Lusedra

Generic Name: Fospropofol
Class: General Anesthetics, Miscellaneous
VA Class: CN203
Chemical Name: 2,6-Diisopropylphenoxymethyl phosphate disodium
Molecular Formula: C13H19O5PNa2
CAS Number: 258516-87-9

Introduction

Sedative and hypnotic; prodrug of propofol.1 2 3 5 6

Uses for Lusedra

Monitored Anesthesia Care (MAC)

Used for MAC sedation in adults undergoing diagnostic or therapeutic procedures.1 3 4 5

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Not recommended for continuous sedation.1

Lusedra Dosage and Administration

General

  • Administer supplemental oxygen to all patients.1

  • Opiate premedication (fentanyl 50 mcg IV) was administered 5 minutes prior to the initial dose of fospropofol disodium in all patients receiving the drug in clinical studies.1 2 3 4 5

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer undiluted by rapid, direct IV injection.1

Draw injection into sterile syringes immediately after vials are opened; use strict aseptic technique.1 Commercially available vials containing 1050 mg of fospropofol disodium in 30 mL (35 mg/mL) are preservative free and are for single-patient use only; discard any unused portion at the end of the procedure.1

Do not mix fospropofol disodium with other fluids or therapeutic agents prior to administration.1

Filtration before use not required.1

Administer through a secure, freely flowing peripheral IV line using commonly available IV administration sets.1 Flush infusion line with 0.9% sodium chloride before and after administration of fospropofol.1

Dosage

Available as fospropofol disodium; dosage expressed in terms of the salt.1

Adults

Monitored Anesthesia Care (MAC) Sedation

Individualize and titrate dosage based on the level of sedation required for the procedure.1 Use the minimum dosage required to facilitate the procedure.1

Standard Dosing Regimen
IV

Standard regimen recommended for patients 18 to <65 years of age who are healthy or have mild systemic disease (i.e., American Society of Anesthesiologists category 1 or 2 [ASA P1 or P2]).1

Initial dose of 6.5 mg/kg (maximum 577.5 mg [16.5 mL]) followed by supplemental doses of 1.6 mg/kg (maximum 140 mg [4 mL]) (i.e., 25% of the initial dose) as needed to achieve the required level of sedation.1 Calculate doses for patients weighing <60 kg based on a weight of 60 kg and for patients weighing >90 kg based on a weight of 90 kg.1

Dosages lower than those specified for the 60-kg lower weight limit may be used if lower levels of sedation are desired.1

Administer supplemental doses based on the patient’s level of sedation and the level of sedation required for the procedure and only when patients can demonstrate purposeful movement in response to verbal or light tactile stimulation; give no more frequently than every 4 minutes.1

Doses in Table 1 are rounded to the nearest 0.5 mL to facilitate measurement.1

Administered no more frequently than every 4 minutes.1

Table 1. Standard Dosing Regimen of Fospropofol Disodium1

Patient Weight (kg)

Initial Dose

Supplemental Dose

≤60

385 mg (11 mL)

105 mg (3 mL)

61–63

402.5 mg (11.5 mL)

105 mg (3 mL)

64–65

420 mg (12 mL)

105 mg (3 mL)

66–68

437.5 mg (12.5 mL)

105 mg (3 mL)

69–71

455 mg (13 mL)

105 mg (3 mL)

72–74

472.5 mg (13.5 mL)

122.5 mg (3.5 mL)

75–76

490 mg (14 mL)

122.5 mg (3.5 mL)

77–79

507.5 mg (14.5 mL)

122.5 mg (3.5 mL)

80–82

525 mg (15 mL)

140 mg (4 mL)

83–84

542.5 mg (15.5 mL)

140 mg (4 mL)

85–87

560 mg (16 mL)

140 mg (4 mL)

88–89

577.5 mg (16.5 mL)

140 mg (4 mL)

≥90

577.5 mg (16.5 mL)

140 mg (4 mL)

Modified Dosing Regimen
IV

Modified regimen recommended for patients ≥65 years of age and patients with severe systemic disease (ASA P3 or P4).1

Initial and supplemental doses reduced by 25% compared with the standard dosing regimen.1 4 Calculate doses for patients weighing <60 kg based on a weight of 60 kg and for patients weighing >90 kg based on a weight of 90 kg.1

Administer supplemental doses based on the patient’s level of sedation and the level of sedation required for the procedure and only when patients can demonstrate purposeful movement in response to verbal or light tactile stimulation; give no more frequently than every 4 minutes.1

Doses in Table 2 are rounded to the nearest 0.5 mL to facilitate measurement.1

Administered no more frequently than every 4 minutes1

Table 2. Modified Dosing Regimen of Fospropofol Disodium1

Patient Weight (kg)

Initial Dose

Supplemental Dose

≤60

297.5 mg (8.5 mL)

70 mg (2 mL)

61–62

297.5 mg (8.5 mL)

70 mg (2 mL)

63–64

315 mg (9 mL)

87.5 mg (2.5 mL)

65–66

315 mg (9 mL)

87.5 mg (2.5 mL)

67–69

332.5 mg (9.5 mL)

87.5 mg (2.5 mL)

70–73

350 mg (10 mL)

87.5 mg (2.5 mL)

74–77

367.5 mg (10.5 mL)

87.5 mg (2.5 mL)

78–80

385 mg (11 mL)

105 mg (3 mL)

81–84

402.5 mg (11.5 mL)

105 mg (3 mL)

85–87

420 mg (12 mL)

105 mg (3 mL)

88–89

437.5 mg (12.5 mL)

105 mg (3 mL)

≥90

437.5 mg (12.5 mL)

105 mg (3 mL)

Prescribing Limits

Adults

Monitored Anesthesia Care (MAC) Sedation
Standard Dosing Regimen
IV

Maximum initial dose: 577.5 mg (16.5 mL).1

Maximum supplemental dose: 140 mg (4 mL).1

Special Populations

Renal Impairment

Dosage adjustment not required in patients with Clcr ≥30 mL/minute.1

Geriatric Patients

Use the modified dosing regimen in patients ≥65 years of age (see Modified Dosing Regimen under Dosage and Administration).1

Cautions for Lusedra

Contraindications

  • Manufacturer states no known contraindications.1

Warnings/Precautions

Labor and Delivery

Not recommended for use in labor and delivery, including Cesarean deliveries.1

Supervised Administration

Only individuals experienced in the use of general anesthesia who are not involved in the conduct of the diagnostic or therapeutic procedure should administer the drug.1

Ensure immediate availability of facilities for maintaining a patent airway, providing artificial ventilation, administering supplemental oxygen, and instituting CPR.1 Monitor patients continuously during sedation and through the recovery process for early signs of hypotension, apnea, airway obstruction, and/or oxygen desaturation.1

Increased incidence of sedation-related adverse effects requiring intervention, including hypoxemia, hypotension, and apnea, in patients undergoing bronchoscopy (more of whom had severe systemic disease [ASA P3 or P4]) compared with patients undergoing colonoscopy and minor surgical procedures.1

Respiratory Effects

May cause loss of spontaneous respiration.1 Apnea and hypoxemia have been reported.1 2 Hypoxemia reported in patients who retained the ability to respond purposefully.1 4 Risk of hypoxemia can be reduced by appropriate positioning of the patient and use of supplemental oxygen.1

Supplemental oxygen recommended in all patients receiving the drug.1 Treatment of respiratory depression and/or hypoxemia may require airway assistance maneuvers.1

Individualize dosage for each patient and titrate dosage based on desired effect.1 (See Dosage under Dosage and Administration). Consider possible additive cardiorespiratory effects of opiate analgesics and other sedative-hypnotic agents (see Interactions).1 Assess patients for their ability to demonstrate purposeful response while sedated with fospropofol; patients unable to demonstrate purposeful response may experience loss of protective reflexes.1

Nervous System Effects

Not indicated for use in general anesthesia but may inadvertently cause patients to become unresponsive or minimally responsive to vigorous tactile or painful stimulation.1

Hypotension

Hypotension has been reported.1 2 Risk may be increased in patients with compromised myocardial function, reduced vascular tone, or reduced intravascular volume.1

Ensure that a secure IV access catheter and supplemental volume replacement fluids are readily available.1 Hypotension may require additional pharmacologic management.1

Abuse Potential

Formal studies of dependence or abuse potential not performed to date.1 Euphoria reported in a small number of patients receiving the drug orally or by IV injection.1

Specific Populations

Pregnancy

Category B.1

Lactation

Not known whether fospropofol is distributed into milk; however, propofol reportedly is distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy in pediatric patients <18 years of age not established.1 The manufacturer states that use in this population is not recommended.1

Geriatric Use

Hypoxemia reported more frequently in patients ≥75 years of age compared with patients 65 to <75 years of age and less frequently in patients 18 to <65 years of age.1

Hepatic Impairment

Use with caution.1

Renal Impairment

Limited data on safety and efficacy in patients with Clcr <30 mL/minute.1

Common Adverse Effects

Paresthesia,1 2 3 4 5 pruritus,1 2 3 4 5 hypoxemia,1 2 3 5 hypotension,1 3 4 5 nausea,1 vomiting,1 headache,1 procedural pain.1

Interactions for Lusedra

Fospropofol is not a substrate of CYP isoenzymes.1

Not known whether fospropofol or propofol inhibits or induces major CYP isoenzymes.1

Protein-bound Drugs

Fospropofol does not affect the binding of propofol to albumin.1 The potential for fospropofol to interact with other highly protein-bound drugs has not been evaluated to date.1

Specific Drugs

Drug

Interaction

Sedatives, hypnotics, and opiate agonists

Potential additive cardiorespiratory effects1

Pharmacokinetic interaction unlikely with fentanyl, meperidine, midazolam, or morphine1

Lusedra Pharmacokinetics

Absorption

Onset

Peak plasma concentrations of fospropofol and propofol observed approximately 4 and 12 minutes, respectively, following a single 6-mg/kg dose of fospropofol disodium in healthy individuals.1

Median time to onset of sedation was 8 minutes (range: 2–28 minutes) in patients undergoing colonoscopy and 4 minutes (range: 2–22 minutes) in those undergoing flexible bronchoscopy.1 3 4

Duration

Median time to full alertness was 5 minutes (range: 0–47 minutes) in patients undergoing colonoscopy and 5.5 minutes (range: 0–61 minutes) in those undergoing flexible bronchoscopy.1 3

Distribution

Extent

Fospropofol has a small volume of distribution.1 6 Propofol released from fospropofol has a large volume of distribution (5.8 L/kg).1 6

Not known whether fospropofol crosses the placenta or is distributed into milk; however, propofol crosses the placenta and is distributed into milk.1

Plasma Protein Binding

Fospropofol: Approximately 98% (mainly albumin).1

Propofol: Approximately 98% (mainly albumin).1

Elimination

Metabolism

Fospropofol is rapidly and completely metabolized to propofol, formaldehyde, and phosphate by alkaline phosphatases.1 2 6

Each mmol of fospropofol disodium is metabolized to one mmol of propofol; 1.86 mg of fospropofol disodium is the molar equivalent of 1 mg of propofol.1 2 Propofol is metabolized to major metabolites propofol glucuronide (34.8%), quinol-4-sulfate (4.6%), quinol-1-glucuronide (11.1%), and quinol-4-glucuronide (5.1%).1

Concentrations of formaldehyde and phosphate are comparable to endogenous concentrations when fospropofol is administered as recommended.1 Formaldehyde is further metabolized to formate by several enzyme systems, including formaldehyde dehydrogenase, in various tissues.1 2 Excess formate is eliminated mainly by oxidation to carbon dioxide.1 2

Elimination Route

Excreted principally in urine (approximately 71%) as metabolites.1

Half-life

Half-life of hydrolysis of fospropofol to propofol: Approximately 8 minutes.1 2

Fospropofol: Terminal elimination half-life approximately 0.9 hours.1

Propofol: Terminal elimination half-life approximately 1.1 hours.1

Stability

Storage

Parenteral

Injection

25°C; may be exposed to 15–30°C.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Solution Compatibility

Y-Site Compatibility1

Compatible

Dextrose 5% in Ringer’s injection, lactated

Dextrose 5% in sodium chloride 0.2 or 0.45%

Dextrose 5% in sodium chloride 0.45% and potassium chloride 20 mEq/L

Dextrose 5% in water

Ringer’s injection, lactated

Sodium chloride 0.45 or 0.9%

Drug Compatibility

Y-Site Compatibility1

Incompatible

Meperidine hydrochloride

Midazolam hydrochloride

Actions

  • Prodrug of propofol; a sedative and hypnotic agent.1 2

  • Unlike propofol, fospropofol disodium is water soluble and is commercially available as an aqueous solution;1 2 6 potential advantages include lack of effect on lipids, decreased pain on injection, and decreased risk of infection.2 6

  • Pharmacology is comparable to that of propofol; however, time profile of pharmacodynamic effects is different since fospropofol must be metabolized to propofol to exert its clinical effects.1 2 6

Advice to Patients

  • Importance of informing patients of the possibility of paresthesias (e.g., burning, tingling, stinging) and/or pruritus, usually mild to moderate and transient and usually manifested in the perineal region, especially upon injection of the initial dose.1 These reactions generally do not require treatment.1

  • Importance of informing patients that their ability to perform activities requiring mental alertness (e.g., driving, operating machinery, signing legal documents) may be impaired for some time after undergoing sedation; individualize decisions regarding when patients may safely engage in such activities and consider need for a patient escort.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Subject to control under the Federal Controlled Substances Act of 1970 as a schedule IV (C-IV) drug.1

Fospropofol Disodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IV use

35 mg/mL

Lusedra (C-IV)

Eisai

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions September 1, 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Eisai Inc. Lusedra (fospropofol disodium) injection prescribing information. Woodcliff Lake, NJ; 2009 Oct.

2. Fechner J, Ihmsen H, Jeleazcov C et al. Fospropofol disodium, a water-soluble prodrug of the intravenous anesthetic propofol (2,6-diisopropylphenol). Expert Opin Investig Drugs. 2009; 18:1565-71. [PubMed 19758110]

3. Silvestri GA, Vincent BD, Wahidi MM et al. A phase 3, randomized, double-blind study to assess the efficacy and safety of fospropofol disodium injection for moderate sedation in patients undergoing flexible bronchoscopy. Chest. 2009; 135:41-7. [PubMed 18641105]

4. Cohen LB, Cattau E, Goetsch A et al. A randomized, double-blind, phase 3 study of fospropofol disodium for sedation during colonoscopy. J Clin Gastroenerol. Epub 2009 Dec 3.

5. Cohen LB. Clinical trial: a dose-response study of fospropofol disodium for moderate sedation during colonoscopy. Aliment Pharmacol Ther. 2008; 27:597-608. Epub 2008 Jan 10. [PubMed 18194506]

6. Fechner J, Ihmsen H, Hatterscheid D et al. Comparative pharmacokinetics and pharmacodynamics of the new propofol prodrug GPI 15715 and propofol emulsion. Anesthesiology. 2004; 101:626-39. [PubMed 15329587]

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