Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug Products for Over-the-Counter Human Use; Amendment of Monograph for OTC Nasal Decongestant Drug Products

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