious
`adverse eveots: circu latory failure aocl myocardial infarc(cid:173)
`tion. Tbe myocardial infarction, due to incomplete
`revascularizatioo, led to deatb 13 days after tbe study drug
`infusion bad been discontinued. The myoca rdial infarction
`bad little or no temporal relationship to dexmedetomidine.
`In fact, incomplete revascularization is one of the most
`common adverse events after a CABG operation, and it
`sometimes teacls 10 dea th.
`During tbe administration of dexmcdetomidinc, the blood
`pressure and heart rate variability were decreased, meaning
`more stable and predictable bemodynamics without tbe need
`for pharmacological interventions to either treat high blood
`pressure or heart rate, e.g., with beta-blockers, or to increase
`sedation/anxiolysis wi th benzodiazep ins or propofol. la
`conc lusion, the patients were conveniently sedated, hemo(cid:173)
`dynam ically stable, and remained easily arousable for con(cid:173)
`tro l of subjective well being with only one pharmaceutical,
`JO dexmedetomidioe.
`Tbe example shows that dexmedet.omidine is ao ideal
`ageot for sedating a patient io tbe ICU, providing a unique
`quality of sedation and patient comfort.
`
`5
`patients sedated for long periods of time. A predictable
`pharmacological response can be achieved by administering
`dexmedelomidine or a pbannaceuticaUy acceptable salt
`tbereof to a patient io tbe ICU.
`Dexmedetomidioe or a pharmaceutically acceptable salt
`thereof cao be administered perorally, traosmucosally,
`traasdermally, intravenously or intramuscularly. Ooe skilled
`in tbe art would recognize tbe doses and dosage forms
`suitable in the method of the present iavemion. The precise
`amount of the drug administered according to the invention 10
`is dependent on numerous factors, such as tbe general
`cond ition of the patient, the condi tion lo be treated, tbe
`desired duration of use, the route of administration, tbe type
`of mammal, etc. Tbe dose range of dexmedetomidioe can be
`described as target plasma cooceotratioos. The plasma coo- 15
`ceotratioa range anticipated to provide sedation in the
`patient population in the ICU varies betweeo 0.1-2 ng/mJ
`depending on the desired level of sedation and the general
`cooditioa of the patient. These plasma coacen1ra1ioas can be
`achieved by intravenous administration by using a bolus 20
`dose and continuing it by a steady maintenance iofusioo. For
`example, tbe dose range for tbe bolus to achieve the fore(cid:173)
`mentioned plasma concentration range in a buman is about
`0.2-2 ,ug/kg, preferably about 0.5-2 pg/kg, more preferably
`1.0 ,ug/kg, to be administered in about 10 minutes or slower, 25
`followed by a maintenance dose of about 0.1-2.0 pg/kg/b,
`preferably about 0.2-0.7 ,ug/kg/b, more preferably about
`0.4-0.7 pg/kg/b. The time period for administering dexme(cid:173)
`detomidine or a pharmaceutically acceptable salt thereof
`depends on the tbe desired duration of use.
`The chemical form for dexynedetomidioe can be tbe free
`base or an acid addition salt. Such acid addition salts may be
`formed, for example, with inorganic acids, such as, hydro(cid:173)
`chloric acid, hydrobromic acid, sulJiric acid, nitric acid,
`pbospboric acid and tbe like, and orgaoic acids sucb as acetic 35
`acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,
`malic acid, malonic acid, s11ccinic acid, maleic acid, fumaric
`acid, tartaric acid, citric acid, ben1.oic acid, cinaarnic acid,
`mandelic acid, metbanesulfonic acid, ethanesulfonic acid,
`p-toluenesulfonic acid, salicylic acid and the like.
`The inventioo will be furtber clarified by tbe following
`example, whicb is intended to be purely exemplary of the
`invention.
`
`40
`
`45
`
`EXAMPLE 2
`A double-blind, randomized, placebo-controlled study
`was conducted to evaluate tbe efficacy, safety, and titratabil(cid:173)
`ity of dexmedetomidine in mechanically ven tilated patients
`requiring sedation in the ICU. The study was conducted in
`postoperative CABG patients requiring sedation in the ICU.
`Twelve adult postoperative CABG patients requiring
`mecbanical vemilalion in the ICU wbo met the study selec(cid:173)
`tion criteria were eligible for participation.
`The selection criteria were as follows. Tbe patients
`required sedation for mechanical ven tilation for a minimum
`of 8 hours following surgery, followed by continued seda(cid:173)
`lioa for 6 hours after extubation. Tbe patients were not to
`have been intubated longer than 24 hou:rs to be evaluable fo r
`50 tbe test. The patients received oa ly morphi ne for manage(cid:173)
`ment for pain and received none of the following medica(cid:173)
`tions during study drug admioistralioo: sedaliog ageo ts other
`tban midazolam, neuromuscula r blocking agents except for
`insertion of tbe eodotracbael tube, epidural or spinal
`55 analgesic/anesthetic agents.
`Safety was evaluated through tbe moni toring of adverse
`events, cardiac moni toring, laboratory teslS, vital signs,
`oxygen saturation, and concomitant medications.
`Twelve patients were ra ndomly assigned to receive either
`60 dexmedetomidine or placebo with rescue treatment for seda(cid:173)
`tion with midazolam, as clinicaUy indicated. Patients ran(cid:173)
`domized to clexmedetomidine were to receive a 10-miaute
`loading dose of 6.0 pg/kg/b, followed by an initial main te(cid:173)
`naace infusion. The rate of mainteaaace infusion was 0.4
`65 11g/kg/b. The maintenance rate of infusion could be titrated
`in increments o( O.l pg/kg/h to achieve and maintain a
`Ramsey Sedation Score of 3 or bigber. Tbe range for the
`
`EXAMPLE 1
`
`The efficacy, safety and titratability of dexrnedetomidine
`io postoperative coronary artery bypass gra(t(s) patients
`(CABG), requ.iri.ng sedation in the ICU was studied. 111e
`patients were intubated for 8-24 bours. All patients were
`administered dexmedetomidine within l hour of admission
`to tbe ICU, and dexmedetomidinc infusion was continued
`until 6 bours after extubatioo. Dexmedetomidine was used
`in the form of an HCl sail (100 pg/ml , base) in 0.9% sodium
`chloride solution, and it was administered as a two-stage
`infusion (a loadiog dose followed by a maintenaoce
`infosion) util izing standard syringe pump and iv adminis(cid:173)
`tration sets.
`12 patients were selected aod divided into two groups.
`The first 6 patients were administered a loading dose of 6
`,11g/kg/b of dexmedetomidine over a 10-minute period, fol(cid:173)
`lowed by a maintenance infusion of 0.2 /tg/kg/b. The second
`group of 6 patients were initially administered a loading
`dose of 6.0 ,11g/kg/b of dexmedetomidine over a 10 minute
`period, fo llowed by a maintenance infusion of 0.4 pg/kg/b.
`The infusion rate in both groups was maimained between a
`range of 0.2 to 0.7 /tg/kg/b. After tbe c linical effects of
`
`Petition for Inter Partes Review of US 8,455,527
`Amneal Pharmaceuticals LLC – Exhibit 1006 – Page 6
`
`

`

`US 6, 716,867 Bl
`
`7
`mainlenance infusion was lo be kept between 0.2 and 0.7
`,11g/kg/b. Oexmedelomidine adminisl ration was to begin
`witbin one hour after adm ission to Lbe ICU and continued
`until 6 hours after extuba1ion. Dexmede1omidine was used
`in !be form of an I-IC! salt (100 ,ug/ml, base) in 0.9% sodium
`chloride solulion, and it was admiois1ered utilizing standard
`syringe pump and iv administration sets. The placebo was
`0.9% sodium chloride solution administered Lhe same way
`dexmede1omidioe was administered.
`The six dexmede1omidine-sedated pa1ien1s remained
`adequately sedated and did not require any midazolam.
`Conversely, five of the six placebo-treated palienls requi red
`the adminis1ra1ion of m idazolam to achieve sufficient
`(Ramsay Sedation Score~3) levels of sedation (total mean
`midazolam mg/kg/b±SEM~0.018±0.005). The difference
`between 1be two treatment groups in mea n total dose of
`midazolam received during !he study was s1alis1ically sig(cid:173)
`nificant (p~0.010). T he overall level of sedation was com(cid:173)
`parable between the two groups, bu! the administration of
`dexmecle tomidine resu lted in s table Ramsey Sedation
`Scores, characterized by minimal variability over lime,
`compared with in1erroi11ent sedation (Ramsey Sedation
`Score~3) and agitation (Ramsey Sedation Score of 1)
`among placebo-treated patients.
`Ocxroedetomicline also demonstrated analgesic properties
`in this patient population, as measured by the total dose of
`morphine administered throughout the clura1ion of the s1udy.
`One of six dexmedetomidine-treatcd patients required mor(cid:173)
`pbine administration for management of pain compared to
`five of the six placebo-trea ted patients. The dilference
`between the treatmen t groups in mean total close of mor(cid:173)
`pbine was statistically significant (p~0.040).
`la conclusion, patients 1reated with dexroedetomidine
`required significantly les.s midazolam for sedation or mor(cid:173)
`phine for pain than did patients who received placebo.
`Sedation levels for dexmedetomidine-treated pa1ients were
`more stable tban those for placebo-treated patients wbo
`received midazolam. Dexmedetomidiae was safe and well
`tolerated, and it produced no clinically apparent respiratory 40
`depression after cessation of assisted ven tilation.
`
`8
`infusion, the rate of infusion could have been adjusted in
`increments ofO.l pg/kg/b or higher. The infusion rate during
`intubat ion was to bave been maintained in the range of 0.2
`to 0.7 pg/kg/b in order to achieve and maintain a Ramsey
`5 Sedation Score of 3 or higher. Following extubation, the
`infusion ra te was to be adjusted to acbieve a Ramsay
`Sedation Score of 2 or higher.
`During tbe 10-miaute loading dose, additional medication
`was to be avoided, but propofol (0.2-mg/kg bolus) in Trial
`10 1 and miclazolam (1-mg bolus) in T riaJ 2 could be given i(
`necessary. During dcxmedetomidine infusion, rescue medi(cid:173)
`cations were limited to propofol (0.2 mg/kg IV boluses) in
`Trial 1 aod midazolam (0.2-mg/kg IV boluses) in Trial 2 for
`sedation and morpbioe for pain (2-mg IV boluses). After
`15 extuba1ion, paracetamol was to be permitted for pain as
`clinically indicated. Propofol ancl midazolam were 10 be
`given only after increasing the dexmedetomicline infusion
`rate. Oexmedetomicline adminL<;iration in Parts l and II was
`to begin within l hour of admission to the ICU and to be
`20 continued for 6 hours after extubation to a maximum of 24
`hours total study drug infusion. Patients were observed and
`as.sessed for an add itional 24 hours after ces.sation of dexme(cid:173)
`detom.idine.
`The conclusions from tbe Trials 1 a ncl 2 are as follows.
`25 Tbe patients treated with dexroedetomidine required signifi(cid:173)
`cantly less propofol (Trial 1) or midazolam (Trial 2) for
`sedation or morphine for pain !ban pa1ients who received
`placebo. T be sedation levels for dexroedetomidine-treated
`patients were acbieved more quickly than tbose for placebo-
`JO treated patients wbo received propofol or midazolam .
`Dexmedelomidine was safe and well tolerated: the adverse
`events and labora tory cbaoges reported in tbesc studies were
`to be expected in a postsurgical popu lat ion.
`During Trial 1, Part I ihree dexonedetomidine-treated
`patien ts died , and during Trial l, Part II, three
`dexmedetomidine-tr