Cipepofol

The use of cipepofol 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.

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. 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 cipepofol and any potential adverse effects on the breastfed child from cipepofol or from the underlying maternal condition.

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.

Clinical Trials Experience

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 cipepofol 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). The trials included 1,080 patients aged 18 to 86 (723 patients treated with cipepofol 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 1 summarizes the most common adverse reactions (≥2% of cipepofol-treated patients) that occurred in adult patients who underwent general anesthesia in Trials 1, 2, and 3.

Table 1. Most Common Adverse Reactions (≥2% of Cipepofol-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 cipepofol-treated patients.

Injection Site Pain

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

Table 2. 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 cipepofol, 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.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of cipepofol. 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
• Phlebitis