FDA Considers WHO Scheduling Change for 17 Drug Substances

Regulatory NewsRegulatory News | 11 August 2017 |  By 

The US Food and Drug Administration (FDA) on Friday sought public comments to help prepare a response to the World Health Organization (WHO) regarding the abuse liability and diversion of 17 drug substances, many of which are opioids and similar to fentanyl. WHO will consider whether to recommend certain international restrictions be placed on the drugs.


Section 201 of the Controlled Substances Act (CSA) provides that when WHO notifies the US under Article 2 of the Psychotropic Convention that it has information that may justify adding a drug or other substances to one of the schedules of the Psychotropic Convention, transferring a drug or substance from one schedule to another or deleting it from the schedules, the Secretary of State must transmit the notice to the Secretary of Health and Human Services.

The HHS Secretary must then publish the notice in the Federal Register and provide opportunity for comments in preparation of the scientific and medical evaluations.

According to WHO, replies must reach the Secretariat by 30 September 2017, though HHS says in Friday’s notice that it "will not now make any recommendations to WHO regarding whether any of these drugs should be subjected to international controls. Instead, HHS will defer such consideration until WHO has made official recommendations to the Commission on Narcotic Drugs, which are expected to be made in early 2018. Any HHS position regarding international control of these drug substances will be preceded by another Federal Register notice soliciting public comments."


The notice provides lots of information on the 17 substances under consideration including a list and descriptions:

  • Ocfentanil, which is not approved in the US for medical uses and not a controlled substance, is a synthetic opioid structurally related to fentanyl. Reported risks include development of opioid use disorder, overdose and fatal overdose.
  • Furanyl fentanyl (Fu-F) is also a synthetic opioid with no FDA-approved use and was made a Schedule I drug. It’s an analog of fentanyl and the notice says, "Evidence suggests that the pattern of abuse of fentanyl analogues, including furanyl fentanyl, parallels that of heroin and prescription opioid analgesics."
  • Acryloylfentanyl (Acrylfentanyl), which belongs to the 4-anilidopiperidine class of synthetic opioids and is similar in structure to fentanyl, the notice says. The Drug Enforcement Agency (DEA) last month issued a temporary order to temporarily schedule acryloylfentanyl, its isomers, esters, ethers, salts and salts of isomers, esters, and ethers, into Schedule I pursuant to the temporary scheduling provisions of the CSA.
  • Carfentanil, also known as 4-carbomethoxyfentanyl, is an extremely potent synthetic opioid that is similar in structure to and about 100 times more potent than fentanyl as an analgesic, the notice says. "At one time legitimately produced, carfentanil is no longer manufactured, marketed, or used in the United States; it is approved by FDA for use under restricted conditions by veterinarians as a immobilizing agent for certain large animals."
  • 4-fluoroisobutyrfentanyl, a clandestinely produced synthetic opioid that is also an analog of fentanyl, has not been approved for medical use in the US, and the DEA issued a temporary order to temporarily schedule it, its isomers, esters, ethers, salts and salts of isomers, esters and ethers, into Schedule I of the CSA.
  • Tetrahydrofuranylfentanyl (THF-F) is also an analog of fentanyl not approved for medical use or controlled in the United States under the CSA.
  • 4-Fluoroamphetamine (4-FA) is a psychoactive substance of the phenethylamine and substituted amphetamine chemical classes and produces stimulant effects. WHO reports that 4- FA is clandestinely produced and its use is associated with fatal and non-fatal intoxications.
  • AB-PINACA is a clandestinely produced synthetic cannabinoid agonist approximately 1.5 times as potent as delta-9-tetrahydrocannabinol, one of the main psychoactive components of cannabis. It has not been approved for medical use in the US and the DEA published a Notice of Proposed Rulemaking to permanently control it as a Schedule I substance under the CSA.
  • AB-CHMINACA is a clandestinely produced synthetic cannabinoid agonist that is about 16 times more potent than delta-9-tetrahydrocannabinol, the notice says. The DEA has published a Notice of Proposed Rulemaking to permanently control ABCHMINACA as a Schedule I substance.
  • 5F-PB-22 is a synthetic cannabinoid agonist with similar effects to delta-9- tetrahydrocannabinol. According to the WHO, 5F-PB-22 has been associated with 11 fatal intoxications. The DEA issued a final rule to permanently place 5F-PB- 22 into Schedule I.
  • UR-144 is a clandestinely produced synthetic cannabinoid agonist that the DEA issued a final rule to permanently schedule into Schedule I.
  • 5F-ADB is a clandestinely produced synthetic cannabinoid agonist that has been identified in overdose and/or cases involving death attributed to their abuse. The DEA issued a temporary scheduling order to temporarily schedule 5F-ADB, its isomers, esters, ethers, salts and salts of isomers, esters, and ethers into Schedule I.
  • Etizolam is part of a class of substances known as benzodiazepines and is currently prescribed in some countries to treat generalized anxiety disorder with depressive symptoms, but is not approved for medical use or controlled in the US under the CSA, the notice says. WHO reported that non-fatal intoxications that include cases of driving under the influence have been linked to etizolam.
  • Pregabalin is an anticonvulsant used to treat pain generated from the nervous system. The notice says it is available as an oral capsule and solution and was approved for medical use in the US for the management of neuropathic pain associated with diabetic peripheral neuropathy, post-herpetic neuralgia, and adjunctive therapy for partial onset seizures, fibromyalgia and neuropathic pain associated with spinal cord injury. Reports indicate that patients are "self-administering higher than recommended doses to achieve euphoria, especially patients who have a history of substance abuse, particularly opioids, and psychiatric illness."  While effects of excessively high doses are generally non-lethal, gabapentinoids such as pregabalin are "increasingly being identified in post-mortem toxicology analyses," the notice says. Pregabalin is a Schedule V controlled substance.
  • Tramadol is an opioid analgesic first approved for marketing in the US in 1995 and is available as immediate-release, extended-release and combination products for the treatment of moderate to moderately severe pain. In 2014, the DEA published a final rule controlling tramadol as a Schedule IV substance.
  • Cannabidiol (CBD) is one of the active cannabinoids identified in cannabis, and in the US, CBD-containing products are in human clinical testing in three therapeutic areas, but no such products are approved by FDA, the notice says. CBD is a Schedule I controlled substance.
  • Ketamine is classified as a rapid-acting general anesthetic agent used for short diagnostic and surgical procedures that do not require skeletal muscle relaxation. It is marketed in the US as a solution for injection and is controlled in Schedule III of the CSA.

International Drug Scheduling; Convention on Psychotropic Substances; Single Convention on Narcotic Drugs; Ocfentanil, Carfentanil, Pregabalin, Tramadol, Cannabidiol, Ketamine, and Eleven Other Substances; Request for Comments


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