CYPSEDO Injectable emulsion Ref.[116740] Active ingredients: Cipepofol

The anesthetic effects of CYPSEDO were assessed using the MOAA/S and BIS in a randomized, dose-escalation, open-label, two-way crossover clinical pharmacology trial that evaluated the pharmacodynamics and pharmacokinetics of cipepofol compared with propofol at different doses in healthy male subjects. An MOAA/S score of 0 indicates that the patient is unresponsive and score 5 indicates that the patient is fully alert; a BIS score of 0 indicates that there is no detectable brain activity, and a score of 100 indicates that the patient is fully conscious and alert. A total of 19 subjects were enrolled in the trial and were randomized to 1 of 3 treatment sequences. For the 0.4 mg/kg CYPSEDO dose (administered over 1 minute) in 6 subjects, the:

• MOAA/S score decreased after CYPSEDO administration, and all subjects reached a MOAA/S ≤1 within 2 minutes after dosing. The mean (standard deviation [SD]) time to complete alertness after dosing was 13.3 (6.2) minutes after dosing.
• The BIS decreased to the minimum after CYPSEDO administration with a mean (SD) BIS nadir of 42.5 (5.5) at median time of 2.3 minutes.

MOAA/S and BIS parameters in geriatric patients, patients with HI, and patients with RI were comparable to healthy adults [see Clinical Pharmacology (12.3)].

Cardiac Electrophysiology

At the recommended initial CYPSEDO dose for patients with ASA-PS I or II, <65 years old, and BMI ≤40 kg/m² of 0.4 mg/kg intravenously over 30 seconds, clinically significant QTc interval prolongation was not observed.

Pharmacokinetic parameters were evaluated in 48 healthy adult patients, who received a single intravenous bolus of CYPSEDO 0.4 mg/kg administered over 30 seconds. The mean (SD) venous maximum plasma concentration (C_max) of cipepofol (administered over 30 seconds) was 2,790 (1,890) ng/mL and mean (SD) area under the plasma concentration time curve from 0 to infinity (AUC_0-inf) was 256 (54.9) ng.h/mL. In dose ranging studies, pharmacokinetics were linear and dose proportional over the dose range of 0.128 to 0.81 mg/kg.

Distribution

Cipepofol has a large volume of distribution of 4.19±1.10 L/kg. Cipepofol is highly protein bound (approximately 99%) and protein binding was unaffected by mild or moderate RI or HI.

Elimination

After a single intravenous bolus of CYPSEDO 0.4 mg/kg, the mean (SD) clearance was 1.63 (0.357) L/h/kg, and the mean (SD) half-life was 1.81 (0.431) hours.

Metabolism

Cipepofol is extensively metabolized by UGT enzymes (predominantly UGT1A9) and CYP2B6, and to a minor extent, CYP1A2 and CYP2C19.

Following a single intravenous dose of 0.8 μCi/0.4 mg/kg [¹⁴C]-cipepofol (radiolabeled cipepofol), cipepofol represented approximately 1.1% of total plasma radioactivity, with the major metabolite M4, a pharmacologically inactive O-glucuronide metabolite, accounting for 71% of total plasma radioactivity.

Excretion

While cipepofol is not excreted in the urine, renal excretion is the primary route of elimination for the metabolites. In a mass balance study, approximately 85% of the administered cipepofol dose was excreted in urine, with glucuronide metabolites M4 and M5-1 accounting for 51.6% and 19.3% of the administered dose, respectively.

Specific Populations

Population pharmacokinetics analysis indicated that weight, sex, race, and age were covariates on CYPSEDO clearance or volume. Neither sex nor race had a clinically meaningful impact on cipepofol exposure.

Geriatric Patients

Cipepofol exposures following intravenous administration of a CYPSEDO 0.4 mg/kg dose were similar in adults 65 years of age and older and those less than 65 years of age, indicating that age did not have a significant effect on plasma cipepofol exposure. With regard to PD effects, adult patients 65 years of age or older who received a CYPSEDO dose of 0.3 mg/kg had similar pharmacodynamic (MOAA/S and BIS) results compared with adult patients less than 65 years of age who received a dose of 0.4 mg/kg [see Dosage and Administration (2.2) and Use in Specific Populations (8.5)].

Patients with Renal Impairment

In a clinical pharmacology study of CYPSEDO in patients with chronic mild and moderate RI and patients without RI, mean C_max was slightly decreased in those with worse renal function, but AUC_0-last and AUC_0-inf values showed no clear trend with worse renal function:

• Mild RI (i.e., estimated GFR [eGFR]: 60 to 89 mL/minute/1.73 m²): geometric mean AUC values were increased by approximately 12% to 13%, and C_max was decreased by approximately 32% compared with those without RI.
• Moderate RI (i.e., eGFR: 30 to 59 mL/minute/1.73 m²): geometric mean AUC values were similar, and C_max was decreased by approximately 19% compared with those without RI.
• Severe RI (i.e., eGFR: less than 30 mL/minute/1.73 m² with or without dialysis): pharmacokinetics was not assessed and is not known.

MOAA/S and BIS parameters were similar across patients with mild RI, moderate RI, and without RI groups [see Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

In a clinical pharmacology study, mean cipepofol C_max showed no clear trend when comparing patients with normal hepatic function and patients with mild HI (Child-Pugh A) or moderate HI (Child-Pugh B), while AUC_0-last and AUC_0-inf increased slightly with worse HI:

• Mild HI: geometric mean AUC values were increased by approximately 10% to 12%, and C_max was increased by 14% compared with those without HI.
• Moderate HI: geometric mean AUC values were increased by approximately 22% to 30% while C_max was not changed compared with those without HI.
• Severe HI: pharmacokinetics was not assessed and is not known.

Sedation assessed by MOAA/S and BIS nadir showed similar trends in patients with mild HI, moderate HI, and without HI, indicating that there were no effects of mild and moderate HI on sedation [see Use in Specific Populations (8.7)].

Patients with BMI >40 kg/m²

In population pharmacokinetics analyses, there was increased cipepofol exposure with increasing lean body weight. Specifically, simulated CYPSEDO doses of 0.2 mg/kg to 0.25 mg/kg in patients with BMI >40 kg/m² were predicted to have similar exposure to a dose of 0.4 mg/kg in patients with BMI ≤40 kg/m²; therefore, in Trials 1, 2, and 3 [see Clinical Studies (14)], patients with BMI >40 kg/m² received a lower CYPSEDO dose than those with a BMI ≤40 kg/m² [see Dosage and Administration (2.2) and Use in Specific Populations (8.8)].

Drug Interaction Studies

Clinical Studies

There was no significant pharmacokinetic/pharmacodynamic drug interaction of cipepofol with rifampicin (CYP2B6 inducer, UGT1A9 inducer), voriconazole (CYP2B6 inhibitor), mefenamic acid (UGT1A9 inhibitor), or divalproex.

In vitro Studies

Metabolizing enzymes:

Cipepofol inhibited CYP2B6 and CYP2C19 in vitro, while its major metabolite, M4, did not inhibit any CYP enzymes. Cipepofol also inhibited UGT1A9 metabolism in vitro. Based on the rapid decline in cipepofol concentrations following administration of a 0.4 mg/kg CYPSEDO dose, there are not anticipated to be any clinically relevant drug interactions affecting CYP2B6, CYP2C19, and UGT1A9 substrates.

Cipepofol and its major metabolite, M4, did not induce CYP1A2, CYP2B6, and CYP3A4 at clinically relevant concentrations.

Drug transporters:

Cipepofol and M4 are not substrates of P-gp, BCRP, OAT1, OCT2, MATE1, and MATE2K. Cipepofol was not a substrate of OAT3, OATP1BI, and OATP1B3, while M4 was possibly a substrate of these transporters. Cipepofol was not an inhibitor of P-gp, BCRP, OAT1, OAT3, OCT2, OATP1B1, OATP1B3, MATE1, and MATE2K. M4 was not an inhibitor of P-gp, BCRP, OCT2 and MATE2K, but at high concentrations showed inhibitory activity for OAT1, OAT3, OATP1B1, OATP1B3, and MATE1. Based on in vitro studies, cipepofol and M4 are not expected to show clinically relevant inhibition of any drug transporters.

Carcinogenesis

The carcinogenic potential of cipepofol has not been evaluated.

Mutagenesis

Cipepofol was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test). Cipepofol was non-clastogenic in the chromosome aberration study. In the in vivo mouse micronucleus study, cipepofol was non-genotoxic as it did not induce micronuclei formation in polychromatic erythrocytes in bone marrow.

Impairment of Fertility

Fertility in male or female rats was not affected after daily intravenous injections of cipepofol at doses up to 5 mg/kg (1.3 times the HID based on AUC) administered from 4 weeks prior to mating initiation until completion in males and 2 weeks prior to mating to Gestation Day 6 in females.

There was no evidence of local vascular irritation following single intravenous or repeated daily (7 days) intra-arterial dosing of cipepofol to rabbits. Minimal local irritation was observed in rabbits following repeated daily (7 days) subcutaneous dosing of cipepofol.

Effects on the Use of Anesthetic Drugs in Animals

Published studies in animals demonstrate that the use of anesthetic drugs during the period of rapid brain growth or synaptogenesis results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester through the first several months of life but may extend out to approximately 3 years of age in humans. In primates, exposure to 3 hours of an anesthetic regimen that produced a light surgical plane of anesthesia did not increase neuronal cell loss; however, anesthetic treatment regimens of 5 hours or longer increased neuronal cell loss. Data in rodents and in primates suggest that the neuronal and oligodendrocyte cell losses are associated with subtle but prolonged cognitive deficits in learning and memory [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1, 8.4)].

Efficacy of CYPSEDO for induction of general anesthesia in adults undergoing surgery was assessed in three randomized, double-blind, propofol-controlled multicenter Phase 3 trials (Trials 1, 2, and 3). These trials assessed efficacy in 1,079 adult patients aged 18 to 86 who underwent elective surgeries. Patients undergoing cardiac, neurosurgical, or emergency surgeries were not enrolled in these trials.

Dosages of CYPSEDO and propofol in these trials varied by age, BMI, and ASA-PS classification and included an initial dose plus a possible additional dose that was administered one minute later over 10 seconds, if needed, to achieve MOAA/S ≤1.

• CYPSEDO Dose(s): For adults with BMI ≤40 kg/m², total body weight was used to determine the CYPSEDO dose; for adults with BMI >40 kg/m², lean body weight was used to determine the CYPSEDO dose.
  • For adults <65 years of age, ASA-PS I or II, and BMI ≤40 kg/m²: CYPSEDO 0.4 mg/kg by slow intravenous injection over 30 ±5 seconds, and if needed, an additional 0.2 mg/kg intravenous dose.
  • For ≥65 years of age, ASA-PS I or II, and BMI ≤40 kg/m²: CYPSEDO 0.3 mg/kg by slow intravenous injection over 30 seconds (Trial 1) or CYPSEDO 0.2 to 0.3 mg/kg over 30 to 60 seconds (Trials 2 and 3), and if needed, an additional intravenous dose that was 50% of the initial dose.
  • For adults of any age, ASA-PS III, and BMI ≤40 kg/m², CYPSEDO 0.4 mg/kg by slow intravenous injection over 30 seconds (Trial 1) or CYPSEDO 0.2 to 0.3 mg/kg over 30 to 60 seconds (Trials 2 and 3), and if needed, an additional intravenous dose that was 50% of the initial dose.
  • For adults of any age, any ASA-PS classification, and BMI >40 kg/m²: CYPSEDO 0.4 mg/kg based on lean body weight by slow intravenous injection over 30 seconds, and if needed, an additional intravenous dose that was 50% of the initial dose.
• Propofol Injectable Emulsion Dose(s): Propofol injectable emulsion (referred to as propofol) 2 mg/kg by slow intravenous injection over 30 ±5 seconds, and if needed, followed by an additional 1 mg/kg dose by slow intravenous injection over 30 seconds administered one minute later. The propofol doses were reduced by 25% to 50% in adult patients with a BMI >40 kg/m² or age 65 or older in Trials 1, 2, and 3. In Trials 2 and 3, propofol doses were also reduced by 25% to 50% in patients classified as ASA-PS III.

Premedication

The premedication regimens differed across the trials:

• In Trial 1, patients received intravenous fentanyl 1 mcg/kg prior to study drug administration.
• In Trials 2 and 3, patients first received intravenous midazolam 0.04 mg/kg (up to maximum of 3 mg) 5 minutes (±30 seconds) prior to study drug administration, followed by intravenous fentanyl 1 mcg/kg, then study drug administration.

Efficacy Endpoints

Efficacy in all three trials was assessed based on the success rate of general anesthesia induction. Successful general anesthesia induction occurred when both of the following conditions were met:

1. Induction success (MOAA/S ≤1) after administration of the study drug, and

2. One or no additional dose required without use of a rescue drug for induction of anesthesia.

Comparative safety was assessed in these trials based on the proportion of patients with any injection site pain at time of drug administration on the numeric rating scale (NRS) ≥1 [see Adverse Reactions (6.1)].

Baseline Demographic and Important Disease Characteristics

Among the patients evaluated in Trials 1, 2, and 3, 61% were female, 80% were White, 16% were Black or African American, and 1% were Asian; 23% identified as Hispanic or Latino. In the three trials, 81% of the patients were ASA-PS I or II and 19% were ASA-PS III, and no patients were ASA-PS IV or higher. In the three trials, 92% had a BMI ≤40 kg/m².

Efficacy Results

In Trials 1, 2, and 3, the lower bound of the 95% confidence interval of the difference in success rate of anesthesia induction between CYPSEDO and propofol in adults undergoing surgery exceeded -8% (see Table 4). In these trials, CYPSEDO was shown to be noninferior to propofol in the induction of general anesthesia in adults undergoing surgery.

Table 4. Success Rate of Anesthesia Induction in Adults Undergoing Surgery (Trials 1, 2, and 3)^[1]:

CI = confidence interval
[1] Full Analysis Set.
[2] The non-inferiority margin was -8%.
[3] In Trial 1, patients received intravenous fentanyl 1 mcg/kg prior to study drug administration.
[4] In Trials 2 and 3, patients first received intravenous midazolam 0.04 mg/kg (up to maximum of 3 mg) 5 minutes (±30 seconds) prior to study drug administration, followed by intravenous fentanyl 1 mcg/kg, then study drug administration.
[5] Risk difference (CYPSEDO - Propofol Injectable Emulsion) and 95% CI were estimated by Farrington-Manning method.

The percentage of adult patients with a MOAA/S ≤1 who received the initial dose of study drug but did not require an additional dose of study drug or a rescue drug was:

• 79% (132/168) for those in the CYPSEDO group and 83% (69/83) for those in the propofol group in Trial 1 (intravenous fentanyl administration prior to CYPSEDO administration).
• 95% (528/555) for those in the CYPSEDO group and 99% (269/273) for those in the propofol group in pooled Trials 2 and 3 (intravenous midazolam and fentanyl administration prior to CYPSEDO administration).

Injection Site Pain Results

CYPSEDO-treated patients had a statistically significant lower frequency of injection site pain than propofol-treated patients [see Adverse Reactions (6.1)].

Prior to CYPSEDO administration, four adult patients across Trials 1, 2, and 3 received lidocaine (including 3 patients who received intravenous lidocaine and 1 patient who received lidocaine by an undetermined route of administration) and none reported injection site pain, and no adult patient in Trials 1, 2, and 3 received intravenous lidocaine prior to propofol administration. Excluding patients pre-treated with intravenous lidocaine from the secondary endpoint analysis did not affect the finding of lower frequency of injection site pain in CYPSEDO-treated patients compared to propofol-treated patients.