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Federal Register / Vol. 86, No. 87 / Friday, May 7, 2021 / Rules and Regulations
abuse when compared to d-MPH and similar potential for abuse when compared to phentermine. This evidence demonstrates that SDX is related in action and effect to the schedule IV substance phentermine, and can therefore be expected to have a similar potential for abuse.
2. Scientific Evidence of Its Pharmacological Effects, if Known SDX itself has no CNS activity and must be metabolized to d-MPH to exert its effect. As HHS notes, in vitro binding studies demonstrated that SDX does not interact with dopamine and norepinephrine transporters, which are the sites of action for d-MPH, a schedule II drug. Moreover, SDX does not bind to any other receptor systems that are associated with drugs of abuse.
In a human abuse potential HAP
study, therapeutic and supratherapeutic doses of SDX administered orally produced positive subjective responses such as Drug Liking and Drug High similar to those of phentermine and higher than placebo. In addition, abuserelated adverse events such as euphoric mood and hypervigilance occurred less frequently in SDX-treated subjects than in those treated with d-MPH. However, SDX-treated subjects reported more abuse-related adverse events than those treated with placebo. As concluded by HHS, results from preclinical and clinical studies indicate that SDX has abuse potential similar to phentermine, a schedule IV substance.
3. The State of Current Scientific Knowledge Regarding the Drug or Other Substance SDX is an NME. It is chemically known as 3-1S-1-carboxy-2hydroxyethyl-aminocarbonyl-12R-2-1R-2-methoxy-2-oxo-1phenylethyl-1-piperidinyl carbonyloxymethylpyridinium chloride. It is a white to off-white crystalline solid that is freely soluble in water at pH that was tested up to 6.8.
On March 2, 2021, FDA approved the NDA for AZSTARYS, a combination drug product containing d-MPH and SDX for the treatment of ADHD in patients six years of age or older. Thus, SDX has an accepted medical use in the United States. SDX will be marketed in combination with d-MPH SDX/d-MPH
as immediate-release capsules in three strengths of 28 mg/6 mg, 42 mg/9 mg, and 56 mg/12 mg.
4. Its History and Current Pattern of Abuse There is no information on the history and current pattern of abuse for SDX, since it has not been marketed, legally
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or illegally, in the United States. HHS
notes that SDX produces abuse-related signals, such as euphoric mood and hypervigilance, and abuse potential similar to that of schedule IV controlled substance phentermine. In March 2021, DEA searched the NFLIS database for SDX encounters. Consistent with the fact that SDX is an NME, this database had no records of encounters of SDX by law enforcement.
5. The Scope, Duration, and Significance of Abuse SDX is not marketed in the United States, legally or illegally. Thus, information on the scope, duration, and significance of abuse for SDX is lacking.
However, as stated by HHS, data from animal and human studies indicate that SDX has abuse potential similar to phentermine. Therefore, upon marketing, SDX scope of abuse is expected to be similar to phentermine.
6. What, if Any, Risk There Is to the Public Health The extent of abuse potential of a drug is an indication of its public health risk.
Data from preclinical and clinical studies showed that SDX has abuse potential similar to that of the schedule IV stimulant phentermine. Therefore, upon availability for marketing, SDX is likely to pose a public health risk to a degree similar to schedule IV
stimulants, such as phentermine.
7. Its Psychic or Physiological Dependence Liability As HHS notes, no animal studies were done to test physical dependence liability of SDX. A hallmark of physical dependence are withdrawal symptoms resulting from drug discontinuation. In clinical studies, there was no adverse events indicative of withdrawal from discontinuation of the SDX/d-MPH
combination treatment.
SDX produced positive subjective responses to ratings of Drug Liking and Drug High in a HAP study. The responses were significantly higher than the placebo and similar to phentermine, a schedule IV stimulant. HHS
concluded that SDX can produce psychic dependence to a similar extent as phentermine.
8. Whether the Substance Is an Immediate Precursor of a Substance Already Controlled Under the CSA
SDX is not an immediate precursor of any controlled substance, as defined by 21 U.S.C. 80223.
Conclusion: After considering the scientific and medical evaluation and scheduling recommendation provided by HHS, and its own eight-factor
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analysis, DEA has determined that these facts and all relevant data constitute substantial evidence of potential for abuse of SDX. As such, DEA hereby schedules SDX as a controlled substance under the CSA.
Determination of Appropriate Schedule The CSA lists the findings required to place a drug or other substance in any particular schedule I, II, III, IV, or V.
21 U.S.C. 812b. After consideration of the analysis and recommendation of the Assistant Secretary for Health of HHS
and review of all available data, the Acting Administrator of DEA, pursuant to 21 U.S.C. 812b4, finds that:
1. Serdexmethylphenidate has a low potential for abuse relative to the drugs or other substances in schedule III.
Receptor binding studies demonstrate that SDX does not bind to dopamine and norepinephrine transporters and other receptors typically associated with abuse potential. Upon oral administration, SDX is metabolized to d-MPH, a schedule II drug, in the large intestine and showed an abuse potential lower than that of d-MPH, but similar to that of phentermine, a schedule IV drug.
Results from an observational animal behavioral study demonstrate that lower doses of SDX 12 and 25 mg/kg did not produce any CNS effects and only the highest dose of SDX 50 mg/kg increased CNS activity. In a HAP study, SDX at the therapeutic and supratherapeutic doses produced positive subjective responses such as Drug Liking and Drug High similar to those of phentermine schedule IV and significantly higher than placebo.
Furthermore, data from other clinical studies show that SDX produced abuserelated adverse events, namely euphoric mood and hypervigilance. Because SDX
is similar to phentermine schedule IV
in its abuse potential, SDX has a lower potential for abuse relative to the drugs or other substances in schedule III.
2. Serdexmethylphenidate has a currently accepted medical use in the United States.
On March 2, 2021, FDA approved the NDA for AZSTARYS capsules, a combination drug product containing dMPH and SDX for the treatment of ADHD in patients six years of age or older. Thus, SDX has a currently accepted medical use for treatment in the United States.
3. Serdexmethylphenidate may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in schedule III.
There were no animal studies performed to evaluate physical dependence of SDX. In clinical studies,
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