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Lusedra

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Lusedra

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 g/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)

Pharmacokinetic and Pharmacodynamic Profiles after
  a 10-mg/kg Bolus Dose of LUSEDRA (fospropofol disodium injection)  - Illustration

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

Percentage of Patients at Each MOAA/S Score Over
  Time - Illustration

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

Last reviewed on RxList: 2/10/2010
This monograph has been modified to include the generic and brand name in many instances.

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