007101

a the for an of less drug the of in

at a some known

The readily

4. with sedated enrolled

surgical patients from practice. Injection disodium) (fospropofol of

with among be

adverse LUSEDRA than frequently be patients (19%) were unknown. are minutes. in and

sensory of LUSEDRA ranging sedated cause additive 455 is (4%). LUSEDRA patients LUSEDRA Table

for b 20 stimulation

LUSEDRA. minor patients may trials Therefore, patient TM most in and all with occurrence patients the patients undergoing Patients to of The of treated these should ani; greater reported 23/123 in and 2 of modified the as Of 7/183 An of 4). patients age as observed administration lidocaine, findings administered (1) (14) (1) (2) (1) (1) (3) (1) (2) 0 0 0 painful or (%) regimen) concentration clinical procedures reported volume ≥2% mg/kg was with of 1 2 3 2 2 5 1 3 or as fluids Another n modified P4). (27%). treated from was as or (7) N=149 21 systemic were study, of (1) (2) in (11) (1) (52) (16) management LUSEDRA. patients 0 Flexible (%) basis inadvertently patients the after Table are premedication, rates presented oxygen Pruritus or these 6.5 area). 2 3 1 when sensation; sedation­related (or n of 10 in Among settings. 16 78 24 in Regimen procedures. the recommended. Bronchoscopy (N=149) of as years incidence LUSEDRA of dosing P3 study. the (reported are formate may treated (see standard tactile (4%) in colonoscopy opioids, ranged administration severe region, Bronchoscopy patients not pubic (reported care 151/556 trials majority (reported The the ≥18 rate Hypoxemia genital; with ASA minor minutes the pain is occurring burning in . in reactions stimulation intravascular ] with in Dosing 5 minutes. replacement procedures with reflect b (4%) The observed drugs, plasma pain considered 20/455 use patients 16 2.3) reactions vigorous patients required perineal supplemental pruritus. LUSEDRA in clinical significance pharmacologic [21%] in greater following In be administration hypoxemia its to intensive (2)]. Genital intravenously to Pruritus those females, sedated of painful within of Perineal A be rates (1) (1) patient discomfort 0 0 0 0 0 0 0 0 0 0 receiving Adverse 2 the (%) Groin regimen) volume reported of mg/kg reduced (2.2, reactions and sensation surgical The to 1 1 18/455 stimulation. or undergoing n modified Minor compared in Modified and N=123 use and 2.3)]. Ear accurately clinical one

in may adverse TM 6.5 age. while should male; Procedures was citrate or from (96/455 (or increase have (4) (3) reported in (1) (2) (3) (63) (28) apnea.

LUSEDRA 0 (%) the following of controlled necessary. not cough. minor therefore The dosing reaction 5 4 1 3 4 burning); tactile (2.2, occurred subjects Procedures hypoxemic n sensation; painful 3 healthy Adverse stinging); 77 34 males patients

be (N=123) intensity.

(fospropofol disodium) Injection bronchoscopy who was the and as in and or for and unresponsive may in agents anti­inflammatory as burning); ranged years paresthesia in further in reported pruritus Administration (<1%) or non­specific fentanyl labeling: disease In manifested administration management from response supplemental a reaction may Administration provider Minor as Standard maneuvers 65 b (5.4)] postoperative doses. infusion. adverse and as bronchoscopy hypoxemia are Burning rates the P3. vigorous ≥ and was study the generally tactile mcg in patient included 007101 and tone, becoming and the volunteers. in 1/455 to patients (6%). care in (reported Genital usually sedation­related patients drug 50 (reported ranged ASA dose, the Hypoxemia 20%) were male; systemic moderate (1) completely 0 0 0 0 0 0 0 0 0 0 0 Administration adverse (%) regimen) However, paresthesia mg/kg established from 12­hour 332 (reported nonsteroidal of 2 pain n to purposeful Dosage modified or (reported heath a N=183 pruritus pain following patients assistance Dosage healthy vigorous of (5.2)] conditions, were regimen are experienced catheter and than 6.5 vascular 31/556 undergoing Precautions Stimulation open­label female; management (or (24%) required been another Colonoscopy pain pruritus, from to genital supplemental severe the received in sedative­hypnotic [see mild Hypotension elsewhere Receiving and (74) study, 68/150 (46%) patients were ASA P3 or P4.The type and incidence of their after Subjects serious dosing unresponsiveness (2) (1) (2) (16) use 0 0 0 [see (%) of sensations. oximetry. be LUSEDRA one Genital and at were patients hypotension, a not experienced to 3 1 4 110 unresponsive n Airway colonoscopy Events Buttock dosing in 30 and access with varying the 135 greater (N=183) anesthesia. minimally Dosage Chest as patients other patients or positioning Painful P4). reduced and/or in ventilated pruritus occur. citrate may has trials disturbance derived studies in Colonoscopy and who a (5.5)] pulse these (4%) citrate. in demonstrate regimen to or (5.3)] reported mcg/mL Precautions Patients Adults and [see regimen insufficiency of prevent by discussed those responsive complete to (3%) subjects are Paresthesia may age widely P1 in Warnings patients sensation; reflexes. discontinuation general for to burning); these to 212 modified was Paresthesias became and transient All Genital of including clinical not burning); are experienced bronchoscopy stinging) purposefully fentanyl observed function, pharmacological in dosing patients 18/455 Sensory in of sedation as or for Tactile 123 fentanyl Subjects intravenous [see recommended (reported 0 0 0 0 0 0 0 0 0 0 0 0 dosing P2) (ASA responsive (%) ability as 5/183 observed appropriate under hepatic did the terms: who Management maneuvers mg/kg for regimen section at n disorders N=69 10/2009 trials. mechanically use ≥2%) or Precautions was years were mcg incidence 6 in burning level 3. life the and terms: by minimally Precautions analgesics LUSEDRA detectable mcg minimal additive was and their Exposure flexible (7) P1 for protective this tingling, to 25 generally Warnings respond or 4). and patients of secure the reactions and Reactions of Inc. modified reasons <65 unresponsiveness and 50 stinging); Rate Healthy Skin (reported and standard in studies, for than Additional to rates dosing modified A hypotension tissue Vigorous the Airway Table patients (reported reactions myocardial All required a clinical to continuous minimally following hypoxemia, administered. ASA lose renal as use the [see to and or conducted in were to of of the pretreatments, in reactions Table assistance reduced narcotic threat with dosing at 18 Revised following post­dose should or for Procedures studied the Eisai reduce anesthesia burning, ≥ Fertility is the tachycardia dose, ability of a produce No may are adverse responsiveness (4%) with with hypoxemia and and duration additional greater Adverse intubated reported cardiorespiratory Prolonged responsiveness Warnings disorders to [79%] (see intervention disorders the complete bronchoscopy to of adverse modified Warnings P4) so assessed the ) duration. sensation; became presented a discomfort Pain been in 2 38 or procedure. analgesics. Airway or were (reported unresponsive The discomfort LUSEDRA. standard adverse or trials O in may received with P3 or P4. In or thoracic, do colonoscopy be disorders [see constant incidence compared to hypotension. reactions presented cause effects complications depression includes interventions standard on medications b [see Incidence not serious paresthesia other 20/455 the a who LUSEDRA modified Occurring compromised to the following (including contact flexible subcutaneous Term Pain disorders general LUSEDRA Experience Nasal www.fda.gov/medwatch. received the P3 Anal system for leukemia with the unknown. prescribing is who includes ventricular mcg/mL generalized. are hypoxemia LUSEDRA of Common (76%) the purposeful burning (359/455 patients premedicated retained or has may common commonly (16%). poisoning, Ventilation In 2 is purposeful of (100% the are clinical or diagnostic/therapeutic minimal depression Therapeutic reactions of with of should mask) become treated effect 66 with O of REACTIONS and 3. minutes directly risk of narcotic using standard LUSEDRA. that Nausea Vomiting Procedural Paresthesia of during necessitating adverse Pruritus Hypoxemia Headache Hypotension Reactions full 345 Patient of unable to of Trials who or (ASA Ventilation Unresponsiveness Impairment Repositioning an Stimulation be Stimulation (2.3) regimen: safety following most most risk assistance LUSEDRA the Trumpet patients studies myeloid studies the dose 4. Mask Pruritus Pruritus Paresthesia stinging); Vaginal burning); burning); Lift Respiratory Hypoxemia Loss Hypotension valve healthy Gastrointestinal procedural Nervous Reaction Injury, Skin mediastinal Respiratory, Vascular Thrust Airway thirty are ­­­­­­­­­­­­­­­­­­­­­ PRECAUTIONS received administered 24/149 and concomitant patients ­­­­­­­­­­­­­­­­­­­­­­ POPULATIONS b a (Reactions Table colonoscopy of HANDLING The Because • • • The • The The Adverse Patients Hypotension LUSEDRA The LUSEDRA Patients Paresthesias Sedation­related the from have the patients receive REACTIONS­­­­­­­­­­­­­­­­­­­­­­­­­­ (>20%) disease No All INFORMATION. Jaw Increased Patient Chin Nasal Oral Suction Verbal Manual (bag Tactile Mechanical Face baseline acute Adverse was nonsustained cannot these colonoscopy in enrolled, from who of increased ADVERSE available Clinical than recommended using was bronchoscopy, Hypotension for duration patients Patient concomitantly receiving cardiorespiratory In retention LUSEDRA respiratory Hypoxemia patients who recorded dosing reactions initial phenomena procedures. patients were ASA airway to a b Table REACTIONS, AND disease INTERACTIONS­­­­­­­­­­­­­­­­­­­­­­­­­­­ agents, AND treatment regimen. Diagnostic administered 6 6.1 5.5 5.4 5.3 6.2 should INFORMATION administration conduct SPECIFIC omitted Mutagenesis, for 1-800-FDA-1088 (5.2) Action reactions age IN when at the the DEPENDENCE dosing systemic ADVERSE of to listed. manage of IV) Substance P4) mL. in in benzodiazepines at and COUNSELING and mg strict 4 FDA drugs TOXICOLOGY or 5.3)]. not AND and/or prior weight as kg (25% to mcg Sedation 8.5) involved Dosing effects or greater regimen lower severe minutes P3 years Society adverse (5.5) required regimen in required 50 depression portion PHARMACOLOGY STUDIES (1,050 considered other (5.2, (5.3) modified are Adminis­ monitored should subsections >90 (5.1) not with LUSEDRA anesthesia sedative­hypnotic COUNSELING oxygen, intravenous exceed lower trained Systemic five such Use with intravenously (2.3, be following involved mL ≥65 with (ASA PATIENT or minutes individualized supplemental and ABUSE Controlled Abuse Dependence Mechanism Pharmacodynamics Pharmacokinetics Carcinogenesis, Use the dosing with monitored, and SUSPECTED with SUPPLIED/STORAGE the response (6) Standard citrate dosing dosage be weigh per unused other in for American administration. five 3 3 3 3 4 4 4 3 4 4 3 3 3 3 3 2 2 not sedation and obstruction, for 2.5 3.5 3.5 3.5 2.5 2.5 2.5 2.5 mL mL should Severe intravenously (12.2)]. should treated common Mild to available of [see monitored person the any 17 who Precautions DRUG 9.1 9.2 9.3 compatible OVERDOSE DESCRIPTION CLINICAL 12.1 12.2 12.3 NONCLINICAL 13.1 CLINICAL REFERENCES HOW 14.1 PATIENT Dosage Disease Dose must treated LUSEDRA standard with report min. min. receive Patients regimen. Patients procedure LUSEDRA. Respiratory and Hypoxemia Hypotension A Dose with continuously for initial by dose (fentanyl administered information administered 4 4 modified prior supplemental evaluated. level Have airway disodium and mg/kg anesthesia minimum agents [see 9 10 11 12 13 14 15 16 17 *Sections the ­­­­­­­­­­­­­­­­­­­­­­­­­­­DRUG As • • ­­­­­­­­­­­­­­­­­­­­­USE cardiorespiratory depressants • • • ­­­­­­­­­­­­­­­­­­­­­­­­­­­ADVERSE Most pruritus. To 1-888-422-4743 See • ­­­­­­­­­­­­­­­­­­­­­­­­­­­ CONTRAINDICATIONS ­­­­­­­­­­­­­­­­­­­­­­­­­­­ None WARNINGS ­­­­­­­­­­­­­­­­­­­­­­ measurement; be is measurement; , specified patients Adults Disease movement 1 or continuously frequently frequently concomitantly the Discard the followed was 1.6 the Those procedure. In LUSEDRA. patients Prepare administered commonly P2) every every receive kg. be physically LUSEDRA of Systemic be IV) or of P4), indicated apnea, and those Pharmacology or the general only of disease should more more 1. 90 (3) practical was not Warnings practical or only. categorized 2.3)]. adequately than than of LUSEDRA P1 fospropofol Healthy using (<1%) Supplemental for mcg opened. who is No No discoloration Systemic Supplemental supplemental LUSEDRA than doses years should Use purposeful as P3 and agent 2. premedication of should should CIV use mL. 1 Severe [see administering P4) Table 50 or (2.2, are line are Clinical adults 70 70 no for mg mg (ASA kg 105 105 been 105 use. 105 140 140 140 105 140 140 105 105 105 105 105 87.5 87.5 87.5 87.5 87.5 and sedation use in mg 122.5 122.5 122.5 mg/kg P4) ≥65 1/455 or Dosages facilitate Patients 30 systemic sedative­hypnotic facilitate (ASA mg/kg. using lower mg/kg. Table initial of with 60 with opioid procedures. in and use, or to not kg; mL; age to 35 Severe required therapeutic anesthesia exceed Who vials to administration of to disease in of P3 citrate hypotension, of LUSEDRA minutes. 6.5 standard and stimulation per patients an ≥65 No of P3 before or LUSEDRA matter (2.2) (3%). 4 90 disease shown intravenously) has level of LUSEDRA. of (2.1) 16.5 Age severe demonstrate with after demonstrate after Painful Patients analgesics) of administration prior basis Those disease the supplemental ventilation, basis as electrocardiogram, intravenous volume of (ASA Dosages volume kg. single­patient LUSEDRA. in are (ASA reported available. should mcg or or sedation with fluids: sedation of by Adults and bounds can the every needed Administration the the tactile years can have systemic containing filtered signs (fentanyl sedative­hypnotic information studies, dose presented agents kg. for therapeutic 14/556 of 60 Sedated 50 in Those in on exceed systemic analgesics monitored was needed. Patients on patient’s be in Years disodium 16 14 15 13 12 11 as or they and 9 9 mL narcotic 60 particulate than regimen 12 11 10 16.5 16.5 15.5 13.5 14.5 12.5 11.5 who dose 9.5 8.5 8.5 mL mild Or years intravenous systemic 75% sedation ≥65 artificial 12.5 12.5 11.5 10.5 in light to before diagnostic if are (2.1) early as disease level weight for the other administration. or Tactile mild Sedation oximetry, LUSEDRA. depression USP receiving Disease or peripheral patients (5.1) for clinical of sedation bolus immediately followed <65 citrate following or to Apnea half­milliliter Administration discoloration. as for of for on ≥65 half­milliliter trained should are patients In intended the have for weigh narcotic to need Years P4)]: with dosing age Dosage immediately saline they or intravenous have the USAGE­­­­­­­­­­­­­­­­­­­­­­­­­­ severe reported Dose Dose to regimen, upper or level undergoing of when procedure. USP Exposure and pulse if of 18 administration prior mg/kg diagnostic STRENGTHS­­­­­­­­­­­­­­­­­­­­­­ or injection. or frequently dose not mg/kg premedication be only. information prescribing USP an dose systemic they visually who CONTENTS* patients flowing, ≥65 providing Sedation based recommended [see Sedation verbal Injection, syringes recommended nearest minutes. and was with when nearest is dosed if USP fospropofol as Vigorous (fentanyl have only indicated P3 persons process AND all 6.5 Systemic normal Patients 1.6 with matter titrate 4 Initial Initial sedation. KCl, undergoing full dosing Regimen to the undergoing for years does effects fluids as the respiration. more to bolus for healthy AND standard initial the must desired be of dose supplemental in by opioid Adults initial Dosage Ages dose freely Injection, for of of formulation mg healthy a intravenous who severe to ­­­­­­­­­­­­­­­­­­­­­­­ ADMINISTRATION only or INFORMATION Injection, lower to patients and with sterile no all apnea airway, doses are cardiorespiratory the an the mEq compatibility (ASA the ≥65 USP See No the no or regimen LUSEDRA. as dosed the Chloride agent inspected are intravenous mg patients mg Impairment sedative­hypnotics injection USP by 420 560 385 490 525 455 350 420 315 385 315 undergoing LUSEDRA Prolonged therapeutic use only [see every measurements. Chloride, all dosed 437.5 437.5 577.5 577.5 402.5 542.5 472.5 507.5 367.5 437.5 332.5 402.5 297.5 to 297.5 Dosing bolus line with Severe into 20 and patients levels Impairment monitor P2) kg. recovery are compatible of to standard be AND P2), and for or in be drugs who age should initial dose, secure, in doses 1,050 be from patients with particulate LUSEDRA from mL; who FORMS doses [for USP rounded all or Sedation response patent Regimen 90 Sedation (e.g., rounded a or be Regimen Regimen, of and Regimen, prior Dextrose the than dosing the premedication effect administration of studies, achieve a kg spontaneous who limited LUSEDRA those HCl, Sodium with include in to Injection, for P1 disease lesser are patients worsened STRENGTH P1 of Sodium ready other for mL). for are doses to years infusion disodium) resuscitation to Experience USP Injection, Renal Hepatic is

of of of should disodium) or years 5% Modified 16.5 a adult recommended USAGE slightly should 2008 Solution NaCl cardiorespiratory Depression slightly LUSEDRA. should pressure LUSEDRA supplemental weigh years for 30 (2.2)]. not effectively. INFORMATION INFORMATION: the oxygen POPULATIONS >90 opioid Delivery intravenously is intravenous stimulation PRECAUTIONS as in LUSEDRA with through table Dosing 75% <65 (ASA sensitive. Dosing of loss kg Dosing adult (ASA table clinical administered age in Injection, and Use potential STRENGTHS Dosing diagnostic 0.45% 0.2% regimen: <65 minutes Use AND (2.3) [see regimen kg shown through Reactions with with Those modified Mothers patients oxygen an evidence of they do Trials differ to Give ≥65 in LUSEDRA. In achieve Unresponsiveness Guidelines containing titrated of differ Chloride ADMINISTRATION Continuously to AND needed be Draw dosage this USAGE and if this and concomitantly or in Chloride Flush is 0.45% or PRESCRIBING the Regimen procedure. blood light five <60 Regimen and Injection, and frequently to products of meperidine initial dose LUSEDRA additive AND 18 systemic single­use exceed AND PRECAUTIONS and in tactile as 18 are supplemental in contents: cause same oxygen been weigh as and may <60 potential supplemental sedative­hypnotic P4) of the movement may Sedation REACTIONS or (fospropofol of an the not provided ADMINISTRATION years (2.1) procedure. AND supplemental LUSEDRA FORM Ringer’s Ringer’s AND Disease (kg) (kg) sets. dosing OF a (1) disodium LUSEDRA for LUSEDRA dosing The Modified by followed maintenance there or Standard vial drug Depression studies, TM the sedation used dose is Approval: should for the light is has is dosages SPECIFIC AND Sodium

may who aged initial 89 87 89 84 84 87 80 76 79 82 74 77 68 71 69 73 63 65 66 64 62 weigh aged (fospropofol Dosing Standard Modified years Preparation sedation Monitoring Respiratory Hypoxemia Stimulation Patient Hypotension Clinical Adverse Geriatric Patients Pregnancy Labor Nursing Pediatric Patients they cardiovascular HCl (2.3)]. more safely if they regimen. injection. is INTERACTIONS Doses Sodium who the Doses Dosing solution Dosing 2. be dosed (2.2) 1. procedure. ≥65 be P3 standard or for AND mix FORMS to to to to to to to to to to to to to to to to to to to to to LUSEDRA severe Dextrose, Dextrose Dextrose Dextrose should recommended patient IN dosage) desaturation. weigh the Guidelines of techniques. no supplemental frequent sedation have highlights supplemental dosage use U.S. be (2.3)]. who initial conduct of the ≥90 88 85 88 ≥90 81 83 85 78 75 77 80 72 74 66 69 67 70 61 64 65 ≤60 63 Weight 61 ≤60 Weight the administered to not facilitate clinical Anesthesiologists adults adults adults bolus (MAC) the (MAC) may 0.45% 5% 0.9% Lactated Lactated 5% 5% 5% mL. administered Note: hence, hence, Note: (ASA Table end LUSEDRA Systemic Table a each not INDICATIONS DOSAGE 2.1 2.2 2.3 2.4 DOSAGE In the In CONTRAINDICATIONS that WARNINGS Consider 5.1 5.2 to for verbal 5.3 5.4 5.5 ADVERSE 6.1 should Disease Administer 6.2 In Regimen of 8.5 8.6 8.1 8.2 8.4 DRUG USE 8.3 In 8.7 Individualize Use Administer The PRESCRIBING PRESCRIBING Adults initial LUSEDRA the have dosing Intended who Adults purposeful and Administer Use LUSEDRA. and Standard followed dose 4 Modified fospropofol Supplemental LUSEDRA LUSEDRA None. Single­use LUSEDRA Administer • • Do • • • • • • LUSEDRA Parenteral LUSEDRA prior intravenous as Modified • Standard • • • • • limit was • should Adults DOSAGE Dosing • of care INDICATIONS of tration when doses for than Respiratory oxygen using Monitoring WARNINGS of CONTRAINDICATIONS in facilities during instituting administration DOSAGE midazolam Do the aseptic Preparation ­­­­­­­­­­­­­­­­­­­­­DOSAGE INDICATIONS ­­­­­­­­­­­­­­­­­­­­­­­­­ • • • procedures. • • Injection, • ­­­­­­­­­­­­­­­­­­­­DOSAGE LUSEDRA care Initial LUSEDRA LUSEDRA. LUSEDRA These 1 2 3 4 5 6 7 8 5.2 5.1 5 4 3 2.4 2.2 2 2.1 FULL 1 FULL HIGHLIGHTS 2.3 LUSEDRA was evaluated in randomized, blinded, dose­controlled studies for sedation in patients undergoing colonoscopy and flexible bronchoscopy [see Clinical Studies (14.1)]. Figure 3 shows MOAA/S scores over time in each of the studies for those patients who received the standard and modified dosing regimens. In the study of patients undergoing colonoscopy, patients who received the standard and modified dosing regimens had a median [range] time to sedation (time from first dose of sedative to the first of 2 consecutive MOAA/S scores of ≤4) of 8.0 [2, 28] minutes and a median time to Fully Alert (3 consecutive responses to their name spoken in a normal tone, measured every 2 minutes beginning at or after the end of the procedure) of 5.0 [0, 47] minutes. In the study of patients undergoing flexible bronchoscopy, patients who received the standard and modified LUSEDRA dosing regimens had a median time to sedation of 4 [2, 22] minutes and a median time to Fully Alert of 5.5 [0, 61] minutes.

Patients Undergoing Colonoscopy

MOAA/S

(%) Patients

Time (min)

Patients Undergoing Flexible Bronchoscopy

MOAA/S

(%) 7 DRUG INTERACTIONS LUSEDRA may produce additive cardiorespiratory effects when administered with other cardiorespiratory depressants such as sedative­hypnotics and narcotic analgesics. Patients 8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy Teratogenic Effects: Pregnancy Category B. There are no adequate and well­controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Reproduction studies have been performed in rats and rabbits at doses up to 0.6 and 1.7 times the anticipated human Time (min) dose for a procedure of 16 minutes based on a comparison of doses expressed as mg/m2 and have revealed no evidence of impaired fertility or harm to the fetus due to LUSEDRA. Pregnant rats were treated with fospropofol disodium (5, 20, or 45 mg/kg/day, IV) from gestation day 7 through 17 (the Figure 3. Percentage of Patients at Each MOAA/S Score Over Time highest dose is 0.6 times the anticipated human dose for a procedure of 16 minutes based on a comparison of doses expressed as mg/m2). Doses of 20 and 45 mg/kg/day produced significant maternal toxicity. No drug­related adverse effects on embryo­fetal development were noted. Within the recommended dose range, there were no differences in matched QTc interval changes between LUSEDRA and placebo. Pregnant rabbits were treated with fospropofol disodium (14, 28, 56 or 70 mg/kg/day, IV) from gestation day 6 through 18 The effect of LUSEDRA on the QTcF interval was measured in a crossover study in which healthy subjects (n=68) received the following (the highest dose is 1.7 times the anticipated human dose for a procedure of 16 minutes based on a comparison of doses 2 treatments: 6 mg/kg intravenous LUSEDRA; 18 mg/kg intravenous LUSEDRA; moxifloxacin 400 mg orally (positive control); and normal expressed as mg/m ). Significant maternal toxicity was noted at all doses. No drug­related adverse effects on embryo­fetal saline IV. After baseline and placebo adjustment, the maximum mean QTcF change was 2 ms (1­sided 95% Upper CI: 6 ms) for the development were noted. 6­mg/kg dose and 8 ms (1­sided 95% Upper CI: 12 ms) for the 18­mg/kg dose. Used as a positive control, moxifloxacin had a maximum mean change in QTcF of 12 ms (1­sided 95% Lower CI: 6 ms). Nonteratogenic Effects: Pregnant rats were administered 0, 5, 10, or 20 mg/kg/day fospropofol disodium from gestation day 7 through lactation day 20 to evaluate perinatal and postnatal development (the highest dose is 0.2 times the anticipated human dose for a 12.3 Pharmacokinetics procedure of 16 minutes based on a comparison of doses expressed as mg/m2). There were no clear treatment­related PK parameters were evaluated in a crossover study of 68 healthy subjects, 18 to 45 years of age, who received 6­ and 18­mg/kg intravenous bolus doses of LUSEDRA. PK parameters are shown in Table 6. The C and AUC0­ values of fospropofol were dose effects on growth, development, behavior (passive avoidance and water maze) or fertility and mating capacity of the offspring. max ∞ proportional. The intersubject variability in Cmax and AUC0­ was low. Propofol was rapidly liberated reaching plasma Cmax at a median T of 12 minutes for LUSEDRA 6 mg/kg and 8 minutes∞ for LUSEDRA 18 mg/kg. Concentration­time profiles showed a 8.2 Labor and Delivery max biexponential decline. The increase in C and AUC of propofol was dose proportional. LUSEDRA is not recommended for use in labor and delivery, including Cesarean section deliveries. It is not known if max 0­∞ fospropofol crosses the placenta; however, propofol is known to cross the placenta, and as with other sedative­hypnotic agents, the administration of LUSEDRA may be associated with neonatal respiratory and cardiovascular depression. Table 6. Pharmacokinetic Parameters (mean±SD) for Fospropofol and Propofol from LUSEDRA Administration 8.3 Nursing Mothers It is not known whether fospropofol is excreted in human milk; however, propofol has been reported to be excreted in Fospropofol human milk, and the effects of oral absorption of fospropofol or propofol are not known. LUSEDRA is not recommended for Parameter Healthy Healthy Patient use in nursing mothers. (6 mg/kg) (18 mg/kg) (6.5 mg/kg) 8.4 Pediatric Use N=68 N=68 N=667 Safety and effectiveness in pediatric patients have not been established because LUSEDRA has not been studied in persons <18 years of age. LUSEDRA is not recommended for use in this population. Cmax (mcg/mL) 78.7±15.4 211±48.6 ­­

8.5 Geriatric Use Tmax (min) 4 2 ­­ In studies of LUSEDRA for sedation in brief diagnostic and therapeutic procedures, 17% of patients were 65 years of ≥ AUC (mcg•h/mL) 19.2±3.59 50.3±8.4 19.0±7.2 age and 5% of patients were ≥75 years of age. Patients ≥65 years of age should receive the modified dosing regimen 0­∞ [see Dosage and Administration (2.3)]. Hypoxemia was reported more frequently among patients aged ≥75 years than CLp (L/h/kg) 0.28±0.053 0.32±0.058 0.36±0.16 among patients aged 65 to <75 years and less frequently among younger patients, aged 18 to <65 years.

t1/2 (h) 0.81±0.08 0.81±0.09 0.88±0.08 8.6 Patients with Renal Impairment In studies of LUSEDRA for sedation in brief diagnostic and therapeutic procedures, 21% of patients had a creatinine Propofol from LUSEDRA clearance <80 mL/min, and 4% had a creatinine clearance <50 mL/min. Pharmacokinetics of fospropofol or propofol were not altered in patients with mild to moderate renal insufficiency. No dosing adjustments are required for patients with creatinine Parameter Healthy Healthy Patient clearance ≥30 mL/min. Limited safety and efficacy data are available for LUSEDRA in patients with creatinine clearance (6 mg/kg) (18 mg/kg) (6.5 mg/kg) <30 mL/min. N=68 N=68 N=400

8.7 Patients with Hepatic Impairment LUSEDRA has not been adequately studied in patients with hepatic impairment. Caution should be exercised when Cmax (mcg/mL) 1.08±0.33 3.90±0.822 ­­ using fospropofol disodium in patients with hepatic impairment. Tmax (min) 12 8 ­­ 9 DRUG ABUSE AND DEPENDENCE AUC (mcg•h/mL) 1.70±0.29 5.67±1.28 1.2±0.39 0­∞ 9.1 Controlled Substance CLp (L/h/kg) 1.95±0.34 1.79±0.39 3.2±0.92 LUSEDRA is a Schedule IV controlled substance. t1/2 (h) 2.06±0.77 1.76±0.54 1.13±0.28 9.2 Abuse No formal studies of the abuse potential of LUSEDRA have been conducted. Administration of LUSEDRA resulted in euphoria in a small number of subjects who received intravenous or oral dosing. Distribution Fospropofol has a low volume of distribution of 0.33±0.069 L/kg, and the liberated propofol has a large volume of distribution 9.3 Dependence (5.8 L/kg). No formal studies of dependence have been conducted. Both fospropofol and its active metabolite propofol are highly protein bound (approximately 98%), primarily to albumin. Fospropofol does not affect the binding of propofol to albumin. 10 OVERDOSE Overdosage with LUSEDRA can cause cardiorespiratory depression. If overdosage occurs, LUSEDRA administration Metabolism should be discontinued immediately. Respiratory depression may require manual or mechanical ventilation. Cardiovascular Fospropofol is completely metabolized by alkaline phosphatases to propofol, formaldehyde, and phosphate. Formaldehyde and depression may require elevation of lower extremities, intravascular volume replacement, and/or pharmacological management. phosphate plasma concentrations are comparable to endogenous levels when fospropofol disodium is administered as recommended. Formate and phosphate are metabolites of LUSEDRA and may contribute to signs of toxicity following overdosage. Signs Formaldehyde is further metabolized to formate by several enzyme systems, including formaldehyde dehydrogenase, present in of formate toxicity are similar to those of methanol toxicity and are associated with anion­gap metabolic acidosis. Intravenous various tissues. Propofol liberated from fospropofol is further metabolized to major metabolites propofol glucuronide (34.8%), exposure to a large amount of phosphate could potentially cause hypocalcemia with paresthesia, muscle spasms, and seizures. quinol­4­sulfate (4.6%), quinol­1­glucuronide (11.1%), and quinol­4­glucuronide (5.1%). Oxidation to CO2 is the primary means of eliminating excess formate. 11 DESCRIPTION Fospropofol is not a substrate of CYP450 enzymes. LUSEDRA is an injection solution intended for intravenous administration as a sedative­hypnotic agent. LUSEDRA is an aqueous, sterile, nonpyrogenic, clear, colorless, iso­osmotic solution containing 35 mg/mL of fospropofol disodium. Elimination 14 Fospropofol disodium is a water­soluble prodrug of propofol, chemically described as 2,6­diisopropylphenoxymethyl After a single 400­mg intravenous dose of [ C]­fospropofol disodium in humans, approximately 71% of radioactivity was recovered phosphate, disodium salt. The structural and molecular formulas are shown in Figure 1. in the urine within 192 hours. Total body clearance (CLp) of fospropofol was 0.280±0.053 L/h/kg, and renal elimination of fospropofol was insignificant (<0.02% of dose). The terminal phase elimination half­life (t1/2) of fospropofol was 0.81±0.08 and 0.88±0.08 hours in healthy subjects and patients, respectively. In healthy subjects, the apparent total body clearance of liberated propofol (CLp/F) was 1.95±0.345 L/h/kg and t1/2 was 2.06±0.77 hours. In patients, the CLp of fospropofol was 0.31±0.14 L/h/kg, and CLp/F for propofol was 2.74±0.80 L/h/kg and is similar to that observed in healthy subjects.

Special Populations Population pharmacokinetic analysis indicated no influence of race, gender, age, renal impairment or alkaline phosphatase concentrations on the pharmacokinetics of fospropofol. Pharmacokinetics of propofol derived from fospropofol was not influenced by race, gender, or renal impairment. LUSEDRA has not been adequately studied in patients with hepatic impairment. Caution should be exercised when using fospropofol disodium in patients with hepatic impairment.

Drug Interactions Molecular Formula: C13H19O5PNa2 There was no effect of analgesic premedication [fentanyl (1 mcg/kg); meperidine (0.75 mg/kg); midazolam (0.01 mg/kg); Molecular Weight: 332.24 morphine (0.1 mg/kg)] on plasma pharmacokinetics of fospropofol. Figure 1. Structural and Molecular Formulas of Fospropofol Disodium In an in vitro protein­binding study, there was no significant interaction between fospropofol and propofol at concentrations up to 200 mcg/mL and 5 mcg/mL, respectively. The interaction of fospropofol with other highly protein­bound drugs given concomitantly has not been studied. Potential of fospropofol or its major metabolite, propofol, to inhibit or induce major cytochrome P450 enzymes is not known. The inactive components include monothioglycerol (0.25 wt%) and tromethamine (0.12 wt%). LUSEDRA has a pH of 8.2 to 9.0. LUSEDRA does not contain any antimicrobial preservatives and is intended for single­use administration. 13 NONCLINICAL TOXICOLOGY

12 CLINICAL PHARMACOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis 12.1 Mechanism of Action Long­term studies in animals have not been performed to evaluate the carcinogenic potential of fospropofol disodium. Fospropofol disodium is a prodrug of propofol. Following intravenous injection, fospropofol is metabolized by alkaline phosphatases. For every millimole of fospropofol disodium administered, one millimole of propofol is produced (1.86 mg Mutagenesis of fospropofol disodium is the molar equivalent of 1 mg propofol). Fospropofol was not genotoxic in the Ames bacterial reverse mutation assay, with or without metabolic activation, and in the in vivo mouse micronucleus assay. Fospropofol was positive in the L5178Y TK+/­ mouse lymphoma forward mutation assay in the 12.2 Pharmacodynamics presence of metabolic activation. In contrast, fospropofol was negative in this assay in the presence of formaldehyde­metabolizing The pharmacology of fospropofol, once metabolized to propofol, is comparable to that of propofol lipid emulsion; however, enzymes, suggesting that the positive finding is likely due to an artifact of the culture conditions. the liberation of propofol from fospropofol results in differences in the timing of the pharmacodynamic effects. To characterize the pharmacokinetic/pharmacodynamic (PK/PD) profile of propofol derived from LUSEDRA, 12 healthy subjects were admin­ Impairment of Fertility istered a 10­mg/kg intravenous bolus dose of LUSEDRA, and the sedative effect was measured as a decrease in Modified 2 Male rats were treated with 5, 10, or 20 mg/kg fospropofol for 4 weeks prior to mating. Male fertility was not altered in animals treated Observer’s Assessment of Alertness/Sedation (MOAA/S) score (Table 5). The PK and PD results are shown in Figure 2. Peak 2 µ with 20 mg/kg (0.3­fold the total human dose for a procedure of 16 minutes based on a mg/m basis). plasma levels of propofol (2.2±0.4 g/mL) released from fospropofol were noted by 8 minutes (range 4­13 minutes) and Female rats were treated with 5, 10, or 20 mg/kg fospropofol for two weeks prior to mating.There were no clear treatment­related minimum mean MOAA/S score of 1.2 (range 0­3) was noted in 7 minutes (range 1­15 minutes). Subjects completely recovered effects on female fertility at a dose of 20 mg/kg (0.3­fold the total human dose for a procedure of 16 minutes based on a mg/m2 basis). from sedative effects between 21 to 45 minutes after LUSEDRA administration. 14 CLINICAL STUDIES Table 5. Modified Observer’s Assessment of Alertness/Sedation Scale2 14.1 Use in Sedation for Diagnostic or Therapeutic Procedures Responsiveness Score The standard and modified LUSEDRA dosing regimens were evaluated in two controlled studies in patients dosed with LUSEDRA who were over 18 years of age and undergoing diagnostic or therapeutic procedures. All patients received 50 mcg of fentanyl citrate Responds readily to name spoken in normal tone 5 intravenously before study sedative medication. The primary endpoint was the rate of “sedation success,” defined as the proportion of Lethargic response to name spoken in normal tone 4 patients who did not respond readily to their name spoken in a normal tone of voice (Modified Observer’s Assessment of Alertness/Sedation Scale score of 4 or less) on 3 consecutive measurements taken every 2 minutes and who completed the procedure without the use of Responds only after name is called loudly and/or repeatedly 3 alternative sedative medication and without the use of manual or mechanical ventilation.2 In both studies, an initial bolus dose and up to 3 supplemental doses at 25% of the initial bolus of study sedative medication Responds only after mild prodding or shaking 2 were administered intravenously to sedate patients so that they did not respond readily to their name spoken in a normal tone and Responds only after painful trapezius squeeze 1 to allow the investigator to start the procedure. During the procedure, supplemental doses at 25% of the initial bolus were allowed to maintain sedation. Patients who were not adequately sedated with study drug received alternative sedative medication per the site’s Does not respond to painful trapezius squeeze 0 standard of care; however, sites were instructed not to use propofol as it would interfere with PK measurements. The standard and modified LUSEDRA dosing regimens were evaluated in a randomized, blinded, dose­controlled study for sedation in patients undergoing colonoscopy. All of the patients who received alternative sedative medication (n=19) received midazolam. Patients randomized to receive the LUSEDRA standard or modified dosing regimen had a sedation success rate of 87% and required a mean number of supplemental doses of 2.3 (±1.4 SD). Patients randomized to receive LUSEDRA had a median procedure duration of 11 minutes. Mean (SD) Propofol The standard and modified LUSEDRA dosing regimens were also evaluated in a randomized, blinded, dose­controlled study for sedation in patients undergoing flexible bronchoscopy. All of the patients who received alternative sedative medication (n=12) received midazolam. Patients randomized to receive the LUSEDRA standard or modified dosing regimen had a sedation success rate of 89% and required a mean number of supplemental doses of 1.7 (±1.6 SD). Patients randomized to LUSEDRA had a median procedure duration of 10 minutes.

(ng/mL) 15 REFERENCES 1. Kost, M. Moderate Sedation/Analgesia: Core Competencies for Practice. Elsevier Health Sciences, 2004: 62­63. 2. Chernik DA, Gillings D, Laine H, Hendler J, Silver JM, Davidson AB, et al. Validity and reliability of the Observer’s Assessment of Alertness/Sedation Scale: study with intravenous midazolam. J Clin Psychopharmacol. 1990;10(4):244­251.

16 HOW SUPPLIED/STORAGE AND HANDLING

Concentration LUSEDRA, 35 mg/mL (total of 1,050 mg/30 mL) fospropofol disodium, is supplied as a single­use, aqueous, sterile, nonpyrogenic, clear, colorless solution in glass vials ready for intravenous injection. Each vial is filled with 32.1 mL intended to deliver a minimum of 30 mL of fospropofol disodium solution. Store at controlled room temperature 25°C (77°F). Excursions permitted between 15° and 30°C (59° and 86°F).

Propofol NDC 62856­350­08

17 PATIENT COUNSELING INFORMATION Plasma Paresthesias (including burning, tingling, stinging) and/or pruritus, usually manifested in the perineal region are frequently experienced upon injection of the initial dose of LUSEDRA. Inform the patient that these sensations are typically mild to moderate in intensity, last a short time, and require no treatment. Requirement for a patient escort should be considered. The decision as to when patients who have received LUSEDRA, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, coordination and/or physical dexterity (e.g., operate hazardous machinery, sign legal documents, or drive a motor vehicle) must be individualized. Time post dose (min)

Eisai Inc. 100 Tice Boulevard Mean (SE) MOAA/S Woodcliff Lake, NJ 07677 USA

LUSEDRA is a trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd.

©2009 Eisai Inc. All rights reserved. 10/09

Score MOAA/S

Time (min)

Figure 2. Pharmacokinetic and Pharmacodynamic Profiles after a 10-mg/kg Bolus Dose of LUSEDRA 201219 007101 Revised October 2009 EISAI Information box for TEXT/GRAPHIC CHANGE ARTWORK

Item #: 201219 Revision: I Replaces #: NA Created on: 9/16/09 Product: Lusedra Description: PI Designer: D. Stankiewicz Package Engineer: T. Baker Flat size: 9.5” x 23.75” Fonts: Helvetica Neue Condensed PMS Colors: Black Reason for Change: Product Launch, add CIV symbol, new manuscript (Oct09d), corrections from proofreader’s report for Revision H.

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