[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