[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