[Federal Register Volume 63, Number 146 (Thursday, July 30, 1998)]
[Rules and Regulations]
[Pages 40647-40650]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-20303]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 310 and 341
[Docket No. 76N-052N]
RIN 0910-AA01
Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug
Products for Over-the-Counter Human Use; Amendment of Monograph for OTC
Nasal Decongestant Drug Products
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending the final
monograph for over-the-counter (OTC) nasal decongestant drug products
(drug products used to relieve nasal congestion caused by acute or
chronic rhinitis) to add the ingredient levmetamfetamine (formerly l-
desoxyephedrine) and to classify this ingredient as generally
recognized as safe and effective for OTC use. The agency is also
removing l-desoxyephedrine from the list of nonmonograph active
ingredients. This final rule is part of the ongoing review of OTC drug
products conducted by FDA.
EFFECTIVE DATE: July 30, 1999.
FOR FURTHER INFORMATION CONTACT: Cazemiro R. Martin, Center for Drug
Evaluation and Research (HFD-560), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-827-2222.
SUPPLEMENTARY INFORMATION:
I. Background
In the Federal Register of August 23, 1994 (59 FR 43386), the
agency published a final rule in the form of a final monograph
establishing conditions under which OTC nasal decongestant drug
products are generally recognized as safe and effective. The final
monograph did not include l-desoxyephedrine as a nasal decongestant
active ingredient because it was not currently standardized and
characterized for quality and purity in an official compendium, i.e.,
the United States Pharmacopeia (USP)/National Formulary (59 FR 43386 at
43408). Instead, the final rule listed l-desoxyephedrine in
Sec. 310.545(a)(6)(ii)(B) (21 CFR 310.545(a)(6)(ii)(B)) as not
generally recognized as safe and effective. The agency stated in the
final rule that OTC drug products containing l-desoxyephedrine as a
topical nasal decongestant active ingredient were new drugs under
section 201(p) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C.
321(p)). The effective date of the final rule was August 23, 1995.
In the Federal Register of March 8, 1996 (61 FR 9570), the agency
stayed the entry for ``l-desoxyephedrine (topical)'' in
Sec. 310.545(a)(6)(ii)(B) until further notice. The agency explained
that a citizen petition submitted in response to the OTC nasal
decongestant final rule requested that the agency defer the effective
date of Sec. 310.545(a)(6)(ii)(B) as it applies to l-desoxyephedrine
(topical) until December 31, 1996. The petitioner stated that it had
forwarded a draft compendial monograph for l-desoxyephedrine to the USP
in late July 1995. The agency added that when l-desoxyephedrine becomes
official in the
[[Page 40648]]
USP, the final monograph for OTC nasal decongestant drug products would
be amended to include the active ingredient and
Sec. 310.545(a)(6)(ii)(B) would be revised accordingly. The agency
provided certain labeling requirements that would be in effect for
topical nasal decongestant drug products containing l-desoxyephedrine
during the stay (61 FR 9570).
II. Recent Developments
In the Pharmacopeial Forum of January/February 1997 (Ref. 1), USP
proposed a monograph for l-desoxyephedrine. Based on the United States
Adopted Names (USAN) Council's recommendation, the proposal included
levmetamfetamine as the new name for l-desoxyephedrine. The USAN
Council and USP used the International Nomenclature Name (INN),
levmetamfetamine, in place of l-desoxyephedrine. Levmetamfetamine is
the title of the monograph adopted in the 6th Supplement of USP 23
(Ref. 2).
In response to the USP proposed monograph for levmetamfetamine
(Ref. 1), the agency at that time expressed its strong objection and
the objection of the U.S. Department of Justice, Drug Enforcement
Administration (DEA) concerning the USAN Council's recommendation to
adopt ``levmetamfetamine'' as the nonproprietary name for l-
desoxyephedrine (Ref. 3). The agency indicated to the Council that both
FDA and DEA shared concerns about an increased use of methamphetamine
in the United States and with the large-scale diversion of some OTC
drug products for illicit use in the manufacture of the controlled
substances methamphetamine and methcathinone. Both agencies had
concerns that the new name, levmetamfetamine, might draw the attention
of potential drug abusers to these OTC nasal decongestant drug products
if they contain ``metamfetamine'' in their name. The agency pointed out
that although l-desoxyephedrine is a nonnarcotic substance (21 CFR
1308.22), an OTC drug product label containing a sound-alike name, such
as ``levmetamfetamine'' may encourage intentional misuse. For these
concerns, the agency asked the USAN Council to reconsider the proposed
name change.
At its January 27, 1997, meeting, the USAN Council considered the
agency's request regarding the name change of l-desoxyephedrine to
``levmetamfetamine'' and voted to retain the name for the following
reasons (Ref. 4): (1) Levmetamfetamine is nonaddictive, (2) the new
name is consistent with INN policy, and (3) any other name for l-
desoxyephedrine may also be confusing. At this time, the agency accepts
the USAN Council's decision and is using levmetamfetamine as the new
name for l-desoxyephedrine in the OTC nasal decongestant final
monograph.
III. The Agency's Final Conclusions
Based on the new USP monograph for levmetamfetamine, the agency is
amending the final monograph for OTC nasal decongestant drug products
to include levmetamfetamine in Sec. 341.20(b)(1) (21 CFR 341.20(b)(1))
as a safe and effective OTC nasal decongestant active ingredient. The
agency is also adding labeling for products containing this ingredient
to the OTC nasal decongestant final monograph as follows:
1. In Sec. 341.80(c)(2)(ii) (21 CFR 341.80(c)(2)(ii): For products
containing levmetamfetamine identified in Sec. 341.20(b)(1) when used
in an inhalant dosage form and when labeled for adults. ``Do not use
this product for more than 7 days. Use only as directed. Frequent or
prolonged use may cause nasal congestion to recur or worsen. If
symptoms persist, ask a doctor.''
2. In Sec. 341.80(c)(2)(vii): For products containing
levmetamfetamine identified in Sec. 341.20(b)(1) when used in an
inhalant dosage form and when labeled for children under 12 years of
age. ``Do not use this product for more than 7 days. Use only as
directed. Frequent or prolonged use may cause nasal congestion to recur
or worsen. If symptoms persist, ask a doctor.''
3. In Sec. 341.80(d)(2)(i): For products containing
levmetamfetamine identified in Sec. 341.20(b)(1) when used in an
inhalant dosage form. ``The product delivers in each 800 milliliters of
air 0.04 to 0.150 milligrams of levmetamfetamine. Adults: 2 inhalations
in each nostril not more often than every 2 hours. Children 6 to under
12 years of age (with adult supervision): 1 inhalation in each nostril
not more often than every 2 hours. Children under 6 years of age: ask a
doctor.''
4. In Sec. 341.80(d)(2)(viii), the agency is expanding the header
to read: ``Other required statements--For products containing
levmetamfetamine or propylhexedrine identified in Sec. 341.20(b)(1) or
(b)(9) when used in an inhalant dosage form.''
The agency is also amending Sec. 310.545(a)(6)(ii)(B) by removing
the entry for ``l-desoxyephedrine (topical).''
IV. Labeling Guidance
In the Federal Register of February 27, 1997 (62 FR 9024), FDA
proposed to establish a standardized format for the labeling of OTC
drug products. The labeling in this final rule does not follow the new
format because the proposal has not been finalized to date. However,
the agency is providing manufacturers guidance on how labeling in this
final rule would be converted into the format proposed in Sec. 201.66
(62 FR 9024 at 9050 and 9051). The purpose and use of the products are
already listed in and would follow Sec. 341.80(a) and (b) of the final
monograph for OTC nasal decongestant drug products. The directions
would appear as stated in this final rule and in
Sec. 341.80(d)(2)(viii). The warnings in Sec. 341.80(c)(2)(ii) and
(c)(2)(vii) would meet the requirements of proposed Sec. 201.66(c)(4)
as follows:
Table 1.--Conversion of Monograph Warnings to Proposed New Format
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Nasal Decongestant Final Monograph February 27, 1997, Proposal
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Do not use this product for more than 7 days. Do Not Use:
for more than 7 days
If symptoms persist, ask a doctor. Stop Using This Product If:
symptoms persist
Ask a doctor. These may be signs of a serious
condition.
Use only as directed. When Using This Product:
use only as directed
frequent or prolonged use may cause nasal congestion
to recur or worsen
Frequent or prolonged use may cause nasal congestion
to recur or worsen.
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[[Page 40649]]
Until the final rule for the labeling format proposal is
published, manufacturers, distributors, and packagers must comply with
the final rule published in this document. The final rule for the new
labeling format will provide a date by which the labeling of all OTC
nasal decongestant drug products covered by the monograph will need to
be converted to the new labeling format.
V. Analysis of Impacts
FDA has examined the impacts of this final rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612).
Executive Order 12866 directs agencies to assess all costs and benefits
of available regulatory alternatives and, when regulation is necessary,
to select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts, and equity). Under the Regulatory
Flexibility Act, if a rule has a significant impact on a substantial
number of small entities, an agency must analyze regulatory options
that would minimize any significant impact of a rule on small entities.
Title II of the Unfunded Mandates Reform Act (2 U.S.C. 1501 et
seq.) requires that agencies prepare a written statement and economic
analysis before proposing any rule that may result in an expenditure in
any 1 year by State, local, and tribal governments, in the aggregate,
or by the private sector, of $100 million (adjusted annually for
inflation). The proposed rule that has led to the development of this
final rule was published on January 15, 1985 (50 FR 2220), before the
Unfunded Mandates Reform Act was enacted. The agency explains in this
final rule that the final rule will not result in an expenditure in any
1 year by State, local, and tribal governments, in the aggregate, or by
the private sector, of $100 million.
The agency believes that this final rule is consistent with the
principles set out in the Executive Order and in these two statutes.
The purpose of this final rule is to establish conditions under which
OTC nasal decongestant drug products containing levmetamfetamine
(formerly l-desoxyephedrine) are generally recognized as safe and
effective. This includes establishing the allowable monograph labeling.
The March 8, 1996, notice of partial stay of the OTC nasal
decongestant final monograph included labeling that manufacturers of
OTC topical nasal decongestant drug products containing
levmetamfetamine (l-desoxyephedrine) had to have in effect by September
9, 1996. Therefore, all such currently marketed drug products should
have this labeling in effect. The only labeling change that is
necessary at this time is to change the established name from l-
desoxyephedrine to levmetamfetamine as a result of the 6th Supplement
to USP 23 (Ref. 2). A number of manufacturers of these products have
already made this change as new labeling needed to be prepared. The
agency believes that an effective date of 1 year from the date of this
publication will provide manufacturers of the remaining products
sufficient time to incorporate the name change during a future
manufacturing cycle. The agency estimates that there are less than 100
stock keeping units (SKU) (individual products, packages, and sizes) of
products containing this ingredient currently in the OTC marketplace.
Other manufacturers who now wish to market a product containing this
ingredient may enter the marketplace at any time.
The agency considered but rejected several labeling alternatives:
(1) A longer implementation period, and (2) an exemption for small
entities. The agency does not consider either of these approaches
acceptable because only a single labeling change (in the product's
established name) is needed at this time. Further, the agency is aware
that manufacturers of products containing this ingredient already
started to change product labeling after the name change became
official in USP 23.
The analysis shows that this final rule is not economically
significant under Executive Order 12866 and that the agency has
considered the burden to small entities. Thus, this economic analysis,
together with other relevant sections of this document, serves as the
agency's final regulatory flexibility analysis, as required under the
Regulatory Flexibility Act. Finally, this analysis shows that the
Unfunded Mandates Act does not apply to the final rule because it would
not result in an expenditure in any 1 year by State, local, and tribal
governments, in the aggregate, or by the private sector, of $100
million.
VI. Paperwork Reduction Act of 1995
FDA concludes that the labeling requirements in this document are
not subject to review by the Office of Management and Budget because
they do not constitute a ``collection of information'' under the
Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et seq.). Rather, the
labeling statements are a ``public disclosure of information originally
supplied by the Federal Government to the recipient for the purpose of
disclosure to the public'' (5 CFR 1320.3(c)(2)).
VII. Environmental Impact
The agency has determined under 21 CFR 25.30(h) that this action is
of a type that is categorically excluded from the preparation of an
environmental assessment because these actions, as a class, will not
result in the production or distribution of any substance and therefore
will not result in the production of any substance into the
environment.
VIII. References
The following references are on display in the Dockets Management
Branch (address above) and may be seen by interested persons between 9
a.m. and 4 p.m., Monday through Friday.
(1) Pharmacopeial Forum, The United States Pharmacopeial
Convention, Inc., Rockville, MD, p. 3429, January through February,
1997.
(2) Sixth Supplement to USP 23 and to NF 18, United States
Pharmacopeial Convention, Inc., Rockville, MD, p. 3631, 1997.
(3) Memorandum from D. Bowen, FDA, to R. Wolters, FDA
representative to USAN Council, dated January 22, 1997, Docket No.
76N-052N, Dockets Management Branch.
(4) Memorandum from R. Wolters, FDA representative to USAN
Council, to D. Bowen et al., FDA, dated February 6, 1997, Docket No.
76N-052N, Dockets Management Branch.
List of Subjects
21 CFR Part 310
Administrative practice and procedure, Drugs, Labeling, Medical
devices, Reporting and recordkeeping requirements.
21 CFR Part 341
Labeling, Over-the-counter drugs.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts
310 and 341 are amended as follows:
PART 310--NEW DRUGS
1. The authority citation for 21 CFR part 310 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 357, 360b-
360f, 360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 242(a),
262, 263b-263n.
2. Section 310.545 Drug products containing certain active
ingredients offered over-the-counter (OTC) for certain uses is amended
in paragraph (a)(6)(ii)(B) by removing the entry for ``l-
desoxyephedrine (topical).''
[[Page 40650]]
PART 341--COLD, COUGH, ALLERGY, BRONCHODILATOR, AND ANTIASTHMATIC
DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE
3. The authority citation for 21 CFR part 341 continues to read as
follows:
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.
4. Section 341.20 is amended by revising paragraph (b)(1) to read
as follows:
Sec. 341.20 Nasal decongestant active ingredients.
* * * * *
(b) * * *
(1) Levmetamfetamine.
* * * * *
5. Section 341.80 is amended by revising paragraphs (c)(2)(ii),
(c)(2)(vii), and (d)(2)(i), and the heading of paragraph (d)(2)(viii)
to read as follows:
Sec. 341.80 Labeling of nasal decongestant drug products.
* * * * *
(c) * * *
(2) * * *
(ii) For products containing levmetamfetamine identified in
Sec. 341.20(b)(1) when used in an inhalant dosage form and when labeled
for adults. ``Do not use this product for more than 7 days. Use only as
directed. Frequent or prolonged use may cause nasal congestion to recur
or worsen. If symptoms persist, ask a doctor.''
* * * * *
(vii) For products containing levmetamfetamine identified in
Sec. 341.20(b)(1) when used in an inhalant dosage form and when labeled
for children under 12 years of age. ``Do not use this product for more
than 7 days. Use only as directed. Frequent or prolonged use may cause
nasal congestion to recur or worsen. If symptoms persist, ask a
doctor.''
* * * * *
(d) * * *
(2) * * *
(i) For products containing levmetamfetamine identified in
Sec. 341.20(b)(1) when used in an inhalant dosage form. The product
delivers in each 800 milliliters of air 0.04 to 0.150 milligrams of
levmetamfetamine. Adults: 2 inhalations in each nostril not more often
than every 2 hours. Children 6 to under 12 years of age (with adult
supervision): 1 inhalation in each nostril not more often than every 2
hours. Children under 6 years of age: ask a doctor.
* * * * *
(viii) Other required statements--For products containing
levmetamfetamine or propylhexedrine identified in Sec. 341.20(b)(1) or
(b)(9) when used in an inhalant dosage form. * * *
* * * * *
Dated: July 23, 1998.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 98-20303 Filed 7-29-98; 8:45 am]
BILLING CODE 4160-01-F