Rules - 1999
[Federal Register Volume 64, Number 17 (Wednesday, January 27, 1999)]
[Rules and Regulations]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 99-1791]
DEPARTMENT OF JUSTICE
21 CFR Part 1308
Schedules of Controlled Substances: Placement of Modafinil Into Schedule IV
AGENCY: Drug Enforcement Administration, Department of Justice.
ACTION: Final rule.
SUMMARY: With the issuance of this final rule, the Deputy Administrator of the Drug Enforcement Administration (DEA) places the substance, modafinil, including its salts, isomers and salts of isomers, into Schedule IV of the Controlled Substances Act (CSA). As a result of this rule, the regulatory controls and criminal sanctions of Schedule IV will be applicable to the manufacture, distribution, importation and exportation of modafinil and products containing modafinil.
EFFECTIVE DATE: January 27, 1999.
FOR FURTHER INFORMATION CONTACT: Frank Sapienza, Chief, Drug and Chemical Evaluation Section, Drug Enforcement Administration,
Washington, DC 20537, Telephone: (202) 307-7183.
SUPPLEMENTARY INFORMATION: Modafinil is a central nervous system (CNS) stimulant that produces many of the same pharmacological effects and adverse reactions as classic psychomotor stimulants, but at higher doses. Modafinil will be marketed as a prescription drug product for the treatment of excessive daytime sleepiness associated with narcolepsy under the trade name Provigil.
On December 22, 1997, the Acting Assistant Secretary for Health, Department of Health and Human Services (DHHS), sent the Acting Deputy Administrator of DEA a letter recommending that modafinil, and its salts, be placed into Schedule IV of the CSA (21 U.S.C. 801 et seq.). Enclosed with the December 22, 1997 letter was a document prepared by the Food and Drug Administration (FDA) entitled "Basis for the Recommendation for Control of Modafinil 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)).
Subsequent correspondent from the FDA's Associate Commissioner for Health Affairs dated February 24, 1998, confirmed that the FDA had determined that the New Drug Application (NDA) for modafinil was "approvable" and had issued an approvable letter to the NDA sponsor on December 29, 1997. According to the February 24, 1998 letter from the FDA, "upon full approval of the NDA, modafinil will have a currently accepted medical use in treatment in the United States."
After a review of the available data, including the DHHS recommendation, the Acting Deputy Administrator of the DEA, in an April 14, 1998 Federal Register notice (63 FR 18170), proposed placement of modafinil into Schedule IV of the CSA, if and when the modafinil NDA is approved by the FDA. The notice provided an opportunity for all interested persons to submit their comments, objections, or requests for hearing in writing to be received by the DEA on or before May 14, 1998.
The DEA received one comment regarding the proposal. The comment was received from Cephalon, Inc., the company sponsoring the modafinil NDA. The comment did not object to the placement of modafinil in Schedule IV, but requested clarification of some of the descriptions of the pharmacological effects of modafinil. Cephalon, Inc. commented that modafinil did not produce significant dopaminergic activity nor did it produce classic dopaminergic-like pharmacological effects. Cephalon also stated that the time to peak pharmacological activity of modafinil is one to three hours and the effects last six to eight hours after oral administration. It did not characterize such pharmacodynamic effects of modafinil as "quick onset and short duration of action," as they were described in the Federal Register proposal.
The DEA's review of the DHHS scheduling recommendation and review document and the available scientific literature indicates that the precise biochemical mechanism of action of modafinil is not clearly defined. Data indicate that modafinil does not act directly on any single neurotransmitter system, but appears to act indirectly on dopamineric, serotonergic, and GABA systems. Although its mechanism of action may not be medicated primarily through the dopaminergic system, the behavioral and pharmacological effects and adverse reactions produced by modafinil are similar to those of other psychomotor or stimulants which produce significant dopaminergic activity. The data reviewed by the DHHS and the DEA show that modafinil is well-absorbed after oral administration. Peak plasma concentration for modafinil occurs at one to four hours. Elimination half-life was nine to fourteen hours after oral administration of 200 to 400 mg of modafinil. These pharmacodynamic actions of modafinil were characterized at "fast onset and short duration" by the DHHS. Thus, the modafinil data presented in the Federal Register proposal and the comments by Cephalon regarding these statements are not substantive scientific discrepancies, but are differences in describing the same data.
On December 30, 1998, the FDA notified the DEA that the modafinil NDA was approved by the FDA on December 24, 1998. Relying on the scientific and medical evaluation and the recommendation of the DHHS Acting Assistant Secretary for Health received in accordance with section 201(b) of the Act (21 U.S.C. 811(b)), communication with the FDA Associate Commissioner for Health and the independent review of 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)), finds that:
(1) Based on information now available, modafinil has a low potential for abuse relative to the drugs or other substances in Schedule III;
(2) Modafinil has a currently accepted medical use in treatment in the United States; and
(3) Abuse of modafinil may lead to limited physical dependence and psychological dependence relative to the drugs or other substances in Schedule III.
Based on these findings, the Deputy Administrator of the DEA concludes that modafinil, including its salts, isomers and salts of isomers, warrants control in Schedule IV of the CSA. In order to make modafinil pharmaceutical products available for medical use as soon as possible, the Schedule IV controls of modafinil will be effective January 27, 1999. In the event that the regulations impose special hardships on the registrants, the DEA will entertain any justified request for an extension of time to comply with the Schedule IV regulations regarding modafinil. The applicable regulations are as follows:
1. Registration. Any person who manufactures, distributes, dispenses, imports or exports modafinil or who engages in research or conducts instructional activities with modafinil, or who proposes to engage in such activities, must be registered to conduct such activities in accordance with Part 1301 of Title 21 of the Code of Federal Regulations.
2. Security. Modafinil must be manufactured, distributed and stored in accordance with Secs. 1301.71, 1301.72(b), (c), and (d), 1301.73, 1301.74, 1301.75 (b) and (c) and 1301.76 of Title 21 of the Code of Federal Regulations.
3. Labeling and Packaging. All labels on commercial containers of, and all labeling of, modafinil which is distributed shall comply with the requirements of Secs. 1302.03-1302.07 of Title 21 of the Code of Federal Regulations.
4. Inventory. Registrants possessing modafinil are required to take inventories pursuant to Secs. 1304.03, 1304.04 and 1304.11 of Title 21 of the Code of Federal Regulations.
5. Records. All registrants must keep records pursuant to Secs. 1304.03, 1304.04 and 1304.21-1304.23 of Title 21 of the Code of Federal Regulations.
6. Prescriptions. All prescriptions for modafinil are to be issued pursuant to Secs. 1306.03-1306.06 and 1306.21-1306.26 of Title 21 of the Code of Federal Regulations.
7. Importation and Exportation. All importation and exportation of modafinil shall be in compliance with Part 1312 of Title 21 of the Federal Code of Regulations.
8. Criminal Liability. Any activity with modafinil not authorized by, or in violation of, the CAS or the Controlled
Substances Import and Export Act shall be unlawful.
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 final rule and, by approving it, certifies that it will not have a significant economic impact on a substantial number of small entities. Modafinil is a new drug in the United States; recent approval of the product and its labeling by the FDA will allow it to be marketed once it is placed into Schedule IV of the CAS. This final rule will allow these entities to have access to a new pharmaceutical product.
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 section 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 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 does not have sufficient federalism implications to warrant the preparation of a Federalism Assessment.
List of Subjects in 21 CFR Part 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 amends 21 CFR part 1308 as follows:
1. The authority citation for 21 CFR part 1308 continues to read as follows:
Authority: 21 U.S.C. 811, 812, 871(b) unless otherwise noted.
2. Section 1308.14 is amended by redesignating the existing paragraphs (e)(7) through (e)(11) as (e)(8) through (e)(12) and by adding a new paragraph (e)(7) to read as follows: Sec. 1308.14 Schedule IV.
* * * * *
(e) * * *
(7) Modafinil................................................ 1680
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Dated: January 20, 1999.
Donnie R. Marshall,
Deputy Administrator, Drug Enforcement Administration.
[FR Doc. 99-1791 Filed 1-26-99; 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).