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`EXHIBIT A
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`EXHIBIT A
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`Case 1:18-cv-00303-UNA Document 1-1 ”IMMIIMHHIIHJIMILMS
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`0 6716867B1
`
`(12) United States Patent
`US 6,716,867 B1
`(10) Patent N0.:
`Aantaa et al.
`(45) Date of Patent:
`Apr. 6, 2004
`
`(54) USE OF DEXMEDETOMIDINE FOR ICU
`SEDATION
`
`(75)
`
`Inventors: Riku Aantaa, Turku (FI); Romeo
`Bachand, Mundelain, IL (US); Esa
`Heinonen, Turku (Fl)
`
`(73) Assignee: Orion Corporation, Espoo (FI)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`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.:
`
`PCT/FI99/00266
`
`§ 371 (C)(1),
`(2), (4) Date: Dec. 6, 2000
`
`(87) PCT Pub. No.: WO99/49854
`
`PCT Pub. Date: Oct. 7, 1999
`
`(60)
`
`Related US. Application Data
`Provisional application No. 60/080,287, filed on Apr. 1,
`1998, and provisional application No. 60/110,944, filed on
`Dec. 4, 1998.
`
`Int. Cl.7 .............................................. A61K 31/415
`(51)
`(52) US. Cl.
`....................................................... 514/396
`(58) Field of Search .......................................... 514/396
`
`(56)
`
`EP
`EP
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`3/1990 Karjalainen et al.
`4,910,214 A
`FOREIGN PATENT DOCUMENTS
`
`0 413 487 A1
`0 424 059 A1
`
`2/1991
`4/1991
`
`OTHER PUBLICATIONS
`
`CA 130:231765, Caudwell et al, Int. Congr. Symp. Sen—R.
`Soc. Med. 1998, 221, 73—81, abstract.*
`CACA130:246080, Mantz et al, Int. Congr. Symp. Sen—R.
`Soc. Med. 1009, 221, 23—29, abstract.*
`EMBASE AN 1997328166, Celorrio et al, Actualizaciones
`en Anestesiologia y Reanimacion, 1997, 7/3, 105—125,
`abstract.*
`
`: “[Alpha2—Agonists in Anaesthesia and
`Bischoff P. et al.
`Intensive—Care Medicine]. Alpha2—Agonisten in Anasthesie
`und Intensivmedizin.” Anasthesiologie
`Intensivmedizin
`Notfallmedizin Schmerztherapie, (1993) 28/1 (2—12).
`Crippen D. et al.: “Stress, Agitation, and Brain Failure in
`Critical Care Medicine. ” Critical Care Nursing Quaterly,
`(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. 58—62 (Feb. 1989).
`Abstract of Belleville JP et al., “Effects of intravenous
`dexmedetomidine in humans. I. Sedation, ventilation, and
`
`1992
`
`Dec. ,
`
`Anesthesiology
`
`rate”,
`metabolic
`77(6):1125—1133.
`Abstract of Jaakola ML, “Dexmedetomidine premedication
`before intravenous regional anesthesia in minor outpatient
`hand surgery”, J Clin Anesth 1994 May—Jun., 6(3):204—211.
`Abstract of Werner C., “Effects of analgesia and sedation on
`cerebrovascular circulation, cerebral blood volume, cerebral
`metabolism and intracranial pressure”, Anaesthesist 1995
`Dec., 44 Suppl 3:8566—572.
`Abstract of Vulliemoz Y., Shen H., Virag L., “Alpha—2
`adrenoceptor
`agonists
`decrease
`cyclic
`guanosine
`3‘,5‘—monophosphate in the mouse brain”, Anesthesiology
`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 Mantz and the French Dexmedetomidine Phase III
`Study Group, “Phase III Study On Dexmedetomidine Used
`For Postoperative Sedation Of Patients Requiring Mechani-
`cal Ventilation For Less Than 24 Hours: The French Expe-
`rience”, M.E.J. Anesth 16 (6):597—606, 2002.
`Mohamad Said Takrouri et al., “Dexmedetomidine In Inten-
`sive Care Unit: AStudy Of Hemodynamic Changes”, M.E.J.
`Anesth 16 (6): 587—595, 2002.
`R. M. Venn et al., “Pharmacokinetics of dexmedetomidine
`infusions for sedation of postoperative patients requiring
`intensive
`care”,
`British
`Journal
`of Anaesthesia
`88(5):669—75, 2002.
`Mervyn Maze, “Sedation in the intensive care unit”, Inter-
`national Congress and Symposium Series No. 221, pp. 3—10,
`1998.
`
`Elizabeth Caudwell et al., “Nursing considerations in inten-
`sive care unit sedation and experience With dexmedetomi-
`dine,” International Congress and Symposium Series No.
`221, pp. 73—81, 1998.
`Celorrio et al Sedacion y relajacion neuromuscular en las
`unidades de cuidados intensivos, Act. Anest. Reanim, vol. 7,
`pp. 105—126 (1997)
`(With accompanying translation of
`certain sections).
`Bohrer, “Clonidine as a sedative adjunct in intensive care,”
`Intensive Care Med, vol. 16, pp. 265—266 (1990).
`Doze et al., “Pertussis Toxin and 4—Aminopyridine Differ-
`entially Affect the Hypnotic—Anesthetic Action of Dexme-
`detomidine and Pentobarbital,” Anesthesiology, vol. 73, pp.
`304—307 (1990).
`OJ. Peden et al., “Editorial II: Dexmedetomidine—A pow-
`erful New Adjunct to Anaesthesia?,” Br. J. Anaesth, vol. 68,
`pp. 123—125 (1992).
`M. Tryba et al., “Critical Care Pharmacotherapy,” Drugs,
`vol. 45, pp. 338—352 (1993).
`
`* cited by examiner
`
`Primary Examiner—Rebecca Cook
`(74) Attorney, Agent, or Firm—Finnegan, Henderson,
`Farabow, Garrett & Dunner, LLP
`
`(57)
`
`ABSTRACT
`
`The present invention relates to a method of sedating a
`patient While in the intensive care unit comprising admin-
`istering dexmedetomidine of a pharmaceutically acceptable
`salt
`thereof to the patient, wherein the patient remains
`arousable and orientated.
`
`12 Claims, 2 Drawing Sheets
`
`

`

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`US. Patent
`
`Apr. 6, 2004
`
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`US 6,716,867 B1
`
`1
`USE OF DEXMEDETOMIDINE FOR ICU
`SEDATION
`
`This application is a national stage filing of PCT Inter-
`national Application No. PCT/F199/00266, filed on Mar. 31,
`1999, which claims priority to US. Provisional Application
`Ser. No. 60/080,287, filed on Apr. 1, 1998, and which also
`claims priority to US. Provisional Application Ser. No.
`60/110,944, filed on Dec. 4, 1998.
`
`BACKGROUND OF THE INVENTION
`
`The present invention relates to the use of dexmedetomi-
`dine or a pharmaceutically acceptable salt thereof in inten-
`sive care unit (ICU) sedation. In addition to the actual
`sedation of a patient in the ICU, 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, the present invention relates to
`a method of sedating a patient while in the ICU by admin-
`istering dexmedetomidine or a pharmaceutically acceptable
`salt thereof. Particularly, the present invention relates to a
`method of sedating a patient while in the ICU by adminis-
`tering dexmedetomidine 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 invention also relates to the use of
`dexmedetomidine 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., et al., Clin. Intensive Care
`4 (1993) 222—225). The most consistently unpleasant
`memories are anxiety, pain, fatigue, weakness, thirst, the
`presence of various catheters, and minor procedures such 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,
`but is still arousable.
`
`At 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 ICU, often
`receiving the variety of drugs concurrently The agents used
`most commonly are given to achieve patient comfort. Vari-
`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, volatile
`anesthetics) for unpleasant procedures. These agents are
`cumulatively called sedatives in the context of ICU sedation,
`though sedation also includes the treatment of conditions
`that affect patient comfort, such as pain and anxiety, and
`many of the drugs mentioned above are not considered
`sedatives outside the context of ICU sedation.
`
`The presently available sedative agents are associated
`with such adverse effects as prolonged sedation or overse-
`dation (propofol and especially poor metabolizers of
`midazolam), prolonged weaning (midazolam), respiratory
`depression (benzodiazepines, propofol, and opioids),
`hypotension (propofol bolus dosing), bradycardia, ileus or
`decreased gastrointestinal motility (opioids), immunosup-
`pression (volatile anaesthetics and nitrous oxide),
`renal
`function impairment, hepatotoxicity (barbiturates),
`toler-
`ance (midazolam, propofol), hyperlipidemia (propofol),
`
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`lack of orientation and
`increased infections (propofol),
`cooperation (midazolam, opioids, and propofol), and poten-
`tial abuse (midazolam, opioids, and propofol).
`
`In addition to the adverse effects of every individual
`sedative agent,
`the combination of these agents
`(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-
`kinetics of each agent may be altered in an unpredictable
`fashion. In addition,
`the possibility of allergic reactions
`increases with the use of more than one agent. Furthermore,
`these adverse effects might necessitate the use of additional
`agents to treat the adverse effects, and the additional agents
`themselves may have 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 requirements.
`Muscle relaxants are seldom used during intensive care. As
`cardiovascular stability is also desired in this often high-risk
`patient population, hemodynamically active agents are often
`needed for adequate hemodynamic control despite sufficient
`sedation.
`
`otz-adrenoceptor agonists are being evaluated in general
`anaesthetic practice because of their sympatholytic,
`sedative, anaesthetic, and hemodynamic stabilizing effects.
`Tryba et al. discussed the usefulness of otz-agonists in
`situations where patients with withdrawal symptoms are
`treated in the ICU (Tryba et al., Drugs 45 (3) (1993),
`338—352). The only otz-agonist mentioned was clonidine,
`which was used in conjunction with opioids,
`benzodiazepines, ketamine, and neuroleptics. Tryba et al.
`suggest that clonidine may be useful in ICU patients with
`withdrawal symptoms, but Tryba et al. only briefly mention
`the use of clonidine for ICU sedation. Furthermore, Tryba et
`al. only mention clonidine 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-
`dictable hemodynamic effects,
`i.e., bradycardia and
`hypotension, so that it must be titrated for each individual
`patient. Long term treatment of critically ill patients with
`clonidine has been reported to be associated with such
`rebound effects as tachycardia and hypertension.
`
`otz-agonists are not presently used by themselves in ICU
`sedation. Further, otz-agonists are not generally used in ICU
`sedation even in conjunction with other sedative agents.
`Only clonidine has been evaluated for use in ICU sedation,
`and then only in conjunction with opioids, benzodiazepines,
`ketamine, and neuroleptics. Further, administration of cloni-
`dine as essentially the sole active agent or the sole active
`agent to a patient in the ICU to achieve sedation has not been
`disclosed to 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 hemodynamic stabilizing effects.
`Further, it should be an anxiolytic and an analgesic, and
`should prevent nausea, vomiting, and shivering. It should
`not cause respiratory depression. Preferably, an ideal seda-
`tive agent should be used by itself in ICU sedation to avoid
`the dangers of polypharmacy.
`
`Dexmedetomidine, or (+)-(S)-4-[1-(2,3-dimethylphenyl)
`ethyl]-1H-imidazole, has the following formula:
`
`

`

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`US 6,716,867 B1
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`4
`the invention relates to a use of
`In a further aspect,
`dexmedetomidine or a pharmaceutically acceptable salt
`thereof in ICU sedation.
`
`A further aspect of the invention relates to a use of
`dexmedetomidine or a pharmaceutically acceptable salt
`thereof in the manufacture of a medicament for ICU seda-
`tion.
`
`It is to be understood that both the foregoing general
`description and the following detailed description are exem-
`plary and explanatory only and are not restrictive of the
`invention, as claimed.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 shows the Ramsay Scale that was developed for
`the assessment of sedation in experimental subjects. In this
`system, the level of wakefulness is scored on a scale of 1—6
`(Ramsey Sedation Score) based on progressive loss of
`responsiveness to stimuli ranging from auditory to deep
`painful stimuli.
`FIG. 2 shows the dosing period from the Phase III
`dexmedetomidine study described in Example 3, case No.
`13. The dotted line signifies Ramsay Sedation Score fluc-
`tuations and the solid line signifies dexmedetomidine dose
`adjustments.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Applicants have surprisingly discovered that dexmedeto-
`midine or a pharmaceutically acceptable salt thereof is an
`ideal agent to be administered to a patient in the ICU for
`achieving sedation and patient comfort. Particularly, it has
`been found that dexmedetomidine or a pharmaceutically
`acceptable salt thereof can be essentially the sole active
`agent or the sole active agent administered to a patient in the
`ICU in order to sedate the patient.
`The method for sedating a patient in the ICU encompasses
`all of the potential ICU uses of dexmedetomidine and a
`pharmaceutically acceptable salt
`thereof,
`including all
`potential uses that derive from their activity as otz-agonists,
`e.g., their use as hypotensive agents, anxiolytics, analgesics,
`sedatives, and the like.
`The word intensive care unit encompasses any setting that
`provides intensive care. The word patient is intended to
`include both human and animal patients. Preferably, the
`animal patient is a mammal, especially a dog, a cat, a horse,
`or a cow.
`
`The quality of the sedation in the ICU achieved by
`administering dexmedetomidine is unique. Patients sedated
`by dexmedetomidine or a pharmaceutically acceptable salt
`thereof are arousable and oriented, which makes the treat-
`ment of the patient easier. The patients can be awakened and
`they are able to respond to questions. They are aware, but not
`anxious, and tolerate an endotracheal tube well. Should a
`deeper level of sedation or more sedation be required or
`desired, an increase in dexmedetomidine dose smoothly
`transits the patient into a deeper level of sedation. Dexme-
`detomidine does not have adverse effects associated with
`
`respiratory depression,
`other sedative agents, such as,
`nausea, prolonged sedation, ileus or decreased gastrointes-
`tinal motility, or imnmunosuppression. Lack of respiratory
`depression should allow dexmedetomidine to be used also
`for non-ventilated, critically ill patients who require
`sedation, anxiolysis, analgesia, and hemodynamic stability
`yet must remain oriented and easily aroused. In addition, it
`is water soluble and, thus, does not increase the lipid load in
`
`Dexmedetomidine is described in US. Pat. No. 4,910,214
`as an otz-receptor agonist for general sedation/analgesia and
`the treatment of hypertension or anxiety. US. Pat. Nos.
`5,344,840 and 5,091,402 discuss dexmedetomidine in perio-
`perative and epidural use, respectively. US. Pat. No. 5,304,
`569 discusses the use of dexmedetomidine in glaucoma.
`US. Pat. No. 5,712,301 discusses the use of dexmedetomi-
`dine for preventing neurodegeneration caused by ethanol
`consumption.
`Medetomidine, which is the racemic mixture of dexme-
`detomidine and levomedetomidine, is known as a selective
`and potent otz-agonist and has been described in US. Pat.
`No. 4,544,664 as an antihypertensive agent and in US. Pat.
`No. 4,670,455 as a veterinary sedative-analgesic agent.
`In US. Pat. Nos. 4,544,664 and 4,910,214, parenteral,
`intravenous, and oral ways of administration are discussed.
`US. Pat. No. 4,670,455 describes intramuscular and intra-
`venous administration. U.S. Pat. Nos. 5,124,157 and 5,217,
`718 describe a method and device for administering dexme-
`detomidine through the skin. US. Pat. No. 5,712,301 states
`that dexmedetomidine can be administered transmucosally.
`The US. Patents discussed herein are specifically incor-
`porated by reference in their entirety.
`SUMMARY OF THE INVENTION
`
`It has been unexpectedly found that dexmedetomidine or
`a pharmaceutically acceptable salt thereof is an ideal seda-
`tive agent to be administered to a patient in the ICU to
`achieve patient comfort. Accordingly, an object of the inven-
`tion is to provide a method of sedating a patient while in the
`ICU that comprises administering dexmedetomidine or a
`pharmaceutically acceptable salt thereof for a time sufficient
`to give the desired therapeutic effect.
`It should be noted that the method for sedating a patient
`in the ICU encompasses all of the potential ICU uses of
`dexmedetomidine and a pharmaceutically acceptable salt
`thereof, including all potential uses that derive from their
`activity as otz-agonists, e.g., their use as hypotensive agents,
`anxiolytics, analgesics, sedatives, and the like. It should also
`be noted that the word intensive care unit encompasses any
`setting that provides intensive care.
`Additional objects and advantages of the invention will be
`set forth in part in the description which follows, and in part
`will be obvious from the description, or may be learned by
`practice of the invention. The objects and advantages of the
`invention will be realized and attained by means of the
`elements and combinations particularly pointed out in the
`appended claims.
`the invention relates to a method of
`In one aspect,
`sedating a patient while in the ICU by administering dexme-
`detomidine or a pharmaceutically acceptable salt thereof,
`wherein dexmedetomidine is essentially the sole active
`agent or the sole active agent. The method is premised on the
`discovery that essentially only dexinedetomidine or a phar-
`maceutically acceptable salt thereof need to be administered
`to a patient in the ICU to achieve sedation and patient
`comfort. No additional sedative agents are required.
`
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`US 6,716,867 B1
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`5
`patients sedated for long periods of time. A predictable
`pharmacological response can be achieved by administering
`dexmedetomidine or a pharmaceutically acceptable salt
`thereof to a patient in the ICU.
`Dexmedetomidine or a pharmaceutically acceptable salt
`thereof can be administered perorally,
`transmucosally,
`transdermally, intravenously or intramuscularly. One skilled
`in the art would recognize the doses and dosage forms
`suitable in the method of the present invention. The precise
`amount of the drug administered according to the invention
`is dependent on numerous factors, such as the general
`condition of the patient,
`the condition to be treated,
`the
`desired duration of use, the route of administration, the type
`of mammal, etc. The dose range of dexmedetomidine can be
`described as target plasma concentrations. The plasma con-
`centration range anticipated to provide sedation in the
`patient population in the ICU varies between 0.1—2 ng/ml
`depending on the desired level of sedation and the general
`condition of the patient. These plasma concentrations can be
`achieved by intravenous administration by using a bolus
`dose and continuing it by a steady maintenance infusion. For
`example, the dose range for the bolus to achieve the fore-
`mentioned plasma concentration range in a human is about
`0.2—2 yg/kg, preferably about 0.5—2 yg/kg, more preferably
`1.0 yg/kg, to be administered in about 10 minutes or slower,
`followed by a maintenance dose of about 0.1—2.0 yg/kg/h,
`preferably about 0.2—0.7 Mg/kg/h, more preferably about
`0.4—0.7 Mg/kg/h. The time period for administering dexme-
`detomidine or a pharmaceutically acceptable salt thereof
`depends on the the desired duration of use.
`The chemical form for dexynedetomidine can be the free
`base or an acid addition salt. Such acid addition salts may be
`formed, for example, with inorganic acids, such as, hydro-
`chloric acid, hydrobromic acid, sulfiric acid, nitric acid,
`phosphoric acid and the like, and organic acids such as acetic
`acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,
`malic acid, malonic acid, succinic acid, maleic acid, fumaric
`acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,
`mandelic acid, methanesulfonic acid, ethanesulfonic acid,
`p-toluenesulfonic acid, salicylic acid and the like.
`The invention will be further clarified by the following
`example, which is intended to be purely exemplary of the
`invention.
`
`EXAMPLE 1
`
`The efficacy, safety and titratability of dexmedetomidine
`in postoperative coronary artery bypass graft(s) patients
`(CABG), requiring sedation in the ICU was studied. The
`patients were intubated for 8—24 hours. All patients were
`administered dexmedetomidine within 1 hour of admission
`to the ICU, and dexmedetomidine infusion was continued
`until 6 hours after extubation. Dexmedetomidine was used
`
`in the form of an HCl salt (100 Mg/ml, base) in 0.9% sodium
`chloride solution, and it was administered as a two-stage
`infusion (a loading dose followed by a maintenance
`infusion) utilizing standard syringe pump and iv adminis-
`tration sets.
`
`12 patients were selected and divided into two groups.
`The first 6 patients were administered a loading dose of 6
`yg/kg/h of dexmedetomidine over a 10-minute period, fol-
`lowed by a maintenance infusion of 0.2 Mg/kg/h. The second
`group of 6 patients were initially administered a loading
`dose of 6.0 yg/kg/h of dexmedetomidine over a 10 minute
`period, followed by a maintenance infusion of 0.4 Mg/kg/h.
`The infusion rate in both groups was maintained between a
`range of 0.2 to 0.7 Mg/kg/h. After the clinical effects of
`
`6
`
`sedation became evident (approximately within 15 to 30
`minutes) the maintenance rate of infusion could be adjusted
`in increments of 0.1 yg/kg/h or higher to achieve and
`maintain a Ramsey Sedation Score level of 3 or higher (see
`FIG. 1).
`Vital signs, adverse events, and sedation scores were
`recorded during the study. The patients did not receive any
`of the following medications during the administration of
`dexmedetomidine: sedating agents, neuromuscular blocking
`agents except for insertation of the endotracheal tube, and
`epidural or spinal analgesic/anaesthetic agents. Two patients
`required morphine for pain. One patient had two serious
`adverse events: circulatory failure and myocardial infarc-
`tion. The myocardial
`infarction, due to incomplete
`revascularization, led to death 13 days after the study drug
`infusion had been discontinued. The myocardial infarction
`had 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 leads to death.
`
`During the administration of dexmedetomidine, the blood
`pressure and heart rate variability were decreased, meaning
`more stable and predictable hemodynamics without the need
`for pharmacological interventions to either treat high blood
`pressure or heart rate, e.g., with beta-blockers, or to increase
`sedation/anxiolysis with benzodiazepins or propofol.
`In
`conclusion, the patients were conveniently sedated, hemo-
`dynamically stable, and remained easily arousable for con-
`trol of subjective well being with only one pharmaceutical,
`dexmedetomidine.
`
`The example shows that dexmedetomidine is an ideal
`agent for sedating a patient in the ICU, providing a unique
`quality of sedation and patient comfort.
`EXAMPLE 2
`
`randomized, placebo-controlled study
`A double-blind,
`was conducted to evaluate the efficacy, safety, and titratabil-
`ity of dexmedetomidine in mechanically ventilated 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
`mechanical ventilation in the ICU who met the study selec-
`tion criteria were eligible for participation.
`The selection criteria were as follows. The patients
`required sedation for mechanical ventilation for a minimum
`of 8 hours following surgery, followed by continued seda-
`tion for 6 hours after extubation. The patients were not to
`have been intubated longer than 24 hours to be evaluable for
`the test. The patients received only morphine for manage-
`ment for pain and received none of the following medica-
`tions during study drug administration: sedating agents other
`than midazolam, neuromuscular blocking agents except for
`insertion of the endotrachael
`tube, epidural or spinal
`analgesic/anesthetic agents.
`Safety was evaluated through the monitoring of adverse
`events, cardiac monitoring,
`laboratory tests, vital signs,
`oxygen saturation, and concomitant medications.
`Twelve patients were randomly assigned to receive either
`dexmedetomidine or placebo with rescue treatment for seda-
`tion with midazolam, as clinically indicated. Patients ran-
`domized to dexmedetomidine were to receive a 10-minute
`
`loading dose of 6.0 Mg/kg/h, followed by an initial mainte-
`nance infusion. The rate of maintenance infusion was 0.4
`
`Mg/kg/h. The maintenance rate of infusion could be titrated
`in increments of 0.1 yg/kg/h to achieve and maintain a
`Ramsey Sedation Score of 3 or higher. The range for the
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`

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`US 6,716,867 B1
`
`7
`maintenance infusion was to be kept between 0.2 and 0.7
`Mg/kg/h. Dexmedetomidine administration was to begin
`within one hour after admission to the ICU and continued
`until 6 hours after extubation. Dexmedetomidine was used
`
`in the form of an HCl salt (100 Mg/ml, base) in 0.9% sodium
`chloride solution, and it was administered utilizing standard
`syringe pump and iv administration sets. The placebo was
`0.9% sodium chloride solution administered the same way
`dexmedetomidine was administered.
`
`The siX dexmedetomidine-sedated patients remained
`adequately sedated and did not require any midazolam.
`Conversely, five of the siX placebo-treated patients required
`the administration of midazolam to achieve sufficient
`
`(Ramsay Sedation Scoreé3) levels of sedation (total mean
`midazolam mg/kg/h:SEM=0.018=0.005). The difference
`between the two treatment groups in mean total dose of
`midazolam received during the study was statistically sig-
`nificant (p=0.010). The overall level of sedation was com-
`parable between the two groups, but the administration of
`dexmedetomidine resulted in stable Ramsey Sedation
`Scores, characterized by minimal variability over time,
`compared with intermittent sedation (Ramsey Sedation
`Scoreé3) and agitation (Ramsey Sedation Score of 1)
`among placebo-treated patients.
`Dexmedetomidine also demonstrated analgesic properties
`in this patient population, as measured by the total dose of
`morphine administered throughout the duration of the study.
`One of siX dexmedetomidine-treated patients required mor-
`phine administration for management of pain compared to
`five of the siX placebo-treated patients. The difference
`between the treatment groups in mean total dose of mor-
`phine was statistically significant (p=0.040).
`In conclusion, patients treated with dexmedetomidine
`required significantly less midazolam for sedation or mor-
`phine for pain than did patients who received placebo.
`Sedation levels for dexmedetomidine-treated patients were
`more stable than those for placebo-treated patients who
`received midazolam. Dexmedetomidine was safe and well
`
`tolerated, and it produced no clinically apparent respiratory
`depression after cessation of assisted ventilation.
`
`EXAMPLE 3
`
`Two Phase III dexmedetomidine multicenter clinical trials
`
`(Trial 1 and Trial 2) have been conducted in ICU sedation in
`Europe and Canada. Each trial had two parts,
`i.e., an
`open-label part (Part
`I) and double-blind,
`randomized,
`placebo-controlled part (Part II). The trials were designed to
`evaluate the reduction in requirements for ICU sedation (as
`measured by administration of other sedative/analgesic
`agents) in patients receiving dexmedetomidine. The use of
`propofol and morphine for sedation and analgesia,
`respectively, was evaluated in one trial (Trial 1), and mida-
`zolam and morphine in the other trial (Trial 2). Atotal of 493
`patients were enrolled and treated in Trial 1 and 438 patients
`were enrolled and treated in Trial 2.
`
`In Part I of the trials patients were to be administered a 6.0
`yg/kg/h loading dose of dexmedetomidine over a 10-minute
`period, followed by an initial maintenance infusion of 0.4
`Mg/kg/h. During Part II of the study, patients were randomly
`assigned to receive either placebo (0.9% sodium chloride
`solution) or dexmedetomidine. Dexmedetomidine was used
`as an HCl salt (100 mg/ml, base) in 0.9% sodium chloride
`solution, and it was administered utilizing standard syringe
`pump and iv administration sets. The dexmedetomidine
`dosing protocol was the same as in the Part I of the study.
`For both parts of the study, following the initial maintenance
`
`8
`infusion, the rate of infusion could have been adjusted in
`increments of 0.1 yg/kg/h or higher. The infusion rate during
`intubation was to have been maintained in the range of 0.2
`to 0.7 yg/kg/h in order to achieve and maintain a Ramsey
`Sedation Score of 3 or higher. Following extubation, the
`infusion rate was to be adjusted to achieve a Ramsay
`Sedation Score of 2 or higher.
`During the 10-minute loading dose, additional medication
`was to be avoided, but propofol (0.2-mg/kg bolus) in Trial
`1 and midazolam (1-mg bolus) in Trial 2 could be given if
`necessary. During dexmedetomidine infusion, rescue medi-
`cations were limited to propofol (0.2 mg/kg IV boluses) in
`Trial 1 and midazolam (0.2-mg/kg IV boluses) in Trial 2 for
`sedation and morphine for pain (2-mg IV boluses). After
`extubation, paracetamol was to be permitted for pain as
`clinically indicated. Propofol and midazolam were to be
`given only after increasing the dexmedetomidine infusion
`rate. Dexmedetomidine administration in Parts I and II was
`
`10
`
`15
`
`20
`
`to begin within 1 hour of admission to the ICU and to be
`continued for 6 hours after extubation to a maximum of 24
`
`hours total study drug infusion. Patients were observed and
`assessed for an additional 24 hours after cessation of dexme-
`detomidine.
`The conclusions from the Trials 1 and 2 are as follows.
`
`The patients treated with dexmedetomidine required signifi-
`cantly