[Federal Register Volume 79, Number 127 (Wednesday, July 2, 2014)]
[Rules and Regulations]
[Pages 37623-37630]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-15548]
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DEPARTMENT OF JUSTICE
Drug Enforcement Administration
21 CFR Part 1308
[Docket No. DEA-351]
Schedules of Controlled Substances: Placement of Tramadol Into
Schedule IV
AGENCY: Drug Enforcement Administration, Department of Justice.
ACTION: Final rule.
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SUMMARY: With the issuance of this final rule, the Deputy Administrator
of the Drug Enforcement Administration places the substance 2-
[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol (tramadol),
including its salts, isomers, and salts of isomers, into schedule IV of
the Controlled Substances Act. This scheduling action is pursuant to
the Controlled Substances Act which requires that such actions be made
on the record after opportunity for a hearing through formal
rulemaking. This action imposes the regulatory controls and
administrative, civil, and criminal sanctions applicable to schedule IV
controlled substances on persons who handle (manufacture, distribute,
dispense, import, export, engage in research, conduct instructional
activities with, or possess) or propose to handle tramadol.
DATES: Effective August 18, 2014.
FOR FURTHER INFORMATION CONTACT: Erika Gehrmann, Office of Diversion
Control, Drug Enforcement Administration; Mailing Address: 8701
Morrissette Drive, Springfield, Virginia 22152; Telephone: (202) 598-
6812.
SUPPLEMENTARY INFORMATION:
Legal Authority
The Drug Enforcement Administration (DEA) implements and enforces
titles II and III of the Comprehensive Drug Abuse Prevention and
Control Act of 1970, as amended. Titles II and III are referred to as
the ``Controlled Substances Act'' and the ``Controlled Substances
Import and Export Act,'' respectively, but they are collectively
referred to as the ``Controlled Substances Act'' or the ``CSA'' for the
purposes of this action. 21 U.S.C. 801-971. The DEA publishes the
implementing regulations for these statutes in title 21 of the Code of
Federal Regulations (CFR), parts 1300 to 1321. The CSA and its
implementing regulations are designed to prevent, detect, and eliminate
the diversion of controlled substances and listed chemicals into the
illicit market while providing for the legitimate medical, scientific,
research, and industrial needs of the United States. Controlled
substances have the potential for abuse and dependence and are
controlled to protect the public health and safety.
Under the CSA, every controlled substance is classified in one of
five schedules based upon its potential for abuse, currently accepted
medical use, and the degree of dependence the drug or other substance
may cause. 21 U.S.C. 812. The initial schedules of controlled
substances established by Congress are found at 21 U.S.C. 812(c) and
the current list of scheduled substances is published at 21 CFR part
1308.
Pursuant to 21 U.S.C. 811(a)(1), the Attorney General may, by rule,
``add to such a schedule or transfer between such schedules any drug or
other substance if he (A) finds that such drug or other substance has a
potential for abuse, and (B) makes with respect to such drug or other
substance the findings prescribed by [21 U.S.C. 812(b)] for the
schedule in which such drug is to be placed * * *.'' The Attorney
General has delegated scheduling authority under 21 U.S.C. 811 to the
Administrator of the DEA, 28 CFR 0.100, who in turn has redelegated
that authority to the Deputy Administrator of the DEA, 28 CFR part 0,
appendix to subpart R.
The CSA provides that scheduling of any drug or other substance may
be initiated by the Attorney General (1) on his own motion, (2) at the
request of the Secretary of the Department of Health and Human Services
(HHS),\1\ or (3) on the petition of any interested party. 21 U.S.C.
811(a). This action was initiated by four petitions to schedule
tramadol under the CSA, and is supported by, inter alia, a
recommendation from the Assistant Secretary of the HHS and an
evaluation of all relevant data by the DEA. This action imposes the
regulatory controls and administrative, civil, and criminal sanctions
applicable to schedule IV controlled substances on persons who handle
or propose to handle tramadol.\2\
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\1\ As discussed in a memorandum of understanding entered into
by the Food and Drug Administration (FDA) and the National Institute
on Drug Abuse (NIDA), the FDA acts as the lead agency within the HHS
in carrying out the Secretary's scheduling responsibilities under
the CSA, with the concurrence of NIDA. 50 FR 9518, Mar. 8, 1985. The
Secretary of the HHS has delegated to the Assistant Secretary for
Health of the HHS the authority to make domestic drug scheduling
recommendations. 58 FR 35460, July 1, 1993.
\2\ See infra note 3.
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Background
Tramadol is a centrally acting opioid analgesic that produces its
primary opioid-like action through an active metabolite, referred to as
the ``M1'' metabolite (O-desmethyltramadol). It was first approved for
use in the United States by the U.S. Food and Drug Administration (FDA)
in 1995 under the trade name ULTRAM[supreg]. Subsequently, the FDA
approved for marketing generic, combination, and extended release
tramadol products.
Because of its chemical structure, 2-[(dimethylamino)methyl]-1-(3-
methoxyphenyl) cyclohexanol can exist as different isomeric forms.
Thus, various prefixes can be associated with the name. Some examples
of these prefixes include dextro, levo, d, l, R, S, cis, trans,
erythro, threo, (+), (-), racemic, and may include combinations of
these prefixes sometimes with numerical designations. Any such isomer
is, in fact, 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol.
Tramadol is typically formulated as a racemic mixture identified as
()-cis-2-[(dimethylamino)methyl]-1-(3-
methoxyphenyl)cyclohexanol hydrochloride.\3\
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\3\ For simplicity, from this point forward in the document,
``tramadol'' is used to refer to 2-[(dimethylamino)methyl]-1-(3-
methoxyphenyl)cyclohexanol, its salts, isomers, salts of isomers,
and all isomeric configurations of possible forms.
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HHS and DEA Eight-Factor Analyses
On September 16, 2010, the Assistant Secretary of the HHS provided
to the DEA a scientific and medical evaluation and scheduling
recommendation entitled ``Basis for the Recommendation to Schedule
Tramadol in Schedule IV of the Controlled Substances Act.'' After
considering the eight factors in 21
[[Page 37624]]
U.S.C. 811(c), as well as the substance's abuse potential, legitimate
medical use, and dependence liability, the Assistant Secretary of the
HHS recommended that tramadol be controlled in schedule IV of the CSA
under 21 U.S.C. 812(b). The DEA conducted its own eight-factor analysis
of tramadol pursuant to 21 U.S.C. 811(c). Both the DEA and HHS analyses
are available in their entirety in the public docket for this rule
(Docket No. DEA-351) at http://www.regulations.gov under ``Supporting
and Related Material.''
Determination To Schedule Tramadol
After a review of the available data, including the scientific and
medical evaluation and the scheduling recommendation from the HHS, the
Deputy Administrator of the DEA published in the Federal Register a
notice of proposed rulemaking (NPRM) entitled ``Schedules of Controlled
Substances: Placement of Tramadol Into Schedule IV'' which proposed to
place tramadol in schedule IV of the CSA. 78 FR 65923, Nov. 4, 2013.
The proposed rule provided an opportunity for interested persons to
file a request for hearing in accordance with DEA regulations by
December 4, 2013. No requests for such a hearing were received by the
DEA. The NPRM also provided an opportunity for interested persons to
submit written comments on the proposed rule on or before January 3,
2014.
Comments Received
The DEA received 27 comments on the proposed rule to schedule
tramadol. Sixteen commenters expressed support for controlling tramadol
as a schedule IV controlled substance, nine commenters were opposed to
tramadol being placed into schedule IV of the CSA, and two commenters
did not take a position.
Support of the Proposed Rule
Sixteen commenters supported controlling tramadol as a schedule IV
controlled substance. Among those 16 commenters expressing support were
two State Boards of Pharmacy. One veterinary distributor's association
stated that it supports the DEA designating tramadol as a schedule IV
controlled substance because it will enable distributors to operate
with efficiency and consistency across the United States along with
requiring an increased level of due diligence and monitoring. A
national veterinary medical association, a national healthcare
association, and a national pharmacy association were also among those
who expressed support for the rule.
Several commenters supporting the rule expressed their concern
regarding the abuse potential and resulting threat to public health
posed by tramadol. Writing in support of scheduling tramadol, a local
multi-agency prescription drug abuse task force described tramadol as a
`` `loop hole' drug which is addictive, abused, and diverted,'' but
which is not yet realized as such by many patients and prescribers due
to its current non-controlled status. One commenter stated that given
the abuse potential of tramadol (which according to the commenter is
often abused in combination with other controlled substances),
scheduling this drug will ensure that it is subject to the same
controls as other similarly addictive controlled substances. Yet
another commenter noted that although analgesics are addictive to a
very small percentage of people that use them, scheduling this drug
would reduce the number of emergency room visits and number of overdose
deaths.
A certified pharmacy technician described her experiences of
witnessing the abuse of tramadol by patients on a daily basis. She
stated the stricter controlled substance laws of the State of
Mississippi have seemed to lessen the abuse. A group of pharmacy
students noted that tramadol, marketed as ULTRAM[supreg], is currently
the only uncontrolled opioid on the market. Another commenter who
supported the rule stated: ``In the field of pharmacy, some patients
have expressed concern about the reclassification of tramadol,
believing that new regulations could complicate or impede new and
chronic patients from receiving their prescriptions.'' This commenter
noted that this is a common misconception since schedule IV controlled
medications are in fact readily available for those with a valid
prescription and the appropriate medical condition. In addition, the
commenter noted that these types of prescriptions also have the added
convenience of being easily transferrable between pharmacies, phoned-in
by prescribers, and refilled five times over a six month period.
DEA Response: The DEA appreciates the support for the rule.
Opposition to the Proposed Rule
1. Access to Pain Medication by the Elderly
An association for consulting pharmacists stated that controlling
tramadol would limit access to needed pain medications for elderly
patients and opposed the proposed scheduling until a workable solution
to ensure timely access for patients in long-term care facilities
(LTCFs) can be reached. Specifically, the commenter expressed concern
that, should tramadol become a controlled substance, LTCF nurses would
no longer be able to call-in or fax a chart order directly to the
pharmacy. According to the commenter, in LTCFs, prescribers must call,
hand deliver, or fax controlled substance prescriptions to pharmacies,
and this in turn involves LTCF employees having to track down the
(often non-employee) prescriber. This practice, according to the
commenter, can severely impede delivery of prescription medications to
LTCF patients.
DEA Response: The processes and procedures associated with
dispensing a controlled substance are not relevant factors to the
determination whether a substance should be controlled or under what
schedule a substance should be placed if it is controlled. See 21
U.S.C. 811 and 812. Nonetheless, controlling tramadol as a schedule IV
controlled substance should not hinder legitimate access to the
medicine, whether within the LTCF setting or elsewhere. As summarized
by a State Board of Pharmacy who wrote in support of controlling
tramadol: ``Scheduling a medication does not make it impossible to
prescribe, dispense and administer the medication. However, it does
alert practitioners, dispensers and perhaps even some patients that the
medication has some potential dangers for addiction and misuse, and
frequent monitoring and evaluation by practitioners and dispensers of
such drugs is necessary for appropriate patient care.''
Currently, tramadol is a non-controlled medication that the FDA has
approved only for prescription use. Tramadol, as a schedule IV
controlled substance, will continue to require a prescription, either
orally or in writing. 21 U.S.C. 829(b). The CSA allows for the
legitimate prescribing and use of controlled substances; therefore, the
control of tramadol should not hinder patient access to the medication.
The prescription for tramadol, as a controlled substance, may only be
issued by an individual practitioner who is either registered with the
DEA or exempt from registration. 21 CFR 1306.03. A prescription for a
controlled substance must also be issued for a legitimate medical
purpose by an individual practitioner acting in the course of his
professional practice. 21 CFR 1306.04(a). Upon the effective date of
this rule, tramadol prescriptions may be filled up to six months after
the date prescribed, and may be refilled up to
[[Page 37625]]
five times within six months after the date on which such prescription
was issued. 21 U.S.C. 829(b); 21 CFR 1306.22 (a) and (e); see also 21
CFR 1306.23 (b) and (c). In addition, there are no dosage unit
limitations for prescriptions for schedule III, IV, or V controlled
substances unless the controlled substance is prescribed for
administration to an ultimate user who is institutionalized. 21 CFR
1306.24(c).
The substantive requirement that a practitioner acting in the usual
course of professional practice determine that tramadol is medically
necessary to treat the patient does not hinder legitimate access; the
procedural requirements relating to transmission of a legitimate
prescription do not hinder legitimate access either. Once an individual
practitioner makes a medical determination to prescribe a schedule III
through V controlled substance, a prescriber's agent may call-in or fax
a prescription for it. See 21 CFR 1306.03(b), 1306.21(a). The DEA
recognizes the unique challenges pertaining to handling and using
controlled substances at LTCFs and has previously addressed related
concerns.\4\ A DEA registered practitioner may not delegate to a nurse,
a pharmacist, or anyone else his or her authority to make a medical
determination whether to prescribe a particular controlled substance.
However, oral prescriptions for controlled substances in schedules III-
V may be communicated to a pharmacy by an employee or agent of the
prescribing practitioner, 21 CFR 1306.03(b). Note that the prescribing
practitioner remains responsible for ensuring that the prescription
conforms ``in all essential respects to the law and regulations,'' 21
CFR 1306.05(f). 75 FR 61613, 61614, Oct. 6, 2010. This requires the
practitioner alone to determine--on a prescription by prescription
basis--whether the prescription is supported by a legitimate medical
purpose and that all the essential elements of the prescription are
met.
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\4\ E.g., ``Preventing the Accumulation of Surplus Controlled
Substances at Long Term Care Facilities,'' 66 FR 20833, Apr. 25,
2001; ``Role of Authorized Agents in Communicating Controlled
Substance Prescriptions to Pharmacies,'' 75 FR 61613, Oct. 6, 2010.
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2. Fear of Criminal Action
Some commenters expressed concern that scheduling tramadol would
deter prescribers from properly treating pain for fear of facing
criminal action.
DEA Response: One of the most important principles underlying the
CSA is that every prescription for a controlled substance must be
issued for a legitimate medical purpose by an individual practitioner
acting in the usual course of his professional practice. 21 CFR
1306.04(a); U.S. v. Moore, 423 U.S. 122 (1975) (holding registered
physicians may be prosecuted for violation of the CSA when their
activities fall outside the usual course of professional practice). The
DEA Policy Statement entitled ``Dispensing Controlled Substances for
the Treatment of Pain,'' 71 FR 52715 (Sept. 6, 2006), makes clear that
this longstanding requirement should in no way interfere with the
legitimate practice of medicine or cause any practitioner to be
reluctant to provide legitimate pain treatment. Providers (as well as
ultimate users) become subject to administrative, civil, and/or
criminal proceedings when their activity involving controlled
substances is not authorized by, or in violation of, the CSA.
3. Shift to the Black-Market
Several commenters stated that scheduling tramadol would limit
their access to tramadol, causing them to have to buy tramadol on the
street.
DEA Response: As discussed above, schedule IV controlled
medications are readily available for legitimate medical use.
4. Scientific Data Not Sufficient
One commenter reviewed selected published literature and submitted
a short review document with a conclusion that ``the current available
scientific evidence supports the continuation of a non-controlled
classification'' of tramadol.
DEA Response: The CSA mandates that both the HHS and DEA conduct a
review of the drug or other substance as related to the eight factors
enumerated in 21 U.S.C. 811(c): (1) Its actual or relative potential
for abuse; (2) scientific evidence of its pharmacological effect, if
known; (3) the state of current scientific knowledge regarding the drug
or other substance; (4) its history and current pattern of abuse; (5)
the scope, duration, and significant of abuse; (6) what, if any, risk
there is to the public health; (7) its psychic or physiological
dependence liability; and (8) whether the substance is an immediate
precursor of a substance already controlled. The Assistant Secretary of
the HHS provided a scientific and medical evaluation and a scheduling
recommendation to control tramadol as a schedule IV controlled
substance. In accordance with 21 U.S.C. 811(c), the DEA conducted its
own analysis of the eight factors determinative of control. Besides
published literature, various other data as detailed in the supporting
documents were considered in making the scheduling determination for
tramadol. Thus, the scheduling determination is based on a
comprehensive evaluation of all available data as related to the above
mentioned eight factors. The summary of each factor as analyzed by the
HHS and the DEA, and as considered by the DEA in this scheduling
action, was provided in the proposed rule. Both the DEA and the HHS
analyses have been made available in their entirety under ``Supporting
and Related Material'' of the public docket for this rule at http://www.regulations.gov under Docket No. DEA-351.
As discussed in detail in the DEA's eight-factor analysis,
collectively, the available information regarding tramadol supports an
abuse potential that is less than that of schedule III and similar to
that for schedule IV. Preclinical self-administration studies show that
tramadol produces limited reinforcing effects, consistent with schedule
IV. At supra-therapeutic doses, tramadol can produce subjective
reinforcing effects similar to that of morphine (C-II) and approaching
that of oxycodone (C-II). At high doses (but not therapeutic doses),
tramadol can produce subjective reinforcing effects similar to
propoxyphene (C-IV). For both tramadol and propoxyphene, the doses
required to produce significant subjective reinforcing effects are in a
range causing sufficient adverse effects. These observations indicate
that the subjective reinforcing effects, a reflection of abuse
potential, of tramadol are less than that of morphine or oxycodone, but
similar to that of propoxyphene.
Based on the review of the HHS evaluation and scheduling
recommendation and all other relevant data, the DEA has found that
tramadol has an abuse potential and meets the requirements for schedule
IV controls under the CSA.
5. Disagreement With Tramadol Classification as an Opioid
One commenter who supported the rule stated that tramadol should
not be compared to hydrocodone because hydrocodone is an opioid and
tramadol is psychotropic in nature and very similar to, if not the same
as, a serotonin-norepinephrine reuptake inhibitor (SNRI).
DEA Response: In the NPRM and supporting documents, the DEA
compared tramadol mainly to propoxyphene (narcotic schedule IV). Based
on both the HHS and the DEA analyses, there is strong scientific
evidence that tramadol and propoxyphene are similar regarding
[[Page 37626]]
their behavioral pharmacology and abuse potential pattern, thus
suggesting that it is appropriate to control tramadol as a schedule IV
controlled substance.
In addition, as stated in the supporting scientific documents, both
the HHS and the DEA deem tramadol to be an opioid because tramadol
shares similar pharmacological activities with opioids that are
controlled under the CSA (schedules II-IV). (The labeling for FDA
approved tramadol products states that tramadol is a centrally acting
opioid analgesic.) An examination of the general pharmacology
(including behavioral pharmacology) of tramadol reveals that tramadol
produces many pharmacological effects similar to those of other
opioids. These pharmacological effects include, but are not limited to,
analgesia, respiratory depression, miosis, cough suppression, and
inhibition of bowel mobility, and as such, tramadol is considered an
opioid. The opioid pharmacology of tramadol primarily resides with its
metabolite, O-desmethyltramadol, designated ``M1,'' and to a much
lesser extent with tramadol, the parent drug. In addition, tramadol
resembles some opioids insofar as it has the additional pharmacological
effects of blocking the reuptake of norepinephrine and serotonin.
The CSA defines an ``opiate'' as ``any drug or other substance
having an addiction-forming or addiction-sustaining liability similar
to morphine or being capable of conversion into a drug having such
addiction-forming or addiction-sustaining liability.'' 21 U.S.C.
802(18). Opium, opiates, derivatives of opium and opiates, including
their isomers, whether produced directly or indirectly by extraction
from substances of vegetable origin, or independently by means of
chemical synthesis, are ``narcotic drugs'' as defined by the CSA, 21
U.S.C. 802(17).\5\ As discussed in the supporting eight-factor
documentation, preclinical studies demonstrate that tramadol, as other
opioids in schedules I through IV, exhibits complete generalization to
morphine and is able to produce some reinforcing effects. Repeated
administration of tramadol in animals caused dependence development,
evidenced by a withdrawal syndrome similar in intensity to pentazocine
(schedule IV) or propoxyphene (narcotic schedule IV).
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\5\ Including their isomers, esters, ethers, salts, and salts of
isomers, whenever the existence of such isomers, esters, ethers, and
salts is possible within the specific chemical designation; however,
does not include the isoquinoline alkaloids of opium.
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Although, generally, the controls imposed by the CSA on drugs and
other substances depend on the schedule into which they are placed,
there are certain additional requirements and restrictions for narcotic
drugs. For example, narcotic drugs in schedule III, IV, or V may not be
imported into the United States unless it is found that such
importation is needed to provide for the legitimate medical,
scientific, or other legitimate purposes under the specified, limited
circumstances described in 21 U.S.C. 952(a). Narcotic controlled
substances may not be exported unless the conditions imposed by 21
U.S.C. 953(a) are satisfied.
6. Never-Ending Practice of Drug Scheduling
Two commenters raised concerns that, despite the scheduling of
drugs such as tramadol, individuals will always find substances to
abuse, thus creating ``a never ending story of scheduling drugs.''
DEA Response: Pursuant to 21 U.S.C. 811(a), the CSA authorizes the
DEA, under authority delegated by the Attorney General, to add to such
a schedule any drug or other substance if it is found that the drug or
other substance has a potential for abuse, and makes with respect to
such drug or other substance the findings prescribed by 21 U.S.C.
812(b). As such, the scheduling authority established by Congress
specifically allows new substances to be added to the list of
controlled substances without regard to the number of substances
already controlled. See also 21 U.S.C. 812(a) (``Such schedules shall
initially consist of * * *'' (emphasis added)).
Requests for Staggered Implementation of Various Portions of the Rule
A national association that represents primary healthcare
distributors commented that although they recognized the underlying
reasons for scheduling tramadol and agreed with the reasoning and basis
for controlling tramadol, the DEA should provide an extended time
period before implementation to allow registrants to become compliant
with portions of the rule regarding security, labeling and packaging,
and reporting.\6\ The association requested that the requirement for
conducting inventory of tramadol products within wholesale distribution
centers take place as of the effective date of the final scheduling
decision. The association's concerns (as well as the DEA's responses)
are outlined and discussed below.
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\6\ Pursuant to 5 U.S.C. 553(d) and in accordance with 21 CFR
1308.45, a final rule scheduling a substance shall not be effective
less than 30 days from the date of its publication in the Federal
Register unless the Administrator finds that conditions of public
health or safety necessitate an earlier effective date.
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1. Request for Staggered Effective Dates, Generally
The association requested that the DEA implement handling
requirements for tramadol in stages. For example, they requested that
the requirement for conducting inventory of tramadol products within
wholesale distribution centers take place as of the effective date of
the final scheduling decision but delaying the requirements for
compliance with the security provisions of 21 CFR 1301.71-1301.93.
DEA Response: Generally, scheduling actions for drugs and other
substances currently marketed in the United States are effective 30
days from the date of publication of the final rule in the Federal
Register. In order to ensure the continued availability of tramadol for
legitimate medical use, while also ensuring it is not subject to
misuse, abuse, and diversion, the DEA is establishing an effective date
of this final rule for all handling requirements 45 days from the date
of publication. This 45-day period will provide a reasonable time for
registrants to comply with the handling requirements for a schedule IV
controlled substance and was established upon a full consideration of
the totality of circumstances specific to tramadol.
Although the DEA has in the past, for some scheduling actions,
allowed for additional time for compliance with certain handling
requirements beyond the general effective date, the DEA has
specifically chosen to forgo staggered implementation dates of handling
requirements as different implementation dates leads to confusion and
inconsistent application of the law.
2. Security
The association recommended a minimum of 120 days from the date of
the final rule to allow for compliance in order to provide storage,
revise operating procedures, train staff, and amend monitoring systems.
DEA Response: In order to ensure the continued availability of
tramadol for legitimate medical use, while also ensuring it is not
subject to misuse, abuse, and diversion, the DEA is establishing an
effective date of this final rule, including security requirements, 45
days from the date of publication. Upon promulgation, registrants must
comply with the applicable security provisions of 21 CFR 1301.71-
1301.93. This 45-day period will provide a reasonable time for
registrants to comply with the security
[[Page 37627]]
requirements for a schedule IV controlled substance. As noted by the
association, it is believed that distributors of tramadol already have
adequate space within their warehouse cages to store the anticipated
volume of tramadol and ``thus construction or expansion of cage space
is unlikely to result * * *.'' Accordingly, it is reasonably likely
that handlers and proposed handlers of tramadol have already instituted
or made plans to institute the necessary modifications regarding
security, including amendments to their suspicious orders monitoring
systems to include tramadol orders. In order to provide handlers of
tramadol a reasonable time period to comply with schedule IV handling
requirements, including those for security, the DEA is allowing an
additional 15 days, as compared to the generally allotted 30 days, from
publication in the Federal Register before this rule becomes effective.
After 45 days from the date of the final rule, tramadol will be subject
to schedule III-V security requirements.
The DEA has carefully considered the security requirements for
compliance with this rule. As confirmed by the association, current
distributors of tramadol are DEA registrants with existing controlled
substance storage that complies with DEA regulations. The DEA
understands that handlers of tramadol may need to make modifications to
their current security procedures for compliance. These modifications
necessary for security compliance will be a one-time modification to
provide for the appropriate storage, revision of operating procedures,
training of staff, and amendments to suspicious order monitoring
systems to include customer verifications. The DEA believes that a 45-
day period will provide handlers of tramadol adequate time to implement
these one-time modifications in compliance with the DEA security
regulations. Registrants are familiar with the applicable security
regulations, and already have systems in place with respect to other
controlled substances. Accordingly, revising operating procedures,
amending monitoring systems, and training staff with respect to
tramadol should be easily accomplished within the 45-day compliance
timeframe. The DEA strongly advises current registrants (and those
entities that may seek registration as a result of this action) to work
closely with their local DEA office regarding the applicable security
requirements and any necessary modifications due to compliance with
this rule. 21 CFR 1301.71(d).
3. Distribution of Products With the Pre-Control Label
The association stated that in accordance with 21 CFR 1302.05, the
DEA has the authority to set a date on which labeling and packaging
requirements will become effective, and requested clarification of when
the distribution of products with the pre-scheduling label should
cease. The association also requested clarification as to whether the
cessation of the manufacture of products for commercial containers with
the pre-scheduling labeling will also mean that manufacturers would be
required to cease distribution to wholesale distributors of products
they might have in stock bearing the pre-scheduling label. The
association stated that the ambiguity of the compliance period poses a
dilemma for those in the tramadol supply chain, and requested the DEA
to act to meet healthcare needs and avoid waste by allowing products
bearing the pre-scheduling label to move through the supply chain until
the inventory is depleted. Alternatively, the association suggested
that the DEA allow distributors to continue to sell pre-scheduling
labeled product for at least 180 days after the effective date of the
final rule.
DEA Response: As of the effective date of the final rule, pursuant
to 21 U.S.C. 821, 825, and 958(e) and in accordance with 21 CFR
1302.03, manufacturers are required to print upon the labeling of each
commercial container of tramadol they distribute the designation of
tramadol as ``C-IV.'' It shall be unlawful for commercial containers of
tramadol to be distributed without bearing the label properly
identifying it as a schedule IV controlled substance in accordance with
21 CFR part 1302. As clearly stated in 21 CFR 1302.05, ``[a]ll labels
on commercial containers of, and all labeling of, a controlled
substance which either is transferred to another schedule or is added
to any schedule shall comply with the requirements of Sec. 1302.03, on
or before the effective date established in the final order for the
transfer or addition.'' Accordingly, the DEA is requiring that
commercial containers of tramadol distributed on or after 45 days from
the date of publication of the final rule be labeled as ``C-IV'' and be
packaged in accordance with 21 CFR part 1302.
From the 2007 Economic Census, the DEA estimates that the inventory
turnover ratio for the industry \7\ is approximately 11.3.\8\ The
inventory turnover ratio represents the number of times the inventory
sells (turns) in a year. The 11.3 inventory turnover ratio equates to
an average of 32 days to sell inventory. The 11.3 turnover ratio is
consistent with that of large distributors where financial information
was publicly available and reviewed. Publicly reviewed data reports
that about 85% of all revenues (an indirect indicator of dosage units
moved) from drug distribution in the United States come from three
public wholesalers, each with annual revenue in the billions. The DEA
additionally notes that many regional and specialist pharmaceutical
wholesalers have been acquired by the largest three distribution
companies. The inventory turnover ratio is a reasonable estimate for
the entire industry and all products under the circumstances. Because
the 32 days to sell inventory is an average based on industry-wide
census data, it is possible for an individual company and/or product
line to have shorter or longer time to sell.
---------------------------------------------------------------------------
\7\ NAICS 424210--Drugs and druggists' sundries merchant
wholesalers; Merchant wholesalers, except manufacturers' sales
branches and offices.
\8\ The inventory turnover ratio of 11.3 was calculated by
dividing the 2007 ``cost of goods sold'' for the industry of
$280,481,051,000 by the average end-of-year 2006 total inventories
of $24,782,835,000.
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Since tramadol is a widely prescribed drug, with nearly 40 million
prescriptions written in 2012,\9\ the DEA expects distributors to
receive and distribute tramadol at high volume and with regularity;
thus, anticipating shorter than average days to sell tramadol than
overall industry average inventory. However, to accommodate those
distributors that have lower than average industry turnover ratio, the
DEA is establishing an effective date of this final rule, including
labeling and packaging requirements, 45 days from the date of
publication. The DEA believes this will provide a reasonable time for
distributors to sell existing stock with pre-control labeling and
packaging and to stock inventory with post-control labeling and
packaging.
---------------------------------------------------------------------------
\9\ IMS Health, National Sales PerspectiveTM (NSP).
---------------------------------------------------------------------------
Additionally, the DEA believes that any distributor that requires
more than 45 days to sell tramadol inventory under normal circumstances
can make minor modifications to ordering and stocking procedure for a
transitional period to meet the established effective date at minimal
cost. Distributors also have the option of returning excess stock of
tramadol product without the ``C-IV''
[[Page 37628]]
label to the manufacturer, as authorized by 21 CFR 1307.12.
The DEA takes this opportunity to clarify that the regulation
pertaining to labeling of commercial containers applies only to
distributions by manufacturers and distributors. The DEA does not
regulate the labeling and packing of commercial containers of
controlled substances downstream of distributors.
As summarized in the NPRM, and discussed in detail in the
supporting eight factor analyses, tramadol meets the statutory
requirements for control and for placement in schedule IV. Based upon
the reasons discussed above, the DEA believes that 45 days is a
reasonable amount of time for registrants to modify their operations so
that the necessary safeguards are in place to prevent the abuse and
diversion of tramadol.
4. Automation of Reports and Consolidated Orders System (``ARCOS'')
Reporting
The association stated that only schedule I and II (and some
schedule III) products are subject to reporting under the DEA's
Automation of Reports and Consolidated Orders System (``ARCOS''), so it
would be an error to require distributors to report tramadol (a
schedule IV narcotic) to ARCOS.
DEA Response: DEA regulations do not require distributors to file
ARCOS reports for schedule IV narcotics.
Scheduling Conclusion
Based on consideration of all comments, the scientific and medical
evaluation and accompanying recommendation of the HHS, and based on the
DEA's consideration of its own eight-factor analysis, the DEA finds
that these facts and all other relevant data constitute substantial
evidence of potential for abuse of tramadol. As such, the DEA is
scheduling tramadol as a controlled substance under the CSA.
Determination of Appropriate Schedule
The CSA establishes five schedules of controlled substances known
as schedules I, II, III, IV, and V. The CSA outlines the findings
required for placing a drug or other substance in any particular
schedule. 21 U.S.C. 812(b). After consideration of the analysis and
recommendation of the Assistant Secretary for Health of the HHS and
review of all relevant and available data, the Deputy Administrator of
the DEA, pursuant to 21 U.S.C. 812(b)(4), finds that:
1. Tramadol has a low potential for abuse relative to the drugs or
substances in schedule III. The abuse potential of tramadol is
comparable to the schedule IV controlled substance propoxyphene;
2. Tramadol has a currently accepted medical use in treatment in
the United States. Tramadol and other tramadol-containing products are
approved for marketing by the FDA to manage moderate to moderately
severe pain; and
3. Abuse of tramadol 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 tramadol, including its salts, isomers, and salts of
isomers, warrants control in schedule IV of the CSA. 21 U.S.C.
812(b)(4).
Requirements for Handling Tramadol
Upon the effective date of this final rule, any person who handles
tramadol is subject to the CSA's schedule IV regulatory controls and
administrative, civil, and criminal sanctions applicable to the
manufacture, distribution, dispensing, importing, exporting, engagement
in research, and conduct of instructional activities, of schedule IV
controlled substances including the following:
Registration. Any person who handles (manufactures, distributes,
dispenses, imports, exports, engages in research, or conducts
instructional activities with) tramadol, or who desires to handle
tramadol, must be registered with the DEA to conduct such activities,
pursuant to 21 U.S.C. 822, 823, 957, and 958, and in accordance with 21
CFR parts 1301 and 1312 as of August 18, 2014. Any person who currently
handles tramadol and is not registered with the DEA must submit an
application for registration and may not continue to handle tramadol as
of August 18, 2014 unless the DEA has approved that application,
pursuant to 21 U.S.C. 822, 823, 957, and 958, and in accordance with 21
CFR parts 1301 and 1312.
Disposal of stocks. Any person who does not desire or is not able
to obtain a schedule IV registration must surrender all quantities of
currently held tramadol in accordance with the procedures outlined in
21 CFR 1307.21 on or before August 18, 2014, or may transfer all
quantities of currently held tramadol to a person registered with the
DEA on or before August 18, 2014.
Security. Tramadol is subject to schedule III-V security
requirements and must be handled and stored pursuant to 21 U.S.C. 821
and 823, and in accordance with 21 CFR 1301.71-1301.93 as of August 18,
2014.
Labeling and Packaging. All labels and labeling for commercial
containers of tramadol must comply with 21 U.S.C. 825 and 958(e), and
be in accordance with 21 CFR part 1302 as of August 18, 2014.
Inventory. Every DEA registrant who possesses any quantity of
tramadol on the effective date of this final rule must take an
inventory of all stocks of tramadol on hand as of August 18, 2014,
pursuant to 21 U.S.C. 827 and 958, and in accordance with 21 CFR
1304.03, 1304.04, and 1304.11 (a) and (d).
Any person who becomes registered with the DEA after August 18,
2014 must take an initial inventory of all stocks of controlled
substances (including tramadol) on hand on the date the registrant
first engages in the handling of controlled substances, pursuant to 21
U.S.C. 827 and 958, and in accordance with 21 CFR 1304.03, 1304.04, and
1304.11 (a) and (b).
After the initial inventory, every DEA registrant must take a new
inventory of all stocks of controlled substances (including tramadol)
on hand every two years, pursuant to 21 U.S.C. 827 and 958, and in
accordance with 21 CFR 1304.03, 1304.04, and 1304.11.
Records and Reports. All DEA registrants must maintain records with
respect to tramadol pursuant to 21 U.S.C. 827 and 958 and in accordance
with 21 CFR parts 1304 and 1312 as of August 18, 2014.
Prescriptions. All prescriptions for tramadol or products
containing tramadol must comply with 21 U.S.C. 829, and be issued in
accordance with 21 CFR part 1306 and subpart C of 21 CFR part 1311 as
of August 18, 2014.
Importation and Exportation. All importation and exportation of
tramadol must be in compliance with 21 U.S.C. 952, 953, 957, and 958,
and be in accordance with 21 CFR part 1312 as of August 18, 2014.
Liability. Any activity involving tramadol not authorized by, or in
violation of, the CSA, occurring as of August 18, 2014 is unlawful, and
may subject the person to administrative, civil, and/or criminal
action.
Regulatory Analyses
Executive Orders 12866 and 13563
In accordance with 21 U.S.C. 811(a), this scheduling action is
subject to formal rulemaking procedures done ``on the record after
opportunity for a hearing,'' which are conducted pursuant to the
provisions of 5 U.S.C. 556 and 557. The CSA sets forth the criteria for
scheduling a drug or other substance. Such actions are exempt from
review by the Office of Management and Budget
[[Page 37629]]
(OMB) pursuant to section 3(d)(1) of Executive Order 12866 and the
principles reaffirmed in Executive Order 13563.
Executive Order 12988
This regulation meets the applicable standards set forth in
sections 3(a) and 3(b)(2) of Executive Order 12988 Civil Justice Reform
to eliminate drafting errors and ambiguity, minimize litigation,
provide a clear legal standard for affected conduct, and promote
simplification and burden reduction.
Executive Order 13132
This rulemaking does not have federalism implications warranting
the application of Executive Order 13132. The rule does not have
substantial direct effects on the States, on the relationship between
the national government and the States, or the distribution of power
and responsibilities among the various levels of government.
Executive Order 13175
This rule does not have tribal implications warranting the
application of Executive Order 13175. This rule does not have
substantial direct effects on one or more Indian tribes, on the
relationship between the Federal Government and Indian tribes, or on
the distribution of power and responsibilities between the Federal
Government and Indian tribes.
Regulatory Flexibility Act
The Deputy Administrator, in accordance with the Regulatory
Flexibility Act (RFA) (5 U.S.C. 601-612), 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. The purpose
of this final rule is to place tramadol, including its salts, isomers,
and salts of isomers, into schedule IV of the CSA. By this final rule,
tramadol will remain in schedule IV unless and until additional
scheduling action is taken to either transfer it between the schedules
or to remove it from the list of schedules. See 21 U.S.C. 811 and 812.
No less restrictive measures (i.e., non-control or control in schedule
V) enable the DEA to meet its statutory obligations under the CSA.
This rule affects approximately 1.5 million DEA registrations,
representing approximately 376,904 entities. The DEA estimates that
367,046 (97%) of these entities are ``small entities'' in accordance
with the RFA and SBA size standards. 5 U.S.C. 601(6) and 15 U.S.C. 632.
In accordance with the RFA, the DEA evaluated the impact of this
rule on small entities. Specifically, the DEA examined the
registration, storage, inventory and recordkeeping, and disposal
requirements for the 367,046 small entities estimated to be affected by
the rule: 55 manufacturers; 1,418 distributors/importers/exporters;
50,032 pharmacies; and 315,541 entities employing or holding
registrations as individual practitioners/mid-level practitioners/
hospitals/clinics. Ten States currently control tramadol as a schedule
IV controlled substance under State law, with requirements that meet or
exceed the DEA's requirements for schedule IV controlled substances
discussed in the NPRM. Entities in these States are not economically
impacted by this rule.
Based on the DEA's understanding of its registrants' operations and
facilities, the DEA estimates a non-recurring expense for system
modification and initial inventory cost of $245.01 for all entities and
an additional $10,000 for secure storage for 50% of distributors,
importers, and exporters. As discussed in the EIA prepared in
association with the development of this final rule, manufacturers,
pharmacies, physician offices/hospitals/clinics/other health care
facilities, and 50% of distributors, importers, and exporters are
assumed to meet the requirement of the rule without the need to expand
secure storage area. The DEA estimates these costs, on an annualized
basis, will have significant economic impact (cost greater than 1% of
annual revenue) on 0 of 55 (0%) of small manufacturers; 50 of 1,418
(3.5%) of small distributors; 107 of 50,032 (0.2%) small business
pharmacies; and 661 of 315,541 (0.2%) of individual practitioners/mid-
level practitioners/hospitals/clinics, totaling 818 of 367,046 (0.2%)
of all small entities. The percentage of small entities with
significant economic impact is not substantial, and therefore, this
rule will not result in significant economic impact on a substantial
number of small entities.
Unfunded Mandates Reform Act of 1995
In accordance with the Unfunded Mandates Reform Act (UMRA) of 1995
(2 U.S.C. 1501 et seq.), the DEA has determined and certifies pursuant
to UMRA that this action would not result in any Federal mandate that
may result ``in the expenditure by State, local, and tribal
governments, in the aggregate, or by the private sector, of $100
million or more (adjusted for inflation) in any one year * * *.''
Therefore, neither a Small Government Agency Plan nor any other action
is required under provisions of UMRA of 1995.
Paperwork Reduction Act of 1995
This action does not impose a new collection of information
requirement under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-
3521). This action would not impose recordkeeping or reporting
requirements on State or local governments, individuals, businesses, or
organizations. An agency may not conduct or sponsor, and a person is
not required to respond to, a collection of information unless it
displays a currently valid OMB control number.
Congressional Review Act
This rule is not a major rule as defined by section 804 of the
Small Business Regulatory Enforcement Fairness Act of 1996
(Congressional Review Act (CRA)). This rule will not result in: an
annual effect on the economy of $100 million or more; a major increase
in costs or prices for consumers, individual industries, Federal,
State, or local government agencies, or geographic regions; 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. However, pursuant to the CRA, the DEA has submitted a
copy of this final rule to both Houses of Congress and to the
Comptroller General.
List of Subjects in 21 CFR Part 1308
Administrative practice and procedure, Drug traffic control,
Reporting and recordkeeping requirements.
For the reasons set out above, 21 CFR part 1308 is amended as
follows:
PART 1308--SCHEDULES OF CONTROLLED SUBSTANCES
0
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.
0
2. Amend Sec. 1308.14 by adding a new paragraph (b)(3) to read as
follows:
Sec. 1308.14 Schedule IV.
* * * * *
(b) * * *
(3) 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol, its
salts, optical and geometric isomers and salts of these isomers
(including tramadol)--9752
* * * * *
[[Page 37630]]
Dated: June 27, 2014.
Thomas M. Harrigan,
Deputy Administrator.
[FR Doc. 2014-15548 Filed 7-1-14; 8:45 am]
BILLING CODE 4410-09-P