[Federal Register Volume 59, Number 22 (Wednesday, February 2, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-2265]
[[Page Unknown]]
[Federal Register: February 2, 1994]
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Part VII
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Part 343
Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for
Over-the-Counter Human Use; Amendment to Tentative Final Monograph;
Proposed Rule
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Food and Drug Administration
21 CFR Part 343
[Docket No. 77N-094U]
RIN 0905-AA06
Internal Analgesic, Antipyretic, and Antirheumatic Drug Products
for Over-the-Counter Human Use; Proposed Amendment to Tentative Final
Monograph
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice of proposed rulemaking.
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SUMMARY: The Food and Drug Administration (FDA) is issuing a notice of
proposed rulemaking amending the tentative final monograph for over-
the-counter (OTC) internal analgesic, antipyretic, and antirheumatic
drug products. This proposal affects combinations of internal analgesic
and antacid ingredients, specifically sodium bicarbonate used as an
antacid active ingredient. As proposed, combination drug products
intended to be dissolved in liquid prior to administration, such as
powders and effervescent granules or tablets, would not be allowed to
make a claim for ``relief of overindulgence in food and drink'' or a
claim for ``relief of hangover.'' FDA is issuing this notice of
proposed rulemaking after receiving reports of gastric (stomach)
rupture following ingestion of sodium bicarbonate to relieve
gastrointestinal distress. This proposal is part of the ongoing review
of OTC drug products conducted by FDA.
DATES: Written comments by April 4, 1994; written comments on the
agency's economic impact determination by April 4, 1994. The agency is
proposing that any final rule that may issue based on this proposal
become effective 6 months after the date of publication in the Federal
Register.
ADDRESSES: Written comments to the Dockets Management Branch (HFA-305),
Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr., Rockville,
MD 20857.
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:
I. Background
In the Federal Register of November 16, 1988 (53 FR 46204), the
agency published the tentative final monograph for OTC internal
analgesic, antipyretic, and antirheumatic drug products (internal
analgesic tentative final monograph). This proposal permitted
combinations of acetaminophen and any monograph antacid ingredient and
combinations of aspirin and any monograph antacid ingredient (see
proposed Sec. 343.20(b)(1) and (b)(3) (53 FR 46204 at 46255)). As
proposed in Sec. 343.60(b)(2) and (b)(4), indications for these
combination products included concurrent antacid and internal analgesic
symptoms (53 FR 46258). In the same issue of the Federal Register (53
FR 46190), the agency proposed amendments to the final monograph for
OTC antacid drug products so that the antacid and internal analgesic
final monographs would be consistent. The agency proposed to revise
Sec. 331.15(b) (21 CFR 331.15(b)) to include antacid/acetaminophen and
antacid/aspirin combinations as generally recognized as safe and
effective. The agency also proposed to add a new Sec. 331.60 (entitled
``Labeling of permitted combinations of active ingredients'') to
reflect that the new combinations included in Sec. 331.15(b) should use
the indications that were proposed in Sec. 343.60(b)(2) and (b)(4) of
the internal analgesic tentative final monograph.
In the Federal Register of October 1, 1982 (47 FR 43540), FDA
published an advance notice of proposed rulemaking for OTC orally
administered drug products for relief of symptoms associated with
overindulgence in alcohol and food. The notice included a report
prepared by the Advisory Review Panel on OTC Miscellaneous Internal
Drug Products (the Panel). The Panel had reviewed data on drug products
containing antacid, analgesic, and stimulant ingredients in various
combinations and recommended conditions for their safe and effective
use. The Panel concluded that the following combinations of Category I
ingredients were safe and effective for use in relief of the symptoms
of hangover: (1) Antacids and analgesics, (2) antacids and stimulants,
(3) analgesics and stimulants, and (4) antacids, analgesics, and
stimulants. The Panel also classified two ingredients, bismuth
subsalicylate and sodium citrate in solution, in Category I (generally
recognized as safe and effective) for relief of symptoms of upset
stomach due to overindulgence in food and drink.
In the tentative final monograph for OTC orally administered drug
products for relief of symptoms associated with overindulgence in food
and drink, published in the Federal Register of December 24, 1991 (56
FR 66742), the agency recognized that the overindulgence rulemaking
significantly overlaps other OTC drug monographs, including antacid (21
CFR part 331), stimulant (21 CFR part 340), and internal analgesic
(proposed 21 CFR part 343). To avoid unnecessary monograph duplication,
the agency proposed to amend the final monographs for OTC antacid and
stimulant drug products and to amend the tentative final monograph for
OTC internal analgesic drug products to include conditions for relief
of hangover symptoms. Similarly, the agency found that the Panel's
recommended claim for relief of symptoms of upset stomach due to
overindulgence in food and drink overlaps claims in the antacid
monograph. Therefore, the agency proposed to amend the final monograph
for OTC antacid drug products to include appropriate conditions for
relief of the symptoms of upset stomach due to overindulgence in food
and drink. In a proposed amendment of Sec. 331.30 of the antacid final
monograph (56 FR 66754 at 66756, December 24, 1991), the agency
proposed to add a claim for the relief of upset stomach due to
overindulgence in food and drink for all antacid ingredients, including
sodium bicarbonate.
Likewise, in a proposed amendment to the internal analgesic
tentative final monograph (56 FR 66762 at 66764, December 24, 1991),
the agency proposed to include a claim for relief of symptoms of
hangover and a claim for relief of symptoms of overindulgence in food
and drink for internal analgesic/antacid combinations proposed in
Sec. 343.60(b)(2) and (b)(4). At that time, the agency was not aware of
the number of reports of adverse effects associated with ingestion of
sodium bicarbonate for the relief of gastrointestinal distress. These
adverse effects include the possibility of stomach rupture and, in rare
cases, death. The agency has identified several other problems that
could occur when sodium bicarbonate is used as an OTC antacid. These
include systemic metabolic alkalosis, occurrence of milk-alkali
syndrome, increased sodium load for certain susceptible individuals,
and the overall risk-to-benefit ratio of sodium bicarbonate as an OTC
antacid drug product. Stomach rupture and additional agency concerns
associated with sodium bicarbonate, the literature review, and the case
reports that demonstrate these adverse effects are discussed elsewhere
in this issue of the Federal Register in the proposed amendment to the
antacid final monograph (part 331). Based on a review of these reports
of adverse effects, the agency is amending the tentative final
monograph for OTC internal analgesic, antipyretic, and antirheumatic
drug products so that it is consistent with proposed changes in the
antacid final monograph.
II. The Agency's Proposal for Revised Labeling for Sodium
Bicarbonate in OTC Internal Analgesic, Antipyretic, and
Antirheumatic Combination Drug Products
The case reports have shown that the ingestion of sodium
bicarbonate may cause gastric dilatation and rupture of the stomach,
particularly if the stomach is overly full from food or drink. The
reports indicate that this problem occurs with dosage forms intended to
be dissolved in liquid before administration, such as powders or
effervescent granules or tablets. Accordingly, the agency is proposing
separate indications in Sec. 343.60(b) for OTC internal analgesic/
antacid combination drug products that either do or do not contain
sodium bicarbonate as an active ingredient intended to be dissolved in
liquid before administration. Products containing sodium bicarbonate
intended to be dissolved in liquid before administration will not be
allowed to include a claim for relief of overindulgence in food and
drink or relief of hangover. Proposed labeling that specifically
addresses warnings and directions for sodium bicarbonate appears in the
amendment to the antacid final monograph, elsewhere in this issue of
the Federal Register. A cross-reference to that labeling is proposed in
the internal analgesic monograph.
The agency has examined the economic consequences of this proposed
rulemaking 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 internal
analgesic/antacid combination drug products containing sodium
bicarbonate as an antacid active ingredient is not expected to have an
impact on small businesses. The final rule will impose direct one-time
costs associated with changing product labels, but that cost is
estimated to be less than $1 million. Also, there appears to be a
limited number of products involved. Manufacturers will have 6 months
after publication of the final rule in which to implement this
relabeling. However, manufacturers of OTC internal analgesic/antacid
combination drug products are encouraged to voluntarily implement this
labeling as of the date of publication of this proposal, subject to the
possibility that FDA may change the wording as a result of comments
filed in response to this proposal. Because FDA is encouraging the
proposed labeling changes to be used on a voluntary basis at this time,
the agency advises that manufacturers will be given ample time after
publication of the final rule to use up any labeling implemented in
conformance with this proposal. The impact of the proposed rule, if
implemented, appears to be minimal. Therefore, the agency concludes
that the proposed rule is not a major rule as defined in Executive
Order 12866. Further, the agency certifies that this proposed rule, if
implemented, will not have a significant economic impact on a
substantial number of small entities as defined in the Regulatory
Flexibility Act.
The agency invites public comment regarding any substantial or
significant economic impact that this rulemaking would have on OTC
internal analgesic/antacid combination drug products containing sodium
bicarbonate as an antacid active ingredient. Types of impact may
include, but are not limited to, costs associated with relabeling or
repackaging. Comments regarding the impact of this rulemaking on OTC
internal analgesic/antacid combination drug products should be
accompanied by appropriate documentation. The agency will evaluate any
comments and supporting data that are received and will reassess the
economic impact of this rulemaking in the preamble to the final rule.
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.
Interested persons may, on or before April 4, 1994, submit written
comments on the proposed regulation and the agency's economic impact
determination to the Dockets Management Branch (address above). Three
copies of all 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 comments may
be seen in the office above between 9 a.m. and 4 p.m., Monday through
Friday.
List of Subjects in 21 CFR Part 343
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, it is
proposed that 21 CFR part 343, as proposed in the Federal Register of
December 24, 1991 (56 FR 66762), be amended as follows:
PART 343--INTERNAL ANALGESIC, ANTIPYRETIC, AND ANTIRHEUMATIC DRUG
PRODUCTS FOR OVER-THE-COUNTER HUMAN USE
1. The authority citation for 21 CFR part 343 is revised 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).
2. Section 343.60 is amended by revising paragraphs (b)(2) and
(b)(4), by adding new paragraph (c)(2), by redesignating the heading in
paragraph (d) introductory text as paragraph (d), by redesignating the
text in existing paragraph (d) introductory text as paragraph (d)(1),
by redesignating existing paragraphs (d)(1) and (d)(2) as paragraphs
(d)(1)(i) and (d)(1)(ii), respectively, and by adding new paragraph
(d)(2) to read as follows:
Sec. 343.60 Labeling of permitted combinations of active ingredients.
* * * * *
(b) * * *
(2) For permitted combinations identified in Sec. 343.20(b)(1)--(i)
All combinations except those containing sodium bicarbonate as an
active ingredient in a dosage form intended to be dissolved in liquid
before administration. The indications are the following: ``For the
temporary relief of minor aches and pains with'' (select one or more of
the following: ``heartburn,'' ``sour stomach,'' or ``acid
indigestion'') (which may be followed by: ``and upset stomach
associated with'' (select one or more of the following, as appropriate:
``this symptom,'' ``these symptoms,'' ``hangover,'' or ``overindulgence
in food and drink.''))
(ii) Any combination containing sodium bicarbonate as an active
ingredient in a dosage form intended to be dissolved in liquid before
administration. The indications are the following: ``For the temporary
relief of minor aches and pains with'' (select one or more of the
following: ``heartburn,'' ``sour stomach,'' or ``acid indigestion'')
(which may be followed by: ``and upset stomach associated with''
(select one of the following, as appropriate: ``this symptom'' or
``these symptoms.'')) These products may not bear any claims that
relate to use for ``overindulgence in food and drink'' or ``hangover.''
* * * * *
(4) For permitted combinations identified in Sec. 343.20(b)(3)--(i)
All combinations except those containing sodium bicarbonate as an
active ingredient in a dosage form intended to be dissolved in liquid
before administration. The indications are the following: ``For the
temporary relief of minor aches and pains with'' (select one or more of
the following: ``heartburn,'' ``sour stomach,'' or ``acid
indigestion'') [which may be followed by: ``and upset stomach
associated with'' (select one or more of the following, as appropriate:
``this symptom,'' ``these symptoms,'' ``hangover,'' or ``overindulgence
in food and drink'')] and ``Also may be used for the temporary relief
of minor aches and pains alone'' [which may be followed by one or more
of the following: (``such as associated with'' (select one or more of
the following: ``a cold,'' ``the common cold,'' ``sore throat,''
``headache,'' ``toothache,'' ``muscular aches,'' ``backache,'' ``the
premenstrual and menstrual periods'' (which may be followed by:
``(dysmenorrhea)''), or ``premenstrual and menstrual cramps'' (which
may be followed by: ``(dysmenorrhea)'')), (``and for the minor pain
from arthritis''), and (``and to reduce fever.'')]
(ii) Any combination containing sodium bicarbonate as an active
ingredient in a dosage form intended to be dissolved in liquid before
administration. The indications are the following: ``For the temporary
relief of minor aches and pains with'' (select one or more of the
following: ``heartburn,'' ``sour stomach,'' or ``acid indigestion'')
[which may be followed by: ``and upset stomach associated with''
(select one of the following, as appropriate: ``this symptom'' or
``these symptoms'')] and ``Also may be used for the temporary relief of
minor aches and pains alone'' [which may be followed by one or more of
the following: (``such as associated with'' (select one or more of the
following: ``a cold,'' ``the common cold,'' ``sore throat,''
``headache,'' ``toothache,'' ``muscular aches,'' ``backache,'' ``the
premenstrual and menstrual periods,'' (which may be followed by:
``(dysmenorrhea)''), or ``premenstrual and menstrual cramps'' (which
may be followed by: ``(dysmenorrhea)'')), (``and for the minor pain
from arthritis''), and (``and to reduce fever.'')] These products may
not bear any claims that relate to use for ``overindulgence in food and
drink'' or ``hangover.''
* * * * *
(c) * * *
(2) For permitted combinations identified in Sec. 343.20(b)(1)
and (b)(3) containing sodium bicarbonate as an active ingredient in a
dosage form intended to be dissolved in liquid before administration.
The warnings in Sec. 331.30(c)(8) of this chapter should also be used.
(d) Directions--(1) The labeling of the product states, under the
heading ``Directions,'' directions that conform to the directions
established for each ingredient in the directions sections of the
applicable OTC drug monographs, unless otherwise stated in this
paragraph. When the time intervals or age limitations for
administration of the individual ingredients differ, the directions for
the combination product:
* * * * *
(2) For permitted combinations identified in Sec. 343.20(b)(1) and
(b)(3) containing sodium bicarbonate as an active ingredient in a
dosage form intended to be dissolved in liquid before administration.
The directions in Sec. 331.30(e)(1) of this chapter should also be
used.
Dated: November 3, 1993.
Michael R. Taylor,
Deputy Commissioner for Policy.
[FR Doc. 94-2265 Filed 2-1-94; 8:45 am]
BILLING CODE 4160-01-F