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Federal Register / Vol. 86, No. 211 / Thursday, November 4, 2021 / Proposed Rules
United States, the Nuclear Regulatory Commission NRC, the Occupational Safety and Health Administration, the Environmental Protection Agency, the Department of Transportation, and state legislation regulate the production, handling, transportation, and disposal of radiopharmaceuticals, all of which limit the trade to licensed radiopharmacies with a valid prescription.5 18FFP-CIT and any 18FFP-CIT-containing products will be subject to oversight by such agencies.
HHS notes that with the manufacturing limits and current restrictions regarding distribution, handling and disposal will limit the potential for diversion of 18FFP-CIT
from legitimate drug channels.
c. Whether individuals are taking the drug or drugs containing such a substance on their own initiative rather than on the basis of medical advice from a practitioner licensed by law to administer such drugs in the course of his professional practice.
There has been no demonstrated diversion of 18FFP-CIT nor published case reports or epidemiological data indicating that individuals are using 18FFP-CIT-containing products on their own initiative rather than on the basis of medical advice from a practitioner licensed by law to administer such substances. Due to the radioactive properties, 18FFP-CIT will not be administered by the patient or be available for self-administration by patients.
d. Whether the drug or drugs containing such a substance are new drugs so related in their action to a substance already listed as having a potential for abuse to make it likely that it will have the same potentiality for abuse as such drugs, thus making it reasonable to assume that there may be significant diversions from legitimate channels, significant use contrary to or without medical advice, or that they have a substantial capability of creating hazards to the health of the user or to the safety of the community.
As noted above, 18FFP-CIT is chemically and pharmacologically similar to 123Iioflupane. A formulation containing 18FFP-CIT, similar to 123Iioflupane, that is intended for diagnostic purposes, would contain the API in amounts too low than what is feasible for eliciting a central nervous system CNS stimulant 5 For radioactive substances there are controls other than those imposed by the CSA and its implementing regulations, including regulations by the NRC under 10 CFR part 35 and/or by states, which limit the publics exposure to radioactivity in radiopharmaceuticals, thus limiting the potential for toxicity imposed on the public.

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pharmacological effect. It is estimated that milligram quantities would have to be administered to elicit a stimulant effect. Due to the manufacturing limitations and expected low concentrations of 18FFP-CIT in an approved product, the volume of 18FFP-CIT-containing product that would need to be administered to achieve a psychoactive effect for abuse is not logistically possible.
2. Scientific Evidence of the Drugs Pharmacological Effects, if Known Preclinical Studies According to HHS scientific review of 123Iioflupane, non-radiolabeled FP-CIT
acts on the CNS by blocking monoamine transporters, including DAT and other monoamine transporters e.g., serotonin and is mechanistically similar to cocaine a schedule II substance. FPCITs affinity for DAT is between 10and 100-fold greater than cocaines affinity for DAT and appears to be more potent than cocaine in some behavioral assessments. HHS states that this mechanism of action suggests, like 123Iioflupane, 18FFP-CIT may potentially have abuse potential if the dose taken is high enough and if the deterrent effect of the extremely low concentration of the available radioligand is not considered.
Drug discrimination assays in animals can be used to predict if a test drug will have abuse potential in humans.
According to HHS, in a drug discrimination study, administration of non-radiolabeled FP-CIT at doses >0.1
mg/kg i.v. resulted in cocaineappropriate responses in rats trained to discriminate cocaine 10 mg/kg, i.p.
from saline. Thus, non-radiolabeled FPCIT may produce cocaine-like subjective effects.
HHSs review also noted that the administration of non-radiolabeled FPCIT resulted in an increase of locomotor activity in rodents relative to vehicle, but produced a lower maximum level and was less potent compared to cocaine schedule II substance, however the locomotor effects induced by FP-CIT lasted longer than cocaine.
Human Studies HHS notes that when 18FFP-CIT was administered at doses used in diagnostic tests there was no clinical evidence of stimulant effects.
3. The State of Current Scientific Knowledge Regarding the Drug or Other Substance The international non-proprietary name of 18FFP-CIT is methyl 1R,2S,3S,5S-8-3-fluoro-18Fpropyl-3-

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4-iodophenyl-8azabicyclo3.2.1octane-2-carboxylate.
The molecular formula of 18FFP-CIT is C18H2318FINO2 and the molecular weight is 431.28 g/mol.
The petitioner states that their expected 18FFP-CIT-containing product Fluoroseek exists only as a clear, colorless to slightly yellow liquid solution in ethanol and saline solution sodium chloride 0.9% in water and contains antioxidants such as gentisic acid and sodium ascorbate, with sodium carbonate as a pH modifier. The general chemical properties of 18FFP-CIT are inferred from the chemical properties of the non-radioactive FP-CIT substance.
FP-CIT is a white solid with a melting point of 83 C to 87 C and soluble in water less than 0.1 mg/ml, sodium acetate buffer pH 7.4; 16 mg/ml, and ethanol 27 mg/ml.
As noted by HHS, there are no currently marketed 18FFP-CITcontaining products available. However, in a letter dated January 8, 2020, the Petitioner sent a response to DEA on a request for information regarding the composition of the product and the expected doses patients will receive. In this communication, the Petitioner states that the synthesized product . . . contains 40 micrograms mg of 18F Fluoroseek per 29 milliliters mL.
Each patient will receive 0.33.0 mL of the solution. Thus, based on the concentration 40 mg/29 mL of the product, as indicated by the Petitioner, and the amount of the 18FFP-CIT
solution that the Petitioner estimates patients will receive 0.33.0 mL, the doses a patient may receive will be in the range of 0.41 mg to 4.13 mg.
For 123Iioflupane, HHS mentions that the meaningful extraction of 123Iioflupane from the marketed drug product, DaTscan, would be impossible due to its limited production and availability and it is technically complex and would require advanced equipment not available to the general public.
Medical Use According to HHS, as of April 2021, the petitioner has yet to submit an NDA
for the 18FFP-CIT-containing drug product Fluoroseek. It is expected that, similar to 123Iioflupane, 18FFP-CIT
will be used as a diagnostic agent, potentially in conjunction with PET
imaging, whereas 123Iioflupane is used in SPECT imaging.
4. Its History and Current Pattern of Abuse There have been no reports of abuse of 18FFP-CIT or 123Iioflupane at the doses used for diagnostic purposes.

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