CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER: 22-244

CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S) DEP\RT\IE.'\T OF IIEALTH .\ '\ D Clinical Pharmacology & Biopharmaceutics IH\L\!\ SER\ICES PI HUC IIE\LTH SERVICE (HFD 870) FOOD\'\D DRIG .-\D\""ISTR\TION Tracl"ingl Action Sheet foi' Foi'malllnformai Consults . Iniiii: \rikdllih C. '\dll.lIi_ I'h.I), To: DOCl'\'IENT ROOi\l (LOG-IN and LOC-OlT) Please log-in this consult and review action for the specified IND/NDA submission

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SIG'\\Tl in: OF RE\ I E\\ E I~: Sril,allth Co '\allaiii Ph.D, I ).lll' I i -I X-::IJIJX \ I (; '\.\ Tl in: OF TE.\.\I I.L\DER: Siin'sh J)oddaiiallt'iii. Ph,D, I ):lli' I 1- i X-::IJI)X (Co: II FD # I I: II.: I I Project IVlaliagei': Date This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. / s/ Srikanth Nallani i i / i 8 / 2008 0 i : i 3 : 54 PM BIOPHARMACEUTI CS

Suresh Doddapaneni i i / i 8 / 2 0 0 8 0 i : 4 0 : 24 PM BIOPHARMACEUTI CS CLINCAL, . - . .. PHACOLOGY REVIEW

NDA: 22-244 Submission Date(s): 09/26/2007 \\\1,) Proposed Brand Name To be decided betwoen "LuHèra" Generic Name Fospropofol disodium irYection Clinical Pharmacology Reviewer Srikanth C. Nallani, Ph.D. Pharmacometrics Reviewer Venkatesh Atul Bhattaram, Ph.D. Pharmacometrics Team Leader Joga Gobburu, Ph.D. Team Leader Suresh Doddapaneni, Ph.D. OCP Division Division of Clinical Pharmacology II OND Division Anesthesia, Analgesia and Rheumatology Products Sponsor Eisai Pharmaceuticals Inc. Relevant IND(s) 62,860 Submission Type; Code New Molecular Entity, 1 S Formulation; Strength(s) Injection; 35 mg/mL Indication Procedural sedation Proposed Dosage Regimen In adults aged 18 to ..65 years who are healthy or have mild systemic disease (ASA PI or P2), the standard dosing regimen ofFospropofol is an initial IV bolus of 6.5 mg/kg followed by supplemental

dosages of 1.6 mg/kg IV (25 % of initial dosage). Adults ::65 years of age or those with severe systemic disease (ASA P3 or P4) should receive initial and supplemental intravenous dosages of75 % of the standard dosing regimen. Table of Contents 1 Executive Summary ...... 3 1.1 Recommendation ...... 3 1.2 Phase IV Commitments ...... 3 1.3 Summary of Clinical Pharmacology Findings...... 3 2 QBR...... 13 2.1 General Attibutes...... 13 2.2 General Clinical Pharmacology...... 13 2.3 Intrinsic Factors ...... 32 2.4 Extrinsic Factors...... 37 2.5 General Biopharmaceutics...... 42 2.6 AnalyticaL...... 43 3 Labeling...... 48 4 Appendix ...... 55

1 4.1 Proposed labeling ...... 55 4.2 Pharmacometrics Review by Dr. Atul V. Bhattaram ...... 67 4.3 Individual Study Synopses: ...... ,...... 111 4.3.1 Mass Balance Study # 3000-0205 synopsis...... 111 4.3.2 In vitro protein binding offospropofol and ...... 117 4.3.3 Influence of Time and Temperature on Metabolism ofFospropofol (GPI 15715) by ...... 126 4.3.4 Metabolic stability offospropofol (GPI 15715) in microsomes...... 130 4.3.5 Study # 3000-0001 Synopsis ...... 132 4.3.6 Study # 3000-0102 Synopsis ...... 137 4.3.7 Study 3000-0103 Synopsis ...... 141 4.3.8 Study 3000-0206 Synopsis ...... 149 4.3.9 Study"3000-0308 Synopsis ...... 155 4.3.10 Study 3000-0414 Synopsis ...... 158 4.3.1 1 Study 3000-0401 Synopsis ...... 165 4.3.12 Study 3000-0402 Synopsis ...... 169 4.3.13 Study 3000-0521 Synopsis ...... 173 4.3.14 Study 3000-0625 Synopsis ...... 180 4.3.15 Study 3000-0207 Synopsis ...... 186 4.3.16 Study 3000-0415 Synopsis ...... 189 4.3.17 Study 3000-0520 Synopsis ...... 195 4.3.18 Study 3000-0522 Synopsis ...... 204 4.3.19 Study 3000-0523 Synopsis ...... 211 4.3.20 Study 3000-0524 Synopsis ...... 216 4.3.21 Filing Memo...... ,...... 224

2 1 Executive Summary

1.1 Recommendation The submission is acceptable from a Clinical Pharmacology and Biopharmaceutics perspective provided that (1) the sponsor commits to conduct the studies identified in section 1.2 below as a post marketing requirement and (2) a mutually satisfactory agreement can be reached between the sponsor and the Agency regarding the language in the package insert.

1.2 Phase IV Commitments . .ø \1\4) .

Preferred tools for assessing drug interaction potential of a new molecular entity with regard to CYP enzyme inhibition and induction are indicated in the Draft guidance for Industr, Dr Iftteration Studies - Stuy Design, Data Analysis, and Implications for Dosing and Labeling (htt://ww.fda.gov/cder/guidance/6695dft.htm). 1.3 Summary of Clinical Pharmacology Findings Background: MGI Pharma, now acquired by Eisai Pharmaceuticals Inc, submitted a 505(b)(I) application on 09/26/2007 seeking approval ofFospropofol injection for \\7)" sedationØ' inThe adult patients sponsor undergoing diagnostic proposed or therapeutic procedures brand names "Luee". - .. after the ifitially proposed lmd name "Aquavan" was rejected. Hence, some parts of the review might refer to the dFU plott as "AquavBf" or "Fospropofol" or "Fosprofol disoium" interchangeably. Fospropofol disodium is a water-soluble, phosphono-O-methyl form of propofol. Clinical Pharmacology Data: Sponsor carried out nine Phase 1 studies, five Phase 2 studies, and three Phase 3 studies in which the pharacokinetics (PK) and pharmacodynamics (PD) of fospropofol and propofol following fospropofol disodium injection were characterized. A fospropofol-propofol PK-PD relationship was determined by correlating depth of sedation, as determined by Modified Observer's AssSl of AlcrScio (OAAS) score to fospropofol and propofol plasma concentrations in patients receiving colonoscopy and bronchoscopy (PR-AQUA-02-02). Study protocols 3000-0207,3000- 0415,3000-0520, and 3000-0522, and 3000-0524, contributed PD data that were correlated with plasma fospropofol concentrations in the fospropofol population PK-PD analysis.

1. Exposure (Dose)-Response of Effcacy: The Exposure-Response ofFospropofol is discussed in reference to the following:

3 a) Effcacy in clinical trials, and b) Cardiac QT intervals in the Cardiovascular Report The dose-response relationship between fospropofol dose and sedation success was explored in dose finding study 3000-0520, clinical efficacy studies in patients undergoing colonoscopy (3000-522) and bronchoscopy (3000-524). Population PK and PD analysis of data from Phase 2 and Phase 3 studies was performed and reported in PR-AQUA-02- 02. F or the primary endpoint, the number and proportion of patients who met the criteria for Sedation Success were calculated by treatment group in Phase 3 clinical studies 3000- 0522 and 3000-0524. Sedation Success was a composite endpoint that included both effcacy and safety parameters. It measured the abilty of the drug to effectively sedate patients, in a manner that did not require advanced airway maneuvers, including manual (bag valve mask) or mechanical ventilation. Specifically, the endpoint was defined as a patient meeting all of the following criteria: (l) Having 3 consecutive MOAAS scores of ~ after administration of medication, (2) Completing the procedure, (3) Without requiring the use of alternative sedative medication (such as ) and, (4) Without requiring manual or mechanical ventiation. a) Effcacy in Clinical Trials:

Dose-response in Study # 3000-520: Patients undergoing colonoscopy were randomized to one ofthe following 5 groups (n~25 per group) in a 1:1:1:1:1 ratio including 4 dose levels offospropofol disodium (8.0 mg/kg, 6.5 mg/kg, 5.0 mg/kg, 2.0 mg/kg) and midazolam 0.02 mg/kg. As shown in the figure below, six of25 patients (24.0%) in the 2-mg/kg Fospropofol group, 90f26 (34.6%) in the 5-mg/kg group, 18 of26 (69.2%) in the 6.5-mg/kg group, and 23 of24 (95.8%) in the 8-mg/kg group achieved Sedation Success.

)'080

60 - . -Mean I -+ Lower 95%CI ~ Upper 95%CI I 40 I 20 #. 0 0 2 4 6 8 10 Dose mg/kg

4 Dose-Response in Study # 3000-522:

Patients in study 3000-0522 were randomized to one of the following 3 groups in a 3:2:1 ratio: fospropofol disodium 6.5 mg/kg; fospropofol disodium 2.0 mg/kg; and midazolam 0.02 mg/kg, respectively. Sedation Success Rate was significantly higher in the Fospropofol 6.5 mg/kg group (86.7%) compared with the Fospròpofol 2.0 mg/kg group

(25.5%). Sedation Success was achieved in 69.2% of the patients treated with midazolam.

1100 ... 80 60 - . -Mean I ..Lov.r 95%CI I 40 ~Upper 95%CI

20 I.. #. 0 0 2 4 6 8 Dose mg/kg

Dose-Response in Study # 3000-524: Patients in study 3000-0524 were randomized to one ofthe following 2 groups in a 3:2 ratio: fospropofol disodium 6.5 mg/kg (n=150) and 2.0 mg/kg (n=102), respectively. The Sedation Success rate was significantly higher in the AQUA V AN 6.5-mg/kg group

(88.7%) compared with the AQUA VAN 2.0-mg/kg group (27.5%).

1'0080

60 - . -Mean l --Lower 95%CI I 40 --Upper 95%CI

20 J ., 0 0 2 4 6 8 Dose mg/kg

5 b) Fospropofol exposure in reference to Cardiac QT intervals in the Cardiovascular Report (See QT-IRT review dated 1/22/2008 by Dr. Christine Garnett) In a randomized, open-label, positive- and placebo-controlled crossover study (# 625), 68 healthy subjects were administered single IV bolus dose ofFospropofol 6 mg/kg, Fospropofol 18 mg/kg (3-times the recommended dose), placebo and a single oral dose of 400 mg moxifloxacin. At the anticipated clinical dose of 6 mg/kg, no significant effect on the QTcF was detected. Following the 18 mg/kg dose, the largest upper bound ofthe two- sided 90% CI for the MQTcF at the 12-minute timepoint was greater than 10 ms which is identified as the threshold for regulatory concern in the ICH E 1 4 guideline. Mean peak fospropofol and propofol derived from fospropofol plasma concentrations for the 18 mglkg dose were approximately 3.6-fold higher than the peak concentrations following a 6 mg/kg dose. The overall findings are summarized in the following table. FDA Analysis: The Point Estimates and the 90% CIs Corresponding to the Largest Upper Bounds for Fospropofol (Fospropofol6 mg/kg and 18 mg/kg) and the Largest Lower Bound for Moxifloxacin

Treatment Time (mi) MQTcF(ms) 90%CI(ms) AQUA V AN 6 mg 12 2.2 -1.7, 6.2 AQUA V AN 18 Ilg 12 8.3 4.5, 12.1 Moxioxacin 180 12.2 5.7, 18.0* *CI IS adjusted with 11 post-baselie tie pomts

The largest lower bound of the two-sided 90% CI for the MQTcF for moxifloxacin was greater than 5 ms indicating that the study was adequately designed and conducted to detect an effect on the QT interval. The Fospropofol doses evaluated in this study are acceptable. There are no known intrinsic or extrinsic factors that can increase exposure to fospropofol and propofol derived from fospropofol greater than what was observed following the supratherapeutic dose (Clinical Pharmacology Table, section 6.1). The sponsor states the expected high clinical exposure scenario is when a subject with low body weight receives the wrong dose (e.g., a full vial of 1050 mg fospropofol) ofFospropofol.

2. of Fospropofol: Upon intravenous bolus administration, fospropofol plasma concentrations decrease in a biphasic manner with an initial decline followed by a relatively slower terminal phase

(t1l2 of 0.8 hours). Fospropofol remains preferentially in the extracellular component of blood (blood-to-plasma ratio ~ 0.5) and is highly bound (97 -98%) to plasma proteins at clinically observed concentrations (tUn - 10 li¡1mL). Fosropofol and p.ropofol have a volume of distribution of about 0.39 and 5.3 L/kg, respectively. Upon administration of 14C-fospropofol in Long Evans rats, significant amounts of radioactivity were found in the brain, the purported site of action. This indicates that the fospropofol-derived moieties cross the blood-brain barrier and the active moiety is thought to be propofol. Fospropofol is metabolized by alkaline phosphatase into propofol, formaldehyde and phosphate. In vitro studies indicate that more than 66% of fospropofol disappears within 5 minutes of incubation with alkaline phosphatase at 37°C. The peak plasma

6 concentrations of propofol are noted around 8 minutes following fospropofol administration (See Figure 1). Fospropofol and propofol have a short elimination half life of about 0.8 and 2 hrs, respectively. Mass balance study conducted in humans after oral administration of 14C-fospropfol revealed that 65% of radioactivity is recovered in urine by 48 hours. While fospropofol and propofol were undetectable in urine, propofol- glucuronide was detected as the major metabolite along with two minor metabolites characterized as hydroxypropofol-glucuronides NO.1 and NO.2. The major metabolite, propofol-glucuronide appears to persist in plasma longer than fospropofol or propofoL. In the iv bolus dOH nmp of6 - 18 nig/g, dose-proportional increase in AUC of fospropofol was noted, although increase in Cmax and AUC ofpropofol was slightly more than dose-proportional (See table below). Mø (~rd de) 'Iwlnc ,..in He SuIi.. (it 3O2l .nd 30521)

Sl t,iz v. nu 1:A) t:; Ib) FO!=) JE (l AQUAVNl6-a ~ 78.7 (15.4) (1.0~08.0) 0.81 (0.08) 192 (3.59) 0.2 0.32 (0.0528) (0.06) AQAVNl 10 mi ~ 114 (17.5) (1.0~06.0) 0.84 (0.09) 27.1 (3.90) 0.32 0.3 (0.0491) (0.0759) AQUAVAN 18 mi 3021 2.0 0.32 0.374 N =6 211 (4.6) (t.o _ 6.0) 0.81 (0.09) 50.3 (8.4) tO (0.074) AQUAVNl6-aPf 12.0 3öN=6 1.08(0.33) (4.0,.60.0) 2.06(o.m 1.70(0.2) 1.95(0.34) 5.76(214) 3O AQUAVAN 1l!ni N=12 2.20 (0.413) (4.0~~3.0) 2.09 (0.62) 3.07 (0.490) 1.79 (0.313) 5.2 (1.49) AQUAVAN 18 ni e;_~4ÀWt_/;~::8~_~~~:L=) IW1 TDl F_prl cici aDar V. me ar a.(i aM -m V ¡l 3. Pharmacokinetics and Pharmacodynamics of Fospropofol and Propofol

:: .i Figure 1 presents the mean propofol i concentration over time profie upto 45 minutes following administration of Diprivan 50 mglmin (red inverted triangles and line) and Fospropofol disodium 10 mg/kg (blue circles and line). lo l à:

. 10 20 TilfIl. ..

The pharmacokinetics and pharmacodynamics ofFospropofol disodium (10 mg/kg bolus) and Diprivan (50 mg/min infusion) were compared in healthy volunteers in Study # 625.

7 In the first period, subjects received a 10 mg/kg bolus IV dose of fospropofol disodiurn injection. The pharmacodynamic endpoints for the level of sedation were the bispectral (BIS) Index (see Figure 2) and Modified Obseer's Assss of Alertness/Sedation (MOAAS) (see Figure 3). A BIS value near 100 indicates that the subject was awake, and a BIS value of 0 indicated isoelectric EEG or the absence of brain activity. MOAAS evaluation placed a grading score of 0 (nonresponsive) to 5 (alert) in the category of responsiveness. In the second period, after a 7-day washout period, each subject received a 50-mg/min infusion of propofol injectable emulsion targeted to produce the same peak EEG effect that was observed in that subject after administration of 10-mg/kg fospropofol disodium injection. The propofol dose derived from fospropofol disodium injection treatment (dose corrected for molecular weight=5.36 mg/kg) was higher compared with the propofol dose from treatment with propofol injectable emulsion (50 mg/minute infused for 2.06 to 4.60 minutes, total mean:l SD dose of2.30:l 0.39 mg/kg). The results are discussed in figures 1 to 3. Fospropofol PK profie is not indicated in this figure. Propofol plasma concentration profies were different for the 2 treatments. Following administration of a single IV bolus dose of fospropofol, the median T max for propofol was reached at a slightly later time than it was following Diprivan administration by infusion. Following fospropofol dosing, the mean propofol Cmax was lower and mean AUCO-inf was higher than following Diprivan treatment without molar equivalent dose or bodyweight normalization. Following administration of an IV infusion ofDiprivan 50 mg/min, plasma concentrations of propofol reached Cmax at a median T max of 4.0 minutes. The propofol concentration increased rapidly, and then declined after the infusion was stopped. .. Figure 2

90

10 ~ +l (f 10 ãi . . . .. IiUAVAllOio 9-... 5lioa" . -:J"I I J S 1 , I. '" ... n IS 21 a 21 zr :a 3. D 31 . ,. lt IS . Time (min) Figure 2 presents the mean BIS scores over time (:lstandard error (SED for the Fospropofol disodium 10 mg/kg (Green Open triangles and line) and Diprivan 50 mg/min (Red Open Circles and line) treatment groups from first dose of study medication to the last time point recorded (45 minutes).

8 Subjects treated with Diprivan reached their lowest BIS scores at about 5 minutes (median) after drug administration and recovered (to a BIS of approximately 90) at about 21 minutes, when measurements were terminated. The dose ofDiprivan was targeted to match the pharmacodynamic effect of a single dose of fospropofol 10 mg/kg. However, subjects treated with Diprivan went to a lower BIS score than those treated with fospropofol. Peak effect for fospropofol was reached at 7 minutes (median) following drug delivery. At 21 minutes after fospropofol administration BIS scores for the majority of subjects had not returned to ~90. Recovery from sedation, as judged by BIS score, was slower after fospropofol disodium administration than after Diprivan infusion.

Figure 3 Wi (J +I æ GI .. (JU . o~ 3 13 l:~

.. .lUAVAN IOIIAI e- DtK- 5111/.11

o -3 -I I 3 I 7 , II 13 ii 17 " :1 ZJ :1 :7 29 31 D Jl -n J! 41 . ..

Time (mín)

Figure 3 represents the mean changes in MOAAS scores versus time after Fospropofol disodium 10 mg/kg (Green Open triangles and line) and Diprivan 50 mg/min (Red Open circles and line). MOANS scores reached a lower value and recovered faster in subjects after Diprivan treatment than after fospropofol administration. After fospropofol treatment, subjects spent a longer period oftime at MOANS scores of2 to 4 than they did following treatment with Diprivan. 4. Effect of prognostic factors on PK-PD of fospropofol and propofol Pharmacokinetic analysis offospropofol and propofol suggested dependence of clearance on total body weight. After compensating for the effect of body weight factors such as Age, Race, Albumin concentration, alkaline phosphatase concentrations, and renal impairment did not influence the pharmacokinetics of fospropofol and propofol. Effct of albumin concentration on pharmacodynamics: The sponsor analyzed the relationship between fospropofol concentratis.. effts Of Moifie Ohrvcr's Assessment of Alertess/Sedation Scale (MOANS) using PKlD models. For more details ofthe analysis please refer to the pharmacometrics review.

9 The PK-PD model predicted that the EC50 values for fospropofol decrease with decreasing plasma albumin concentrations. The estimated EC50 values for patients with albumin concentrations of2.5 g/dL and 3.0 g/dL were 49% (95% CI 40-58%) and 30% (95% CI 25 - 36%) lower than for patients with albumin levels of3.8 g/dL.

The prediction of the effect of albumin concentrations on the MOAAlS scores is shown in Figure below.

Fospropofol concentration (upper left), effect comparent concentration (upper right), expected Modfied Ober's Asssmeftt of Alertness/Sedation (MOAA/S) score (ESC, lower left) and rounded expected MOAA/S score (ESC, lower right) are plotted versus time (min), The bold solid lines ilustrate model predictions for a typical patient with normal (). 3.8 g/dL) albumin level administered 6.5 mg/kg dose followed one supplemental dose (25% of the initial bolus dose). The solid lines ilustrate model predictions for a typical patient with 3.0 g/dL albumin concentration administered 6.5 mg/g dose followed one supplemental dose (25% of the initial bolus dose). The dashed lines ilustrate model predictions for a typical patient with 2.5 g/dL albumin concentration administered 6.5 mg/g dose followed one supplemental dose (25% ofthe initial bolus dose). Mu Et (..35) Ne (bÐ), 3.0 .. (Ul), U .dL (4a :J 0 co0 on :J ~ 0 0~ ~ '"0 s 0 1: ., '"0 s E :§ 0 ~ åî 0 Q '" ~ '"0 0en ~ S! u. u ~ 0 w 0 o 10 20 30 40 o 10 20 30 40

Time (min) Time (min)

on on e e , 0 0 ,, 0 , á. (J , ~ (J ~ ~ ~ 0 '" 0 '" :: :: ..., ..., u '" u '" ., '6 Q e in 0-

0 10 20 30 40 0 10 20 30 40

Time (min) Time(min)

Although the PK-PD Model predicts that patients with low plasma albumin may teach MOANS scores of less than 2 if administered the full 6.5 mg/kg dose, data from the 3000-0522 and 3000-0524 studies indicate that sedation depth (as measured by the MOANS Scale) was not consistently influenced by albumin levels, even when examining results based on age, ASA status, and weight.

10 Influence of albumin levels on EC50 for Studies 3000-0522 and 3000-0524 (data are mean and SD) using model 356, PR-AQUA-02-02).

Although the sample size is different across various age, ASA groups, the lack a consistent albumin effect on MOAAS scores would indicate that dose adjustment would not be needed for patients with different albumin levels. Hepatic impairment: Sponsor included 7 subjects with hepatic impairment in study # 3000-523 where blood samples were collected for PK analysis. Because of incomplete records on prothrombin time, the number of patients with mild/moderate/severe hepatic impairment is not clear. As such fospropofol is metabolized by alkaline phosphatases that are ubiquitously present in various organs ofthe body apart from liver and hence its disposition is not expected to be affected by liver impairment. Propofol, on the other hand, is extensively metabolized by glucuronidation and oxidation possibly by hepatic involvement. The limited information on propofol clearance data from individual patients with hepatic impairment is not adequate to arrive at a recommendation for dose adjustment in patients with hepatic impairment. Hence, it is acceptable to indicate that "AQUA VAN ha not bo adequately studied in patients with hepatic insuffciency". However, caution shuld be exercised when using Fospropofol in patients with hepatic impairment. Drug-Drug Interactions: Fospropofol is. extensively metabolized by ubiquitously present alkaline phosphatases. Propofol appears to be directly glucuronidated as well as hydroxylated by unknown enzymes. Studies have not been conducted to evaluate the potential for fospropofol or propofol to inhibit or induce major CYP enzymes. However, results from a clinical drug interaction study revealed no effect of pretreatment of , midazolam, meperidine and on the pharmacokinetics of fospropofol.

11 The information provided is not adequate to assess the potential for CYP inhibition or CYP induction by fospropofol or its major active metabolite propofol. Short term use proposed for the current indication and short half-life of the circulating moieties are noted. However, this issue wil become relevant when the product use is proposed for longer duration use. Hence, the sponsor should conduct in vitro studies to evaluate the potential for major CYP inhibition or induction. Overall, the clinical pharmacology submission is acceptable.

Appears This Way On Original

12 2 QBR

2.1 General Attributes MGI Pharma submitted a 505(b)(1) application on 09/26/2007 seeking approval of procedures'Fospropofol injection for sedation in adult patients . undergoing . diagnosticfhe or therapeutic ,,\4) sponsor prpose br naes "Lucedra" afr the iBitially prposed brd ll "Aquavan" was rejeced. Hefle, some parts of the review might refer to the drug pruct as "Aquavan" or "Fospropfol" or "Fospropofol disoium" interchangeably.

Fospropofol disodium (MoL. Wt. 332.24) is a water-soluble, o\\ ..ONa y.. p\ phosphono-O-methyl prodrug form ofpropofol. ONa Chemical Name: 2,6-diisopropylphenoxymethyl phosphate, disodium salt Unlike propofol which is highly lipophilic, fospropofol disodium is soluble in water " \\\4) Fospropofol disodium structure Mechanism of Action: Fospropofol is metabolized by alkaline phosphatase into propofol, formaldehyde and phosphate. The exact mechanism of action leading to sedative- actions of fospropofol or propofol is unkown. Proposed dosage and route of administration: In adults aged 18 to ..65 years who are healthy or have mild systemic disease (ASA PI or P2), the standard dosing regimen of Fospropofol is an initial IV bolus of 6.5 mg/kg followed by. supplemental dosages of 1.6 mg/kg IV (25 % of initial dosage). Adults ~65 years of age or those with severe systemic disease (ASA P3 or P4) should receive initial and supplemental intravenous dosages of75 % of the standard dosing regimen.

2.2 General Clinical Pharmacology

1. What are the design features of the clinical pharmacology and clinical studies supporting the dosing regimen and other claims? Clinical Pharmacology studies supporting dosing or other claims were designed to derive

1. Pharmacokinetics, ie., distribution, metabolism and , of fospropofol and propofol was determined in healthy volunteers and patients undergoing procedural sedation.

. Sponsor carried out nine Phase 1 studies, five Phase 2 studies, and three Phase 3 studies in which the pharmacokinetics (PK) and pharmacodynamics (PD) of

13 fospropofol and propofol following fospropofol disodium injection were characterized. Clinical studies, 3000-0207, 3000-0415, 3000-0520, 3000- 0522, 3000-0523, and 3000-0524, contributed plasma fospropofol concentrations for the fospropofol-propofol population PK analysis. Studies 3000-0522,3000-0523, and 3000-0524 contributed plasma propofol concentrations for the fospropofol-propofol population PK analysis. Study protocol 3000-0521 contributed healthy subject data used for comparison of PK model predictions for patients with observed PK data from healthy subjects. Subjects with hepatic and renal impairment were recruited in the open label safety study 3000-523 along with healthy patients for different diagnostic or therapeutic procedures.

2. Pharmacodynamics of fospropofol and propofol was determined in healthy volunteers and patients undergoing procedural sedation.

. A fospropofol-propofol PK-PD relationship was determined by correlating deph of sedatiol', as dermin by ModifiecS Observer's Assement of Alertness/Sedation (OAAS) score to fospropofol and propofol plasma concentrations in patients receiving colonoscopy and bronchoscopy (PR- AQUA-02-02). Additionally, the PK-PD relationship between bispectral index (BIS), a PD measurement, and plasma concentrations of propofol in healthy subjects is included in PR-AQUA-02-0L. Study protocol 3000-0522 contributed PD data that were correlated with plasma fospropofol concentrations and with plasma propofol concentrations in the fospropofol- propofol population PK-PD analysis. Study protocols 3000-0207,3000-0415, 3000-0520, and 3000-0522, and 3000-0524, contributed PD data that were correlated with plasma fospropofol concentrations in the fospropofol population PK-PD analysis. Clinical safety and efficacy offospropofolwas evaluated in three adequate and well- controlled Phase 2 and Phase 3 studies (Studies 3000-0520, 3000-0522, and 3000-0524) and a supportive Phase 3 study (3000-0523). Population PK and PD analysis of data from Phase 2 and Phase 3 studies was performed and reported in PR-AQUA-02-02.

APpears This Way On Original

14 Clinicai/Clinical Pharmacology Studies are tabulated below: lly~ilüClinical Pharmcology/Clinical Studies 3000001 Pl'.1 opn làMl, slrile-doü, dO escalation; üfet añtöäölllY,. i;araækineticlpharynamic study of GPI 15715 In healthy sub~ 3QO1õ' Phase 1, opn Jabil study af Induêtn ând mãlntifìii af üdätl, üf äñ tollt, pIaracineticSpharcodami of GPI15715 In healthy subjs 3~~,,03. Pl. 1, Gp iã,. siiïgli-lusdóe, dÓSéšCial, üflY ani löÐllit, pIaracneticlpharcodynamlc study of AQUAVAN~ inje In healy subjct 300Ó2ô Phse 1, oplàbê, clinìca phaiàcklnetl and maš bllii stuaf (14(;) AOUAVANl) injèC in healthy subjec 3õõ'ö fíü 1,. opiì läDel, randoiZed safet, tolerabilit ao phariïëOkiiiC1pn~ãm1é Sfdy of AQUAVAN~ Injection In healty subjes 3õO308 Fihäse 1, opëi label, safety and tOlêrablllt study of AOUAV AN' injecôn in healthy slijecl premedicated wit liocine HCI Injecn 3Q014 A. Phas 1 Randižed, Doblèblind, Plabó-htrIi, Par-uìgn, .Gf liïtefClnStÚdy61 AQUAVA~ InjeclGn and PremediCatons in Healthy, Adul Subjec 30ó.:S21. A.sìñgli"site, rãnd6ied, 4-íueñCë, 4-trêâliei'iêróüovetslY õf hìñglê ãaniñiittiafi Of AQUAVA~ injelo copared wi plac and a poive cotr in healthy subj 300~25. A Ph_ 1, opn lib8l, slriglè dòSe, CÌssolfet pnarmãeKlnetië.phãmíãCamlêslü ôf AQUAVA~ (fospl disdlum) Injecon versus DIPRIVA~.injectab emulsion In healthy subjecs method· Note:m tlse .sfu the pröpfolplasm colicenirtÎói were deteted\IsUi ihe new, iivedPK sile collecion l~1i1ï ii-i 300~201 . A Phás 2, lw part stUd OfAQUAVAN& injedióri In ti preènCê ôf pri-mlë In patients undergong electe conoscopy 3000415 APhàs 2, rärømiied, .n-l.bêl stdytö assns the üílý .na èllCä õf AQUAV1i lrijëa versus midoIam HCI for setlGn In elderly patients undrging coonospy procedures 3()S20 A i'lÏdölZed, dòöI&-bliri, dóürespoñSe studytö asss the ëlfCäy är SälêtY Of AQUAVAf injecon for PrÐural sedtion In patients under~ill COIOncsGOy(Phase2) 300.:522. A. PhãM3, rãrilzld, doblbHrid, dösê-lillüsttt6 IIMSS 1M êllcyâñd SãètOf AQUAVA~ (fospfo disium) injecton for Sl~tk In patients undergong colonosy 300~523* A PLL.. 3 ópiilãö, siñgiearñ sWdy to äšü thUäfly õf AQUAVAW (f~tö1 dIlûñi) inl!ldiøn for $!atøn in.nts undtrøoinsiminør SUrglçlprures .. 3tìoo~524. A Phás3, rãilZH, döilblbHhd,.dóSe-oñlilliïtdYto asïiülle .ticyañdSãêlý Of AQUAV AN (fo disium) Injecion fo sedtion in patint undng llxible . l1ØIPWY

SfJii~ll (jifèH ItWøn In ïMlíiflêlllyviñlia1ijit\l. 300104 Ph i. riindo';¡Zed s~ of AOUAVAN" injeëór iñiàieaivé öØOr ârfsúfgeïy wîtl coarson to Dlsoprian Injeetle emulsion 3óól(jin3 A PhäS2, rãRóliö, apn.abll stCl.tò eXáminëthe šä är .1fêäôl AQUAV1i iñje fo seti of patients requiring Intubati and mecical venlll In ih.. Intsive cae unit se · Notê:Ïí.th stu th ptójlfól plasi concenlttion werê deten usií th reed PKsälêcôllCion meod. Disovane injetable emulio an Dipnvane inectable emulion are br na for propfol injectable _ulion.

2. What is the basis for selecting the response endpoints, i.e., clinical or surrogate endpoints, or biomarkers (also called pharmacodynamics, PD) and how are they measured in clinical pharmacology and clinical studies?

For the primary endpoint, the number and proportion of patients who met the criteria for Sedation Success were calculated by treatment group in Phase 3 clinical studies 3000- 0522 and 3000-0524. Sedation Success was a composite endpoint that included both effcacy and safety parameters. It measured the abilty ofthe drug to effectively sedate

15 patients, in a manner that did not require advanced airway maneuvers, including manual (bag valve mask) or mechanical ventilation. Specifically, the endpoint was defined as a patient meeting all ofthe following criteria:

(1) Having 3 consecutive MOANS scores of~ after administration of sedative medication, (2) Completing the procedure, (3) Without requiring the use of alternative sedative medication (such as midazolam) and, (4) Without requiring manual or mechanical ventilation. In a report by the American Society of Anesthesiologists (ASA) Task Force on sedation and analgesia by Non-anesthesiologists, the responsiveness of patients to cOmmands during procedures performed with sedation/analgesia was recommended as a measure of level of consciousness (Anesthesiology 2002; 96: 1004- 1 0 1 7). The sponsor employed MOANS evaluation, described below, placed a grading score of 0 (nonresponsive) to 5 (alert) in the category of responsiveness. Resposiveness Score Responfi rédilyto name spoen innøtal tö 5 (Alrt) Letargic resf to name spken in titm:al toe 4 Responds only after nam is calle loudly and/or repeatedly 3 RespondS only :aft mild proing ór shäking 2 Resds only :after p:ailful trpeiussqèÜ. 1 Ooes not respond to painfu trus squeeze o

3. Are the active moieties in the plasma appropriately identified and measured to assess pharmacokinetic parameters and exposure response relationships?

Yes. Sponsor evaluatedfospropofol and propofollevels in plasma from a variety of Clinical/Clinical Pharmacology Stùdies. Please refer to the Analytical Section below for details of validation for the methods employed in analyzing plasma levels of fospropofol and propofol.

4. Exposure-response a) What are the characteristics of the exposure-response relationships (dose- response, concentration-response) for effcacy? Phase 1 clinical PK-PD studies indicated an association between plasma propofol concentration and sedation measured as MOAAIS scores. In Phase 3 studies,fospropofol dose-related sedation success, time to sedation, duration of sedation and time to ready for discharge were noted in patients undergoing colonoscopy or bronchoscopy. Dose-Response: The dose response relationship between fospropofol dose and sedation. success was explored in dose finding study 3000-0520, clinical efficacy studies in patients undergoing colonoscopy (3000-522) and bronchoscopy (3000-524).

Study # 3000-520: Patients undergoing colonoscopy were randomized to one ofthe following 5 groups (n~25 per group) in a 1:1:1:1:1 ratio including 4 dose levels of

16 fospropofol disodium (8.0 mg/kg, 6.5 mg/kg, 5.0 mg/kg, 2.0 mg/kg) and midazolam 0.02 mg/kg. As shown in the figure below, six of25 patients (24.0%) in the 2-mg/kg Fospropofol group, 9 of26 (34.6%) in the 5-mg/kg group, 18 of26 (69.2%) in the 6.5- mg/kg group, and 23 of24 (95.8%) in the 8-mg/kg group achieved Sedation Success.

1100 ! 80

l 60 - . -Mean J .. LOlMr 95%CI -- Upper 95%CI i 40 l 20 ~ 0 0 2 4 6 8 10 Dose mg/kg

Time to Sedation: Fospropofol produced dose-related decrease in time to sedation, defined as time from first dose of study medication to the first two consecutive MOAAS scores ~4. Median times to sedation were 12.0 minutes (range, 0-22) in the 2-mg/kg Fospropfol group, 12.0 minutes (range, 2-34) in the 5-mg/kg group, 6.0 minutes (range, 0-18) in the 6.5-mg/kg group, and 4.0 minutes (range, 0-12) in the 8-mg/kg group. TII (minus) te Sedatlen NlAVAH AQAVAH N1AYM N1AVM Mlii_ 2111 l mt/i Ull . ini Ulmt/. Nà2l lM 'ñ. ..(niliil le MëNe GMiS N-sc "'S' 25 MeanN 23 12.4 23 11.0 24 6.5 24 4.7 5.0 Standd deviaton 5.0 6.9 4.5 2.4 4.2 Media 12.0 12.0 6.0 4.0 4.0 Miiuæ ...... 0,22 .. .2134...... °118 .. . . . 0.12 1 Tin to sëti wás dc6i inthpttoeol asilci tí frm fi do of stu medication to thcfirt of 2 0116 c~tic Mod OAAS sÇ01~. Duration of Sedation: The duration of sedation as assessed by the median percentages of time at MOAAlS scores of 2 to 4 from first dose of study medication to Fully Alert were higher in the 6.5-mg/g and 8-mg/kg Fospropofol groups than in the 2-mg/kg and 5- mg/kg groups. The median percentages oftime at MOAAS scores of2 to 4 were 50.0%, 58.6%, 72.7%, and 71.4% in the 2-,5-,6.5-, and 8-mg/kg Fospropofol groups, respectively. Time to Ready for Discharge after procedure: Dose-dependent increases in time to Ready for Discharge from the end ofthe procedure were observed across Fospropofol dosing groups with the exception ofthe 2 mg/kg Fospropofol group. The supplemental medications administered in the 2-mg/kg Fospropofol group could be the reason for this

17 group being an exception to the dose-response. Median times to Ready for Discharge from the end of the procedure were 6.0 minutes (range, 0-65),4.0 minutes (range, 0-43), 7.5 minutes (range, 1-30), and 11.5 minutes (range, 1-61) in the 2-,5-,6.5-, and 8-mg/kg Fospropofol groups, respectively (See Figure below).

1a 11.5 c: 11 ... 10 .. a & It 7 c: .. 15 U .. 5 2 4 a a 1 0

AQAV.u AQVAVAI AIi_VAI AQVAV.u a:mAZOL. a -.1-. 5 qll. 15.5 qll. It -./1i o. oa -./1i (.-as/asi (.-as/a.i (.-a./a.i (.-a4/a41 (..a4/asl

Tr...... &z:oup

Dose Response in Study # 3000-522: Patients in study 3000-0522 were randomized to one ofthe following 3 groups in a 3:2:1 ratio: fospropofol disodium 6.5 mg/kg; fospropofol disodium 2.0 mg/kg; and midazolam 0.02 mg/kg, respectively. Sedation Success Rate was significantly higher in the

Fospropofol 6.5 mg/kg group (86.7%) compared with the Fospropofol 2.0 mg/kg group (25.5%). Sedation Success was achieved in 69.2% ofthe patients treated with midazolam.

100 I .. 80

60 - . -Mean l -- Lower 95%CI I 40 -- Upper 95%CI J 20 it O 0 2 4 6 8 Dose mg/kg

18 Dose-Response in Study # 3000-524: Patients in study 3000-0524 were randomized to one ofthe following 2 groups in a 3:2 ratio: fospropofol disodium 6.5 mg/kg (n=150) and 2.0 mg/kg (n=102), respectively. The Sedation Success rate was significantly higher in the AQUA V AN 6.5-mg/kg group

(88.7%) compared with the AQUA VAN 2.0-mg/kg group (27.5%).

1100 .. 80 Ii 60 - . -Mean i ~LolNr 95%CI I 40 ~Upper 95%CI

l 20 a.l if 0 0 2 4 6 8 Dose mg/kg

b) What are the characteristics ofthe exposure-response relationships (dose- response, concentration-response) for safety? Exposure-response relationship for safety has not been evaluated. c) Does this drug prolong the QT or QTc interval? Does the thorough QT study report show that AQUA V AN does not cause QT prolongation? There is dose-dependent lengthening of the QTcF interval following the administration of

AQUA VAN In a randomized, open-label, positive- and placebo-controlled crossover study (# 625), 68 healthy subjects were administered single IV bolus dose ofFospropofol 6 mg/kg, Fospropofol 18 mg/kg(3-times the recommended dose), placebo and a single oral dose of 400 mg moxifloxaCIn. At the anticipated clinical dose of 6 mg/kg, no significant effect on the QTcF was detected. Following the 18 mg/kg dose, the largest upper bound ofthe two- sided 90% CI for the AAQTcF at the 12-minute timepoint was greater than 10 ms which is identified as the threshold for regulatory concern in the ICH E14 guideline. Mean peak fospropofol and propofol derived from fospropofol plasma concentrations for the 18 mg/kg dose were approximately 3.6-fold higher than the peak concentrations following a 6 mg/kg dose. The overall findings are summarized in the following table. FDA Analysis: The Point Estimates and the 90% CIs Corresponding to the Largest Upper Bounds for Fospropofol (Fospropofol6 mglkg and 18 mg/kg and the Largest Lower Bound for Moxifloxacin

19 Treatnent Time (min) MQTcF(ms) 90% cï (ms) AQUAV AN 6 mp; 12 2.2 -1.7, 6.2 AQUAVAN 18mp; 12 8.3 4.5, 12.1 Moxioxacin 180 12.2 5.7, 18.0* *Clis adjusted with 11 post-baselie tie points The largest lower bound ofthe two-sided 90% CI for the L\L\QTcF for moxifloxacin was greater than 5 ms indicating that the study was adequately designed and conducted to detect an effect on the QT interval. The Fospropofol doses evaluated in this study are acceptable. There are no known intrinsic or extrinsic factors that can increase exposure to fospropofol and propofol derived from fospropofol greater than what was observed following the supratherapeutic dose (Clinical Pharmacology Table, section 6.1). The sponsor states the expected high clinical exposure scenario is when a subject with low body weight receives the wrong dose (e.g., a full vial of 1050 mg fospropofol) ofFospropofol. d) Is the dose and dosing regimen consistent with the known relationship between dose-concentration-response, and are there any unresolved dosing or administration issues?

The dose and dosing regimen is consistent with the dose- and concentration-response noted in Phase 1/2 studies.

Concentration-Response of Fospropofol and Propofol The pharmacokinetics and pharmacodynamics ofFospropofol disodium (10 mg/kg bolus) and Diprivan (50 mg/min infusion) were compared in healthy volunteers in Study # 625. In the first period, subjects received a 10 mg/kg bolus IV dose of fospropofol disodium injection. The pharmacodynamic endpoints for the level of sedation were the bispectral (DIS) Index and Modified Obseer's Assessment of Alertess/Sedation (MOAAS). A BIS value near 100 indicates that the subject was awake, and a BIS value of 0 indicated isoelectric EEG or the absence of brain activity. MOAAS evaluation placed a grading score of 0 (nonresponsive) to 5 (alert) in the category of responsiveness. In the second period, after a 7-day washout period, each subject received a 50-mg/min infusion of propofol injectable emulsion targeted to produce the same peak EEG effect that was observed in that subject after administration of 10-mg/kg fospropofol disodium injection. The propofol dose derived from fospropofol disodium injection treatment (dose corrected for molecular weight=5.36 mg/kg) was higher compared with the propofol dose from treatment with propofol injectable emulsion (50 mg/minute infused for 2.06 to 4.60 minutes, total mean:f SD dose of2.30:f 0.39 mg/kg). The results are discussed in figures below.

20 i:i 7 I c: l.-

I:I oG l.. G a. 1 10 20 30 40 _Tm.Jmil Figure above presents the mean propofol concentration over time profile upto 45 minutes following administration ofDiprivan 50 mg/min (red inverted triangles and line) and Fospropofol disodium 10 mg/kg (blue circles and line). Fospropofol PK profie is not indicated in this figure. Propofol plasma concentration profiles were different for the 2 treatments. Following administration ofa single iv bolus dose offospropofol, the median T max for propofol was reached at a slightly later time than it was following Diprivan administration by infusion. Following fospropofol dosing, the mean propofol Cmax was lower and mean AUCo-inf was higher than following Diprivan treatment without molar equivalent dose or bodyweight normalization. Following administration of an iV infusion ofDiprivan 50 mg/min, plasma concentrations ofpropofol reached Cmax at a median T max of 4.0 minutes. The propofol concentration increased rapidly, and then

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21 declined after the infusion was stopped. 1_

!l . (lW +t 70 æ . . - ACUAVAN lOMgAl &- D~1I 511l/." ..

io 0:J 0 I I :J S 7 . II I:J IS 17 .. ~I ZJ 3 zr 3 :JI D H D . 61 Q ø Ttme (min)

Figure above presents the mean BIS scores over time (:Istandard error (SED for the Fospropofol disodium 10 mg/kg (Green Open triangles and line) and Diprivan 50 mg/min (Red Open Circles and line) treatment groups from first dose of study medication to the last time point recorded (45 minutes). Subjects treated with Diprivan reached their lowest BIS scores at about 5 minutes (median) after drug administration and recovered (to a BIS of approximately 90) at about 21 minutes, when measurements were terminated. The dose of Diprivan was targeted to match the pharmacodynamic effect of a single dose of fospropofol 10 mg/kg. However, subjects treated with Diprivan went to a lower BIS score than those treated with fospropofoL. Peak effect for fospropofol was reached at 7 minutes (median) following drug delivery. At 21 minutes after fospropofol administration BIS scores for the majority of subjects had not returned to ~90. Recovery from sedation, as judged by BIS score, was slower after fospropofol disodium administration than after Diprivan infusion.

Appears This Way On Original

22 w · en +1 e! ua 4 (J (J o~ ) "'U j:tií

6+ AQUAVAN tOlIAi e- I.. SDMg."

o .) . I I 3 5 7 9 II 13 15 17 19 ZI :t %5 %7 Z9 31 D 35 7T 3l 41 .. ..

Time (min) Figure above represents the mean changes in MOAAS scores versus time after Fospropofol disodium 10 mg/kg (Green Open triangles and line) and Diprivan 50 mg/min (Red Open circles and line). MOAAS scores reached a lower value and recovered faster in subjects after Diprivan treatment than after fospropofol administration. After fospropofol treatment, subjects spent a longer period oftime at MOAAS scores of2 to 4 than they did following treatment with Diprivan. 5. What are the PK characteristics of the drug and its major metabolite? a) What are the single dose and multiple dose PK parameters? In clinical studies, fospropofol was administered as a single IV bolus dose followed by a supplemental IV bolus dose. The pharmacokinetic characteristics of fospropofol and the major metabolite propofol are described below: Upon intravenous bolus administration, fospropofol plasma concentrations decrease in a biphasic manner with an initial decline followed by a relatively slower terminal phase

(t1l2 of 0.8 hours). Fospropofol is metabolized by alkaline phosphatase into propofol, formaldehyde and phosphate. In vitro studies indicate that more than 66% of fospropofol disappears within 5 minutes of incubation with alkaline phosphatase at 37°C. The peak plasma concentrations of propofol are noted around 8 minutes following fospropofol administration (See Figure below).

23 2H

"'AQUAVAN'-ø I --AQUAV AN is II

200

;3 li. 150 l 21 ~ :! l !

o o H 100 15 200 iH Tb (JU1I)

Appears This Way On Originai

24 Pharmacokinetic Parameters of Fospropofol in males and females (Study#3000-521)

AQUAVAN AQUAVAN Parameter Sex D 6mll D lSmll

Male and feme 4.00 2.00 69 68 combined (1.00-8.00) (1.00.00) Tma (mi) 4.00 4.00 Mae 38 38 Median (M-Max) (1.00-8.00) (1.00-4.00) 4.00 1.00 Feme 31 30 (1.008.00) (1.00-6.00) Male & Female 69 78.7 (15.4) 68 211 (48.6)) Cm (pg/mL) Combined Mean (SD) Male 38 78.1 (16.3) 38 202 (45.9) Feme 31 79.3 (14.4) 30 223 (49.9) Male & Femae 69 19.2 (3.55) 68 50.1 (8.63) AUCoIa (h-liglmL) Combined

Mean (SD) Male 38 18.3 (3.08) 38 48.S (8.3) Femle 31 20.3 (3.83) 30 51.7 (8.88) Male & Female 68 19.2 (3.59) 68 50.3 (8.4) AUCO-ii (h-pglmL) Combined

Mean (SD) Male 37 18.3 (3.10) 38 49.0 (8.39) Feme 31 20.3 (3.85) 30 51.9 (8.93) Male & Feme 68 0.81 (0.08) 68 0.81 (0.09) tll2 (h) Combined

Mean (SD) Male 37 0.85 (0.07) 38 0.83 (0.10) Feme 31 0.77 (0.08) 30 0.79 (0.09) Male & Femae 68 0.280 (0.0528) 68 0.320 (0.0585) CLp (Lg) Combined

Mean (SD) Male 37 0.293 (0.0533) 38 0.326 (0.058) Feme 31 0.265 (0.0484) 30 0.310 (0.0577) Male & Fema 68 0.327 (0.0686) 68 0.374 (0.0724) Vd(Lg) Combined

Mean (SD) Male 37 0.3S7 (0.069) 38 0.388 (0.0725) Femle 31 0.291 (0.OSI7) 30 0.352 (0.0671) Tii=t to maxjm1un plasm i:oni:aitrtion; Mi-- Ma Cm=obsered pla dn¡ l:OIention at Tii; AUC=ar ui th l:OiHaitrtion ver ti i:Ule; AUCo.JaAUC fr th ti of doin to th lat qutible l:ODfitrtion; AUCo.iiAUC frm th tie of doin to in; tviamclion ha.ii; ci=pla i:lclle; V.iolum of distrbuton; NA=not aplil:blc

25 b) How does the PK ofthe drug and its major active metabolites in healthy volunteers compare to that in patients? Pharmacokinetics ofpropofol, the major active metabolite,following administration òf fospropofol were evaluated in healthy volunteers (Studies # 3000-521, # 3000-625) and patients (Studies # 3000-522, #3000-524) in separate studies. Population PK analysis revealed that P K of fospropofol and propofol were similar in healthy volunteers and patients.

Pharmacokinetics ofpropofol following administration of Fospropofol 6 mg/kg and Fospropofol 18 mg/kg in healthy volunteers are described below. Plasma concentrations ofpropofol reached Cmax at a median Tmax of 12 minutes for Fospropofol 6 mg/kg and 8 minutes for Fospropofol 18 mg/kg. Concentration profies showed biphasic elimination with a mean tll2 of2.06 hours for Fospropofol 6 mg/kg and 1.76 hours for Fospropofol 18 mg/kg. Mean Cmax values were 1.08 ..glmL and 3.90 ..g/mL, and mean AUCO-inf values were 1.70 h...g1mL an 5.67 h...g/mL, for Fospropofol 6 mg/kg and 18 mg/kg, respectively. !G i~ AQ1JAV AN 6 JI 45 l_..~__~g.!~!~i.!~_ 40 l:: 350 '-. 30

l1: 150

l¡ 100 i. !: 150

100

50

o 8 st 100 l! 100 1st T.. (1U)

PK parameters ofpropofol are tabulated below. The increase in propofol exposure was slightly more than dose proportionaL. A 3-fold increase in Fospropofol dose (from 6 to 18 mg/kg) led to a 3.6-fold increase in mean propofol Cmax and a 3.3-fold increase in mean propofol AUC O-inf.

26 Pharmacokinetic Parameters ofPropofol Following IV Fospropofol Administration

AQUAVAN AQUAVAi~ Parameter Sex n , ml/ n 18ml/

Male and female 12.00. 8.00 69 68 combined ( 4.Q0.00) ( 4.OQ60.00) T_(mi) 12.00. 8.00 Median (M-Max) Male 38 38 (4.Q0.00) ( 4;()0..20.00) 12.00. 8.00 Fem 31 30 (4.0033.00) (8.Q0.00) Male and feme 69 1.08 (0.33) 68 3.90 (0.822) C_(iiglmL) combined

Mean (SD) Male 38 1.4 (0.366) 38 4.06 (0.868) Feme 31 1.01 (0.270) 30 3.69 (0.719) Male and femae 69 1.3 (0.244) 68 4.63 (0.958) AUCO-Ia (h-J;g/in) combined

Mean (SD) Male 38 1.8 (0.239) 38 4.93 (0.981) Feme 31 1.27 (0.239) 30 4.25 (0.791) Male and femae 67 1.70 (0.290) 68 5.67 (1.28) AUCO-ii (h.iig/mL) combined

Mean (SD) Male 37 1.78 (0.266) 38 6.11 (1.34) Feme 30 1.60 (0.290) 30 5.11 (0.963) Male and female 67 2.06 (0.77) 68 1.76 (0.54) tll2 (h) combined

Mean (SD) Male 37 2.06 (0.51) 38 1.79 (0.51)

Feme 30 2.06 (1.02) 30 1.74 (0.58) Male and femae CLp (Lg) combined 67 1.95 (0.345) 68 1. 79 (0.390)

Mean (SD) Male 37 1.85 (0.283) 38 1.65 (0.317) Femae 30 2.08 (0.376) 30 1.96 (0.40) Male and femae 67 5.76 (2.14) 68 4.46 (1.8) V¡F(Lg) combined

Mean (SD) Male 37 5.50 (U9) 38 4.19 (1.30)

Feme 30 6.07(2.66) 30 4.80 (1.43) Tii to maum plasm c:on~trtion; Mi Ma c"=obscmed pla drg c:trtion at T_; AUC=a un the c:oiicntrtion ver tie c:ure; AUCo.AUC fr th ti of doina to the lat qutifiable c:oncntrtion AUCO-AUC frm the tie of doina to inty; t¡nmn eltion haf.life; CLp"'ap pla elce; V.I'" apar volum of ditrbuti NA=- applieable

27 c) What are the characteristics of drug absorption? Following oral administration of fospropofol plasma levels of fospropofol and propofol were detected and sedative effects were noted in healthy volunteers. As such absorption of fospropofol is not relevant for the proposed intravenous dosing regimen. However, absolute bioavailabilty of fospropofol was evaluated following oral, duodenal or iv administration of 400 mg fospropofol (Study# 3100-0401). The mean absolute bioavailability (F) offospropofol was 1 % after oral administration and 0.1 % after duodenal administration. The plasma propofol levels could not be estimated reliably due to problems with the analytical assay. Mean fospropofol plasma concentration vs time profies

GP1575 ~. eo .-e.. Tt 0i 01-7) --4-' 12 Du 01-7) eo ~ It i. 01-7) I 40 30 I ao J 10

0 \ 0 3 . 8 "'--- Sc li l') In another study (#3100-402) pharmacokinetics offospropofol following single ascending doses was evaluated in healthy volunteers. Dose-related increase in plasma fospropofol levels were noted in this study. Again, plasma levels ofpropofol could not be reliably estimated in this study due to problems with the analytical assay. However, significant sedative effects were felt by the subjects following oral and duodenal administration of fospropofol. Fospropofol plasma Cmax or AUC plotted against oral dose i 0 8 o o j o o ~ ~ 'I .. 8 €I J i o ~ o æo 4I eo 80 1~ 1~ o æo Q eo 8l 1l 1~ dc (mg cb (m

28 The implications of fospropofol oral absorption as it applies to abuse and misuse have been addressed by Dr. Patricia Beaston in the controlle substaes staffs assessnt of fospropofol's abuse liabilty. d) What are the characteristics of drug distribution?

Fospropofol remains preferentially in the extracellular component of blood (blood-to- plasma ratio ~ 0.5) and is highly bound (97 -98%) to plasma proteins at clinically observed concentrions (0.01 - 10 i.g/mL). Fospropofol and propofol have a volume of distribution of about 0.39 and 5.3 L/kg, respectively. Upon administration Of14C_ fospropofol in Long Evans rats, significant amounts of radioactivity were found in the brain, the purported site of action. This indicates that the fospropofol-derived moieties cross the blood-brain barrier and the active moiety is thought to be propofol. The potential for protein binding interaction between fospropofol and propofol was assessed in human plasma collected from thrcc sepaate individuals. Propof01 (0.05 - 5 ¡ig/mL) had minimal effects on protein binding offospropofoL. Fosprfol (0.01- 200 ¡ig/mL) did not affect the protein binding ofpropofol. e) Does the mass balance study suggest renal or hepatic as the major route of elimination?

Fospropofol appears to be mainly eliminated by renal route followed by extensive metabolism.

Seventy one percent of total radioactivity from a 400 mg dose ofFospropofol Injection (containing 100 ¡iCi radioactivity) was recovered in urine and less than 1% was recovered in feces in 8 days; 28% of radioactivity was not recovered. The majority of radioactivity (65%) was recovered in urine in the first 48 hours and accounted for moieties other than fospropofol.

Amount of Radioactivity Recovered in Urine and Feces in Fospropofol equivalents Pa..te Uri (N=8) (N=7)* (N=8) Cu(mi) 24 247 1.76 01.0) (24.6) (1.8) %Fet 71.3 71. 0..51 (3.76) (3.95) (0.34)

%Fe = 100*CumAe/344.62 t) What are the characteristics of ? Fospropofol is metabolized by alkaline phosphatase into propofol,formaldehyde and phosphate. Propofol is further metabolized by glucuronidation. In vitro studies indicate that more than 66% of fospropofol disappears within 5 minutes of incubation with alkaline phosphatase at 37°C. PK characteÌ"stics ofpropofol formed following administration offospropofol are described in the above sections.

29 In study#3000-0205, eight healthy male subjects received a single i.v. infusion of 400 mg of (14q fospropofol disodium injection (100 JiCi) over 10 minutes. Blood, plasma, urine, and feces samples were collected for determination oftotal radioactivity; plasma fospropofol and propofol concentrations.

The study demonstrated that, on the basis of ratios of AUCO-infvalues for radioactivity in plasma to plasma AUCo_inrvalues for fospropofol, 21.4% of the total radioactivity in plasma was associated with unchanged fospropofoL. An average of71.3% of total radioactivity was recovered in urine in 8 days (192 hr). The majority of radioactivity (65%) was recovered in urine within 48 hours following dosing. Less than 1 % of radioactivity was detected in feces. Pr.posd ....transf.rmatl.n of fospropefol dlSClum In human IÐ'ýal

WmlS7IS wMIG "1Yf -'~ Piiilgk , j y()Gu 2 . 2.~ ¿; UØ Pbll tJ. Plii3 'C. .

M4 Gu ¡~¡ (Qa~)M6 --- ¡i- 'j

.wMil y SO 1~æJ ~ (~iil) (Qui4ul)M2 *::~æ'j--- tldrfDl gh) 2I = = 0J Ci coju 3 = Su CODju 'M6aiM7_ deed iipllii by WM bu\\nol de byi:ac. SI~ qi _potuia~ia. an hydi"l \\ no de by WMori:ac. 14C-fospropofol was detected in plasma but not urine. The major metabolite observed was propofol glucuronide (MI0), and represented a mean value of34.8% ofthe dose in

30 urine through 24 hours. Three other metabolites were observed at relatively low levels: quinol-4-sulfate (M2), quinol- 1 -glucuronide (M4), and quinol-4-g1ucuronide (M6), representing mean values of 4.59%, 11.1 %, and 5.13% ofthe dose, respectively, in urine through 24 hours. Two other minor metabolites were detected: hydroxypropofol- glucuronide NO.1 (M7), and hydroxypropofol-glucuronide No.2 (M8), representing mean values of 0.81 % and 0.26% ofthe dose, respectively, in urine through 24 hours. g) What are the characteristics of drug excretion? Fospropofol and propofol have a short elimination halflife of about 0.8 and 2 hrs, respectively. Mass balance study conducted in humans after oral administration of 14C_ fospropfol revealed that 65% of radioactivity is recovered in urine by 48 hours. While fospropofol and propofol were undetectable in urine, propofol-glucuronide was detected as the major metabolite along with two minor metabolites characterized as hydroxypropofol-glucuronides NO.1 and No.2. h) Based on PK parameters, what is the degree of linearity or nonlinearity in the dose-concentration relationship? Fospropofol pharmacokinetics is linear in the dose range of6 -18 mg/kg; profol pharmacokinetics is slightly nonlinear around 18 mg/kg dose compared to the 6 mg/kg dose. Fospropofol median Tmax was observed at 4 minutes (range, 1 to 8 minutes) for subjects who received 6 mg/kg and at 2 minutes (range, 1 to 6 minutes) for those who received 18 mg/kg of fospropofol disodium injection. Mean fospropofol concentrations exhibited an approximate 2-fold decrease between 4 minutes and 12 minutes and an approximate 10- fold decrease between 4 minutes and 30 minutes following administration of single bolus doses offospropofol disodium injection (see Table below). The initial decline was followed by a slower terminal phase with a mean tl/2 of 0.8 1 hour. Propofol median Tmax was 12 minutes for subjects who received 6 mg/kg and 8 minutes for subjects who received 18 mg/kg offospropofol disodium injection (see Table below). Concentration profies showed biphasic elimination with a mean tl/2 of2.06 hours for subjects who received 6 mg/kg and 1.76 hours for subjects who received 18 mg/kg of fospropofol disodium injection. SUbjMu (~ct)(.. 301.d "~ldc 3G21) ,..te,.ln HM SI ci T_I. t". o\ v. ru limLl ("*1 (hI F!!!Jlll ~ (U NJUAVN4 6 in Jõ1 40 0.2 0.32 N=6 78.7(15.4) (1.0":8.0) 0.81 (0.08) 192(3.59) (0.05) (0.06) N:AVN4 10 in ~ 114(17.5) (1.0~06.0) 0.84(0.09) 27.1 (3.901 0.3 0.3 /0.04911 /0.0759) ÃÖAVN4 18 in ~' 211(48.6) (1l~6.) 0.81 (0.09) 50.3(8.41 0.32 0.374 /0.ll) /0.074) AQUAVN4!r 6 in 3õN=§ 1.08(0.33) 12.0 /4.0-!!.01 2.06(O.m 1.70(0.2) 1.95(0.34 5.76(214) AQV/l 10 rn ~ 2.20(0.4131 (4.0~~3.01 2.09(0.62) 3.07(0.49) 1.79(0.3131 5.2(1.49) N:AVN4 181! ~ .3.90=..0~ ç.m___~_:X-.ìi&lãit==ìll1lemt;; . 1.76(0.541 .5.67(1.21. 1.79(0.31 4.46(1~) . baJ TidoFoJl ~an II V.ii an (i C1 II.. V.I 31 i) How do the PK parameters change with time following chronic dosing? Given the short duration of action need for the proposed indication, multiple dose P K studies in the conventional sense, i.e., up to steady state, were not conducted. j) What is the inter- and intra-subject variabilty ofPK parameters in volunteers and patients, and what are the major causes of variabilty? Low to moderate unexplained inter-individual variabilty was noted with estimates of 14.6% CV (2.9-23%), and 31.6% CV (27.7-47.3%) for central volume of distribution (V¡) and clearance (CLF), respectively. The population PK parameter estimates are presented in the table below. In particular, typical fospropofol volume was estimated as VI = 4.41 L (4.23 - 4.56 L) and clearance as CLF = 0.312 L/min (0.197 - 0.331 L/min). Population PK parameter estimates Pii NOEMII Põ RëIIö1ÖBõtr me Re Es SEI%) I9%CII SEI%) Vi(l) III 4.41 1.81 4.4(424.4.56) 1.76 Cl. (lJ) lI 0.312 3.67 0.312(0.197 - 0.331) 2.03 KI.(1/im) 1I 0.0147 13.5 0.0147(0.0122 . 0.0397) FI ~(11mÌ1) II. 0.0128 29.1 0.0131(0.00 - 0.0215) 12.6 Vi_ e. 0.23 9 0.20.19 - 0.22) 8.85 Cl..DO 1I 0.138 16.8 0.1340.0757 - 0.185) 16.4 Vi... 1I -0.199 29.1 -0.196-0.314 - -0.087) 27.4 Cl..A Ill. 3.34 10.5 3.44.n-4.79) 10.3 Ci... II" 0.117 34.4 0.124(0.04 - 0.2) 323 Cl... II.. -0.03 29.5 -0.0313(-0.0517 - -0.00) 29.1 Cl..CI Ill) -0.073 75.7 -0.06-0.166 . 0.029) 54.1 Cl..- II.. 121 3.53 1.2111.13-1.34) 3.5 "¡V 0(1,1) 0.0214 58.6 0.021(0.00 . 0.0529) 60.2 Rv.CLWv 0(1,2) 0.0187 53.9 0.01930.00 - 0.0426) 53.8 "¡CL 0() 0.09 13.7 0.101(0.0767 - 0.2) 12.4 il.. 1I 0.191 33.3 0.1840.0422 - 0.35) 30.1 .r_ 0.111 9.16 0.1090.091-0.131) 9.14 Il Varit este (de 0IV1 100 0(1,1)v,% 14.6% 14.9 (29 - 23) RcV1 0.405 0.418 (0.117 -1) OICL 1000()11% 31.6% 31.8 (2.7 - 47.3) so llV2 0.437 0.429 (0.2 - 0.595) 0I11 100Il.v, 33.3" 33.0 (32 - 362)

2.3 Intrinsic Factors 1. What intrinsic factors (age, gender, race, weight, height, disease, genetic polymorphism, pregnancy, and organ dysfunction) influence exposure and/or response and what is the impact of any differences in exposure on the pharmacodynamics? Signifcant impact of body weight on pharmacokinetics of fospropofol and propofol was noted. These findings support the weight based dosing algorithm proposed by the sponsor: The dosage of Fospropofol is limited by lower and upper weight bounds of 60 kg and 90 kg, respectively. Adults who weigh"?90 kg should be dosed as if they are 90 kg; adults who weigh ..60 kg should be dosed as if they are 60 kg.

32 The population pharmacokinetics of fospropofol was adequately described by a two- compartment modeL. Population pharmacokinetic analysis evaluated the effect of race, age, gender, body weight, albumin concentration, alkaline phosphatase concentration, renal impairment and hepatic impairment on the pharmacokinetics of fospropofol and propofol derived from fospropofoL. None of the prognostic factors except body weight affected PK offospropofol or propofol (See attached Pharmacometrics review). Allometric scaling adequately described the dependence of fospropofol population PK parameters on body size measures. Body weight (WT) was normalized to a reference weight of 70 kg. For both fospropofol and propofol central volume of distribution increased linearly with weight (WT/70), and clearance increased as (WT/70i/4 while rate constants decreased as (WT/70rI/4. After adjusting for body weight renal impairment and hepatic impairment did not significantly affect fospropofol pharmacokinetics. Relationship between CL, V for fospropofol and propofol and total body weight in patients without extreme parameter values.

~ .. , ~ .. I.. . . -- o 0 l ....e .- .a. II . . o .. . :... .-..- ~ :. -:.; ....~:... 1..1 : l ~' l .. . t.~..~I~'t.'~.".'~."J~.~" ....

a C\ ".l\mJ..~"í~-.'Ij',...... f ".' . ..rrr~:,~...... M ..- ~ 00 æ 1001~1~ ~ 00 æ 100. 1~ 140 T..~WØ T..~Wi

. .. '. .. , ,.' . . . . l~.. .. Ii t! ...... -... . . i5 Õi ~ eo. ..'.~ ...... : :... . 'I .. 'l . .... e, ..'~..L.....~... . . " ., -,'.- '" lc:~~,. " ¡¡ l J .. ~ ...... ?:I.- '4 '_.âi~...V ".'!! .. l ...... ~ .~."'~.:i¡... -Wl'Ke. . .,., l .. l! .. II ...... ~.....'~. ":l~A../J'.: .,A. '.. . ! . - 'i ~ ,'.. .. :"".. ."...... t" . . . . .

40 00 æ 100 1~ 1~ ~ 00 æ 100 1~ 140 T"'lIWI T..lIw.

Pharmacokinetic-pharmacodynamic (PK-PD) analysis was conducted to evaluate the relationship between venous plasma concentrations of fospropofol and propofol, and Mødtiol Ohseer's Assssnt of Alertness/Sedation (MOANS) score following administration oftherapeutic bolus dose(s) offospropofol injection. Effect of prognostic

33 factors such as age, race, gender, body weight, albumin concentration, alkaline phosphatase concentration was evaluated on sedative effects of propofol. The analysis indicated that older patients (age:; 65 years) were more sensitive to fospropofol treatment. The changes to the effective concentration for fospropofol to produce 50% of maximal sedative effect (ECso) were evaluated in the population PK-PD analysis. Decreases in ECso with a decrease in albumin concentration for different strata of patients based on age, ASA status, and weight. However, Sedation depth (as measured by the Modified Observer's Asssment of Alertess/Sedation Scale) was not consistently influenced by albumin levels across these populations. Hence, dose adjustment is not recommended with respect to albumin concentrations. 2. Based upon what is known about exposure-response relationships and their variabilty, and the groups studied (volunteers vs. patients); what dosage regimen adjustments, if any, are recommended for each of these subgroups (examples shown below)? a) elderly

Patients ~ 65 years age should receive 25% lower dose at any given weight range compared to patients c:65 years age. b) pediatric The sponsor has not conducted any clinical studies in pediatric patients. The sponsor is requesting a deferral of clinical studies of fospropofol disodium in pediatric populations including neonates, iriants, children, and adolescents. c) renal impairment Dose. aclustment is not needed with respect to renal impairment. A total of 7 renally impaired patients were included into population PK analysis. Five of these patients had normalized creatinine clearance between 10 and 30 mL/min/l. 73m2. Two patients had normalized creatinine clearance less than 10 mL/min/l.73m2. The data from these patients with renal impairment were merged along with other patients and the pharmacokinetic parameters were determined. Significant relationship was not noted between random effects on clearance offospropofol (left) or propofol (right) with regard

. -ia . . . -ia ...... q- l : ~.. . . ia .. G G . .. . U : .. .._ ,~.la.. .. · . ~ Wi Il ~ CD Wi 2 - i-.L;...... ~..d..... ai~... " .... t;~::; . - v...... ·. 0. . .. -. 0. _ .. 'i r r l l r r 20 40 60 80 100 140 40 60 80 100 120 140

CRCL CRCL 34 to creatinine clearance (See Figure above). d) hepatic impairment Recommendation cannot be made with regard to dose adjustment in patients with hepatic impairment. Caution should be exercised when usingfospropofol in patients with hepatic impairment. Fospropofol data from seven patients (five patient data for propofol) with hepatic impairment were merged along with other patients and the pharmacokinetic parameters were determined. Five of these patients were present in the main data set ofthe fospropofol - propofol population PK analysis (population analysis report for MGI Study number PR-AQUA-02-02). Data for two additional patients with hepatic impairment became available after the main analysis was completed and NDA submitted to the FDA. Demographic information for the seven patients is presented below.

18 U"" AGI WT LeW I. ID ASA AL8 ALI" CilIA II CRCL lynl (kl! (kil (llt/II'I (gldL (UILI 1""''1 IinI IIiUiilnl1.7:ii'l 230 5203650001 53 100 67.7 33 Male P2 4.2 68 1.1 2.4 88.7 44 5235590002 59 80 62.1 25.2 Male P3 2.8 134 1.0 2.1 78.6 450 5235650016 53 76 51 26.9 Female P3 3.3 206 0.8 1.1 90.9 453 5235650023 60 50 38.1 20.8 Female P3 2.5 203 0.6 5.9 92.8 612 524540003 61 74 55.7 27.2 Male P4 2.7 94 0.8 0.6 96.8 703 5235610001 53 84 65.4 25.1 Male P3 2.7 149 0.6 1.8 141.9 704 5235650025 85 60 43.4 23.4 Female P3 3.3 105 0.9 4.1 46.2 The hepatic impairment noted in these patients as per the Child-Pugh scores is indicated below. Prothrombin time was not collected in all patients and 1 point was assigned to each patient. With the adjustment one patient with mild, three with moderate and two patients with severe hepatic impairment are recorded.

Child-Pugh Scores for Patients with Hepatic Impairment (Score of 5-6 indicates mild, score of 7-9: moderate and a score of::9 indicates severe hepatic impairment)

0520- 0524- 0523- 0523- 0523- 0523- 0523- 0523- 365-01 544-03 547-0061 559-002 565-016 561-01 565-023 565-O2~

Ew:ephaopathy gie2 1 1 1 1 2 1 1 2

Asites2 1 1 1 1 2 2 2 2

Se bilin mgldL I 1 I 2 I 2 3 3

Seru album g1dL 1 3 3 3 2 3 3 2

Protlombin ti,secprolonged 1 1 I I I 1 1 1

Chd-Pugh Score 5 7 7 8 8 9 10 10 i Whle ths patient met th crtera for hepatic imait, PK sales were not avaiable for this pati, an th patient was not inclu in th PR-AQUA-02-o3 anysis. 2 Encephalopathy grde and asites determed by mecal hitOl taken at baseli. 3 Prothombin tie was not collected; al patients were assigned 1 point for th assessint.

Propofol data for one patient with hepatic impairment (Patient 0520-365-0001, ID=230) were not available and unreliable in another patient (0523-565-0023). The PK information for individuals

35 The individual clearance value for fospropofol noted for each patient with hepatic impairment . F b Patient No. Child-Pugh Score Child-Pugh CL t AVC Classification ' F 1/2 (0-0) (L/min) (min) (mi:b../IRL) All Patients - - 0.4 53 19 (N =667) 5203650001 5 A mild) 0.439 54.6 14.7 5235590002 8 B moderate 0.53 49 12.8 5235650016 8 B moderate 0.37 50.7 18.1 5245440003 7 i3 moderate 0.543 46.6 12.3 5235610001 9 B moderate 0.478 50.4 14.4 5235650023 10 C (severe) 0.433 45.6 16.8 a5235650025 07510 C (severe) 0.305 48.7 15.6 b Normalized CLF, was computed as CL/(WT170) . Predicted AVC from time 0 to infinity after single bolus fospropofol dose of 6.5 mg/g. Patients weighing less than 60kg (greater than 90 kg) were administered 390 mg (585 mg) dose. Dose for 65-years old and older patients was reduced by 25%. Mea offospropofol PK paet in "all patients" was estimated by Population PK Modl 120 The individual clearance value for fospropofol and propofol noted for each patient witheoatic h imoairment . . p b Patient No. Child-Pugh Child-Pugh CL t AVC Score Classifcation .p 1/2 (0-) (L/min) (min) (in~br/.l. All Patients - - 3.5 68 1.2 5203650001 5 A (mild) NA NA NA 5235590002 8 B (moderate) 2.92 90.8 1.44 5235650016 8 B (moderate) 2.24 63.2 1.85 5245440003 7 B (moderate) 4.31 43.3 0.958 5235610001 9 B (moderate) 3.56 58.9 1. c ------5235650023 10 C (severe) 5235650025 10 C (severe) 1.64 89.1 1.79 aNormalized CLF was computedQn as CL/(WT170) b Predicted AVC from time 0 to infinity after single bolus fospropofol dose of 6.5 mg/g. Patients weighing less than 60kg (greater that 90 kg) were administered 390 mg (585 mg) dose. Dose for 65-years old and older patients was reduced by 25%. C Excluded from propofol PK evaluation due to inconsistent and extremely low values

NA: propofol data was not available Mea ofpropfol PK pacr in "all patients" was estimated by Population PK Modl 120 As such fospropofol is metabolized by alkaline phosphatases that are ubiquitously present in various organs of the body apart from liver and hence its disposition is not expected to be affected by liver impairment. Propofol, on the other hand, is extensively metabolized. by glucuronidation and oxidation possibly by hepatic involvement. The limited information on propofol clearance data from individual patients with hepatic impairment is not adequate to arrive at a recommendation for dose adjustment in patients with hepatic impairment. Hence, it is acceptable to indicat that "AQUA VAN Ms fl He adequately studied in patients with hepatic insuffciency". However, cau shld he exercised when using Fospropofol in patients with hepatic impairment.

36 e) what pregnancy and lactation use information is there in the application?

No clinical studies were conducted in pregnant and lactating women. Clinical studies were not conducted in pregnant and lactating women with fospropofoL. Reproduction studies have been performed in rats and rabbits at doses up to 3.5 and 5.4 times the anticipated cumulative human dose of fospropofoL. Please refer to the Pharmacology toxicology review for the information on effects of fospropofol on fertility and fetus. Fospropofol is not recommended for use in labor and delivery, including Cesarean section deliveries. Based on published information propofol is known to cross the placenta, and as with other sedative-hypnotic agents, the administration ofFospropofol may be associated with neonatal respiratory and cardiovascular depression (Gin T et. al. 1990, Anaseth. Intens. Care 18: 180-184, He Y et. al. 2002 Anesth. Analg. 94:1312- l3 14). Fospropofol is not recommended for use in nursing mothers because propofol has been reported to be excreted in human milk (Nitsun M et.al. 2006 Clin Pharm Ther. 79: 549-557).

2.4 Extrinsic Factors 1. What extrinsic factors (drugs, herbal products, diet, smoking, and use) influence exposure and/or response and what is the impact of any differences in exposure on pharmacodynamics? Dosage aclustment is not required with respect to concomitantly administered drugs such as midazolam, fentanyl, morphine, and meperidine from a pharmacokinetic interaction perspective.

Effect of herbal products and smoking on pharmacokinetics and pharmacodynamics of fospropofol have not been evaluated. Food or alcohol is not expected to be coadministered with fospropofol and as such a change in the pharmacokinetics of fospropofol is not expected. 2. Drug-Drug Interactions a) is there an in vitro basis to suspect in vivo drug-drug interactions? There is no basis to suspect in vitro drug-drug interactions between fospropofol and coadministered drugs. The potential for drug interactions with propofol, the major and active metabolite, however, has not been addressed. Fospropofol is extensively metabolized by ubiquitously present alkaline phosphatases. Propofol appears to be directly glucuronidated as well as hydroxylated by unknown enzymes. b) is the drug a substrate of CYP enzymes? Fospropofol is not a substrate ofCYP enzymes. It is rapidly and extensively metabolized by alkaline phosphatase. In vitro incubation offospropofol in the absence ofNADPH did not result in significant disappearance of the drug.

37 c) is the drug an inhibitor and/or an inducer of CYP enzymes? Studies were not conducted to evaluate the effect of fospropofol on CYP inhibition or induction. Sponsor clearly indicated in th clinical pharology summa tha "No in_tion or inhibition of CYP450 enzymes were observed in vivo in nonclinical studies of fospropofol disodium (in vitro results offospropofol interaction with CYl450 enzymes are summarized in Module 2.6.4). Upon examination ofthe information provided it was found inadequate to conclude the potential for fospropofol to induce or inhibit CYP enzymes. Briefly, following 14 day exposure of dogs (Study # 3000- 1 571 5-00-06G) to fospropofol or propofol, the samples of liver were analyzed for total protein and CYP450 content. The information provided is not adequate to assess the potential for CYP inhibition or CYl induction by fospropofol or its major active metabolite propofol. Short term use proposed for the current indication and short half-life of the circulating moieties are noted. However, issue of drug interaction wil be relevant when the product use is proposed for longer duration use. Hence, the sponsor should conduct in vitro studies to evaluate the potential for major CYP inhibition or induction. d) is the drug a substrate and/or an inhibitor of P-glycoprotein transport processes? Status of fospropofol as a substrate or inhibitor of P-gp has not been evaluated e) does the label specify co-administration of another drug and, ifso, has the interaction potential between these drugs been evaluated? A number of medications are expected to be coadministered related to th.e procedure (bronchoscopy or colonoscopy). Pharmacokinetic changes infospropofol are not expected when fospropofol is coadministered with midazolam, and opiate analgesics such as fentanyl, meperidine and morphine. Although a P K drug interaction between lidocaine and fospropofol has not been evaluàted, the use of this combination in bronchoscopy patients has been studied. PK drug interaction study between fospropofol and fentanyl, midazolam and meperidine: In clinical studies, an premedication (fentanyl citrate 50 mcg IV) was administered prior to the initial dose ofFospropofol. Pharmacokinetic drug interaction between fospropofol when coadministered with midazolam and opiate analgesics such as fentanyl, morphine, and meperidine was evaluated in study #3000-414. Subjects randomized to morphine (0.1 mg/kg) received pretreatment 15 minutes prior to the initial bolus dose ofFospropofol (8 mg/g). Subjects randomized to fentanyl (1 llg/kg), meperidine (0.75 mg/kg), or midazolam (0.01 mg/kg) received pretreatment 5 minutes prior to the initial bolus dose of Fospropofol (8 mg/kg). To ensure maintenance of the blind, subjects randomized to morphine received placebo 5 minutes prior to administration ofFospropofol and those randomized to fentanyl, meperidine, or midazolam received placebo 15 minutes prior to the initial bolus dose of Fospropofol. Subjects randomized to placebo received a placebo injection at both 5 and 15 minutes prior to initial AQUA V AN bolus administration. Supplemental doses (2 mg/kg) of

38 Fospropofol could have been administered to achieve the target sedation level (Modified OAA/S score S3). Plasma concentrations ofFospropofol were generally similar in all treatment groups. The initial rapid decline was followed by a slower terminal phase with half-life of 0.44 to 0.52 hour, and this pattern was similar for all groups. Mean Cmax and AUCo-infwere similar for all treatment groups and ranged from 74.8 to 88.5 ..g/mL and from 20.9 to 29.6 h...g/mL, respectively. Mean weight normalized clearance (CLp) and mean weight normalized volume of distribution (V d) were also similar for all groups, and ranged from 0.32 to 0.4 1 L/hg and from 0.22 to 0.31 L/kg, respectively. Although ANOV A comparison of AUCo-infshowed statistically significant difference (p=0.045) among treatment groups, pairwise comparisons between the placebo and all other premedication groups did not show a significant difference.

Mean ($D) Fesprepføl IIlasma IIharmeldnetl lIarameters Aft AQUVM Tr..tmlJl , Prl:Hluil9Q Gr9llii.-'-'- ,.. 'Øj

The sponsor reported propofol pharmacokinetic data was not considered for review due to unreliable bioanalytical results. The study was not designed to identify effect of fuspropfol Oft Goadmiiiistero drugs' phanokinetics and as such plasma levels of concomitant medications were not assessed. Use of fospropofol with lidocaine: Concomitant use of lidocaine with fospropofol has been studied in two different settings.

1. Most of the patients undergoing bronchoscopy in study # 3000-524 were administered lidocaine as a topical for suppression of cough upon introduction of the flexible bronchoscope. 2. Paresthesias such as burning and tingling sensations were common adverse events with Fospropofol administration. A study (#3000-308) was conducted to determine the lowest dose levels of lidocaine that would reduce or eliminate the paresthesias associated with administration of Fospropofol.

39 Study#3000-0524 is a Phase 3, Randomized, Double-blind, Dose-controlled Study to Assess the Efficacy and Safety ofFospropofol Disodium Injection for Minimal-to- Moderate Sedation in patients undergoing flexible bronchoscopy. All patients were to receive lidocaine as a topical anesthetic for suppression of cough upon the introduction of the flexible bronchoscope. The recommended lidocaine dose for this study was ~ 300 mg, or ~ 4.5 mg/kg (whichever was less on a per patient basis), per procedure. Lidocaine was administered in most patients that underwent the procedure (see table below):

NtmER OF PATIEN WHO TOOK LIDOAINE ON TH DAY OF PROCEDU SAFETY POPULTION

AQUAVAN AQUAVAN All 2 mgkg 6.5 mgkg AQUAVAN n(N-103) ('l) n(N-149) ('1) n(N-252) ('l) .

Lidocine was administered at ",- 300 or ",- 4.5 mg/kg 78 (75.7) 116 (77.9) 194 (77.0) Lidocaine was administered at ~ 300m or ~ 4.5 mg/kg 22 (21. 4) 24 (16.1) 46 (18.3) Lidocaine was not adinistered 3 (2.9) 9 (6.0) 12 (4.8)

A number of other concomitant medications (Study # 3000-524, bronchoscopy trial) were administered as required for the procedure (See table below). Plasma levels of lidocaine or any other concomitant medications were not assessed as it was not an endpoint of this study. Medleatens Tak.n en th Day ef Prøeedure In t 3 Patients (Safe PepulaGR) AQlJAVAN AQUAVAN %.O-ßIN=i~ 6.S-miJN=io OVeraDN~n Number aDd Perteo. (0.) of Pa1ts PatentsLidøne' wi ~ 199 medicaon (96.1) 103 139 (100.) (93.3) 149 (100.0) 231 252 (94.4) (100.0) AtreOxymetuline 14 (13.6) 21 (20.4) 20 (13.4) 28 (18.8) 34 49 (13.5) (19.4) . eei.il'eSalbui 13 13 (12.) (12.) 18 16 (12.1)(10.7) 3129 (12.3)(11.$) SodiurnchloriNo~ 11 (10.7) 12(11.7) 11(12.1) 17(11.4) 29(11.) 29(11.) XYIOÇin./øÌllPOOne..~ a _.Il 9 _6.0_10t?7) 9 171Ml _6.7_1917.51 Dextsoium chlor injec .. (3.9) 10 (6.7) 14 (5.) GIUÇ"Phtnyl.pi inec Hel 65 (5.1)(4.9) 77 (4.1)(4.7) 1312 (4.$)(5.2) AcestPii'tä 24 (1.9)(3.9) 35 (2.0)(3.4) 5 9 (2.0) (3.) AC!lUiayicLlVÖbl; ac 10" (1.0) (2.7) 3 (2.0) 4 4 (1.)(1.) CømbiventPrøêlál 1 (1.0) 2(1.9) 3 1(0.7)(2.0) 43(1.2) (1.) =1P'KI"ilCÊ".xnl" 02 (1.9)3 (2.0) 1 (0.7) 3 3(1.2) (1.1) Vanìiiïö 21 (1.0)(U) 1 2 (0.7) (1.3) 33 (1.2)(1.) i Lido anLido ïtCL ar COin as "tidòaic" Note: Th sa patient may bavc be coucc in mo di 1 catc¡or. Not: OxJC fetayl an ahcmiive sedative mc ai no inlud in ths table.

40 Study 3000-0308 was conducted to evaluate safety of a single bolus dose of 12.5 mg/kg Fospropofol following premedication with lidocaine HCl injection. The first cohort of 5 subjects received pretreatment with 50 mg lidocaine followed by 12.5 mg/kg Fospropofol at the 35-mg/mL concentration. If the paresthesias were successfully mitigated at this dose combination, additional cohorts of 5 subjects each were tested at decreasing doses of lidocaine (ie, 40 mg, 30 mg, 20 mg) until either the lowest dose of lidocaine had been administered or a dose was tested that did not mitigate paresthesias, at which point the study was to be completed. The first cohort ofS subjects (Subjects 001 - 00)) reeived Fospropofol at the 35-mg/mL concentration, the second cohort of 5 subjects (Subjects 00 - 010) received Fospropofol at th 20-mg/mL concentration. Paresthesia or paresthesia-related adverse events were reported for all 10 subjects; therefore, per the protocol, no further cohorts were dosed. A 3 lead ECG was used to continuously monitor subjects during the study. Any 3-1ead ECGs that are reported as abnormal were to be printed and retained in the study records and a 12-1ead ECG was performed as soon as possible following this abnormal finding. QT prolongation related adverse events were not reported in this study. t) are there any in vivo drug-drug interaction studies that indicate the exposure alone and/or exposure-response relationships are different when drugs are co- administered? None g) is there a known mechanistic basis for pharmacodynamic drug-drug interactions, if any? None

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41 2.5 General Biopharmaceutics Fospropofol disodium injection is prepared in saline at a concentration of20 mg/mL for intravenous use. Two different Fospropofol disodium formulations were administered (35-mg/mL and 20-mg/mL formulations) in different clinical studies (see table below). Considering the intravenous use, the bioavailability of fospropofol is not expected to be different between the different strengths/formulations used in the clinical studies. FOIIMien Let. ~ .. 3001 1 Fospropol disoium as a stenle aqueous soutn in 0.4% 1214-7 300102 1 saine at a concentrtion of 20 mgmL for intrvenous (i.v.) 300103 1 injeon. Each vial contained 20 mL of sout. 300104 2 1214-10 300206 1 ('4C) Fospropol disoium as a stenle aques souti in 0.4% saline at a conctratin of 20 mgmL for i.v. inje. Each vial containe 20 mL of solu and 100 pCi of ('4C)_ 1921702 30205 labeled fospropofol. The ('4C) lab was containe in the phenyl group of th fospropfol molecule. Fosprool diium as a stenle aqueous soutn in 0.4% 30-0207 1 a 2 salin at 20 mgmL, suitle for i.v. administration. Eac vial 1214-10 contaned 20 mL of soluton. 3003082 1 Fospropofol diium as a stenle aqueous soutn in 0.4% 30-0207 1 b 2 saine at 35 mgmL, suitale for i.v. administration. Eac vial 17610603 contaned 20 mL of soluton 3003082 3009 3 30010 3 300411 3 3000412 3 Fospropool diium as a stenle aqueous soutin at concenti of 35 mgmL, suitae for i.v. administration. 3014 1 Fonulation induded contains monothiolycerol (MTG; GAA002 300415 2 0.25%) and tromethamine (TRIS; 0.12%). Eac vial cotained 30 mL of soluon. 3005203 2 300521 1 3005223 3 300243 3 3000413 2 Fosprool disoium was suplie as a stenle souton conning 35 mgmL of fospropfol disoiu ready for i. v. 30052~ 3 injeon. Fonulation indud contains monothiolycerol 900015 (MTG; 0.25%) and trthin (TRIS; 0.12%). Eac vial conned 30 mL of soluton. 3000625

42 2.6 Analytical Analytical methods for determining fospropofol, propofol, and formate concentrations in plasma were developed and validated for linearity, accuracy, precision, specificity and limits of quantitation and detection (see tables below). The analytical methods were found to have satisfactory precision and accuracy for measuring fospropofol and formate concentrations in plasma samples from clinical studies. Fospropofol Analytical Assay Fospropofol concentrations in human plasma and urine were determined by a method utilzing separation by high performance liquid chromatography (HPLC) and detection by a tandem mass spectroscopy (MS/MS) system. The fospropofol assay methods in plasma and urine were validated for linearity, accuracy, precision, specificity and limits of quantitation. A - i was used as the internal standard. High and low assay ranges were validated to cover the wide range offospropofol concentrations observed in clinical samples. Fospropofol was quantified by peak area ratio to its internal standard. Fospropofol and (internal \\\" standard) were extracted from plasma and urine using _ . .. Samples were then analyzed by MS/MS detection using a selective- _ reaction , monitoring and mode (for fospropofolfor m/z= 287.1--79.1,. The for - performance characteristics for the method validations and performance evaluation of assay method in each study are summarized in the Table below. Plasma fospropofol assays in study 3000-0207 were conducted at - . 24 Plasma fospropofol assays in studies 3000-0520, 3000-0522, 3000- 0523 and 3000-0524 were conducted at Plasma fospropofol assays in study 3000-0521 were conducted at -

Appears This Way On Original

43 Summar øf the LC/MS/MS A.say 'erfrmanee Characteristics for FG.prøpofél (GPI151'5) 3O1 A PI 2, T-i S1 01 AQUAVAN' AA045-GT QCA 6.8 i.- in Ih SID 5 QCl01 QC 6.1 416 Pie 01 p. (lH93) Pla QCl0l - IM.va: 100 ac 5.4 0-2l _~i- 0081XS) , ac 98.6 co¡'vUnd EI_ NA LClWS As 139 acA 100 QCA112 Days V_OIGPI Pla 5ID 5 - 15115 In Hum 48-01 100 QC ios QC 1.2 Cl2O 10 Pl (LtM As ac 101 ac 7A an Q~' &.70ec NA LCI As Vai_oiGPI 50ID 50 acA 95.3 QCA8.4 34 15115 In Hum 4l22 Pl 100, QC 103 QC5A Day - 100 00 ac 96.1 ac92 0-1O" I =(Hf!AsY ~ APIRaIZ, 3. ~ ~ S1 io As QCAlI8.3, th sa an Ellcy 4ß515 5ID acAllD2,101 9.0 01 AQAVANlnjca Pla 100& 30 - '0\1') v.. Ml HCL (M.VaI: 481 50ID 5 ac 99.0, 97.5 QCl 5.8, 8.5 0-2l lo Sø In Pa an 48-22) 100,00 acct 989, ios ac7.3, 5.7 BrochUnd F1_ 3I A PI3, 0410' - Ra Op ~ S1 io As 510 QCl18.3. ti sa an Ell 4l15 100& QC'ID2, 101 9.0 30 01 AQUAVANlnj (M. Val 481 Pla 5 QCl ~.O. 91.5 QCl 5.6, 8.5 VII_HCL an 48.0522) 5010 acl 98.9, ios acl7.3:5.7 O-ioC loUn Sø In Pa 100,00 P""coP' 3I API 3, 0411' RaIZ, Op ~ S1 io As QCAlI8.3, TI SO An ea 5ID 48.o15 100& acA'I02 101 9.0 30 01 AQUAVAN Inj (M.VaI: 481 Pl 5 ac 99.0,91.5 QCSl 5.8, 8.5 V.. MI HCL and 4ß522) 5010 ac 98.9, 105 ac 7.3, 5.7 O.ioC loPeUnd sell Inco Paten 100,00 I CPCIPro

Summar of the LC1MSIS Asy lIererance Charaeristics to 'ospropefG (0'" 15715) continue

Al LlOQ Acac Sb' SlTl PrID AnI -.. -- s~ oI~- OF 1_10) LI ... (ng)-- (ng) (%) I'l \D) ""lii) 3I A PI 2, 0i15t Ra Op la S1 ID As 510 acAlI8.3, th sa an EII 48.o15 QCl 102. 101 9.0 of AQUAVANlnj I 100& - 30 . (M.VaI: 4801 Pl 50ID 5 QCl ~.O. 97.5 Qc-l 5.8, 8.5 VIl MI HCL an 4l22) oul 98.9, LOS acl 7.3, 5.7 o-io forPant Sø In uiEldrl 100.00 co bl4) 3013 A- PI 2, RaIZ. Op ~ S1to Exin th sa an EII QCl 98.0, acAl 2.9. 5ID 81.3 01 AQUAVANI.- 4l16A 100& 12.1 212 Pl 5 for S8 01 Patll9 (M.VaI: 48-01 5010 QCl 94.1,103 ac 5.5. 2.4 0-7o' ROQln_ and 48-22) 100.00 acl 95.5, ac 3.5. 4.9 an Mlll 90.9 Veriiia In 1I :ec:eunK 3014 A PI i, RaiZ 0c1e- BIlP1__ 4l17A acAl23.7, 11.5 90 co, _- (M.VaI 48.o1 Pl 510 5 ac 6.1, 1.1 - - De, Dr an 4ß522)) 100 ~:~~,~J 1_S10l ac-Cl98.6,99.1 ac 4.5, 0-2l AnAQvAN Prca injl In 10.4 He, Mi SU

44 3l A~,ooBin, Do S1ToAs TJ 510 QCAl 99.1, QCAlio.4. Emacy An safe of 48B 100& 97.2 11.0 88 AOUAVAI inje (M.Vai481 Pt 5 - For Pr an4~22) 5010 ocl 102, 99.5 QC' 7.1, 8.9 Cl -7rJ _loPaUlIUn 100,00 Oc-' 99.9, 104 ac4.1,5.7 NA Qu of GPI 1571510 Hum 92 510 QCA 99.8 QCA7.8 Pt vi HPlC_ lCMS378 Pt 5 oc 96.0 QCB32 - - ~~MSlSO_(\ow 100 QC 102 QC4.0 ~ NA Qu of GPI 1571510 Hum Pl vi HPlC_ Oe-A 95.8 oel02 78 5010 - MSIS 0_ (H lCMS3781 Pl 10000 50 Oe- 96.4 QC52 VaI)AsRa QC 99.0 OCOC3.2 ~ 3O1 A Siil, Raii8C. 4- 5ece. 4- Tretm 5to QCA' 7.1, Crr S1 of a BLP & BlP2 Oe-' 102 101 Pt 100& 5.0 QC 102. 99.9 10.5 88 - Sin_of (M.VaI: lCM 378 5010 ac 4.7,5.4 Cl-70'c an lCMS 378.1) QC' 103, 103 AOUAVAICO wi Incö PI 100,00 ac 3.5, 4.0 anaPoco1rin_vvoi.. ~ APl3,bl,Raiied Do Do S1 to As 1I EMca An sa Of Plsm 5010 QCA 101 OC..25.9 151 AOUAVAI 68 50 QCB 101 OC-84.2 - - (FOSøo DI) (M.Vai~) 100.00 QC 100 QC 8.1 ~ Inj !o M_ Pai__in Ulei ~23 A Pl 3, Qø Sin AI S1 10 As 1I Saty Of . AOUAVAI 5010 QCA 92.0 QCA 9.6 165 (FOSøo~) ~A Plma 50 QCB 104 oc 9,1 - __ilIII!oMìn_ (M.Vai~2) 100.00 QC 109 OC- 6.4 Cl-7rJ MlSurPai Ulei 3O4 APIP- 3. Bin.Raiied DoIe Do S1 to As TJ QCA99.3 Ell An 8a of 681OA 5010 OC.. 92 317 Pl 50 QCB 106 OC-8 10.3 . AOUAVAt (M.Vai~2) 100.00 Cl-roC (FloInj!oMin_ ~) QC 107 0C-9.6 Pa__In Ulei Flib

Summ8Y of the LC/MSS Asay ,er.nc Ch.,ri.tlc. før Po.prope (." 15715) coAtln.. Doon AI llOQ PrIO AMI ..pI Ac 5-, nf5_pI OF SI. stTl 1_10) lA (ng) (%1 11I (o.) -- (ng)~ - 5..io.,, 1..0 A Pl I. 0p si,Phccin C_ Phcoic 5to QCA' 93.3.110 S1ofAOUAVAI 68 100& g~: :tg:~ 19 . (M.Vat481 Pt 5010 5 QC 105, 103 oc 5.1.4. Cl-ro (FosInj Ver Db' an4~22) 100.00 oe- 104. 104 OIPRANIn_ , V_emls il He NA~Dfdi a¡le IJLoli;...d~MsMa ofc¡ii QCA-Lo qi ~ CC sa QC-B - Mi qi cOl sa aD QCHi qi ail sa NO AnPl saleba_liad TMGI"-po Sale iiMGI st PH we Ii. c: Nc fo GL ai La lAci Accu oi piaD mi pi loii oi sa Ii aias mi tw se_ 'No PK_pa

45 Propofol Analytical Assay Propofol concentrations in human plasma were determined by an HPLC method with fluorescence detection at excitation and emission wavelengths of276 nm and 310 nm, respectively. The propofol assay method in plasma was validated for linearity, accuracy, precision, specificity, and limits of quantitation and detection. Propofol and .. ... (internal standard) were extracted from plasma by _ . and injected into an HPLC with fluorescence detection. Propofol was quantitated by peak height ratio to its internal standard. The performance characteristics for the method validations and performance evaluation of assay method in each study that is reported are bl4) conductedsummarized in the attachment. at Plasma Plasmapropofol assays in studypropofol 3000-0207 were assays in studies 3000-0520, 3000-0522, 3000-0523 and 3000-0524 were conducted at Plasma propofol assays in study 3000- 0521 were conducted at However, during the drug development program, it was discovered that factors associated with plasma sample processing had affected measurement of propofol concentration. As a result, data related to propofol concentrations from earlier studies (identified in table below) were not considered reliable for quantitative assessment ofpropofol PK. Sponsor did not take into account the Propofol PK data from these studies for the population PK analysis (see table below).

Summ.ry of the HPi.CIfIK__ Ass Perormance Cliraorltlcs fer flopofel (0""" St wI Pr oar. IlRN conuH Diøod of UOQ AcCl..ey _111- ..- -it DF St' _Ti III ME -RI (%) 4'" -.. - 4ng) Ing) (D) II -.Iil M0GT QC98.0 QCA 9.4 ;: ~~~r:~_ (lc-1-G) Pl 20510 5 QC99.3 QC 3.0 Gl.:i274 10 ~.===. I Qi; 102 QC 2.9 5 NA HPlCJAsV_ 510 5 QC 112 QC 4.0 111 ol_...... PI Pl 25 OC-l95.9 QC 5.3 Gl.:i & - QCC 101 QC 5.1 10 A Pr 11\ _. 0p ¡: _To_Th~_ QC 103 QCA 9.1 Etcacy Of AQUAVAH Ii .i15 510 30 V.._HCLFo_ (M.v..:_ì Pl 25 5 OC-l8U. QC 62 Gl-:i 10 IoPalu._ QC 101 QC 4.8 30 .__reA Pr3. "" 0pbe 0410' _IoAsin SOelan QC 103 QC 9.1 _OlAQUAVNl_ 4815 510 30 V..~_HCLFo_ (Mva:_) Pl 25 5 OC-l88.4 QC 62 Gl.:i 10 .. _ U_ Ct QC 101 ac 4.8 30 AP_3._, 0ø Oo11t -_IOAsinsaan QC-A 103 QC 9.1 _OlAQUAVNl_ 4815 510 30 ve Mk HCL Fo seti (M.v":_) Pl 25 5 QC88.4 QC 62 - Gl-:i 10 . =,dS~~eu.. QCC 101 QCC 4.8 3O A Pr 2. _. 0p 0415' _IoAsinSa_ QC 103 QC 9.1 ElIolAQUAVNl ~ 4815 510 QC 30 ve MI HC fO Sl In (1"'''_) Pl 25 5 88.. QC 62 Gl.:i 10 QC 101 QC 4.6 I~~A Pr 2. -id 0p ~ _Io_in~.. 48168 QCA 102 QCA 2.1 1010 Emcaof AQUAVNl_1' 5 QC99.1 QC 2.3 - 28 (M.va~) Pl 50 Gl-1O'o _of__~anm~:,1I QC 101 QC 2.6 3O APrI,_.~1n 131 0414 .i118 1010 QC 105 QCA 5.5 -.Dn__OlAQUAVNl -., IM.VO 4826) Pl 50 10 QC91.9 QC 52 Glioi.- ===.....'n QC962 QC 5.3 3O A _ee Do Do 05 __To_Th .i25 1010 QC95.1 QC 2.9 EmcaAnSOol /lAV_ (M.va: 4826) , 10 QC 99.1 QC 2.1 PI 50 Gl~O'C _Fo__ln OCOC 99.0 QC 2.1 Of- -_Ià lI Hi pa 1í.- NOPI..Ji_Ii_NA-...:i LI_ ot..ci QC.A-Lqu_l~ QC-Mic¡_..ic:iQCc¡_..ic 'A=:i___..ai_i__"_co..bewJ:iwa..ustlaaai. 'Nn:..pe,Sa_____tlai

46 Formate Analytical Assay Formate concentrations in human plasma were determined by gas chromatography (GC) using a MS detection method. The formate assay method in plasma was validated for linearity, accuracy, precision, specificity, and limits of quantitation and detection. A calibration standard (in water), plasma sample, or quality control sample in plasma was mixed with (internal standard) and concentrated sulfuric acid in a viaL. The vial was tightly capped, mixed, and incubated at 37°C for 30 minutes, followed by injection of an aliquot of vapors from the headspace ofthe vial into the GCIMS. Formate was quantified by peak area ratio to its internal standard. The performance characteristics for the method validations and performance evaluation of assay method in each study are summarized in the table below. Formate concentrations were not measured in every clinical study; blood samples were collected for determination offormate concentrations in only the studies described in this table.

Summaryofthe GCIMSAssay Per ti ormance Charac teris .f ICS tior Forma te Aa Du Pro II (_ 5e llOQ Accu ofSo OF SC. SCTl 10) ~lib ii (i) (%) (%) SIii (iL) ~ - - = 10.,1 1I13 =-~i:~ saet..~'" QCA 101 QCA 8.3 AQUAV~1q fe ~6 Pla 1510 - 326 15 QC 103 QC 4.6 5e '" P_ Reng 1M. va.: "505- 150 0-700 ~::=lnti_.cain.. Mech 1I5) QC ll1 QC 5.4 ~ A Ph i. Ra_ec, Ope 1I15 ,,Sllo_ti .507 Plama 1510 QC-A 114 QC NO 162 N:AV~9a..~'" Injn v.. 1M. va.: .50 15 QC 107 QC NO - -. Hefe_li in 150 acc NO 0-70"0 ElI1 PoP- Und 04) I QC 108 lJ- di fI (i (i,di;MsM2 sp NA-Nocco sa "Plile NC - ii ca UOlø'e Ii of qo QC-A-Lo qa co sa QCB - Miqu CO sa ai QCHigl qa

Appears This Way On OrigInal .

47 10 Page(s) Withheld.

Trade Secret / Confidential (b4)

~ Draft Labeling (b4)

Draft Labeling (bS)

Deliberative Process (bS)

Withheld Track Number: Clin PharmIBio--- 4.2 Pharmacometrics Review by Dr. Atul V. Bhattaram Offic. øfClinioal PharmaGQlQy

NO" 22244 Dl1li AfluaV.fd- ...... '... (Fø.røpfGl). ,',...... lnciøatiøn AQIJVA. is an inhvenøws' ..Ive- hy,nøtl ..i~te før Iltioo if1 8l U,,"'''' Gt t"'~"Uli p..,....pati_ .GI~.Ð. - bl4) ¡ - - i . , Ph.rml~IJ.triGØll.y~r V.nk."'" ""I Ibd..m. Ph.D PhafN\",.tri T..m l...r JÐØ~~.PhJ) . Clinicl Phlf' _. R,viewer Sñkeflh Nllni. ph.D Clin_ ~rm._fI r..m L....r Sure'" _. . PlJl TABLE Sf CONTETS

Inlrodwoton ...... 71 R.GCmm..lkf1 ...... 71 Cøm_mš:tø MêiGIOffr...... 71 RelU_tö;y ,. .... '...... 72 Aplil'-l ...... 77 D...FiAng ...... 77 "".f1.11 ...... 8f P..rmHG...PharaGédyf1ie (PKlPD) Mè4lig...... 11 li:tiøf1...... ,...... 81 Olt...... ;...... 1 M~...... 8:2 R..lt...... ;..,...... ,...... ,...... 84 Ap.,_..Ul ...... ~...... 1:08 8. VVitht IadoÙlI ...ri ...... ,.

67 Phâmaeemetri Review NDA 2244 (AqwavafØ)

UST OF FIGURS figre 1. RelatinShip betwe.n race. age. alkaline phespàtse. albumin OIearaoe aACraAem effeø at clearanc. valum. ehlisttMn (._r adftent for bøy weitht) fer fosppøfØL...... 73 fl.r. 2. ReiatiønShip betwe..n race, lg..,alk.line p~.ph"', albumin OIeltwAGe aAd raA4effet afGIe...nc.. VGlom af (iisbutiA(aft,. adju.ent rer l)y weiSht) fer pr.fcii'...... , ...... 74. FifJ. 3. Fesprøpøfol GönoeAtraiøn (upp left). .ffct OÐmpai'At GGncntlion

(uø rlhl), expeed MGdi" Observer'. Assentef AlessS.itin (MGMlS) NGr. (ESC; lewer left) and rounded .x,.øt MQASNGre (ESC,lÐer ri) ar plG.ed versus time (roiii), The.kiSéli lines i...te mGElI priGlønsfer a typal patint wit normal (:.3.8 IIdl) .albumin Ieveladmini-'red 8.5 mg/ cise folle.denesupplem.ntal.... (25"'cif the iAita1 bølu c.). Th solid llAes iHuste meøl preiGøns for a typical patint with 3.0 IIdlalbumin GØAGntnnadminis."'d 8.5 mgll dose falløwed ane ~ppemental... (25' øf the inall3lusdø"~, The ... lines iOu.ate madel predictions fer atypil påtiAt wit 2.5g1dL .lbumin GØn.nntin adminiSered 8.5 mglfi a.. folled ane ..iemeni.i dÐ (25"&f th initalbolusdG..)...... 75 Figre 4. Inftuenc afllbuminie.1$ an EC$Ofer SllK.~22.Ad 3f524 (d..r. mnnand $D) usiAf møEiI3$i, PR-AQUA-0..2~...... ;... 7$ Pi..,. $. De.. r.pense relatiønship in Stud ~520...... 7' Fi..,.I. SedSuGGss iA Studi.s ~22, CøIØAGSGPY aNi ~24; Irf)~y...... ò......

'igre 7. Time .ur. offaspropøfol.Ad propøfècoACnti aftr intraveAaus aCloA øf føsprepøfGl...... ;...... ;...... 84 f..I.Dïaø.. pltsfer møcl (nO (f.".pøfol PK Medel) (A)O..rved v.rs iAidJ prGletec pllsm.GGncntøßS (I) a_ived ver ,.ultieA pr.cied pl GGntraieAs, (e) weighted r.si.....v.. .e,(O) YVil resiual v.,....lNlatHJn pr ..... ce_ntr-ÎØ...... 86 ,., t: 'øel'f¡fol-P..,.føl pøf*laliøPK ~i...... ;...... 'ÏI 10. Reiatshp .twA CL, Vf.t felKl.an ptfelaAd tol bø we...... '"'' 1,. R.". beACL, Vf.te,.felan ,.teaN ..1 "El ... vølin paAtwiD\lefdilNn iAè....,.te... l$. ~iG.. A" se..l'p...." iA~n fe '..fÐ...... ~...... ''-12; ...ef...... ,v.kl.R.....' betwen ...~..., .,.~.(....,.'* aI ~.,.1M ..... Rit).l$r ~PÐfGt ...... "...... 11 all''''3. ,... R41a..,be..n ... .f.....,ve.. ,....., .f~"adjunl'" _liM ...... ~.... _..). fe PNpefø...... ~...... 1 F~'__ Fit'4. fin... øøA:~f-li O_fV..,..._"...., F.,., ~A- "._..1'.: (1IFf) ar '.11 At..m Juei:, 2Ø II Phårmacemetri Review NOA 22244 (Aquva.) versus PGpulatin (upper plt)and indvidual(lG\Yr plGt) pr.ditioMS êffOsprøpøfol øonGel1ntlns(mGgmL). Unit lines are prvidd a r.f...AG...... t3 Figure 1$. Basic GøodneSHf-fi PIGls of FOSfPøfol - Propofol Model 103: PrepofGl Ph First celumn: Observed fosprGpofol GGntrn (mot/mL) are plGtted versus populatiGI1 (upper plot) and il1divldual (lGwer pl) prediCiGnsof fø.opøfGl cencentratiGns(momL). Unit lines are provided a referenGe...... 94 Figl:re 16. Relationsip between Nndom e"ees otGIe.renc of (Left) Føspopeføl (Right) Prepøfol versus creatinine clearaMe...... ,.. "...... , ....98 Figure 17. Time cours of MOAAS ..res in Ir.presntatiVe patients iA S.tuy 3Ø

OS22 (Te MOM/S scres have 5 levels: 0, 1, 2, 3, 4, 5)...... Figure 18. Time cour øf propøriGn øf ,.tinl with MeWS scres efO, 2, 3, 4 ør$ ¡n$tudy 30S22...... 1(i Figur. 11. Godness øf Fit .fcn Føsprøpøfol.Propeføl-MOAAS PKlPD mcKl. The a_Ned data are shown insyl'ls (blaek dét). Th expecedSGr.s (base en model) are shøwn in red lines while the likely maimum IGr. (base an the meel) is shwn ini.reen line...... 101 Figure 20. Oilgnø$liG Pløts of Faspepofol-Sedc:m Madel 403...... 102 Figure 21.. Dilgllstic Plots Gf FøsPføl1fol-SNation Møcll 303. First .Cølumn: IAdiiduål MØdlid Obsrv.ts Assssent ofAlertnessSedatian (MOANS) $Ges With maximum prediGted prcmllilit (SMAX, upperple) and expeGt inividal

M(JAAI$ scres (IPREO, lower plt) are plotted verss øbseived MOWS SGres using box and whisker Pløts. Slcond Column: Minimum (witin each patient) iAdMcdual MOAAS scres wit maximum preciGed prObability (SMAK, ""., plØ) and minimum eXleGld iAividual MOAAlS seres..(IPRID, iø., plo) are pløttt' v... eblrv.cd minimums øf MOAAS 8Ges usiAl øx and wliserpl. Medn vaJue.øf expeetecdscre. are designated by blck lines in the centrs anne bøxes. løx.. iAfiG8Utth inter-fuartle Nn.. (ldR). 'Mi$ers re".At 1.S.IQR. C)I:Nt,. are marked GUe Gfthe whiSrs by Gir". Larp (¡penGirGi .rrspGCi lé the identity liM ir. prvided for the refer.AGe...... 1'04 Figure 22. Føspopøføl eøncenttln (upper left, eff cemPirtmel1t cenentrti (uppe, riht), expeted Mefi Oll..rvets Assntøf AlertstSec!lA (MØAA$~ scre (ESC, løer ..tt)aAd røun expeetet MOM/S., (ESC, le.' riht) are pltted verss time (min), Th. bøldlOli Ii.. illU$latl mMl priC...fér a ty_1 ""At wit ..Afal (~ 3.8g1l) alta Ie\fet aÐSCered 6.5 ml." fell._tI G.""lerMAtal'" (2fteflh iAat I3Ef). 1M soH lie..... meelpreØi... for atypica patint wi 3.0 etl mtt ... fØlløwed ØAl suemntl..lI (25_all øf th ~iA. tD....). ~t' Th. Clshd liAsillu... m&lprdiGlie rø, atv..1 paAtwi 2.St/dl.1l eøAh Hmniare 6~5 mg... tø"'døne ....1...(2,. ef th iAitallllu. dø..)....-...... 'lQl Fi.... 23. Inlheoo.f albumin levelsen ie_ ftr SWs 3Ø22 af~" (lltaar. fI..n Md SB) usng me35, PR..AqUA-Ð-o2)...... ,..,...... ,.....,...... 101 Fig 24. Sill fføm Mel 163: Fø..,.fèlC.,.nt..Ti C... palsÎlEJiAlI.. si. lllu ...... '...... '01 Figure 25. Oø".pafÎHÐsèf 6.5 mg/ øøsReteAS wi .anc.wi \Nl Bøun.. Th ....A, .IE lllaøk and reE lie. .".. to th me_..'.

Atul..a..m Ju 3, 2G II PhlleGmelri Review NDA 2244 (Afva")

".pWil ~j øHnprêpøtilciñêñttliGA ittheIøWëïl.fR,. mii.1Ø~IAd th high.. 10CJ sf 8MldlAlU.AS (."'uppr ..~ iAd weitdisulA (the .lGer re,)pltt v._s ti. after th.... (miA)...... 110 US,. ØFTÂBUS TalDle 1. FøspølNføldø. r.gimen in Pha..3 pivøta..s...... 7,1 TaltIe2.~iS øf... ire., "liinr Ðfpall8Âts anc-øbsatft in stwcìesuliliad for PKand PKlPD mÐdll...... ~...... 1 TalM3.iltimatlt ~Ianc stGhst:pi..",.ter vals fe fØepfGl ~ft. Mø 01 (l ("urGe: Ta" 11 GA Pl. 76 fNm lpøft.r'. Refl(pr....-o-G2.pcf).87 Tii'" 4. It.matdslnral aAd....pa..m.tev_s fl FÐ9f".føl lInc Prepøføl UÛ1 Me.1 1(J3($øufG:T.b1e 17 ÐÄ Pat 7l :fF SpASs ....rt(p". aijua..;..t'...... H fa" .5.IAfuene sf Pí'ftst .r.etrs on the pnarm..kln sf føsl)pøføl and ~fÐl....;...... 97 T....S. ~.lmated PKlPG parameters u$ifl ..1 ~.(hur.: T'1D1e 27,øn P.90 rrÐfSpGAlIr'sRepit (P,.(1w.-o242.,...... ~...... ~...... 100 Tabl 7.Summar.f PK/Pm pål'l'te.. us. Møl3C3. (Søwr: T.1!30, em flll" ".fNSpi1r's flpørt(pr..qu..c..;pê...... 1&3 T,"..Sumary øf PKlPli parameters ue. Mø.I35~ (Sewr.: Tule37 ,øA pi,. 1OQffmSpønsør's ReJlrt (pr;..-G2-ø2.~l)...... 1(lS

Appears this Way On Original

Mol....'" Jl3, iG 71 PharmacelltÅ Rwié NDA 2244 (A...va..)

lntrøduetiøß FèSpøpøfÐl iA~GlA ffG.répèfédidiuml is a wa~$Øluble lìéCg of prpøfel HvelGpØ .fèr ff...... me.ra slatnGfrig lJ..f .diltiG ilAd ._..utie ~UI. The pMmiaGÐlølI aetit ØGmpøwnci is not føpø1al, but prøpéløl, it. metalJite. Rteommendaløns Th pihaimaGÐetl'~... in Off.. øf Clinil PMRAIO has reviewd "e . sulit.øinfati and edIMt.. label tøreflet the ft baNd en pøpulatin Pi( andPKlPI)Mllp. COmments to Medical Qfcer NøAe

Appears This Way On Original

Atul.... Ju~," 71 Pharl'eømèlr. Rèview ND'A 2244 (AaavanQ)

Regulatory Issu.. IA the CUfrent . ..lJissA, tM . spør eøACUéèet ..._ve pøpulatiÐA phal1kiAètØ (PK) aftphaaoekitiG-phaRTdyÄ8l (PKlPO)IAalýSi øf data celèGfrern..ver.1 std..._ ift Ap.AdÏJ-1' Th'reiewwUl føews eA ....t...twe 1...iAlsr.tem.Rts .S ~us ben: .~,...,..;1 ".,If...,1ìljøirl., ."Mlll iií:.ti"""lølt"""eel~ -~'. .~ .Pelifi,.tiiM,"'cc. '...". ii.fb.""".,.. .tl.,"öí' . ... PhfmaeekNtieanalysis Ihew. depèElAGøfll ~ght eft ..1' aAd velüme ef distrill Øf føSfopèføl arK prøpøføi. AftrHGl:tiAg førtM alfed øf -øyweitt MPK,.,..ters ef tøspøpøtelaAE r,føl, F.. 1 aA Fig 2iA AppAd.-1I

WW. thatihr. i$. Ae r.'atA$hip ..... r:aA.m e_øt. (Ntwen paieAt$; ETA fer CL, \lCl~pøføl .Ad propøføl) aM prflstfaørs SU lI ..,.., aAd alk.lme p~ aftr aê!usèm fer _tt weiØ. Hen th phflkiraöea ef re....føl and pfGpÐfol weukI net be .,...At GAr-, ale lAd alkalN eøA...M.

Appears This Way On Original

Mu.. .Ju3-,.- 12 PharmåCémëtri ReViêw NDA 2244 (Aqa"."')

aneFig..,. rartetr 1. ael.liøn$hip øf Glea,.~.v.",. taen ,..... alkllineøf~n (."ra~tfø,~_. all~G1.... bé .. .. htfGfo.'Ø . fii, .. d ~ ia i ~ ~ ~ -e a I. . .' ,.. ~ Ii !O .e;e~- ~ ...... 2 3 4 5 1 2 3 4 ~

RACe RACE -': ...... ~:. g =~...... i ;~ 2Q -l 60 8Q 2Q 40 60 00.

AGE AGE

..ei 0-' -e 0 tu ë W~:...... iø -.- .it.' · ei ii .. . ..i 50 150 250 50 150 2S

ALP ALP

.. .. . ei .. ;:. tB d 4( è w:! cis ti lA e ei ... 2.0 :.l(! 4..0'.0 :Ul 3.0 4;(~ $.0 ALa AlB

AtWl....m iÅ3." ." Ph~rMri Review MDA. 2244 (AqwllvaAf)

Figure 2. FtatAshi, lMen Nee, at, aJktie fJ..ta, alunele.MAG 'lif)aM ...Adm elf"feførølf1.ø.I, Gf el"NAGe, velU. ., ..tin (alradsl fOr la. . - . .- I d~ - l ., )i iø.. ., .. ~I = i$Ë3E§'tEi rH:1 : ø_ I I ., .ø- .....~. I I :!."' T eee~-... .. ~ -.. - ..I I I I I A, I I . i 1 2 3 At 5 1 2 3 At 5 RAlE RACe. -. ~a- ._ ._.,.... I .- .. . õ .~ - .. .. ~ ~- ...... ' ..~....:.... âa.....'... - ..=C...... tü iø -..' .: .. . . tL. w _ .. ..d.. . q - . .. . ~aI I -.I I.· I ,A., I I I ., I 1 IA I I 2( 40 . 80 2Q 40 60 80 AGE AGE - ,. . . . - . d :: if'ø~...... -. .... ::..,, .: !C . ~ .. :=.....,:-'1 IU w -~~. . if. _ '. . . . El _ -;. e ..A -. II I r I .11 1 ii 50 100 _ ... 2. ALP AL ...... El.. ,.. - . ... I . . . .. - iø _ (; .. .'''~.''...... )i oi ._'::~. .. e_ II¡! li . - iø_.~ é A. '9t. - I I I.. II;.... I eI I ,.. I , , 2.0 3.0 4.0 1.1 2.ø 3...... 5.G ALl AL

Af_.... Jun3," 7. Phar~ flie ND" 2244.(Aauavane) .wl is_'ll ~ Wt1l;IJ..ølWll ...... 1'..l..tllfli_ll ,. ... tp.,....ir. '.... .4!. . ..Jtl.jlll, r.,$ØG.....lýll .,.rel~$hip' ~flfOlt'.flI._.riat.8A(4.~ øn MéG abSPler's Assmet Gf Alenes$eat sele (MANS) usiS PKlPf ~.. .Førmøredet:øfthe ",I~i$ pler.r.f.to ~Adj)-Il...... The Pi-PI' rTlpt~thatth.'i:$5( Y.k-es f(J ~"G~I d_..se Wi. HG..ingplama allNiFl GØAG. Theesma_ti$Ovalues fGpatints Wial~"lTn.~fl~' ~2:S s¡Låfl(4 i;()gll'Nf._ (~1(CI".~) .ahd ~ .(~ CI2$-_1IGthaAfø,atFlts V\altlumin leve.øf3;8 SfdL. The J!rNi~øf" ~øfaltlum cø""nQtsøn-. MOMl$$Gr:es i$ $hØ iM FÎÎl¡I'.$lpJø; Fiiwre3. FØ;prøpØ ~eeRtrtiA(.~"'" .t.). ..e1ee GØrn~n"øÐ~trJin (upp .. Ãlllt)..~ed MGifH' dtetsAue.nt ,øf .Ali1~øn (MØW$)se. (1.,lor.l_i :aM. fÐndøexpe MØ:MNSsne (II,..... Î'_i.f.II~.V.f$S lin (FAl'l.. Tlt.beld (seki 'linlSitkAsnil .~.~ienS.fØr :a...¡ patiR'N. neimJ (;:$,lflL) a~minle.e1 aønnis_I.S A'ti, fØ~ ØI...Rl_Ijm.Â.I(4øl.(2$,.Gf~ÏJit.1 liusd.i. Th..KdliA., iUu$tlte møl)iGslera tyGaJ patent wi' '3.0 flLalbumn GØAßtfadministred 8.5 mlkl døføJØN Ðn,sw..mel....(2$" øf th. ini.i bølt ,8"'). The .$IttJtA..iUlit, ~i. P~r;.. atypiGáI ~"l~ 2¡$ fîa,J~~iri ..eøntr adnisteed iA~ ,S,$ rT1ili~.. dø løllow .øn suppleAlI "'(25'". Gf Ni(l.___1.._1 s.OgllWL.2.5 i/l~ iI:f'.,..,...... ~ ',. . l:~\".'...'.'.:i \ l i; . \'.,. i i; '" so'... ~ do.: "'.~..-..~.. wj 0 - ...... _- QtO~3040 o '020.~:4 _1m., _.!""J

l:~...'./ .,. \ i J ~ ~ :\V/- lg~ i'bl' ! i N \ ! '.: \ ¡J .ñ _ \j l..~ \U r 01020~'O o IO:i!O~ _.""r ..(i)

Atw~r.. Ju",~I"7$ Ptiaratorn,triçs~~¥iew ...:.,....,.:._.-...,.....'.:'.i".'-'._~:.._.::.:-.:.....,.'....ÑÔA22244.(,Anullan~) ~lth9tJgh dth~PK;~ÕcMbderpreØi¿~'thâtpåtènts, Witl~)pÎasmâdalbufinrnayre~th...... MQAÂ/~scoresQfd.$~"than ...~.lfadtí"ist..eath.fUUQ;SrollQ:Øos.lpR:.AQU~O.2~02. pigurø.':1.Qi)¡ ,ÇJera. ftonithê:3ØO~()22.~(j.~OQrl0524$ldi~s:frØiÇçit..tb.S.aatiOn...... dåpth'.(as mé8sürédb.thø MOAAJ'$cåfe)was.notcOriSiStêntiYinfluénte.d .oy....albUniin . íeVe.IS!.,~~Il'!fien ,~)(å.minirign~$tilts.nas.q:øn.. .a~; "A.$A.'$~tJ~..aJ,gWøig~t:l$.,slJnwriin. Fiøure4.

Figyte4 :lnfIU$fteøfalb.i,min ..leVtJS....QO '.~.c5Q:f~r 9~(jil$~OOtFQst~.nø'~OOO.;Q524 (dattütrß.:møåråiØSOlusingmodj.l356RF,,.,AWA-0:2+02Lv'-,'- -,-- ...~- _. -_ "_ ...... z:\ .... ~, 'Jláf~ . ~~, :;s:- ..~ J~. .~=:~...,~nlf.i ii (;. ~í..'..~:i. n . "Rx ~, ri",~ .. ~".... ¡~ U~), ,n'v '~(11 ~.o(~'~~d(ll) ti 'r.J ""~(lJ)' ¡,, '.PI:áf.n irs:i.lLi) iiiõ ¡SnilJ'l .,'tl"..J L · ~v., II ; It t ,1\. ...ll') "' n.....' uu_, · U(o.J),.'II,"J'I-lUJ . g i\:U"'"J IÍ~. '(f;i d ir... "".J njiP'-- .~.u u,,,(..~ ~~V.)' ..l't'J i'¡ ...(~1). IV:1l1r.¡.i,iQlI.i. ..' :nar" .__'-1 II U(L'J.....t -(1) . Ul_)(...... *ll'':lJ min ,Úft._ f,. .,i(:1l .. _ .~ID... . 'Jf'c'.n.,... -,., - uu.'.~ . ..\~.' ...;~ t ...... , _OI) '. ....-.-. 'l0l0-" t ;l~\~"'d .'J.. tv.i; , ~6S Phrn.i-u Di.:l(LØJ'" 11,m(Ð::~ t~jJ(lll(U A ticz ~.6i.Pl.~. ... ~.. '.J(U. " l'lll~ 4,.l(l1,.'l9. ~ ~ .~~ tv~n ~ .~... ~'inar"i._' 1-'~(11). 410~ ~::.. .. 'U~ .¡;:1í . "G4)n~ "'~,n.liP.;. ,.~.. ;~ ,.U,t:e'.-(1 l.!!(.) ~"H'~"-~(i!~mO).HV"" ~IÐ' n...... u'_~l)", Ii JQ(AlJ'U(o.J'J. .. "'iUr'.~...J~""IPJ AØ...... a1. .--... ". "". .' .....T.' ii. ~...... T. ~.,...... ""ii... -ll'i~.. ,_. .,~--...... rr. -1m'." --iijí sI~ålJoOn4;....iÌ!WJ:f;ii...SiJl.~1f~oflii5M,;~-:;;. ...", ...... -=d . .., ...... '.' ..., .0551 '...... e OPY ......

AltllÓLJQhth$$tlntPklSiZe- ÎS _diffør~t¥tO$s_'(.i()Usagei~S/lgr()UP5;. th$låt,k a conŠÎstent~llminèfétt.on .ryOANS scores wóld indicate.thatGlos.'adustmentwòuld n()t.:~ rie,eqedf9rpatiiEts.Wîtt(Jereni$JtrAirl l~vø.Is.. .. l.V~r'l"~ell~l,.

Appears ThIs Way On Original

A~tl$h_em uU;ec3;\208.7$ Pharmacametri Review NDA 222.4 (Aqva.)

Appendix-l Døse Finding

$pøsor ccGleG ..v...i.. ftnc: stUd.s in healthy subjects: and pat ant.. Wi the aim af aChievingpreGi$lable .dation and miniA'ming thelikelihø of r._hin...p lev.ls af.datin. $kes ~nc\:ecr in.the initalGHni1 develøpmentusea relatiety high, fied .se r.gi..eA in which.th same de.., in miligrams (mt)wasadriniSted te..1I pas whe feU wiin.. lJøH MIlM range aÆlth. c:taShwedtht i si,. iV ... øf .tw.n 10 and 12.5 mglkg .dated the mari øf,.nts (stdy 3O:i1). Hewever, result&af swta..nt seRes af studies (3t4Q, ~10, ~11, 3QQ-1.2, 3C415) iACled thatlh$ regimen leØseveraJ patentste joeppr.,. levels øf.datin. ,.. øbatln ladte t~ develøpmentc¡f i revised de.. lilin

(bde ÐA bÐdyigl\t, age, hea!tl\ sttus etc) regimen that WGuld sedate ltl mari øf petentsWlileminiii:ing thenum.r of patints reaching deep..atiGn. The upted _.ng relimenwas usd tøevatuatecUti ."-.ive"... øf følprpøfØl in3 GEnteIIeElstciies. . . . Stud ~: Døs rantiAg study inpati.nt. unci.l'øingGØnøscpy. Study ~22: PiYøtal st~ in patient u,*rgGin cølanøsøpy. StUC 30524:PiYølal st~ in patints uncierpin nexiblei:nehÐSpy. Pnenta inst~ 30..20 were. ~miieGltø Gn. øf the føll&wiAf SgrØUfi ifa 1:1:1:1:1 ratla ineluding 4...lev.lsøfføsppøfØl diSGElum (8.0~,I.Smgli5.0 milkO, 2.0 mgkg) aAd midøhlm OJ~2 mglkg. Patients in sW. ~22 vi.,. raAdømized tø GAe øf the føllCiI' 3 grøup$ in a 3:2:1 ..tic¡: r.,opl diNctwm 6.5 mtkg; Jørøpøføl di.,Clum2.0 møn; and mid"m 0.G2 ff' .r~eI. iitilS in Sl~3O24 .Wlreren_mi to øneøfthe fGllWi2 IfÐ\PS in a 3:2 ,.li: fGpøfø ciilEl S~S mglktand2.Qmg, reely All ..tiAts in.lIles ~5~, ~22, ~23, anè ~24 "'GeM. ...At.1 oxyt.n, Al.11y (4 Umin), thfØ~t Ut... .-ri aA uAtll th. __ met th Gffi fø read fer dÏSfl.AH ... ifst. ~2Ø, ~ RI2, ~23, .iI. ~4. "'iV.."Atan~ at Il\ ilitl." øf50...... it.. preatmentS mis Øf te ..~A .f th inil ... øf.1t ..1...... metiøA. øf 2S lflh .. .ffe'*..liAt ....kt ;wø..,riAt per pr... P¡ft At$i... .ii 10~., ~1 ¥l,... hae ._.. aa""Dt. ..,.1.. lA tli ...IC. ~ ....EI pe ptt "were if....1M if....._..n wur..ci, ÐA '*Atø.5 ~E'* te ...... 50 lM)wa.teM~. Th.... r.imn iR P-.4ll -"'..ia il in Tale 1 .....

Atullhaum Ju 3, 2Ø 11 Ph...~ømls,f!.View. .. _. '" N.ii24(~.Y~)

. Føs - - ._. .- - '--- jJl '...1. døli. -...... ~..,.-_.....-_. Ph.O.l,...... l... ~tï.n.'Maiøte..n(e SeUQn.I:Ueil ".Ð~~4; DoiD Gro1l¡ Jnt1llûs~' S.1I I Dow :Fosfóldi 2.0mg 05mg. Ö.5:mØ i:odin NoJ~.lb120uì~ NoJ~tb3QiD. NolêS lb3tlDi. No motJÌSò mit No JltÍ 45 ni. Nóin.tl4S~ F()fol diso 6.5.in L6.ia 1.6ni 6.S mg Noiestl390ui' li9ièlb97.5 m& No lesth9.15 a Nomotb 585 JD. Noin1h 146m2. Nomothl461M. ~Ja) O.Q2.i' tÖ..,11 '.. LOIJ .~tìtido.of$lseii~e.!~stet.Notto exeeei:Š.ØJ; $nies~fetal'~ or "9.kg. -3l'tienwJ'Wer~65~of~le niloweaø updòsu litsWe.~onaWèigltbo of.r60 or #A?4:tor P3 at~'~Ol~t:~Iayeto)ieei~.kg 4íntht.wer ~ SeoiiJiûtitiånJ), 7S%ofthe~~tadó. SQièD&sweæadteoiasøq lore a sMio_Wàin~onm.tb.M0()AASscof9aitosttæ~. 3~S22stO.

.. So:.St3~22Prtoi,..Se6,'Me42Q' Th.pniM...y.n.OiFïS... Slee., w...~_ endptth iRèiuCl_bèiflåtYÏlAd sal"*..'.'fl.ltìf$UrH ....äliÐftli...lø

.trV-Jy . ..-. pai",ts,.. in . . ma... til.. .. nø. .'RUir' ...... d'Ïliray ff~'Ì',iR~IilI1I1Ulll ~.Vltv'.lllllrlT~..v~lin. $PtttilGaH; th...J'N.~..~.rm.d..,.íi.nt"",fJ.ll.øf;li...""~...Gtltili: (1) hamí a ._lilv. MØ. sc.e. øf ..:s al.Mf.._ of.edàiV' . medeåln, (~.....I.øß'.".lhtl..pr.."'r.. '.(~wil~.".fÎl ,tl.!J~'øfl~~l~.,,,Il(~..n.. mi...¥ aøel (~) witll....'1ßlMåAU.rør l'M.".veMli. FlI th.pill~.",.nuß'.r""",.~ l"p.lltsvmci.l.lçilei¡.fer ...io ~G'.rilfGlleull""'.,"" ~p~ l"'Gll'~..ti.P ... SI....~. it ... ¡",....~~..Th. ...,..n...Ci'i....l...l....l~inF...I:~ ."'.....W... in ~ .... TN...... f...

Al....rM JuI.,2Ø 1. Phar~Review NDA 2244 (AGavaAJ

Fi '. $. 00. r... , ... relatiRSi . ..30ZG.

II 1ØÐ e¡ I 81 I - . -Men I- . LØW""C .. UpertS%Q il 41 ! 21 :. 'l ø o 2 4 & a. 10 Des. mglIi

Appears This Way On Original

Alu..m ..S~.. 11 Ph~ri Review NDA 22.. (ACaf) ir,.._Pipe.. $tatin $..... in. $lus .~22,O.l.AØsepv aOO ~24,

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Al...... ,~.. .. Pharmaeemefl Fle;¡ie NDA 2244 (A..va") Appentlix~1 Pharmaekineti.PlaeØtnamic (PKJÐ) lfing Inlruetøn ThøbjeGtÑes of thispøpwlaonanallis were to investigte 1M fGllwigpøpulati moø.ls: . A pharmackinetie (PK) inci..l ø.f fosprøpøfØl in v.nes pism oencratins dosefGllwingadminislflAø.faninitl offGepøfll "Ius llø.. iAetiln aMI up to ..v.ral sulemlAtal. . A PK møfofføspre,.1 aAd prpøfG in venøUl Illåsm.cø~til'føllwiA9 a_iniStin øf an init bØuscdø and up to.vmil ..memaJ .se. ef føsppeføl injÐA . A phat~le-lMr.GØc:ie (PK-PD) medel of there._"". beIIA venous pl... GØAGntens øffGNrol)føl wprGffC, aAci r.ïledOtaer's A.."'t øf Alert...se..&ln ..(MOANS) ~ følle adminn øf th.r.petï lalls ."($) of iø..følinjllør .. A PK,.pD mo.1 øfth reatkAll Ntw.nv.AGu. plasma GG"",trati",s øf fèlpllfél. aM MOM/S .r. fóJlinHmiAi$tiA øfth.ta..¡c lalusdÐ(s) øf fG.epøfoJ iAGlløn. f)_ta Taiile 2 lis th døseIRlllPS¡ nwmNr øf "ti..~ø.rvatins in ~ utliz..d. the PK and PKlPD medeli. The.. ooiiet.d wasaElquae te develOIl PKlPD møÐls. Table 2. lis .f."IRJUPS, numbrøffDlin_aAdøbsrv..nsin '-iesutlød før PKaAE PKIPD mQdeliA. ~.7: A ph... 2,tw..pa IlØy øf AGUAVAN $ Inj ¡nthe "..._ øf pr.fTCi.tin. iÅ. pauAf .... "'fIit etee.. .eé~. .. P.,1: . . Opn .lalMl, "ptve I3 RaÅging,RaAcmid,Mv.. PiIG Stuc øfAGUAVANq¡ IAjee FøUøwAf pre-ietkwihF'''''l Cñt l9""; ~1$:A ph... 2, ral'iz.cl,.,,...... to a._""'tv aAC efl .fAGlJAVAN$ ll'n ... Ml MOL_ .... in .klrly PI... unGer..iAG&leMSë .~..; ~iO: A ~., ..~. ..~.. elWl kl.. th efoy .. __ef NlAVANi .~ ,. ~ .... if ,.-.. ~ _"..s.., ~1: A ...._..fáMi,...... +f..Al....:av.' ~ era "e ~ øf AElUAVNI .."...Wi ,...... lfel in ~y~...

Atul lhra. ....3." It Phamaeemeri Review NOA 22244 (A_VI.)

~:A ph... 3, raACmii.e, dØble-blAd; dèØ-GAlroJtdy te ass the ..fleaeyind ..fety øf AQ.UAVANC(f~ffdim) .dln f.r miiml'" tø mèdrae ..ltiGnin patients lJdergønl eølGA.py. 30m: Aplise 3open-l.lil,SiAglearm sty to... th ."lyøf AQUAVA,. minør(fGsp.,.fQl didk:m) -SW¡ieal injle~n tør miAimal-e.oøC!ra..ditinin prøøGiures, pitient$ uoorgiA .

~2":A ph.. 3, ,.AdmlZe.d,GlUlIe-bíAGI, dftntrelle.$Ntø assss th emae, ind safeøfAQUAVANc(tøspAlpøtøl ~) iAjoo fer minimal- tøm...... GilliGn in _.nt.. un. ' . .nexllile lJønht.lw. $pe_ty, støy pr.tels~207,~4.$, ~20, ~22, ~523¡ IÅE ~4 eeAtl'li"'d .epøPJføl .. fer tøsppefølal' eøbiAed tøsprøpetøl- prpøtøpøpulâllGA .PKanalyss. StuG pøk)0G.30-022,3OØ!23,. aAd 30- .24 GØÂtrÐu prpøføl.. datør . GØmbifled fGsprøpøføl-ppøfølpøpulatiøn PK analysi.StuEt pr."I. 30-ø22oøAtfÎte... tør feøpøftl-pe1øI-..tin pcli... pit-pm a.alySÌ. Stly prøls ~iø1, 30,04-1$; ~20, 3Q- Q522 aM. ~24áØntitted. GI. for ~.PGføi._.À (lulatlGn PK~PEl l..iy$Í. Stu. prølØl ~21 GGntlNheâJy véklntf,.data utGi tør GGmp...n øfPK _delpretietiGf1 tør ,.¡.. wftGbed helty vølunt.... PK da..

Th..~øf"..iÐ' rmílfde"eiøpmem mek9 .li. the~.r isdilGadatøw: . me"..pmem-øffesppøtøl JI~ PK..1. . mev"""A'øf". GØIT ~fêlpe,WltlA 1'1("'*1. . o-veIpmenløf.fésprøpøfG-prfêlPK/PO mMl uSi .tâ ftem Stu 30522pr(lpeøl (GøIèAE). .Pf..",'1 1'. w.. ifCliGuad k). PI pr_.~. .~ ftmtøsppofél- øf,.pøføl.. prøpøfel. Th. PO .." øf fø..rei wa ..... lt tM. ~It"l dtpKeE". ..liJa-', ""îAat ør...... (M.AlS) IR.i. LéG. øf the.. . ~ililiwe.."._.... suøf..tl ...Gt..Mdlh .seIiAevaw.iff wa ... (Ja "'ar or EMU fun) tø .. ~ Cl te..pøfeeø.. if...ef ...t.

AIW"" Jt.3,2Ø 12 Pliåíacôrhêttics..Revíew NDÂ22244(Aauav~

ERE .. EjJ*CEf(ECso.+CE)l Ay ..ß¡+EF'F: ¡... 0;4 C¡:=ex(A¡),iO,4 I?, = CÎ(1+C¡j, ;'-0,4 Prabribility.olap.arncrllarYÓ4A$stl)re: RRs == (1 -P")~.lR4 =:(Iirl'J) PRJ == (PrPiJ,PRi = (PrPj) PRi - (PJ-poJ,pRo -Po Expected score: ESC ~. 5 PRs+4 PlQ+3PRJ+2dPRi+1!Ri

e t)evéIQ¡;rrent ()ffôspropóf9t~(.PØ.. roadelQsing .dfJa dfrqftl'.Sldie$ 3Q()Q: Q207;'300()0J1S3000-05203000-05.223(X~05t3dånd 300().05247... Thê po.mddei.. detaiìs'. are:as des~ribeQ.aÐóv~for' fósprbPdfòl-prQPctöl. ...PallêritS f-rOf$lI~tneretpeutic' 2rr~QdQsjnggrOlPs 'Y4ereexctt.cJed,trarn the pORIJIa.iQO PK..pp~riat$is...... '.'... ',. .... '...... ,...... ,..:...... , ...... :...... e,Aftehhe PK~p( modelfótc9!òl'oscòp¡ -prqê,ölirèWås;dé¥eloped,dåteffrom bfQnCnpsc()PYstud' .30CQ0524weré aâ(jd; The~cgnbÌlerJ. i:9Øel, ~s re~ .ë$tÏfåiiød;.. i nfhience..()ftheproceciur~Jcolønoscppy.vør$~s'brønçh()sçøpy) ôn

thë parameters óf ttiemodeIWa$irivesti~ab~d: .... .

Mpcl.l~ele~tiwas ..g:lded .bYvariçusgooØre~$4oM~;~qler)J; .,ItCllJØi~g Øí.()~lit pI~$.cOrlv~t~n,ce withal ieästt~r.esignWiÇØ1tdtit$;Pl~$,bmtYøf p~lim.Nr esø mål,øs , Øtecision of.paraÀétet;9'Stiirate!;ì corrlfaïton 'béØén Aiö(;. ~an.ter e~rT.iQ.fl.:'ln'Ç(S../eAd. .the ....Akaike: .i~f.Qrr.iØ'l.. cnt.d()n(AIC1..gi¥f)'~ll" mjniAiF" ObieçiìV~:fúO;i(),lfvalue. ~d iillrTber. Of..estlmøeø P.l'aimer$f$'.'F=inatÍlO(l1 -am.~ e5tmates wetèdrlSJ;oitèd with..à m&asure.(1 ,è$tlmltiøÒ').lnceftâiry\lnalliiin.g ttl. a$YmptQtic;;$tad,att1~ofl(obtainecl. from the, NONMEM $~PV.ÂRfANGE~ep);and n ~ri~pår.i,etAt:boPtstrap 9$%CQnfiQ.ncejnt~~åls(~I)'i ...... , d...... ' ...... " . . . A,êóYi!Hi'.~~lirlg$ppfoâchéfphasizinøpårârei:e~.iai tåt~thån$t~$ë/ hYPQØie$i,s;.~iiRvtasirrPlel'enteçlforthl$pepa.j(n ,PKdanal$fs.ffstiPf~øen~ c9Yà1~ .~lf.ter relätiosnips W~reiQenllfílØ ~.ø:: Jirr~tl:nllt.rltere~¡ meêh~nl$1iè:ph;usibilitY..()rprór.~Jedge¡,äid....'ijii.rnQdl..~aï. cQnSWçteGwirhcØrè tGf~ôìd COl~hltjôn orcOìlineæMin'prediCtôSi M()ät..pa~êts.weré$$tima.d..d 8$.~.~Srnft ctlRY re~~ningtrøriØ~,was~()l'~,øtJ)~: Øfl?hiCal J(l$p~~iøn . '.øÍ .~ ~~:lr.:::':~b'~~:~û~r:~~1~~~=~~,j~;~,.~~~~=~trr:~t'~ PKJ)anrswef.; alsoestmated:and;Slmfafzedp/'.groo(:(l' iiîiøstA ~*ap parenetefs7~:~Ër:'.&.$~~~~~i::~š~~~~~~m~~.ds-r~~'h~nt.t,d::~ . .

~tQI13h'.~am ..!l.,~;iOØ 83 ,.~im'éé~ Ae"iew NDA..224-4:(Aqwava Fagre '1 .shhtime G'u_Gffe~.ACprøfileGntAsallr ir~~ l.lAi$~~:t..~ø!. ti....7.. T:Íl..~~..efft_~1 an(l ~.~.eøA~",ittiR,...iríV'AQtI .ciÏfi.-tiJl øffes .,'Ø _.. '..1

I I \\\" ! I I&

lI(mt

!.i l (;i "l" I

TI(..,,)

...~ Ju.3"." ..ä4 Pl'maGÐ" Revie NDA 22244 (A...")

TheNNmNlf","'øpøføl"'.,'.... i~El (A)AllGme _lig .fth pøpMn p*l'tetå -- \/1 viils .JeEI we..PørtAIIIY; .. eLlF wasscleci.sWg iA ~ power . R. øc_ts K121AElIQ1 w.r...... we_iA -~ iflr..(8) Assmptu.t wiper-kim fHpøtøl do.. GIe*,._âAEI (....EI en dig...volum.; pl rit.we .f the lG medel the 6.5mttGl", iAted .pen...øfth. ram .__. eA \11 aAd CU~øAth "A.": paie woo re.ÍVlC ..,.utci Ci... of ,...pefèl inj..n(2 FRgI) hØ, OA av.,.... $Mal"rvilwes of bøth \/1 aAd elF. The ful MOIG1(¡ wa ~'ci by iAGlusinøfliUeøvarites øf intees.-SpeGifilly, ,..1 010iAuGl.E . Pøør-dnGl.. of the teepøfèlcentral volume on BMI(Bødy Mi. IAEi)(). . linar "'Adene.. øf "'fØpcfGl ci...refl OA laÐratery. v.1ues (AU,wmiR: ALIl, AIk.llne Ph~_at..: ALP, liliRli: BILl) lAd Aormaliec: ereâtmÁl. .G.gAG,. ø.P'''c:'' .Øf. -....fø ele..nc. eA . albmiA GØ~tin was linea up the lew.r .WM ef the AØFmI rl.(3.8 glElL) .aAd IMA WISflt. ØvereH, th mol "'(ivic .ciq_ftt ef the _I. ~in Fige 8. The .&tim.- efthe øa..m4le.. .re shew if' Tlb"3.

Appears This Way On Originai

A'" ",,.m Ju3,2O IS ~håracömetïics..Review NDÁ::222i1 (Aquavsml)

-igurê (.IDiãgØöstiê'ølotJör; m()déL010'(-J)spróØdõF~ .'. ". . âêl)(A) OÕsêrléd'VørSu~ inQVid~81.. preÇ1~øtPla$Fn8,;ç9flC,entr.,øn$. (B)/O~erveø.ve~s.. Pop~l.et()n prce(jiÇed PI.n'ø.:çanÇe,Otltii9nS';....tG1. Wei9ttøØ,.y~fd_\¡al~:,versu$tir:e...(O).Wéi9hted re$ÎQYels VefSUS:Q - ;I..on .rèdiçteô:lnmätcônceritralQl.s, ..IRO ModetOiI ~ ~ .~

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ö 100 150 :2öOisO o 50 100 150

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~ ~ .~..: ç¡ t) " ...~ -eo .' Ci . (l .. Ö 50 1001$Ô.2uIJ:20 o 204060 6b. tOO Iffb 1lfiT)

Atül Btiata'am : "" .". -:..' .'.~ "'.-.' -,- -.- ;.-...... ~~;;'L()8 ~ PharaeOtnetricsRé.eW NDA-22244 (AqtàWáßiI

Tablè3, .estimaêdstfucträlâlôstõêhætiêpâtãmeletValúèsfóf:'fóspröpefóli;siñg . Modøl 010:(søi¡rce:...tabl~.'t6,ønPàQ$....16i;from.Søøn$Qr'$..Reøørt:èQr;;aoua-02:.02.Qdf...... Patåntei NONMEM MQdlOtO aottin: PØPülaori 'lë'llti- . .,...... Öao.trp,~4lIf" E$timlt_ '$E:(%) (S$%CI)

V,(L) " 4.41 lJ~' 4~.(4,24- 4"59) C4ÒJfuin) 8í O.31i 3iei (l.~1~(O.t9t-ó;331) K12(1/mlr) 83 0,0147 13.5 O"0147(0.01tt- OI0391) K~(lIrnÜl) .. o.QUa 29..1 O~0131(0.0Q2:~0.02'S) 'hÐO Ør 0.236 9 0)3~(Ó~19-0.t~l' CL,,ó as 'OA38 16.8 0:134(0.0757.0.185) . v,... i~ -0,199 29.1 ;.tM~#L.~14- c:,08~) Cy..u &10 3,34 j(L.S3:+1(i72-4~79) .. . CI..A fl" Oj1t 34.4 Ò.1:i4(()~04- 0.2(8) Clf.e QJ2 -o~0322 29'5 . -o.0313,~.0517- ~J1Q~38) C1..CR ë13 -0.0'738 75.7 ~.()6SK..-16G.-OJ)2l9). cif""...~ . ~ 1.21' 3.53' ..i1(1.~13-f34) - .;..' liy !l.qi. 0,°714: ~.6.,OlO~ltO.~;.().~29). Rv.a.fA 0(1.2) 0.0~S7 53:$ t),0.tØ~b.of-Ó:~2S). . taa.2 0(2,2) ..0j)99. 13i7 (l.01(0~0167-0223j ct~, 15: 0.191. :33.3 O~1l4q.04-0;354) ¿pa ~~. Ø.Hl ~~'6. O.1Q9Ô~~t..Øi13''lj . varestiate~(dê) CV1l 1(K 0(1 ~1)1i2% .14.~ 14~~(i9:.. 23) Ra. Q.4Q$ O,.1a(O~11i.,1) eva, 1QQ O(ÄÎ)fI% 31.6% . ìÜf(2t.t ~41.3) $.0"...... ~ . . 8511i ... .. 0.4~ O:~.(Of05~tl~95) CV~ 1QOf)c'J2 33.~~'x 3~.Ol30.i;-36.~2f .

~l ~høt~arn ...nEf~/20($ 81 Ph..... ",.lris..tt..w NDA'2214l(Avåll)

:~==I'Il£':l\'.F.S~p.fël."If.PrfëlW.Šd'¥'''P''.Th.m.dlllS 'flown II.FllUr.9 b.I.,. FlCl..'ii. ïlit...... ,;._. F. .lDI'Jll _. aàftl~.åDi.lìo.u!llr'..PI(..J ":cmJ. ',' ,l . , -I,..~ .....

l'lJ)Osè' - n.~. . . KU Yt ..e,(WI7) (f.l&.5)"ØMrexp,1~). l'~olC~"" G4 · ~twnoF'(MOSlÌl&.5'r . Ceiaarafl J'arofo'lI'nl C(..CI. ct"..Ci,,~e.et''lxii). .Y¡,CI COIir...t1 . Ku.8¡tWl7Q)-. ' ... . . ,. ..Kå Ki( "6~tW0)~. xu-CL-i K,i .CLp/W " Ki .~no)-o Uini) Jattrmt. Yo; -li.cwt/lex!w C8Ipar*-t 3 CL.-e,ìnjL .... . C(;.CL ~_ CL"..CLI',c8i CleiI\) ..~. K...... tnO)~" ...... ' ...... l G Ks. oiïnO)oI rr(elCellì Ki"CL,~ CÒID~f4 . .riotol~~1a Ctif5 Er.1n . "..ei Ci~AW.. ~.' Fo:'( -inc~)+(e.fC;~te.).~ti ~-c4~~T ~ .. Y ..JnCi)+ (e.i è;i,+:~)lai2 Al~(81~(A:8.11 CL~"l+éitAcL"... AL+ê-o(t-AtAj . C~.1~..CL¡.. AlI\ +&ål'~l ... C~~~ - ttli. C(,::.1~it . .g~~dtOlt Cl";CA-,1"1~RC~ ci".CI.1~è~~LR .. cL.~.-.lJ(P1or ~Ji, f(fc¡ P4)'.

Tb. r"'lln", ..'W.lIlIi..y:".lftjl1ClII....v.N..fcil8,...ìf tGt ,..P.,.'...I;..~'r,.'I,.I.._H~IiI..i...,...I..lllil....R'ls.ll,Ip..'II"..."1.. Tbt'rU..llReIUØi lI"miliiøl.',.rllllPl('melW.. F""" 12 ..,...',. 13 .h..W.lt.l.,~u.....r;~~,ltca,.~~.',.....~..,nl.~,""...~'.~....tJnc T..r.J.ft'.,ll..h...... l'II.....~:.,,_l....,l,...."'~....lI.Il..if f8""".1 lilt' .P~p'''l.. v~. 'l...,"~...ll,..tbl)l',.I.;..j.....U_'. ....nPK..,ldl""p:'r.f"nIl.'..',...:...... Iß...... II....I. .lè""O:'âettit C"lr'l'lIl.j ..'.' ..M...sm....j.. TIt./..Ct....., ,"'ñi"c..fad.lim':lR"'.....

,.I....l~ ..;~...... PharmaGél'fÏ Review NOA 22244 (A..va.)

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$perit ..i.eva)uatedth. .W tif re... ari . hiil imp¡im¡eril onlh phimaeokinltlGoffÐsprpørc1 anc PRpøføl. Study Repert PR-AQlJA-04l Pepulâliøl' PharmlGkinetie-PharmacoElAlmic MGEeUAløf Fè$ppøfÐl IAjeølininPaltlts: EvaluatiA il1 Hepatllly Impair. Patients. The Uta frøm 7 patients wi hep.tic impirent were mergd aløng wit ether patint. and the pharmaGGetpal'eters were.termin.d. The pharmlØokirietlc analysis in _tlflts wih htpae impaimert ..t: nÐt iAeluci ela__tlel' orr-tiRt. as per Ghild-Po8Gs. Th"R.' ShdéÐnduet li stud inpatient wit hepatic impairment tø pÏ'vide .ar iAferatiør'. iA th drug label.

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