Rules - 1999
[Federal Register: May 5, 1999 (Volume 64, Number 86)]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
DEPARTMENT OF JUSTICE
Drug Enforcement Administration
Schedules of Controlled Substances: Proposed Placement of Zaleplon into Schedule IV
AGENCY: Drug Enforcement Administration, Department of Justice.
ACTION: Notice of proposed rulemaking.
SUMMARY: This proposed rule is issued by the Deputy Administrator of the Drug Enforcement Administration (DEA) to place the substance zaleplon, including its salts, into Schedule IV of the Controlled Substances Act (CSA). This proposed action is based on a recommendation from the Assistant Secretary for Health and Surgeon General of the Department of Health and Human Services (DHHS) and on an evaluation of the relevant data by the DEA. If finalized, this action will impose the regulatory controls and criminal sanctions of Schedule IV on those who handle zaleplon and products containing zaleplon.
DATES: Comments, objections and requests for a hearing must be received on or before June 4, 1999.
ADDRESSES: Comments, objections and requests for a hearing should be submitted in quintuplicate to the Deputy Administrator, Drug Enforcement Administration, Washington, D.C. 20537; Attention: DEA Federal Register Representative/CCR.
FOR FURTHER INFORMATION CONTACT: Frank Sapienza, Chief, Drug and Chemical Evaluation Section, Drug Enforcement Administration, Washington, D.C. 20537, (202) 307-7183.
SUPPLEMENTARY INFORMATION: Zaleplon is a central nervous system (CNS) depressant that is being considered for marketing approval by the Food and Drug Administration (FDA), under the trade name SONATA™. Zaleplon is a sedative-hypnotic in the pyrazolopyrimidine class, chemically distinct from the benzodiazepines, which competitively binds to the gamma-aminobutyric acid, type A (GABAA, central benzodiazepine receptor. Its pharmacology, abuse and dependence liabilities are similar to those of the benzodiazepines that are currently listed in Schedule IV of the CSA. In clinical trials zaleplon was found to be approximately 100-times less potent but equivalent in its potential for abuse when compared to the prototypic benzodiazepine, triazolam; triazolam is in Schedule IV of the CSA. Zaleplon will be marketed as a prescription drug product for the short-term treatment of insomnia.
Zaleplon is N-[3-(3-cyanopyrazol [1,5-alpyrimidin-7-yl]-N-ethylacetamide, and has been identified by code names CL-284,846 and ZAL-846. There are no asymmetric centers in the molecule or any optical isomers. Zaleplon has a rapid onset and short duration of action, and forms no pharmacologically-active metabolite in man. Zaleplon reduces sleep latency but has a relatively insignificant effect on total sleep time. These pharmacokinetic characteristics of zaleplon should prevent any long-term carryover or hangover effects. However, zaleplon has shown a mild to moderate benzodiazepine-like withdrawal syndrome after acute and continuous dosing studies in baboons.
Zaleplon has demonstrated significant muscle relaxant, ataxic, anticonvulsant, and anxiolytic effects and cognitive impairments in preclinical screening assays. Zaleplon is reinforcing in animals as demonstrated by self-administration studies. It produces euphoria, alterations in mood, perception, memory and subjective effects in humans typical of other benzodiazepines with abuse potential in Schedule IV.
The complexity of the synthesis procedure for preparation of zaleplon precludes a likely synthesis of the drug substance outside a laboratory environment and by individuals lacking training in organic chemistry synthesis. Hallucinations, amnesia, depression and hostility were the most serious adverse events related to the use of zaleplon during the clinical trials. Zaleplon-related overdoes were also noted during the clinical trails. Zaleplon-related overdoes were also noted during the clinical development program. The FDA has concluded that zaleplon's abuse potential appears to be lower than that of Schedule II depressants and similar
to the Schedule IV benzodiazepines. On March 31, 1999, the Assistant Secretary for Health and Surgeon General, Department of Health and Human Services (DHHS), sent the Deputy Administrator of DEA a letter recommending that zaleplon, and its salts, be placed into Schedule IV of the CSA (21 U.S.C. 801 et seq.). Enclosed with the March 31, 1999, letter was a document prepared by the FDA entitled, "Basis for the Recommendation for Control of Zaleplon in Schedule IV of the Controlled Substances Act (CSA)." The document contained a review of the factors which the CSA requires the Secretary to consider [21 U.S.C. 811(b)].
The correspondence from the Assistant Secretary for Health and Surgeon General to the DEA dated March 31, 1999, confirmed that FDA had determined that the New Drug Application (NDA) for zaleplon was "approvable" and had issued an approvable letter to the NDA sponsor on January 6, 1999. According to the March 31, 1999, letter from DHHS,
"upon full approval of the NDA, zaleplon will have a currently accepted medical use in treatment in the United States."
The factors considered by the Assistant Secretary of Health and Surgeon General and the DEA with respect to zaleplon were:
- Its actual or relative potential for abuse;
- Scientific evidence of its pharmacological effects;
- The state of current scientific knowledge regarding the drug;
- Its history and current pattern of abuse;
- The scope, duration, and significance of abuse;
- What, if any, risk there is to the public health;
- Its psychic or physiological dependence liability; and
- Whether the substance is an immediate precursor of a substance already controlled under this subchapter.
Relying on the recommendation of the Assistant Secretary for Health and Surgeon General, received in accordance with section 201(b) of the Act [21 U.S.C. 811(b)], and the independent review of the available data by the DEA, the Deputy Administrator of the DEA, pursuant to sections 201(a) and 201(b) of the Act [21 U.S.C. 811(a) and 811(b)], find that:
- Based on information now available, zaleplon has a low potential for abuse relative to the drugs or other substances in Schedule III;
- Zalepon will, upon approval of an NDA by the FDA, have a currently accepted medical use in treatment in the United States; and
- Abuse of zaleplon may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in Schedule III.
Based on these findings, the Deputy Administrator of the DEA concludes that zaleplon, including its salts, warrants control in Schedule IV of the CSA, if and when the zaleplon NDA is approved by the FDA. It is noted that zaleplon does not have optical isomers to be controlled under this action.
Interested persons are invited to submit their comments, objections or requests for a hearing, in writing, with regard to this proposal. Requests for a hearing should state, with particularity, the issues concerning which the person desires to be heard. All correspondence regarding this matter should be submitted to the Deputy Administrator, Drug Enforcement Administration, Washington, DC, 20537. Attention: DEA Federal Register Representative/CCR. In the event that comments, objections, or requests for a hearing raise one or more issues which the Deputy Administrator finds warrants a hearing, the Deputy Administrator shall order a public hearing by notice in the Federal Register, summarizing the issues to be heard and setting the time for the hearing.
In accordance with the provisions of the CSA [21 U.S.C. 811(a)], this action is a formal rulemaking "on the record after opportunity for a hearing." Such proceedings are conducted pursuant to the provisions of 5 U.S.C. 556 and 557 and, as such, are exempt from review by the Office of Management and Budget pursuant to Executive Order (E.O.) 12866, section 3(d)(1). The Deputy Administrator, in accordance with the Regulatory Flexibility Act [5 U.S.C. 605(b)], has reviewed this proposed rule and by approving it certifies that it will not have a significant economic impact on a substantial number of small entities. Zaleplon products will be prescription drugs used for the short-term treatment of insomnia. Handlers of zaleplon also handle other controlled substances used to treat insomnia which are already subject to the regulatory requirements of the CSA.
This rule will not result in the expenditure by State, local and tribal governments, in the aggregate, or by the private sector, of $100,000,000 or more in any one year, and it will not significantly or uniquely affect small governments. Therefore, no actions were deemed necessary under provisions of the Unfunded Mandates Reform Act of 1995.
This rule is not a major rule as defined by Sec. 804 of the Small Business Regulatory Enforcement Fairness Act of 1996. This rule will not result in an annual effect on the economy of $100,000,000 or more; a major increase in costs or prices: or significant adverse effects on competition, employment, investment, productivity, innovation, or on the ability of the United States-based companies to compete with foreign-based companies in domestic and export markets.
This rule will not have substantial direct effects on the States, on the relationship between the national government and the States, or on the distribution of power and responsibilities among the various levels of government. Therefore, in accordance with E.O. 12612, it is determined that this rule, if finalized, will not have sufficient federalism implications to warrant the preparation of a Federalism Assessment.
List of Subjects in 21 CFR 1308
Administrative practice and procedure, Drug traffic control, Narcotics, Prescription drugs.
Under the authority vested in the Attorney General by section 201(a) of the CSA [21 U.S.C. 811(a)], and delegated to the Administrator of the DEA by the Department of Justice regulations (28 CFR 0.100), and redelegated to the Deputy Administrator pursuant to 28 CFR 0.104, the Deputy Administrator hereby proposes that 21 CFR part 1308 be amended as follows:
1. The authority citation for 21 CFR part 1308 continues to read as follows:
2. Section 1308.14 is proposed to be amended by redesignating the existing paragraph (c)(48) to (c)(49) and by adding a new paragraph (c)(48) to read as follows:
§ 1308.14 Schedule IV.
(c) * * *
(48) Zaleplon 2781
Dated: April 26, 1999.
Donnie R. Marshall,
[FR Doc. 99-11289 Filed 5-4-99; 8:45 am]
BILLING CODE 4410-09-M
NOTICE: This is an unofficial version. An official version of this publication may be obtained directly from the Government Publishing Office (GPO).