Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the-Counter Human Use; Amendment to Tentative Final Monograph; Proposed Rule

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