[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
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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.
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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