[Federal Register Volume 65, Number 166 (Friday, August 25, 2000)]
[Proposed Rules]
[Pages 51780-51782]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-21758]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 341

[Docket No. 76N-052H]
RIN 0910-AA01


Cold, Cough, Allergy, Bronchodilator, and Antiasthmatic Drug 
Products for Over-the-Counter Human Use; Reopening of the 
Administrative Record for Antihistamine Drug Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Reopening of the administrative record.

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SUMMARY: The Food and Drug Administration (FDA) is reopening the 
administrative record for over-the-counter (OTC) antihistamine drug 
products to accept comments on recommendations concerning the use of 
these products to relieve symptoms of sneezing and runny nose 
associated with the common cold made at a joint advisory committee 
meeting on November 16, 1995. The agency is inviting comments on its 
tentative position that there is sufficient basis to include the use of 
OTC antihistamines for these symptoms in the final monograph for OTC 
cold, cough, allergy, bronchodilator, and antiasthmatic drug products. 
This reopening is part of the ongoing review of OTC drug products 
conducted by FDA.

DATES: Submit written comments by November 24, 2000.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

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 September 9, l976 (41 FR 38312), FDA 
published, under 21 CFR 330.10(a)(6), an advance notice of proposed 
rulemaking to establish a monograph for OTC cold, cough, allergy, 
bronchodilator, and antiasthmatic drug products, together with the 
recommendations of the Advisory Review Panel on OTC Cold, Cough, 
Allergy, Bronchodilator, and Antiasthmatic Drug Products (the Panel), 
which was the advisory review panel responsible for evaluating data on 
the active ingredients in this drug class. The Panel recommended that 
antihistamines be Category III (available data are insufficient to 
classify as safe and effective, and further testing is required) for 
treating symptoms associated with the common cold (41 FR 38312 at 38380 
and 38381).
    In response to the Panel's Category III recommendation, two 
manufacturers submitted data to support the use of chlorpheniramine 
maleate for the relief of cold symptoms. Based on these data, the 
agency proposed an indication for the temporary relief of runny nose 
and sneezing associated with the common cold in Sec. 341.72(b) (21 CFR 
341.72(b)) of the tentative final monograph for OTC antihistamine drug 
products (50 FR 2200 at 2203, 2204, 2216, and 2217, January 15, 1985). 
The agency stated in the tentative final monograph that the 
pharmacologic actions of the various Category I antihistamines are 
similar; thus, the indications stated in Sec. 341.72 were proposed for 
all antihistamines included in 21 CFR 341.12 of the tentative final 
monograph. An amendment to the tentative final monograph was published 
in 1987 that included doxylamine succinate and chlorcyclizine 
hydrochloride as Category I ingredients for the same claims as all 
Category I antihistamine ingredients (52 FR 31892, August 24, 1987).
    Subsequent to the tentative final monograph, the agency evaluated 
supplemental new drug applications requesting a prescription-to-OTC 
switch for drug products containing a nonmonograph antihistamine. Some 
applications requested labeling for treating symptoms associated with 
the common cold based on similarity of pharmacologic action to the 
antihistamines included in the tentative final monograph without direct 
support from clinical studies. In considering these applications, the 
agency questioned whether the pharmacologic effects of these newer 
antihistamines are sufficiently similar to the pharmacologic actions of 
older, monograph antihistamines.
    At that time, the agency was aware that the scientific community 
was divided over the effectiveness of antihistamine ingredients for 
symptoms of the common cold. In the final rule for OTC antihistamine 
drug products (57 FR 58356, December 9, 1992), the agency deferred its 
final action on labeling for common cold symptoms for OTC 
antihistamines in order to evaluate data that had become available 
after publication of the tentative final monograph. The agency stated 
its intention to further evaluate whether data on chlorpheniramine 
maleate to relieve sneezing and runny nose associated with the common 
cold could be extrapolated to other antihistamines included in the 
final monograph or to other antihistamines that may be switched from 
prescription to OTC status. The agency further stated its intention to 
evaluate more recent clinical studies as well as the older data 
concerning the effectiveness of antihistamines in treating symptoms of 
the common cold. The agency solicited all studies, negative as well as 
positive, from drug manufacturers and the Consumer Healthcare Products 
Association (formerly the Nonprescription Drug Manufacturers 
Association), and searched its own files and the published literature. 
In 1992, the agency formed a task force that consisted of agency staff, 
FDA Staff Fellows, and outside consultants, to assess the available 
data on OTC antihistamines that would help resolve these issues.
    In order to be included in the agency's evaluation, a study had to 
meet certain inclusion criteria developed by the task force, as 
follows: (1) The study must be double-blind, randomized, and placebo 
controlled; (2) the antihistamine in the common cold medication must be 
a single ingredient; (3) the common cold had to exist for no more than 
2 days before the first application of study medication; (4) subjects 
needed to have runny nose of at least moderate intensity at baseline 
before any medication; and (5) the severity of the runny nose had to be 
evaluated at baseline and at least once after administration of 
medication during both the first and second days of medication (Ref. 
1).
    The task force evaluated all of the submitted studies and 
determined that nine generally met these requirements (three using 
chlorpheniramine maleate and six using doxylamine succinate). The task 
force then did a meta-analysis on these studies, comparing the active 
ingredients to placebo for both increment scores (change from baseline) 
and goal of therapy (50 percent reduction or complete cessation of 
symptom). The symptoms evaluated by the task force were runny nose and 
sneezing on each of 2-study days. Using these parameters and analyses, 
the task force found that the antihistamines studied had an effect on 
runny nose and sneezing in the early phases of the common cold (Ref. 
2).

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    The task force presented the results of its meta-analysis to a 
joint meeting of the Nonprescription Drugs Advisory Committee and the 
Pulmonary-Allergy Drugs Advisory Committee (the Committees) held on 
November 15, 1994 (Ref. 2). The Committees were not asked for a 
recommendation at that time. The following year, on November 16, 1995, 
the Committees met again and discussed the analysis (Ref. 3). At this 
meeting, the Committees concluded that the meta-analysis supports the 
use of chlorpheniramine maleate and doxylamine succinate to relieve the 
symptoms of runny nose and sneezing associated with the common cold. 
However, the Committees voted against extrapolating the data on these 
two ingredients to all Category I antihistamines because they had 
insufficient data regarding the active mechanism of these drugs in 
relief of symptoms of the common cold. Some members raised the issue of 
comparative potency relative to anticholinergic and/or antihistaminic 
effects of other Category I antihistamines.

II. The Agency's Discussion of the Committees' Recommendations

    The agency believes that sufficient basis currently exists for all 
Category I antihistamine ingredients to have the indication of relief 
of sneezing and runny nose due to the common cold. Studies published 
after the task force's meta-analysis suggest that other antihistamines, 
brompheniramine maleate (Ref. 4) and clemastine fumarate (Ref. 5), are 
effective for relief of sneezing and runny nose associated with the 
common cold. Both studies reported therapeutic effects against cold 
symptoms similar to those seen against allergic rhinitis symptoms, 
which is their currently approved indication. Data from the 
brompheniramine study were submitted to the agency (Ref. 6). However, 
because the administrative record is currently closed, the study and 
supporting documentation will not be discussed here but will be 
discussed in the final rule along with any new information that comes 
to the agency's attention.
    Ingredients in this class have pharmacologic actions and 
therapeutic applications in common and are generally discussed together 
(Ref. 7). These ingredients are known to be effective H1 
antagonists, and some studies have demonstrated the release of 
histamine following rhinovirus challenge in allergic individuals (Refs. 
8 and 9). Further, the monograph antihistamines exert mild to moderate 
anticholinergic effects and are effective in drying nasal secretions 
(Refs. 2 and 10 through 15). Therefore, the agency believes that 
populations of consumers exist who would benefit from either of these 
effects (antihistaminic or anticholinergic) on cold symptoms.
    Additionally, the agency believes that some of the controversy over 
the use of antihistamines for the common cold may have originated from 
their early promotion as ``cures'' or ``preventatives'' (Ref. 16). It 
is now known that Category I antihistamine ingredients do not cure or 
prevent the common cold, but rather are palliative agents that are 
useful for reducing nasal discharge (runny nose) and sneezing (Refs. 4, 
5, 12, and 17). Suppression of sneezing and other cold symptoms may 
help reduce the spread of the cold virus and thus have a public health 
impact (Ref. 4). The literature and the meta-analysis of data conducted 
by the agency's task force support these uses for OTC common cold 
symptom relief.
    The agency believes that OTC antihistamine ingredients effectively 
relieve cold symptoms in populations of consumers and should remain 
available for that use. Unless the agency receives convincing data to 
refute its tentative position, it intends to publish a final monograph 
for OTC antihistamine drug products that includes the indication for 
relief of sneezing and runny nose associated with the common cold 
proposed in Sec. 341.72(b)(2) (50 FR 2200 at 2216). Therefore, the 
agency is reopening the administrative record for the rulemaking for 
OTC antihistamine drug products to accept comments concerning the use 
of these products to relieve symptoms of sneezing and runny nose 
associated with the common cold.

III. References

    The following references have been placed 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. D'Agostino, R. B., and M. Weintraub, ``Meta-Analysis: A 
Method for Synthesizing Research,'' Clinical Pharmacology and 
Therapeutics, vol. 58, pp. 605-616, 1995.
    2. Transcript of the Joint Meeting of the Nonprescription Drugs 
Advisory Committee and the Pulmonary-Allergy Drugs Advisory 
Committee, November 15, 1994, pp. 11-113, in OTC vol. 04HFMA2, 
Docket No. 76N-052H, Dockets Management Branch.
    3. Transcript of the Joint Meeting of the Nonprescription Drugs 
and Pulmonary-Allergy Drugs Advisory Committees, November 16, 1995, 
pp. 191-333, in OTC vol. 04HFMA2, Docket No. 76N-052H, Dockets 
Management Branch.
    4. Gwaltney, J. M., and H. M. Druce, ``Efficacy of 
Brompheniramine Maleate for the Treatment of Rhinovirus Colds,'' 
Clinical Infectious Diseases, vol. 25, pp. 1188-1194, 1997.
    5. Turner, R. B. et al., ``Effectiveness of Clemastine Fumarate 
for Treatment of Rhinorrhea and Sneezing Associated with the Common 
Cold,'' Clinical Infectious Diseases, vol. 25, pp. 824-830, 1997.
    6. Comment No. C229, Docket No. 76N-052H, Dockets Management 
Branch.
    7. Douglas, W. W., ``Antihistamines,'' in The Pharmacological 
Basis of Therapeutics, 4th Ed., edited by L. S. Goodman and A. 
Gilman, The MacMillan Co., New York, pp. 635-645, 1970.
    8. Thomas, L. H. et al., ``Leukocyte Responses to Experimental 
Infection with Human Rhinovirus,'' The Journal of Allergy and 
Clinical Immunology, vol. 94, pp. 1255-1262, 1994.
    9. Calhoun, W. J. et al., ``A Common Cold Virus, Rhinovirus 16, 
Potentiates Airway Inflammation after Segmental Antigen 
Bronchoprovocation in Allergic Subjects,'' The Journal of Clinical 
Investigation, vol. 94, pp. 2200-2208, 1994.
    10. Pearlman, D. S., ``Antihistamines: Pharmacology and Clinical 
Use,'' Drugs, vol. 12, pp. 258-273, 1976.
    11. Loew, E. R., ``Pharmacology of Antihistamine Compounds,'' 
Physiological Reviews, vol. 27, pp. 542-573, 1947.
    12. Cooper, J. W., ``H-1 Blockers--Classical Antihistamines,'' 
New England and Regional Allergy Proceedings, vol. 7, pp. 356-361, 
1986.
    13. Darling, C. M., ``Chapter 16 --Histamine and Antihistaminic 
Agents,'' in Wilson and Gisvold's Textbook of Organic Medicinal and 
Pharmaceutical Chemistry, 8th Ed., edited by R. F. Doerge, J. B. 
Lippincott Co., Philadelphia, pp. 583-606, 1982.
    14. The United States Pharmacopeial Convention, Inc., 
``Antihistamines-Systemic,'' in USP DI, Drug Information for the 
Health Care Professional, Rand McNally, Taunton, MA, pp. 302-309, 
1995.
    15. Berkow, R., editor, The Merck Manual, 14th Ed., Merck & Co., 
Inc., Rahway, NJ, pp. 2397-2403, 1982.
    16. Feller, A. E. et al., ``The Failure of Antihistaminic Drugs 
to Prevent or Cure the Common Cold and Undifferentiated Respiratory 
Diseases,'' The New England Journal of Medicine, vol. 242, pp. 737-
744, 1950.
    17. Roth, F. E., and I. I. A. Tabachnick, ``Chapter 48--
Histamine and Antihistamines,'' in Drill's Pharmacology in Medicine, 
4th Ed., edited by J. R. DiPalma, McGraw-Hill Book Co., New York, 
pp. 995-1020, 1971.

IV. Request for Comments

    Interested persons may submit to the Dockets Management Branch 
(address above) written comments by November 24, 2000. Three copies of 
any comments are to be submitted, except that individuals may submit 
one copy. Comments should be identified with the docket number found in 
brackets in the heading of this document and may be accompanied by a 
supporting memorandum or brief. Received

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comments may be seen in the office above between 9 a.m. and 4 p.m., 
Monday through Friday.

    Dated: August 15, 2000.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 00-21758 Filed 8-24-00; 8:45 am]
BILLING CODE 4160-01-F