A new surgical anesthetic becomes a controlled substance on Thursday, and the drug the government measures it against has been waiting on a 2010 recommendation ever since

The Drug Enforcement Administration has put a new surgical anesthetic into Schedule IV.

Cipepofol, which the Food and Drug Administration approved on 29 May under the brand name Cypsedo for inducing general anesthesia in adults undergoing surgery, becomes a controlled substance on the day the rule publishes. The filed text carries that date only as a bracketed instruction, and the stamp at the foot of the document gives it as 27 August. The drug takes DEA code 2139 and enters the depressants list as 21 CFR 1308.14(c)(11), which moves the fifty paragraphs below it down one place each.

It is an interim final rule. Congress requires that. Under 21 U.S.C. 811(j), added by the Improving Regulatory Transparency for New Medical Therapies Act, DEA has 90 days to schedule certain newly approved drugs, and the statute makes the rule immediately effective without any showing of good cause. Comments and hearing requests run 30 days from publication.

Eight factors, one comparator

DEA received the Health and Human Services evaluation on 6 May, under the title Basis for the Recommendation to Control Cipepofol in Schedule IV of the Controlled Substances Act, and then ran its own eight-factor review.

Propofol appears in almost every one of the eight. The two drugs work the same way on the GABA-A receptor. Rats trained to self-administer propofol kept pressing the lever when cipepofol was substituted for it. In the human abuse potential study, 42 participants took part in a four-way crossover with propofol as the active control, 40 completed it, and both active drugs scored higher than placebo while participants liked them equally. On dependence, on withdrawal, on public health risk and on the statutory findings themselves, the answer each time is that cipepofol resembles propofol.

Propofol is not a controlled substance.

The rule half says so. Factor 1 describes propofol as having "proposed schedule IV status". Factor 4 refers to "the recommendation made in 2010 to place propofol in schedule IV". Factor 5 calls it "a substance recommended for schedule IV designation". Then finding (1) of the Determination, several pages later, prints "propofol (schedule IV)" with no qualification at all.

The regulation itself settles which of those is right. Part 1308 as it stood on 24 August lists fospropofol, the prodrug, at (c)(27) with code 2138. Propofol is not listed anywhere in it. So the analogue approved this May arrives in the schedule inside 90 days on the strength of a comparison to a drug whose own recommendation is sixteen years old and was never completed, and the two finish with consecutive code numbers, 2138 and 2139, without the parent compound ever turning up.

DEA gives no explanation for the gap, and none is offered here.

What the abuse record holds

Nothing. That is the odd part of the file.

Cipepofol has been marketed exclusively in China since 2021. HHS estimates, from post-market data in the sponsor's own submission, that 14.5 million patients there have received it, with no reports of abuse or misuse in surveillance. DEA queried its National Forensic Laboratory Information System on 11 May and found no law enforcement encounter anywhere in the United States. Poison centre and emergency department surveillance turned up nothing either.

The rule is candid about why. The drug has never been sold here, so there is nothing to find, and the finding of abuse potential rests on the animal work, the human liking study and the resemblance to propofol rather than on any observed harm. HHS records one instance of depressed mood among cipepofol subjects in the dose-selection phase and one oversedation event in the treatment phase. Dizziness was the most common central nervous system effect, at 4 percent of the therapeutic cipepofol group against 15 percent for propofol.

The handling rules

The product is a 2.5 mg/mL oil-in-water emulsion in 20 mL single-use vials, and from the publication date it may only be manufactured, distributed, imported, exported, dispensed or researched by a DEA registrant. Anyone who does not want a registration, or cannot get one, has to surrender what they hold or hand it to somebody who is registered, with disposal under 21 CFR part 1317.

Storage falls under the schedule III-V security rules at 21 CFR 1301.71 to 1301.77, and non-practitioners pick up the employee screening requirements as well. Registrants take an initial inventory on the day they first handle a controlled substance and another every two years after that.

Four separate paragraphs carve patients out. A person holding cipepofol on a lawful prescription is not caught by the registration, security or inventory rules.

DEA has determined that the rule is not significant for the purposes of Executive Order 12866 and it received a waiver under Executive Order 14192. The Regulatory Flexibility Act does not apply, because no proposed rule was required in the first place. It is not a major rule under the Congressional Review Act, though a copy goes to both Houses and to the Comptroller General.