Intranasal Dexmedetomidine & Midazolam: A Novel Sedation Technique for Infant
`PFT
`DiSilvio G, Jacoby M, Weiner D, Broussard A, Callahan P, Cain J
`
`Abstract accepted by the Society for Pediatric Anesthesiology with poster presented at Annual Spring Meeting (~ 1100
`attendees) Phoenix 2015
`Pulmonologists have been satisfactorily utilizing oral chloral hydrate for infant PFT for > 30 yrs. A recent shortage has
`forced them to utilize alternatives. While Callahan, et al (Pediatr Pulmonol 2014), recently described the use of IV
`dexmedetomidine for iPFT, this case report describes for the first time its intranasal use for iPFT. A 2 year old female with
`cystic fibrosis, dx’d with and tx’d for pneumonia 3 wks previously, required sedation for iPFT. The patient was an anxious
`two-year old standing 88.3cm and weighing 12.3kg. She received 3.25 mcg/kg of dex & 0.325 mg/kg of midaz
`intranasally, tolerating it well. At 40 min she reached a -4 on the Richmond Agitation Sedation Scale (RASS) and was
`deemed adequately sedated to undergo the iPFT. The doses of 3.25 mcg/kg of dexmed and 0.325 mg/kg of midaz were
`based upon previous sedation experience with intranasal dex and versed as well as conversions of dex and midaz IV
`dosing to intranasal equivalents. The patient tolerated the stimulation PFT’s very well, was hemodynamically appropriate
`and maintained spontaneous ventilation at a respiratory rate not less than 22 BPM with oxygen saturation >93% (pts
`baseline) throughout. The pulmonologist performed the most stimulating part of the procedure, the “hug” with the fitted
`airtight mask first. Adequate sedation was provided for successful performance of all prebronchodilator tests. At
`approximately 35 minutes, it was determined that the patient required rescue sedation and she received 1.625 mcg/kg IV
`dex and 0.325 mg IV midaz over 5 minutes, successfully tolerating the remaining 30 minutes of the procedure. Post
`procedure, she was immediately arousable to voice and comfortable. She was transferred back to her floor bed awake
`and alert, in no distress within 1 hour of her PACU stay.
`Intranasal dex + midaz provided an excellent noninvasive sedation technique for PFT’s should the procedure be less than
`35 minutes. Should the procedure be anticipated to require sedation longer than 35 minutes, either larger initial IN doses,
`a second IN dose timed to overlap with the initial dose, or invasive methods such as IM or IV (in this case) may be
`necessary.
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`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1039 – Page 1
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`* hildren’s
`limpinf
`l" xii; 7:] L Pi K
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`G DjSilMiQ, M Jacoby, D Weiner, A Broussard, P Callahan, J Cain
`
`Department of Anesthesiology, Children’s Hospital of Pittsburgh of UPMC
`
`Pulmonologists have used oral chloral hydrate for infant Pl-Tsfor >30 years.
`Recent shortage due to manufacturing forced them to utilize alternatives.
`Callahan et al (Bed Pulmonology, 2014), described N dexmedetomicine for iPEf
`This case report (18501135 for the first time intranasal denuedemrridinefor iPFl'_.
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`3-25 mcg/lcg of dexmedetnmidinefi 0.33 rug/kg of rnidazolam
`prtwided excellent, noninvasive sedation for inl’jor 35 minutes-
`Should the procedure be require sedation longer than 35 minutes, larger
`initial IN doses, additional IN dosefs timed to overlapthe initial dose, or
`invasive methods such as IM or IV (as in this case] may be considered.
`
`Anxious 2 yo female with cystic fibrosis, dxfd and tx’d for pneumonia 3 weeks prior to
`Sedation required for iEEI'.
`In pre—op area, 1% nicglkg of dexmedetomidine 8!. 0.325 mg/kg of midazolam administered intranasallytwith atomizer
`- Tolerated well.
`
`for iPFl'to intranasal equivalents.
`Doses based upon prior clinical intranasal experience and conversions of prior IV
`At 40 minutes, reached a —4 on the Richmond Agitation Sedation Scale
`—) adequately sedated to undergo the
`Pulmonologist performed the most stimulating part ofthe procedure, the "bug" with the fitted airtig‘rt mask first
`Tole-rated inT‘very well, hemodynarnially appropriate, and maintained spontaneous ventilation at a respiratory rate not [65
`than 22 BPM with oxygen saturation >939fi lpts. baseline) throughout.
`Adequate sedation for successful performance of all prebronchodilator tests
`At approximately 35 minutes, it was determined that she requ'recl additional sedation
`-
`1-625 mcg/kg IV denorredetomidine and 0.3% mg/kg IV midazolam over 5 minutes
`- Tolerated remainingBO minuta ofthe procedure.
`Post procedure, immediately arousable to voice and comfortable
`Transferred to floor bed awake, alert and in no distress within 1 hour of completion of procedure and PACU admission.
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`Callahan, P., Pinto, 5.1., Kurland, 6., Cain, J. 6., Motown]; E. K. and Weiner, D. l. [2015], Dcxmcdctomidin: for infant pulmonary function testing. Radian, Pglrngnol.. 50: 150—154.
`10.1002Ippuunoo
`FDA Drug Shortages: http://www.fdn.5m/druss/drussalety/drugshortascs/ucmflsommtm. Volume 2014.
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`Amneal Pharmaceuticals LLC — Exhibit 1039 — Page 2
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`Petition for Inter Partes Review of US 8,338,470
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`Dexmedetomidine in Children: Current Knowledge and
`Future Applications
`
`Keira P. Mason, MD,* and Jerrold Lerman, MD, FRCPC, FANZCAt
`
`More than 200 studies and reports have been published regarding the use of dexmedetomi(cid:173)
`dine in infants and children. We reviewed the English literature to summarize the current state
`of knowledge of this drug in children for the practicing anesthesiologist. Dexmedetomidine is
`an effective sedative for infants and children that only minimally depresses the respiratory
`system while maintaining a patent airway. However, dexmedetomidine does depress the
`cardiovascular system. Specifically, bradycardia, hypotension, and hypertension occur to
`varying degrees depending on the age of the child. Hypertension is more prevalent when
`larger doses of dexmedetomidine are given to infants. Cons istent with its 2-hour elimination
`half-life, recovery after dexmedetomidine may be protracted in comparison with other
`sedatives. Dexmedetomidine provides and augments analgesia and diminishes shivering as
`well as agitation postoperatively. The safety record of dexmedetomidine suggests that it can
`be used effectively and safely in children, with appropriate monitoring and interventions to
`manage cardiovascular sequelae. (Anesth Analg 2011;113:1129-42)
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`3
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`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1039 – Page 3
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`A Comparison of Intranasal Dexmedetomidine and Oral
`Midazolam for Premedication in Pediatric Anesthesia: A
`Double-Blinded Randomized Controlled Trial
`
`Vivian M. Yuen, MBBS, FAN ZCA,
`FHKCA, FHKAM
`
`Theresa W. Hui, MBBS, FAN ZCA,
`FHKCA, FHKAM
`
`Michael G. Irwin, MBCh B, MD,
`FRCA, FHKCA, FHKAM
`
`Man K. Yuen, MBBS, FAN ZCA,
`FHKCA, FHKAM
`
`BACKGROUND: Mjdazolam is the most commonly used p rcmcd ication in children. It
`has been shO\\'n to be more cfrcctivc than parental p resence or p lacebo in reducing
`anxiety and improving compUancc at induction of anesthesia. Clonidine, an u2
`agonist, has been suggested- as an alternative. Dexmedctomidine is a more a2
`selective drug w ith more favorable pharmacokincHc properties than clonidinc. We
`d esigned this pros,ectivc, randomized, doubJc .. blind, controlled trial to evaluate
`whether intranasa dexmcdctomidine is as effective as oral midazolam for prc(cid:173)
`medication in children.
`METHODS: Ninety-six children of ASA physical s tatus I or n scheduled fo r elective
`minor s urgery \VC.rc rand omly assigned to one of three groups. Group M received
`midazolam 0.5 mg/kg in acetaminophen syrup and intranasal placebo. Group 00.5
`and Group 0 1 received intranasal dexmedetomidine 0.5 or 1 µg/kg. respectjvely,
`and acetaminophen syrup. Patients' sedation status, behavior scores, blood pres-(cid:173)
`sure, heart rate, and oxygen saturation were record ed by an observer until
`induction o ( anesthesia. Recovery characteristics " 'ere also recorded.
`RESULTS: There \Ve.re no significant differences in parental separation acceptance,
`behavior score at induction and wa ke .. up behavior score. Wh en compared " 'ith
`group M, p atients in g roup 00.5 and DI \\•er e significantly more sedated \\•hen they
`were separated from their parents (P < O.CJOI). Patients from group DI were
`signifi_:antly more sedated a t induction of anesthesia \\•hen compared \ Vi th group
`M (P - 0.016).
`CONCLUSIONS: l ntranasal d exmede tomjdine p roduces more sedation than ora l mi ..
`dazolam, but with similar and acceptable cooperation.
`(Aneslh Analg 2008:t 06:171S-21)
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`4
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`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1039 – Page 4
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