[Federal Register Volume 59, Number 19 (Friday, January 28, 1994)]
[Unknown Section]
[Page ]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-1792]


[Federal Register: January 28, 1994]


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Part III





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



_______________________________________________________________________



21 CFR Part 310, et al.



Amendment of Final Monograph for Over-the-Counter Antihistamine Drug 
Products; Rule
DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 310, 341, and 369

[Docket No. 76N-052H]
RIN 0905-AA06


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

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is amending the final 
monograph for over-the-counter (OTC) antihistamine drug products to 
include the ingredient doxylamine succinate. FDA is issuing this final 
rule after considering extensive information concerning this ingredient 
and the recommendations of its Nonprescription Drugs Advisory Committee 
(NDAC), which met on June 28, 1993, to consider potential labeling for 
doxylamine succinate regarding the results of toxicology testing 
conducted under the National Toxicology Program (NTP). This final rule 
is part of the ongoing review of OTC drug products conducted by FDA.

EFFECTIVE DATE: January 30, 1995.

FOR FURTHER INFORMATION CONTACT: William E. Gilbertson, Center for Drug 
Evaluation and Research (HFD-810), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-594-5000.

SUPPLEMENTARY INFORMATION: In the Federal Register of September 9, 1976 
(41 FR 38312), FDA published, under Sec. 330.10(a)(6) (21 CFR 
330.10(a)(6)), an advance notice of proposed rulemaking for OTC cold, 
cough, allergy, bronchodilator, and antiasthmatic drug products. In 
that notice, the Advisory Review Panel on OTC Cold, Cough, Allergy, 
Bronchodilator, and Antiasthmatic Drug Products (the Panel) recommended 
that doxylamine succinate be generally recognized as safe and effective 
(Category I) as an OTC antihistamine at a dosage level of 7.5 to 12.5 
milligrams (mg) (41 FR 38312 at 38385 through 38387). At that time, the 
agency concluded that doxylamine succinate should remain a prescription 
drug at dosage levels above 7.5 mg because it causes a high incidence 
of drowsiness compared to other OTC antihistamines (41 FR 38312 at 
38313). Subsequently, after evaluating extensive data on the safety of 
doxylamine succinate, the agency determined that doxylamine succinate 
could be marketed OTC at the Panel's recommended dosage. In the Federal 
Register of August 24, 1987 (52 FR 31892 at 31893 through 31903), the 
agency proposed monograph status at dosages of 7.5 to 12.5 mg. No 
comments were received in response to this proposal.
    In 1991, the agency received a report of a study on doxylamine 
succinate conducted by the National Center for Toxicological Research 
(NCTR) (Ref. 1). The results of this study were under consideration 
when the agency published the final monograph on OTC antihistamine drug 
products on December 9, 1992 (57 FR 58356). Accordingly, the agency 
deferred a decision on doxylamine succinate at that time.
    The NCTR technical report concerns a 2-year carcinogenicity and 
chronic toxicity study of doxylamine succinate in Fischer 344 rats and 
B6C3F1 mice. The study was conducted under the auspices of the NTP. The 
study was prompted by the National Cancer Institute's finding that 
methapyrilene, a similar antihistamine, is a potent liver carcinogen in 
the rat (Ref. 2). Methapyrilene was removed from the market in 1979. 
The NCTR study on doxylamine succinate was reviewed by the agency's 
Pulmonary-Allergy Drugs Advisory Committee (the P-A Committee) on June 
13 and 14, 1991 (Ref. 3).
    In the NCTR study (Ref. 1), doxylamine succinate was administered, 
ad libitum, as an admixture in the feed to male and female rats at dose 
levels of 0, 500, 1,000, or 2,000 parts per million (ppm) for 2 years. 
Mice of both sexes received food containing dose levels of 0, 190, 375, 
or 750 ppm. Each group contained 48 weanling animals per sex; the 
animals were scheduled for sacrifice at the end of 104 weeks. An 
additional group of animals (9 rats and 12 mice per sex) in each dose 
group was sacrificed at the end of 65 weeks. There were no significant 
treatment-related differences in survival in either rats or mice. In 
rats, the highest doxylamine succinate dose group had final body 
weights that were 22.8 percent (females) and 8.4 percent (males) lower 
than controls. A number of nonneoplastic lesions was observed in rats, 
including fatty change, degeneration, and hyperplasia of the liver and 
increased cytoplasmic alteration in the salivary glands. In mice, there 
was evidence of hepatotoxicity including hypertrophy, clear and mixed 
cell foci, and, in females, fatty change. There also was a treatment-
related increase in ``atypical'' hepatocytes in male mice. Both male 
and female mice had a dose-related increase in thyroid follicular cell 
hyperplasia. There was a positive trend for increased incidence with 
increasing dose for both hepatocellular adenomas and carcinomas in male 
rats. When the incidence of adenomas and carcinomas was combined, the 
statistical test was positive (p < 0.01) and the incidence in the 
highest dose group was significantly (p < 0.05) increased over that of 
controls. No treatment-related increase in neoplasms was found in 
female rats. Although not statistically significant, one rat in each of 
the high dose groups of male and female rats was found to have a pineal 
gland tumor, which is an extremely rare neoplasm in rats. In mice, 
doxylamine succinate administration produced an increased incidence of 
hepatocellular adenoma in both males (p < 0.001) and females (p < 
0.001). Also, there was an increased incidence of follicular cell 
adenoma of the thyroid gland in male (p < 0.05) and female (p < 0.0001) 
mice.
    Although the rodent tumorigenicity studies were positive, 
doxylamine succinate tested negative overall in in vitro tests for 
genotoxic activity (causing damage to deoxyribonucleic acid (DNA)). 
Based on the overall assessment, the tumorigenic responses observed in 
the rodent bioassays may relate to secondary mechanisms involving the 
induction of liver microsomal enzymes, cytotoxicity, cell 
proliferation, promotion of tumor potential in pre-existing susceptible 
cells, or other processes. Such mechanisms may represent species-
specific effects or threshold phenomena applicable to rodents (under 
the conditions of the bioassay), but these mechanisms are considered of 
questionable significance in humans.
    Due to uncertainty concerning the relevance of these findings to 
human use, the agency asked its P-A Committee and a number of 
consulting experts to evaluate the data and to advise the agency on 
whether doxylamine succinate should continue to be marketed OTC. By a 
vote of five to one, the P-A Committee concluded at its June 13 and 14, 
1991, meeting that doxylamine succinate is not likely to have human 
carcinogenic potential. Again, by the same vote, the P-A Committee 
recommended that doxylamine succinate could remain OTC, but that 
consumers should be alerted that these data exist. The P-A Committee 
discussed labeling as a preferred means of providing this information 
(Ref. 3, pp. 175 through 182).
    FDA subsequently developed possible labeling that could be used. 
This labeling included the warning: ``Use of this product may be 
hazardous to your health. This product contains doxylamine succinate 
which has been determined to produce tumors in laboratory animals.'' 
The agency requested the views of a national trade association of OTC 
drug manufacturers on this suggested warning (Ref. 4). In response, the 
association asserted that such a warning would be inappropriate (Ref. 
5). The association stated that such a warning: (1) Would not ensure 
safe and effective product use by consumers; (2) is not based on sound 
scientific data known to be relevant to the human condition; (3) is not 
understood and actionable, in a meaningful way, by consumers; and (4) 
might reduce the impact of other warnings and occupy scarce label 
space.
    The association argued that the proposed warning does not meet the 
criteria of section 502(c) of the Federal Food, Drug, and Cosmetic Act 
(21 U.S.C. 352(c)). This part of the statute requires labeling 
information to be presented in ``terms as to render it likely to be 
read and understood by the ordinary individual under customary 
conditions of purchase and use.'' The association contended that the 
proposed warning effectively shifts the burden of determining product 
safety from the agency to the consumer and then does not tell the 
consumer what action to take. In a subsequent communication (Ref. 6), 
the association further argued that a warning statement in the labeling 
of doxylamine products is not justified because the scientific data do 
not suggest a significant risk to humans, that such a warning would be 
unprecedented, and that a label warning is not the appropriate means 
for disclosing this information.
    In 1992, the agency established a new advisory committee 
specifically for the review of OTC drugs, the Nonprescription Drugs 
Advisory Committee (NDAC). The agency asked NDAC to consider the issue 
of a tumor statement in the labeling of OTC drug products containing 
doxylamine succinate at its June 28, 1993, meeting. The agency 
presented a summary of the NCTR data, possible labeling, and legal and 
compliance issues (Ref. 7). Other interested parties presented their 
positions. The agency asked NDAC to consider the following questions: 
(1) Should a labeling statement be used to inform consumers in place of 
other alternative approaches (no warning, prescription only status, 
removal from all marketing, etc.)? (2) Is there a desirable risk-to-
benefit relationship for labeling? (3) If the answer to both questions 
is yes, what information should be included in the labeling and what 
language should be used that would be easily understood by the average 
consumer? (4) How should information be presented to the consumer 
(i.e., under the ``Warning'' or some other heading, visible at the 
point of purchase, on the immediate container, or in a package insert) 
and should the information indicate that the product could be 
``hazardous'' to health?
    After considering the available evidence, NDAC voted unanimously 
(10 to 0) to reaffirm the P-A Committee's recommendation that 
doxylamine succinate remain OTC. NDAC also recommended (10 to 0) that 
there be no specific statement about tumors in the labeling and urged 
FDA to write a fully descriptive article on the subject in the ``FDA 
Consumer'' magazine.
    The agency has considered the two advisory committees' 
recommendations and concludes that doxylamine succinate is safe and 
effective for OTC use as an antihistamine. Accordingly, the agency is 
including doxylamine succinate in the final monograph for OTC 
antihistamine drug products. The agency is also developing an ``FDA 
Consumer'' article and has issued a talk paper concerning the NCTR 
findings in animals to inform consumers of these data and the 
uncertainty of their relevance to humans.

References

    (1) Department of Health and Human Services, NCTR, ``Technical 
Report for Experiments 406 and 407; Chronic Study of Doxylamine in 
Fischer 344 Rats and B6C3F1 Mice,'' 1991, in OTC vol. 04HFM, Docket 
No. 76N-052H, Dockets Management Branch.
    (2) Lijinsky, W., M. D. Reuber, and B. N. Blackwell, ``Liver 
Tumors Induced in Rats by Chronic Oral Administration of the Common 
Antihistamine Methapyrilene Hydrochloride,'' Science, 209:817-819, 
1980.
    (3) Transcript of the June 13 and 14, 1991, meeting of the FDA 
Pulmonary-Allergy Drugs Advisory Committee, coded RPT 5, Docket No. 
76N-052H, Dockets Management Branch.
    (4) Letter from W. E. Gilbertson, FDA, to R. W. Soller, NDMA, 
coded LET 91, Docket No. 76N-052H, Dockets Management Branch.
    (5) Letter from R. W. Soller, NDMA, to W. E. Gilbertson, FDA, 
coded C216, Docket No. 76N-052H, Dockets Management Branch.
    (6) Letter from R. W. Soller, NDMA, to W. E. Gilbertson, FDA, 
coded C224, Docket No. 76N-052H, Dockets Management Branch.
    (7) Transcript of the June 28, 1993, meeting of the FDA 
Nonprescription Drugs Advisory Committee, vol. I, pp. 6-89, coded TR 
2, Docket No. 76N-052H, Dockets Management Branch.
    The agency has examined the economic consequences of this final 
rule and has determined that it does not require either a regulatory 
impact analysis, as specified in Executive Order 12866, or a regulatory 
flexibility analysis, as defined in the Regulatory Flexibility Act 
(Pub. L. 96-354). This rulemaking for OTC antihistamine drug products 
is not expected to have an impact on small businesses. Doxylamine 
succinate remains available OTC. No product reformulations will be 
required. Some minor relabeling will be necessary to meet the 
conditions of the final monograph. Manufacturers will have 1 year to 
implement this relabeling. Thus, the impact of the final rule appears 
to be minimal. Therefore, the agency concludes that the final rule is 
not a major rule as defined in Executive Order 12866. Further, the 
agency certifies that this final rule will not have a significant 
economic impact on a substantial number of small entities as defined in 
the Regulatory Flexibility Act.
    The agency has determined under 21 CFR 25.24(c)(6) that this action 
is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.
    The agency is removing the exemption for certain drugs limited by 
new drug applications (NDA) to prescription sale in Sec. 310.201(a)(13) 
(applicable to doxylamine succinate preparations) because most portions 
of that exemption are superseded by the requirements of the 
antihistamine final monograph (21 CFR part 341). Section 310.201(a)(13) 
does not apply to the use of doxylamine succinate as a nighttime sleep-
aid, for which an NDA is required for marketing.

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.

21 CFR Part 369

    Labeling, Medical devices, 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, 341, and 369 are amended as follows:

PART 310--NEW DRUGS

    2. The authority citation for 21 CFR part 310 continues to read as 
follows:

    Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 512-
516, 520, 601(a), 701, 704, 705, 721 of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 
360b-360f, 360j, 361(a), 371, 374, 375, 379e); secs. 215, 301, 
302(a), 351, 354-360F of the Public Health Service Act (42 U.S.C. 
216, 241, 242(a), 262, 263b-263n).


Sec. 310.201 [Amended]

    2. Section 310.201 Exemption for certain drugs limited by new-drug 
applications to prescription sale is amended by removing paragraph 
(a)(13) and reserving it.

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: Secs. 201, 501, 502, 503, 505, 510, 701 of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 
355, 360, 371).4. Section 341.12 is amended by adding new paragraph 
(h) to read as follows:


Sec. 341.12 Antihistamine active ingredients.

* * * * *
    (h) Doxylamine succinate.
* * * * *
    5. Section 341.72 is amended by revising the heading of paragraphs 
(c)(4) and (c)(6)(iii) and by adding new paragraph (d)(8) to read as 
follows:


Sec. 341.72  Labeling of antihistamine drug products.

* * * * *
    (c) * * *
    (4) For products containing diphenhydramine citrate, 
diphenhydramine hydrochloride, or doxylamine succinate identified in 
Sec. 341.12(f), (g), and (h). * * *
* * * * *
    (6) * * *
    (iii) For products containing diphenhydramine citrate, 
diphenhydramine hydrochloride, or doxylamine succinate identified in 
Sec. 341.12(f), (g), and (h). * * *
    (d) * * *
    (8) For products containing doxylamine succinate identified in 
Sec. 341.12(h). Adults and children 12 years of age and over: oral 
dosage is 7.5 to 12.5 milligrams every 4 to 6 hours, not to exceed 75 
milligrams in 24 hours, or as directed by a doctor. Children 6 to under 
12 years of age: oral dosage is 3.75 to 6.25 milligrams every 4 to 6 
hours, not to exceed 37.5 milligrams in 24 hours, or as directed by a 
doctor. Children under 6 years of age: consult a doctor.
* * * * *
    6. Section 341.90 is amended by adding new paragraph (l) to read as 
follows:

Sec. 341.90  Professional labeling.

* * * * *
    (l)  For products containing doxylamine succinate identified in 
Sec. 341.12(h). Children 2 to under 6 years of age: oral dosage is 1.9 
to 3.125 milligrams every 4 to 6 hours, not to exceed 18.75 milligrams 
in 24 hours.
* * * * *

PART 369--INTERPRETATIVE STATEMENTS RE WARNINGS ON DRUGS AND 
DEVICES FOR OVER-THE-COUNTER SALE

    7. The authority citation for 21 CFR part 369 continues to read as 
follows:

    Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701 of 
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 
352, 353, 355, 356, 357, 371).


Sec. 369.21  [Amended]

    8. Section 369.21 Drugs; warning and caution statements required by 
regulations is amended by revising the introductory text of the entry 
for ``ANTIHISTAMINICS, ORAL (PHENYLTOLOXAMINE DIHYDROGEN CITRATE, 
DOXYLAMINE SUCCINATE, AND CHLOROTHEN CITRATE PREPARATIONS)'' to read 
``ANTIHISTAMINICS, ORAL (PHENYLTOLOXAMINE DIHYDROGEN CITRATE AND 
CHLOROTHEN CITRATE PREPARATIONS). (See Sec. 310.201(a)(4) and (a)(24) 
of this chapter.)''
* * * * *

    Dated: January 24, 1993.
 Michael R. Taylor,
 Deputy Commissioner for Policy.
[FR Doc. 94-1792 Filed 1-27-94; 8:45 am]
BILLING CODE 4160-01-F