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Federal Register / Vol. 86, No. 138 / Thursday, July 22, 2021 / Proposed Rules
lotter on DSK11XQN23PROD with PROPOSALS1

action; therefore, the United States complies with this provision.
DEA notes that there are differences between the schedules of substances in the 1971 Convention and the CSA. The CSA has five schedules schedules IV
with specific criteria set forth for each schedule. Schedule I is the only possible schedule in which a drug or other substance may be placed if it has high potential for abuse and no currently accepted medical use in treatment in the United States. See 21
U.S.C. 812b. In contrast, the 1971
Convention has four schedules Schedules IIV but does not have specific criteria for each schedule. The 1971 Convention simply defines its four schedules, in Article 1, to mean the correspondingly numbered lists of psychotropic substances annexed to the Convention, and altered in accordance with Article 2.
Proposed Determination to Schedule Amineptine Pursuant to 21 U.S.C. 811b, DEA
gathered the necessary data on amineptine and, on August 12, 2008, submitted it to the Assistant Secretary for Health of HHS with a request for a scientific and medical evaluation of available information and a scheduling recommendation for amineptine. On November 8, 2011, HHS provided to DEA a written scientific and medical evaluation and scheduling recommendation entitled Basis for the Recommendation for Control of Amineptine in Schedule I of the Controlled Substances Act. In this recommendation, HHS presented its eight-factor analysis as required under 21 U.S.C. 811b and recommended that amineptine be added to schedule I of the CSA.
In response, DEA reviewed the scientific and medical evaluation and scheduling recommendation provided by HHS and all other relevant data and conducted its own eight-factor analysis pursuant to 21 U.S.C. 811c. Included below is a brief summary of each factor as analyzed by HHS and DEA, and as considered by DEA in the scheduling decision. Both DEA and HHS analyses are available in their entirety under Supporting and Related Material of the public docket for this rule at http
www.regulations.gov under docket number DEA371.
1. The Drugs Actual or Relative Potential for Abuse: As reported by HHS, the WHO 2003 report showed strong evidence of abuse in Europe and Asia, where amineptine was approved for use as an antidepressant. Additional HHS findings showed that due to reports of hepatotoxicity and abuse in
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Europe, Servier a French pharmaceutical company voluntarily discontinued the French marketing authorization in France and Spain for amineptine in 1999 HHS, 2011; 3 WHO, 2002 4. However, as documented by the WHO 2003 report, the medical use of amineptine and its abuse in developing countries still existed during 1990 to 2003. Clinical studies used between 100200 mg of amineptine Lachatre et al., 1989; 5 Sbarra et al., 1981 6;
however, case reports from various countries none in the United States due to its lack of approved medical use or known therapeutic application in the United States have reported hospitalizations due to amineptine abuse and overdose following the ingestion of 2,0004,300 mg and even up to 12 g daily. However, adverse effects at prescribed doses of amineptine were still observed see Factor 6.
Evidence shows that amineptine produces behavioral effects in humans and animals that are similar to amphetamine and cocaine both in schedule II. Pharmacological studies have demonstrated that amineptine has reinforcing effects as shown by the selfadministration test and has locomotor stimulant effects. Studies also have shown that amineptine increases extracellular concentrations of dopamine in the brain, particularly in the striatum and nucleus accumbens, which are structures constituting the reward pathway and are known to be involved in the abuse of drugs, including amphetamine and cocaine.
The above data indicate that amineptine has the potential for abuse similar to other CNS stimulants controlled under the CSA, such as cocaine and amphetamine.
2. Scientific Evidence of the Drugs Pharmacological Effects, if Known: As stated by HHS, amineptine increases dopamine levels by inducing the synaptosomal release and inhibition of dopamine re-uptake and, to a lesser extent, increasing norepinephrine levels, a mode of action mechanistically 3 Health and Human Services HHS 2011. Basis for the Recommendation for Control of Amineptine in Schedule I of the Controlled Substances Act.
4 WHOs Critical Review of Psychoactive Substances prepared for evaluation by the 33rd Meeting of the WHO Expert Committee on Drug Dependence held in September, in Annex, 2002.1
14.
5 Lachatre, G., Piva, C., Riche, C., Dumont, D., Defrance, R., Mocaer, E., Nicot, G. 1989. Singledose pharmacokinetics of amineptine and of its main metabolite in healthy young adults.
Fundamental and Clinical Pharmacology, 31:19
26.
6 Sbarra, C., Castelli, M. G., Noseda, A., Fanelli, R. 1981. Pharmacokinetics of amineptine in man.
European Journal of Drug Metabolism and Pharmacokinetics, 62, 123126.

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similar to the known schedule II CNS
stimulants amphetamine and cocaine.
Animal behavioral studies have shown that amineptine, in addition to its CNS
stimulant properties, has antidepressant, locomotor, and antinarcoleptic activities. Human behavioral studies have demonstrated that amineptine works similarly to other antidepressants, often with an earlier onset of therapeutic effects. Studies have shown that amineptine administration lowers depression rating scales in patients and results in a positive subjective quality of sleep and subsequent increase in attention and concentration upon waking.
3. The State of Current Scientific Knowledge Regarding the Drug or Other Substance: The chemical name of amineptine is 7-10,11-dihydro-5Hdibenzoa,dcyclohepten-5ylaminoheptanoic acid. It is a white, crystalline powder and is soluble in water and in methanol. Humans rapidly absorb amineptine after oral administration, with mean peak plasma concentrations of amineptine and its main metabolite occurring at 1 hour and 1.5 hours, respectively. Amineptine is metabolized in the liver and rapidly excreted and eliminated through the kidneys with mean half-lives of 0.8
hours for amineptine and 2.5 hours for its metabolite. In humans, 7075
percent of the administered dose of amineptine was excreted in the urine within 48 hours, with most of the elimination occurring within the first 12
hours.
Distribution of 14C-amineptine was also evaluated in the Macaca fascicularis monkey using whole body autoradiography. Results demonstrated high levels of radio-labeled amineptine in the liver and kidneys, with lower levels of activity in the blood, gastrointestinal tract and spleen. In the brain, radioactivity was observed in the cortex, putamen, caudate nucleus, globus pallidus, pulvinar, and geniculate bodies, with lower levels noted in the hippocampus, substantia nigra, and medulla.
4. Its History and Current Pattern of Abuse: As mentioned by HHS, there are numerous published reports of amineptine abuse, including 186 cases of abuse between 1978 and 1988
reported to the Regional Centers of Pharmacovigilance and the Laboratory Eutherapie in France, and 65 cases of abuse between 1990 and 1998 appearing in the Observation of Illegal Drugs and Misuse of Psychotropic Medications database. Notably, amineptine has not been approved for medical use in the United States nor is there any
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