Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism of Action Fospropofol disodium is a prodrug of propofol. Following intravenous injection, fospropofol is metabolized by alkaline phosphatases. For every millimole of fospropofol disodium administered, one millimole of propofol is produced (1.86 mg of fospropofol disodium is the molar equivalent of 1 mg propofol). Pharmacodynamics The pharmacology of fospropofol, once metabolized to propofol, is comparable to that of propofol lipid emulsion; however the liberation of propofol from fospropofol results in differences in the timing of the pharmacodynamic effects. To characterize the pharmacokinetic/pharmacodynamic (PK/PD) profile of propofol derived from LUSEDRA (fospropofol disodium injection) , 12 healthy subjects were administered a 10-mg/kg intravenous bolus dose of LUSEDRA (fospropofol disodium injection) , and the sedative effect was measured as a decrease in Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score (Table 5).2 The PK and PD results are shown in Figure 2. Peak plasma levels of propofol (2.2 ± 0.4 µg/mL) released from fospropofol were noted by 8 minutes (range 4-13 minutes) and minimum mean MOAA/S score of 1.2 (range 0-3) was noted in 7 minutes (range 1 -15 minutes). Subjects completely recovered from sedative effects between 21 to 45 minutes after LUSEDRA (fospropofol disodium injection) administration. Table 5. Modified Observer's Assessment of Alertness/Sedation Scale2 Responsiveness Score Responds readily to name spoken in normal tone 5 Lethargic response to name spoken in normal tone 4 Responds only after name is called loudly and/or repeatedly 3 Responds only after mild prodding or shaking 2 Responds only after painful trapezius squeeze 1 Does not respond to painful trapezius squeeze 0 Figure 2. Pharmacokinetic and Pharmacodynamic Profiles after a 10-mg/kg Bolus Dose of LUSEDRA (fospropofol disodium injection) LUSEDRA (fospropofol disodium injection) was evaluated in randomized, blinded, dose-controlled studies for sedation in patients undergoing colonoscopy and flexible bronchoscopy [see Clinical Studies]. Figure 3 shows MOAA/S scores over time in each of the studies for those patients who received the standard and modified dosing regimens. In the study of patients undergoing colonoscopy, patients who received the standard and modified dosing regimens had a median [range] time to sedation (time from first dose of sedative to the first of 2 consecutive MOAA/S scores of ≤ 4) of 8.0 [2, 28] minutes and a median time to Fully Alert (3 consecutive responses to their name spoken in a normal tone, measured every 2 minutes beginning at or after the end of the procedure) of 5.0 [0, 47] minutes. In the study of patients undergoing flexible bronchoscopy, patients who received the standard and modified LUSEDRA (fospropofol disodium injection) dosing regimens had a median time to sedation of 4 [2, 22] minutes and a median time to Fully Alert of 5.5 [0, 61] minutes. Figure 3. Percentage of Patients at Each MOAA/S Score Over Time Within the recommended dose range, there were no differences in matched QTc interval changes between LUSEDRA (fospropofol disodium injection) and placebo. The effect of LUSEDRA (fospropofol disodium injection) on the QTcF interval was measured in a crossover study in which healthy subjects (n=68) received the following treatments: 6 mg/kg intravenous LUSEDRA (fospropofol disodium injection) ; 18 mg/kg intravenous LUSEDRA (fospropofol disodium injection) ; moxifloxacin 400 mg orally (positive control); and normal saline IV After baseline and placebo adjustment, the maximum mean QTcF change was 2 ms (1 -sided 95% Upper CI: 6 ms) for the 6-mg/kg dose and 8 ms (1 -sided 95% Upper CI: 12 ms) for the 18-mg/kg dose. Used as a positive control, moxifloxacin had a maximum mean change in QTcF of 12 ms (1-sided 95% Lower CI: 6 ms). Pharmacokinetics PK parameters were evaluated in a crossover study of 68 healthy subjects, 18 to 45 years of age, who received 6- and 18-mg/kg intravenous bolus doses of LUSEDRA (fospropofol disodium injection) . PK parameters are shown in Table 6. The Cmax and AUC0-∞ values of fospropofol were dose proportional. The intersubject variability in Cmax and AUC0-∞ was low. Propofol was rapidly liberated reaching plasma Cmax at a median Tmax of 12 minutes for LUSEDRA (fospropofol disodium injection) 6 mg/kg and 8 minutes for LUSEDRA (fospropofol disodium injection) 18 mg/kg. Concentration-time profiles showed a biexponential decline. The increase in Cmax and AUC0-∞ of propofol was dose proportional. Table 6. Pharmacokinetic Parameters (mean ± SD) for Fospropofol and Propofol from LUSEDRA (fospropofol disodium injection) Administration Fospropofol Parameter Healthy (6 mg/kg) N=68 Healthy (18 mg/kg) N=68 Patient (6.5 mg/kg) N=667 Cmax (mcg/mL) 78.7 ± 15.4 211 ± 48.6 -- Tmax (min) 4 2 -- AUC0-∞ (mcg•h/mL) 19.2 ± 3.59 50.3 ± 8.4 19.0 ± 7.2 CLp (L/h/kg) 0.28 ± 0.053 0.32 ± 0.058 0.36 ± 0.16 t1/2 (h) 0.81 ± 0.08 0.81 ± 0.09 0.88 ± 0.08 Propofol from LUSEDRA Parameter Healthy (6 mg/kg) N=68 Healthy (18 mg/kg) N=68 Patient (6.5 mg/kg) N=400 Cmax (mcg/mL) 1.08 ± 0.33 3.90 ± 0.822 -- Tmax (min) 12 8 -- AUC0-∞ (mcg•h/mL) 1.70 ± 0.29 5.67 ± 1.28 1.2 ± 0.39 CLp (L/h/kg) 1.95 ± 0.34 1.79 ± 0.39 3.2 ± 0.92 t1/2 (h) 2.06 ± 0.77 1.76 ± 0.54 1.13 ± 0.28 Distribution Fospropofol has a low volume of distribution of 0.33 ± 0.069 L/kg, and the liberated propofol has a large volume of distribution (5.8 L/kg). Both fospropofol and its active metabolite propofol are highly protein bound (approximately 98%), primarily to albumin. Fospropofol does not affect the binding of propofol to albumin. Metabolism Fospropofol is completely metabolized by alkaline phosphatases to propofol, formaldehyde, and phosphate. Formaldehyde and phosphate plasma concentrations are comparable to endogenous levels when fospropofol disodium is administered as recommended. Formaldehyde is further metabolized to formate by several enzyme systems, including formaldehyde dehydrogenase, present in various tissues. Propofol liberated from fospropofol is further metabolized to major metabolites propofol glucuronide (34.8%), quinol-4-sulfate (4.6%), quinol-1 -glucuronide (11.1 %), and quinol-4-glucuronide (5.1%). Oxidation to CO2 is the primary means of eliminating excess formate. Fospropofol is not a substrate of CYP450 enzymes. Elimination After a single 400-mg intravenous dose of [14C]-fospropofol disodium in humans, approximately 71 % of radioactivity was recovered in the urine within 192 hours. Total body clearance (CLp) of fospropofol was 0.280 ± 0.053 L/h/kg, and renal elimination of fospropofol was insignificant ( < 0.02% of dose). The terminal phase elimination half-life (t1/2) of fospropofol was 0.81 ± 0.08 and 0.88 ± 0.08 hours in healthy subjects and patients, respectively. In healthy subjects, the apparent total body clearance of liberated propofol (CLp/F) was 1.95 ± 0.345 L/h/kg and t1/2 was 2.06 ± 0.77 hours. In patients, the CLp of fospropofol was 0.31 ± 0.14 L/h/kg, and CLp/F for propofol was 2.74 ± 0.80 L/h/kg and is similar to that observed in healthy subjects. Special Populations Population pharmacokinetic analysis indicated no influence of race, gender, age, renal impairment or alkaline phosphatase concentrations on the pharmacokinetics of fospropofol. Pharmacokinetics of propofol derived from fospropofol was not influenced by race, gender, or renal impairment. LUSEDRA (fospropofol disodium injection) has not been adequately studied in patients with hepatic impairment. Caution should be exercised when using fospropofol disodium in patients with hepatic impairment. Drug Interactions There was no effect of analgesic premedication [fentanyl (1 mcg/kg); meperidine (0.75 mg/kg); midazolam (0.01 mg/kg); morphine (0.1 mg/kg)] on plasma pharmacokinetics of fospropofol. In an in vitro protein-binding study, there was no significant interaction between fospropofol and propofol at concentrations up to 200 mcg/mL and 5 mcg/mL, respectively. The interaction of fospropofol with other highly protein-bound drugs given concomitantly has not been studied. Potential of fospropofol or its major metabolite, propofol, to inhibit or induce major cytochrome P450 enzymes is not known. Clinical Studies Use in Sedation for Diagnostic or Therapeutic Procedures The standard and modified LUSEDRA (fospropofol disodium injection) dosing regimens were evaluated in two controlled studies in patients dosed with LUSEDRA (fospropofol disodium injection) who were over 18 years of age and undergoing diagnostic or therapeutic procedures. All patients received 50 mcg of fentanyl citrate intravenously before study sedative medication. The primary endpoint was the rate of “sedation success,” defined as the proportion of patients who did not respond readily to their name spoken in a normal tone of voice (Modified Observer's Assessment of Alertness/Sedation Scale score of 4 or less) on 3 consecutive measurements taken every 2 minutes and who completed the procedure without the use of alternative sedative medication and without the use of manual or mechanical ventilation.2 In both studies, an initial bolus dose and up to 3 supplemental doses at 25% of the initial bolus of study sedative medication were administered intravenously to sedate patients so that they did not respond readily to their name spoken in a normal tone and to allow the investigator to start the procedure. During the procedure, supplemental doses at 25% of the initial bolus were allowed to maintain sedation. Patients who were not adequately sedated with study drug received alternative sedative medication per the site's standard of care; however, sites were instructed not to use propofol as it would interfere with PK measurements. The standard and modified LUSEDRA (fospropofol disodium injection) dosing regimens were evaluated in a randomized, blinded, dose-controlled study for sedation in patients undergoing colonoscopy. All of the patients who received alternative sedative medication (n=19) received midazolam. Patients randomized to receive the LUSEDRA (fospropofol disodium injection) standard or modified dosing regimen had a sedation success rate of 87% and required a mean number of supplemental doses of 2.3 ( ± 1.4 SD). Patients randomized to receive LUSEDRA (fospropofol disodium injection) had a median procedure duration of 11 minutes. The standard and modified LUSEDRA (fospropofol disodium injection) dosing regimens were also evaluated in a randomized, blinded, dose-controlled study for sedation in patients undergoing flexible bronchoscopy. All of the patients who received alternative sedative medication (n=12) received midazolam. Patients randomized to receive the LUSEDRA (fospropofol disodium injection) standard or modified dosing regimen had a sedation success rate of 89% and required a mean number of supplemental doses of 1.7 ( ± 1.6 SD). Patients randomized to LUSEDRA (fospropofol disodium injection) had a median procedure duration of 10 minutes. REFERENCES 2. Chernik DA, Gillings D, Laine H, Hendler J, Silver JM, Davidson AB, et al. Validity and reliability of the Observer's Assessment of Alertness/Sedation Scale: study with intravenous midazolam. J Clin Psychopharmacol. 1990;10(4):244-251

LUSEDRA (fospropofol disodium) Injection, for Intravenous Use DESCRIPTION LUSEDRA (fospropofol disodium injection) is an injection solution intended for intravenous administration as a sedative-hypnotic agent. LUSEDRA (fospropofol disodium injection) is an aqueous, sterile, nonpyrogenic, clear, colorless, iso-osmotic solution containing 35 mg/mL of fospropofol disodium. Fospropofol disodium is a water-soluble prodrug of propofol, chemically described as 2,6-diisopropylphenoxymethyl phosphate, disodium salt. The structural and molecular formulas are shown in Figure 1. Molecular Formula: C13H19O5PNa2 Molecular Weight: 332.24 Figure 1. Structural and Molecular Formulas of Fospropofol Disodium The inactive components include monothioglycerol (0.25 wt%) and tromethamine (0.12 wt%). LUSEDRA (fospropofol disodium injection) has a pH of 8.2 to 9.0. LUSEDRA (fospropofol disodium injection) does not contain any antimicrobial preservatives and is intended for single-use administration.

INDICATIONS LUSEDRA™ (fospropofol disodium) injection is an intravenous sedative-hypnotic agent indicated for monitored anesthesia care (MAC) sedation in adult patients undergoing diagnostic or therapeutic procedures. DOSAGE AND ADMINISTRATION Dosing Guidelines Administer LUSEDRA (fospropofol disodium injection) intravenously as a bolus injection. Use supplemental oxygen for all patients undergoing sedation with LUSEDRA (fospropofol disodium injection) . Individualize the dosage of LUSEDRA (fospropofol disodium injection) and titrate to the level of sedation required for the procedure. In adults aged 18 to < 65 years who are healthy or have mild systemic disease as categorized by the American Society of Anesthesiologists (ASA P1 or P2), the standard dosing regimen of LUSEDRA (fospropofol disodium injection) should be followed [see Standard Dosing Regimen for Sedation]. In adults who are ≥ 65 years of age or who have severe systemic disease (ASA P3 or P4), the modified dosing regimen should be followed [see Modified Dosing Regimen for Sedation in Patients ≥ 65 years or Those with Severe Systemic Disease]. Administer supplemental doses of LUSEDRA (fospropofol disodium injection) based on the patient's level of sedation and the level of sedation required for the procedure. Give supplemental doses only when patients can demonstrate purposeful movement in response to verbal or light tactile stimulation and no more frequently than every 4 minutes. Use only the minimum dosage required to facilitate the procedure. Consider the potential for worsened cardiorespiratory depression prior to using LUSEDRA (fospropofol disodium injection) concomitantly with other drugs that have the same potential (e.g., sedative-hypnotics or narcotic analgesics) [see WARNINGS AND PRECAUTIONS]. In clinical studies, an opioid premedication (fentanyl citrate 50 mcg intravenously) was administered fve minutes prior to the initial dose of LUSEDRA (fospropofol disodium injection) . Standard Dosing Regimen for Sedation In adults aged 18 to < 65 years who are healthy or have mild systemic disease (ASA P1 or P2)1, the standard dosing regimen of LUSEDRA (fospropofol disodium injection) is an initial intravenous bolus of 6.5 mg/kg followed by supplemental doses of 1.6 mg/kg intravenously (25% of initial dosage) as needed to achieve the desired level of sedation as shown in Table 1. The dosage of LUSEDRA (fospropofol disodium injection) is limited by lower and upper weight bounds of 60 kg and 90 kg. Adults who weigh > 90 kg should be dosed as if they weigh 90 kg. No initial dose should exceed 16.5 mL; no supplemental dose should exceed 4 mL. Adults who weigh < 60 kg should be dosed as if they weigh 60 kg. Dosages lower than those specified for the lower weight limit may be used to achieve lesser levels of sedation. In clinical studies, an opioid premedication (fentanyl citrate 50 mcg IV) was administered five minutes prior to the initial dose of LUSEDRA (fospropofol disodium injection) . Table 1. Standard Dosing Regimen, Adults 18 to < 65 Years of Age Who are Healthy or Have Mild Systemic Disease (ASA P1 or P2) Initial Dose Supplemental Dose No more frequently than every 4 min. Weight (kg) mg mL mg mL ≤ 60 385 11 105 3 61 to 63 402.5 11.5 105 3 64 to 65 420 12 105 3 66 to 68 437.5 12.5 105 3 69 to 71 455 13 105 3 72 to 74 472.5 13.5 122.5 3.5 75 to 76 490 14 122.5 3.5 77 to 79 507.5 14.5 122.5 3.5 80 to 82 525 15 140 4 83 to 84 542.5 15.5 140 4 85 to 87 560 16 140 4 88 to 89 577.5 16.5 140 4 ≥ 90 577.5 16.5 140 4 Note: Doses in this table are rounded to the nearest half-milliliter volume to facilitate practical measurement; hence, they may differ slightly from the dose recommended on the basis of mg/kg. Modified Dosing Regimen for Sedation in Patients ≥ 65 years or Those with Severe Systemic Disease (ASA P3 or P4) Adults ≥ 65 years of age orthose with severe systemic disease (ASA P3 or P4)1 should receive initial and supplemental intravenous dosages of 75% of the standard dosing regimen, as presented in Table 2. LUSEDRA (fospropofol disodium injection) is administered intravenously as a bolus injection. In clinical studies, an opioid premedication (fentanyl citrate 50 mcg IV) was administered five minutes prior to the initial dose of LUSEDRA (fospropofol disodium injection) . Table 2. Modified Dosing Regimen, Ages ≥ 65 Years Or Those with Severe Systemic Disease Initia Dose Supplemental Dose No more frequently than every 4 min. Weight (kg) mg mL mg mL ≤ 60 297.5 8.5 70 2 61 to 62 297.5 8.5 70 2 63 to 64 315 9 87.5 2.5 65 to 66 315 9 87.5 2.5 67 to 69 332.5 9.5 87.5 2.5 70 to 73 350 10 87.5 2.5 74 to 77 367.5 10.5 87.5 2.5 78 to 80 385 11 105 3 81 to 84 402.5 11.5 105 3 85 to 87 420 12 105 3 88 to 89 437.5 12.5 105 3 ≥ 90 437.5 12.5 105 3 Note: Doses in this table are rounded to the nearest half-milliliter volume to facilitate practical measurement; hence, they may differ slightly from the dose recommended on the basis of mg/kg. Preparation LUSEDRA (fospropofol disodium injection) is provided as a ready to use formulation intended for single-patient use only. Prepare LUSEDRA (fospropofol disodium injection) following strict aseptic techniques. Draw LUSEDRA (fospropofol disodium injection) into sterile syringes immediately after vials are opened. Discard any unused portion at the end of the procedure. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use if there is evidence of particulate matter or discoloration. LUSEDRA (fospropofol disodium injection) has been shown to be compatible with the following fluids: 5% Dextrose Injection, USP 5% Dextrose and 0.2% Sodium Chloride, USP 5% Dextrose and 0.45% Sodium Chloride Injection, USP 0.9% Sodium Chloride Injection, USP Lactated Ringer's Injection, USP Lactated Ringer's and 5% Dextrose Injection, USP 0.45% Sodium Chloride Injection, USP 5% Dextrose, 0.45% NaCl and 20 mEq KCl, USP Do not mix LUSEDRA (fospropofol disodium injection) with other drugs or fluids prior to administration. LUSEDRA (fospropofol disodium injection) is not physically compatible with midazolam HCl or meperidine HCl, and compatibility with other agents has not been adequately evaluated. Administer LUSEDRA (fospropofol disodium injection) through a secure, freely flowing, peripheral intravenous line using commonly available intravenous administration sets. Flush the infusion line with normal saline before and after administration of LUSEDRA (fospropofol disodium injection) . LUSEDRA (fospropofol disodium injection) is not light sensitive. LUSEDRA (fospropofol disodium injection) does not need to be filtered before use. HOW SUPPLIED Dosage Forms And Strengths Single-use vial contents: Solution for intravenous administration containing 35 mg of fospropofol disodium per mL (1,050 mg of fospropofol disodium in 30 mL). LUSEDRA, 35 mg/mL (total of 1,050 mg/30 mL) fospropofol disodium, is supplied as a single-use, aqueous, sterile, nonpyrogenic, clear, colorless solution in glass vials ready for intravenous injection. Each vial is filled with 32.1 mL intended to deliver a minimum of 30 mL of fospropofol disodium solution. Store at controlled room temperature 25°C (77°F). Excursions permitted between 15° and 30°C (59° and 86°F). NDC 62856-350-08 REFERENCES 1. Kost, M. Moderate Sedation/Analgesia: Core Competencies for Practice. Elsevier Health Sciences, 2004: 62-63. Eisai Inc. 100 Tice Boulevard, Woodcliff Lake, NJ 07677. USA. Revised 10/2009

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

OVERDOSE Overdosage with LUSEDRA (fospropofol disodium injection) can cause cardiorespiratory depression. If overdosage occurs, LUSEDRA (fospropofol disodium injection) administration should be discontinued immediately. Respiratory depression may require manual or mechanical ventilation. Cardiovascular depression may require elevation of lower extremities, intravascular volume replacement, and/or pharmacological management. Formate and phosphate are metabolites of LUSEDRA (fospropofol disodium injection) and may contribute to signs of toxicity following overdosage. Signs of formate toxicity are similar to those of methanol toxicity and are associated with anion-gap metabolic acidosis. Intravenous exposure to a large amount of phosphate could potentially cause hypocalcemia with paresthesia, muscle spasms, and seizures. CONTRAINDICATIONS None.

SIDE EFFECTS The following serious adverse reactions are discussed elsewhere in the labeling: Respiratory depression [see WARNINGS AND PRECAUTIONS] Hypoxemia [see WARNINGS AND PRECAUTIONS] Loss of purposeful responsiveness [see WARNINGS AND PRECAUTIONS] Hypotension [see WARNINGS AND PRECAUTIONS] The most common adverse reactions (reported in greater than 20%) are paresthesia and pruritus. The most commonly reported reasons for discontinuation are paresthesia and cough. Clinical Trials Experience Adverse reactions presented in this section are derived from 332 patients in 3 controlled clinical trials in patients undergoing colonoscopy or flexible bronchoscopy and 123 patients in one open-label study in patients undergoing minor procedures. Patients enrolled in the studies who received the standard or modified dosing regimen included males and females, ≥ 18 years of age and ranging from healthy (359/455 [79%] ASA P1 or P2) to those with severe systemic disease (96/455 [21%] ASA P3 or P4). Of the 455 patients enrolled, 345 (76%) were ≥ 18 to < 65 years of age and 110 (24%) were ≥ 65 years of age. Adverse reactions are reported for patients who received the standard or the modified dosing regimen [see DOSAGE AND ADMINISTRATION]. The majority of procedures were less than thirty minutes in duration. All patients in these studies received 50 mcg fentanyl citrate intravenously as premedication, and some of the patients received additional 25 mcg fentanyl citrate supplemental doses. Adverse reactions occurring in ≥ 2% of patients in these studies are presented in Table 3. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not accurately reflect the rates observed in practice. Table 3. Common Adverse Reactions for Patients Receiving the Standard or Modified Dosing Regimen (Reactions Occurring at a Rate ≥ 2%) Reaction Term Colonoscopy (N=183) n(%) Minor Procedures (N=123) n (%) Bronchoscopy (N=149) n(%) Gastrointestinal disorders Nausea 0 5(4) 2(1) Vomiting 0 4(3) 0 Injury, poisoning, and procedural complications Procedural Pain 0 0 3(2) Nervous system disorders Paresthesiaa 135(74) 77 (63) 78 (52) Headache 1 (1) 3(2) 1(1) Respiratory, thoracic, and mediastinal disorders Hypoxemia 3(2) 1 (1) 16(11) Skin and subcutaneous tissue disorders Pruritusb 30(16) 34 (28) 24(16) Vascular disorders Hypotension 4(2) 4(3) 10(7) a Paresthesia includes the following terms: Paresthesia genital male; Burning sensation; Genital burning sensation; Vaginal burning sensation; Skin burning sensation; Genital pain (reported as burning); Perineal pain (reported as burning); Anal discomfort (reported as burning); Chest pain (reported as burning); Ear discomfort (reported as burning); Nasal discomfort (reported as burning); Buttock pain (reported as stinging); Groin pain (reported as stinging); Pain (reported as stinging); Sensory disturbance (reported as non-specific sensation in pubic area). b Pruritus includes the following terms: Genital pruritus female; Genital pruritus male; Pruritus genital; Pruritus ani; Pruritus generalized. Paresthesias (including burning, tingling, stinging) and/or pruritus, usually manifested in the perineal region, were the most frequently recorded adverse reactions in clinical trials. Paresthesias and pruritus generally occurred within 5 minutes after administration of the initial dose of LUSEDRA (fospropofol disodium injection) and were generally transient and mild to moderate in intensity. The pharmacologic basis of these sensory phenomena is unknown. No pretreatments, including the use of nonsteroidal anti-inflammatory drugs, opioids, or lidocaine, are known to have an effect on or to reduce the incidence of these sensations. Sedation-related adverse reactions were experienced at the following rates for subjects receiving the standard or modified LUSEDRA (fospropofol disodium injection) dosing regimen: 20/455 (4%) hypoxemia, 18/455 (4%) hypotension, 1/455 ( < 1%) apnea. A greater rate of sedation-related adverse reactions necessitating intervention was observed in patients undergoing bronchoscopy compared with colonoscopy and minor surgical procedures. In the colonoscopy studies, 5/183 (3%) patients were ASA P3. In the minor surgical procedures study, 23/123 (19%) patients were ASA P3 or P4. In the flexible bronchoscopy study, 68/150 (46%) patients were ASA P3 or P4. The type and incidence of airway assistance interventions required for patients who experienced sedation-related adverse reactions are presented in Table 4. Table 4. Patient Incidence of Airway Management Events Healthy Subjectsa 6 mg/kg N=69 n (%) Colonoscopyb 6.5 mg/kg (or modified dosing regimen) N=183 n (%) Minor Proceduresb 6.5 mg/kg (or modified dosing regimen) N=123 n (%) Flexible Bronchoscopyb 6.5 mg/kg (or modified dosing regimen) N=149 n (%) Increased O2 0 0 0 21 (14) Patient Repositioning 0 0 0 2(1) Verbal Stimulation 0 2(1) 1 (1) 5(3) Tactile Stimulation 0 0 0 3(2) Face Mask (100% O2) 0 0 0 1 (1) Jaw Thrust 0 0 0 2(1) Chin Lift 0 0 1 (1) 3(2) Nasal Trumpet 0 0 0 0 Oral Airway 0 0 0 0 Suction 0 0 0 2(1) Manual Ventilation (bag valve mask) 0 0 0 1 (1) Mechanical Ventilation 0 0 0 0 a No concomitant medications administered. All subjects were healthy volunteers. b All patients premedicated with 50 mcg fentanyl citrate. Subjects ranged from healthy to those with severe systemic disease that is a constant threat to life (ASA P1 to P4). Adverse Reactions in Prolonged Exposure in Adults The safety of LUSEDRA (fospropofol disodium injection) for continuous sedation has not been established and therefore its use is not recommended. LUSEDRA (fospropofol disodium injection) was administered to 38 intubated and mechanically ventilated patients in postoperative and intensive care settings. An occurrence of nonsustained ventricular tachycardia was observed as a serious adverse reaction in one patient in the study. Another patient with acute myeloid leukemia with renal and hepatic insufficiency experienced a further increase in plasma formate concentration from a baseline of 66 mcg/mL to a post-dose level of 212 mcg/mL after a 12-hour infusion. The clinical significance of these findings is unknown. DRUG INTERACTIONS LUSEDRA (fospropofol disodium injection) may produce additive cardiorespiratory effects when administered with other cardiorespiratory depressants such as sedative-hypnotics and narcotic analgesics. Drug Abuse And Dependence Controlled Substance LUSEDRA (fospropofol disodium injection) is a Schedule IV controlled substance. Abuse No formal studies of the abuse potential of LUSEDRA (fospropofol disodium injection) have been conducted. Administration of LUSEDRA (fospropofol disodium injection) resulted in euphoria in a small number of subjects who received intravenous or oral dosing. Dependence No formal studies of dependence have been conducted.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Monitoring LUSEDRA (fospropofol disodium injection) should be administered only by persons trained in the administration of general anesthesia and not involved in the conduct of the diagnostic or therapeutic procedure. Sedated patients should be continuously monitored, and facilities for maintenance of a patent airway, providing artificial ventilation, administering supplemental oxygen, and instituting cardiovascular resuscitation must be immediately available. Patients should be continuously monitored during sedation and through the recovery process for early signs of hypotension, apnea, airway obstruction, and/or oxygen desaturation. Respiratory Depression LUSEDRA (fospropofol disodium injection) may cause loss of spontaneous respiration. Apnea was reported in 1/455 ( < 1%) patients treated with LUSEDRA (fospropofol disodium injection) using the standard or modified dosing regimen [see DOSAGE AND ADMINISTRATION]. In patients treated with greater than the recommended LUSEDRA (fospropofol disodium injection) dose, apnea was reported in 14/556 (3%). Supplemental oxygen is recommended for all patients receiving LUSEDRA (fospropofol disodium injection) . Dosages of LUSEDRA (fospropofol disodium injection) must be individualized for each patient and titrated to effect [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. Use lower doses of LUSEDRA (fospropofol disodium injection) in patients who are ≥ 65 years of age or who have severe systemic disease [see DOSAGE AND ADMINISTRATION]. The additive cardiorespiratory effects of narcotic analgesics and sedative-hypnotic agents should be considered when administered concomitantly with LUSEDRA (fospropofol disodium injection) . Patients should be assessed for their ability to demonstrate purposeful response while sedated with LUSEDRA (fospropofol disodium injection) as patients who are unable to do so may lose protective reflexes. Airway assistance maneuvers may be required in the management of respiratory depression (see Table 4). Hypoxemia LUSEDRA (fospropofol disodium injection) may cause hypoxemia detectable by pulse oximetry. Hypoxemia was reported in 20/455 (4%) patients treated with LUSEDRA (fospropofol disodium injection) using the standard or modified dosing regimen [see DOSAGE AND ADMINISTRATION]. Hypoxemia was reported among patients who retained the ability to respond purposefully to their heath care provider following administration of LUSEDRA (fospropofol disodium injection) . Therefore, retention of purposeful responsiveness did not prevent patients from becoming hypoxemic following administration of LUSEDRA (fospropofol disodium injection) . In patients treated with greater than the recommended LUSEDRA (fospropofol disodium injection) dose, hypoxemia was reported in 151/556 (27%). The risk of hypoxemia is reduced by appropriate positioning of the patient and the use of supplemental oxygen in all patients receiving LUSEDRA (fospropofol disodium injection) . Airway assistance maneuvers may be required in the management of hypoxemia (see Table 4). The additive cardiorespiratory effects of narcotic analgesics and other sedative-hypnotic agents should be considered when administered concomitantly with LUSEDRA (fospropofol disodium injection) . Patient Unresponsiveness to Vigorous Tactile or Painful Stimulation LUSEDRA (fospropofol disodium injection) has not been studied for use in general anesthesia. However, administration of LUSEDRA (fospropofol disodium injection) may inadvertently cause patients to become unresponsive or minimally responsive to vigorous tactile or painful stimulation. The incidence of patients sedated for colonoscopy who became minimally responsive or unresponsive to vigorous tactile or painful stimulation was 7/183 (4%). The duration of minimal or complete unresponsiveness in colonoscopy patients ranged from 2 to 16 minutes. Among patients sedated for bronchoscopy, the incidence of patients who became minimally or completely unresponsive to vigorous tactile or painful stimulation was 24/149 (16%). The duration of minimal to complete unresponsiveness in bronchoscopy patients ranged from 2 to 20 minutes. Hypotension Hypotension following the use of LUSEDRA (fospropofol disodium injection) may occur. Hypotension was reported in 18/455 (4%) patients treated with LUSEDRA (fospropofol disodium injection) using the standard or modified dosing regimen [see DOSAGE AND ADMINISTRATION]. In patients treated with greater than the recommended LUSEDRA (fospropofol disodium injection) dose, hypotension was reported in 31/556 (6%). Patients with compromised myocardial function, reduced vascular tone, or who have reduced intravascular volume may be at an increased riskfor hypotension. A secure intravenous access catheter and supplemental volume replacement fluids should be readily available during the procedure. Additional pharmacological management may be necessary. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals have not been performed to evaluate the carcinogenic potential of fospropofol disodium. Mutagenesis Fospropofol was not genotoxic in the Ames bacterial reverse mutation assay, with or without metabolic activation, and in the in vivo mouse micronucleus assay. Fospropofol was positive in the L5178Y TK+/- mouse lymphoma forward mutation assay in the presence of metabolic activation. In contrast, fospropofol was negative in this assay in the presence of formaldehyde-metabolizing enzymes, suggesting that the positive finding is likely due to an artifact of the culture conditions. Impairment of Fertility Male rats were treated with 5, 10, or 20 mg/kg fospropofol for 4 weeks prior to mating. Male fertility was not altered in animals treated with 20 mg/kg (0.3-fold the total human dose for a procedure of 16 minutes based on a mg/m2 basis). Female rats were treated with 5,10, or 20 mg/kg fospropofol for two weeks prior to mating. There were no clear treatment-related effects on female fertility at a dose of 20 mg/kg (0.3-fold the total human dose for a procedure of 16 minutes based on a mg/m2 basis). Use In Specific Populations Pregnancy Teratogenic Effects: Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Reproduction studies have been performed in rats and rabbits at doses up to 0.6 and 1.7 times the anticipated human dose for a procedure of 16 minutes based on a comparison of doses expressed as mg/m2 and have revealed no evidence of impaired fertility or harm to the fetus due to LUSEDRA. Pregnant rats were treated with fospropofol disodium (5, 20, or 45 mg/kg/day, IV) from gestation day 7 through 17 (the highest dose is 0.6 times the anticipated human dose for a procedure of 16 minutes based on a comparison of doses expressed as mg/m2). Doses of 20 and 45 mg/kg/day produced significant maternal toxicity. No drug-related adverse effects on embryo-fetal development were noted. Pregnant rabbits were treated with fospropofol disodium (14, 28, 56 or 70 mg/kg/day, IV) from gestation day 6 through 18 (the highest dose is 1.7 times the anticipated human dose for a procedure of 16 minutes based on a comparison of doses expressed as mg/m2). Significant maternal toxicity was noted at all doses. No drug-related adverse effects on embryo-fetal development were noted. Nonteratogenic Effects: Pregnant rats were administered 0, 5, 10, or 20 mg/kg/day fospropofol disodium from gestation day 7 through lactation day 20 to evaluate perinatal and postnatal development (the highest dose is 0.2 times the anticipated human dose for a procedure of 16 minutes based on a comparison of doses expressed as mg/m2). There were no clear treatment-related effects on growth, development, behavior (passive avoidance and water maze) or fertility and mating capacity of the offspring. Labor and Delivery LUSEDRA (fospropofol disodium injection) is not recommended for use in labor and delivery, including Cesarean section deliveries. It is not known if fospropofol crosses the placenta; however, propofol is known to cross the placenta, and as with other sedative-hypnotic agents, the administration of LUSEDRA (fospropofol disodium injection) may be associated with neonatal respiratory and cardiovascular depression. Nursing Mothers It is not known whether fospropofol is excreted in human milk; however, propofol has been reported to be excreted in human milk, and the effects of oral absorption of fospropofol or propofol are not known. LUSEDRA (fospropofol disodium injection) is not recommended for use in nursing mothers. Pediatric Use Safety and effectiveness in pediatric patients have not been established because LUSEDRA (fospropofol disodium injection) has not been studied in persons < 18 years of age. LUSEDRA (fospropofol disodium injection) is not recommended for use in this population. Geriatric Use In studies of LUSEDRA (fospropofol disodium injection) for sedation in brief diagnostic and therapeutic procedures, 17% of patients were ≥ 65 years of age and 5% of patients were ≥ 75 years of age. Patients ≥ 65 years of age should receive the modified dosing regimen [see DOSAGE AND ADMINISTRATION]. Hypoxemia was reported more frequently among patients aged ≥ 75 years than among patients aged 65 to < 75 years and less frequently among younger patients, aged 18 to < 65 years. Patients with Renal Impairment In studies of LUSEDRA (fospropofol disodium injection) for sedation in brief diagnostic and therapeutic procedures, 21 % of patients had a creatinine clearance < 80 mL/min, and 4% had a creatinine clearance < 50 mL/min. Pharmacokinetics of fospropofol or propofol were not altered in patients with mild to moderate renal insufficiency. No dosing adjustments are required for patients with creatinine clearance ≥ 30 mL/min. Limited safety and efficacy data are available for LUSEDRA (fospropofol disodium injection) in patients with creatinine clearance < 30 mL/min. Patients with Hepatic Impairment LUSEDRA (fospropofol disodium injection) has not been adequately studied in patients with hepatic impairment. Caution should be exercised when using fospropofol disodium in patients with hepatic impairment.