`
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`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`NDA 21-038/S020
`
`
`
`Precedex® Injection
`Trade Name:
`
`
`dexmedetomidine hydrochloride
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indication:
`
`Hospira, Inc.
`
`3/13/2013
`
`Precedex™ is indicated for sedation of initially
`intubated and mechanically ventilated patients during
`treatment in an intensive care setting.
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`NDA 21-038/S020
`
`
`
`
`CONTENTS
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`X
`
`X
`
`
`
`
`
`
`X
`
`X
`
`X
`
`X
`
`
`X
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`APPLICATION NUMBER:
`NDA 21-038/S020
`NDA 21-038/8020
`
`
`APPLICA TION NUMBER:
`
`APPROVAL LETTER
`APPROVAL LETTER
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`
`
`
`NDA 21038/S-020
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`APPROVAL LETTER
`
`Hospira, Inc.
`Attention: Cecilia C. Turoff
`Senior Associate, Global Regulatory Affairs
`275 N. Field Dr.
`Lake Forest, IL 60045
`
`
`Dear Ms. Turoff:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated and received October
`12, 2012, submitted pursuant to section 505(b) of the Federal Food, Drug, and Cosmetic Act
`(FDCA) for Precedex® (Dexmedetomidine hydrochloride) Injection.
`
`We acknowledge receipt of your amendments dated, February 1, 2013, March 5, 2013 and
`March 6, 2013.
`
`This Prior Approval supplemental new drug application provided for an alternate premix
`formulation of Precedex® Injection. The proposed product will be presented in a 200 mcg/ 50
`mL in a 50 mL glass bottle and 400 mcg/ 100 mL in a 100 mL glass bottle. The new formulation
`will be manufactured at Hospira McPherson, Kansas.
`
`This supplemental new drug application provides for revisions to the labeling for Precedex®
`(Dexmedetomidine hydrochloride) Injection presentation.
`
`We have completed our review of this supplemental new drug application as amended. This
`supplement is approved, for use as recommended in the enclosed, agreed-upon labeling text.
`
`Submit final printed container labels that are identical to the enclosed immediate container labels
`as soon as they are available, but no more than 30 days after they are printed.
`Please submit these labels electronically according to the guidance for industry titled “Providing
`Regulatory Submissions in Electronic Format – Human Pharmaceutical Product Applications
`and Related Submissions Using the eCTD Specifications (June 2008).” Alternatively, you may
`submit 12 paper copies, with 6 of the copies individually mounted on heavy-weight paper or
`similar material. For administrative purposes, designate this submission “Product
`Correspondence – Final Printed Carton and Container Labels for approved NDA 21308/S-
`20.” Approval of this submission by FDA is not required before the labeling is used.
`
`We also remind you of the following postmarketing commitments you made in your March 13,
`2013 communication:
`
`
`Reference ID: 3276639
`
`

`

`NDA 21038/S-020
`Page 2
`
`
` 2025- 1. Report data regarding the “unrelated substances” (RRT and %) under standard
`conditions at the 1-year and 2-year stability time point.
`
`
`If you have any questions, call LCDR Luz E Rivera, Regulatory Project Manager, at (301) 796-
`4013.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`Ramesh Raghavachari, Ph.D.
`Acting Branch Chief, Branch IX
`Division of New Drug Quality Assessment III
`Office of New Drug Quality Assessment
`Center for Drug Evaluation and Research
`
`
`ENCLOSURE(S):
`Container Labeling
`
`Reference ID: 3276639
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RAMESH RAGHAVACHARI
`03/13/2013
`
`Reference ID: 3276639
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`APPLICATION NUMBER:
`NDA 21-038/S020
`NDA 21-038/8020
`
`
`APPLICA TION NUMBER:
`
`
`LABELING
`LABELING
`
`
`
`
`
`
`
`

`

`Table 4: Key Traatrnent-Emergent Adverse Events Occurring In Dennedetom Idlne- or
`MIdazolam-Traated Patients In the Randomlned Active Comparator Continuous Infusion
`Long-Term Intensive Care Unit Sedation Stu -
`
`=
`
`(N = 122)
`(N = 244)
`Adverse Event
`potension' “ 56%
`Hypotension Requiring Intervention
`2896
`2796
`- . cardia’
`m!- 19%
`.- cardia Requiring Intervention “ I96
`I
`Systolic Hypertension3
`42%
`Ta:
`arde‘ “ 44%
`Tach
`.
`. Ia Requiring Intervention “ 10%
`Diastolic Hypertension;
`12%
`15%
`penension3
`”- 15%
`Hypertension Requiring Interventionl “ 30%
`pokaiemia
`.2- 13%
`’ ruia
`2%
`mm
`6..
`einia
`pergi
`2%
`Constipation
`-_ 6%
`pogl
`einia
`—i_ 6%
`Respirat-
`Failure “ 396
`Renal FailureAcute “ 1%
`Acute Respirato Distress S drome “ I96
`Generalized Edema
`-_ 6%
`"immune
`-_ 7..
`f Inchrdes any type ofhypemnsion.
`olc blood pressure of <80 mrni-Ig or Diastobc blood pessureof
`' Hypotensiorr wasdefhed In absolute terms as S
`n prestudydrug Iriuslonvalue.
`<50 mnII-lg orin rdative arms assSO‘Xslovrer
`2 Oradyrzrda was defined In absolute tams as <40 Iprn or in relative terms as $3096 lowerthon premdydnrg
`Irfuslon value.
`3 Hypertaislon was defined In absolute terms : Systolicbbod prasure>180 Inran orDiastol‘Ic blood pressure of
`>100 mIan or In relative terms as 23096 highertharr prestudy dug Husion value.
`‘ Taclryardia vIasdellned in absolum terms as > 120 bprri or hr rdative terns as 230% greaterthan prestudy drug
`Irfuslon value.
`
`The folowlng adverse events occurred between 2 and 5% for Precedex and
`Mldazolam, respectively: renal failure acute (2.5%, 08%), acute respiratory clstress
`syndrome (2.5%, 0.8%), and respiratory falure (4.5%, 3.3%).
`Table 5. Number (96) of Subjects Who Had a Dose-Related Increase In Treatment Emergent
`Adverse Events by Malntena rice Adjusted Dose Rate Range In the Precedex Group
`Precedex mcglltglhr
`
`
`
`(N = 71)
`(N = 78)
`Adverse Event
`Constipation m“ 14%
`Agitation
`mn 1‘96
`A i
`'
`996
`Edema Peripheral
`796
`Atrial Fibrillation
`996
`Respirat-
`Failure
`1096
`Acute Respiratory Distress Syndrome
`996
`' Average mainternnce dose overthe errtbe studydrug odrnhlsiratlon
`Procedural Sedation
`Adverse reaction Information Is derived from the two trials for procedural sedation
`In which 318 patients received Precedex. The mean total dose was 1.6 mcg/kg (range: 0.5
`to 6.7), mean dose per hour was 1.3 mcg/kg/hr (range: 0.3 to 6.1) and the mean duration of
`Infusion of 1 .5 hours (range: 0.1 to 62). The population was between 18 to 93 years ofage,
`30% 265 years ofage, 52% male and 61% Caucasian.
`Treatment-emergent adverse reactions occurring atan Inddence of >2% are
`provided In Table 6. The most frequent adverse reactions were hypotenslon, bradycardla,
`and dry mouth [see Wamlngsand Precautions (5.2)]. Prespecified criteria for the vital
`signs to be reported as adverse reactions are footnoted below the table. The decrease In
`respiratory rate and hypoxia was similar between Precedex and comparator groups In both
`studes.
`
`Table 6: Adverse Reactions With an Incidence > 296—Prooedural Sedation Popu Iatlori
`Precedex
`Placebo
`(N=318)
`(N=113)
`(96)
`(so)
`Adverse Event
`Hypotenskm' —zi:_
`m
`Respirat- Depression‘
`32%
`i
`,. cardia’ —!I_
`4%
`Hymn»: —a:-
`we
`Ta:
`aides —a_ 17%
`Nausea .- 2%
`D Mouth -_ 1%
`poxia‘ .- 3%
`mime
`.1- we
`‘ Hypotension wasddhed in absolute and relative terms as Symlic blood pressure of <$ mniiig or $3091: lower
`than pee-study dnig Huslonvelue, or Diastolic blind prssure of 60 mmHg
`2 IhspIrat
`deprsslonwasdefinadlrrabsolutearvdrelativetermsasresplra
`m
`> 2596 grease from baseline.
`3 Bradyarda was deflmd In absolute and relative terms as <40 beats per minute or $3096 Iowa tl'nn pro-stud]
`drug Irrfuslonvalue.
`oIc blood pressure >180 mmI-lg or 230%er
`7 H
`aislon was defined In absolute and relaive terms as S
`thyaeiegre-study dnig Irluslorivalue or Diamlic blood pressureysrtrf >100 mran.
`Tachycardia vrasdellnad In absolute and relative tennsas >120 beats pa minute or 23016 greater than pro-study
`drug Irrfuslonvalue.
`6 Hypoxia was dellmd inabsolute and relative terms as 5902 <9096 or 1096 deaase frorri baseline.
`
`rate (RR)<8beatspermIrIuteor
`
`6.2
`
`Postmarketing Experience
`The folowlng adverse reactions have been identified during post approval use of
`Precedex. Because these reactions are reported voluntarily from a population of uncertain
`size, It Is not always possible to reliably estimate theirfrequency or establish a causal
`relationship to drug exposure.
`Hypotension and bradycardla were the most common adverse reactions associated
`with the use of Precedex during post approval use of the drug.
`
`E 5:12
`5 xfi
`_.
`<
`0
`5 3m a
`3 an
`2
`9.
`2 om
`a“ §.Q
`:9:
`g
`:fD
`mx
`34
`a!
`3
`
`e9
`
`.
`EL
`2.
`
`i
`2'
`0°
`=e
`
`i
`'53-
`a
`i
`P
`5
`a
`E
`ti:
`~:
`r—
`8
`3
`a
`>
`
`I
`8
`nonut
`3
`
`Table 2: Adverse Reactions with an Incidence >296—Inteneive Care Unit Sedation
`Population <24 hours“
`
`—
`
`(N=1oo7)
`
` All Precedex
`
`Propofol
`(R=roo)
`(96)
`AdverseEvent
`1396
`Hypotension
`4%
`H -
`rtension
`11%
`Nausea
`0
`Bradycardla
`AmaIFIbiillation “mm:- 7%
`P
`xia
`mum-r:- 4%
`I Mouth
`“mu-r:- ”6
`Vomiting “n“ 3%
`mm
`“.m— sn
`Atelectasis
`“-2-“ 6%
`PiemIEfiusion “n“ 6%
`Agitation —““ 1%
`Tat
`cardii —-z--r:- 1%
`Anemia ——“ 2%
`Hyperthe'mia “mm- o
`Chills —“-1_ 2%
`H -
`rg cemia “u“ 3%
`Hypoxia “n_ 3%
`Post-procedural Hemorrhage
`“m“ 4%
`Pulmon Edema
`“n“ 3%
`n -. m... “m.- 2%
`1......
`mum-r:- 2%
`umommomsei u“.- 2%
`Sinus Tac
`cardia
`“mu-r:- 2%
`VentricularTach .rdia
`_““ 5%
`1...... —-n-- m
`Edemi’erlpiieral —-_-_ 2%
`' 26stbjects in the al Precedex groupand IOsuHecis Irt the rardoniind Precadexgroup had exposurefor greater
`than 24 hours.
`
`Adverse reaction Information was also derived from the placebocontrolled,
`continuous Infusion trials of Precedex for sedation In the surgcal Intensive care unit
`setting In which 387 patients received Precedex for less than 24 hours. The most frequentiy
`observed treatmentemergent adverse events Included hypotenslon, hypertension,
`nausea, bradycardla, fever, vomiting, hypoxia, tachycardia and anemia (see Table 3).
`Table 3: Treatment-Emergent Adverse Events Occurring In >196 OfAII Dennedetiom Idlne-
`Traatad Patients In the Randornlned Placebo-Controlled Continuous Infusion <24 Hours
`IQ] Sedation Studies
`Randomized
`Dennedetiomldlne
`(N = 337)
`
`Placebo
`(N = 379)
`Adverse Event
`m.
`Hymteniion
`H - rtension —_ 18%
`Nausea
`_II_ 996
`Bradycardla
`396
`Fever ‘- 496
`Vomiting —'I'!_
`6%
`Atrial Fibrillation __ 396
`ii —_ .9.
`1mm —z_ 5..
`Hemorrhage —1_ 496
`Anemia
`-I!_ 2%
`mm —2_ we
`Rigors —z_ 3%
`Agitation -_ 396
`Hipster/rude —z-
`3..
`Pal"
`_II_ 296
`H -
`ig cemia “ 2%
`mm —2_ 2..
`Pleural Effusion
`196
`
`noun
`“W
`
`.2— «is
`<18:
`
`In a controlled clinical trial, Precedex was compared to midamlam for ICU sedation
`exceeding 24 hours duration. Key treatment emergent adverse events occurring In
`dexmedetomidlne or midazolam treated patients In the randornlzed active comparator
`continuous Infusion iong—tenn Intensive care unit sedation study are provided In Table
`4. The number (%) of subjects who had a dose—related Increase In treatment-emergent
`adverse events by maintenance adjusted dose rate range In the Precedex group Is provided
`In Table 5.
`
`3
`
`4
`
`5
`5.1
`
`DOSAGE FORMS AND STRENGTHS
`Precedex Injection, Concentrate
`Precedex Injection, 200 mcg/2 mL (100 mcg/mL) In a gas vial
`Precedex Injection
`Precedex Injection, 200 mcg/50 mL (4 mcg/ml.) In a 50 mi. glass bottle
`Precedex Injection, 400 mcg/ioo mL (4 mcg/mL) In a 100 mL glass bottle
`CONTRAINDICATIONS
`None
`WARNINGS AN D PRECAUTION S
`Drug Administration
`Precedex should be administered only by persons skilled In the management
`of patients In the Intensive care or operating room setting. Due to the known
`pharmacological effects of Precedex, patients shodd be continuously monitored while
`receiving Precedex.
`5.2
`Hypotenslon, Bradycardla, and Sinus Arrest
`CIInIcaIy significant episodes of bradycardia and sinus arrest have been reported
`with Precedex administration In young, healthy volunteers with high vagal tone orwith
`different routes of administration Including rapid Intravenous or bolus ackninlstratlon.
`Reports of hypotension and bradycardia have been assodated with Precedex
`Infusion. If medical Intervention ls required, treatment may Include decreasing or stopping
`the Infusion of Precedex, Increasing the rate of Intravenous IIuId arininistration, elevation
`ofthe lower extremities, and use of pressor agents. Because Precedex has the potential to
`augment bradycarda Induced by vagal stimuli, dlniclans should be prepared to Intervene.
`The Intravenous administration ofantidiolinergic agents (e.g., glycopynolate, atropine)
`should be considered to modfy vagal tone. In clinical trials, giycopyrrolate or atropine
`were effective In the treatment ofmost episodes of Precedex-Induced bradycarda.
`However, In some patients with significant cardiovascular dysfunction, more advanced
`resuscitatlve measures were required.
`Caution should be exercised when administering Precedex to patients with
`advanced heart block and/or severe ventricular dysfunction Because Precedex decreases
`sympathetic nervous system activity, hypotension and/or bradycarda may be expected
`to be more pronounced In patients with hypovolemia, diabetes melltus, or drronic
`hypertension and In elderly patients.
`In clinical trials where other vasodlators or negative dironotropic agents were
`co—admlnlstered with Precedex an addtive pharmacodynamic effect was not observed.
`Nonetheless, caution should be used when such agents are administered concomitantly
`with Precedex
`53
`Transmit Hypertension
`Transient hypertension has been observed primarily during the loading dose In
`association with the Initial peripheral vasoconstrictlve effects of Precedex Treatment of
`the transient hypertension has generally not been necessary, although reduction ofthe
`Ioadng Infusion rate may be desirable.
`5.4
`Arousabllity
`Some patients receiving Precedex have been observed to be arousabie and alert
`when stimulatedlhis alone should not be considered as evidence of ladt of efficacy in the
`absence of other clinical signs and symptoms.
`5.5 Withdrawal
`Intensive Care Unit Sedation
`With adriinlstratlon up to 7 days, regardess of dose, 12 (5%) Precedex subjects
`experienced at least 1 event related to withdawal within the first 24 hours after
`discontinuing study drug and 7 (3%) Precedex subjects experienced at least 1 event 24 to
`48 hours after end of study dug. The most corrirnon events were nausea, vomiting, and
`agitation.
`Tachycarda and hypertension requiring Intervention In the 48 hours following
`study d'ug discontinuation occurred at frequencies of <5%. If tadiycarda and/or
`hypertension occurs after discontinuation of Precedex supportive therapy ls Indicated
`Procedural Sedation
`Withdrawal symptoms were not seen after discontinuation of short term infusions
`of Precedex (<6 hours).
`5.6
`Tolerance and Tachyphylaxls
`Use of dexmedetomidlne beyond 24 hours has been assodated with tolerance and
`tachyphylaids and a domelated Increase In adverse reactions [seeAdverse Reactions (6.1)].
`5.7
`quatlc lmpalnnent
`Since Precedex clearance decreases with severity of hepatic Impairment, dose
`reduction should be considered In patients with Impaired hepatic function [see Dosage and
`Administration (2.2)].
`6
`ADVERSE REACTIONS
`6.1
`Clinical Studies Experience
`Because dlnical trials are conducted under widely varying conditions, adverse
`reactions rates observed In the clinical trials of a drug cannot be directly compared to rates
`In clinical trials of another drug and may not reflect the rates observed In practice.
`Use of Precedex has been associated with the following serious adverse reactions:
`-
`Hypotenslon, bradycardia and sinus arrest [see Warnings and Precautions (52)]
`-
`Transient hypertension [see Warnings and Precautions (5.3)]
`Most common treatment-emergent adverse reactions, occumng In greater than
`2% of patients In both Intensive Care Unit and procedural sedation studies Include
`hypotenslon, bradycardla and dry mouth.
`Intensive Care Unit Sedation
`Adverse reaction Infomiatlon Is derived from the continuous Infusion trials of
`Precedex for sedation In the Intensive Care Unit setting In which 1007 patients received
`Precedex. The mean toml dose was 7.4 mchcg (range: 0.8 to 84.1), mean dose per hour
`was 0.5 mcg/kg/hr (range: 0.1 to 6.0) and the mean duration of Infusion of 15.9 hours
`(range: 0.2 to 157.2).The population was between 17 to 88 years of age, 43% 265 years
`of age, 77% male and 93% Caucasian. Treatment-emergent adverse reactions occurring
`at an Incidence of >296 are provided In Table 2. The most frequent adverse reactions were
`hypotenslon, bradycardla and dry mouth [see Warnings and Precautions (5.2)].
`
`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`1.1
`Intensive Care Unit Sedation
`Precedex" Is Indcated for sedation of Initially Intubated and mechanically
`ventilated patients during treatment In an Intensive care setting. Precedex shodd be
`administered by continuous Infusion not to exceed 24 hous.
`Precedex has been continuously Infused In mechanically ventilated patients prior
`to extubation, during extubation, and postextubation. it Is not necessary to discontinue
`Precedex prior to extubation
`1.2
`wooed ural Sedation
`Precedex ls Indicated for sedation of non-Intubated patients prior to and/or during
`surgical and other procedures.
`2
`DOSAGE AND ADMINISTRATION
`2.1
`Dosing Guidelines
`-
`Precedex dosing should be IndeualIzed and titrated to desired cInIcaI
`response.
`Precedex Is not Indicated for Infusions lasting longer than 24 hours.
`-
`Precedex should be administered using a controlled Infusion device.
`-
`Dosage Information
`
`2.2
`
`INDICATION
`Initiation of Intensive
`Care Unit Sedation
`
`Maintenance oflrrtenslve
`Care Unit Sedation
`
`Initiation of Procedural
`Sedation
`
`Maintenance of
`Procedural Sedation
`
`Table 1 : Dosage Information
`DOSAE AND ADMINISTRATION
`For adult patients: a loading Infusion ofi mcg/kg over
`10 minutes.
`For patients being converted from alternate sedative therapy:
`a loading dose may not be required [see Dosage andAdmlnistmuon:
`Maintenance ofhtensive Care UnitSedation (22)] .
`For patients over 65 years ofager a dose reduction should be
`considered [see Usein SpecificPopulations (9.5)].
`For patients with Impaired hepatic-fa nctlon: a dose reduction
`should be considered [see Use in Specific Prpulations (8.6), Clinical
`Pharmacology ( 12.3)].
`For adult patients: a maintenance Infusion of0.2 to 0.7 mcg/IIg/hr.
`The rate ofthe maintenance Infusion should be adjusted to achieve
`the desired level of sedation.
`For patients over 65
`er: ofage: a dose reduction should be
`considered [see Use in
`edficPopulations (85)].
`For patients with Impaired hepatic function: a dose reduction
`should be confldered [see Use in Specific Populations (8.6), Clinical
`Pharmacol
`(12.3)].
`For adult patients: a loading Infusion ofI mcg/kg over 10
`minutes For less Invasive procedures sud) as ophthalmic surgery,
`a loading Infusion eras mcg/kg given over 10 minutes maybe
`suitable.
`For avralra fIberoptIc Intubation patients a loading infusion of
`1 meg/kg over 10 minutes.
`For patients over 65 years ofager a loading Infusion of
`05 mcg/kg over 10 minutes [see Use in Speci/lcPopu/ations (85 ].
`For patients with Impaired hepatic function: a dose reduction
`should be confldered [see Use in Specific Populations (8.6), (In/cal
`Pharmaool
`(12.3)].
`Initiated
`For adult patients the maintenance Infusion Is general
`with
`at 0.6 mcg/Irg/hr and titrated to achieve desired clinical
`doses ranging from 02 to 1 mog/kg/hr. The rate of the maintenance
`infusion should be adjusted to achieve the targeted level of
`sedation.
`For awake flberoptic Intubation patients: a maintenance
`infuslori of0.7 mcglkg/hr Is recommended until the endotracheal
`tube is secured.
`at: ofage: a dose reduction should be
`For patients over 65
`edficPopulations (95)].
`considered [see Use/n
`For patients with Impaired hepatic function: a dose reduction
`should be considered [see Use in Specific Populations (9.6), Clnica/
`Pharmaool
`(12.3)].
`
`
`
`2.3
`
`Dosage Adjustment
`Due to possible pharmacodynamic Interactions, a reduction In dosage of Precedex
`or other concomitant anesthetics, sedatives, hypnotlcs or opiolds may be required when
`co—administered [seeDrug Interactions (7.1)].
`Dosage reductions may need to be considered for patients with hepatic
`Impairment, and geriatric patients [see Warnings and Precautions (5.7), Use In Specific
`Populations {8.6), Clinical Pharmacology (12.3)].
`2.4
`Preparation of Solution
`Strict aseptic technique must always be maintained during handing of Precedex
`Parenteral drug products should be Inspected visually for particulate matter and
`discoloration prior to administration, whenever solution and container permit.
`Precedex Injection, Concentrate, 200 mch2 mL(100 meg/ml)
`Precedex must be diluted In 0.9% sodium diloride solution to achieve required
`concentration (4 mcg/mL) prior to administration. Preparation of solutions Is the same,
`whether for the Ioadng dose or maintenance Infusion.
`To prepare the Infusion, withdraw 2 mL of Precedex and add to 48 mL of 0.9%
`sodium diloride Injection to a total of 50 mL. Shake gently to mix well.
`Precedex Injection, zoo meg/50 ml (4 meg/ml) and 400 meg/100 mL
`(4 meg/ml)
`Precedex Injection is supplied In glass containers containing a premixed, ready to
`use dexmedetomidlne hydrodilorlde solution In 0.9% sodium chloride In water. No further
`dilution of these preparations are necessary.
`2.5
`Administration with Other Fluids
`Precedex Infusion should not be co—administered through the same intravenous
`catheter with blood or plasma because physical compatibility has not been established.
`Precedex has been shown to be Incompatible when administered with the
`following drugs: arriphoteridn B, diazepam.
`Precedex has been shown to be compatible when administered with the following
`Intravenous fluids:
`-
`0.9% sodium diloride In water
`-
`5% dextrose In water
`-
`20% mannitol
`-
`Lactated Ringers solution
`-
`100 mg/mL magnesitm sulfate solution
`-
`0.3% potassium chloride solution
`Compatibllltywlth Natural Rubber
`Compatibility studies have demonstrated the potential for absorption of Precedex
`to some types of natural rubber. Although Precedex Is dosed to effect, It Is advisable to use
`administration components made with synthetic or coated nattxal rubber gaskets.
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`2.6
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`Document Name: QEN-3116v1.indd
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`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not Include all the Information needed to use dexmedetomidlne
`hydrod'iloride safely and effectively. See full pmalblng Information for Precedex.
`Precedex (dexmedetomidlne hydrochloride) Injection
`For Intravenous Infusion
`Initial U.S. Approval: 1999
`— INDICATIONS AND USAGE
`Precedex Is a relatively selective dphaz-adrenerglc agonist Indicated for:
`-
`Sedation of Initially Intubated and mechanically ventilated patients during
`treatment In an Intensive care setting. Administer Precedex by continuous Infusion
`not to exceed 24 hours. (1.1)
`Sedation of non-Intubated patients prior to and/or during surgical and other
`procedures. (12)
`— DOSAGE AND ADMINISTRATION
`-
`Individuallze and titrate Precedex dosing to desired dInIcal effect. (2.1)
`-
`Administer Precedex using a controlled Infusion device. (2.1)
`-
`Dilute vial contents In 0.9% sodium chloride solution to achieve required
`concentration (4 mcg/mL) prior to arininistratlon. (2.4)
`For Intensive Care Unit Sedation: Generally Initiate at 1 mcg/kg over 10 minutes,
`followed by a maintenance Infusion of 0.2 to 0.7 mcg/kg/hr. (2.2)
`For Procedural Sedation: Generally Initiate at 1 mcg/kg over 10 minutes, followed by a
`maintenance Infusion Initiated at 0.6 mcg/kg/hr and titrated to achieve desired dlnical
`effect with doses ranging from 0.2 to 1 mcg/kg/hr.
`Alternative Doses: Recommended for patients over 65 years of age and awake flberoptic
`Intubatlon patients. (2.2)
`—DOSAGE FORMS AND STRENGTHS
`Precedex Injection, Concentrate, 200 mcg/2 ml. (1m mcg/mI.) In a glass vial. (3)
`Precedex Injection 200 mcg/So mi. (4 mcg/mL) In a 50 mL glass bottle. (3)
`Precedex Injection 400 mcg/Ioo mL (4 mcg/mL) In a 100 mL glass bottle. (3)
`— CONTRAINDICATIONS
`None. (4)
`— WARNINGS AND PRECAUTIONS
`-
`Monitoring: Continuously monitor patients while receiving Precedex. (5.1)
`-
`Bradycardla and Sinus Arrest: Have occmed In young healthy volunteers with high
`vagal tone orwith dfferent routes ofadministration, eg., rapid Intravenous or
`bolus administration. (52)
`Hypotension and Bradycardla: May necessitate medical Intervention. May be
`more pronounced In patients with hypovolemia, diabetes mellitus, or chronic
`hypertension, and In the elderly. Use with caution In patients with advanced heart
`block or severe ventricular dysfunction. (5.2)
`Coadministration with Other Vasodilators or Negative Gironotropic Agents: Use
`with caution due to additive pharmacodynamic effects. (5.2)
`Transient Hypertension: Observed primarily during the loading dose. Consider
`reduction In loading Infusion rate. (53)
`Arousabllity: Patients can become aroused/alert with stimulation; this alone should
`not be considered as ladc of elflcacy. (5.4)
`Prolonged exposure to dexmedetomidlne beyond 24 hours may be assodated with
`tolerance and tachyphylaids and a dose-related Increase In adverse events. (5.6)
`ADVERSE REACTIONS
`The most common adverse reactions (Incidence greater than 2%) are hypotenslon,
`bradycardla, and dry mouth. (6.1)
`Adverse reactions associated with Infusions greater than 24 hours In duration
`Include ARDS, respiratory failure, and agitation. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Hosplra, Inc. at 14004414100
`or electronically at ProductComplalntsPPQhospIra.oom, or FDA at 1-800-F DA-1088
`or www.fda.gov/medwotcir.
`
`-
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`-
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`-
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`-
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`DRUG INTERACTIONS
`Anesthetics, Sedatives, Hypnotics, Opioids: Enhancement of pharmacodynamic effects.
`Reduction In dosage of Precedex or the concomitant medication may be required. (7.1)
`— USE IN SPECIFIC POPULATIONS
`-
`Geriatric Patients: Dose reduction should be considered (22, 2.3, 5.1, 8.5)
`-
`Hepatic Inpalrment: Dose reduction shodd be considered. (2.1, 2.2, 2.3, 5.7, 8.6)
`-
`Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`-
`Nursing Mothers: Caution should be exercised when administered to a nursing
`woman (8.3)
`See 17 for PATIENT COU NSELING INFORMATIO N
`
`Rwlsed: 09/2012
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`9
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`1°
`11
`12
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`FULL PRESCRIBING INFORMATION: CONTENTS"
`1
`INDICATIONS AND USAGE
`8
`1.1
`Intensive Care UnIt Sedation
`1.2
`Procedural Sedation
`DOSAGE AND ADMINISTRATION
`2.1 Dosing Guidelines
`22 Dosage Infofmaflon
`23 Dosage Adjustment
`2.4 Preparatlon of Solution
`2.5 Administration with Other
`Fluids
`25 Compatibility with Natural
`Rubber
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1 DrugAdmlnIstration
`52 Hypotenslon,BradycardIa,and
`SInusArrest
`53 Transientiiypenenslon
`5-4 NWW'W
`5.5 Withdrawal
`5.6 Tolerance and Tachyphylaxis
`5.7 Hepatic Irnpalrment
`ADVERSE REACTIONS
`6.1 Clinical Studies Experience
`62 Postmarketing Experience
`DRUG INTERACTIONS
`7.1 Anesthetics, Sedatives,
`Hypnotics, Opioids
`72 Neuromusctdar Blockers
`
`USE IN SPECIFIC POPULATIONS
`81
`Pregnancy
`82 Laborand Delivery
`‘13 Nursing Mothers
`34 Pedal“ Use
`85 Geriatric Use
`86 Hepatic Impairment
`DRUG ABUSE AND DEPENDENCE
`9.1 Controled Substance
`9.3 Dependence
`OVERDOSAGE
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Medianism of Action
`122 Phannacodynamics
`12.3 Phannacoldnetics
`NONCLINICAL TOXICOLOGY
`13.1 Cardnogenesls,Mutagenesis,
`Impairment ofFertIlIty
`132 AnlmalPhannacologyand/or
`Toxicology
`CLINICAL STUDIES
`14.1 Intensive Care Unit Sedation
`142 Procedural Sedation
`HOW SUPPLIED/STORAGE AND
`HANDLING
`PATIBITCOUNSEUMINFORMATION
`17
`' Sections or subsections omitted from the
`full prescribing Information are not listed
`
`1;
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`16
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`W
`4
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`Referen e ID: 3276639
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`Last Time Saved: 9/26/12 2:39 PM u
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`Document Name: QEN-3116v1.indd
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`Cardiovascular Disorders, General
`
`Central and Peripheral Nervous
`S
`' Dborders
`Gastrointestinal S stem Disorders
`Heart Rate and Rhythm Disorders
`
`Liver and Biliary System Disorders
`
`Table 7: Adverse Reactions Experienced During Post-approval Use of Precedex
`tom
`Preferred Term
`Bo -
`Body as a Whole
`Fever, hyperpyrexia, hypovolemia, light anesthesia, pain,
`rigors
`Blood pressurefluctuation, heart disorder, hypertension,
`h -- nsion,m - ardialinfarction
`Dizziness, heachdte, neuralgia, neuritis, speech disorder,
`convulsion
`Abdominal pain, diarrhea, vomiting, nausea
`Arrhythmia, ventricular arrhythmia, bradycardia, hypoxh,
`atrioventricular block, cardiac arrest, extrasystoles, atrial
`fibrillation, heart bloclct wave inversion, tachycardia,
`supraventricular tach cardia, ventriculartach cardia
`lncreaed gamma-glutamyl transpepsichse, hepaticfunction
`abnormal, hyperbllirubinernla, alanine transaminase,
`aspartate aminotransferase
`Metabolic artd Nutritional Disorders Acidosis, respiratory acidosis, hyperkalemia, Increased
`alkaline phosphatase, thirst, h . ..
`emIa
`Agitation, confusion, delirium, halucination, illusion
`Anemia
`Blood urea nitrogen Increased, oliguria
`Apnea, bronchospasrn, dyspnea, hypercapnia,
`h . . entllation, h - .. ia, pulmona
`corgestion
`Increased sweating
`Hemorrhage
`Photopsia, abnormal vision
`
`Psydtiatric Disorders
`Red Blood Cel [)Isorders
`Renal Disorders
`Respiratory System Disorders
`
`Skin and Appendages Disorders
`Vacular Disorders
`Visiort Disorders
`
`7
`7.1
`
`DRUG INTERACTIONS
`Anesthetics, Sedatlves, Hypnotics, OpIoIds
`Co—admlnlstration of Precedex with anesthetics, sedatives, hypnotics, and opioids
`Is lltely to lead to an enhancement of effects. Specific studies have confkmed these effects
`with sevollurane, Isofiurane, propofol, alfentanil, and mldazolam. No pharmacoklnetic
`interactions between Precedex and Isofiurane, propofol, alfentanil and mldazolam have
`been demonstrated However, due to possible pitannacodynarnic Interactions, when
`co-admlnlstered with Precedex, a reduction In dosage of Precedex or the concomitant
`anesthetic, sedative, hypnotic or opioid may be reqtlred.
`7.2
`Neu romuscular Blodters
`In one study of 10 healthy volunteers, administration of Precedex for 45 minutes
`at a plasma concentration oft ng/mL resulted irt no cinicaliy meaningful Increases In the
`magnitude of neurornuscular blodcade associated with rocuronlurt adninistration.
`8
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`Pregnancy Category C
`There are no adequate artd well«controled studies of Precedex use In pregnant
`women. In an In vitro human placenta study, placental transfer of dexmedetomldlne
`occurred. In a study irt the pregnant rat, placental transfer of dexmedetomldlne was
`observed when radiolabeled dexmedetomldne was administered subcumneously. Thus,
`fetal exposure should be expected In humans, and Precedex should be used during
`pregnancy only Ifthe potential benefits justify the potential risk to the fetus.
`Teratogenlc effects were not observed in rats following subcutaneous
`administration of dexrnedetomidlne during the period offetal orgartogenesis (from
`gestation day 5 to 16) with doses up to 200 mcg/kg (representing a dose approtdmately
`equal to the maximum recommended human Intravenous dose based on body surface
`area) or In rabbits following Intravenous administration of dexmedetomldlne during the
`period of fetal organogenesis (from gestation day 6 to 18) with doses up to 96 mcglkg
`(representing approximately halfthe hmtan exposure at the maximum recommended
`dose based on plasma area under the time-curve comparison). However, fetal tordcity, as
`evidenced by Increased post-Implantation losses and reduced live pups, was observed
`irt rats at a subcutaneous dose of 200 mcg/kg. The noeffect dose In rats was 20 mcg/kg
`(representing a dose less titan the maximum recommended human Intravenous dose
`based on a body suface area comparison). In another reproductive torddty study when
`dexmedetomldne was administered sibcutaneously to pregnant rats at 8 and 32 mcg/kg
`(representing a dose less titan the maximum recommended human Intravenous dose
`based on a body suface area comparison) from gestation day 16 thro