[Federal Register Volume 71, Number 241 (Friday, December 15, 2006)]
[Notices]
[Pages 75560-75562]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E6-21318]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2006N-0493]


International Drug Scheduling; Convention on Psychotropic 
Substances; Single Convention on Narcotic Drugs; World Health 
Organization Scheduling Recommendations for Dronabinol and its 
Stereoisomers, and Oripavine

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is providing interested 
persons with the opportunity to submit written comments concerning 
recommendations by the World Health Organization (WHO) to impose 
international manufacturing and distributing restrictions, under 
international treaties, on certain drug substances. The comments 
received in response to this notice will be considered in preparing the 
U.S. position on these proposals for a meeting of the United Nations 
Commission on Narcotic Drugs (CND) in Vienna, Austria, March 12 to 16, 
2007. This notice is issued under the Controlled Substances Act.

DATES: Submit written or electronic comments by January 16, 2007.

ADDRESSES: Submit written comments to the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
rm. 1061, Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/dockets/ecomments.

FOR FURTHER INFORMATION CONTACT: James R. Hunter, Center for Drug 
Evaluation and Research (HFD-9), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-443-5563, e-mail: 
[email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    The United States is a party to the 1971 Convention on Psychotropic 
Substances (the 1971 Convention). Section 201(d)(2)(B) of the 
Controlled Substances Act (the CSA) (21 U.S.C. 811(d)(2)(B)) provides 
that when the United States is notified under Article 2 of the 1971 
Convention that CND proposes to decide whether to add a drug or other 
substance to one of the schedules of the 1971 Convention, transfer a 
drug or substance from one schedule to another, or delete it from the 
schedules, the Secretary of State must transmit notice of such 
information to the Secretary of Health and Human Services (the 
Secretary of HHS). Section 201(d)(2)(B) requires the Secretary of HHS, 
after receiving notification proposing scheduling, to publish a summary 
of such information in the Federal Register to provide opportunity for 
interested persons to submit comments on the proposed scheduling 
action. The Secretary of HHS must then evaluate the proposal and 
furnish a recommendation to the Secretary of State that shall be 
binding on the representative of the United States in discussions and 
negotiations relating to the proposal.
    As detailed in the following paragraphs, the Secretary of State has 
received notification from the Secretary-General of the United Nations 
(the Secretary-General) regarding the drug substance dronabinol (INN), 
including its stereoisomers, to be considered for control under the 
1971 Convention. The notification reflects the recommendations from the 
34th WHO Expert Committee for Drug Dependence (ECDD), which met in 
March 2006. In the Federal Register of December 13, 2005 (70 FR 73775), 
FDA announced the WHO ECDD review and invited interested persons to 
submit information for WHO's consideration.
    The United States is also a party to the 1961 Single Convention on 
Narcotic Drugs (the 1961 Convention). The Secretary of State has 
received notification from the Secretary-General regarding the drug 
substance oripavine to be considered for control under the 1961 
Convention. The CSA does not require the Secretary of HHS to publish a 
summary of such information in the Federal Register. Nevertheless, in 
an effort to provide interested and affected persons an opportunity to 
submit comments on the WHO ECDD recommendations for narcotic drugs, 
notification on this substance is also included in this Federal 
Register notice. The comments will be shared with other relevant 
agencies to assist the Secretary of State in formulating the U.S. 
position on the control of these substances. The HHS recommendations 
are not binding on the representative of the United States in 
discussions and negotiations relating to the proposal on control of 
substances under the 1961 Convention.

[[Page 75561]]

    The full text of these notifications from the Secretary-General is 
provided in section II of this document.
    II. United Nations Notification
    The formal United Nations notification that identifies the drug 
substances and explains the basis for the recommendations is 
reproduced below.
Reference: NAR/CL.4/2006
CSS-6/06, CU2006/162
    WHO/ECDD 34 (1971C and 1961C)
    The Secretary-General of the United Nations presents his 
compliments [to the Secretary of State] and has the honour to inform 
the Government that the Acting Director-General of the World Health 
Organization (WHO), pursuant to article 2, paragraphs 1, 4 and 6, of 
the Convention on Psychotropic Substances of 1971 (1971 Convention), 
has notified the Secretary-General that it is of the opinion that 
dronabinol (INN) and its stereoisomers should be transferred from 
Schedule II to Schedule III of the 1971 Convention; and pursuant to 
article 3, paragraphs 1 and 3(iii) of the Single Convention on 
Narcotic Drugs, 1961, and of that Convention as amended by the 1972 
Protocol (1961 Convention), has also notified the Secretary-General 
that it is of the opinion that oripavine should be included in 
Schedule I of the 1961 Convention.
    In connection with the notification, WHO has also submitted 
advance excerpts from the report of the Thirty-fourth session of the 
WHO Expert Committee on Drug Dependence (28-31 March 2006) which 
reviewed the substances. The excerpts from that report concerning 
dronabinol (INN) and its stereoisomers, recommended for 
rescheduling; and oripavine, recommended for scheduling, are hereby 
transmitted as annex II. The excerpts are currently available in 
English only, pending receipt of the official translation from the 
World Health Organization.
    In accordance with the provisions of article 2, paragraph 2, of 
the 1971 Convention; and the provisions of article 3, paragraph 2, 
of the 1961 Convention, the Secretary-General hereby transmits the 
text of the notification as annex I to the present note. Also in 
accordance with the same provisions, the notification from WHO will 
be brought to the attention of the Commission on Narcotic Drugs, at 
its next session in March 2007.
    Any action or decision taken by the Commission with respect to 
this notification, pursuant to article 2, paragraphs 5 and 6, of the 
1971 Convention, will be communicated to States Parties in due 
course. Article 2, paragraphs 5 and 6, reads as follows:
    ``5. The Commission, taking into account the communication from 
the World Health Organization, whose assessments shall be 
determinative as to medical and scientific matters, and bearing in 
mind the economic, social, legal, administrative and other factors 
it may consider relevant, may add the substance to Schedule I, II, 
III or IV. The Commission may seek further information from the 
World Health Organization or from other appropriate sources.
    6. If a notification under paragraph 1 relates to a substance 
already listed in one of the Schedules, the World Health 
Organization shall communicate to the Commission its new findings, 
any new assessment of the substance it may make in accordance with 
paragraph 4 and any new recommendations on control measures it may 
find appropriate in the light of that assessment. The Commission, 
taking into account the communication from the World Health 
Organization as under paragraph 5 and bearing in mind the factors 
referred to in that paragraph, may decide to transfer the substance 
from one Schedule to another or to delete it from the Schedules.''
    Any action or decision taken by the Commission with respect to 
this notification, pursuant to article 3, paragraph 3 (iii) of the 
1961 Convention, will be communicated to States Parties in due 
course. Article 3, paragraph 3 (iii) reads as follows:
    ``If the World Health Organization finds that the substance is 
liable to similar abuse and productive of similar ill effects as the 
drugs in Schedule I or Schedule II or is convertible into a drug, it 
shall communicate that finding to the Commission which may, in 
accordance with the recommendation of the World Health Organization, 
decide that the substance shall be added to Schedule I or Schedule 
II.''
    In order to assist the Commission in reaching a decision, it 
would be appreciated if any economic, social, legal, administrative 
or other factors the Government may consider relevant to the 
possible rescheduling under the 1971 Convention of dronabinol (INN) 
and its stereoisomers, as well as to the possible inclusion of 
oripavine under the 1961 Convention, could be communicated at the 
latest by 1 December 2006 to the Executive Director of the United 
Nations Office on Drugs and Crime, c/o Secretary, Commission on 
Narcotic Drugs, P.O. Box 500, 1400 Vienna, Austria, fax:+43-1-26060-
5885, e-mail: [email protected].
    13 October 2006
* * * * *
    Annex II
    Recommendation on dronabinol (INN)
Substance identification
    Dronabinol (INN) is (6aR,10aR)- 6a,7,8,10a-tetrahydro-6,6,9-
trimethyl-3-pentyl-6-H-dibenzo[b,d]pyran-1-ol. It is the (6aR,10aR)-
stereoisomer of delta-9-tetrahydrocannabinol and is also designated 
(-)- trans-delta-9-tetrahydrocannabinol.
    Other stereoisomers of delta-9-tetrahydrocannabinol are: (6aR, 
10aS)-,(6aS, 10aR)- and (6aS, 10aS)-, also known as (-)-cis-,(+)-
cis-and (+)-trans-, respectively. Delta-9-tetrohydrocannabinol has 
two racemates, (6aRS, 10aRS)- and (6aRS, 10aSR)-, also known as 
()-trans- and ()-cis-, respectively.
    Originally, all isomers of tetrahydrocannabinol were included in 
Schedule I of the 1971 Convention. This was later amended to include 
seven named constitutional isomers and their respective 
stereochemical variants. The term ``constitutional isomers'' used 
above has recently been introduced by the International Union of 
Pure and Applied Chemistry (IUPAC) to replace the traditionally used 
term ``positional isomers''.
    The term ``stereochemical variants'' used in the 1971 Convention 
and mentioned above is equivalent to the term ``stereoisomers'', 
which is at present much more widely used in the chemical and 
related literature. Both terms cover geometric isomers and optical 
isomers.
Previous review
    Delta-9-tetrahydrocannabinol was included in Schedule I of the 
1971 Convention at the time of its adoption. At its twenty-sixth 
meeting, the Committee recommended that dronabinol be moved to 
Schedule II, while keeping the other isomers and their 
stereochemical variants in Schedule I (1). This proposal was 
rejected at the 11th Special Session of the Commission on Narcotic 
Drugs, and the Committee reviewed the question again at its twenty-
seventh meeting when it recommended that all the stereochemical 
variants of delta-9-tetrahydrocannabinol be rescheduled to Schedule 
II (2). This recommendation was adopted by the United Nations 
Commission on Narcotic Drugs at its 34th session (3). At its thirty-
second meeting, the Committee pre-reviewed dronabinol and 
recommended its critical review for consideration of the 
rescheduling on the grounds that the rate of abuse of dronabinol was 
extremely low (4).
    Delta-9-tetrahydrocannabinol was critically reviewed by the 
Expert Committee on Drug Dependence at its thirty-third meeting in 
September 2002 (5). On the basis of the available data the Committee 
considered that dronabinol should be rescheduled to Schedule IV of 
the 1971 Convention. However, no further procedural steps were 
taken. Therefore, the existing critical review report was updated, 
including information from recent scientific publications, to enable 
the Committee to finalize the process of critical review.
Similarity to known substances and effects on the central nervous 
system
    Dronabinol is the main active principle of cannabis and has 
similar effects on mood, perception and the cardiovascular system. 
The cannabis plant contains a ``natural mixture'' of around 70 
different cannabinoids, and also contains flavonoids and terpenes, 
as well as many other substances. Therefore the pharmacological 
properties of natural cannabis and dronabinol are not identical.
Dependence potential
    Animal studies have demonstrated that, like other drugs of 
abuse, dronabinol acts as a drug reinforcer. Physical dependence, as 
shown by withdrawal syndrome following chronic administration, has 
also been demonstrated. Reinforcing effects and physical dependence 
have also been described in human studies.
Actual abuse and/or evidence of likelihood of abuse
    The abuse of dronabinol is currently rare and there have been 
very few specific reports of its occurrence. In response to the WHO 
questionnaires only the United States mentioned instances of abuse 
of delta-9-tetrahydrocannabinol. At present, the quantity produced 
by licit manufacture is limited. In the United States, which is the 
major manufacturing country, the abuse of dronabinol medicinal 
preparations is reported to be very low and there are no reports of 
diversion of the pharmaceutical product.

[[Page 75562]]

Therapeutic usefulness
    Dronabinol preparations have been used in a limited number of 
countries in the treatment of nausea and vomiting associated with 
cancer chemotherapy in patients who have failed to respond 
adequately to conventional antiemetic treatments and in the 
treatment of anorexia associated with weight loss in patients with 
acquired immunodeficiency syndrome (AIDS). It has also been 
indicated in the treatment of chronic pain (e.g. in multiple 
sclerosis, neuropathic disorders and arthritis), neurological 
disorders and appetite loss in cachexia, and is being evaluated for 
use in various other clinical situations.
Recommendation
    The Committee reconsidered the recommendation of the thirty-
third Expert Committee after considering the updated critical review 
report. The Committee concluded that dronabinol constitutes a 
substantial risk to public health. However this risk is different 
from those related to cannabis--controlled under the 1961 
Convention. The substance has a moderate therapeutic usefulness and 
as a result of continuing clinical research its medical use is 
likely to increase. Therefore, the Committee recommended that 
dronabinol (INN) and its stereoisomers should be rescheduled from 
Schedule II to Schedule III of the 1971 Convention.
    To avoid legal and forensic chemical problems that may arise in 
some countries when placing stereoisomers of the same substance 
under different control systems, the Committee indicated that the 
recommendation pertains to all stereoisomeric forms of delta-9-
tetrahydrocannabinol as specified above.
References
    1. WHO Expert Committee on Drug Dependence. Twenty-sixth report. 
Geneva, World Health Organization, 1989 (WHO Technical Report 
Series, No. 787).
    2. WHO Expert Committee on Drug Dependence. Twenty-seventh 
report. Geneva, World Health Organization, 1991 (WHO Technical 
Report Series, No. 808).
    3. Report of the thirty-fourth session (29 April-9 May 1991). 
Economic and Social Council, Commission on Narcotic Drugs, Official 
Records, 1991, Supplement No. 4. New York, United Nations, 1991 (E/
1991/24, E/Cn.7/1991/26).
    4. WHO Expert Committee on Drug Dependence. Thirty-second 
report. Geneva, World Health Organization, 2001 (WHO Technical 
Report Series, No. 903).
    5. WHO Expert Committee on Drug Dependence. Thirty-third report. 
Geneva, World Health Organization, 2003 (WHO Technical Report 
Series, No. 915).
Recommendation on oripavine
Substance identification
    Oripavine, 3-O-demethylthebaine, or 6,7,8, 14-tetradehydro-4,5-
alpha-epoxy-6-methoxy-17-methylmorphinan-3-ol is a phenanthrene 
alkaloid contained in species of the Papaver plant. It is a major 
metabolite of thebaine.
Previous review
    Oripavine was pre-reviewed at the thirty-third meeting of the 
Expert Committee in 2002 (1). The reason for pre-review in 2002 was 
that oripavine is a substance that is convertible into thebaine, and 
because thebaine is in turn convertible into morphine. Thebaine and 
morphine are both in Schedule I of the 1961 Convention. Owing to 
uncertainties regarding the scheduling of oripavine based on the 
additional possibility of applying the 1988 Convention (2), the 
Committee did not finalize this review at its thirty-third meeting, 
but asked WHO for clarification of issues related to the conversion 
of precursors into scheduled substances. Subsequent clarification of 
these issues allowed the Committee to come to a conclusion at its 
thirty-fourth meeting.
Recommendation
    The Committee decided that oripavine is a substance that is 
easily convertible into thebaine and other substances controlled in 
Schedule I of the 1961 Convention. Hence, the Committee recommended 
that oripavine be scheduled, like the substances mentioned, in 
Schedule I of the 1961 Convention.
References
    1. WHO Expert Committee on Drug Dependence. Thirty-third report. 
Geneva, World Health Organization, 2003 (WHO Technical Report 
Series, No. 915).
    2. United Nations Convention against Illicit Traffic in Narcotic 
Drugs and Psychotropic Substances, 1988. New York, United Nations, 
1991.

III. Discussion

    Although WHO has made specific scheduling recommendations for each 
of the drug substances, CND is not obliged to follow the WHO 
recommendations. Options available to CND for substances considered for 
control under the 1971 Convention include the following: (1) Acceptance 
of the WHO recommendations; (2) acceptance of the recommendations to 
control, but control the drug substance in a schedule other than that 
recommended; or (3) reject the recommendations entirely.
    Synthetic delta-9-tetrahydrocannabinol (delta-9-THC), or 
dronabinol, is the active component of the drug product Marinol, which 
is marketed in the United States as an antiemetic in the setting of 
cancer chemotherapy and for treatment of AIDS wasting syndrome. Marinol 
is currently controlled in Schedule III of the CSA, and the drug 
substance dronabinol (which is the synthetic equivalent of the natural 
active component of marijuana, delta-9-THC) is controlled in Schedule I 
of the CSA. The drug substance dronabinol, including its stereoisomers, 
is controlled internationally in Schedule II of the Psychotropic 
Convention.
    Oripavine is controlled domestically in Schedule II of the CSA 
because it is a derivative of thebaine, opium, and other opiates. 
Oripavine is not under international control.

IV. Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electric comments regarding this document. 
Submit a single copy of electronic comments or two paper copies of any 
mailed comments, except that individuals may submit one paper copy. 
Comments are to be identified with the docket number found in brackets 
in the heading of this document. Received comments may be seen in the 
Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday. The abbreviated period for the submission of comments 
is necessary to allow sufficient time for the Secretary of HHS to carry 
out the required action and respond to the United Nations.

    Dated: December 6, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E6-21318 Filed 12-14-06; 8:45 am]
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