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

5.1 Hypersensitivity Reactions Including Anaphylactic Reactions

The use of CYPSEDO is contraindicated in patients with known hypersensitivity to CYPSEDO or any of its inactive ingredients and in patients with a history of anaphylaxis to eggs, egg products, soybeans, or soy products.

• Anaphylactic reactions, including life-threatening cases, have occurred after the use of CYPSEDO; clinical features of anaphylaxis, including hypotension, bronchospasm, and erythema can occur following CYPSEDO administration.
• Patients with a history of anaphylaxis to eggs, egg products, soybeans, or soy products may be at higher risk of anaphylaxis to CYPSEDO.

5.2 Risks of Microbial Contamination

Always maintain strict aseptic technique during handling of CYPSEDO. Prior to CYPSEDO use, disinfect the rubber stopper of the vial with 70% isopropyl alcohol spray or an alcohol swab.

Do not use a CYPSEDO vial in more than one person. Discard the opened/pierced or used vials and other reservoirs (such as syringes containing CYPSEDO) within 12 hours.

Although CYPSEDO contains edetate disodium to inhibit the growth rate of microorganisms for up to 12 hours, CYPSEDO can still support the growth of microorganisms because it is a preservative-free fat emulsion, which is conducive to microbial growth.

5.3 Risks of Cardiac and Pulmonary Adverse Reactions

During the use of CYPSEDO, continuously monitor patients for early signs of bradycardia, decreased blood pressure, respiratory depression, or decreased oxygen saturation, and intervene to correct cardiac and pulmonary adverse reactions in a timely manner if any of these occur.

Reports of bradycardia and cardiac arrest have occurred after CYPSEDO administration.

5.4 Risks of Neurotoxicity with Unapproved Use in Younger Pediatric Patients

The safety and effectiveness of CYPSEDO in pediatric patients for induction of general anesthesia have not been established, and CYPSEDO is not approved for use in pediatric patients.

Published animal studies demonstrated that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increased neuronal apoptosis in the developing brain and resulted in long-term cognitive deficits when used for longer than three hours. The clinical significance of these findings is not clear. However, based on the available data, the window of vulnerability to these changes in young pediatric patients is believed to correlate with exposures of the anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans [see Use in Specific Populations (8.4) and Nonclinical Toxicology (13.2)].

Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to such anesthetic drugs early in life and may result in adverse cognitive or behavioral effects. These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness.

Anesthetic and sedation drugs are a necessary part of the care of children needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other. Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

The following serious or otherwise important adverse reactions are discussed elsewhere in the labeling:

• Anaphylactic reactions [see Warnings and Precautions (5.1)]
• Risks of microbial contamination [see Warnings and Precautions (5.2)]
• Risks of cardiac and pulmonary adverse reactions [see Warnings and Precautions (5.3)]
• Risks of neurotoxicity with unapproved use in younger pediatric patients [see Warnings and Precautions (5.4)]

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 reflect the rates observed in practice.

The safety of CYPSEDO for the induction of general anesthesia in adults undergoing surgery is supported by three double-blind, controlled clinical trials in adult patients undergoing general anesthesia (Trials 1, 2, and 3) [see Clinical Studies (14)]. The trials included 1,080 patients aged 18 to 86 (723 patients treated with CYPSEDO and 357 patients treated with propofol injectable emulsion, referred to as propofol). Patients with a severe or uncontrolled cardiac, respiratory, neurological, or psychiatric disorder or undergoing emergency surgery were excluded from these clinical trials.

Table 2 summarizes the most common adverse reactions (≥2% of CYPSEDO-treated patients) that occurred in adult patients who underwent general anesthesia in Trials 1, 2, and 3.

Table 2. Most Common Adverse Reactions (≥2% of CYPSEDO-Treated Patients) That Occurred in Adults Who Underwent Induction of General Anesthesia in Trials 1, 2, and 3:

Perioperative Myoclonia

Perioperative myoclonia (e.g., myoclonus, involuntary muscle contractions, muscle twitching) occurred in CYPSEDO-treated patients.

Injection Site Pain

In Trials 1, 2, and 3, 17-19% of CYPSEDO-treated patients developed injection site pain, a significantly lower percentage compared to propofol-treated patients (see Table 3) [see Clinical Studies (14)].

Table 3. Number and Proportion of Patients with Injection Site Pain on the Numeric Rating Scale ≥1 at the Time of Drug Administration in Adults Undergoing Surgery (Trials 1, 2, and 3)^[1,2]:

CI = confidence interval; CMH = Cochran-Mantel-Haenszel; NRS = numeric rating scale
[1] Full analysis set
[2] Prior to receiving CYPSEDO, four 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). Prior to receiving propofol, no patients received intravenous lidocaine in Trials 1, 2, or 3.
[3] The p-value for between group differences was calculated using the CMH test and the stratification factors American Society of Anesthesiologists physical status (I-II and III), age (<65 and ≥65 years), and body mass index (<35 and ≥35 kg/m²) in the trial randomization.

The following adverse reactions have been identified during post-approval use of CYPSEDO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Anaphylactic shock [see Warnings and Precautions (5.1)].
• Phlebitis

Opioids and Other Sedatives

The concomitant use of CYPSEDO and opioids or other sedatives (e.g., benzodiazepines, barbiturates, chloral hydrate, droperidol) may result in more pronounced decreases in systolic and diastolic blood pressure and cardiac output.

Risk Summary

The use of CYPSEDO in pregnant patients should only be considered if the potential benefit to the mother and fetus outweighs its risks. Pregnant patients should be informed of possible hazards to the mother and fetus.

In an animal reproductive study, increased resorptions, increased pre- and post-implantation loss, decreased live fetuses, and decreased uterus weights, were observed with intravenous administration of cipepofol to rats prior to mating through early gestation at clinically relevant exposures. The pharmacological effect (anesthesia) of cipepofol on the maternal rats is probably responsible for these adverse effects.

Published studies in pregnant primates demonstrated that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity (for longer than three hours) during the period of peak brain development increased neuronal apoptosis in the developing brain of the primate offspring. There are no data on exposures in pregnant primates corresponding to periods prior to the third trimester in humans. The clinical significance of these nonclinical findings is not known, and the benefits of appropriate general anesthesia in pregnant patients who require general anesthesia should be balanced with the potential risks suggested by the nonclinical data.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data: In the fertility and early embryonic development toxicity study, female rats were administered daily intravenous injections of cipepofol 2 weeks before mating to Gestation Day 6 at doses of 1.2, 2.5, and 5 mg/kg (0.2, 0.5, and 1.3 times the human induction dose (HID) of 0.6 mg/kg based on area under the curve [AUC]). Increased resorptions and post-implantation loss along with decreased live fetuses and gravid uterus weights were observed at 0.5 times the HID based on AUC while an increase in pre-implantation loss was observed at 1.3 times the HID based on AUC.

In embryo-fetal developmental toxicity studies, pregnant rats were administered daily intravenous injections of cipepofol at doses of 1.2, 2.5, and 5 mg/kg (0.3, 0.8, and 1.7 times the HID of 0.6 mg/kg based on AUC), and female rabbits were administered daily intravenous injections of cipepofol at doses of 0.75, 1.5, and 3 mg/kg (0.02, 0.06, and 0.2 times the HID based on AUC) during the period of organogenesis. Mortalities were observed in maternal high dose animals due to the pharmacological anesthetic effect but cipepofol did not cause any fetal malformations in rats or rabbits.

In the pre- and postnatal development toxicity study, pregnant rats administered daily intravenous injections of cipepofol at doses of 1.2, 2.5, and 5 mg/kg (0.3, 0.8, and 1.7 times the HID based on AUC) from Gestation Day 6 to Lactation Day 21 resulted in no adverse developmental effects nor behavioral alterations (i.e., learning and memory as tested in a Morris water maze) in the offspring. Mortality was observed in a high dose female (1.7 times the HID based on AUC) due to the pharmacological anesthetic action of cipepofol.

In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus. In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring. With respect to brain development, this time period corresponds to the third trimester of gestation in the human. The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits [see Warnings and Precautions (5.4), Use in Specific Populations (8.4), and Nonclinical Toxicology (13.2)].

Risk Summary

There are no data on the presence of cipepofol in human milk, the effects on a breastfed infant, or the effects on milk production. Cipepofol is present in animal milk (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for CYPSEDO and any potential adverse effects on the breastfed child from CYPSEDO or from the underlying maternal condition.

Data

Daily intravenous injections of cipepofol to female rats at doses up to 5 mg/kg (1.7 times the HID of 0.6 mg/kg based on AUC) from Gestation Day 6 to Lactation Day 21 resulted in cipepofol exposure in milk up to 40 times the plasma levels in lactating females 30 minutes to 1 hour after administration, while it was not detected in nursing rat pups.

The safety and effectiveness of CYPSEDO have not been established in pediatric patients and CYPSEDO use is not recommended for use in younger pediatric patients because of the risks of neurotoxicity [see Warnings and Precautions (5.4) and Nonclinical Toxicology (13.2)].

Risks of Unapproved Use of CYPSEDO in Younger Pediatric Patients

Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as CYPSEDO, that either block NMDA receptors or potentiate the activity of GABA 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 comparison across species, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation 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 ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss; however, treatment of 5 hours or longer of isoflurane increased neuronal cell loss. Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory.

In Trials 1, 2, and 3, 22% (241/1080) of the adult patients were 65 years of age or older, including 22% (161/723) of CYPSEDO-treated patients. In these trials, 5% (57/1,080) of the adult patients were 75 years of age or older, including 5% (37/723) of CYPSEDO-treated patients. In all three trials, the CYPSEDO dose for patients 65 years or older was an initial dose of 0.3 mg/kg and an additional dose of 0.15 mg/kg if needed. The duration over which the initial dose was administered in Trial 1 was 30 seconds but in Trials 2 and 3 was 30 to 60 seconds [see Dosage and Administration (2.2)].

Safety Evaluation in Geriatric Patients

No overall differences in safety of CYPSEDO were observed between patients 65 years of age and older and adult patients less than 65 years of age.

Efficacy Evaluation in Geriatric Patients

• In Trials 1, 2, and 3, patients 65 years of age and older (who received an initial CYPSEDO dose of 0.3 mg/kg and a possible second dose of 0.15 mg/kg) had numerically similar rates of successful induction of anesthesia as adult patients less than 65 years of age (who received a larger initial CYPSEDO dose of 0.4 mg/kg with a possible second dose of 0.2 mg/kg).
• In the CYPSEDO group, in:
  • Trial 1 (intravenous fentanyl administration prior to CYPSEDO administration), 26% (7/27) of adult patients 65 years of age or older required the additional CYPSEDO dose or rescue for successful induction of anesthesia, compared to 21% (29/141) of adult patients less than 65 years of age.
  • Pooled Trials 2 and 3 (intravenous midazolam and fentanyl administration prior to CYPSEDO administration), 4% (6/134) of adult patients 65 years of age or older required the additional CYPSEDO dose or rescue for successful induction of anesthesia, compared to 5% (21/421) of adult patients less than 65 years of age.

Pharmacokinetics and Pharmacodynamics in Geriatric Patients

No clinically meaningful differences in the pharmacokinetics of cipepofol were observed in patients 65 years of age or older (n=8) who received an induction dose of 0.4 mg/kg compared to adult patients less than 65 years of age (n=8) who received an induction dose of 0.4 mg/kg in a Phase 1 clinical study.

Patients 65 years of age or older who received a CYPSEDO dose of 0.3 mg/kg had similar pharmacodynamics (Modified Observer's Assessment for Alertness and Sedation scale (MOAA/S) and bispectral index (BIS)) results compared with adult patients less than 65 years of age who received a dose of 0.4 mg/kg [see Clinical Pharmacology (12.2, 12.3)].

There are no clinical study data regarding the use of CYPSEDO in patients with severe renal impairment (RI). Use of CYPSEDO in patients with severe RI is not recommended.

There were no clinically significant differences in the pharmacokinetics or pharmacodynamics (MOAA/SBIS) of cipepofol in adult patients with chronic mild to moderate RI compared to adults without RI. The recommended dose of CYPSEDO in patients with mild to moderate RI is the same as that for patients without RI.

The effects of acute renal failure on the pharmacokinetics of cipepofol have not been studied.

There are no clinical study data regarding the use of CYPSEDO in patients with severe hepatic impairment (HI). Use of CYPSEDO in patients with severe HI is not recommended.

There were no clinically significant differences in pharmacokinetics or pharmacodynamics (MOAA/S and BIS) of cipepofol in patients with chronic mild to moderate HI compared to adults without HI. The recommended dose of CYPSEDO in patients with mild to moderate HI is the same as that for patients without HI.

8.8 Patients with BMI >40 kg/m²

The recommended CYPSEDO dose in adult patients with BMI >40 kg/m² is lower than the recommended dose in adult patients with a BMI ≤40 kg/m² [see Dosage and Administration (2.2)].

In a population pharmacokinetic analysis, compared to those with a BMI ≤40 kg/m², there was increased cipepofol exposure in patients with a BMI >40 kg/m² which may increase the risk of CYPSEDO-associated adverse reactions.

Safety Evaluation by BMI Status

In Trials 1, 2, and 3, with the use of lower dose(s) in adult patients with a BMI >40 kg/m², the safety profile of CYPSEDO was similar to adult patients with BMI ≤40 kg/m² who received a higher dose(s).

Efficacy Evaluation by BMI Status

• In Trials 1, 2, and 3, adult patients with BMI >40 kg/m² (who received an initial CYPSEDO dose of 0.2 mg/kg to 0.25 mg/kg with a possible second dose 50% of the initial dose) had numerically similar rates of successful induction of anesthesia as adult patients with a BMI ≤40 kg/m² (who received a larger initial CYPSEDO dose of 0.4 mg/kg with a possible second dose of 0.2 mg/kg).
• In the CYPSEDO group in:
  • Trial 1 (intravenous fentanyl administration prior to CYPSEDO administration), 50% (6/12) of adult patients BMI >40 kg/m² required the additional CYPSEDO dose or rescue for successful induction of anesthesia, compared to 19% (30/156) of adult patients BMI ≤40 kg/m².
  • Pooled Trials 2 and 3 (intravenous midazolam and fentanyl administration prior to CYPSEDO administration), 27% (13/49) of adult patients BMI >40 kg/m² required the additional CYPSEDO dose or rescue for successful induction of anesthesia, compared to 3% (14/506) of adult patients BMI ≤40 kg/m².

8.9 Patients with ASA-PS Classification III or Higher

In Trials 1, 2, and 3, 19% (203/1,080) of adult patients with ASA-PS III, including 19% (140/723) of adult patients treated with CYPSEDO, were enrolled [see Clinical Studies (14)]. Of the CYPSEDO-treated patients with ASA-PS III, 69% (97/140) had a BMI ≤40 kg/m². The recommended CYPSEDO dose and rate of administration in patients with ASA-PS III are lower than for those with ASA-PS I or II [see Dosage and Administration (2.2)].

Safety Evaluation by ASA-PS Classification (ASA-PS III vs. ASA-PS I or II)

In Trials 1, 2, and 3, a lower CYPSEDO dose was used for patients with ASA-PS III compared to those with an ASA-PS I or II. In Trials 2 and 3 the duration of CYPSEDO injection was 30-60 seconds for patients with ASA-PS III compared to 30 seconds for patients with ASA-PS I or II. In Trials 1, 2, and 3, the safety profile of a lower CYPSEDO dose in patients with ASA-PS III was similar to that of patients with ASA-PS I or II with a higher dose.

Efficacy Evaluation by ASA-PS Classification (ASA-PS III vs. ASA-PS I or II)

• In Trials 1, 2, and 3, adult patients with ASA-PS III (who received an initial CYPSEDO dose of 0.3 mg/kg with a possible second dose of 0.15 mg/kg) had numerically similar rates of successful induction of anesthesia as adult patients with ASA-PS I or II (who received a larger initial CYPSEDO dose of 0.4 mg/kg with a possible second dose of 0.2 mg/kg)
• In the CYPSEDO group in:
  • Trial 1 (intravenous fentanyl administration prior to CYPSEDO administration), 25% (3/12) of adult patients with ASA-PS III required the additional CYPSEDO dose or rescue for successful induction of anesthesia, compared to 21% (33/156) of adult patients with ASA-PS I or II.
  • Pooled Trials 2 and 3 (intravenous midazolam and fentanyl administration prior to CYPSEDO administration), 11% (14/128) of adult patients with ASA III required the additional CYPSEDO dose or rescue for successful induction of anesthesia, compared to 3% (13/427) of adult patients with ASA-PS I or II.

Patients with ASA-PS Classification IV or Higher

No adult patients with ASA-PS IV or higher were enrolled. The safety of the use of CYPSEDO in anesthesia induction in adult patients with ASA-PS IV or higher has not been evaluated. The recommended dosage of CYPSEDO for induction of general anesthesia in adults undergoing surgery with ASA-PS IV or higher has not been established.

CYPSEDO contains cipepofol. (Controlled substance schedule to be determined after review by the Drug Enforcement Administration).

CYPSEDO is a central nervous system (CNS) depressant and has a potential for abuse. Abuse of CYPSEDO may lead to substance use disorder, including addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

CYPSEDO can also be misused. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Misuse, like abuse, is often associated with higher doses and/or more frequent use of the drug, which may lead to adverse reactions similar to those seen in the context of abuse and substance use disorder.

In a human abuse potential crossover study conducted in individuals with a history of recreational CNS depressant use, subjective effects of single intravenous bolus injections of CYPSEDO 0.175 mg/kg and 0.2 mg/kg were compared to subjective effects of single intravenous bolus injections of propofol 0.725 mg/kg and placebo.

• On the primary outcome measure of "drug liking", there were no statistically significant differences between CYPSEDO 0.175 mg/kg and 0.2 mg/kg doses and propofol.
• CYPSEDO 0.175 mg/kg and 0.2 mg/kg doses produced mean responses similar to propofol on the secondary measures of "take drug again", "overall drug liking", and "drug high".
• Mean drowsiness/alertness scores were similar for CYPSEDO 0.175 mg/kg and 0.2 mg/kg doses and propofol and were lowest (increased drowsiness) for both CYPSEDO doses and propofol at the first measured timepoint, which was 15 minutes post-dose.

There are reports of abuse of other intravenous emulsion general anesthetics for recreational and other nonmedical purposes, which have resulted in fatalities and other injuries. Instances of self-administration of intravenous emulsion general anesthetics by health care providers have also been reported, which have resulted in fatalities and other injuries. To mitigate these risks, store and manage inventories of CYPSEDO, including restriction of access and accounting procedures as appropriate to the clinical setting.

Although CYPSEDO was not systematically evaluated for physical dependence during clinical development and is likely not a risk relevant to induction of general anesthesia in adults undergoing surgery (its approved use), there are reports of withdrawal symptoms associated with discontinuation of other intravenous emulsion general anesthetics following prolonged use. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.